Advanced Clinical Naturopathic Medicine 0729542653, 9780729542654

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Advanced Clinical Naturopathic Medicine Leah Hechtman MSci Med(RHHG), BHSc(Nat), ND, FNHAA Director, The Natural Health and Fertility Centre, Sydney, Australia

Table of Contents Instructions for online access Cover image Title Page Copyright Acknowledgments Preface About the Author List of Contributors 1 Global naturopathic medicine Global scope of naturopathic medicine Global health governance: the World Health Organisation Global representation: the World Naturopathic Federation A global profession – similarities and differences References 2 Environmental medicine History-taking

Who is susceptible? Environmental triggers of disease Toxicants Electromagnetic fields Allergens References 3 Chelation Description History Chelating agents Chelatable toxicants Assessment of toxic metals Challenge testing Side effects References 4 Detoxification Introduction/overview Toxins/toxicants Assessment of toxins/toxicants Organs involved in toxin elimination Detoxification strategies References 5 Naturopathic hydrotherapy Introduction Modern naturopathic hydrotherapy Hydrotherapy and its connection to modern naturopathic clinical theory The effects of water on tissues and systems

General guidelines for administering hydrotherapy Contraindications, cautions and dysfunctional reactions Commonly prescribed naturopathic hydrotherapy treatments Evidence supporting therapeutic uses of water Acknowledgments References 6 The microbiome Overview The dermatological microbiota The nasopharyngeal microbiota The oral microbiota The breastmilk microbiota The vaginal microbiota The gastrointestinal microbiota References 7 Methylation Introduction Developmental and evolutionary origins Chemistry and biochemistry of the methyl group Revision of key biochemical structures Revision of basic molecular biology Methylation and mitochondria Transcription and translation Protein synthesis Protein methylation and post-translational modification Epigenetics, methylation and gene expression Metabolic pathways

Altered methylation patterns: hypomethylation and hypermethylation Beyond genetics: methylation and our broader physiology Key nutrients Methylation deficits and associated conditions Special topics Laboratory assessment of methylation Therapeutics and prescriptions References 8 Genetics and epigenetics The ‘omics’ revolution Regulation of genetic screening Introduction to DNA and gene expression The role of genetic testing in healthcare Putting it all together References 9 Mind–body medicine Introduction Biomedicine Mind–body medicine Mind–body therapeutics References 10 Sports naturopathy Introduction Exercise physiology Energy requirements Carbohydrates Protein

Fats Fuelling for training and recovery Hydration and dehydration Fuelling for competitions and race day Drugs in sport Evidence-based supplements Working with sports clients References 11 Fertility – Female and male Epidemiology Classification References Appendix 11.1 Fertility chart Appendix 11.2 Timeline of embryonic development Appendix 11.3 hCG interpretation Appendix 11.4 General IVF protocol Appendix 11.5 WHO criteria – semen analysis Appendix 11.6 WHO Guidelines for Semen Analysis (2010, 5th edition) 12 Miscarriage Overview and definition Statistics Risk of miscarriage by number of weeks of gestation of pregnancy Risk of miscarriage by maternal age Fetal heart rate as miscarriage risk determinant Aetiology of miscarriages Treatment approaches Therapeutic rationale for botanical medicines

Nutritional medicine (dietary) Therapeutic rationale for nutritional medicines References 13 Pregnancy and labour Introduction Epidemiology Models of antenatal care The role of the naturopath Modes of delivery Emotional and psychological wellbeing Epigenetics and the origins of disease Safety issues in pregnancy Nutritional assessment Weight in pregnancy Nutritional Medicine – Dietary Nutritional Medicine – Supplementation Trimester 1 Trimester 2 Third trimester Labour and childbirth Fourth trimester: the postnatal period The pregnancy care plan References Appendix 13.1 Tools to assess NVP Appendix 13.2 Edinburgh Postnatal Depression Scale (EPDS) 14 Breastfeeding Introduction

The World Health Organization recommendations for breastfeeding Historical context Breastfeeding: barriers and enablers Working with new mothers – the role of the naturopath Functions of breastfeeding Nutritional considerations for the breastfeeding mother The breast milk microbiome Anatomy and physiology of lactation Breastfeeding initiation Breastfeeding support Common breastfeeding challenges Medications/drugs and breastfeeding Breastfeeding and HIV Maternal infant sleep and breastfeeding Conclusion References 15 Infancy Introduction Good referral practice The fourth trimester: the newborn 0–3 months Arrival Growth and development Shaping the early intestinal microbiota Infant gastrointestinal development Nutritional requirements 0–12 months Introduction of solids Naturopathic management of common infantile presentations Common infantile presentations

References 16 Paediatrics and adolescence Introduction Dosage calculations Growth and developmental nutrition – 12–36 months – the toddler Nutritional requirements – 12–36 months – the toddler Growth and developmental nutrition – middle childhood – 36 months–10 years Nutritional requirements – middle childhood – 36 months–10 years Growth and developmental nutrition – adolescence – 10 years and older Nutritional requirements – adolescence – 10 years and older Specific conditions Environmental chemicals and paediatric and adolescent health References Appendix 16.1 Dietary planning Appendix 16.2 Essential oils 17 Geriatrics Introduction Epidemiology Ageing Assessment Geriatric syndromes Pharmacokinetics, polypharmacy and posology Diet and nutritional issues References 18 Autism spectrum disorder (ASD) Epidemiology Overview

Classification Contributing factors Diagnosis The biomedical approach to autism and ASD Attention deficit (hyperactivity) disorder – AD(H)D References 19 Down syndrome Introduction Prenatal diagnosis Diagnosis at birth: impact on parents Improving cognitive potential through enhanced pregnancy care Family Infant care Childhood–school-age years Adolescence Adulthood End-of-life care Specific health concerns Therapeutic considerations Therapeutic application References Appendix 19.1 Sexual health resources for parents, carers and health professionals working with people with Down syndrome and other learning disabilities Appendix 19.2 Sexual health resources for people with Down syndrome and other learning disabilities, with the support of carers or family members Appendix 19.3 Plymouth dementia screening checklist 20 The endocannabinoid system and cannabis Introduction

Evolution of the endocannabinoid system Anatomy of the endocannabinoid system Physiology of the endocannabinoid system The ECS and clinical challenges The genus Cannabis References 21 Cancer – Advanced I Cancer pathogenesis and treatment Scope of practice for the natural healthcare provider Case studies of most common types of cancer to highlight approach References 22 Cancer – Advanced II Part A Part B References 23 HIV (human immunodeficiency virus) HIV statistics (World Health Organization [WHO] HIV/AIDS statistics and data) AIDS statistics, Classification AIDS definition Aetiology HIV overview Differential diagnosis Naturopathic diagnosis Monitoring the patient Specific naturopathic investigations

Historical perspective Naturopathic perspective Stages of treatment Nutritional medicine (dietary) Nutritional medicine (supplemental) Herbal medicine Lifestyle recommendations References 24 Lyme disease and co-infections Introduction Broadening the definition of Lyme disease Stages of Lyme disease Epidemiology of Lyme disease How is Lyme transmitted? Signs and symptoms of Lyme disease Testing for Lyme disease Treatment of Lyme disease Naturopathic approaches to Lyme disease and co-infections Conclusion References Index Interactions table Herb/nutrient–drug interactions tables References

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Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a maQer of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. National Library of Australia Cataloguing-in-Publication Data

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Acknowledgments It is with much gratitude that we birth Advanced Clinical Naturopathic Medicine (ACNM). ACNM was developed from a yearning to contribute more deeply to the naturopathic body of work, to support the development of the evolving profession and to guide clinicians and students through complicated areas of expertise and specialisation. ACNM brings together a team of true experts to achieve this vision. As with CNM, a book of this depth requires the commitment and dedication of a number of individuals, and I am again deeply grateful to and humbled by those I have been privileged to work with to achieve this collaborative goal. In order of their contribution, my appreciation to Natalie Cook, Nicole Bijlsma, Dr Joseph Pizzorno, Dr John Nowicki, Dr Kate Broderick, Dr Jason Hawrelak, Dr Joanna HarneK, Annalies Corse, Dr Rhona Creegan, Dr Margaret Smith, Dr Brad Lichtenstein, Kira Sutherland, Angela Hywood, Jane Hutchens, Dawn WhiKen, Tabitha McIntosh, Helen Padarin, Belinda Robson, Justin Sinclair, Dr Janet Schloss, Manuela Boyle, Teresa Mitchell-PaKerson and Dr Nicola McFadzean Ducharme. A special note of gratitude goes to Liesl BloK for her contribution of each of the interaction tables for each chapter; as well as Lisa Costa Bir for the dietary plans for each condition. It has been an honour to include your contributions, learn from you and understand your knowledge and expertise more deeply. Additionally, my heartfelt thanks to Dr Sue Evans for writing the Foreword of this text. For this volume, I was intent on ensuring a balance of the sexes and ideally wanted someone Australian who I perceive as a wise elder, firmly rooted in the history and tradition of our treatments and philosophies and connected to and practising our evolving practice. Sue, you embody all of these admirable aKributes and your humble wisdom shines through as always. Thank you. My sincere appreciation to the wonderful team at Elsevier. The integrity of those involved was highly evident and I am most appreciative of their respective kindness, commitment and dedication to producing the best possible text. Much gratitude to Larissa Norrie, Vanessa Ridehalgh, Shruti Raj, Katie Millar and others. Thank you to Cheryl le Roux for your dedication and commitment to the project as my research assistant. Your ongoing enthusiasm, kindness and ethical core strove to ensure we produced the most accurate and thorough work. I am blessed to be able to work with you. Many thanks for puKing up with my perpetual enquiring mind. To my colleagues at UNSW, it is from my connections with you all that I am able to critically assess and contribute meaningfully in an academic context. You have supported me to seek and

find answers to my enquiries which consistently provide foundational platforms with which to expand as a clinician and educator. Learning, growth and contribution are some of my core values, and my gratitude for these opportunities that you bestow on me are heartfelt and celebrated. Thank you. To my fellow colleagues clinically and academically, lecturers past and present, mentors and friends, I am blessed to have connected with incredible people who challenge, inspire and guide me so that we can all contribute more meaningfully and help others. A special thank you to my family, friends and spiritual family. Your love, compassion and kindness enrich and support me to be of greater service and contribution. Finally, my gratitude to my patients – past, present and future. It is the relationships I share with my patients, their stories, journeys and experiences that drive me to seek out answers to understand and to provide help and support. Without these heartfelt experiences, I would not be as moved or determined to push, to search, to seek and to find how I can help. When your heart is touched and a connection felt, it is the humility of the experience that opens up the universe to you to find answers. I am deeply grateful for each person I am privileged to treat.

Preface The release of Advanced Clinical Naturopathic Medicine (ACNM) is a hallmark achievement supporting the evolving practice of the profession. No longer limited to merely general practice, clinicians have broadened and expanded into specialty practices. This shift in our treatment has seen more specific courses and sub-practices develop, with clinicians narrowing their focus to key areas of expertise. That the contributors in ACNM are experts in their fields is evident. All have completed advanced training and have years of clinical experience and a deep love of their specialty areas. The chapters showcase the many diverse pathways within the profession and highlight both the opportunities for aspiring clinicians as well as the depth of practice required to truly excel in these specialty areas of expertise. Each contributor elevates their knowledge. All aspects of their careers aptly highlight the commitment and dedication required to perfect and hone their craft. ACNM offers both new and experienced clinicians, educators and researchers an opportunity to dive into the hearts and minds of these leaders. It showcases how truly transformative and effective naturopathy is and offers insight into the depth of our practice. As with Clinical Naturopathic Medicine, the publishing of this text is an opportunity for the profession to reclaim and celebrate our vital role in the healthcare system. Our system of healing is unique and relevant; our treatments efficacious and therapeutic; our methodology and outcomes logical and supportive. I hope this text provides assurance for clinicians and gives them confidence to take on more responsibility and be more active in the welfare of their patients’ wellbeing; certainty to be more forthright and transparent with treatment strategies, methodologies and approaches; and determination to consistently strive for excellence and have the patient's best interests at heart. Naturopathic core principles guide our intentions, with patient-centred care as the primary principle. Our elders always focused on the importance of the inter-relationship between clinician, patient and nature. My hope is that ACNM provides the platform with which to seek answers and formulate the best care possible. Leah Hechtman

March 2020

About the Author MSciMed(RHHG), BHSc(Naturopathy), ND, FNHAA Leah is an experienced and respected clinician and has been in private practice for over 20 years. She specialises in fertility, pregnancy and reproductive healthcare for men and women and holds fellowships and memberships with a number of International organisations. She has completed extensive advanced training and is currently completing her PhD through the School of Women's and Children's Health (Faculty of Medicine [UNSW]). Leah is the Director of The Natural Health and Fertility Centre in Sydney, Australia, where she maintains her clinical practice. She is a keynote speaker at conferences locally and internationally to both the functional and the complementary medicine communities as well as the wider fertility and gynaecological areas of medicine. She is the author of multiple seminal naturopathic textbooks and is a contributor to journals and other texts within the naturopathic and functional medicine areas, as well as general gynaecology, fertility and infertility. Most importantly, she is a mother to two gorgeous boys who keep her grounded, humbled and consciously aware. They have helped and continue to help her be a beTer version of herself and provide insight and direction for her spiritual practice.

List of Contributors Nicole Bijlsma ND, BHScAc(HONS), Grad Dip OHS, Adv Dip Building Biology RMIT researcher Vice President of Australasian Society of Building Biologists, Australia Liesl BloC PGradDip(MM), BPharm, BHSc(Herbal Med), AdvDip(Nat), Cert IV Assessment & Workplace Training, Adjunct Senior Lecturer, School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Western Australia, Australia Kate Broderick BSc, JD, DNM, DipAcu Lecturer, Naturopathic Medicine, Endeavour College of Natural Health, Adelaide, South Australia, Australia Anam Chara Natural Health, Adelaide, South Australia, Australia Manuela Malaguti Boyle MPH, MHSc, BHSc(Complementary Medicine), BA(Journalism), Adv Dip Naturopathy Certified Functional Medicine Practitioner Institute of Functional Medicine, Washington, United States Fellow of Integrative Oncology University of Arizona, USA Clinician Author Public speaker Expert Advisor SDG 3 WHIS, United Kingdom, NHAA Australia, AIMA Australia Natalie Cook MPH, BHSc(Nat), BCom(Mkt) Director of Innovation, Industry & Employability, Health, Torrens University Australia (Southern School of Natural Therapies and Australasian College of Natural Therapies), FiVroy, Victoria, Australia Fellow and Past President of the Naturopaths and Herbalists Association of Australia CommiWee member, World Naturopathic Federation Annalies Corse BMedSc, BHSc Senior Lecturer, Health and Medical Sciences, Laureate Universities, Sydney, New South Wales, Australia Naturopathic Practitioner, Private Clinical Practice, Sydney, New South Wales, Australia Academic Writer, Postgrad Lecturer, Presenter, Medical and Health Sciences, New South Wales,

Australia Lisa Costa Bir BAppSc(Nat), GradDip(Nat), MATMS, Lecturer and Supervisor, Nutrition and Naturopathy, Endeavour College of Natural Health, Sydney, New South Wales, Australia Rhona Creegan PhD, MSc Clinical Biochemistry, MSc Nutrition Medicine, BSc Biomedical Sciences, Owner Omega Nutrition Health, Perth, Western Australia, Australia Nicola Ducharme ND, BHSc(Naturopathy), BA, Doctorate of Naturopathic Medicine, Bastyr University, SeaWle, WA, USA Owner and Medical Director of RestorMedicine, San Diego, CA, USA Creator of Lyme-Ed Online Programs For Patients and Practitioners Author of The Lyme Diet, The Beginners Guide to Lyme Disease, Lyme Disease in Australia, Lyme Brain Joanna HarneC PhD, MHSc, BHSc(Complementary Medicine), Grad Dip Clin Nutrition, Grad Cert Educational Studies, Adv Dip Naturopathy Lecturer Complementary Medicines, The University of Sydney School of Pharmacy, Faculty of Medicine and Health, New South Wales, Australia Fellow of the Australian Research Centre in Complementary and Integrative Medicine, Ultimo, New South Wales, Australia Jason Hawrelak ND, BNat(Hons), PhD, FNHAA, MASN, FACN Senior Lecturer in Complementary and Alternative Medicines, College of Health & Medicine, University of Tasmania Visiting Research Fellow, Australian Research Centre for Complementary & Integrative Medicine, University of Technology Sydney Clinical Director, Goulds Natural Medicine, Hobart, Tasmania, Australia Leah Hechtman MSciMed(RHHG), BHSc(Nat), ND, FNHAA, Fertility Centre, Sydney, New South Wales, Australia

Director, The Natural Health and

Jane Hutchens MScMed(RH&HG), BHealthSc, AdvDipNat, BA, RN Research Assistant, Australian Centre for Public and Population Health Research, The University of Technology, Sydney, New South Wales, Australia Lecturer, Torrens University, Pyrmont, New South Wales, Australia Private Practitioner, Minerva Natural Health & Fertility, Blaxland, NSW, Australia Angela Hywood BHSc(Complementary Medicine), AdvDipCN, AdvDipNat, AdvDipMH, DipNFM Brad S. Lichtenstein ND, BCB, BCB-HRV, Kenmore, WA

Associate and Clinical Professor, Bastyr University,

Tabitha McIntosh BMedSci, AdvDipNat, DipNut, PostGradCert Nutritional and Environmental Science, Director Awaken Your Health, NSW, Australia

Teresa Mitchell-Paterson AdvDip(Nat), BHSc(CompMed), MHSc(HumNut), Senior Lecturer, Nutritional Medicine, Torrens University, Sydney, New South Wales, Australia John Nowicki BS(Biology), ND,

Independent Medical Researcher/Writer/Editor, SeaWle, USA

Helen Padarin BHSc(Nat), ND, DN, DBM, DRM, Herbalist, Sydney, New South Wales, Australia

Clinical Naturopath, Nutritionist and

Joseph Pizzorno BS(Chemistry), ND Founding President, Bastyr University, Washington, United States Co-editor, Textbook of Natural Medicine Editor-in-Chief, Integrative Medicine, A Clinician's Journal Chair, Board of Directors, Institute for Functional Medicine Member, Board of Directors, Institute for Naturopathic Medicine, SeaWle, USA Belinda Robson MHlthSc(DD), BNat, AssocDegAppSc Member of the Naturopaths and Herbalist Association of Australia Goulds Natural Medicine, Hobart, Tasmania, Australia Janet Schloss PhD(medicine), PGC-Clin Nut, AdvDip-HS(Nat), DipNut, Dip HM, BARM Endeavour College of Natural Health, 269 Wickham St, Fortitude Valley Qld 4006 Fellow at ARCCIM University of Technology Sydney, Ultimo NSW Justin Sinclair MHerbMed(USyd), BHSc(Nat) Research Fellow, NICM Health Research Institute, Western Sydney University, New South Wales, Australia Coordinator, Australian Medicinal Cannabis Research & Education Collaboration, New South Wales, Australia Principal Consultant, Traditional Medicine Consultancy, Sydney, New South Wales, Australia Scientific Advisory Board, United in Compassion (Registered Charity) Dr Margaret Smith NZCS, FNZIMLS, MHGSA, BSc(Hons), PhD, Molecular Geneticist, smartDNA Pty Ltd, MHTP Translational Research Facility, Level H04 27-31 Wright Street, Clayton, Victoria 3168, Australia Kira Sutherland PostGradDip(Sports Nutrition/IOC), BHSc, AdvDipNat, AdvDipNut, AdvDipHM, DipHom Lecturer Naturopathy and Nutritional Medicine, Endeavour College of Natural Health, Sydney, New South Wales, Australia Lecturer Naturopathy and Nutritional Medicine, Torrens University, Sydney, New South Wales, Australia Member of the Australian Traditional Medicine Society Dawn WhiCen BNat(Hons), IBCLC Unit Coordinator, College of Health and Medicine, University of Tasmania, Australia Clinical Director, Goulds Natural Medicine, Hobart, Tasmania, Australia Researcher and Educator, ProbioticAdvisor.com

1

Global naturopathic medicine Natalie Cook

Naturopathic medicine draws on a rich history of practice that extends many thousands of years. Humans have long needed to rely on the resources of nature for health and healing, and the use of plants as therapeutic agents is well documented through the history of human civilisation. Using plants as a source of medicine as well as for their nutritional value has consistently been observed in cultures over time. Other therapies, including the use of water, heat and cold, and other therapeutic regimens have also variously been used to harness the healing power of nature or vis medicatrix naturae. Naturopathy grew from these traditions around the turn of the 20th century and is today practised in over 80 countries around the world. Modern naturopathy combines the best of traditional medicine with contemporary science as a practice that is steeped in tradition while incorporating modern clinical advances. The manner in which the profession is recognised and regulated varies around the world; however, consistency in core beliefs as well as commitment to high standards in education, practice and codes of conduct bind the profession together as a system of medicine that makes a positive contribution to global health.

Global scope of naturopathic medicine If we could look at a time-lapse image of naturopathy as it has spread around the world from its beginnings until today, we would commence viewing in the 1800s in Europe, specifically in Germany and Austria. The early work of Vincent PriessniN (1847–1884) and Johann Schroth (1798–1856) from Austria together with Sebastian Kneipp (1821–1897) and Louis Kuhne (1835–1901) from Germany brought together a number of modalities including herbal medicine, hydrotherapy and nutrition, and their ‘Nature Cure’ movement laid the foundation for modern naturopathy. Benedict Lust (1872–1945), an American who became a student of Kneipp after being cured by his treatments, moved back to the United States in the 1890s and popularised the term ‘naturopathy’ that was coined by John Scheel around 1900. Prior to this, the term ‘naturheilkunde’ was first documented by German physician Lorenz Geich (1798–1835), while ‘naturheilkuner’ was used by Kneipp. John Scheel translated these terms into English as ‘naturopathy’ and Lust bought the right to use this term in 1901. Lust went on to found the American School of Naturopathy in New York City as well as the Naturopathic Society of America, which later became the American Naturopathic Association, and thus is regarded as the father of modern naturopathy for the English-speaking world.[1] The practice of naturopathy spread from these two epicentres in Germanic Europe and north eastern America as students of those forefathers migrated throughout the US and Europe, and swiftly extended as far as Australia by 1904. Today, naturopathy is practised in over 80 countries – over one-third of the countries around the world – by an estimated 75 000–100 000 practitioners.[2,3] The greatest concentrations are found in Germany and Spain, with a reported 20 000 practitioners in each country, and generally it holds true that the longer naturopathy has been practised in a country, the more naturopaths are found to practise there.[2]

FIGURE 1.1

Countries that practise naturopathic medicine, by world region*[3]

The scale of naturopathic medicine can be beder appreciated by considering this summary of key figures, which are likely conservative estimates as the global profession continues to be beder understood[3]:

• Countries that practise naturopathic medicine = 80+ • National professional associations = 80+ • Naturopathic educational institutions = 90+ • Naturopathic research centres = 20+

Naturopathic practice by world region Terminology The most common term for those practising naturopathy used in nearly 80% of the world is ‘naturopath’. Some countries refer to practitioners as a naturopathic doctor or naturopathic physician, and approximately 10% refer to practitioners as a ‘natural medicine doctor’ or ‘heilpraktiker’. Other terms that may be used around the world to represent naturopathy include: Nature Cure, Natural Medicine, Naturopathía, Naturopathie, Praticien de santé – Naturopathe, Terapêuticas Não Convencionais, Medicina Naturista, Naturopatia ou Medicina Natural, Naturheilkunde.[2] The terms ‘naturopath’ and ‘naturopathic doctor’ are prevalent in English and non-English-speaking countries alike and although similar, the terms tend not to be interchangeable. History, culture, education and the regulatory environment of the countries in which they practise shape the different

terms used to describe practitioners of naturopathy. Naturopaths and naturopathic doctors in particular tend to be differentiated by levels of education and regulation. While there is a great deal of alignment with the fundamental principles and philosophy taught in both cases, the term naturopathic doctor is used in countries where the education standards require more hours and with a greater emphasis on medical assessment in addition to holistic understanding. This often then corresponds to increased scope of practice, as more physically invasive examinations (such as taking blood) and laboratory testing may be included. The regulatory environment supporting naturopathic doctors may include government accreditation of institutions as well as uniform board exams to gain entry to the profession as a registered practitioner. Countries such as the US, Canada and South Africa register their naturopathic practitioners as naturopathic doctors and follow this model. Other countries, such as Australia, may be well recognised for their high standards of education yet are not regulated by national or regional government accreditation processes for either practitioners or institutions. The profession is not subject to statutory regulation and the education required of a naturopath, while based on a strong health science foundation, tends to have some limitations in terms of scope of practice (for more detail, refer to the section ‘A global profession – similarities and differences’, which discusses the similarities and differences around the world).

Global impact It is difficult to quantify the impact of naturopathy globally. Arguably, a focus on preventive health and a reduction in reliance on mainstream health systems would suggest that naturopathy could play a significant role in global health goals. Indicators that can be measured in support of this notion include the degree to which traditional medicine is used, particularly in developing countries. The economic value of the herbal and supplement industries is also relevant in considering impact, as naturopathy is a system of health that often prescribes the use of herbal and nutritional supplements. Additionally, as naturopathic practice takes a proactive stance in relation to disease prevention and patient education, it aligns naturally with local and global public health goals.[4] In a number of countries (such as some African nations), traditional medicine practitioners outnumber medical doctors by a factor of 80 : 1. In these circumstances, traditional medicine is the only viable medical choice for many people.[5] Additionally, where traditional medicine has a strong historical basis and cultural influence, such as in developed countries including Singapore or Korea, it is often preferred even when contemporary medicine services are available.[5] Herbal medicine sales may be difficult to measure, as regulations differ around the world and definitions of plants as foods or medicines may also vary. As an indication of scale, Chinese herbal medicine sales were worth an estimated US$83.1 billion globally in 2012.[5] In the US, expenditure on natural products was US$14.8 billion in 2008.[5] Market research analysing the worldwide market for herbal supplements estimates this to grow to US$115 billion by 2020.[6]

Global health governance: the World Health Organisation The World Health Organization (WHO) recognises the important role traditional and complementary medicine (T&CM) plays as part of a global healthcare solution. The following statement made in a speech at the International Conference on Traditional Medicine for South-East Asian Countries (February 2013) reaffirms this value: Traditional medicines, of proven quality, safety, and efficacy, contribute to the goal of ensuring that all people have access to care. For many millions of people, herbal medicines, traditional treatments, and traditional practitioners are the main source of health care, and sometimes the only source of care. This is care that is close to homes, accessible and affordable. It is also culturally acceptable and trusted by large numbers of people. The affordability of most traditional medicines makes them all the more attractive at a time of soaring health-care costs and nearly universal austerity. Traditional medicine also stands out as a way of coping with the relentless rise of chronic non-communicable diseases. WHO Director-General (2013), Dr Margaret Chan[5] p. 16

It is important to context naturopathy within WHO policy. Traditional medicine is differentiated from Complementary and Alternative Medicine (CAM), with the former term applied to health systems indigenous to different cultures ‘used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental illness.’[5] While in many cases the terms are used interchangeably, the WHO defines CAM as ‘a broad set of health care practices that are not part of that country's own tradition and are not integrated into the dominant health care system’.[5] Given this distinction, and for the purposes of considering global recognition, naturopathy is considered as CAM, although much of the WHO guidelines and policy relate to both without differentiation.

WHO Traditional Medicine Strategy 2014–2023 This strategy document outlines the goals, objectives and actions of the WHO in supporting use of T&CM in a safe, respectful, cost-efficient and effective manner.[5] This applies to all modalities that may be considered T&CM, including naturopathy, and builds on previous WHO reports including the International Meeting on Global Atlas of Traditional Medicine and the WHO Traditional Medicine Strategy 2002-2005. The goals and objectives of the strategy revolve around the quality and affordable provision of healthcare, which supports the United Nations resolution for universal health coverage, which is considered an essential component of the United Nations sustainable development goals for health.[7] A brief summary of the key elements of the strategy follows:

WHO traditional and complementary medicine goals Whether as a continuing part of traditional cultural behaviour or as a growing practice in Western countries, T&CM plays a recognised role in global health, and the WHO seeks to harness this contribution in line with the broader mission of ensuring the fundamental right to health for all people of the globe via universal health coverage. The strategy articulates two goals in achieving this[4]: 1 harnessing the potential contribution of T&CM to health, wellness and people-centred healthcare 2 promoting the safe and effective use of T&CM by regulating, researching and integrating TM products, practitioners and practice into health systems, where appropriate.

WHO traditional and complementary medicine objectives T&CM represents many different health professions globally. Some are steeped in long history of use, while others such as naturopathy have a more recent history. Recognising this diversity both across countries and within countries, yet across modalities, the WHO strives for consistency in policy, safety access and usage: 1 Policy – integrate T&CM within national healthcare systems, where feasible, by developing and implementing national T&CM policies and programs. 2 Safety, efficacy and quality – promote the safety, efficacy and quality of T&CM by expanding the knowledge base, and providing guidance on regulatory and quality assurance standards. 3 Access – increase the availability and affordability of T&CM, with an emphasis on access for poor populations. 4 Rational use – promote therapeutically sound use of appropriate T&CM by practitioners and consumers.

Actions at a country level The WHO recognises challenges associated with achieving these objectives. Challenges include appropriate education and training, professional regulation, research and assurance of product quality, safety and efficacy. The strategy focuses on three key actions member states are encouraged to take: 1 build the knowledge base that will allow T&CM to be managed actively through appropriate national policies that understand and recognise the role and potential of T&CM. 2 strengthen the quality assurance, safety, proper use and effectiveness of T&CM by regulating products, practices and practitioners through T&CM education and training, skills development, services and therapies. 3 promote universal health coverage by integrating T&CM services into health service delivery and self-healthcare by capitalising on their potential contribution to improve health services and health outcomes, and by ensuring users are able to make informed choices about selfhealthcare.

WHO benchmarks for training The WHO has developed benchmarks for training for a number of T&CM practices including traditional Chinese medicine, chiropractic, osteopathy and naturopathy. The benchmarks for naturopathy are broad, and it should be noted that a number of the consultants involved in creating the naturopathic document were from Ayurvedic medicine and Chinese medicine rather than naturopathic representatives. Areas of study deemed as a requirement include: (1) basic sciences, including anatomy, physiology and pathology; (2) clinical sciences including physical examination and clinical assessment; (3) naturopathic sciences, modalities and principles, including naturopathic history and philosophy, botanical medicine and nutrition; and (4) clinical training and supervised practice.[8]

Regulatory systems Countries are responsible for establishing their own medicines regulatory authorities (MRAs), and the WHO stipulates these should have a ‘solid legal basis … sustainable financing, access to up-to-date evidence based information (and) capacity to exert effective market control’.[8] In Australia, this agency is the Therapeutic Goods Authority (TGA); in the United States, it is the US Food and Drug Administration (FDA). Often, however, these agencies do not have sufficient knowledge of T&CM. One area of confusion is due to the fact that a plant may be considered as a food, a supplement or a herbal medicine in different countries. The WHO recommendations only extend to the therapeutic substances, not the practice of T&CM.[9]

World health assembly Every year the WHO convenes a World Health Assembly (WHA) in Geneva, SwiNerland. This is the decision-making function of the WHO where all member countries across the six world regions are represented. It is the largest, most important health assembly in the world, and at the 68th World Health Assembly in 2015, representatives from the World Naturopathic Federation (WNF) were in adendance to begin formalising relations with the WHO. In 2016 at the 69th World Health Assembly, resolution WHA69.24 ‘Strengthening integrated people-centred health services’ urged WHO member states to ‘integrate, where appropriate, T&CM into health services, based on national context and knowledge-based policies, while assuring the safety, quality and effectiveness of health services and taking into account a holistic approach to health’.[10]

Global representation: the World Naturopathic Federation It is in the best interests of health professions that are practised around the world to have national bodies that support and promote their system of medicine, and to address issues that affect the profession globally. These bodies also provide a vehicle to consult with international organisations such as the WHO and the United Nations on key initiatives. To do so, a federation of national associations must be formed according to WHO guidelines; until recently, while other global professions such as chiropractic and traditional Chinese medicine had been represented at this level, naturopathy had not. To meet WHO guidelines, federations must have member countries from all WHO world regions who are able to vote, and the governing board must also demonstrate global representation. The formation of the WNF in 2015 ensured that naturopathy too has a voice on the world stage. A world federation such as this is able to address issues that affect the profession at large and support standards of education, accreditation and regulation for the profession globally.[11]

History The WNF was officially incorporated as a not-for-profit organisation in Canada in November 2014. This followed a number of years of work by a small group of dedicated naturopathic practitioners to ensure the naturopathic profession was represented in a way that befits the significant numbers of practitioners positively contributing to healthcare around the world. This was preceded by several key events including the 1st International Congress on Naturopathic Medicine (ICNM) held in Paris in 2013, at which discussions were held about forming a formal world naturopathic

organisation. At the 2nd ICNM conference in Paris in July 2014, a meeting of over 30 naturopaths/naturopathic doctors from 20 countries agreed that the WNF would be established. An interim commidee was formed consisting of representatives from Australia, Belgium, Canada, France, India, New Zealand, Spain and the US. The inaugural meeting of the WNF was hosted at the Canadian Association of Naturopathic Doctors (CAND) Health Fusion conference in Calgary in June 2015. The initial executive of the WNF was formed by four practitioners from around the world who had been involved in various aspects of the formation of the WNF: Dr Iva Lloyd, ND from Canada (President of the WNF), Dr Tina Hausser, HP, ND from Spain (Vice President of the WNF), Ysu Umbalo, ND from DR Congo (Secretary of the WNF) and Michael Cronin from the US (Treasurer of the WNF). Additionally, Dr Jon Wardle, PhD from Australia, and Dr Tabatha Parker, ND from the US, who founded Naturopathic Doctors International, were appointed Co-Secretaries General.[2,12]

Membership of the WNF The primary voting members of the WNF are national naturopathic organisations from countries that practise naturopathy. The largest national professional association in a country that represents naturopathy (as its primary focus) can join as a full member to represent its country. In some instances, a country-based federation of several associations may perform this role, although each country still has only one vote. Full members all share a common commitment to high standards of education, training and professionalism within their country. Associate members are regional naturopathic professional associations that likewise share goals and objectives that are consistent with those of the WNF. Education providers that focus on the education of naturopaths and naturopathic doctors are also able to join the WNF as educational members; like associate members, they are not able to vote, but they are able to observe meetings and participate in working groups. Additionally, as a not-for-profit organisation, the WNF receives financial support from corporate, private and non-profit sponsors. All WHO world regions are represented through membership of the WNF, which is governed by an Executive Council composed of 11 full members, four of which are the WNF Officers.[12]

What the WNF does The vision of the WNF is to provide a global voice for naturopathy. The mission is to support the growth and diversity of naturopathic medicine worldwide including the appropriate regulation and recognition of naturopathic medicine. In accordance with this, championing accreditation and the highest educational standards for the naturopathic profession is a key focus, as is encouraging naturopathic research. Additionally, the WNF maintains a database of naturopathic organisations, regulation, accreditation, conferences and research activities.[11] In practical terms, this has generated information that has previously not been available, including surveys to understand and map the naturopathic profession around the world; without this work, much of the detail found in the remainder of this chapter would not be possible. The WNF produced three key documents within the first two years of formation: the World Naturopathic Profession Report in 2015,[2] the Naturopathic Roots Report in 2016[13] and the 2016 Naturopathic Numbers Report.[3] The information in these reports is based on surveying naturopathic associations and education providers around the world. The reports are intended to ‘assess the status of the naturopathic profession worldwide’[2] and to ‘codify the foundational knowledge of naturopathy including naturopathic history, definitions, principles and theories from around the world’.[13] Additionally, the WNF collaborates with the WHO to update naturopathic benchmarks as part of the WHO Definitions Project. Professional Mapping Initiatives include examining regulatory and educational infrastructure and policy frameworks that impact on the development of naturopathic medicine within each country around the world. Research Initiatives collect and support ongoing quality naturopathic research. An important milestone for the WNF was the 2016 World Health Assembly adended by WNF Officers (Iva Lloyd, President and Tina Hausser, Vice President) and Co-Secretaries General (Tabatha Parker and Jon Wardle). Meetings with Dr Zhang Qi, who is responsible for T&CM, commenced the process towards official collaboration between the WNF and the WHO, further securing the voice for naturopathic medicine on the world health stage.

A global profession – similarities and differences The practice of naturopathy is defined by guiding principles and a holistic approach to health and wellbeing – characteristics that are common to the practice around the world. This essential core is flanked by regional differences, and it is through exploring these similarities and differences that we can beder understand the factors that define and differentiate the practice of naturopathy and the environment in which this occurs, starting with the foundation of naturopathic principles and then considering the education systems that reinforce these through each generation of graduates. The subsequent practice of naturopathy is where more variation is observed around the world through a range of modalities that are influenced by history, culture, education and regulation. Regulation of the profession is perhaps the area of greatest divergence as recognition, registration and regulation models all differ country by country. The following sections summarise the similarities and differences between naturopathy around the world and are predominantly based on the results of surveys conducted by the WNF and reported in the World Naturopathic Profession Report in 2015[2] and the Naturopathic Roots Report in 2016. [14] Although in some instances the response numbers are low, this is the first systematic examination of the profession globally and provides good insight and a foundation upon which further knowledge and understanding can be developed.

Naturopathic principles Naturopathy is a traditional system of medicine practised in many countries. A system of medicine is defined by integrated principles, philosophies, theories and practice of health and disease,[14] and although naturopathic practitioners use an eclectic array of treatment disciplines, there is a consistent core of philosophy and practice around the world. The philosophical approach to naturopathy is reflected in six key principles that, although based on traditional values, were formalised in relatively recent times (1989) by the two North American national naturopathic associations (the American Association of Naturopathic Physicians [AANP] and the Canadian Association of Naturopathic Doctors [CAND]).[15] The six naturopathic principles are: 1 First, Do No Harm (primum non nocere) 2 Healing Power of Nature (vis medicatrix naturae) 3 Treat the Cause (tolle causam)

4 Treat The Whole Person (tolle totum) 5 Doctor as Teacher (docere) 6 Disease Prevention and Health Promotion There is a high degree of agreement around the world that these principles reflect the basis of naturopathic practice, indicating that despite other differences in education, specific modes of practice or regulation, the profession is based on strong common principles.[2] This alignment of principles not only informs educational curriculum but is also influenced by the prevailing theories that are taught. The role of education institutions in maintaining naturopathic principles and high standards of education is paramount in the ongoing sustainability of the profession.

Naturopathic education and training While there are over 90 institutions teaching naturopathy around the world, these are concentrated in several key geographical regions, with approximately half found in Europe.[3] Given the important role of this region in naturopathic history, this is not surprising; however, it does highlight the reality that over half of the countries where naturopathy is practised do not have locally based educational institutions. Table 1.1 shows the number of naturopathic education institutions by world region. TABLE 1.1 Number of naturopathic education institutions by world region Total number of naturopathic educational institutions by world region Africa Asia Eastern Mediterranean Europe Latin America North America Western Pacific Total

2 22 1 42 12 9 6 94

The genesis of naturopathic teaching institutions starts in 1902 with the formation of the American School of Naturopathy in New York by Benedict Lust. A number of European naturopathic schools also started in the 1920s, such as the Heilpraktiker-Fachschule founded by Josef Angerer (1907– 1987) in Munich, Germany, which remains in operation today as the Joseph Angerer Schule. A number of students from Lust's American School of Naturopathy transferred their knowledge and skills to other parts of the world including Spain, by José Castro Blanco (1890–1981), and South America, by Professor Juan Estève Dulin in Argentina, Rosendo Arguello Ramirez in Nicaragua and Juan Antigas y Escobar in Cuba.[1,13] This process of migration from a central point over the past 100 years helps explain the relatively high degree of alignment between naturopathic educational institutions as to what is taught.

Education standards The WHO describes type I training programs as a minimum standard for naturopathic training, ‘aimed at those who have no prior medical or other health-care training or experience. They are designed to produce naturopathic practitioners who are qualified to practise as primary-contact and primary-care practitioners’.[8] A minimum of 1500 hours of study is required with at least 400 hours of supervised clinical training over a two-year full time study period (or longer as equivalent). In practice, there is quite a degree of variation in naturopathic training around the world. A 2015 WNF survey of 85 naturopathic education institutions from 49 different countries identified course duration variation from as low as 1200 hours to some courses requiring over 4000 hours of study. Those at the higher end of the scale tend to align with those courses where the resultant qualification is one of naturopathic doctor such as in North America. The majority of naturopathic courses around the world comprise 3000 hours of study for the course.[2,13] There also tends to be a correlation between the level of course accreditation and the length of the course as shown in Fig. 1.2.

FIGURE 1.2

Type of naturopathic programs based on length

Fig. 1.2 categorises courses as government-accredited, self- or voluntary-accredited, and non-accredited programs. In some instances, the same body accredits education providers as well as course content, which is the situation in the US and Canada. In other regions, such as Australia, separate bodies regulate training providers and professional course content requirements. In some countries, courses may not be subject to either government or voluntary accreditation at all.[2,13]

Entry requirements to study naturopathy vary around the world, mostly in direct relation to the level of government accreditation requirements of the education institutions; that is, those in jurisdictions where the professional and education standards are government accredited tend to have more stringent requirements. In countries such as the US and Canada, where this is the case, an undergraduate degree is required to enrol in naturopathy and standardised exit exams are also part of adaining a qualification in these countries. The US, Canada and South Africa all also have governmentapproved independent accreditation agencies to maintain these standards of education and graduation. Elsewhere in the world, such as in Australia, where the qualification for all enrolments after 2016 is a bachelor's degree, previous undergraduate qualifications are not required and exit exams vary between education providers.[2,13]

Areas of study Naturopathy courses tend to focus on health sciences, with the sciences forming the core or backbone of the course and naturopathic areas of study built around these foundational requirements. The areas of study common to naturopathic education programs are as follows[2,8]: 1 basic sciences – including anatomy and physiology, biochemistry and pathology 2 clinical sciences – including clinical assessment and diagnosis 3 naturopathic sciences, modalities and principles – including naturopathic history and philosophy, nutrition and botanical medicine 4 clinical training and application – including observation and supervised practice. While these areas of study are ubiquitous, the time spent within a course on a given study area varies according to where educational institutions are located. For example, those in Europe spend the most time on naturopathic history and philosophy, while Asian schools on average spend a greater percentage of time on the sciences.[2,13] The high level of agreement internationally in regards to the naturopathic principles is reflected in the consistency with which these areas are incorporated into naturopathic education. A common element of naturopathic courses is teaching students to treat the whole person as well as a focus on disease prevention and health promotion. The remaining four principles likewise are incorporated into virtually all curricula – First, Do No Harm; Healing Power of Nature; Treat the Cause; and Doctor as Teacher.[13] The importance of naturopathic philosophies and theories in course content may be summarised in the following quote: Naturopathic medicine is a philosophical system of medicine defined by its principles and theories and supported by research. Ensuring that naturopathic programs have a strong focus on naturopathic principles and theories is key to maintaining the essence of naturopathy from generation to generation.[3]

Naturopathic philosophies, theories and modalities are subject to cultural and historical influences and show variability as to what is taught around the world in naturopathic courses. The philosophy of vitalism, or vital force, for instance, is taught universally, as are naturopathic cures. The treatment modalities that may be taught under the umbrella of naturopathic cures, however, are quite variable, as evidenced by the range of modalities practised (see the section ‘Naturopathic practice’). Naturopathic philosophies and theories taught at the majority (over 70%) of naturopathic institutions globally in order of prevalence include[13]: 1 Vital Force* 2 Integration of the Individual* 3 Naturopathic Cures* 4 Value of Fever 5 Therapeutic Order 6 Triad of Health 7 Unity of Disease 8 Hering's Law of Cure 9 Theory of Toxaemia 10 Humoral Theory *These are taught nearly universally (96%).

Continuing professional development/education (CPD or CPE) Continuing education is generally required as part of mandatory or voluntary regulation of the profession where stipulated hours of additional study or professional development must be demonstrated to maintain professional membership and/or registration. Continuing education may be formal by way of further study, or through adending seminars most commonly provided by naturopathic associations. Seminars may also be offered by industry such as by complementary medicine companies. In some regions, requirements exist to ensure this education differs from marketing or promotion activity to be eligible as a professional development activity. More informal professional development is also achieved though peer and mentor support arrangements and self-study and research.[2,13]

Naturopathic practice There is no ‘one size fits all’ for naturopaths. The range of treatment modalities that may be considered ‘naturopathic’ and how prevalent these are in practice is influenced by history, culture, professional regulation and any type of practice employed by the practitioner. The following lists the most common naturopathic modalities around the world[13]:

• Clinical Nutrition • Botanical Medicine (Herbalism) • Physical Medicine • Homeopathic Medicine • Hydrotherapy – Water Cure

• Prevention and Lifestyle Counselling • Hygiene Therapy • Nature Cure. Additionally, practitioners may be trained in other areas, some of which are clearly influenced by history and culture. For example, naturopaths practising in India incorporate Ayurvedic medicine, commonly as part of a qualification that also includes yoga training Bachelor of Naturopathy and Yogic Sciences (BNYS). In other jurisdictions, such as North America, education and practice regulations allow for naturopathic doctors to administer intravenous treatments and perform minor surgery as part of their scope of practice. Other areas that may be included in training and practice additionally include: acupuncture, prescription rights, chelation therapy and colon therapy.[2,13] The environment in which a practitioner completed their naturopathic education and training also varies and may influence not only the modalities practised, but also the application of them. The majority of naturopaths work in private practice, either as a solo practitioner or as part of a multipractitioner clinic. Additionally, an estimated 10% of naturopaths are engaged in research and education or work in the complementary medicine industry.[3] It is possible for naturopaths or naturopathic doctors to work in hospital sedings, depending on the jurisdiction, but this is not common, except in India, where it is much more prevalent due to a more traditional focus on nature care in an in-clinic seding.[2,13] Private practice consultations tend to be, on average, significantly longer than those of medical doctors. They tend to be consumed with detailed case taking and clinical assessment of the patient as well as generating prescriptions that may include diet and lifestyle recommendations and herbal and nutritional supplements that may be pre-formulated, extemporaneously formulated or compounded and dispensed on a case-by-case basis. The majority of initial consultations are at least an hour and follow-up visits are commonly 45 minutes in duration.[2,13]

Naturopathic regulation Professional recognition and systems of regulation are perhaps the areas of greatest difference in naturopathic practice around the world. In some regions, the profession is subject to a national regulatory environment and registration; in others this may vary within a country on a state by state basis, while in other parts of the world various models of self regulation exist. At the minimum, regulation of a health profession provides codes of professional conduct that must be adhered to. Scope of practice and protection of title may also form part of the regulatory process. What is consistent is that where statutory regulation through registration does not exist, there is a strong current of sentiment within the profession to be beder recognised and endorsed as part of the primary healthcare system.

Regulatory models Naturopathic medicine is regulated in approximately 50% of the world. A third of practising countries are unregulated; however, it is not illegal to practise naturopathy in those areas. Regulation takes a number of forms; for example, in the US and Canada practitioners must study at a government-accredited institution and sit a board exam to gain ‘licensure’ to practise as a naturopathic doctor in the states and territories where licensing laws exist. Other non-accredited education institutions exist and practitioners who graduate from these may practise as naturopaths.[2] In Australia, the profession of naturopathy lacks government regulation through a centralised registration body, and instead operates under a less formal third-party regulation of the profession. The professional associations maintain their own codes of conduct, and professional indemnity (malpractice) insurance is only available for practitioners who meet the associations’ membership requirements. This includes an appropriate level of education as well as maintaining annual professional development requirements and first aid certification. Additionally, private health insurers will only provide rebates for consultations with practitioners who are verified members of a professional association.[2]

Scope of practice The acts that a naturopathic practitioner can perform are generally limited by the scope of education received, which in turn tends to inform professional insurance coverage. Some acts may be frankly prohibited. The regions with the highest levels of recognition tend to have the greatest access to a range of practice options including internal gynaecological examinations, intravenous therapies, minor surgery and laboratory testing. The most common modalities practised as part of naturopathy can be seen in Table 1.2. TABLE 1.2 Common naturopathic therapies used in practice Therapy

Prevalence allowed in practice

Hydrotherapy Massage techniques Botanical medicine Physical medicine practices Energetic therapies Lifestyle counselling Clinical nutrition TCM practices Homeopathy Colonics

93% 88% 87% 85% 85% 80% 80% 79% 77% 75%

Prescribing nutritional supplements and herbal formulations is a common tool of trade in naturopathic practice, and maintaining an in-practice dispensary is usual in Africa, South East Asia, North America and the Western Pacific. In other world regions, this is less usual and is prohibited in some European and Latin American countries where direct dispensing to patients is not possible.[2] The ability to order laboratory tests also varies around the globe with some practitioners able to not only order laboratory testing but also to take the sample in some instances, such as naturopathic doctors taking blood tests. Where licensed as primary care practitioners, this generally also extends to the ability to order diagnostic imaging such as x-rays. Others may be limited to the ability to order functional pathology tests such as hair, saliva and stool testing, while some are prohibited from ordering or accessing such testing at all.[2]

Use of title Protection of title allows for use of certain professional titles to be protected for use by appropriately qualified practitioners. The level of protection is generally tied to regulatory models and may additionally be covered under regional or national legislation. For example, in the US only graduates of accredited naturopathic medicine courses who have additionally passed a board examination may be licensed to practise as naturopathic doctors. In Germany, the title Heilpraktiker may be used only upon passing a state examination process. In countries such as Spain and Australia, which also have a long history and large numbers of naturopaths, the title of naturopath is not protected, meaning that anyone can call themselves a naturopath and practise even if not appropriately trained.[2]

Professional representation Some countries have only one national association, while others have multiple professional associations. These may have differing geographical jurisdictions, represent different education standards or have other more philosophical differences within the same geographical areas. As a general rule, those countries more recently establishing associations establish one national body, as is the case in many African nations. In countries with longer histories of practice in an unregulated professional environment such as in Australia and New Zealand, there are multiple associations, some of which represent a variety of ‘natural health’ modalities.[2] The core foundations of naturopathic principles temper the rich diversity in the nuances of naturopathic practice. As a result, what is seen is a global span of practice that has more similarities than differences and that forms a global profession. While naturopathy is relatively young compared to some traditional medicines, its historical roots in botanical medicines and other nature-based cures provides practitioners with strong links to tradition. Combined with contemporary science, naturopathic medicine provides an important element in healthcare provision that is recognised for its value by the WHO. The future of global naturopathic medicine must be shaped by a commitment to high standards of education and practice and a united voice for the profession.

Naturopathy by world region This final section briefly outlines the history and current practice of naturopathy around the world. The regions are those used by the WHO and WNF. African region (countries where naturopathy is practised): Botswana, Democratic Republic of Congo, Ghana, Kenya, Mauritius, Namibia, Nigeria, South Africa, United Republic of Tanzania, Zambia and Zimbabwe. T&CM is practised, taught and regulated variously throughout Africa. With tens of thousands of years of human habitation, long-standing traditional medicine systems have developed throughout the continent. In many parts of Sub-Saharan Africa, reliance on traditional medicine still prevails, as the accessibility to modern medicine practitioners and facilities can be limited. In countries where malaria may afflict children (such as Ghana, Mali, Nigeria and Zambia), home herbal medicine use is the primary treatment for malarial fever in 60% of children.[5] The WHO estimates that 60–80% of people in the African region rely on traditional medicine for their primary healthcare. Traditional medicine is commonly used to treat non-serious, acute illnesses, but also extends to those living with chronic illness such as HIV/AIDS due to limited access to appropriate medication. Practitioners employ herbal medicines, but may also practise bone seding and manage more complex psychiatric conditions as part of traditional practices.[16] Against this backdrop, naturopathy is clearly a relative newcomer. It was introduced to South Africa after World War II and Zambia in the 1960s by an American, Dr Foster, who was both a medical and a naturopathic doctor.[2] Nonetheless, there are several educational institutions including the University of Western Cape in South Africa and the Zambia Institute of Natural Medicine and Research (also known as the Zinare Centre for Complementary Medicine Studies), both of which offer courses spanning 4200 hours.[13] The University of Western Cape offers a five-year double degree which allows graduates to register as a doctor within the studied discipline.[2,17] The profession is regulated by the Allied Health Professions Council of South Africa (AHPCSA), which was established by the Allied Health Professions Act, 63 of 1982.[18] See Table 1.3 for information regarding naturopathy in Africa. TABLE 1.3 Naturopathy in Africa: regional snapshot Countries practising naturopathy

11 (representing 23% of countries in this region)

Number of national naturopathic organisations Number of regional naturopathic organisations Number of other naturopathic organisations Number of educational institutions Estimated number of naturopaths

5 – – 2 100–1000

[2,3]

South East Asia region (countries where naturopathy is practised): India, Indonesia, Nepal and Thailand. Traditional medicine practices in South East Asia are represented strongly by Ayurvedic, Unani and Siddha philosophies, with Ayurveda arguably the best known in Western cultures. These systems of medicine are known by regionally specific names including Jamu in Indonesia, Dhivelhibeys in the Maldives and Koryo medicine in the Democratic People's Republic of Korea. Several countries, including Bhutan, Myanmar, Nepal and Bangladesh, recognise traditional medicines as valuable contributors to population healthcare and protect these values under Acts of Parliament.[19] Countries both large and small in the region have rich histories of traditional medicine. Although small, Bhutan is known as Menjong Gyalkhab, meaning ‘land of medicinal plants’, alluding to its rich abundance of herbal medicines used as part of the traditional medicine system known as Sowa Rigpa. This system evolved from Tibetan medicine and developed after the arrival of Shabdrung Rinpoche from Tibet Region of China in the 16th century.[20] Ayurvedic, meaning ‘science of life’, medicine was first documented somewhere between 2500 and 500 BC in India and, as such, is one of the longest continually practised systems of medicine in the world. India's massive population requires significant healthcare resources and it is estimated that 70% of the poorer, rural populations rely on Ayurvedic medicine for their healthcare needs.[21] Homeopathy is a comparatively recent addition and was introduced to India in the 1830s during homeopathy founder Samuel Hahnemann's lifetime. The relative cost effectiveness of this modality has seen its popularity flourish and there are now many homeopathic as well as naturopathic training institutions, practitioners and specialised

hospitals throughout the country.[22] Acharya Puccha Venkata Ramaiah originally brought the practice of naturopathy to India around 1885 after having trained under the German naturopath Louis Kuhne. Naturopathic practice was then revived in the 1940s thanks to support from Mahatma Gandhi. In Nepal, naturopathy started in 1968.[2] In India naturopathic education courses are combined with yoga and known as a Bachelor of Naturopathy and Yogic Sciences (BNYS). This is a fiveand-a-half-year full-time medical degree that is recognised by the Indian government under the Ministry of AYUSH (Ayurveda, Yoga and Naturopathy, Unani, Siddha, Homoeopathy).[2] See Table 1.4 for information regarding naturopathy in South East Asia. TABLE 1.4 Naturopathy in South East Asia: regional snapshot Countries practising naturopathy

4 (representing 36% of countries in this region)

Number of national naturopathic organisations Number of regional naturopathic organisations Number of other naturopathic organisations Number of educational institutions Estimated number of naturopaths

2 11 3 22 ?

[2,3]

Eastern Mediterranean region (countries where naturopathy is practised): Bahrain, Egypt, Kuwait, Morocco, Qatar, Saudi Arabia and United Arab Emirates. Traditional Arabic and Islamic medicine developed in the eastern Mediterranean region with its generous natural repository of herbal medicines. The medical system developed in the Middle Ages as Arab herbalists, pharmacologists, chemists and physicians built on the ancient medicinal practices of Mesopotamia, Greece, Rome, Persia and India. This legacy is considered an important foundation for contemporary medicine as it developed in Europe. Most famously, the work of Ibn Sina (Avicena in the West), known as Al-Qanun-fil-Tib (Canon of Medicine), plays an important role in the history of medicine. This book remained relevant for over 600 years and was published more than 35 times during the 15th and 16th centuries alone.[23] While the medieval Islamic world was spread broadly, wars, including those with the Odoman Empire, caused the Islamic civilisation into decline by the end of the 1400s.[24] Traditional medicine remains important in the region, with 88% of the WHO member states of the region acknowledging its continued use. Approximately 40% had established a national policy on T&CM as of 2010.[5] As for regulation, the WHO[5] declared that ‘Five Member States reported that they already had regulations for practitioners, with explicit regulations for different disciplines such as acupuncture, ayurveda, homeopathy and herbal medicine in four of them’ (p. 64). The WNF understands that the first legally practising naturopathic doctor in Saudi Arabia was a graduate from the National College of Natural Medicine (NCNM) in the US who began practice in 2005.[2] See Table 1.5 for information regarding naturopathy in the Eastern Mediterranean. TABLE 1.5 Naturopathy in Eastern Mediterranean: regional snapshot Countries practising naturopathy

7 (representing 32% of countries in this region)

Number of national naturopathic organisations Number of regional naturopathic organisations Number of other naturopathic organisations Number of educational institutions Estimated number of naturopaths

2 — — 1 90% acid; succimer; DMSA; chemet) as DMSA-cysteine disulfide conjugates

Oxygen and sulgydryl

Sodium 2,3-bis(sulfanyl)propane-1-sulfonate (sodium 84% of IV dose excreted dimercaptopropanesulfonate; DMPS; unithiol) through urine

Oxygen and sulgydryl

2-[2-[bis(carboxymethyl)amino]ethyl(carboxymethyl)amino]acetic acid (ethylenediaminetetraacetic acid; edetic acid; EDTA; endrate; sequestrol; endathamil) (2S)-2-amino-3-methyl-3-sulfanylbutanoic acid (3sulfanyl-D-valine; penicillamine; mercaptyl; Dpenicillamine; cuprimine)

Not metabolised. Excreted unchanged, generally bound with a different cation Rarely excreted unchanged; excreted mainly as disulfides

Oxygen

2,3-bis(sulfanyl)propan-1-ol (dimercaprol; British anti-Lewisite; BAL; 2,3-dimercaptopropanol; dicaptol)

Excreted unchanged in urine

Lead Arsenic Mercury Cadmium Silver Tin Copper Mercury Arsenic Lead Cadmium Tin Silver Copper, selenium, zinc, magnesium Lead Cadmium Zinc

Oxygen, hydroxyl, sulgydryl and amine

Copper Arsenic Zinc Mercury Lead Sulgydryl Arsenic and hydroxyl Gold Mercury Lead (BAL in combination with CaNa2EDTA)

Desferrioxamine or deferoxamine (DFO) DFO is a high molecular weight, highly hydrophilic chelator that was first introduced in the 1960s in short-term studies of iron-loaded patients.[13] It is a naturally occurring iron chelator produced by Streptomyces pilosus, and was the first iron chelator approved for human use.[14] Deferoxamine prevents iron-catalysed free radical reactions and is used in the treatment of acute iron poisoning and in iron storage disease such as beta-thalassaemia. DFO is poorly

absorbed orally and rapidly metabolised in plasma,[15,16] and therefore requires prolonged parenteral infusions (12 hours) to reach plateau plasma concentrations.[17] The usual regimen is 25 to 50 mg/kg/day as a continuous subcutaneous infusion given over 8 to 12 hours. DFO is effective at lowering serum ferritin and hepatic iron levels[18,19] and preventing endocrine complications,[20] and is associated with a reduction in cardiac complications.[21] DFO has also been used in aluminium toxicity because of its high affinity for aluminium and the high stability of the DFO-Al complex.[22] In animal studies, DFO reduced tissue aluminium concentrations,[23] reversed aluminium-induced LPO[24] and partially reversed aluminium-induced neurofibrillary degeneration.[25] The burden of prolonged subcutaneous infusions, adverse reactions (primarily pain) and high cost are limiting factors, and as a result, poor compliance remains a significant problem with administration of DFO. Preventable, premature deaths related to iron overload continue to occur.[26]

Dimercaprol (BAL) Dimercaprol or British anti-Lewisite (BAL) was originally developed to counteract arseniccontaining war gases,[27] but it is now used for the treatment of poisoning with toxic metals such as arsenic, gold, lead and mercury. Dimercaprol is not absorbed orally and must be administered by deep intramuscular injection. BAL is given in a dose of 2.5-5.0 mg/kg intramuscularly (IM) every 4 hours for 48 hours and then 2.5 mg/kg intramuscularly every 12 hours for 1–2 weeks, as necessary. Blood concentrations peak about 30 minutes after IM administration. Dimercaprol has two sulgydryl groups and forms a stable dimercaptide ring with arsenic. It is metabolised predominantly by glucuronic conjugation, and the metabolites are then excreted in the urine. BAL has several drawbacks including: its low therapeutic index, its tendency to redistribute metals (e.g. arsenic) to other organs, the need for intramuscular injection and its unpleasant odour.[28] Dimercaprol is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency because of the risk of haemolysis.[29] BAL is formulated with peanut oil, which increases the adverse effects and is absolutely contraindicated in individuals with peanut allergy.

2,3-dimercaptopropane-1-sulfonate (DMPS) DMPS was developed in 1951 and patented under the name Dimaval by Heyl Chem-Fabrik GmbH (Berlin) for the treatment of mercury overload. DMPS is not currently approved by the US Food and Drug Administration for metal treatment, although it has been used to treat acute arsenic poisoning.[30] DMPS is a water-soluble dithiol, with an oral bioavailability of the parent drug of approximately 39%. After intravenous administration, DMPS is rapidly transformed to disulfide forms, and the metabolites (acyclical and cyclical disulfide chelates) are excreted in the urine. The elimination half-life of total DMPS is 20 hours.[31] DMPS increases urinary excretion of arsenic, cadmium, lead and mercury and has been shown to

increase excretion of essential trace metals (copper, selenium, zinc, magnesium), necessitating supplementation before and after treatment.[32] Standard oral dosing of DMPS is 10 mg/kg, 5 days on and 9 days off. IV DMPS (3 mg/kg) is dosed once or twice monthly. Transdermal application of DMPS has shown no evidence of absorption into the blood or enhanced mercury excretion.[33]

2,3-dimercaptosuccinic acid (DMSA) DMSA is a sulgydryl-containing, water soluble, chelating agent developed in the 1950s as an alternative to more toxic chelating agents. After oral administration, DMSA is absorbed quite rapidly. It has a half-life of 2–3 hours in the blood and is equally excreted through urine and bile.[34] DMSA accumulates in the kidney where it is extensively metabolised in humans to mixed disulfides of cysteine.[35] Approximately 10–25% of an orally administered dose of DMSA is excreted in urine, the majority (>90%) as DMSA-cysteine disulfide conjugates. Urinary excretion of the unaltered (not metabolised) drug peaks at about 2 hours and is essentially complete by 9 hours, whereas urinary excretion of altered DMSA peaks at about 4 hours and is not complete for 24–48 hours.[36] In up to 60% of patients treated at full dosages with DMSA, there is a transient modest rise (typically 14%) in transaminase activity during treatment. Skin reactions occur in approximately 6% of treated patients. It is worth noting that in patients with intestinal dysbiosis, DMSA may have decreased intestinal absorption.[37] The sulgydryl group binds tightly to metals located on kidney tissue surfaces and carries them out of the body. Hundreds of articles have been published showing the effectiveness of DMSA in the binding and excretion of toxic metals. DMSA increases urinary excretion of arsenic, cadmium, lead and mercury. DMSA is FDA approved for the treatment of lead, and although it has demonstrated the ability to reduce mercury levels, it is not FDA approved for mercury toxicity.[38] The full body-weight dose for DMSA is 30 mg/kg/day given in three divided doses of 10 mg/kg each. Dividing the daily dose into three considers the DMSA peak in both the blood and urine that occurs 4 hours post consumption.[39] DMSA is typically given for 5 days, followed by a 9-day rest period, with follow-up metal mobilisation testing done every five cycles. When used with lead-burdened individuals, the blood lead level rebounds close to pre-DMSA levels within 2 weeks of DMSA cessation.[40] If one of the therapeutic goals is reduction of blood lead levels (BLLs), then a rest of less than 14 days between cycles is recommended. There is no single established protocol for DMSA in the treatment of lead that is universally accepted and followed. The dosing is based on either body weight or body surface area. The use of body-weight doses of DMSA has been shown to be safe in children as young as 12 months of age.[41] No harm was observed even after a DMSA overdose (185 mg/kg) in a 3-year-old child.[42] The following protocols have all been utilised:

• 10 mg/kg every 8 hours for a total of 30 mg/kg/day for 5 days, followed by 10 mg/kg twice daily for another 14 days.

• 1050 mg/M2(body size)/day for 7 days, then 700 mg/M2/day for 19 days. • 10 mg/kg every second day for a month • 30 mg/kg divided into three daily doses (during waking hours) for 5 days, wait 9 days and then repeat. • 30 mg/kg divided into three daily doses (during waking hours) for 2 days, wait 5 days and then repeat. This protocol is used in people who begin to experience increased symptoms from mercury mobilisation on day three of DMSA. Using one of the above protocols, a study of Chinese children with BLLs between 10 and 25 micrograms/dL examined the efficacy of DMSA at the 10 mg/kg level every second day for a month.[43] One of the treatment groups received concurrent daily doses of 1250 mg of calcium and 200 mg of ascorbic acid in addition to the DMSA. The combination of DMSA and nutrients proved to be more efficacious in reducing BLLs, rebalancing ALAD levels and reducing bone lead levels. DMSA was shown to be safe and effective in removing toxic metals (especially lead) and dramatically effective at normalising red blood cell (RBC) glutathione (GSH) in children with autism.[44] A randomised, double-blind controlled trial of children with autism showed reductions in measures of the severity of autism associated with the difference in urinary excretion of toxic metals before and following treatment with DMSA.[45] Regression analysis found that the body burden of toxic metals was significantly related to the variations in the severity of autism. The metals of greatest influence were lead, antimony, mercury, tin and aluminium.

2-amino-3-mercapto-3 methylbutyric acid (D-penicillamine) Penicillamine is a sulfur-containing amino acid and is a degradation product of penicillin. Because the levorotatory isomer is toxic, D-penicillamine is used for medicinal purposes. Acetylpenicillamine is a weaker chelating agent than penicillamine and has been used in the treatment of mercury poisoning.[46] Approximately 50–70% of D-penicillamine is absorbed after oral administration and reaches peak plasma concentrations 1.5–4 hours after ingestion. [47] Penicillamine has a half-life of less than 1 hour and is rapidly cleared in the urine, primarily as low-molecular weight disulfides.[48] Penicillamine can form chelates with many metal ions. The stability of complexes of metals with penicillamine varies in ascending order (i.e. from highest to lowest): mercury, lead, nickel, copper, zinc, cadmium, cobalt, iron and manganese.[49] Penicillamine is used for the treatment of lead poisoning as a chelating agent and is used for the elimination of copper in Wilson's disease. In cases of human poisoning, D-penicillamine has been shown to increase the excretion of lead,[50] arsenic[51] and mercury.[52] However, chelating metals does not necessarily ameliorate toxicity, and, as observed in lead poisoning, relocation of metals may

aggravate toxicity and may account for transient worsening upon commencement of penicillamine therapy.[53]

2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino] acetic acid (EDTA) EDTA is often used to chelate metals because it has high formation constants with several of them.[54] Table 3.2 provides a list of the logarithm values of formation constants of deprotonated EDTA with some metal ions. The formation constant for mercury (Hg2+) is more than 10 orders of magnitude greater than that for calcium (Ca2+), and the formation constant for lead (Pb2+) is about 10 orders of magnitude greater than magnesium (Mg2+). The fact that the formation constants are generally greater for toxic metals than for essential minerals lends a significant safety factor to long-term EDTA use. However, when used in humans and animals, EDTA does not appreciably mobilise mercury. Close monitoring for adverse effects and mineral imbalances is necessary, and oral supplementation with trace minerals (Cu, Zn, Ca, Mg) is appropriate to avoid deficiencies. TABLE 3.2

Metal ion formation constants for EDTA[55] Ion

Formation constant (log10 Kf)

Fe3+ Hg2+ Cu2+ Pb2+ Zn2+ Cd2+ Al3+ Fe2+ Ca2+ Mg2+ Na+ K+ 20°C, 0.1M ion

25.10 21.70 18.80 18.04 16.50 16.40 16.30 14.32 10.69 8.79 1.66 0.80

CaNa2EDTA is not metabolised, and EDTA chelates are excreted rapidly in the urine.

EDTA binds lead and cadmium strongly and may bind to mercury if other minerals are depleted. The typical dose of intravenous CaEDTA is 50 mg/kg with saline to proper osmolarity delivered over 20 minutes. In animal studies, the lowest dose of EDTA reported to cause toxicity was 750 mg/kg/day, which is equivalent to 45 g/day for a 60-kg person.[55]

N-acetylcysteine (NAC) NAC is a non-toxic N-acetyl derivative of cysteine containing a thiol group. NAC is widely

available, relatively inexpensive, easily administered and well tolerated by patients. It is distributed mainly to extracellular water and is rapidly eliminated in urine, with approximately one-third excreted during the first 12 hours after administration.[56] In humans, the half-life of NAC in blood plasma is approximately 2 hours. In urine, NAC is excreted as the symmetrical disulfide, the mixed disulfide with cysteine and as the free thiol. [57]

NAC is a potent antioxidant/detoxicant that does not alter tissue distribution of essential trace metals (Ca, Mg, Fe, Zn and Cu).[58] NAC produces a transient, dose-dependent increase in urinary excretion of methylmercury (MeHg) that is proportional to the body burden and can decrease brain and fetal levels of methylmercury.[59] Typical oral dose of NAC is 30 mg/kg daily.

Other Studies show that supplementation of antioxidants along with a chelating agent proves to be a berer treatment regimen than monotherapy with chelating agents. Several nutrients including alpha-lipoic-acid,[60] probiotics, vitamin E, melatonin and fibre used concurrently with DMSA not only provide greater reversal of lead-induced biochemical and physiological damage, but significantly increase the excretion of lead itself.[61] Co-administration of NAC with DMSA provided greater lead excretion, likely because cysteine-conjugated DMSA carries the greatest amount of lead from the body.[62] Alpha-lipoic acid has also been shown to prevent neuronal damage from mercury, as well as increase its excretion. Unfortunately, most of the data are from animal studies where the antioxidant substances were injected into the animals, and therefore, lirle to no data exists on the most beneficial doses of these agents for humans. Spirulina platensis has been found to protect against toxic metal-induced organ damage as well as to prevent anaemia, leukopenia and the deposition of metals in the brain. Forty-one patients with chronic arsenic poisoning were randomly treated orally by either placebo or spirulina extract (250 mg) plus zinc (2 mg) twice daily for 16 weeks.[63] There was a sharp increase in urinary excretion of arsenic (138 micrograms/L) at 4 weeks following spirulina plus zinc administration, and the effect was continued for another 2 weeks. Spirulina extract plus zinc removed 47.1% of arsenic from scalp hair. Products containing modified citrus pectin plus alginate have been reported to reduce lead and mercury (74% average decrease) in case studies.[64] However, virtually all the data has been from one group of researchers and does not hold up under closer scrutiny.[65]

Chelatable toxicants Aluminium Principles of toxicity Aluminium is a toxic metal with no known physiological role. Acute toxicity is rare.

Aluminium binds to phospholipids, stimulates iron-initiated LPO and it reacts with oxygen to form Al-O2– that increases oxidation of amino acids, leading to generation of protein carbonyls.[66] These reactions reduce the activity of glutathione peroxidase, superoxide dismutase and catalase.[67] The facilitation of superoxide-driven biological oxidation by aluminium has been shown to result from an interaction between the metal and the superoxide radical anion.[68,69] Aluminium may cause impairments in mitochondrial bioenergetics, leading to the generation of oxidative stress and the gradual accumulation of oxidatively modified cellular proteins.[70]

Sources Aluminium is the most widely distributed metal in the environment and exposure occurs through air, food and water. Aluminium sulfate is used as a flocculating agent in the treatment of drinking water and aluminium hydroxide is used therapeutically as a phosphate-binding agent and an antacid. Chronic aluminium toxicity may occur as a result of chronic exposure to extremely high levels of aluminium-containing compounds (e.g. antacids) or direct inoculation of aluminium via dialysates, parenteral nutrition or implanted foreign materials.[71,72] Aluminium levels in water supplies can be a potential hazard to renal dialysis patients, entering the body across the dialysis membrane and bypassing intestinal absorption. However, acute aluminium toxicity is now quite rare because the water used in dialysis is treated to remove contaminated metals. Occupational exposure to aluminium compounds primarily occurs through inhalation of airborne particles in dusts and fumes. The air inside aluminium smelters, foundries and remelting plants can contain significant concentrations of aluminium.[73]

Body load In general, inhaled soluble particles (e.g. aluminium sulfate, hydrated aluminium chloride and aluminium nitrate) are rapidly absorbed from the lungs, while the less soluble particles (e.g. aluminium metal, aluminium oxide, aluminium hydroxide, aluminium phosphate and aluminium silicate) are retained in the lungs and then slowly released into the systemic circulation.[74] Aluminium is poorly absorbed from the gastrointestinal tract. The usual daily dietary intake of aluminium is 5 to 10 mg. However, most aluminium-containing compounds are relatively insoluble at physiological pH, limiting absorption of aluminium through ingestion.[75] The majority of aluminium is excreted in urine, accomplished by filtration from the blood by the glomerulus of the kidney.[76] If not filtered by the kidneys, aluminium binds to proteins such as transferrin and is distributed throughout the body. Most healthy adults tolerate comparatively large repeated daily oral aluminium exposures (up to 3500–7200 mg/day) without any adverse effect, but other individuals (e.g. pre-term infants, young children, those with reduced kidney function) can be at serious risk for systemic aluminium intoxication even at lower doses.[77] Aluminium has been shown to

accumulate in several mammalian tissues including the brain, bones, liver and kidneys.[78,79]

Clinical manifestations The brain appears to be the most vulnerable to the toxic effects of aluminium, and a potential link has been observed between aluminium and Alzheimer's disease, amyotrophic lateral sclerosis (ALS; motor neurone disease [MND]) and autism spectrum disorders.[80] Additional neurological consequences of toxic aluminium exposure include encephalopathy, seizures, parkinsonism and death.[81,82] Aluminium is certainly a potential contributor to the onset, progression and aggressiveness of neurological disease.[83] In workers exposed to aluminium for several years, concerns exist surrounding reduced arention span, impaired cognition and deficits in fine motor skills.[84] Although a causal link has not been proven, several studies have positive outcomes using chelation in the treatment of conditions associated with aluminium overload. Aluminium toxicity in patients with renal dysfunction causes osteodystrophy and gradual dementia.[85] Pulmonary fibrosis has been reported in relation to aluminium exposure.[86] Higher concentrations of aluminium have been found in tissue bioptates along with elevated serum aluminium levels in patients with laryngeal papilloma and laryngeal cancer.[87]

Diagnostic testing Acute aluminium toxicity is diagnosed using plasma concentration levels. When performing biological monitoring of aluminium, measurement of urinary levels is recommended due to the higher sensitivity compared to the measurement of aluminium in plasma.[88,89] Preclinical neurotoxic effects have been observed when serum aluminium levels exceed 10 micrograms/L[90] and serum aluminium levels of 6.8–9.5 micrograms/L, and urinary aluminium levels of 4–6 micromols/L appear to represent a threshold for observed neurological effects.[91]

Management/therapy DFO is a trivalent ion chelator that can remove excess aluminium from the body. A small cohort, 2-year, single-blind study of patients with Alzheimer's disease treated with DFO (125 mg intramuscularly twice daily, 5 days per week, for 24 months) demonstrated a significant reduction in the rate of decline of daily living skills in the DFO-treated group compared to the placebo or no-treatment groups.[92] Among haemodialysis patients with aluminium overload, treatment with DFO at both the standard dose (5 mg/kg/week) and the low dose (2.5 mg/kg/week) offered similar therapeutic effects and successful treatment response rates. [93]

Arsenic Principles of toxicity After exposure to arsine gas, absorbed arsine enters RBCs and is oxidised to arsenic

dihydride and elemental arsenic. These derivatives combine with red cell sulgydryl groups, which results in cell membrane instability and haemolysis. The main mechanism by which monomethylarsonous acid (MMA) and inorganic arsenicals cause cellular and tissue damage is through oxidative stress.[94] Oxidative damage to the DNA results in increased urinary excretion of 8-hydroxy-2’-deoxyguanosine (8-OHdG), which is a valuable marker for both oxidative stress and chronic disease risk.[95] Increases in urinary 8-OHdG levels have been found in those drinking groundwater high in arsenic as well as those occupationally exposed to arsenic.[96] Under physiological conditions, arsenic may also induce toxic effects through the formation of hydrogen peroxide.[97] Higher levels of MMA have also been linked to the presence of elevated homocysteine levels, possibly due to overall methylation defects.[98] Mechanisms of arsenic carcinogenesis include oxidative damage,[99] epigenetic effects[100] and interference with DNA repair.[101]

Sources Arsenic is a ubiquitous metalloid in our food, air and water and is found in both inorganic forms (as trivalent or pentavalent states) and organic forms. Water and dietary sources of arsenic remain the bulk of exposure sources.[102] Groundwater provides a continuous source of inorganic arsenic and its metabolites, while foods provide more of the organic arsenicals (e.g. arsenobetaine, arsenocholine, arsenosugars and arsenolipids), which have very short half-lives and are considered virtually non-toxic. Seafood, rice, mushrooms and poultry are the main food sources of arsenic.[103] Arsenobetaine is primarily found in seafood. Organically grown rice has also been found to have elevated levels of arsenic.[104] Groundwater is the most common source of arsenic exposure. Arsenic levels up to 3100 micrograms/L have been found in well water samples in regions of the United States.[105] Bangladesh, Taiwan Province of China, Chile, Argentina, China and India have groundwater arsenic levels that are typically >300 micrograms/L (ranging up to 7550 micrograms/L in Argentina). Chronic arsenic poisoning is found in these areas in people drinking an average of 3.3 L of water daily, while those consuming ≤1.9 L have not exhibited poisoning.[106] Arsenic is present in cigarere smoke, and is found in higher levels in smokers.[107,108] Arsenic is a component of certain pigments used in glass making, thereby increasing exposure in individuals working with those colours in glass blowing.[109,110]

Body load Elemental arsenic is insoluble in water and bodily fluids, is insignificantly absorbed and is non-toxic. Arsine gas is the most toxic form of arsenic. Both the gastrointestinal and the respiratory tracts absorb arsenic and then widely distribute it through the body, where it is reduced to arsenite (III) and then methylated.[111] A single pass through this methylation pathway produces monomethylarsonous acid (+3) (MMA). MMA can then be passed through the pathway a second time to produce dimethylarsonous acid (+3) (DMA). Methylation primarily occurs enzymatically through the action of arsenic (+3 oxidation)

methyltransferases (AS3MT), but can also occur non-enzymatically in the presence of either methylcobalamin or GSH.[112] Ninety-five per cent of methylated inorganic arsenic is excreted in the urine, and 5% is excreted in the bile. Most of the arsenic is eliminated in the first few days, but over time, arsenic can accumulate in hair, nails and skin.

Clinical manifestations Acute and chronic arsenic exposure causes a variety of health effects including dermal changes (e.g. pigmentation, hyperkeratosis and ulceration), respiratory, pulmonary, cardiovascular, gastrointestinal, haematological, hepatic, renal, neurological, developmental, reproductive, immunological, genotoxic, mutagenic and carcinogenic effects.[113] Arsenic ingestion produces violent gastrointestinal pain, haemorrhagic gastroenteritis and vomiting with shock developing. After a latent period of 2–24 hours, exposed individuals experience massive haemolysis, malaise, headache, weakness, dyspnoea, hepatomegaly, jaundice, haemoglobinuria and renal failure. Persistent diarrhoea, dermatitis, haematuria, proteinuria, acute tubular necrosis and polyneuropathy are evidence of chronic ingestion.[114] Lethal doses of arsenates are 5–50 mg/kg, and lethal doses of arsenites are 20 micrograms/dL over a period of 4 weeks are the current maximum allowable levels for industrial serings. Pregnant women are advised to have BLLs 3.0 1.34 (top tertile) 1.51 2.55 2.0–3.0 14.1 (MCPP) 5.9 (MCOP) 5.9 (MBzP) 1.62 (DEHP, adults) 1.77 (HMW, adults) 2.84 (LMW, children) 4.29 (MiBP, male children)

Cadmium

Lead Organochlorine pesticides

Organophosphate pesticides PCBs Bisphenol A

Polybrominated diphenyl ethers Phthalates

Obesity

Toxins/toxicants A toxin is technically defined as a poisonous substance produced by living cells or organisms that when introduced into the body can cause disease. A broader definition would include not only biologically produced substances, but any agent that

exerts undesirable effects on physiological function. For this chapter, sources of toxins are grouped into one of three categories: exogenous, endogenous and toxins of choice. Oxidative damage to cells has long been associated with the development of many chronic diseases, including cancer, heart disease and diabetes. Reactive oxygen species (ROS) (e.g. superoxide radicals, hydrogen peroxide and hydroxyl radicals) are produced through normal biochemical processes in the body such as oxidative phosphorylation in the mitochondria during the production of ATP. They are also produced throughout the body by the cytochrome P450 system that is active in the production, metabolism and catabolism of numerous compounds in the body. In addition, ROS are generated by white blood cells that aeack bacterial invaders and by peroxisomes that break down faey acids. These prooxidants then aeack and damage lipids, nucleic acids and proteins, leading to DNA damage, abnormal protein folding, lipid peroxidation and mitochondrial membrane damage. Environmental toxicants can easily increase the pro-oxidant load and imbalance the system, leading to greater risk of disease.[3] In fact, a twin-study in Denmark revealed that the bulk of oxidative damage is due to environmental factors.[4]

Sources Exogenous Exogenous toxins are comprised of toxic agents that arise from external factors. Sources are primarily environmental and include metals, chemicals (inorganic, fluoride, organic, persistent organic pollutants, drugs, etc.), moulds, radiation (e.g. light, medical, mobile phones) and particulate maeer. It is estimated that over 60 000 different chemicals are now in use, with 6.5 billion pounds of chemicals released into the air per year in the US alone. Considering only 20% of disease is genetically influenced and 80% of disease results from diet, lifestyle and environmental factors, there is mounting evidence that this high level of toxin exposure is responsible for the rising incidence of chronic disease. Mould Indoor environments contain a complex mixture of live and dead microorganisms, fragments of dead organisms, toxins, allergens, volatile microbial organic compounds and other chemicals. Damp building materials contribute to the production of undesirable organisms and toxins including: 1) the growth of moulds which release biological agents, toxic chemicals and spores; 2) the growth of bacteria which release biological agents, toxic chemicals and spores; 3) protozoal growth; 4) virus survival; 5) the proliferation of dust mites (arachnids of many different species); 6) the proliferation of rodents and cockroaches which can carry infectious organisms; and 7) the release of chemicals and particles from building materials. The primary mechanisms for damp-building toxicity include: immunological (e.g. stimulation, suppression, autoimmunity), toxic (e.g. neurotoxicity, genotoxicity, reproductive damage) and inflammatory. Moulds are fungi that grow best in warm, damp and humid conditions. In general, any area with a relative humidity of greater than 80% in the presence of metabolisable organic materials supports their growth. Research shows that as many as 50% of residential and work environments have water damage, and 10–50% of indoor environments in Europe, North America, Australia, India and Japan have clinically significant mould problems.[5] The primary mechanisms for dampbuilding toxicity include: immunological (e.g. stimulation, suppression, autoimmunity), toxic (e.g. neurotoxicity, genotoxicity, reproductive damage) and inflammatory. Toxic metabolites have various physiological effects including disrupting mitochondrial function, misbalancing nitric oxide synthesis, inflammatory mediators, neurotoxicity, cytotoxicity, immune suppression, carcinogenesis and mutagenesis.[6] When adding in biochemical individuality, almost any chronic clinical condition could be caused by these toxins. Toxic metals Toxic metals are considered major environmental pollutants and are a common underlying factor in most cases of toxicant overload. Metals are used in a variety of industrial processes and, as a result, human exposure has dramatically increased during the past 50 years. The general population is exposed to metals at trace concentrations either voluntarily, through supplementation, or involuntarily, through intake of contaminated food and water or contact with contaminated soil, dust or air. Toxic metals cause damage in a variety of ways including: increasing free radical production, enzyme poisoning, direct DNA damage, endocrine disruption and mitochondrial or cell wall damage.[7] The severity of signs and symptoms resulting from metal toxicity vary based upon several factors including the dose, route of exposure and chemical species, as well as the age, gender, genetics and nutritional status of exposed individuals. Early symptoms can include impaired ability to think or concentrate, fatigue, headache, indigestion, tremors, poor coordination, myalgia, anaemia, asthma, allergies, ‘brain fog’, infertility and temperature dysregulation. Mercury is found globally in all populations that have been tested. The primary form of mercury in both hair and blood is MeHg, with over 90% coming from the consumption of ocean fish and shellfish. Total blood mercury levels are directly

associated with fish intake. Mercury is a ubiquitous environmental pollutant and is toxic at any level. MeHg is a potent neurotoxin via several mechanisms including demyelination, oxidative stress and autonomic dysfunction.[8] Metallic mercury interrupts the normal uptake and release of neurotransmieers and can result in excitability and irritability. Mercury causes a great deal of oxidative damage throughout the body including to the DNA. Hydroxyl radical damage to the DNA results in elevated levels of 8-OHdG in the urine. In one study, people without occupational exposure to mercury with mean blood and urine mercury levels of 0.91 microgram/L and 0.95 microgram/L had urinary 8-OHdG levels that averaged 2.08 ng/mg cr. (range 0.95–4.7).[9] The primary mechanism of mercury hepatotoxicity may be related to poisoning of cysteinecontaining proteins and glutathione (GSH) depletion.[10] The two greatest sources of non-occupational environmental lead contamination came from the addition of tetraethyl lead to commercial petrol (from 1920 until the mid 1980s) and its use as a colour-enhancing additive to paint (until the 1970s). Lead is found ubiquitously in populations throughout the world. It is readily absorbed through both the respiratory and the gastrointestinal tracts. Gastrointestinal absorption of lead in children can be up to five times greater than in adults who are exposed to the same sources.[11] Lead not only generates ROS, but also causes a reduction in the activity of ROS-quenching enzymes such as superoxide dismutase, catalase and glutathione peroxidase, resulting in diminished antioxidant defence. In adults, lead-associated oxidative stress is associated with an increase in urinary 8-OHdG levels,[12] but such an increase has not been seen in children with similar blood lead levels (BLLs).[13] Chronic low-level lead exposure is associated with several adverse health conditions. No threshold for safety exists. Cumulative lead burden in adults, via bone lead assessment, has been associated with the risk of developing parkinsonism,[14,15] Alzheimer's disease[16] and decreased cognition.[17] Several studies have found that lead correlated with renal dysfunction,[18,19] neurobehavioural dysfunction[20] and declines in function of the peripheral nervous system,[21] and some evidence shows decreased IQ in children with supposedly safe (70% of a healthy ecosystem. This single genus dominance is unique, not only among human microbiomes, but also among other mammalian vagina ecosystems, where lactobacilli usually comprise 133%. Carriers of the CYP1A2 gene rs762551 C allele are slow metabolisers.[117]

Next steps: Food sensitivities and future treatment directions If variants in any of these genes or other genes associated with food sensitivities are identified, the following tests should also be considered: • Testing for insulin resistance for hypertension (as above) • ADMA • Serum transglutaminase IgA, gliadin IgG and gliadin IgA (need to consume gluten prior to the test) • Faecal transglutaminase IgA (need to consume gluten prior to the test) • Small intestinal bacterial overgrowth/dysbiosis causing secondary lactose intolerance.

Oxidative stress Oxidation is a normal part of metabolism and cellular signalling but when the generation of oxidation overwhelms the endogenous and exogenous antioxidant systems, cellular damage can occur. Genetic variants in several genes that code for cellular antioxidant enzyme systems can influence enzyme function and knowing whether they have such variants can be useful for patients who want to understand their need for antioxidant support, patients interested in anti-ageing strategies, disease prevention and preconception care for males to ensure good sperm quality. The clinical benefit is multifactorial, providing information in relation to antioxidant support and as part of an anti-ageing strategy with the main areas of influence being weight management, cardiovascular health, blood sugar levels, respiratory function, joint mobility, immune response, brain health and preconception care. Manganese superoxide dismutase MnSOD (rs4880) is a mitochondrial biomarker for oxidative stress that neutralises superoxide, a toxic type of free radical. Glutathione peroxidase (rs1050450) is a selenium-dependent glutathione.[118,119] Dietary sources of selenium are Brazil nuts, shell fish, meat, eggs, mushrooms and grains. Catalase (rs1001179) reduces oxidative stress by converting hydrogen peroxide into water and oxygen.[120,121]

N e x t s t e p s : O x i d a t i ve s t r e s s a n d f u t u r e t r e a t m e n t d i r e c t i o n s If variants in any of these genes or other genes associated with oxidation are identified, the following tests should also be considered: • Oxidative damage markers including: – Urinary 8-OHdG (8-hydroxydeoxyguanosine – DNA damage) – Urinary allantoin (muscle damage) – Red cell carbonyl proteins (advanced glycation end (AGE) product proteins)

– Urinary malonyldialdehyde (faZy acid and cell membrane oxidation) • Mineral status to assess cofactors such as manganese and selenium • Organic acids test to assess glutathione, CoQ10 and vitamin C status.

Methylation The process of methylation can be thought of as an on/off switch and involves the addition of a methyl group (CH3). This process is involved in hundreds of reactions involving DNA synthesis and repair, immune function, mitochondrial energy generation, detoxification and antioxidant pathways, hormone metabolism and neurotransmiZer and catecholamine pathways. Abnormalities in the methylation cycle/pathways can have far-reaching consequences for health (see Table 8.1). TABLE 8.1 Biochemical processes involving methylation and adverse consequences Biochemical process

Adverse consequence

DNA and RNA NeurotransmiZers Cell membranes Hormones Immune function Detoxification Energy generation

Turn on/off genetic expression and enzymes Depression, anxiety, cognition (adrenaline, noradrenaline, dopamine, serotonin) Neuro-degeneration, membrane receptors and fluidity, lipid abnormalities Thyroid abnormalities, stress response, poor sleep, oestrogen metabolism Poor wound healing, infection, autoimmunity, cancer, food allergies Degenerative disease, cancer, food sensitivities, increased oxidation and inflammation, antioxidants (glutathione) Chronic fatigue, mitochondrial abnormalities (carnitine, CoQ10)

Source: © Reproduced by kind permission of Dr Rhona Creegan and Dr Margaret Smith.

The methyl group is supplied by the integrated function of the methionine, folate and biopterin pathways. There are many genetic variants in the numerous genes involved in these pathways. Genetic variants in the MTHFR gene can reduce the methylfolate available for the methylation of cobalamin, which is required for the conversion of homocysteine to methionine and subsequently the production of SAMe, the major methyl donor in the body. This variant sometimes leads to elevated homocysteine[122] and s-adenosyl-homocysteine, which are risk factors for cardiovascular disease.[123] S-adenosyl-homocysteine is a potent inhibitor of methyltransferase enzymes[124] required for numerous methylation reactions such as catechol-O-methyltransferase (COMT) involved in neurotransmiZer and oestrogen metabolism and phosphatidylethanolamine-methyltransferase (PEMT) required for the production of phosphatidylcholine for membrane function and synthesis of choline and acetylcholine. Variants in the MTHFR gene are often tested for to assess the function of methylation and research has focused on two SNPs: C677T and A1298C. Tables 8.2 and 8.3 highlight the effects of these two common genetic variants on enzyme activity and homocysteine levels.[123,125] TABLE 8.2

MTHFR enzyme activity for the combined SNP contributions of C677T and A1298C polymorphisms MTHFR enzyme activity

MTHFR genotype 1298AA homozygous normal 1298AC heterozygous one C allele 1298CC homozygous two C alleles

677CC 677CT 677TT homozygous heterozygous homozygous normal one T allele two TT alleles 100% normal enzyme 65% normal enzyme activity 25% normal enzyme activity activity 83% normal enzyme activity 48% normal enzyme activity Not known

61% normal enzyme activity Not known

Source: © Reproduced by kind permission of Dr Margaret Smith (SmartDNA).

Not known

TABLE 8.3

MTHFR enzyme activity and homocysteine level MTHFR enzyme and homocysteine

MTHFR genotype 1298AA homozygous normal 1298AC heterozygous one C allele 1298CC homozygous two C alleles

*

677CC homozygous normal No impact on homocysteine metabolism

677CT heterozygous one T allele No impact on homocysteine metabolism

677TT homozygous two TT alleles Associated with elevated homocysteine level

No impact on homocysteine metabolism

Associated with elevated homocysteine level

Associated with elevated homocysteine level*

No impact on homocysteine metabolism

Associated with elevated homocysteine level*

Associated with elevated homocysteine level*

Rare MTHFR gene SNP pairing. Refer to hwww.omim.org/entry/607093

Source: © Reproduced by kind permission of Dr Margaret Smith (SmartDNA).

Because the methylation cycle involves complex interactions of integrated pathways, genetic variants in other genes should be considered when making therapeutic decisions. Some of these include MTR, MTRR, TCN2, SLC19A1, CBS, MTHFD1 involved with methionine synthesis, remethylation of vitamin B12, transport of B12, folate and choline, interconversion of folates and the transsulfuration pathway for producing cysteine and glutathione. Variants in these genes can also influence methylation pathways and affect plasma levels of homocysteine.[126,127] If therapeutic decisions are based solely on MTHFR variants and plasma homocysteine levels, the wrong therapeutic strategies may be used. For example, certain variants in the transsulfuration pathway (CBS rs234706 699C>T) may upregulate the cystationineβ-synthase enzyme, which converts homocysteine to cystathionine and can lower homocysteine levels. However, the activity of this enzyme is upregulated in the presence of oxidative stress, even when the wild-type gene is present, as it acts as a redox sensor to increase production of glutathionine in times of need.[128,129] Most identified variants in genes involved in the methylation cycle lead to elevated homocysteine and S-adenosylhomocysteine (SAH). The impact of these variants on methylation status varies depending on factors such as nutrient availability, overall requirement for methylation reactions at a given time, oxidative stress and overall toxin load. Homocysteine can be measured in the blood and elevated levels are a risk factor for cardiovascular disease. If homocysteine is elevated, support nutrients such as folate, vitamin B12, vitamin B2, vitamin B6, choline and trimethylglycine (betaine) can be used to lower levels. The form of the nutrients used will depend on the genetic variants identified and needs to be individualised. Nutrient status can be assessed by various methods including urine organic acid and amino acid testing. Urine organic acid testing provides a functional assessment of the nutrients by measuring the nutrient sensitive pathways and whether the reactions are proceeding (e.g. methylmalonic acid for vitamin B12 and foriminoglutamic acid [FIGLU] or pyrimidine metabolites for folate status). The form of folate may be important, depending on the SNPs; individuals appear to react differently to the various activated forms (methylfolate vs folinic vs folic acid). There is considerable confusion among practitioners about the various forms of folate. One report showed that unmetabolised folic acid reduced the activity of natural killer cells[130] but this has not been verified in subsequent studies and any role for unmetabolised folic acid as a contributor to disease is disputed.[131] It is likely that the enzyme dihydrofolate reductase (DHFR, which reduces dietary folic acid into active folates) becomes saturated when folic acid intake is high and that the unmetabolised folic acid is a transient phenomenon. As folic acid is not a cofactor for any biochemical reactions, it is unlikely to adversely affect pathways, although this is still an active area of research. The active forms of folate supplements may be beneficial if the DHFR activity is reduced, such as with genetic variants, excess alcohol consumption and certain medications. If homocysteine levels are normal or low, methylation may still be impaired, as an upregulated cystathionine B synthase (CBS) enzyme in the transsulfuration pathway may be diverting the homocysteine away from regenerating methionine. A plasma methylation profile can be used to functionally assess the methylation cycle. The ratio between SAMe and SAH is important. SAH is a potent inhibitor of methyltransferase enzymes, including DNMT (epigenetic regulation), HNMT (histamine metabolism) and COMT (neurotransmiZer and oestrogen metabolism). This test will also measure cystathionine levels. An important cause of abnormal methylation is inhibition of many of the enzymes by accumulation of toxins regardless of genetic status, although this is exacerbated by genetic variants and subsequent

reduced enzyme function. It is a perpetuating cycle where toxins inhibit the enzymes and methylation is required for detoxification pathways. Methylation pathways provide the methyl and glycine groups directly in phase II liver pathways and support the transsulfuration pathway to produce glutathione for the glutathione transferase enzymes in phase II conjugation. Many of these enzymes (CBS) and phase I cytochrome p450 detoxification enzymes are dependent on the synthesis of haem and therefore overall toxin burden can be assessed by measuring urinary porphyrins, heavy metals or environmental pollutants.

M e t h yl a t i o n g e n e t i c s a n d f u t u r e t r e a t m e n t d i r e c t i o n s If variants in any of these genes or other genes associated with methylation are identified, the following tests should also be considered: • Plasma methylation profile (SAMe, SAH, SAMe:SAH ratio, homocysteine, cystathionine, methionine) • Folate metabolism profile (5-MTHF, folinic acid, THF) • Urinary porphyrins (intermediates in haem pathways) • Hepatic detoxification profiles • Heavy metals (hair, urine or blood) • Urine organic acids (nutrient status, mitochondrial function, neurotransmiZer metabolism, ammonia) • Urine amino acids • Urine pyrroles (for zinc and vitamin B6 status) • Urine hormone metabolites, including oestrogen and cortisol • Histamine (take caution with this assessment as a significant amount may be produced in gut).

Detoxification Detoxification of exogenous and endogenous compounds is vital for health in order to prevent the accumulation of potentially harmful substances including products of metabolism, hormones, heavy metals, pharmaceuticals and pollutants. Detoxification occurs mainly in the liver by phase I and phase II reactions. Phase I activates compounds by the action of the cytochrome P450 enzymes, followed by conjugation of these reactive intermediates in phase II. Phase II conjugates are more water-soluble and can be excreted from the body via the bile and kidneys in phase III. There is substrate competition between the detoxification enzymes which, when combined with the polymorphic nature of the genes that encode for these enzymes, can slow down or speed up removal of compounds, resulting in excess accumulation of unwanted substances (such as environmental chemicals and hormones), and altered elimination of pharmaceutical compounds, resulting in reduced efficacy or enhanced toxicity. This is the basis of pharmacogenetics which is applied to several areas of medicine, including oncology, psychiatry, cardiology and pain management. The genes encoding CYP2D6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 account for the metabolism of 80–90% of all prescription drugs and testing for genetic variants in these genes may help reduce adverse drug reactions, especially in the modern era of polypharmacy.[132,133] Oestrone (E1) and oestradiol (E2) are metabolised to 2-, 4- and 16-hydroxy metabolites. These metabolites are further metabolised into methylated products. Variants in the CYP450s and methylating enzymes involved can therefore lead to abnormal amounts of the metabolites, which differ in their oestrogenicity and effect on disease risk. CYP1A1 catalyses the 2-hydroxylation of E1 (oestrone) and E2 (oestradiol) to form the catechols 2-hydroxy-E1 (2OHE1) and 2-hydroxy-E2 (2-OHE2). These are considered more anti-oestrogenic than the 4-OH and 16-OH metabolites and are therefore considered more protective in terms of breast cancer risk.[134] The CYP1A1 rs4646903 variant has been shown to increase enzyme activity.[135] Additionally, CYP1A1 activates pro-carcinogens such as polycyclic aromatic hydrocarbons (PAH) and heterocyclic aromatic amines (HA) found in tobacco smoke and chargrilled meat, which have been reported to play a role in the development of some cancers such as lung and breast. Females with CYP1B1 rs1056836 CG or GG who smoke have been shown to have a 2.3-fold increased risk of developing breast cancer.[136] CYP1B1 hydroxylates E1 and E2 into the 4-OH metabolites, which are mutagenic.[137] It also produces toxic intermediates from xeno-oestrogens that mimic oestrogens by binding to oestrogen receptors. The CYP1B1 rs1056836

variant is upregulated by xeno-oestrogens, which increases production of the 4-OH metabolites and has been shown to increase risk of uterine fibroids and breast and prostate cancer.[134,138,139] Once the 2- and 4-hydroxylated metabolites are produced, they are methylated (inactivated) by COMT, which relies on adequate enzyme activity and which can be slowed by various SNPs in both MTHFR and COMT (rs4680). Accumulated fat-soluble 4-hydroxy oestrone can be further oxidised to produce catechol quinones, which can damage DNA and activate oncogenes.[140] If variants in phase I and oestrogen metabolism genes are present as described, exposure, PAHs, PCBs and xeno-oestrogens should be reduced. Activity of COMT may also be impaired with being overweight, excessive alcohol consumption and stress. Glutathione-S-transferase enzymes detoxify many water-soluble environmental toxins including solvents, PAHs, steroids, herbicides, pesticides, lipid peroxidases and heavy metals (mercury, cadmium and lead) by conjugating glutathione with phase I derived products. Decreased glutathione conjugation capacity can therefore overwhelm detoxification capacity, leading to toxin accumulation and increased oxidative stress. Copy number variations in the GSTT1 and GSTM1 enzymes are associated with less effective detoxification of potential carcinogens and an increased susceptibility to heavy metal accumulation and some types of cancer.[141] When looking at the copy number of a gene, the variant is assigned as being either present or absent (null). The GSTP1 gene encodes for the glutathione-Stransferase P1 enzyme located in the brain, skin and lungs and is involved in detoxification of carcinogens, xenobiotics, steroids, heavy metals and oxidative stress. The rs1695 variant produces an enzyme with lower activity and less detoxification capacity. The association between certain dietary components (e.g. isothiocyanates in cruciferous vegetables) and reduced cancer risk is thought to be due to the effect on the detoxification genes/enzymes including CYP1A1, GSTT1 and GSTM1.[142,143] Analysis of genetic variants in the detoxification genes is important therefore for identification of risk of the damaging effects of both endogenous and exogenous toxin exposure and the implementation of dietary and lifestyle strategies to assist with the detoxification capacity.

D e t o x i fic a t i o n g e n e t i c s a n d f u t u r e t r e a t m e n t d i r e c t i o n s If variants in any of these genes or other genes associated with detoxification are identified, the following tests should also be considered: • Phase I liver detoxification profile – caffeine clearance. • Phase II liver detoxification profile – measures of glucuronidation, glycination, glutathionation and sulfation. • Urine mercapturic acid. • Profiles looking at toxic exposure to volatile solvents, chlorinated pesticides, polychlorinated biphenyls, organophosphates, bisphenol A, phthalates and parabens. • Urine organic acids. • Urinary oestrogen metabolites. • Heavy metal analysis. • Oxidative stress markers (as described). • Methylation assessment (as described).

Putting it all together If genetic variants are identified in any genes, additional testing may be required to determine whether the variants are affecting biochemical pathways at a functional level. As many modern chronic health concerns are multifactorial in aetiology, it is likely that abnormalities in metabolic function, detoxification, oxidation, inflammation and methylation are present, which can be made worse when biochemical weaknesses are exposed by underlying genetic variability. The genetic polymorphisms do not indicate the presence of disease, but when used in combination with the individual's clinical presentation, information on their diet, lifestyle, environment and specific biochemical testing, powerful personalised interventions can be employed. The best time to assess genetic variability is when the person is well, because ultimately the goal is to prevent the development of chronic conditions by focusing on where any weaknesses in their biochemistry lie. However, many

practitioners see patients who are trying to regain lost health and genomic profiling will assist in revealing possible dysfunctional pathways. Our health is a complex interaction of diet, lifestyle and environment with our genome and microbiome, involving numerous signalling molecules to provide metabolic and survival cues that instruct our genes to express or repress (epigenetics), so that appropriate biochemical pathways are activated/deactivated to ensure survival. When imbalances in metabolism, detoxification, inflammation, methylation, glycation and oxidation occur, there will also be abnormalities with hormones, neurotransmiZers, gut function and energy generation. Knowing our biochemical vulnerabilities is a key piece of the complex health puzzle. With certain genotypes, general diet and lifestyle recommendations can be made, but specific recommendations should not usually be made based on genotype alone – this needs to be based on phenotype.

References [1] Karki R, Pandya D, Elston RC, et al. Defining ‘mutation’ and ‘polymorphism’ in the era of personal genomics. BMC Med Genomics. 2015;8:37. [2] Burdge GC, Lillycrop KA. Nutrition, epigenetics, and developmental plasticity: implications for understanding human disease. Annu Rev Nutr. 2010;30:315–339. [3] Feil R, Berger F. Convergent evolution of genomic imprinting in plants and mammals. Trends Genet. 2007;23(4):192–199. [4] Court F, Tayama C, Romanelli V, et al. Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment. Genome Res. 2014;24(4):554–569. [5] Tycko B, Morison IM. Physiological functions of imprinted genes. J Cell Physiol. 2002;192(3):245–258. [6] Isles AR, Holland AJ. Imprinted genes and mother–offspring interactions. Early Hum Dev. 2005;81(1):73–77. [7] Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet. 2007;8(4):253–262. [8] Painter RC, Roseboom TJ, Bossuyt PM, et al. Adult mortality at age 57 after prenatal exposure to the Dutch famine. Eur J Epidemiol. 2005;20(8):673–676. [9] Heijmans BT, Tobi EW, Stein AD, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA. 2008;105(44):17046–17049. [10] van Os J, Selten JP. Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands. Br J Psychiatry. 1998;172:324–326. [11] St Clair D, Xu M, Wang P, et al. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959–1961. JAMA. 2005;294(5):557–562. [12] Egger G, Liang G, Aparicio A, et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004;429(6990):457–463. [13] Saha A, WiZmeyer J, Cairns BR. Chromatin remodelling: the industrial revolution of DNA around histones. Nat Rev Mol Cell Biol. 2006;7(6):437–447. [14] hZps://en.wikipedia.org/wiki/Epigenetics. [15] Issa JP. CpG island methylator phenotype in cancer. Nat Rev Cancer. 2004;4(12):988–993. [16] Cuozzo C, Porcellini A, Angrisano T, et al. DNA damage, homology-directed repair, and DNA methylation. PLoS Genet. 2007;3(7):e110. [17] Pfeifer GP, Kadam S, Jin SG. 5-hydroxymethylcytosine and its potential roles in development and cancer. Epigenetics Chromatin. 2013;6(1):10. [18] Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013;502(7472):472–479. [19] Holliday R. Epigenetics: a historical overview. Epigenetics. 2006;1(2):76–80. [20] Clapier CR, Cairns BR. The biology of chromatin remodeling complexes. Annu Rev Biochem. 2009;78:273–304. [21] Ernst J, Kellis M. Discovery and characterization of chromatin states for systematic annotation of the

human genome. Nat Biotechnol. 2010;28(8):817–825. [22] Chi P, Allis CD, Wang GG. Covalent histone modifications: miswriZen, misinterpreted and mis-erased in human cancers. Nat Rev Cancer. 2010;10(7):457–469. [23] Turner BM. Reading signals on the nucleosome with a new nomenclature for modified histones. Nat Struct Mol Biol. 2005;12(2):110–112. [24] Cosgrove MS, Boeke JD, Wolberger C. Regulated nucleosome mobility and the histone code. Nat Struct Mol Biol. 2004;11(11):1037–1043. [25] Selhub J. Homocysteine metabolism. Annu Rev Nutr. 1999;19:217–246. [26] Chen NC, Yang F, Capecci LM, et al. Regulation of homocysteine metabolism and methylation in human and mouse tissues. FASEB J. 2010;24(8):2804–2817. [27] Fang M, Chen D, Yang CS. Dietary polyphenols may affect DNA methylation. J Nutr. 2007;137(1 Suppl.):223S–228S. [28] Gerhauser C. Epigenetic impact of dietary isothiocyanates in cancer chemoprevention. Curr Opin Clin Nutr Metab Care. 2013;16(4):405–410. [29] Gerhauser C. Cancer chemoprevention and nutriepigenetics: state of the art and future challenges. Top Curr Chem. 2013;329:73–132. [30] Valinluck V, Tsai HH, Rogstad DK, et al. Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res. 2004;32(14):4100–4108. [31] Chia N, Wang L, Lu X, et al. Hypothesis: environmental regulation of 5-hydroxymethylcytosine by oxidative stress. Epigenetics. 2011;6(7):853–856. [32] Niedzwiecki MM, Hall MN, Liu X, et al. Blood glutathione redox status and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults. Epigenetics. 2013;8(7):730–738. [33] Chao S, Roberts JS, Marteau TM, et al. Health behavior changes after genetic risk assessment for Alzheimer disease: the REVEAL Study. Alzheimer Dis Assoc Disord. 2008;22(1):94–97. [34] Bloss CS, Schork NJ, Topol EJ. Effect of direct-to-consumer genomewide profiling to assess disease risk. N Engl J Med. 2011;364(6):524–534. [35] Gropper SS, Groff J. Advanced nutrition and human metabolism. 4th ed. Thomson Wadsworth: Belmont, CA; 2004. [36] Puglielli L, Tanzi RE, Kovacs DM. Alzheimer's disease: the cholesterol connection. Nat Neurosci. 2003;6(4):345–351. [37] WoolleZ LA, Spady DK, Dietschy JM. Saturated and unsaturated faZy acids independently regulate low density lipoprotein receptor activity and production rate. J Lipid Res. 1992;33(1):77–88. [38] Spady DK, WoolleZ LA, Dietschy JM. Regulation of plasma LDL-cholesterol levels by dietary cholesterol and faZy acids. Annu Rev Nutr. 1993;13:355–381. [39] Summers SA. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res. 2006;45(1):42–72. [40] Chavez JA, Summers SA. A ceramide-centric view of insulin resistance. Cell Metab. 2012;15(5):585–594. [41] Dobrzyn P, Jazurek M, Dobrzyn A. Stearoyl-CoA desaturase and insulin signaling: what is the molecular switch? Biochim Biophys Acta. 2010;1797(6–7):1189–1194. [42] Davidson MH. Mechanisms for the hypotriglyceridemic effect of marine omega-3 faZy acids. Am J Cardiol. 2006;98(4A):27i–33i. [43] Ascherio A, Katan MB, Zock PL, et al. Trans faZy acids and coronary heart disease. N Engl J Med. 1999;340(25):1994–1998. [44] Mauger JF, Lichtenstein AH, Ausman LM, et al. Effect of different forms of dietary hydrogenated fats on LDL particle size. Am J Clin Nutr. 2003;78(3):370–375. [45] Khan SA, Vanden Heuvel JP. Role of nuclear receptors in the regulation of gene expression by dietary faZy acids (review). J Nutr Biochem. 2003;14(10):554–567. [46] Vanden Heuvel JP. Cardiovascular disease-related genes and regulation by diet. Curr Atheroscler Rep. 2009;11(6):448–455. [47] Vanden Heuvel JP. Diet, faZy acids, and regulation of genes important for heart disease. Curr Atheroscler

Rep. 2004;6(6):432–440. [48] MaZhan NR, Welty FK, BarreZ PH, et al. Dietary hydrogenated fat increases high-density lipoprotein apoA-I catabolism and decreases low-density lipoprotein apoB-100 catabolism in hypercholesterolemic women. Arterioscler Thromb Vasc Biol. 2004;24(6):1092–1097. [49] van Tol A, Zock PL, van Gent T, et al. Dietary trans faZy acids increase serum cholesterylester transfer protein activity in man. Atherosclerosis. 1995;115(1):129–134. [50] Parks JS, Huggins KW, Gebre AK, et al. Phosphatidylcholine fluidity and structure affect lecithin:cholesterol acyltransferase activity. J Lipid Res. 2000;41(4):546–553. [51] Duncan D, Morais J, Muniz N, et al. Lipoprotein subfraction testing with the lipoprint R system: easy, accurate and comprehensive. [Presented at CLAS, Northbrook, IL; May] 2004. [52] Lamarche B, Tchernof A, Moorjani S, et al. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study. Circulation. 1997;95(1):69–75. [53] Mack WJ, Krauss RM, Hodis HN. Lipoprotein subclasses in the Monitored Atherosclerosis Regression Study (MARS). Treatment effects and relation to coronary angiographic progression. Arterioscler Thromb Vasc Biol. 1996;16(5):697–704. [54] Rajman I, Maxwell S, Cramb R, et al. Particle size: the key to the atherogenic lipoprotein? QJM. 1994;87(12):709–720. [55] Kholodova YD, Harris WS. Identification and characteristic of LDL-subfractions in human plasma. Ukr Biokhim Zh. 1995;67(6):60–65. [56] Fisher EA, Feig JE, Hewing B, et al. High-density lipoprotein function, dysfunction, and reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 2012;32(12):2813–2820. [57] Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev. 2006;58(3):342–374. [58] Dullaart RP. Increased coronary heart disease risk determined by high high-density lipoprotein cholesterol and C-reactive protein: modulation by variation in the CETP gene. Arterioscler Thromb Vasc Biol. 2010;30(8):1502–1503. [59] Navab M, Reddy ST, Van Lenten BJ, et al. HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat Rev Cardiol. 2011;8(4):222–232. [60] Oravec S, Dostal E, Dukat A, et al. HDL subfractions analysis: a new laboratory diagnostic assay for patients with cardiovascular diseases and dyslipoproteinemia. Neuro Endocrinol LeE. 2011;32(4):502–509. [61] Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368(14):1279–1290. [62] Rall SC Jr, Weisgraber KH, Mahley RW. Human apolipoprotein E. The complete amino acid sequence. J Biol Chem. 1982;257(8):4171–4178. [63] Weisgraber KH, Innerarity TL, Mahley RW. Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine–arginine interchange at a single site. J Biol Chem. 1982;257(5):2518– 2521. [64] Eisenberg DT, Kuzawa CW, Hayes MG. Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history. Am J Phys Anthropol. 2010;143(1):100–111. [65] Grammer TB, Hoffmann MM, Scharnagl H, et al. Smoking, apolipoprotein E genotypes, and mortality (the Ludwigshafen Risk and Cardiovascular Health study). Eur Heart J. 2013;34(17):1298–1305. [66] Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS. J Lipid Res. 2009;50(Suppl.):S183–8. [67] Corella D, Tucker K, Lahoz C, et al. Alcohol drinking determines the effect of the APOE locus on LDLcholesterol concentrations in men: the Framingham Offspring Study. Am J Clin Nutr. 2001;73(4):736–745. [68] Kathiresan S, Willer CJ, Peloso GM, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009;41(1):56–65. [69] Santoro N, Zhang CK, Zhao H, et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with faZy liver in obese children and adolescents. Hepatology. 2012;55(3):781–789.

[70] Kinnunen PK, Jackson RL, Smith LC, et al. Activation of lipoprotein lipase by native and synthetic fragments of human plasma apolipoprotein C-II. Proc Natl Acad Sci USA. 1977;74(11):4848–4851. [71] Barzilai N, A~mon G, Schechter C, et al. Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA. 2003;290(15):2030–2040. [72] Schulze F, Lenzen H, Hanefeld C, et al. Asymmetric dimethylarginine is an independent risk factor for coronary heart disease: results from the multicenter Coronary Artery Risk Determination investigating the Influence of ADMA Concentration (CARDIAC) study. Am Heart J. 2006;152(3):493.e1–493.e8. [73] Mazidi M, Rezaie P, Kengne AP, et al. Gut microbiome and metabolic syndrome. Diabetes Metab Syndr. 2016;10(2 Suppl. 1):S150–7. [74] Phillips CM, Goumidi L, Bertrais S, et al. ACC2 gene polymorphisms, metabolic syndrome, and gene– nutrient interactions with dietary fat. J Lipid Res. 2010;51(12):3500–3507. [75] Phillips CM, Goumidi L, Bertrais S, et al. Gene–nutrient interactions with dietary fat modulate the association between genetic variation of the ACSL1 gene and metabolic syndrome. J Lipid Res. 2010;51(7):1793–1800. [76] Renström F, Shungin D, Johansson I, et al. Genetic predisposition to long-term nondiabetic deteriorations in glucose homeostasis: ten-year follow-up of the GLACIER study. Diabetes. 2011;60(1):345–354. [77] Zeggini E, Weedon MN, Lindgren CM, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007;316(5829):1336–1341. [78] ScoZ LJ, Mohlke KL, Bonnycastle LL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007;316(5829):1341–1345. [79] Dupuis J, Langenberg C, Prokopenko I, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010;42(2):105–116. [80] Speakman JR, Rance KA, Johnstone AM. Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity (Silver Spring). 2008;16(8):1961–1965. [81] Frayling TM, Timpson NJ, Weedon MN, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316(5826):889–894. [82] Sonestedt E, Roos C, Gullberg B, et al. Fat and carbohydrate intake modify the association between genetic variation in the FTO genotype and obesity. Am J Clin Nutr. 2009;90(5):1418–1425. [83] Kilpelainen TO, Qi L, Brage S, et al. Physical activity aZenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children. PLoS Med. 2011;8(11):e1001116. [84] Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 2000;14(2):121–141. [85] Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409–435. [86] Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nat Med. 2004;10(4):355– 361. [87] Yamauchi T, Kamon J, Waki H, et al. The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem. 2001;276(44):41245–41254. [88] Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature. 2008;454(7203):470–477. [89] Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998;98(19):2088–2093. [90] Lehmann JM, Moore LB, Smith-Oliver TA, et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995;270(22):12953–12956. [91] Kilpelainen TO, Lakka TA, Laaksonen DE, et al. SNPs in PPARG associate with type 2 diabetes and interact with physical activity. Med Sci Sports Exerc. 2008;40(1):25–33. [92] Hsiao TJ, Lin E. The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma (PPARG) gene in relation to obesity and metabolic phenotypes in a Taiwanese population. Endocrine.

2015;48(3):786–793. [93] Rocha RM, Barra GB, Rosa EC, et al. Prevalence of the rs1801282 single nucleotide polymorphism of the PPARG gene in patients with metabolic syndrome. Arch Endocrinol Metab. 2015;59(4):297–302. [94] Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102(7):1369–1376. [95] Louis E, Franchimont D, Piron A, et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol. 1998;113(3):401–406. [96] Benjamin EJ, Dupuis J, Larson MG, et al. Genome-wide association with select biomarker traits in the Framingham Heart Study. BMC Med Genet. 2007;8(Suppl. 1):S11. [97] Urpi-Sarda M, Casas R, Chiva-Blanch G, et al. Virgin olive oil and nuts as key foods of the Mediterranean diet effects on inflammatory biomakers related to atherosclerosis. Pharmacol Res. 2012;65(6):577–583. [98] Pascual M, Nieto A, Mataran L, et al. IL-6 promoter polymorphisms in rheumatoid arthritis. Genes Immun. 2000;1(5):338–340. [99] Elahi MM, Asotra K, Matata BM, et al. Tumor necrosis factor alpha-308 gene locus promoter polymorphism: an analysis of association with health and disease. Biochim Biophys Acta. 2009;1792(3):163–172. [100] Hage FG, Szalai AJ. C-reactive protein gene polymorphisms, C-reactive protein blood levels, and cardiovascular disease risk. J Am Coll Cardiol. 2007;50(12):1115–1122. [101] Wypasek E, Potaczek DP, Undas A. Association of the C-reactive protein gene (CRP) rs1205 C>T polymorphism with aortic valve calcification in patients with aortic stenosis. Int J Mol Sci. 2015;16(10):23745–23759. [102] EllioZ P, Chambers JC, Zhang W, et al. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA. 2009;302(1):37–48. [103] EiriksdoZir G, Smith AV, Aspelund T, et al. The interaction of adiposity with the CRP gene affects CRP levels: age, gene/environment susceptibility – Reykjavik study. Int J Obes (Lond). 2009;33(2):267–272. [104] Yamagishi K, Tanigawa T, Cui R, et al. High sodium intake strengthens the association of ACE I/D polymorphism with blood pressure in a community. Am J Hypertens. 2007;20(7):751–757. [105] Zhang L, Miyaki K, Araki J, et al. Interaction of angiotensin I-converting enzyme insertion-deletion polymorphism and daily salt intake influences hypertension in Japanese men. Hypertens Res. 2006;29(10):751–758. [106] Norat T, Bowman R, Luben R, et al. Blood pressure and interactions between the angiotensin polymorphism AGT M235T and sodium intake: a cross-sectional population study. Am J Clin Nutr. 2008;88(2):392–397. [107] Giner V, Poch E, Bragulat E, et al. Renin-angiotensin system genetic polymorphisms and salt sensitivity in essential hypertension. Hypertension. 2000;35(1 Pt 2):512–517. [108] Poch E, Gonzalez D, Giner V, et al. Molecular basis of salt sensitivity in human hypertension. Evaluation of renin-angiotensin-aldosterone system gene polymorphisms. Hypertension. 2001;38(5):1204– 1209. [109] Hunt SC, Cook NR, Oberman A, et al. Angiotensinogen genotype, sodium reduction, weight loss, and prevention of hypertension: trials of hypertension prevention, phase II. Hypertension. 1998;32(3):393–401. [110] Anderson RP. Coeliac disease is on the rise. Med J Aust. 2011;194(6):278–279. [111] Anderson RP. Coeliac disease. Aust Fam Physician. 2005;34(4):239–242. [112] Pie~ak MM, Schofield TC, McGinniss MJ, et al. Stratifying risk for celiac disease in a large at-risk United States population by using HLA alleles. Clin Gastroenterol Hepatol. 2009;7(9):966–971. [113] Monsuur AJ, de Bakker PI, Zhernakova A, et al. Effective detection of human leukocyte antigen risk alleles in celiac disease using tag single nucleotide polymorphisms. PLoS ONE. 2008;3(5):e2270. [114] Koskinen L, Romanos J, Kaukinen K, et al. Cost-effective HLA typing with tagging SNPs predicts celiac

disease risk haplotypes in the Finnish, Hungarian, and Italian populations. Immunogenetics. 2009;61(4):247–256. [115] EnaZah NS, Sahi T, Savilahti E, et al. Identification of a variant associated with adult-type hypolactasia. Nat Genet. 2002;30(2):233–237. [116] Yang A, Palmer AA, de Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (Berl). 2010;211(3):245–257. [117] Josse AR, Da Costa LA, Campos H, et al. Associations between polymorphisms in the AHR and CYP1A1-CYP1A2 gene regions and habitual caffeine consumption. Am J Clin Nutr. 2012;96(3):665–671. [118] Pourvali K, Abbasi M, MoZaghi A. Role of superoxide dismutase 2 gene ala16val polymorphism and total antioxidant capacity in diabetes and its complications. Avicenna J Med Biotechnol. 2016;8(2):48–56. [119] Soerensen M, Christensen K, Stevnsner T, et al. The Mn-superoxide dismutase single nucleotide polymorphism rs4880 and the glutathione peroxidase 1 single nucleotide polymorphism rs1050450 are associated with aging and longevity in the oldest old. Mech Ageing Dev. 2009;130(5):308–314. [120] Goth L, Nagy T, Kosa Z, et al. Effects of rs769217 and rs1001179 polymorphisms of catalase gene on blood catalase, carbohydrate and lipid biomarkers in diabetes mellitus. Free Radic Res. 2012;46(10):1249– 1257. [121] Wenten M, Gauderman WJ, Berhane K, et al. Functional variants in the catalase and myeloperoxidase genes, ambient air pollution, and respiratory-related school absences: an example of epistasis in gene– environment interactions. Am J Epidemiol. 2009;170(12):1494–1501. [122] Hustad S, MidZun O, Schneede J, et al. The methylenetetrahydrofolate reductase 677C→T polymorphism as a modulator of a B vitamin network with major effects on homocysteine metabolism. Am J Hum Genet. 2007;80(5):846–855. [123] Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111–113. [124] Kennedy BP, BoZiglieri T, Arning E, et al. Elevated S-adenosylhomocysteine in Alzheimer brain: influence on methyltransferases and cognitive function. J Neural Transm (Vienna). 2004;111(4):547–567. [125] Weisberg I, Tran P, Christensen B, et al. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64(3):169–172. [126] Fredriksen A, Meyer K, Ueland PM, et al. Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism. Hum Mutat. 2007;28(9):856–865. [127] Lord RFK. Significance of low plasma homocysteine. Metametrix Clinical Laboratories. [Available from] www.metametrix.com; 2006. [128] Jhee KH, Kruger WD. The role of cystathionine beta-synthase in homocysteine metabolism. Antioxid Redox Signal. 2005;7(5–6):813–822. [129] Banerjee R, Zou CG. Redox regulation and reaction mechanism of human cystathionine-beta-synthase: a PLP-dependent hemesensor protein. Arch Biochem Biophys. 2005;433(1):144–156. [130] Troen AM, Mitchell B, Sorensen B, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr. 2006;136(1):189–194. [131] Obeid R, Herrmann W. The emerging role of unmetabolized folic acid in human diseases: myth or reality? Curr Drug Metab. 2012;13(8):1184–1195. [132] Gomes AM, Winter S, Klein K, et al. Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation. Pharmacogenomics. 2009;10(4):579–599. [133] Hart SN, Wang S, Nakamoto K, et al. Genetic polymorphisms in cytochrome P450 oxidoreductase influence microsomal P450-catalyzed drug metabolism. Pharmacogenet Genomics. 2008;18(1):11–24. [134] Meilahn EN, De Stavola B, Allen DS, et al. Do urinary oestrogen metabolites predict breast cancer? Guernsey III cohort follow-up. Br J Cancer. 1998;78(9):1250–1255. [135] Oliveira CB, Cardoso-Filho C, Bossi LS, et al. Association of CYP1A1 A4889G and T6235C polymorphisms with the risk of sporadic breast cancer in Brazilian women. Clinics (Sao Paulo).

2015;70(10):680–685. [136] Feldman DN, Feldman JG, GreenblaZ R, et al. CYP1A1 genotype modifies the impact of smoking on effectiveness of HAART among women. AIDS Educ Prev. 2009;21(3 Suppl.):81–93. [137] Mauras N, Santen RJ, Colon-Otero G, et al. Estrogens and their genotoxic metabolites are increased in obese prepubertal girls. J Clin Endocrinol Metab. 2015;100(6):2322–2328. [138] Reddy EK, Mansfield CM, Hartman GV, et al. Carcinoma of the uterine cervix: review of experience at University of Kansas Medical Center. Cancer. 1981;47(7):1916–1919. [139] Tang YM, Green BL, Chen GF, et al. Human CYP1B1 Leu432Val gene polymorphism: ethnic distribution in African-Americans, Caucasians and Chinese; oestradiol hydroxylase activity; and distribution in prostate cancer cases and controls. Pharmacogenetics. 2000;10(9):761–766. [140] Parl FF, Dawling S, Roodi N, et al. Estrogen metabolism and breast cancer: a risk model. Ann N Y Acad Sci. 2009;1155:68–75. [141] Norskov MS, Frikke-Schmidt R, Bojesen SE, et al. Copy number variation in glutathione-S-transferase T1 and M1 predicts incidence and 5-year survival from prostate and bladder cancer, and incidence of corpus uteri cancer in the general population. Pharmacogenomics J. 2011;11(4):292–299. [142] Brennan P, Hsu CC, Moullan N, et al. Effect of cruciferous vegetables on lung cancer in patients stratified by genetic status: a mendelian randomisation approach. Lancet. 2005;366(9496):1558–1560. [143] Palli D, Masala G, Peluso M, et al. The effects of diet on DNA bulky adduct levels are strongly modified by GSTM1 genotype: a study on 634 subjects. Carcinogenesis. 2004;25(4):577–584.

9

Mind–body medicine Brad S Lichtenstein

Introduction Western medicine has been steeped in a dichotomous split between mind and body for centuries. Traditional and indigenous healing methods do not suffer from this same bipolar relationship when either classifying illness or addressing methods of healing.[1–4] The conventional Western paradigm fails to integrate these two worlds, segregating conditions into either psychological or physiological constructs. At its very foundation, naturopathic medicine is an integrated, person-centred approach, whose practice is based on a codified system of theories and principles.[5,6] In relation to conventional biomedical care, naturopathic medicine embraces a holistic paradigm where body and mind are inseparable and a single provider treats all aspects of the person rather than distinct components. Mind– body medicine, a subdiscipline of behavioural medicine, is an approach to care that seeks to create and restore health, rather than eradicate disease, through the interplay of mind and its capacity to affect bodily function and symptoms. Thus, mind–body medicine aligns well with the principles of naturopathic medicine.

Biomedicine In his article, ‘Role of behavioral medicine in primary care’, Feldman defines behavioural medicine ‘as an interdisciplinary field that aims to integrate the biological and psychosocial perspective on human behavior and apply them to the practice of medicine’.[7] He makes a point of using the word ‘medicine’ since it implies actively providing care, which includes the treatment of illness and disease, as well as prevention. The definition put forth by the Society of Behavioral Medicine (SBM), a not-for-profit organisation comprised of practitioners from a wide array of professions, does not differ significantly from that of Feldman. The SBM defines behavioural medicine as an ‘interdisciplinary field concerned with the development and integration of behavioral, psychosocial, and biomedical science knowledge and techniques relevant to the understanding of health and illness, and the application of this knowledge and these techniques to prevention, diagnosis, treatment, and

rehabilitation’.[8] These definitions also describe naturopathic medicine, as the core principles are the same.

The biomedical approach The emergence of behavioural medicine in the 1970s was a reaction to the reductionist biomedical approach to disease. Throughout much of the 20th century, the prevailing healthcare paradigm was biomedical. According to the biomedical approach:

• The cause of disease is some force or entity outside the individual, such as a pathogen or trauma • Responsibility for care falls upon another, such as a doctor, nurse or other practitioner, who administers a treatment to target the specific disease entity • Health does not exist on a continuum but is stated in absolute terms – an individual is either healthy or ill • The interaction between mind and body is irrelevant, since thoughts and emotions do not contribute to the individual's state of health.

The biopsychosocial model In 1977, Engel[9,10] argued for a biopsychosocial model in healthcare, recognising that the biomedical approach works well for the treatment of acute pathology, yet fails to successfully treat the majority of chronic diseases, to which Engel believed lifestyle and behavioural factors directly contributed. These factors are not only psycho-emotional, such as how emotional states affect disease (e.g. the impact of anger and anxiety on cardiovascular disease), or the relationship of emotions to disease (e.g. the increased prevalence of depression in those with cancer). Additional factors are socioeconomic, political and cultural: issues such as equality, diversity, social justice and socioeconomic status are inseparable and intrinsic to behavioural medicine and the biopsychosocial paradigm. Complete healing cannot take place if these factors are ignored. According to Kroenke and Mangelsdorff,[11] 80% of patients who present to primary care providers have no diagnosable organic aetiology, and only 10% present with psychological disorders without any physiological symptomology as cofactors. Gatchel and Oordt[12] estimated that up to 70% of medical visits to primary care providers are for problems related to psychosocial issues. Since primary care providers treat patients throughout their entire lifespan, they tend to see a wide array of conditions. While these may include specific psychological or psychiatric conditions (e.g. anxiety, depression, poscraumatic stress disorder [PTSD]), the majority of complaints – up to 85% in one estimate – are considered somatic with no organic aetiology by conventional medical standards. For these conditions

(e.g. tension headaches, insomnia, chronic pain, irritable bowel syndrome [IBS]), medication is often unwarranted or unnecessary, although patients continue to seek treatment from biomedical primary care providers.

Integrated science model Sahler and Carr[13] have presented an integrated science model for healthcare that identifies five domains covering all aspects of the biopsychosocial model. The patient is viewed as a complex system with all of these variables influencing their life and behaviours. Comprehensive care must include a full evaluation and assessment of each of these domains:

• Biological • Environmental • Cognitive • Behavioural • Sociocultural. For some, this list remains incomplete. Depending on definition, emotional and spiritual domains are distinct from the others and warrant acention since they hold tremendous influence on health and wellness, as will be discussed later in this chapter. The idea of viewing the patient in a comprehensive, multidimensional manner is far from revolutionary to the naturopathic doctor. The formal definition adopted by the house of delegates of the American Association of Naturopathic Physicians states that:[14] Naturopathic medicine is a distinct system of primary health care – an art, science, philosophy and practice of diagnosis, treatment and prevention of illness. Naturopathic medicine is distinguished by the principles upon which its practice is based. These principles are continually reexamined in the light of scientific advances. The techniques of naturopathic medicine include modern and traditional, scientific and empirical methods. The following principles are the foundation of naturopathic medical practice:

• The Healing Power of Nature (Vis Medicatrix Naturae): Naturopathic medicine recognizes an inherent self-healing process in the person which is ordered and intelligent. Naturopathic physicians act to identify and remove obstacles to healing and recovery, and to facilitate and augment this inherent self-healing process. • Identify and Treat the Causes (Tolle Causam): The naturopathic physician seeks to identify and remove the underlying causes of illness, rather than to merely eliminate or suppress symptoms. • First Do No Harm (Primum Non Nocere): Naturopathic physicians follow

three guidelines to avoid harming the patient: – Utilize methods and medicinal substances which minimize the risk of harmful side effects, using the least force necessary to diagnose and treat; – Avoid when possible the harmful suppression of symptoms; – Acknowledge, respect, and work with the individual's self-healing process. • Doctor as Teacher (Docere): Naturopathic physicians educate their patients and encourage self-responsibility for health. They also recognize and employ the therapeutic potential of the doctor–patient relationship. • Treat the Whole Person (Tolle Totum): Naturopathic physicians treat each patient by taking into account individual physical, mental, emotional, genetic, environmental, social, and other factors. Since total health also includes spiritual health, naturopathic physicians encourage individuals to pursue their personal spiritual development. • Prevention (Preventare): Naturopathic physicians emphasize the prevention of disease – assessing risk factors, heredity, and susceptibility to disease and making appropriate interventions in partnership with their patients to prevent illness. Naturopathic medicine is commiQed to the creation of a healthy world in which humanity may thrive. We could argue, then, that behavioural medicine is an alternative expression of the principles and theory of naturopathic medicine developed for conventional mainstream medical culture. When naturopaths claim to treat the whole person (Tolle Totum) and address the cause or causes (Tolle Causam) of suffering, naturopathic medicine is a biopsychosocial model that examines the multifactorial determinants of health. When treatment is not hurried and is carefully considered, naturopathic medicine maintains the principle of First Do No Harm (Primum Non Nocere). Furthermore, a significant amount of behavioural medicine research has been conducted around the prevention of disease in conventional care (Preventare). Finally, the naturopathic model of healing states that illness occurs when a disturbance disrupts the vital force. While conventional biomedicine seeks to treat a pathogen or physical trauma as sole disturbance, an integrated naturopathic model acempts to examine all domains, including the biological, but also the environmental, cognitive, emotional, behavioural, socio-political and spiritual disturbances that impact on health and wellbeing.

Mind–body medicine Mind–body medicine, as a modality, falls under the heading of behavioural medicine. The National Institutes of Health (NIH) define mind–body therapies as ‘interventions that use a

variety of techniques designed to facilitate the mind's capacity to affect bodily function and symptoms’.[15] A broader and more inclusive definition from the National Center for Complementary and Alternative Medicine (NCCAM) defines mind–body medicine as any approach that enhances the ‘interactions among the brain, mind, body and behavior, and on the powerful ways in which emotional, mental, social, spiritual, and behavioral factors can directly affect health’. The techniques and practices that fall into this category are any ‘intervention strategies believed to promote health; [such as] relaxation, hypnosis, visual imagery, meditation, yoga, biofeedback, tai chi, qi gong, cognitive-behavioral therapies, group support, autogenic training, and spirituality’.[16] Some authors also include other practices such as automatic writing, humour, music, dance and exercise. Regardless of the type of practice, several key factors are important:

• Mind–body medicine emphasises the individual's innate capacity for growth and healing • Mind–body medicine focuses on quality of life, self-awareness, selfknowledge and self-empowerment • Mind–body medicine views disease as a means of transformation rather than something to be cured and eradicated • Mind–body medicine practitioners consider themselves to be trainers and catalysts, and see the individuals with whom they work as empowered partners, rather than sick or diseased patients. An increasing number of patients are using both traditional healing practices (such as Ayurveda, yoga, qi gong, Sufi healing and shamanic, faith and psychic healing) and integrative practices (such as naturopathic medicine, traditional Chinese medicine and Western herbalism) concurrently with conventional medical approaches.[3] According to the 2015 US National Health Statistics Report[17] reviewing trends from 2002 to 2012, the use of mind–body approaches has increased over time:

• Yoga, tai chi and qi gong practice has increased linearly over time. Yoga was the most commonly used of these three at all time points – While all age groups showed increased use of yoga over the 10-year period, use decreased with age. The highest prevalence was in adults aged 18–44. No significant differences were observed in yoga use among adults aged 45–64 and those aged 65 and over between 2002 and 2007; however, an increase was seen between 2007 and 2012 for both age groups – Use of yoga among Hispanic and non-Hispanic black adults doubled

between 2007 and 2012. Non-Hispanic white adults showed a consistent increase in yoga use across time. Use of yoga among nonHispanic other adults increased by approximately 30% from 2002 to 2012 • Deep-breathing exercises were the second most commonly used mind– body medicine approach, used independently or as a part of other approaches • Meditation was among the top five most commonly used approaches • Biofeedback, guided imagery and hypnosis had consistently low prevalence and had no significant changes across time.

Mechanisms of action Identifying specific mechanisms of action in regards to mind–body medicine is challenging. This can negatively influence consensus among disciplines.[18] A few considerations include outcome measures and techniques used (many and varied within the field). Despite these challenges, research continues. As the name implies, mind–body medicine has a bidirectional mechanism of action, involving both top-down (brain down to peripheral tissues) and bocom-up (peripheral tissues up to the brain) feedback loop systems. Telles and colleagues[19] state that mind–body medicine practices have numerous mechanisms of action at multiple levels with bidirectional feedback loops. Not only have mind–body medicine practices demonstrated efficacy in improving acute and chronic pain, anxiety, depression, poscraumatic stress, insomnia, hypertension and irritable bowel syndrome, but studies have also identified physiological changes due to these practices including decreased inflammatory response, improved immune parameters, enhanced glucose tolerance and increased cardiac-vagal tone and cardiovascular function. These changes support the concept of creating or maintaining psychophysiological balance. Pioneers in the field of mind–body medicine, such as Edmund Jacobson, developer of progressive muscle relaxation, and Johannes Heinrich Schulo, developer of autogenic training, emphasised relaxation versus treating particular pathology, despite the fact that both techniques have demonstrated improvement for a multitude of illnesses and symptoms.[20,21]

Stress, stressors and the stress response The Oxford English Dictionary defines stress as ‘hardship, adversity or affliction’, yet the word ‘stress’ first appeared around the 14th century in Middle French from the word destresse (‘distress’), which had its roots in the Latin word strictus, meaning ‘to compress’. Initially, the word ‘stress’ involved a physical force, but by the 16th century it had entered the common vernacular connoting overwork or fatigue as a result of subjecting an entity to force or strain. Thus stress occurs whenever an individual feels a disruption in normal

function, equilibrium or homeostasis. The agent of that change, that which causes the disruption, is referred to as the stressor, and can exist on all levels including environmental (e.g. excessive temperature, pollution, natural disasters), social (e.g. crowding, traffic, war), physiological (e.g. disease, broken bones, allergens) and psychological (e.g. guilt, shame, humiliation, worry, rumination). In the naturopathic model of healing, the stressor is the stimulus that disturbs the vital force, which can be acute or short term, chronic or long term, or episodic, coming and going. This way of classifying stressors reflects the five domains of the integrated science model, and understanding the nature of each can inform treatment. The process that the mind and body undergo to restore balance after exposure to a stressor is considered the stress response and it too can be acute, chronic or episodic. The stress response is a constellation of events, which involve a stimulus (stressor – a force), that causes some sort of reaction in the brain that activates a physiological reaction in the body. Homeostasis is the state of physical balance, thought of as an ideal set point reached through local regulatory mechanisms. Claude Bernard first used this term in the mid-19th century, believing that the body needs to maintain a constant state of internal balance, or the le milieu interieur. Body temperature, blood pH and oxygen concentrations are all examples of systems that operate and function in a very narrow band and must be kept very consistent. Not all physiological systems need to stay constant. Allostasis refers to constancy through change, where the ideal depends on the conditions and stability is maintained through change. This form of stability can be achieved through physiological or behavioural change, such as alterations in hormones and cytokines. In the short term, these changes can be adaptive, bringing about stability. Processes like respiration and heart rate require constancy through change in order to maintain overall health. Running to catch a bus that is pulling away from the bus stop is one example. Muscles contract, the heart pounds faster and breathing quickens and deepens. Once the bus is boarded and a seat is found, these systems secle down: they changed to match the physiological and metabolic demands of the moment. Heart rate, breathing rate and muscle tension should not stay constant, but adjust to demand. Allostasis can go awry, as in chronic stress, where the mind and body perpetually respond without rest. The term ‘allostatic load’ was coined by McEwan and Stellar[22] to describe the damaging consequences of continual and chronic exposure to stress. Neural and neuroendocrine responses designed to keep the body balanced through change continually fluctuate, causing the systems to break down and function improperly. This wear and tear results from repeated and continued cycles of allostasis. According to the cognitive appraisal theory of stress, the stressor itself does not induce the stress response, rather the individual's perception determines:

• The likelihood of a response • The type of response

• The degree of response. Individual assessment of an event, positive or negative, affects outcomes. Therefore, psychotherapy often views stress as a response rather than a stimulus. Much of mind–body medicine involves shifting perspective, reframing or reappraising expectations. Not all stress is bad, and not all stressors induce a negative response. Stress is simply a force exerted on a system, such as gravity. In a weightless environment, muscles atrophy without the force of gravity to act on them. Such types of stress can be called eustress, or good stress, as opposed to dys-stress. Keller and colleagues[23] demonstrated that people who appraised their physical experiences as bad, negative or detrimental had poorer physical and mental health, with a 43% increased risk of dying prematurely. When participants interpreted any observed changes in their pulse or breathing rate as negative, such as indicating some physiological pathology, increased blood pressure was observed in these individuals. On the other hand, participants who appraised the same physiological changes more positively, such as indications of excitement or engagement, felt more alive and energised, had greater confidence and vitality and suffered from less anxiety and depression. Furthermore, the positive group maintained relaxed blood vessels despite an elevated heart rate.

Emotional resilience Some people tend to be more inclined towards emotional resiliency than others. In her research, Kobassa[24] found that resilient individuals, including some survivors of cancer and other diseases, demonstrated hardiness, consisting of:

• Commitment • Challenge • Control. Commitment involves appraising life more broadly than one singular domain, such as an individual thinking that they are more than their diagnosis or career. Commitment is the state of actively participating in life. The individual is commiced to their health, and views themselves as an integral part of their own healthcare team. Rather than blindly following every suggestion made by their provider, those with commitment remain active and engaged with a sense of agency and purpose. Furthermore, they continue to participate in all aspects of their life and engage in meaningful relationships and activities like family, spiritual and religious groups, exercise and hobbies. Regarding the control parameter, the individual realises that while they may not be able to control the events around them, such as whether or not they get a particular disease, they can control their appraisal of the events and can choose to adapt to the situation at hand. Those able to do this have more emotional resiliency.

The challenge parameter involves appraisal of the actual event or issue itself. Those with this characteristic frame all information received, from diagnosis to prognosis, as a challenge with which to work and an opportunity for growth rather than a threat. People who exhibit the challenge parameter do not spend much time asking, Why me? but ask rather What now? Mind–body medicine approaches focus on strengthening resiliency, and hence hardiness, through reappraising stressors as challenges and helping patients find inner strength.

Stress response Once a stressor has been perceived and appraised negatively, the stress response begins. All perceptions of stress involve safety in one way or another. When a threat to our safety is perceived, whether immediate and physical, such as a car speeding through a red light, or more existential, such as a mortgage payment due, the nervous system, and particularly the amygdala of the limbic system, activates. One of the main functions of the amygdala is to assess for safety. Whenever a situation is deemed unsafe, the amygdala stimulates the nervous system. Walter Cannon, a medical doctor and physiologist, coined the phrase the ‘fight or flight response’ in 1915 after he conducted experiments on laboratory animals by exposing them to extremes in temperature or lack of food and water. His subjects activated the same physiological responses as if fleeing or fighting a predator. Cannon believed this to be an evolutionarily adaptive survival mechanism. He was one of the first doctors to recognise that mental–emotional stressors in humans can incite the same mechanisms and to urge doctors to discuss psychological wellbeing with their patients as well. Considering the prevailing biomedical paradigm of the times, this was revolutionary. Hans Selye elaborated on Cannon's model almost by accident. A young endocrinologist at McGill University in the 1930s, Selye was studying the effects of ovarian extract in rats. On autopsy at the end of the study, Selye found that his rats had peptic and duodenal ulcers, enlarged adrenal glands and atrophied thymus and other lymphatic tissues. At first he was excited, believing that he had found a new hormone; however, his enthusiasm quickly waned when he realised that his control subjects, rats injected with pure saline alone, experienced the same physiological changes. Selye went on to repeat the experiment with other injections, such as formalin, and other types of stressors, such as exposure to different temperatures, exercise, pain, etc. No macer what the stressor, Selye observed similar physiological findings, leading him to outline his general adaptation syndrome of stress. The reactions listed are not solely physiological, but cover all domains of behavioural health. The phases of his general adaptation syndrome are as follows: 1 Alarm phase: similar to Cannon's fight or flight response, this occurs on first exposure to the stressor and disruption of homeostasis. 2 Resistance phase: the body begins to adapt to continued exposure to stress. The body returns to the prior state of arousal only as long as the necessary material for energy expenditure is available.

3 Exhaustion and burnout phase: energy stores have been completely depleted and the body is no longer able to mount a resistance. Permanent damage and illness or death result. A great example of this is salmon: after their evolutionary drive to swim upstream and spawn, salmon die of exhaustion and burnout. Two adaptive response systems are engaged during the general adaptation syndrome: the sympathetic adrenal medullary (SAM) axis and the hypothalamic pituitary adrenal (HPA) axis. Activation of the SAM axis is swift, occurring within seconds of a perceived threat, stimulating the locus coeruleus, located in the pons of the brainstem, to signal the preganglionic nerve fibres of the spinal cord to release acetylcholine, causing the adrenal medulla to secrete noradrenaline and adrenaline directly into the bloodstream through postganglionic nerve fibres. These catecholamines stimulate the liver to convert glycogen to glucose to release into the bloodstream for fuel, to allow for an increase in metabolic activity, heart rate, respiration, blood pressure, blood flow to the muscles, pupil size and platelet aggregation. Simultaneously, less vital systems, including urinary output and digestive function, decrease. The HPA axis is often considered the long-term system. Most modern stressors are not short in duration. In long-term situations, the HPA axis kicks in several minutes later and is longer acting. When a threat is detected, the hypothalamus releases corticotropin-releasing hormone (CRH) within 15 seconds, which then signals the anterior pituitary to release adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal cortex to release mineralocorticoids and glucocorticoids. Mineralocorticoids directly impact the kidneys by causing the retention of sodium and water, thus increasing blood pressure and volume. Glucocorticoids enable fats and proteins to be converted to glucose for immediate energy, thereby increasing blood glucose, energy levels and pain threshold. Immunologically, glucocorticoids induce a shift from Th1-directed (cell mediated) immunity to Th2-directed (antibody) immunity. This decreases a host of cytokines involved in immunity, such as IL-1, IL-2, TNF-α and IFN gamma and alpha, while increasing the pro-inflammatory cytokines, such as IL-4, IL-10, IL-13 and cAMP. As a result, NK cell cytotoxicity decreases and CD4:CD8 ratios fall, limiting the ability to fight microbes. In the acute phase, both the SAM and the HPA axes are activated. As a stressor continues, the resistance phase begins and SAM activity declines as the HPA axis takes over. Should the stressor resolve, the entire system returns to homeostasis. However, often this is not the case. Dickerson and Kemeny[25] note that the types of stressors that lead to the greatest release of glucocorticoids and ACTH are those that are uncontrollable or performance tasks that involve evaluation by others. Most individuals reporting chronic ongoing stress seem to have a stressor in these categories, which only maintains the cycle. If the stress continues for too long, exhaustion occurs and SAM activity re-emerges. At this point, organ and tissue damage ensue until inevitable collapse.

Polyvagal theory and the vagus nerve

While these models have been used to describe stress for quite some time, Stephen Porges[26– 30] has outlined a phylogenetically ordered, adaptive neuroregulation of the autonomic nervous system, expanding on the work of Cannon and Selye. Porges suggests that the nervous system is ordered along a continuum from threat to safety, initiating distinct involuntary subsystems that are linked to behaviour. According to Porges’ polyvagal theory, during periods of perceived threat the first subsystem activated for all mammals is the ancient and oldest branch of the vagus nerve (the 10th cranial nerve), which is unmyelinated and arises from the dorsal motor nucleus. Activation of this subsystem results in immobilisation of the entire mind/body, with commonly expressed behaviours of vasovagal syncope, feigning death, dissociation, withdrawal and shutdown. This strategy can be lifesustaining if predators deem such immobilisation as death and therefore an unappetising meal. The second subsystem, activation of the sympathetic nervous system, is the traditional fight-or-flight reaction with the strategy of mobilisation to escape danger. The third subsystem is engaged only in times of perceived safety. Here, the newer and myelinated branch of the ventral vagal complex, only seen in mammals, arises from the nucleus ambiguus. Activation of this vagal system leads to social engagement, with such overt behavioural changes as slower and deeper breathing, softening of the facial muscles, and increased intonation and prosody of the voice. The first and third subsystems (immobilisation and social engagement) are innervated by the parasympathetic nervous system. Thus the belief that all stress responses result from sympathetic activation is unsubstantiated. The vagal nerve is bidirectional, providing enervation to organs and viscera, as well as afferent communication about the state of such tissues back to the brain. Approximately 80% of all vagal fibres are sensory, and only 15% of the total motor fibres (20%) are myelinated. When activated in times of safety rather than threat, the dorsal motor vagus functions in growth and regeneration by regulating the activity of sub-diaphragmatic organs. In contrast, the ventral vagus regulates supra-diaphragmatic organs such as the heart and lungs. The newer subsystem has an inhibitory impact on the first and second subsystems. Thus social engagement and communication in a safe environment can ‘turn off’ the immobilisation and mobilisation systems by slowing down the heart and breathing rate. The ventral vagal complex comprises neurophysiologically connected nerves that innervate muscles of the head and neck necessary for social engagement, namely larynx and facial muscles, allowing the individual to regulate the tone, pitch and prosody of the voice and demonstrate facial expressions that signal listening, caring and acentiveness. Thus activating the social engagement system can dampen the SAM and HPA axes, alter the immunological response and create a sense of calm, peace and relaxation.[30] Table 9.1 outlines the phylogenetic stages of the polyvagal theory as outline by Porges.

TABLE 9.1

Phylogenetic stages of Porges’ polyvagal theory Phase ANS component 1st 2nd 3rd

Unmyelinated vagus (dorsal vagal complex) Sympathetic adrenal system Myelinated vagus (ventral vagal complex)

Lower motor neuron

Neurobiological adaptive function

Dorsal motor Immobilisation (feigning death, fainting, passive nucleus of the vagus avoidance) Spinal cord Mobilisation (fight-or-flight, active avoidance) Nucleus ambiguus

Social engagement, social communication, selfsoothing and calming, inhibiting arousal

Source: Modified from Porges, SW. The polyvagal perspective. Biological Psychology 2007;74:120.

Trauma research grounded in the polyvagal theory posits that individuals can become neurobiologically conditioned for a predominance in one subsystem over another. Perpetual activation of either the immobilisation or the mobilisation subsystem will have psychological and physiological consequences downstream. Regardless of theory, perpetual activation of the stress response has been associated with a wide array of symptoms and diseases including cardiovascular disease, recurrent colds and flu, poor wound healing and tissue destruction, weight gain, insomnia, chronic fatigue and disruption of memory. On the other hand, use of mind–body medicine techniques has been correlated with improvement of the immune system, as well as a 43% reduction in healthcare use.[31] The approach of mind–body medicine is not eradication of any particular disease, but cultivation of resilience, balance and social engagement. Researchers resist the claim that stress is a causative factor for any particular disease, yet understanding the proposed stress response systems outlined above, chronic immobilisation or mobilisation fails to improve health. Rather than validate any particular mind–body technique for treatment of a specific disease, shifting the neurobiological adaptive response towards social engagement and ventral vagal activation may be the more appropriate approach.

Self-stressing theory Determining which of the numerous mind–body approaches to use can be confusing. Researchers and clinicians typically focus on one particular method, failing to address variations in individual stress response pacerns. To address this issue, Smith[32,33] has proposed a self-stress theory, recognising that individuals maintain and perpetuate heightened nervous system arousal by responding to stressors in one of six particular psychological or physiological pacerns (outlined below). Interestingly, each pacern corresponds to a family or group of mind–body techniques. To obtain optimal results, providers and patients need to select the strategy that matches the self-stress target. However, Smith does not imply that only one mind–body approach be reserved for a particular target. Rather, the pacerns should be considered as a guide to navigate the field of mind–body practices.

When their safety is called into question, people respond in one of the following six ways:

• Stressed posture and position: the individual reacts to stressors by adopting a physical posture to create a sense of safety. For instance, the person could collapse and curl up, or stand more erect and thrust the chest forwards. If a stress posture becomes habituated and maintained over time, the person's health declines due to restriction and lack of movement. Blood flow decreases and muscle tension increases, leading to exhaustion and fatigue • Stressed skeletal muscles: various emotions are associated with overt muscular pacerns.[34] Muscle tension and bracing is often seen in anxiety disorder, for instance. An individual who responds to stress by contracting skeletal muscles is chronically ready to fight or flee. This pacern is commonly demonstrated by those with a chronic mobilisation subsystem • Stressed breathing: activation of immobilisation and mobilisation subsystems alters breathing, leading to erratic, uneven, shallow breathing, potentially punctuated with sighs, breath holding, gasps and yawns. Breathing volume may grow deeper. All of these changes alters blood pH mediated by CO2 and O2 levels, and hence lead to a variety of health complications • Stressed body focus: the individual experiences an intensification of somatic complaints, such as rapid heart rate, increased breathing or digestive discomfort, simply by directing their acention to the symptoms. Consider an individual in the midst of a panic acack who is focusing on their breathing: they begin to hyperventilate, worrying that they are not gecing enough oxygen. Not only is this untrue, but an intense focus on the symptom aggravates their condition and perpetuates the over-breathing, creating more anxiety • Stressed emotion: in order to manage stress, the individual compensates by engaging in scenarios or self-talk that intensify and perpetuate the already distressing effect • Stressed aQention: this strategy is exemplified by a ruminating mind, intent on solving the problem of safety. Thoughts and cognitions end up shifting away from the experience of the present moment towards multi-

tasking. Individuals may demonstrate more than one of these strategies when confronted with triggers and a threat to safety, but identifying the predominant pacern can aid in selecting the most beneficial corresponding mind–body intervention. Table 9.2 lists the mind–body practices associated with each stress response pacern. These practices include the following: TABLE 9.2 Self-stressing theory Stress response pa>ern

Associated mind–body practice

Stressed posture and position Stressed skeletal muscles Stressed breathing Stressed body focus Stressed emotion Stressed acention

Stretching exercises, yoga, Pilates and movement Progressive muscle relaxation Breathing exercises Autogenic training Guided imagery/visualisation/self-talk, hypnotherapy Meditation and mindfulness

• Stretching exercises: any mind–body approach that incorporates stretching of the muscles with postural awareness would fit into this category. This includes the movement and postural portion of yoga as well as approaches that increase awareness of posture and position such as Pilates, the Feldenkrais method, the Alexander technique and somatics • Progressive muscle relaxation: in order to release chronically constricted skeletal muscles, the individual must be aware of the tension. Progressive muscle relaxation involves systematically tensing then releasing specific muscles groups in order to bring about a state of relaxation • Breathing exercises: any modality that involves awareness and alteration of the breath would be classified as breathing exercises – such as any yoga technique that focuses on the breath, as well as spiritual practices and religious practices that involve chanting or recitation of prayers which impact the breathing rate • Autogenic training: developed by Johannes Schulo in the 1920s, this involves silent and self-generated repetition of specific phrases about particular physical sensations, such as heaviness and warmth. Directing acention to a particular body part, the individual repeats to themselves, for example, ‘My arm is heavy’. This shifts acention away from worrying about distressing physical sensations and induces a state of calm and

relaxation • Imagery, self-talk: rather than rehearsing negative affect-arousing narratives, this approach employs positive imagery and affirmations. It includes mind–body therapies such as hypnosis and some spiritual or religious practices such as loving kindness or compassion meditation • Meditation and mindfulness: mindfulness can be defined as acention to the present moment without judgment. It involves focusing the mind away from distraction or rumination, such as the physical postures in yoga when acention is completely directed to the experience of the physical sensation within the pose • Smith distinguishes three types of relaxation methods: self-relaxation, assisted relaxation and casual relaxation – In self-relaxation, the individual doesn't rely on anything or anyone in order to engage in the process. Listening to a recorded guided meditation may be considered self-relaxation if afterwards the individual can recall the instructions and practise on their own – Assisted-relaxation techniques require someone or something in the process, such as computer screens and hardware, massage practitioners, music or animals for ‘pet therapy’ – Casual relaxation comprises those daily activities that induce a relaxation response without that being the intention, such as reading, exercising, listening to music (when not used therapeutically) and stroking a pet.

Placebo While an in-depth review is beyond the scope of this book, any discussion of mind–body medicine demands, at the very least, a brief mention of placebo, since a few critics of mind– body medicine have claimed that the benefits seen are no more than a placebo response. Any treatment – whether substance, procedure or device – that is deemed pharmacologically and physiologically inert and incapable of producing a physiological change is considered a placebo. Placebo effects are responses that ensue from administration of the placebo. However, as Finniss and colleagues explain,[35] these definitions are problematic for clinicians and researchers based on their inherent contradiction. Despite reports of positive outcomes, how can placebos produce a physiological effect if they are inert? Finniss and colleagues suggest shifting the focus away from the placebo itself, instead emphasising the mechanisms through which observed responses occur. Taking a biopsychosocial perspective

to treatment, or the patient–practitioner relationship, the placebo responses can then be acributed to the ‘context’ of the therapeutic delivery.[35,36] Just as orienting strategy (immobilisation, mobilisation, social engagement) results in activation of various neurological subsystems, researchers have begun outlining the neurological and neurochemical mediators induced by placebo effects, which are witnessed in all therapeutic encounters whether the specific therapeutics are active or inert. External and internal biopsychosocial cues are perceived and interpreted by the patient, which colour the treatment context and induce brain–mind responses and neurochemical changes. Tables 9.3 and 9.4 provide examples of several external and internal biopsychosocial contexts that surround the treatment encounter, potentially generating placebo effects. TABLE 9.3 External biopsychosocial contexts and the placebo effect External context Location

Treatment type

Treatment duration/frequency Verbal

Social

Example Emergency room Community clinic Doctor's office Pharmacological – oral, IV, injection, surgical Physical involving touch Verbal – talk therapy Device administered Single incident Single or multiple daily treatment ‘This will make you feel becer quickly’ ‘You’ll feel a quick jab but then it will be brief’ ‘This will take the pain away’ Communication style and empathy Eye contact Body language Prosody and intonation of voice White coat, gloves, stethoscope

Source: Adapted from Wager TD, Atlas LY. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci 2015;16:403–18.

TABLE 9.4 Internal biopsychosocial contexts and the placebo effect Internal context

Example

Expectations (of future responses)

‘Pain will go away’ ‘Medication will help’ ‘My doctor cares’ Relief of symptoms following treatment Improved performance after treatment Past witnessing of another person responding positively to a treatment ‘My doctor cares about me’ ‘I am safe now’ ‘This feels calming’ ‘I am less anxious’

Past experience Memory Meaning Emotions

Source: Adapted from Wager TD, Atlas LY. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci 2015;16:403–18.

Based on what has been presented thus far about orientation strategy and the goal of the naturopathic doctor steeped in mind–body medicine, rather than speaking of placebo effects, the changes witnessed – both the subjective report of the patient, and neurological and neurohormonal mediators – are merely results of shifting orientation towards safety. Only when patients feel safe can they begin to assign new meaning to their symptoms, healthcare providers, treatment regimen and the world. Once they are able to socially engage with their care, neurological changes take place that decrease stress hormones, shift the neuroendocrine-immune systems and impact health.

Mind–body therapeutics The following discussion introduces various mind–body medicine therapeutics in more detail. Using Smith's categorisation as a frame of reference, the techniques are discussed in reverse order, starting with meditation and mindfulness, as they are the basis of all other modalities.

Meditation and mindfulness Meditation Throughout the literature, consensual agreement about the definition of meditation is difficult to find and this speaks to the issues regarding evaluation of meditation-based therapies. Smith recognises that several therapies overlap in implementation. Most researchers agree that the process of meditation involves some level of mental focus and concentration. The word ‘meditation’ itself is derived from the Latin, meditari, meaning ‘to participate in contemplation or deliberation’. Shapiro and colleagues[37] describe meditation as a family of self-regulation practices that aim to bring mental processes under voluntary control through focusing acention, resulting in psychological and spiritual wellbeing and

maturity. While historically used for spiritual and religious pursuits, meditation may or may not have any connection with religious contemplation or introspection. Cardoso and colleagues[38] have outlined the distinct components found in the multitude of meditation practices reviewed – any mind–body approach incorporating these components can therefore be considered meditation:

• The techniques are specific and clearly defined • Physical (and muscular) relaxation occurs at some point during the process • Cognitive (mental or logical) relaxation occurs during the process, which involves releasing expectations for a particular outcome, along with analytical and judgmental thought • The process is a self-induced state and can be practised without requiring any support (this supports Smith's self-relaxation category) • ‘Self-focus skill’ describes the direction and focus of acention; it is also known as the anchor. Broadly speaking, meditation is an intentional self-regulatory process of directing and focusing one's acention for the purpose of self-inquiry. Depending on the form of meditation, the object of focus, also known as the anchor, may vary. The anchor is used to direct acention away from unwanted cognitive processes, such as rumination, judgment, analysis, sleepiness, lethargy and boredom. Meditation practices can be categorised into two groups based on their anchor:[39]

• Concentration meditation practices use a single point of focus to give the mind an object on which to grasp in an acempt to still the mind. The use of a word or phrase, or mantra, is at the root of transcendental meditation created by Maharishi Mahesh Yogi. Through silent repetition, one directs the mind back to the anchor to prevent its wandering • Mindfulness is a broader approach that is reviewed more fully below. Briefly, during mindfulness, the entire spectrum of experiences that arise moment to moment, thoughts, sensations and emotions, are observed and noted without judgment or reactivity. Whenever distractions arise, the distraction is acknowledged before acention is redirected back to the anchor. Although not universal, breathing work is a common factor in several forms of meditation. Sustaining focus on a specific object of acention has been described as executive acention or conflict monitoring, and several studies have reported that meditating

for even short periods of time can improve scores on acention regulation measurements.[40] Many people struggle with meditation, believing that their mind should be blank without thoughts, yet this is not necessarily the goal. Through daily practice, meditation trains the mind to develop a capacity for acention and focus. Emphasising the neurological changes of meditation practice, Oc and colleagues note: ‘[f]rom a scientific perspective, the effects of these traditional exercises are based on the plasticity of the brain. Sustained efforts to focus acention and to cultivate emotional balance leave traces in the underlying neural substrate and circuitry. Over time, these changes in brain structure in turn support the intended changes in mental faculties and personality’.[41] However, the goal is not a calm and relaxed state of being, but remaining present to momentary experiences without the need to dissociate or distract away from them. Hussain and Bhushan[39] highlight their review of 813 meditation studies by the University of Alberta Evidence-Based Practice Center, which categorises meditation practices into five groups (again we see overlap based on self-stressing theory):

• Mantra meditation (comprising transcendental meditation (TM), relaxation response and clinically standardised meditation) • Mindfulness meditation (comprising Vipassana, Zen Buddhist meditation, mindfulness based on stress reduction and mindfulnessbased cognitive therapy) • Yoga (based on Indian Yogic tradition developed by Patanjali, incorporating a variety of techniques like body postures, breath control and meditation) • Tai chi (based on Chinese martial arts that incorporate various slow rhythmic movements to emphasise force and complete relaxation) • Qi gong (based on Chinese practice that combines breathing pacerns with various physical postures, bodily movements and meditation). Mindfulness As a mind–body medicine approach, mindfulness is considered the technique best suited for those with stressed acention. The term ‘mindful’ can be found in the English language as early as the 14th century and denoted acention, being cautious, careful and paying heed. In the 16th century, the word ‘mindfulness’ became synonymous with ‘acention’, ‘awareness’ and ‘memory’. The first use of the English word ‘mindfulness’ can be acributed to the British civil servant, Thomas William Rhys Davids (1843–1922), who translated original Buddhist Pali texts into English. Struggling to encapsulate the essence of the Buddhist term sati, Davids initially used words such as ‘recollect’ and ‘remember’, and this perpetual remembering focused on the present moment. Slowly the term ‘mindfulness’ became

synonymous with this process.[42] Modern definitions elaborate on this process of remembering. Bishop and colleagues[43] define mindfulness as ‘non-elaborative, nonjudgmental, present-centered awareness in which each thought, feeling, or sensation that arises in the acentional field is acknowledged and accepted as it is’. Kabat-Zinn,[44] creator of Mindfulness-Based Stress Reduction, describes mindfulness as the ‘awareness that emerges through paying acention on purpose, in the present moment, and non-judgmentally to the unfolding of experience moment by moment’. Mindfulness can be conceptualised as a state rather than a trait,[45] which requires continual practice to train cognitive capacity for sustained focus and concentration. The anchor is the experience of the arising present moment, which can focus on internal or external objects. Originating from within, internal objects of focus pertain to bodily sensations (heat, cold, vibration, pain, pressure) or cognitions (this is boring, my body aches, how long do I have to sit here?). External objects are experienced as arising from outside the person (visual objects, scents, sounds). For either type of object, should the focus drift from the anchor, the individual gently remembers to turn their acention back to the experience of the phenomenon or the arising present moment sensations and thoughts. Two concepts are fundamental to the practice of mindfulness: non-elaboration and nonjudgment. Whenever thoughts arise that describe, evaluate or analyse the experienced phenomenon, elaboration and judgment occur. This may take the form of thoughts about sensations or thoughts about thoughts. Rather than becoming stuck in cycles of ceaseless ruminations, mindfulness practice reminds us to return our acention to the present experience. Distress and suffering increase when the ruminations involve cognitive appraisal of the currently arising phenomenon. When mind and body, thoughts and sensations are deemed ‘good’ or ‘bad’, stress response subsystems activate, since these experiences are perceived through the lens of safety. Cravings, desires, aversions and rejections all arise, and subsequently acempts are made to avoid or distract from the potential threat of the undesired experience. Mindfulness offers freedom from suffering through the practice of sustaining acention on unpleasant or painful sensations and cognitions without judgment or elaboration, thereby reducing emotional reactivity, building tolerance and cultivating a new way of orienting our experiences. Regardless of the desire or aversion for the phenomenon, in order to approach a mindful state, the individual must orient to every phenomenon with openness, curiosity and acceptance.[43] The Five Facet Mindfulness Questionnaire was developed by Baer and colleagues[46] to identify mindfulness behaviours. These include:

• Observing (sustaining acention on the internal or external anchor or phenomenon) • Describing (providing a cognitive label of the anchor) • Acting with awareness (remaining present to the momentary experience without acting habitually without awareness)

• Non-judging of inner experience (suspending judgment of experienced phenomenon) • Non-reactivity to inner experience (suspending elaboration of the experienced phenomenon to refrain from emotionally reacting to the experience). The definition of mindfulness poses an interesting conundrum for researchers. Since mindfulness is about process not outcome, studying mindfulness as a treatment of particular conditions appears incongruous. Simply put, mindfulness is the goal of mindfulness. Clinging to any desired outcome is antithetical to its basic tenets. However, the association between mindlessness and health has been reported. Chronic rumination and perseveration have been associated with poorer overall outcomes, such as elevated heart rate, decreased heart rate volume (HRV), increased risk of cardiovascular disease and poor sleep.[47] Conversely, mindfulness training has been reported to improve health parameters. Davidson and colleagues[48] noted how 25 healthy subjects showed increased antibody production in response to flu vaccination after 8 weeks of training, while Carlson and colleagues[49] found a decrease in cortisol levels and systolic blood pressure in participants with breast and prostate cancer after training, with a continual reduction in Th1 (pro-inflammatory) cytokines one-year post follow-up. Women recently diagnosed with breast cancer who participated in an 8-week mindfulness-based stress reduction (MBSR) intervention demonstrated reduced levels of stress hormones, becer immune system biomarkers, improved coping skills and becer quality of life.[50] Paul and colleagues[51] found a reduction in susceptibility to depression and other psychological states from a decrease in rumination through mindfulness training. Numerous studies have examined the connection between mindfulness and meditation and changes in morphological and neurological brain structure. As Fox and colleagues[52] point out in their meta-analysis and review of 21 neuroimaging studies, determining a causative relationship between meditation and alterations in brain structure remains suspect. However, after reviewing these studies with more than 300 meditation practitioners, they found approximately 123 morphological brain differences. Of most interest are studies comparing meditation-naïve and meditation-experienced practitioners, where significant changes in morphology were seen. This begs the question: were such changes pre-existing, predisposing practitioners to meditation? Or were these changes enhanced by practice? Though unanswered, most surprising was the evidence that minimal time was required practising meditation before structural changes were observed. Fox identified the most consistently altered areas of the brain as follows:

• Left rostrolateral prefrontal cortex (involved in introspection and metacognition, abstract information processing and integration of

cognitive process as relates to higher order behavioural goals) • Anterior/midcingulate cortex (crucial for executive acention, selfcontrol and emotional regulation, focused-problem solving, orienting, alerting and diminished acentional blink effect) • Primary and secondary somatosensory cortices (involved with tactile information processing, pressure, temperature, pain, proprioception) • Anterior insula (involved in enhanced body awareness) • Orbitofrontal cortex (involved in discerning relationship between stimuli and motivational outcome; connected to primary sensory areas, as well as limbic structures such as amygdala, striatum and hypothalamus) • Left inferior temporal gyrus (involved in high-level visual processing, potentially related to visual imagery arising during meditation versus visual perception) • Hippocampus (involved in memory processing and emotional learning, associated with appropriateness of expression of stress response). Brewer[53] found reduced activation in the default mode network, an area of the brain that includes the posterior cingulate cortex, the precuneus and temporoparietal junction, and the angular gyrus. This decreased functional connectivity may potentially explain how experienced meditators demonstrate less rumination and an increased ability to focus on a single anchor. Hölzel[40] found a decrease in right basolateral amygdala grey macer density in participants after an 8-week mindfulness training program, and correlated this with decreased perceived stress. Zeidan and colleagues[54] found reduction in pain correlating to pain-related activation of the contralateral primary somatosensory cortex in those trained in mindfulness for only 4 days. What can be concluded from all of this? Meditation and mindfulness are orientation strategies that affect the stress response, which in turn impacts the neurological, immunological and endocrine systems. Mindfulness can reduce rumination and negative thinking, which is linked to improved overall health. Even within a short period of time, structural changes can be seen on fMRI in individuals trained in meditation and mindfulness.

Spirituality, religion and prayer If the word ‘meditation’ has its roots in contemplation, it stands to reason that spirituality – a contemplation on the sacred and the transcendent – fits under the heading of mind–body

medicine. As mentioned earlier, mind–body, behavioural and naturopathic medicine emphasise integration of all parts of the individual, but trends in conventional care are also moving in this direction. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO)[55] has stated that ‘patients deserve care, treatment, and services that safeguard their personal dignity and respect their cultural, psychosocial, and spiritual values. These values often influence the patient's perceptions and needs. By understanding and respecting these values, providers can meet care, treatment, and service needs and preferences.’ Spirituality is commonly defined as a subjective human experience of the sacred in life connected with a search for understanding and meaning.[56–58] Elkins and colleagues[59] describe spirituality as a multidimensional way of experiencing and being in the world that arises from an awareness of a transcendent dimension. Spirituality is characterised by certain specific values about life (self, others, world, nature and the sense of ultimate) and consists of nine major components. According to Elkins and colleagues, all people with a sense of spirituality share these common components, despite individual variations in each component: 1 Transcendent dimension: the acceptance in and belief of a transcendent dimension consisting of something beyond the self and what is seen. 2 Meaning and purpose in life: an authentic belief that all life and personal existence has significance, importance, meaning and purpose. 3 Mission in life: the recognition that in order to fulfil our purpose, we must pursue our particular life ‘vocation’. 4 Sacredness of life: a sense that all life, not just certain events or aspects, are ‘holy’ and worthy of awe, wonder and reverence; the ability to separate mundane and sacred, as all life is valued and appreciated. 5 Material value: the understanding that money and material possessions are useful tools for daily living, yet are unable to provide a life of meaning and purpose. 6 Altruism: the recognition of interconnectedness of all life and all people, with a deeply held belief that as one person suffers, all people suffer, leading to a sense of social justice. 7 Idealism: holding high values and ideals for the becerment of the world and each person, including oneself. 8 Awareness of the tragic: the insight and acknowledgment that joy, value and meaning are all inextricably linked to pain, loss and suffering. 9 Fruits of spirituality: the experience that engaging in spirituality enriches and benefits life in the present moment through improved relationships with the self, others, nature, life and the world. Based on these components, an individual can be spiritual and live a spiritual existence, yet fail to follow any particular religious tradition. Religion acempts to answer spiritual

questions about existence, providing value and purpose through an organised and systematic set of beliefs, teachings and practices. Religion requires a group, collective or community that share a common framework. By providing structure for enquiry, spiritual needs may be met. For the remainder of this chapter, the term ‘spirituality’ is used to discuss both concepts in mind–body medicine. The association between spirituality and health is quite strong. First, spiritual beliefs influence how an individual experiences their state of health, since concepts like illness and disease are inseparable from worldview. Any holistic, person-centred paradigm recognises that how a patient responds to a diagnosis is contingent on their appraisal of the diagnosis, which can activate various subsystems of the stress response. If the individual embraces a spiritual orientation, feels a connection with the transcendent, has a sense that all life is sacred, yet recognises and appreciates the tragic events, they may be more inclined to perceive a terminal diagnosis as a step in their path towards connection with the Divine. Without any spiritual belief, a patient may feel adrift and alone, perceiving any ailment as unjustified victimisation. Second, since spiritual beliefs affect appraisal, they impact medical choices. In interviews with 21 doctors about the relationship between spirituality and health, all practitioners agreed that spiritual beliefs influenced a patient's understanding and meaning of illness.[60] When spirituality supported coping skills, doctors deemed it as a positive association. However, when spiritual beliefs contradicted or conflicted with medical recommendations and advice, doctors considered spirituality as harmful. Third, mounting evidence shows a positive relationship between spirituality and health outcomes. Regarding the connection between mental health and spirituality, Koenig[61] reports that prior to the year 2000, more than 700 studies examined this relationship, and ‘nearly 500 of those studies demonstrated a significant positive association with becer mental health, greater well-being, or lower substance abuse’. Furthermore, other significant mental health associations were decreases in anxiety and depression, rates of suicide and rates of substance abuse and increases in sense of wellbeing, marital satisfaction and stability, social support and sense of purpose and meaning in life. If spiritual beliefs improve mental health outcomes, improvements in physical health parameters should be found as well, modulated by a reduction in the stress response. A review of the literature by Clark[62] found that spiritual beliefs were associated with decreases in mortality rates from cancer, cardiovascular disease, blood pressure and cholesterol and increases in immune function, health behaviours (increased exercise and sleep, and reduction in smoking) and longevity. Finally, patients want their emotional and spiritual needs to be met by their medical providers. Studies show that 77% of patients want to have their spiritual concerns discussed by their providers, yet only 10–20% of practitioners engage in such conversations.[63–65] If they were gravely ill, 66% of patients report that they would want their providers to enquire about their religious beliefs, while up to 40% believe that doctors should ask about spirituality to a greater extent than they do. In order to create a therapeutic alliance,

enquiring about a patient's beliefs may be one of the single most important factors in healing, allowing them to relax into the medical visit or procedure with a sense of safety, social engagement and trust. Many doctors agree with patients on this macer: 77% want patients to share their religious beliefs during the medical encounter, and an even greater percentage, 96%, believe that spiritual wellbeing is important to overall health. However, doctors surveyed felt inadequately trained (59%), unable to determine which patients were interested in such conversations (56%) and reported lack of time (71%) as the biggest challenges to broaching spiritual conversations.[63–67] Other reasons cited included lack of comfort and fear of reaching beyond their level of expertise. However, as Koenig[61] points out, doctors constantly screen for a wide array of health conditions, many of which are beyond their expertise and require consultation with a specialist. If during a conversation about spiritual needs, the doctor deems an expert is warranted, a referral to a chaplain or other spiritual advisor can easily be made.

Taking a spiritual history Initiating spiritual conversations may appear daunting, yet several authors have outlined clear and concise questions that practitioners can use. For example, Lo and colleagues[68] recommend starting with these questions: 1 Is faith (religion, spirituality) important to you in this illness? 2 Has faith been important to you at other times in your life? 3 Do you have someone to talk to about religious macers? 4 Would you like to explore religious macers with someone? Anandarajah and Hight[65] propose the following to assist in spiritual assessment: H: enquire about sources of Hope, meaning, comfort, strength, peace, love and connection O: ask about participating in any particular Organised religion P: discuss any Personal spirituality or Practices E: explore how spiritual issues might have an Effect on medical care and End-of-life. Underwood and Teresi[69] created the Daily Spiritual Experience Scale to assist in understanding the link between spirituality and health and wellbeing. The first 15 questions are answered on a Likert scale ranging from ‘never experience’ a particular item to ‘experience many times a day’ while the final question is scaled from ‘not at all’ to ‘as close as possible’: 1 I feel God's presence. 2 I experience a connection to all of life.

3 During worship, or at other times when connecting with God, I feel joy which lifts me out of my daily concerns. 4 I find strength in my religion or spirituality. 5 I find comfort in my religion or spirituality. 6 I feel deep inner peace and harmony. 7 I ask for God's help in the midst of daily activities. 8 I feel guided by God in the midst of daily activities. 9 I feel God's love for me, directly. 10 I feel God's love for me, through others. 11 I am spiritually touched by beauty of creation. 12 I feel thankful for my blessings. 13 I feel a selfless caring for others. 14 I accept others even when they do things I think are wrong. 15 I desire to be closer to God or in unison with the Divine. 16 In general, how close do you feel to God? Conversations about spirituality are a mind–body medicine practice. Such discussions in no way necessitate the need to pray within the medical visit. According to Koenig,[61] praying with a patient is appropriate when the patient directly request this, if the patient is highly religious, if the patient and practitioner are of a similar religious background, and when the situation is serious and warrants prayer. However, practitioners should consent only if they feel comfortable doing so. Otherwise, they should consult a chaplain, family member or someone of the same religious and spiritual background to assist, never losing sight of the ultimate goal – to create a sense understanding, support and care, allowing for social engagement and balance of the nervous system.

Guided imagery, hypnosis and autogenic training For those who engage in mental scenarios or self-talk that perpetuates and intensifies their emotional reactions when stressed, guided imagery and hypnosis are the associated selfrelaxation strategies. Forms of imagery and hypnosis have been practised throughout the millennia, yet French pharmacist Émile Coué de la Châtaigneraie has been credited by some as the father of guided imagery. Coué firmly believed that healing is linked to imagination, and that the object of our mental focus impacts both body and mind. In 1922 he wrote Self Mastery through Autosuggestion, providing instructions on positive suggestions to manifest health and wellbeing. Imagery, also known as visualisation, has been defined by Achterberg as ‘the thought process that invokes and uses senses: vision, audition, smell, taste’, as well as the ‘senses of movement, position, and touch’.[70] Since all senses are activated in the process, imagery is the preferred term. These images are internal mental representations of real or imaginary experiences in the absence of any external stimuli. When guided, a practitioner or therapist

introduces the images, yet audio recordings may be considered guided as well. The goal, however, is the ability to self-generate images. Initially, imagery may focus on general relaxation combined with techniques like muscle relaxation or breathing. With mastery, the process shifts to addressing a specific issue or health condition. Guided imagery is commonly used for relaxation and stress reduction, pain management, immune system regulation and healing.[71–77] Imagery may take many forms, according to Naparstek in her influential book on the subject:[78]

• Feel-state imagery: recalling an image that induces a positive emotion, like a safe place or peaceful secing • End-state imagery: visualising the desired state or outcome occurring in the present, such as passing a final exam or finishing a race • Energetic imagery: imagining healing waves emicing from the area of pain or discomfort, unblocking the flow of energy • Cellular imagery: imagining healing and repairing of cellular level processes, as in imagining immune cells killing cancer cells • Physiological imagery: picturing the body in a state of healing, such as imagining a painfully contracted muscle softening and relaxing • Metaphoric imagery: using specific symbols or metaphors as images, such as picturing immune cells to be Pac-Men or sharks acacking cancer cells • Psychological imagery: changing an emotional state by imagining adopting a compassionate response, such as imagining the love and compassion your grandmother might express towards you • Spiritual imagery: envisioning connection with a transcendent higher power or Divinity. Imagery has been suggested as the basis of hypnosis, or at least a subcategory of the modality due to the similarities in techniques.[75,79,80] In Europe, Anton Mesmer was one of the first to popularise a consistent methodology for hypnosis, although it was not until the 1950s that hypnotherapy became more widely embraced as a serious mind–body modality. Hypnosis has been described as a trance-like state in which focus and concentration are increased. Techniques are typically guided at the onset of training. The practitioner (hypnotist) suggests words or phrases for mental repetition along with images to activate the senses, although audio recordings may be used. Hypnosis is indicated for situations where guided imagery is warranted and efficacious, such as relaxation, pain relief (e.g. headaches, chronic low back pain, arthritis, burns, postoperative healing), anxiety, depression and

phobias.[81,82] The first step in hypnosis is called induction, where a series of instructions is provided to assist the person in voluntarily invoking an absorbed acentional state of focus. Inductions are voluntary and can be cognitive instructions – ‘Focus on the feeling of your tummy rising and falling as you breathe’ – or cognitive strategies (guided imagery) – ‘Imagine your mind and body growing more and more relaxed as you descend a flight of stairs.’ Although frequently the case, induction need not involve relaxation. Induction is used to prepare the person for suggestions. Suggestions consist of statements describing changes in experience and do not require the participant's volitional engagement – ‘Your legs are becoming heavy; you find you are unable to move them.’ What enables a person to become hypnotised? The Stanford Hypnotic Susceptibility Scale was created in 1959 by Weioenhoffer and Hildgard to assess the degree of responsiveness to hypnotic suggestion while performing a series of 12 activities.[83] A sample task might include the person keeping their arm at shoulder height during the suggestion of holding a heavy object. Should their arm begin to lower, a positive score is given. Research has shown that a person's susceptibility to hypnosis remains fairly stable throughout adult life, regardless of how hard they might try to be hypnotised. Susceptibility doesn't seem to be linked to psychological or personality traits, and identical twins show a greater likelihood than same-sex fraternal twins for susceptibility.[84] In one study, those who were highly hypnotisable had a 32% larger rostrum of the corpus callosum on brain imaging, the area of the brain responsible for acention and inhibition of unwanted stimuli.[85] Furthermore, in another study a 16% increase in blood flow was seen on fMRI during hypnosis, and decreased activation of the default mode network.[86] Autogenic training, created by Johannes Schulo and expanded on by Wolfgang Luthe, is a structured form of guided imagery. Though often defined as self-hypnosis, autogenic training more accurately translated as self-regulation. Autogenic training was conceived as a means of self-empowerment, where the individual heals themselves without the assistance of a practitioner. As categorised by Smith, autogenic training is appropriate for those with a somaticised stress response where acending to a specific bodily sensation evokes or intensifies it. Initially taught individually or in groups, autogenic training involves silent recitation of self-suggestion phrases, called formulas, using physiological imagery to passively induce a relaxed and calm somatic process.[87,88] The formulas are introduced one at a time, in a consistent order, over an 8-week period, with daily home practice required for mastery. Here is the classic list of six bodily sensations induced with their associated formula to be recited silently:

• Heavy: ‘My arms (legs, low back, jaw, etc.) are heavy’ • Warm: ‘My arms (legs, low back, jaw, etc.) are warm’ • Cardiac: ‘My heart is steady and calm’ • Breath: ‘My breath breathes me’

• Solar plexus: ‘My abdomen is warm’ • Forehead: ‘My forehead is cool’. Similar to mindfulness, autogenic training is approached with an acitude of passive concentration, a non-judgmental mindset where the individual remains detached from the outcome (non-striving). The benefits of all three of these techniques (guided imagery, hypnosis and autogenic training) may rest in the shift in subjective experience that interrupts rumination and reframes negative beliefs and appraisals to those that are more pleasant or favourable. With practice and mastery come a sense of internal locus of control, a reduction in anxiety and an increased sense of wellbeing. Decreased rumination reduces sympathetic nervous system and HPA axis activation, and normalises immune function, as seen in appropriate changes in white blood cell counts.[72,75,89] When practised in an environment with reduced sensory stimulation, similar outcomes are seen with all three approaches; namely, a reduction in sympathetic tone, and balance between sympathetic and parasympathetic activity.

Progressive muscle relaxation For those who respond to stressors by tensing their muscles, progressive muscle relaxation, also known as progressive relaxation or muscle relaxation therapy, is the indicated tool. Progressive muscle relaxation is a classic example of the bocom-up approach to mind–body medicine, which emphasises changing the physical body to influence mental and emotional states, rather than focusing on calming the mind first. In fact, Edmund Jacobson, who developed progressive muscle relaxation, rarely addressed mental relaxation or training, considering the release of muscular tension all that was required. He believed it was inaccurate to assume that thinking was generated solely in the brain. For him, cognition was an entire mind–body event.[90] This worldview took shape for Jacobson in the 1930s after observing minute physical movements in his patients that accompanied stressful and anxious thoughts. His emotionally tense patients demonstrated chronic muscle tension with increased startle reflexes. He proposed that an emotionally calm state was impossible when muscles were physically contracted, and his research was able to demonstrate how cognition slowed down when muscles became more relaxed. His system of progressive muscle relaxation taught patients to regulate skeletal muscle tension in order to reduce unwanted emotional and mental states.[91] Muscles are the anchor in progressive muscle relaxation. Finding a comfortable and relaxed posture, usually reclining, in a room free from distractions and interruptions, the patient is instructed to remain still and silent throughout, since talking engages facial muscles, which activate the nervous system. The practitioner guides the patient in a series of contractions and relaxations targeting muscles in a systematic way. The key is to keep the other muscles completely still and passive, especially muscles that were just contracted then relaxed. In Jacobson's classic methodology, the dominant arm was used to differentiate

between maximum to minimum levels of tension. Contractions are held for approximately 5–7 seconds, then swiftly and completely disengaged in an acempt to drop tension below baseline levels. Once able to detect the presence and degree of tension, the patient practises relaxing muscles at will. Ultimately this will generalise to other areas of the body as the patient masters greater control of physical tension. Jacobson's basic protocol consisted of many stages and was time-intensive. More than 50 private sessions per year, each lasting upwards of 60 minutes, along with hour-long daily practice at home were required. Bernstein and Borkovec[92] abbreviated Jacobson's protocol and combined it with cognitive-behavioural therapy to teach patients stress reduction. Training can be as brief as 8–12 weekly sessions, with 20 minutes of home practice per day. Initially 16 muscle groups are trained; over time, muscles are combined into groups of seven and four. Finally, relaxation is practised without the need for a tension-release cycle by recalling the muscle(s), recalling and counting backwards, then counting alone.[93] Table 9.5 details one potential training schedule. TABLE 9.5

Sample progressive muscle relaxation training schedule 16 muscle group series

Muscle group 1. Dominant hand and forearm 2. Dominant upper arm 3. Nondominant hand and forearm 4. Nondominant upper arm 5. Forehead 6. Upper cheeks and nose 7. Lower face 8. Neck

9. Chest, shoulders, upper back 10. Abdomen

Instructions (Keep all other muscles, especially those previously contracted-released, still, relaxed and unengaged) Make a fist with the dominant hand.

Press the dominant elbow into the chair. Make a fist with the non-dominant hand.

Press the non-dominant elbow into the chair.

Raise the eyebrows as high as possible. Squeeze the eyes together as if squinting, while wrinkling the nose. Clench the teeth and pull the corners of the mouth back as if showing the teeth. If reclining, slightly press the back of the head into the chair. Without head support, neck counterpose (moving antagonist muscles): acempt to raise the chin while simultaneously lowering it.* Draw the shoulders and shoulder blades back and together while taking a deep breath and holding it. Abdominal counterpose: acempt to draw in the abdomen while simultaneously pushing it

out. Simultaneously contract the muscles on the top and bocom of the dominant upper leg.

11. Dominant upper leg 12. Dominant calf Point the dominant toes towards the head.* 13. Dominant foot Point the dominant toes downwards, turn the foot inwards and curl the toes under.* 14. NonSimultaneously contract the muscles on the top and bocom of the non-dominant upper leg. dominant upper leg 15. NonPoint the non-dominant toes towards the head.* dominant calf 16. NonPoint the non-dominant toes downwards, turn the foot inwards and curl the toes under.* dominant foot Seven muscle group series 1. Dominant hand, forearm and upper arm 2. Non-dominant hand, forearm and upper arm 3. All facial muscles 4. Neck* 5. Chest, shoulders, upper back and abdomen 6. Dominant upper leg, calf and foot* 7. Non-dominant upper leg, calf and foot* Four muscle group series 1. Both arms and hands 2. Face and neck* 3. Chest, shoulders, back and abdomen 4. Both legs and feet *

To prevent cramping, avoid contracting muscles as vigorously.

Several authors argue that while learning to decrease muscle tension and become more relaxed is important overall, progressive muscle relaxation alone is insufficient to interrupt anxiety or panic reactions. Jacobson's concepts have been modified and combined with other techniques for additional benefit or to address particular conditions. For example, in 1967 Farmer combined tension and release cycles with breathing and silent recitation of relaxing words, while Burrows (1976), Kleinsorge and Klumbies (1964) and Boom and Richardson (1931) combined elements of progressive muscle relaxation with imagery and autogenic-type phrases. Wolpe incorporated muscle relaxation in his process of systematic desensitisation, while the modification by Öst led to applied relaxation, efficacious in the treatment of phobias, panic and generalised anxiety.[94–96] Lehrer and colleagues[97] outline the typical steps in the abbreviated progressive muscle relaxation protocol as follows: 1 Ask the patient to adopt a comfortable, relaxed, reclined posture and to remain still so as not to engage any muscles. 2 Direct the patient to focus their acention on the specific targeted muscle group. 3 Direct the patient to tense the muscle group for 5–7 seconds, breathing freely while tensing.

4 Direct the patient to relax the muscle group swiftly, completely and instantly. 5 Direct the patient to focus on the sensations of relaxation for 30–40 seconds. 6 Prior to moving to a new muscle group, ask the patient if the muscle group is relaxed. Invite them to respond with a movement of a finger to prevent nervous system activation through speaking. If still tense, repeat the tension-relaxation cycle for 50–60 seconds up to five times. 7 Repeat the process for the specified sequence of muscles. 8 When all muscle groups are relaxed, review each group with the patient. 9 To end the session, instruct the patient to move their feet, arms, head and neck. In addition to efficacy in reducing anxiety and panic,[95,98,99] progressive muscle relaxation has shown promise in addressing conditions such as depression,[93] acention deficit hyperactivity disorder (by improving acention and decreasing impulsivity),[100] trauma (by improving distress tolerance), cardiovascular disease (by decreasing heart rate and decreasing diastolic and systolic blood pressure),[101] inflammation (by decreasing TNF-α and IL-6)[102] and Parkinson's disease (by increasing dopamine and adrenaline levels).[103]

Stretching and movement: yoga Stretching and movement is the category of mind–body medicine techniques appropriate for those who respond to stress by changing their posture. Numerous movement-oriented approaches exist, but this chapter concentrates on yoga, the most commonly used mind– body modality according to the 2015 US National Health Statistics Reports.[17] The word ‘yoga’ comes from the Sanskrit term yuj, which means ‘to yoke’ or ‘to join’ – yoga is considered the practice of forging a union of mind, body and spirit. Originating around 4000 years ago in India, yoga is a comprehensive philosophical system leading to self-awareness. [104] Although modern-day practice tends to highlight postures, known as asanas, yoga is more than a physical discipline. In the Yoga Sutras, Patanjali codified eight parts to the practice of yoga in the 2nd century (asthanga in Sanskrit means eight limbs). Known as Raja, or royal yoga, this system details the following limbs:[105]

• Yamas: moral and ethical code of behaviour • Niyamas: techniques for self-discipline • Asanas: postures for cleansing the physical body to prepare it for higher states of consciousness and meditation • Pranayama: breathing exercises, also used for physical purification and to raise energy • Pratyahara: sensory withdrawal practice to prevent distraction from mundane experiences • Dhyana: concentration practices to expand awareness and direct focus,

called dharana • Meditation • Samadhi: enlightenment or union with universal consciousness. All forms of yoga strive to bring mind, body and spirit together in order to achieve the ultimate goal of Samadhi. Some systems of yoga arose between the 6th and 15th centuries, each underscoring a different path to reach transcendence. Hatha Yoga used physical development as the means to obtain divine union, while Jnana (also known as Gnyana) Yoga used introspection, knowledge, contemplation and wisdom to identify ultimate Truth. Intense spiritual devotion, love, compassion and service to God were the way to reach Samadhi in Bhakti Yoga, while Karma Yoga focused on the law of cause and effect to engage practical action and service to others to discover enlightenment.[105] Since yoga incorporates physical posture with breathing and mental focus, determining the precise form of yoga acributing to the growth change can be a challenge, especially when studies often fail to detail the therapeutic intervention. However, it should come as no surprise that yoga demonstrates improvements in stress, mood and symptoms. According to Khalsa,[106] reduction in the HPA axis and autonomic nervous system activation, along with decreased basal glucocorticoids and catecholamines, reduced metabolic rate and oxygen consumption, and increased parasympathetic activity, may be the mechanisms behind yoga's health benefits. Salmon and colleagues[107] have identified positive changes in chronic low back pain, irritable bowel syndrome, type II diabetes and chronic disease. Physiological changes in body weight, blood pressure, cholesterol and blood glucose levels have also been reported. Questions about the safety of yoga have been raised on several occasions. In a systematic review and meta-analysis of randomised control trials of yoga, Cramer found that, when compared with standard physical exercise, yoga is a safe intervention with no differences in the frequency of adverse events or dropouts due to adverse events between the comparison groups.[108]

Breathwork The second most popular mind–body method, breathwork, can be examined through the lens of yoga, as a component to another modality such as meditation, autogenic training or progressive muscle relaxation, or as an isolated practice. In Sanskrit, the term prana means ‘life force’, and in yogic philosophy life force is said to be regulated through breathing. Pranayama, one of the limbs of yoga, involves breathing practices designed to control this vital life force energy in order to purify the mind and body from toxic energies.[109] With the exception of mindfulness training, all breathwork involves manipulation of one or more of the following components:

• Timing/rate: number of breaths per minute, the inhalation to exhalation

ratio, and pausing or retaining the breath • Volume: the amount of air inhaled, exhaled or retained • Location/placement: nose versus mouth breathing, diaphragmatic versus thoracic/clavicular breathing • Effort: laboured or easy breathing, the smoothness of transitions between the stages of breathing, recruitment of extra muscles • Posture: physical alignment facilitating laboured or effortless breath. For instance, sudarshan kriya is a cyclic pranayama practice that adjusts the rate and timing of breathing with several longer breaths followed by medium and short breaths.[109] In alternate nostril breathing, known as nadi shodhana, the flow of air is controlled by closing one nostril at various times during the inhalation and exhalation cycle.[110] Buteyko breathing involves holding the breath after a normal exhalation for upwards of 60 seconds to change CO2 and O2 levels in the bloodstream.[111] Whole-person breathing teaches slow, diaphragmatic breathing, typically 4–8 breaths per minute, in a smooth, effortless fashion. [112]

Breathing impacts health by improving cardiovascular and neurological functions. Specifically defining the exact mechanism may be easy to grasp yet challenging to outline. Due to the complexity of the process of respiration, discussion on its mechanism of action is beyond the scope of this book. Research suggests that sudarshan kriya results in changes in immune function (decrease in neutrophils, increase in NK cells), mood, such as anxiety and depression (mediated by elevation in oxytocin, decrease in glucocorticoids and ATCH) and blood pressure (reduction in diastolic blood pressure).[113] Breathwork in general has been shown to impact cardiovascular health by increasing vagal tone, improving chemoreflex and baroreflex sensitivity, increasing heart rate variability and decreasing sympathetic excitation. In their review of the literature, Brown and colleagues[114] cite research that demonstrates psychological improvement from breathwork for those with poscraumatic stress disorder, anxiety, panic, stress and depression.

Biofeedback Biofeedback capitalises on the work of all previously mentioned mind–body approaches. Schwaro[115] defines biofeedback as: a process that enables an individual to learn how to change physiological activity for the purpose of improving health and performance. Precise instruments measure physiological activity such as brainwaves, heart function, breathing, muscle activity, and skin temperature. These instruments rapidly and accurately ‘feed back’ information to the user. The presentation of this information – often in conjunction with changes in thinking, emotions, and behavior – support desired physiological changes. Over time, these changes can endure without continued use of instrument.

The common physiological systems measured are:

• Electromyographic activity: measures muscular contraction • Electrodermal activity: measures skin conduction and resistance based on amount of sweat on the palms of the hands or soles of the feet • Temperature: measures peripheral temperature, reflects blood vessel dilation or contraction • Pulse: measures heart rate • Respiration: measures breathing rate • Electroencephalography: measures brain waves. While machinery is typically used, anything can function as a biofeedback sensor – a mirror, a thermometer, a practitioner's hands, even a practitioner's words – as long as information about physiological processes can be fed back then used to modify physical responses. When combined with other techniques, biofeedback allows the individual to ‘see’ in real time how their body responds to practice. For instance, practising autogenic training while connected to electromyography and temperature sensors, the individual can see whether visualising and reciting the phrase, ‘My right arm is heavy and warm’, decreases muscle contraction and increases hand temperature.

References [1] Vukic A, Gregory D, Martin-Misener R, et al. Aboriginal and Western conceptions of mental health and illness. Pimatisiwin. 2011;9(1):65–86. [2] So JK. Somatization as cultural idiom of distress: rethinking mind and body in a multicultural society. Couns Psychol Q. 2008;21(2):167–174. [3] Moodley R, Sutherland P, Oulanova O. Traditional healing, the body and mind in psychotherapy. Couns Psychol Q. 2008;21(2):153–165. [4] Benning TB. Should psychiatrists resurrect the body? Adv Mind Body Med. 2016;30(1):32–38. [5] Fleming S, Gutknecht NC. Naturopathy and the primary care office. Prim Care. 2010;37:119–136. [6] Dunn N. Naturopathic medicine: what a patient expects? J Fam Pract. 2005;54(12):1067–1072. [7] Feldman MD, Berkowio SA. Role of behavioral medicine in primary care. Curr Opin Psychiatry. 2012;25(2):121–127. [8] Society for Behavioral Medicine. Behavioral medicine: definition. [Available from] www.sbm.org/resources/education/behavioral-medicine. [9] Engel GL. The need for a new medical model: a challenge for biomedicine. Science. 1977;196(4286):129–136. [10] Engel GL. The clinical application of the biopsychosocial model. Am J

Psychiatry. 1980;137(5):101–124. [11] Kroenke K, Mangelsdorff AD. Common symptoms in ambulatory care: incidence, evaluation, therapy, and outcome. Am J Med. 1989;86(3):262–266. [12] Gatchel RJ, Oordt MS. Clinical health psychology and primary care: practical advice and clinical guidance for successful collaboration. American Psychological Association: Washington, DC; 2003. [13] Sahler OJZ, Carr JE, Frank JB, et al. The behavioral sciences and health care. 3rd ed. Hegrefe Publishing: Cambridge MA; 2012. [14] Snider P, Zeff J. Report of the Select CommiQee on the Definition of Naturopathic Medicine. AANP: Washington, DC; 1988. [15] National Center for Complementary and Integrative Medicine. Mind and body information for researchers. [Available from] hcp://nccam.nih.gov/grants/mindbody. [16] National Center for Complementary and Alternative Medicine (NCCAM). Mind-body medicine: an overview. NCCAM; 2007. [17] Clarke TC, Black LI, Stussman BJ, et al. Trends in the use of complementary health approaches among adults: United States, 2002–2012. Natl Health Stat Report. 2015;79:1–15. [18] Wahbeh H, Haywood A, Kaufman K, et al. Mind-body medicine and immune system outcomes: a systematic review. Open Complement Med J. 2009;1:25–34. [19] Telles S, Gerbarg P, Kozasa EH. Physiological effects of mind and body practices. Biomed Res Int. 2015;1–2. [20] Jacobson E. Progressive relaxation. 2nd ed. University of Chicago Press: Chicago; 1938. [21] Luthe W, Schulo JH. Autogenic therapy: applications in psychotherapy. Gronne Stacon: New York; 1969. [22] McEwan BS, Stellar E. Stress and the individual: mechanisms leading to disease. Arch Intern Med. 1993;153(18):2093–2101. [23] Keller A, Lioelman K, Wisk LE, et al. Does perception that stress affects health macer? The association with health and mortality. Health Psychol. 2012;32(5):677–684. [24] Kobassa SC, Pucceci MC. Personality and social resources in stress resistance. J Pers Soc Psychol. 1983;45(4):839–850. [25] Dickerson SS, Kemeny ME. Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull. 2004;130(3):355– 391. [26] Porges SW. Orienting in a defensive world: mammalian modification of our evolutionary heritage – a polyvagal theory. Psychophysiology. 1995;32:301–318. [27] Porges SW. The polyvagal perspective. Biol Psychol. 2007;74:116–143.

[28] Porges SW. The polyvagal theory: new insights into adaptive reactions of the autonomic nervous system. Cleve Clin J Med. 2009;76(2):S86–90. [29] Porges SW, Furman SA. The early development of the autonomic nervous system provides a neural platform for social behavior: a polyvagal perspective. Infant Child Dev. 2011;20(1):106–118. [30] Geller SM, Porges SW. Therapeutic presence: neurophysiological mechanism mediating feeling safe in therapeutic relationships. J Psychother Integr. 2014;24(3):178–192. [31] Stahl JE, Dossec ML, LaJoie AS, et al. Relaxation response and resiliency training and its effect on healthcare resource utilization. PLoS ONE. 2015;10(10):1–14. [32] Smith JC. The new psychology of relaxation and renewal. Biofeedback. 2007;35(3):85–89. [33] Smith JC. Relaxation today. Schwaro MS, Adrasik F. Biofeedback: a practitioner's guide. 4th ed. Guilford Press: New York; 2015:189–195. [34] Craske MG, Rauch SL, Ursana R, et al. What is anxiety disorder? Depress Anxiety. 2009;26:1066–1085. [35] Finniss DG, Kaptchuk TJ, Miller F, et al. Placebo effects: biological, clinical and ethical advances. Lancet. 2010;375(9715):686–695. [36] Wager TD, Atlas LY. The neuroscience of placebo effects: connecting context, learning and health. Nat Rev Neurosci. 2015;16:403–418. [37] Shapiro SL, Walsh R, Bricon WB. An analysis of recent meditation research and suggestions for future directions. J Medit & Medit Res. 2003;3:69–90. [38] Cardoso R, de Souza E, Camano L, et al. Meditation in health: an operational definition. Brain Res Brain Res Protoc. 2004;14:58–60. [39] Hussain D, Bhushan B. Psychology of meditation and health: present status and future directions. Int J Psychol Psychol Ther. 2010;10(3):439–451. [40] Hölzel BK, Lazar SW, Gard T, et al. Does mindfulness meditation work? Proposing mechanisms of action from a conceptual and neural perspective. Perspect Psychol Sci. 2011;6:537–559. [41] Oc U, Vaitl D, Hölzel B. Brain structure and meditation: how spiritual practices shape the brain. Walach H, Schmidt S, Jonas WB. Neuroscience, consciousness, and spirituality. Springer: New York; 2011:119–128. [42] Shonin E, van Gordon W, Singh NN. Buddhist foundations of mindfulness. Springer: New York; 2015:97. [43] Bishop SR, Lau M, Shapiro S, et al. Mindfulness: a proposed operational definition. Clin Psychol Sci Pract. 2004;11(3):230–241. [44] Kabat-Zinn J. Mindfulness-based interventions in context: past, present, and future. Clin Psychol Sci Pract. 2003;10(2):144–156.

[45] Davis D, Hayes J. What are the benefits of mindfulness? A practice review of psychotherapy-related research. Psychotherapy (Chic). 2011;48(2):198–208. [46] Baer RA, Smith GT, Hopkins J, et al. Using self-report assessment methods to explore facets of mindfulness. Assessment. 2006;13:27–45. [47] Brosschot JF, Gerin W, Thayer JF. The perseverative cognition hypothesis: a review of worry, prolonged stress-related physiological activation, and health. J Psychosom Res. 2006;60:113–124. [48] Davidson RJ, Kabat-Zinn J, Schumacher J, et al. Alterations in brain and immune function produced by mindfulness meditation. Psychosom Med. 2003;65:564–570. [49] Carlson LE, Speca M, Faris P, et al. One year pre-post intervention follow-up of psychological, immune, endocrine and blood pressure outcomes of mindfulness-based stress reduction (MBSR) in breast and prostate cancer outpatients. Brain Behav Immun. 2007;21:1038–1049. [50] Witek-Janusek L, Albuquerque K, Chroniak KR, et al. Effect of mindfulness based stress reduction on immune function, quality of life and coping in women newly diagnosed with early stage breast cancer. Brain Behav Immun. 2008;22:969–981. [51] Paul NA, Stanton SJ, Greeson JM, et al. Psychological and neural mechanisms of trait mindfulness in reducing depression vulnerability. Soc Cogn Affect Neurosci. 2013;8:56–64. [52] Fox KCR, Nijeboer S, Dixon ML, et al. Chirstoff K. Is meditation associated with altered brain structure? A systematic review and meta-analysis of morphometric neuroimaging in meditation practitioners. Neurosci Biobehav Rev. 2014;43:48–73. [53] Brewer JA, Worhunsky PD, Grey JR, et al. Meditation experience is associated with differences in default mode network activity and connectivity. Proc Natl Acad Sci USA. 2011;108(50):20254–20259. [54] Zeidan F, Martucci KT, Kraft RA, et al. Brain mechanisms supporting modulation of pain by mindfulness meditation. J Neurosci. 2011;31(14):5540– 5548. [55] Joint Commission Resources. 2007 comprehensive accreditation manual for hospitals: the official handbook. Joint Commission on Accreditation of Healthcare Organizations: Oakbrook Terrace, IL; 2007. [56] Vaughan F. Spiritual issues in psychotherapy. J Transpers Psychol. 1991;23:105– 119. [57] Sheehan MN. Spirituality and the care of people with life-threatening illnesses. Tech Reg Anesth Pain Manag. 2005;9(3):109–113. [58] McDonald C, Wall K, Corwin D, et al. The perceived effects of psycho-spiritual

integrative therapy and community support groups on coping with breast cancer: a qualitative analysis. Eur J Pers Cent Healthc. 2012;1(2):298–309. [59] Elkins DN, Hedstrom LJ, Hughes LL, et al. Toward a humanisticphenomenological spirituality: definition, description, and measurement. J Humanist Psychol. 1998;28(4):5–18. [60] Curlin FA, Roach CJ, Gorawara-Bhat R, et al. How are religion and spirituality related to health? South Med J. 2005;98(8):761–766. [61] Koenig HG. Religion, spirituality, and medicine: research findings and implications for clinical practice. South Med J. 2004;97(12):1194–1200. [62] Clark PA, Drain M, Malone MP. Addressing patients’ emotional and spiritual needs. Jt Comm J Qual Saf. 2003;29(12):659–670. [63] King DE, Bushwick B. Beliefs and acitudes of hospital inpatients about faith healing and prayer. J Fam Pract. 1994;39:349–352. [64] Maugans TA, Wadland WC. Religion and family medicine: a survey of physicians and patients. J Fam Pract. 1991;32:210–213. [65] Anandarajah G, Hight E. Spirituality and medical practice: using the HOPE questions as a practice tool for spiritual assessment. Am Fam Physician. 2001;63(1):81–88. [66] Oyama O, Koenig HG. Religious beliefs and practices in family medicine. Arch Fam Med. 1998;7:431–435. [67] Ehman JW, Oc BB, Short TH, et al. Do patients want physicians to inquire about their spiritual or religious beliefs if they become gravely ill? Arch Intern Med. 1999;159:1803–1806. [68] Lo B, Quill T, Tulsky J. Discussing palliative care with patients. Ann Intern Med. 1999;130(9):772–774. [69] Underwood LG, Teresi J. The Daily Spiritual Experience Scale: development, theoretical description, reliability, exploratory factor analysis, and preliminary construct validity using health related data. Anns Behav Med. 2002;24(1):22–33. [70] Achterberg J. Imagery in healing. Shambala: Boston, MA; 1985. [71] Lewandowski W, Jacobson A. Bridging the gap between mind and body: a biobehavioral model of the effects of guided imagery on pain, pain disability, and depression. Pain Manag Nurs. 2013;14(4):368–378. [72] Lewandowski W, Jacobson A, Palmieri PA, et al. Biological mechanism related to the effectiveness of guided imagery for chronic pain. Biol Res Nurs. 2011;13(4):364–375. [73] Posadzki P, Lewandowski W, Terry R, et al. Guided imagery for nonmusculoskeletal pain: a systematic review of randomized clinical trials. J Pain Symptom Manage. 2012;44(1):95–104. [74] Gozales AE, Ledesma RJA, Perry SM, et al. Effects of guided imagery on

postoperative outcomes in patients undergoing same-day surgical procedures: a randomized, single-blind study. AANA J. 2010;78(3):185–188. [75] Trakhtenberg E. The effects of guided imagery on immune system: a critical review. Int J Neurosci. 2008;118:839–855. [76] van Kuiken D. A meta-analysis of the effect of guided imagery practice on outcomes. J Holist Nurs. 2004;22(2):164–179. [77] Halpin LS, Speir AM, CapoBianco P, et al. Guided imagery in cardiac surgery. Outcomes Manag. 2002;6(3):132–137. [78] Naparstek B. Staying well with guided imagery. How to harness the power of your imagination for health and healing. Hachece Book Group: New York; 1994. [79] Miller GE, Cohen S. Psychological interventions and the immune system: a meta-analytic review and critique. Health Psychol. 2001;20(1):47–63. [80] Rider MS, Achterberg J. Effect of music-assisted imagery on neutrophils and lymphocytes. Biofeedback Self Regul. 1989;14:247–257. [81] Montgomery GH, DuHamel KN, Redd WH. A meta-analysis of hypnotically induced analgesia: how effective is hypnosis? Int J Clin Exp Hypn. 2000;48(2):134–149. [82] Walker WR. Hypnosis as an adjunct in management of pain. South Med J. 1980;73(3):362–364. [83] Benham G, Smith N, Nash MR. Hypnotic susceptibility scales: are the mean scores increasing? Int J Clin Exp Hypn. 2002;50(1):5–16. [84] Lichtenberg P, Bachner-Melman R, Ebstein RP, et al. Hypnotic susceptibility: multidimensional relationship with Cloninger's tridimensional personality questionniare, COMPT polymorphisms, absorption, and acentional characteristics. Int J Clin Exp Hypn. 2003;52(1):47–72. [85] Horton JE, Crawford HJ, Harrington G, et al. Increased anterior corpus callosum size associated positively with hypnotizability and the ability to control pain. Brain. 2004;127(Pt 8):1741–1747. [86] Vanhaudenhuyse A, Laureys S, Faymonville ME. Neurophysiology of hypnosis. Clin Neurophysiol. 2014;44:343–353. [87] Stecer F, Kupper S. Autogenic training: a meta-analysis of clinical outcome studies. Appl Psychophysiol Biofeedback. 2002;27(1):45–98. [88] Kanji N, Ernst E. Autogenic training for stress and anxiety: a systematic review. Complement Ther Med. 2000;8:106–110. [89] Serra D, Parris CR, Carper E, et al. Outcomes of guided Imagery in Patients Receiving Radiation Therapy for Breast Cancer. Clin J Oncol Nurs. 2012;16(6):617–623. [90] Elton D, Burrows GD, Stanley GV. Relaxation theory and practice. Aust J Physiother. 1978;24(3):143–149.

[91] Jacobson E. Progressive relaxation. University of Chicago Press: Chicago; 1938. [92] Bernstein DA, Borkovec TD. Progressive relaxation training: a manual for the helping professions. Research Press: Champaign, IL; 1973. [93] Safi SZ. A fresh look at the potential mechanisms of progressive muscle relaxation therapy on depression in female patients with multiple sclerosis. Iran J Psychiatry Behav Sci. 2015;9:340–348. [94] Elton D, Burrows GD, Stanley GV. Relaxation theory and practice. Aust J Physiother. 1978;24(3):143–149. [95] Conrad A, Roth WT. Muscle relaxation therapy for anxiety disorders: it works but how? J Anxiety Disord. 2006;21:243–264. [96] Hayes-Skelton SA, Roemer L. A contemporary view of applied relaxation for generalized anxiety disorder. Cogn Behav Ther. 2014;42(4):1–12. [97] Lehrer PM, Woolfolk RL, Sime WE. Principles and practice of stress management. 3rd ed. The Guilford Press: New York, NY; 2007. [98] Lee EJ, Bhacacharya J, Sohn C, et al. Monochord sounds and progressive muscle relaxation reduce anxiety and improve relaxation during chemotherapy: a pilot EEG study. Complement Ther Med. 2012;20(6):409–416. [99] Ranjita L, Sarada N. Progressive muscle relaxation therapy in anxiety: a neurophysiological study. IOSR-JDMS. 2014;13(2):25–28. [100] Chan E. The role of complementary and alternative medicine in acentiondeficit hyperactivity disorder. J Dev Behav Pediatr. 2002;23(Suppl.). [101] Sheu S, Irvin BL, Lin H, et al. Effects of progressive muscle relaxation on blood pressure and psychosocial status for clients with essential hypertension in Taiwan Province of China. Holist Nurs Pract. 2003;17(1):41–47. [102] Koh KB, Lee Y, Beyn KM, et al. Counter-stress effects of relaxation on proinflammatory and anti-inflammatory cytokines. Brain Behav Immun. 2008;22(8):1130–1137. [103] Hernandez-Reif M, Field T, Largie S, et al. Parkinson's disease symptoms are differentially affected by massage therapy vs. progressive muscle relaxation: a pilot study. J Bodyw Mov Ther. 2002;6(3):177–182. [104] Riley D. Hatha yoga and the treatment of illness. Altern Ther Health Med. 2004;10(2):20–21. [105] da Silva TL, Ravindran LN, Ravindran AV. Yoga in the treatment of mood and anxiety disorders: a review. Asian J Psychiatr. 2009;2(2009):6–16. [106] Khalsa SBS. Yoga as a Therapeutic intervention: a bibliometric analysis of published research studies. Indian J Physiol Pharmacol. 2004;48(3):269–285. [107] Salmon P, Lush E, Jablonski M, et al. Yoga and mindfulness: clinical aspects of an ancient mind/body practice. Cogn Behav Pract. 2009;16:59–72. [108] Cramer H, Ward L, Saper R, et al. The safety of yoga: a systematic review and

meta-analysis of randomized controlled trials. Am J Epidemiol. 2015;1–13. [109] Brown RP, Gerbarg PL. Yoga breathing, meditation and longevity. Ann N Y Acad Sci. 2009;1172:54–62. [110] Dhanvijay AD, Bagade AH, Choudhary AK, et al. Alternate nostril breathing and autonomic function in healthy young adults. IOSR-JDMS. 2015;14(3):62–65. [111] Cooper S, Oborne J, Newton S, et al. Effect of two breathing exercises (Buteyko and pranayama) in asthma: a randomised controlled trial. Thorax. 2003;58:674– 679. [112] Peper E, Tibbecs V. Effortless diaphragmatic breathing. Phys Ther Prod. 1994;6(2):67–71. [113] Sharma P, Thapliyal A, Chandra T, et al. Rhythmic breathing: immunological, biochemical, and physiological effects on health. Adv Mind Body Med. 2015;29(1):18–25. [114] Brown RP, Gerbarg PL, Muench F. Breathing practices for treatment of psychiatric and stress-related medical conditions. Psychiatr Clin North Am. 2013;36:121–140. [115] Schwaro MS, Adrasik F. Biofeedback. A practitioner's guide. 4th ed. The Guilford Press: New York, NY; 2016.

10

Sports naturopathy Kira Sutherland

Introduction The concept of using foods and fluids to enhance sports performance is not new. As far back as ancient Greece it is known that athletes focused on their diet before competition or sport. As the Olympic mo=o states, ‘Faster, Higher, Stronger’ – and this is what athletes and those participating in sport are looking for. Much of what is covered in this chapter pertains to people participating in sports at a medium to high level. Although these principles can be adjusted and applied to anyone participating in physical fitness and recreation, most of the research and clinical suggestions are for those involved in physical activity on a regular basis. Sports nutrition is the domain of dietitians and sports scientists. It is a heavily researched field of human nutrition and biochemistry. As a naturopath approaching the use of sports nutrition there are many philosophical differences that need to be put aside, as the application of dietetics-style sports nutrition will need to prevail in the idea that fuelling the body for sport may not always follow the food-is-medicine guidelines of naturopathic nutrition. This is not to say that many sports nutrition principles cannot be brought within naturopathic principles, but at times use of glucose, sucrose or large doses of sodium, for example, may be required to keep an athlete moving and safe. As naturopaths learn to apply these principles, it is up to each practitioner and their clients to find their level of food as medicine versus food as fuel during sport. A complete overview of all sports nutrition principles is beyond the scope of this book, but this chapter aims to teach the basics of fuelling for active people and athletes and to bring an understanding of its application in everyday life.

Exercise physiology Energy metabolism A basic understanding of how the body uses macronutrients as fuel during different types of output and exercise is vital to the application of sports nutrition principles. A good

understanding of exercise physiology goes a long way to interpreting why certain sports nutrition principles are applied and when. A short summary is provided below; more detail can be found in other publications.[1,2] Many systems must coordinate when a body is in motion. Exercise requires an increase in energy metabolism, while fuel and oxygen must be supplied to the working muscles. The body must a=empt to remove heat and waste products while also trying to maintain fluid and electrolyte balance.

Energy systems A clear understanding of the body's three energy systems is vital. The aerobic (oxidative) and anaerobic (phosphate or glycolytic) systems use different fuels and are available for differing intensities and types of exercise. Knowing the metabolic profile of a sport is imperative to applying accurate sports nutrition principles for supporting optimum training, recovery and competition. Figs 10.1 and 10.2 and Table 10.1 review these three systems.[2–4]

FIGURE 10.1 Energy systems of the body Jeukendrup AE, Gleeson M. Sports nutrition: an introduction to energy production and performance. 4th edn. Champaign, IL: Human Kinetics Publishers; 2004.

FIGURE 10.2 Interaction of metabolic energy systems Baker JS, McCormick MC, Robergs RA. Interaction among skeletal muscle metabolic energy systems during intense exercise. Journal of Nutrition and Metabolism 2010:1–13.

TABLE 10.1

Working energy systems Phosphate (anaerobic) Intensity of effort

Very high intensity 95–100% of maximum effort, explosive Duration Approximately 8–10 seconds Fuel

Phosphocreatine (PC) and adenosine triphosphate (ATP)

Glycolytic (anaerobic) High intensity 60–95% of maximum effort Primary system for highintensity exercise lasting 10– 180 seconds Carbohydrate in the form of muscle glycogen and blood glucose

Oxidative metabolism (aerobic) Low intensity Up to 60% of maximum effort Primary system for exercise lasting longer than 2 minutes Carbohydrates Muscle/liver glycogen Fats Intramuscular lipids Adipose triglycerides Amino acids from Muscle Liver Blood Gut Exogenous sources can also be used for energy production in prolonged exercise

The phosphate system has a high power output but can supply energy for only a very short period of time; however, replenishment of this system is rapid. The glycolytic system has a greater ability for adenosine triphosphate (ATP) generation but has a lower power output and a much slower ability to replenish itself as glycogen (carbohydrate) stores must be replaced. Oxidative/aerobic metabolism of carbohydrate (CHO) and lipids provides the vast majority of ATP for muscle contraction. Amino acid oxidation occurs to a limited extent. The contribution of carbohydrate or lipids is influenced by the person's exercise intensity, diet prior to exercise, substrate availability and fitness level as well as environmental factors such as hot or cold climates. No energy system is ever used exclusively, and the systems do not run independently of each other. Many factors come into play as to which system is used and to what extent, including the intensity, type, duration and frequency of training, and the person's overall fitness level, gender and substrate availability (see Table 10.2). TABLE 10.2

Approximate contributions of anaerobic and aerobic energy supply to total energy demand in races over different distances Distance

Duration (min)

Anaerobic (%)

Aerobic (%)

100 m 400 m 800 m 1500 m 5000 m 10 000 m 42.2 km

0 : 9.58 0 : 43.18 1 : 40.91 3 : 26.00 12 : 37.35 26 : 17.53 122 : 57

90 70 40 20 5 3 1

10 30 60 80 95 97 99

Note: The times given are for the men's world records for these distances in 2014. Source: Maughan R, Shirreffs S. Physiology of sport. In Burke L, Deakin V. Clinical sports nutrition. 5th edn. Australia: McGraw-Hill Australia; 2015.

Fuel sources Muscle glycogen is important for both intense and prolonged forms of exercise (see Fig. 10.3). Its rate of usage is most rapid during the early stages of exercise and is correlated to exercise intensity. As exercise continues and muscle glycogen declines, blood glucose becomes an important carbohydrate fuel source. Exogenous carbohydrate eaten at this time can become a major source of fuel during prolonged events.

FIGURE 10.3 Glycogen storage in the body Jeukendrup AE, Gleeson M. Sports nutrition: an introduction to energy production and performance. 4th edn. Champaign, IL: Human Kinetics Publishers; 2004.

Muscle also obtains energy from the beta oxidation of plasma free fa=y acids (FFAs), from lipolysis of adipose tissue. Its use as a fuel may reduce the reliance on glycogen stores and blood glucose, especially during prolonged exercise such as endurance events. The body's use of differing substrates is primarily influenced by the intensity of exercise, as well as the style of diet the athlete chooses to follow. Fig. 10.4 illustrates the percentage of different fuels the body uses at increasing levels of activity.[5] Regarding diet, if an endurance athlete eats a higher carbohydrate diet in the days prior to an event – be=er known as carbohydrate loading – their body will have a higher volume of muscle glycogen prior to the event, as well as an increased rate of glycolysis at rest and during exercise. If an athlete eats a higher fat diet with lower carbohydrate levels, this will shift metabolism during aerobic exercise in favour of fat oxidation.[4] The idea of eating a high-fat, low-carbohydrate (HFLC) diet is increasing in popularity and its merits and limitations are discussed later in this chapter.

FIGURE 10.4 Fuel usage breakdown Tucker R. Exercise and weight loss, part 3: fat. The Science of Sport; 2010 [Cited 18 December 2016. Available from http://sportsscientists.com/2010/01/exercise-andweight-loss-part-3-fat.]

Energy requirements Proper energy intake is the foundation of an athlete's health and ability to perform. There are multiple ways to measure energy and food intake, such as using diet apps, a food frequency questionnaire, 24-hour recall or a simple food diary kept for 3–7 days. Each method has its benefits and limitations but most likely an athlete will underreport their volume of eating no ma=er which method is used. Although no method is perfect, it is important to obtain and assess an athlete's daily intake of foods, liquids and supplements in order to have an overall understanding of kilojoule intake, food preferences and timing habits of eating around training. Factors that increase an athlete's energy requirements include increased training and intensity, a hot or cold climate, high altitude, certain injuries, caffeine intake, an increase in the body's fat-free mass and potentially the luteal phase of the female cycle.[6,7] Factors that may decrease energy requirements include decreased training volume and intensity, ageing, a decrease in muscle mass and potentially the follicular phase of the reproductive cycle.[8] When working with physically active people it is important to match food intake with energy expenditure. The volume of training can change dramatically from pre-season to mid-season or even on a daily basis depending on the training program and rest days. It is vital to take such factors into account when designing food intake and meal plans. What an athlete needs to eat on a double-session training day is very different from their intake on a rest day. The need for athletes to maintain a healthy body composition and weight is vital for performance as well as their mental state. There is a balancing act that must occur between

maintaining muscle mass, decreasing fat mass and fuelling properly for high-level training and performance. Each sport has its own metabolic profile and potential range of optimum body composition: practitioners must be aware of these parameters and consider what is potentially a=ainable for their patients. In addition, many people engaging in sports will not fit this ‘metabolic profile’ and care needs to be taken to avoid disordered eating habits, body image issues and so on. Practitioners should be aware of the warning signs for such disorders and refer their patients when needed to other healthcare professionals as appropriate, such as doctors, sports psychologists and dietitians.

Carbohydrates Carbohydrates are vital to fuel an exercising body: they are the dominant fuel source for anaerobic (glycolytic) activity and are one of the two main sources for aerobic activity. The amount of carbohydrate stored within the body (glycogen) is limited but can be manipulated via training and dietary intake on a daily basis.[8] Low glycogen stores are associated with fatigue, reduced work rate, impaired skill and concentration as well as an increased perception of effort.[6] The amount of glycogen within the muscle cells plays a role in regulating muscle adaptation to training by altering the physical, metabolic and hormonal environment in which the signalling responses to exercise are exerted.[9] Training and nutrition strategies that use carbohydrate restriction before, during and after training or in an overall diet are referred to as ‘training low’ and are being recognised as having potential benefit for certain sports or specific training sessions.[10] The amount of carbohydrate a person needs to consume on a daily basis will vary depending on many factors. No longer are strict ‘high-carb’ guidelines being given, but rather varying amounts of intake are suggested depending on training goals, the volume of exercise undertaken and proximity to competition or race day. Nutrition strategies are focusing on high performance or training adaptations with the nutrition tailored depending on the desired outcomes.

Carbohydrate intake guidelines Guidelines for suggested carbohydrate intake are provided according to:

• The athlete's body weight • The type of exercise undertaken and the training goals • The timing of carbohydrate intake needed in relation to training or competition • The volume of carbohydrate needed over the day in relation to training volume

• The athlete's total energy needs and body composition goals. A higher carbohydrate intake is recommended when undertaking high-quality training, while a lower intake is suggested prior to training to promote stimulus response and prior to adaptive training with lower glycogen stores.[11] See Table 10.4 below for more details on adjusting carbohydrate intake for differing training goals. Most importantly, carbohydrate targets should be individualised for an athlete's specific needs. Carbohydrate recommendations were previously given as a percentage of daily diet. New guidelines aim to move away from daily percentages as these were found to be too general and hard to apply in real food terms. The most recent recommendations are given in calculations of training volume and grams per kilogram of body weight. The guidelines are not absolute amounts that must be followed: individual variations must be taken into account, as some athletes will perform be=er at the higher end of the recommendations while others will prefer the lower end. Table 10.3 is a simplified table of general recommendations by the International Society of Sports Nutrition, while Table 10.4 is part of the 2010 IOC guidelines for carbohydrate in a training diet.[12,13] It is imperative that the practitioner understands an athlete's sport, its time commitment, energy system usage and general training schedule in order to use these guidelines. TABLE 10.3 Carbohydrate intake suggestions for physical activity Activity level

Grams/kg/day

30–60 minutes/day, 3–4 times/week 5–7 hours /week Moderate to high intensity, 2–3 hours/day, 5–6 times/week High-volume intense exercise, 3–6 hours/day, 1–2 sessions day, 5–6 times/week

3–5 4–6 5–8 8–10

Source: Potgieter S. Sport nutrition: a review of the latest guidelines for exercise and sport nutrition from the American College of Sport Nutrition, the International Olympic Committee and the International Society for Sports Nutrition. South African Journal of Clinical Nutrition 2013;26(1):6–16.

TABLE 10.4

Carbohydrate targets Situation

Carbohydrate targes

Comments on type and timing of carbohydrate intake

Daily needs for fuel and recovery 1. The following targets are intended to provide high carbohydrate availability (i.e. to meet the carbohydrate needs of the muscles and central nervous system) for different exercise loads for scenarios where it is important to exercise with high quality and/or at high intensity. These general recommendations should be fine-tuned with individual consideration of total energy needs, specific training needs and feedback from training performance.

2. On occasions when exercise quality or intensity is less important, it may be less important to achieve these carbohydrate targets or to arrange carbohydrate intake over the day to optimise availability for specific sessions. In these cases, carbohydrate intake may be chosen to suit energy goals, food preferences or food availability. 3. In some scenarios, when the focus is on enhancing the training stimulus or adaptive response, low carbohydrate availability may be deliberately achieved by reducing total carbohydrate intake or by manipulating carbohydrate intake related to training sessions (e.g. training in a fasted state, undertaking a second session of exercise without adequate opportunity for refuelling after the first session). Light Low-intensity or skill3–5 g/kg of • Timing carbohydrate intake over the day may be based activities athlete's manipulated to promote high carbohydrate body availability for a specific session by consuming weight/day carbohydrate before or during the session, or in recovery from a previous session. Moderate Moderate exercise 5–7 g/kg/day • Otherwise, as long as total fuel needs are provided, program (e.g. ~1 h per the pa=ern of intake may simply be guided by day) convenience and individual choice. High Endurance program 6–10 g/kg/day • Athletes should choose nutrient-rich carbohydrate (e.g. 1–3 h/day sources to allow overall nutrient needs to be met. moderate to highintensity exercise) Very high Extreme 8–12 g/kg/day commitment (e.g. 4–5 h/day moderate to highintensity exercise Acute fuelling strategies These guidelines promote high carbohydrate availability to promote optimal performance in competition or key training sessions. General Preparation for 7–12 g/kg per • Athletes may choose carbohydrate-rich sources that fuelling up events < 90 min 24 h as for are low in exercise daily fuel • fibre/residue and easily consumed to ensure that fuel needs targets are met, and to meet goals for gut comfort or lighter ‘racing weight’. Carbohydrate Preparation for 36–48 h of 10– loading events >90 min of 12 g/kg body sustained/intermi=ent weight per 24 exercise h Speedy 60 1–4 g/kg • Timing, amount and type of carbohydrate foods and fuelling min consumed 1–4 drinks should be chosen to suit the practical needs of h before the event and individual preferences/experiences. exercise • Choices high in fat/protein/fibre may need to be avoided to reduce risk of gastrointestinal issues during the event. • Low glycaemic index choices may provide a more sustained source of fuel for situations where carbohydrate cannot be consumed during exercise.

During brief 2.5–3 h

Not needed Small amounts • A range of drinks and sports products can provide including easily consumed carbohydrate. mouth rinse • The frequent contact of carbohydrate with the mouth and oral cavity can stimulate parts of the brain and central nervous system to enhance perceptions of wellbeing and increase self-chosen work outputs. 30–60 g/h • Carbohydrate intake provides a source of fuel for the muscles to supplement endogenous stores. • Opportunities to consume food and drink vary according to the rules and nature of each sport. • A range of everyday dietary choices and specialised sports products ranging in form from liquid to solid may be useful. • Athletes should experiment to find a refuelling plan that suits their individual goals including hydration needs and gut comfort. Up to 90 g/h • As above. • Higher intakes of carbohydrate are associated with be=er performance. • Products providing multiple transportable carbohydrates (glucose:fructose mixtures) achieve high rates of oxidation of carbohydrate consumed during exercise.

Source: Burke LM, Hawley JA, Wong SHS, Jeukendrup AE. Carbohydrates for training and competition. Journal of Sports Sciences 2011;29(supp1):S17–27.

Considerations for carbohydrate choices The choice of carbohydrate use has become a ‘hot’ topic of late. There are many differing opinions regarding this choice and it is up to the individual athlete and their practitioner to decide what works best for them. Issues to consider when choosing a carbohydrate source include:

• Personal food preference and willingness to consume foods in the quantities needed • Food convenience and availability • How much money the athlete has for a ‘food budget’ • Whether the athlete is travelling after training and needs something compact and portable • Whether refuelling is time-sensitive due to further training on the same day and thus there is a need for quick glycogen recovery • Whether the athlete is a=empting to follow ‘train low’ or ‘sleep low’

practices (low-glycogen training – see below) • Food allergies and sensitivities; digestive comfort • Whether nutrient-dense foods are needed in order to achieve higher carbohydrate intake targets • Whether other macronutrients are needed in the same meal for recovery (such as protein) • Whether the athlete has dietary restrictions such as coeliac, vegetarian or paleo • Whether the meal needs to be low in fibre, residue, protein or fat due to timing near an event • Whether the athlete has goals of weight loss or muscle gain. Another factor to take into consideration is who is doing the cooking for the athlete – are they living with their parents, by themselves or with others who are sharing the meal preparation? Above all, the athlete needs to be motivated to eat the meals that are suggested. It is useless trying to make an athlete, especially a teenager, eat a food or meal they do not like. They will be more likely to skip this meal and thus compromise their glycogen stores and recovery. Table 10.5 gives examples of carbohydrate sources in approximately 30-g amounts for ease of calculating volumes needed. It includes a range of examples and is not meant to be a list of ‘health’ foods, as it contains foods that are not within normal naturopathic suggestions but that athletes may use during training or events where high-glycaemic index (GI), low-fibre carbohydrates are needed.

TABLE 10.5

What 30 g carbohydrate looks like General carbohydrates (30 g) Bread 2 slices Bread roll 1 roll Crumpet 1.5 Weet-Bix 3 Cereal (average) ½ cup Rice cakes 4 Yoghurt, plain full-fat 300 g Milk 600 mL Chocolate muesli bar 2 Concentrated forms of carbohydrate (30 g) Fruit juice 300 mL Soft drink 250–300 mL Jam 2 tablespoons Sugar 2 tablespoons Sports gel 1–1.5 packets Fruit (30 g) Fruit salad 1 cup Banana 1 large Dried figs 4 medium Peach 2 large Sultanas/raisins 1/3 cup/45 g Dates 6 small Dates 2.5–3 large Kiwi 3 Rock melon 2.2 cups Pineapple 1.5 cups Carbohydrate-dense vegetables (30 g) Taro root 90 g Bu=ernut pumpkin 300 g Sweet potato 150 g Yam 100–110 g

Pasta, cooked Rice, cooked Hot-cross bun Untoasted muesli Cooked oats Pancakes Fruit-flavoured yoghurt Muesli bar Crisp bread

¾ cup ½ cup 1 average ½ cup 1 cup 2 average 200 g 1–2 (read label) 6 biscuits

Cordial Sports drink Jellybeans Honey Maple syrup

300 mL 350–400 mL 10 2 tablespoons 2 tablespoons

Orange/apple/pear Grapes Dried apricots Watermelon Blueberries Strawberries Raspberries Mango Avocado Nectarine

2 medium 1 cup (12–14) 10 halves 3 cups 1.5 cups 3 cups 2 cups 1 medium 2 2

White potato Carrots Beetroot Sweetcorn

140 g 300 g 300 g 120 g

Wholefoods versus fuelling for sport The recent focus on wholefoods and minimal sugar and processed food intake to decrease inflammation is a great move towards improved general health. However, at times athletes will need to ingest more concentrated sugars depending on their chosen sport and fuelling needs. In many endurance sports (lasting longer than 2 hours) it is vital for an athlete to have a portable, non-perishable, fast-digesting carbohydrate for fuel as their glycogen stores become depleted. Sports drinks, gels and chews have been created specifically for this need. There are wholefood options, but these may not be the most realistic choice during a race or hectic training schedule.

Carbohydrates do not always have to come from grains – many people focus on ge=ing the majority of their carbohydrate from fruit and vegetables. Rather, the individual needs to be aware of the volume of carbohydrate in different foods and their individual needs. Each person functions be=er on differing amounts: athletes should start on the lower end of the guidelines and see how they feel, working their way higher if needed, depending on their sport, volume of training and energy levels.

Protein Protein is of major importance for all athletes as it is involved in recovery, muscle building, supporting the immune system, repair and adaptation post-exercise. Exercise in combination with an adequate protein intake provides the body with the stimulus and fuel for the synthesis of contractile and metabolic proteins.[14,15] The rise in leucine concentrations and supply of exogenous amino acids is suggested to be the stimulus for this activity.[16] Research with resistance exercise has shown an upregulation of muscle protein synthesis (MPS) for at least 24 hours post-exercise and an increased sensitivity to proteins ingested.[17]

Current recommendations and variable needs Recommendations for protein now focus on the timing of protein intake throughout the day as well as intake post-training[15] rather than just the total daily intake. Protein intake should be assessed using the following criteria: total daily protein needs, placement for intake throughout the day, post-training needs, quality of protein ingested such as high biological value and leucine content. Current data suggest that dietary protein intake necessary to support metabolic adaptation, repair and remodelling and for protein turnover generally ranges from 1.2 to 2.0 g/kg/d.[7] Guidelines based on per meal intake suggest 0.25–0.3 g/kg body weight, providing ∼10 g essential amino acids in the early recovery phase (0–2 hours) post-exercise to optimise muscle protein synthesis, as well as other meals and snacks.[6,15,18,19] This is approximately 15–25 g of protein post-training for an average-size athlete. More or less may be needed depending on the athlete's body size. Recent research has also shown that whole-body resistance training may benefit from an intake of up to 40 g of protein to enhance muscle protein synthesis.[20] Higher intake of protein can be applied in such situations as short-term high-intensity training or when there is a decreased energy budget in order to lose weight while supporting retention of muscle mass.[14,21]

Fats Fat is an essential part of an athlete's healthy diet. It is needed to provide fuel for the body, to assist in the absorption of fat-soluble vitamins, as part of cell membranes, for hormone production and for insulation and protection of vital organs. Each athlete will have an individual amount of fat needed in their diet depending on their body weight, body

composition goals, training volume, sport of choice and nutrition goals such as fat adaptation strategies. Fat intake of less than 20% is not recommended for athletes unless it occurs in the few days before an endurance event and carbohydrate loading is being undertaken. Typical ranges vary from 20% to 35% of total energy intake for daily training. The goal is to choose healthy fats and to be aware of the overall intake in relation to body composition goals. Healthy fats to focus on are olive oil, linseed (flax) oil, avocados, coconut oil, deep-sea oily fish, raw seeds and nuts.

Fuel source Fat is used as a major fuel source along with carbohydrate during aerobic exercise. The burning of fat as a fuel plays an important role in sparing glycogen stores during exercise up to moderate intensities. Consuming a higher fat diet while training can potentially increase fat oxidation levels, decrease reliance on glycogen and endogenous carbohydrates, and delay fatigue in endurance events.[22]

Fat adaptation strategies Training with low glycogen stores is becoming increasingly popular with endurance athletes and those wanting to further use body fat stores for fuel. Recent research has suggested that doing this leads to improvements in increased lipid oxidation, mitochondrial biogenesis and increased fatigue resistance.[23,24] There are multiple ways in which to ‘train low’ and each needs to be considered in its application, ability for the athlete to adhere to such eating schedules and ability to maintain high performance levels when necessary. The research in this area is expanding and will provide more information in the next few years. Most important for the practitioner is to consider the type of athlete and sport that may benefit from this protocol, rather than applying such ideas to all sports in a generalised manner. Indepth explanation of this topic as well as research and discussion on fat adaptation is available in several articles.[22,25–28] Table 10.6 outlines some strategies used to ‘train low’.[29–34] TABLE 10.6 Strategies used to ‘train low’ Strategy

Application

Training in a fasted state Training twice per day Restricting carbohydrate intake during recovery period posttraining Sleep low

6–10 h after consumption of last meal Second session performed with low glycogen stores Decrease carbohydrate available post-training

Source: [29–34].

Training in the evening, sleeping without carbohydrate replenishment and performing morning training to further decrease glycogen stores

The benefits of such applications need to be considered within the whole picture of wellbeing. Previous research has shown that increasing training stress may influence immune function, leading to an increased risk of illness or injury[35] and thus limiting performance gains if the athlete must take time out of training to recover from being unwell. One of the major issues with the use of these new strategies is an awareness of which sports may benefit from such methods and which may be hindered or have a negligible benefit for effort involved. The research to date is equivocal as to performance benefits for many sports and there is the potential for the downregulation of carbohydrate oxidation at higher levels. [36,37] It is of li=le use for a sprint athlete or swimmer who needs to perform at high intensity to upregulate fat burning when the majority of their performance needs to be well above their anaerobic threshold. The idea of fat adaptation can be applied to many sports in the offseason when lower intensity training may be undertaken for the time it takes to ‘adapt’. The use of fat adaptation or low-carbohydrate high-fat diets can be more easily applied to people trying to stay fit, lose weight and not be competitive within their sport, especially in the first few months of its application. Great consideration needs to be given as to which sports and athletes may benefit from such approaches and who may be disadvantaged. The next decade of research in this area will be fascinating to watch.

Fuelling for training and recovery Pre-training Eating before training depends on multiple factors and ultimately needs to suit the athlete and their digestive system. Factors that need to be considered are the length of the session, the time of day the training is occurring, whether there are two training sessions per day or only one, the type of session occurring and the goal of the session, and the person's ability to handle food pre-training. If the session being performed is 1 hour or less, it can easily be done with no food intake beforehand or a small snack of mainly carbohydrate. If the training is occurring early in the morning, many athletes find they don't like to eat anything then as it can make them feel unwell; if this is the case, training on empty is fine. Others don't feel well training on empty and thus need to consume a small snack. If a high-intensity, weights or strenuous session is planned, most athletes find a small snack helps them to have enough energy through the demanding session. When a session is longer than 1 hour, it is best to have a small snack before training to help sustain energy levels. For training sessions longer than 1.5 hours the athlete will probably need to fuel during the session as well. If the session is occurring later in the day, aim for a meal 2 hours prior to training or a small snack half an hour to an hour beforehand consisting of mainly carbohydrate with a li=le protein for stable blood sugar levels.

Food choices Food choices for pre-training can be almost anything that suits the athlete and their tastes.

Common choices are banana, fresh dates, toast or gluten-free toast with nut bu=er and honey or avocado, healthy muesli bars, sports bars or homemade date-and-nut bars or a piece of fresh fruit. Approximately 20–30 g of carbohydrate is a volume that's easy to consume pretraining without creating digestive distress. It becomes a trial and error of what works for the individual.

Eating during training and sports An athlete's training goals must be taken into consideration when deciding whether they should eat during training. Other factors include the length of the session; the goals of the session; whether the session is high intensity, slow and longer endurance, or strength; the time of day; what meals have already been eaten; and whether it is the only session of the day or there are multiple training sessions. Many people become focused on the idea of ‘fat burning’ within a training session and undertake exercise with prior food and no kilojoule intake during the session. At times this can benefit an athlete, but for a high-intensity session or strength work it may be more advantageous for the athlete to consume a small amount of carbohydrate during the session in order to finish their training strong and well-fuelled. The following sections explain these ideas in more detail.

Session length A training session 75 minutes should be fuelled by fluids and foods consumed during the session. Athletes can eat prior to training if that is their choice but sessions of this length and longer are assisted by ingestion of carbohydrate during sport. Athletes should aim to consume 30–60 g of carbohydrate per hour for sessions of this nature. Fluid intake is also vital for longer sessions (see the hydration section below). The specific amount required depends on the athlete's training intensity, session goals and digestive comfort. Creating a quality sports nutrition plan is vital to get the most out of a training session. It is also important to consume foods or sports gels with an adequate amount of water to facilitate rapid absorption of both foods and fluids across the intestinal lining (approximately 250–300 mL for 20–25 g of carbohydrate). However, combining foods/gels with a sports drink containing carbohydrate will greatly decrease gastrointestinal absorption rates and is more likely to cause gastrointestinal disturbances. Foods and fluids must be absorbed, not just consumed, in order to assist the body. Suggested food options during training include sports bars, sports drinks, gels and chews, banana, dates, muesli bars, and bread with honey or nut bu=er. Ultimately, it's about what suits the athlete and their stomach. There are many recipes for homemade sports drinks and gels to keep exposure to sucrose and artificial colourings to a minimum if that is what is desired.

Multiple transportable carbohydrates Fig. 10.5[38] is an easy-to-follow guide to the volume of carbohydrate needed to be ingested depending on the length of exercise session or race. The values are not absolute and intake ultimately needs to be tailored for each individual, their digestive comfort and their training or racing needs.

FIGURE 10.5

Recommended carbohydrate intake during exercise www.mysportscience.com

Research shows that up to 90 g of multiple transportable carbohydrates can be ingested[39] during endurance events but for some athletes this will be far too much for their digestive system to handle, thus the recommendation of upwards of 60 g of carbohydrate per hour rather than a definitive amount. Each person will have to practise their intake, trialling multiple forms of carbohydrate at differing amounts to know where their individual best intake resides. Starting at the lower end of the scale and working upwards is an easier way to trial such a process than starting high and experiencing gut issues until personal comfort is reached. Glucose can be absorbed at a rate of 60 g per hour through the digestive system, see Fig. 10.6.[40] Research has shown that it is possible to eat upwards of this amount if multiple sources of carbohydrate are ingested, such as a 2 : 1 glucose/fructose combination. Fructose is absorbed through a different pathway in the gut lining than glucose, thus enabling higher volumes of carbohydrate ingestion when glucose transports are already saturated.[39,41–43]

FIGURE 10.6

Absorption of carbohydrates www.mysportsscience.com

A naturopathic perspective The use of pure sugars, specifically fructose, is a controversial topic within complementary medicine. The general population ingests large volumes of processed foods and sugars and as practitioners there is a move to decrease sugar intake. When applying holistic health principles to sports nutrition research there is a divide regarding how to optimise an athlete's performance while a=empting to do as li=le harm as possible. There is the option to use wholefoods instead of sports products, especially during training, but when an athlete is undertaking an event that lasts 4–6 hours or an entire day they need compact, heat-stable nutrition. Many athletes prefer to use wholefoods but care must be taken not to use highfibre foods that slow the gastrointestinal emptying rate and potentially cause more issues than benefits. The choice of which sugars to use in training and racing is up to the practitioner and their awareness of current science, as well as ultimately what works for the athlete and their digestive system.

Protein during training The benefit of eating protein during training is inconclusive. There is some evidence that adding a small amount of protein to carbohydrate in a ratio of 4 : 1 during exercise may have

some benefit. There is a potential improvement in endurance performance, increasing muscle glycogen stores, reducing muscle damage and promoting be=er training adaptations after resistance training.[44] The most recent joint position statement[6] states that ‘Protein ingestion pre and during exercise seems to have less of an impact on muscle protein synthesis (MPS) than the post exercise provision but may still enhance muscle reconditioning depending on the type of training that takes place’. Though not considered necessary for everyone, whether to eat protein during training will depend on the goals of the athlete and the training involved. Those wanting to focus on muscle protein synthesis after resistance exercise and those looking to enhance recovery from ultra-endurance training may benefit from protein intake pre- and during training.[6] Ultra-endurance athletes often choose to intake a small amount of protein and sometimes fat during events for stabilisation of blood sugar levels, for flavour variety as well as for alternative fuel sources and potentially increasing time to exhaustion. Examples are demonstrated in case study 1. For a review of the ingestion of protein during training, see the article by van Loon.[45]

Post-exercise nutrition Goals post-exercise Athletes may have the following post-exercise goals:

• Change the body from a catabolic state to an anabolic state • Replace glycogen stores • Repair damaged tissue and build muscle • Support immune function • Replace fluid and electrolyte losses. Post-training is the most vital time in an athlete's day to get their nutrition correct. The body has been challenged, has used fuels and fluids and is in a catabolic state. Proper nutrition protocols post-training can have far-reaching effects in many areas of health as well as recovery from training. Depending on the type of training the nutrition goals will vary slightly, but there are many similarities no ma=er the sport.

Time between training sessions If there are fewer than 8 hours between training sessions, carbohydrate intake should start as soon as possible post-training in order to facilitate glycogen replacement. Glycogen storage rates are at their highest in the first hour after exercise.[46,47] Glycogen synthase has been activated as well as an increase in insulin sensitivity[48] and muscle cell membrane permeability to glucose[49] post-exercise. Common recommendations are to eat a meal or snack within 30–60 minutes. Many athletes will not feel hungry at this time but encouraging them not to wait to eat will potentially enhance their recovery. A small snack or liquid meal

replacement/smoothie is often an easy alternative until a proper meal can be eaten. A small amount of protein (20–25 g) at this time is also beneficial for recovery, as noted above. With an athlete undertaking two training sessions per day the importance of restocking glycogen after the first session is vital for a quality second session. Medium to high GI carbohydrate may be consumed at this time to enhance the speed of glucose delivery to the body. If there is longer recovery between sessions (i.e. 24 hours), the pa=ern of meals and snacks is not as important, but it is still wise to eat a meal or snack close to finishing a training session to assist in recovery and glycogen replacement. Suggested volumes for carbohydrate intake are shown in Tables 10.3 and 10.4 and range from 1 g/kg to 1.5 g/kg in the hour posttraining. Protein is also beneficial at this time in the suggested amount of 0.25–0.3 g/kg for the meal post-training. Over-restrictive eating in the post-exercise window can lead to suboptimal training, poor recovery, potential immune issues, lack of energy and a decrease in training adaptations.

Other considerations in eating post-training Common suggestions for post-training ratios of carbohydrate to protein are 3–4 : 1, depending on the sport and individual needs.[12] See Tables 10.7 and 10.11 below for many foods and their approximate carbohydrate and protein amounts. (It is important to note that these suggestions are for an athlete's needs – as a practitioner working with individuals who want to stay fit and exercise but potentially do not do large volumes of training, these intake levels may be too high.) Trial and error, awareness of training volume and individual variation all need to be taken into account. Start at the lower end of the scale and adjust up or down depending on training volume and the athlete's feedback regarding energy levels, ability to sustain training and overall wellbeing. If an individual undertakes only a light training session, the levels may be adjusted lower to accommodate the decreased urgency for glycogen replacement post-training and consider intake to be consumed with regular meals and snacks.

Post-training protein needs Protein is important for the recovery phase after training to promote muscle hypertrophy, support the immune system and assist the repair and adaptations that occur in the body following exercise. The most recent guidelines recommend 0.25–0.3 g/kg of protein be consumed in the post-training meal.[14] Intact protein or a complete mixture of amino acids is also important.[50] Note that if insufficient volume of carbohydrate is ingested in the 4 hours post-training it can be augmented by the intake of protein (20–25 g) and thus assist in glycogen storage. If sufficient intake of carbohydrate occurs, the added protein will not give a further benefit to glycogen levels.[51] Protein needs and muscle protein synthesis Muscle protein synthesis after resistance exercise is an area of great focus in post-training fuelling suggestions. Recent research focuses on a variety of factors including the amount of

protein ingested, the source of protein, and the potential distribution and timing of postexercise protein ingestion.[52] Fig. 10.7 summarises important points when focusing on muscle protein synthesis.

FIGURE 10.7 Schematic showing how resistance exercise variables and protein ingestion can impact muscle protein turnover MPS, muscle protein synthesis; MPB, muscle protein breakdown; PRO, protein. Morton JP, Croft L, Bartlett JD, et al. Reduced carbohydrate availability does not modulate training-induced heat shock protein adaptations but does upregulate oxidative enzyme activity in human skeletal muscle. Journal of Applied Physiology 2009;106(5):1513–21.

Protein amounts Table 10.7 lists the amount of protein in common serving sizes. The foods shown are not necessarily high in protein, or healthy; they are given as examples only. All amounts are approximate.

TABLE 10.7 The amount of protein in common serving sizes Food

Protein (g)

Almond bu=er 1 tbsp Almonds 33 g Anchovies (5) 20 g Bacon 2 slices, thick-style Baked beans 220 g, cooked Brown rice 1/2 cup, cooked Cashews 25 g, raw Chicken breast 100 g, cooked Co=age cheese 100 g Egg (1) 50 g, raw Egg whites (2) 70 g, raw Feta 28 g Fish 120 g, cooked Goats cheese 100 g, soft Greek yoghurt 150 g, full-fat Haloumi 30 g Kidney beans 175 g, cooked Lean beef or lamb 120 g, cooked Milk 250 mL, low-fat 2% Mozzarella 60 g Muesli 100 g, not toasted Muesli 100 g, toasted Oysters 50 g, raw Pine nuts 33 g Protein powder, 1 serve Quinoa 85 g, dry Rico=a cheese 246 g Rolled oats 100 g, raw Salmon 100 g, cooked Snapper/swordfish 85 g, cooked Soymilk 250 mL Sunflower seeds 33 g Tofu 100 g Tuna 100 g, tinned White rice ½ cup, cooked

2 6.6 5.8 10–12 20 2.3 4 20–25 15–18 5–6 7–8 4 20 18–19 11–12 6 6.7 25 11 11–12 11 9 6 4.3 20–25 12 28 11–14 25 21 7 7.6 12 25 2.1

Hydration and dehydration Dehydration can be a serious problem for athletes and affect their ability to perform. For every 1% of body weight lost via dehydration, blood volume decreases by 2.5%, muscle water decreases by 1% and the body's core temperature can increase by 0.4–0.5°C. Losses

equal to 2% of body mass are sufficient to cause a detectable decrease in performance and a risk of nausea, vomiting, diarrhoea and other gastrointestinal problems.[53] Table 10.8 outlines the signs and symptoms of dehydration.[54] TABLE 10.8 Signs and symptoms of dehydration Mild dehydration Dry lips and mouth Thirst Low urine output Moderate dehydration Thirst Very dry mouth Sunken eyes Tenting of skin when pinched with no bounce back Low or no urine output Severe dehydration – all signs of ‘Moderate’ plus Rapid and weak pulse Cold hands and feet Rapid breathing Blue lips Lethargic, comatose, seizures Requires immediate hospitalisation

Source: Meletis C. Dehydration: an imbalance of water and electrolytes. Water International 2002 27(3):456.

Compromises in exercise performance Many athletes are under the misconception that they can train their body to cope with dehydration. This is not the case and they would do well to prevent dehydration from occurring. When working with athletes it is important to explain the potential loss of performance that occurs when a person becomes dehydrated (see Table 10.9).[55–57] It is also important to enlighten athletes on the dangers of over-hydration and hyponatraemia. Individual fluid intake should be calculated and practised for appropriate temperatures and climates in order to safely prescribe the required volume of fluid replacement.

TABLE 10.9 How dehydration compromises exercise performance Dehydration may compromise exercise performance by causing the following: Increased perception of effort and decreased work capacity Increased risk of heat illness In a cold environment, cooling of core and limb temperature may lead to decreased performance Impaired skill and concentration Decline in cardiovascular and thermoregulatory function Reduced rate of fluid absorption from the intestines, making it difficult to rehydrate Thirst, irritability, dizziness, weakness, headache, chills, cramps, nausea, vomiting

Source: Murray R. Fluid needs in hot and cold environments. International Journal of Sport Nutrition 1995;5(s1):S62–73. Casa DJ, DeMartini JK, Bergeron MF, et al. National Athletic Trainers’ Association position statement: Exertional heat illnesses. Journal of Athletic Training 2015;50(9):986–1000.

Heat risks The temperature a person exercises in can greatly influence their sweat rate. Climates at or below 20–21°C have insignificant dehydration effects if the exercise is 90 minutes at this temperature can lead to dehydration of more than 2% and impair performance. In a hot climate such as 31°C, exercise >60 minutes in duration can significantly impair performance if fluids are not ingested.[58,59]

Sweat rate Factors that affect the sweat rate include:

• Genetics • Body size – larger athletes tend to have increased sweat rates • Fitness – fi=er people sweat earlier and in larger quantities • Environment – sweat losses are higher in heat and humidity • Intensity – sweat losses increase the harder a person exercises.

Maintaining adequate fluid intake Maintaining adequate fluid intake is vital for people undertaking sports, especially in hot environments such as Australia. The goal of drinking during exercise is to address the sweat losses that occur and to assist thermoregulation without drinking in excess of one's sweat

rate. Fluid deficits after training need to be replenished: ingestion of fluids with post-exercise meals will aid the retention of fluids due to the food's sodium content.[60] Athletes should aim to replace 150% of their post-exercise fluid deficit over the next 2–4 hours as fluid losses via urine and sweating will continue during the recovery period. Athletes can estimate their own fluid requirements[60] by weighing themselves before and after a 1-hour exercise session in different seasons, temperatures, sports, etc.: each kg of weight lost is equivalent to approximately 1 L of fluid loss. There is only a small error (∼10%) in this assumption.[58] Athletes cannot train their body to adapt to dehydration. It is important for athletes to practise their fluid intake during training to train their body for the intake of larger volumes.[57,61] An intake of 400–800 mL is a good starting point until the person knows their sweat rate.[59]

Fluid choices Which fluids should be consumed is an area of great debate within sports nutrition and especially in naturopathic medicine. The inclusion of bright artificial colours and highfructose corn syrup leaves many athletes and practitioners feeling very negative about sports drinks. However, the market now contains many drinks with more natural sugars as well as no colouring. The aim of sports drinks is to fuel an athlete with carbohydrate, electrolytes and water. There is a time and a place for their use, but unfortunately the general population is choosing them when they are not needed.

Sports drinks For increased absorption of fluids via the small intestines, the carbohydrate content of a sports drink should be 8% (8 g per 100 mL of fluid) or lower.[62] Drinks that contain higher than a 10% solution will inhibit absorption rates and decrease the amount of fuel ge=ing to the working muscles, potentially causing gastrointestinal disturbances. Research has shown[39] that glucose and maltodextrin saturate the intestinal transporters at 60 g/h but with the inclusion of fructose up to another 30 g can be consumed if needed (2 : 1 glucose to fructose ratio). This volume of carbohydrate may not be necessary or even tolerable for an athlete and they must trial the intake of carbohydrate that works for them while exercising. Sweat losses lead to a loss of electrolytes, with higher losses of sodium and chloride and smaller amounts of potassium, calcium and magnesium.[63] Sodium and other electrolytes are added to drinks and sports drinks to: encourage fluid intake by driving the thirst mechanism, increase fluid absorption and retention and assist with salt replacement for athletes in endurance events. Electrolyte capsules and water-dissolving (effervescent) tablets are available for those looking for electrolyte replacement without the added carbohydrate of sports drinks. Sports drinks are designed to be used during extended sporting events, when the need for fluids, electrolytes and carbohydrate is high. It is possible to consume other foods or gels and chews with plain water for the same outcome, but there are times when drinks are the

easiest, most portable form of fuelling. During endurance events and sports taking place in hot environments, such products can be invaluable. It is up to the practitioner's discretion and ultimately the athlete to choose what works for them and their specific sport's profile. Sodium needs may be quite high when competing in hot environments or endurance sports or when the individual is a high sweater. If an athlete consumes fluid without adequate sodium or consumes more fluid than their sweat rate, the issue of hyponatraemia becomes a real danger. Most sports drinks do not contain sufficient sodium to equal blood sodium levels as the taste would be a deterrent to ad lib ingestion. Caution and care need to be taken in certain endurance events with electrolyte ingestion, and specifically with sodium amounts. Extracellular sodium levels should remain between 130 and 160 mmol/L or issues of hyponatraemia can occur. This volume of sodium intake can be ingested through fluids, gels, foods and capsules. The sodium level in many sports drinks is 10–25 mmol/L – this is enough to stimulate the thirst mechanism and enhance fluid absorption but is insufficient to meet total sodium needs.[62] Higher sodium sports drinks (30–50 mmol/L) and gels may be of use if the taste can be tolerated.[64] The need for electrolyte or sodium tablets is dependent on the event being undertaken and the choice of food eaten during the event, as well as the sodium losses of the athlete. What to look for in a sports drink Look for the following in a sports drink:

• 4–8% carbohydrate (4–8 g carbohydrate per 100 mL) – the amount of carbohydrate will depend on what fuelling strategy is needed • 10–25 mmol/L sodium – aim for higher sodium levels if exercising in hot/humid environment or if known high sweating athlete • Broad spectrum of electrolytes • Affordable and tastes good. Table 10.10 outlines some ready-made sports drinks currently on the market.

TABLE 10.10 Sports drinks Drink

Carbohydrate (%)

Sodium (mmol/L)

Gatorade PowerAde Endura Staminade sport PB Cola Coconut water

6 8 6 7.5 6.8 11 3–4

18 12 14 14 25 Low Low

Homemade sports drinks Homemade sports drinks are becoming popular as people try to avoid high-fructose corn syrup and food colourings. They are not always as scientific in their recipes, especially with sodium content, but they are easy and very inexpensive to make. The internet has hundreds of examples, but the following basic recipe makes a 6% solution (6 g per 100 mL of fluid) Recipe for homemade sports drink

• 4 tbsp maple syrup • 1 L warm water • 450 mg sea salt Mix the ingredients together until the maple syrup and salt has dissolved. Alternatively, replace the maple syrup with one of the following:

• 4 tbsp honey or rice malt syrup • 60 g pure glucose • 450 mg sea salt • 500 mL of fruit juice plus 500 mL of water (although this much fructose could be hard on the stomach to absorb; and it is only 55 g of carbohydrate on average) • 2.5 tbsp glucose (40 g carbohydrate) plus 240 mL fruit juice (approximately 20 g of carbohydrate), a 2 : 1 glucose to fructose mix. Alternative fluids Coconut water has gained in popularity as a sports drink recently. It typically contains less carbohydrate and sodium than a standard sports drink but has no added food colourings. Research so far has not shown it to be more or less effective in rehydration than water or sports drinks, but neither has it been found to be worse.[65–67] If preferred as a drink post-

training, there is no problem with using coconut water, although it is potentially an expensive alternative to plain water. Furthermore, in an endurance event lasting a few hours or longer it would be insufficient to supply all the necessary carbohydrate and sodium. Some research has noted gastrointestinal upset with coconut water in certain individuals, as well as decreased intake due to taste, while other studies have found increased intake due to palatability and fewer stomach issues with fresh coconut water compared with commercial sports drinks or bo=led coconut water. Many fluids have been assessed for their ability to rehydrate after exercise in comparison to water. Recent research[68] has developed a beverage index for assessing a fluid's ability to rehydrate. Among the top performers are oral rehydration mix, orange juice, full-fat and skim milk and sports drink.

Carbohydrate content of foods and drinks When working with athletes and giving them macronutrient targets to aim for, it is very useful to get them to do the calculations themselves so that they learn about the volume of food they need to ingest. Smartphone apps are also a fantastic tool to empower patients and enable them to track their intake and energy expenditure. Table 10.11 lists the carbohydrate content of many fruits and vegetables as well as milk, milk alternatives and seeds/nuts. It does not contain grain or breads as these are previously covered in Table 10.5 or can be calculated from the back of the packaging. TABLE 10.11

Carbohydrate content of foods and drinks Vegetables

Volume

Avocado Asparagus Artichoke hearts Brussel sprouts Broccoli Beetroot Carrots Cauliflower Cabbage (raw) Capsicum Cherry tomato Cucumber Celery Chard (Swiss) Corn (sweet) Eggplant (cooked) Kale (raw) Kimchi Lentils (boiled)

½ cup ½ cup ½ cup ½ cup ½ cup ½ cup ½ cup ½ cup 1 cup ½ cup 5 pieces ¼ of 2 stalks 1 cup ½ cup ½ cup 1 cup 1 cup ¼ cup

Amount of carbohydrate (g) 115 g 90 g 85 g 80 g 80 g 85 g 80 g 50 g 70 g 75 g 85 g 75 g 80 g 36 g 82 g 50 g 67 g 150 g 50 g

10 4 10 6 5.5 8 5.8 2.6 4 3.5 3.3 2.7 2.4 1.6 20 4.3 6.7 6 10

Le=uce Mushrooms Onions (raw) Onions (red) Peas (sugar/snap) Pumpkin (cooked) Radicchio Radish Sauerkraut Seaweed (kelp) Seaweed (spirulina) Tofu Spinach (raw) Squash, bu=ernut (cooked) Sweet potato (cooked) Tomato (raw) Zucchini Fruits Apple Apricot (dried) Banana Blackberries Blueberries Cherries Cranberries (raw) Dates Figs (fresh) Grapefruit Grapes Grapes (raisins) Guava Kiwi fruit Lemon Mandarin orange Mango Melon Melon (water) Orange Papaya Passionfruit Peach Pear Pineapple Plum (large) Pomegranate Prunes (dried) Raspberries

1 cup 1 cup ½ cup ½ cup ½ cup ½ cup 1 cup 6 pieces ½ cup ½ cup ½ cup 1 cup ½ cup ½ cup 1 piece ½ cup Volume 1 piece ¼ cup 1 medium ½ cup ½ cup ½ cup ½ cup ¼ cup 2 pieces ½ cup ½ cup ¼ cup 1 piece 1 piece 1 piece 1 medium ½ cup ½ cup ½ cup 1 piece ½ cup 1 piece 1 medium 1 piece ½ cup 1 piece 1 piece 2 pieces ½ cup

55 g 85 g 80 g 60 g 32 g 125 g 40 g 30 g 118 g 40 g 8g 90 g 30 g 100 g 100 g 125 g 90 g 135 g 33 g 115 g 75 g 75 g 75 g 55 g 45 g 100 g 115 g 75 g 40 g 55 g 75 g 110 g 88 g 85 g 85 g 75 g 130 g 70 g 18 g 150 g 150 g 78 g 66 g 155 g 17 g 62 g

1.5 2.8 7.5 5.8 2.4 6 1.8 1 5.1 3.8 1.8 2.2 1.1 11 20 4.8 4 Amount of carbohydrate (g) 10 20 25 8 9.5 10 6.7 33.5 19 12.2 14 32.5 8 11 11 11 14 6 5.7 15 7 4.2 14.3 20 10 7.5 26 10.7 7.3

Strawberries Tangerine Seeds and nuts Almonds Almond bu=er Brazil nuts Cashews Cashew bu=er Flax/linseed Hazelnuts Macadamias Peanuts Pecans Pine nuts Pistachios Pumpkin seeds / pepitas Sesame seeds Sesame bu=er / tahini Sunflower seeds Sunflower seed bu=er Walnuts Milks Cows milk Lactose-free milk Rice milk Soy milk Coconut milk Almond milk Cashew milk

½ cup 1 piece Volume ¼ cup 1 Tbs ¼ cup ¼ cup 1 Tbs ¼ cup ¼ cup ¼ cup avoid ¼ cup 1 Tbs ¼ cup ¼ cup 3 Tbs 1 Tbs 1 Tbs 1 Tbs ¼ cup Volume 1 cup 1 cup 1 cup 1 cup 1 cup 1 cup 1 cup

72 g 88 g 35 g 16 g 35 g 35 g 16 g 45 g 30 g 35 g 27 g 9g 30 g 57 g 10 g 15 g 8g 16 g 30 g 245 mL 245 mL 240 mL 240 mL 240 mL 240 mL 240 mL

5.5 11.7 Amount of carbohydrate (g) 6 3.5 4.3 11 4.5 12.3 5.2 4.5 3.8 1 8.5 7.6 2.4 3.2 1.8 4.4 4 Amount of carbohydrate (g) 12 12 25 14 7 8 9

Fuelling for competitions and race day The precise nutritional needs of each sport during competitions or race days vary greatly depending on many factors, including the duration of the sport and whether there are multiple heats or games in one day. This chapter introduces the basic principles of eating for exercise, as an in-depth description of competition nutrition is beyond the scope of this textbook. The Australian Institute of Sport (AIS) and Sports Dietitians Australia both have indepth handouts that focus on individual sports' needs during competitions or race day: see www.ausport.gov.au/ais/nutrition and www.sportsdietitians.com.au/factsheets. The case studies provided at the end of this chapter cover both training nutrition and race day needs in an a=empt to demonstrate the use of sports nutrition on competition days. One case covers endurance sport and the other covers a competition day for a competitive swimmer.

Drugs in sport

Within the sporting arena, whether athletes are competing at a professional or Olympic level, routine drug testing occurs. It is an unfortunate part of sport that some competitors choose to take illegal and banned substances in order to enhance their performance. If an athlete tests positive, they can be banned for 2 years or face up to a life-time ban. Within the banned list are not only drugs but also certain methods of doping, medications and herbal substances. The World Anti-Doping Agency (WADA) is responsible for the World Anti-Doping Code and publishes a document aiming to harmonise regulations on doping in all sports and countries. Within Australia the Australian Sports Anti-Doping Authority (ASADA) governs sports and regulations regarding such ma=ers. Education and information are available to athletes, with yearly updates on both organisations’ websites. It is up to individual athletes to make themselves aware of all the rules and regulations: failure to do so has severe penalties. The volume and variety of supplements available via pharmacies, health-food stores, practitioners and the internet is astounding. The assurance of quality within a product is under the regulation of each country's ‘code’ of manufacturing and this leaves athletes at risk of an accidental ‘positive’ result if a product contains banned substances. Naturopathic practitioners must be aware of these guidelines and regulations. In Australia, manufacturing of supplements falls under the jurisdiction of the Therapeutic Goods Administration (TGA). Australia has very strict rules and testing procedures but this is by no means a guarantee of no prohibited substances. Neither the TGA nor Australian supplement companies can give a guarantee of product. Third-party independent testing companies are available to test batches of product for prohibited substances and an athlete and their practitioner would be advised to only use products that have been through such a process. The assumption that a product is ‘clean’ because it contains no banned substances is a very dangerous a=itude to take. Cross-contamination within manufacturing can occur and lead to an accidental ‘positive’. Other companies may knowingly place banned substances into products yet fail to disclose all ingredients. Geyer and colleagues purchased and analysed 634 supplements from 215 suppliers in 13 countries and found that 94 supplements (15%) contained banned substances.[69] The AIS and ASADA have lists of banned substances on their websites. The AIS has created the AIS Sports Supplement Framework to educate athletes regarding the ranking of sports foods and supplements for scientific evidence, safety, legality and potential for improving sports performance. The AIS’ ABCD classification system outlined in Table 10.12 is for sports foods and individual ingredients rather than specific supplements and brands. [70]

TABLE 10.12

The AIS ABCD classification system for sports foods and supplement ingredients Group A Overview of category Sub-categories Evidence level Sports foods – specialised products used to provide a Supported for use practical source of nutrients when it is impractical to

Examples Sports drink Sports gel

in specific situations in sport using evidencebased protocols. Use within supplement programs Provided or permi=ed for use by some athletes according to best practice protocols.

Group B Overview of category Evidence level Deserving of further research and could be considered for provision to athletes under a research protocol or case-managed monitoring situation. Use within supplement programs Provided to athletes within research or clinical monitoring situations.

consume everyday foods.

Medical supplements – used to treat clinical issues, including diagnosed nutrient deficiencies. Requires individual dispensing and supervision by appropriate sports medicine/science practitioner Performance supplements – used to directly contribute to optimal performance. Should be used in individualised protocols under the direction of an appropriate sports medicine/science practitioner. While there may be a general evidence base for these products, additional research may often be required to fine-tune protocols for individualised and event-specific use.

Sports confectionery Liquid meal Whey protein Sports bar Electrolyte replacement Iron supplement Calcium supplement Multivitamin/mineral Vitamin D Probiotics (gut/immune) Caffeine B-alanine Bicarbonate Beetroot juice Creatine

Sub-categories Examples Food polyphenols – food chemicals that have purported Quercetin bioactivity, including antioxidant and anti-inflammatory Tart cherry juice activity. May be consumed in food form or as isolated Exotic berries (acai, goji chemical.Other etc.) Curcumin Antioxidants C and E Carnitine HMB Glutamine Fish oils Glucosamine

Group C Overview of category Sub-categories Examples Evidence level Category A and B products used outside approved See list for Category A Have li=le protocols. and B products. meaningful proof The rest – if you can't find an ingredient or product Fact sheets and research of beneficial in Groups A, B or D, it probably deserves to be here. summaries on some effects. supplements of interest Note that the Framework will no longer name Group Use within that belong in Group C C supplements or supplement ingredients in this supplement may be found on the ‘A–Z top-line layer of information. This will avoid the programs of Supplements’ page in

Not provided to athletes within supplement programs. May be permi=ed for individualised use by an athlete where there is specific approval from (or reporting to) a sports supplement panel.

perception that these supplements are special.

Group D Overview of category Sub-categories use within AIS system Evidence level Stimulants Banned or at high h=p://list.wada-ama.org risk of contamination with substances that could lead to a positive drug Prohormones and hormone boosters test. h=p://list.wada-ama.org Use within supplement programs Should not be used by athletes. GH releasers and ‘peptides’ h=p://list.wada-ama.org Technically, while these are sometimes sold as supplements (or have been described as such) they are usually unapproved pharmaceutical products. Other h=p://list.wada-ama.org

the AIS Sports Nutrition section of the ASC website.

Examples

Ephedrine Strychnine Sibutramine Methylhexanamine (DMAA) Other herbal stimulants DHEA Androstenedione 19-norandrostenione/ol Other prohormones Tribulus terrestris and other testosterone boosters Maca root powder

Glycerol used for re/hyperhydration strategies – banned as a plasma expander Colostrum – not recommended by WADA due to the inclusion of growth factors in its composition

Source: Australian Sports Commission. ABCD Classification; 2016 [Cited 19 December 2016. Available from www.ausport.gov.au/ais/nutrition/supplements/classification.]

Evidence-based supplements The American College of Sports Medicine's joint position statement on nutrition and athletic performance contains a table of dietary supplements and sports foods with evidence-based uses in sports nutrition (see Table 10.13). This table is not exhaustive: many nutrients that are not on the list may have benefit but research is not significant enough or may show both negative and positive effects and thus is not included. An example is vitamins C and E being nutrients that in high doses have been found to reduce indices of oxidative damage but have also been shown to have detrimental effects on the adaptive and recovery processes of exercise as they can interfere with the signalling functions of reactive oxygen species.[71] Sousa and colleagues[72] have wri=en a comprehensive review on dietary strategies for reducing exercise-induced muscle damage looking at both wholefoods and specific nutrients. The evidence behind certain complementary medicines may be strong but it is not specific for sports performance. Thus practitioners need to use their knowledge and understanding of human physiology and biochemistry to assist athletes and those undertaking sports to enhance their health in a holistic manner. TABLE 10.13

Dietary supplements and sports foods with evidence-based uses in sports nutrition Category

Example

Sports food

Sports drinks Sports confectionery Sports gels Electrolyte supplements Protein supplements Liquid meal supplements Medical Iron supplements supplements Calcium supplements Vitamin D supplements Multi-vitamin/mineral Omega-3 fa=y acids Specific Ergogenic effects performance Creatine

Improves performance of repeated bouts of high-intensity exercise with short recovery periods

Use Practical choice to meet sports nutritional goals especially when access to food, opportunities to consume nutrients or gastrointestinal concerns make it difficult to consume traditional food and beverages Prevention or treatment of nutrient deficiency under the supervision of appropriate medical/nutritional expert

Concern Cost is greater than whole foods May be used unnecessarily or in inappropriate protocols

May be self-prescribed unnecessarily without appropriate supervision or monitoring

Evidence Burke & Cato (2015)

Burke & Cato (2015)

Physiological Concerns regarding Evidence effects/mechanism of ergogenic effect Increases Creatine and Associated with Tarnopolsky Phosphocreatine acute weight gain (2010) concentrations (0.6–1 kg) which may May also have other be in weight effects such as sensitive sports enhancement of glycogen May cause

- Direct effect on competition performance - Enhanced capacity for training

storage and direct effect on muscle protein

Caffeine

Reduces perception of fatigue Allows exercise to be sustained at optimal intensity/output for longer

Adenosine antagonist with effects on many body targets including central nervous system Promotes Ca2+ release from sarcoplasmic reticulum

Sodium bicarbonate

Improves performance of events that would otherwise be limited by acid– base disturbances associated with high rates of anaerobic glycolysis - High intensity events of 1–7 minutes - Repeated highintensity sprints - Capacity for high-intensity ‘sprint’ during endurance exercise

Beta-alanine

Improves performance of events that would otherwise be limited by acid– base disturbances

gastrointestinal problems Some products may not contain appropriate amounts of creatine

Causes side effects Astorino & (tremor, anxiety, Roberson increased heart rate, (2010) etc.) when consumed Tarnopolsky in very high doses (2010) Rules of National Burke et al. Collegiate Athletic (2013) Association competition prohibit the intake of large doses that produce urinary caffeine levels exceeding 15 micrograms/mL Some products do not disclose caffeine dose or may contain other stimulants When taken as an acute dose May cause Carr et al. (2011) pre-exercise, increases gastrointestinal side extracellular buffering effects which cause capacity performance impairment rather than benefit

When taken in a chronic protocol, achieves increase in muscle carnosine (intracellular buffer)

Some products with rapid absorption may cause paraesthesia (tingling sensation)

Quesnele et al. (2014)

Nitrate

associated with high rates of anaerobic glycolysis - Mostly targeted at high-intensity exercise lasting 60– 240 seconds - May enhance training capacity Improves exercise tolerance and economy Improves performance in endurance exercise at least in non-elite athletes

Increases plasma nitrite concentrations to increase production of nitric oxide with various vascular and metabolic effects that reduces O2 cost of exercise

Consumption in Jones (2014) concentrated food sources (e.g. beetroot juice) may cause gut discomfort and discolouration of urine Efficacy seems less clear cut in highcalibre athletes

Source: [108–115]

Evidence-based, non-sports specific supplements The information in Table 10.14 is specifically for those athletes competing at the higher levels of sport: the use of nutritional supplements and herbal medicine for non-drug tested athletes is not an issue. The use of complementary medicine to enhance general wellbeing, support the body while under stress, correct nutritional deficiencies and support the immune and musculoskeletal system are areas that naturopaths are well educated in.

TABLE 10.14

Evidence-based functional foods Functional food

Justification/action

Tart cherry juice

Facilitates recovery by modulating inflammation [73–79] and/or oxidative stress; reduces some markers of muscle damage including muscle pain and soreness Antioxidant, anti-inflammatory, decreases pain, [80,81] decreases oedema, increases nitric oxide Immune and digestive system support, decreased [82–84] incidence of illness (URTI) and decreased illness duration For a review of some of these foods in relation to exercise-induced muscle damage, see the article by Sousa and colleagues.[72] Comprehensive reviews on many foods and supplements can be found at www.examine.com.[85]

Turmeric/curcumin Probiotics

Other foods of interest: berries, blueberries, green tea, pomegranate, spirulina, mushrooms (beta-glucans) and bromelain (pineapple), pickle juice, ginger and bi=er tonics

Evidence

However, the application of naturopathic principles to the domain of sports nutrition is a newer concept. The ability of naturopaths to look at athletes from a holistic perspective gives athletes a further area of support beyond macronutrient-based sports nutrition guidelines. The ability to go beyond dietary interventions and support the body's systems with herbal medicine and nutrients enables a more holistic treatment of athletes and their needs.

Nutrients and foods Proper nutrition is vital for sports performance. As training loads increase, so too do the demands on the body for many nutrients. There is a growing body of evidence for the use of functional foods and nutritional supplements for athletes. Funding for research in this area is on the increase as science looks to natural foods and nutrients to support energy demands and overall health. Table 10.15 contains a general list of nutrients that may benefit individuals undertaking exercise; this is not an evidence-based list specific to athletes (that can be found in Table 10.14 above). It also contains the RDI (recommended dietary intake) for each nutrient.[86] Athletes’ needs may be higher, especially during times of large-volume training, but foods should always be the focus first, with supplements used when there is a dietary shortfall or when an injury or illness potentially increases needs. TABLE 10.15

Nutrients Nutrient

Justification

RDI

Alpha lipoic Blood sugar regulation No RDI available acid Bioflavonoids Enhances the absorption of vitamin C; helps No RDI available maintain the health of small blood vessel

Dietary source Red meat, liver, heart, kidney Citrus fruits, buckwheat, vegetables

Calcium

Chromium

walls Bone health; muscle contraction; nerve impulse transmission

1000–1300 mg/day

Component of glucose tolerance factor, required for blood sugar regulation, glucose and fat metabolism Minimises oxidative damage; necessary for cellular metabolic processes and ATP production The most prevalent amino acid in muscles, important in maintaining immune function; a key nutrient for the health of the intestines and digestive tract integrity

25–35 micrograms/day

Iodine

Healthy thyroid function

150 micrograms/day

Iron

Involved in transportation and storage of 8–18 mg/day oxygen in the body and in the creation of energy; involved in general growth, reproduction, healing and the immune system; indicated in anaemia Essential for hundreds of enzymatic 310–420 mg/day reactions in the body, the burning of glucose for fuel and for muscle contractions; assists in carbohydrate and fat metabolism, DNA and protein synthesis, active transport of ions across cell membranes Antioxidant (reactive scavenging species) No RDI available

Coenzyme Q10 Glutamine

Magnesium

N-acetylcysteine (NAC) Omega-3 fa=y acids

Precursor to eicosanoids; anti-inflammatory and cell wall integrity

No RDI available

No RDI available

90–160 mg/day (DHA + EPA + DPA) 2800–3800 mg/day adequate intake (AI) as no RDI available

Potassium

Maintains fluid balance; principal cation of intracellular fluid; involved with nerve impulse transmission

Probiotics

Help strengthen digestive tract health and support immune system, potentially reducing the incidence of some illnesses

Strain dependent; multi-strains are advisable

Quercetin and other plant polyphenols

Antioxidant, anti-inflammatory, antipathogenic

No RDI available

Almonds, dairy, figs, small fish with edible bones, tahini, sesame seeds, molasses, tofu, green leafy vegetables Apples, asparagus, oysters, prunes, cheese, meat, broccoli, apples, bananas Almonds, broccoli, mackerel, sardines, salmon, sesame seeds Beans, legumes, co=age cheese, ham, most protein sources, rico=a cheese, rolled oats, whey protein and products Iodised salt, seaweed, seafood Red meat, apricots, oysters, sunflower seeds, pumpkin seeds, pine nuts, spinach, molasses, kidney beans Green leafy vegetables, cocoa, almonds, brewer's yeast, cashews, kelp, wheat bran, wheatgerm, buckwheat, nuts and seeds Supplement only

Salmon, sardines, trout, herring, mackerel Vegetables, sardines, avocados, bananas, dates, citrus fruits, yams, squash, Swiss chard, artichokes, spinach, tomatoes Yoghurt, miso soup, sauerkraut, kefir, kombucha, pickles, tempeh, kimchi Cocoa, apples, pears, pomegranates, citrus fruits, red grapes, green leafy vegetables, red wine, green

tea Silica

Repair of scar tissue; reduction of adhesion formation

No RDI available

Sodium

Assists in absorption of glucose, amino acids and water; regulator of extracellular fluid status; involved with electrochemical gradient; important for nerve cell transition, muscle contraction and heart function

Vitamin A

Involved in supporting normal immune system function; antioxidant; involved in synthesis of proteins and red blood cell development

460–920 mg/day Western diet likely ample, may need supplementation in some endurance and ultra-endurance events (see case study 1) 700–900 micrograms/day

Vitamin B1

Co-enzyme in the body with essential roles in metabolism and ATP production; synthesis in DNA and RNA

(thiamine)

Vitamin B2 (riboflavin)

Vitamin B3 (niacin)

Vitamin B5 (pantothenic acid) Vitamin B6 (pyridoxine)

Vitamin B9 (folic acid) Vitamin B12

Vitamin C

1.1–1.2 mg/day

Co-factor within numerous enzyme systems 1.1–1.3 mg/day within the body; red blood cell production; part of the electron transporter FAD Required for energy production (part of electron transporter NAD); involved in the synthesis of certain hormones (e.g. oestrogen, progesterone and testosterone); assists in DNA repair

14–16 mg/day

Required for steroid hormone, cholesterol 4–6 mg/day and neurotransmi=er production, formation of acetyl-CoA Helps in the creation of neurotransmi=ers and steroid hormones; supports nervous and immune systems

1.3–1.5 mg/day

Co-enzyme in the metabolism of amino and 400 micrograms/day nucleic acids; assists in red blood cell creation Enzyme co-factor in creating and 2.4 micrograms/day maintaining nerve and red blood cells and DNA synthesis Antioxidant, immune stimulant 45 mg/day

Barley, oats, wholegrain cereals, root vegetables, horsetail tea Table salt, wholegrains, vegetables, meats, legumes, nuts and seeds, sports drinks, many packaged foods

Kohlrabi; egg yolk; carrots; apricots; cod and salmon liver oil; green leafy vegetables; red, yellow and orange fruits and vegetables Legumes, wheatgerm, wholegrains, nuts, asparagus, le=uce, mushrooms, lentils Avocados, beans, sprouts, broccoli, eggs, milk, mushrooms, asparagus, green leafy vegetables Almonds, chicken, eggs, legumes, salmon, sardines, tuna, asparagus, mushrooms, halibut, sea vegetables such as kelp and wakame, lentils and lima beans Avocados, egg yolk, sweet potato, green vegetables, cauliflower, broccoli, mushrooms Chicken, egg yolk, legumes, salmon, tuna, walnuts, beans, oats, potato, bananas, hazelnuts Leafy green vegetables, lentils, eggs, beans, citrus and wholegrains Salmon, sardines, egg yolk, oysters, trout, beef, yoghurt, tuna, fermented foods Blackcurrants, kiwi fruits,

Vitamin D3

Key role in immunity and bone health

Vitamin E

Antioxidant; helps support the immune system; aids to protect cells from damage

Zinc

Involved in muscle growth; vital for the immune system and hormone creation; role in the structure of proteins and cell walls (membranes), regulation of gene expression, cell signalling and nerve impulse transmission

5–10.0 micrograms /day 7–10 mg/day (natural mixed forms) 8–14 mg/day

mangoes, guava, rosehips, strawberries, parsley, citrus fruits Fish liver oils, egg yolk, sprouted seeds, milk Almonds, wheatgerm, safflower, egg yolks, corn, beef, nuts Beef, baked beans, wholegrains, oysters, pumpkin seeds, cashews, sunflower seeds, sesame seeds, wild game, poultry

Source: ww.nrv.gov.au/nutrients

Herbal medicines An array of herbal medicines can be used to support the body while undertaking large volumes of exercise. Their application should follow traditional naturopathic concepts of treating and supporting the whole person. Many classes of herbs shown in Table 10.16 are given for general support or are indicated in acute situations where athletes undertake high volumes of training that are exhausting, leading to overtraining and immune suppression.[87] When applying support with herbal medicine, practitioners should view each athlete, their sport, training volume, previous medical history, current medications, stress levels, and so on. TABLE 10.16

Herbal medicine classes Potential holistic application to sport

Specific herbal medicine classes

Action

Examples

Adaptogen

Increases resistance to High-volume training, • Panax ginseng physical, environmental, overtraining and exhaustion (Korean emotional or biological ginseng) stress; assists the body in • Eleutherococcus adapting at heightened senticosus times of stress (Siberian ginseng) • Panax quinquefolius (American ginseng) • Astragalus membranaceus (Astragalus)

Adrenal tonic

Aids in nourishing and renewing the adrenal gland, where there has been stress leading to exhaustion and debility

Anodyne/analgesic

Used to relieve pain

Antibacterial/antiviral/antimicrobial Destroys or inhibits bacterial or viral growth

Anti-inflammatory

Reduces the response to

• Rhodiola rosea (Rhodiola) • Schisandra chinensis (Schisandra) • Withania somnifera (Ashwagandha) • Codonopsis pilosula (Codonopsis) • Bacopa monnieri (Bacopa/Brahmi) • Lentinula edodes (Shiitake) High-volume training; • Glycyrrhiza adrenal support glabra (Liquorice) • Withania somnifera (Ashwagandha) • Rehmannia glutinosa (Rehmannia) Assists in pain relief from • Corydalis training and delayed-onset ambigua muscle soreness (Corydalis) • Curcuma longa (Turmeric) Athletes with immunity • Echinacea spp. issues; increased incidence (Echinacea) of upper respiratory tract • Sambucus nigra infections; supports the (Elder) immune system while under • Hydrastis heavy training load canadensis (Golden seal) • Glycyrrhiza glabra (Liquorice) • Berberis vulgaris (Barberry) • Allium sativum (Garlic) • Astragalus membranaceus (Astragalus) • Hypericum perforatum (St John's wort) Assists the body during • Curcuma longa

(musculoskeletal)

Antioxidant

Antispasmodic (muscles)

Bi=er tonic

Blood sugar modulator/regulator

injury, infection or irritation

inflammation caused by injury and training

(Turmeric) • Zingiber officinale (Ginger) • Rehmannia glutinosa (Rehmannia) • Centella asiatica (Gotu kola) • Salix alba (White willow) Protects the body from Oxidative damage due to • Schisandra oxidative damage and is training load chinensis a potential free radical (Schisandra) scavenger • Rhodiola rosea (Rhodiola) • Curcuma longa (Turmeric) • Rosmarinus officinalis (Rosemary) • Olea Europa (Olive leaf) Reduces muscular Injury and spasm due to • Chamomilla cramping, spasm or training and racing recutita tension (Chamomile) • Coleus forskohlii (Coleus) • Glycyrrhiza glabra (Liquorice) • Viburnum opulus (Cramp bark) • Mentha x piperita (Peppermint) • Corydalis ambigua (Corydalis) Promotes appetite, Increases appetite when • Gentiana lutea digestion and absorption suppressed due to heavy (Gentian) of nutrients training load and exhaustion • Andrographis paniculata (Andrographis) • Cynara scolymus (Globe artichoke) • Picrorhiza kurroa (Picrorhiza) Assists to regulate the Assists in general health and • Codonopsis concentration of blood blood sugar regulation, pilosula

Connective tissue regenerator

Energy production

Immunomodulator/stimulant

Lymphatic

Nervine tonic

glucose

weight maintenance

(Codonopsis) • Gymnema sylvestre (Gymnema) • Cinnamomum zeylanicum (Cinnamon) • Glycyrrhiza glabra (Liquorice)

Assists to regenerate tissues that provide support and structure in the body Assists in energy production

Assists in healing and injury • Centella Asiatica from sport (Gotu kola)

Assists in energy production • Eleutherococcus and wellbeing senticosus (Siberian ginseng) • Panax ginseng (Korean ginseng) • Rhodiola rosea (Rhodiola) Assists, enhances or Supports immune system • Echinacea spp. modifies immune under heavy training load (Echinacea) functions and regulation • Astragalus membranaceus (Astragalus) • Cordyceps militaris (Cordyceps) Improves the flow of Supports immune system • Galium aparine lymphatic fluid or and recovery with increased (Cleavers) drainage lymphatic flow • Phytolacca decandra (Poke root) • Calendula officinalis (Calendula) Nourishes and Supports holistically for • Melissa officinalis strengthens the nervous exhausted and stressed (Lemon balm) system and its function; athletes; increases relaxation • Scutellaria can have a relaxant effect to assist in sleep and lateriflora on the body recovery (Skullcap) • Verbena officinalis (Vervain) • Leonurus cardiaca

Sleep enhancement, hypnotic/sedative

Assists the body and nervous system in relaxing and higher quality sleep

(Motherwort) • Avena sativa (Oats) • Bacopa monnieri (Bacopa/Brahmi) • Hypericum perforatum (St John's wort) • Zizyphus spinosa (Zizyphus) • Passiflora incarnata (Passionflower) • Withania somnifera (Ashwagandha) Assists the body in recovery • Chamomilla from training; supports recutita healthy immune system and (Chamomile) weight management via • Scutellaria enhancing sleep; potentially lateriflora decreases stress levels (Skullcap) • Eschscholzia californica (California poppy) • Lavandula angustifolia (Lavender) • Passiflora incarnata (Passionflower) • Piscidia erythrina (Jamaican dogwood) • Valeriana officinalis (Valerian) • Zizyphus spinosa (Zizyphus)

Specific herbal medicines and sports performance The term ‘adaptogen’ is applied to a classification of herbs containing phytonutrients that assist in the regulation of metabolism when the body is under physical or mental stress. They help the body adapt by (a) normalising system functions, (b) developing resistance to future such stress and (c) elevating the body's functioning to a higher level of performance.[88,89] The use of adaptogens to support the wellbeing of athletes is an area where naturopathic

practitioners can greatly assist their patients. Supporting the body in times of stress, from both daily life and training, can have a large impact on an individual's health and wellbeing. There is varied research as to the use of the following adaptogens with athletes and this is an area of future investigation that should be undertaken with well-designed trials to bring these ancient herbs into the 21st century of evidence-based complementary medicine. Korean ginseng Korean ginseng has been investigated for its adaptogenic and stress-a=enuating activity. It has been shown to enhance cognitive performance in healthy young adults[90,91] but review of data by Bucci[92] showed the effect of ginseng on human exercise performance to be doseand duration-of-supplementation-sensitive. In chronic use it is believed to improve cardiorespiratory function and lower lactate concentrations in the blood, as well as improving physical performance. Its effects were more noted for those in a poor physical condition.[93] Chen and colleagues[94] suggest future studies take into consideration number of participants, longer length of trial and dosage to be=er substantiate the ergogenic effects of Korean ginseng on humans and exercise performance. Siberian ginseng Siberian ginseng is a herb with long traditional use as an adaptogen and to combat fatigue and exhaustion. Recent research that examined the impact of an 8-week intake of the herb found that it enhances endurance capacity, elevates cardiovascular function and has a metabolic glycogen-sparing effect in recreationally trained athletes.[95] Much of the research on Siberian ginseng is from Russia and is either unavailable or dated, although substantial in its claims and participant numbers. Goulet and Dionne[96] reviewed the literature on Siberian ginseng and found the methodology in many trials to be weak. Eschback and colleagues[97] produced no significant results from their trial but supplementation was only administered for one week prior to testing. Traditional use of Siberian ginseng is much longer in its administration and it is typically used at times of debility, exhaustion and convalescence. Further research would be of interest with well-controlled methodology, traditional dosages and length of administration. Rhodiola Rhodiola has robust traditional and pharmacological evidence of use in fatigue and potential emerging evidence for cognition and mood enhancement.[98] Research has demonstrated a decrease in fatigue and an increased perception of wellbeing as related to life stress.[99] Further studies have shown a decrease in C-reactive protein and creatine kinase levels in exhaustive exercise,[100,101] thus having potential application in decreasing muscle damage from physical activity. Rhodiola appears to be able to reduce the effects of physical exhaustion and fatigue experienced from life stress and low-intensity exercise.[102] Ashwagandha

Traditionally ashwagandha has been used as a tonic and adaptogen in Ayurvedic medicine for supporting those with general debility, nervous exhaustion, muscular fatigue and memory and sleep issues. It has been shown to relieve insomnia and stress-induced depression,[103] which could potentially aid athletes if they fall into overtraining issues where stress and sleeplessness become a concern. It has also been shown to reduce cortisol levels and thus assist in the immunosuppression that occurs with high stress.[104] It can assist both sedentary and athletic populations by improving physical performance and memory.[105] Wankhede[106] recently found that supplementation is associated with significant increases in muscle mass and strength, and suggests it has potential to be used alongside strength training.

Working with sports clients Sportspeople are some of the most positive patients to work with. Their a=itude, motivation and willingness to take on large-scale changes to diet and lifestyle are impressive. It is common to be working with such people to reach optimum health rather than dealing with chronic disease and long-term poor health habits. They can be fast to adopt changes suggested and at times may even need to be slowed down in their optimism for overhauling their entire food intake. Practitioners working with athletes who already have a good standard of health with no underlying issues may only need two or three appointments as the practitioner takes on more of an education role regarding sports nutrition principles and practices. The harder aspects of working with sportspeople comes in the form of a singular focus leaning towards obsessiveness around food choices, weight, body fat and training schedules. They can be motivated but at the same time want results very quickly, and at times the human body doesn't heal as quickly as they want it to. Teaching moderation and passive recovery in the form of good sleep hygiene, rest days when unwell and relaxing their eating regimen at times can be difficult. The media and internet are great sources of information for many athletes and practitioners may have to ‘retrain’ patients into a more evidence-based approach to food and health that may be contradictory to what they have read on the internet or learned from their training partners. One of the largest hurdles in working with athletes and those undertaking high volumes of training is to teach them to rest and take time off from their training when they are unwell. Many athletes have a fear of losing fitness or muscle mass or not being ready for an upcoming race or event. Practitioners need to explain the dangers of further immune stress and that taking a few days off to let the body recover may be far less intrusive to a training schedule than trying to train through an illness and prolonging ultimate recovery. The idea of nourishing the body and supporting its inherent needs is a concept that many hyperfocused athletes find hard to incorporate into their fitness and health regimens.

Application of scientific and naturopathic principles

Understanding the science and principles of sports nutrition is one thing, but learning how to apply them with patients is another. What needs to be taken into consideration and how should research be used? What is the evidence-based science and on whom was research done? Is the research applicable to the patient and their level of sport participation and fitness? After using the applicable research, what individual things need to be considered with the specific person? Practitioners must be aware of and educated in differentiating between clearly evidence-based research and media hype and testimonials by elite athletes or well-wri=en marketing hype by companies. Athlete endorsements are not proof that a certain diet or supplement works: the latest ‘fad diet’ can be just that, a fad and not an evidence-based nutritional approach. Evidence-based sports nutrition should always be the foundation for patient treatment protocols, and then individual variation and the application of naturopathic principles can be brought in to complement the case in hand. Athletes are not just their sport – the rest of their stress and lifestyle will have a dynamic influence on their health and this needs to be assessed and treated.

Case taking Things to consider about a sports patient that may be different from a non-athlete patient include the following:

• Are they an elite/professional athlete who will be drug tested and thus giving anything more than food and diet suggestions takes on a much larger consideration? • Are they a serious competitor, trying to qualify for Masters or world championships within their age group, or are they a weekend warrior just out having fun? • What is their general fitness routine, training schedule, racing schedule or competition season? • Is there a clear understanding by both practitioner and patient of the metabolic profile and demands of the sport being undertaken? • Is there a need for training nutrition and a separate protocol for race day nutrition? These questions do not form part of the regular case history and questions asked in a naturopathic consultation. Understanding the individual and their sport is of utmost importance before an evidence-based protocol of sports nutrition can be suggested.

Food diary A seven-day food, fluid and training diary undertaken by the patient before the first

appointment can be vital in helping the practitioner to understand the patient's needs. However, not all people are motivated to keep a food diary and there are multiple ways to assess a person's intake of food and fluids. Nutrition apps for smartphones, taking photos of foods eaten and simply keeping a paper journal diary can all be used. A food, fluid and training diary gives great insight into the patient's general habits, snacking routine, food likes and dislikes, and intake of supplements, powders, gels and bars, as well as presenting the practitioner with a foundation of food intake to build on rather than suggesting a completely different diet from what the person normally eats. The less change the practitioner suggests, the more likely the person will be able to follow the new protocol. The diary also provides information on the person's training schedule, length of training sessions, types of exercise undertaken and hydration habits (or lack thereof). In addition, a well-planned diary can be constructed to chart the person's digestive function, bowel movements, emotional state at the time of eating and stress levels. The following should be considered when undertaking a food, fluid and training diary:

• It is important to record the exact time of food and fluid intake for the entire day (e.g. 7.30 am, not ‘breakfast’), as there is a need to understand what foods and fluids are consumed before, during and after training • The length of the training session, the time of day it occurred and the type of exercise need to be considered in order to construct a meal plan that fits into the patient's lifestyle and habits • The food and fluids taken during training sessions will give a clear understanding of the patient's habits in fuelling, over-fuelling or underfuelling their training sessions • Single or double training sessions per day will make a big difference to kilojoule and carbohydrate needs, and post-training fuelling will become more important in order to replenish glycogen stores for the second session of the day unless ‘training low’ is being implemented. Issues to consider when assessing a food diary include the following:

• Is there adequate protein at each meal and snacks for the training volume undertaken? • Is the patient eating at the appropriate time post-training and with the right volume of carbohydrates and protein for their individual needs? • Is the patient hi=ing their carbohydrate targets each day or eating their carbohydrates at the appropriate meals if they are ‘training low’?

• Is the patient over-focusing on the li=le things and missing the big picture of food intake and general health? • How is the patient's hydration intake? Is it adequate and at the correct time for training? • When the patient is craving or eating sweets, is it a mental or a physical craving? Are they eating at appropriate times in order to avoid blood sugar lows that may trigger sweet cravings? • Is the patient taking too many supplements in order to enhance performance and not focusing on the basics of good sports nutrition? Where do they need supplement support and what can be done using a food first protocol? • Does the patient follow good meal preparation and planning or are they short of time, defaulting to unhealthy choices because of lack of availability? If so, what can be done about this, such as weekly meal planning, shopping and preparation, or home delivery of groceries or pre-made meals? • Does the patient know what healthy snacks can be found at supermarkets and convenience stores if they get caught short rather than skipping meals or making poor choices?

Systems review Sports patients may arrive at the naturopathic consultation as healthy individuals. The case history may be shortened, depending on the person. Many athletes want only a food and fuelling focus and are not aware or overly concerned with other body systems and their workings. Practitioners need to consider their holistic training as well as the patient's wants in order to support what the individual is seeking from the appointment. Areas of greater concern for many athletes seeking a holistic focus to their health include a medical history, blood tests, previous injuries, sporting background, weight concerns, ability to recover quickly, energy levels, immune system issues, musculoskeletal problems, digestion and bowel health, kilojoule intake adjustment, sleep, work–life balance and stress management. Note with athletes that it is best to take bloods at least 24 hours after the person's last training session. Exercise can create false results for many blood tests, especially iron studies. Ask the person to abstain from exercise as they will not know this. The morning after a full rest day is best as the person will have had more than 30–35 hours without training.

Considerations with athletes As noted previously, athletes have different needs to regular naturopathic patients dealing

with chronic health issues. Many of the general wellness suggestions given will be the same, as all individuals need certain volumes of sleep, fluids, etc. However, the questions a practitioner may also need to cover when working with athletes include:

• What sport is being undertaken (power, endurance etc.)? • How long is the sports season and where is the person currently in the season? • In what environment does the sport occur? Is it a summer or winter sport? Does it occur outdoors or indoors? • How often does the person train? Daily, twice per day or a few times per week? • What time of day does training or racing occur and for how long? • What foods does the person consume pre-, during and post-training or racing? • What is the food availability at the training venue? • Who does the person live with and who is involved in meal preparation and shopping? If they live in a dormitory or on campus at an institution, what foods are available for them there? What is the person's ability and desire to cook their own food? What is their general a=itude to cooking and money spent on food? There are many more things to consider for the individual athlete, but the above questions are a great starting point in understanding an individual's nutritional needs and habits.

Race day/competition considerations Considerations for racing and competition include:

• What are the person's food needs in the week or days leading up to a race? • Does the person need to change their diet to increase carbohydrates and so on? • What is the food availability if the person is flying to another country or town? What are they allowed to take with them across international borders? • What does the person need to consume during a race? Has this been planned appropriately?

Special needs of certain athletic populations This chapter covers many of the basics of working with athletes and gives general guidelines and recommendations. Each sport has its own metabolic profile and this must always be considered, along with the individual si=ing in front of the practitioner. There are also ‘special populations’ that partake in sport and need more specific assistance and guidelines. This includes injured athletes, children, teens, vegetarians, vegans, diabetics and those with food allergies, eating disorders, compromised immune systems, digestive or female reproductive disorders, bone density issues or needing a change in body composition and fat loss. The special needs of these groups is beyond the scope of this textbook but more information can be found in research papers such as the ACSM position statement[6] or textbooks such as Clinical Sports Nutrition.[107]

Knowing your limits as a practitioner It is vital that naturopathic practitioners know their limits and abilities in treating individuals. When these limits of expertise are reached it is vital that practitioners refer on or ask for assistance from professionals whose scope of knowledge or practice can assist the patient. Professionals who may need to be called on when working with the sporting population include:

• General practitioners • Sports doctors • Sports psychologists • Exercise physiologists • Sports dietitians • Coaches/trainers • Physiotherapists/massage therapists • Chiropractors, osteopaths, acupuncturists. Case study 1: general and race nutrition for a female triathlete A healthy triathlete is looking to increase her energy, support her immune system and learn the basics of healthy naturopathic sports nutrition.

Overview KW, a 35-year-old female athlete, presented with minimal health concerns and no longstanding health issues. She was seeking education around diet and sport as she was aiming to race a long-distance triathlon within 3 months. She is an age group triathlete, which means she competes within a 5-year age bracket against other women, and is

undertaking the sport for fun. General information

• Female • Age 35 • Height 173 cm • Weight 60 kg (healthy range for height) • Average sweat rate 600–800 mL per hour • Racing Ironman triathlon in 3 months’ time • Estimated finish time 11.5–13 hours • Works full-time in an office with flexible schedule. Systems review

• Digestion, gastrointestinal tract and bowels: no issues • Female cycle: 26–28 days, 5-day bleed with nothing remarkable, mild sugar cravings • Immune system slightly compromised from high training load, urinary tract infections (URTIs) every 2–3 months lasting 3–5 days, with only 3 days taken off training • Cramping in legs and feet, especially with swimming or long training sessions, 2–3 times per week • Work stress 7/10, life stress 6/10 • Sleeps 7 hours per night due to early training • Complains of tiredness and inability to stay awake at work • Happy with current weight • No known food allergies or sensitivities. Training schedule (variable and flexible as per workload and tiredness)

Monday Tuesday Wednesday Thursday Friday Saturday Sunday

AM

PM

Rest day Bike 1–2 hours Swim 1–1.5 hours Bike 1–2 hours Run 1 hour Bike 4–7 hours, run 30 minutes Run 1–2.5 hours

Yoga or Pilates Run 1–1.5 hours

Race

• Start at 7.00 am

Swim 1–1.5 hours Swim 1 hour Rest

• 3.8-km swim in open water (1 hour to 1 hour 10) • 180-km bike ride (aiming for 6 hours) • 42.2-marathon run (aiming for 4–4.5 hours). Food, fluid and supplement diary

• 7-day food training diary completed • Forgets to eat after training as rushing to work • Generally healthy choices: organic fruit and vegetables and meats • Low fish intake • Poor snack choices when tired from training • No food allergies or sensitivities, limits gluten by choice, fine with dairy • Good amount of carbohydrate; protein intake slightly low • Fluid intake of 1–1.5 L plus training fluid though can be forgetful • 2 black coffees per day with a dash of milk, or a cappuccino • 2–3 glasses of wine per week, dropping to zero closer to race • Takes no supplements unless unwell. Investigations referral

The following investigations were ordered: • FBC (full blood count) • Iron studies • Vitamin D • TSH (thyroid-stimulating hormone) test. KW had very few health complaints and thus the investigations requested were minimal. Many athletes need li=le blood work as they are healthy eaters who get more than adequate exercise and are seeing the practitioner for optimum health rather than chronic disease. KW's fatigue was not low enough to request further testing, as a change in diet and supplementation of nutritionals and herbal medicine was the first line of treatment. Investigation results Investigation

Result

Treatment

FBC Iron studies Vitamin D TSH

Within range Ferritin low, 15 micrograms/L 45 nmol/L, mild deficiency 1.8 mU/L

None given Supplementation given Supplementation given None given, within range

Treatment protocol

KW is a typical endurance athlete who is pushing her body at work as well as through sports. Education focused on general eating for sports and recovery to support her heavy training load. Initial treatment

• Increase protein intake to match training needs. Started with 1.5 g/kg of body weight = 90 g of protein spread throughout the day with 20–25 g in the post-training meal. • Post-training carbohydrate targets to be met for optimum glycogen synthesis and recovery, especially on double training days. Started with 1 g/kg of body weight post-training = 60 g and will assess results at next appointment. • Eat within 30 minutes of finishing all training sessions in correct carbohydrate to protein ratios. • Increase sleep to 8 hours per night and nap when possible. • Focus on protein at each meal and snack. • Red meat 2–3 times per week for increased iron needs, eaten with vitamin C foods for increased absorption. • Suggested increase in fish intake inclusive of sardines and herring for vitamin D needs. • Suggested healthier snacks and preparing foods on Sunday to be ready for the week ahead. Suggested meal ideas Breakfast

Lunch and dinner

Snacks

Other

150 g plain full-fat yoghurt with 1 piece of fruit and 25 g raw seeds/nuts; can add protein powder if necessary, honey if need more carbs

120 g meat (20–25 g protein) such as red meat, chicken, fish plus vegetable stir fry and rice or sweet potato

120 g plain yoghurt and ½ punnet of berries or 20 g seeds and nuts on top

Smoothie: 20 g protein powder, liquid of choice, 1 frozen banana, ½ cup frozen berries, honey to taste, yoghurt if desired

120 g meat (20–25 g protein) such as red meat, chicken, fish plus unlimited veggie salad and starchy vegetables if posttraining

Fluids: best is water, mineral water and herbal tea Need 1.5 L per day plus training fluids 2 coffees per day, try to limit milk (black is best), no sugar; substitute with green tea

2–3 tbsp hummus or ÄaÄiki with veggie sticks (carrot, zucchini, cucumber, capsicum) Porridge with LSA (linseeds, Fri=ata (eggs and veggies) plus Miso soup and 1 sunflower seeds and almonds) unlimited salad boiled egg or 20 g raw seeds/nuts or protein powder and a few sultanas or berries 2 eggs scrambled with stir fry Steamed or baked veggies plus Healthy sports bar of veggies (onions, capsicum, 120–150 g meat/fish/beans/tofu or homemade zucchini, mushrooms) and 2 (20–25 g protein) protein ball

Limit alcohol, best none in 6 weeks before race

1 meal per day should be free of grains/potato/sweet

pieces wholemeal or glutenfree toast 2 eggs with spinach, fe=a and mushroom sauté and 2 pieces of toast Recovery drink with correct carb:protein ratio if after training 120–150 g co=age cheese plus 1 piece of fruit and 25 g seeds and nuts

2 eggs plus tomato, bacon, spinach, avocado and sweet potato mash or 2 pieces of toast

Meat lasagne with veggies or salad or thin-crust pizza with healthy toppings (protein and veggies) Homemade slow-cook stew/soup with protein and veggies, add quinoa, potato, sweet potato or rice Vegetarian protein source that = 20–25 g protein (beans, tofu, tempeh) plus salad or stir fry and rice/quinoa if need to add carbohydrate

Wrap or sandwich with 100 g protein of choice (20 g of pure protein) and plenty of veggies/salad; use a salad leaf to wrap if wanting no grain

Buckwheat pancakes with Recovery drink if short of time maple syrup, plain yoghurt and post-training (4 : 1 ratio) and fruit (Saturday or Sunday after long training session)

potato/bread/corn/rice, best not the meal posttraining 45 g raw Starchy carbohydrate is seeds/nuts plus 1 best consumed in a piece fresh fruit or meal post-training 3 fresh dates (within 30 minutes) cup co=age Any breakfast can be eaten for lunch or cheese plus veggie dinner, and vice versa sticks Small smoothie or 1 piece of fruit, coconut water and 20 g protein powder

Post-training 4 : 1 or 3 : 1 ratio of carb:protein is best recovery ratio Within 30 minutes Do not skip meals, especially posttraining

Turmeric tea, 45 g seeds and nuts

Continue to keep a food and training diary Treats happen, try for 2 squares of dark chocolate Meals post-training need to hit carbohydrate and protein goals Meals not around training are great to have a small amount of protein and salad

Small beetroot and fe=a salad

Suggested nutrient requirements Nutrient

Dosage

Rationale

Magnesium Probiotic (multi-strain)

350 mg/day 1 capsule/day 2 capsules/day 2000 mg/day

Energy production, muscle cramping, stress, assists sleep Supports immune system and digestive function

B complex High-strength fish oil (omega 3 fa=y acids) Vitamin D3 Iron Vitamin C with bioflavonoids

1000–2000 IU/day 30–40 mg/day 2000 mg/day (or more)

Supports energy production, stress support Low fish intake in diet, cell membrane support, assists with fatsoluble vitamin absorption Mild deficiency, immune support Borderline ferritin levels, oxygenation of blood, endurance sport increasing demand, immune support Immune support, antioxidant; given when acute URTI, not given all the time as can potentially inhibit training adaptations

Suggested herbal medicines Herbal medicine

Quantity Rationale

Withania somnifera 40 mL (Ashwagandha) Rehmannia glutinosa (Rehmannia) 40 mL Echinacea spp. (Echinacea) 40 mL Astragalus membranaceus (Astragalus) Glycyrrhiza glabra (Liquorice) Phytolacca decandra (Poke root)

Stress, exhaustion, sleep

40 mL

Immune support, adrenal restorative, anti-inflammatory Immune support and modulation, lymphatic, increased incidence of URTI Immune support, tonic

40 mL 5 mL

Immune support, adrenal support Lymphatic, general support

Dosage: 7 mL BD in a small amount of water or juice. Source: Thomsen M, Gennat H. Phytotherapy: a clinical handbook. 4th edn. Hobart: Global Natural Medicine; 2009

At the time of presentation KW did not have an URTI but had previously had one the month before and was prone to infections. She was complaining of tiredness and is undergoing a large volume of training (upwards of 10–15 hours per week depending on her schedule). The herbal tonic was designed to support the immune system and the lymphatics: KW was in need of a general adaptogen tonic and immune support. This combination of herbs is a common recipe used with athletes, although with long-term use it is advisable to supply other adaptogens.

Herbal teas recommended as coffee alternatives and for general health and wellbeing Herbal tea

Justification

Ayurvedic Vata tea (combination of digestive, nervine and aromatic herbs) Matricaria recutita (Chamomile) Camellia sinensis (Green tea) Taraxacum officinalis (Dandelion)

Assists digestion and relaxes the nervous system before bed Digestive, nervine before bed Antioxidant, coffee substitute Liver support, coffee alternative

Follow-up

KW returned 3 weeks later to review protocols, assess energy levels and report on dietary changes. Her assessment of her health is as follows: • Energy fantastic, now 8/10, and hoping it will go higher as iron levels increase • Sleeping 8 hours per night with much less sleepiness during the day, except on really hard training days • Eating after training is a big focus and she has noticed a substantial difference in her energy levels, ability to train hard and, most helpfully, she has fewer cravings for sugar and bad snacks • Eating plan is great, loving the ideas and implementing most of the suggestions • Has not had an URTI since her first visit • Periods normal • Seeking assistance with her race nutrition plan at this appointment • Sweat rate for the bike is 800 mL/hour • Sweat rate for run is 600–700 mL/hour. Treatment plan

KW is doing so well that the treatment plan will stay the same up to and including her race in 2 months’ time. Supplements and herbal medicine will stay the same unless she has an URTI or is unwell and then a specific immune mix will be used. Adaptogens in her mix will be varied with substitution of Rhodiola and Siberian or Korean ginseng likely for Glycyrrhiza and Rehmannia as race time approaches. The largest part of the treatment plan is to teach KW about race nutrition for an endurance event. Specific protocols need to be followed for the few days before the race as she will benefit from an adapted carbohydrate loading protocol since her race will take her more than 11 hours. In addition, there is the actual protocol for during the race. Endurance events that last for more than 2 hours need specific guidelines so that athletes fuel themselves properly every hour while trying to minimise fatigue, gastric discomfort, dehydration and glycogen depletion. KW is given the following guidelines for adapted carbohydrate loading and foods to be eaten in the 2–3 days before the race as well as on the day itself. Nutrition protocol for the 3 days prior to the race/adjusted carb loading

• Increase carbohydrate intake to 65–75% of total daily intake • Suggestion: intake 8–12 g of carbohydrate per kg of body weight (KW is 60 kg so 480–720 g of carbohydrate per day) • Since KW has not carb loaded before and is not an elite athlete, her chosen level will be at the lower end of this range. It is up to KW to trial how she feels on different amounts and then move forward with the plan • KW is aiming for 480–500 g of carbohydrate per day, which is a large volume for most people. This will increase her glycogen stores above normal, giving her more fuel reserves for race day • For every gram of glycogen, the body holds approximately 2.5 g water – thus KW will be holding extra water in her body, which will be of benefit come race day. This can amount to an extra 2 kg in body weight • As KW's carbohydrate increases she will need to decrease her fibre, protein and fat volumes, as this is not about kilojoule loading but carb loading • Many athletes feel much be=er on race day by minimising high-fibre foods so their gut is lighter and they are less likely to have gastrointestinal problems • Carb loading has been shown to enhance endurance and postpone fatigue in endurance athletes competing at a steady state. It does not help them go faster. Carb loading is where naturopathic nutrition sometimes has to take a back seat. KW will need to consume large volumes of carbohydrate and thus may need to eat dense forms such as white rice, fruit juice, honey, jam, dates, flavoured yoghurt and sports drinks. Some athletes also eat gummy bears and other lollies. It is up to the athlete and how they want to roll with their nutrition. The following meal suggestions are provided to KW as examples of higher carbohydrate, lower fibre meals for the few days before the race. KW will calculate the exact volume of meals using her specific target goals from the carbohydrate tables.

Eating with increased carbohydrate intake pre-race Breakfast

Lunch and dinner

Snacks

Other

Yoghurt with 1–2 pieces of fruit and a sprinkle of seeds and nuts

120–150 g protein such as red meat, chicken, fish plus vegetable stir fry (unlimited veggies) and white rice

Fluids: best is water, mineral water and herbal tea to keep fluid levels topped up for race day

Smoothie: 20 g protein powder, yoghurt, fluid of choice (juice, milk, coconut water etc.), 1 banana, cup

120–150 g protein plus unlimited veggie salad and 1 of the following: toast, pasta, potato, sweet potato or rice

Yoghurt with a piece of fruit and 1 tbsp honey (berries, banana, fresh dates etc.) Hummus or guacamole and rice crackers or crumpets with honey

Muesli bar, glutenfree muesli bar, hotcross bun or highcarb sports bar Jelly snakes or jelly beans

Add a li=le extra salt to food in the few days before the race

berries and honey Porridge (oats, quinoa or rice) with a few sultanas or strawberries and some honey (not race morning as high fibre (too much fibre)) 2 eggs cooked as preferred, 1/3 avocado and 2–3 pieces of low-fibre or gluten-free toast plus fruit or juice 2 eggs with spinach, fe=a and mushroom sauté and 2– 3 pieces toast or potato/sweet potato mash 150 g of low -fibre cereal (2 cups) plus milk, 1 banana and berries/dates

Pancakes with maple syrup, yoghurt and fresh fruit

2–3 crumpets with honey or jam and a nut bu=er

Fri=ata (eggs and veggies with a lot of potato and sweet potato) plus salad

Baked veggies plus 120–150 g meat/fish/other protein source Lasagne made with a lot of veggies or served with a salad Homemade slow-cook stew/ goulash with protein and many veggies; add potato, sweet potato or rice for increased carbohydrate Wrap or sandwich with 120 g protein and plentiful veggies/salad or baked potato Recovery drink in a 4 : 1 (carb:protein) ratio

If you are short on carbohydrate it is okay to add a few jelly snakes, honey or sports drink to get to your carbohydrate goals Fresh fruit, dried Best to avoid alcohol in the fruit or dates and week before the race: beer small amount of raw is not good for nuts carbohydrate loading

Do not over-hydrate, but be sure not to be dehydrated

Chocolate milk, fruit Any breakfast can be eaten juice, sports drink, 4 for lunch or dinner, and : 1 recovery drink vice versa are great high carbohydrate snacks Small smoothie: see Post-training 4 : 1 breakfast recipe carb:protein is your best recovery ratio Within 30 minutes Rice pudding or If in doubt use a food diary sushi rolls with rice app such as mynetdiary or myfitnesspal

The following meal plan suggestions equate to approximately 480 g of carbohydrate: Breakfast • 200 g vanilla yoghurt (45 g carbohydrate) • 1 large banana (30 g carbohydrate) or 3 large dates • 2 tbsp honey (30 g) • Sprinkle of seeds/nuts (minimal carbs).

Snack • Sports bar (45 g carbohydrate) • Fruit juice 250 mL (30 g). Lunch • 2 pieces of bread (30 g) • Salad for sandwich such as tomatoes, le=uce, etc. (10 g carbohydrate) • Protein for sandwich such as chicken or turkey • 1 cup of grapes (30 g carbohydrate). Snack • 3 tbsp hummus (6–7 g carbohydrate) • 15 rice crackers (30 g) • Chocolate milk 350 mL (35 g carbohydrate) or fruit juice 300 mL (33 g carbohydrate). Dinner • Protein of choice (beef, lamb, chicken, fish) • 1.5 cups white rice (65 g) • Tamari sauce to add extra sodium • Stir fry veggies (approx. 20–30 g). After-dinner snack • 15 jelly beans (45 g) or • 1.5 hot-cross buns (45 g) or • 120 g vanilla yoghurt plus 2 large dates (45 g). Race morning nutrition

• Discussed with KW that race morning can be very nervous time: stomach and digestion can feel poor and nerves can make you feel like you don't want to eat • The golden rule is to never eat or drink anything new on race morning • The entire race day nutrition plan should have been trialled at least twice on long training days to know it works and feels great • Timing of pre-race meal depends on what time KW wants to get up • Race start is 7 am and KW needs to be there 1–1.5 hours before this to check in and

get ready • KW will wake around 4.30 am; she needs to eat a meal that has time to digest before the race start • Aim on race morning is to eat a meal that contains 1–4 g of carbohydrate per kg of body weight to replenish liver glycogen stores and be ready for race start. KW has trialled a 2 g/kg of body weight breakfast and feels comfortable with this (at 60 kg of body weight = 120 g of carbohydrate; if her nerves get really bad, she will drop this to 100 g). The meal needs to be high in low-fibre, easy-to-digest carbohydrate with only a small portion of protein or fat • Many athletes love oats on race morning but if they tend to have gastrointestinal issues during races they should have a less fibrous breakfast like creamed rice. Breakfast options

• Recovery drink 4 : 1 ratio (carb:protein) • Bread with jam or honey and a nut bu=er • Crumpets and honey • Banana and dates • Smoothie or sports bars • Top-up fluid. Race nutrition plan Pre-race/swim

• Water only in the last hour before race start and then 15 minutes out have either a gel with 300 mL water or a 300 mL sports drink. This will provide carbohydrate during the swim when KW is unable to eat anything. Bike

• Once out of the water and onto the bike, intake water only for 15–20 minutes to flush the system and let heart rate se=le down, find your rhythm • Aiming for 60 g of carbohydrate per hour • Fluid rate: 800 mL/hour – adjust up or down depending on temperature and weather • Salt tablets: 500 mg every hour or 1 g every second hour to keep levels topped up; continue with this on the run • KW's gel choice has 30 g of carbohydrate, so intake a gel every 30 minutes with 350 mL of water • Plus sip extra water during the hour to get intake to 800 mL/hour • Solid food eaten 2–3 times on the ride for fullness and flavour change, often in hours

2 and 4 for an estimated 6-hour ride • KW's choice is a sports bar high in carbohydrate and low in protein, fibre and fat, cut into portions of 30 g of carbohydrate each so that she replaces a gel with the bar • Food options to eat on the ride: bars, banana, dates, Vegemite sandwich with white bread, gels, carbohydrate chew, gummy bears, preÄels or just about anything that dense in carbohydrate that can be digested • No food or gel with sports drink – only water to dilute contents in stomach for fast absorption • Have plenty of water with solid food and remember to chew • Set watch to beep every 30 minutes as a reminder to eat • If get really uncomfortable in the stomach and feel like nothing is digesting, sip water and skip one eating session, allowing digestion to ride/rest for a while. Examples of how and when food and fluid will be ingested on the bike ride Time ingested

Food: 30 g carbohydrate

Fluid

0–15 minutes 15–30 minutes 30–60 minutes 60 minutes 1 hour 30 minutes 2 hours 2 hours 30 minutes And so on

— Gel Gel Gel Gel Bar/food Gel

Water only 350 mL water 350–400 mL water 350–400 mL water 350–400 mL water 350–400 mL water 350–400 mL water

Run

• On the run KW's digestion is more temperamental so she will consume only 50 g per hour of carbohydrate • Fluid intake needs be about around 600 mL/hour • Swap to a different carbohydrate gel that has only 25 g of carbohydrate to make calculations easier • Have 1 gel every 30 minutes with 250–300 mL water • Have 1 gel that contains caffeine every 3 gels to assist in delaying fatigue • Continue with salt/electrolyte tablets • Have just gels, water and salt tablets on the run • If need solid food, drop a gel and have a banana or 3 dates or approximately 400 mL sports drink. Race plans can include sports drinks but for simplicity's sake KW has chosen not to. In long-distance events water, sports drinks and degassed cola will be available for athletes

at drink stations. Food is often available as well in the form of fruit, gummy lollies and cookies. Lists are available pre-race of what is being offered. Other important information Flavour fatigue

• If you hit flavour fatigue with the gels, you may like to move to cola • Aim to consume about 400–450 mL cola per hour to get enough carbs • Consume some water to dilute the cola as it's 11%: at a drink station aim for 150–200 mL cola and a few sips of water • Practise what 100 mL and 200 mL of fluid looks like. Stomach issues and how you ‘feel’

• If your stomach feels too full, burping or sloshing, let it ride, only sipping water and slow down slightly to increase digestion function • Always check in with yourself and ‘feel’ how you are going, especially with your digestion • Don't force food/fluids down • Best of all, enjoy the race!

Case study 2: an elite male swimmer A swimmer competing at a high level needs a nutrition focus on both training days and carnival days where he is competing in multiple heats. The information from this case study can easily be applied to other sports with multiple races or games per day.

Overview TD, an 18-year-old male swimmer, has a high training load. He is mid-season and is looking to maintain his weight and muscle mass while increasing his energy for training and racing. He has been a competitive swimmer since the age of 10. He is not currently drug tested, although if he goes further this will be the case. General information

• Male • Age 18 • Height 187 cm • Weight 80 kg. Systems review

• Digestion, gastrointestinal tract and bowels: normal, no issues • Immune system: strong, only 1–2 infections per year, recovers quickly • Musculoskeletal: no issues • Skin: mild facial acne since puberty and at times on upper back but not recently • Sleeps 9 hours per night, would like more but gets to the pool at 5 am • Stress 7–8/10 due to final year of high school and exams • Happy with current weight and muscle mass • No known food allergies or sensitivities. Training schedule (variable)

Monday Tuesday Wednesday Thursday Friday Saturday Sunday

AM

PM

Swim 5–6.30 Swim 5–7.00 endurance session Swim 5–6.30 Swim 5–6.30 Swim 5–6.30 Race (all-day carnival) Day off or further racing

Pilates 1 hour Weights 1 hour Weights or Pilates 1 hour Run 1 hour Rest

Race day

Competes in 2–3 events over the course of the day Sometimes heats and finals occur on the same day, other times the final is on the next day Races last 3%): – congenital uterine anomaly – fibroids – endometrial polyps – poor cervical mucus quantity/quality (due to smoking, infection); mucus hostility (sperm antibodies) – uterine synechiae or adhesions (Asherman's syndrome).

Optimising natural fertility When presented with a couple who have experienced infertility, it is essential to ascertain their existing fertility strategies and any assessment tools they use to detect ovulation.

Conception Humans reproduce by the coming together of two cells (gametes) – an ovum, or egg, which is produced by the woman, and a sperm, which is produced by the man. Each gamete contributes half of the genetic material in the resulting individual. For normal conception to take place, therefore, the man must be able to produce a sufficient number of normal, actively moving sperm, and the woman must be able to produce a healthy egg. In addition, the parts of the woman's body that carry and sustain a fertilised egg must all be fully functional. The mature egg can survive for only 24–36 hours after ovulation. Sperm can survive in the presence of fertile-quality cervical fluid for 3–5 days. At ejaculation, the sperm swim, guided by the fertile cervical fluid, through the cervix and into the uterus. The uterus contracts in such a way as to help move the sperm up into the fallopian tubes to reach the egg. However, so many sperm are lost along the way that only a few hundred get this far. Around the egg is a shell (the zona pellucida). Once a single sperm has penetrated this shell, it sets up a barrier that further sperm are unable to penetrate. The head of this single sperm releases its contents inside the egg, and the egg is said to have been fertilised. The egg (a cell) then begins to divide and grow, and becomes an embryo. Over the course of about 3 days, the embryo moves along the fallopian tube, via muscle action and the movement of fine hairs (cilia), into the uterus. After about another 3 days, the embryo implants in the endometrium. Once it has implanted, it starts to produce a hormone called human chorionic gonadotrophin (hCG), and the pregnancy can be detected. All pregnancy tests done on blood or urine test for the presence of hCG.

Sperm production The male genital system consists of the testes, a system of ducts and some other glands

opening into the ducts. The testes produce sperm and testosterone. Sperm are produced by repeated division of cells in small, coiled tubules within the testes at an average rate of approximately 100 million/day in healthy young men. Sperm production is a lengthy process; from the beginning of the division of the stem cell to the appearance of mature sperm in the semen takes 72–76 days. Leading from each testis is a long, highly coiled tube called an epididymis. The sperm spend 2–10 days passing through the epididymis, during which time they mature and become capable of swimming and penetrating oocytes. At the beginning of ejaculation, sperm are transported from the tail of the epididymis via the vas deferens to the urethra. The seminal vesicles, prostate gland and Cowper's glands secrete most of the volume of semen – these secretions help deliver the sperm during ejaculation. The volume of liquid coming from the two epididymides is less than 5% of the total semen volume. Approximately 60% of the semen volume comes from the seminal vesicles, and 30% from the prostate gland. The average semen volume for healthy men ejaculating every 2 days is 3 mL, and the sperm concentration is 85 million/mL (for more detail, see below). During ejaculation, usually the sperm and the prostatic fluid come out first, and the seminal vesicle fluid follows. The seminal vesicle fluid coagulates, giving the semen a lumpy, gel-like appearance. Liquefaction occurs after 20 minutes or so and the gel disappears.

Maturing fertility Fertility is generally highest in the first months of unprotected sex and declines gradually thereafter in the population as a whole. If no conception occurs within the first 3 months, monthly fecundity decreases substantially among those who continue their efforts to conceive.[14]

Frequency of intercourse In some cases, practitioners may need to explain the basics of the reproductive process. Assessment and discussion is best conducted earlier in the treatment process to avoid misinterpretation and misunderstanding. In the past decade, abstinence intervals have varied greatly. A widely held misinterpretation is that frequent ejaculations decrease male fertility. A retrospective study analysed 9489 men with normal semen quality, sperm concentration and sperm motility, and found that profiles remained normal even with daily ejaculation.[15] Of more importance is the finding that in males with abnormalities such as oligozoospermia, low sperm concentration and low sperm motility, fertility may be higher with more frequent (daily) ejaculation.[15] Couples should be informed that reproductive efficiency increases with the frequency of intercourse, and is highest when intercourse occurs every 1–2 days. However, optimal frequency is best defined by the couple's own preference within this context.

Fertile window The fertile window is best defined as the 6-day interval ending on the day of ovulation.[16] As oestrogen increases in the woman in the lead up to ovulation, she produces fertile-quality

cervical fluid. This fluid then provides a medium to protect the sperm from the acidic pH of the vagina, a medium for the sperm to travel in, and sustenance for the sperm to survive. Sperm are theoretically able to survive for up to 5 days in the presence of this fluid.

Making babies There are a number of recommendations available. However, some are simply ridiculous, and others unnecessary. Ultimately, conception simply requires one sperm to meet one oocyte. A number of general recommendations can be followed to increase the chances of natural conception. During intercourse, the woman's position should encourage a slight pelvis tilt (pillow under hips) and positions where the sperm cannot leak from the vagina. Experts therefore recommend that a couple avoids having sex in positions that defy gravity (as this lessens the likelihood of the man's sperm reaching the cervix) and chooses positions that encourage deeper penetration in order to place sperm as close as possible to the cervix. Sperm can be found in the cervical canal seconds after ejaculation, regardless of coital position, but increasing the quantity of sperm that can pass through the cervical opening is advisable. The use of lubricants should be discouraged as most act as mild contraceptives (see the discussion later in this chapter). It is required that the sperm travel time through the cervix is minimal. However, a lack of movement and activity after ejaculation is advisable. Women do not need to literally have their legs raised in the air, but they should be encouraged to avoid urinating for a minimum of 10 minutes after intercourse. In addition, some research suggests that the female orgasm is important in promoting sperm transport. Research suggests that orgasm should be encouraged after ejaculation, as the contractions that accompany the female orgasm may help carry sperm further into the cervix. However, there is no known relationship between orgasm and fertility outcome. Ultimately, the focus should be on love making and not baby making, as this can cause unnecessary stress and pressure on the couple.

Age on fertility Age is rapidly becoming the biggest preventable cause of failure to conceive. Approximately 20% of women wait until after age 35 years to begin their families. Several factors have contributed to this trend:

• contraception is readily available • more women are in the workforce and furthering their careers • women are marrying at an older age • the divorce rate remains high • married couples are delaying pregnancy until they are more financially secure

• many women do not realise that their fertility begins to decline in their late twenties or early thirties. After 35 years of age, a woman's fertility declines rapidly in conjunction with deteriorating egg quality. She may enter oopause in her thirties, depending on her genetic make-up, and this will further reduce her fertility. Even though women today are healthier and taking be^er care of themselves than ever before, improved health in later life does not offset the natural age-related decline in fertility. While at the age of 35 years over 95% of healthy couples will conceive within 3 years of trying, by age 38 years, this figure has dropped to 77%. By the age of 41 years, less than half of healthy couples will conceive after 3 years of trying (see Table 11.2). TABLE 11.2 Age and fertility in partnered women[13] Age group (years)

Infertile (%)

Chance of remaining childless (%)

20–24 25–29 30–34 35–39 40–44

7 9 15 22 29

6 9 15 30 64

The effects of ageing A number of considerations regarding the effects of age on fertility should be considered, and these are described below (see Table 11.3).

TABLE 11.3 The effects of ageing Ovarian function

As women age, fertility declines due to normal age-related changes that occur in the ovaries. Women are born with all the eggs they will ever have, with approximately 300 000 follicles remaining at menarche. She then will lose between 20 and 30 follicles each cycle. Of the eggs remaining at puberty, it is believed that approximately 360–400 of these follicles, over 30 years, will mature and be released by the body, with the remainder being lost from each cycle. The rest will undergo atresia – a degenerative process that occurs regardless of whether a woman is pregnant, has normal menstrual cycles, uses birth control or is undergoing infertility treatment. Smoking appears to accelerate atresia and is linked to earlier menopause. Ovarian Ovarian reserve declines with each cycle. Diminished ovarian reserve is usually age related reserve and occurs due to the natural loss of eggs and decrease in the average quality of the eggs that remain. The remaining eggs become ‘poor responders’ to follicle-stimulating hormone (FSH) and luteinising hormone (LH), thus shortening menstrual cycles. Young women may also have reduced ovarian reserve due to smoking, family history of premature menopause and prior ovarian surgery. Premature ovarian failure is unfortunately common, and comprehensive investigations are required. Genetic Ageing affects oocyte quality and increases the chance of neonatal genetic abnormalities. (See abnormalities Table 11.4 for elaboration.) Miscarriage Older oocytes increase the risk of miscarriage. (See Table 11.5 for elaboration.) risk Ageing male While men can father children when they are older, as men age their testes reduce in size and get softer, sperm morphology and motility tend to decline and there is a slightly higher risk of gene defects in their sperm. Ageing men may develop medical illnesses that adversely affect their sexual and reproductive function.

TABLE 11.4 Maternal age and risk of chromosomal abnormality in newborns[13] Maternal age (years)

Risk of Down syndrome

Total risk of chromosomal abnormalities

20 25 30 35 40 41 42 43 44 45 46 47 48 49

1/1667 1/1250 1/952 1/378 1/106 1/82 1/63 1/49 1/38 1/30 1/23 1/18 1/14 1/11

1/526 1/476 1/385 1/192 1/66 1/53 1/42 1/33 1/26 1/21 1/16 1/13 1/10 1/8

TABLE 11.5 Maternal age and miscarriage risk[13] Maternal age (years)

Spontaneous abortion (%)

15–19 20–24 25–29 30–34 35–39 40–44 ≥45

10 10 10 12 18 34 53

Weight balance Obesity Obesity has an impact on reproduction in women in a number of ways (see Table 11.6).[17]

TABLE 11.6 Impact of obesity on fertility[17] Ovulation potential

Ovulation returns with a relatively modest degree of weight loss from diet and exercise. Approximately 90% of obese women will resume ovulation if they lose >5% of their pre-treatment weight, and 30% will conceive. In very obese women, this is a higher pregnancy rate than can be expected from a single IVF cycle, so this is incredibly encouraging for obese women wishing to have children. IVF outcome The success rate of assisted reproductive techniques is reduced in obese women. IVF success rates may be reduced by as much as 25% in obese patients, and 50% in very obese patients. IVF centres are very reluctant to perform fertility treatment on women with a BMI greater than 35 kg/m2, and generally recommend a target BMI of 30 kg/m2 before starting the treatment.[18] Semen Obese men are also at risk. The effect of weight loss on male fertility is less well understood, analysis but weight loss does seem to lead to an improvement in testosterone levels and sexual dysfunction. Obese men generally have lower sperm counts (up to 50%), reduced spermatogenesis, increased DNA fragmentation of sperm and increased levels of erectile dysfunction. Hormonal changes are primarily responsible for the changes in obese men. The level of total and free testosterone is reduced in obese men in proportion to the level of obesity. Oestrogen is increased due to the peripheral aromatisation of androgens in adipose tissue. The oestrogens produced have a negative feedback effect on gonadotrophin production, reducing FSH. A reduction in the level of FSH in obese men reduces testosterone production and spermatogenesis. Increased body fat and a sedentary lifestyle are also associated with raised testicular temperature, which further adversely affects spermatogenesis.[18] Heat stress modifies gene expression in the testes, causing impaired spermatogenesis. Sperm cells are extremely vulnerable and respond by apoptosis and DNA damage.[19] Miscarriage The risk of miscarriage in the first trimester increases from 12 to 15% in normal-weight women (under 37 years old) to 31% for BMI > 35 kg/m2. The rate of recurrent miscarriage increases fourfold in obese women. Birth defects Maternal obesity has a detrimental impact on fetal development (e.g. three times the risk of neural tube defects, structural heart defects). Folic acid supplementation is less effective in preventing neural tube defects, so high-dose supplementation is required for obese women (always beneficial to calculate nutrient requirements based on patient's presenting weight). Pregnancy Pregnancy complications are more common in obese women (gestational diabetes is six times complications more common); pregnancy-induced hypertensive diseases are more common (gestational hypertension and preeclampsia). Complications increase the risk of premature delivery/caesarean section. Babies born to obese women have heavier birthweights (fetal macrosomia) which increases the risk of traumatic vaginal delivery. There is a higher complication rate for caesarean and vaginal deliveries in obese women (e.g. excessive blood loss, thromboembolic disease and post-operative infection). Pregnancy Increasing BMI increases risk of stillbirth (two times the risk vs normal-weight women). outcomes The newborn Maternal obesity carries long-term risks for the newborn infant (e.g. increased risk of being overweight as adults and having weight-related diseases in adulthood).

BMI classification The BMI classification uses the definitions outlined in Table 11.7.[20]

TABLE 11.7 BMI classification BMI (kg/m2)

Classification

Less than 18.5 18.5–24.9 25–29.9 30-40 >40

Underweight Healthy weight range Overweight Obese Morbidly obese

Anorexia Women with a BMI 40% progressive, >50% motile) >3 >32% (range 31–34%) with forward movement >58% (range 55–63%) live 4% (range 3–4%) normal forms Note: the trial wash can provide specific information about morphological abnormalities (i.e. head, neck, tail) 13 micromol/ejaculate >20 mU/ejaculate

TABLE 11.29

Interpretation and treatment for semen analysis Semen parameter

Treatment

General parameters Specimen Incomplete samples are frequent and will distort readings. Assessment can only be done by reviewing a full sample due to variations in prostatic secretion versus epididymis involvement Analysis time Samples that are assessed after longer than 60 minutes will produce inaccurate findings Appearance Debris, clumping, viscosity or liquefaction issues can suggest systemic congestion, poor hydration, poor elimination or immune processes. It can also indicate poor ejaculation frequency pH pH control is essential for sperm survival. An abnormally high or low semen pH can kill sperm or affect their ability to move or to penetrate an egg. The pH of the sample will be affected if there is a delay between sample collection and analysis. If the pH is 4% normal forms and provides stricter criteria for subcategories associated with morphology. (See Appendix 11.6.) Morphology is often a direct reflection of generalised toxicity in the body as semen is a by-product of the body and is a major eliminatory channel. Detoxification, avoidance of environmental toxins and immaculate dietary practices are essential. Key nutrients in sperm structure must be considered including essential fa^y acids, antioxidants especially coenzyme Q10, zinc, selenium and protein. Immune involvement PeroxidaseThe presence of white blood cells or bacteria indicates that an infection is present (genitopositive urinary). Even in the absence of a relevant history or symptoms, the finding of a high leucocytes white cell count may prompt investigation of infection and may warrant a course of appropriate antibiotic therapy. Such infections may contribute to sperm damage and are easily treatable. Identification of infection is the primary objective with subsequent targeted treatment to eradicate the infection. It is essential to assess the partner if infection is detected. MAR test The immune system produces antibodies as part of the normal defence against foreign (motile substances and organisms. Sperm are normally protected from exposure to immune sperm with system. However, some men produce sperm antibodies following surgery or trauma to bound the testicles. In other men, there is no apparent cause for their development. The particles) antibodies a^ach to the surface of the sperm and reduce their life span, impair sperm Immunobead motility and ability to penetrate the partner's cervical mucus. Antibodies located on the test (motile sperm head may prevent the sperm fertilising the egg. spermatozoa Abstinence or barrier methods until the immune system is regulated and concurrent with bound autoimmune treatment is essential through herbal medicines, dietary modifications, beads) lifestyle modifications and nutritional supplementation. (refers to assessment for sperm antibodies) GAM or isotype

DNA fragmentation Once male germ cells have completed meiosis, they lose their capacity for DNA repair, discard their cytoplasm (containing the defensive enzymes that protect most cell types from oxidative stress) and eventually become separated from the Sertoli cells that have nursed and protected them throughout their differentiation into spermatozoa. In this isolated state, spermatozoa must spend a week or so journeying through the male reproductive tract and, uniquely in our species, a further period (up to 3 or 4 days) in the female tract waiting for an egg. During this period of isolation, sperm DNA is vulnerable to damage by both xenobiotics and electromagnetic radiation. Such DNA damage is associated with male infertility, and its aberrant repair in the fertilised egg may result in mutations in the embryo with the potential to either induce abortion or impair the health and fertility of the offspring.[32,34] Treatment consists of environmental review and modification as well as exceptionally high doses of antioxidant prescription. Other Seminal zinc Low levels suggest supplementation is required. Seminal fructose Normal levels are 300 mg/100 mL ejaculate. Absence may indicate that the man was born without seminal vesicles or may have a blockage of seminal vesicles. As such, referral is essential for further investigations.

Sperm chromatin structure assay (SCSA) Research indicates that sperm with high levels of DNA fragmentation have a lower probability of producing a successful pregnancy. Samples with a DFI >29% are likely to have significantly reduced fertility potential, including a significant reduction in term pregnancies and an increase in the miscarriage rate. Sperm that appear to be normal by traditional semen analysis parameters may have extensive DNA fragmentation. The DFI threshold for humans was first established in the Georgetown Male Factor Infertility Study, which used data from 200 presumed fertile couples a^empting to conceive naturally.[60] Fertility data from this study were used to establish the statistical thresholds of DFI >30% for ‘significant lack of’, DFI 15–30% for ‘reasonable’ and DFI 60 min/day) increased the risk of anovulation, and vigorous exercise of 30–60 min/day reduced the risk of anovulatory infertility. These effects are probably produced via modulation of the hypothalamic– pituitary–gonadal (HPG) axis due to increased activity of the hypothalamic–pituitary– adrenal (HPA) axis. In overweight and obese women (with or without PCOS), exercise contributed to lower insulin and free androgen levels, leading to the restoration of HPA regulation of ovulation.[311] Conversely, very low physical activity may increase the risk of menstrual cycle disruptions in healthy women and may have a detrimental effect on reproductive health.[312] An observational study of obese women undergoing ART (n = 216) found that women who exercised regularly had an over three-fold higher success rate with IVF compared to those

who were sedentary.[313] Lubricants Cervical fluid

A number of medications affect the quality of cervical fluid and interfere with conception outcome. These include antihistamines, some cough mixtures, dicyclomine, progesterone (taken prior to or at ovulation), propantheline and tamoxifen. Effect on sperm

Many studies have found a deleterious effect of personal lubricants on sperm function, such as motility, including a decreased ability of sperm to penetrate cervical mucus after exposure to lubricants. Several studies have shown that commonly used lubricants kill sperm equivalently to contraceptive jellies.[314–326] Some lubricants and gels have been incorrectly labelled as ‘non-spermicidal’.[327] Optimal lubricants

Ideal lubricants are those that are most natural and do not affect the pH of the vagina. The optimal lubricant is egg whites as they have a similar nutritional profile to cervical mucus and an ability to sustain the longevity of sperm.

Treating the male Nutritional medicine (dietary) Therapeutic objectives

1 Provide nutritional sustenance to foster health and wellbeing. 2 Improve fertility parameters. 3 Avoid dietary factors that compound infertility, such as sugar, caffeine, alcohol, trans fa@y acids and anything that deviates from a wholefood diet. 4 Address macro- and micronutrient deficiencies, paying particular a@ention to hydration and protein requirements. Specific dietary treatments Dietary inclusions Oily fish

Adequate intake of omega-3 fa@y acids is required to ensure stable cell membrane fluidity and energy production of the sperm. Similarly to their female counterparts, patients must be educated about the high methylmercury content of some fish. Acknowledging that the male component makes up half of the genetic material of the future child, the same recommendations of avoidance of high mercury containing fish should apply to men. The general recommendation by naturopaths is to avoid all high methylmercury-content fish throughout the preconception window. Wholefood diet

A healthy diet provides a wide variety of nutrients required for the development and maturation of healthy sperm. While an unbalanced diet characterised by a low intake of minerals and vitamins has been associated with subfertility,[88,89] a wholefood diet based on a variety of fresh, seasonal foods, organic where possible, will contain a blend of synergistic nutrients required for healthy preconception. A prospective study in the US of 155 male partners in subfertile couples found that total fruit and vegetable consumption was not related to semen quality parameters; however, high-pesticide-residue fruit and vegetable intake was.[328] Foods such as processed meats and smallgoods should always be avoided due to negative impact on sperm parameters.[329] A study comparing two different dietary pa@erns found that adhering to a prudent diet (high intake of fish, chicken, fruits, vegetables, legumes and whole grains) was associated with increased sperm motility. Adherence to a Western diet (high intake of red and processed meat, refined grains, pizza, snacks, high-energy drinks and sweets) was not associated with any semen parameter.[330] Similarly, a recent review of observational studies concluded that adherence to a healthy diet (such as the Mediterranean diet pa@ern and diets characterised by higher intakes of seafood, poultry, whole grains, fruits and vegetables in

non-Mediterranean countries) has been consistently associated with be@er semen parameters in a wide range of studies in North America, Europe, the Middle East and East Asia.[331–333] It has been shown that following a diet characterised by higher intakes of legumes, vegetables, cereals, fruits and olive oil, and low intakes of dairy, mayonnaise, margarines, sauces, snacks and sweets is associated with semen quality – particularly sperm concentration and progressive motility – among men from couples planning pregnancy.[334] A study in men with asthenozoospermia showed an association between following a dietary nutrient intake pa@ern comprising mainly antioxidants, vitamin D, fibre and polyunsaturated fa@y acids and a significantly lower risk of asthenozoospermia.[335] A longitudinal study on the effects of dairy on semen parameters found that low-fat dairy intake (particularly low-fat milk) was associated with increased sperm concentrations and motility, whereas cheese intake was associated with lower sperm concentration.[336] Protein

Please review the discussion on protein and fertility in the Treating the female section for more information. Antioxidant-rich foods

Acknowledging the role of oxidative stress and its detrimental effects on male fertility, the inclusion of a wide variety of dietary antioxidants is recommended. Antioxidants are well known for their health benefits and have demonstrated significant benefits in improving a wide range of fertility outcomes, including effects on sperm health. Phyto-oestrogens

There is conflicting information available on the effect of phyto-oestrogens on sperm parameters and fertility. Various studies have found improvements in sperm count and motility with soy consumption; others have found the intake of soy and isoflavones was inversely related to sperm concentration.[337] A 2010 meta-analysis found that neither soy foods nor isoflavone supplement intake has an effect on testosterone levels.[338] A recent prospective cohort study found that soy food intake in men was not related to clinical outcomes among couples a@ending a fertility clinic.[339] Dietary exclusions Caffeine

An in vitro study on the effects of caffeine on Sertoli cell metabolism and oxidative profile found that high dosages of caffeine increased protein oxidative damage in the cells, but moderate doses of caffeine stimulated lactate production, which can promote germ cell survival. Moderate consumption of caffeine appears to be safe in male reproductive health in this study.[340] This is supported by an analysis of a cohort of 4474 semen samples in an epidemiological study which found that semen volumes were higher among caffeine consumers, but concentration was lower. No relationship was observed for motility,

morphology or DNA fragmentation.[341] A study of more than 2500 Danish men investigating caffeine intake from various sources, including cola, found that caffeine intake of less than 800 mg/day and cola consumption of less than 14 bo@les (500 mL) per week was not associated with reduced semen quality. There was an apparent threshold with cola consumption of 1 L per day, which was associated with a reduction in sperm quality. The authors concluded that this effect is probably due to constituents in cola other than caffeine, or the effects might be associated with a less healthy diet and lifestyle of high-quantity cola consumers.[342] In summary, a recent systematic review of the relationship between caffeine and parameters of male fertility found that caffeine intake may negatively affect male reproductive function; however, the data to date are inconsistent and inconclusive.[343] As far as ART outcomes are concerned, an observational study on the effects of caffeine and alcohol on men at a fertility clinic found no association between caffeine or alcohol intake on semen parameters. However, pretreatment caffeine and alcohol intake did affect live birth outcome after ART. Caffeine intake was associated with a lower probability of achieving live birth.[344] Alcohol

The data on alcohol consumption and its relationship with fertility is mixed. While some have suggested there is no link between alcohol and fertility,[104] others have shown a direct link to decreased male fertility. Alcohol consumption has been shown to impair gonadal function and is associated with defective sperm morphology, impaired sperm motility and lowered sperm counts.[48,345] A review of the literature in 2013 suggested that alcohol consumption alters sperm parameters (most commonly morphologically abnormal spermatozoa) and testicular pathology. It is noted that genetic factors as well as nutritional deficiencies may modulate the impact of alcohol on spermatogenesis.[346] More recently, a cross-sectional study of 8344 healthy men in Europe and the US found that moderate alcohol intake was not associated with a reduction in semen quality. However, this study only looked at alcohol consumed the week prior to the semen testing, which does not account for the long term effects of alcohol consumption.[347] Another study of 347 men investigating the effect of the past 5 days’ worth of alcohol intake found that alcohol intake was associated with impairment of most semen characteristics. There was a tendency towards lower semen parameters with higher intake of alcohol, but no statistically significant dose–response association was found.[348] A recent review of 15 cross-sectional studies has shown a detrimental effect of daily, but not occasional, alcohol consumption on semen volume and morphology. This suggests that a moderate consumption of alcohol should not adversely affect semen quality parameters.[349] Without further rigorous studies, the best available evidence suggests that alcohol intake and fertility are linked only with high levels of consumption (more than eight drinks per week or more than 40 g alcohol per day, depending on the study).[350] From a naturopathic perspective, however, it is highly advisable for those wanting to

optimise their fertility to exclude all alcohol from their diet. A case report of a 6-year followup of a male patient showed that stopping alcohol consumption led to a rapid, dramatic improvement in semen characteristics. Normal semen parameters were observed after 3 months.[351] Dietary fats

A preliminary cross-sectional study of 99 men a@ending a fertility clinic found that high intake of saturated fat was negatively associated with sperm count and sperm concentration, and a higher intake of omega-3 fats in the diet was positively related to sperm morphology. Nutrient intake was estimated based on food frequency questionnaires. Total energy intake, age, abstinence time, BMI, smoking and intake of alcohol and caffeine were adjusted for in this study.[352] In support of these results, a Danish study of young men (n = 701) and a crosssectional study of 120 men found that intake of saturated fat was associated with lower sperm count, sperm concentration and sperm volume.[353,354] The consumption of trans fats compromises male fertility. These fats cannot be endogenously synthesised, and excessive consumption contributes to fat accumulation within the testicular environment.[355] A cross-sectional study of 209 men found that trans fa@y acid intake was inversely related to total sperm count.[356] An analysis of the same set of data found that trans fa@y acid intake was also inversely related to testicular volume, while the intake of omega-3 polyunsaturated fa@y acids was positively related to testicular volume. [357]

High-energy diets and obesity

It has been suggested that the overconsumption of high-energy diets disrupt the male reproductive function at either central (HTP axis) and/or gonadal levels, affecting testicular physiology and disrupting its metabolism and bioenergetics capacity. This might lead to adverse reproductive outcomes such as inefficient energy supply to germ cells, sperm defects or spermatogenesis issues. High-energy intake enhances oxidative stress within the testicular environment. The major decline in fertility seen in high-energy diets might largely be due to the types of fats consumed.[355] High consumption of sugar-sweetened beverages has been associated with lower sperm motility among healthy young men. The association was stronger in lean men and absent in overweight or obese men.[358] Overconsumption of high-energy diets leads to weight gain and obesity, and reduced fertility is recognised as one of the consequences of obesity promoted by dietary lifestyle. Obesity adversely affects sperm concentration and may affect sperm quality, in particular altering the physical and molecular structure of germ cells in the testes and, ultimately, mature sperm. Obesity is linked to low serum testosterone levels. However, treatment with exogenous testosterone is likely to have a further adverse effect on fertility.[359,360] A metaanalysis of 21 studies demonstrated an increased risk of azoospermia or oligozoospermia in overweight or obese men.[361] Obesity induces a state of inflammation with increased proinflammatory cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin-6 in

the serum, testicular tissue and seminal plasma. In the testes, pro-inflammatory cytokines can directly impair the seminiferous epithelium. A pro-inflammatory state can also damage epididymal epithelium function, impeding sperm maturation and fertilisation ability.[362] Obesity also causes damage to DNA and plasma membrane integrity in sperm due to excess ROS and oxidative stress.[363] Obesity has been shown to affect semen parameters, including decreased sperm concentration, decreased sperm motility and vitality and increased abnormal morphology.[363–366] A 2011 Danish cohort study on the effects of weight reduction in severely obese (BMI >33) males established an association between obesity and poor semen quality. A 15% reduction in weight over 14 weeks led to improvements in total sperm count, semen volume, testosterone, sex-hormone-binding globulin and anti-Müllerian hormone. The study group that lost more weight had a statistically significant increase in total sperm count and normal sperm morphology.[367] Maintaining an adequate or normal body weight is an important factor for male fertility.[368] Furthermore, epidemiological and animal studies have shown that obese fathers are more likely to father an obese child, with metabolic and reproductive health consequences passed on to the next generation. Animal studies have shown that simple diet and exercise interventions can reverse the damaging effect of obesity on sperm function.[360] Metabolic syndrome and sperm parameters

In a small case-controlled pilot study, it was shown that men with metabolic syndrome have compromised sperm parameters. It is hypothesised that a systemic inflammatory state with associated oxidative stress may provide an explanation.[369]

Sample daily diet

BREAKFAST

LUNCH

DINNER

SNACK

Tomato, grapefruit and carrot juice Omele@e served with potato, ample leafy greens and avocado

Regular consumption of tomato juice has been shown to improve sperm motility in infertile men,[370] thus improving chances of conception. The antioxidant action of lycopene, beta-carotene and retinol reduces sperm DNA fragmentation and lipid peroxidation,[371] suggesting wholefoods containing these constituents, such as tomato, grapefruit and carrot, should be consumed regularly in the diet. Uncooked leafy greens and avocado contain optimal quantities of folate. Low folate is associated with reduced sperm density and count[372] as well as increased sperm DNA damage.[373] Animal studies also suggest that paternal folate deficiency increases the risk of birth defects in the offspring, highlighting the importance of folate beyond male fertility.[374] Walnut-pestoSperm are made up of a high proportion of polyunsaturated fa@y acids, crusted salmon and the presence of these is required for healthy fertilisation. In particular, with buckwheat the human sperm head contains a higher concentration of DHA and is pasta and sensitive to dietary omega-3 PUFA.[375] Walnuts and salmon are both marinated roast sources of omega-3 fa@y acids. Consumption of supplemental DHA is vegetables: carrot, associated with improved seminal antioxidant status and decreased sperm eggplant, leek, DNA fragmentation[376]; thus, it can be hypothesised that oily fish in the rocket and chives diet would produce similar benefits. Tomato-based Since oxidative stress increases sperm membrane lipid peroxidation, bolognaise sauce DNA damage and apoptosis, leading to decreased sperm viability and made with extra motility, a diet rich in antioxidants from fruits and vegetables should virgin olive oil, be emphasised for optimal sperm function. tomato passata, Cooked tomato products contain lycopene. Lycopene concentration is tomato paste; increased from cooked rather than raw foods and in the presence of mixed vegetables fats. Favourites such as spaghe@i bolognaise can be modified to a served with healthier version to support sperm health. The lycopene in cooked zucchini noodles tomato products increases in bioavailability when consumed with (zoodles) healthy oils (e.g. extra virgin olive oil or avocado). Trail mix: Sunflower and pumpkin seeds offer zinc. Zinc is found in sunflower walnuts, and pumpkin seeds and is required for testosterone production, sunflower spermatogenesis and sperm motility, and may protect sperm from seeds, pumpkin chromosomal damage.[377] Brazil nuts contain selenium. Selenium is a seeds, goji powerful antioxidant that may improve sperm morphology and berries, Brazil concentration. nuts Salsa is a source of lycopene. Avocado in combination with tomato Salsa and salsa has been shown to increase lycopene and beta-carotene levels in guacamole with humans compared to when salsa is consumed alone.[378] rice crackers

Nutritional medicine (supplemental) Therapeutic objectives

1 Address deficiencies and provide nutrient repletion to restore nutrient pathways. 2 Improve fertility potential and relevant fertility factors. 3 Address a@enuating factors such as infection, inflammation, toxicity and stress.

4 Provide antioxidants to reduce oxidation influence on gametes. 5 Support communication between the endocrine and reproductive systems. 6 Support hormone production and delivery to all reproductive tissues. 7 Encourage optimal eliminatory pathways. 8 Support optimal general health. Specific nutrients required Amino acids Arginine

Arginine is an amino acid that may be used to enhance male fertility. Via its role as a precursor to nitric oxide synthesis, arginine is required for angiogenesis, spermatogenesis, fertility and hormone secretion.[125] In males, a combination of antioxidants and arginine appears to be useful for increasing the health of sperm, and thus leading to increased chance of optimal fertility. An improvement in semen parameters was observed in a double-blind, randomised, placebocontrolled, cross-over clinical trial examining the effects of Prelox, a combination of 80 mg/day Pycnogenol and 3 g/d L-arginine-L-aspartate.[379] In 50 males with idiopathic infertility, over a treatment period of 4 weeks there was an observed significant increase in ejaculate volume, concentration and number of spermatozoa and percentage of vital spermatozoa compared to placebo. The percentage of spermatozoa with good progressing motility also increased significantly, while the percentage of immotile spermatozoa decreased. This appears to be due to a combination of the antioxidant activity of Pycnogenol and/or the activity of arginine to stimulate the activity of endothelial nitric oxide synthase, leading to enhanced motility of spermatozoa. L-carnitine

Carnitine is a naturally occurring amino acid that plays a vital role in fa@y acid metabolism for energy. It is essential to ensure that it is prescribed in the L-form and not the DL-form. It works synergistically with CoQ10, and it is advisable to co-prescribe these two nutrients together. Carnitine is found in high concentrations in the seminal fluid, where it functions as an energy substrate for the sperm, assisting in their motility and maturation. Carnitine also functions as an antioxidant, providing protection against ROS. Clinical trials have demonstrated the ability of carnitine, in combination with other nutrients, to improve sperm motility in men. In a placebo-controlled, double-blind, randomised study, 60 infertile male with a low sperm concentration and poorly motile sperm were administered a combined treatment of Lcarnitine (2 g/day) and L-acetylcarnitine (1 g/day) or placebo for 6 months.[380] Increased sperm parameters were observed after combined carnitine treatment. The most significant improvement in sperm motility (both forward and total) was seen in patients who had lower

initial absolute values of motile sperm (15%), suggesting that this is a contributing factor to the clinical syndrome of recurrent miscarriage.[55] Sperm quality critically depends on the amount of damage to the sperm DNA, or DNA fragmentation. It is remarkable that this testing technology exists for men. However, to date, no such testing technology is available to assess the DNA integrity of a woman's oocytes. Sperm DNA fragmentation has liXle to nothing to do with the parameters that are measured on the routine semen analysis. Rather, it is a completely independent variable. Men with otherwise seemingly normal semen analyses as set by the World Health Organization can have a high degree of DNA damage, and men with what was called very poor spermatozoa quality can have very liXle DNA damage.[56] More importantly, what has also been demonstrated is that the degree of DNA fragmentation correlates very highly with the inability of the sperm to initiate a birth regardless of the type of conception, be it natural, IVF or ICSI technologies. Spermatozoa with high DNA fragmentation may fertilise an oocyte, but subsequent embryo development stops before implantation, or it may even initiate a pregnancy, but there is a significantly higher likelihood that it will result in miscarriage. The causes of DNA fragmentation are chemical and toxin exposure, heat exposure, testicular varicoeles, infection, advanced paternal age, smoking, testicular cancer, radiation exposure and any other factors that cause elevation in free radical level in semen. It is known that the egg has the capacity to repair some DNA damage in the sperm. However, extensive DNA fragmentation most likely cannot be repaired by the egg, and the spontaneous miscarriage rate is approximately two times higher if a man has more than 30% of sperm showing DNA fragmentation. DNA fragmentation is an excellent marker for exposure to potential reproductive toxicants and a diagnostic/prognostic tool for potential male infertility.[57] Social and dietary toxins such as alcohol, caffeine and trans faXy acids (hydrogenated oils) need to be completely avoided in order to improve sperm health. Alcohol consumption in men has been shown to be associated with poor sperm parameters. From a naturopathic perspective, all alcohol should be excluded from the diet for a minimum of 4 months prior to conceiving for both partners when they are trying to conceive, particularity for those who have experienced miscarriage. Excessive consumption of refined processed sugars, trans fats, caffeine and sugar are pro-inflammatory and risk increased oxidative stress. Oxidative stress is a proposed aetiology of fragmentation of sperm DNA. For more information, please refer to Chapter 11: Fertility – Female and Male.

Recommended investigations The causes of miscarriage are broad and varied, coming from both maternal and paternal factors. A comprehensive approach to investigation is always absolutely necessary. Naturopathically, we respect that our reproductive system is not isolated and is affected by our diet, lifestyle, emotions, thoughts and environment. No system can be considered in isolation, especially the immune system.[58] Thorough investigations are said to have mental and emotional benefit for couples who experience the heartbreak of miscarriage. Patients are frantically looking for answers to the ‘why?’, as opposed to simply being told their miscarriage was due to simply ‘misfortune’. Currently, the patient's doctor or specilaist will only investigate when the patient has experienced 2–3 prior miscarriages. It is warranted to investigate after only one miscarriage. Miscarriage can be preventable if the problems can be identified and treated. A thorough investigation often will identify multifaceted issues, giving clarity to treatment direction. See Table 12.7, Table 12.8 and Table 12.9. TABLE 12.7

Miscarriage screen: female blood tests

Assessment Test Immunological Lupus anticoagulant Immunoglobulin A (IgA) Anti-gliadin antibodies IgA Anti-gliadin antibodies IgG Antinuclear antibodies (ANA) Transglutaminase antibodies Endomysial antibodies Anti-dsDNA Immunophenotypes: natural killer (NK) cells Thyroid peroxidase antibody (TPO Ab) Thyroglobulin antibody (TG Ab) Thyroid stimulating hormone receptor antibody (TR Ab) or TSH receptor antibodies Thrombotic factors Protein C Protein S Anti thrombin III APC resistance Mucosal immunity Immunoglobulin A IgA Tissue transglutaminase antibodies (TTG) Anti-endomysial IgA Anti-gliadin IgA Anti-gliadin IgG Infective Mycoplasma hominis (S) PCR Ureaplasma PCR Listeria monocytogenes PCR Chlamydia PCR Toxoplasmosis PCR Syphilis Hep B Hep C HIV Rubella Endocrine Female hormone tracking FSH, LH, E2, prolactin, P4 Fasting insulin Fasting glucose Glucose tolerance test Haemoglobin A1c, A1C (HbA1c) Human chorionic gonadotropin (hCG)

Total testosterone Free testosterone FAI Sex hormone binding globulin (SHBG) Prolactin TSH

Free T4

Reference range 24–38 s 0.69–30.9 g/L 35 kg/m2 • High or low birth-weight infant • Previous macrosomia (baby with birth weight >4500 g or >90th percentile) • Polycystic ovary syndrome • Insulin resistance (before and in early pregnancy) • Medications: corticosteroids, antipsychotics.[313,349] Assessment Most women will be asymptomatic (a few may have the classic triad of polydipsia, polyphagia and polyuria) and routine testing with a 75 g oral glucose tolerance test (OGTT) is recommended at 24–28 weeks gestation.[349] Women with one or more risk factors may be screened earlier and more often. The International Association of Diabetes and Pregnancy Study Group Consensus Panel A provides threshold values for the diagnosis of GDM as shown in Table 13.8: a diagnosis is made on any one of the following values.[350]

TABLE 13.8 Threshold values for the diagnosis of GDM Glucose measure

mmol/L

Fasting plasma glucose 1-hour plasma glucose 2-hour plasma glucose

≥5.1 ≥10.0 ≥8.5

Source: International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33(3):676–82.

Complications Maternal complications of GDM include infertility, hypoglycaemia or hyperglycaemia, later development of type 2 diabetes, spontaneous abortion, preeclampsia and caesarean birth (due to macrosomia). Infant complications include macrosomia, physical and mental abnormalities, hypoglycaemia, respiratory distress, death, shoulder dystocia, bone fracture, nerve palsy and increased risk of developing metabolic and cardiovascular disease in adulthood. Management Prevention is clearly the best approach and this is where preconception planning and care are critical. Normalising glucose control, exercising regularly and achieving a healthy weight are core preconception goals. Pregnancy goals are to stabilise blood glucose levels and prevent complications of poorly controlled GDM. Medical management

Medical management includes dietary and lifestyle advice and pharmaceutical agents, typically metformin and glibenclamide oral preparations and subcutaneous insulin. Because of the increased risk of developing type 2 diabetes – especially if risk factors of advanced maternal age, obesity and ethnicity are present – a postnatal OGTT is recommended at 6–12 weeks postpartum and thereafter every 1–2 years. Alternatively, a HbA1c may be performed. [349]

Glycaemic targets in GDM:

• Fasting capillary BSL: ≤5.0 mmol/L • 1 hour after commencing meal BSL: ≤7.4 mmol/L • 2 hours after commencing meal BSL: ≤6.7 mmol/L.[349] Naturopathic management

Naturopathic management includes excellent preconception care to optimise maternal health and reduce the risk of developing GDM. Dietary support is central to effective management of GDM and is as per type 2 diabetes dietary management:

• Provide dietary and nutritional support to ensure that GWG guidelines are met • Follow low GI diet/Mediterranean-style diet • Undertake regular moderate exercise (e.g. 30-minute walk daily) • Ensure adequate fibre intake (satiation and aids in reducing excessive peaks in BSL) • Ensure low saturated fats and transfaUy acids • Provide food sources of omega-3 faUy acids such as sardines. A Mediterranean-style diet has been shown to reduce the risk of GDM.[351] A 2015 systematic review found that a dietary paUern rich in fruit, vegetables, whole grains and fish, and low in red and processed meat (fewer than 3 serves per week), refined grains and highfat dairy reduced the risk of developing GDM, although it did not quantify dairy serves or forms.[351] Supplementation:

• Zinc 25–60 mg • Chromium picolinate 200 micrograms • Magnesium 400–800 mg • Selenium 50–100 micrograms • Natal formula/B complex • EFAs, 400–600 mg each of EPA and DHA • ALA 300–400 micrograms • Protein: 1.2 g/kg • Vitamin B12 – metformin lowers total (not storage) of B12 so supplementation is suggested[352] • Vitamin D3 1000–4000 IU, dependent of blood tests • Probiotics. An increasing number of studies are investigating the role of probiotics in GDM management and a recent study found that supplementing with probiotics (probiotic capsules of four bacterial strains each of >4 × 109 CFU Lactobacillus acidophilus LA-5, Bifidobacterium BB-12, Streptococcus thermophilus STY-31 and Lactobacillus delbrueckii bulgaricus LBY-27) over 6 weeks lowered fasting blood glucose, reduced weight gain in the last 2 weeks of the 6-week study and reduced insulin resistance.[353] Low B12 has been associated with increased adiposity and insulin resistance and a recent study in the UK found that obese women were at risk of B12 deficiency; this in turn was

associated with a two-times probability of developing GDM.[164] A recent randomised controlled trial assessed the effects of omega-3 supplementation on inflammatory and oxidative markers in women with GDM. The women received 1000 mg of omega-3 faUy acid supplements (containing 180 mg eicosapentaenoic acid and 120 mg docosahexaenoic acid) or placebo for 6 weeks. This produced a significant decrease in hsCRP and plasma malondialdehyde and resulted in lower rates of infant hyperbilirubinaemia and hospitalisation.[354] A study on selenium supplementation (200 micrograms) for 6 weeks commencing between 24 and 28 weeks gestation resulted in a significant reduction in fasting plasma glucose and serum insulin levels and an increase in insulin sensitivity.[355] In addition, there was a reduction in hsCRP, thus showing an overall improvement in blood glucose management and a reduction in markers of oxidative stress. A study using a supplement of 250 mg of magnesium for 6 weeks similarly found improvements in glucose control, insulin levels, triglycerides and hsCRP and fewer hospitalisations for newborns.[256] Herbal medicine

Gymnema sylvestre traditionally has been used to lower BSL, but there is no research on GDM and no safety data to assess. Cinnamon spp have been shown to be effective in type 2 diabetes but are contraindicated in pregnancy.[43]

Iron deficiency anaemia of pregnancy Iron is essential for normal fetal development and some adverse effects caused by deficiency cannot be reversed by later addition to the diet. Iron deficiency is a common nutritional deficiency and studies on pregnant women consistently show iron deficiency and iron deficiency anaemia in pregnant women. A review of 1224 women as part of the US National Health and Nutrition Examination Survey (NHANES) 1999–2006 found that iron deficiency prevalence in pregnant women increased significantly with each trimester: 6.9% in trimester 1, 14.3% in trimester 2 and 29.5% in trimester 3. Women with two or more children and women with short interpregnancy intervals had the highest prevalence of iron deficiency.[356] Many women enter pregnancy with marginal iron stores (due to menstrual loss, poor intake and absorption, or other reasons) and the additional demands of pregnancy cannot be met. In a normal singleton pregnancy a total of 1000 mg of iron is required, with approximately 300 mg being delivered to the fetus, which preferentially obtains iron, folate and vitamin B12 from the mother. Maternal iron is transferred to the fetus via serum transferrin, which binds to receptors on the apical surface of the placental syncytiotrophoblast. Iron is then released from these receptors and binds to ferritin in placenta cells, where it is transferred to apotransferrin, which enters into the fetal circulation as holotransferrin.[357] If maternal iron levels are low, the placenta increases the number of transferrin receptors to facilitate more uptake of iron in an aUempt to protect the fetus from depletion, which further reduces maternal levels. Iron levels are affected by both iron intake and haemodilution. Starting around week 6 the maternal blood volume progressively increases until about 30 weeks, when it plateaus. For a

singleton pregnancy the average increase in blood volume is 40–50%. The blood plasma volume also increases progressively from around week 6 until week 30, when it too plateaus. Blood plasma volume increases by around 50% and this represents approximately 1200–1300 mL.[245] RBC mass begins to increase around week 10 and continues to rise until delivery. RBC mass increases around 18% by term: supplementing can increase this to 30%. The plasma volume increases to a greater degree than the RBC mass and then plateaus at week 30, so the maternal haematocrit falls, most notably around weeks 30–34. After this time, the reduction in haematocrit may lessen as the RBC mass continues to grow and the plasma volume plateaus.[28,245] This may not represent a pathological state, but rather normal maternal physiology. In a normal pregnancy and uncomplicated birth, if the mother has adequate iron stores her haematocrit and haemoglobin levels return to normal by 6 weeks postpartum.[358] The average blood loss in a normal vaginal delivery is 500 mL, which equates to around 250 mg of elemental iron and a ferritin level of 30 micrograms/L. Women who have a caesarean section have double the blood and iron loss.[251] Aetiology Around 75% of anaemia in pregnancy is due to iron deficiency (1 mL of erythrocytes contains 1.1 mg iron). Other causes include excessive haemodilution, deficiency in folate and B12, bleeding, haemolytic disorders, bone marrow suppression, chronic blood loss and haematological malignancies. Without supplementation, deficiency may occur in up to 50% of women. Risk factors In addition to the known causes above (e.g. blood loss), the following are risk factors for iron deficiency anaemia:

• Previous anaemia • Known haemoglobinopathy • Multiparity (3 or more) • Interpartum spacing 1.5 L of water per day Coffee reduced to 2 cups per day, none after 3 pm

Nutritional supplementation

Nutritional deficiencies were addressed through diet and supplementation. Iodine, zinc, selenium and iron were provided to support normal thyroid function, to reduce the risk of auto-antibody production and to support energy production. Selenium, zinc, vitamin C and EFAs were provided for their antioxidant and anti-inflammatory effects and iron was provided to correct the iron deficiency. Iron and zinc doses were not at the higher end of the therapeutic range as they may have been lower due to the inflammation that was present. It was unclear whether the ferritin level was elevated due to inflammation and thus would normally be lower. Zinc was also indicated in the management of anxiety and depression and to correct the imbalance in the copper:zinc ratio (aiming for a ratio of 1 : 1). Vitamin D supplementation was supplied to correct the deficiency and for its role in inflammation, immune function and mental health and cognitive function. No specific supplement was given for constipation as it was hoped that this would be resolved through diet and exercise. Vitamin C was included for adrenal function and gum health and a methylated B complex was added for neurological function, energy production and liver support. • Iron: 30 mg/day (with vitamin C and bioflavonoids) • Vitamin D: 4000 IU/day • Zinc: 30 mg/day • Omega-3: EFA, 3 mg, including 1020 mg EPA and 720 mg DHA • Selenium: 200 micrograms/day • Iodine: 150 micrograms/day • Vitamin C: 1000 mg/twice daily • Methylated B complex/day. Herbal medicine

Herbal medicine was used to modulate the GABA pathway and reduce anxiety (Piper methysticum, Passiflora incarnata), to modulate monamines (Hypericum perforatum, Rhodiola rosea), as a traditional anxiolytic for women (Leonurus cardiaca), as an adrenal tonic and anti-inflammatory (Glycyrrhiza glabra)

and as an adaptogen/tonic (Withania somnifera, Rhodiola rosea). Withania also supports the conversion of T4 to T3. Gentiana lutea was added as a bider digestive and hepatic and to stimulate appetite. A separate sleeping aid was not provided initially as ME wanted to first try the relaxation techniques provided by the psychologist. If one was required, the recommendation was for a simple preparation of Piper methysticum extract as it aids sleep and is anxiolytic. • Herbal formula – Rhodiola rosea 2 : 1 60 mL – Withania somnifera 2 : 1 50 mL – Leonurus cardiaca 1 : 2 30 mL – Passiflora incarnata 1 : 2 40 mL – Gentiana lutea 1 : 2 20 mL dose 5 mL tds – Hypericum perforatum tablets, 1.8 g 1 tablet extract tds • Tisanes: ME was advised to drink 2 or more cups of herbal tisanes a day, including a blend of Passiflora incarnata, Verbena officinalis and Glycyrrhiza glabra (which also sated the desire for a sweet taste). Follow-up

ME returned 2 weeks later having been 75% compliant with her supplements and herbal medicine and having significantly improved her diet. She had only been for a walk twice, as she was not confident enough to go without DF. Her anxiety was reduced but still impacting her life, as was her depression. She was less constipated and was sleeping 4–5 hours per night. The plan was to continue the current regimen and encourage her to walk with friends and to continue the relaxation techniques provided by the psychologist. The regimen was reduced as her symptoms and health improved and her pathology results normalised over the following months, with omega-3 fady acid and a B complex as the only long-term supplements required.

References [1] Australian Government. 2015 intergenerational report: Australia in 2055. [Commonwealth of Australia; Available from] www.treasury.gov.au/PublicationsAndMedia/Publications/2015/2015-IntergenerationalReport; 2015. [2] Australian Institute of Health and Welfare (AIHW), Hilder L, Li Z, et al. Stillbirths in Australia, 1999–2009. Perinatal Statistics Series no. 29. Cat. no. PER 63. [Canberra: AIHW National Perinatal Epidemiology and Statistics Unit; Available from] www.aihw.gov.au/WorkArea/DownloadAsset.aspx?id=60129548877; 2014. [3] Australian Institute of Health and Welfare (AIHW). Perinatal data portal. [Available from] www.aihw.gov.au/perinatal-data. [4] Australian Institute of Health and Welfare (AIHW). Australia's mothers and babies, 2013: in brief. Perinatal Statistics Series no. 31. Cat no. PER 72. [Canberra: AIHW] 2015. [5] Australian Health Ministers’ Conference. National Maternity Services Plan 2010. [Canberra] 2010. [6] Australian Institute of Health and Welfare (AIHW). Australia's health 2014. Australia's Health Series no.14. Cat. no. AUS 178. [Canberra: AIHW] 2014. [7] OECD. Health at a glance 2011: OECD indicators. OECD Publishing: Paris; 2011.

[8] Steel A, Adams J. The role of naturopathy in pregnancy, labour and post-natal care: broadening the evidence base. Complement Ther Clin Pract. 2011;17(4):189–192. [9] Steel A, Adams J, Sibbrid D, et al. Utilisation of complementary and alternative medicine (CAM) practitioners within maternity care provision: results from a nationally representative cohort study of 1835 pregnant women. BMC Pregnancy Childbirth. 2012;12(1):146. [10] Frawley J, Adams J, Sibbrid D, et al. Prevalence and determinants of complementary and alternative medicine use during pregnancy: results from a nationally representative sample of Australian pregnant women. Aust NZ J Obstet Gynaecol. 2013;53(4):347–352. [11] Holst L, Wright D, Haavil S, et al. Safety and efficacy of herbal remedies in obstetrics: review and clinical implications. Midwifery. 2011;27(1):80–86. [12] Nordeng H, Bayne K, Havnen GC, et al. Use of herbal drugs during pregnancy among 600 Norwegian women in relation to concurrent use of conventional drugs and pregnancy outcome. Complement Ther Clin Pr. 2011;17(3):147–151. [13] Birdee GS, Kemper KJ, Rothman R, et al. Use of complementary and alternative medicine during pregnancy and the postpartum period: an analysis of the National Health Interview Survey. J Womens Health (Larchmt). 2014;23(10):824–829. [14] Moussally K, Oriachi D, Berard A. Herbal products used during pregnancy: prevalence and predictors. Pharmacoepidemiol Drug Saf. 2009;18(6):454–461. [15] Kennedy DA, Lupadelli A, Koren G, et al. Safety classification of herbal medicines used in pregnancy in a multinational study. BMC Complement Altern Med. 2016;16:2012. [16] Guise JM, Eden K, Emeis C, et al. Vaginal birth after cesarean: new insights. Evid Rep Technol Assess. 2010;191:1–397. [17] Dodd JM, Crowther CA, Huertas E, et al. Planned elective repeat caesarean section versus planned vaginal birth for women with a previous caesarean birth. Cochrane Database Syst Rev. 2013;(12) [CD004224]. [18] Leved KM, Smith CA, Bensoussan A, et al. Complementary therapies for labour and birth study: a randomised controlled trial of antenatal integrative medicine for pain management in labour. BMJ Open. 2016;6(7):e010691. [19] Fairbrother N, Janssen P, Antony M, et al. Perinatal anxiety disorder prevalence and incidence. J Affect Disord. 2016;200:148–155. [20] Walsh D. The hidden experience of violence during pregnancy: a study of 400 pregnant Australian women. Aust J Prim Heal. 2008;14(1):97–105. [21] Bailey BA. Partner violence during pregnancy: prevalence, effects, screening, and management. Int J Womens Health. 2010;2:183–197. [22] Hoang TN, Van TN, Gammeltoft TW, et al. Association between intimate partner violence during pregnancy and adverse pregnancy outcomes in Vietnam: a prospective cohort study. PLoS ONE. 2016. [23] Australian Bureau of Statistics. Personal Safety Survey, Australia, 2012. Australian Bureau of Statistics: Canberra; 2013. [24] Jahanfar S, Howard LM, Medley N. Interventions for preventing or reducing domestic violence against pregnant women. Cochrane Database Syst Rev. 2014;(11) [CD009414]. [25] Rosenfeld CS. Homage to the ‘H’ in developmental origins of health and disease. J Dev Orig Heal Dis. 2017;8(1):8–29.

[26] Guardino CM, Scheder CD, Saxbe DE, et al. Diurnal salivary cortisol paderns prior to pregnancy predict infant birth weight. Heal Psychol. 2016;35(6):625–633. [27] Hocher B. More than genes: the advanced fetal programming hypothesis. J Reprod Immunol. 2014;104–105:8–11. [28] Lowensohn R, Stadler D, Naze C. Current concepts of maternal nutrtition. Obstet Gynecol Surv. 2016;71(7):413–426. [29] Marques AH, O'Connor TG, Roth C, et al. The influence of maternal prenatal and early childhood nutrition and maternal prenatal stress on offspring immune system development and neurodevelopmental disorders. Front Neurosci. 2013;7(120). [30] Vickers MH. Early life nutrition, epigenetics and programming of later life disease. Nutrients. 2014;6(6):2165–2178. [31] Geraghty AA, Lindsay KL, Alberdi G, et al. Nutrition during pregnancy impacts offspring's epigenetic status: evidence from human and animal studies. Nutr Metab Insights. 2015;8(Suppl. 1):41–47. [32] von Meyenn F, Reik W. Forget the parents: epigenetic reprogramming in human germ cells. Cell. 2015;161(6):1248–1251. [33] Zeng Y, Zhou Y, Chen P, et al. Use of complementary and alternative medicine across the childbirth spectrum in China. Complement Ther Med. 2014;22(6):1047–1052. [34] Al-Ramahi R, Jaradat N, Adawi D. Use of herbal medicines during pregnancy in a group of Palestinian women. J Ethnopharmaco. 2013;150(1):79–84. [35] Forster DA, Wills G, Denning A, et al. The use of folic acid and other vitamins before and during pregnancy in a group of women in Melbourne, Australia. Birth. 2009;25(2):134–146. [36] Maats FH, Crowther CA. Paderns of vitamin, mineral and herbal supplement use prior to and during pregnancy. Aust NZ J Obs Gynaecol. 2002;42(2):494–496. [37] Masih SP, Plumptre L, Ly A, et al. Pregnant Canadian women achieve recommended intakes of one-carbon nutrients through prenatal supplementation but the supplement composition, including choline, requires reconsideration. J Nutr. 2015;145(8):1824–1834. [38] Bixenstine PJ, Cheng TL, Cheng D, et al. Folic acid supplementation before pregnancy: reasons for non-use and association with preconception counseling HHS public access. Matern Child Heal J. 2015;19(9):1974–1984. [39] Strouss L, Mackley A, Guillen U, et al. Complementary and alternative medicine use in women during pregnancy: do their healthcare providers know? BMC Complement Altern Med. 2014;14(85):1–9. [40] Stephens S, Wilson G. Prescribing in pregnant women: guide to general principles. Prescriber. 2009;20(23–24):1–4. [41] Kovacic P, Somanathen R. Mechanism of teratogenesis: electron transfer, reactive oxygen species, and antioxidants. Birth Defects Res C Embryo Today. 2006;78(4):308–325. [42] Freyer AM. Drug-prescribing challenges during pregnancy. Obstet Gynaecol Reprod Med. 2008;18(7):180–186. [43] Braun L, Cohen M. Herbs and Natural supplements: an evidence-based guide. 4th ed. Elsevier: Sydney; 2015. [44] Centres for Disease Control and Prevention (CDC). Birth defects. [Available from] www.cdc.gov/ncbddd/birthdefects/index.html. [45] Abeywardana S, Sullivan EA. Congenital anomalies in Australia 2002–2003. Birth Anomalies

Series no. 3. Cat. no. PER 41. [Sydney] 2002. [46] Webster WS, Freeman JAD. Is this drug safe in pregnancy? Reprod Toxicol. 2001;15(6):619– 629. [47] Bone K, Mills S. Principles and practice of phytotherapy: modern herbal medicine. 2nd ed. Churchill Livingstone: Philadelphia; 2013. [48] Mills S, Bone K. The essential guide to herbal safety. Elsevier: Philadelphia; 2005. [49] Romm A. Botanical medicine for women's health. Elsevier: Philadelphia; 2010. [50] Thomas SHL, Yates LM. Prescribing without evidence: pregnancy. Br J Clin Pharmacol. 2012;74(4):691–697. [51] Kovacs CS, Ralston SH. Presentation and management of osteoporosis presenting in association with pregnancy or lactation. Osteoporos Int. 2015;26(9):2223–2241. [52] Institute of Medicine (IOM). Weight gain during pregnancy: reexamining the guidelines. National Academies Press: Washington; 2009:1–2. [53] Beyerlein A, Schiessl B, vonKries R. Associations of gestational weight loss with birthrelated outcome: a retrospective cohort study. BJOG. 2011;118(1):55–61. [54] Kapadia MZ, Park CK, Beyene J, et al. Weight loss instead of weight gain within the guidelines in obese women during pregnancy: a systematic review and meta-analyses of maternal and infant outcomes. PLoS ONE. 2015;10(7). [55] Institute of Medicine (IOM). Weight gain during pregnancy: reexamining the guidelines. National Academies Press: Washington; 2009. [56] Australian Government Department of Health and NZ MoH. Nutrient reference values. [Available from] www.nrv.gov.au/dietary-energy. [57] De Jersey SJ, Nicholson JM, Callaway LK, et al. A prospective study of pregnancy weight gain in Australian women. Aust NZ J Obstet Gynaecol. 2012;52(6):545–551. [58] Jeffs E, Haszard J, Sharp B, et al. Pregnant women lack accurate knowledge of their BMI and recommended gestation weight gain. NZ Med J. 2016;129(1439):37–45. [59] Bookari K, Yeatman H, Williamson M. Australian pregnant women's awareness of gestational weight gain and dietary guidelines: opportunity for action. J Pregnancy. 2016. [60] Horvix West E, Hark L, Catalano P. Nutrition during pregnancy. Gabbe S, Niebyl J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [61] Australian Bureau of Statistics. Overweight and obesity. 4338.0 Profiles of Health, Australia, 2011–13. [Canberra: ABS] 2013. [62] Craig R, Fuller E, Mindell J. Health Survey for England 2014: health, social care and lifestyles. [London] 2014. [63] Morgan KL, Rahman MA, Hill RA, et al. Obesity in pregnancy: infant health service utilisation and costs on the NHS Centre for the Development and Evaluation of Complex Interventions for Public Health Improvement. BMJ Open. 2015;5. [64] Widen EM, Whyad RM, Hoepner LA, et al. Excessive gestational weight gain is associated with long-term body fat and weight retention at 7 y postpartum in African American and Dominican mothers with underweight, normal, and overweight prepregnancy BMI. Am J Clin Nutr. 2015;102(6):1460–1467. [65] Stotland NE, Bodnar LM, Abrams B. Maternal nutrition. Creasy RK, Resnik R, Iams JD, et al. Creasy & Resnik's maternal-fetal medicine: principles and practice. 7th ed. Elsevier:

Philadelphia; 2014. [66] McAree T, Jacobs B, Manickavasagar T, et al. Vitamin D deficiency in pregnancy: still a public health issue. Matern Child Nutr. 2013;9(1):23–30. [67] Shub A, Huning EY, Campbell KJ, et al. Pregnant women's knowledge of weight, weight gain, complications of obesity and weight management strategies in pregnancy. BMC Res Notes. 2013;6(278). [68] Drehmer M, Duncan BB, Kac G, et al. Association of second and third trimester weight gain in pregnancy with maternal and fetal outcomes. PLoS ONE. 2013. [69] Godoy AC, do Nascimento SL, Garanhani Surita F. A systematic review and meta-analysis of gestational weight gain recommendations and related outcomes in Brazil. Clin (San Paulo). 2015;70(11):758–764. [70] Castillo H, Santos I, Matijasevich A. Maternal pre-pregnancy BMI, gestational weight gain and breastfeeding. Eur J Clin Nutr. 2016;70:431–436. [71] Park S, Sappenfield WM, Bish C, et al. Assessment of the Institute of Medicine recommendations for weight gain during pregnancy: Florida, 2004–2007. Matern Child Health J. 2011. [72] Simas TAM, Waring ME, Liao X, et al. Prepregnancy weight, gestational weight gain, and risk of growth affected neonates. J Womens Health (Larchmt). 2011;21(4):410–417. [73] Lemas DJ, Young BE, Baker PR, et al. Alterations in human milk leptin and insulin are associated with early changes in the infant intestinal microbiome. Am J Clin Nutr. 2016;103(5):1291–1300. [74] Bodnar LM, Pugh SJ, Abrams B, et al. Gestational weight gain in twin pregnancies and maternal and child health: a systematic review. J Perinatol. 2014;34(4):252–263. [75] Bacak S, Zozzaro-Smith P, Glanx J, et al. Impact of weight gain in triplet pregnancies on perinatal outcomes. Am J Obstet Gynecol. 2015;212(1):S275–6. [76] Johnston RC, Erfani H, Shamshirsaz A, et al. Optimal weight gain in triplet pregnancies. J Matern Fetal Neonatal Med. 2017;31(6):1–22. [77] Bricker L, Reed K, Wood L, et al. Nutritional advice for improving outcomes in multiple pregnancies. Cochrane Database Syst Rev. 2015;(11) [CD008867]. [78] Martin JA, Hamilton BE, Osterman MJK. Three decades of twin births in the United States, 1980–2009. Centers for Disease Control and Prevention: Atlanta; 2012:1–8. [79] Australian Bureau of Statistics. Births. 3301.0 Births, Australia. [Available from] www.abs.gov.au/AUSSTATS; 2015. [80] Fertility Society of Australia. Code of Practice for Assisted Reproductive Technology Units. [South Melbourne: Fertility Society of Australia] 2014. [81] Craig WJ, Mangels AR, American Dietetic Association. Position of the American Dietetic Association: vegetarian diets. J Am Diet Assoc. 2009;109:1266–1282. [82] Piccoli GB, Clari R, Vigodi FN, et al. Vegan-vegetarian diets in pregnancy: danger or panacea? A systematic narrative review. BJOG. 2015;122(5):623–633. [83] Australian Institute of Health and Welfare (AIHW). Risk factors: teenage pregnancy. [Canberra: AIHW] 2016. [84] Montgomery KS. Improving nutrition in pregnant adolescents: recommendations for clinical practitioners. J Perinat Educ. 2003;12(2):22–30. [85] Lee S, Guillet R, Cooper EM, et al. Prevalence of anemia and associations between neonatal

iron status, hepcidin, and maternal iron status among neonates born to pregnant adolescents. Pediatr Res. 2016;79(1–1):42–48. [86] Ball SJ, Pereira G, Jacoby P, et al. Re-evaluation of link between interpregnancy interval and adverse birth outcomes: retrospective cohort study matching two intervals per mother. Br Med J. 2014;69(12):717–719. [87] Gemmill A, Lindberg L. Short interpregnancy intervals in the United States. Obs Gynecol. 2013;122(1):64–71. [88] Cofer FG, Fridman M, Lawton E, et al. Interpregnancy interval and childbirth outcomes in California, 2007–2009. Matern Child Heal J. 2016;20(Suppl. 1):43–51. [89] Chen I, Jhangri GS, Chandra S. Relationship between interpregnancy interval and congenital anomalies. Am J Obs Gynecol. 2014;210(6):564.e1–564.e8. [90] Hure A, Young A, Smith R, et al. Diet and pregnancy status in Australian women. Public Health Nutr. 2008;12(6):853–861. [91] de Jersey SJ, Nicholson JM, Callaway LK, et al. An observational study of nutrition and physical activity behaviours, knowledge, and advice in pregnancy. BMC Pregnancy Childbirth. 2013;13:115. [92] Food Standards Australia and New Zealand. Mercury in fish. [Available from] www.foodstandards.gov.au/consumer/chemicals/mercury/Pages/default.aspx. [93] US Food & Drug Administration. What you need to know about mercury in fish and shellfish. [Available from] www.fda.gov/food/resourcesforyou/consumers/ucm110591.htm. [94] Grosso LM, Bracken MB. Caffeine metabolism, genetics, and perinatal outcomes: a review of exposure assessment considerations during pregnancy. Ann Epidemiol. 2005;15(6):460–466. [95] Ebrahimi A, Habibi-Khorassani M, Akher FB, et al. Caffeine as base analogue of adenine or guanine: a theoretical study. J Mol Graph Model. 2013;42:81–91. [96] Li J, Zhao H, Song J-M, et al. A meta-analysis of risk of pregnancy loss and caffeine and coffee consumption during pregnancy. Int J Gynecol Obstet. 2015;130:116–122. [97] Gaskins AJ, Rich-Edwards JW, Williams PL, et al. Pre-pregnancy caffeine and caffeinated beverage intake and risk of spontaneous abortion. Eur J Nutr. 2018;57(1):105–107. [98] Victoria Escolano-Margarit M, Campoy C, Carmen Ramírez-Tortosa M, et al. Effects of fish oil supplementation on the fady acid profile in erythrocyte membrane and plasma phospholipids of pregnant women and their offspring: a randomised controlled trial. Br J Nutr. 2016;109:1647–1656. [99] Meher A, Randhir K, Mehendale S, et al. Maternal fady acids and their association with birth outcome: a prospective study. PLoS ONE. 2016;11(1). [100] Bobiński R, Mikulska M. The ins and outs of maternal-fetal fady acid metabolism. Acta Biochim Pol. 2015;62(3):499–507. [101] Makrides M, Best K. The role of DHA in the first 1000 days: docosahexaenoic acid and preterm birth. Nutr Metab. 2016;69:30–34. [102] Pinto TJP, Farias DR, Rebelo F, et al. Lower inter-partum interval and unhealthy life-style factors are inversely associated with n-3 essential fady acids changes during pregnancy: a prospective cohort with Brazilian women. PLoS ONE. 2015;10(3). [103] Leventakou V, Roumeliotaki T, Martinez D, et al. Fish intake during pregnancy, fetal growth, and gestational length in 19 European birth cohort studies. Am J Clin Nutr. 2014;99(3):506–516.

[104] Lazzarin N, Vaquero E, Exacoustos C, et al. Low-dose aspirin and omega-3 fady acids improve uterine artery blood flow velocity in women with recurrent miscarriage due to impaired uterine perfusion. Fertil Steril. 2009;92(1):296. [105] Carta G, Iovenidi P, Falciglia K. Recurrent miscarriage associated with antiphospholipid antibodies: prophylactic treatment with low-dose aspirin and fish oil derivates. Clin Exp Obs Gynecol. 2005;32(1):49–51. [106] Swanson D, Block R, Mousa SA. Omega-3 fady acids EPA and DHA: health benefits throughout life. Adv Nutr. 2012;3:1–7. [107] Anderson G, Maes M. Postpartum depression: psychoneuroimmunological underpinnings and treatment. Neuropsychiatr Dis Treat. 2013;9:277–287. [108] Chong MF, Ong YL, Calder PC, et al. Long-chain polyunsaturated fady acid status during pregnancy and maternal mental health in pregnancy and the postpartum period: results from the GUSTO study. J Clin Psychiatry. 2015;76(7):e848–56. [109] Hamazaki K, Harauma A, Otaka Y, et al. Serum n-3 polyunsaturated fady acids and psychological distress in early pregnancy: Adjunct Study of Japan Environment and Children's Study. Transl Psychiatry. 2016;6:e737. [110] Pinto TJ, Vilela AA, Farias DR, et al. Serum n-3 polyunsaturated fady acids are inversely associated with longitudinal changes in depressive symptoms during pregnancy. Epidemiol Psychiatr Sci. 2016. [111] Makrides M, Duly L, Olsen SF. Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by pre-eclampsia or intrauterine growth restriction. Cochrane Database Syst Rev. 2006;(3) [CD003402]. [112] Lapido OA. Nutrition in pregnancy: mineral and vitamin supplements. Am J Clin Nutr. 2010;72(1):280s–290s. [113] Gabbe S, Niebyl J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [114] Grieger JA, Clifton VL. A review of the impact of dietary intakes in human pregnancy on infant birthweight. Nutrients. 2015;7:153–178. [115] Abdou E, Hazell AS. Thiamine deficiency: an update of pathophysiologic mechanisms and future therapeutic considerations. Neurochem Res. 2014;40(2):353–361. [116] Bâ A. Comparative effects of alcohol and thiamine deficiency on the developing central nervous system. Behav Brain Res. 2011;225(1):235–242. [117] Bâ A. Alcohol and B1 vitamin deficiency-related stillbirths. J Matern Fetal Neonatal Med. 2009;22(5):452–457. [118] Krapels IPC, Van Rooij IALM, Ocké MC, et al. Maternal dietary B vitamin intake, other than folate, and the association with orofacial cleft in the offspring. Eur J Nutr. 2004;43(1):7–14. [119] Kerns JC, Arundel C, Chawla LS. Thiamin deficiency in people with obesity. Adv Nutr. 2015;6:147–153. [120] Chan J, Deng L, Mikael LG, et al. Low dietary choline and low dietary riboflavin during pregnancy influence reproductive outcomes and heart development in mice. Am J Clin Nutr. 2010;91(4):1035–1043. [121] Smedts HPM, Rakhshandehroo M, Verkleij-Hagoort AC, et al. Maternal intake of fat, riboflavin and nicotinamide and the risk of having offspring with congenital heart defects. Eur J Nutr. 2008;47(7):357–365.

[122] Neugebauer J, Zanre Y, Wacker J. Riboflavin supplementation and preeclampsia. Int J Gynaecol Obs. 2006;93(2):136–137. [123] Molina L, Rivas V, Sanchez R, et al. PROPER: a pilot study of the role of riboflavin supplementation for the prevention of preeclampsia. Int J Biol Biomed Eng. 2012;6(1):43–50. [124] Li F, Fushima T, Oyanagi G, et al. Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia. Proc Natl Acad Sci. 2016;113(47):13450–13455. [125] Tian Y-J, Luo N, Chen N-N, et al. Maternal nicotinamide supplementation causes global DNA hypomethylation, uracil hypo-incorporation and gene expression changes in fetal rats. Br J Nutr. 2014;111(9):1594–1601. [126] El-Heis S, Crozier S, Robinson S, et al. Higher maternal serum concentrations of nicotinamide and related metabolites in late pregnancy are associated with a lower risk of offspring atopic eczema at age 12 months. Europe PMC Funders Group. Clin Exp Allergy. 2016;46(10):1337–1343. [127] Scheller K, Röckl T, Scheller C, et al. Lower concentrations of B-vitamin subgroups in the serum and amniotic fluid correlate to cleft lip and palate appearance in the offspring of A/WySn mice. J Oral Maxillofac Surg. 2013;71(9). [128] Haggarty P, Campbell DM, Duthie S, et al. Diet and deprivation in pregnancy. Br J Nutr. 2009;102(10):1487–1497. [129] Kalhan S. One carbon metabolism in pregnancy: impact on maternal, fetal and neonatal health. Mol Cell Endocrinol. 2016;435:48–60. [130] Dror DK, Allen LH. Interventions with vitamins B6, B12 and C in pregnancy. Paediatr Perinat Epidemiol. 2012;26(Suppl. 1):55–74. [131] Ronnenberg AG, Venners SA, Xu X, et al. Preconception B-vitamin and homocysteine status, conception, and early pregnancy loss. Am J Epidemiol. 2007;166(3):304–312. [132] Hovdenak N, Haram K. Influence of mineral and vitamin supplements on pregnancy outcome. Eur J Obstet Gynecol Reprod Biol. 2012;164:127–132. [133] Agarwal N, Dora S, Kriplani A, et al. Response of therapy with vitamin B6, B12 and folic acid on homocysteine level and pregnancy outcome in hyperhomocysteinemia with unexplained recurrent aborts. Int J Gynecol Obstet. 2012;119(3):S759. [134] Cikot RJ, Steegers-Theunissen RP, Thomas CM, et al. Longitudinal vitamin and homocysteine levels in normal pregnancy. Br J Nutr. 2001;85(1):49–58. [135] Suren P, Roth C, Bresnahan M, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. J Am Med Assoc. 2013;309(6):570–577. [136] Laanpere M, Altmae S, Stavreus-Evers A, et al. Folate-mediated one-carbon metabolism and its effect on female fertility and pregnancy viability. Nutr Rev. 2010;68(2):99–113. [137] Sayyah-Melli M, Ghorbanihaghjo A, Alizadeh M, et al. The effect of high dose folic acid throughout pregnancy on homocysteine (Hcy) concentration and pre-eclampsia: a randomized clinical trial. PLoS ONE. 2016;11(5):1–11. [138] Wu X, Zhao L, Zhu H, et al. Association between the MTHFR C677T polymorphism and recurrent pregnancy loss: a meta-analysis. Genet Test Mol Biomarkers. 2012;16(7):806–811. [139] Wu X, Yang K, Tang X, et al. Folate metabolism gene polymorphisms MTHFR C677T and A1298C and risk for preeclampsia: a meta-analysis. J Assist Reprod Genet. 2015;32(5):797–805. [140] Nair RR, Khanna A, Singh R, et al. Association of maternal and fetal MTHFR A1298C

polymorphism with the risk of pregnancy loss: a study of an Indian population and a metaanalysis. Fertil Steril. 2013;99(5):1311–1318. [141] Allen L, De Benoist B, Dary O, et al. Guidelines on food fortification with micronutrients. WHO: Geneva; 2006. [142] Food Fortification Initiative. Global progress. [Available from] www.ffinetwork.org/global_progress/index.php. [143] Bailey LB, Stover PJ, Mcnulty H, et al. Biomarkers of Nutrition for development: folate review. J Nutr. 2015;145(7):1–45. [144] Crider KS, Bailey LB, Berry RJ. Folic acid food fortification: its history, effect, concerns, and future directions. Nutrients. 2011;3(3):370–384. [145] New Zealand Ministry of Health. Folate/folic acid. [Available from] www.health.govt.nz/our-work/preventative-health-wellness/nutrition/folate-folicacid#current_polic. [146] National Perinatal Unit. Neural tube defects in Australia, 2007–2011. [Canberra: Commonwealth of Australia] 2011. [147] Daly LE, Kirke PN, Molloy A, et al. Folate levels and neural tube defects: implications for prevention. JAMA. 1995;274(21):1698–1702. [148] Crider KS, Devine O, Hao L, et al. Population red blood cell folate concentrations for prevention of neural tube defects: bayesian model. BMJ. 2014;349:g4554. [149] World Health Organization. Guideline optimal serum and red blood cell folate concentrations in women of reprodutive age for prevention of NTD. World Heal Organ. 2015;1542:33–36. [150] Czeizal AE, Duda I. Prevention of the first occurence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992;327(10):685–691. [151] Berry RJ, Li Z, Erickson JD, et al. Prevention of neural-tube defects with folic acid in China. English J. 1999;341(20):1485. [152] De-Regil LM, Fernández-Gaxiola AC, Dowswell T, et al. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database Syst Rev. 2014;2(10):1–135. [153] Kim H, Kim K-N, Hwang J-Y, et al. Relation between serum folate status and blood mercury concentrations in pregnant women. Nutrition. 2013;29(3):514–518. [154] Centres for Disease Control and Prevention. Folic acid: data and statistics. [Available from] www.cdc.gov/NCBDDD/folicacid/data.html. [155] McKeating A, Farren M, Cawley S, et al. Maternal folic acid supplementation trends 2009– 2013. Acta Obs Gynecol Scand. 2015;94(7):727–733. [156] Pre-Conception Health Special Interest Group. Micronutrient (folic acid, iodine and vitamin D) supplements pre-conception and during pregnancy. [Melbourne: Fertility Society Australia] 2016 [p. 1–4]. [157] Hekmatdoost A, Vahid F, Yari Z, et al. Methyltetrahydrofolate vs folic acid supplementation in idiopathic recurrent miscarriage with respect to methylenetetrahydrofolate reductase C677T and A1298C polymorphisms: a randomized controlled trial. PLoS ONE. 2015;10(12):1–12. [158] Gernand AD, Schulze KJ, Stewart CP, et al. Micronutrient deficiencies in pregnancy worldwide: health effects and prevention HHS Public Access. Nat Rev Endocrinol.

2016;12(5):274–289. [159] Kumar KA, Lalitha A, Pavithra D, et al. Maternal dietary folate and/or vitamin B12 restrictions alter body composition (adiposity) and lipid metabolism in Wistar rat offspring. J Nutr Biochem. 2013;24(1):25–31. [160] Jamshed Siddiqui M, Sze Min C, Kumar Verma R, et al. Role of complementary and alternative medicine in geriatric care: a mini review. Pharmacogn Rev. 2014;8(16):81–87. [161] Sukumar N, Rafnsson SB, Kandala NB, et al. Prevalence of vitamin B12 insufficiency during pregnancy and its effect on offspring birth weight: a systematic review and meta-analysis. Am J Clin Nutr. 2016;103(5):1232–1251. [162] Finkelstein JL, Layden AJ, Stover PJ. Vitamin B12 and perinatal health. Adv Nutr. 2015;6(5):552–563. [163] Singer AW, Selvin S, Block G, et al. Maternal prenatal intake of one-carbon metabolism nutrients and risk of childhood leukemia. Cancer Causes Control. 2016;27(7):929–940. [164] Sukumar N, Wilson S, Venkataraman H, et al. Low vitamin B12 in pregnancy is associated with maternal obesity and gestational diabetes. Endocr Abstr. 2015;39:206. [165] Rizzo G, Laganà AS, Maria A, et al. Vitamin B12 among vegetarians: status, assessment and supplementation. Nutrients. 2016;8(767):1–23. [166] Thakkar K, Billa G. Treatment of vitamin B12 deficiency-methylcobalamine? Cyancobalamine? Hydroxocobalamin? Clearing the confusion. Eur J Clin Nutr. 2015;69(1):1– 2. [167] Furukawa S, Nakajima A, Sameshima H. The longitudinal change of extracellular antioxidant status during pregnancy using an electron spin resonance method. J Matern Fetal Neonatal Med. 2016;18:2994–2999. [168] Mistry HD, Williams PJ. The importance of antioxidant micronutrients in pregnancy. Oxid Med Cell Longev. 2011;841749. [169] Ramiro-Cortijo D, Herrera T, Rodríguez-Rodríguez P, et al. Maternal plasma antioxidant status in the first trimester of pregnancy and development of obstetric complications. Placenta. 2016;47:37–45. [170] Mistry HD, Gill CA, Kurlak LO, et al. Association between maternal micronutrient status, oxidative stress, and common genetic variants in antioxidant enzymes at 15 weeks gestation in nulliparous women who subsequently develop preeclampsia. Free Radic Biol Med. 2015;78:147–155. [171] D'Souza V, Rani A, Patil V, et al. Increased oxidative stress from early pregnancy in women who develop preeclampsia. Clin Exp Hypertens. 2016;38(2):225–232. [172] Cohen JM, Beddaoui M, Kramer MS, et al. Maternal antioxidant levels in pregnancy and risk of preeclampsia and small for gestational age birth: a systematic review and metaanalysis. PLoS ONE. 2015;10(8). [173] Gandley R, Abramovic A. PP170. Prenatal vitamin C and E supplementation is associated with a reduction in placental abruption and preterm birth in smokers. Pregnancy Hypertens. 2012;2(3):331–332. [174] Yung H-W, Alnaes-Katjavivi P, Jones CJP, et al. Placental endoplasmic reticulum stress in gestational diabetes: the potential for therapeutic intervention with chemical chaperones and antioxidants. Diabetologia. 2016;59:2240–2250. [175] Rumbold A, Ota E, Nagata C, et al. Vitamin C supplementation in pregnancy. Cochrane

Database Syst Rev. 2015;(9) [CD004072]. [176] Abo-Elmady DM, Badawy EA, Hussein JS, et al. Role of heme oxygenase, leptin, coenzyme Q10 and trace elements in pre-eclamptic women. Indian J Clin Biochem. 2012;27(4):379–384. [177] Guan Z, Li HF, Guo LL, et al. Effects of vitamin C, vitamin E, and molecular hydrogen on the placental function in trophoblast cells. Arch Gynecol Obstet. 2015;292(2):337–342. [178] Shearer KD, Stoney PN, Morgan PJ, et al. A vitamin for the brain. Trends Neurosci. 2012;35(12):733–741. [179] Agarwal K, Dabke AT, Phuljhele NL, et al. Factors affecting serum vitamin A levels in matched maternal-cord pairs. Indian J Pediatr. 2008;75(5):443–446. [180] Christian P, Klemm R, Shamim AA, et al. Effects of vitamin A and beta-carotene supplementation on birth size and length of gestation in rural Bangladesh: a clusterrandomized trial. Am J Clin Nutr. 2013;97(1):188–194. [181] McCauley ME, van den Broek N, Dou L, et al. Vitamin A supplementation during pregnancy for maternal and newborn outcomes. Cochrane Database Syst Rev. 2015;(10) [CD008666]. [182] Shah D, Nagarajan N. Luteal insufficiency in first trimester. Indian J Endocrinol Metab. 2013;17(1):44–49. [183] Weinert LS, Silveiro SP. Maternal-fetal impact of vitamin D deficiency: a critical review. Matern Child Health J. 2014;19(1):94–101. [184] De-Regil LM, Palacios C, Lombardo LK, et al. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev. 2016;(1) [CD008873]. [185] Baca K, Simhan HN, Plad RW, et al. Low maternal 25-hydroxyvitamin D concentration increases the risk of severe and mild preeclampsia. Ann Epidemiol. 2016;26(12):853–857. [186] Gernand AD, Simhan HN, Caritis S, et al. Maternal vitamin D status and small-forgestational-age offspring in women at high risk for preeclampsia. Obstet Gynecol. 2014;123(1):40–48. [187] Kiely ME, Zhang JY, Kinsella M, et al. Vitamin D status is associated with uteroplacental dysfunction indicated by pre-eclampsia and small-for-gestational-age birth in a large prospective pregnancy cohort in Ireland with low vitamin D status. Am J Clin Nutr. 2016;104(2):354–361. [188] Miliku K, Vinkhuyzen A, Blanken LM, et al. Maternal vitamin D concentrations during pregnancy, fetal growth paderns, and risks of adverse birth outcomes. Am J Clin Nutr. 2016;103(6):1514–1522. [189] Andersen LB, Jorgensen JS, Jensen TK, et al. Vitamin D insufficiency is associated with increased risk of first trimester miscarriage in the Odense Child Cohort. Am J Clin Nutr. 2015;102(3):633–638. [190] Stubbs G, Henley K, Green J. Autism: will vitamin D supplementation during pregnancy and early childhood reduce the recurrence rate of autism in newborn siblings? Med Hypotheses. 2016;88:74–78. [191] Vinkhuyzen AAE, Eyles DW, Burne TH, et al. Gestational vitamin D deficiency and autismrelated traits: the Generation R Study. Molec Psychiatr. 2018; 10.1038/mp.2016.213 [advance online publication 29 November 2016]. [192] Munger KL, Aivo J, Hongell K, et al. Vitamin D Status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish maternity cohort. JAMA Neurol.

2016;73(5):515–519. [193] McGrath JJ, Burne TH, Féron F, et al. Developmental vitamin D deficiency and risk of schizophrenia: a 10-year update. Schizophr Bull. 2010;36(6):1073–1078. [194] Belderbos ME, Houben ML, Wilbrink B, et al. Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis. Pediatrics. 2011;127:e1513–20. [195] Urrutia-Pereira M, Solé D. Vitamin D deficiency in pregnancy and its impact of the fetus, the newborn and in childhood. Rev Paul Pediatr. 2015;33(1):104–113. [196] Wall CR, Stewart AW, Camargo CA, et al. Vitamin D activity of breast milk in women randomly assigned to vitamin D3 supplementation during pregnancy. Am J Clin Nutr. 2015;103(2):382–388. [197] Nowson CA, McGrath JJ, Ebeling PR, et al. Vitamin D and health in adults in Australia and New Zealand. Med J Aust. 2012;196(11):686–687. [198] Royal College of Obstetricians & Gynecologists. Vitamin D in pregnancy. Scientific Impact Paper no. 43. [London] 2014. [199] Burris HH, Camargo CA. Vitamin D and gestational diabetes mellitus. Curr Diab Rep. 2014;14(1):451. [200] Arnold DL, Enquobahrie DA, Qiu C, et al. Early pregnancy maternal vitamin D concentrations and risk of gestational diabetes mellitus. Paediatr Perinat Epidemiol. 2015;29(3):200–210. [201] Institute of Medicine (IOM), Ross AC, Taylor CL, et al. Dietary reference intakes for calcium and vitamin D. The National Academies Press: Washington, DC; 2011. [202] Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–1930. [203] Daly RM, Gagno C, Lu ZX, et al. Prevalence of vitamin D deficiency and its determinants in Australian adults aged 25 years and older: a national, population-based study. Clin Endocrinol (Oxf). 2012;77(1):26–35. [204] Mohammad KI, Kassab M, Shaban I, et al. Postpartum evaluation of vitamin D among a sample of Jordanian women. J Obs Gynaecol. 2016;18. [205] Yu CK, Sykes L, Sethi M, et al. Vitamin D deficiency and supplementation during pregnancy. Clin Endocrinol. 2009;70:685–690. [206] Hollis BW, Johnson D, Hulsey TC, et al. Vitamin D supplementation during pregnancy: double blind, randomized clinical trial of safety and effectiveness. Women's Heal. 2012;8(3):323–340. [207] Hamilton SA, McNeil R, Hollis BW, et al. Profound vitamin D deficiency in a diverse group of women during pregnancy living in a sun-rich environment at latitude 32N. Int J Endocrinol. 2010. [208] Thomas CE, Guillet R, Queenan RA, et al. Vitamin D status is inversely associated with anemia and serum erythropoietin during pregnancy. Am J Clin Nutr. 2015;102(5):1088–1095. [209] Rumbold A, Ota E, Hori H, et al. Vitamin E supplementation in pregnancy. Cochrane Database Syst Rev. 2015;(9) [CD004069]. [210] Shamim AA, Schulze K, Merrill RD, et al. First-trimester plasma tocopherols are associated with risk of miscarriage in rural Bangladesh. Am J Clin Nutr. 2015;101(2):294–301. [211] Lippi G, Franchini M. Vitamin K in neonates: facts and myths. Blood Transfus. 2011;9(1):4–9.

[212] Mock D. Marginal biotin deficiency is common in normal human pregnancy and is highly teratogenic in mice. J Nutr. 2009;139(1):154–157. [213] Agrawal S, Agrawal A, Said HM. Biotin deficiency enhances the inflammatory response of human dendritic cells. Am J Physiol Cell Physiol. 2016;311(3):C386–91. [214] Perry CA, West AA, Gayle A, et al. Pregnancy and lactation alter biomarkers of biotin metabolism in women consuming a controlled diet. J Nutr. 2014;144:1977–1984. [215] Mock D. Adequate intake of biotin in pregnancy: why bother? J Nutr. 2014;144(12):1885– 1886. [216] Zeisel SH. Nutrition in pregnancy: the argument for including a source of choline. Int J Wom Health. 2013;5(1):193–199. [217] Caudill M. Pre- and postnatal health: evidence of increased choline needs. J Am Diet Assoc. 2010;10(8):1198–1206. [218] Wozniak JR, Fuglestad AJ, Eckerle JK, et al. Choline supplementation in children with fetal alcohol spectrum disorders: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2015;102(5):1113–1125. [219] Grieger JA, Clifton VL. A review of the impact of dietary intake in human pregnancy on infant birthweight. Nutrients. 2015;7:153–178. [220] Edinger AS, Lamadrid-Figueroa H, Téllez-Rojo MM, et al. Effect of calcium supplementation on blood lead levels in pregnancy: a randomized placebo-controlled trial. Environ Health Perspect. 2009;117(11):26. [221] Hofmeyr GJ, Lawrie TA, Atallah AN, et al. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev. 2014; (6) [CD001059]. [222] World Health Organization (WHO). Guideline: calcium supplementation in pregnant women. WHO: Geneva; 2013 [Available from] www.who.int/about. [223] Buppasiri P, Lumbiganon P, Thinkamrop J, et al. Calcium supplementation (other than for preventing or treating hypertension) for improving pregnancy and infant outcomes. Cochrane Database Syst Rev. 2011;(10) [CD007079]. [224] Berry C, Ada MG. Hypertensive disorders in pregnancy. World J Nephrol. 2016;5(5):418–428. [225] Woods SE, Ghodsi V, Engel A, et al. Serum chromium and gestational diabetes. J Am Board Fam Med. 2008;21(2):153–157. [226] Sundararaman PG, Sridhar GR, Sujatha V, et al. Serum chromium levels in gestational diabetes mellitus. Indian J Endocrinol Metab. 2012;16:S70–3. [227] Skeaff SA. Iodine deficiency in pregnancy: the effect on neurodevelopment in the child. Nutrients. 2011;3(2):265–273. [228] Zimmermann MB. The role of iodine in human growth and development. Semin Cell Dev Biol. 2011;22:645–652. [229] Gallego G, Goodall S, Eastman CJ. Iodine defiency in Australia: is iodine supplementation for pregnant and lactating women warranted? Med J Aust. 2010;192(8):461–463. [230] Bath SC, Furmidge-Owen VL, Redman CWG, et al. Gestational changes in iodine status in a cohort study of pregnant women from the United Kingdom. Am J Clin Nutr. 2015;1180–1187. [231] Andersson M, De Benoist B, Delange F, et al. Prevention and control of iodine deficiency in pregnant and lactating women and in children less than 2 years old: conclusions and recommendations of the Technical Consultation WHO Secretariat on behalf of the

participants to the Consultation. Public Heal Nutr. 2007;10(12A):1606–1611. [232] Eastman CJ. Screening for thyroid disease and iodine deficiency. Pathology. 2012;44(2):153– 159. [233] Brantsæter AL, Abel MH, Haugen M, et al. Risk of suboptimal iodine intake in pregnant Norwegian women. Nutrients. 2013;5(2):424–440. [234] Hamrosi MA, Wallace EM, Riley MD. Iodine status in pregnant women living in Melbourne differs by ethnic group. Asia Pac J Clin Nutr. 2005;14(1):27–31. [235] Blumenthal N, Byth K, Eastman CJ. Iodine intake and thyroid function in pregnant women in a private clinical practice in northwestern Sydney before mandatory fortification of bread with iodised salt. J Thyroid Res. 2012. [236] Clifton VL, Hodyl NA, Fogarty PA, et al. The impact of iodine supplementation and bread fortification on urinary iodine concentrations in a mildly iodine-deficient population of pregnant women in South Australia. Nutr J. 2013;12:1. [237] Hynes KL, Otahal P, Hay I, et al. Mild iodine deficiency during pregnancy is associated with reduced educational outcomes in the offspring: 9-year follow-up of the gestational iodine cohort. J Clin Endocrinol Metab. 2013;98(5):1954–1962. [238] Qian M, Wang D, Watkins WE, et al. The effects of iodine on intelligence in children: a meta-analysis of studies conducted in China. Asia Pacific J Clin Nutr. 2005;14(1):32–43. [239] Connelly KJ, Boston BA, Pearce EN, et al. Congenital hypothyroidism caused by excess prenatal maternal iodine ingestion. J Pediatr. 2012;161(4):760–762. [240] Thaker VV, Leung AM, Braverman LE, et al. Iodine-induced hypothyroidism in full-term infants with congenital heart disease: more common than currently appreciated? J Clin Endocrinol Metab. 2014;99(10):3521–3526. [241] Sun X, Shan Z, Teng W. Effects of increased iodine intake on thyroid disorders. Endocrinol Metab. 2014;29(3):240–247. [242] Guan H, Li C, Fan C, et al. High iodine intake is a risk factor of post-partum thyroiditis: result of a survey from Shenyang, China. J Endocrinol Invest. 2005;28(10):876–881. [243] De Leo S, Pearce EN, Braverman LE. Iodine supplemenation in women during preconception, pregnancy and lactation: current clinical practice by US obstetricians and midwives. Thyroid. 2017;27(3):434–439. [244] Charlton K, Yeatman H, Lucas C, et al. Poor knowledge and practices related to iodine nutrition during pregnancy and lactation in Australian women: pre- and post-iodine fortification. Nutrients. 2012;4:1317–1327. [245] Antony KM, Racusin DA, Aagaard K, et al. Maternal physiology. Gabbe S, Niebyl J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [246] Choudhury V, Amin SB, Agarwal A, et al. Latent iron deficiency at birth influences auditory neural maturation in late preterm and term infants. Am J Clin Nutr. 2015;102(5):1030–1034. [247] Amin SB, Orlando M, Eddins A, et al. In utero iron status and auditory neural maturation in premature infants as evaluated by auditory brainstem response. J Pediatr. 2010;156(3):377– 381. [248] Behboudi-Gandevani S, Safary K, Moghaddam-Banaem L, et al. The relationship between maternal serum iron and zinc levels and their nutritional intakes in early pregnancy with

gestational diabetes. Biol Trace Elem Res. 2013;154(1):7–13. [249] Bao W, Chavarro JE, Tobias DK, et al. Long-term risk of type 2 diabetes in relation to habitual iron intake in women with a history of gestational diabetes: a prospective cohort study. Am J Clin Nutr. 2016;103(2):375–381. [250] Rawal S, Hinkle SN, Bao W, et al. A longitudinal study of iron status during pregnancy and the risk of gestational diabetes: findings from a prospective, multiracial cohort. Diabetologica. 2016;1–9. [251] Kidson-Gerber G, Zheng S. Iron deficiency in pregnancy: what you need to know. MedicineToday. 2016;17(4):41–46. [252] Pavord S, Myers B, Robinson S, et al. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol. 2012;156(5):588–600. [253] Jafrin W, Mia AR, Chakraborty PK, et al. An evaluation of serum magnesium status in preeclampsia compared to the normal pregnancy. Mymensingh Med J. 2014;23(4):649–653. [254] Rylander R. Magnesium in pregnancy blood pressure and pre-eclampsia: a review. Pregnancy Hypertens. 2014;4:146–149. [255] Nestler A, Rylander R, Kolisek M, et al. Blood pressure in pregnancy and magnesium sensitive genes. Pregnancy Hypertens. 2014;4:41–45. [256] Asemi Z, Karamali M, Jamilian M, et al. Magnesium supplementation affects metabolic status and pregnancy outcomes in gestational diabetes: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2015;102:222–229. [257] Goker TU, Tasdemir N, Kilic S, et al. Alterations of ionized and total magnesium levels in pregnant women with gestational diabetes mellitus. Gynecol Obs Invest. 2015;79(1):19–24. [258] Mostafavi E, Nargesi AA, Asbagh FA, et al. Abdominal obesity and gestational diabetes: the interactive role of magnesium. Magnes Res. 2015;28(4):116–125. [259] Supakatisant C, Phupong V. Oral magnesium for relief in pregnancy-induced leg cramps: a randomised controlled trial. Matern Child Nutr. 2015;11(2):139–145. [260] Rayman MP, Bath SC, Westaway J, et al. Selenium status in UK pregnant women and its relationship with hypertensive conditions of pregnancy. Br J Nutr. 2015;113:249–258. [261] Mistry HD, Kurlak LO, Young SD, et al. Maternal selenium, copper and zinc concentrations in pregnancy associated with small-for-gestational-age infants. Matern Child Nutr. 2014;10(3):327–334. [262] Tsuzuki S, Morimoto N, Hosokawa S, et al. Associations of maternal and neonatal serum trace element concentrations with neonatal birth weight. PLoS ONE. 2013;8(9):e75627. [263] Kong FJ, Ma LL, Chen SP, et al. Serum selenium level and gestational diabetes mellitus: a systematic review and meta-analysis. Nutr J. 2016;15(94):1–10. [264] Askari G, Iraj B, Salehi-Abargouei A, et al. The association between serum selenium and gestational diabetes mellitus: a systematic review and meta-analysis. J Trace Elem Med Biol. 2015;29:195–201. [265] Terrin G, Canani RB, Di Chiara M, et al. Zinc in early life: a key element in the fetus and preterm neonate. Nutrients. 2015;7:10427–10446. [266] Darnton-Hill I. Zinc supplementation during pregnancy: biological, behavioural and contextual rationale. [Available from] www.who.int/elena/bbc/zinc_pregnancy/en. [267] Vela G, Stark P, Socha M, et al. Zinc in gut–brain interaction in autism and neurological disorders. Neural Plast. 2015;972791.

[268] Chaffee BW, King JC. Effect of zinc supplementation on pregnancy and infant outcomes: a systematic review. Paediatr Perinat Epidemiol. 2012;26(Suppl. 1):118–137. [269] Vashum KP, McEvoy M, Milton AH, et al. Dietary zinc is associated with a lower incidence of depression: findings from two Australian cohorts. J Affect Disord. 2014;166:249–257. [270] Roomruangwong C, Kanchanatawan B, Sirivichayakul S, et al. Lower serum zinc and higher CRP strongly predict prenatal depression and physio-somatic symptoms, which all together predict postnatal depressive symptoms. Mol Neurobiol. 2016;1–10. [271] Swardfager W, Herrmann N, Mazereeuw G, et al. Zinc in depression: a meta-analysis. Biol Psychiatry. 2013;74(15):872–878. [272] Donangelo CM, King JC. Maternal zinc intake and homeostatic adjustments during pregnancy and lactation. Nutrients. 2012;4:782–798. [273] Khadem N, Mohammadzadeh A, Farhat A, et al. Relationship between low birth weight neonate and maternal serum zinc concentration. Iran Red Crescent Med J. 2012;14(4):240–244. [274] Ota E, Mori R, Middleton P, et al. Zinc supplementation for improving pregnancy and infant outcome. Cochrane Database Syst Rev. 2015;(2) [CD000230]. [275] Ma Y, Shen X, Zhang D. The relationship between serum zinc level and preeclampsia: a meta-analysis. Nutrients. 2015;7(9):7806–7820. [276] Ilmonen J, Isolauri E, Poussa T, et al. Impact of dietary counselling and probiotic intervention on maternal anthropometric measurements during and after pregnancy: a randomized placebo-controlled trial. Clin Nutr. 2011;30(2):156–164. [277] Doege K, Grajecki D, Zyriax BC, et al. Impact of maternal supplementation with probiotics during pregnancy on atopic eczema in childhood: a meta-analysis. Br J Nutr. 2016;10:1–6. [278] Fiocchi A, Pawankar R, Cuello-Garcia C, et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): probiotics. WAO J. 2015;8(4):1–13. [279] Mendling W. Vaginal microbiota. Adv Exp Med Biol. 2016;902:83–93. [280] Nuriel-Ohayon M, Neuman H, Koren O. Microbial changes during pregnancy, birth, and infancy. Front Microbiol. 2016;7(1031):1–13. [281] Cole LA. hCG, the wonder of today's science. Reprod Biol Endocrinol. 2012;10(24):1–18. [282] Cole LA. Biological functions of hCG and hCG-related molecules. Reprod Biol Endocrinol. 2010;8(102):127–135. [283] Critchfield AS, Yao G, Jaishankar A, et al. Cervical mucus properties stratify risk for preterm birth. PLoS ONE. 2013;8(8):e69528. [284] Mestman JH. Thyroid and parathyroid diseases in pregnancy. Gabbe S, Niebyl J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [285] Burton GJ, Sibley CP, Jauniaux ERM, et al. Placental anatomy and physiology placental physiology 12. Gabbe S, Niebyl J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [286] Kim JH, Shin MS, Yi G, et al. Serum biomarkers for predicting pregnancy outcome in women undergoing IVF: human chorionic gonadotropin, progesterone, and inhibin A level at 11 days post-ET. Clin Exp Reprod Med. 2012;39(1):28–32. [287] Pan FC, Brissova M. Pancreas development in humans. Curr Opin Endocrinol Diabetes Ob. 2014;21(2):77–82. [288] Gregory KD, Ramos DE, Jauniaux ERM. Preconception and prenatal care. Gabbe S, Niebyl

J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [289] The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Prenatal screening and diagnosis of chromosomal and genetic conditions in the fetus in pregnancy. [East Melbourne] 2016. [290] Bromley B, Shipp TD. First-trimester imaging. Creasy RK, Resnik R, Iams JD, et al. Creasy and Resnik's maternal-fetal medicine: principles and practice. 7th ed. Elsevier: Philadelphia; 2014. [291] Park SY, Jang IA, Lee MA, et al. Screening for chromosomal abnormalities using combined test in the first trimester of pregnancy. Obs Gynecol Sci. 2016;59(5):357–366. [292] Gagnon A, Wilson RD, Audibert F, et al. Obstetrical complications associated with abnormal maternal serum markers analytes. J Obs Gynaecol Can. 2008;30(10):918–949. [293] Enciso M, Sarasa J, Xanthopoulou L, et al. Polymorphisms in the MTHFR gene influence embryo viability and the incidence of aneuploidy. Hum Genet. 2016;135(5):555–568. [294] Wapner RJ. Prenatal diagnosis of congenital disorders. Creasy RK, Resnik R, Iams JD, et al. Creasy and Resnik's maternal-fetal medicine: principles and practice. 7th ed. Elsevier: Philadelphia; 2014. [295] Wah YM, Leung TY, Cheng YK, et al. Procedure-related fetal loss following chorionic villus sampling after first-trimester aneuploidy screening. Fetal Diagn Ther. 2016;41(3):184–190. [296] O'Donnell A, McParlin C, Robson SC, et al. Treatments for hyperemesis gravidarum and nausea and vomiting in pregnancy: a systematic review and economic assessment. Heal Technol Assess. 2016;20(74):1–268. [297] Cappell MS. Gastrointestinal disorders during pregnancy. Gabbe S, Niebyl J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [298] Kelly TF, Savides TJ. Gastrointestinal disease in pregnancy. Creasy RK, Resnik R, Iams JD, et al. Creasy and Resnik's maternal-fetal medicine: principles and practice. 7th ed. Elsevier: Philadelphia; 2014. [299] Chortatos A, Haugen M, Iversen O, et al. Pregnancy complications and birth outcomes among women experiencing nausea only or nausea and vomiting during pregnancy in the Norwegian Mother and Child Cohort Study. BMC Pregnancy Childbirth. 2015;15:138. [300] Viljoen E, Visser J, Koen N, et al. A systematic review and meta-analysis of the effect and safety of ginger in the treatment of pregnancy-associated nausea and vomiting. Nutr J. 2014;13(1):20. [301] Goodwin TM, Poursharif B, Korst LM, et al. Secular trends in the treatment of hyperemesis gravidarum. Am J Perinatol. 2008;25(3):141–147. [302] Quinlan JD, Hill DA. Nausea and vomiting of pregnancy. Am Fam Physician. 2003;68(1):121–128. [303] Koren G, Madjunkova S, Maltepe C. The protective effects of nausea and vomiting of pregnancy against adverse fetal outcome: a systematic review. Reprod Toxicol. 2014;47:77–80. [304] Veenendaal M, van Abeelen A, Painter R, et al. Consequences of hyperemesis gravidarum for offspring: a systematic review and meta-analysis. BJOG. 2011;118:1302–1313. [305] Bolin M, Åkerud H, Cnadingius S, et al. Hyperemesis gravidarum and risks of placental dysfunction disorders: a population-based cohort study. BJOG. 2013;120(5):541–547. [306] Walstab J, Krüger D, Stark T, et al. Ginger and its pungent constituents non-competitively inhibit activation of human recombinant and native 5-HT3 receptors of enteric neurons.

Neurogastroenterol Motil. 2013;25(5):439–447. [307] Jin Z, Lee G, Kim S, et al. Ginger and its pungent constituents non-competitively inhibit serotonin currents on visceral afferent neurons. Korean J Physiol Pharmacol. 2014;18:149–153. [308] Madhews A, Haas DM, O'Mathúna DP, et al. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. 2015;(9) [CD007575]. [309] Food Standards Australia and New Zealand. Listeria and food: advice for people at risk. [Available from] www.foodstandards.gov.au/publications/pages/listeriabrochuretext.aspx. [310] Duff P, Birsner M. Maternal and perinatal infection in pregnancy: bacterial. Gabbe SG, Niebyl JR, Simpson JL, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [311] SA Health. Toxoplasma infection: including symptoms, treatment and prevention. [Available from] www.sahealth.sa.gov.au/wps/wcm/connect/public+content/sa+health+internet/health+topics. [312] Nazik E, Eryilmaz G. Incidence of pregnancy-related discomforts and management approaches to relieve them among pregnant women. J Clin Nurs. 2014;23(11–12):1736–1750. [313] Landon MB, Catalano PM, Gabbe SG. Diabetes mellitus complicating pregnancy. Gabbe SG, Niebyl JR, Simpson JL, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [314] Liu JH. Endocrinology of pregnancy. Creasy RK, Resnik R, Iams JD, et al. Creasy & Resnik's maternal-fetal medicine: principles and practice. 7th ed. Elsevier: Philadelphia; 2014. [315] Ide M, Papapanou PN. Epidemiology of association between maternal periodontal disease and adverse pregnancy outcomes: systematic review. J Clin Periodontol. 2013;(Suppl. 14):S181–94. [316] Abariga SA, Whitcomb BW. Periodontitis and gestational diabetes mellitus: a systematic review and meta-analysis of observational studies. BMC Pregnancy Childbirth. 2016;16(344). [317] Moeindarbari S, Tara F, Lotfalizadeh M. The effect of diagnostic amniocentesis and its complications on early spontaneous abortion. Electron Physician. 2016;8(8):2787–2792. [318] Malfertheiner M, Malfertheiner P, Costa SD, et al. Extraesophageal symptoms of gastroesophageal reflux disease during pregnancy. J Gastroentero. 2015;53(9):1080–1083. [319] Sibai BM. Preeclampsia and hypertensive disorders. Gabbe S, Niebyl J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [320] Markham KB, Funai EF. Pregnancy-related hypertension. Creasy RK, Resnik R, Iams JD, et al. Creasy and Resnik's maternal-fetal medicine: principles and practice. 7th ed. Elsevier: Philadelphia; 2014. [321] Hariharan N, Shoemaker A, Wagner S. Pathophysiology of hypertension in preeclampsia. Microvasc Res. 2017;13(2):33–37. [322] Zeng Y, Li M, Chen Y, et al. Homocysteine, endothelin-1 and nitric oxide in patients with hypertensive disorders complicating pregnancy. Int J Clin Exp Pathol. 2015;8(11):15275– 15279. [323] Bilodeau JF. Maternal and placental antioxidant response to preeclampsia: impact on vasoactive eicosanoids. Placenta. 2014;28:S32–8. [324] Makrides M, Crosby DD, Bain E, et al. Magnesium supplementation in pregnancy. Cochrane Database Syst Rev. 2014;(4) [CD000937]. [325] Imdad A, Bhuda ZA. Effects of calcium supplementation during pregnancy on maternal,

fetal and birth outcomes. Paediatr Perinat Epidemiol. 2012;(Suppl. 1):138–152. [326] Mustafa R, Ahmed S, Gupta A, et al. A comprehensive review of hypertension in pregnancy. J Pregnancy. 2012. [327] Schoenaker D, Soedamah-Muthu S, Callaway L, et al. Prepregnancy dietary paderns and risk of developing hypertensive disorders of pregnancy: results from the Australian Longitudinal Study on Women's Health. Am J Clin Nutr. 2015;102(1):94–101. [328] Bullarbo M, Ödman N, Nestler A, et al. Magnesium supplementation to prevent high blood pressure in pregnancy: a randomised placebo control trial. Arch Gynecol Obs. 2013;288(6):1269–1274. [329] Hofmeyr GJ, Lawrie TA, Atallah AN, et al. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev. 2010; (8) [CD001059]. [330] Haddy FJ, Vanhoude PM, Feletou M. Role of potassium in regulating blood flow and blood pressure. Am J Physiol Regul Integr Comp Physiol. 2006;290(3):R546–52. [331] Yilmax MI, Solak Y, Covic A, et al. Renal anemia of inflammation: the name is selfexplanatory. Blood Purif. 2011;32(3):220–225. [332] Jensen CL. Effects of omega 3 fady acids during pregnancy and lactation. Am J Clin Nutr. 2006;83(6):S1452–7. [333] Dorniak-Wall T, Grivell RM, Dekker GA, et al. The role of L-arginine in the prevention and treatment of pre-eclampsia: a systematic review of randomised trials. J Hum Hypertens. 2014;28(4):230–235. [334] Dignon A, Reddington A. The physical effect of exercise in pregnancy on pre-eclampsia, gestational diabetes, birthweight and type of delivery: a structured review. [Available from] www.rcm.org.uk/learning-and-career/learning-and-research/ebm-articles/the-physicaleffect-of-exercise-in-pregnancy. [335] Yao M, Ritchie HE, Brown-Woodman PD. A reproductive screening test of hawthorn. J Ethnopharmacol. 2008;118(1):127–132. [336] Ross MG, Gore Ervin M. Fetal development and physiology. Gabbe S, Niebyl J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [337] The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Maternal Group B Streptococcus in pregnancy: screening and management. [East Melbourne] 2016. [338] Rönnqvist PD, Forsgren-Brusk UB, Grahn-Håkansson E. Lactobacilli in the female genital tract in relation to other genital microbes and vaginal pH. Acta Obs Gynecol Scand. 2006;85(6):726–738. [339] Wang AR, Kroumpouzos G. Skin disease and pregnancy. Gabbe S, Niebyl J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [340] Jurecka W. Pregnancy dermatoses. Lebwohl MG, Heymann WR, Berth-Jones J, et al. Treatment of skin disease: comprehensive therapeutic strategies. 4th ed. Elsevier: Philadelphia; 2014. [341] Rapini RP. The skin and pregnancy. Creasy RK, Resnik R, Iams JD, et al. Creasy and Resnik's maternal-fetal medicine: principles and practice. 7th ed. 2014 [Philadelphia: Elsevier]. [342] Dixon PH, Williamson C. The pathophysiology of intrahepatic cholestasis of pregnancy. Clin Res Hepatol Gastroenterol. 2016;40(2):141–153.

[343] Williamson C, Mackillop L, Heneghan M. Diseases of the liver, biliary system, and pancreas. Creasy RK, Resnik R, Iams JD, et al. Creasy and Resnik's maternal-fetal medicine: principles and practice. 7th ed. Elsevier: Philadelphia; 2014. [344] Cappell MS. Hepatic disorder during pregnancy. Gabbe S, Niebyl J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [345] Moses RG, Morris G, Petocz P, et al. Impact of the potential new diagnostic criteria on the prevalence of gestational diabetes mellitus in Australia. Med J Aust. 2011;194:338–340. [346] DeSisto CL, Kim SY, Sharma AJ. Prevalence estimates of gestational diabetes mellitus in the United States, Pregnancy Risk Assessment Monitoring System (PRAMS), 2007–2010. Prev Chronic Dis. 2014;11. [347] McGovern A, Butler L, Jones S, et al. Diabetes screening after gestational diabetes in England: a quantitative retrospective cohort study. Br J Gen Pr. 2014;64(618):e17–23. [348] Moore T, Haugel-De Mouzon S, Catalanon P. Diabetes in pregnancy. Creasy RK, Resnik R, Iams JD, et al. Creasy & Resnik's maternal-fetal medicine: principles and practice. 7th ed. Elsevier: Philadelphia; 2014. [349] Nankervis A, Conn J. Gestational diabetes mellitus: negotiating the confusion. Aust Fam Phys. 2013;42(8):528–531. [350] International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Mexger BE, Gabbe SG, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676–682. [351] Schoenaker DA, Mishra GD, Callaway LK, et al. The role of energy, nutrients, foods, and dietary paderns in the development of gestational diabetes mellitus: a systematic review of observational studies. Diabetes Care. 2016;39:16–23. [352] Gatford KL, Houda CM, Lu ZX, et al. Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment. Diabetes Obes Metab. 2013;15(7):660–667. [353] Dolatkhah N, Hajifaraji M, Abbasalizadeh F, et al. Is there a value for probiotic supplements in gestational diabetes mellitus? A randomized clinical trial. J Heal Popul Nutr. 2015;33:25. [354] Jamilian M, Samimi M, Kolahdooz F, et al. Omega-3 fady acid supplementation affects pregnancy outcomes in gestational diabetes: a randomized, double-blind, placebocontrolled trial. J Matern Fetal Neonatal Med. 2016;29(4):669–675. [355] Asemi Z, Jamilian M, Mesdaghinia E, et al. Effects of selenium supplementation on glucose homeostasis, inflammation, and oxidative stress in gestational diabetes: randomized, double-blind, placebo-controlled trial. Nutrition. 2015;31:1235–1242. [356] Mei Z, Cogswell ME, Looker AC, et al. Assessment of iron status in US pregnant women from the National Health and Nutrition Examination Survey (NHANES). Am J Clin Nutr. 2011;93:1312–1320. [357] Kilpatrick SJ. Anemia and pregnancy. Creasy RK, Resnik R, Iams JD, et al. Creasy & Resnik's maternal-fetal medicine: principles and practice. 7th ed. Elsevier: Philadelphia; 2014. [358] Samuels P. Hematologic complications of pregnancy. Gabbe S, Niebyl J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [359] King Edward Memorial Hospital. Anaemia in pregnancy: clinical guideline. [Perth: Govt

Western Australia, Dept Health] 2013. [360] Yakoob MY, Bhuda ZA. Effect of routine iron supplementation with or without folic acid on anemia during pregnancy. BMC Public Health. 2011;11(Suppl. 3):S21. [361] Demirel G, Golbasi Z. Effect of perineal massage on the rate of episiotomy and perineal tearing. Int J Gynaecol Obs. 2015;131(2):183–186. [362] Beckman MM, Stock OM. Antenatal perineal massage for reducing perineal trauma. Cochrane Database Syst Rev. 2013;(4) [CD005123]. [363] Holst L, Haavik S, Nordeng H. Raspberry leaf: should it be recommended to pregnant women? Complement Ther Clin Pract. 2009;15(4):204–208. [364] Parsons M, Simpson M, Ponton T. Raspberry leaf and its effect on labour: safety and efficacy. Aust Coll Midwives Inc J. 1999;12(3):20–25. [365] Simpson M, Parson M, Greenwood J, et al. Raspberry leaf in pregnancy: its safety and efficacy in labor. J Midwif Wom Heal. 2001;46(2):51–59. [366] Hall HG, McKenna LG, Griffiths DL. Complementary and alternative medicine for induction of labour. Women Birth. 2012;25(3):142–148. [367] Price C, Robinson S. Birth: conceiving, nurturing and giving birth to your baby. MacMillan: Sydney; 2004. [368] Wang H, Hu YF, Hao JH, et al. Maternal serum zinc concentration during pregnancy is inversely associated with risk of preterm birth in a Chinese population. J Nutr. 2016;146(3):509–512. [369] Hechtman L. Pregnancy intensive seminar: the fundamentals for health professionals. Integria: Sydney; 2014. [370] Berghella V, Mackeen D, Jauniaux ER. Cesarean delivery. Gabbe SG, Niebyl JR, Simpson JL, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [371] Bayes S, Fenwick J, Hauck Y. Becoming redundant: Australian women's experiences of pregnancy after being unexpectedly scheduled for a medically necessary term elective cesarean section. Int J Childbirth. 2012;2(2):73–84. [372] Stevens J, Schmied V, Burns E, et al. A juxtaposition of birth and surgery: providing skin-toskin contact in the operating theatre and recovery. Midwifery. 2016;37:41–48. [373] Moore ER, Anderson GC, Bergman N, et al. Early skin-to-skin contact for mothers and their healthy newborn infants. Cochrane Database Syst Rev. 2012;(5) [CD003519]. [374] Stevens J, Schmied V, Burns E, et al. Immediate or early skin-to-skin contact after a caesarean section: a review of the literature. Matern Child Nutr. 2014;10(4):456–473. [375] Neu J, Rushing J. Cesarean versus vaginal delivery: long-term infant outcomes and the hygiene hypothesis. Clin Perinatol. 2011;38(2):321–331. [376] Arrieta MC, Stiemsma LT, Amenyogbe N, et al. The intestinal microbiome in early life: health and disease. Front Immunol. 2014;5:427. [377] Almgren M, Schlinzig T, Gomez-Cabrero D, et al. Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant: implications for future health? Am J Obs Gynecol. 2014;211(5):502.e1–502.e8. [378] Blustein J, Adina T, Liu M, et al. Association of caesarean delivery with child adiposity from age 6 weeks to 15 years. Int J Obes. 2013;37:900–906. [379] Bager P, Simonsen J, Nielsen NM, et al. Cesarean section and offspring's risk of inflammatory bowel disease: a national cohort study. Inflamm Bowel Dis. 2012;18(5):857–862.

[380] Li Y, Tian Y, Zhu W, et al. Cesarean delivery and risk of inflammatory bowel disease: a systematic review and meta-analysis. Scand J Gastroenterol. 2014;49(7):834–844. [381] Vindigni SM, Zisman TL, Suskind DL, et al. Therapeutic advances in gastroenterology. Ther Adv Gastroenterol. 2016;9(4):606–625. [382] Decker E, Hornef M, Stockinger S. Cesarean delivery is associated with celiac disease but not inflammatory bowel disease in children. Gut Microbes. 2011;2:91–98. [383] Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med. 2016;22(3):250– 253. [384] Perinatal Anxiety & Depression Australia (PANDA). Perinatal anxiety & depression Australia. [Available from] www.panda.org.au/practical-information/information-for-men. [385] American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSMV. American Psychiatric Publishing: Washington, DC; 2013. [386] Austin MP, Highet N, Guidelines Expert Advisory Commidee. Clinical practice guidelines for depression and related disorders — anxiety, bipolar disorder and puerperal psychosis — in the perinatal period: a guideline for primary care health professionals. [Melbourne: beyondblue] 2011. [387] Wisner KL, Sit DKY, Bogen DL, et al. Mental health and behavioral disorders in pregnancy. Gabbe S, Niebyl J, Simpson J, et al. Obstetrics: normal and problem pregnancies. 7th ed. Elsevier: Philadelphia; 2017. [388] Yonkers KA. Management of depression and psychoses in pregnancy and in the puerperium. Creasy RK, Resnik R, Iams JD, et al. Creasy & Resnik's maternal-fetal medicine: principles and practice. 7th ed. Elsevier: Philadelphia; 2014. [389] Pedersen CA, Johnson JL, Silva S, et al. Antenatal thyroid correlates of postpartum depression. Psychoneuroendocrinol. 2007;32(3):235–245. [390] Bunevicius R, Kusminskas L, Mickuviene N, et al. Depressive disorder and thyroid axis functioning during pregnancy. World J Biol Psychiatr. 2009;10(4):324–329. [391] Pedersen C, Leserman J, Garcia N, et al. Late pregnancy thyroid-binding globulin predicts perinatal depression. Psychoneuroendocrinol. 2016;65:84–93. [392] Edler Schiller C, Melxer-Brody S, Rubinow DR. The role of reproductive hormones in postpartum depression. CNS Spectr. 2015;20(1):48–59. [393] World Health Organization (WHO). Maternal mental health and child health and development in resource-constrained sejings. Report of a UNFPA/WHO International Expert Meeting: The Interface Between Reproductive Health and Mental Health. WHO: Geneva; 2009. [394] Rechenberg K, Humphries D. Nutritional interventions in depression and perinatal depression. Yale J Biol Med. 2013;86(2):127–137. [395] Rees AM, Austin MP, Parker GB. Omega-3 fady acids as a treatment for perinatal depression: randomized double-blind placebo-controlled trial. Aust NZ J Psychiatry. 2008;42(3):199–205. [396] Nader S. Thyroid disease and pregnancy. Creasy RK, Resnik R, Iams JD, et al. Creasy & Resnik's maternal-fetal medicine: principles and practice. 7th ed. Elsevier: Philadelphia; 2014. [397] Lazarus JH. The continuing saga of postpartum thyroiditis. J Clin Endocrinol Metab. 2011;96:614.

Appendix 13.1 Tools to assess NVP

Tool

Description

PUQE: Pregnancy-Unique Quantification of Emesis and Nausea

Three questions regarding nausea, vomiting and retching during previous 12 or 24 hours For each component: 0 = no symptoms, 5 = worst possible symptoms Maximum score = 15 Score ≥13 indicates severe symptoms RINVR: Rhodes Index of Eight questions about duration, amount, frequency and distress caused by symptoms of Nausea, Vomiting and nausea, vomiting and retching Retching For each component: 0 = no symptoms, 5 = worst possible symptoms Maximum score = 40 Score ≥33 indicates severe symptoms McGill Nausea Questionnaire Measures nausea only using a nausea rating index that has nine sets of words that describe sensory, affective, evaluative and miscellaneous afferent feelings related to nausea that women rank An overall nausea index: 0–5, where 0 = no symptoms, 5 = excruciating symptoms Plus a VAS: 0 cm = no nausea, 10 cm = extreme nausea NVPI: Nausea and Vomiting of Three questions relating to nausea, retching and vomiting over the past 7 days Pregnancy Instrument For each component: 0 = no symptoms, 5 = worst possible symptoms Maximum score = 15 Score ≥8 indicates severe symptoms VAS: Visual Analogue Scale Patients rate their symptoms on a scale of 0–10, where 0 = no symptoms and 10 = extreme symptoms Source: Adapted from O'Donnell A, McParlin C, Robson SC, Beyer F, Moloney E, Bryant A et al. Treatments for hyperemesis gravidarum and nausea and vomiting in pregnancy: a systematic review and economic assessment. Heal Technol Assess 2016;20(74).

Appendix 13.2 Edinburgh Postnatal Depression Scale (EPDS) Question 1. I have been able to laugh and see the funny side of things □ As much as I always could □ Not quite so much now □ Definitely not so much now □ Not at all 2. I have looked forward with enjoyment to things □ As much as I ever did □ Rather less than I used to □ Definitely less than I used to □ Hardly at all 3. I have blamed myself unnecessarily when things went wrong □ Yes, most of the time □ Yes, some of the time □ Not very often □ No, never 4. I have been anxious or worried for no good reason □ No, not at all □ Hardly ever □ Yes, sometimes □ Yes, very often 5. I have felt scared or panicky for no very good reason □ Yes, quite a lot □ Yes, sometimes □ No, not much □ No, not at all

Score 0 1 2 3 0 1 2 3 3 2 1 0 0 1 2 3 3 2 1 0

6. Things have been geding on top of me □ Yes, most of the time I haven't been able to cope at all □ Yes, sometimes I haven't been coping as well as usual □ No, most of the time I have coped quite well □ No, I have been coping as well as ever 7. I have been so unhappy that I have had difficulty sleeping □ Yes, most of the time □ Yes, sometimes □ Not very often □ No, not at all 8. I have felt sad or miserable □ Yes, most of the time □ Yes, quite often □ Not very often □ No, not at all 9. I have been so unhappy that I have been crying □ Yes, most of the time □ Yes, quite often □ Only occasionally □ No, never 10. The thought of harming myself has occurred to me □ Yes, quite often □ Sometimes □ Hardly ever □ Never

3 2 1 0 3 2 1 0 3 2 1 0 3 2 1 0 3 2 1 0

Source: Murray D, Cox J. Screening for depression during pregnancy with the Edinburgh Depression Scale (EDDS). J Reprod Infant Psych 1990;8(2):99–107.

Scoring 0–9: Scores in this range may indicate the presence of some symptoms of distress that may be short-lived and are less likely to interfere with day-to-day ability to function at home or at work. However, if these symptoms have persisted more than a week or two, further enquiry is warranted. 10–12: Scores within this range indicate the presence of symptoms of distress that may be discomforting. Repeat the EDS in 2 weeks time and continue monitoring progress regularly. If the scores increase to above 12, assess further and consider referral as needed. 13 +: Scores above 12 require further assessment and appropriate management as the likelihood of depression is high. Referral to a psychiatrist/psychologist may be necessary. Item 10: Any woman who scores 1, 2 or 3 on item 10 requires further evaluation before leaving the office to ensure her own safety and that of her baby.

14

Breastfeeding Dawn Whi)en

Introduction Breastfeeding is the biological norm. It facilitates an extra-uterine link between mother and child.[1] As such, breastfeeding continues many of the functions of the placenta, including protection of the infant from illness, nutritional nourishment and promoting and regulating development. Furthermore, it supports neural–hormonal homeostatic regulation, promotes bonding and is a source of comfort and even pain relief for the infant.[2–4] Breastfeeding also has health and neuroprotective functions for mothers, many of which have been underrealised until recently. Suboptimal breastfeeding in the US is estimated to be the cause of 3340 maternal deaths (due to myocardial infarction, breast cancer and diabetes) and 721 paediatric deaths annually.[5] When practitioners work to protect the breastfeeding dyad, they support the short- and long-term health of the mother and child. Each mother–baby breastfeeding relationship (or dyad) is unique, and many mothers experience challenges during breastfeeding despite breastfeeding being normal and natural. There are a range of social–cultural and physiological factors that can contribute to breastfeeding challenges which will be explored in this chapter alongside practical and naturopathic strategies that can be utilised to help resolve them. There are three key health professional areas of competency that are fundamental to supporting mothers with breastfeeding challenges: 1 good knowledge of human lactation physiology, including an appreciation for what is normal in breastfeeding 2 good referral practices that ensure mothers are connected with appropriate services and support to help them to resolve challenges quickly. 3 Sensitive and responsive communication skills enabling the communication of accurate information while remaining sensitive to the mother's needs. A core aspect of this is being sensitive to where a mother ‘is at’ in her breastfeeding and motherhood journey, and endeavouring to meet her there.

The World Health Organization recommendations for breastfeeding The World Health Organization (WHO) recommends 6 months exclusive breastfeeding, followed by continued breastfeeding for the first 2 years or beyond.[6] These recommendations are made for all countries,[7] as breastfeeding is a significant determinant of health in both affluent and economically disadvantaged countries. Exclusive breastfeeding means oral ingestion of only breast milk, with the exception of required medications. No water, juices, breast milk substitutes or solid foods are given.[6] The WHO estimates that globally only 38% of infants are exclusively breastfed for 6 months.[8] Data from Australia, Canada and the US show that these countries fare worse than the global average, with less than 25% of infants exclusively breastfed to the age of 6 months. [9–11] Furthermore, the 2010 National Health Survey found that only 1% of UK infants were exclusively breastfed to 6 months.[12] Interestingly, breastfeeding initiation rates are quite promising in Australia, with rates ranging up to 90%.[10] However, by 4 months only half of infants are receiving any breast milk. In the US and the UK, a similar padern is evident, with an national initiation rate of 81%, followed by a substantial drop in both exclusive and any breastfeeding, according to recent surveys in both countries.[11,12] Furthermore, only 33% and 5% of Australian 9-month-olds and 24-month-olds, respectively, receive any breast milk.[10] Based on the data available, it would appear that most children in these countries are not being breastfed according to WHO recommendations, and that there is a steady decline in breastfeeding and breastfeeding exclusivity following promising initiation rates. This prompts the question: why is this the case in these comparatively well-resourced countries?

Historical context While challenges with breastfeeding efficacy have existed throughout the ages, there are some unique aspects to the challenges and barriers for mothers today. During the past century we have seen a rise in the use of breast milk substitutes, owing to the successful marketing of these substitutes through direct promotion to the public and through strong relationships with hospitals and health professionals.[13,14] In the early 1970s, breastfeeding hit an all-time low, with only 25% of babies being breastfed beyond 1 week of age in the US[15] and 36% being breastfed on discharge from hospital in Australia.[13] This means that many new mothers today have not been breastfed themselves or have been breastfed partially for only a short period. Furthermore, it means that the important support people in a new mother's life such as her own mother, in-laws, aunties and significant health professionals may often not have been breastfed, and are likely to have received inaccurate and unhelpful advice on breastfeeding. Unfortunately, mothers today still receive advice, such as feed scheduling resembling formula-feeding practices (author's observation from clinical practice), which is detrimental to breastfeeding success. Another consequence of the low breastfeeding rates of the 1970s and 1980s is that many

mothers today have not had the opportunity to learn about normal breastfeeding behaviour through passive exposure. Since the 1970s, there has been a steady effort directed at restoring and developing breastfeeding-friendly culture and practices in hospitals, the community and the work place. [14]

The WHO International Code of Marketing of Breast milk Substitutes was developed in 1981 and all United Nations member states were encouraged to include the code in their legislation. The aim of this code is to protect and promote breastfeeding and to limit the use of breast milk substitutes to only situations where they are medically necessary, by preventing aggressive advertising of breast milk substitutes.[16] Two key elements of the code include: 1) prohibiting the marketing of formula, artificial teats or bodles to parents or the general public; and 2) not allowing the practice of giving free formula samples to parents, pregnant women, health professionals or health services and hospitals. Interestingly, a recent Hong Kong (China) study found that when hospitals switched to paying market price and no longer accepted free formula, in-hospital exclusive breastfeeding rates increased from 17.9% to 41.4%.[17] Currently, only 70% of countries have taken on at least some elements of the WHO code, including the UK, Iran, Brazil and Papua New Guinea.[18] In the US, industry adherence to the WHO code is voluntary as the WHO code is in conflict with the US's free trade legislation. Canada has only implemented a small portion of the elements. In Australia, a self-regulating industry agreement is in place, the Marketing in Australia of Infant Formulas (MAIF) Agreement, that encompasses only some aspects of the code and relies on voluntary adherence by industry signatories.[16] The Baby-Friendly Hospital Initiative (BFHI) was launched in 1991 by the WHO and UNICEF as a key strategy to protect and promote breastfeeding.[19] The BFHI requires hospitals to put in place ‘Ten Steps’ (see Box 14.1), key components being: avoiding the use of artificial teats, avoiding formula supplementation in hospitals unless it is medically indicated, keeping mothers and babies together and supporting access to ongoing breastfeeding support. BFHI-certified hospitals are required to adhere to the WHO code, including paying market price for infant formula.

Box 14.1

BFHI ten steps by WHO and UNICEF[19] 1. Have a wriden breastfeeding policy that is routinely communicated to all healthcare staff. 2. Train all healthcare staff in the skills necessary to implement this policy. 3. Inform all pregnant women about the benefits and management of breastfeeding. 4. Revised in 2009 to: Place babies in skin-to-skin contact with their mothers

immediately following birth for at least an hour. Encourage mothers to recognise when their babies are ready to be breastfed and offer help if needed.[20] It is preferable that babies be left even longer than an hour, if feasible, as they may take longer than 60 minutes to breastfeed. (Previously Step 4 stated: Help mothers initiate breastfeeding within a half-hour of birth.) 5. Show mothers how to breastfeed and how to maintain lactation, even if they should be separated from their infants. 6. Give newborn infants no food or drink other than breast milk, unless medically indicated. 7. Practise rooming-in: allow mothers and infants to remain together 24 hours a day. 8. Encourage breastfeeding on demand. 9. Give no artificial teats or pacifiers to breastfeeding infants. 10. Foster the establishment of breastfeeding support groups and refer mothers to them on discharge from the hospital or clinic.

While there have been many positive outcomes owing to these efforts, there still remain challenges in these areas. Australia and the US have not signed the WHO code.[18] Some hospital practices still negatively impact on breastfeeding, and there are issues with compliance among BFHI-certified hospitals.[21] Ultimately, it is the combination of the hospital policies and the staff aditude and culture around breastfeeding that will determine the care experienced by mothers and babies. It is unfortunate that many hospitals claim to be too resource poor to maintain the 10 steps for infants in neonatal intensive care and special care units (NICUs), commonly neglecting to facilitate mothers being able to stay with their infants despite a growing body of evidence demonstrating the value of NICUs being designed to facilitate parents’ ‘24-hour’ presence with regards to infant stress, maternal confidence, reduced pharmacological interventions, reduced sepsis and beder breastfeeding rates.[22,23] Pressures to return to work, community aditudes towards breastfeeding in public and difficulties accessing breastfeeding help all continue to challenge the return of a breastfeeding-friendly culture.

Breastfeeding: barriers and enablers Factors that impact on breastfeeding outcomes for mothers and babies If practitioners can develop an understanding of the barriers and enabling factors (outlined in Tables 14.1 and 14.2) that may impact on the breastfeeding dyad and breastfeeding success, then this can help them to have insight into some of the less visible obstacles mothers face. This can also assist the clinician to keep a big picture view, where each mother

is seen as part of a cultural web of influence, and we avoid seeing the mother at fault when breastfeeding does not work out. Importantly, an awareness of the social–cultural and maternal-centred barriers that impede breastfeeding confidence can prompt tailored preventive interventions. TABLE 14.1 Social–cultural and maternal factors that present barriers to breastfeeding[9,24–30] Social–cultural barriers Mother was not breastfed Grandmother's aditude may be a particularly potent determinant. A 2016 systematic review found that a grandmother's negative views of breastfeeding was associated with a 70% decrease in the likelihood of breastfeeding.[26] The family stories and a mother's exposure to breastfeeding prior to being pregnant are likely to influence her sense of breastfeeding self-efficacy. Friends and family did not breastfeed This is a widely reported trend.[25,27,31] A 2016 study provides some interesting insight, finding that feeding advice from those regarded as important support people influenced breastfeeding outcomes. Further advice that promoted breastfeeding, formula feeding or mixed feeding matched the feeding experiences of the provider.[27] Partner/father not supportive Paternal support and greater paternal breastfeeding education increases breastfeeding initiation rates. [32,33]

Lower education level Lack of tertiary education in particular.[34] Lower socioeconomic status Maternal age Generally younger maternal age is associated with poorer breastfeeding outcomes; however, findings are inconsistent, and in some populations, older first-time mothers have poorer breastfeeding outcomes than younger mothers. Race and ethnicity There are racial differences in breastfeeding rates that frequently echo socioeconomic paderns. In the US, African Americans, North American Indians and Hispanics have breastfeeding rates substantially lower than the national average.[35,36] Conversely, mothers with Black or Asiatic ethnicity have beder breastfeeding rates in the UK.[12] In Australia, Aboriginal and Torres Strait Islander people have poorer breastfeeding rates than the national average, particularly in rural and regional areas.[37] Early return-to-work pressure Lack of paid maternity leave is associated with lower breastfeeding initiation and lower rates of exclusive breastfeeding, indicating that return-to-work pressure may impact on early breastfeeding decisions.[9,34,38,39] Flexible arrangements for return to work (including reduced hours and work from home options) that are compatible with breastfeeding may have further protective effects of longer-term breastfeeding outcomes.[40] Aditudes towards breastfeeding in the workplace also appear to impact on breastfeeding.[40] Mode of conception The use of assisted reproductory technology (ART) is associated with exposure to a number of risk factors that predict poorer breastfeeding outcomes, including higher risk or preterm birth, caesarean

birth, thyroid disease, polycystic ovary syndrome (PCOS) and higher risk of perceived lactational insufficiency.[41–43] One study found ART users had twice the rate of caesarean births and that caesarean births in this population predicted poor breastfeeding outcomes.[42] Maternal factors Obesity Obesity is a risk factor for premature cessation of breastfeeding. This is thought to be multifactorial. A recent Australian study found that obese woman anticipated social discomfort both breastfeeding in public and with close friends and family.[44] Obesity can also be associated with delayed lactogenesis II, low supply and less intention to breastfeed.[45] The lader may be associated with anticipated social discomfort. Newby et al.suggest that interventions during pregnancy that address body image issues in relation to breastfeeding may support and facilitate breastfeeding success for obese mothers and their infants.[44] Perinatal depression An association between postnatal depression symptoms (PDS) and breastfeeding problems is well established.[46,47] Some studies have found that breastfeeding difficulties and premature cessation of breastfeeding may also be causal and/or a multiplier for PDS,[46,48,49] suggesting there is a two-way street between PDS and breastfeeding cessation. Sense of overwhelm may contribute to risk of breastfeeding cessation.[50] Bascom et al., in a US study of 1271 women with PDS, found that the presence of postnatal depression symptoms was associated with ‘too many household chores’ as a primary reason for breastfeeding cessation prior to 6 months.[50]

TABLE 14.2

Healthcare practices that act as breastfeeding barriers and enablers Barriers Birth interventions Caesarean birth (planned and emergency) Labour induction with synthetic oxytocin[51] Pethidine[52,53] Epidural,[52,54,55] especially when infant not fully rooming in[55] Traumatic birth experiences[56] Note: a long labour or stressful birth experience may also impact on breastfeeding independent of birth interventions Separation of mother and baby[57–60] Delayed first breastfeed[61] Supplemental feeds given in hospital[61–64] Note: judicious use of supplemental feeds does not appear to impair breastfeeding rates according to preliminary studies.[65,66] However reasons for inhospital supplementation are frequently in conflict with evidence[24,67] (i.e. not judicious). Use of artificial teats, boQles and dummies/pacifiers[61,68] Limited breastfeeding support after hospital discharge[25] Conflicting advice from healthcare practitioners[69,70] Poor advice and lack of encouragement from health professionals due to health professional knowledge deficit[70,71] Being born on a Saturday[72]; hence, limited access to in-hospital breastfeeding support

Enablers Prenatal breastfeeding education[73] Birth support – continuity of midwifery care and doula support[74] Note: these factors also have a protective effect on breastfeeding when interventions such as instrument and caesarean birth have occurred – maternal support and empowerment in these scenarios protects breastfeeding. Skin-to-skin contact – mother and baby skin-toskin contact immediate and uninterrupted after birth[24,57–59] Skin-to-skin contact immediately after caesarean birth increases breastfeeding successes[75] Delay weighing and other routine procedures for at least an hour after birth and until after the baby has had first breastfeed Mother and baby rooming in[19,76] Consistent advice given by health professionals with good breastfeeding knowledge[69,70,76] Health professionals supportive of breastfeeding[71,73] Continued breastfeeding support after discharge[19] Connection to breastfeeding peer-support groups[73,77,78] Medicare-reimbursed lactation support after discharge[79]

Tailored interventions to address breastfeeding barriers

• Unpacking the family stories around breastfeeding when there are negative beliefs within the family. Explanations about breastfeeding physiology can help bring insight to why previous family members had trouble, and how poor breastfeeding advice such as feed scheduling may have jeopardised breastfeeding. • Building rapport and working to educate fathers and partners so they are more likely to be supportive of breastfeeding. • Exploring creative options to reduce return-to-work pressure and/or to find solutions around continued breastfeeding while working.

• Connecting women with breastfeeding-friendly communities both locally and through social media. • Being on the lookout for signs of perinatal depression and preemptively providing support to work through body image issues. Healthcare practices that act as breastfeeding barriers and enablers Numerous healthcare practices can have an impact on breastfeeding (see Table 14.2). Hence, promoting parental access to appropriate perinatal support and education is an important aspect of protecting breastfeeding. When birth becomes more complicated, it is invaluable for parents and birth support people to have an understanding of how to protect breastfeeding under these circumstances. Key actions the naturopath can undertake during the prenatal period to protect breastfeeding include:

• Encourage parental access to prenatal breastfeeding education. • Connect mothers with good breastfeeding support within their local area, including peer support services (through organisations such as the Australian Breastfeeding Association and La Leche League) and International Board Certified Lactation Consultants. • Encourage mothers to get help early when challenges arise, such as pain or discomfort with breastfeeding, from the above organisations and health professionals. • Encourage parents to explore their birth preparation and birth support options. • Encourage parents to write a breastfeeding plan that includes requests to hospital and birth support people for immediate uninterrupted skinto-skin contact and the avoidance, where possible, of separation, artificial feeds, use of teats and dummies and the minimisation of strong odours. Draft breastfeeding plans are available from the Australian Breastfeeding Association website. • Reinforce the value of skin-to-skin contact both immediately following birth and during the early weeks of life. Skin-to-skin contact: – promotes maternal infant adachment – promotes infant cardiovascular and thermal regulation[75] – reduces pain for the infant[80] – supports maternal milk supply and effective adachment

– reduces artificial milk supplementation[57,75] For the mother and infant who have experienced early separation time, skin-to-skin contact is especially important. Social–cultural barriers and enablers, maternal factors and healthcare practices create the context in which a mother's breastfeeding journey begins. All of these factors will have an impact on her breastfeeding intent and breastfeeding self-efficacy. Breastfeeding self-efficacy can be described as the mother's belief and confidence that she will resolve breastfeeding challenges, and her drive to experiment and find solutions to breastfeeding problems that may arise. The breastfeeding obstacles that are most frequently cited as the reason for early discontinuation of breastfeeding are outlined in Table 14.3. These include perceived low milk supply, breast or nipple pain and having a fussy or unsedled baby.[25,81,82] TABLE 14.3 Common reasons mothers give for premature cessation of breastfeeding Perceived insufficient milk supply[24,25,81,83–85] (see page 491) Baby is fussy/unseQled – see Clinical Natural Medicine Chapter 23 section ‘The unsedled and unsoothable infant’. Note: babies who are unsedled are at greater risk of supplementation as this prompts parents to perceive the mother has insufficient milk.[86–88] Nipple or breast pain[82] (see page 503 and 507) Baby ‘had trouble sucking or latching’[83,84] Anticipating returning to work[85,89] Maternal fatigue perceived to be related to breastfeeding[85] Mother taking medication – ceases breastfeeding because of own concern or on advice of health professional[90] (see page 514)

Working with new mothers – the role of the naturopath Maternal intention to breastfeed and self-efficacy are influenced by the many factors discussed above. Becoming a mother is a profound life-altering experience, and sensitivity to this is imperative in the provision of health support. Three early transitional postnatal phases were described by Rubin in the 1960s, and provide a model for understanding some aspects of early mothering behaviour and needs[91] (see Box 14.2). More contemporary understanding of the motherhood transition suggests that these phases are not distinct, but that mothers display aspects of them at different timepoints.[92] A more recent view has been put forward that pregnancy and early motherhood is a state of continual transformation.[93]

Box 14.2

Rubin's puerperal change model

Taking-in phase (1–2 days following birth) – mothers are often vulnerable. She accepts help from others, accepts being cared for, reacts passively to advice and often has a need to talk through her birth experience to help her process it. She is in the immediate stage of physical recovery from the birth. Taking-hold phase – mother's focus turns to mothering. She is focused on the present, often self-critical and impatient with self to learn. She displays a high level of focus on her infant and may be anxious about her infant's care. LeQing-go phase – mother experiences identity adjustment: loss of old self (which may be associated with some unexpected grief) and beginning of new self as mother. She accepts the permanence of the infant as a person in her life. Maternal support, stress and mental health state are factors that modify adaptation and adainment of maternal self-efficacy.[94] Unfortunately current social constructs mean that many new mothers are isolated, with limited or deficient access to both practical and emotional support.[95] First-time mothers can benefit from peer support from other new mothers to help normalise some of the challenging feelings they experience.[93,96] Traumatic birth experiences can add an under layer of post-trauma stress. In the US, up to 45% of mothers describe their birth as traumatic, 18% display symptoms of post-traumatic stress and 3.5–7.5% have symptoms consistent with post-traumatic stress disorder.[95] By contrast, studies of Swedish mothers found that 9% described their birth as traumatic and 1.3% had symptoms consistent with post-traumatic stress disorder.[95] Practitioners’ alertness to the possibility of birth trauma, and where appropriate, referral to appropriate support services, may facilitate mothers’ recovery from these experiences. Kendall-Tacked suggests that the most important message practitioners can give mothers is that these ‘difficult beginnings don't have to be a blueprint for the rest of their mothering career and don't have to dictate what subsequent births are like’.[95] New mothers are experiencing changes in many spheres: physical, practical, hormonal, sense of self and emotional change. As they transition this period, they often report a sense of overwhelm which is exacerbated by the common experience of receiving conflicting advice from health professionals.[69,70] To ensure that naturopathic support doesn't contribute to this sense of overload, practitioners can:

• Devote time to listening to the mother's concerns. • Ask the mother about the advice she has been given by other health professionals. • Reinforce the aspects of this advice that seems helpful and try to avoid giving conflicting advice. • Encourage the mother to experiment and see what works for her and

her baby. • Keep treatment suggestions simple and doable. • Provide simple wriden information. • Ensure that the mother's immediate concerns are addressed even if they do not seem the highest priority to the practitioner. The naturopath is well placed to capture opportunities to protect and promote breastfeeding. These sometimes brief interactions may have a profound impact on a mother and baby's breastfeeding journey and on a mother's subsequent breastfeeding journeys. One of the most important roles the naturopath can play is identifying when referral for breastfeeding support is appropriate.

The value of good referral practice The importance of referring women who are having breastfeeding difficulties to experienced certified lactation consultants and breastfeeding support services cannot be emphasised enough. When challenges are addressed and resolved quickly, breastfeeding is more likely to continue. In some cases, a team approach including the involvement of a paediatrician, paediatric speech pathologist, lactation consultant and naturopath/herbalist may be indicated. The team approach works well when practitioners are aware of their area of expertise and their limitations. One of the factors hindering effective health professional support of breastfeeding women is the contradictory advice they receive, especially from practitioners with inadequate training in lactation physiology.[69] Another important role the naturopath can play is to reassure mothers about normal breastfeeding and infant behaviour and to help the mother to access accurate information. When it comes to providing accurate information about the risks of breastfeeding cessation and the introduction of breast milk substitutes, health professionals often feel a tension between supporting parents to make an informed choice (informed consent), on the one hand, and wanting to avoid exacerbating the mother's feeling of guilt or judgment.[97] This is delicate territory, not least because parents do have a right to accurate information. Sometimes the impact of this can be softened by celebrating the breastfeeding outcomes that the mother and baby have had, rather than focusing entirely on the negative implications of a feeding choice. Sometimes it is helpful to remind mothers that it does not need to be an allor-nothing decision. Any breastfeeding has value. Mothers might find shorter breastfeeding goals more within their coping capacity. When a mother of a newborn is experiencing significant challenges, she may find thinking about a goal of exclusively breastfeeding for the next 6 months is impossible and discouraging. She may, however, find seding a goal to exclusively breastfeed for the next 4 days or a week is manageable. From this place, a new goal can be set based on how breastfeeding is going. Practitioners need to be aware of their own story. Studies indicate that health professionals’ own breastfeeding experiences influence the care and advice they provide

mothers.[98,99] When the practitioner has a sense of the historical and cultural breastfeeding context, including the many enabling and inhibiting factors at play, it may assist them to hold a broad view of each presentation related to breastfeeding and to ‘meet the mother where she is at’; that is, apply a rather dynamic approach to breastfeeding promotion by sensing and communicating in a responsive way to the mother.

Functions of breastfeeding Breastfeeding is an integral part of the reproductory process, and the functions it has for the mother and child continue to be uncovered. The role human milk plays in providing nourishment for the infant is well appreciated, as is to a lesser extent its role in immune protection (discussed in detail below). Less appreciated are the many other functions of breastfeeding, which have far-ranging lifelong effects on the health of mothers and children (see Table 14.4). The functions of breastfeeding in most cases are ‘dose dependent’. In other words, there is a direct correlation between breastfeeding duration (as well as duration of exclusive breastfeeding) and the functional health effects for the mother and child. TABLE 14.4

Functions of breastfeeding for mother and child Functions for child Protection from infection

Establishment and nourishment of gut microbiota

Developmental programming

Examples Mother–baby hybrid immune system – Non-specific immune defences > Bacterial and viral blocking agents[100,101] > Antimicrobial agents[102] > Non-specific immune cells[103] – Specific antibody defence > Specific antibodies > Immune cell pathogen-primed responses[103] Hypothesis that bacteria are selectively sampled and transferred from mother's colon to breast milk[104] Breast milk contains numerous probiotic bacteria[105–108] Prebiotic human oligosaccharides with a unique paQern from each mother[101] Other factors in breast milk shape the microbiota, including: lactoferrin,[100,102] lysozymes, [102] lactose,[109,110] haptocorrin (vitamin B12-binding protein), bile salt-stimulated lipase, κcasein and human milk mucins,[102,111] glycolipids, glycoproteins and glycopeptides[101] Epigenetic modulators program development for a number of systems: • Gastrointestinal – mucosa maturation, reduced permeability, maturation of the enteric nervous system, promoting immune tolerance • Immunological • Neurological • Vascular – breast milk contains angiopoietins Breast milk components involved include: stem cells, immune cells, growth factors,

cytokines, hormones, gangliosides and neurotrophic factors[112–114] Nutrition and Nutrients are supplied in a highly bioavailable form.[1,115] Furthermore, the compositions of hydration preterm milk, colostrum and transitional milk are different from mature milk, reflecting the higher needs for protein and some nutrients[116] Fat and carbohydrate composition of the breast milk changes during a feed, during the day and over the course of lactation[117] Composition is dynamic and responsive to feeding frequency,[117] providing a means of adapting to the hydration and nutritional needs of the infant Breast milk contains amylase[118] and bile salt-stimulated lipase,[119,120] which assist with the digestion of starches and lipids Hormonal Metabolic regulation and imprinting[121] regulation Circadian rhythm – hormonal input[122] Comfort, stress Breastfeeding before and during immunisations reduces pain according to a systematic reduction and review of 10 studies[3] pain relief One study found that breastfeeding was associated with beder cortisol recovery following stress exposure[2] Cholecystokinin hormone is released in response to suckling to a lipid-rich breastfeed, and promotes digestion as well as satiety, relaxation and pain relief[123,124] Neurocognitive Exposure to oxytocin and breastfeeding behaviour, such as maternal eye contact and tactile development[125– sensory input, are thought to contribute to neurocognitive development and learnt capacity to 127] recognise and respond to social cues[125–128] Orthodontic and Breastfeeding appears to be associated with healthy orofacial development. But this may be facial structural mediated by longer breastfeeding duration, reducing non-nutritive sucking of fingers and development dummies[129] Functions for Examples mother Support Reduced postnatal blood loss, supports uterine return to normal size, lactational amenorrhoea recovery from facilitating child spacing and building of iron stores, prevents anaemia[130] pregnancy and birth NeuroMaternal hormones – support adaptation to motherhood[48] protective Metabolic Lactation suggested to provide ‘a reset’ to the adverse metabolic profile women are regulation exposed to during pregnancy[131] Oxytocin may mediate cardiovascular regulatory effects[132] Reproductory Low oestrogen profile balances the high oestrogen and oncogenic exposure period of hormone pregnancy and potentially provides normalised oestrogen exposure from a life span exposure perspective. regulation

Immune protection as a primary function Contemporary perspectives informed by evolutionary science suggest that the primary function of mammalian milk is actually protection from infection, and that over time, additional secondary functions, including nutrition, have evolved. The mammary gland is thought to have evolved from an ancestral apocrine-like gland associated with hair follicles. [103] The earliest form of lactation may have been by the synapsids in the form of

antimicrobial substances secreted from skin to protect soft egg shells from microbial growth. The modified hair follicles seen in monotremes, such as the platypus, further support this concept.[133] Many of the nutritional components in breast milk have anti-microbial actions and have their molecular origin based on immune defence compounds, further suggesting an initial function of protection.[103,133] This proposition, that the function of protection came first, frames the value of breastfeeding differently from when it is seen primarily as nutrition. It could be argued that part of the infant's immune system resides in its mother, and the breast is the connection between the mother and the offspring. Hence the concept of the maternal–infant hybrid immune system.

The maternal–infant hybrid immune system Tursruyer et al. proposed that the infant immune system is only complete in the presence of breast milk.[134] See Figure 14.1. Breast milk contains non-specific defence in the form of: immune cells, probiotic bacteria, prebiotic components, bacterial and viral blocking agents (human milk oligosaccharides, glycolipids and glycoproteins)[100,101] and antimicrobial agents (lactoferrin, lysozymes, fady acids, actoperoxidase).[102] Human milk also contains specific immune protection through antibodies and leukocytes, providing protection from pathogens to which the mother and infant are exposed.[103] Interestingly, a rise in breast milk leukocytes has been observed when mothers are asymptomatic but the infant has an infection, including respiratory infection, gastrointestinal infection or roseola infantum,[103] suggesting that the maternal immune system is responsive to the infant's state of health. Highlighting the immune system role of the breast, a 4-month-old infant consumes on average 75 mg of secretory immunoglobulin A (SIgA) per kg of body weight per 24 hours. This is almost twice the amount a non-lactating adult produces per kg of body weight.[133]

FIGURE 14.1

Breast milk – neonatal immune system[134]

Summary of other known functions for the infant Human milk provides tailored nutrition and hydration to the infant, which adapts depending on the age of the infant[116] and time of day.[116] The composition of milk at the beginning and the end of a feed is different, with more fat being present as the breast is comparatively ‘emptier’.[116] Nutrients are delivered in highly bioavailable forms. Breast milk provides the complete nutritional needs, including hydration, until around 6 months of age, at which point complementary foods are needed to meet the iron and zinc needs of the infant.[135–137] Breast milk continues to be the most nutritionally complete food in an infant's diet for the remainder of the first and during the second year of life.[136] When co-ingested, breast milk may assist with the digestibility of solid foods via the presence of amylase[118]

and bile salt-stimulated lipase[119,120] in breast milk. Furthermore, it promotes tolerance to dietary proteins via the presence of SIgA and other factors in milk.[138] Maternal nutrient status impacts on some aspects of breast milk composition, while many components, macronutrients in particular and some minerals, are regulated independent of maternal status (see Tables 14.7–14.9). Breast milk contains species-specific growth and neurotrophic factors and stem cells that promote and regulate the development of the gastrointestinal mucosa, the enteric nervous system, the infant's immune system, the neurological system and the vascular system.[112–114] Hormonal factors present in milk support the regulation of circadian and metabolic systems. [121,122,139,140] Breastfeeding promotes neurocognitive and social development,[125–128,141] provides comfort and pain relief[3] and is a rich source of sensory nourishment for the infant. Furthermore, it may support the healthy development of the orofacial muscles and oral cavity.[142] And not least, breastfeeding helps to establish and nourishes a healthy infant gut microbiota (see below).

Functions for mothers and the mother–baby dyad For the mother–baby dyad, breastfeeding promotes bonding and synchronised care. Breastfeeding has neuroprotective and maternal adaptation and resilience-promoting effects on the mother,[143,144] largely thought to be mediated by oxytocin exposure.[145] Hence, breastfeeding provides a protective buffer for the maternal brain during a major life transition, and as such, is associated with reduced risk and reduced severity of mood and depressive disturbances for the mother.[143,145,146] Breastfeeding also protects against maternal infant neglect.[147] Through promoting lactational amenorrhoea, breastfeeding provides an opportunity for mothers to re-establish iron stores from pregnancy.[130] Oxytocin release during breastfeeding initiation assists with uterine contraction and reducing postnatal blood loss. [130]

What is probably least appreciated about breastfeeding is its role in the metabolic and hormonal health of the mother. The breastfeeding state provides a period of lower oestrogen exposure that may balance the higher oestrogen states of pregnancy and ovulational cycling. Breastfeeding also primes women for the maintenance of healthy insulin sensitivity in later years.[131] Breastfeeding is theorised to provide a reproductory hormone and metabolic ‘reset phase’ that balances the unfavourable metabolic,[131] and potentially the oncogenic, profile women are exposed to during pregnancy. Further breastfeeding exposes the breast to breast milk factors such as HAMLET (a human milk complex of alpha-lactalbumin and oleic acid), which appear to induce tumour cell death.[148] Hence, for the duration of breastfeeding, the breast may be bathed in an anti-cancer milieu.

Risks associated with suboptimal breastfeeding for infants The risks to infants who are suboptimally breastfed are numerous (see Table 14.5). For this

reason, promotion and protection of breastfeeding is arguably one of the most important health interventions. Accordingly, a recent systematic review found that breastfeeding was the nutrition-related factor that made the biggest difference to long-term health outcomes. [149] A 2016 systematic review predicted that globally, 13.8% (823 000) of annual deaths in children under the age of two would not occur if breastfeeding neared the WHO recommendations.[150] The myth that insufficient breastfeeding is only life-threatening in developing countries has been dispelled by data collected over the past decade, showing that premature cessation and insufficient exclusive breastfeeding are associated with increased risk of child mortality, severe infection and hospitalisation in countries such as Australia, the UK and the US.[5,151–157]

TABLE 14.5

Risks associated with insufficient breastfeeding for mothers and children (based mostly on data from economically advantaged countries such as Australia, the US, Germany and the UK) Updated from[158] Child

Mother

Child mortality (all causes)

Maternal child abuse and neglect

SIDS

Child, adolescent and adult mental health problems

[150–153]

[150,159,160]

Hospitalisation [150,154,155,161–163]

Lower respiratory tract infection [153,161]

Wheeze [164]

Gastroenteritis [161]

Otitis media [150,165,166]

Urinary tract infection [167]

[147]

Postnatal anaemia [195,196]

Increased anxiety and depression (in mothers with preexisting postnatal depression and anxiety) [146]

Longer duration breastfeeding gives greater protection AQention deficit hyperactivity against: disorder and autism Ovarian cancer [141,177]

[178,179]

[197–201]

Developmental delay

Endometrial cancer

Poorer motor development adolescence

Breast cancer

Reduced IQ or related measure

[207,208]

Depression in adulthood

Vascular calcification

[180,181]

[182]

[126,127,150,183] [184]

[202,203]

[150,204–206]

Breast cancer mortality Thyroid cancer [209] [210]

Inflammatory Obesity bowel disease[168] [150,173,185,186] Coeliac disease Cardiovascular disease

Myocardial infarction

[169–171]

[173,187]

Childhood leukaemia

Diabetes types 1 and 2

Metabolic syndrome

Snoring

Hypertension

Necrotising enterocolitis

[191]

Dental malocclusion

Osteoporotic fracture

Primary enuresis

Rheumatoid arthritis

[172,173]

[174–176]

[188–190]

[142,192] [193]

[204]

Type 2 diabetes [211–214] [215–217] [132]

[178,204,218,219] [220,221]

Delayed spontaneous enuresis [194]

Risks associated with suboptimal breastfeeding for mothers The risk to mothers who do not breastfeed, or who prematurely cease breastfeeding, are arguably under-appreciated (see Table 14.5). Suboptimal breastfeeding in the US is estimated to be the cause of 3340 maternal deaths (due to myocardial infarction, breast cancer and diabetes).[5] Hence, Batrick et al. argue that breastfeeding is just as much a women's health issue as it is a child health issue.[5] Suboptimal breastfeeding increases the risk of the other reproductory cancers, both ovarian[197] and uterine.[202] Furthermore, suboptimal breastfeeding is a risk factor for anxiety and postnatal depression, with this association being bi-directional.[46,48,49]

Establish and nourish the infant microbiome Breast milk nourishes and fosters the development of a healthy gastrointestinal microbiome. The microbiome of the exclusively breastfed infant is dominated by several Bifidobacterium spp. and has been coined the milk-oriented microbiome (MOM) because of the composition characteristics.[222] The MOM assists in protecting the infant from infection through competitive inhibition of pathogenic bacteria[222] and promotes a healthy intestinal barrier function. It is thought to be integral in preventing necrotising enterocolitis. The MOM interacts with the host in myriad ways, supporting healthy immune development, oral tolerance[223] and metabolic regulation, and may play a role in neurocognitive development. [100,224–226]

Breast milk as a source of bacteria Accumulating evidence indicates that breast milk is an important source of bacteria, some of which appear to colonise the infant's intestine, including species from the Bifidobacterium, Lactobacillus, Staphylococcus, Faecalibacterium, Bacteroides and Roseburia genera. Identical strains from these genera have been isolated from the milk of mothers and their infant's faeces.[105–108] Jost et al. found matched strains across 10 different genera in maternal faeces, breast milk and infant faeces.[106] Colonisation persistence of the infant at 6 months of age has been observed for Bifidobacterium maternal/infant matched strains.[105] One study indicated that breast milk is a reservoir for Bifidobacterium strains, but suggested that there was a possibility that some of these strains are initially shared from the newborn to the breast milk microbiota, as they were detected in some infants’ faeces prior to breast milk.[107] This same study detected Bifidobacterium strains in some newborns’ meconium stools on the first day of life, suggesting their initial inoculation occurred either in utero or following vaginal delivery. However, Bifidobacterium strains have been identified in colostrum samples prior to any breastfeeding by other researchers.[224,227]

The entero–mammary pathway It has been postulated that an entero–mammary pathway exists whereby bacteria are selectively sampled from the mother's colon and transported via mononuclear immune cells to the breast.[104] The presence of multiple matched strains in maternal faeces, breast milk and infant faeces[105,106] supports this hypothesis, as does animal evidence from both mouse and cow models.[228] Other studies have found that maternal ingestion of some specific bacterial strains (L. reuteri strain Protectus, L. rhamnosus GG, L. fermentum CECT5716) was associated with detection of these same strains in infant stool[229] and/or breast milk.[230,231] Transfer into breast milk appears to be strain specific as other probiotic strains administered to lactating women have not been detected in infant faeces after maternal administration.[229] Given the probable presence of the entero–mammary pathway,[104] the maternal intestinal microbiome may determine some aspects of the breast milk microbiota and the species and

strain composition available to the infant. This suggests a mechanism by which the maternal intestinal microbiome influences the health of the infant. In support of this are the findings of Grönlund et al., showing that maternal intestinal bifidobacteria status correlated with bifidobacteria colonisation of the infant at age 1 year and 6 months.[232]

Breast milk prebiotics There are multiple prebiotics present in human milk. Human milk oligosaccharides (HMOs) are a group of diversely structured sugar molecules that are probably the most well-known prebiotics in human milk. Bifidobacterium strains, in particular, appear to utilise HMOs.[233,234] Each mother has a genetically determined unique set of HMOs in her milk which in turn uniquely cultivate bacteria in the infant's gut.[101] HMOs are the third most abundant component in breast milk, present at a concentration of 5–15 g per litre. To date, 200 different HMOs have been identified, and it has been suggested that the characterisation of further HMOs is limited by the constraints of analytical technology.[101] Of interest, the presence of some types of HMOs (produced by women positive for the Lewis gene which regulates one type of sugar linkage present in some HMOs) may protect infants from neonatal group B streptococcus infection.[235] Other important prebiotic components include glycolipids, glycoproteins and glycopeptides.[101] Furthermore, lactose is a conditional prebiotic, and undigested lactose in the infant's colon may support the growth of bifidobacteria and lactobacilli[109,110] and be associated with suppressed growth of Bacteroides and Clostridia spp.[109]

Other factors that favourably influence the infant's microbiome Breast milk includes other bioactive components that also support the development of a healthy microbiome. Lactoferrin holds iron in a form that prevents bacteria from utilising it. [100] Free iron has the potential to cause dysbiosis and mucosal inflammation and increase the risk of bacterial infection.[236,237] Lactoferrin also has bactericidal effects – it binds to Gramnegative bacteria and disrupts their cellular membranes. Lysozymes (another bioactive breast milk protein) work in concert with lactoferrin, entering the bacterial cells lactoferrin has disrupted and effectively killing the bacteria. One study found that lactoferrin was active against Streptococcus mutans, Streptococcus pneumoniae, Escherichia coli, Vibrio cholerae, Pseudomonas aeroginosa and Candida albicans.[102] HMOs prevent mucosa adachment of potential pathogens as well as being prebiotics.[100] Several other components in breast milk are active against unfavourable bacteria including: haptocorrin (vitamin-B12-binding protein), bile salt-stimulated lipase, κ-casein and human milk mucins.[102,111] Many of the bioactive compounds in human milk work together synergistically. Furthermore, these components are able to resist digestion and are found in infant faeces.[102] See Table 14.6. TABLE 14.6

Bioactive components of human milk (mature) Components Cells (10 000–13 million cells/mL)[103]

Growth factors

Hormones

Cytokines and chemokines Carbohydrates

Lipids Proteins Note: the human milk proteome includes 976 identified proteins and many of these have immune-related properties[240]

Subcomponents

Functions

Stem cells

Developmental programming: Secrete growth factors including vascular endothelial growth factor, hepatocyte growth factor[238] Transferred and integrated into different tissues of the breast-fed offspring[239] Leukocytes 200– Immunomodulatory effects – defence, immune system 260 000 programming[103,240] leukocytes/mL Bacteria Seeding for the infant including transfer from maternal gastrointestinal system Mammary protection Many Developmental and metabolic programming Examples include: neurotrophic factors – brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), glial fibrillary acidic protein (GFAP), fibroblast growth factor 21 (FGF21), lysophosphatidic acid (LPA) and autotaxin (ATX)[112] Many Developmental and metabolic programming Examples include: melatonin, growth hormone, leptin, insulin, adiponectin, ghrelin, resistin, obestatin, peptide YY, glucagon-like peptide 1, calcitonin, somato​statin[121,139,140,241] Many Immunomodulation and inflammation regulation Lactose 7 g/100 Conditional prebiotic[109,110] mL Human milk Prebiotic oligosaccharides The combination and specific structures are genetically 0.5 to 1.5 g/100 determined. HMOs also function as surface-protecting mL decoys preventing bacterial and viral infections in the gut, respiratory tract and urinary tract[242,243] Galactolipids Prebiotic and viral bacterial receptor binding[243] Gangliosides Support neonatal brain development and myelination[244] AlphaPart of HAMLET promotes tumour cell apoptosis[245,246] lactalbumin Human Highly bio-available form of iron, bacteriostatic[247,248] lactoferrin May support cognitive development[249] SIgA Immune protection, promotion of tolerance, reduced allergen IgG exposure[134,250] Lysozyme and Antimicrobial protection[102] actoperoxidase microRNAs These enter the systemic circulation and exert tissue-specific immunoprotective and developmental functions[251]

Note: This is a list of examples, not an exhaustive list.

Allergy prevention Breastfeeding is thought to promote tolerance via a number of mechanisms including: nourishing the infant's microbiome, supporting healthy barrier function,[223] and antibody and cytokine tolerance promotion.[250,252] A 2015 systematic review that included 89 studies concluded that longer duration of breastfeeding was associated with less asthma at 5–18 years.[253] In addition, the studies found some evidence (while not as strong) for protection against eczema and allergic rhinitis.[253] A greater effect was seen in low- and middle-income countries. It was suggested that protection from infection was an important mechanism for reducing asthma development. Breastfeeding during solid introduction, in particular while introducing potential allergens, has the potential to promote tolerance.[254–257]

Nutritional considerations for the breastfeeding mother As with pregnancy, the special care of certain nutrients is important for the health of both the mother and the child. From a practical perspective, the time to discuss breastfeeding nutrition is during the third trimester. Some clearly wriden recommendations can go a long way, providing information that can be referred back to and reduces ‘consultation overload’ during the busy early weeks postnatally. Breastfeeding mothers need healthy food fast. The ideal situation is to have support with meals for the early weeks. Short of this, mothers will benefit by preparing and freezing some healthy meal bases ahead of time, and by having some simple wholesome meal and snack ideas (see the Sample meal plan below).

Sample meal plan

Meal

Menu

Meal is a rich source of:

Breakfast

Breakfast bowl • 2 tablespoons ground organic flaxseeds • 1 tablespoon chia seeds • 2 teaspoons lecithin • ¼ to ½ cup organic berries (thawed frozen or fresh) • ½ cup yoghurt containing prebiotics (i.e. L. rhamnosus GG) • Handful of organic almonds and 2 Brazil nuts • Additional chopped fruit as desired Avocado on sourdough bread or wholegrain gluten-free alternative

Calcium, polyphenols and other antioxidants, prebiotics, choline, vitamin E, protein, probiotics, alphalinolenic acid, potassium

Morning snack Lunch

Lunch Buddha bowl • ½ to 1 cup of the cooked mix mung bean rice mix (see below) • 2 cups of leafy greens (e.g. dark green and red leduce leaves) • 1 tablespoon pumpkin seeds • A drizzle of tahini • A drizzle of apple cider vinegar • A handful of cherry tomatoes • Top with a poached or fried egg (DHA-rich source) Mung bean and rice preparation Precook brown rice and mung beans and store in fridge. To prepare, mix ½ cup of red or brown rice with ½ cup of mung beans. Add 3 cups of water, bring to the boil and simmer on low heat for about 30 minutes. Stir occasionally. Once cooled, store in the fridge and use as a base. Afternoon Sardines on whole crackers and piece of fruit snack Alternative Raw carrot and hummus snack Dinner Slow-cooked root vegetable stew Add to a slow cooker: sweet potato, potato, red quinoa, purple carrots, beetroot, a protein source (tofu, legume or clean meat option), herbs and spices – in particular, consider carminative spices such as coriander, cumin, turmeric. Fifteen minutes prior to serving up, add sliced fennel and other leafy greens. Serve and add drizzle of olive oil and cracked pepper to taste

Afterdinner snack

Fruit

Vitamin E, carotenoids, folate, potassium Protein, resistant starch, polyphenols, folate, calcium, magnesium, vitamin C, B group vitamins, choline, DHA, carotenoids, potassium Greens considered lactogenic[31]

EPA, DHA, calcium, protein Vitamin C, fibre, polyphenols etc. Protein, resistant starch, polyphenols, carotenoids, potassium, folate, B vitamins Note: root vegetables and fennel vegetable traditionally considered lactogenic[31] Vitamin C, fibre, polyphenols etc.

Note: ideally new parents have help with meals during the first 4 weeks postnatally. Some will have eager friends who organise meal rosters and friends and families who make elaborate celebratory meals that are left at the door without expectation of visiting. The meals above are designed for minimal preparation and maximum effect. Some young infants may be sensitive to allium family foods and raw cruciferous vegetables.

With regard to breastfeeding nutrition, nutrients are divided into two categories: group 1 and group 2 (see Tables 14.7–14.9). The breast milk concentration of group 1 nutrients are dependent on maternal status, while the group 2 nutrients are regulated independently of maternal status. There are some nutrients for which poor maternal status is common and others that may be tightly regulated with some consequences to the mother's nutrient stores. These are considered priority nutrients (listed in Table 14.7 and detailed in Tables 14.8–14.9), and with a few exceptions they tend be similar to the nutrients that need special care during pregnancy. TABLE 14.7

Group 1 and group 2 nutrients for lactating mothers Group 1 nutrients (dependent on maternal status) Vitamin A Vitamin C Vitamin D Vitamin E Thiamine Riboflavin Vitamin B6

Maternal inadequate intake common Vitamin D Vitamin B12 Choline Iodine Selenium DHA

Group 2 nutrients (regulated independent of maternal status) Folate Calcium Zinc Iron Magnesium Copper

Maternal inadequate intake common Folate Zinc Calcium

Vitamin B12 Choline Iodine Selenium DHA More detail relating to each nutrient is included in Tables 14.8 and 14.9. It is prudent to supplement mothers with all of the nutrients listed in the lower row unless dietary sources are adequate. Some mothers may have insufficient intake of other nutrients listed above.

TABLE 14.8 Group 1 nutrients for lactating women – maternal intake or status correlates with breast milk content Nutrient information (group 1 nutrients) Vitamin A Fetal hepatic liver stores accumulate throughout pregnancy, and particularly during the third trimester with increased placental transfer.[258] The vitamin A content of breast milk is greater during the early months of lactation,[259] probably to facilitate the development of neonatal liver stores. A dynamic relationship between maternal hepatic stores and breast milk vitamin A appears to exist. Maternal vitamin A stores begin replenishing from 6 months postnatally, yet hepatic stores do not correlate with breast milk, suggesting that vitamin A in breast milk is at least partially

Maternal intake/dosage recommendations Individualise Ensure dietary sources When dietary sources are inadequate, supplement with

regulated independently of maternal status.[259] Nevertheless, Vitamin A is considered a group 1 nutrient because maternal deficiency (which is common in developing countries) results in lower breast milk vitamin A.[258] The preterm infant has a greatest risk of vitamin A deficiency owing to shorter gestation and subsequent inadequate hepatic stores.[258] In addition, some findings suggest that preterm breast milk may have lower vitamin A content than term milk. [258] Of note, hind milk has a higher vitamin A content because the vitamin is present in the lipid fraction of the milk.[260] Hence, milk sample collection technique may be a confounding factor with these and other findings. Maternal vitamin A supplementation can influence breast milk vitamin A, but only at higher-end doses. Most of the research in this area has been done in resourcepoor countries where a single mega-dose is the most feasible option. While this is probably not the most ideal dosage regimen, a systematic review of 11 studies found that a single mega-dose of 200 000 IU increases breast milk vitamin A concentrations,[261] and breast milk vitamin A concentrations seem to be maintained for at least the first 4 weeks.[262] Interestingly, a 2016 Cochrane systematic review found that there were no benefits to maternal or child morbidity or mortality with this practice.[263] Furthermore, rises in breast milk vitamin A may be in part related to correction of maternal vitamin A deficiency. A maternal daily dose of 5000 IU over the first month of lactation would appear a reasonable strategy to maintain good breast milk vitamin A if maternal vitamin A insufficiency is suspected. It is prudent to keep the portion supplied by retinol to 3000 IU to be in keeping with a dosage range that would be acceptable (in terms of perceived risk) in the event of an unexpected pregnancy. Of interest, the WHO recommends 10 000 IU of retinol vitamin A daily to pregnant women suspected of deficiency.[264] The RDIs for lactating women set by the US Institute of Medicine (IOM) and National Health and Medical Reserch Council (NHMRC) are 1110 IU[265] and 840–900 IU[266] per day, respectively. Vitamin C Maternal vitamin C intake consistently correlates with breast milk vitamin C, according to several observation studies.[267–269] One study found that vitamin C from dietary sources had a greater effect on breast milk vitamin C than that from supplements, and correlated with lower risk of atopy.[269] However, this may equally have been related to higher maternal fruit and vegetable consumption. Another study found that supplementing 500 mg of vitamin C along with 100 IU of vitamin E per day improved the antioxidant capacity of breast milk.[270] Breast milk vitamin C would appear to be easily maintained with a diet rich in fresh fruit and vegetables, or with supplementation in the order of 500 mg of vitamin C daily for mothers on restrictive diets. Vitamin D Breast milk vitamin D content reflects maternal vitamin D intake.[271] Some researchers propose that because most transfer of vitamin D is in the parent form cholecalciferol (vitamin D3), daily dosing of vitamin D3 or, alternatively, tri-weekly maternal adequate UVB exposure may be necessary to ensure good breast milk transfer of vitamin D.[271,272] However, not all clinical study findings support the need for daily exposure to the parent compound.[273] For clinical purposes, it seems appropriate to both maintain daily vitamin D (through supplementation or triweekly adequate sun exposure when this is acceptable and feasible) and obtain optimal maternal status. An RDI of 400 IU for infants has been derived in part for protection against rickets,

5000 IU daily comprising a maximum of 3000 IU direct vitamin A (retinol)

Supplement with 500 mg/day of vitamin C when maternal fresh fruit and vegetable intake is restricted

Individualise to achieve status >100 nmol/L and < 130 nmol/L Appropriate maintenance dose may range from 2000 IU to 6000 IU and needs to be triturated based on status and the

for which the dose is 400 IU.[274] In some countries, it is recommended to give all exclusively breastfed infants 400 IU daily from birth. Maternal vitamin D supplementation is arguably preferable to infant vitamin D supplementation. Infant vitamin D supplementation may undermine the mother's confidence in her breast milk adequacy, it exposes the immature gastrointestinal tract of the infant to excipients and furthermore treating the mother also provides maternal protection from vitamin D deficiency. Findings from clinical studies based in the US indicate that daily maternal supplementation of 6400 IU of vitamin D3 raises breast milk vitamin D

factors discussed

concentrations sufficiently to meet the infant's RDI.[272,275] In addition, infant serum vitamin D levels were no different when groups receiving maternal dose of 6400 IU were compared to infants supplemented directly with 400 IU.[272] A study utilising 2000 IU daily improved breast milk vitamin D content, but did not raise the mean concentration to a level that would supply the infant RDI.[276] Hollis and colleagues found that a maternal dose of 4000 IU came closer than 2000 IU to supplying the infant RDI, providing the infant with a daily intake of 135 IU and 70 IU, respectively.[277] Thiele et al. compared a maternal vitamin D dose of 3800 IU to 400 IU, both given throughout pregnancy and lactation, and found 4–6-week-old exclusively breastfed infants in the active and control group had an average status of 62 nmol/L and 42.5 nmol/L, respectively.[278] Interestingly, vitamin D levels of all infants were lower at 4–6 weeks than they were at birth.[278] Variations relating to geographical location, season, lifestyle, sun exposure and skin pigmentation should be taken into consideration when extrapolating these findings to the individual. An additional consideration is that breast milk vitamin D content may be underestimated because, like vitamin A, breast milk vitamin D is present in the lipid fraction of the mother's milk. Extrapolating from the study by Wagner et al.,[275] a maternal 25-hydroxyvitamin D status of >110 nmol/L appears to be associated with adequate breast milk vitamin D concentrations. It appears prudent to maintain maternal status between 110 and 130 nmol/L to ensure vitamin D sufficiency in the infant and avoid the potential for adverse effects. The IOM proposes there is a potential for adverse effects at a status greater than >150 nmol/L, and that levels over 500 nmol/L are toxic.[279] Note on optimal vitamin D status The optimal vitamin D range is still debated, with different sufficiency values proposed by different organisations. The respective sufficiency values proposed for the IOM, Endocrine Society and Vitamin D Council are >50 nmol/L,[280] >75 nmol/L[281] and >100 nmol/L[282] respectively. Based on physiological parameters including adequate breast milk transfer and appropriate suppression of parathyroid hormone, disease prevention and approximated values likely to represent evolutionary equivalency, Baggerly et al. propose an optimal status of 120 nmol/L (but not greater).[283] Vitamin E During pregnancy, placental transfer of vitamin E is limited. Consequently, the neonate has minimal stores at birth and depends entirely on breast milk as a source. [284] Vitamin E concentrations are highest in colostrum and reduce as breast milk transitions to mature milk. Infants consume larger volumes of mature milk; hence, daily infant vitamin E intake may be similar. While maternal stores may impact on breast milk vitamin E status, maternal serum levels and habitual daily dietary intake do not correlate with breast milk levels.

Ensure good dietary sources When dietary intake is insufficient, consider supplementation

[284,285]

However, a single 400 IU vitamin E dose was associated with increased with 100 IU/day in [284,286] colostrum and transitional milk vitamin E concentration 24 hours later. It is a natural form not clear whether this indicates that higher-dose vitamin E may influence breast containing mixed milk concentration overall or that this effect is specific to the colostrum and tocopherols transitional breast milk phase. These studies also found that natural vitamin E was more effective at raising colostrum levels than synthetic vitamin E.[284,286] One study found that a 100 IU/day dose of vitamin E (form not available) combined with 500 mg/day of vitamin C improved the antioxidant capacity of breast milk indirectly.[270] Based on the current data, it would seem that including dietary sources that supply natural tocopherols and maintain maternal vitamin E status is adequate for most women. For women with poor nutrient intake, supplementation with a natural form of vitamin E is prudent. The IOM and the NHMRC set the RDI and AI at 28.4 IU[265] and 16.4 IU[266] respectively. Ensuring intake is adequate to also contribute to maternal stores may be more appropriate, such as 100 IU in the form of natural alpha tocopherol and mixed tocopherols obtained through diet or supplementation, if necessary. Thiamine 5 mg daily Thiamine is actively transported into breast milk. Supplementation increases breast milk concentration in deficient women but not in replete women.[287] The IOM RDA for thiamine during lactation is 1.4 mg/day.[288] Given there are a range of dietary factors that can reduce thiamine bioavailability,[289] it may be prudent to aim for a daily intake higher than the RDI during pregnancy and lactation. Riboflavin Breast milk levels strongly correlate with dietary intake. Breast milk riboflavin is present in the coenzyme form flavin adenine dinucleotide (54%), as well as free riboflavin (39%).[288] Supplementation of riboflavin increases free riboflavin but not flavin adenine dinucleotide.[287] The IOM and the NHMRC have both set the RDI for lactation at 1.6 mg/day.[265,266] However, a dose of 1.8 mg daily did not result in sufficient breast milk levels in a population of riboflavin-deficient mothers.[287] Based on this finding, a dosage of 10 mg/day may be more appropriate when maternal riboflavin insufficiency is suspected. Note: riboflavin supplementation can result in yellow colouring of infant's urine, which could be confused with signs of dehydration or insufficient breast milk intake. Vitamin B6

When dietary intake is insufficient, consider supplementation of 10 mg daily

15 mg daily

Following pyridoxine hydrochloride supplementation, there is a rapid increase in breast milk pyridoxal, pyridoxamine and pyridoxal phosphate, occurring over a 3to 8-hour period.[288] Pyridoxal 5 phosphate (the biologically active form) is also present in breast milk in comparatively low levels.[290] The vitamin B6 RDI set by the NHMRC for lactation is 2 mg per day.[266] To promote good breast milk transfer, a daily intake of 10–15 mg is recommended.[288] A mix of pyridoxine hydrochloride and pyridoxal 5 phosphate may be the most appropriate B6 supplement option, to ensure both bioavailability and maternal access to the active form in the case of inborn errors in metabolism.[291] Vitamin B12 Infantile Vitamin B12 deficiency infers risk of anaemia and severe impaired [292]

neurological development at a critical time point. Maternal deficiency is associated with low breast milk B12 concentrations. Furthermore, low maternal

500–1000 micrograms daily until adequate

status during pregnancy results in poor infant vitamin B12 stores at birth. Classic maternal risk factors are vegan, vegetarian or low-animal-food diet, malabsorption issues and pernicious anaemia. However, a 2016 systematic review found that vitamin B12 insufficiency is also common in non-vegetarian populations.[293] Additionally, a recent UK study found that 12% of pregnant women had low serum B12 levels.[294] Maternal supplementation with 250 micrograms daily throughout pregnancy and breastfeeding is associated with improved breast milk vitamin B12 levels.[295] In light of how common vitamin B12 insufficiency is, prudent supplementation of vitamin

maternal status confirmed and monitored Ideally, this is made up with a combination of methylcobalamin and adenosylcobalamin

B12 during pregnancy and breastfeeding is recommended. An oral dose of 1000

micrograms appears to be sufficient in individuals with pernicious anaemia,[296] indicating that a dose of this order overcomes malabsorption barriers. Ensuring the adequacy of vitamin B12 dose is a priority in this population. Serum B12 assay has limited value in predicting B12 status.[297] Due to the complexities of cobalamin

physiology, a full panel of markers is necessary for accurate status assessment and would suggest sufficiency when serum B12 is >300 pmol/L, total serum holotranscobalamin is 40–125 pmol/L, plasma homocysteine is cold packs after feeds help with pain > alternating hot and cold applications assists with recovery generally • Rest – Bed rest (support needed with baby and home)

After ensuring all the above strategies are in place, in particular frequent effective milk removal, naturopathic treatments can be added. Herbal medicine can be a wonderful adjunct to the above. A herbal formula tailored to the individual may include agents with the following actions: immune modulation, restorative, adaptogenic, nervine, lymphatic, circulatory stimulant, anti-inflammatory, antioxidant and antibacterial (see Table 14.25 and Box 14.4). The value of topical applications such as a herbal cream should not be underestimated. A therapeutic cream can be massaged into the affected area, and a heat pack can be used to help the therapeutic agents penetrate (see Box 14.5). Care needs to be taken to avoid the nipple area and to prevent the infant from ingesting the cream or residue.

TABLE 14.25

Herbal medicines as adjunctive treatment for mastitis Immune support • Echinacea spp., Piper longum, Andrographis paniculata (some suggest caution) Lymphatics – to support effective lymphatic drainage of the breast • Echinacea spp., low-dose Phytolacca decandra, Calendula officinalis, Galium aparine Circulatory stimulants – work in tandem with the lymphatics • Zingiber officinale, Origanum vulgare ssp. hirtum, Piper longum, Curcuma longa, Zanthoxylum clava-herculis Nervine-building herbs • Rationale for including nerviness: – stress response can play a role in mastitis pathophysiology – nervines may assist with MER – nervines may be especially useful for preventing recurrence • Verbena officinalis, Withania somnifera, Lavandula angustifolia, Chamomilla recutita, Leonorus cardiaca Antimicrobial herbs • Origanum vulgare ssp. hirtum, Allium sativum – fresh where maternal ingestion is tolerated by the infant Contraindications • Generally avoid use of herbs that reduce milk supply – Salvia officinalis • Caution with use of strong galactagogues – Trigonella foenum-graecum – Foeniculum vulgare – Pimpinella anisum – Galega officinalis

Box 14.4

Example herbal formulas Herbal formula for mastitis example 1 When stress and exhaustion appear to be part of the history. Echinacea Oregano Lavender Ginger Shatavari

40 mL 15 mL 10 mL 5 mL 25 mL

Dose: 5–7.5 mL four t.d.s. until symptoms are at least 75% be=er (typically within 24–48 hours), then taper down. When convenient take after breastfeeding

Herbal formula for mastitis example 2 History suggests prolonged milk stasis due to recent history of infrequent breastfeeding.

Echinacea Calendula Turmeric Ginger Long pepper

35 mL 15 mL 35 mL 7.5 mL 7.5 mL

Similar dosage recommendations to above

Box 14.5

Example herbal cream ingredients Herbal cream for mastitis example Ginger (1 : 2) tincture 10% Poke root (1 : 10) tincture 10% Lavender essential oil 3%

In an olive oil and beeswax base

Recommendations Apply with massage to affected area four times daily after a breastfeeding For prevention of recurrence, massage once daily

Caution Prevent infant ingestion by: • avoiding areola • allowing time to soak in before li=le hands get to it • applying heat to increase penetration

It should be noted that the primary aim of management is to overcome the acute episode. Therefore, therapies focused on this should be prioritised. Stage two is working to prevent recurrence (see below).

A note on probiotics in acute mastitis It has been proposed that probiotics could be an alternative to antibiotics for the treatment of infective mastitis based on the results of a comparator study.[231] However, the antibiotics employed in this study varied and many would be deemed unsuitable for the treatment of mastitis. So it has been argued that the study did not adequately test the hypothesis.[568] Interestingly, the efficacy of antibiotics for the treatment of mastitis has not been established,

according to a 2013 Cochrane review.[569] Arroyo found that 3 weeks of treatment with probiotics appeared to be superior to antibiotic treatment.[569] While acceptable in chronic breast pain, this treatment timeframe is completely unacceptable in acute mastitis. Probiotics should be viewed as a useful adjunct, but their efficacy in acute mastitis is yet to be established as they may not be sufficiently rapid in their action. They are, however, highly valuable in the prevention of mastitis recurrence (see below), and depending on the mother's budget, they can be commenced during the acute phase of mastitis.

Follow-up and limits of therapy Appropriate follow-up is a duty of care in this scenario. The clinician needs to make contact at least every 12–24 hours during the acute phase of the condition to assess response to treatment and the need for referral for antibiotics. While in most cases antibiotics can be avoided, it is important to have a clear clinical framework to avoid pu=ing women at risk of damage to the breast, breast abscess or, in the worst-case scenario, septicaemia. The ABM recommends antibiotic treatment if the woman is not improving within 24 hours or if she is acutely unwell.[559] Given the potential negative sequelae associated with antibiotic treatment, it could be argued that there is scope for allowing a li=le more time prior to considering antibiotics. Particularly so if the core aspects of treatment are combined with a herbal medicine approach. A proposed practice guideline for naturopaths is set out in Box 14.6.

Box 14.6

Proposed practice guidelines for referral of women with mastitis Refer to a doctor with good breastfeeding knowledge to discuss antibiotics when: Severe: • especially if present for more than 12–24 hours • redness spreading, persistent high fever Poor response to treatment: • no improvement within 24–48 hours of comprehensive treatment • ge=ing worse within 12–24 hours despite comprehensive treatment Note: when antibiotics are prescribed, it is critical that an appropriate antibiotic is selected as the common mastitis pathogens are penicillin resistant. Follow-up within 12–24 hours is essential during the acute stage of mastitis.

Infective versus non-infective mastitis Distinguishing between infective and non-infective mastitis is difficult. The relevance of fever in mastitis is commonly misunderstood. As discussed previously, fever in mastitis means that pyrogens have entered the blood stream, and in the case of mastitis, this may be milk proteins or bacteria products. Culturing of breast milk is not valid for diagnosing infective mastitis because of skin flora contamination and the normal bacteria present in breast milk. Kvist et al. found that women with mastitis symptoms were more likely to have positive cultures for common mastitis pathogens Staphylococcus aureus (45% vs 31% P = 0.001) and group-B streptococci (GBS) (21% vs 10% P 3 kg over the past 3 months) • Appetite • Mobility • Psychological stress of acute illness • Dementia/psychological problems • BMI (or calf circumference if BMI unavailable). MST • Weight loss (1–5 kg, 6–10 kg, 11–15 kg or >15 kg) over the past 6 months • Appetite. SNAQ65+ • Weight loss (>4 kg unintentional loss in the past months) • Mid-upper arm circumference • Appetite and functionality.

Comments

Validated for early detection of undernutrition Malnourished and frailty in community-dwelling people aged • At risk of ≥65 years of age. malnutrition • Normal nutritional status.

• High risk Developed and validated for acute hospital, • Medium risk oncology and residential care patients. • Low risk. •

Designed for community-living older adults.

Malnourished • At risk of malnutrition • Normal nutritional status.

Geriatric syndromes The term ‘geriatric syndromes’ (previously known as the giants of geriatrics) has been developed to identify and define conditions that are primarily seen in older adults but that do not readily fit within a systems approach to pathophysiology.[112,113] Geriatric syndromes are a heterogeneous group of conditions and while as yet poorly defined, they are associated with reduced quality of life and increased morbidity and mortality.[112,113] There is no universally agreed list of geriatric syndromes but the most commonly cited are frailty, sarcopenia, falls, depression, delirium, functional decline, anorexia of ageing and malnutrition, polypharmacy, dizziness, syncope, urinary incontinence and pressure ulcers. [112]

Common features of geriatric syndromes include their prevalence among adults 65 years and older, especially the frail elderly. There are numerous and compounding contributing factors involving multiple organ systems and shared risk factors including increasing age, cognitive and functional impairment and impaired mobility.[112] In clinical presentation the primary complaint may not represent the specific pathophysiological processes that initiated the decline in health status. For example, a urinary tract infection may not be mentioned as

the health complaint, but it may be the underlying event that triggers the presenting complaint of delirium. In this way the two conditions, urinary infection and neurological alteration, illustrate some of the atypical presentations of disease already discussed. This apparent separation between origin and expression of pathology in distinct and distant organs is described by Inouye[112] as ‘a disconnect between the site of the underlying physiologic insult and the resulting clinical symptom’. Assessment and diagnosis are not linear, nor do they follow an obvious cause-and-effect model, and the syndromes characteristically involve several body systems and thus professional disciplines.

Frailty Frailty results from a multi-system reduction in reserve capacity which increases the individual's vulnerability for developing greater dependency, as well as increasing mortality when exposed to a stressor.[114] Avoidance of frailty is a major challenge, yet it represents the best possible outcome as the ability to recover from frailty is limited (see Fig. 17.1). Analyses of studies on the prevalence of frailty average 9% for frailty and 44.2% for pre-frailty.[115] A consensus statement on frailty from European and US societies is noted in Box 17.4.[114]

FIGURE 17.1

Reduced reserve and recovery in frail older adults

Box 17.4

A consensus statement on frailty Definition The consensus definition of physical frailty is ‘a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced

physiologic function that increases an individual's vulnerability for developing increased dependency and/or death.’

Screening • Simple rapid screening tests have been developed and validated, such as the simple FRAIL scale • All persons older than 70 years and all individuals with significant weight loss (≥5%) due to chronic disease should be screened for frailty.

Intervention Physical frailty can potentially be prevented or treated with specific modalities, such as: • Exercise • Protein-calorie supplementation • Vitamin D • Reduced polypharmacy. Source: Adapted from Morley JE, Vellas B, Abellan van Kan, G et al. Frailty consensus: a call to action. J Am Med Dir Assoc 2013;14(6):392–7.

Frailty results from cumulative decline across multiple physiological systems and is associated with adverse outcomes. It is the end point of physiological decline compounded with environmental insults, multi-morbidity, malnutrition and age. While there is overlap, frailty is not synonymous with disability, which is an inability to perform ADLs; for example, in a study of people diagnosed with frailty, 27% had neither disability nor comorbidity.[39]

Assessment criteria Assessment of frailty is based on meeting three of the following five screening criteria: 1 Weight loss: low baseline weight, unintentional weight loss of more than 5% or 4 kg over 12 months 2 Exhaustion: self-report of excess effort required, unusually tired and weak, low rated energy (0–10) 3 Low physical activity 4 Slowness: timed walking 4 m 5 Weakness: grip strength.[7,39,41,116] Frailty is also characterised by increased levels of inflammatory markers (IL-6, C-reactive

protein) and D-dimer and an elevated white cell count.[41] The degree of frailty can be quantified using the Clinical Frailty Scale, shown in Table 17.7. TABLE 17.7 Clinical Frailty Scale Grade

Plain language Common characteristics descriptor

1

Very fit

2 3

Well Well, with treated comorbid disease Apparently vulnerable

4

5 6 7 8

Mildly frail Moderately frail Severely frail Terminally ill

Robust, active, energetic, motivated and fit. Usually exercises regularly and is in the fi]est group for their age; commonly describes their health as ‘excellent’. Without active or symptomatic disease, but less fit than people in category 1. Disease symptoms are well controlled compared with those in category 4.

Although not frankly dependent, commonly complains of being ‘slowed up’ or has disease symptoms or self-rates health as ‘fair’, at best. If cognitively impaired, they do not meet dementia criteria. Shows limited dependence on others for IADLs. Needs help with instrumental and some personal ADLs. Walking commonly is restricted. Completely dependent on others for personal ADLs Terminally ill.

Source: Adapted from [116].

Malnutrition is one of the key determinants of frailty; it is modifiable to varying degrees and is both a cause and a result of frailty.[102] In particular, known modifiable risks for frailty include protein energy malnutrition and deficiency of vitamin D and selenium.[102,117] A review of the results of 4731 US adults aged 60 years or older from the Third National Health and Nutrition Examination Survey (NHANES) analysed frailty, energy, biomarkers of nutritional status and food insufficiency.[117] Perhaps surprisingly, the prevalence of frailty was highest among people who were obese (20.8%), followed by overweight (18.4%) and normal weight (16.1%) and was lowest among people who were underweight (13.8%); this is indicative of obesogenic sarcopenia. Regardless of BMI, daily energy intake was lowest in people who were frail, followed by those who were pre-frail and was highest in people who were not frail, with frail people consuming 9% fewer calories (151 calories) than the not-frail group. In addition, serum albumin, carotenoids and selenium levels were lower in frail adults than in not-frail adults.

Sarcopenia Sarcopenia is a change in body composition associated with ageing. Specifically, it is a syndrome characterised by progressive and generalised loss of skeletal muscle mass and strength.[15,102,118–120] Sarcopenia in the elderly is an independent predictor of poor gait, falls,

fractures and other disability.[121] It is associated with adverse outcomes, reduced QOL, increased complications from hospitalisation and morbidity.[118,119] The prevalence of sarcopenia is reported variably from approximately 30% in people over 60 years of age to around 50% in those aged 75 years or more.[102] With sarcopenia there is reduced muscle mass, infiltration of muscle with fat and connective tissue, a decrease in muscle fibres (a greater loss of type II fibres than type I fibres), disorganisation of myofilaments, proliferation on endoplasmic reticulum, a decrease in the number of motor units and accumulation of the ‘ageing pigment’ lipofuscin.[119] At a basic level the loss of muscle mass is partially due to reduced physical activity and in part due to the diminished size, and to a lesser degree the diminished number, of motor neurons. [39] It is estimated that there is a 30% decline in muscle mass from the third to the eighth decade, predominantly type II fibres, resulting in a significant reduction of VO2 max and force contraction.[15] Age-related changes to collagen fibres within joints contribute to reduced elasticity and movement. Maximum muscle strength decreases by about 20–40% by the seventh to eighth decade due to the large loss of skeletal muscle fibres and concomitant reduction in the number of motor neurons.[7] As with all geriatric syndromes, the development of sarcopenia is multifactorial. The reduced size and number of motor neurons and loss of skeletal muscle mass is exacerbated by physical inactivity. Other factors that influence sarcopenia development are:

• Neurological decline • Reduced anabolic hormone levels (testosterone, oestrogens, growth hormone, insulin-like growth factor-1) • Reduced vitamin D and parathyroid hormone • Inflammatory pathway activation and increased pro-inflammatory cytokines (especially TNF-α, IL-6) • Oxidative stress • Changes in the mitochondrial function of muscle cells • Chronic illness (reduces physical activity, promotes inflammation) • Fa]y infiltration of muscle • Protein/energy malnutrition • Reduced intake of vitamin D.[7,119,122,123] Sarcopenic obesity Sarcopenic obesity is the co-occurrence of sarcopenic age-related loss of skeletal muscle and excess body fat. Sarcopenic obesity increases with age, as the metabolic rate continues to fall, lean muscle mass diminishes and there is limited physical activity, all of which both cause and are a result of sarcopenic obesity.[102] Increased weight and reduced strength make these

older adults at particular risk of adverse outcomes and functional decline.[102] It has been suggested that sarcopenic obesity can predict disability more than sarcopenia or obesity as independent conditions.[123] The risk factors for sarcopenic obesity are an overlap of those for obesity and sarcopenia: malnutrition with excess energy intake, insulin resistance, inactivity, low-grade inflammation, and hormonal and peptide influences.[102] The increasing prevalence of overweight and obesity in young and middle-aged adults signals a potential increase in the prevalence of sarcopenic obesity in older adults in the coming decades. Intervention is complex and the focus needs to be on preventing the development of sarcopenia and sarcopenic obesity. Physical activity, in particular resistance training, is the most effective strategy to maintain and gain lean muscle mass. This can be supported by improving nutritional intake and status, with a particular focus on adequate protein and vitamin D and reducing inflammation.[123]

Falls Falls are an archetypal geriatric syndrome because they are due to multiple interacting conditions that create and worsen reduced tolerance to any type of external stress that is characteristic of ageing.[124] It is estimated that more than one-third of community-living older adults fall each year and more than half of those have recurrent falls.[125] Falls are associated with significant morbidity and mortality, with 20–30% of falls causing moderate to severe injuries including cuts and head injuries, and approximately 3–5% of falls resulting in fractures.[17,125] Further, falls account for two-thirds of injury-related deaths in those aged 85 years and older and are the leading cause of death from injury in adults aged 65 years and older.[17,125] In Australia in 2011–12, 96 385 people aged 65 and over were hospitalised for a fall-related injury, which is three and a half times as many as for 45–64 year olds. The rate of hospitalisation increases dramatically with age: for women aged 65–69, the age-specific rate of hospitalised falls was 1100 cases per 100 000 population, compared with 9451 cases per 100 000 for women aged 85–89. For men, the equivalent rates were 737 and 6383 per 100 000 men. [125] A fractured hip (neck of femur) has major consequences with increased short- and longterm morbidity: the death rate is up to 24% in the first 3 months post-surgery.[126] In addition, there is loss of mobility and independence and an increased requirement to move to residential care facilities. Risk factors for falls are outlined in Table 17.8.

TABLE 17.8

Falls risk factors

Extrinsic

Intrinsic: physical

• Living alone (also greater risk of not being able to get help) • Trip and slip hazards, e.g. rugs, uneven flooring, wet floors • Poor lighting • Clu]ered walkways • Footwear and clothing • Inappropriate walking aids (or inappropriate use of those devices) • Lack of handrails • Poor stair design.

• Poor mobility • Impaired balance and gait • Visual impairment • Reduced muscle strength • Poor reaction times • A history of falls • Postural hypotension • Incontinence • Polypharmacy, CNS-active medications • Comorbidities, especially cardiovascular and circulatory, COPD, arthritis and neurological disorders • Sedentary behaviour • Nutritional deficiencies, especially vitamin D.

Intrinsic: psychological and cognitive • Fear of falling (a major risk) • Cognitive impairment, even subtle deficits • Confusion • Delirium • Depression.

Source: [124,125,127].

Interventions for falls are based on a risk management approach. The risks are identified and either eliminated (e.g. occupational therapy review, installation of handrails and removal of rugs) or reduced (e.g. exercise physiology and physiotherapy to improve strength and balance, nutritional enhancement, medications review).

Pain Pain is not restricted to older adults, but the prevalence is high and it is an important contributor to reduced QOL, reduced mobility and subsequent loss of muscle mass, sarcopenia and increased frailty. In addition, pain is associated with increased need for analgesia and associated risks of polypharmacy. Pain may be under-reported as it is perceived as a normal part of ageing.[7]

Depression Depression is not exclusive to older adults and is discussed in full in Chapter 21. It is included here as it is a significant and common cause of morbidity and mortality in the elderly and it may be under-diagnosed or misdiagnosed (e.g. as dementia).[7] Depression is a key contributory factor for undernutrition which underpins geriatric syndromes and functional decline.[128] The prevalence of depression is estimated to be 10–19% among those aged 75 or over.[129,130] Residents in aged-care facilities are thought to have a prevalence of depression up to 35%; in addition, anxiety may also be present in 10% of older adults.[129] Assessment tools such as the Geriatric Depression Scale[131] may aid in diagnosis. The risk

factors for depression in old age are inclusive for a large proportion of older people, as follows:

• Being female (though suicide is higher in men) • Loss or adverse life events • Medical disorders such as stroke, cardiovascular disease (conversely, depression is also a recognised risk factor for cardiovascular disease) • Prior depression or mental illness • Neurodegenerative disease – three to four times more common with dementia • Isolation.[9,129,130] Depression in older people may be under-diagnosed and treatment responses may not be significant or sustained. A review of the course of depression in 285 older people found that almost half (48.4%) of those who were clinically depressed at the commencement of the study also suffered from a depressive disorder 2 years later. Those with more severe symptoms of depression, comorbidities and a younger age of onset were at a higher risk of persistent or recurrent depression.[132] Further, findings showed that late-life depression often has a chronic nature even when treated according to age-specific guidelines.[132] See Table 17.9 for signs and symptoms of depression in older people. TABLE 17.9

Signs and symptoms of depression in older people Thoughts

Feelings

Physical symptoms

• Indecisiveness • Apathy • Loss of self-esteem • Persistent suicidal thoughts • Negative comments like ‘I'm a failure’, ‘It's my fault’ or ‘Life isn't worth living’ • Excessive concerns about financial situation • Perceived change of status within the family.

• Moodiness or irritability, which may present as anger or aggressiveness • Sadness, hopelessness or emptiness • Feeling overwhelmed • Feeling worthless or guilty.

• Cognitive problems, including memory problems • Insomnia, hypersomnia • Persistent fatigue • Slowed movements • Somatic symptoms: headaches, backache, pain • Digestive disturbances including changes in bowel habits • Agitation, hand wringing, pacing • Anorexia • Significant weight change.

Source: Beyondblue. Signs and symptoms of anxiety and depression in older people. Beyondblue. [Cited 16 September 2016. Available from www.beyondblue.org.au/who-does-it-affect/older-people/signs-and-symptoms-ofdepression-in-older-people.]

Suicide rates are alarmingly high in older males.[130,133,134] In Australia in 2013, the highest age-specific suicide death rate for males was observed in the 85 years and over age group (38.3 per 100 000 males).[133] The lowest age-specific death rate (outside 0–14-year-olds) for female deaths was in the 80–84 year age group (4.0 deaths per 100 000). Risk factors for suicide include psychological, social and physical factors such as severe depression, loneliness, social isolation and lack of social support; chronic ill-health and pain; and loss of autonomy and reduced QOL.

Delirium Delirium is an acute neuropsychiatric disorder of a]ention and cognition.[135] It is characterised by a reduced clarity of awareness of the environment and a decreased ability to focus, maintain or shift a]ention.[16] While delirium is associated with worsening dementia severity, declining functional status and higher mortality in those with dementia, delirium and dementia are two discrete entities.[135] Table 17.10 compares the features of delirium and dementia. TABLE 17.10 Features of delirium compared with dementia Feature

Delirium

Dementia

Onset Course

Memory

Acute (most cases) Fluctuating levels of consciousness over the day, lucid at times Hours to weeks Reversible Abnormally low or high, agitated and distracted Perceptual disturbance, e.g. visual hallucinations; impaired visuospatial orientation Disorganised, difficulty with concentration, orientation and a]ention Immediate and recent memory impaired

Thoughts Speech Psychomotor activity Physical illness or medication causative

Disorganised Incoherent, slow or rapid Increased, shifting or reduced Frequently, e.g. febrile illness, drug toxicity or organ failure

Insidious Generally stable (exacerbated by delirium) Months to years Irreversible Usually normal Usually normal, no hallucinations Normal unless advanced disease Recent and remote memory impaired Impoverished Word-finding difficulty Often normal Usually absent

Duration Alertness Perception A]ention

Source: Adapted from Browne W, Nair K. Geriatric medicine. In: Talley NJ, Frankhum B, Currow D (eds). Essentials of internal medicine. 3rd edn. Philadelphia: Churchill Livingstone; 2015, pp. 777–90. Hevesi ZG, Hammel LL. Geriatric disorders. In: Hines LH, Marschall KE (eds). Stoelting's anesthesia and co-existing disease. 6th edn. Philadelphia: Saunders; 2012, pp. 642–54. Heflin MT, Cohen HJ. The Aging Patient. In: Benjamin IJ, Griggs RC, Wing EJ, et al (eds). Andreoli and Carpenter's Cecil essentials of medicine. Philadelphia: Elsevier; 2016. Davis DH, Muniz Terrara G, Keage H, et al. Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain 2012;135(Pt 9):2809–16.

A common presentation of delirium is postoperatively or with bacteraemia. Estimates of prevalence in hospital se]ings vary from 10% to 30% of all hospitalised elderly people[16] and up to 50% of older adults in surgical units.[7] The lack of definitive prevalence statistics is due to probable under-reporting and under-diagnosis, including the condition being incorrectly a]ributed to dementia or drug reactions.[7] That said, polypharmacy and altered pharmacokinetics and pharmacodynamics are key risk factors for delirium – an estimated 39% of delirium cases are due to medications.[99]

Elder abuse The WHO defines elder mistreatment as ‘a single or repeated act or lack of appropriate action occurring within any relationship where there is an expectation of trust, which causes harm or distress to an older person’.[136] In addition, the US National Research Council definition includes ‘failure by a caregiver to satisfy the elder's basic needs or to protect the elder from harm’.[137] See Table 17.11 for categories of elder abuse. The incidence and prevalence of elder abuse is unclear as it is unrecognised, under-reported, insidious and hidden.[7] In 2015 the WHO reported that estimated prevalence rates in high- or middleincome countries ranged from 2% to 14%.[11] In contrast, the Australian Longitudinal Study on Women's Health suggests that neglect could be as high as 20% among women in the older age group.[138] The perpetrator may be a family member and the older person may feel too vulnerable, disempowered and ashamed to disclose abuse.[7] Unlike mandatory reporting for vulnerable children, there are no protective and screening measures in place for vulnerable older people.

TABLE 17.11

Categories of elder abuse Psychological abuse Inflicting mental stress via actions and threats that cause fear, violence, isolation, deprivation and feelings of shame and powerlessness. Includes: • Verbal abuse • Intimidation • Humiliation • Threats to put the older person into residential care • Social abuse (e.g. isolating from others).

Physical abuse Sexual abuse Nonaccidental acts that result in physical pain or injury, or physical coercion. Examples include any form of assault such as: • Hi]ing • Slapping • Shoving • Pushing • Burning • Using physical restraint such as tying a person to a chair or bed • Locking a person in a room.

Financial abuse

Unwanted sexual acts, The illegal use, including sexual contact, improper use or rape, language or mismanagement exploitative behaviour of a person's where the person's consent money, was not obtained or where property or consent was obtained financial through coercion. Sexual resources. For abuse can also include example: sexually exploitative or • Taking a loan with shaming acts such as: a promise of • Leaving a person in a state of repayment but not undress paying the money • Forced viewing of sexually back explicit materials or images • Stealing money or • Sexually suggestive comments using an older • Exhibitionism person's banking • Inappropriate touching and credit card • Uninvited sexual approaches. without consent • Forcefully encouraging changes to a will or other legal document • Sale of any property or assets without authority or consent • Forced transfers of property.

Neglect Active neglect is the deliberate withholding of basic care or necessities, including: • Leaving an older person in an unsafe place or state • Stopping access to medical treatment • Abandonment • Not providing adequate clothing or sufficient food and liquids • Untreated illnesses • Over- or undermedicating. Passive neglect is the failure to provide proper care, due to carer stress, lack of knowledge or ability. It may occur unintentionally and may simply require ge]ing additional support to assist the carer and older person.

Source: Tinker A, Biggs S, Manthorpe J. The mistreatment and neglect of frail older people. In: Fillit HM, Rockwood K, Young J (eds). Brocklehurst's textbook of geriatric medicine and gerontology. 8th edn. Philadelphia: Elsevier; 2017. Seniors Rights Victoria. Your rights: elder abuse. [Cited 20 September 2016. Available from https://seniorsrights.org.au.][140]

A systematic review of risk factors for elder abuse categorised risks according to four domains:

• Factors associated with the older person, such as cognitive impairment, behavioural problems, psychiatric or psychological problems, functional dependency, ill-health, frailty, low income, trauma or past abuse, and ethnicity • Factors associated with the perpetrator, such as caregiver burden or stress, psychiatric illness or psychological problems • Factors associated with relationships, including family disharmony, poor or conflictual relationships • Environmental factors such as low social support and living with others including in residential care.[137,139] An older person may show evidence of physical trauma or behavioural and cognitive change if subject to abuse; they will become withdrawn, anxious and depressed.

Pharmacokinetics, polypharmacy and posology This section reviews issues relating to pharmaceuticals and older people, including clinical evidence, pharmacokinetics, pharmacodynamics, polypharmacy, adverse reactions and risk management. In the absence of a body of evidence for complementary medicines and older patients, it may be appropriate to extrapolate the learnings from pharmaceuticals to natural therapies.

Epidemiology of medication use and potential issues An ageing population has an increased prevalence of multiple medical conditions and thus medication use, as pharmacological management may be seen as the most appropriate therapeutic intervention with advancing age. People aged 65 years and older are prescribed medications more frequently than any other age group and increasingly will be taking more than one medication. In Australia half of all people aged between 65 and 74 years and twothirds of those aged 75 years and over report taking five or more medicines daily.[141] Data from the US National Health and Nutrition Examination Survey (NHANES)[142] for 37 959 adults (20 years and older) showed an 8% increase in overall use of prescription drugs from 1999–2000 to 59% for 2011–2012. In the same period the prevalence of polypharmacy (defined as ≥5 medications) in older adults rose from an estimated 8.2% to 15%. In the US, people aged 65 years and older comprise only 13% of the population, yet account for more than 33% of total outpatient spending on prescription medications. It is anticipated that by 2020 people 65 years and older will account for 50% of all medication use. In the past decade, the average number of items prescribed for each person per year in England increased by 53.8% from 11.9% in 2001 to 18.3% in 2011.[143] A large ScoYish study has confirmed the considerable and increasing prevalence of polypharmacy: 12% of patients were dispensed five or more drugs in 1995, rising to 22% in 2010; and 1.9% of patients were dispensed 10 or more drugs in 1995, rising to 5.8% in 2010.[144] The study also reviewed prescriptions for all 310 000 adult residents in the Tayside region in 1995 and 2010 and found that the proportion of adults dispensed five or more medications doubled to 20.8%, and the proportion dispensed 10 or more tripled to 5.8%. Increasing age was strongly associated with more medications (especially in the 10 or more group), as was living in socioeconomic disadvantage and living in care facilities. Reflecting the complexity and risks of polypharmacy, those with a greater number of drugs experienced the greater number of drug interactions. While the overall proportion of adverse drug interactions more than doubled to 13% of adults in 2012, this was most likely in those taking a greater number of drugs (10.4% for those on two to four drugs, compared with 80.8% for those taking 15 or more).[144] In addition to the increasing prevalence of disease states in the aged, medication use is also increasing due to preventive or risk-reduction interventions, especially for cardiovascular

and cerebrovascular disease where interventions are aimed at reducing stroke, heart aYack and multi-infarct dementias.[143] While an increased level of medication use may be indicated in the management of multiple pathology states, it does not come without risks and it requires methodical and careful monitoring and clinical practice. This statement can also be applied to the use of herbal medicines and nutritional supplements. The potential issues of polypharmacy or of ‘polyCM’ are exponentially increased if both exist in the same individual – partially because of the increased interactions, partially because of the inherent physiological changes in the older person and critically because of the significant knowledge gap of what the impact of the multiplicity of diverse therapeutic agents in the elderly might be.

Clinical trials in the elderly There is an ever-increasing array of medications available, including for ‘anti-ageing’ purposes, with 435 new drugs in phase I to phase III trials in the US as of 2015.[145] While most governments have identified the risks of medication use in the elderly and implemented a range of strategies to reduce adverse events, a key area that remains unanswered is the lack of clinical trials involving elderly people. In 2011 the European Medicines Agency published the EMA Geriatric Medicines Strategy, a document with a vision statement that included the intention of ‘… ensuring that medicines used by geriatric patients are of high quality, and appropriately researched and evaluated, throughout the lifecycle of the product, for use in this population’.[146] The Agency produced a plan including audit, education and validation of practice tools, but as yet there is no plan for addressing the issue of appropriate research and evaluation of medication use in the elderly. There are almost no clinical drug trials on ‘old elderly’ people (aged 85 years and over) and these are the people most likely to use medications and to use multiple medications. When an older cohort is included in pharmaceutical clinical drug trials it is typically ‘young elderly’ and usually excludes those with multiple comorbidities and who are taking multiple medications to best control for confounders in the analysis.[147] Further, there may be issues with ethics, frailty and vulnerability, cognitive decline and valid informed consent when including the old elderly in trials. One well-known exception to the exclusion of elderly adults is the Hypertension in the Very Elderly Trial, where participants were over 80 years of age; however, they were ‘well elderly’ and it was a single-issue trial on hypertension.[148] The main trial was terminated for ethical reasons in 2007 by the Independent Trial Steering CommiYee, as the independent Data Monitoring CommiYee noted a significant reduction in all-cause mortality in participants on active treatment at the second interim analysis, and while this can be seen as a good outcome, it does limit the scope of the trial.[149] Interestingly, a later Cochrane Review of treating hypertension in healthy people over 60 years of age found benefit only in those 60–80 years of age, not those who were older.[150] Clinical trials may fail to accurately identify adverse drug events and drug interactions in older patients and, while necessary, frequently the outcome measures are very restricted and

so fail to consider the impact of the medication on QOL measures and personal and social aspects such as care needs.[143] As such, there is often an inadequate analysis of the burden of treatment and the cost–benefits of medication use in the elderly. Another limitation of most pharmaceutical and health research is that it is focused on single issues and single interventions, thus omiYing the multi-morbidity and polypharmacyprone elderly. Furthermore, this single-disease framework is characteristic of most health services, medical and health education and clinical guidelines developed to inform practice, which therefore fail to incorporate the complexities of progressive ageing. The paucity of drug trials involving the elderly, and the very limited nature of those trials, raises the question of the generalisability of the study results. For example, can a trial on a new antihypertensive conducted on a cohort of men 50–70 years of age and without multiple comorbidities be extrapolated in a meaningful way for an 80-year-old woman with diabetes, Hashimoto's disease and depression? Further, there is limited research comparing various options for the management of a single clinical condition, thus impacting on a prescriber's ability to make an informed clinical decision – how to choose one over the other.[147] The lack of research including the elderly in clinical drug trials is echoed by limited postrelease surveillance and reporting. That is, how has the medication been tolerated, what is the efficacy, what have the adverse reactions been in a complex and heterogeneous elderly population? Knowledge of adverse events relies upon clinicians writing case reports for publication or presentation and reporting to the relevant regulatory agencies, which is a very passive and inadequate approach. There is a presumed under-reporting of adverse medication events and this is compounded by a lack of information about the denominator population with which to compare outcomes and health status and thus make informed analysis regarding the perceived adverse event.[145,147]

Pharmacokinetics Pharmacokinetics is the study of tissue sensitivity, drug absorption, distribution, metabolism and excretion. Physiological changes with ageing may impact on each of these processes, are variable and difficult to predict and have varying clinical significance (see Table 17.12).[150,151] Further, alterations in pharmacokinetics may be seen in the aged, but not because of age, but instead due to disease states (e.g. coeliac disease).

TABLE 17.12

Age-related physiology and stages of pharmacokinetics Pharmacokinetic Age-related changes function

Clinical effect

Tissue sensitivity

• More or less sensitivity to a given medication.

Absorption

Distribution

Metabolism

Excretion

Alterations in: • Cell receptor numbers and affinity • Nuclear responses • Second messenger function • P-glycoprotein function. Decrease in: • Intestinal blood flow • Absorptive surface Gastrointestinal motility Increase in: • Gastric pH. Decrease in: • Total body water • Serum albumin and alpha-1-acid glycoprotein* • Lean body mass Increase in: • Body fat. Decrease in: • Liver volume • Hepatic blood flow • Enzyme activity (cytochrome P450 family). Decrease in: • Renal perfusion • Glomerular filtration • Tubular secretion.

• Least affected by changes associated with ageing, even with stated physiological changes as most oral drugs absorbed by passive diffusion • Most relevant for drugs that require acid environment, e.g. calcium carbonate (thus use Ca citrate) • Some enteric-coated drugs may dissolve more quickly with increased gastric pH. • Higher concentration of drugs • Longer elimination half-life of lipid-soluble drugs • More widely distributed fat-soluble and less widely distributed water-soluble drugs.

• Decreased biotransformation and first-pass metabolism • Decreased phase 1 reaction activity and prolonged half-life for some drugs.

• Decreased renal elimination of drugs.

*

Alpha-1-acid glycoprotein (AGP, also known as AAG or orosomucoid) is an important plasma protein involved in the binding and transport of many drugs, especially basic compounds.[152] Source: Adapted from Musini VM, Tejani AM, Bassett K, et al. Pharmacotherapy for hypertension in the elderly. Cochrane Database Syst Rev 2009;4. Cepeda OA, Morley JE. Polypharmacy. In: Sinclair AJ, Morley JE, Vellas B (eds). Principles and practice of geriatric medicine. 5th edn. Chichester: John Wiley; 2012, pp. 145–51.

The reduction in serum albumin with age (amplified in illness) is due to reduced liver synthesis and to cytokine excess and this can markedly reduce drug binding and thus increase the amount of free circulating drugs. Reduced renal excretion of drugs is a key area of risk for the elderly and even in healthy elderly people there is a reduced renal mass and

blood flow and reduced muscle mass (which complicates evaluation of renal function if relying on creatinine clearance). CKD can be insidious as it is possible to lose up to 90% of kidney function before becoming overtly symptomatic, highlighting the importance of assessing renal function regardless of symptoms. Perhaps due to the stealth nature of CKD in the earlier stages, it has a high prevalence in many countries, including Australia where in 2011–2012 the overall prevalence was 10%.[153] This rate increases dramatically with age, with the rate in people 75 years and older at 42%. Polypharmacy affects both CKD and acute renal failure (ARF). In a study of 20 790 patients in Taiwan Province of China the extent and duration of polypharmacy was positively associated with ARF: polypharmacy over 31–90 days had an odds ratio of 1.33 for developing ARF and polypharmacy over 181 days had an odds ratio of 1.65 for developing ARF. The mortality rate for people hospitalised with ARF is approximately 45%.[154] Cytochrome P450 (CYP450) enzymes are a group of enzymes responsible for the production of cholesterol, steroids, prostacyclins and thromboxane A2 as well as being responsible for the detoxification of foreign chemicals and the metabolism of drugs. There are more than 50 CYP450 enzymes, but CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 metabolise 80–90% of drugs. These enzymes are predominantly expressed in the liver, but they also occur in the small intestine (reducing drug bioavailability), lungs, placenta and kidneys.[155,156] Inducers increase CYP450 enzyme activity by increasing enzyme synthesis, inhibitors reduce synthesis and other substances act as substrates. Pharmaceuticals and herbal medicines are known to induce and/or inhibit CYP450 enzymes and this can affect the response to the drug or herbs as well as impact on the body's ability to metabolise other drugs. The extent to which this occurs, and the translation between measureable CYP450 change and clinical significance, is variable. In addition, genetic polymorphisms may affect CYP450 function and ageing reduces CYP450 expression and function.[155,156] P-glycoprotein (P-gp) is an efflux membrane transporter responsible for limiting cellular uptake and the distribution of xenobiotics and toxic substances. It is widely distributed throughout the body in organs or tissues with an excretory and/or barrier function such as on the surface of hepatocytes, the epithelial cells of the renal tubules, intestine, placenta and testes, and it is highly expressed at the vessel walls of the brain capillaries.[155,157,158] At the blood–brain barrier P-gp extrudes a range of unrelated compounds from the brain and is thus thought to be central to protecting the brain from accumulation of potentially toxic substances, including drugs.[157,158] A gender difference exists for P-gp expression between men and women; for example, hepatic P-gp expression is 2.4-fold lower in females and some of this effect may be due to the influence of oestrogen and progesterone (previously or at the time of study).[158] This, in addition to lean mass, fat mass and water distribution, may determine gender differences in drug efficacy and adverse drug reactions. Ageing is associated with a decreased P-gp function and may be a key mechanism behind increased sensitivity and drug toxicity and increased CNS side effects of drugs that cross the

blood–brain barrier as seen in older adults. In addition, the older person may be taking drugs that inhibit or downregulate P-gp function, which further impairs the protective function of P-gp. Reduced P-gp function may increase vulnerability to both exogenous and endogenous neurotoxins (such as amyloid-beta, the protein that accumulates in the brain in Alzheimer's disease); thus it is implicated in the pathogenesis of neurodegenerative diseases of ageing. It is noted that reduced P-gp function is seen to a greater degree in women, which corresponds with the higher prevalence of diseases such as Alzheimer's in women.[157] Table 17.13 outlines the key physiological impacts of ageing on medication use. TABLE 17.13

Summary of key physiological impacts of ageing on medication use System

Age-related physiological changes

Implication for medication use

Renal

• Reduced renal mass and blood flow • Reduced glomerular filtration. • Reduced intestinal blood flow • Reduced gastric motility • Decreased mucosal absorptive surface.

• Reduced excretion • Greater vulnerability to renal insult. • In general, slightly reduced absorption of most drugs • Active transport of some nutrients, glucose, calcium, vitamin B12 and leucine is impaired.

GIT

Hepatic

• Reduced albumin and protein ingestion and • Decreased biotransformation and first-pass synthesis metabolism • Reduced metabolic clearance by the liver. • Reduced drug binding and increased free bioactive drug. Cardiovascular • Reduced cardiac reserve (including reduced • More vulnerable to drugs but less sensitive to compliance and contractility, hypertension, drugs acting on beta-adrenergic pathways. ventricular hypertrophy) • Decreased function of beta-adrenergic receptors. Respiratory • Reduced elasticity, functional volume and • Reduced beta-adrenoceptor responsiveness, vital capacity thus reduced responsiveness to beta-agonist • Increased work of breathing. medication Endocrine • Decreased insulin sensitivity and secretion • Impact on renal function and drug excretion. and decreased glucose tolerance. Neurological • Reduced brain mass and neurons • Impaired cognition with cholinergics • Altered calcium homeostasis and receptor • Exaggerated response to CNS active drugs; function and sensitivity (e.g. GABA increased sedation, increased sensitivity to receptors) opioids and general anaesthesia. • Reduced functional activity of P-gp efflux pump in the blood–brain barrier. Metabolic • Decreased lean mass and total body water • Reduced absorption • Increased body fat • Altered distribution of drugs • Decreased albumin • Reduced creatinine and impact on renal • Decreased gastric and intestinal secretions assessment. • Decreased mucosal surface. Source: Welker KL, Mycyk MB. Pharmacology in the geriatric patient. Emerg Med Clin North Am 2016;34:4469– 81. Jansen PAF, Brouwers JRBJ. Clinical pharmacology in old persons. Scientifica (Cairo) 2012;1–32.[160]

Pharmacodynamics Pharmacodynamics refers to the effect of drugs on the body. It involves receptor sensitivity and binding, post-receptor effects and chemical interactions. That is, whereas pharmacokinetics is the study of how the body affects the drug, pharmacodynamics looks at how the drug affects the body. Both pharmacokinetics and pharmacodynamics influence dosing, drug effects and potential adverse drug effects, though as previously discussed, research on pharmacodynamics in geriatrics is minimal and what research there has been is difficult to make generalisable.[151,161] There is variability in sensitivity to the effects of drugs as well as inter-individual variability. For example, older people are typically more sensitive to opioids and sedatives but less sensitive to drugs acting on beta-adrenergic pathways.[151]

Pharmacogenetics/pharmacogenomics Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways. Clinical pharmacogenetics describes whether individual variances in the expression of a protein or an enzyme affect the metabolism of a drug. These genetic variances may lead to changes in the levels of active or inactive metabolites, and may inform altered dosing or the use of a different drug.[162] The US Food and Drug Administration (FDA) states that drug labelling with information on genomic biomarkers may describe:

• Drug exposure and clinical response variability • Risk of adverse events • Genotype-specific dosing • Mechanisms of drug action • Polymorphic drug target and disposition genes.[163] The FDA provides a list of currently FDA-approved drugs with pharmacogenomics information in their labelling. For example for codeine, the pharmacogenomics biomarker is CYP2D and the specific group affected is CYP2D6 ultrarapid metabolisers, and the boxed warning on the label notes warning and precautions in this group.[163]

Epigenetics The inter-individual variance in drug response exceeds what can be aYributed to pharmacokinetics, pharmacodynamics and pharmacogenetics, especially with the exaggerated variance in the elderly. The term ‘epigenetics’ describes genetic information that is ‘epi’ (‘beyond’ or ‘above’) the information coded solely by our genetic code. Epigenetics refers to cellular and physiological phenotypic trait variations that result from environmental factors that switch genes on and off and affect cell gene expression.[164] These epigenetic mechanisms are present in all genes and it is believed that the main mechanisms of epigenetics changes are methylation (DNA and protein, especially histones) and microRNA

(miRNA) interference in gene expression.[165,166] Such epigenetic mechanisms regulate genomic activity beyond simple transcriptional factor inducer or repressor functions of genes to generate mRNA.[165] Epigenetic regulation of gene activity is important in maintaining normal phenotypic activity of cells, as disruptions are implicated in ageing as well as having a role in the development of neurodegenerative diseases such as Alzheimer's and cancer.[165,166] In healthy people the tendency is towards global genome hypomethylation but with specific areas of hypermethylation.[166] With age, the shift is towards general hypermethylation of promoter regions and genes regulated by DNA expression tend to reduce their expression; this includes drug metabolising enzymes, drug transporters and drug receptors and other genes involved in drug metabolism and distribution.[166] Environmental factors that may have accelerated ageing may thus effect epigenetic changes, which then affect drug metabolism, therapeutic efficacy and adverse reactions, and these in turn may further accelerate ageing. The area of pharmacogenetics and epigenetics, and similarly nutrigenomics, is subject to increasing investigation and in future may facilitate personalised prescriptions that afford greater therapeutic efficacy and reduced adverse reactions.

Polypharmacy Polypharmacy is a recognised risk factor for poor clinical outcomes and adverse drug reactions, especially for elderly persons; however, despite agreement that it is a significant risk there is not a consistent and agreed definition of polypharmacy. Definitions range from the use of two medications to the use of nine or more medications.[147] Given that the medications may indeed be essential, the number or quantity of medications alone is not adequate in defining polypharmacy and more recent definitions of polypharmacy also address issues of the quality of medications and of prescribing practices (see Fig. 17.2).[167] Further, regardless of the number of medications, some drugs are inherently higher risk (e.g. anticoagulants), have a very narrow therapeutic window (e.g. insulin) or may not be appropriate in the elderly due to known side effects.[38,167] An Australian study by Gnjidic et al.[168] aimed to ‘determine an optimal discriminating number of concomitant medications associated with geriatric syndromes, functional outcomes, and mortality in communitydwelling older men’. The review of 51 705 men aged 70 years and older concluded that five or more medications should be used as the numerical definition of polypharmacy when assessing the risk of medication-related adverse outcomes in older people.

FIGURE 17.2

Aspects of polypharmacy in geriatrics

While no consensus definition of polypharmacy exists, the most commonly used definition is the use of more than five drugs and/or more medications than required.[167] That said, in the case of chronic and complex care, five medications may be too low, so any definition must have a caveat of individuation applied.[143,145] A British review of polypharmacy and medication safety qualified the term polypharmacy, using the following definitions: Appropriate polypharmacy is defined as prescribing for an individual for complex conditions or for multiple conditions in circumstances where medicines use has been optimised and where the medicines are prescribed according to best evidence. Problematic polypharmacy is defined as the prescribing of multiple medications inappropriately, or where the intended benefit of the medication is not realised.[143]

Complementary medicines (CM) and polypharmacy Polypharmacy usually refers to prescribed medications, presumably due to the fact that if a medication is restricted to prescription-only it holds greater potential risks. Polypharmacy research and interventions therefore often do not include over-the-counter pharmaceuticals the patient uses, let alone herbal medicines and nutritional supplements.[167] It is currently impossible to quantify the impact of concurrent complementary medicine (CM) use and polypharmacy. It is possible that the additive effects may be significantly deleterious, and it is also possible that the inclusion of CM reduces the dose requirements of pharmaceuticals, thereby reducing the risks associated with polypharmacy and adverse drug reactions while improving outcomes. The innumerable combinations of drugs and herbs and/or supplements are further complicated by the marked inter-individual variability in the physiological effects of ageing on pharmacokinetics and pharmacodynamics in the aged population. This substantial lack of knowledge and clinical evidence about the intersection of polypharmacy and CM use necessitates prudent prescribing by the naturopath. Reviews from multiple countries identify CM use in the elderly but research is often limited to targeting specific cohorts or single diseases or conditions (e.g. use in menopause or community-dwelling versus residential care). Prevalence is varied and reported to be as high as 53–62.7%.[169,170] A review of 25 papers on CM use in the elderly found that use transcends

culture or geography but that the specific therapies chosen are often informed by the individual's cultural or ethnic heritage.[171] For example, a study of 1475 Lebanese elders found that nearly 30% used CM and for this group that meant herbal medicine in 75% of cases.[172] On the other hand a German study found herbal medicines represented only 33% of CM use and dietary supplements represented 35% of CM use.[173] The specific conditions that CM is used for varies among the aged, as seen in an American review comparing CM use in baby boomers (born 1946–1964) and the so-called silent generation (born 1925–1945).[174] The ‘young elderly’ baby boomers were more likely to use CM within the past year, 43.1% compared with 35.4% for the ‘older elderly’, and the baby boomers were more likely to use CM for heart disease, cancer and diabetes. In both groups CM use was associated with chronic pain. Older people chose to use CM for a wide range of reasons including wanting the ‘best of both worlds’ (using both CM and orthodox pharmaceuticals), desire for autonomy in healthcare decisions and wanting to be active in managing their own health, engagement with traditional knowledge and practices, dislike of the effects of pharmaceuticals, disillusionment with conventional medicine, negative experiences with conventional practitioners, the desire to postpone or minimise age-related deterioration and mortality, and the perception that ‘natural products’ are safe.[170,175] The Australian Longitudinal Study of Ageing (ALSA) is an ongoing multidisciplinary prospective study of the older population that commenced in 1992 in South Australia. Data from this study have been analysed on paYerns of CM and OTC medication use for 2087 adults aged 65 years and over living in the community or residential aged care facilities.[176] The results show an increase in CM use from 12.8% in 2000–2001 to 17% in 2003–2004. The most commonly used CM in 2003–2004 were vitamins and minerals (14%), herbal medicine (5.5%) – in particular garlic, celery and ginkgo biloba (5.5%) – nutritional supplements (7.6%), especially cod liver oil, fish oil and glucosamine and combination products (5.1%). A 2011 review by Yen et al.[177] surveyed 2540 Australians aged 50 years and older about consultations with CM practitioners and revealed a disparity between CM use and CM professional consultation. Only 8.8% of respondents reported seeing a CM practitioner in the past 3 months, most commonly for musculoskeletal conditions (osteoporosis, arthritis), pain or depression/anxiety. The lack of professional advice increases the risk of adverse effects, drug–CM interactions and negative clinical outcomes for the older patient. In addition to not seeking professional advice for CM use from a CM professional, many also did not seek information from other health professionals and only a minority disclosed CM use to their doctor.[171,172] A German study of 400 people aged 70 years and over found that 61.3% used some CM (dietary supplements 35.5%, herbal medicines 33.3% and external preparations 26.8%) and while many said they did not assess or did not know how to assess for drug–CM interactions, 3% identified a drug–CM interaction.[173] The lack of professional consultations may reflect lack of knowledge, financial limitations, restricted mobility and independence, a lack of perceived need or low health literacy. Health literacy refers to possessing skills and knowledge about health and healthcare, including the

ability to identify, understand and communicate health information, seek appropriate care and make informed decisions about healthcare.[169] Systematic reviews of relevant literature conclude that low levels of health literacy are associated with poorer health and treatment outcomes including poor medication compliance, increased admissions to emergency departments, reduced ability to interpret labels and health messages, poorer health status and increased mortality among the elderly.[169] A review of health literacy and CM use in New South Wales found that the three domains that older people performed worst in were appraisal of health information, the ability to find good information and navigating the healthcare system.[169] Conflicting and unreliable information was a notable issue, in particular the media and internet sources. The issue of quality of information extends to professional sources and creates challenges for health professionals and community members alike.[155]

Risk factors for receiving polypharmacy Increasing age is a key risk for polypharmacy, though there is evidence that being on a few medications when younger also increases the risk.[159] Additional factors include:

• Frequent healthcare/doctor visits • Poor communication • Having multiple healthcare providers • Fragmented medical/healthcare • Poor prescribing practices • Poor or absent monitoring and reviewing practices.[147] Other factors are yet to be fully elucidated but include location, practitioner beliefs and the education, race and socioeconomic status of the older person.[144,147,178] For example, a study that compared medication prescriptions in six European cities collected prospective data from 900 consecutive older patients admiYed to six university teaching hospitals in Geneva (Swiwerland), Madrid (Spain), Ostend (Belgium), Perugia (Italy), Prague (Czech Republic) and Cork (Ireland) and found very high levels of polypharmacy (more than 10 medications), ranging from 4% of patients in regional Perugia to 21% in the city of Geneva. This finding reflects differences in potentially inappropriately prescribed medicines unrelated to age variations.[178]

Risks of polypharmacy Polypharmacy is associated with increased admissions to hospital, functional and cognitive impairment, geriatric syndromes (delirium, falls or frailty) and mortality. Additional negative consequences are poorer health outcomes (adverse drug reactions, adverse drug withdrawal events, therapeutic failure), declining nutritional status, excessive cost and reduced QOL.[141,145,179] The number of possible drug–drug interactions (and potentially

herb–herb and herb–drug interactions) rises sharply with concurrent use of five or more drugs, meaning that the addition of only one more drug can have significant impacts. An Australian prospective 16-week cohort study evaluated drug interactions in 275 patients aged 65 years and older with polypharmacy (>5 drugs) admiYed to a community hospital. [178] The prevalence of potential CYP-mediated drug–drug interactions was 80%: the probability of at least one CYP-mediated drug–drug interaction was 50% for people taking 5–9 drugs, 81% for 10–14 drugs, 92% for 15–19 drugs and 100% for 20 or more drugs. Each additional drug introduced to a five-drug regimen conferred a 12% increased risk of a potential CYP-mediated drug–drug interaction.[180] Polypharmacy is strongly associated with delirium, especially if the elderly person presents to the emergency department with new delirium, with medication found to be the leading cause of delirium in up to 39% of cases.[181] Catic et al.[181] have identified risk factors for developing delirium as follows:

• Nine or more chronic medications • 12 or more doses of medications per day • Six or more concurrent chronic dosages • History of previous drug reactions • Low body weight • Age greater than 85 years • Estimated creatinine clearance 70 years: 300 mg

19–30 years: 310 mg 31–70 years: 320 mg Pregnancy: 350–400 mg Lactation: 310–360 mg 19–30 years: 400 mg 31–70 years: 420 mg

>50 years: 320 mg >70 years: 420 mg

9–13 years: 6 mg (UL: 25 mg) 14–18 years: 7 mg 14–18 years: 10 mg (UL: 35 mg) 9–13 years: 0.92 mg (UL: 11 mg) 14–18 years: 1.06 mg (UL: 17 mg)

19–70 years: 8 mg Pregnancy: 11 mg Lactation: 12 mg 19–70 years: 14 mg (UL: 40 mg)

>70 years: 8 mg >70 years: 14 mg (UL: 40 mg)

1–6 years: 0.27 mg (UL 1–3 years: 3 mg) 6–8 years: 0.85 mg (UL: 4–8 years: 6 mg) Current RDI and EAR are inadequate to maintain or increase serum vitamin D levels in sunshine-limited or deprived populations. Higher serum vitamin D is necessary for managing increased prevalence of autoimmune conditions, infections and oxidative stress. Aim to build serum levels to 100–200 nmol/L. Dosing of children and adolescents: 1000 IU/14 kg body weight per day for maintenance; upper limit for building vitamin D levels is 2000 IU/14 kg body weight. 2.5 micrograms 1–3 years: 25 9–13 years: 45 derived from micrograms micrograms breast milk 4–8 years: 35 14–18 years: micrograms 55 micrograms 0–1 year: 1–5 years: encourage active encourage play. Young children should be floor-based active for at least 3 hours every play in safe day, spread out throughout the environment. day. 5–17 years: at least 60 minutes of moderate to vigorous intensity exercise daily, including aerobic and strengthening exercises.

1.0–1.5 mg (UL: 20 mg)

1.0–1.5 mg

5000 IU per day in sunlight-deprived populations 5000 IU per day in sunlightand pregnancy. deprived populations. 6400 IU/day is the highest daily dose that has been demonstrated to be safe in pregnancy. 7000 IU per day required in lactation.

19–70 years: 60 micrograms 19–70 years: 70 micrograms

19–70 years: 60 micrograms 19–70 years: 70 micrograms

18–64 years: at least 150 minutes of moderate to vigorous intensity exercise per week, with additional health benefits achieved at 300 minutes per week. Muscle strengthening exercises should be done at least twice per week. 65+ years: in older adults, physical activity includes activities of daily living, leisure activities, incidental exercise, sports and planned activities. A minimum of 150 minutes per week is recommended, with additional health benefits achieved with 300 minutes per week and aerobic bursts of at least 10 minutes. Physical activity should include balance-promoting activities 3 days per week, and muscle strengthening activities at least 2 days per week. Adjust activities to level of ability.

No standard recommendations exist for supplementing boron. Boron requirements are easily fulfilled through a healthy well-balanced diet.[378]

Source: Adapted from [368–377]

Life expectancy and quality of life There have been substantial advances in life expectancy for people with Down syndrome over the last two decades, largely due to improvements in healthcare. Higher detection of health problems with routine screening in childhood enables congenital health problems to be more effectively managed and so they are less likely to lead to secondary disabilities or increased mortality.[134] Health-related quality of life is a measure that takes into account physical and mental health and the impact this has on satisfaction with life.[379] Increased incidence of health problems in people with Down syndrome impacts on quality of life and wellbeing. Quality of life for older people with Down syndrome seems strongly related to level of community participation, socialisation and self-determination.[379]

Premature ageing: dementia, cognitive decline and Alzheimer's disease Increased life expectancy for people with Down syndrome, through improvements in healthcare, has necessitated advancements in research into differences in ageing in this population. Premature ageing is common in people with Down syndrome and includes earlier onset of cognitive decline, cataracts, dementia and musculoskeletal disorders.[134] Loss of social and conceptual skills has stronger association with age-related decline than adaptive skill loss in Down syndrome.[380] This would suggest that with appropriate support, people with Down syndrome can be encouraged to maintain autonomy and activity into their later years.[380] However, other studies report that older people with Down syndrome may also lose practical skills associated with activities of daily living, as well as communication and memory decline.[381] Neuro-inflammation is implicated in the pathogenesis of Alzheimer's disease and is more prevalent in people with Down syndrome due to over-expression of genes involved in pro-inflammatory processes.[382] Specifically, increases in amyloid plaques, higher levels of inflammation and increased neurofibrillary tangles are observed in people with Down syndrome from the age of 40 onwards.[383] The incidence of Alzheimer's disease in people with Down syndrome is approximately 10– 15% in those aged 40–50 and up to 50% in people over 50.[384] Comparatively, the rate of Alzheimer's disease in the general population is 9% in people over 65.[385] Screening for Alzheimer's disease should occur once every 2 years for people with Down syndrome from the age of 40 onwards, and annually after 50 years of age. While there is no cure for Alzheimer's disease, detection in this population will help identify changes to the level of support needed and precipitate planning of ongoing care. Awareness of carers and family members to be observant of changes in behaviour and cognitive function facilitates the detection of onset of decline, which may be difficult for the individual to express due to communication deficits. [386] It is generally recommended that people with Down syndrome are supported to remain living in their own home with additional support as needed, as this is associated with bener quality of life outcomes.[387] People with Down syndrome are more likely than people with other intellectual disabilities to remain living with family members as they age.[387] Early-onset Alzheimer's disease creates additional challenges for family carers, who may be ageing themselves. Alzheimer's disease changes include behavioural changes (e.g. wandering), cognitive decline, personality changes (e.g. aggression), incontinence and reduced capacity for self-care and activities of daily living.[387] These changes may precipitate carers seeking additional support, though most families prefer to keep their loved one at home rather than admining them to an aged care facility.[387] Changes may be gradual, or quite sudden. The Plymouth dementia screening checklist (see Appendix 19.3) is an effective tool for assessing the need for referral for dementia assessment.[388] The checklist can easily be filled out by family or paid carers. In the general population, a score of three or above indicates the need for dementia assessment.[388] In a clinical trial, the checklist had a 72% sensitivity in the general population, though it was found that the majority of false negatives occurred in people with Down syndrome.[388] The study authors recommend that people with Down syndrome scoring one or two on the checklist should be referred for dementia assessment.[388] Whitwham et al. report that false positives with this screening were 12.5%, though a quarter of these patients were diagnosed with dementia within the following year and a further quarter were undergoing dementia investigations within the following year.[388] This may suggest that the screening checklist is also effective at indicating early pre-clinical signs of dementia and is thus a very useful low-cost method of tracking decline over time. Medical therapies used in the treatment of Alzheimer's disease in the general population are not necessarily effective for people with Down syndrome. A recent study of memantine in people with Down syndrome showed no significant difference in cognitive decline, challenging behaviours, independent ability or global outcomes.[389] People with Down syndrome and cognitive decline are generally much younger than people with Alzheimer's disease in the general population, and show distinct differences in neurological function, myelination and amyloid clearance.[389] Supporting healthy ageing in people with Down syndrome is imperative to improving quality of life outcomes and must begin earlier than in the general population due to earlier onset of age-associated decline. Recommendations as stipulated in the NHMRC 2013 Australian Dietary Guidelines include a plant food-based diet rich in fresh vegetables, fruit, wholegrains and legumes, with moderate intake of dairy products (if tolerated) or other calcium-enriched alternatives, lean meat, poultry,

fish, eggs and plenty of water.[390] Early onset of ageing is correlated with lack of activity and engagement in activities of daily living in early adulthood in people with Down syndrome.[391] To an extent this may reflect differences in severity of disability and functional abilities. Sedentary lifestyles are, however, a significant problem for many people with disabilities and in Down syndrome appear to hasten age-related decline. This is not limited to cognitive decline, but also includes frailty, sensory loss (vision and hearing), sleep disturbance and loss of language skills.[391] Encouraging community participation, daily exercise and engagement in activities of self-care and daily living is therefore essential throughout the entire life span for people with Down syndrome. Inflammation and oxidative stress play a significant role in age-related cognitive decline, neurodegeneration and Alzheimer's disease pathological processes in the brain.[392] While there is linle evidence for the use of natural medicines in people with cognitive decline and Down syndrome, supplements and herbal medicines that are neuroprotective and enhance cognition have the potential to improve quality of life outcomes for these patients. To date, clinical trials in people with Down syndrome and dementia have demonstrated that supplementation improves blood antioxidant levels but does not improve clinical outcomes.[393,394] Treatment resistance in older people with Down syndrome may result from the complex nature of neurofibrillary tangles and plaque deposition, which begin very early in life. It is possible that antioxidant therapy in Down syndrome needs to occur earlier in the life span to reduce degenerative changes, and that by the time dementia or predementia symptoms present, neurodegeneration is too advanced for antioxidant therapy to produce a measureable effect. Thiel and Fowkes suggest that nutrients such as vitamins B6, C and E, selenium, zinc, alpha-lipoic acid and carnitine that have a role in free radical scavenging and reducing the accumulation of glycation end products may have a slowing effect on neurodegeneration and age-associated decline in people with Down syndrome.[347] Long-term cohort studies are necessary to confirm or dismiss this theory. However, given the tolerability of antioxidants, and that oxidative stress plays a significant role in many of the pathologies present in patients with Down syndrome, it is reasonable that antioxidant supplementation is an appropriate recommendation. Emphasis on a broad and antioxidant-rich diet should be part of routine care for people of all ages with Down syndrome. Additional supplementation with key antioxidants and minerals may have a role in decelerating cognitive decline and neurodegeneration when started at younger ages.

Therapeutic considerations Health surveillance and timely intervention are of great importance for the multitude of health problems people with Down syndrome face throughout their lives. Naturopaths and herbalists perform a key role in comprehensive healthcare. Longer appointment times allow sufficient scope to assess changes in health status over time, progress with therapies and planning for long-term health maintenance. It is insufficient to assume that another health professional is responsible for health surveillance: holistic care entails a broad overview of the patient's health, alongside keen anention to detail to ensure health issues are not overlooked. Good communication with other health practitioners who are also involved in the patient's care is essential to coordinate and bener inform clinical practice.

Therapeutic application Clinical examination and investigations Good clinical observation, sound case-taking skills and competence in physical examination are necessary to detect, manage and, where appropriate, refer patients with Down syndrome. Essential clinical examination procedures are included in Table 19.8. TABLE 19.8 Clinical examination procedures for health surveillance in people with Down syndrome Examination or investigation

Rationale

Blood pressure BMI Lung auscultation Random blood glucose Temperature Urinalysis Waist circumference

Cardiovascular risk High risk of obesity and metabolic syndrome Increased frequency and severity of respiratory tract infections Diabetes risk Thyroid risk Detect urinary tract infections, early signs of kidney and liver disease, blood sugar control High risk of obesity and metabolic syndrome

More specialised assessment is also necessary on a regular basis to detect changes in health status early and allow for more timely intervention. Screening tests and investigations recommended for routine health assessment are included in Table 19.9. TABLE 19.9 Health screening by the patient's GP or specialist for people with Down syndrome Investigation

Frequency

Cardiac assessment

Cardiac assessment by a cardiologist by 6 weeks of age. Auscultate for signs of acquired heart disease at every health assessment. Annually from 12 months. At birth and annually from 12 months. At birth and annually from 12 months. Newborn hearing screen. Comprehensive hearing assessment by 10 months of age. Annual hearing assessment prior to school age. Hearing assessment once every 2 years from school age onwards. Annually from 12 months. Enquire about breathing at every health assessment. At birth and annually from 12 months, including TSH, T4 and thyroid antibodies. Newborn assessment. Formal eye and vision assessment at 18–24 months. Vision assessment once every 2 years thereafter, unless more frequently recommended by an optometrist or ophthalmologist. Annually.

Coeliac screen ESR & CRP Full blood count Hearing assessment

Iron studies Sleep-related breathing Thyroid studies Vision assessment

Vitamin D Source: [395]

Nutritional medicine (dietary) Oral motor difficulties result in parents reporting that some children with Down syndrome swallow food without chewing and that meal choices reflect concerns about choking risk and soft textures to enable easier consumption.[396] These difficulties may persist through to adolescence, and for some people oral difficulties remain in adulthood.[74] Obesity risk in people of all ages with Down syndrome is high, due to lower metabolic rate, low muscle tone and a tendency towards a sedentary lifestyle. Prevalence for obesity necessitates adherence to a healthy, well-balanced, antioxidant-rich, low glycaemic index diet. Naturopaths are well-placed to guide dietary interventions to improve nutrient intake and health outcomes. Key considerations in tailoring nutritional interventions are included in Table 19.10.

TABLE 19.10 Key nutritional considerations for people with Down syndrome Food or food components

Considerations and recommendations

Fruit Vegetables

Adequate intake of a range of fresh fruit. Include berries regularly to improve antioxidant intake, and polyphenols to improve gastrointestinal microbiota. Vegetable intake should include a broad range of types and colours, including green leafy vegetables, brassicas, root vegetables, legumes and curbits. A range of cooked and raw vegetables should be encouraged, including salads. Protein Protein may include a range of animal and non-animal sources, such as lean meat, fish, eggs, nuts, legumes, dairy and soy products. Encouraging people with Down syndrome to increase the proportion of vegetarian sources of protein will also serve to increase fibre intake and have beneficial effects on gastrointestinal flora. Fibre A range of soluble and insoluble fibre should be consumed daily to optimise gastrointestinal flora and reduce tendency towards constipation. This should include vegetables (including skins where reasonable), fruit, legumes, nuts, seeds and wholegrains. Carbohydrate A low glycaemic index diet should be encouraged. Carbohydrates should be from wholegrain sources wherever possible to improve fibre and nutrient intake. Antioxidants Diet should contain a range of antioxidant-rich foods daily. This includes brightly coloured fruits (including berries), vegetables and herbs. Fresh and dried herbs that contain substantial antioxidants include turmeric, rosemary, basil, oregano and parsley. Fat Foods rich in beneficial fats should be included in the diet, such as olive oil, avocados, nuts, seeds and fish. Saturated fats and trans fats should be limited, by choosing low-fat meats and avoiding processed foods. Supplementation Supplementation should be considered for any at-risk nutrients and will vary depending on individual dietary allergies or intolerances. Vitamin D Vitamin D is a growing concern, due to indoor lifestyles and sedentary behaviours. Consider risk factors including geographic location, regularity of unprotected time in the sun, premature skin ageing and skin pigmentation. Serum vitamin D testing is advisable for individuals who meet one or more risk factors.

A gluten-free diet is advocated due to a higher incidence of autoimmune disease including coeliac disease and thyroiditis being reported in individuals with Down syndrome. Implementation of a gluten-free diet is associated with a number of benefits including improved behaviour with less irritability.[397] Individuals with Down syndrome have higher rates of overweight and obesity than those without Down syndrome, in part due to unfavourable diet, decreased metabolic rate and a tendency towards sedentary behaviours. Higher incidence of hypothyroidism also contributes towards weight gain, and may be clinical or subclinical. Meal planning should take this into account. Earlier onset and higher incidence of dementia, Alzheimer's disease and cognitive decline should also be considered in meal planning. While research currently offers no solutions once cognitive decline has been noted, improved dietary practices in earlier life are advisable. Though no research exists as yet, it is proposed that a Mediterraneanstyle diet rich in omega-3 fagy acids, anti-inflammatory constituents and antioxidants has been linked to lower rates of dementia in other groups and may be useful for individuals with Down syndrome to reduce cognitive and memory decline. By necessity the naturopathic consultation involves a certain amount of trouble-shooting, solution finding and strategising with patients with Down syndrome and their families or carers. Each situation will be unique and entail case-specific challenges. Working with patients and their families to explore obstacles to sound nutrition and dietary intake is part of the process. Some challenges will be due to oral motor and physiological difficulties, others may be psychological, social or financial or due to time constraints. Patient autonomy and self-determination must be respected at all times, while also guiding, educating and supporting patients to understand the importance of nutrition to their overall health and wellbeing. Improving nutritional intake will have a positive impact on all other areas of the patient's health, and is thus an essential part of their care.

Dietary inclusions Include:

• Calcium-rich foods • High-fibre foods such as fruit and vegetables, legumes, nuts and seeds, wholegrains • Low glycaemic index meals; high glycaemic index foods should be balanced within meal planning with foods that lower the overall glycaemic impact – this includes sources of beneficial fats and protein • Antioxidants from multiple sources. Dietary exclusions Consider a gluten-free diet due to the higher incidence of coeliac disease in this population. While regular testing is pertinent as a screening tool, it will not detect non-coeliac gluten enteropathy. A strict 8-week gluten exclusion followed by a gluten challenge for any patient who appears to have unresolved gastrointestinal upset, which may or may not be related to gluten, is a practical way of assessing the patient's symptomatic response where pathological testing is inconclusive. Dairy exclusion may also be warranted for patients who appear to have a dairy protein allergy. This may present as chronic catarrh or eczema. A strict dairy exclusion for 8 weeks followed by reintroduction is a viable means of assessing this.

Sample daily diet

Breakfast Smoothie: berries, banana, flaxseed oil, live yoghurt and mixed crushed nuts (including 2–4 Brazil nuts).

Lunch Gluten-free wrap with hummus, boiled egg, tomato, cucumber, mixed leguce or baby spinach, nori or wakame flakes, and avocado. Dinner Baked or grilled fresh fish with steamed sweet potato or baby potatoes and a fresh green salad (e.g. mixed green leguce and baby spinach, sautéed mushrooms, cashews/almonds/pepitas/pine nuts, thinly sliced fresh beetroot, carrot, radish, tamarillo/blackcurrants/tomato). Snacks At least two pieces of fruit, as seasonally appropriate. Other low glycaemic index, nutrient-dense, lower-kilojoule snack options include: Cherry tomatoes, vegetable sticks (cucumber, carrot, beetroot, celery) and hummus Rice cakes with mixed nut spread or avocado and tomato Trail mix made with raw nuts and seeds Homemade gluten-free cake or slice. Improve nutrient density by supplementing gluten-free flour with buckwheat flour, almond or coconut flour, and ground sesame seeds. Beverages 1.5–2 L water per day.

A smoothie provides an antioxidant-rich breakfast, which may help counter the impact of oxidative stress. Additionally, it is easy to digest given the higher incidence of dysphagia as a result of structural and anatomical issues in this population. Brazil nuts provide selenium, which is essential for thyroid function, an important consideration for people with Down syndrome due to the higher incidence of autoimmune thyroid disease. Including a source of high-quality protein (e.g. lean meat, eggs, tofu, lentils and legumes) will reduce the overall glycaemic index of the meal. The addition of nori or wakame provides minerals, in particular iodine, for healthy thyroid function. Though no research exists as yet, it is proposed that a Mediterranean-style diet may be useful for individuals with Down syndrome to reduce cognitive and memory decline. The addition of a salad dressing using both olive oil and apple cider vinegar will slow the blood sugar rise after the meal and is a valuable source of antioxidants and beneficial fats.

Fresh fruit is rich in vitamin C to help counter the increased risk of periodontal disease seen in people with Down syndrome.

Avoid soft drinks and pre-packaged juices, as these contribute significantly to sugar intake, blood sugar spikes and kilojoule intake. Green tea and other enjoyable herbal teas contribute to antioxidant and fluid intake.

Source: Nisihara RM, Bonacin M, da Silva Kooe LM, et al. Monitoring gluten-free diet in coeliac patients with Down's syndrome. J Hum Nutr Diet 2014;27(Suppl 2):1–3. doi:10.1111/jhn.12137; Zigman WB. Atypical aging in Down syndrome. Dev Disabil Res Rev 2013;18(1):1–67; Rafii MS. Improving memory and cognition in individuals with Down syndrome. CNS Drugs 2016;30(7):567–73. doi:10.1007/s40263-016-0353-4; Petersson SD, Philippou E. Mediterranean diet, cognitive function, and dementia: a systematic review of the evidence. Adv Nutr 2016;7(5):889–904. doi:10.3945/an.116.012138.

Nutritional medicine (supplemental) Supplementation will vary on a case-by-case basis, depending on the health status of the patient, dietary intake and the health issues they present with. It is important that the practitioner is aware they are not treating Down syndrome but a subset of the population with a greater predisposition to a range of health conditions, poorer access to healthcare and greater need for health surveillance. Evidence for nutrient supplementation specifically for people with Down syndrome is provided in Table 19.11.

TABLE 19.11

Therapeutically beneficial supplementation for people with Down syndrome Nutrient

Supportive research

Alpha-lipoic acid and L-cysteine Coenzyme Q10 (CoQ10)

30-day treatment with alpha-lipoic acid and L-cysteine followed by 30 days washout resulted in significantly improved antioxidant serum concentrations. Assessing a clinically relevant effect was outside the scope of this trial.[398] 10 mg/kg/day in children with Down syndrome for 4 weeks was well tolerated, though dosing needs to consider palatability. Improved plasma levels of CoQ10 were observed with divided dosing.[399] 10 mg/kg/day CoQ10 in children with Down syndrome for 4 weeks normalised antioxidant:oxidant imbalance.[400] 4 mg/kg/day CoQ10 for 20 months in children aged 5–17 years with Down syndrome produced a significant rise in plasma CoQ10.[401] Epigallocatechin Improvement of skeletal parameters, including bone mineral density.[402] gallate (EGCG): Inhibition of DYRK1A gene (involved in brain morphogenesis, learning impairments), resulting in reduced brain morphogenesis defects.[403] mouse models Improvement in synaptic pathways and methylation activity.[404] 2 weeks of EGCG treatment in mouse pups from 3 days old induced restoration of neurogenesis, and improved hippocampal granule cell numbers and synaptic proteins in the hippocanthus and neural cortex, but none of these effects was maintained 30 days after cessation of treatment.[405] Resveratrol and EGCG demonstrated improvements in mitochondrial dysfunction in hippocampal progenitor cells.[406] EGCG: 9 mg/kg/day EGCG combined with cognitive training for 12 months was more effective than cognitive training and placebo for improving memory, inhibition human trials control and adaptive skills in young adults with Down syndrome.[407] Multivitamin and Multivitamin preparation (high dose of 11 vitamins, low dose of 8 minerals) or placebo was given to 20 children with Down syndrome for 8 months. No minerals significant difference was observed in IQ, behaviour, speech and language development, school achievement, growth or health.[408] Vitamin B6 Supplementation with vitamin B6 from infancy (under 8 weeks old) for 3 years in a double-blind study in 19 children (25 mg/kg/day for the first 6 months, 35 mg/kg/day thereafter, or placebo) and an open trial of 400 older children (15–65 mg/kg/day) for up to 8 years. No change in psychological testing at 3 years old, but significantly beger social development in the treatment group at 6 years old. The open trial revealed tolerance issues, including photosensitivity, sun blisters, vomiting and peripheral neuropathy.[409] Supplementation with vitamin B6 from infancy (under 8 weeks old) for 3 years in a double-blind study in 19 children (25 mg/kg/day for the first 6 months, 35 Vitamin D

Vitamin E

Vitamins E and C

Vitamins E and C and alpha-lipoic acid Zinc

mg/kg/day thereafter, or placebo). Significant improvement in cortical auditory evoked potentials at 3 years old but not 1 year old.[410] Vitamin D deficiency is common in people with Down syndrome and increases predisposition to developing autoimmune disease. Obesity, sedentary lifestyles and already existing autoimmune disease increase vitamin D deficiency.[411] In recent history, people with Down syndrome were at risk of vitamin D deficiency due to institutionalisation. While institutionalisation of people with intellectual disabilities is being phased out in most developed countries globally, vitamin D deficiency is still prevalent due to sedentary lifestyle pagerns.[412] 400 IU/day significantly reduced oxidative stress in children with Down syndrome. No negative effects were reported.[413] 100 micrograms vitamin E/day reduced chromosomal and lymphocyte damage secondary to increased oxidative stress.[414] 1000 IU vitamin E orally twice daily or placebo, given for 3 years, to 337 people with Down syndrome over 50 years of age did not slow the onset of ageing or have a clinically significant effect on cognition, functionality or behaviour. No markers of antioxidant status were measured.[394] 500 mg/day vitamin C and 400 mg/day vitamin E over 6 months produced measureable reduction in oxidative stress, increased plasma concentration of vitamin E and restored glutathione blood levels in children with Down syndrome.[415] 500 mg/day vitamin C and 400 mg/day vitamin E over 6 months persistently agenuated oxidative stress 6 months after cessation of supplementation in children with Down syndrome.[416] Treatment group was given 900 IU alpha tocopherol, 200 mg ascorbic acid and 600 mg alpha-lipoic acid twice daily and a multivitamin supplement once daily, plus standard dementia medication (acetylcholinesterase inhibitor) for 2 years. Participants were patients with Down syndrome and pre-dementia diagnosis. Increased blood levels of vitamin E were measured, but no clinically discernible therapeutic effect was observed. No adverse events or safety issues were reported.[393] Zinc supplementation (1 mg elemental zinc (sulfate)/kg bodyweight per day for 4 months) in children with Down syndrome accelerated the rate of DNA repair to a level that was similar to control participants.[417] Zinc supplementation (1 mg elemental zinc (sulfate)/kg bodyweight per day for 4 months) in boys with Down syndrome reduced the number of infective episodes and the number of days with an elevated body temperature. Girls in this study had a lower baseline of infections, which remained low after zinc supplementation.[418] Zinc supplementation in children (25 mg per day for children aged 1–9 years; 50 mg per day for children aged 10–19 years) for 3 months produced lower incidence of cough and fever, but did not alter other clinically relevant variables.[419] Surveyed dietary intake for zinc is similar to age-matched peers, but lower levels of serum zinc suggest altered metabolism. Zinc supplementation (30 mg zinc daily for 4 weeks) in adolescents with Down syndrome (aged 10–19 years) was effective in improving plasma and erythrocyte concentrations of zinc, but had no influence on thyroid hormone metabolism.[420] Level of zinc deficiency in people with Down syndrome was not found to be correlated with particular comorbidities, including growth hormone dysfunction and immune system irregularities, or predisposition to coeliac disease or hypothyroidism.[421] Oral administration of zinc sulfate (20 mg/kg/day for 2 months) resulted in increased DNA synthesis and improved lymphocyte proliferative response.[422]

Zinc is involved in over 300 enzyme processes within the human body and is a catalytic metal in many other metabolic functions.[423] Multiple studies have found zinc to be lower in people with Down syndrome across a range of age groups.[418,422,424,425] Stabile et al. found that only some children with Down syndrome were zinc deficient (20%) and that the effect of zinc on the immune system was transitory. Increased lymphocyte proliferation, however, was demonstrated with zinc supplementation.[422] While nutritional intake in adolescents with Down syndrome is not significantly different from that of the general population, zinc status has been found to be lower, as measured by plasma and urine concentrations, and is elevated in erythrocytes.[420] Romano et al. conducted a study of the levels of zinc deficiency in people with Down syndrome and found that severity of zinc deficiency was not correlated with particular comorbidities, including growth hormone dysfunction, immune system irregularities, predisposition to coeliac disease or hypothyroidism.[421] It is likely that more than one factor is involved in the incidence of these disorders and so it is unsurprising that this study did not find a direct correlation. While zinc deficiency in isolation will not cause these conditions, it is likely that it may contribute to disease progression. Zinc absorption is also lower in older people. Maintaining adequate zinc status is important for cellular proliferation and differentiation, growth factors, cell growth arrest, apoptosis, oncogene expression, chemokines and hormone function.[423] Zinc plays a critical role in immune function through both cellular maturation and migration of immune cells.[423] It is also implicated in inflammatory processes, through cytokine production, and is involved in DNA-repair during accelerated oxidative stress associated with ageing.[423] Current studies on zinc supplementation in Down syndrome are sparse but, as a critical nutrient that is well-tolerated and has been found to be deficient in both ageing populations and people with Down syndrome throughout the life span, zinc supplementation is worth considering. Carnosine has a potential role in Down syndrome, as it is involved in free radical scavenging and has been shown to have anti-inflammatory properties.[347] Potential for reducing cognitive impairment and cognitive decline has been proposed by some authors,[347] though as yet no clinical

trials have been conducted to assess the benefits of supplementation. Acetyl-L-carnitine has been found to be lower in children with Down syndrome than in age-matched peers.[426] Acetyl-L-carnitine has been clinically trialled in an elderly population and found to reduce physical and mental fatigue, and improve exercise tolerance and cognitive status.[427] This has potential application for people with Down syndrome. One small study (n = 40) of men with Down syndrome found no significant improvement with a dose of 10–30 mg/kg/day acetyl-L-carnitine on neurological, cognitive, behavioural or social functions.[428] Higher doses may be needed to achieve a clinically significant result, though further research is needed to support this. Cysteine has been observed to be elevated in people with Down syndrome, possibly due to over-expression of genes involved in enzyme production that convert homocysteine to cysteine.[347] N-acetyl-cysteine is an anti-glycation agent and has been proposed for use in people with Down syndrome; however, there is limited evidence that it may induce seizures in susceptible individuals and no direct evidence of beneficial effects.[347] Resveratrol, present in red wine, is a potent antioxidant able to penetrate the blood–brain barrier and is associated with lower incidence of Alzheimer's disease.[429] Other benefits in patients with Alzheimer's disease include weight loss, fat loss and enhanced mitochondrial biogenesis.[429] To date, research on resveratrol is limited, with only a single animal trial conducted in Down syndrome, with positive effects.[406] Preliminary research suggests that resveratrol is well-tolerated and may help reduce the premature neurological ageing that occurs in Down syndrome, though further research is needed to confirm this. While human clinical trials on people with Down syndrome for herbal, nutritional and supplemental therapies are scarce, often inconsistent or based on inadequate dosing regimens, many of the above nutrients and antioxidants can be sourced through a varied and well-balanced diet. Common sense and sound knowledge of nutritional and herbal medicine should guide therapeutic interventions in the management of the many health complaints that arise in people with Down syndrome. Nutrients to consider supplementing for specific health presentations are included in Table 19.12. TABLE 19.12

Nutrients to consider supplementing for health conditions arising in people with Down syndrome Condition

Nutrients to consider supplementing

Anxiety and depression

Antioxidants Curcumin Magnesium

Methylated B vitamins, including folic acid Omega-3 fagy acids Vitamin D Zinc

Arthropathy

Chronic constipation

Antioxidants Curcumin Omega-3 fagy acids Ground flaxseeds Lactulose

Partially hydrolysed guar gum Probiotics: Lactobacillus acidophilus La-14 Bifidobacterium longum Bl-05 Lactobacillus plantarum Lp-115 Coeliac disease

Adult dosage

Child dosage

Include a range of antioxidants from dietary sources. Dose will vary depending on body size. Ensure supplement includes piperine, quercetin or a phospholipid to improve absorption. Inclusion of curcumin in the diet may be preferable in very young children. 150–600 mg/day 3–8 years: 80–150 mg/day 9–15 years: 240–360 mg/day 15+ years: dose as for adults depending on child's size While epidemiological research suggests a link between depression and low B vitamin intake, particularly B12 and folate, current evidence for supplementing B vitamins is inconsistent. Given the methylation issues inherent in people with Down syndrome, supplementation is likely to be beneficial and warrants further research. Supplementation with a high-quality methylated B complex is likely to be more beneficial than isolated B vitamins. >3000 mg/day 1000–5000 mg/day 2000–5000 IU per day 1000 IU per 14 kg body weight for maintenance or 2000 IU per 14 kg body weight for building vitamin D levels 15–30 mg/day 1–3 years: 3–5 mg 4–8 years: 4–10 mg 9–13 years: 10–20 mg 14–18 years: 15–30 mg Include a range of antioxidants from dietary sources. Dose will vary depending on body size. Ensure supplement includes piperine, quercetin or a phospholipid to improve absorption. Inclusion of curcumin in the diet may be preferable in very young children. 6000–16 000 mg/day 1000–5000 mg/day 1–2 tablespoons daily ½–1 tablespoon daily 20–30 mL acute dose Acute dose: Maintenance dose: 5–15 mL maintenance dose 1–6 years: 10 mL 3000 mg/day 1000–5000 mg/day Probiotics: 109–1011 organisms 109–1011 organisms Lactobacillus rhamnosus per strain per strain LGG Saccharomyces cerevisiae var boulardii (biocodex strain) Protein powder Protein supplement may be useful for patients with dysphagia or other oral motor difficulties. Preference food sources of protein and

Diabetes and metabolic syndrome

Eczema

Growth failure and/or developmental delay

Zinc

supplement additional protein as needed on a case-by-case basis. 15–30 mg/day

Chromium L-carnitine Magnesium

200–600 micrograms/day 2–4 g/day 150–600 mg/day

Zinc

15–30 mg/day

Antioxidants Omega-3 fagy acids Prebiotics: Fructooligosaccharides Probiotics: Lactobacillus rhamnosus LGG Lactobacillus reuteri MM53 Selenium Vitamin C Vitamin D

Include a range of antioxidants from dietary sources. >3000 mg/day 3–10 g daily

Zinc

15–30 mg/day

Glutamine Multivitamin and minerals Omega-3 fagy acids Protein powder Vitamin D

N/A N/A N/A N/A N/A

Zinc

N/A

109– 1011 organisms per strain

100–200 micrograms/day 1000–3000 mg/day 5000 IU per day in sunlight-deprived populations.

Hyper-thyroidism Antioxidants Selenium Zinc

Include a range of antioxidants from dietary sources. 200 micrograms/day 15–30 mg/day

Hypo-thyroidism

Antioxidants Iodine

Include a range of antioxidants from dietary sources. 150–290 micrograms/day

Selenium Zinc

200 micrograms/day 15–30 mg/day

Leukaemia Osteoporosis And osteopenia

Boron Calcium

Magnesium

Vitamin D Vitamin K

Zinc

1–3 years: 3–5 mg 4–8 years: 4–10 mg 9–13 years: 10–20 mg 14–18 years: 15–30 mg

3–8 years: 80–150 mg/day 9–15 years: 240–360 mg/day 15+ years: dose as for adults depending on child's size 1–3 years: 3–5 mg 4–8 years: 4–10 mg 9–13 years: 10–20 mg 14–18 years: 15–30 mg 1000–5000 mg/day 3–10 g daily 109– 1011 organisms per strain

25–100 micrograms/day 500–2000 mg/day 1000 IU per 14 kg bodyweight for maintenance or 2000 IU per 14 kg body weight for building vitamin D levels 1–3 years: 3–5 mg 4–8 years: 4–10 mg 9–13 years: 10–20 mg 14–18 years: 15–30 mg 0.3–0.5 g/kg High-quality paediatric multivitamin and mineral powder 1000–3000 mg/day Case-dependent 1000 IU per 14 kg bodyweight for maintenance, or 2000 IU per 14 kg body weight for building vitamin D levels 1–3 years: 3–5 mg 4–8 years: 4–10 mg 9–13 years: 10–20 mg 14–18 years: 15–30 mg 25–100 micrograms/day 1–3 years: 3–5 mg 4–8 years: 4–10 mg 9–13 years: 10–20 mg 14–18 years: 15–30 mg 14 years: 150 micrograms/day

25–100 micrograms/day 1–3 years: 3–5 mg 4–8 years: 4–10 mg 9–13 years: 10–20 mg 14–18 years: 15–30 mg Supplements for patients with leukaemia need to be considered within the context of medications and other concomitant therapies. Supportive therapies for people with Down syndrome follow the same guidelines as for the general population. 0.2–1 mg/day 2 mg per day estimated daily intake 1000–1300 mg/day 1–3 years: 500 mg 4–8 years: 700 mg 9–11 years: 1000 mg 12–18 years: 1300 mg 150–600 mg/day 3–8 years: 80–150 mg/day 9–15 years: 240–360 mg/day 15+ years: dose as for adults depending on child's size 5000 IU per day in sunlight-deprived populations 1000 IU per 14 kg body weight for maintenance or 2000 IU per 14 kg body weight for building vitamin D levels 60–70 micrograms 1–3 years: 25 micrograms 4–8 years: 35 micrograms 9–13 years: 45 micrograms 14–18 years: 55 micrograms 15–30 mg/day 1–3 years: 3–5 mg 4–8 years: 4–10 mg 9–13 years: 10–20 mg

Oxidative stress and premature ageing

Persistent infections and poor immune function

Post-surgery

Seizures and epilepsy

Alpha-lipoic acid Antioxidants Co-enzyme Q10 Epigallocatechin gallate (EGCG) Multivitamin and minerals Vitamin C Vitamin D

600–1200 mg/day Include a range of antioxidants from dietary sources. 150–300 mg 9 mg/kg

Zinc

15–30 mg/day

Antioxidants Calcium

Include a range of antioxidants from dietary sources. 1000–1300 mg/day

14–18 years: 15–30 mg Doses have not been established for children. 4–10 mg/kg/day CoQ10 Older adolescents: 9 mg/kg

Clinical decision will vary depending on the needs of the patient, quality of dietary intake and patient budget. 1000–3000 mg/day 500–2000 mg/day 5000 IU per day in sunlight-deprived populations 1000 IU per 14 kg body weight for maintenance or 2000 IU per 14 kg body weight for building vitamin D levels Vitamin E 500 IU/day 100 IU/day Zinc 15–30 mg/day 1–3 years: 3–5 mg 4–8 years: 4–10 mg 9–13 years: 10–20 mg 14–18 years: 15–30 mg Antioxidants Include a range of antioxidants from dietary sources. Prebiotic: 3–10 g/day 3–10 g/day Fructooligosaccharides 5–15 mL/day 2.5–10 mL/day Lactulose Probiotic: 109 organisms 109 organisms Lactobacillus rhamnosus LGG Vitamin A 3000–5000 IU/day 1000–2000 IU/day Vitamin C 2000–3000 mg/day 500–2000 mg/day Vitamin D 5000 IU per day in sunlight-deprived populations 1000 IU per 14 kg body weight for maintenance or 2000 IU per 14 kg body weight for building vitamin D levels Zinc 15–30 mg/day 1–3 years: 3–5 mg 4–8 years: 4–10 mg 9–13 years: 10–20 mg 14–18 years: 15–30 mg Glutamine 10–20 g/day Multivitamin and minerals Clinical decision will vary depending on the needs of the patient, High-quality paediatric multivitamin and mineral powder. quality of dietary intake and patient budget. Omega-3 fagy acids >3000 mg/day 1000–5000 mg/day Protein powder Protein supplement may be useful for patients with dysphagia or other oral motor difficulties. Preference food sources of protein and supplement additional protein as needed on a case-by-case basis.

Curcumin Electrolytes Magnesium

Methylated B vitamins, including folic acid Omega-3 fagy acids Selenium Vitamin C Vitamin D Zinc

1–3 years: 3–5 mg 4–8 years: 4–10 mg 9–13 years: 10–20 mg 14–18 years: 15–30 mg

1–3 years: 500 mg 4–8 years: 700 mg 9–11 years: 1000 mg 12–18 years: 1300 mg Dose will vary depending on body size. Ensure supplement includes piperine, quercetin or a phospholipid to improve absorption. Inclusion of curcumin in the diet may be preferable in very young children. Dose as needed in 500 mL–1 L of water. 150–600 mg/day 3–8 years: 80–150 mg/day 9–15 years: 240–360 mg/day 15+ years: dose as for adults depending on child's size. Supplementation with a high-quality methylated B complex is likely to be more beneficial than isolated B vitamins.

>3000 mg/day 200 micrograms/day 1000–3000 mg/day 5000 IU per day in sunlight-deprived populations 15–30 mg/day

1000–5000 mg/day 25–100 micrograms/day 500–2000 mg/day 1000 IU per 14 kg body weight for maintenance or 2000 IU per 14 kg body weight for building vitamin D levels 1–3 years: 3–5 mg 4–8 years: 4–10 mg 9–13 years: 10–20 mg 14–18 years: 15–30 mg

Source: [430]

Herbal medicine Therapeutic objectives for people with Down syndrome are focused on improving access to quality healthcare, health surveillance and improving the management of acute and chronic health conditions and comorbidities. Herbal medicines used will vary depending on the specific health problems individual patients present with. Herbs that exhibit strong antioxidant activity are of particular importance for people with Down syndrome. Curcumin, the active component in Curcuma longa (turmeric), is a potent anti-inflammatory and antioxidant and demonstrates neuroprotective effects through free radical scavenging.[350] Ginkgo biloba is known for its antioxidant properties and has been shown to improve cognitive function in patients with Alzheimer's disease.[350] Other strongly antioxidant herbs, particularly those with evidence of a history of use for cognitive support, should be considered. These include, but are not limited to, Pinus pinaster (maritime pine), Rosmarinus officinalis (rosemary), Salvia officinalis (sage), Melissa officinalis (lemon balm), Ocimum tenuiflorum (Krishna tulsi) and Panax ginseng (Korean ginseng). Table 19.13 includes a range of herbs that may be

useful in the management of health conditions experienced by people with Down syndrome. Consider potential herb–drug interactions in the choice of herbal medicines when patients are taking prescribed medications. TABLE 19.13

Potential herbal medicines to consider in the treatment of health complaints experienced by people with Down syndrome System

Therapeutic objective

Herbal medicine

Cardiac

Cardiotonic and cardioprotective

Crataegus oxycanthus (hawthorn) Leonuris cardiaca (motherwort) Terminalia arjuna (arjuna) Allium sativum (garlic) Leonuris cardiaca (motherwort) Olea europaea (olive leaf) Tilia europaea (linden, or lime blossom) Viscum album (mistletoe) Camellia sinensis (green tea) Calendula officinalis (calendula) Glycyrrhiza glabra (liquorice) Hypericum perforatum (St John's wort) Lavandula officinalis (lavender) Matricaria recutita (chamomile) Plantago lanceolata (ribwort) Allium sativum (garlic) Camellia sinensis (green tea) Hydrastis canadensis (golden seal) Melaleuca alternifolia (tea tree) Ocimum tenuiflorum (Krishna tulsi) Origanum vulgare (oregano) Rosmarinus officinalis (rosemary) Salvia officinalis (sage) Thymus vulgaris (thyme) Topical: Aloe barbadensis (aloe vera) Plantago lanceolata (ribwort) Vitellaria paradoxa, formerly known as Butyrospermum parkii (shea buger) Bacopa monnieri (brahmi) Camellia sinensis (green tea) Ginkgo biloba (ginkgo) Rosmarinus officinalis (rosemary) Salvia officinalis (sage) Melissa officinalis (lemon balm) Panax ginseng (Korean ginseng) Allium sativum (garlic) Camellia sinensis (green tea) Hydrastis canadensis (golden seal) Ocimum tenuiflorum (Krishna tulsi) Origanum vulgare (oregano) Propolis Commiphora myrrha (myrrh) Salvia officinalis (sage) Thymus vulgaris (thyme) Pimpinella anisum (aniseed) Thymus vulgaris (thyme) Adhatoda vasica (adhatoda) Eucalyptus globulus (southern blue gum) Mentha x piperita (peppermint) Codonopsis pilosula (codonopsis) Glycyrrhiza glabra (liquorice) Plantago lanceolata (ribwort) Verbascum thapsus (mullein) Marrubium vulgare (white horehound) Origanum vulgare (oregano) Polygala tenuifolia (polygala) Thymus vulgaris (thyme) Verbascum thapsus (mullein) Achillea millefolium (yarrow) Eupatorium perfoliatum (boneset) Andrographis paniculata (andrographis) Uncaria tomentosa (cat's claw) Echinacea spp. (echinacea) Eleutherococcus senticosus (Siberian ginseng) Panax ginseng (Korean ginseng) Panax quinquefolius (American ginseng) Astragalus membranaceus (astragalus) Codonopsis pilosula (codonopsis) Eleutherococcus senticosus (Siberian ginseng) Panax ginseng (Korean ginseng) Panax quinquefolius (American ginseng)

Hypotensive

Dental Dermatological

Improve oral flora Anti-inflammatory

Antimicrobial

Vulnerary

Developmental delay and learning difficulties

Cognitive enhancer/brain tonic

ENT and other respiratory disorders

Antimicrobial

Anti-spasmodic

Decongestant Demulcent

Expectorant

Febrifuge Immune stimulant

Immune tonic

Sutherlandia frutescens (Sutherlandia) Withania somnifera (ashwagandha) Lung tonic

Lymphatic

Mucolytic

Sinus tonic

Endocrine

Hypoglycaemic

Thyroid stimulant

Gastrointestinal

Thyroid suppressant Alleviate constipation

Carminative

Emollients

Manage gastro-oesophageal reflux

Haematological

Nutritive/blood building

Neuropsychiatric

Adaptogens

Anti-depressant

Enhance cognitive function

Neuroprotective Reduce anxiety

Inula helenium (elecampane) Panax quinquefolius (American ginseng) Verbascum thapsus (mullein) Calendula officinalis (calendula) Galium aparine (clivers) Phytolacca decandra (poke root) Glycyrrhiza glabra (liquorice) Polygala tenuifolia (polygala) Sanguinaria canadensis (bloodroot) Hydrastis canadensis (golden seal) Hyssopus officinalis (hyssop) Solidago canadensis (golden rod) Cinnamomum zeylanicum (true cinnamon) Galega officinalis (goat's rue) Gymnema sylvestre (gymnema) Momordica charantia (biger melon) Trigonella foenum-graecum (fenugreek) Coleus forskohlii (coleus) Fucus vesiculosus (bladderwrack) Lycopus virginicus (bugleweed) Linum usitatissimum (flaxseed) Rhamnus purshiana (cascara sagrada) Rheum palmatum (rhubarb) Rumex crispus (yellow dock) Ulmus rubra (slippery elm) Angelica archangelica (angelica) Anethum graveolens (dill) Carum carvi (caraway) Cinnamomum zeylanicum (true cinnamon) Foeniculum vulgare (fennel) Hyssopus officinalis (hyssop) Lavandula officinalis (lavender) Matricaria recutita (chamomile) Melissa officinalis (lemon balm) Mentha × piperita (peppermint) Nepeta cataria (catnip) Pimpinella anisum (aniseed) Zingiber officinale (ginger) Althaea officinalis (marshmallow) Plantago lanceolata (ribwort) Ulmus rubra (slippery elm) Althaea officinalis (marshmallow) Filipendula ulmaria (meadowsweet) Ulmus rubra (slippery elm) Codonopsis pilosula (codonopsis) Eleutherococcus senticosus (Siberian ginseng) Panax ginseng (Korean ginseng) Panax quinquefolius (American ginseng) Urtica dioca (negle) Withania somnifera (ashwagandha) Codonopsis pilosula (codonopsis) Eleutherococcus senticosus (Siberian ginseng) Panax ginseng (Korean ginseng) Panax quinquefolius (American ginseng) Rhodiola rosea (Arctic rose) Withania somnifera (ashwagandha) Avena sativa (green oats) Crocus sativus (saffron) Hypericum perforatum (St John's wort) Lavandula officinalis (lavender) Leonurus cardiaca (motherwort) Melissa officinalis (lemon balm) Sceletium tortuosum (sceletium) Verbena officinalis (vervain) Bacopa monnieri (brahmi) Melissa officinalis (lemon balm) Ocimum tenuiflorum (Krishna tulsi) Rosmarinus officinalis (rosemary) Salvia officinalis (sage) Centella asiatica (gotu kola) Curcuma longa (turmeric) Avena sativa (green oats) Crocus sativus (saffron) Eschscholzia californica (Californian poppy) Hypericum perforatum (St John's wort) Lavandula officinalis (lavender) Leonurus cardiaca (motherwort)

Matricaria chamomilla (chamomile) Melissa officinalis (lemon balm) Passiflora incarnata (passionflower) Piper methysticum (kava) Sceletium tortuosum (sceletium) Scutellaria lateriflora (skullcap) Valeriana officinalis (valerian) Verbena officinalis (vervain) Sedative

Metabolic

Metabolic stimulant

Ophthalmic

Anti-inflammatory Microvascular tonic

Orthopaedic

Anti-rheumatic/anti-inflammatory

Spasmolytic

Sexual and reproductive health: female

Anodyne

Luteal phase tonic Ovulatory tonic Uterine tonic

Sexual and reproductive health: male

Tonic

Eschscholzia californica (Californian poppy) Lavandula officinalis (lavender) Passiflora incarnata (passionflower) Piper methysticum (kava) Valeriana officinalis (valerian) Zizyphus spinosa (zizyphus) Camellia sinensis (green tea) Coleus forskohlii (coleus) Eleutherococcus senticosus (Siberian ginseng) Panax ginseng (Korean ginseng) Panax quinquefolius (American ginseng) Topical: Plantago lanceolata (ribwort) (dilute in saline) Pinus pinaster (maritime pine) Vaccinium myrtillus (bilberry) Vitis vinifera (grape: skin and seed) Apium graveolens (celery seed) Boswellia serrata (boswellia) Curcuma longa (turmeric) Harpagophytum procumbens (devil's claw) Salix alba (willow bark) Urtica dioca (negle) Corydalis ambigua (corydalis) Piper methysticum (kava) Valeriana officinalis (valerian) Viburnum opulus (cramp bark) Corydalis ambigua (corydalis) Matricaria chamomilla (chamomile) Piscidia piscipula (Jamaican dogwood) Viburnum opulus (cramp bark) Viburnum prunifolium (black haw) Vitex agnus-castus (chaste tree) Paeonia lactiflora (peony) Alchemilla vulgaris (lady's mantle) Rubus idaeus (raspberry leaf) Viburnum prunifolium (black haw) Panax ginseng (Korean ginseng) Serenoa repens (saw palmego) Smilax ornata (sarsaparilla) Turnera diffusa (damiana) Withania somnifera (ashwagandha)

Green tea contains multiple antioxidant compounds including EGCG, which has demonstrated anti-cancer and antioxidant properties and may reduce neurodegenerative processes.[350] To date, most research on EGCG in Down syndrome has been conducted in mouse models. While one cannot directly extrapolate benefit in humans from these studies, they do demonstrate potential therapeutic benefits, including improved bone mineral density, neurotransmiger and synaptic enhancement and reduced maladaptive neurogenesis (see Table 19.11). To date only one study has investigated EGCG in humans as well as mice: de la Torre et al. demonstrated improvements in visual memory recognition, spatial working memory, social functioning and quality of life in adolescents with Down syndrome.[407] Further research is needed to explore the therapeutic potential of EGCG in young and older people with Down syndrome.

Lifestyle: exercise Exercise requirements follow the same guidelines as for the general population and should be adapted to the physical capabilities of the patient. While physical impairments may limit some types of exercise, more often than not activities are possible with a greater degree of support. For babies aged 0–1 year old, encourage floor-based play in safe environments.[374] Floor-based play not only is a valuable form of exercise, but also facilitates interaction with objects and the environment, family members and carers, and provides great scope for environmental enrichment. Children aged 1–5 years should be encouraged to engage in active play. Young children should be active for at least 3 hours every day, spread out throughout the day. [374] This should include a broad range of activities that encourage muscular development, balance, proprioception and intellectual stimulation. School-aged children (aged 5–17 years) should engage in at least 1 hour of moderate to vigorous intensity exercise daily, including aerobic and strengthening exercises.[375] Healthy exercise practices established during childhood may reduce the tendency towards sedentary activity and may help establish a lifelong habitual exercise. In adults, physical activity includes activities of daily living, leisure activities, incidental exercise, sports and planned activities. A minimum of 150 minutes per week is recommended, with additional health benefits achieved with 300 minutes per week, including aerobic bursts of at least 10 minutes. In older adults (50–70 years), physical activity should include balance-promoting activities 3 days per week, and muscle strengthening activities at least 2 days per week. The type of activities enjoyed will need to be adjusted to accommodate the individual's physical abilities.[377]

Case study 19.4 Overview Wendy, a 42-year-old woman with Down syndrome, presents with a recent history of irregular menses, mood swings, night sweats and irritability. Her menstrual history is unremarkable and her periods were regular and non-painful until 6 months ago. She lives in a group home with two other women with intellectual disabilities. Wendy and her housemates have support workers who assist them with evening meal preparation and domestic duties. The household food budget is shared; the three women eat together most nights and organise other meals independently of each other. Wendy is assertive with her ideas and is frustrated when people don't take the time to understand what she has to say. Her speech is intelligible, but words are often poorly formed due to oral motor difficulties and an oversized tongue. Wendy was accompanied by her carer for the initial appointment. Relevant health history

Wendy was born at 41 weeks’ gestation via normal vaginal delivery and was breastfed for 14 months. She has no history of congenital heart disease. Wendy suffered frequent respiratory tract infections as a child, including recurrent middle ear infections, croup and pneumonia, resulting in frequent antibiotic use and many hospitalisations. Adenoidectomy and tonsillectomy were performed at 4 years old. Wendy works 4 days per week at a local disability support agency. She reports that she is not stressed, though on further questioning she reveals she has frequent disagreements with one of her housemates. Wendy has lived in the group home for 8 months following the death of her father and her mother moving into an aged care facility. Prior to this she lived in the family home with her ageing parents. Her mother has multiple autoimmune conditions, has become increasingly frail over the last decade and decided she could no longer care for herself or Wendy following her husband's death. Wendy has dinner with her mother once a week, which she tearfully says is not enough. She has one sister and three nephews, who she has ligle contact with, even though they live within 10 km of Wendy. Wendy does not drive and feels her sister makes ligle effort to include her in their lives. She misses living with her family and sometimes cries herself to sleep. Her carer reports that she tends to be withdrawn in the evenings and that her boss has expressed concern that she is listless and less focused at work. Wendy has received no counselling, and has ligle understanding of death. Wendy says she gets very tired and wants to take a nap at work, but is not allowed. She has gained 6 kg over the last 8 months. She has had no other contact with health professionals in the last 2 years. Wendy is not currently taking any supplements or pharmaceutical medications. Clinical examination Height: 148 cm Waist circumference: 88 cm Breathing: 24 breaths per minute Urinalysis: Specific gravity: 1.030 pH: 5.0 Otherwise NAD

Weight: 71 kg Blood pressure: 134/77 mmHg

BMI: 32 (obese) Pulse: 77 bpm

Temperature 35.9°C (per axilla)

Blood glucose: 7.8 mmol/L (fruitcake and coffee 30 minutes prior to appointment)

Physical appearance: Wendy appears flushed and out of breath. She is visibly obese, with central obesity. She has mild vertical ridging on her nails, some white flecks and 3-second capillary refill. She is a ligle bashful when she talks about eating fruitcake prior to her appointment.

Treatment protocol Initial appointment

Treatment considerations: • Menstrual irregularities consistent with early menopause • Unexplained weight gain • Possible depression • Inadequate bereavement support • Dislocation and isolation from family • Inadequate health surveillance

Prescription

Rationale

Herbal medicine

200 mL herbal tincture Leonurus cardiaca 80 Crocus sativum 40 Actaea racemosa 30 Salvia officinalis 50 Dose: take 7.5 mL in a ligle water twice daily Nutritional medicine Vitamin D: 5000 IU per day from March to November Activated B complex Dietary Increase green leafy vegetables Berries: ¼–½ cup daily Therapeutically active yoghurt Increase water intake Further Iron studies investigations Thyroid function test Full blood count ESR/CRP Fasting blood glucose Referral Bereavement counselling

Thymoleptic Anti-depressant Clinically shown to reduce hot flushes Cooling, cognition enhancer Wendy lives in a region where vitamin D deficiency is endemic; vitamin D deficiency contributes to depression MTHFR implicated in Down syndrome and depression Inadequate dietary intake of vegetables, water and antioxidants

Heavy menstrual loss Unexplained fatigue

Inadequate support following loss of father, dislocation from family

Follow-up Wendy was feeling significantly beger at her second appointment. She had been to see her GP, who ordered multiple blood tests. Her iron stores were low, but no other abnormalities were detected. She had also had her first appointment with a counsellor, who she seemed happy with. Wendy discussed having a beger understanding about where her father had ‘gone’ and though she still felt sad, she felt more at peace with his passing. She had been compliant with the herbs and did not mind that they tasted ‘yucky’ because they made her feel happier. Her carer reported she was arguing less with her housemate and was motivated to help more with the evening cooking. This consultation focused on educating Wendy about menopause, the changes that were happening in her body, and encouraging further improvements to her dietary intake. Prescription Herbal medicine Nutritional medicine Dietary

Educational resources

Lifestyle

Referral

Rationale Continue with herbal tincture Continue with vitamin D and activated B complex 25 mg iron bisglycinate for 3 months, then re-test Low glycaemic index diet Increase fresh fruit and vegetables Increase wholegrains Life Without Barriers (hgp://www.lwb.org.au) Lifestyle Easy Cookbooks (hgps://www.easycookbook.org/home) Encourage participation in local Down syndrome support group Increase exercise: 30–45 minutes of walking daily Organise travel training through support workers Continue with bereavement counselling

Low iron stores Central obesity, possible insulin resistance Improve nutritional intake Increase fibre intake Support services for people of all ages with disabilities Easy-to-prepare, simple nutritious meals designed for people with intellectual disabilities; laminated for easy cleaning Increase community participation Exercise is associated with many health benefits, including improved mood, weight management and easier menopause transition Greater transport independence would allow Wendy more freedom to visit her mother and sister Bereavement support for people with intellectual disabilities is typically lacking and can lead to pathological grieving processes

Ongoing support Wendy intends to continue seeing her counsellor and her naturopath as needed for further support. She is enjoying having greater control over what she eats, and at follow up 2 months later had lost 3 kg. She has taken up table tennis through her local Down syndrome support group and has joined a local choir. She has started travel training and is learning the bus routes to various services in her community. Wendy is happier, healthier and enjoying making new friends.

References [1] Hickey F, Hickey E, Summar KL. Medical update for children with Down syndrome for the pediatrician and family practitioner. Adv Pediatr. 2012;59(1):137–157. [2] Araujo BH, Torres LB, Guilhoto LM. Cerebal overinhibition could be the basis for the high prevalence of epilepsy in persons with Down syndrome. Epilepsy Behav. 2015;53:120–125. [3] Hibaoui Y, Grad I, Letourneau A, et al. Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21. EMBO Mol Med. 2014;6(2):259–277. [4] Rachidi M, Lopes C. Mental retardation in Down syndrome: from gene dosage imbalance to molecular and cellular mechanisms. Neurosci Res. 2007;59(4):349–369. [5] Mazurek DWJ. Down syndrome: genetic and nutritional aspects of accompanying disorders. Rocz Panstw Zakl Hig. 2015;66(3):189– 194. [6] Durvasula S, Beange H. Health inequalities in people with intellectual disability: strategies for improvement. Health Promotion J Austr. 2001;11(1):27–31. [7] Trollor J, Ruffell B, Tracy J, et al. Intellectual disability health content within medical curriculum: an audit of what our future doctors

are taught. BMC Med Educ. 2016;16(105):1–9. [8] Wallace RA, Beange H. On the need for a specialist service within the generic hospital seging for the adult patient with intellectual disability and physical health problems. J Intellect Dev Disabil. 2008;33(4):354–361. [9] [NSW Disability Inclusion Act 2014; Available from:] www.legislation.nsw.gov.au. [10] Daunhauer LA, Fidler DJ, Will E. School function in students with Down syndrome. Am J Occup Ther. 2014;68(2):167–176. [11] Herron-Foster BJ, Bustos JJ. Special needs: caring for the older adult with Down syndrome. Medsurg Nurs. 2014;23(225):2014. [12] Baum RA, Nash PL, Foster JE, et al. Primary care of children and adolescents with Down syndrome: an update. Curr Probl Pediatr Adolesc Health Care. 2008;38(8):241–261. [13] Pikora TJ, Bourke J, Bathgate K, et al. Health conditions and their impact among adolescents and young adults with Down syndrome. PLoS ONE. 2014;9(5):e96868. [14] Ross WT, Olsen M. Care of the adult patient with Down syndrome. South Med J. 2014;107(11):715–721. [15] Foley KR, Jacoby P, Girdler S, et al. Functioning and post-school transition outcomes for young people with Down syndrome. Child Care Health Dev. 2013;39(6):789–800. [16] Czeizel AE, Puho E. Maternal use of nutritional supplements during the first month of pregnancy and decreased risk of Down's syndrome: case-control study. Nutrition. 2005;21(6):698–704 [discussion 74]. [17] Sukla KK, Jaiswal SK, Rai AK, et al. Role of folate-homocysteine pathway gene polymorphisms and nutritional cofactors in Down syndrome: a triad study. Hum Reprod. 2015;30(8):1982–1993. [18] Bozovic IB, Stankovic A, Zivkovic M, et al. Altered LINE-1 methylation in mothers of children with Down syndrome. PLoS ONE. 2015;10(5):e0127423. [19] Locke AE, Dooley KJ, Tinker SW, et al. Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome. Genet Epidemiol. 2010;34(6):613–623. [20] van Driel LMJW, de Jonge R, Helbing WA, et al. Maternal global methylation status and risk of congenital heart diseases. Obst Gynecol. 2008;112(2):277–283. [21] Brandalize AP, Bandinelli E, dos Santos PA, et al. Evaluation of C677T and A1298C polymorphisms of the MTHFR gene as maternal risk factors for Down syndrome and congenital heart defects. Am J Med Genet A. 2009;149A(10):2080–2087. [22] Acacio GL, Barini R, Bertuzzo CS, et al. Methylenetetrahydrofolate reductase gene polymorphisms and their association with trisomy 21. Prenat Diagn. 2005;25(13):1196–1199. [23] Barkai G, Arbuzova S, Berkenstadt M, et al. Frequency of Down's syndrome and neural-tube defects in the same family. Lancet. 2003;361:1331–1335. [24] Martin I, Gibert MJ, Aulesa C, et al. Bauca JM. Comparing outcomes and costs between contingent and combined first-trimester screening strategies for Down's syndrome. Eur J Obstet Gynecol Reprod Biol. 2015;189:13–18. [25] McEwan A, Godfrey A, Wilkins J. Screening for Down syndrome. Obst Gynaecol Reprod Med. 2012;22(3):70–75. [26] Dreux S, Nguyen C, Czerkiewicz I, et al. Down syndrome maternal serum marker screening after 18 weeks of gestation: a countrywide study. Am J Obstet Gynecol. 2013;208(5):e1–5. [27] Lee FK, Chen LC, Cheong ML, et al. First trimester combined test for Down syndrome screening in unselected pregnancies: a report of a 13-year experience. Taiwan Province of China J Obstet Gynecol. 2013;52(4):523–526. [28] Cheng P-J, Chu D-C, Chueh H-Y, et al. Elevated maternal midtrimester serum free b-human chorionic gonadotropin levels in vegetarian pregnancies that cause increased false-positive Down syndrome screening results. Am J Obst Gynecol. 2004;190:442–447. [29] Porreco RP, Garite TJ, Maurel K, et al. Noninvasive prenatal screening for fetal trisomies 21, 18, 13 and the common sex chromosome aneuploidies from maternal blood using massively parallel genomic sequencing of DNA. [the; Obstetrix Collaborative Research] Am J Obstet Gynecol. 2014;211(4):e1–12. [30] van den Heuvel A, Chigy L, Dormandy E, et al. Will the introduction of non-invasive prenatal diagnostic testing erode informed choices? An experimental study of health care professionals. Patient Educ Couns. 2010;78(1):24–28. [31] Lewis C, Silcock C, Chigy LS. Non-invasive prenatal testing for Down's syndrome: pregnant women's views and likely uptake. Public Health Genomics. 2013;16(5):223–232. [32] Deng C, Yi L, Mu Y, et al. Recent trends in the birth prevalence of Down syndrome in China: impact of prenatal diagnosis and subsequent terminations. Prenat Diagn. 2015;35(4):311–318. [33] Lou S, Mikkelsen L, Hvidman L, et al. Does screening for Down's syndrome cause anxiety in pregnant women? A systematic review. Acta Obstet Gynecol Scand. 2015;94(1):15–27. [34] Charleton PM, Dennis J, Marder E. Medical management of children with Down syndrome. Paediatr Child Health. 2010;20(7):331–337. [35] Mansfield C, Hopfer S, Marteau TM. Termination rates after prenatal diagnosis of Down syndrome, spina bifida, anencephaly, and Turner and Klinefelter syndromes: a systematic literature review. Prenat Diagn. 1999;19:808–812. [36] Collins VR, Muggli EE, Riley M, et al. Is Down syndrome a disappearing birth defect? J Pediatr. 2008;152(1):20–24. [37] Korenromp MJ, Page-Christiaens GC, van den Bout J, et al. Maternal decision to terminate pregnancy in case of Down syndrome. Am J Obstet Gynecol. 2007;196(2):e1–11. [38] Natoli JL, Ackerman DL, McDermog S, et al. Prenatal diagnosis of Down syndrome: a systematic review of termination rates (1995– 2011). Prenat Diagn. 2012;32(2):142–153. [39] Frati P, Gulino M, Turillazzi E, et al. The physician's breach of the duty to inform the parent of deformities and abnormalities in the foetus: ‘wrongful life’ actions, a new frontier of medical responsibility. J Matern Fetal Neonatal Med. 2014;27(11):1113–1117. [40] Skotko BG, Davidson EJ, Weintraub GS. Contributions of a specialty clinic for children and adolescents with Down syndrome. Am J Med Genet A. 2013;161A(3):430–437. [41] Nelson Goff BS, Springer N, Foote LC, et al. Receiving the initial Down syndrome diagnosis: a comparison of prenatal and postnatal

parent group experiences. Intellect Dev Disabil. 2013;51(6):446–457. [42] Strecker S, Hazelwood ZJ, Shakespeare-Finch J. Postdiagnosis personal growth in an Australian population of parents raising children with developmental disability. J Intellect Dev Disabil. 2013;39(1):1–9. [43] Raina P, O'Donnell M, Schwellnus H, et al. Caregiving process and caregiver burden: conceptual models to guide research and practice. BMC Pediatr. 2004;4(1):1–13. [44] Abbeduto L, Mallick Seloer M, Shaguck P. Psychological Well-being and coping in mothers of youths with autism, Down syndrome, or fragile X syndrome. Am J Ment Retard. 2004;109(3):237–254. [45] Thomas GM. An elephant in the consultation room? Configuring Down syndrome in British antenatal care. Med Anthropol Q. 2016;30(2):238–258. [46] Thomas M, Weisman SM. Calcium supplementation during pregnancy and lactation: effects on the mother and the fetus. Am J Obstet Gynecol. 2006;194(4):937–945. [47] Gomes S, Lopes C, Pinto E. Folate and folic acid in the periconceptional period: recommendations from official health organizations in thirty-six countries worldwide and WHO. Public Health Nutr. 2016;19(1):176–189. [48] Wang T, Zhang HP, Zhang X, et al. Is folate status a risk factor for asthma or other allergic diseases? Allergy Asthma Immunol Res. 2015;7(6):538–546. [49] Cavalli P. Prevention of neural tube defects and proper folate periconceptional supplementation. J Prenatal Med. 2008;2(4):40–41. [50] Charoenratana C, Leelapat P, Traisrisilp K, et al. Maternal iodine insufficiency and adverse pregnancy outcomes. Matern Child Nutr. 2016;12(4):680–687. [51] Berbel P, Obregon MJ, Bernal J, et al. Iodine supplementation during pregnancy: a public health challenge. Trends Endocrinol Metab. 2007;18(9):338–343. [52] Shi X, Han C, Li C, et al. Optimal and safe upper limits of iodine intake for early pregnancy in iodine-sufficient regions: a crosssectional study of 7190 pregnant women in China. J Clin Endocrinol Metab. 2015;100(4):1630–1638. [53] Best CM, Pressman EK, Cao C, et al. Maternal iron status during pregnancy compared with neonatal iron status beger predicts placental iron transporter expression in humans. FASEBJ. 2016;30(10):3541–3550. [54] Veltri F, Decaillet S, Kleynen P, et al. Prevalence of thyroid autoimmunity and dysfunction in women with iron deficiency during early pregnancy: is it altered? Eur J Endocrinol. 2016;175(3):191–199. [55] Khambalia AZ, Aimone A, Nagubandi P, et al. High maternal iron status, dietary iron intake and iron supplement use in pregnancy and risk of gestational diabetes mellitus: a prospective study and systematic review. Diabet Med. 2016;33(9):1211–1221. [56] Milman N. Iron in pregnancy: how do we secure an appropriate iron status in the mother and child? Ann Nutr Metab. 2011;59(1):50– 54. [57] Dalton LM, Ni Fhloinn DM, Gaydadzhieva GT, et al. Magnesium in pregnancy. Nutr Rev. 2016;74(9):549–557. [58] Jamilian M, Samimi M, Kolahdooz F, et al. Omega-3 fagy acid supplementation affects pregnancy outcomes in gestational diabetes: a randomized, double-blind, placebo-controlled trial. J Matern Fetal Neonatal Med. 2016;29(4):669–675. [59] Saccone G, Saccone I, Berghella V. Omega-3 long-chain polyunsaturated fagy acids and fish oil supplementation during pregnancy: which evidence? J Matern Fetal Neonatal Med. 2016;29(15):2389–2397. [60] Hawrelak J. Prebiotics. Braun L, Cohen M. Herbs and natural supplements. 4th ed. Elsevier: Sydney; 2015:760–770. [61] Hawrelak J. Probiotics. Braun L, Cohen M. Herbs and natural supplements. 4th ed. Elsevier: Sydney; 2015:979–994. [62] Skroder HM, Hamadani JD, Tofail F, et al. Selenium status in pregnancy influences children's cognitive function at 1.5 years of age. Clin Nutr. 2015;34(5):923–930. [63] Pieczynska J, Grajeta H. The role of selenium in human conception and pregnancy. J Trace Elem Med Biol. 2015;29:31–38. [64] Rumbold A, Ota E, Nagata C, et al. Vitamin C supplementation in pregnancy. Cochrane Database Syst Rev. 2015;(9) [CD004072]. [65] Al-Garawi A, Carey VJ, Chhabra D, et al. The role of vitamin D in the transcriptional program of human pregnancy. PLoS ONE. 2016;11(10):e0163832. [66] Awker AL, Herbranson AT, Rhee TG, et al. Impact of a vitamin D protocol in pregnancy at an urban women's health clinic. Ann Pharmacother. 2016;50(11):935–941. [67] Grant CC, Crane J, Mitchell EA, et al. Vitamin D supplementation during pregnancy and infancy reduces aeroallergen sensitization: a randomized controlled trial. Allergy. 2016;71(9):1325–1334. [68] Morris SK, Pell LG, Rahman MZ, et al. Maternal vitamin D supplementation during pregnancy and lactation to prevent acute respiratory infections in infancy in Dhaka, Bangladesh (MDARI trial): protocol for a prospective cohort study nested within a randomized controlled trial. BMC Pregnancy Childbirth. 2016;16(1):309. [69] Pludowski P, Holick MF, Pilz S, et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality: a review of recent evidence. Autoimmun Rev. 2013;12(10):976–989. [70] Ley SH, Hanley AJ, Sermer M, et al. Lower dietary vitamin E intake during the second trimester is associated with insulin resistance and hyperglycemia later in pregnancy. Eur J Clin Nutr. 2013;67(11):1154–1156. [71] Conde-Agudelo A, Romero R, Kusanovic JP, et al. Supplementation with vitamins C and E during pregnancy for the prevention of preeclampsia and other adverse maternal and perinatal outcomes: a systematic review and metaanalysis. Am J Obstet Gynecol. 2011;204(6):503.e1–503.e12. [72] Zahiri Sorouri Z, Sadeghi H, Pourmarzi D. The effect of zinc supplementation on pregnancy outcome: a randomized controlled trial. J Matern Fetal Neonatal Med. 2016;29(13):2194–2198. [73] Nossier SA, Naeim NE, El-Sayed NA, et al. The effect of zinc supplementation on pregnancy outcomes: a double-blind, randomised controlled trial, Egypt. Br J Nutr. 2015;114(2):274–285. [74] Smith CH, Teo Y, Simpson S. An observational study of adults with Down syndrome eating independently. Dysphagia. 2014;29(1):52–

60. [75] Reilly D, Huws J, Hastings R, et al. Life and death of a child with Down syndrome and a congenital heart condition: experiences of six couples. Intellect Dev Disabil. 2010;48(6):403–416. [76] van Hooste A, Maes B. Family factors in the early development of children with Down syndrome. J Early Intervention. 2003;25(4):296– 309. [77] Bunt CW, Bunt SK. Role of the family physician in the care of children with Down syndrome. Am Fam Phys. 2014;90(12):851–858. [78] Leonard S, Beaver C, Pegerson B, et al. Survival of infants born with Down's syndrome: 1980–96. Paediatr Perinatal Epidemiol. 2000;14:163–171. [79] Mann JP, Statnikov E, Modi N, et al. Management and outcomes of neonates with Down syndrome admiged to neonatal units. Birth Defects Res A Clin Mol Teratol. 2016;106:468–474. [80] World Health Organization. Breastfeeding. [Available from:] hgps://www.who.int/nutrition/topics/exclusive_breastfeeding/en/; 2016. [81] Australian Breastfeeding Association. Breastfeeding your baby with Down syndrome. [Available from:] hgps://www.breastfeeding.asn.au/bf-info/down; 2015. [82] La Leche League International. Is it possible to breastfeed my baby who was born with Down syndrome?. 2016. [83] Canadian Down Syndrome Society. Breastfeeding a baby with Down syndrome. [Available from:] hgps://www.ndsccenter.org/wpcontent/uploads/CDSS_breastfeeding_brochure.pdf; 2016. [84] Buzunariz Martinez N, Martinez Garcia M. Psychomotor development in children with Down syndrome and physiotherapy in early intervention. Int Med J Down Syndrome. 2008;12(2):28–32. [85] Purpura G, Tinelli F, Bargagna S, et al. Effect of early multisensory massage intervention on visual functions in infants with Down syndrome. Early Hum Dev. 2014;90(12):809–813. [86] Capone GT. Down syndrome: genetic insights and thoughts of early intervention. Infant Young Child. 2004;17(1):45–48. [87] Skeels HM, Dyer HB. A study of the effects of differential stimulation on mentally retarded children. Proc Am Assoc Mental Deficiency. 1939;44(1):114–136 [(Republished in Blacher J, Baker BL (eds). The best of AAMR. Families and mental retardation: a collection of notable AAMR journal articles across the 20th century. Washington DC: American Association on Mental Retardation; 2002, p. 19– 33.)]. [88] Channell MM, Thurman AJ, Kover ST, et al. Pagerns of change in nonverbal cognition in adolescents with Down syndrome. Res Dev Disabil. 2014;35(11):2933–2941. [89] Cardoso AC, Campos AC, Santos MM, et al. Motor performance of children with Down syndrome and typical development at 2 to 4 and 26 months. Pediatr Phys Ther. 2015;27(2):135–141. [90] Melyn MA, White DT. Mental and developmental milestones of noninstitutionalized Down's syndrome children. Pediatrics. 1973;52(4):542–545. [91] Pueschel SM. As cited in: Cohen WI. Down syndrome: care of the child and family. Levine MD, Carey WB, Crocker AC. Developmental-behavioral pediatrics. 3rd ed. WB Saunders: Philadelphia; 1978:241–248. [92] Frank K, Esbensen AJ. Fine motor and self-care milestones for individuals with Down syndrome using a retrospective chart review. J Intellect Disabil Res. 2015;59(8):719–729. [93] Cleland J, Wood S, Hardcastle W, et al. Relationship between speech, oromotor, language and cognitive abilities in children with Down's syndrome. Int J Lang Commun Disord. 2010;45(1):83–95. [94] Koriakin TA, McCurdy MD, Papazoglou A, et al. Classification of intellectual disability using the Wechsler Intelligence Scale for Children: full scale IQ or general abilities index? Dev Med Child Neurol. 2013;55(9):840–845. [95] Log IT, Dierssen M. Cognitive deficits and associated neurological complications in individuals with Down's syndrome. Lancet Neurol. 2010;9(6):623–633. [96] Costanzo F, Varuzza C, Menghini D, et al. Executive functions in intellectual disabilities: a comparison between Williams syndrome and Down syndrome. Res Dev Disabil. 2013;34(5):1770–1780. [97] Trezise KL, Gray KM, Sheppard DM. Agention and vigilance in children with Down syndrome. J App Research Intellect Disabil. 2008;21(6):502–508. [98] Roch M, Florit E, Levorato C. Follow-up study on reading comprehension in Down's syndrome: the role of reading skills and listening comprehension. Int J Lang Commun Disord. 2011;46(2):231–242. [99] de la Iglesia CJF, Buceta JM, Campos A. Prose learning in children and adults with Down syndrome: the use of visual and mental image strategies to improve recall. J Intellect Dev Disabil. 2005;30(4):199–206. [100] Conners FA, Rosenquist CJ, Arneg L, et al. Improving memory span in children with Down syndrome. J Intellect Disabil Res. 2008;52(Pt 3):244–255. [101] Amaral MF, Drummond Ade F, Coster WJ, et al. Household task participation of children and adolescents with cerebral palsy, Down syndrome and typical development. Res Dev Disabil. 2014;35(2):414–422. [102] Van Gameren-Oosterom HB, Fekkes M, Reijneveld SA, et al. Practical and social skills of 16–19-year-olds with Down syndrome: independence still far away. Res Dev Disabil. 2013;34(12):4599–4607. [103] Bouck EC. Reports of life skills training for students with intellectual disabilities in and out of school. J Intellect Disabil Res. 2010;54(12):1093–1103. [104] Buckley S, Bird G, Sacks B, et al. A comparison of mainstream and special education for teenagers with Down syndrome. Down Syndrome Res Pract. 2006;9(3):54–67. [105] Su CY, Lin YH, Wu YY, et al. The role of cognition and adaptive behavior in employment of people with mental retardation. Res Dev Disabil. 2008;29(1):83–95. [106] van Gameren-Oosterom HB, Fekkes M, van Wouwe JP, et al. Problem behavior of individuals with Down syndrome in a nationwide

cohort assessed in late adolescence. J Pediatr. 2013;163(5):1396–1401. [107] Wuang Y, Su CY. Pagerns of participation and enjoyment in adolescents with Down syndrome. Res Dev Disabil. 2012;33(3):841–848. [108] Bertoli M, Biasini G, Calignano MT, et al. Needs and challenges of daily life for people with Down syndrome residing in the city of Rome, Italy. J Intellect Disabil Res. 2011;55(8):801–820. [109] Foley KR, Girdler S, Bouck J, et al. Influence of the environment on participation in social roles for young adults with Down syndrome. PLoS ONE. 2014;9(9):e108413. [110] Verdonschot MM, de Wige LP, Reichrath E, et al. Community participation of people with an intellectual disability: a review of empirical findings. J Intellect Disabil Res. 2009;53(4):303–318. [111] Holwerda A, van der Klink JJ, de Boer MR, et al. Predictors of work participation of young adults with mild intellectual disabilities. Res Dev Disabil. 2013;34(6):1982–1990. [112] Feldman DC. The role of physical disabilities in early career: vocational choice, the school-to-work transition, and becoming established. Hum Res Manag Rev. 2004;14(3):247–274. [113] Sabbatino ED, Macrine SL. Start on success: a model transition program for high school students with disabilities. Preventing School Failure. 2007;52(1):33–39. [114] Wehman P, Chan F, Ditchman N, et al. Effect of supported employment on vocational rehabilitation outcomes of transition-age youth with intellectual and developmental disabilities: a case control study. Intellect Dev Disabil. 2014;52(4):296–310. [115] Danielsson H, Henry L, Messer D, et al. Developmental delays in phonological recoding among children and adolescents with Down syndrome and Williams syndrome. Res Dev Disabil. 2016;55:64–76. [116] Haveman M, Tillman V, Stoppler R, et al. Mobility and public transport use abilities of children and young adults with intellectual disabilities: results from the 3-year Nordhorn Public Transportation Intervention Study. J Pol Pract Intellect Disabil. 2013;10(4):289–299. [117] Furniss KA, Loverseed A, Lippold T, et al. The views of people who care for adults with Down's syndrome and dementia: a service evaluation. Br J Learn Disabil. 2012;40(4):318–327. [118] Read S, Morris H. Living and dying with dignity. The best practice guide to end-of-life care for people with a learning disability. Mecap, The Voice of Learning Disability: London; 2008. [119] McEvoy J, MacHale R, Tierney E. Concept of death and perceptions of bereavement in adults with intellectual disabilities. J Intellect Disabil Res. 2012;56(2):191–203. [120] Hill DA, Gridley G, Cnagingus S, et al. Mortality and cancer incidence among people with Down syndrome. Arch Int Med. 2003;13:705–711. [121] Tracy J. Australians with Down syndrome: health magers. Aus Fam Phys. 2011;40(4):202. [122] Akinci O, Mihci E, Tacoy S, et al. Neutrophil oxidative metabolism in Down syndrome patients with congenital heart defects. Environ Mol Mutagen. 2010;51(1):57–63. [123] Bravo-Valenzuela N, Passarelli MLB, Coates MV, et al. Weight and height recovery in children with Down syndrome and congenital heart disease. Rev Bras Cir Cardiovasc. 2011;26(1):61–68. [124] Dimopoulos K. Kempny A. Patients with Down syndrome and congenital heart disease: survival is improving, but challenges remain. Heart. 2016;102(19):1515–1517. [125] Espinola-Zavaleta N, Soto ME, Romero-Gonzalez A, et al. Prevalence of congenital heart disease and pulmonary hypertension in Down's syndrome: an echocardiographic study. J Cardiovasc Ultrasound. 2015;23(2):72–77. [126] Bergstrom S, Carr H, Petersson G, et al. Trends in congenital heart defects in infants with Down syndrome. Pediatrics. 2016;138(1). [127] Faria PF, Nicolau JAZ, Melek M, et al. Association between congenital heart defects and severe infections in children with Down syndrome. Revista Portuguesa de Cardiologia (English Edition). 2014;33(1):15–18. [128] Flanders L, Tulloh R. Cardiac problems in Down syndrome. Paediatr Child Health. 2011;21(1):25–31. [129] Alsaied T, Marino BS, Esbensen AJ, et al. Does congenital heart disease affect neurodevelopmental outcomes in children with Down syndrome? Congen Heart Dis. 2016;11(1):26–33. [130] Visootsak J, Hess B, Bakeman R, et al. Effect of congenital heart defects on language development in toddlers with Down syndrome. J Intellect Disabil Res. 2013;57(9):887–892. [131] Visootsak J, Mahle WT, Kirshbom PM, et al. Neurodevelopmental outcomes in children with Down syndrome and congenital heart defects. Am J Med Genet A. 2011;155A(11):2688–2691. [132] Roussot MA, Lawrenson JB, Hewitson J, et al. Is cardiac surgery warranted in children with Down syndrome? S Afr Med J. 2006;96(9):924–930. [133] Fudge JC Jr, Li S, Jaggers J, et al. Congenital heart surgery outcomes in Down syndrome: analysis of a national clinical database. Pediatrics. 2010;126(2):315–322. [134] Real de Asua D, Quero M, Moldenhauer F, et al. Clinical profile and main comorbidities of Spanish adults with Down syndrome. Eur J Intern Med. 2015;26(6):385–391. [135] Goi G, Baquero-Herrera C, Licastro F, et al. Advanced oxidation protein products (AOPP) and high-sensitive C-reactive protein (hsCRP) in an ‘atheroma-free model’: Down's syndrome. Int J Cardiol. 2006;113(3):427–429. [136] Baraona F, Gurvio M, Landzberg MJ, et al. Hospitalizations and mortality in the United States for adults with Down syndrome and congenital heart disease. Am J Cardiol. 2013;111(7):1046–1051. [137] de Moura CP, Andrade D, Cunha LM, et al. Down syndrome: otolaryngological effects of rapid maxillary expansion. J Laryngol Otol. 2008;122(12):1318–1324. [138] Barankin B, Guenther L. Dermatological manifestations of Down's syndrome. J Cutan Med Surg. 2001;5(4):289–293. [139] Bates B. Skin and mucosal conditions prevalent in Down syndrome (Clinical Rounds). Skin Allergy News. 2005;36(4). [140] Madan V, Williams J, Lear JT. Dermatological manifestations of Down's syndrome. Clin Exp Dermatol. 2006;31(5):623–629.

[141] Schepis C, Barone C, Siragusa M, et al. An updated survey on skin conditions in Down syndrome. Dermatology. 2002;205(3):234–238. [142] Daneshpazhooh M, Nazemi TM, Bigdeloo L, et al. Mucocutaneous findings in 100 children with Down syndrome. Pediatr Dermatol. 2007;24(3):317–320. [143] McDowell KM, Craven DI. Pulmonary complications of Down syndrome during childhood. J Pediatr. 2011;158(2):319–325. [144] Weijerman ME, Brand PL, van Furth MA, et al. Recurrent wheeze in children with Down syndrome: is it asthma? Acta Paediatr. 2011;100(11):e194–7. [145] Zachariah P, Rugenber M, Simoes EA. Down syndrome and hospitalizations due to respiratory syncytial virus: a population-based study. J Pediatr. 2012;160(5):827–831 [e1]. [146] Stagliano DR, Nylund CM, Eide MB, et al. Children with Down syndrome are high-risk for severe respiratory syncytial virus disease. J Pediatr. 2015;166(3):703–709 [e2]. [147] Mannan SE, Yousef E, Hossain J. Prevalence of positive skin prick test results in children with Down syndrome: a case-control study. Ann Allergy Asthma Immunol. 2009;102(3):205–209. [148] Carlstedt K, Henningsson G, Dahllöf G. A four-year longitudinal study of palatal plate therapy in children with Down syndrome: effects on oral motor function, articulation and communication preferences. Acta Odontol Scand. 2009;61(1):39–46. [149] Barr E, Dungworth J, Hunter K, et al. The prevalence of ear, nose and throat disorders in preschool children with Down's syndrome in Glasgow. Sco` Med J. 2011;56(2):98–103. [150] Hellstrom S, Groth A, Jorgensen F, et al. Ventilation tube treatment: a systematic review of the literature. Otolaryngol Head Neck Surg. 2011;145(3):383–395. [151] Maris M, Verhulst S, Wojciechowski M, et al. Sleep problems and obstructive sleep apnea in children with Down syndrome, an overview. Int J Pediatr Otorhinolaryngol. 2016;82:12–15. [152] Venekamp RP, Hearne BJ, Chandrasekharan D, et al. Tonsillectomy or adenotonsillectomy versus non-surgical management for obstructive sleep-disordered breathing in children. Cochrane Database Syst Rev. 2015;(10) [CD011165]. [153] Chin CJ, Khami MM, Husein M. A general review of the otolaryngologic manifestations of Down syndrome. Int J Pediatr Otorhinolaryngol. 2014;78(6):899–904. [154] Kiani R, Miller H. Sensory impairment and intellectual disability. Adv Psychiatric Treat. 2010;16(3):228–235. [155] Musat MD, Zah L, Danciulescu R, et al. The endocrine and metabolic profile in adult patients with Down syndrome. The Endocrine Society's 93rd Annual Meeting & Expo, 4–7 June 2011, Boston. [156] Campos C, Guzman R, Lopez-Fernandez E, et al. Evaluation of urinary biomarkers of oxidative/nitrosative stress in adolescents and adults with Down syndrome. Biochim Biophys Acta. 2011;1812(7):760–768. [157] Cento RM, Raqusa L, Proto C, et al. Basal body temperature curves and endocrine pagern of menstrual cycles in Down syndrome. Gynecol Endocrinol. 1996;10(2):133–137. [158] Suzuki K, Nakajima K, Kamimura S, et al. Eight case reports on sex-hormone profiles in sexually mature male Down syndrome. Int J Urol. 2010;17(12):1008–1010. [159] Eisermann MM, DeLaRaillère A, Dellatolas G, et al. Infantile spasms in Down syndrome: effects of delayed anticonvulsive treatment. Epilepsy Res. 2003;55:1–2. [160] Meeus M, Kenis S, Wojciechowski M, et al. Epilepsy in children with Down syndrome: not so benign as generally accepted. Acta Neurol Belgica. 2015;115(4):569–573. [161] Shimakawa S, Tanabe T, Ono M, et al. Incidence of febrile seizure in patients with Down syndrome. Pediatr Int. 2015;57(4):670–672. [162] Goldberg-Stern H, Strawsberg RH, Peagerson B, et al. Seizure frequency and characteristics in children with Down syndrome. Brain Dev. 2001;23(6):375–378. [163] Lee J, Lee JH, Yu HJ, et al. Prognostic factors of infantile spasms: role of treatment options including a ketogenic diet. Brain Dev. 2013;35(8):821–826. [164] Ulate-Campos A, Nascimento A, Ortez C. Down's syndrome and epilepsy. International Medical Review on Down Syndrome. 2014;18(1):3–8. [165] Chang P, Zuckermann AM, Williams S, et al. Seizure control by derivatives of medium chain fagy acids associated with the ketogenic diet show novel branching-point structure for enhanced potency. J Pharmacol Exp Ther. 2015;352(1):43–52. [166] Henderson CB, Filloux FM, Alder SC, et al. Efficacy of the ketogenic diet as a treatment option for epilepsy: meta-analysis. J Child Neurol. 2006;21(3):193–198. [167] Hong AM, Turner Z, Hamdy RF, et al. Infantile spasms treated with the ketogenic diet: prospective single-center experience in 104 consecutive infants. Epilepsia. 2010;51(8):1403–1407. [168] Kang HC, Lee YJ, Lee JS, et al. Comparison of short- versus long-term ketogenic diet for intractable infantile spasms. Epilepsia. 2011;52(4):781–787. [169] Kayyali HR, Gustafson M, Myers T, et al. Ketogenic diet efficacy in the treatment of intractable epileptic spasms. Pediatr Neurol. 2014;50(3):224–227. [170] Kossoff EH, Hedderick EF, Turner Z, et al. A case-control evaluation of the ketogenic diet versus ACTH for new-onset infantile spasms. Epilepsia. 2008;49(9):1504–1509. [171] Pires ME, Ilea A, Bourel E, et al. Ketogenic diet for infantile spasms refractory to first-line treatments: an open prospective study. Epilepsy Res. 2013;105(1–2):189–194. [172] Hussain SA, Shin JH, Shih EJ, et al. Limited efficacy of the ketogenic diet in the treatment of highly refractory epileptic spasms. Seizure. 2016;35:59–64. [173] Caraballo R, Vaccarezza M, Cersosimo R, et al. Long-term follow-up of the ketogenic diet for refractory epilepsy: multicenter Argentinean experience in 216 pediatric patients. Seizure. 2011;20(8):640–645.

[174] Barca D, Tarta-Asene O, Dica A, et al. Intellectual disability and epilepsy in Down syndrome. Maedica. 2014;9(4):344. [175] Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013;29(3):574–577. [176] Detyniecki K, Hirsch L. Marijuana use in epilepsy: the myth and the reality. Curr Neurol Neurosci Rep. 2015;15(10):65. [177] Gross DW, Hamm J, Ashworth NL, et al. Marijuana use and epilepsy: prevalence in patients of a tertiary care epilepsy center. Neurology. 2004;62(11):2095–2097. [178] Jones NA, Glyn SE, Akiyama S, et al. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012;21(5):344–352. [179] Kolikonda MK, Srinivasan K, Manasa E, et al. Medical marijuana for epilepsy? Innov Clin Neurosci. 2015;13. [180] Rosemergy I, Adler J, Psirides A. Cannabidiol oil in the treatment of super refractory status epilepticus. A case report. Seizure. 2016;35:56–58. [181] Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014;55(6):783–786. [182] Mehla J, Reeta KH, Gupta P, et al. Protective effect of curcumin against seizures and cognitive impairment in a pentylenetetrazolekindled epileptic rat model. Life Sci. 2010;87(19–22):596–603. [183] DeGiorgio CM, Miller PR, Harper R, et al. Fish oil (n-3 fagy acids) in drug resistant epilepsy: a randomised placebo-controlled crossover study. J Neurol Neurosurg Psychiatr. 2015;86(1):65–70. [184] Khayat H, Awadalla M, Waked A. Marzook Z. Polyunsaturated fagy acids in children with idiopathic intractable epilepsy serum levels and therapeutic response. J Pediatr Neurol. 2010;8:175–178. [185] Reda DM, Abd-El-Fatah NK, Omar Tel S, et al. Fish oil intake and seizure control in children with medically resistant epilepsy. N Am J Med Sci. 2015;7(7):317–321. [186] Schlanger S, Shinioky M, Yam D. Diet enriched with omega-3 fagy acids alleviates convulsion symptoms in epilepsy patients. Epilepsia. 2002;43(2):103–104. [187] Osborn KE, Shytle RD, Frontera AT, et al. Addressing potential role of magnesium dyshomeostasis to improve treatment efficacy for epilepsy: a reexamination of the literature. J Clin Pharmacol. 2016;56(3):260–265. [188] Yuen AW, Sander JW. Can magnesium supplementation reduce seizures in people with epilepsy? A hypothesis. Epilepsy Res. 2012;100(1–2):152–156. [189] Prasad DK, Shaheen U, Satyanarayana U, et al. Association of serum trace elements and minerals with genetic generalized epilepsy and idiopathic intractable epilepsy. Neurochem Res. 2014;39(12):2370–2376. [190] Espinosa PS, Perez DL, Abner E, et al. Association of antiepileptic drugs, vitamin D, and calcium supplementation with bone fracture occurrence in epilepsy patients. Clin Neurol Neurosurg. 2011;113(7):548–551. [191] Jo BW, Shim YJ, Choi JH, et al. Formula fed twin infants with recurrent hypocalcemic seizures with vitamin D deficient rickets and hyperphosphatemia. Ann Pediatr Endocrinol Metab. 2015;20(2):102–105. [192] Mantadakis E, Deftereos S, Tsouvala E, et al. Seizures as initial manifestation of vitamin D-deficiency rickets in a 5-month-old exclusively breastfed infant. Pediatr Neonatol. 2012;53(6):384–386. [193] Ashrafi MR, Shabanian R, Abbaskhanian A, et al. Selenium and intractable epilepsy: is there any correlation? Pediatr Neurol. 2007;36(1):25–29. [194] Naziroglu M. Role of selenium on calcium signaling and oxidative stress-induced molecular pathways in epilepsy. Neurochem Res. 2009;34(12):2181–2191. [195] Seven M, Basaran SY, Cengiz M, et al. Deficiency of selenium and zinc as a causative factor for idiopathic intractable epilepsy. Epilepsy Res. 2013;104(1–2):35–39. [196] Solovyev ND. Importance of selenium and selenoprotein for brain function: from antioxidant protection to neuronal signalling. J Inorg Biochem. 2015;153:1–12. [197] Wojciak RW, Mojs E, Stanislawska-Kubiak M, et al. The serum zinc, copper, iron, and chromium concentrations in epileptic children. Epilepsy Res. 2013;104(1–2):40–44. [198] Calabro RS, Italiano D, Gervasi G, et al. Single tonic-clonic seizure after energy drink abuse. Epilepsy Behav. 2012;23(3):384–385. [199] Kaufman KR, Sacdeo RC. Caffeinated beverages and decreased seizure control. Seizure. 2003;12(7):519–521. [200] Moore JL. The significance of folic acid for epilepsy patients. Epilepsy Behav. 2005;7(2):172–181. [201] Morrell MJ. Folic acid and epilepsy. Epilepsy Curr. 2002;2:31–34. [202] Baynes K, Tomaszewski Farias S, Gospe S. Pyridoxine-dependent seizures and cognition in adulthood. Devel Med Child Neurol. 2003;45(11):782–785. [203] Gospe SM. Current perspectives on pyridoxine-dependent seizures. J Pediatr. 1998;132(6):919–923. [204] Lee D, Lee YJ, Shin H, et al. Seizures related to vitamin B6 deficiency in adults. J Epilepsy Res. 2015;5:23–24. [205] Ohtahara S, Yamatogi Y, Ohtsuka Y, et al. Vitamin B6 treatment of intractable seizures. Brain Dev. 2011;33(9):783–789. [206] Ohtsuka Y, Ogino T, Asano T, et al. Long-term follow-up of vitamin B6-responsive West syndrome. Pediatr Neurol. 2000;23(3):202– 206. [207] Stockler S, Plecko B, Gospe SM Jr, et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab. 2011;104(1–2):48–60. [208] Benbir G, Uysal S, Saltik S, et al. Seizures during treatment of vitamin B12 deficiency. Seizure. 2007;16(1):69–73. [209] Gonzalez-Ramirez M, Razo-Juarez LI, Sauer-Ramirez JL, et al. Anticonvulsive effect of vitamin C on pentylenetetrazol-induced seizures in immature rats. Pharmacol Biochem Behav. 2010;97(2):267–272. [210] Santos LF, Freitas RL, Xavier SM, et al. Neuroprotective actions of vitamin C related to decreased lipid peroxidation and increased catalase activity in adult rats after pilocarpine-induced seizures. Pharmacol Biochem Behav. 2008;89(1):1–5.

[211] Basatemur E, Sutcliffe A. Incidence of hypocalcemic seizures due to vitamin D deficiency in children in the United Kingdom and Ireland. J Clin Endocrinol Metab. 2015;100(1):E91–5. [212] Hollo A, Clemens Z, Kamondi A, et al. Correction of vitamin D deficiency improves seizure control in epilepsy: a pilot study. Epilepsy Behav. 2012;24(1):131–133. [213] Teagarden DL, Meador KJ, Loring DW. Low vitamin D levels are common in patients with epilepsy. Epilepsy Res. 2014;108(8):1352– 1356. [214] Mehvari J, Motlagh FG, Najafi M, et al. Effects of vitamin E on seizure frequency, electroencephalogram findings, and oxidative stress status of refractory epileptic patients. Adv Biomed Res. 2016;5:36. [215] Saghazadeh A, Mahmoudi M, Meysamie A, et al. Possible role of trace elements in epilepsy and febrile seizures: a meta-analysis. Nutr Rev. 2015;73(11):760–779. [216] d'Orsi G, Specchio LM. Apulian Study Group on Senile Myoclonic E. Progressive myoclonus epilepsy in Down syndrome patients with dementia. J Neurol. 2014;261(8):1584–1597. [217] De Simone R, Puig XS, Gelisse P, et al. Senile myoclonic epilepsy: delineation of a common condition associated with Alzheimer's disease in Down syndrome. Seizure. 2010;19(7):383–389. [218] Sangani M, Shahid A, Amina S, et al. Improvement of myoclonic epilepsy in Down syndrome treated with levetiracetam. Epileptic Disord. 2010;12(2):151–154. [219] Scorza CA, Scorza FA, Arida RM, et al. Sudden unexpected death in people with Down syndrome and epilepsy. Clinics. 2011;66(5):719–720. [220] Nardone R, Brigo F, Trinka E. Acute symptomatic seizures caused by electrolyte disturbances. J Clin Neurol. 2016;12(1):21–33. [221] Mazurek D, Wyka J. Down syndrome-genetic and nutritional aspects of accompanying disorders. Roczniki Państwowego Zakl Hig. 2015;66(3). [222] Souto-Rodríguez R, Barreiro-de-Acosta M, Domínguez-Muñoz JE. Down's syndrome and inflammatory bowel disease: is there a real link. Rev Esp Enferm Dig. 2014;106:220–222. [223] Viegelmann G, Low Y, Sriram B, et al. Achalasia and Down syndrome: a unique association not to be missed. Singapore Med J. 2014;55(7):e107–8. [224] Maloney KW, Taub JW, Ravindranath Y, et al. Down syndrome preleukemia and leukemia. Pediatr Clin North Am. 2015;62(1):121–137. [225] Tsimaras VK, Fotiadou EG. Effect of training on the muscle strength and dynamic balance ability of adults with Down syndrome. J Strength Cond Res. 2004;18(2):343–347. [226] Malak R, Kotwicka M, Krawczyk-Wasielewska A, et al. Motor skills, cognitive development and balance functions of children with Down syndrome. Ann Agricul Environ Med. 2013;20(4):803–806. [227] Cabeza-Ruiz R, Garcia-Masso X, Centeno-Prada RA, et al. Time and frequency analysis of the static balance in young adults with Down syndrome. Gait Posture. 2011;33(1):23–28. [228] Davies RB. Pain in children with Down syndrome: assessment and intervention by parents. Pain Manag Nurs. 2010;11(4):259–267. [229] Valkenburg AJ, Tibboel D, van Dijk M. Pain sensitivity of children with Down syndrome and their siblings: quantitative sensory testing versus parental reports. Dev Med Child Neurol. 2015;57(11):1049–1055. [230] Mafrica F, Schifilliti D, Fodale V. Pain in Down's syndrome. Sci World J. 2006;6:140–147. [231] Hennequin M, Morin C, Feine JS. Pain expression and stimulus localisation in individuals with Down's syndrome. Lancet. 2000;356(9245):1882–1887. [232] Dykens E, Shah B, Davis B, et al. Psychiatric disorders in adolescents and young adults with Down syndrome and other intellectual disabilities. J Neurodev Dis. 2015;7(1). [233] Prasher V. Disintegrative syndrome in young adults. Irish J Psychol Med. 2014;19(03):101. [234] Garvía B, Benejam B. Regression in young adults with Down's syndrome. A three cases review. Int Med Rev Down Syndrome. 2014;18(3):43–46. [235] Myers B, Pueschel SM. Major depression in a small group of adults with Down syndrome. Res Dev Disabil. 1995;16(4):285–299. [236] Walker JC, Dosen A, Buitelaar JK, et al. Depression in Down syndrome: a review of the literature. Res Dev Disabil. 2011;32(5):1432– 1440. [237] Evans DW, Canavera K, Kleinpeter FL, et al. The fears, phobias and anxieties of children with autism spectrum disorders and Down syndrome: comparisons with developmentally and chronologically age matched children. Child Psychiatry Hum Dev. 2005;36(1):3–26. [238] Glenn S, Cunningham C, Nananidou A, et al. Routinised and compulsive-like behaviours in individuals with Down syndrome. J Intellect Disabil Res. 2015;59(11):1061–1070. [239] Uljarevic M, Evans DW. Relationship between repetitive behaviour and fear across normative development, autism spectrum disorder, and down syndrome. Autism Res. 2016. [240] Luke A, Roizen NJ, Sugon M, et al. Energy expenditure in children with Down syndrome: correcting metabolic rate for movement. J Pediatr. 1994;125(5):829–838. [241] Esposito PE, MacDonald M, Hornyak JE, et al. Physical activity pagerns of youth with Down syndrome. Intellect Dev Disabil. 2012;50(2):109–119. [242] Kota SK, Tripathy PR, Kota SK, et al. Type 2 diabetes mellitus: an unusual association with Down's syndrome. Indian J Hum Genet. 2013;19(3):358–359. [243] Curtin C, Bandini LG, Must A, et al. Parent support improves weight loss in adolescents and young adults with Down syndrome. J Pediatr. 2013;163(5):1402–1408.e1. [244] Jinks A, Cogon A, Rylance R. Obesity interventions for people with a learning disability: an integrative literature review. J Adv Nurs. 2011;67(3):460–471.

[245] Kirk SF, Penney TL, McHugh TL, et al. Effective weight management practice: a review of the lifestyle intervention evidence. Int J Obes (Lond). 2012;36(2):178–185. [246] Melville CA, Boyle S, Miller S, et al. An open study of the effectiveness of a multi-component weight-loss intervention for adults with intellectual disabilities and obesity. Br J Nutr. 2011;105(10):1553–1562. [247] Johnson C, Hobson S, Garcia AC, et al. Nutrition and food skills education: for adults with developmental disabilities. Canadian J Diet Prac Res. 2011;72(1):7–13. [248] Robinson KT, Butler J. Understanding the causal factors of obesity using the International Classification of Functioning, Disability and Health. Disabil Rehabil. 2011;33(8):643–651. [249] Slevin E, Northway R. Health promotion for people with intellectual and developmental disabilities. Open University Press/McGraw-Hill Education: Berks, UK; 2014. [250] Rigoldi C, Galli M, Albertini G. Gait development during lifespan in subjects with Down syndrome. Res Dev Disabil. 2011;32(1):158– 163. [251] Wang HY, Long IM, Liu MF. Relationships between task-oriented postural control and motor ability in children and adolescents with Down syndrome. Res Dev Disabil. 2012;33(6):1792–1798. [252] Villarroya MA, Gonzalez-Aguero A, Moros-Garcia T, et al. Static standing balance in adolescents with Down syndrome. Res Dev Disabil. 2012;33(4):1294–1300. [253] Dedlow ER, Siddiqi S, Fillipps DJ, et al. Symptomatic atlantoaxial instability in an adolescent with trisomy 21 (Down's syndrome). Clin Pediatr. 2013;52(7):633–638. [254] Leas D. Atlantoaxial instability. [Medscape; Available from:] hgp://emedicine.medscape.com/article/1265682-overview#a3; 2015. [255] Alvarez N. Atlantoaxial instability in Down syndrome. [Medscape; Available from:] hgp://emedicine.medscape.com/article/1180354overview#a6; 2016. [256] Goelz T, Butler M, Lee PDK, et al. Motor developmental interventions. Butler M, Lee PDK, Whitman BY. Management of Prader-Willi syndrome. Springer: USA; 2006. [257] Pau M, Galli M, Crivellini M, et al. Foot-ground interaction during upright standing in children with Down syndrome. Res Dev Disabil. 2012;33(6):1881–1887. [258] de Hingh YC, van der Vossen PW, Gemen EF, et al. Intrinsic abnormalities of lymphocyte counts in children with Down syndrome. J Pediatr. 2005;147(6):744–747. [259] Carsegi R, Valentini D, Marcellini V, et al. Reduced numbers of switched memory B cells with high terminal differentiation potential in Down syndrome. Europ J Immunol. 2015;45(3):903–914. [260] Bloemers BLP, van Bleek GM, Kimpen JLL, et al. Distinct abnormalities in the innate immune system of children with Down syndrome. J Pediatr. 2005;156(5). [261] Ugazio AG, Maccario R, Notarangelo LD, et al. Immunology of Down syndrome: a review. Am J Med Genet. 1990;37(S7):204–212. [262] Jakubiuk-Tomaszuk A, Sobaniec W, Rusak M, et al. Decrease of interleukin (IL)17A gene expression in leucocytes and in the amount of IL-17A protein in CD4+ T cells in children with Down syndrome. Pharmacol Rep. 2015;67(6):1130–1134. [263] Kusters MAA, Verstegen RHJ, de Vries E. Down syndrome: is it really characterized by precocious immunosenescence? Aging Dis. 2014;2(6):538–545. [264] Verstegen RH, Driessen GJ, Bartol SJ, et al. Defective B-cell memory in patients with Down syndrome. J Allergy Clin Immunol. 2014;134(6):1346–1353.e9. [265] Hioler JK. Acute megakaryoblastic leukemia in Down syndrome. Pediatr Blood Cancer. 2007;49(S7):1066–1069. [266] Arico M, Ziino O, Valsecchi MG, et al. Acute lymphoblastic leukemia and Down syndrome: presenting features and treatment outcome in the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Cancer. 2008;113(3):515–521. [267] Goto H, Kaneko T, Shioda Y, et al. Hematopoietic stem cell transplantation for patients with acute lymphoblastic leukemia and Down syndrome. Pediatr Blood Cancer. 2015;62(1):148–152. [268] Linabery AM, Li W, Roesler MA, et al. Immune-related conditions and acute leukemia in children with Down syndrome: a Children's Oncology Group report. Cancer Epidemiol Biomarkers Prev. 2015;24(2):454–458. [269] Roncadin C, Hioler J, Downie A, et al. Neuropsychological late effects of treatment for acute leukemia in children with Down syndrome. Pediatr Blood Cancer. 2015;62(5):854–858. [270] Revuelta Iniesta R, Rush R, Paciarogi I, et al. Systematic review and meta-analysis: prevalence and possible causes of vitamin D deficiency and insufficiency in pediatric cancer patients. Clin Nutr. 2016;35(1):95–108. [271] Al-Nawakil C, Park S, Chapuis N, et al. Salvage therapy of autoimmune thrombocytopenic purpura revealing non-Hodgkin lymphoma by the thrombopoietin receptor agonist romiplostim. Br J Haematol. 2012;156(1):145–147. [272] Lee HJ, Muindi JR, Tan W, et al. Low 25(OH) vitamin D3 levels are associated with adverse outcome in newly diagnosed, intensively treated adult acute myeloid leukemia. Cancer. 2014;120(4):521–529. [273] Radujkovic A, Schnioler P, Ho AD, et al. Low serum vitamin D levels are associated with shorter survival after first-line azacitidine treatment in patients with myelodysplastic syndrome and secondary oligoblastic acute myeloid leukemia. Clin Nutr. 2016. [274] Aitken RJ, Mehers KL, Williams AJ, et al. Early-onset, coexisting autoimmunity and decreased HLA-mediated susceptibility are the characteristics of diabetes in Down syndrome. Diabetes Care. 2013;36(5):1181–1185. [275] Gimenez-Barcons M, Casteras A, Armengol M, et al. Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens. J Immunol. 2014;193(8):3872–3879. [276] Claret-Torrents C, Goday-Arno A, Cerda-Esteve M, et al. Hyperthyroidism in Down syndrome. Int Med J Down Syndrome. 2009;13(1):2–8. [277] Kariyawasam D, Carre A, Luton D, et al. Down syndrome and nonautoimmune hypothyroidisms in neonates and infants. Horm Res

Paediatr. 2015;83(2):126–131. [278] Leger J, Olivieri A, Donaldson M, et al. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metab. 2014;99(2):363–384. [279] Goday-Arno A, Cerda-Esteva M, Flores-Le-Roux JA, et al. Hyperthyroidism in a population with Down syndrome (DS). Clin Endocrinol. 2009;71(1):110–114. [280] De Luca F, Corrias A, Salerno M, et al. Peculiarities of Graves’ disease in children and adolescents with Down's syndrome. Eur J Endocrinol. 2010;162(3):591–595. [281] Popova G, Paterson WF, Brown A, et al. Hashimoto's thyroiditis in Down's syndrome: clinical presentation and evolution. Horm Res. 2008;70(5):278–284. [282] King K, O'Gorman C, Gallagher S. Thyroid dysfunction in children with Down syndrome: a literature review. Ir J Med Sci. 2014;183(1):1–6. [283] Tenenbaum A, Lebel E, Malkiel S, et al. Euthyroid submedian free T4 and subclinical hypothyroidism may have a detrimental clinical effect in Down syndrome. Horm Res Paediatr. 2012;78(2):113–118. [284] Bhat AS, Chaturvedi MK, Saini S, et al. Prevalence of celiac disease in Indian children with Down syndrome and its clinical and laboratory predictors. Indian J Pediatr. 2013;80(2):114–117. [285] Tonugi E, Bizzaro N. Diagnosis and classification of celiac disease and gluten sensitivity. Autoimmun Rev. 2014;13(4–5):472–476. [286] Carlsson A, Axelsson I, Bourulf S, et al. Prevalence of IgA-antigliadin antibodies and IgA-antiendomysium antibodies related to celiac disease in children with Down syndrome. Pediatrics. 1998;101(2):272–275. [287] Costa Gomes R, Cerqueira Maia J, Fernando Arrais R, et al. The celiac iceberg: from the clinical spectrum to serology and histopathology in children and adolescents with type 1 diabetes mellitus and Down syndrome. Scand J Gastroenterol. 2016;51(2):178– 185. [288] George EK, Mearin ML, Bouquet J, et al. High frequency of celiac disease in Down syndrome. J Pediatr. 1996;128:4. [289] Martinez AR, Jaime BE, Lopez AG, et al. Coeliac disease profile in Down syndrome patients. Int Med Rev Down Syndrome. 2010;14(1):3–9. [290] Szaflarska-Poplawska A, Soroczynska-Wrzyszcz A, Barg E, et al. Assessment of coeliac disease prevalence in patients with Down syndrome in Poland: a multi-centre study. Prz Gastroenterol. 2016;11(1):41–46. [291] Wouters J, Weijerman ME, Van Furth MA, et al. Prospective human leukocyte antigen, endomysium immunoglobulin A antibodies, and transglutaminase antibodies testing for celiac disease in children with Down syndrome. J Pediatr. 2009;154(2):239–242. [292] Mårild K, Stephansson O, Grahnquist L, et al. Down syndrome is associated with elevated risk of celiac disease: a nationwide casecontrol study. J Pediatr. 2013;163(1):237–242. [293] Csizmadia CG, Mearin ML, Oren A, et al. Accuracy and cost-effectiveness of a new strategy to screen for celiac disease in children with Down syndrome. J Pediatr. 2000;137(6):756–761. [294] Cogulu O, Ozikinay F, Gunduz C, et al. Celiac disease in children with Down syndrome: importance of follow-up and serologic screening. Pediatr Int. 2003;45(4):395–399. [295] Hansson T, Dahlbom I, Rogberg S, et al. Antitissue transglutaminase and antithyroid autoantibodies in children with Down syndrome and celiac disease. J Pediatr Gastroenterol Nutr. 2005;40(2):170–174. [296] Langguth D. Coeliac disease testing recommendations. [Sullivan Nicolaides; Available from:] www.snp.com.au/media/274287/coeliac_disease_testing_recommendations.pdf; 2012. [297] Shamaly H, Hartman C, Pollack S, et al. Tissue transglutaminase antibodies are a useful serological marker for the diagnosis of celiac disease in patients with Down syndrome. J Pediatr Gastroenterol Nutr. 2007;44(5):583–586. [298] Depince-Berger A, Cremilieux C, Rinaudo-Gaujous M, et al. A difficult and rare diagnosis of autoimmune enteropathy in a patient affected by Down syndrome. J Clin Immunol. 2016;36(5). [299] Soderbergh A, Gustafsson J, Ekwall O, et al. Autoantibodies linked to autoimmune polyendocrine syndrome type I are prevalent in Down syndrome. Acta Paediatr. 2006;95(12):1657–1660. [300] Gillespie KM, Dix RJ, Williams AJK, et al. Islet autoimmunity in children with Down's syndrome. Diabetes. 2006;55(11):3185–3188. [301] Estefan J, Queriroz M, Costa F, et al. Clinical characteristics of alopecia areata in Down syndrome. Acta Dermatovenerol Croat. 2014;21(4):253–258. [302] Alves R, Ferrando J. Alopecia areata in Down's syndrome. Int Med Rev Down Syndrome. 2011;15(3):34–36. [303] da Rosa Utiyama S, Nisihara R, Nass FR, et al. Autoantibodies in patients with Down syndrome: early senescence of the immune system or precocious markers for immunological diseases? J Paediatr Child Health. 2008;44(4):182–186. [304] Roizen N, Pagerson D. Down's syndrome. Lancet. 2003;361:1281–1289. [305] Juj H, Emery H. The arthropathy of Down syndrome: an underdiagnosed and under-recognized condition. J Paediatr. 2009;154(2):234–238. [306] Naess KA. Development of phonological awareness in Down syndrome: a meta-analysis and empirical study. Dev Psychol. 2016;52(2):177–190. [307] Laws G, Hall A. Early hearing loss and language abilities in children with Down syndrome: early hearing loss and language abilities in children with DS. Int J Lang Commun Disord. 2014;49(3):333–342. [308] Diaz F. Zurron M. Auditory evoked potentials in Down's syndrome. Electroencephalogr Clin Neurophysiol. 1995;96:526–537. [309] Blaser S, Propst EJ, Martin D, et al. Inner ear dysplasia is common in children with Down syndrome (trisomy 21). Laryngoscope. 2006;116(12):2113–2119. [310] Park AH, Wilson MA, Stevens PT, et al. Identification of hearing loss in pediatric patients with Down syndrome. Otolaryngol Head Neck Surg. 2012;146(1):135–140.

[311] Downes A, Anixt JS, Esbensen AJ, et al. Psychotropic medication use in children and adolescents with Down syndrome. J Devel Behav Pediatr. 2015;36(8):613–619. [312] Kerins G, Petrovic K, Bruder M, et al. Medical conditions and medication use in adults with Down syndrome: a descriptive analysis. Down Syndrome Res Pract. 2008;12(2):141–147. [313] Maticka-Tyndale E. Sexual Health for the millennium. A declaration and technical document. Int J Sexual Health. 2008;20:1. [314] Hollomoo A. ‘May we please have sex tonight?’ People with learning difficulties pursuing privacy in residential group segings. Br J Learn Disabil. 2009;37(2):91–97. [315] Young R, Gore N, McCarthy M. Staff agitudes towards sexuality in relation to gender of people with intellectual disability: a qualitative study. J Intellect Dev Disabil. 2012;37(4):343–347. [316] Diekema DS. Involuntary sterilization of persons with mental retardation: an ethical analysis. Ment Retard Dev Disabil Res Rev. 2003;9(1):21–26. [317] Senate Community Affairs Commigee Secretariat, Holland I, McInally G, et al. Involuntary or coerced sterilisation of people with disabilities in Australia. Commonwealth of Australia: Canberra, ACT; 2013. [318] Lockhart K, Guerin S, Shanahan S, et al. Expanding the test of counterfeit deviance: are sexual knowledge, experience and needs a factor in the sexualised challenging behaviour of adults with intellectual disability? Res Dev Disabil. 2010;31(1):117–130. [319] Griffiths D, Hingsburger D, Hoath J, et al. ‘Counterfeit deviance’ revisited. J Appl Res Intell Disabil. 2013;26(5):471–480. [320] World Health Organization (WHO). Promoting sexual and reproductive health for persons with disabilities: WHO/UNFPA guidance note. WHO: Geneva; 2009. [321] Eastgate G, Schreermeyer E, van Driel ML, et al. Intellectual disability, sexuality and sexual abuse prevention: a study of family members and support workers. Aus Fam Phys. 2012;41(3):135. [322] Gill M. Rethinking sexual abuse, questions of consent, and intellectual disability. Sex Res Soc Policy. 2010;7(3):201–213. [323] Burke L, Bedard C, Ludwig S. Dealing with sexual abuse of adults with a developmental disability who also have impaired communication: supportive procedures for detection, disclosure and follow up. Can J Human Sexual. 1998;7(1):79–91. [324] McElduff A, Center J, Beange H. Hypogonadism in men with intellectual disabilities: a population study. J Intellect Dev Disabil. 2003;28(2):163–170. [325] Bobrow M, Barby T, Hajianpour A, et al. Fertility in a male with trisomy 21. J Med Genet. 1992;29(2):141. [326] Sheridan R, Llerena J, Matkins S, et al. Fertility in a male with trisomy 21. J Med Genet. 1989;26(5):294–298. [327] Zühlke C, Thies U, Braulke I, et al. Down syndrome and male fertility: PCR-derived fingerprinting, serological and andrological investigations. Clin Genet. 1994;46(4):324–326. [328] Chew G, Hutson JM. Incidence of cryptorchidism and ascending testes in trisomy 21: a 10-year retrospective review. Pediatr Surg Int. 2004;20(10):744–747. [329] Dada R, Kumar R, Kucheria K. A 2-year-old baby with Down syndrome, cryptorchidism and testicular tumour. Eur J Med Genet. 2006;49(3):265–268. [330] Wilson NJ, Cumella S, Parmenter TR, et al. Penile hygiene: puberty, paraphimosis and personal care for men and boys with an intellectual disability. J Intellect Disabil Res. 2009;53(2):106–114. [331] Goede J, Weijerman ME, Broers CJ, et al. Testicular volume and testicular microlithiasis in boys with Down syndrome. J Urol. 2012;187(3):1012–1017. [332] Costabile RA. How worrisome is testicular microlithiasis? Curr Opin Urol. 2007;17(6):419–423. [333] Vachon L, Fareau GE, Wilson MG, et al. Testicular microlithiasis in patients with Down syndrome. J Pediatr. 2006;149(2):233–236. [334] Goldstein H. Menarche, menstruation, sexual relations and contraception of adolescent females with Down syndrome. Eur J Obstet Gynecol Reprod Biol. 1988;27(4):343–349. [335] Mason L, Cunningham C. An exploration of issues around menstruation for women with Down syndrome and their carers. J Appl Res Intell Disabil. 2008;21(3):257–267. [336] Stinson J, Christian L, Dotson LA. Overcoming barriers to the sexual expression of women with developmental disabilities. Res Pract Persons Severe Disabil. 2002;27(1):18–26. [337] Cancer Council Australia. Breast cancer. [Available from:] www.cancer.org.au/about-cancer/types-of-cancer/breast-cancer.html; 2016. [338] Kwak HI, Gustafson T, Meo RP, et al. Inhibition of breast cancer growth and invasion by single-minded 2s. Carcinogenesis. 2007;28(2):259–266. [339] Chicoine B, Roth M, Chicoine L, et al. Breast cancer screening for women with Down syndrome: lessons learned. Intellect Dev Disabil. 2015;53(2):91–99. [340] Willis D. Breast screening: participation of women with intellectual disabilities: Diane Willis discusses how overdiagnosis of cancer can influence service users’ decisions to take part in screening programmes. Learn Disabil Prac. 2012;16(4):24–26. [341] Seloer GB, Schupf N, Wu H-S. A prospective study of menopause in women with Down's syndrome. J Intellect Disabil Res. 2001;45(1):1–7. [342] Ejskjaer K, Uldbjerg N, Goldstein H. Menstrual profile and early menopause in women with Down syndrome aged 26–40 years. J Intellect Dev Disabil. 2006;31(3):166–171. [343] Jobling A, Cuskelly M. Young people with Down syndrome: a preliminary investigation of health knowledge and associated behaviours. J Intellect Dev Disabil. 2006;31(4):210–218. [344] Havercamp SM, Scog HM. National health surveillance of adults with disabilities, adults with intellectual and developmental disabilities, and adults with no disabilities. Disabil Health J. 2015;8(2):165–172. [345] Mansell J, Beadle-Brown J. Dispersed or clustered housing for disabled adults: a systematic review. National Disability Authority: Dublin; 2009.

[346] Sutherland G, Couch MA, Iacono T. Health issues for adults with developmental disability. Res Develop Disabil. 2002;23(6):422–445. [347] Thiel R, Fowkes SW. Can cognitive deterioration associated with Down syndrome be reduced? Med Hypotheses. 2005;64(3):524–532. [348] Garlet TR, Parisogo EB, de Medeiros G, et al. Systemic oxidative stress in children and teenagers with Down syndrome. Life Sci. 2013;93(16):558–563. [349] Ko JW, Lim SY, Chung KC, et al. Reactive oxygen species mediate IL-8 expression in Down syndrome candidate region-1overexpressed cells. Int J Biochem Cell Biol. 2014;55:164–170. [350] Zana M, Janka Z, Kalman J. Oxidative stress: a bridge between Down's syndrome and Alzheimer's disease. Neurobiol Aging. 2007;28(5):648–676. [351] Perrone S, Longini M, Bellieni CV, et al. Early oxidative stress in amniotic fluid of pregnancies with Down syndrome. Clin Biochem. 2007;40(3–4):177–180. [352] Baptista F, Varela A, Sardinha LB. Bone mineral mass in males and females with and without Down syndrome. Osteoporos Int. 2005;16(4):380–388. [353] Geijer JR, Stanish HI, Draheim CC, et al. Bone mineral density in adults with Down syndrome, intellectual disability, and nondisabled adults. Am J Intellect Dev Disabil. 2014;119(2):107–114. [354] Guijarro M, Valero C, Paule B, et al. Bone mass in young adults with Down syndrome. J Intellect Disabil Res. 2008;52(Pt 3):182–189. [355] Gonzalez-Aguero A, Vicente-Rodriguez G, Moreno LA, et al. Bone mass in male and female children and adolescents with Down syndrome. Osteoporos Int. 2011;22(7):2151–2157. [356] Wu J. Bone mass and density in preadolescent boys with and without Down syndrome. Osteoporos Int. 2013;24(11):2847–2854. [357] Jasien J, Daimon CM, Maudsley S, et al. Aging and bone health in individuals with developmental disabilities. Int J Endocrinol. 2012;469235. [358] Angelopoulou N, Souftas V, Sakadamis A, et al. Bone mineral density in adults with Down's syndrome. Eur Radiol. 1999;9:648–651. [359] Angelopoulou N, Maoiari C, Tsimaras V, et al. Bone mineral density and muscle strength in young men with mental retardation (with and without Down syndrome). Calcif Tissue Int. 2000;66(3):176–180. [360] da Silva VZ, de Franca Barros J, de Azevedo M, et al. Bone mineral density and respiratory muscle strength in male individuals with mental retardation (with and without Down Syndrome). Res Dev Disabil. 2010;31(6):1585–1589. [361] McKelvey KD, Fowler TW, Akel NS, et al. Low bone turnover and low bone density in a cohort of adults with Down syndrome. Osteoporos Int. 2013;24(4):1333–1338. [362] Gonzalez-Aguero A, Vicente-Rodriguez G, Gomez-Cabello A, et al. Cortical and trabecular bone at the radius and tibia in male and female adolescents with Down syndrome: a peripheral quantitative computed tomography (pQCT) study. Osteoporos Int. 2013;24(3):1035–1044. [363] Dreyfus D, Lauer E, Wilkinson J. Characteristics associated with bone mineral density screening in adults with intellectual disabilities. J Am Board Fam Med. 2014;27(1):104–114. [364] Matute-Llorente Á, González-Agüero A, Gómez-Cabello A, et al. Decreased levels of physical activity in adolescents with Down syndrome are related with low bone mineral density: a cross-sectional study. BMC Endocr Disord. 2013;13(1):22. [365] Ferry B, Gavris M, Tifrea C, et al. The bone tissue of children and adolescents with Down syndrome is sensitive to mechanical stress in certain skeletal locations: a 1-year physical training program study. Res Dev Disabil. 2014;35(9):2077–2084. [366] Reza SM, Rasool H, Mansour S, et al. Effects of calcium and training on the development of bone density in children with Down syndrome. Res Dev Disabil. 2013;34(12):4304–4309. [367] Torr J, Strydom A, Pagi P, et al. Aging in Down syndrome: morbidity and mortality. J Pol Pract Intellect Disabil. 2010;7:70–81. [368] Department of Health and Aging. New Zealand Ministry of Health. Nutrient reference values for Australia and New Zealand. National Health and Medical Research Council; 2005. [369] Cannell JJ, Hollis BW. Use of vitamin D in clinical practice. Alt Med Rev. 2008;13(1):6. [370] Hollis BW. Vitamin D requirement during pregnancy and lactation. J Bone Min Res. 2007;22(S2):V39–44. [371] Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–1930. [372] Vitamin D Council. How do I get the vitamin D my body needs?. [Available from:] www.vitamindcouncil.org/about-vitamin-d/how-doi-get-the-vitamin-d-my-body-needs. [373] Dawodu A, Wagner CL. Mother–child vitamin D deficiency: an international perspective. Arch Dis Childhood. 2007;92(9):737–740. [374] Department of Health. Move and play every day. National physical activity recommendations for children 0–5 years. [Available from:] www.health.gov.au/internet/main/publishing.nsf/content/F01F92328EDADA5BCA257BF0001E720D/$File/Move%20and%20play%20every%20d 5 years.PDF; 2014. [375] World Health Organization. Global recommendations on physical activity for health, 5–17 years old. [Available from:] www.who.int/dietphysicalactivity/factsheet_young_people/en; 2011. [376] World Health Organization. Global recommendations on physical activity for health, 18–64 years. [Available from:] www.who.int/dietphysicalactivity/physical-activity-recommendations-18-64years.pdf?ua=1; 2011. [377] World Health Organization. Global recommendations on physical activity for health, 65 years and above. [Available from:] www.who.int/dietphysicalactivity/physical-activity-recommendations-65years.pdf?ua=1; 2011. [378] Institute of Medicine (US). Panel on Micronutrients. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. National Academies Press: Washington, DC; 2002. [379] Graves RJ, Graff JC, Esbensen AJ, et al. Measuring health-related quality of life of adults with Down syndrome. Am J Intellect Dev Disabil. 2016;121(4):312–326. [380] Makary AT, Testa R, Tonge BJ, et al. Association between adaptive behaviour and age in adults with Down syndrome without

dementia: examining the range and severity of adaptive behaviour problems. J Intellect Disabil Res. 2015;59(8):689–702. [381] McLaughlin K, Jones DA. ‘It's all changed’: carers’ experiences of caring for adults who have Down's syndrome and dementia. Br J Learn Disabil. 2010. [382] Wilcock DM, Hurban J, Helman AM, et al. Down syndrome individuals with Alzheimer's disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer's disease. Neurobiol Aging. 2015;36(9):2468–2474. [383] Dekker AD, Strydom A, Coppus AM, et al. Behavioural and psychological symptoms of dementia in Down syndrome: early indicators of clinical Alzheimer's disease? Cortex. 2015;73:36–61. [384] McBrien J. Screening adults with Down's syndrome for early signs of dementia. J Integrat Care. 2009;17(3):3–7. [385] Laver K, Cumming RG, Dyer SM, et al. Clinical practice guidelines for dementia in Australia. Med J Aust. 2016;204(5):191–193. [386] Bishop KM, Hogan M, Janicki MP, et al. Guidelines for dementia-related health advocacy for adults with intellectual disability and dementia: National Task Group on Intellectual Disabilities and Dementia Practices. Intellect Dev Disabil. 2015;53(1):2–29. [387] Janicki MP, Zendell A, DeHaven K. Coping with dementia and older families of adults with Down syndrome. Dementia. 2010;9(3):391–407. [388] Whitwham S, McBrien J, Broom W. Should we refer for a dementia assessment? Br J Learn Disabil. 2010;39(1):17–21. [389] Hanney M, Prasher V, Williams N, et al. Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet. 2012;379(9815):528–536. [390] Brownie S, Muggleston H, Oliver C. The 2013 Australian dietary guidelines and recommendations for older Australians. Aus Fam Phys. 2013;44(5):311. [391] Lin JD, Lin LP, Hsu SW, et al. Are early onset aging conditions correlated to daily activity functions in youth and adults with Down syndrome? Res Dev Disabil. 2014;36C:532–536. [392] Kamer AR, Fortea JO, Videla S, et al. Periodontal disease's contribution to Alzheimer's disease progression in Down syndrome. Alzheimers Dement. 2016;2:49–57. [393] Log IT, Doran E, Nguyen VQ, et al. Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation. Am J Med Genet. 2011;155A(8):1939–1948. [394] Sano M, Aisen P, Andrews HF, et al. Vitamin E in aging persons with Down syndrome: a randomized, placebo-controlled clinical trial. Neurology. 2016;86(22):2071–2076. [395] Charleton PM, Dennis J, Marder E. Medical management of children with Down syndrome. Paediatr Child Health. 2014;24(8):362–369. [396] Collins MSR, Kyle R, Smith S, et al. Coping with the usual family diet eating behaviour and food choices of children with Down's syndrome, autistic spectrum disorders or cri du chat syndrome and comparison groups of siblings. J Learn Disabil. 2003;7(2):137–155. [397] Nisihara R, Bonacin M, da Silva Kooe L, et al. Monitoring gluten-free diet in coeliac patients with Down's syndrome. J Hum Nutr Dietet. 2013;27(2):1–3. [398] Gualandri W, Gualandri L, Demartini G, et al. Redox balance in patients with Down's syndrome before and after dietary supplementation with alpha-lipoic acid and L-cysteine. Int J Clin Pharmocol Res. 2003;23(1):23–30. [399] Miles MV, Pagerson BJ, Schapiro MB, et al. Coenzyme Q10 absorption and tolerance in children with Down syndrome: a doseranging trial. Pediatr Neurol. 2006;35(1):30–37. [400] Miles MV, Pagerson BJ, Chalfonte-Evans ML, et al. Coenzyme Q10 (ubiquinol-10) supplementation improves oxidative imbalance in children with trisomy 21. Pediatr Neurol. 2007;37(6):398–403. [401] Tiano L, Padella L, Santoro L, et al. Prolonged coenzyme Q10 treatment in Down syndrome patients: effect on DNA oxidation. Neurobiol Aging. 2012;33(3):626.e1–626.e8. [402] Abeysekera I, Thomas J, Georgiadis TM, et al. Differential effects of epigallocatechin-3-gallate containing supplements on correcting skeletal defects in a Down syndrome mouse model. Mol Nutr Food Res. 2016;60(4):717–726. [403] Guedj F, Sebrie C, Rivals I, et al. Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. PLoS ONE. 2009;4(2):e4606. [404] Ramakrishna N, Meeker HC, Brown WT. Novel epigenetic regulation of alpha-synuclein expression in Down syndrome. Mol Neurobiol. 2016;53(1):155–162. [405] Stagni F, Giacomini A, Emili M, et al. Short- and long-term effects of neonatal pharmacotherapy with epigallocatechin-3-gallate on hippocampal development in the Ts65Dn mouse model of Down syndrome. Neuroscience. 2016;333:277–301. [406] Valenti D, de Bari L, de Rasmo D, et al. The polyphenols resveratrol and epigallocatechin-3-gallate restore the severe impairment of mitochondria in hippocampal progenitor cells from a Down syndrome mouse model. Biochim Biophys Acta. 2016;1862(6):1093–1104. [407] de la Torre R, de Sola S, Hernandez G, et al. Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(8):801–810. [408] Benneg FC, McClelland S, Kriegsmann EA, et al. Vitamin and mineral supplementation in Down's syndrome. Pediatrics. 1983;72(5):707–713. [409] Coleman M, Sobel S, Bhagavan HN, et al. A double blind study of vitamin B6 in Down's syndrome infants. Part 1: clinical and biochemical results. J Ment Defic Res. 1985;29(Pt 3):233–240. [410] Frager J, Barnet A, Weiss I, et al. A double blind study of vitamin B6 in Down's syndrome infants. Part 2: cortical auditory evoked potentials. J Ment Defic Res. 1985;29(Pt 3):241–246. [411] Stagi S, Lapi E, Romano S, et al. Determinants of vitamin D levels in children and adolescents with Down syndrome. Int J Endocrinol. 2015;896758. [412] Zubillaga P, Garrido A, Mugica I, et al. Effect of vitamin D and calcium supplementation on bone turnover in institutionalized adults with Down's syndrome. Eur J Clin Nutr. 2006;60(5):605–609. [413] Mustafa Nachvak S, Reza Neyestani T, Ali Mahboob S, et al. Alpha-tocopherol supplementation reduces biomarkers of oxidative

stress in children with Down syndrome: a randomized controlled trial. Eur J Clin Nutr. 2014;68(10):1119–1123. [414] Pincheira J, Navarrete MH, de la Torre C, et al. Effect of vitamin E on chromosomal aberrations in lymphocytes from patients with Down's syndrome. Clin Genet. 1999;55:192–197. [415] Parisogo EB, Garlet TR, Cavalli VL, et al. Antioxidant intervention agenuates oxidative stress in children and teenagers with Down syndrome. Res Dev Disabil. 2014;35(6):1228–1236. [416] Parisogo EB, Giarega AG, Zamoner A, et al. Persistence of the benefit of an antioxidant therapy in children and teenagers with Down syndrome. Res Dev Disabil. 2015;45-46:14–20. [417] Chiricolo M, Musa AR, Monti D, et al. Enhanced DNA repair in lymphocytes of Down syndrome patients: the influence of zinc nutritional supplementation. Mutat Res. 1993;295(3):105–111. [418] Licastro F, Chiricolo M, Mocchegiani E, et al. Oral zinc supplementation in Down's syndrome subjects decreased infections and normalized some humoral and cellular immune parameters. J Intellect Disabil Res. 1994;38(2):149–162. [419] Lockitch G, Puteman M, Godolphin W, et al. Infection and immunity in Down syndrome: a trial of long-term low oral doses of zinc. J Pediatr. 1989;114(5):781–787. [420] Marreiro DN, de Sousa AF, Nogueira N, et al. Effect of zinc supplementation on thyroid hormone metabolism of adolescents with Down syndrome. Biol Trace Elem Res. 2009;129(1–3):20–27. [421] Romano C, Peginato R, Ragusa L, et al. Is there a relationship between zinc and the peculiar comorbidities of Down syndrome? Down Syndrome Res Pract. 2002;8(1):25–28. [422] Stabile A, Pesaresi MA, Stabile AM, et al. Immunodeciency and plasma zinc levels in children with Down's syndrome: a long-term follow up of oral zinc supplementation. Clin Immunol Immunopathol. 1991;58:207–216. [423] Mocchegiani E, Costarelli L, Giacconi R, et al. Micronutrient (Zn, Cu, Fe)-gene interactions in ageing and inflammatory age-related diseases: implications for treatments. Ageing Res Rev. 2012;11(2):297–319. [424] Lima AS, Cardoso BR, Cozzolino SF. Nutritional status of zinc in children with Down syndrome. Biol Trace Elem Res. 2010;133(1):20– 28. [425] Marques RC, de Sousa AF, do Monte SJ, et al. Zinc nutritional status in adolescents with Down syndrome. Biol Trace Elem Res. 2007;120(1–3):11–18. [426] Seven M, Cengiz M, Tüzgen S, et al. Plasma carnitine levels in children with Down syndrome. Am J Hum Biol. 2001;13(6):721–725. [427] Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue. Arch Gerontol Geriatr. 2008;46(2):181–190. [428] Pueschel SM. The effect of acetyl-L-carnitine administration on persons with Down syndrome. Res Dev Disabil. 2006;27(6):599–604. [429] Turner RS, Thomas RG, Craft S, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015;85(16):1383–1391. [430] Hawrelak J. Probiotics. Murray M, Pizzorno J. Textbook of natural medicine. Churchill Livingstone: St Louis; 2013:966–978. [431] Anderson J, Hasler K, Yates R, et al. Sexual health and relationships: a review of resources for people with learning disabilities. NHS Health Scotland: Glasgow; 2008.

Appendix 19.1 Sexual health resources for parents, carers and health professionals working with people with Down syndrome and other learning disabilities Resource Hart P, Douglas-Scog S. Ba`eries not included: a sexuality resource pack for working with people with complex communication support needs. Common Knowledge; 2005.

Cooper E. Becoming a woman: a teaching pack on menstruation for women with learning disabilities. Pavilion Publishing; 1999.

Body board (variety of packs available) Headon Productions; 1999.

Dixon H. Chance to choose: sexuality and relationships education for people with learning difficulties. LDA; 2005.

Topics included Masturbation Moral issues Policy issues Relationships Rights and responsibilities Same-sex relationships Sex aids/sex toys Sex and the law Anatomy of sexual organs Body changes Intimate care Menstruation Mood swings Personal hygiene and grooming Puberty Communication skills Drugs Emotions, pregnancy, contraception, love, hygiene Flirting and body language Human reproduction Masturbation Organs of the body Sex and relationships education Sexual intercourse/penetration (Only includes heterosexual sex) Appropriate behaviour Assertiveness Body image Communication skills

Sherlin M, McCormick G. Exploring sexuality and disability: walk your talk. FPA; 1997.

Drury J, Hutchinson L, Wright J. Holding on, le`ing go: sex, sexuality and people with learning disabilities. Souvenir Press; 2000.

How it is: an image vocabulary for children about feelings, rights and safety, personal care and sexuality. NSPCC; 2002.

Atkinson D, Gingell A, Martin J. I have the right to know: how to run a course on sexuality and personal relationships for people with learning disabilities. BILD; 1997.

Meinerohagen K, Kennard M, Hall L. It's my life (picture signed for people working with individuals with hearing impairment or deafness). SIGNALONG Group; 2000.

Contraception Group work Masturbation Menstruation Puberty Relationships Self-esteem STIs — symptoms and consequences Assertiveness Agitudes or agitudinal change Avoiding risky situations Choices, making informed decisions Condoms Disability politics/rights/issues Emergency contraception Heterosexuality Learning disabilities Love Options if pregnant Other disabilities Personal hygiene and grooming Preventing pregnancy Safer sex Sexual health and sexual health services STIs — symptoms and consequences Staff values Disability politics/rights/issues Parenting Relationships Rights and responsibilities Sexual abuse or coercion Sexual health services Sexuality Sexual organs Body changes Communication skills Emotions/feelings Friendships Heterosexuality Intimate care Masturbation Rights and responsibilities Sexual language Sexually explicit material Abortion/termination of pregnancy Anatomy of sexual organs Assertiveness Bisexuality Body changes Contraception Gender differences Homosexuality Masturbation Personal hygiene and grooming Policy issues Pregnancy and parenthood Relationships Reproductive health Rights and responsibilities Self-esteem Sexual behaviour Sexual language STIs — symptoms and consequences Anal sex Anatomy of sexual organs Bisexuality Bullying Circumcision Communication skills Confidentiality Contraception Emotions/feelings Gender issues Heterosexuality Homosexuality Masturbation Medical examinations Menstruation Options if pregnant

Queens Road Sexual Health Team. It's only natural: for parents, carers and others involved in the lives of young people with learning disabilities — a resource which looks at issues of sexuality and sexual health. Barnardos; 1996.

Hingsburger D. Just say know! Understanding and reducing the risk of sexual victimisation of people with developmental disabilities. Diverse City Press; 1995.

Frawley P, Johnson K, Hillier L, Harrison L. Living safer sexual lives: a training and resource pack for people with learning disabilities and those who support them. Pavilion Publishing; 2000.

Making choices, keeping safe. Interagency Guideline for Lothian. Issue 1. Author: NHS Lothian; 2004.

McCarthy M, Thompson D. Sex and the 3Rs – rights, responsibilities and risks:a sex education package for working with people with learning difficulties. Pavilion Publishing; 1998 (rev edn).

Adcock K, Stanley G. Sexual health education and children and young people with learning disabilities: a practical way of working for professionals, parents and carers. BILD/Barnados; 1996. Scog L, Kerr-Edwards L. Talking together … about growing up. FPA; 1999.

Oral sex Pregnancy Puberty Relationships Sexual abuse or coercion Sexual language STIs — symptoms and consequences Transgender issues Confidentiality Parents Relationships Rights and responsibilities Self-esteem Sex and relationships education (SRE) SRE program development STIs — symptoms and consequences Agitudes/agitudinal change Disability politics/rights/issues Gender issues Learning disabilities Parents Power issues in relationships Rights and responsibilities Self-esteem Sex and relationships education Sexual abuse or coercion Staff values Agitudes/agitudinal change Emotions/feelings Friendships Gay men Heterosexuality and homosexuality Learning disabilities Lesbians Love Media Men who have sex with men Parenthood and parents Policy issues Power issues in relationships Relationships rights and responsibilities Same-sex partnerships Self-esteem Sexual abuse or coercion Sexuality Staff values Abortion/termination of pregnancy Bisexuality Choices, making informed decisions Condoms Consent Contraception Emergency contraception Heterosexuality HIV infection/AIDS Homosexuality Intimate care Masturbation Parenthood Preventing pregnancy Privacy Same-sex partnerships Sex and the law Sexual health services Sexually explicit material Anal sex Appropriate touch Contraception Gender differences Heterosexuality Homosexuality Oral sex Pregnancy Saying no to sex Sexual abuse and coercion STIs — symptoms and consequences Group work Sex and relationships education Behaviour

Couwenhoven T. Teaching children with Down syndrome about their bodies, boundaries, and sexuality: a guide for parents and professionals. Woodbine House; 2007.

Body changes Body image Choices, making informed decisions Emotions/feelings Masturbation Menstruation Public/private Relationships Sex and relationships Sexual language Anticipating and understanding puberty Dealing with periods, bras for girls Experiencing erections, wet dreams for boys Explaining sexual relationships Identifying and expressing emotions Labelling and explaining private body parts Preventing sexual abuse Relating to the opposite sex Respecting personal space Sharing parental values about sexuality Showing appropriate levels of affection Teaching self-care and hygiene Understanding gender identity Understanding how Down syndrome affects puberty and fertility rates Understanding norms of privacy

Source: Anderson J, Hasler K, Yates R, et al. Sexual health and relationships: a review of resources for people with learning disabilities. Glasgow: NHS Health Scotland; 2008.

Appendix 19.2 Sexual health resources for people with Down syndrome and other learning disabilities, with the support of carers or family members Resource Hollins S, Sinason V. Bob tells all (books beyond words). Gaskell/Royal College of Psychiatrists; 1992. Fraser J (ed.). Building friendships: a resource pack to help young people make friendships and develop relationships. Brook Publications; 1994.

Cathy has thrush. Women's Health; 2001.

Poynor L et al. Cervical screening: a teaching pack for women with learning disabilities and those who work with them. Surrey Oaklands NHS Trust; 2004.

Hollins S. Falling in love (books beyond words). Gaskell/Royal College of Psychiatrists; 1999.

Feeling grown up. Shepherd School; 1999.

Hollins S, Flynn M, Russell P. George gets smart (books beyond words). Gaskell/Royal College of Psychiatrists; 2001. FAIR/NHS Health Scotland. A guide to examining your breasts. NHS Health Scotland; 2002.

FAIR/NHS Health Scotland. A guide to examining your testicles. NHS Health Scotland; 2002.

Topics included Appropriate sexual and non-sexual behaviour Sexual abuse or coercion Avoiding risky situations Communication skills Friendships and relationships Icebreakers Social skills Building friendships Helping others get to know you Intimate care Medical examinations Personal hygiene and grooming Sexual health services Thrush Anatomy of sexual organs Body changes Cervical cancer Cervical screening Choices and making informed consent Medical examinations Sexual health services Smear tests Communication skills Emotions/feelings Love Parents Privacy Relationships Appropriate behaviour Masturbation Menstruation Personal hygiene and grooming Public/private Wet dreams Friendships Personal hygiene and grooming Breast awareness and screening Choices, making informed decisions Medical examinations Self-examination (breasts) Choices, making informed decisions Self-examination (testicles) Sexual health services

FAIR/NHS Health Scotland. A guide to having a period. NHS Health Scotland; 2003.

FAIR/NHS Lothian. A guide to having a smear test. FAIR Multimedia/NHS Lothian; 2004.

Hollins S, Roth T. Hug me touch me. Gaskell/Royal College of Psychiatrists; 1994.

I want to be a good parent. The BILD parenting series. BILD; 1994 (reprinted 1998).

Hollins S, Sinason V. Jenny speaks out (books beyond words). Gaskell/Royal College of Psychiatrists; 2005. Hollins S, Downer J. Keeping healthy down below (books beyond words). Gaskell/Royal College of Psychiatrists; 2000.

Johns R, Scog L, Bliss J. Let's do it: creative activities for sex education for young people with learning disabilities (3rd edn). Image in Action; 2002.

Marsden L. Let's talk about puberty: a booklet about growing up for young people who have a learning disability. Down's Syndrome Scotland; 2004.

Hollins S, Wilson J. Looking after my balls (books beyond words). Gaskell/Royal College of Psychiatrists; 2004.

Hollins S, Perez W. Looking after my breasts (books beyond words). Gaskell/Royal College of Psychiatrists; 2000. Hollins S, Roth T. Making friends (books beyond words). Gaskell/Royal College of Psychiatrists; 1995.

FAIR/NHS Health Scotland. A man's guide to keeping clean. NHS Health Scotland; 2003.

FAIR/NHS Health Scotland. Shaving card. NHS Health Scotland; 2003. Hollins S, Sinason V. Susan's growing up. Gaskell/Royal College of Psychiatrists; 2001. Thinking about sex? How to use condoms. Caledonia Youth; 1999 (reprinted 2003).

Testicular examination Anatomy of sexual organs Emotions/feelings Intimate care Menstruation Mood swings Personal hygiene and grooming Puberty Sexual health services Anatomy of sexual organs Cervical cancer Cervical screening Medical examinations Smear tests Appropriate behaviour Friendships and relationships Touch Child development Child needs: health, hygiene, warmth, safety, love Feeding children healthy food Parenthood Realities of becoming a parent Communication skills Sexual abuse or coercion Cervical screening Choices, making informed decisions Medical examinations Menstruation Sexual health services Smear tests Anatomy of sexual organs Assertiveness Body changes Body image Condoms Emotions /feelings Gender differences Group work HIV infection/AIDs Masturbation Public/private Relationships Self-esteem Sexual arousal Sexual health services Sexual intercourse/penetration Body changes Body images Choices, making informed decisions Emotions/feelings Masturbation Menstruation Mood swings Personal hygiene and grooming Puberty Self-esteem Sexual arousal Medical examinations Self-examination (testicles) Sexual health services Testicular cancer Breast awareness and screening Mammograms Self-examination (breasts) Appropriate touch Behaviour Emotions/feelings Friendships Anatomy of sexual organs Body image Intimate care Personal hygiene and grooming Laminated card for men with intellectual disabilities with step-by-step guide to wet and dry shaving Menstruation Personal hygiene and grooming Anatomy of sexual organs Condoms Heterosexuality

FAIR/NHS Health Scotland. A woman's guide to keeping clean. NHS Health Scotland; 2003.

Preventing pregnancy Safer sex (Note: only contains heterosexual images) Body image Intimate care Personal hygiene and grooming

Source: Anderson J, Hasler K, Yates R, et al. Sexual health and relationships: a review of resources for people with learning disabilities. Glasgow: NHS Health Scotland; 2008.

Appendix 19.3 Plymouth dementia screening checklist

20

The endocannabinoid system and cannabis Justin S Sinclair

Introduction The endocannabinoid system (ECS) is a relatively recent scientific discovery, with its unearthing owed largely to the research conducted on the Cannabis genus and its unique pharmacological effects. This ubiquitous neuromodulatory system exhibits key functions across many different organ systems, tissues, cells and physiological seDings[1,2] and comprises specific endocannabinoid receptors, the endogenous ligands that bind with these receptors and the enzymes that are responsible for ligand synthesis and degradation. Despite being researched for more than 30 years, there is sparse representation of the endocannabinoid system in current tertiary medicine, nursing and allied health curriculums. This is potentially contributing to a delay in access to Cannabis spp. and cannabinoid-based medicines for certain patient populations in Australia and New Zealand, while also slowing research into our understanding of the aetiological basis behind numerous medical conditions.

Evolution of the endocannabinoid system The evolutionary development of the ECS has taken place over millions of years across diverse biological organisms, with evidence of cannabinoid receptor genes being found in the Deuterostomian invertebrate Ciona intestinalis (sea squirt), suggesting that the receptors developed in this class some 500 million years ago.[3] Recent research has highlighted that genes for these receptors and their related endocannabinoid ligands need to coevolve in order to maintain binding affinities and coordinated gene expression.[4] Further investigation has uncovered that cannabinoid receptors are also distributed widely throughout the vertebrates and have been documented in fish, amphibians, sea urchins, molluscs, leeches and mammals.[5–7] Research into how the phytochemicals in Cannabis spp. interacted with human physiology was a slow evolution also, taking place in three distinct phases. Academic investigation has been impeded largely by inconsistent Cannabis spp. plant samples, prohibitive laws hampering its availability in academic research[2] and a poor understanding of the chemical structure of the plant cannabinoids. With more than 100 phytocannabinoids[8–10] in various Cannabis spp. and strains, many being artefacts of analysis, this made isolation difficult due to similarities in structure and physical properties.[2] Advances in modern analytical separation techniques finally elucidated the main psychoactive principle, the phytocannabinoid known as Δ9tetrahydrocannabinol (THC), in 1964,[11] which led to its chemical synthesis 3 years later.[12] It thus became more readily available for scientific research, allowing for the investigation of its physiological mechanism of action.[13] The first phase in our understanding of the ECS came almost 20 years later in the mid-1980s,[13] when research teams began closing in on potential receptors with which THC interacted. Studies in 1984 elucidated that cannabimimetic agents inhibited cAMP accumulation in neuronal cells via a receptor-mediated cellular response,[14] and in 1988 research undertaken by Mechoulam and colleagues demonstrated that THC was stereospecific, suggesting that it required a specific site of action for binding.[13,15] Later that same year a specific cannabinoid receptor was discovered,[16] with structural expression of this receptor being defined in 1990.[17] This cannabinoid receptor became known as the CB1 receptor and THC binds with relatively high affinity to it within the central nervous system (CNS). Just 3 years later, a second receptor, known as the CB2 receptor, was discovered[18] and it is believed to exist mainly in the peripheral nervous system and tissues. The endogenous ligands that interact with the CB1 and CB2 receptors represent the second phase and were the next piece of the anatomical and physiological puzzle of the ECS. Based on the highly lipophilic structure of the terpenophenolic THC,[10] it was hypothesised that the endogenous ligands would also be lipid derived.[2,13] This hypothesis was later proven correct, with the endocannabinoids being shown to be derivatives of arachidonic acid, which is a progenitor compound to other endogenous molecules such as leukotrienes, thromboxanes, prostacyclins and prostaglandins.[13] Using lipid separation techniques, in 1992 Devane and colleagues[19] isolated anandamide (AEA; N-arachidonoylethanolamine), with a second endocannabinoid known as 2-AG (2-arachidonoylglycerol) being identified in 1995.[20,21] These endocannabinoids are chemically derived from long-chain polyunsaturated faDy acids as amides, esters and even ethers and bind with varying

affinity to the CB1 and CB2 receptors.[5,22] While anandamide and 2-AG are the most studied endocannabinoids currently, others have been identified such as 2-arachidonylglyceryl ether (noladin ether), O-arachidonoyl-ethanolamine (virodhamine) and N-arachidonoyl-dopamine (NADA),[5] but their physiological importance is as yet largely undetermined.[23] Lastly, the third phase includes the enzymes involved in the synthesis and degradation of the endocannabinoids have been described[13] and are continuing to be researched. Various enzymes, such as N-acyltransferase, N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), phospholipase C (PLC) and diacylglycerol lipase (DAGL) are involved in endocannabinoid synthesis, whereas faDy acid amide hydrolase (FAAH) and monoacylglycerol lipase are specific for degradation pathways.[24] All of these components comprising the ECS represent perhaps one of the most significant anatomical and physiological discoveries in the fields of biology, pharmacology and medicine in the last 100 years and open up an entirely new chapter in our understanding of homeostatic mechanisms and regulation within the human organism. The potential of this understanding to enrich our current knowledge base and treatment of numerous idiopathic diseases, disorders and conditions has far-reaching implications, and was made possible by initial research into the cannabis plant and how it impacted human physiology.

Anatomy of the endocannabinoid system The ECS represents a vital and integral neuromodulatory system involved in the regulation of many facets of homeostasis, with cannabinoid receptors widely expressed in many cells and tissues of the body.[23] Essentially, the ECS is comprised of three major components: – Cannabinoid receptors (i.e. CB1 and CB2),[25] which are distributed throughout the various organs and tissues – Endogenous ligands (i.e. endocannabinoids), which interact with these receptors – Enzymes that are involved in synthesis or degradation of the ligands.[3,26–29] Of key clinical interest here is that any individual variability or genetic polymorphic modifications to any one of these components may potentially modify the normal functioning of the entire ECS and the body systems it regulates. This invariably highlights not only the complexity of cannabis pharmacotherapy in clinical application, but also the need for discussion about the concept of a precision-medicine initiative around the medicinal cannabis debate, optimised for individual patients and their physiological expression.

Receptors The CB1 and CB2 cannabinoid receptors belong to the family of 7-transmembrane (comprised of α-helices, a glycosylated amino terminus and an intracellular carboxyl terminus)[25] Gi/o protein-coupled receptors (GPCRs),[13,22,28,30–33] being expressed in abundance in the CNS where it far exceeds those present for the neurotransmiDers it modulates.[27] Widespread tissue distribution of cannabinoid receptor 1 and 2 subtypes is suggestive that they have a broad scope and variance in physiological roles around the body. Recent research has also identified other targets for endocannabinoids, with the G protein-coupled receptor 55 (GPR55)[34] and G protein-coupled receptor 119 (GRP119) being postulated as new members of the cannabinoid receptor family.[25,35] Further research suggests that the transient receptor potential vanilloid 1 (TRPV1) and the peroxisome proliferator-activated receptor (PPAR) α and γ subtypes are also a target for endocannabinoid binding.[13,36,37] The CB1 and CB2 receptors, coupled to Gi/o proteins, demonstrate physiological effects by inhibiting adenylate cyclases (thus inhibiting the conversion of ATP to cyclic AMP),[5,38] stimulating mitogen-activated protein kinases (MAPK) and modulating the activity of K+ and Ca2+ ion channels assisting in transducing the binding of agonists.[39] This laDer protein-mediated modulation of ion channels includes activating inwardly rectifying A-type K+ channels or inhibiting L-, N- and P/Q-type voltage gated Ca2+ channels,[40,41] thus modulating neurotransmiDer release such as inhibiting central neurotransmiDer release with noradrenaline, acetylcholine and glutamate.[25,29,42] CB1 receptors, which have CB1A and CB1B subtypes,[43,44] are encoded by the CNR1 gene[45] and are the most widely expressed GPCRs in the brain and spinal cord, with high density present on presynaptic terminals, particularly of GABAergic and glutamatergic neurons.[23,46–48] CB1 activation inhibits the specific neurotransmiDer release of GABA, glutamate, dopamine, serotonin, acetylcholine, D-aspartate and noradrenaline[49–51] of both excitatory and inhibitory synapses. Thus CB1

receptors are primarily involved in modulation of neurotransmiDer release centrally, but also have roles in causing coronary and cerebral dilation, neuroprotective signalling, relief of pain and promoting neural stem cell differentiation.[52–55] Receptor locations within the CNS include numerous regions within the cortex (see Box 20.1).[2,3,39] Interestingly, there is a paucity of CB1 receptors in the brainstem (specifically the cardiopulmonary centres), which may explain the lack of respiratory

depression in Cannabis spp. overuse compared to that observed in opiate medication overdose, despite CB1 receptors being ten times more common than mu-opioid receptors in the brain.[3] Furthermore, cannabinoid receptors have been shown to colocalise with opioid receptors and may amplify analgesic effects via potential pharmacodynamic activity.[3]

Box 20.1

CNS distribution of CB1 receptors Amygdala Basal ganglia* Cerebellum* Cerebral cortex* – Frontal lobe – Olfactory cortex – Entorhinal cortex – Somatosensory cortex Globus pallidus Hippocampus* Periaqueductal grey maDer Rostroventrolateral medulla (RVM) Spinal interneurons Substantia gelatinosa (spinal cord) Substantia nigra

*

Highest receptor concentration

The CB1 receptor subtype was originally believed to be expressed mainly in the CNS[2]; however, recent research has demonstrated that it is also expressed in peripheral neurons presynaptically and other extra-neural tissues and organs such as adipocytes, myocytes, hepatocytes, epithelial cells, the digestive system, male (e.g. testis) and female reproductive organs, eyes, vascular endothelium, heart, lungs and kidneys and the pituitary, adrenal and thyroid glands,[39,45,56,57] albeit with lower receptor expression levels than observed in the CNS. CB1 is also highly expressed in the enteric nervous system throughout all neuronal types except for inhibitory motor neurons.[58,59] The CB1 receptor is encoded by the CNR1 gene located at chromosome 6q 14-15,[60] for which multiple single-nucleotide

polymorphisms (SNPs) have been documented. Due to such widespread distribution in the CNS, CB1 receptors are thought to be important for motivation, cognition,[2] sedation, pain, appetite regulation and muscle relaxation, and are the predominant targets involved for the psychotropic activity of Cannabis spp. rich in THC or other exogenous cannabinoids. Conversely, CB2 receptors were thought to exist mainly in the periphery and immune cells with liDle, if any, CNS distribution. However, in 2006 researchers discovered the functional expression of this receptor subtype within the brain,[28,61– 63] particularly in microglial cells and more recently neural stem cells.[64] More commonly, CB2 receptors are widely expressed

throughout peripheral tissues within the immune system, including the spleen, thymus, tonsils, mast cells and gastrointestinal tract (GIT).[45] Specific immune cells with high levels of CB2 expression include CD4+ T cells, CD8+ T cells, B-cells, natural killer (NK) cells, macrophages, monocytes and neutrophils.[48,65] The CNR2 gene encodes for the CB2 receptor, with both CB1 and CB2 receptors demonstrating 44% similarity in their amino acid sequences.[45] CB2 receptor expression in peripheral immune cells and tissues is currently considered responsible for the effects that cannabinoids have on immunomodulatory activity,[66] thought largely to be due to the CB2 signalling pathway playing a critical role in regulating microglial activities within the CNS.[67] CB2 receptors do not cause any noted psychoactive activity but they do contribute to local analgesic effects.[3] Furthermore, CB2 receptors demonstrate important neuroprotective and anti-inflammatory activities, with CB2 expression being enhanced by inflammation, which suggests that this receptor subtype may be involved in the endogenous response to injury.[55,68–70] Recent evidence has demonstrated the role of CB2 activation in analgesia in acute and neuropathic models of pain.[71] It has been posited that the CB2 receptor is part of an integral protective system within the body,[2] with Pacher and Mechoulam speculating that:

The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is conceivable that through evolution, analogous biological protective systems have evolved against nonprotein attacks. There is emerging evidence that lipid endocannabinoid signaling through CB2 receptors may represent an example/part of such a protective system.[72]

It should be noted that non-CB1/CB2 receptor effects have been reported in the scientific literature, with examples of certain cannabinoid ligands being mediated by α-7-nicotinic acetylcholine receptors, serotonin type 3 receptors, peroxisome proliferator-activated receptor-α, peroxisome proliferator-activated receptor-γ[37,73] and transient receptor potential vanilloid type 1 (TRPV1) receptors.[25,36,74–76] Interestingly, cannabinoid effects have been noted independent of any currently known receptor types, suggesting the possibility of either as yet unidentified cannabinoid receptor subtypes or the ability of the endocannabinoids to diffuse directly through the cellular phospholipid bilayer.[25,77] The discovery of the cannabinoid receptors and an evolving understanding of the regulatory mechanisms of the ECS, with its subsequent role in the aetiology and pathogenesis of multiple diseases and conditions, has seen the pharmacological development of many synthetic substances that are agonists and antagonists to CB1/CB2 receptors. Examples of CB1 synthetic inverse agonists or antagonists include SR141716A (Rimonabant), AM251 and AM281, while SR144528 and AM630 are selective for CB2 receptors.[25,78] These synthetic derivatives can express very high levels of specificity and affinity for the various cannabinoid receptors, but are not without risks. For example, Rimonabant (Acomplia, Zimulti) was marketed as an anti-obesity drug, but it has been withdrawn from the US market due to serious adverse effects such as suicidality and depression, with a 2006 Cochrane Review suggesting that more rigorous studies are required to examine the safety and efficacy to evaluate the benefit/risk ratio in more detail.[79] Apart from endogenous ligands and synthetically manufactured agonists and antagonists, the CB1 and CB2 receptors can also interact with phytocannabinoids (i.e. secondary plant metabolites of terpenophenolic origin) such as THC and synthetically derived cannabinoids, all with varying receptor affinities and physiological outcomes. This is discussed later under the phytochemistry of the Cannabis genus.

Endogenous ligands (endocannabinoids) Being derivatives of polyunsaturated faDy acids, the endocannabinoids differ structurally from the phytocannabinoids produced in the Cannabis genus or other synthetically derived exocannabinoids.[5] Currently, two main endocannabinoids have emerged in the research as prevalent regulators of synaptic function, anandamide[80] and 2-AG,[20,21] but others have been highlighted in the literature – for example, non-amide derivatives such as virodhamine[81] and ether derivatives such as noladin ether.[25,76,82,83] The laDer, which is generally quite stable in vivo unlike anandamide or 2-AG, is of particular interest in drug development.[84] Furthermore, N-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA) and Nstearoylethanolamine (SEA) have been described as ‘endocannabinoid-like’ compounds found in rat, mouse and human brain tissue,[84,85] but research on their physiological significance is still ongoing.

Anandamide Anandamide was the first endocannabinoid isolated in 1992 and it was named after the Sanskrit word ananda meaning ‘supreme joy’ or ‘bliss’[2] due to its cannabimimetic activity, pertaining to its ability to interact with cannabinoid receptors and mimic the psychotropic effect of THC from Cannabis spp.[84,86] Of all the posited endocannabinoids, anandamide is the most studied in the literature at this time[87] (see Fig. 20.1).

FIGURE 20.1

Chemical structure of anandamide

Interestingly, anandamide binds to cannabinoid receptors with higher affinity (it binds with modestly higher affinity at CB1 receptors in comparison to CB2) than 2-AG[88] but exhibits only partial agonistic activity at both cannabinoid receptor types. It is, however, a full agonist for the TRPV1 receptor, with research suggesting that anandamide activation of cannabinoid receptors regulates TRPV1 responsiveness and that TRPV1 activation regulates anandamide synthesis postsynaptically.[89]

2-AG

Conversely, 2-AG is the most abundant of the currently studied endocannabinoids[55,90] and is considered a fast retrograde synaptic messenger, with recent evidence indicative that it is the most efficacious endogenous ligand for the cannabinoid receptors and the key endocannabinoid involved in retrograde signalling within the brain.[91–93] It is a full agonist of both CB1 and CB2 receptors,[91,94] unlike the only partial agonistic activity of anandamide (see Fig. 20.2).

FIGURE 20.2

Chemical structure of 2-AG

Within the nervous system, endocannabinoids are currently believed to be synthesised on demand (i.e. in response to injury, ischaemia or stress)[13,55] in an activity-dependent manner by the catabolism of phospholipid membrane components located within the postsynaptic neuron.[2,25,58,95] Once manufactured, the endocannabinoids exert physiological effects by travelling back across the synaptic cleft and binding to cannabinoid receptors on presynaptic neurons, inhibiting either inhibitory or excitatory neurotransmiDers. This action is known as retrograde synaptic flow.

Enzymes The endocannabinoid system also incorporates a variety of different enzymes that are responsible for the biosynthesis and catabolism of the endogenous lipid-based ligands. The various endocannabinoids, whether anandamide or 2-AG, are manufactured in an activity-dependent manner (i.e. on demand) in a process that is not yet fully understood but seems to be a response to various pathophysiological stimuli.[13,25,84] While this is believed to be the canonical view currently held in the literature, recent research posits that endocannabinoid production and metabolic control may be complemented by intracellular trafficking and storage in specific reservoirs.[96] Anandamide is synthesised from membrane phospholipid precursors such as N-arachidonoyl phosphatidylethanolamine (NAPE), which is formed by the transfer of arachidonic acid from the sn-1 position of a donor phospholipid to phospatidylethanolamine by the calcium-dependent enzyme N-acyltransferase (see Fig. 20.3).[13,58] Biosynthesis continues with the hydrolysis of NAPE by the enzyme NAPE-PLD,[97] which produces anandamide.[23,98,99] While this is considered one of the main biosynthetic pathways of anandamide, other alternative biochemical pathways for synthesis have been described in the literature,[100] including enzymes such as α/β-hydrolase domain 4 (ABHD4), protein tyrosine phosphatase, non-receptor type 22 (PTPN22) and glycerophosphodiester phosphodiesterase (GDE1).[13]

FIGURE 20.3

Anandamide synthesis and degradation

The catabolism (i.e. hydrolysis) of anandamide is primarily mediated by the enzyme FAAH,[23,101] which degrades anandamide to arachidonic acid and ethanolamine. Alternatively, anandamide can be oxidised by N-acylethanolaminehydrolysing acid amidase (NAAA), cytochrome P450 enzymes, lipoxygenases and cyclooxygenase-2.[13] The more prevalent endocannabinoid, 2-AG, is similarly synthesised from membrane phospholipid precursors (see Fig. 20.4). In contrast, the progenitor compound phosphatidylinositol is degraded to diacylglycerol by the enzyme phospholipase C (PLC) and then to 2-AG by either diacylglycerol lipase α (DAGL α) or diacylglycerol lipase β (DAGL β).[13]

FIGURE 20.4

2-AG synthesis and degradation

The catabolism of 2-AG mimics that of anandamide via oxidative processes of the cytochrome P450 enzymes, lipoxygenases and cyclooxygenase-2; however, the specific degrading enzymes are monoacylglycerol lipase (MAGL) and the membraneassociated α/β-hydrolase domain 6 (ABHD6) and α/β-hydrolase domain 12 (ABHD12) enzymes.[13] End products of enzymatic degradation of 2-AG include arachidonic acid and glycerol. The diverse and complex enzymatic mechanisms involved in endocannabinoid biological metabolism in vivo are important in maintaining the resting ‘tone’ of this entire neuromodulatory system.[13,102] This diversity also highlights that the inherent abundance or deficiency of these enzymes in the individual can have dramatic influence over ECS functioning. As such, if the

enzymes responsible for endocannabinoid degradation are suppressed experimentally, a prolonged therapeutic activity of the endocannabinoids is achieved, demonstrating another promising target for cannabinoid pharmacotherapy.[2,26]

Physiology of the endocannabinoid system Fundamentally, the ECS is largely responsible for homeostatic regulation and physiological balance. Due to the anatomical distribution of the ECS throughout the brain, spinal cord, enteric and peripheral nervous systems,[2] it plays a pivotal role in regulating a broad list of physiological homeostatic processes including the regulation of stress and emotions, digestion, nociception (i.e. pain),[103] cardiovascular[104] and respiratory function,[105] immune function, neural development, synaptic plasticity and learning, memory, movement, metabolism, energy expenditure and balance, inflammation, appetite regulation, sleep/wake cycles, thermogenesis and psychomotor behaviour.[49,50,106–108] Ongoing research into the scope and influence of the ECS in organ system dysfunction and disease should be a priority, as an evolving evidence base is showing that dysfunction or modulation of this system may be where future breakthroughs in understanding disease aetiology, pathogenesis and treatment reside.

Neurological system With its ubiquitous distribution throughout the central and peripheral nervous systems, the ECS may play a meaningful role in various neurological pathophysiologies, such as epilepsy. Early studies have demonstrated defects within the ECS in epilepsy patients, with one study showing patients with newly diagnosed temporal lobe epilepsy exhibiting significantly lower levels of anandamide in their cerebrospinal fluid (CSF) in contrast to healthy controls.[40,109] Further supporting the hypothesis that the ECS may play a role in seizure inhibition in epilepsy was a study on resected tissue following surgery for epilepsy, whereby epilepsy patients demonstrated lower levels of CB1 receptor mRNA expression in the glutamatergic terminals of the dentate gyrus in contrast to postmortem controls of non-epileptic subjects.[40] Interestingly, reduced expression of DAGL α was also found in epilepsy patients, which is the enzyme responsible for 2-AG synthesis postsynaptically.[110] Reduced levels of anandamide have also been identified in the CSF of patients with chronic migraine,[3,111] with subsequent studies showing the gene encoding for the CB1 receptor, CNR1, being linked to a chromosomal region linked with migraine, [112]

and variations in CNR1 gene expression showing predisposition to higher risk of migraine development.[113] Not surprisingly, a clinical endocannabinoid deficiency (CECD) has been posited[114] as being potentially critical in our pathophysiological understanding of migraine and numerous functional pain conditions, such as irritable bowel syndrome (IBS) and fibromyalgia.[3,114] Conversely, elevated levels of endocannabinoids have been noted within normal and abnormal ECS functioning. Increased anandamide plasma levels (but not 2-AG) have been observed after moderate intensity aerobic activity in healthy individuals,[87,115] changing our previous physiological understanding of the association between ‘runner's high’ and reward-seeking behaviours.[116] Additionally, schizophrenia and dysfunction in ECS anatomy and physiology have been observed in the literature. Recent evidence of potential anandamidergic dysfunction has shown markedly increased levels of anandamide in patients with schizophrenia, not only in CSF, but also in plasma, in contrast to healthy controls.[117] Significantly elevated plasma levels of anandamide have been reported in the acute phase of schizophrenia relative to the control group.[118] Moreover, research into the CNR1 gene, which is located on chromosome 6q 14-15, has suggested it may be a susceptibility locus for schizophrenia.[119] SNPs have also been described for the CNR2 gene, which codes for the CB2 receptor, with researchers suggesting that susceptibility for schizophrenia may be increased by a genetically predetermined decrease in functioning of CB2 receptors. [117,120]

Other neurological conditions demonstrate a strong coexistent link between neurodegeneration and inflammation, for which the ECS is being implicated in potential treatment options. Conditions such as HIV-associated dementia and multiple sclerosis (MS) represent inflammatory conditions that lead to wide-ranging neuronal damage, while diseases such as amyotrophic lateral sclerosis ALS [MND – motor neuron disease], Parkinson's disease and Alzheimer's disease are classic neurodegenerative diseases with concurrent tissue inflammation.[121] Marsicano and colleagues posit that neuronal injury and the subsequent release of endocannabinoids may be a protective mechanism,[122] with endocannabinoids, various phytocannabinoids and other exogenous cannabinoids demonstrating neuroprotective activity.[25,54,123] Centonze and colleagues describe a multitude of mechanisms that may be at work in achieving this neuroprotective activity, including: 1 The prevention of excitotoxicity by CB1-receptor-mediated inhibition of glutamate-mediated transmission via the closing of N- and P/Q-type Ca2+ channels 2 A reduction of Ca2+ influx at both the pre- and postsynaptic level, followed by inhibition of subsequent noxious

cascades 3 Antioxidant activity (owing to the phenol group present on certain resorcinol-type cannabinoids) 4 Suppression of the production of tumour necrosis factor-α (TNF-α) 5 Activation of protein B pathway and phosphatidylinositol 3-kinase 6 The induction of the expression of transcription factors and neurotrophins.[121] Both CB1 and CB2 receptors have been found to play an important role in neuroprotection and immunomodulation, respectively,[69,124–127] with ongoing research being conducted internationally, particularly in identifying other cannabinoid receptors within the ECS.

Cardiovascular system With CB1, CB2, endocannabinoids and the associated synthetic and degrading enzymes being present in cardiovascular system (CVS) tissue, the ECS can play an important regulatory role in CVS physiology and the development or progression of common CVS disorders.[13,56,57,128] Studies have demonstrated that in cases of heart failure endocannabinoids are produced by activated monocytes, which in turn contribute to the development of hypotension and negative inotropic activity.[56] Further research shows that under pathophysiological conditions, cardiac myocytes and vascular smooth muscle cells can generate endocannabinoids. These can then interact with CB1 receptors and cause reactive oxygen species and advanced glycation end

product accumulation, which, among other physiological mechanisms, can contribute to cell death and injury.[129,130] Interestingly, upregulation of CB1 receptors and an increase in endocannabinoid expression were noted in the myocardium in these experimental models.[13] Furthermore, this pro-inflammatory effect of CB1 receptors in the CVS has been confirmed in knockout (i.e. of the enzyme FAAH) animal testing and using inhibitors in models of cardiomyopathy and atherosclerosis.[13,130] This CB1 interactivity may pose safety risks, with several case reports showing young adults using cannabis recreationally presenting with CVS problems, but more research is needed to understand the underlying potential risk, the strains of cannabis that may have been used and the potential physiological mechanisms being exploited.[131] Conversely, CB2 receptor involvement in the CVS appears to be protective, with activation decreasing pro-inflammatory and fibrotic responses and initiating protective effects in cardiac myocytes.[13,128] CB2 activation reduces immune cell chemotaxis, inflammatory cell adhesion and cellular activation, which appears to be behind the protective effects in preclinical models of myocardial infarction, stroke, restenosis and atherosclerosis.[128] While a great deal more research into the influence of the ECS over CVS function and pathophysiology is required, it is clear that ECS dysfunction is present (particularly CB1 overactivity) in various CVS diseases and that CB1 antagonists and CB2 agonists are of great clinical interest in pharmacotherapy for specific CVS disorders and conditions.[13]

Gastrointestinal tract As previously mentioned, both CB1 and CB2 receptors are widely distributed throughout the GIT, being highly expressed on enteric nerves and intestinal mucosa. CB1 receptors are specifically present on enteroendocrine cells, immune cells and enterocytes, whereas CB2 expression is mostly observed on immune cells and enterocytes.[13] Recent research has highlighted a

novel mechanism of ECS regulation within the GIT involving the endocannabinoids, primarily 2-AG. While 2-AG is a fast retrograde messenger in neuronal tissue of the brain, within the enteric nervous system it undertakes a previously unknown form of synaptic control involving 2-AG and a purine nucleotide, which work in opposite directions to control synaptic strength[13] and tone. This system has been described as metaplasticity[132] and has reinforced our understanding of the relationship between the GIT and the CNS, showing that virtually all GIT function is regulated by the ECS and that this may lay the foundation for the neuromodulatory control of metabolic and homeostatic functions of the body.[13] Primarily, the ECS is involved in the regulation of nausea, vomiting, food intake and energy,[133] hunger,[134] gastric secretions and gastroprotection, GI motility,[135,136] visceral sensation, ion transport, intestinal inflammation,[137,138] intestinal barrier protection[139] and normal cellular proliferation in the GIT.[140] Most endocannabinoid activity in the GIT is mediated by CB1 receptors under normal physiological conditions, with mesenteric vasodilation, acid suppression, motility stimulation and fluid secretion being examples.[140] With a growing research base demonstrating the connection between a balanced intestinal microbiota and normalised immune, GIT and neurological functioning, it may not surprise many in the naturopathic or herbal fields to read that CB1 expression on enterocytes is regulated by the enteric microbiota, with CB1 activation increasing epithelial permeability by reduced expression of tight gap junction proteins, permiDing bacterial translocation and potential metabolic endotoxaemia[13,139] as sequelae. Blocking CB1 expression therefore may help normalise intestinal barrier function

and has also been investigated for reducing obesity.[13] Conversely, CB2 activation within the GIT can exert a normalising activity in instances of increased gastric motility observed in specific GIT conditions.[136] While an accessory organ of digestion, the liver is also firmly enmeshed in ECS physiology. Both CB1 and CB2 receptors are found in the liver. CB1 receptors are located primarily in stellate cells, hepatocytes and vascular endothelial cells, whereas CB2 receptors are expressed on immune cells, Kupffer cells and myofibroblasts.[13] Activation of the CB1 receptor in the liver promotes vasodilation, which can lead to the development of ascites and increases fat accumulation (faDy liver), insulin resistance[141] and fibrosis.[13] CB2 opposes such changes, reduces cytokine production, is anti-inflammatory (via induction of haemoxygenase-1 switching Kupffer cells from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype), minimises reperfusion injury,[142] is antifibrotic [143,144] and reduces faDy deposition in the liver.[13] This growing understanding of the neuromodulatory role of the ECS and the GIT paves the way to a new perception of gutspecific pathology. Conditions such as IBS,[8] coeliac disease[145] and inflammatory bowel diseases show paDerns of ECS dysfunction or alteration.[146] With CB1 and CB2 receptors and endocannabinoids distributed throughout the enteric nervous system and GIT, and physiological actions that regulate gastric hormone and enteric neurotransmiDer release, suppress immune activation and regulate intestinal permeability,[13] the likelihood that continuing research in this field will unearth new understandings of GIT disease aetiology and pathogenesis is highly plausible.

Immune system As has been demonstrated, CB2 expression predominates in immune cells, particularly CD4+ T-cells, CD8+ T-cells, B-cells, NK cells, macrophages, monocytes and neutrophils. A growing research base shows that anandamide may inhibit immune function by reducing the production of pro-inflammatory cytokines, whereas 2-AG acting through CB2 receptors may inhibit the migratory activities of certain immune cells by modulating various pathways.[13,147] Of particular interest is that studies have shown anandamide reduced IL-6 and IL-8 in human monocytes while also suppressing the release of IL-2, TNF-α and IFN-γ from activated T lymphocytes, the laDer via CB2 receptors.[13,148,149] While more focused human research is needed, a growing body of case study reports in the US suggests that cannabinoid-based therapies may be of benefit in autoimmune, neurodegenerative and neuroinflammatory disorders. While the main focus of this physiological review of the ECS has targeted the larger regulatory systems, evidence exists to show the ECS functioning in a modulatory or regulatory capacity in the skin, muscles, bone and respiratory and reproductive systems. Maccarrone and colleagues provide an excellent review of these systems and ECS involvement.[13,85]

The ECS and clinical challenges There are various clinical challenges in using cannabinoid-based pharmacotherapy for ECS modulation. While certainly not insurmountable, they may require a deviation away from the ‘one size fits all’ pharmaceutical and clinical medical model, to rather embrace a more holistic focus on personalised medicine for the individual. Such deviation can use the latest technological advancements in genetic and biochemical testing to identify mutations and imbalances, respectively, in the individual and therefore allow for accurate dosage titration and even specific cannabis strain or extract selection to develop a patient-centred, customised and highly personalised focus to disease and symptom management.

Clinical endocannabinoid deficiency As already noted, research evidence, along with expert academic and clinical opinion, suggests that a CECD may be a plausible aetiology behind various medical conditions and diseases.[150] In 2008, Russo posited that conditions such as migraine, fibromyalgia and IBS could be due to a CECD.[150] While this is in itself of clinical importance in order to elicit greater understanding of disease aetiology, pathophysiology and potential treatment options for many conditions of unknown cause, perhaps just as important is that it highlights that certain individual differences in endocannabinoid expression may be an important consideration in treatment. The plasma or CSF levels of the various endocannabinoids can be measured to potentially identify ECS involvement and allow for modification or inclusion of various cannabinoid-based therapies, particularly for conditions where current treatment options are resistant.

Receptor expression and genetic polymorphisms Not only can individuals express endocannabinoids at differing levels, but also the receptors they bind to are an important clinical consideration. CNR1 and CNR2 SNPs have been identified, potentially affecting individual receptor expression (upregulation or down-regulation). Of particular interest is CB1 receptor gene SNPs and various halotypes. While their

importance is still a maDer of debate, suggestions that such modifications could increase susceptibility to neuropsychiatric conditions could be plausible.[2,60] Such individual expression could therefore affect both the functional tone of the ECS and how cannabinoid-based therapeutics affect the individual.

ECS enzyme variability While individual receptor expression and endocannabinoid levels are certainly well-established variables that could impact ECS tone and function, so too is any ECS-specific enzyme abundance or deficiency. Endocannabinoids may be affected by innate genetic aberrations or a lack of nutritional components required for their biosynthesis or degradation. Their synthesis and degradation are enzymatically controlled by enzymes such as FAAH, PLC, NAPE and MAGL, identifying yet another potential variable that could impact functional ECS tone and alter cannabinoid-based pharmacotherapy. As can be seen, key to understanding the ECS and its role in homeostatic regulatory mechanisms is that every individual expresses this neuromodulatory system with slight differences. Other variables that need to be considered are age-related changes to organ function as well as individual expression of cytochrome P450 enzymes and pharmacokinetic metabolic biotransformation of key therapeutic constituents of cannabinoid-based pharmacotherapy. The laDer aspect is discussed in greater detail later in the chapter. All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident. Arthur Schopenhauer (1788–1860)

The genus Cannabis The Cannabaceae family (order Rosales) is a relatively small family of flowering plants encompassing around 11 genera and 170 different species.[151] The Cannabis genus encompasses several species that have been highly prized since ancient times for use as a medicine[152] or foodstuff[153] and in textile and cordage production.[154–157] The psychoactive effects of the plant have also seen it used in various spiritual and shamanistic practices and rituals throughout the ages.[158,159]

History of use The inflorescences, seeds, leaves, stems, glandular trichomes and roots of the cannabis plant have been a valuable commodity and medicine to humans for millennia. The plant is believed to have originated in central Asia,[160,161] with 20th-century scholars placing the centre of Cannabis genus diversity in a region extending from the Pamir plain of Tajikistan and bordering Afghanistan, Kyrgyzstan and the Xinjiang region of Western China.[162] However, more recent ethnobotanical modelling suggests it originated in the Himalayan mountains from Kashmir to Nepal and into Bhutan and Burma,[161,163,164] and probably spread from there through human use and trade. Specific psychoactive strains, most likely the broadleaf drug variety Cannabis indica subspp. afghanica, which is rich in THC, originated in the laDer region, spreading through China, India, the Middle East and regions of Northern Africa via established trade routes. The seeds of this subspecies and others would have been highly valued for their medicinal qualities and enabled the spread and cultivation of the plant, as well as its own hybridisation and evolution, across the ancient world. A more detailed review of the ethnobotany of the Cannabis genus and its evolution is provided in Clarke and Merlin, for example.[161] Determining the exact time that our hominoid ancestors started using Cannabis spp. is difficult to quantify due to the fact that its cultivation, use and consumption most probably predated currently accepted archaeological timelines for the appearance of writing in human evolution.[160] Some of the earliest evidence of human usage of Cannabis spp. is as a fibre in a net made by the GraveDians, an Upper Palaeolithic industrial culture situated throughout Europe.[165] Primarily hunters and gatherers, hunting nets made from cannabis fibre used by these people have been dated between 24 980 and 22 870 BCE.[166] Ethnobotanical evidence from Taiwan Province of China posits that cannabis was used as a fibre some 10 000 years ago.[167] More recent archaeological evidence suggests that various Cannabis spp. have been used since the late Neolithic period (4000– 2000 BCE) throughout Asia as a medicine, fibre crop, food and entheogen,[159,168,169] while several respected scholars believe it has been used for at least 10 millennia or possibly longer as a medicine.[155,161,168] Cannabis was a valuable medicine in many cultures in the ancient world. The use of cannabis as a medicine in China was

first aDributed to the Chinese Emperor Shen Nung (ca. 2700 BCE),[157,160,170] based on the Shen-nung Pen-tsao Ching (Divine Husbandman's Materia Medica). Similar evidence has been found in the wriDen histories of India, the Atharvaveda (1500 BCE) and Sushruta Samhita (800–300 BCE).[171,172] Confirmation of the therapeutic use of cannabis also exists from Persia (600 BCE), found in the Zend-Avesta,[172] and Egypt from wriDen evidence[173] encoded within stone in the Pyramid Texts from Memphis (2350 BCE)[162] and later in the Papyrus Ramesseum III (1799 BCE), Hearst Papyrus (ca. 1550 BCE), Ebers Papyrus (ca. 1550 BCE) and Berlin Papyrus (1300 BCE).[162] Because of established trade routes within Asia and the Middle East, this knowledge spread throughout the Mediterranean too, with the Greek historian Herodotus (ca. 484–425 BCE) writing of cannabis use by the Scythians in the 5th century BCE.[167] The classic Greek herbalists Dioscorides, Galen and Pliny[153] wrote of the medicinal virtues of this plant in detail, with Dioscorides describing the plant in his magnum opus, De Materia Medica, which was used throughout the world as a foundational medicinal text for almost 1500 years. Numerous Arabic physicians wrote about cannabis in managing various pathologies, including Ibn al-Baytar, Ishaq Ibn Sulayman[162] and the famous Avicenna, Ibn Sina, who wrote of it in the Canon of Medicine (ca. 1025 CE). While deemed an inebriant and forbidden under Islam recreationally, cannabis was nonetheless still revered as a medicine. With the Muslim conquest of the Iberian peninsula (i.e. Spain and Portugal) in the 7th century, and later parts of North Africa, Cannabis spp. probably spread to places such as Northern Morocco,[174] where it currently inhabits large regions such as the Rif Mountains. From here it could have spread through Western Europe. Credited with bringing Cannabis spp. into Western medicine, the Irish doctor William B. O'Shaughnessy (1809–1889) was an assistant surgeon contracted to the East India Company. He became fascinated with the therapeutic benefits of the Cannabis genus while in India, identifying antiemetic, appetite stimulant, analgesic, muscle relaxant and anticonvulsant actions.[160] He took this information back to London and was elected into the Royal Society as a Fellow for his contributions to science. Following this, cannabis swept through European dispensaries, being used in patent medicines and as a ‘simple’, and included in the United States Dispensatory in 1854.[175] This continued throughout most of the developed world until problems with lack of standardisation, quality assurance and an inability to accurately titrate dose hampered its use in a growing scientific evidence-based medical profession in the early to mid-20th century.[162] In 1937 the passing of the Marijuana Tax Act (US) effectively made cannabis use illegal, even though this was opposed by the American Medical Association at the time. This eventually led to Cannabis spp. being classified as a Schedule 1 drug of addiction in accordance with the Controlled Substances Act (US), and international laws prohibited its trade and use soon after. It is only now, in certain international jurisdictions, and after isolating many of the key phytochemicals within the various Cannabis species, that this herbal medicine is being reintroduced to the medical armamentarium and is gaining acceptance once more.

Botany and morphology Cannabis and its relevant species (Cannabis indica, Cannabis sativa, Cannabis ruderalis) and subspecies of medicinal interest are annual, herbaceous (i.e. green-stemmed), dicotyledonous (i.e. possesses a taproot), dioecious (i.e. female and male reproductive parts occur on separate plants) flowering plants (angiosperms) (see Fig. 20.5).[10,161,176] Rarely, Cannabis spp. may exhibit monoecious characteristics (i.e. male and female reproductive parts occur on the same plant), but true hermaphrodism is uncommon.

FIGURE 20.5

Graphic representation of Cannabis sativa Franz Eugen Köhler's Medizinal-Pflantzen. Published and copyrighted by GeraUntermhaus, FE Köhler in 1887 (1883–1914). Obtained from http://caliban.mpiz-koeln.mpg.de/~stueber/koehler.

Morphologically, Cannabis spp. exhibit a strong taproot (dependent on plant size and genetics) between 120 and 240 mm deep, with a strong erect stem, which is roughly round to hexagonal in cross-section.[10] The stem is usually 1–3 m tall and often hollow, with male plants typically being less tall and robust than female plants.[10] Leaves exhibit opposite or alternate petiolate aDachment with the characteristic palmately compound leaf arrangement comprising 5–11 leaflets, they are typically lanceolate to linear in shape and the leaf margin is serrate, terminating in an acuminate apex.[10] The part of medicinal interest is the unfertilised female inflorescence, which is typically green (occasionally red or purple depending on genetics) and sessile.

Proximal surfaces of the bract are covered in capitate glandular trichomes.[10] The bracteole is covered with resinous glandular trichomes and the calyx measures 2–6 mm in length and contains the ovary which produces the fruit (seed),[161] which is an achene.[10] A full botanical and morphological description of the Cannabis genus is beyond the scope of this textbook. For further information, the American Herbal Pharmacopoeia monograph on Cannabis inflorescence[10] is highly recommended as being authoritative on the subject.

Taxonomy and nomenclature The taxonomic classification of the Cannabis genus has undergone considerable and rigorous academic and legal debate over the last 100 years[177] based on the necessity to provide a scientifically acceptable statement not only to confirm the orientation and hierarchy of the Cannabis genus taxonomically, but also to potentially identify lawful versus illicit species for legal commercial use.[165] Emerging scientific fields such as plant genetics and chemotaxonomy have been added to the arsenal of traditional botanical studies of taxonomy and morphology, enabling detailed analysis of the plant. The evolution of this contentious taxonomic debate has up until recently embraced two major models for the Cannabis genus, believing that it exhibits either monotypic (single species) or polytypic (multiple species) characteristics.[10,153,155] Cannabis sativa was first described by Carl Linnaeus in 1753,[10,165] seDing up a single species orientation for the genus. Some 32 years later, French biologist Jean Lamarck challenged the single species convention by describing Cannabis indica, which exhibited very different morphological characteristics from C. sativa, such as poor bast fibre (phloem), smaller leaves, narrower leaflets, shorter habit and greater use as an inebriant (i.e. psychoactivity).[10] By 1849, Delile had described a new species from China named Cannabis chinensis and later in 1851 described another species Cannabis gigantea.[165,178] Russian botanist Dmitri Janischewsky described a new species named Cannabis ruderalis in 1924, and later in 1929 Vavilov and Bukinich named a new variety of Cannabis indica var kafiristanica.[10,165] With a growing body of botanical evidence, between 1974 and 1980 Schultes[155,179] and Anderson[180] undertook reviews finding evidence supporting the polytypic model, yet Small and Cronquist[181] analysed 350 worldwide accessions in a common garden experiment in 1976 positing that only one polymorphic species, C. sativa, existed. Finally, in 2005 genetic and phytochemical evidence was brought to bear in this growing taxonomic argument by Hillig[182] using cannabinoid[183] and terpene profiles[184] as well as host–parasite data.[10] Findings included the recognition of a sativa gene pool inclusive of seedand fibre-rich landraces located in Central Asia and Europe, an indica gene pool rich in cannabinoids originating from Pakistan, Afghanistan, South America, Southern Asia and Africa, and a third ruderal gene pool from ruderal accessions in Central Asia.[10] This has been further expanded by Clarke and Merlin,[161] based on the work by Hillig, classifying the various Cannabis spp. into different biotypes, as shown in Table 20.1. TABLE 20.1

Different Cannabis spp. gene pools (biotypes) Biotype

Latin binomial

Range

Uses

PA NLHA NLH BLH NLDA NLD BLD

Cannabis ruderalis C. sativa subspp. spontanea C. sativa subspp. sativa C. indica subspp. chinensis C. indica subspp. kafiristanica C. indica subspp. indica C. indica subspp. afghanica

North Central Asia Eastern Europe and Central Asia Europe China, Korea, Japan, Southeast Asia Himalayan foothills Southeast Asia, Middle East Afghanistan and Pakistan

Seed and fibre Seed and fibre Seed and fibre Seed and fibre Drug/hashish Drug/hashish/seed and fibre Drug/hashish

PA, putative ancestor; NLHA, narrow-leaf hemp ancestor; NLH, narrow-leaf hemp; BLH, broad-leaf hemp; NLDA, narrow-leaf drug ancestor; NLD, narrowleaf drug; BLD, broad-leaf drug. Source: Adapted from Clarke R, Merlin MD. Cannabis evolution and ethnobotany. Berkeley, CA: University of California Press; 2013

McPartland[185] has since proposed a revised nomenclature at the 2014 meeting of the International Cannabinoid Research Society. The extensive crossbreeding practices by breeders and natural cross-pollination[10] make accurate botanical identification difficult, and while the introduction of genetics into the taxonomic discussion has certainly increased knowledge, this new nomenclature is not yet universally accepted academically. The International Code of Nomenclature for Cultivated Plants has suggested that a cultonomic, rather than purely botanical, differentiation of nomenclature may be more appropriate in modern applications, as it is based on economically or medicinally important characteristics such as a THC drug group, the cannabidiol (CBD) drug group or fibre-hemp groups.[10] Less contentious are the common names associated with Cannabis spp. and its products, including ganja, hemp, kif, marijuana, bhang, weed, hashish (i.e. pure glandular trichomes), pot, grass, dagga, charas and sinsemilla (i.e. female, unfertilised inflorescence only).[10,161]

Cultivation and growth cycle Cannabis sativa and Cannabis indica are known to be affected by photoperiodism, which is defined as the developmental response or physiological reaction of a plant to the relative length of the daylight cycle. The growth cycle of Cannabis spp. is quite unique. During spring and summer months, when sunlight exposure is approximately 15–18 hours per day (depending on geographical location), the plants undertake vegetative growth. During this phase, they maximise growth of the leaves to produce carbohydrates through photosynthesis, which provides the fuel to increase the growth and vitality of the plant. As the sunlight wanes and reduces in length in autumn and winter, dropping down to 10–12 hours per day,[161] this initiates the process of flowering, which is the main morphological structure of interest medicinally. Conversely, Cannabis ruderalis produces inflorescences based on its age, not light exposure – a flowering process known as autoflowering.[165] As such, this species is favoured among certain social growers who know liDle about the select needs of the plant. The time from seedling to harvest is typically 75 days. Of particular interest is that Cannabis ruderalis is seen as being the species exhibiting the lowest profile of phytochemicals of specific medicinal interest, and is seen as inferior to Cannabis indica and Cannabis sativa and associated hybrids/phenotypes. This understanding of photoperiodism and the regulation of light has enabled cannabis to be grown indoors, a popular method of cultivation in jurisdictions where medicinal and social cannabis use is legal and consistent sunlight is difficult to obtain. Indoor cultivation also enables the tight regulation of factors such as humidity and temperature that optimise phytocannabinoid and terpene production. Growers also use technology that is designed to replicate the sun's UV spectrum by using lights that emit high photosynthetic photon flux density (PPFD). Through the specific use of fluorescent, metal halide, high-pressure sodium and light-emiDing diode technology,[165] plants can grow quickly, but whether these forms of technology can ever truly replicate the broad spectrum of photons available, for free, from the sun is currently a maDer of scientific investigation and debate. Indoor operations use large amounts of energy to power the lighting and cooling systems, which increases costs and contributes to greenhouse gas emissions, therefore making outdoor cultivation or the use of greenhouses with supplemental lighting a more environmentally sustainable and cost-effective option to optimise net clinical and economic benefit. In modern cannabis cultivation, unfertilised female inflorescences (florets) are considered to have the highest concentration of tetrahydocannabinolic acid (THCA), which can be converted into the psychoactive and medicinally potent THC and its derivatives through the use of heat, drying and curing.[10] Numerous other cannabinoids and terpenes are located within the glandular trichomes of the inflorescence.[8] As such, it is common horticultural practice to use female clones[165] from a mother plant, which will be phytochemically and genetically identical if growing conditions are optimally stable. Male plants, once identified after a relatively short period of propagation from seed, are removed early so that they cannot release pollen, which would send female flowers in the surrounding environment to seed and thus reduce the phytochemical concentration of medicinally active constituents.

Cannabis phytochemistry The various species and strains of the Cannabis genus exhibit complex secondary metabolites that can be used as therapeutic agents. Currently researchers have identified more than 750 different phytochemical constituents[10] from Cannabis spp., many of which are located within the specialised glandular trichomes found on the inflorescence of the plant. ElSohly describes a broad spectrum of phytochemical constituents within the plant, including phytocannabinoids (i.e. plant-derived cannabinoids),[5] terpenes, flavonoids, nitrogenous compounds (i.e. alkaloids), amino acids, glycoproteins, enzymes, hydrocarbons, alcohols, aldehydes, ketones, faDy acids, steroids, phenols (non-cannabinoid) and vitamins.[186] Of greatest clinical interest since phytochemical research has been undertaken on the plant are the cannabinoids. Cannabinoid concentration within the plant depends largely on the genetics (genotype), sex and senescence of the plant, but many environmental variables such as light exposure, light intensity, temperature, elevation, soil pH and soil mineral concentration play an important role.[10,176,187,188] To date, more than 66 cannabinoids[5,186,189–193] have been identified, belonging to several subclasses, of which the cannabigerol (CBG) type, cannabichromene (CBC) type, THC type, CBD type, Δ8tetrahydrocannabinol (delta-8-THC) type, cannabinol (CBN) type and cannabinidiol (CBDL) type exist.[5,186,194] The CBN and CBDL types are viewed as being artefacts of oxidation of the parent compounds THC and CBD, respectively.[186,195] All cannabinoids, along with the terpene class, undergo biosynthesis and storage within the glandular trichomes of the plant.[10] Structurally, the cannabinoids are terpeno-phenolic compounds derived from the enzymatic condensation of both a terpene moiety (i.e. geranyl pyrophosphate) and a phenolic moiety (i.e. generally olivetolic or diverinic acid).[196] This is catalysed by the enzyme geranylpyro​phosphate:olivetolate geranyltransferase (GOT) and produces the progenitor compound cannabigerolic acid (CBGA), from which the major cannabinoid acids are derived.[197] Cannabidiolic acid (CBDA), Δ9tetrahydrocannabinolic acid (THCA) and cannabichromenic acid (CBCA) are the main acidic cannabinoids produced from the oxidocyclisation of CBGA by the independent enzymes, CBDA-synthase, THCA-synthase and CBCA-synthase, respectively.

[10,196]

See Fig. 20.6.

FIGURE 20.6

Cannabinoid biosynthesis Adapted from Giacoppo S, Mandolino G, Galuppo M, et al. Cannabinoids: new promising agents in the treatment of neurological diseases. Molecules 2014;19(11):18781–816.

Cannabinoids have certain chemical characteristics that are considered pharmacologically important. Of primary interest is that the cannabinoids are stored in a carboxylated (i.e. COOH) form within the plant, making them cannabinoid acids and devoid of any psychoactive pharmacological effects.[196] This carboxylic acid group is aDached to the phenolic ring of the cannabinoid acid structure[196] and stops the phytochemical from binding to cannabinoid receptors. It is only through exposure to drying or heat that decarboxylation takes place[10,196] and the various cannabinoid acids are converted into their active forms and can thus interact with receptors (see Fig. 20.7).

FIGURE 20.7

The decarboxylation process Adapted from Giacoppo S, Mandolino G, Galuppo M, et al. Cannabinoids: new promising agents in the treatment of neurological diseases. Molecules 2014;19(11):18781–816.

Secondly, the alkyl group positioned at the third carbon atom is deemed an important site for substrate/receptor interactions.[10] In the case of major cannabinoids such as THC, CBG, CBD and CBN, this is typically a pentyl group (C5), but it can also extend to being a propyl group (C3).[198] In such cases, the suffix ‘varin’ is added to the original pentylated analogue, [10] for example cannabivarin (CBV), cannabigerovarin (CBGV), cannabidivarin (CBDV) and tetrahydrocannabivarin (THCV), each of which exerts its own pharmacological activity (see Fig. 20.8),[199,200] but these are much less researched than the major cannabinoids.

FIGURE 20.8 List of actions associated with the cannabinoids. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoidterpenoid entourage effects. Br J Pharmacol 2011;163(7):1344–64. Upton R, ElSohly M, Romm A, et al (eds). Cannabis inflorescence. Scotts Valley, CA: American Herbal Pharmacopoeia; 2013. Elsohly MA, Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 2005;78(5):539–48. Howard P, Twycross R, Shuster J, et al. Cannabinoids. J Pain Symptom Manage 2013;46(1):142–9.

Based on their unique structure, cannabinoids are highly lipophilic, which enables them to both cross the blood–brain barrier and penetrate cellular membranes,[10] allowing many different phytochemical dosage forms to be used in clinical practice. The various major cannabinoids and other phytochemical classes are discussed in more detail below.

Delta-9-THC Having been first discovered in 1964, it is not surprising that there is a large amount of research on this cannabinoid in the literature. Once THCA undergoes decarboxylation, it produces the active compound THC (see Fig. 20.9). Interestingly, THCA is not just a simple progenitor compound, but has been shown to be a TRPA1 partial agonist and a TRPM8 antagonist, both potentially suggestive of a role in analgesia.[201]

FIGURE 20.9

THC structure

THC is a partial agonist[200,202] at both the CB1 and the CB2 receptors with relatively high affinity, expressing similarity to the endogenous cannabinoid anandamide.[8,10,203,204] Interacting with the CB1 receptor, THC is the main psychoactive phytochemical contained within drug varieties of Cannabis spp.; however, its main active metabolite after absorption is 11-OHTHC (11-hydroxy-THC), which is more potent therapeutically[5,200] and has higher permeability for the blood–brain barrier. Of interest is that 11-OH-THC is found in higher amounts after oral ingestion due to liver biotransformation than for inhalant methods of administration. A wide range of therapeutic activity has been described for THC in the literature, including analgesic,[106,205] antiinflammatory, antioxidant, neuroprotective,[206] muscle relaxant,[207] bronchodilatory,[208] antipruritic,[209] anticancer,[210–216] appetite stimulant and antiemetic actions.[8,217] Such pharmacological activity makes it clinically useful for many different

indications, including neuropathic pain,[218,219] migraine,[3] cancer pain,[220,221] chemotherapy-induced nausea and vomiting,[222] chronic pain,[223] weight loss in cancer and AIDS patients (i.e. as an appetite-promoting agent),[224] spinal cord injury,[225] postsurgical pain and phantom limb pain.[10] It also holds value for the management of various neurological disorders such as multiple sclerosis (i.e. muscle spasticity)[226] and Alzheimer's disease,[227] and can lower intraocular pressure in glaucoma.[228] THC exhibits significant anti-inflammatory activity, which may be a mechanism of action of great therapeutic interest, particularly in neurological degenerative disorders (and when combined with other cannabinoids such as CBD),[196] with studies suggesting that THC has 20 times the anti-inflammatory power of aspirin and twice the strength of hydrocortisone. [8,229]

THC is not without adverse effects, however. In numerous clinical studies it has been shown to produce central effects such as anxiety, restlessness and dysphoria in certain individuals or at high dose. Interestingly, when administered with other cannabinoids, particularly CBD, this can be mitigated.

THCV Belonging to the THC cannabinoid type subclass, THCV is the propyl (CH2—CH2—CH3) homologue of THC,[10] but lacks major psychoactive effects. Unlike THC, which is derived from CBGA, THCV is derived when geranyl pyrophosphate binds with divarinolic acid to produce cannabigerovarin acid (CBGVA). Divarinolic acid has two fewer carbon atoms and therefore makes THCV propyl instead of pentyl like THC, CBD, CBG and CBN.[10] CBGVA is then broken down via THCV synthase to tetrahydrocannabivarin carboxylic acid, and in a similar decarboxylation process to CBD and THC via exposure to heat or drying, degrades to THCV (see Fig. 20.10).

FIGURE 20.10

THCV structure

Generally, THCV occurs in cannabis in small concentrations, although plant breeding projects are aiming to soon correct this. THCV is a CB1 antagonist at low doses,[230] but with high doses it can act as an agonist at both the CB1 and the CB2 receptors.[10,231] Research is currently being conducted into its potential appetite suppressant action, with preliminary data suggesting that it can produce weight loss and decreased body fat in animal models.[232] Research has shown anticonvulsant, euphoric, anti-inflammatory and analgesic properties for THCV, as well as antioxidant and neuroprotective effects.[10,231]

CBD CBD is a non-psychoactive cannabinoid with a well-established safety profile[201] that is derived from CBDA once decarboxylation has taken place. Next to THC, it is the most extensively studied cannabinoid, particularly in recent times in the field of epilepsy and other neurological conditions. Intriguingly, CBD displays very liDle affinity for cannabinoid receptors, which probably contributes to its lack of psychotropic activity.[233] As such, emphasis has focused on noncannabinoid receptor interactivity for CBD, with research demonstrating that it is an agonist at serotonin (5-HT1A) receptors and TRPV1 and TRPV2 receptors,[233–235] while also enhancing the activity of α1 and α3 glycine receptors, the transient receptor potential of ankyrin type 1 (TRPA1) channel and PPAR-γ (i.e. at a higher concentration). CBD has been found to be a blocker of the equilibrative nucleoside transporter (ENT) GPR55[236] and the transient receptor potential of melastatin type 8 (TRPM8) channel.[233] This diversity and complexity, along with its unique polyphenolic structure (see Fig. 20.11), makes it both a potent antioxidant and a truly unique multi-target phytochemical.[233]

FIGURE 20.11

CBD structure

CBD is an antagonist of cannabinoid receptors agonists and has been found to reduce the psychoactivity of THC when coadministered, reducing symptoms such as paranoia, dysphoria and anxiety,[237–242] while also potentiating THC's beneficial

effects to enhance its tolerability and broaden its therapeutic scope.[233,243] This phytochemical synergy is discussed later in more detail and is what researchers are terming the ‘entourage effect’. It provides a theory as to why full-spectrum extracts maximising various cannabinoids (and other phytochemicals such as terpenes) may be more effective therapeutically than single active synthetic or naturally derived isolates. With a broad array of interactivity at various receptors, CBD has an equally wide scope therapeutically. CBD has wellresearched anti-inflammatory activity, and it has been suggested that it can enhance adenosine signalling by inhibiting adenosine inactivation.[236] Adenosine A2A receptors can down-regulate immune cell over-reactivity, which can protect from inflammatory damage and pain. While CBD is a potent anti-inflammatory,[244] it also exhibits significant neuroprotective,[25] antioxidant,[245] immunomodulatory,[25] anticonvulsive,[246] antipsychotic,[10,247–249] anxiolytic,[250] antidepressant,[192] hypnotic, sedative, anticancer,[251–256] analgesic and antiemetic activity.[10] Due to a well-established safety and tolerability profile, along with absent psychoactivity, CBD is an incredibly promising agent in a number of medical conditions, particularly neurological conditions. Evidence and research are supportive of the application of CBD therapeutically in conditions such as multiple sclerosis,[25,257] epilepsy,[233,246,258–260] psychosis/schizophrenia,[249,261,262] Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis[263] and neurodegenerative diseases such as Alzheimer's disease,[264] although more research needs to be conducted across many of these conditions to fully understand the mechanisms of action and CBD's therapeutic potential. Interestingly, the propyl analogue of CBD, CBDV, may share a synergistic activity with CBD as it also demonstrates a noted anticonvulsant activity in animal models.[8,265,266]

CBG CBG (see Fig. 20.12) is found in small concentrations in THC-rich strains, but in much higher concentrations in hemp strains commonly grown for fibre or seeds. Viewed as a minor therapeutic cannabinoid, a growing pool of research is making scientists look at this cannabinoid with more clinical interest.

FIGURE 20.12

CBG structure

CBG is a non-psychoactive cannabinoid, with studies demonstrating it exhibits activity such as being a GABA uptake inhibitor,[267] an antagonist to TRPM8[268] and an alpha-2-adrenocorticotropic receptor agonist[269] and shows potential uptake inhibitory activity at 5HT1A receptors.[10,267] Key areas of clinical interest for this cannabinoid are as an antimicrobial agent,[270] in psoriasis due to its ability to inhibit the proliferation of keratinocytes, as a potential anticancer agent[251] and as a potent analgesic exhibiting superiority over THC.[10,229]

CBC Derived from CBGA, CBC (see Fig. 20.13) interacts with TRPV1 with strong affinity and is also a TRPA1 agonist[271] that can inhibit endocannabinoid inactivation, which could explain its anti-inflammatory effect.[10,193] Interestingly, it exhibits poor affinity for the CB1 receptor. Weak anandamide inhibition has also been noted in the literature.[251] Research on CBC is scarce, but demonstrates that this cannabinoid exhibits strong antibacterial activity and mild-to-moderate antifungal activity[272] and is a weak analgesic.[193]

FIGURE 20.13

CBC structure

Delta-8-THC Defined as a lesser cannabinoid, not a great deal of research interest has been expressed in delta-8-THC. While not completely non-psychotropic, it exhibits less psychotropic activity than THC and therefore may be more clinically appropriate. It has been shown to stimulate the appetite, [273] and also possesses antiemetic and analgesic actions.

Terpenes The terpene class can be thought of as the essential oil phytochemical class contained within the glandular trichomes of Cannabis spp., and undergoes synthesis via the terpene moiety geranyl pyrophosphate. This class is responsible for the different aromas and tastes throughout the various strains of the Cannabis genus and is based chemically off the isoprene unit, a 5-carbon structure (see Fig. 20.14).[274] Terpenes found in the Cannabis genus are mainly of monoterpene (C10H16) and sesquiterpene (C15H24) derivation[10]; diterpenes (C20H32) and triterpenes (C30H48) are also observed, but in lesser amounts.[10]

FIGURE 20.14

Isoprene (C5) structure

To date, more than 200 terpenes[275,276] have been identified in the various Cannabis spp., but none of unique presentation within the genus that have not been identified in other flora. While terpene composition within the plant is under genetic control,[277] environmental variables such as light exposure and decreased nitrogen can produce higher terpene yields prior to harvest.[8] Terpenes exhibit their own potent and diverse pharmacology, are highly lipophilic (like the cannabinoids) and have the potential to interact with cell membranes, enzymes, second messenger systems, neurotransmiDer receptors and neuronal ion channels.[8]

Monoterpenes (C10H16) The monoterpene class usually predominates distribution throughout the various Cannabis spp., with 47–92% of volatile oil extracted from the inflorescence coming from this class alone.[276] Examples of note are β-myrcene, pinene and limonene (see Fig. 20.15), with α-pinene and limonene acting as biological insect repellents to protect the plant.[8] Due to their structure, monoterpenes are incredibly volatile and heat-sensitive. They are also prone to loss during storage and drying procedures, so handling crude herb after harvest and appropriate manufacturing procedures are critical to maintaining phytochemical integrity.

FIGURE 20.15

Structural representation of various monoterpenoids (a) β-myrcene (b) limonene (c) α-pinene

β-myrcene With noted sedative, muscle relaxant, analgesic[278] and anti-inflammatory properties,[279] β-myrcene is a very useful therapeutic phytochemical. Evidence suggests that it can block hepatic carcinogenesis by aflotoxin in vitro,[280] although most of its pharmacological actions show prominence in the area of pain management. The anti-inflammatory action has been shown to be due to prostaglandin-E2 (PGE-2),[281] whereas the muscle relaxant action has been shown to potentiate barbiturate sleep time in an animal model.[8] Working by different mechanisms of action to the sedating and analgesic THC, a useful synergy may be therapeutically useful for intractable pain conditions. α-pinene α-pinene, a bicyclic monoterpene, is one of two isomers of pinene that is ubiquitously distributed throughout the plant kingdom.[8,282] It is responsible for the characteristic pine fragrance encountered in the division conipherophyta (i.e. conifers: fir, pine, redwood, spruce, yew, cypress), where it exists as an insect repellent secondary metabolite.[8] Like β-myrcene, it exhibits anti-inflammatory activity but via PGE-1, while uniquely exhibiting bronchodilatory activity via inhalation, and has demonstrated acetylcholinesterase inhibitory activity.[283] Limonene Being the second most distributed terpene in nature, [282] D-limonene is commonly found in members of the Citrus genus

(family Rutaceae). D-limonene is the most common isomer that is used commercially in food and cosmetic production, and like α-pinene it is produced as a secondary metabolite as an antifeedant and insect repellent. D-limonene exhibits a powerful and diverse pharmacology, with antidepressant,[284] anxiolytic,[285] anticancer[286] and immunostimulant actions, the last via inhalation.[8,284] Further research has posited that the anxiolytic action is mediated by increasing serotonin in the pre-frontal cortex mediated by 5-HT1A in animal studies,[287] and later human clinical studies demonstrated normalised Hamilton depression (HAM-D) scores via citrus essential oil aerosol dispersal.[284]

Sesquiterpenes (C15H24) Comprised of three isoprene units, the sesquiterpene class is expressed less than the monoterpenes in most cannabis samples. Surprisingly, over time the levels of sesquiterpenes in plant samples may actually increase due to the evaporation of the more volatile monoterpene class.[276] Representative examples of this class include β-caryophyllene, caryophyllene oxide, αhumulene, farnesene, elemene, trans-nerolidol and bergamotene.[10,184,276,288] β-caryophyllene Commonly distributed throughout plants such as Piper nigrum (black pepper) and Syzygium aromaticum (clove), βcaryophyllene is a secondary metabolite involved as an insect repellent.[277] Therapeutically it exhibits anti-inflammatory activity via PGE-1, along with antimalarial and gastric cytoprotective activity.[8,289] β-caryophyllene has also been shown to be a selective CB2 receptor agonist, directly interacting with the ECS. Caryophyllene oxide Found also in Melissa officinalis (lemon balm), this non-toxic and non-sensitising sesquiterpene is ubiquitously distributed throughout the Cannabis genus, and for this reason it is generally considered to be the substance responsible for cannabis detection by canine drug units.[8] The plant produces this terpenoid as an antifeedant and insecticide, but it also has potent antifungal activity that is required in plant protection.[8] The laDer action has also been demonstrated in an in vitro experimental model for onychomycosis, where it was found to be comparable to ciclopiroxolamine and sulconazole in an 8% preparation that achieved resolution (fungal eradication) within 15 days.[8,290] For a summary of the actions of the major terpenoids within the Cannabis genus, see Fig. 20.16.

FIGURE 20.16 List of actions associated with the terpene class Russo EB. Taming THC: potential cannabis synergy and phytocannabinoidterpenoid entourage effects. Br J Pharmacol 2011;163(7):1344–64. Upton R, ElSohly M, Romm A, et al (eds). Cannabis inflorescence. Scotts Valley, CA: American Herbal Pharmacopoeia; 2013. Noma Y, Asakawa Y. Biotransformation of monoterpenoids by microorganisms, insects, and mammals. In: Baser K, Buchbauer, G (eds). Handbook of essential oils: science, technology, and applications. Boca Raton, FL: CRC Press; 2010.

Flavonoids As of 2013, 29 flavonoids had been characterised within the Cannabis genus, belonging to mainly the flavonol and flavone classes.[291] Many of the flavones and flavonols found in Cannabis spp. are found in numerous other medicinal plants, with specific flavone distribution including luteolin, orientin, vitexin, isovitexin and apigenin, and flavonol-specific examples including kaempferol and quercetin.[10,186] Flavonoids generally exhibit anti-inflammatory activity, with specific flavones such as apigenin expressing phyto-oestrogenic activity. The Cannabis genus, particularly the drug varieties such as Cannabis indica, produce unique flavanones known as cannflavins A, B and C.[10] These flavanones are prenylated aglycones that have been found to inhibit prostaglandin E2 production as well as cyclooxygenase enzymes.[292]

Alkaloids Two alkaloids belonging to the spermidine class (C-21 alkaloids), cannabisativine (C21H39N3O3) and anhydrocannabisativine, have been identified in Cannabis spp. samples.[293] Research is ongoing as to whether they have any specific therapeutically important actions.

Other pharmacological classes Numerous other phytochemical classes are distributed throughout the Cannabis genus, but are beyond the scope of this textbook. While the focus of this chapter is on the Cannabis genus, other herbal medicines also interact with the ECS in meaningful ways. – Piper methysticum (kava-kava) is a social and ritualistic beverage commonly enjoyed throughout Fiji and the Polynesian archipelago. Most studies of standardised extracts of kava lactones have focused on GABAB receptor activity, which modifies muscle tone and anxiety states. However, recently yangonin has been shown to exhibit significant CB1 binding activity, but whether it possesses agonistic or antagonistic activity is still being researched[27]

– Known as Japanese liverwort, Radula perroOetii contains a structural THC analogue known as perroDetinene, but no clinical research has been conducted on its potential cannabimimetic activity.[27] New Zealand liverwort, Radula marginata, possesses perroDetinenic acid,[294] with research indicative that it is a CB1 agonist. The clinical

applications of both plants is currently unknown – Whole plant extracts of Salvia divinorum have tested positive for CB1 activity and the humble Daucus carota (Queen Anne's lace), which contains falcarinol, has been found to covalently bind CB1 receptors acting as an inverse agonist[27] – The purple cone flower (Echinacea spp.) contains alkylamides that have been shown to resemble the structures of anandamide and 2-AG and modulate TNF-α gene expression via the CB2 receptor.[295] CB2 receptor agonism has also been demonstrated along with modulation of cAMP, the ability to inhibit anandamide in vitro, and partial inverse agonist activity at the CB1 receptor.[27,296,297]

It is anticipated that with new understanding of the influence and physiological mechanisms of the ECS, more research will be undertaken into herbal medicines and other natural compounds that may interact with it and exert clinical application.

Phytochemical synergy (entourage effect) The concept of multiple phytochemicals interacting in dynamic and meaningful ways to augment or support each other's absorption, reduce side effects or increase therapeutic potency is not a new concept to naturopathic or herbal practitioners, with examples of synergy being discussed in pharmacopoeias and formulary since ancient times.[298] Multiple herbal medicines, or indeed phytochemicals within the same plant, can have supportive and augmenting effects and complex interactivity. Science is now validating this concept, with Wagner and Ulrich-Merzenich identifying several synergistic mechanisms by which this can occur, including: – Multi-target effects (i.e. targeting multiple receptors or organ systems at one time) – Pharmacokinetic effects (i.e. modifying absorption, distribution, metabolism, excretion [ADME], improving bioavailability or improving solubility) – Modulation of adverse events (i.e. reducing side effects).[299] While studying the interactivity of endogenous faDy acid glycerol esters enhancing 2-AG activity, Ben-Shabat and Mechoulam[300,301] coined the term ‘entourage effect’ to describe this synergy. Since then, research into cannabinoids and terpenes has highlighted that this synergistic phenomenon also occurs between active constituents within the cannabis plant. Several examples of phytochemical synergy have been posited. CBD has been shown to reduce the severity of the psychotropic activity of THC when used in combination,[8] which highlights the benefits of both THC and CBD being included at varying ratios in plant and full spectrum extracts to modify therapeutic outcomes. More interesting is the synergistic potential between cannabinoids and terpenes. β-myrcene, a monoterpene found in Humulus lupulus (common hops) and various other herbal medicines such as cannabis, has muscle relaxant, hypnotic, antiinflammatory and sedative actions associated with its clinical use, so when combined with cannabinoids such as THC or CBD which share similar pharmacological activity, albeit via different mechanisms of action, it may produce a potentiated pharmacodynamic activity and increase therapeutic efficacy. Factor into this pharmacodynamic interaction other antiinflammatory classes such as the flavonoids or cannflavins, and it is possible to understand the potential for cannabis-based therapy using broad-spectrum phytochemical extracts. This level of phytochemical understanding enables plant breeders to select for certain chemotypes to maximise both cannabinoid and terpene profiles for specific medical conditions. This level of ‘phytochemical optimisation’ could represent a new paradigm in not only individual patient care and disease management, but also cannabis extract manufacturing procedures.

Cannabis dosage forms Due to the pronounced lipophilic nature of cannabinoids and terpenes, the dosage form used in therapeutic delivery is a key consideration. Once a specific cannabis strain or single phytochemical has been selected for a certain symptom or condition, the application in an appropriate dosage form is a critical variable that can be the difference between treatment success or failure. Table 20.2 summarises the various advantages and disadvantages facing the application of different cannabis dosage forms.

TABLE 20.2 Summary of cannabis-based dosage forms Dosage form

Advantages

Disadvantages

Smoking

Quick onset of effect; cheap; easy to adjust dosing

Vaporising

Quick onset of effect; beDer for lung health than smoking due to less combustible material Long-lasting duration of effect; option for those who do not smoke or are health conscious Rich in THCA; non-psychoactive

Smoke can irritate the lungs; concurrent pulmonary disease may decrease absorption and effects Vaporising units can be expensive.

Edibles (oral ingestion) Juicing (of fresh plant/no heat) Tinctures/oils Capsules Suppositories Topical

Easy to control dosage; palatable; good for children; longer duration of effect Long-lasting effect; easy to control dosage; option for those who do not smoke Absorbed relatively quickly; long-lasting effect Can be used for local skin conditions; non-psychoactive

Delayed onset of effect due to slower absorption and liver metabolism Not a great deal of evidence to support this dosage form currently Delayed onset of effect due to slower absorption and liver metabolism Delayed onset of effect due to slower absorption and liver metabolism; excipient ingestion Difficult to administer; needs refrigeration Not a great deal of evidence to support this dosage form currently

Cannabis pharmacokinetic interactions Limited research has been undertaken into potential interactions between Cannabis spp. and pharmaceutical medicines, but it is an emerging field now that more is known about the mechanisms of action and receptor activity of cannabinoids and other phytochemical classes. Pharmacokinetics is defined as the quantitative study of the absorption, distribution, metabolism and excretion of a substance/medicine by the body.[302–304] In relation to cannabis and its derived extracts, any significant modification to bioavailability or clearance mechanisms can be potentially clinically meaningful in causing either positive or negative patient outcomes.[302]

Absorption Absorption is of great significance in impacting the bioavailability of orally ingested cannabis dosage forms. Any changes in factors such as gastric pH, gastric output, bile acid concentration, gastrointestinal motility, age-related changes to organ function, local organ (i.e. stomach, small intestine) blood supply or concurrent gastrointestinal pathology can impact on absorption rates.[302] Topical absorption is also worthy of consideration: age-related changes to the skin may modify absorption rates for cannabinoid-based products using transdermal liposomal or ethosomal delivery systems.[305–307]

Metabolism While genetic polymorphisms and individual variability within the ECS has been highlighted as potential challenges in navigating cannabis pharmacotherapy, so too can genetic variability impact on the metabolism of cannabinoids within the body. Distributed in greatest concentrations within the liver,[308] but also in the intestines, skin, kidneys and lungs,[303] the cytochrome P450 (CYP450) enzyme system is a primary site for exogenous pharmaceutical medication and endogenous compound metabolism. The CYP1A2, 2C9, 2C19, 2D6 and 3A4 isoforms are metabolically involved in the processing of more than 50% of pharmaceutical medications.[302,308–310] Induction or inhibition of certain CYP450 enzymes can have serious clinical consequences, particularly when drugs of narrow therapeutic index (NTI) are involved. In such instances, induction of specific isoenzymes can hyper-metabolise medication serum levels and thus reduce therapeutic coverage, whereas inhibition can reduce clearance of medication levels which, after further dosing, can increase circulating levels in the blood and increase risks of toxicity or adverse effects. Both interaction types have potentially serious clinical implications.[302] Individual expression of CYP450 enzymes and their relative concentration and distribution throughout the body is under genetic control.[311] Therefore, not only can certain exogenous substances induce or inhibit normal CYP450 function, but inbuilt genetic polymorphisms need to be considered for clinical cannabinoid optimisation for the individual patient. Individuals classified as poor metabolisers are at higher risk of side effects from drugs, whereas rapid metabolisers may have subtherapeutic plasma concentrations and tissue distribution causing treatment failure due to hyper-metabolism.[302,309,312] This obviously has ramifications for the ingestion of cannabis-based extracts, as well as all xenobiotic drugs. Orally administered cannabis dosage forms are typically absorbed primarily in the small intestine and are subsequently transported to the liver for biotransformation. The enzymes involved in this process are mainly the CYP2C and CYP3A families, where cannabinoids such as THC are transformed into 11-OH-THC, a more potent and therapeutically active form of

THC. This is why edible or orally ingested forms are favoured by pain sufferers – they have a longer duration of effect and higher potency than smoked forms. Another clinically relevant cannabinoid, CBD, also undergoes biotransformation by these enzymes to 7-OH-CBD and 6-OH-CBD, but liDle research has been conducted on these metabolites to date. Worthy of consideration also are age-related changes[313] to liver function or the presence of concurrent hepatic pathology, which could detrimentally impact therapeutic outcomes. Specific Cannabis spp. interactions are aDracting more research interest with the increased therapeutic use of cannabis worldwide. Currently, research has demonstrated that CBD is metabolised by CYP1A1, 1A2, 2C9, 2C19, 2D6, 3A4 and 3A5 isoenzymes in human liver microsomes,[314] with another paper showing that CBD can potently inhibit CYP3A4 and CYP3A5 isoenzymes.[315] This has obvious clinical implications for medications metabolised by these specific enzyme pathways. Furthermore, CYP2C9 inhibition was demonstrated in vitro for multiple cannabinoids contained within cannabis smoke, including THC, CBN and CBD,[315–317] with the last also exhibiting strong CYP2D6 inhibition.[316] Of all the cannabinoids, it appears that CBD is the most potent deactivator of the CYP450 enzyme system, and may actually act as a competitive inhibitor.[318] THC is specifically metabolised by CYP2C9 and CYP3A4 and therefore individuals who are poor metabolisers at these specific isoenzyme sites could potentially exhibit a three-fold higher concentration of THC than rapid metabolisers,[319] greatly increasing their risk of adverse effects such as anxiety, dysphoria and paranoia. Conversely, substances that could inhibit these enzymes are also worthy of clinical consideration, such as cimetidine, metronidazole, fluconazole, amiodarone, phenytoin, valproic acid, clopidogrel and fluoxetine. Such individual genetic variability, coupled with knowledge of current inducers or inhibitors of certain enzyme pathways, could dramatically impact how well tolerated and efficacious cannabis is as a therapeutic substance. Clinically authorised prescribers of cannabis must pay close aDention to such herb–drug interactions, and also consider that treatment failure or adverse effect presentation could actually be based on individual metabolic genetic polymorphisms. With technology in the area of genetic testing advancing rapidly, this is something that could potentially be tested for in patients to optimise therapeutic outcomes and avoid adverse effects.

Cannabis pharmacodynamic interactions While generally easier to predict than pharmacokinetic interactions,[302] numerous pharmacodynamic interactions have been posited for cannabis. Not surprisingly, animal experiments have demonstrated that cannabis may increase the depressant action of pharmaceutical barbiturates and other drug classes such as opiates and benzodiazepines. This is largely due to the presence of the psychoactive constituent THC, which may also potentiate other psychoactive medications in an additive way. While not pharmaceutical, alcohol should also be considered as a CNS depressant and as an important questioning point for patients seeking to use medicinal cannabis. Although evidence is sparse and case studies are lacking, clinicians need to familiarise themselves with the multitude of pharmacological actions of cannabis and cross-check proposed mechanisms with prescription medications. Interestingly, such herb–drug interactions should not always be seen in a negative light, as many positive interactions may be possible from modified (mostly augmented) pharmacodynamic effects that could potentially enable a decrease in drug dosage or lead to a reduction in side effects of the prescribed pharmaceuticals.

Cannabis controversies Cannabis is not without its controversies and a great deal of research has been conducted on its illicit use over the last 50 years. This needs to be kept in mind, as the plant material grown for illicit use – which is what this research has been based on – is certainly not to be misconstrued as the medicinal-grade cannabis available today, regardless whether it has been used for symptomatic amelioration by patients or not. Large variances in quality, adulteration, pesticide residues, heavy metal contamination and the use of various growth hormones may affect the finished plant product. Most illicit strains are grown to maximise THC levels, with liDle other cannabinoid representation present to potentially reduce side effects due to entouragelike effects, or achieve optimised medical benefit. The data on illicit use collected over the last 50 years can skew the results of perceived adverse effects associated with cannabis, have certainly tainted the opinion of doctors in accepting cannabis back into medical use and must therefore be considered when pondering the previously published harm or risk/benefit analysis for the plant. It has long been espoused that cannabis use can lower intelligence quotient (IQ) results in recreational users. While increased consumption of cannabis can certainly cause a decreased functioning of short-term memory in some people, these changes are not permanent and resolve with cessation. Long-term damage or permanent IQ deterioration is unlikely: a longitudinal twin study published in the Proceedings of the National Academy of Sciences in 2016 found that cannabis-using twins failed to show significantly greater IQ decline relative to their abstinent siblings, suggesting that observed declines in IQ

are more aDributable to familial or other factors.[320] Notwithstanding this, the impact of cannabis on the young developing brain is less certain and more research is needed to determine its safety. The links with cannabis causing psychosis or schizophrenia have been a focus for addiction specialists and researchers for decades, with papers suggesting that cannabis increases the risk of both the incidence of psychosis in previously healthy people and a poor prognosis for those with established vulnerability to psychotic disorders.[321] This relationship is often used as an argument against the use of medicinal cannabis, but let us not forget that the mechanisms underlying this association have not been fully elucidated,[322] and our understanding of this mental illness is at best rudimentary. Interestingly, recent research suggests that cannabis in itself does not cause psychosis, but rather that both early use and heavy use of cannabis are more likely in people with a vulnerability to psychosis.[323] Furthermore, Hickman and colleagues have sought to estimate how many cannabis users would need to be prevented from using in order to stop one case of schizophrenia or psychosis, with statistics suggesting that the annual mean number needed to prevent heavy cannabis use and schizophrenia in men ranged from 2800 in those aged 20–24 years to 4700 in those aged 35–39 years.[324] While more research on this relationship needs to be undertaken, it must be reiterated that illicit and medicinal cannabis strains are not synonymous, and that using this as an argument to prohibit the use of medicinal cannabis is laughing in the face of a risk/benefit analysis for those for whom no medical treatment can provide relief. Another well-known controversy surrounding cannabis is its ability to cause dependence. Once again, this is touted as an argument against a compassionate medicinal cannabis access scheme. Anthony and colleagues conducted a study of 8000 people between the ages of 15 and 54 years as part of the National Comorbidity Survey in the US.[325] While it was found that cannabis can indeed cause dependency, it had an estimated prevalence of 4%. Conversely, 24% of participants surveyed had a history of dependence on tobacco (1 in 4) while 14% (1 in 7) had a dependence on alcohol.[325] These are both substances that are licit and legally obtainable and create a huge burden on the Australian healthcare system. According to the Australian government's Quitline, more than 50 Australians die of tobacco-related disease every day, with more than 19 000 deaths in 1998 alone. In 2010, 5500 deaths were aDributed to alcohol, with an additional 157 000 hospitalisations that same year.[326] With such overwhelming statistics showing the harm and cost of these legal substances, in terms of both human suffering and costs to the public purse, hopefully balance can be brought to bear when considering the use of high-quality, expertly cultivated medicinal cannabis for patients requiring compassionate relief from suffering. As Australia, New Zealand and many other countries are engaging in the process to re-introduce medicinal cannabis to the medical armamentarium of approved treatments, it allows for a pensive reflection to see that common sense and the traditional medical use and faith that hundreds of generations have placed in this plant has come full circle and cannabis is being returned to its rightful place. The evidence is not only encouraging, but also in many different areas of medicine it is overwhelming. To state that the evidence associated with cannabis is only anecdotal, as many still do, represents a wilful ignorance of the amassing evidence base of this diverse herbal medicine. It also draws aDention to the broadening divide between hard science and the current evidence-based paradigm of clinical medicine, and the compassionate alleviation of suffering for patients for whom medicine has no answers or treatment. In countries and states where medicinal cannabis has been implemented we can already see evidence of benefit across many different levels. In 2014, Bachhuber and colleagues noted that in 1999–2010 in states where medicinal cannabis was legal, there was a 24.8% lower mean opioid mortality rate compared with states without state medicinal cannabis laws in place.[327] Furthermore, this lowered rate strengthened over time to 33.3% after 6 years of implementation.[327] Such evidence is suggestive that medicinal cannabis may be an exit drug, rather than a gateway drug, which has been the line touted for the last 40 years by addiction specialists. Considering that the Australian Medical Association has issued a statement noting that prescription medicine abuse is a national emergency, such evidence from overseas should be comforting to authorised prescribers of medicinal cannabis moving forwards towards implementation. In US states where medicinal cannabis is used, statistics show a 12% lower rate of Medicare pain relief prescriptions in patients over the age of 65 and 8–13% lower rates of prescription medications used for depression, anxiety, nausea, psychosis and sleep disorders.[328] Considering that severe pain is the single greatest qualifying condition for medicinal cannabis use in patients, and Australia and New Zealand are experiencing a burgeoning ageing population,[329] over the next few years medicinal cannabis could have serious economic benefits that can take some strain off the already struggling healthcare system. Lastly, and perhaps most importantly, patients in palliative care and those suffering from intractable cases of epilepsy or pain may finally have another medical option to provide hope and symptomatic amelioration. Medicinal cannabis may well be the hope that many patients and doctors have been waiting for, and while this author understands that medicinal cannabis is certainly not the panacea that many proclaim it to be, and it will not help all people, it does beg the question that with science's blinkered focus on finding cure, are we losing our ability to act with compassion?

References [1] Mallat A, Teixeira-Clerc F, Lotersztajn S. Cannabinoid signaling and liver therapeutics. J Hepatol. 2013;59(4):891–896. [2] Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu Rev Psychol. 2013;64:21–47. [3] McGeeney BE. Cannabinoids and hallucinogens for headache. Headache. 2013;53(3):447–458. [4] McPartland JM, Norris RW, Kilpatrick CW. Coevolution between cannabinoid receptors and endocannabinoid ligands. Gene. 2007;397(1–2):126–135. [5] Grotenhermen F. Cannabinoids and the endocannabinoid system. Cannabinoids. 2006;1(1):10–14. [6] McPartland JM, Matias I, Di Marzo V, et al. Evolutionary origins of the endocannabinoid system. Gene. 2006;370:64–74. [7] Elphick MR, Satou Y, Satoh N. The invertebrate ancestry of endocannabinoid signalling: an orthologue of vertebrate cannabinoid receptors in the urochordate Ciona intestinalis. Gene. 2003;302(1–2):95–101. [8] Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344–1364. [9] Mehmedic Z, Chandra S, Slade D, et al. Potency trends of Delta9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J Forensic Sci. 2010;55(5):1209–1217. [10] Upton R, ElSohly M, Romm A, et al. Cannabis inflorescence. American Herbal Pharmacopoeia: ScoDs Valley, CA; 2013. [11] Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86:1646–1647. [12] Mechoulam R, Braun P, Gaoni Y. A stereospecific synthesis of (−)-delta 1- and (−)-delta 6tetrahydrocannabinols. J Am Chem Soc. 1967;89:4552–4554. [13] Maccarrone M, Bab I, Biro T, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015;36(5):277–296. [14] HowleD AC, Fleming RM. Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol. 1984;26(3):532–538. [15] Mechoulam R, Feigenbaum JJ, Lander N, et al. Enantiomeric cannabinoids: stereospecificity of psychotropic activity. Experientia. 1988;44(9):762–764. [16] Devane WA, Dysarz FA 3rd, Johnson MR, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34(5):605–613. [17] Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346(6284):561–564. [18] Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365(6441):61–65. [19] Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946–1949. [20] Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50(1):83–90. [21] Sugiura T, Kondo S, Sukagawa A, et al. 2-arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995;215(1):89–97. [22] Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 2004;3(Sept):771–784. [23] Henry RJ, Kerr DM, Finn DP, et al. For whom the endocannabinoid tolls: modulation of innate immune function and implications for psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:167–180. [24] Blankman JL, Simon GM, CravaD BF. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol. 2007;14(12):1347–1356. [25] Sanchez AJ, Garcia-Merino A. Neuroprotective agents: cannabinoids. Clin Immunol. 2012;142(1):57–67. [26] Vemuri VK, Makriyannis A. Medicinal chemistry of cannabinoids. Clin Pharmacol Ther. 2015;97(6):553–558. [27] Russo EB. Beyond cannabis: plants and the endocannabinoid system. Trends Pharmacol Sci. 2016;37(7):594–605. [28] Castillo PE, Younts TJ, Chavez AE, et al. Endocannabinoid signaling and synaptic function. Neuron. 2012;76(1):70–81. [29] Cristino L, Becker T, Di Marzo V. Endocannabinoids and energy homeostasis: an update. Biofactors.

2014;40(4):389–397. [30] Maccarrone M, Guzman M, Mackie K, et al. Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat Rev Neurosci. 2014;15(12):786–801. [31] DiPatrizio NV, Piomelli D. The thrifty lipids: endocannabinoids and the neural control of energy conservation. Trends Neurosci. 2012;35(7):403–411. [32] Galve-Roperh I, Chiurchiu V, Diaz-Alonso J, et al. Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog Lipid Res. 2013;52(4):633–650. [33] Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 1997;77(2):299– 318. [34] Ross RA. The enigmatic pharmacology of GPR55. Trends Pharmacol Sci. 2009;30(3):156–163. [35] Baker D, Pryce G, Davies WL, et al. In silico patent searching reveals a new cannabinoid receptor. Trends Pharmacol Sci. 2006;27(1):1–4. [36] Di Marzo V, De Petrocellis L. Endocannabinoids as regulators of transient receptor potential (TRP) channels: a further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem. 2010;17:1430– 1449. [37] Pistis M, Melis M. From surface to nuclear receptors: the endocannabinoid family extends its assets. Curr Med Chem. 2010;17(14):1450–1467. [38] Heifets BD, Castillo PE. Endocannabinoid signaling and long-term synaptic plasticity. Annu Rev Physiol. 2009;71:283–306. [39] De Petrocellis L, Bifulco M, Ligresti A, et al. Potential use of cannabimimetics in the treatment of cancer. Mechoulam R, Gaoni Y. Cannabinoids as therapeutics. Birkhauser: Basel; 2005:165–182. [40] Friedman D, Devinsky O. Cannabinoids in the treatment of epilepsy. N Engl J Med. 2015;373(11):1048–1058. [41] Kano M. Control of synaptic function by endocannabinoid-mediated retrograde signaling. Proc Jpn Acad Ser B Phys Biol Sci. 2014;90(7):235–250. [42] Mackie K, Lai Y, Westenbroek R, et al. Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J Neurosci. 1995;15(10):6552–6561. [43] Shire D, Carillon C, Kaghad M, et al. An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. J Biol Chem. 1995;270(8):3726–3731. [44] Ryberg E, Vu HK, Larsson N, et al. Identification and characterisation of a novel splice variant of the human CB1 receptor. FEBS LeO. 2005;579(1):259–264. [45] Husni AS, McCurdy CR, Radwan MM, et al. Evaluation of phytocannabinoids from high potency using bioassays to determine structure-activity relationships for cannabinoid receptor 1 and cannabinoid receptor 2. Med Chem Res. 2014;23(9):4295–4300. [46] Herkenham M, Lynn AB, Johnson MR, et al. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci. 1991;11(2):563–583. [47] Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol. 2008;20(Suppl. 1):10–14. [48] HowleD AC, Barth F, Bonner TI, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54(2):161–202. [49] Baron EP. Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: what a long strange trip it's been. Headache. 2015;55(6):885–916. [50] Serrano A, Parsons LH. Endocannabinoid influence in drug reinforcement, dependence and addiction-related behaviors. Pharmacol Ther. 2011;132(3):215–241. [51] Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med. 2008;14(9):923–930. [52] Pacher P, Hasko G. Endocannabinoids and cannabinoid receptors in ischaemia-reperfusion injury and preconditioning. Br J Pharmacol. 2008;153(2):252–262. [53] Aguado T, Romero E, Monory K, et al. The CB1 cannabinoid receptor mediates excitotoxicity-induced neural progenitor proliferation and neurogenesis. J Biol Chem. 2007;282(33):23892–23898. [54] van der Stelt M, Di Marzo V. Cannabinoid receptors and their role in neuroprotection. Neuromolecular Med. 2005;7(1–2):37–50. [55] Latorre JG, Schmidt EB. Cannabis, cannabinoids, and cerebral metabolism: potential applications in stroke and

disorders of the central nervous system. Curr Cardiol Rep. 2015;17(9):627. [56] Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389–462. [57] Steffens S, Pacher P. The activated endocannabinoid system in atherosclerosis: driving force or protective mechanism? Curr Drug Targets. 2015;16(4):334–341. [58] Sharkey KA, Wiley JW. GeDing into the weed: the role of the endocannabinoid system in the brain–gut axis. Gastroenterology. 2016;151(2):252–266. [59] Trautmann SM, Sharkey KA. The endocannabinoid system and its role in regulating the intrinsic neural circuitry of the gastrointestinal tract. Int Rev Neurobiol. 2015;125:85–126. [60] Zhang PW, Ishiguro H, Ohtsuki T, et al. Human cannabinoid receptor 1: 5’ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Mol Psychiatry. 2004;9(10):916– 931. [61] Onaivi ES, Ishiguro H, Gong JP, et al. Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann N Y Acad Sci. 2006;1074:514–536. [62] Onaivi ES, Ishiguro H, Gong JP, et al. Functional expression of brain neuronal CB2 cannabinoid receptors are involved in the effects of drugs of abuse and in depression. Ann N Y Acad Sci. 2008;1139:434–449. [63] Samson MT, Small-Howard A, Shimoda LM, et al. Differential roles of CB1 and CB2 cannabinoid receptors in mast cells. J Immunol. 2003;170(10):4953–4962. [64] Nunez E, Benito C, Pazos MR, et al. Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse. 2004;53(4):208–213. [65] DiDel BN. Direct suppression of autoreactive lymphocytes in the central nervous system via the CB2 receptor. Br J Pharmacol. 2008;153(2):271–276. [66] HowleD AC. The cannabinoid receptors. Prostaglandins Other Lipid Mediat. 2002;68–69:619–631. [67] Tao Y, Li L, Jiang B, et al. Cannabinoid receptor-2 stimulation suppresses neuroinflammation by regulating microglial M1/M2 polarization through the cAMP/PKA pathway in an experimental GMH rat model. Brain Behav Immun. 2016;58:118–129. [68] Atwood BK, Mackie K. CB2: a cannabinoid receptor with an identity crisis. Br J Pharmacol. 2010;160(3):467–479. [69] Benito C, Tolon RM, Pazos MR, et al. Cannabinoid CB2 receptors in human brain inflammation. Br J Pharmacol. 2008;153(2):277–285. [70] Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol. 2005;5(5):400–411. [71] Anand P, Whiteside G, Fowler CJ, et al. Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res Rev. 2009;60(1):255–266. [72] Pacher P, Mechoulam R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res. 2011;50(2):193–211. [73] Chakrabarti B, Persico A, BaDista N, et al. Endocannabinoid signaling in autism. Neurother. 2015;12(4):837–847. [74] Oz M, Zhang L, Ravindran A, et al. Differential effects of endogenous and synthetic cannabinoids on alpha7nicotinic acetylcholine receptor-mediated responses in Xenopus oocytes. J Pharmacol Exp Ther. 2004;310(3):1152–1160. [75] Zygmunt PM, Petersson J, Andersson DA, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400(6743):452–457. [76] De Petrocellis L, Di Marzo V. Non-CB1, non-CB2 receptors for endocannabinoids, plant cannabinoids, and synthetic cannabimimetics: focus on G-protein-coupled receptors and transient receptor potential channels. J Neuroimmune Pharmacol. 2010;5(1):103–121. [77] Mackie K, Stella N. Cannabinoid receptors and endocannabinoids: evidence for new players. AAPS J. 2006;8(2):E298–306. [78] Pertwee R. Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr Med Chem. 2010;17:1360–1381. [79] Curioni C, Andre C. Rimonabant for overweight or obesity. Cochrane Database Syst Rev. 2006;(4) [CD006162]. [80] Devane W, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946–1949. [81] Porter A, Sauer J, Knierman M, et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther. 2002;301:1020–1024. [82] Hanus L, Abu-Lafi S, Fride E, et al. 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid

CB1 receptor. Proc Natl Acad Sci USA. 2001;98:3662–3665. [83] Di Marzo V, Petrosino S. Endocannabinoids and the regulation of their levels in health and disease. Curr Opin Lipidol. 2007;18:129–140. [84] Maccarrone M, Finazzi-Agro A. The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis. Cell Death Differ. 2003;10(9):946–955. [85] Maccarrone M, Finazzi-Agro A. Endocannabinoids and their actions. Vitam Horm. 2002;65:225–255. [86] Mechoulam R, Panikashvili D, Shohami E. Cannabinoids and brain injury: therapeutic implications. Trends Mol Med. 2002;8(2):58–61. [87] Justinova Z, Yasar S, Redhi GH, et al. The endogenous cannabinoid 2-arachidonoylglycerol is intravenously self-administered by squirrel monkeys. J Neurosci. 2011;31(19):7043–7048. [88] Mackie K, Devane WA, Hille B. Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells. Mol Pharmacol. 1993;44(3):498–503. [89] Toth A, Blumberg PM, Boczan J. Anandamide and the vanilloid receptor (TRPV1). Vitam Horm. 2009;81:389– 419. [90] Murataeva N, Straiker A, Mackie K. Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. Br J Pharmacol. 2014;171(6):1379–1391. [91] Sugiura T, Kobayashi Y, Oka S, et al. Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot Essent FaOy Acids. 2002;66(2–3):173–192. [92] Sugiura T, Kishimoto S, Oka S. Gokoh M. Biochemistry, pharmacology and physiology of 2arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Prog Lipid Res. 2006;45(5):405–446. [93] Tanimura A, Yamazaki M, Hashimotodani Y, et al. The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission. Neuron. 2010;65(3):320– 327. [94] Gonsiorek W, Lunn C, Fan X, et al. Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Mol Pharmacol. 2000;57(5):1045–1050. [95] Katona I, Freund TF. Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci. 2012;35:529–558. [96] Maccarrone M, Dainese E, Oddi S. Intracellular trafficking of anandamide: new concepts for signaling. Trends Biochem Sci. 2010;35(11):601–608. [97] Rahman IA, Tsuboi K, Uyama T, et al. New players in the faDy acyl ethanolamide metabolism. Pharmacol Res. 2014;86:1–10. [98] Di Marzo V, Fontana A, Cadas H, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature. 1994;372(6507):686–691. [99] Sugiura T, Kondo S, Sukagawa A, et al. Transacylase-mediated and phosphodiesterase-mediated synthesis of N-arachidonoylethanolamine, an endogenous cannabinoid-receptor ligand, in rat brain microsomes. Comparison with synthesis from free arachidonic acid and ethanolamine. Eur J Biochem. 1996;240(1):53–62. [100] Blankman JL, CravaD BF. Chemical probes of endocannabinoid metabolism. Pharmacol Rev. 2013;65(2):849–871. [101] Walker JM, Krey JF, Chu CJ, et al. Endocannabinoids and related faDy acid derivatives in pain modulation. Chem Phys Lipids. 2002;121(1–2):159–172. [102] Di Marzo V, Maccarrone M. FAAH and anandamide: is 2-AG really the odd one out? Trends Pharmacol Sci. 2008;29(5):229–233. [103] Iversen L, Chapman V. Cannabinoids: a real prospect for pain relief? Curr Opin Pharmacol. 2002;2(1):50–55. [104] Randall MD, Harris D, Kendall DA, et al. Cardiovascular effects of cannabinoids. Pharmacol Ther. 2002;95(2):191–202. [105] Schmid K, Niederhoffer N, Szabo B. Analysis of the respiratory effects of cannabinoids in rats. Naunyn Schmiedebergs Arch Pharmacol. 2003;368(4):301–308. [106] Aggarwal SK. Cannabinergic pain medicine: a concise clinical primer and survey of randomized-controlled trial results. Clin J Pain. 2013;29(2):162–171. [107] Greco R, Gasperi V, Maccarrone M, et al. The endocannabinoid system and migraine. Exp Neurol. 2010;224(1):85–91. [108] Maccarrone M, Gasperi V, Catani MV, et al. The endocannabinoid system and its relevance for nutrition. Annu Rev Nutr. 2010;30:423–440. [109] Romigi A, Bari M, Placidi F, et al. Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced

in patients with untreated newly diagnosed temporal lobe epilepsy. Epilepsia. 2010;51(5):768–772. [110] Ludanyi A, Eross L, Czirjak S, et al. Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. J Neurosci. 2008;28(12):2976–2990. [111] Sarchielli P, Pini LA, Coppola F, et al. Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology. 2007;32(6):1384–1390. [112] Nyholt DR, Morley KI, Ferreira MA, et al. Genomewide significant linkage to migrainous headache on chromosome 5q21. Am J Hum Genet. 2005;77(3):500–512. [113] Juhasz G, Lazary J, Chase D, et al. Variations in the cannabinoid receptor 1 gene predispose to migraine. Neurosci LeO. 2009;461(2):116–120. [114] Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol LeO. 2004;25(1–2):31–39. [115] Sparling PB, Giuffrida A, Piomelli D, et al. Exercise activates the endocannabinoid system. Neuroreport. 2003;14(17):2209–2211. [116] Raichlen DA, Foster AD, Gerdeman GL, et al. Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the ‘runner's high’. J Exp Biol. 2012;215(8):1331–1336. [117] Desfosses J, Stip E, Bentaleb LA, et al. Endocannabinoids and schizophrenia. Pharmaceuticals. 2010;3:3103–3126. [118] De Marchi N, De Petrocellis L, Orlando P, et al. Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis. 2003;2:5. [119] Cao Q, Martinez M, Zhang J, et al. Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees. Genomics. 1997;43(1):1–8. [120] Ishiguro H, Horiuchi Y, Ishikawa M, et al. Brain cannabinoid CB2 receptor in schizophrenia. Biol Psychiatry. 2010;67(10):974–982. [121] Centonze D, Finazzi-Agro A, Bernardi G, et al. The endocannabinoid system in targeting inflammatory neurodegenerative diseases. Trends Pharmacol Sci. 2007;28(4):180–187. [122] Marsicano G, Goodenough S, Monory K, et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003;302(5642):84–88. [123] Sarne Y, Mechoulam R. Cannabinoids: between neuroprotection and neurotoxicity. Curr Drug Targets CNS Neurol Disord. 2005;4(6):677–684. [124] Mechoulam R, Lichtman AH. Neuroscience. Stout guards of the central nervous system. Science. 2003;302(5642):65–67. [125] Croxford JL, Pryce G, Jackson SJ, et al. Cannabinoid-mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis. J Neuroimmunol. 2008;193(1–2):120–129. [126] Jackson SJ, Pryce G, Diemel LT, et al. Cannabinoid-receptor 1 null mice are susceptible to neurofilament damage and caspase 3 activation. Neuroscience. 2005;134(1):261–268. [127] Fernandez-Ruiz J, Pazos MR, Garcia-Arencibia M, et al. Role of CB2 receptors in neuroprotective effects of cannabinoids. Mol Cell Endocrinol. 2008;286(1–2, Suppl. 1):S91–6. [128] Steffens S, Pacher P. Targeting cannabinoid receptor CB(2) in cardiovascular disorders: promises and controversies. Br J Pharmacol. 2012;167(2):313–323. [129] Rajesh M, Batkai S, Kechrid M, et al. Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes. 2012;61(3):716–727. [130] Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease: successes and failures. FEBS J. 2013;280(9):1918–1943. [131] Jouanjus E, Lapeyre-Mestre M, Micallef J. French Association of the Regional Abuse and Dependence Monitoring Centres Working Group on Cannabis Complications. Cannabis use: signal of increasing risk of serious cardiovascular disorders. J Am Heart Assoc. 2014;3(2):e000638. [132] Hons IM, Storr MA, Mackie K, et al. Plasticity of mouse enteric synapses mediated through endocannabinoid and purinergic signaling. Neurogastroenterol Motil. 2012;24(3):e113–24. [133] Piomelli D. A faDy gut feeling. Trends Endocrinol Metab. 2013;24(7):332–341. [134] Sykaras AG, Demenis C, Case RM, et al. Duodenal enteroendocrine I-cells contain mRNA transcripts encoding key endocannabinoid and faDy acid receptors. PLoS ONE. 2012;7(8):e42373. [135] Wright KL, Duncan M, Sharkey KA. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br J Pharmacol. 2008;153(2):263–270.

[136] Duncan M, Mouihate A, Mackie K, et al. Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats. Am J Physiol Gastrointest Liver Physiol. 2008;295(1):G78–87. [137] Fichna J, Bawa M, Thakur GA, et al. Cannabinoids alleviate experimentally induced intestinal inflammation by acting at central and peripheral receptors. PLoS ONE. 2014;9(10):e109115. [138] Kinsey SG, Nomura DK, O'Neal ST, et al. Inhibition of monoacylglycerol lipase aDenuates nonsteroidal antiinflammatory drug-induced gastric hemorrhages in mice. J Pharmacol Exp Ther. 2011;338(3):795–802. [139] Muccioli GG, Naslain D, Backhed F, et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010;6:392. [140] Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther. 2010;126(1):21–38. [141] Liu J, Zhou L, Xiong K, et al. Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice. Gastroenterology. 2012;142(5):1218–1228. [142] Batkai S, Osei-Hyiaman D, Pan H, et al. Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB J. 2007;21(8):1788–1800. [143] Guillot A, Hamdaoui N, Bizy A, et al. Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver. Hepatology. 2014;59(1):296–306. [144] Julien B, Grenard P, Teixeira-Clerc F, et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology. 2005;128(3):742–755. [145] BaDista N, Di Sabatino A, Di Tommaso M, et al. Altered expression of type-1 and type-2 cannabinoid receptors in celiac disease. PLoS ONE. 2013;8(4):e62078. [146] D'Argenio G, Valenti M, Scaglione G, et al. Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation. FASEB J. 2006;20(3):568–570. [147] Liu YJ, Fan HB, Jin Y, et al. Cannabinoid receptor 2 suppresses leukocyte inflammatory migration by modulating the JNK/c-Jun/Alox5 pathway. J Biol Chem. 2013;288(19):13551–13562. [148] Berdyshev EV, Boichot E, Germain N, et al. Influence of faDy acid ethanolamides and delta9tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells. Eur J Pharmacol. 1997;330(2– 3):231–240. [149] Cencioni MT, Chiurchiu V, Catanzaro G, et al. Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB2 receptors. PLoS ONE. 2010;5(1):e8688. [150] Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol LeO. 2008;29(2):192–200. [151] Cannabaceae. Encyclopaedia Britannica. Encyclopaedia Britannica: London; 2016. [152] Hosking RD, Zajicek JP. Therapeutic potential of cannabis in pain medicine. Br J Anaesth. 2008;101(1):59–68. [153] Russo E. History of cannabis as a medicine. Guy G, WhiDle BA, Robson P. The medicinal uses of cannabis and cannabinoids. Pharmaceutical Press: London; 2004:1–16. [154] Kalant H. Medicinal use of cannabis: history and current status. Pain Res Manag. 2001;6(2):80–91. [155] Schultes R. Random thoughts and queries on the botany of cannabis. Joyce C, Curry SH. The botany and chemistry of cannabis. J&A Churchill: London; 1970:11–38. [156] McKim W. Drugs and behavior: an introduction to behavioral pharmacology. 4th ed. Prentice Hall: Saddle River, NJ; 2000. [157] Li H. An archaelogical and historical account of cannabis in China. Econ Bot. 1974;28:437–448. [158] Russo EB, Jiang HE, Li X, et al. Phytochemical and genetic analyses of ancient cannabis from Central Asia. J Exp Bot. 2008;59(15):4171–4182. [159] Jiang HE, Li X, Zhao YX, et al. A new insight into Cannabis sativa (Cannabaceae) utilization from 2500-year-old Yanghai Tombs, Xinjiang, China. J Ethnopharmacol. 2006;108(3):414–422. [160] Ben Amar M. Cannabinoids in medicine: a review of their therapeutic potential. J Ethnopharmacol. 2006;105(1– 2):1–25. [161] Clarke R, Merlin MD. Cannabis evolution and ethnobotany. University of California Press: Berkeley, CA; 2013. [162] Russo EB. History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers. 2007;4(8):1614–1648. [163] Sharma G. Ethnobotany and its significance for cannabis studies in the Himalayas. J Psychedelic Drugs.

1977;9(4):337–339. [164] Sharma G. A botanical survey of cannabis in the Himalayas. J Bomb Nat Hist So. 1980;76:17–20. [165] Green G. The cannabis grow bible. Green Candy Press: San Francisco; 2010. [166] Pringle H. Ice age communities may be earliest known net hunters. Science. 1997;277(5330):1203–1204. [167] Abel E. Marihuana: the first twelve thousand years. Plenum Publishers: New York; 1980. [168] Merlin M. Archaeological evidence for the tradition of psychoactive plant use in the old world. Econ Bot. 2003;57:295–323. [169] Merlin M. Man and marijuana: some aspects of their ancient relationship. Fairleigh Dickinson University Press: Rutherford, NJ; 1972. [170] Maule WJ. Medical uses of marijuana (Cannabis sativa): fact or fallacy? Br J Biomed Sci. 2015;72(2):85–91. [171] Grierson G. The hemp plant in Sanskrit and Hindi literature. Indian Antiq. 1894;Sept:260–262. [172] Russo E. Cannabis in India: ancient lore and modern medicine. Mechoulam R. Cannabinoids as therapeutics. Birkauser Verlag: Swi•erland; 2005. [173] Aboelsoud N. Herbal medicine in ancient Egypt. J Med Plant Res. 2010;4(2):82–86. [174] Merzouki A, Mesa JM. Concerning kif, a Cannabis sativa L. preparation smoked in the Rif mountains of northern Morocco. J Ethnopharmacol. 2002;81(3):403–406. [175] Robson P. Therapeutic aspects of cannabis and cannabinoids. Br J Psychiatry. 2001;178:107–115. [176] Clarke R. Marijuana botany: an advanced study of the propogation and breeding of distinctive cannabis. Ronin Publishing: Oakland, CA; 1981. [177] Small E. On toadstool soup and legal species of marihuana. Plant Science Bulletin. 1975;21:34–39. [178] Dewey L. Yearbook of the United States Department of Agriculture: hemp. Bureau of Plant Industry. 1913. [179] Schultes R, Klein WM, Plowman T, et al. Cannabis: an example of taxonomic neglect. Harv Univ Bot Mus Leafl. 1974;23:337–367. [180] Anderson L. Leaf variation among cannabis species from a controlled garden. Harv Univ Bot Mus Leafl. 1980;28:10. [181] Small E, Cronquist A. A practical and natural taxonomy for cannabis. Taxon. 1976;25:405–435. [182] Hillig KW. Genetic evidence for speciation in cannabis (Cannabaceae). Genet Resour Crop Evol. 2005;52:161–180. [183] Hillig KW, Mahlberg PG. A chemotaxonomic analysis of cannabinoid variation in cannabis (Cannabaceae). Am J Bot. 2004;91(6):966–975. [184] Hillig KW. A chemotaxonomic analysis of terpenoid variation in cannabis. Biochem Syst Ecol. 2004;32:875–891. [185] McPartland JM. Correct(ed) vernacular nomenclature. O'Shaughnessy's J Cannabis Clin Pract. 2015;19. [186] ElSohly M. Chemical constituents of cannabis. Grotenherman F, Russo E. Cannabis and cannabinoids: pharmacology, toxicology and therapeutic potential. Haworth Press Inc: New York; 2002. [187] Chandra S, Lata H, Khan IA, et al. Photosynthetic response of Cannabis sativa L. to variations in photosynthetic photon flux densities, temperature and CO2 conditions. Physiol Mol Biol Plants. 2008;14(4):299–306. [188] Valle J, Vieira JE, Aucelio JG, et al. Influence of photoperiodism on cannabinoid content of Cannabis sativa L. Bull Narc. 1978;30:67–68. [189] Kluger B, Triolo P, Jones W, et al. The therapeutic potential of cannabinoids for movement disorders. Mov Disord. 2015;30(3):313–327. [190] Demuth DG, Molleman A. Cannabinoid signalling. Life Sci. 2006;78(6):549–563. [191] Ashton CH. Pharmacology and effects of cannabis: a brief review. Br J Psychiatry. 2001;178:101–106. [192] Zanelati TV, Biojone C, Moreira FA, et al. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol. 2010;159(1):122–128. [193] Turner CE, ElSohly MA, Boeren EG. Constituents of Cannabis sativa L. XVII. A review of the natural constituents. J Nat Prod. 1980;43(2):169–234. [194] Hanus L, Mechoulam R. Cannabinoid chemistry: an overview. Mechoulam R. Cannabinoids as therapeutics. Birkhauser Verlag: Swi•erland; 2005. [195] ElSohly M, Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci. 2005;78:539–548. [196] Giacoppo S, Mandolino G, Galuppo M, et al. Cannabinoids: new promising agents in the treatment of neurological diseases. Molecules. 2014;19(11):18781–18816. [197] Fellermeier M, Zenk MH. Prenylation of olivetolate by a hemp transferase yields cannabigerolic acid, the precursor of tetrahydrocannabinol. FEBS LeO. 1998;427(2):283–285.

[198] de Zeeuw RA, Wijsbeek J, Breimer DD, et al. Cannabinoids with a propyl side chain in cannabis: occurrence and chromatographic behavior. Science. 1972;175(4023):778–779. [199] ElSohly MA, Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci. 2005;78(5):539–548. [200] Howard P, Twycross R, Shuster J, et al. Cannabinoids. J Pain Symptom Manage. 2013;46(1):142–149. [201] Izzo AA, Borrelli F, Capasso R, et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009;30(10):515–527. [202] Gaoni Y, Mechoulam R. The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish. J Am Chem Soc. 1971;93(1):217–224. [203] Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199–215. [204] HowleD AC, Blume LC, Dalton GD. CB(1) cannabinoid receptors and their associated proteins. Curr Med Chem. 2010;17(14):1382–1393. [205] Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurother. 2009;6(4):713–737. [206] Hampson AJ, Grimaldi M, Axelrod J, et al. Cannabidiol and (-)delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA. 1998;95(14):8268–8273. [207] Kavia RB, De Ridder D, Constantinescu CS, et al. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult Scler. 2010;16(11):1349–1359. [208] Williams SJ, Hartley JP, Graham JD. Bronchodilator effect of delta1-tetrahydrocannabinol administered by aerosol of asthmatic patients. Thorax. 1976;31(6):720–723. [209] Neff GW, O'Brien CB, Reddy KR, et al. Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease. Am J Gastroenterol. 2002;97(8):2117–2119. [210] Munson AE, Harris LS, Friedman MA, et al. Antineoplastic activity of cannabinoids. J Natl Cancer Inst. 1975;55(3):597–602. [211] Sanchez C, Galve-Roperh I, Canova C, et al. Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS LeO. 1998;436(1):6–10. [212] Blazquez C, Salazar M, Carracedo A, et al. Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res. 2008;68(6):1945–1952. [213] Carracedo A, Gironella M, Lorente M, et al. Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res. 2006;66(13):6748–6755. [214] Ruiz L, Miguel A, Diaz-Laviada I. Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. FEBS LeO. 1999;458(3):400–404. [215] Leelawat S, Leelawat K, Narong S, et al. The dual effects of delta(9)-tetrahydrocannabinol on cholangiocarcinoma cells: anti-invasion activity at low concentration and apoptosis induction at high concentration. Cancer Invest. 2010;28(4):357–363. [216] Whyte DA, Al-Hammadi S, Balhaj G, et al. Cannabinoids inhibit cellular respiration of human oral cancer cells. Pharmacology. 2010;85(6):328–335. [217] Machado Rocha FC, Stefano SC, De Cassia Haiek R, et al. Therapeutic use of Cannabis sativa on chemotherapyinduced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care (Engl). 2008;17(5):431–443. [218] Berman JS, Symonds C, Birch R. Efficacy of two cannabis-based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain. 2004;112(3):299– 306. [219] Karst M, Salim K, Burstein S, et al. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA. 2003;290(13):1757–1762. [220] Noyes R Jr, Brunk SF, Avery DA, et al. The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther. 1975;18(1):84–89. [221] Noyes R Jr, Brunk SF, Baram DA, et al. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol. 1975;15(2–3):139–143. [222] McCabe M, Smith FP, Macdonald JS, et al. Efficacy of tetrahydrocannabinol in patients refractory to standard antiemetic therapy. Invest New Drugs. 1988;6(3):243–246. [223] NotcuD W, Price M, Miller R, et al. Initial experiences with medicinal extracts of cannabis for chronic pain:

results from 34 ‘N of 1’ studies. Anaesthesia. 2004;59(5):440–452. [224] Abrams DI, Hilton JF, Leiser RJ, et al. Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial. Ann Intern Med. 2003;139(4):258–266. [225] Wade DT, Robson P, House H, et al. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil. 2003;17(1):21–29. [226] Wade DT, Makela P, Robson P, et al. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler. 2004;10(4):434–441. [227] Currais A, et al. Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids. NPJ Aging Mech Dis. 2016;2. [228] MerriD JC, Crawford WJ, Alexander PC, et al. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology. 1980;87(3):222–228. [229] Evans FJ. Cannabinoids: the separation of central from peripheral effects on a structural basis. Planta Med. 1991;57(7):S60–7. [230] Thomas A, Stevenson LA, Wease KN, et al. Evidence that the plant cannabinoid delta9tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. Br J Pharmacol. 2005;146(7):917–926. [231] Bolognini D, Costa B, Maione S, et al. The plant cannabinoid delta9-tetrahydrocannabivarin can decrease signs of inflammation and inflammatory pain in mice. Br J Pharmacol. 2010;160(3):677–687. [232] Riedel G, Fadda P, McKillop-Smith S, et al. Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. Br J Pharmacol. 2009;156(7):1154–1166. [233] Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791–802. [234] Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134(4):845–852. [235] Russo EB, BurneD A, Hall B, et al. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037–1043. [236] Burstein S. Cannabidiol (CBD) and its analogs: a review of their effects on inflammation. Bioorg Med Chem. 2015;23(7):1377–1385. [237] Karniol IG, Shirakawa I, Kasinski N, et al. Cannabidiol interferes with the effects of delta 9tetrahydrocannabinol in man. Eur J Pharmacol. 1974;28(1):172–177. [238] Dalton WS, Mar• R, Lemberger L, et al. Influence of cannabidiol on delta-9-tetrahydrocannabinol effects. Clin Pharmacol Ther. 1976;19(3):300–309. [239] BhaDacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010;35(3):764–774. [240] Englund A, Morrison PD, NoDage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol. 2013;27(1):19–27. [241] Demirakca T, Sartorius A, Ende G, et al. Diminished gray maDer in the hippocampus of cannabis users: possible protective effects of cannabidiol. Drug Alcohol Depend. 2011;114(2–3):242–245. [242] Zuardi AW, Shirakawa I, Finkelfarb E, et al. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacol. 1982;76(3):245–250. [243] Karniol IG, Carlini EA. Pharmacological interaction between cannabidiol and delta 9-tetrahydrocannabinol. Psychopharmacologia. 1973;33(1):53–70. [244] Mukhopadhyay P, Rajesh M, Horvath B, et al. Cannabidiol protects against hepatic ischemia/reperfusion injury by aDenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radic Biol Med. 2011;50(10):1368–1381. [245] Castillo A, Tolon MR, Fernandez-Ruiz J, et al. The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol Dis. 2010;37(2):434–440. [246] Jones NA, Hill AJ, Smith I, et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther. 2010;332(2):569–577. [247] Zuardi AW, Hallak JE, Dursun SM, et al. Cannabidiol monotherapy for treatment-resistant schizophrenia. J Psychopharmacol. 2006;20(5):683–686.

[248] Morgan CJ, Curran HV. Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis. Br J Psychiatry. 2008;192(4):306–307. [249] Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94. [250] Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology. 2011;36(6):1219–1226. [251] Ligresti A, Moriello AS, Starowicz K, et al. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther. 2006;318(3):1375–1387. [252] Solinas M, Massi P, Cantelmo AR, et al. Cannabidiol inhibits angiogenesis by multiple mechanisms. Br J Pharmacol. 2012;167(6):1218–1231. [253] Vaccani A, Massi P, Colombo A, et al. Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol. 2005;144(8):1032–1036. [254] Shrivastava A, Kuzontkoski PM, Groopman JE, et al. Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Mol Cancer Ther. 2011;10(7):1161– 1172. [255] McKallip RJ, Jia W, Schlomer J, et al. Cannabidiol-induced apoptosis in human leukemia cells: a novel role of cannabidiol in the regulation of p22phox and nox4 expression. Mol Pharmacol. 2006;70(3):897–908. [256] Brown I, Cascio MG, Rotondo D, et al. Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators. Prog Lipid Res. 2013;52(1):80–109. [257] Mecha M, Feliu A, Inigo PM, et al. Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiol Dis. 2013;59:141–150. [258] Cunha JM, Carlini EA, Pereira AE, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology. 1980;21(3):175–185. [259] Hofmann ME, Frazier CJ. Marijuana, endocannabinoids, and epilepsy: potential and challenges for improved therapeutic intervention. Exp Neurol. 2013;244:43–50. [260] Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an openlabel interventional trial. Lancet Neurol. 2016;15(3):270–278. [261] Schubart CD, Sommer IE, Fusar-Poli P, et al. Cannabidiol as a potential treatment for psychosis. Eur Neuropsychopharmacol. 2014;24(1):51–64. [262] Gomes FV, Llorente R, Del Bel EA, et al. Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. Schizophr Res. 2015;164(1–3):155–163. [263] de Lago E, Fernandez-Ruiz J. Cannabinoids and neuroprotection in motor-related disorders. CNS Neurol Disord Drug Targets. 2007;6(6):377–387. [264] Martin-Moreno AM, Reigada D, Ramirez BG, et al. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease. Mol Pharmacol. 2011;79(6):964–973. [265] Hill AJ, Mercier MS, Hill TD, et al. Cannabidivarin is anticonvulsant in mouse and rat. Br J Pharmacol. 2012;167(8):1629–1642. [266] Hill AJ, Weston SE, Jones NA, et al. Delta(9)-tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats. Epilepsia. 2010;51(8):1522–1532. [267] Banerjee SP, Snyder SH, Mechoulam R. Cannabinoids: influence on neurotransmiDer uptake in rat brain synaptosomes. J Pharmacol Exp Ther. 1975;194(1):74–81. [268] De Petrocellis L, Vellani V, Schiano-Moriello A, et al. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther. 2008;325(3):1007–1015. [269] Cascio MG, Gauson LA, Stevenson LA, et al. Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br J Pharmacol. 2010;159(1):129–141. [270] Appendino G, Gibbons S, Giana A, et al. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008;71(8):1427–1430. [271] Romano B, Borrelli F, Fasolino I, et al. The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis. Br J Pharmacol. 2013;169(1):213–229. [272] Turner CE, ElSohly MA. Biological activity of cannabichromene, its homologs and isomers. J Clin Pharmacol. 1981;21(8–9 Suppl.):283S–291S.

[273] Avraham Y, Ben-Shushan D, Breuer A, et al. Very low doses of delta 8-THC increase food consumption and alter neurotransmiDer levels following weight loss. Pharmacol Biochem Behav. 2004;77(4):675–684. [274] Pengelly A. The constituents of medicinal plants: an introduction to the chemistry and therapeutics of herbal medicine. 2nd ed. Allen & Unwin: Sydney; 2004. [275] Brenneisen R. Chemistry and analysis of phytocannabinoids and other cannabis constituents. ElSohly M. Marijuana and the cannabinoids. Humana Press: New York; 2007:17–49. [276] Ross SA, ElSohly MA. The volatile oil composition of fresh and air-dried buds of Cannabis sativa. J Nat Prod. 1996;59(1):49–51. [277] Langenheim JH. Higher plant terpenoids: a phytocentric overview of their ecological roles. J Chem Ecol. 1994;20(6):1223–1280. [278] Rao VS, Menezes AM, Viana GS. Effect of myrcene on nociception in mice. J Pharm Pharmacol. 1990;42(12):877– 878. [279] do Vale TG, Furtado EC, Santos JG Jr, et al. Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) n.e. Brown. Phytomedicine. 2002;9(8):709–714. [280] De-Oliveira AC, Ribeiro-Pinto LF, PaumgarDen JR. In vitro inhibition of CYP2B1 monooxygenase by betamyrcene and other monoterpenoid compounds. Toxicol LeO. 1997;92(1):39–46. [281] LorenzeDi BB, Souza GE, Sarti SJ, et al. Myrcene mimics the peripheral analgesic activity of lemongrass tea. J Ethnopharmacol. 1991;34(1):43–48. [282] Noma Y, Asakawa Y. Biotransformation of monoterpenoids by microorganisms, insects, and mammals. Baser K, Buchbauer G. Handbook of essential oils: science, technology, and applications. CRC Press: Boca Raton, FL; 2010. [283] Perry NS, Houghton PJ, Theobald A, et al. In-vitro inhibition of human erythrocyte acetylcholinesterase by salvia lavandulaefolia essential oil and constituent terpenes. J Pharm Pharmacol. 2000;52(7):895–902. [284] Komori T, Fujiwara R, Tanida M, et al. Effects of citrus fragrance on immune function and depressive states. Neuroimmunomodulation. 1995;2(3):174–180. [285] Carvalho-Freitas MI, Costa M. Anxiolytic and sedative effects of extracts and essential oil from Citrus aurantium L. Biol Pharm Bull. 2002;25(12):1629–1633. [286] Vigushin DM, Poon GK, Boddy A, et al. Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials CommiDee. Cancer Chemother Pharmacol. 1998;42(2):111–117. [287] Komiya M, Takeuchi T, Harada E. Lemon oil vapor causes an anti-stress effect via modulating the 5-HT and DA activities in mice. Behav Brain Res. 2006;172(2):240–249. [288] Fischedick JT, Hazekamp A, Erkelens T, et al. Metabolic fingerprinting of Cannabis sativa L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes. Phytochemistry. 2010;71(17–18):2058–2073. [289] Basile AC, Sertie JA, Freitas PC, et al. Anti-inflammatory activity of oleoresin from Brazilian Copaifera. J Ethnopharmacol. 1988;22(1):101–109. [290] Yang D, Michel L, Chaumont JP, et al. Use of caryophyllene oxide as an antifungal agent in an in vitro experimental model of onychomycosis. Mycopathologia. 1999;148(2):79–82. [291] Vanhoenacker G, Van Rompaey P, De Keukeleire D, et al. Chemotaxonomic features associated with flavonoids of cannabinoid-free cannabis (Cannabis sativa subsp. sativa L.) in relation to hops (Humulus lupulus L). Nat Prod LeO. 2002;16(1):57–63. [292] BarreD ML, Gordon D, Evans FJ. Isolation from Cannabis sativa L. of cannflavin: a novel inhibitor of prostaglandin production. Biochem Pharmacol. 1985;34(11):2019–2024. [293] ElSohly MA, Turner CE, Phoebe CH Jr, et al. Anhydrocannabisativine, a new alkaloid from Cannabis sativa L. J Pharm Sci. 1978;67(1):124. [294] Toyota M, Shimamura T, Ishii H, et al. New bibenzyl cannabinoid from the New Zealand liverwort Radula marginata. Chem Pharm Bull (Tokyo). 2002;50(10):1390–1392. [295] Gertsch J, Schoop R, Kuenzle U, et al. Echinacea alkylamides modulate TNF-alpha gene expression via cannabinoid receptor CB2 and multiple signal transduction pathways. FEBS LeO. 2004;577(3):563–569. [296] Raduner S, Majewska A, Chen JZ, et al. Alkylamides from echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and independent immunomodulatory effects. J Biol Chem. 2006;281(20):14192–14206. [297] Hohmann J, Redei D, Forgo P, et al. Alkamides and a neolignan from Echinacea purpurea roots and the interaction of alkamides with G-protein-coupled cannabinoid receptors. Phytochemistry. 2011;72(14–15):1848–

1853. [298] Bone K. A clinical guide to blending liquid herbs: herbal formulations for the individual patient. Churchill Livingstone: St Louis, MI; 2003. [299] Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine. 2009;16(2–3):97–110. [300] Ben-Shabat S, Fride E, Sheskin T, et al. An entourage effect: inactive endogenous faDy acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol. 1998;353(1):23–31. [301] Mechoulam R, Ben-Shabat S. From gan-zi-gun-nu to anandamide and 2-arachidonoylglycerol: the ongoing story of cannabis. Nat Prod Rep. 1999;16(2):131–143. [302] Sinclair J, Sinclair C. Integrative medicine: polypharmacy. Sarris J. Clinical naturopathy: an evidence-based guide to practice. 2nd ed. Elsevier: Sydney; 2014. [303] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 2nd ed. Elsevier: Sydney; 2007. [304] Mills S, Bone K. The essential guide to herbal safety. Churchill Livingstone: St Louis, MI; 2005. [305] Touitou E, Godin B, Dayan N, et al. Intracellular delivery mediated by an ethosomal carrier. Biomaterials. 2001;22(22):3053–3059. [306] Touitou E, Dayan N, Bergelson L, et al. Ethosomes — novel vesicular carriers for enhanced delivery: characterization and skin penetration properties. J Control Release. 2000;65(3):403–418. [307] Lodzki M, Godin B, Rakou L, et al. Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model. J Control Release. 2003;93(3):377–387. [308] Watkins PB. Drug metabolism by cytochromes P450 in the liver and small bowel. Gastroenterol Clin North Am. 1992;21(3):511–526. [309] Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994;270(1):414–423. [310] Guengerich FP. Cytochrome P450 enzymes. McQueen CA. Comprehensive toxicology. 4th ed. Elsevier; 2010:41– 76. [311] Pirmohamed M, Park BK. Cytochrome P450 enzyme polymorphisms and adverse drug reactions. Toxicology. 2003;192(1):23–32. [312] Shapiro LE, Shear NH. Drug interactions: proteins, pumps, and P-450s. J Am Acad Dermatol. 2002;47(4):467– 488. [313] Klo• U. Effect of age on pharmacokinetics and pharmacodynamics in man. Int J Clin Pharmacol Ther. 1998;36(11):581–585. [314] Jiang R, Yamaori S, Takeda S, et al. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011;89(5–6):165–170. [315] Yamaori S, Koeda K, Kushihara M, et al. Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet. 2012;27(3):294–300. [316] Yamaori S, Okamoto Y, Yamamoto I, et al. Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos. 2011;39(11):2049–2056. [317] Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80(15):1415–1419. [318] DeviD-Lee A. CBD–drug interactions: the role of Cytochrome p450. O'Shaughnessy's J Cannabis Clin Pract. 2015;16:10. [319] Sachse-Seeboth C, Pfeil J, Sehrt D, et al. Interindividual variation in the pharmacokinetics of delta9tetrahydrocannabinol as related to genetic polymorphisms in CYP2C9. Clin Pharmacol Ther. 2009;85(3):273–276. [320] Jackson NJ, Isen JD, Khoddam R, et al. Impact of adolescent marijuana use on intelligence: results from two longitudinal twin studies. Proc Natl Acad Sci USA. 2016;113(5):E500–8. [321] van Os J, Bak M, Hanssen M, et al. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol. 2002;156(4):319–327. [322] Thornicroft G. Cannabis and psychosis. Is there epidemiological evidence for an association? Br J Psychiatry. 1990;157:25–33. [323] Ksir C, Hart CL. Cannabis and Psychosis: a Critical Overview of the Relationship. Curr Psychiatry Rep. 2016;18(2):12.

[324] Hickman M, Vickerman P, Macleod J, et al. If cannabis caused schizophrenia, how many cannabis users may need to be prevented in order to prevent one case of schizophrenia? England and Wales calculations. Addiction. 2009;104(11):1856–1861. [325] Anthony J, Warner LA, Kessler RC. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the national comorbidity survey. Exp Clin Psychopharmacol. 1994;2(3):244–268. [326] Gao C, Ogeil R, Lloyd B. Alcohol's burden of disease in Australia. Canberra: FARE and VicHealth in collaboration with Turning Point. 2014. [327] Bachhuber MA, Saloner B, Cunningham CO, et al. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999–2010. JAMA Intern Med. 2014;174(10):1668–1673. [328] Bradford AC, Bradford WD. Medical marijuana laws reduce prescription medication use in Medicare, part D. Health Aff (Millwood). 2016;35(7):1230–1236. [329] May J. The new age of old age. Sydney Morning Herald. [1 May] 2012.

21

Cancer – Advanced I Dr Janet Schloss

Cancer pathogenesis and treatment Cancer as a disease is a complex system that consists of various theories on pathogenesis. As scientists unravel the pathogenesis of cancer, it has helped not only the understanding of how a cell can transform into a tumour, but also the development of molecular testing that can now diagnose tumour development and provide prognosis for a variety of cancers. The following sections look at cancer pathogenesis understanding and how treatment options are now being developed to combat this insidious disease.

Scientific theories on cancer pathogenesis The development and growth of scientific understanding of cancer has progressed tremendously over the past decade. There are, however, other alternative theories of carcinogenesis, but these theories lack substance and scientific evidence. The five basic theories of cancer pathogenesis are: 1 Mutational theory. The mutation theory of carcinogenesis has been the dominant force behind cancer research and the most prevalent theory for the past century. The basis behind this theory is that cancer is a clonal, cell-based disease and that successive DNA mutations in a cell can cause cancer. Therefore, this means that: 1) cancer is a defect of the control of cell proliferation; and 2) the default state of metazoan cells is quiescence.[1] 2 Genome instability theory. The genetic instability has been hypothesised as the cardinal feature of cancer development. Genetic alterations in all tumours have now been well established, including subtle changes in DNA sequence, in addition to cytogenetically visible changes such as chromosomal losses, gains and translocation. This theory posits that the genetic instability drives tumour progression by generating mutations in oncogenes and tumour-suppressor genes, thereby providing cancer cells with a selective growth advantage.[2] 3 Non-genotoxic theory. The non-genotoxic (epigenetic) theory of carcinogenesis is based

on the thought that to induce tumour formation, disturbance of the balance between cell growth and cell death needs to occur. The posit of this theory is that there is a diverse group of chemicals that can induce tumour formation by mechanisms other than direct DNA damage. It believes that repeated exposure to cytotoxicants can result in chronic cell injury, compensatory cell proliferation, hyperplasia and, ultimately, tumour development. In addition, another class of epigenetic carcinogens can interfere with signal transduction mechanisms and gene expression involved in the regulation of cell growth, cell death and differentiation as well as disturbance of hormonal balance, immunosuppression and chronic inflammation.[3] 4 Darwinian theory. Since the mid 1970s, cancer development has been described as the process of Darwinian evolution. This states that somatic cellular selection and evolution is the fundamental process leading to malignancy and its many manifestations such as neoangiogenesis, evasion of the immune system, metastasis and resistance to therapies. The basis behind this theory is that cancer is a disease of opportunity.[4] 5 Tissue organisation theory. The tissue organisation theory posits that cancer is a tissuebased disease and that proliferation is the default state of all cells based on epistemological and experimental evidence. The premise behind this theory is that carcinogenesis occurs at the tissue level of biological organisation. This implies that chronic abnormal interactions between the mesenchyme/stroma and the parenchyma of a tissue are responsible for the appearance of a tumour, and the default state of all cells is proliferation. In addition, this theory believes that carcinogenesis is a reversible process, as normal tissue in contact with neoplastic tissues may normalise the laYer.[5]

Understanding new molecular pathogenesis and prognostics of cancer Systemic evolutionary theory of cancer pathogenesis This new theory posits that cancer is generated by the demergence of the eukaryotic cell system and then the re-emergence of its archaea (genetic material and cytoplasm) and prokaryotic (mitochondria) subsystems. This re-emergence has uncoordinated behaviour and decreased coordination caused by the change in the organisation of the cell environment, which is mainly due to chronic inflammation, damage to mitochondrial DNA and/or its membrane composition by various agents (e.g. viruses, chemicals, hydrogenated faYy acids) and/or by damage to the nuclear DNA that controls mitochondrial energy production. This in turn can affect metabolic pathways including glycolysis within the tumour cell.[6]

Prognostics of cancer Prognostics of cancer relates to the chances of survival for a person who has cancer. It relates

to the estimate of how the disease will go or unravel for that person. The main factors that influence the prognosis include:

• type of cancer and where it is located in the body • the stage of cancer (i.e. the size of tumour and if it has spread to other parts of the body) • the grade of the cancer (i.e. how abnormal the cancer cells look under a microscope) • what traits the cancer cells possess • the person's age and how healthy they are prior to cancer diagnosis • response to treatment options. Currently, doctors estimate prognosis by using statistics that researchers have collected and collated over many years. The most commonly used statistics include:[7]

• Cancer-specific survival – the percentage of patients with a specific type and stage of cancer who have not died from their cancer during a certain period of time post diagnosis. • Relative survival – the percentage of cancer patients who have survived for a certain period of time after diagnosis compared to people who do not have cancer. • Overall survival – the percentage of people with a specific type and stage of cancer who have not died from any cause during a certain period of time post diagnosis. • Disease-free survival – the percentage of patients who have no signs of cancer during a certain period of time post treatment. In addition to the normal statistics used for prognosis, scientists are trying to develop new and progressive models to assist doctors to be more specific for cancer prognosis. Some of the new developments in prognostic tools include:

• Isolation and characterisation of extracellular vesicles. Extracellular vesicles contain a substantial amount of genetic information that can be transferred to other cells, thereby promoting the progression of metastatic cancer in patients. To date, several methods are being developed to isolate and analyse these vesicles. However, further work is needed to combat certain issues. Nevertheless, extracellular vesicles are

emerging as an important biomarker for cancer diagnosis and prognosis. [8]

• Single cell protein analysis. The area of proteomics is an emerging scientific stream that can assist many aspects of health. The single cell protein analysis is a method by which two protein assays demonstrate that T cells communicate with each other and enhance their cytokine release upon contact. This technique is only new as it was developed through a recent PhD project, and further testing to confirm cancer prognosis technique is warranted.[9] • Epigenetic biomarkers. The development and identification of epigenetic biomarkers is an exciting new area with potential to assist the prognostic ability of doctors. To date, prognostic values of the separate biomarkers are ambiguous with no established standards. However, epigenetic biomarkers still seem to have potential, with further research required.[10] • Multi-omics Data. Currently, there have been individual types of omics data used to separately construct predictive models of a 10-year survival rate for breast cancer patients. The predictive model now constructed with proteome data achieved a beYer predictivity, and was found to outperform other models. Future development of data-driven and domainknowledge-based data fusion methods has the ability to lead to improved predictive ability in biomedicine.[11] • DNA methylation. One of the epigenetic mechanisms of regulating gene expression is cytosine methylation in DNA. This plays an important role in cell differentiation or proliferation. Techniques or methods to determine methylation status of specific DNA are being developed to assist in the prognosis of cancer. Two of these techniques include MAHRM (methylation-specific high-resolution melting) and electrochemistry. These techniques have shown great promise as both were tested successfully, which may lead to more precise diagnostic and prognostics of cancer.[12]

Medicinal cannabis Studies examining the medicinal properties of Cannabis sativa have been increasingly conducted around the world, largely in line with the legalisation of medicinal cannabis occurring in certain states and countries. The medicinal properties identified in these studies

include inhibition of chemotherapy-induced nausea and vomiting, appetite stimulation, pain reduction and decreased inflammation, cell proliferation and cell survival.[13] Based on these medicinal properties, the medical conditions identified for the potential benefits of medicinal cannabis properties include chronic pain, respiratory system disorders, glaucoma, multiple sclerosis, HIV/AIDS, muscle spasms, seizures, severe nausea and cachexia or dramatic weight loss.[14] Cannabis sativa has been found to consist of approximately 60 unique compounds known as cannabinoids. Delta-9-tetrahydrocannabinol (THC) is the most widely studied constituent due to its high potency and abundance in cannabis.[15] Medicinally, THC consists of the main psychoactive component found in cannabis. The other main cannabinoid compound identified for potential beneficial properties is cannabidiol (CBD).[16] Cannabinoid's pharmacological effects are exerted primarily through two specific plasma membrane G-protein-coupled receptors: cannabinoid receptor 1 (CB1) receptors (most commonly located in the hippocampus, basal ganglia and cerebellum) and cannabinoid receptor 2 (CB2) receptors located in peripheral tissues.[13,16] The anti-cancer properties of cannabinoids were recognised in 1975, with Munson et al.[17] showing in vitro and in vivo data on medicinal cannabis Lewis lung adenocarcinoma growth in mice. The cannabinoids delta-9-THC, delta 8-THC and cannabinol (CBN) but not CBD reduced the primary cancer growth.[17] In addition, in vitro work has identified that cannabinoids can limit inflammation, cell proliferation and cell survival via CB1 and CB2 receptors. This is through a variety of intracellular signal-transducing effects such as inhibition of adenylate cyclase (AC), activation of mitogen-activated protein kinase, regulation of calcium and potassium channels (CB1 only) and other signal transduction pathways. Further information pertaining to the medicinal cannabis and the endocannabinoids can be found in Chapter 20: Endocannabinoid System.

Outline of treatment options available to people with cancer In addition to traditional medical treatment for cancer and supportive therapies, there are several options available to people with cancer to assist their treatment or options that are considered to be an ‘alternative’ treatment. Each country enforces its own laws and regulations in regard to treatment options for cancer, with the World Health Organization seYing its own guidelines.[18] Therefore, some of the treatments listed below may be illegal in certain countries but legal in others. There are many alternative therapies available to people – a number of treatments are outlined in Table 21.1. TABLE 21.1 Alternative treatments for cancer Treatment

Description

Artemisia

The most common form of this herb, which is touted to treat cancer, is Artemisia annua. This is a common type of wormwood and is native to Asia. Animal studies and in vitro studies have

indicated potential anti-invasion and anti-metastatic capabilities by participating partially in the inhibition of the cancer cell adhesion to endothelial cells via suppression of vascular cell adhesion molecule-1 and suppression of epithelial-mesenchymal transition (EMT).[19–21] However, there are no human studies that have been conducted to date, so further research is required to validate potential anti-cancer activity. Budwig This protocol primarily involves flaxseed oil with coYage cheese or quark. It was started by Dr protocol Johanna Budwig in 1952, who developed a specific diet to counteract the ‘cancer-causing’ process. The basis of the diet is replacing processed fats with beneficial fats. For further information see the Budwig diet in Chapter 12 of CNM – The Immune System, Part C – Cancer. Frankincense Essential oils such as Frankincense (Boswellia carterii or Ru Xiang) and Sandalwood (Santalum and/or album or Tan Xiang) have been said in Chinese medicine to have cancer preventive and sandalwood therapeutic anti-cancer properties.[22] Currently, only in vitro studies have been conducted on essential oil these essential oils, with positive results indicating induction of apoptosis in cancer cell lines, but therapy further human clinical trials are required.[22–24] Hyperthermia Hyperthermia treatment, which is predominantly used in Europe for cancer, is an emerging cancer treatment worldwide that involves applying heat to a malignant tumour or the whole body of a person with cancer. The heating process can be delivered by using electromagnetic (EM) energy or radiofrequency (RF) or microwave range.[25] Currently, there are clinical trials confirming the use of hyperthermia in conjunction with radiotherapy to help improve the therapeutic outcomes in various tumours. Clinical trials with chemotherapy and hyperthermia are also being conducted.[26] Accurate patient-specific hyperthermia treatment planning is an essential component for effective and safe treatments. Hyperthermia treatment has been found to be a good adjunct to cancer treatment. Iscador Iscador, or mistletoe (Viscum album), is a common complementary medicine used in Europe and (mistletoe) has been an essential part of herbal medicine for thousands of years. It has also been used as an adjuvant cancer therapy for almost a century in Europe. There are a number of published papers and clinical trials conducted on iscador during and post chemotherapy. It is considered a safe and effective adjunctive treatment for cancer that assists in reducing chemotherapy-related toxicity.[27,28] Oxygen therapy and hyperbaric chambers

Proteolytic enzyme therapy

Limited studies have been published on oxygen therapy and hyperbaric chambers as a possible treatment for cancer, but it is promoted as a treatment for cancer. The main peer-reviewed publication on hyperbaric therapy and oxygen therapy as a treatment for cancer was published in 1975 and was a mice study.[29] Hyperbaric oxygen therapy has been stated as treatment for cancer due to the fact that hypoxia is a hallmark of solid tumours and is involved in cell survival, angiogenesis, glycolytic metabolism and metastasis. It has been assumed that increasing oxygenation creates an environment in which cancer cells cannot survive. However, a review conducted in 2012 on hyperbaric oxygen therapy and cancer found that there is no evidence that it has tumour-inhibitory effects.[30] Liquid oxygen is also suggested for cancer patients under the same thought process, but again, there is no literature to support this theory, and to date oxygenation has not been proven to be an effective treatment for cancer, but it may assist with side effects from treatment such as radiation. The theory of enzyme therapy for cancer was initially published in 1911 by John Beard,[31] an English embryologist whose work was forgoYen until the 1950s when Max Wolf and Helene Benitez adopted the concept of systemic enzyme therapy for oncology.[32] The basis of the theory is that oral proteolytic enzymes, when no food is being absorbed, are absorbed and distributed systemically. The initial animal studies showed that the growth of tumours was reduced when exposed to these enzymes. Both in vitro and in vivo studies have been conducted and have demonstrated that it may assist in decreasing tumour-induced and therapy-induced side effects and complaints in oncology. These include nausea, gastrointestinal complaints, fatigue, weight

Vitamin C infusions

loss, restlessness and quality of life. In addition, it was found to increase the response rate of medical treatment, the duration of remissions and the overall survival times.[33] It is still to be proven as an effective alternative therapy for decreasing tumour size, but has promise as an adjunctive cancer treatment. Vitamin C has been long connected with assisting people with cancer; however, confusion regarding the understanding and clinical application of the differences between oral and intravenous use has occurred. Early clinical studies by Linus Pauling[34] showed that high-dose vitamin C given intravenously and orally may improve symptoms and prolong life in patients with terminal cancer. Further scientific studies have now confirmed that oral vitamin C therapy has no benefit against cancer cells.[35] Only intravenous vitamin C can reach the plasma concentration necessary to cause toxicity against cancer cells. It is estimated that between 50 and 100 g of intravenous vitamin C, depending on the weight of a person, can reach the level of above 1000 micromol/L required to cause toxicity for cancer cells. Case studies and a few clinical trials have been conducted to date;[36,37] however, the main issue is that there is still no protocol for intravenous vitamin C, or algorithm for administration. Intravenous vitamin C has potential as an individual treatment as well as an adjunct treatment, but further research is required.

People who have cancer and those who are assisting people with cancer all want the best for the person, and a ‘cure’ if possible. However, it is important to note that not all natural therapies are safe, and each case needs to be considered carefully to find what is best for the individual and the stage they are currently at. Some controversial alternative treatment options that are available and have claimed to ‘cure’ cancer can be seen in Table 21.2. Some of these options may be seen or are classified in certain countries as potentially dangerous. This list is not conclusive as there are quite a number of unsubstantiated alternative treatments for cancer. TABLE 21.2 Controversial cancer treatments Treatment Description Baking soda and black strap molasses

The Trojan horse remedy of mixing baking soda and black strap molasses is a remedy that is supposed to increase the pH immediately in the blood, increase energy levels and the ability of cells to intake oxygen. This treatment has no peer-reviewed evidence to support the theory and there is no evidence that increasing the pH or oxygenation can reduce tumours. However, there are no unforeseen dangers of undertaking this remedy if so desired. Bicarbonate Consuming bicarbonate soda daily is based on the theory of alkalising the body. This theory is a soda cancer myth as the body cannot be alkalised by diet or by taking foods or beverages that are considered alkaline. The body regulates this, not intake. By ingesting bicarbonate soda, stomach acid is decreased, which is good for reflux, but not good before meals. There is no danger if patients want to consume bicarbonate soda on a daily basis, but it must be consumed at least 1 hour post eating. Black salve Black salve, or cansema, is a corrosive agent that consists of a combination of herbs including (cansema) Sanguinaria canadensis (bloodroot) and zinc chloride. Black salve products have been advertised and promoted as a natural remedy for many different types of cancer, but primarily for skin cancers such as melanoma. Both topical and internal use has been suggested. A review conducted in 2014 examined the current literature as this treatment can be dangerous with or without medical supervision.[38] It found that the widespread use of internet non-peer-

Hydrogen peroxide treatment

Laetrile (vitamin B17 or amygdalin)

reviewed information has allowed anecdotal reports of alternative treatments being used for cancer. Laboratory evidence has documented anticarcinogenic and corrosive effects by black salve. Nine case studies have been published and no clinical trials on efficacy and safety have been documented.[38] Therefore, the concept of black salve as a cancer treatment is not unfounded. However, the side effects of the treatment are not well communicated or known and vary from significant cosmetic defects and scarring to unconfirmed clearance of all cancer cells to cancer recurrence or spread, and there has also been one case documented of death.[38] There are many dangers associated with its use and until clinical trials are conducted to prove safety and efficacy, this treatment is not recommended. Despite the numerous side effects, extreme pain and lack of predictable response or evidence that it works, individuals continue to choose this self-treatment over surgery or medical treatment. A survey of 340 adults regarding their perception of the use of black salve found that 17 of the 23 black salve users were unaware of the potential side effects, and 70% did not visit a dermatologist or doctor before treatment with black salve, but rather relied on personal experience of friends and family.[39] Hydrogen peroxide treatment is one of the best known ‘alternative cures’ for cancer. It is promoted as being ‘safe, readily available and dirt cheap’. It is promoted by controversial programs and publications such as the ‘Truth about Cancer’ and involves the ingestion of hydrogen peroxide water. However, to date, no case studies or clinical trials have been published on this treatment. Use of hydrogen peroxide internally, such as intravenous vitamin C, has been documented and found safe, and laboratory investigations of hydrogen peroxide on cells have also found it can induce cancer cell death.[40] Hydrogen peroxide is most commonly used as an oxidising agent. Medically, it has been used for wound irrigation at a concentration of 3%; however, its toxic effects preclude its routine use. Ingestion of hydrogen peroxide is a well-known poison. A 39-year-old man who accidentally ingested 250 mL of unlabelled 35% hydrogen peroxide, thinking it was water, suffered grade 2 diffuse oral, oropharynx and epigastric damage, and was admiYed to hospital. He was considered ‘lucky’ because he realised as soon as he had ingested it that it was caustic, so consumed 500 mL of water and induced vomiting.[41] The patient told emergency staff that the substance was in a friend's fridge and was intended for natural health purposes. He mistook the unlabelled container for water. In conclusion, hydrogen peroxide diluted in water is caustic and is not considered a safe practice or treatment for cancer. Laetrile, vitamin B17, apricot kernels and amygdalin are all names given to the same substance. Laetrile is considered the best known ‘cure for cancer’. The laetrile is used to describe a purified form of the chemical amygdalin, a cyanogenic glycoside found in the pits of many fruits, raw nuts, lima beans, clover and sorghum. In the body, the hydrogen cyanide dissolves to form the cyanide anion. The term vitamin B17 was given to laetrile by E.T. Krebs Jr. It gained popularity in the 1970s as an anti-cancer agent.[42] Laetrile is not approved for use in any country. The studies to date have shown very liYle anticancer activity in animals and no anti-cancer activity in human clinical trials. The side effects associated with laetrile toxicity are very similar to cyanide poisoning. These include liver damage, difficulty walking due to nerve damage, fever, coma and death. The internet as an unpoliced source of information has promoted inappropriate advertising of laetrile, and investigations, charges and convictions of distributors have occurred in a number of countries including the US and Australia.[42] A Cochrane review conducted in 2015 found that claims that laetrile or amygdalin have beneficial effects for cancer patients are not currently supported by sound clinical data.

Machines (e.g. Rife machine)

Urine therapy

Moreover, there is a considerable risk of serious adverse effects from cyanide poisoning after laetrile or amygdalin ingestion. The authors concluded that laetrile as a treatment for cancer is unambiguously negative and is not recommended for use.[43] There are a number of different types of machines that are used as an anti-cancer treatment. Probably the best known is the Rife machine, which was developed by Royal Raymond Rife in 1920. This machine produces electromagnetic energy in the form of electrical impulses which travel in waves. The theory behind these machines is that all parts of the body emit electrical impulses with different frequencies that may vary depending on health or disease, illnesses could be diagnosed by ‘tuning in’ on patients’ blood or handwriting samples, and these diseases could be treated by feeding proper vibrations into the body with these devices. There are several websites claiming that the Rife machine can be used to treat a number of conditions including cancer. New devices, machines or diagnostic or treatment tools are required to undergo a long process of development and clinical trials to prove or disprove if they cause harm or benefit. The Rife machine and similar machines have not been through this process of scientific testing and there is no evidence to indicate that the Rife machine does what its supporters say, nor is there evidence of harm.[44] Therefore, this treatment had no scientific evidence of benefit and harm has not been formally excluded. Urine therapy is based on drinking one's own urine or, in India, drinking cow's urine, as an alternative therapy to treat cancer. There is no scientific evidence for drinking one's own urine as a treatment for cancer to date. India has published studies on cow's urine therapy on various cancer patients.[45] The theory behind the use of cow's urine in India is that cow's blood has life force (pran Shakti), and cow's urine is cow's blood that has been filtered by the kidney. One paper evaluated cow's urine therapy on cancer patients in an 8-day camp. A total of 68 cancer patients completed the survey. Of the 68 patients, five withdrew from the treatment. According to the results of the survey, the symptoms (pain, inflammation, burning sensation, difficulty swallowing, irritation etc.) were decreased in patients undergoing cow's urine therapy.[45] Urine therapy overall, has limited scientific benefit for cancer. It is not recommended but also does no harm.

Myths of cancer Acid/alkaline diet The human body is regulated by homeostasis, with certain areas requiring acidic environments and others requiring alkaline. The pH of individual cells is highly regulated and the extracellular matrix surrounding cells, although slightly less regulated, is the result of a delicate balance between metabolic processes, proton production and transportation, chemical buffering and vascular removal of waste products.[46] Malignant aggressive cells from a solid tumour are different in that they show a pronounced increase in metabolic processes. Aerobic glycolysis is one of the hallmarks of cancer metabolism and results in an increase of protons which, if they stayed within the cell, would cause acidosis and cellular death.[46] Therefore, malignant cancer cells aim to keep intracellular pH consistently alkaline to solve this problem by increasing proton transportation which expels the excess acidity. The accumulation in the extracellular matrix creates a hypoxic and acidic environment around

the tumour. It is important to remember that not all cancer cells express or overexpress the same combination of proton transporters and there are important differences among various tumours – in particular, the slower or less aggressive malignant mitochondrial-based tumours.[46,47] A systematic review on the association between dietary acid load, alkaline water and cancer was conducted and published in 2016.[48] The review evaluated the evidence for a causal relationship between the dietary acid/alkaline and alkaline water for the aetiology and treatment of cancer. Of the 8278 citations, only one study met the inclusion criteria, and no randomised trials were located. The only study found was a cohort study and it revealed no association between the diet acid load and bladder cancer, and no association was found among long-term smokers.[49] Therefore, despite the worldwide promotion of the alkaline diet and water by the internet, media and natural practitioners, there is no actual research to support or disprove this theory. Hence, as a cancer treatment, it is not justified.[48] The acid/alkaline diet, although not proven for cancer prevention or as a treatment, can have benefits because people who follow this diet generally increase their intake of fresh fruits and vegetables and decrease the intake of highly fried and processed foods and red meat. This provides the body with good nutrients and can be beneficial for cancer prevention. High intake of red meat has been found to be associated with a higher risk of allcause cancer and cardiovascular mortality, while the increase of fruits and vegetables has been found to decrease the risk.[50] Sugar feeds cancer The notion that sugar feeds cancer or cancer cells is touted throughout the internet, controversial anti-cancer sites, books and seminars, in addition to clinician/practitioner seminars. This notion is a very oversimplified and unhelpful assumption based on a highly complex area that science is still unravelling. While it is very sensible to limit sugary food or processed foods high in sugar as part of a healthy diet, the thought that sugar actually feeds cancer cells is incorrect. Researchers are investigating the connection, but this notion remains a source of anxiety-inducing speculation and misinformation from media, the internet and so-called ‘experts’. The main metabolic process of tumours varies depending on the tumour type, aggressiveness and requirements of those particular cells. In essence, blood glucose is the main energy source for all cells, and even without carbohydrate intake, the body can make blood glucose from other sources such as amino acids and fat. The theory that sugar feeds cancer is based on the fact that some solid tumours use aerobic glycolysis as their main metabolic system to produce ATP or energy. This increased uptake of blood glucose has been misconstrued into the notion that consumption of sugar feeds cancer cells. The idea that consumption of sugar and carbohydrates feeds cancer cells has influenced people with cancer to avoid all carbohydrate-containing foods. This avoidance is counterproductive in most cases. Moreover, this fear-based approached creates stress and anxiety for the person, which in turn stimulates the fight and flight mechanism, producing hormones that raise

blood glucose levels and suppress the immune system. The science behind some cancer cells does include the upregulation of aerobic glycolysis and is often stimulated by oncogenes. In in vivo studies, researchers have now found that glucose-derived pyruvate can be diverted into the mitochondrial tricarboxylic acid cycle (which all cancer cells still contain) to produce additional energy or intermediates for the synthesis of faYy acids or amino acids such as glutamine.[51,52] Cancer cells can use blood glucose, amino acids or fats as their energy source. Hence, consuming carbohydrates does not ‘feed’ cancer cells as carbohydrates are only one of the cells’ energy sources and restricting them cannot ‘starve’ the tumour.

Modern mainstream treatment, recent developments in genomics/profiling/therapies New developments in immunotherapies and targeted cancer treatments The medical treatment of cancer has been increasingly focused on new, more direct interventions. The development of immunotherapy and targeted cancer treatments has changed the way cancer is treated, developed patient- or mutation-centred care and enhanced the patients’ experience, mortality and quality of life. The mechanism of cancer immunotherapy is the use of specific aspects of the immune system to treat cancer.[53] Some of the new therapies involve antibodies that block the immune checkpoints, cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) and programmed cell-death protein 1 (PD-1 or PD-L1). These new innovations have specially assisted poor response cancers such as melanoma, renal cell carcinoma, bladder cancer, brain tumours and non-small-cell lung cancer.[54] Targeted cancer therapies are different from immunotherapies. These therapies are linked to specific genetic lesions such as epidermal growth factor receptor mutations and inhibitors. Targeted cancer therapy has progressed cancer treatment from the non-selective, chemotherapy cytotoxic agents that have numerous side effects to a revolutionary molecularly targeted therapy.[55] An example of a targeted cancer treatment is Tarceva (erlotinib) for metastatic non-small-cell lung cancer. Genomics and impact on treatment The mapping of the human genome has accelerated the discovery and development of various cancer treatments. The implantation of tumour profiling has already entered the clinic seYing and enhanced current treatment options. Understanding the differences in genomic results between different tumour profiling is becoming increasingly important for both patients and oncologists, but enhancing clinician literacy to applied cancer genomics is still required.[56] Genomic profiling involves scientific assays targeting sequencing panels which may contain between 200 and 500 genes (or, extreme, n = 20 000 genes) that can be implicated in cancer biology or clinical management of cancer. In addition, panel sequencing may

emphasise rapid turnaround time by only profiling small gene sets (n = 15–48 genes). These types of genetic profiling may assist clinicians in predicting mutational load for immunotherapy response or predict DNA mismatch repair protein-deficient tumours through mutational load.[56] Genomic profiling is still a new development and a variety of studies are still being conducted. The use of genomic profiling with the combination of immunotherapy and targeted therapy to enhance the clinical outcome for the patient is a very positive step in cancer treatment. Profiling and staging options now available The tumour/node/metastasis staging system has been in use since the 1940s and has several limitations, including not actually reflecting the status of the solid or haematological cancer to predict prognosis. To resolve this issue, new methods of profiling and staging have been investigated. One of the innovations for profiling is the immunokine profiling for cancer staging.[57] This new form is based on the cytokine levels in tumour-bearing human patients. It has demonstrated that cytokine profiling is differential for local or systemic cancers and provides a beYer predictive tool for oncologists.[57] Precision medicine Precision medicine is used to describe how genetic information about a person's disease or cancer is used to assist in diagnosis or treatment.[58] As cancer is a disease of the genome, understanding the genetic changes that occur in cancer cells assists researchers to find more effective treatment strategies that can tailor the cancer treatment to a person's cancer from their genetic profile.[58] An example of a new cancer treatment that exemplifies precision medicine is the drug imatinib (Gleevec), which was designed to inhibit the altered enzyme produced by a fused version of two genes found in chronic myelogenous leukaemia.[59] Another precision medicine drug that is well known due to its role in breast cancer is trastuzumab (Herceptin), which works only on women whose tumours have a particular genetic prolife called HER-2 positive.[60] There are quite a number of these types of drugs now available to patients, which has taken treatment and survival for patients with cancer to the next level. Targeted chemotherapy and new radiation therapies Chemotherapy, for many cancers and people, is an aggressive but effective treatment, but for most patients, the nasty side effects almost outweigh the benefits. Due to the side effects from systemic exposure to the chemotherapy drugs, scientists are now looking for more effective and less toxic ways of delivering these chemotherapy drugs. This includes the development of targeted chemotherapy and new radiation therapies. One of the new techniques, particularly for liver cancer, is transarterial chemoembolisation.[61] This involves infusing chemotherapy directly into the hepatic artery, as hepatocellular and hepatoma carcinomas get their blood exclusively from this artery. This

technique can also be used for metastatic cancers in the liver for similar reasons. This delivers the chemotherapy directly into the liver and to the tumours. There are still side effects from this technique, but they are not as severe as from systemic chemotherapy. In addition to transarterial chemotherapy, there is also intra-arterial chemotherapy, which is used for cancers such as local invasive bladder cancer.[62] Intratumoural chemotherapy is also an innovative technique for cancers such as nonsmall-cell lung cancer.[63] This is still going through clinical trials but it involves a computed tomography (CT)-guided intratumoural injection into lesion. To date, it has been found to be safe, effective, aggressive (as it creates a high drug concentration in the tumour) and cost effective.[63] In addition to intratumoural chemotherapy, there is now intraperitoneal chemotherapy, whereby a catheter is inserted via laparoscopy for colorectal and ovarian cancer. This catheter sits just under the skin and connects to a large vein in the peritoneum. Chemotherapy drugs are injected through the catheter, directly targeting the cancer cells in the abdomen.[64] New ways of delivering radiation have also been developed to assist in making it safer and more effective. Nanomedicine is one of these developments that has stepped into the spotlight. Nanoparticles have been found to potentiate radiotherapy by specifically delivering radionuclides or radiosensitisers into tumours, which enhances the efficacy and reduces the toxicity of radiation.[65] There are now a number of different types of nanoparticle radiosensitisation available to patients including gold nanoparticle doseenhanced radiation therapy (GNPT)[66] and other metal-based nanoparticle radiosensitisation.[67] Other new developments in radiotherapy include selective internal radiation therapy (SIRT), which has been used for liver metastasis.[68] This technique delivers millions of tiny radioactive microspheres or beads called SIR-Spheres® directly to the liver tumours. Radioprotectors and mitigators of radiation-induced normal tissue injury are also another innovation to try to minimise the damage from radiation. Some of the technology used to reduce the toxicity to normal tissue include conformal radiotherapy, intensity-modulated radiotherapy, image-guided radiotherapy and proton radiotherapy.[69]

Scope of practice for the natural healthcare provider Role of a natural healthcare practitioner in assisting people who have cancer The role of natural healthcare practitioners in assisting people with cancer will vary. Rarely will a natural healthcare practitioner be the primary health professional unless the patient has declined all or certain medical treatment and is relying totally on natural therapy support or treatment. In most situations, the role of the natural healthcare practitioner will be one of integration, complementary collaboration and/or support using complementary medicine.

To clarify the difference, complementary medicine is defined as complementary therapies used together with conventional medicine; alternative medicine is where natural therapies are used in place of conventional medical treatment; and integrative or collaborative medicine is the practice of medicine that reaffirms the importance of the relationship between a practitioner and patient and utilises all appropriate therapeutic approaches, healthcare professionals and disciplines to achieve optimal health and healing. Therefore, the natural healthcare professional's role may be one of the following:

• Primary healthcare practitioner – if the patient declines traditional medical treatment. This role may use alternative medicine techniques. • Complementary healthcare practitioner – supporting the patient by using natural health products, lifestyle advice or techniques to assist them through medical treatment and post treatment. • Integrative practitioner – part of a team of health professionals assisting the patient with their scope of practice to achieve the best health and healing possible. Natural healthcare practitioners may find themselves rotating between these roles between patients, and even for the same patient. What is important is being aware of where you stand when assisting that person.

Language and communication Language, communication and practitioner interaction/relationships with patients is crucial in the wellbeing, health, compliance and mental health of people with cancer. Communication is a multidimensional concept, particularly with people who have or had cancer, as that can be particularly challenging. Unfortunately, it is one of the areas that is less focused on, but it can have the largest impact. Effective treatment and words practitioners use are the basic foundation for responsiveness to treatment, decisions made, positive health outcomes, patient-driven compliance and overall high quality of care.[70] One of the most important aspects is compassion from the practitioner and patient-centred care, which means the interaction is about the patient being heard and listened to, and the words chosen and treatment suggestions are tailored to that person. It is really important to consider the needs of the patients, their perspectives and experiences. Also, provide opportunities for patients to participate in their own care and take note of how to best interact with the patient. The current literature of practitioner–patient communication is that the communication must vary depending on which phase patients are in, and that it should be tailored to their evolving needs, preferences and state. Non-verbal communication, from both the patient and the practitioner, is vital. It is important that the practitioner identifies non-verbal as well as

verbal cues from the patient and responds accordingly. Additionally, the non-verbal expressions and language from the practitioner can influence the patient just as much as the verbal language used. Compassion and empathy are very important traits of practitioners, but patients generally do not like sympathy or being patronised.[71]

Scope of practice within and outside the medical system In addition to language and communication, it is also important to acknowledge your scope of practice with the care of the person with cancer. As with all conditions and people, you should never practise outside your scope of practice. Where needed, refer to professionals if other modalities or assistance are required outside your scope of practice. Within the medical system, the scope of practice of a natural healthcare practitioner is one of support. A patient should never be put in a situation where they are made to choose between the medical fraternity and a natural healthcare practitioner. If a natural healthcare practitioner does not want to collaborate or work with patients who are under care of a medical practitioner, they should state that clearly so the patient is not put into an inappropriate situation.

When patients decline medical treatment If patients decline medical treatment and choose natural alternatives, communication, ethical and legal considerations and outlining very clearly the scope of practice are imperative. Legally and ethically, natural healthcare professionals cannot state that they can ‘cure’ cancer. It is important still to promote hope as well as using evidence-based treatment options. The patient should at all stages know there are no guarantees but that the practitioner will do their best to assist them to achieve their goals.

Legality of treating people with cancer Cancer is considered a ‘red flag’ disease and, as such, legal and ethical considerations are very crucial. In particular, the legality of treating people needs to be understood and adhered to as the risk of legal action against the practitioner is considered to be higher than for other conditions. The general legal principles include:

• Every adult of sound mind has the right to determine what happens or is done to their body. • Any healthcare treatment provided without consent is a trespass. • Consent to treatment is distinct from the duty to warn about potential risks of treatment. • A patient has the right to decline treatment. In general, medical practitioners are ethically and legally obliged to provide patients with

enough information to assist them in making adequately informed healthcare decisions. With the growth of complementary or natural therapy medicine, there has been a blurring of distinctions between complementary medicine and conventional medicine. This is particularly important in countries where natural health modalities are not registered. In natural healthcare modalities that are registered, legal and ethical issues are clearly outlined, whereas in the modalities that are not, there are no clear legal or ethical guidelines. However, all natural healthcare professionals are liable and can be made accountable via the legal system in their country.[72] Understanding your scope of practice and working within that, taking detailed notes and practising within the legal requirements of the country are imperative. This is the same for treating all health conditions, but is emphasised more in ‘red flag’ conditions such as cancer.

Understanding of the oncological system and the options/approaches for engagement Overview of the oncology/medical system Oncology incorporates all aspect of cancer care. This includes prevention, diagnosis and treatment of cancer. The main medical staff involved in oncology include the surgeons, medical oncologists, radiation oncologists, haematology oncologists, cancer care nurses, oncology pharmacists and supportive and oncology palliative care doctors and nurses. In addition, all allied health professionals in oncology are classified under the oncology banner. Primarily, the patients with or who have had cancer will be under a surgeon and/or a medical oncologist and/or a radiation oncologist. All or a combination of these will be the patient's primary carer.

Collaboration Interaction between natural health practitioners and oncology medical staff will vary depending on the primary carer's beliefs regarding natural health. The best interaction a natural health practitioner can have with medical oncology staff is one of professionalism, similar to their interactions with other medical healthcare professionals. This includes wriYen leYers given to the patient for the oncologist or contact with the medical oncologist through email. Treating each professional associated with the person with cancer with respect and collaborating is an important aspect of care. The patient then feels that they are not torn between two different worlds of thought and that they are not having to hide something from either the medical or the natural health practitioners. The idea is to all collaborate professionally to achieve the best practice for the patient. If a natural health professional finds that an oncologist does not want the patient to take any natural supplements throughout treatment, it is recommended that the natural health professional respect the oncologist's decision. The natural health professional may not agree with the statement; however, it is more important that no conflict or confusion for the patient is created. Being diagnosed with cancer and undergoing medical treatment can be stressful

enough without extra stress on the patient. Alternatively, if a patient really wants to take natural supplements throughout their treatment, it is important to do everything possible to work collaboratively with the medical staff to assist this process and make it as easy and stress free as possible for the patient.

Support through surgery, radiation and chemotherapy – concurrent care Support through surgery Supporting patients through surgery for cancer can pose difficulties. Current practice has shown that patients diagnosed with cancer that can be surgically removed undergo surgery within weeks of diagnosis. There are many reasons for this urgency, but the main reason is that overall survival can be assessed from time of diagnosis to time of surgery. It has been found that the shorter the time interval, the beYer statistics for survival. In addition to the stress for the person being diagnosed, beginning treatment is crucial for them to feel that something is being done to eradicate the tumour(s). Surgery may not always be at the start of the cancer treatment. If a tumour is a significant size, chemotherapy and/or radiation may be commenced before surgical removal. Also, if the surgeon did not get clear margins, a second or third surgery may be required. All of these factors need to be taken into consideration when supporting a patient during surgery for cancer. Cessation of natural ingestive products is recommended approximately 1–2 weeks prior to surgery, so the patient may not have time to commence certain supplements prior to surgery. Therefore, support for patients is mostly post surgery. Postsurgery support for tumour removal should focus on:

• wound healing (e.g. zinc, vitamin C, vitamin E, bromelain, wound healing herbs such as Calendula officinalis, Hydrastis canadensis) • increasing immune function/system (e.g. Echinacea purpurea, Uncaria tomentosa, medicinal mushrooms, Astragulus membranaceus, zinc, vitamin C) • restoring nutritional deficiencies (e.g. iron, zinc) • reducing any risk of circulating tumour cells (e.g. Uncaria tomentosa, turmeric) • rebuilding the body to a healthy state prior to the start of further cancer treatment (e.g. adaptogenic herbal medicines such as Eleutherococcus senticosus, Panax ginseng, Withania somnifera, Rhodiola rosea, Centella asiatica) Support through radiation

Radiotherapy uses high-energy radiation to shrink tumours or kill potential cells. It works by damaging the DNA and creating charged particles (free radicals) within the cells that in turn can damage the DNA. Therefore, use of natural therapies during cancer radiation treatment needs to be evidence-based so no interference with the treatment occurs. Vitamin D3 Vitamin D3 has aYracted a lot of aYention during cancer. In particular, a deficiency in

vitamin D3 has been found to increase the severity of side effects from treatment and increase the risk of osteoporosis. An overview of some of the studies on a vitamin D deficiency and radiation can be seen in Table 21.3. Overall, it is recommended that patients undergoing radiotherapy for cancer treatment should take a vitamin D3 oral supplement. TABLE 21.3 Vitamin D3 deficiency and cancer radiotherapy Authors

Explanation of study

Ghorbanzadeh-Moghaddam A, Gholamrezaei A, Hemati S. Int J Radiat Oncol Biol Phys 2015[73] Akinci MB, Sendur MA, Aksoy S et al. Asian Pac J Cancer Prev 2014[74]

Prospective observational study on Vitamin D deficiency was associated with cancer patients receiving pelvic increased severity of radiation-induced radiation (n = 98) acute proctitis A total of 113 colorectal cancer survivors treated with surgery and/or chemotherapy ± radiation were recruited

Alco G, Igdem S, Dincer M, et 186 patients with breast cancer al. Asian Pac J Cancer Prev undergoing chemotherapy and 2014[75] radiation had their vitamin D3

Dose

Results found 96.5% of patients were vitamin D3 deficient and 66.4% had osteopenia/osteoporosis. Authors stated they were not related High prevalence of vitamin D3 (25-OHD) deficiency/insufficiency (70%). Supplementation during is recommended

status measured

Probiotics Probiotics in general have been found to help strengthen homeostasis and reduce side effects associated with cancer treatment. To date, current evidence supporting the use of probiotics as an adjunctive therapy to cancer treatment is limited. However, there is some evidence to show benefit during radiotherapy.[76] A list of studies on probiotics and radiotherapy is listed in Table 21.4.

TABLE 21.4

Probiotic use and cancer radiotherapy Authors

Explanation of study

Dose

Frazzoni L, Marca M, Guido A et al. 2015[77]

Radiotherapy is frequently employed for pelvic cancers. Despite recent advances in irradiation techniques, acute and late-onset radiation-induced gastrointestinal tract toxicity is frequently reported. Review on treatments 67 pelvic cancer patients were randomised to: 1. probiotic capsules (L. casei, L. acidophilus, L. rhamnosus, L. bulgaricus, Bifidobacterium breve, B. longum, Streptococcus thermophilus) 2. probiotic caps plus honey 3. placebo capsules Probiotics during radiotherapy may reduce risk of heart disease Enterococcus lactis protects against acetaminophen(paracetamol-) induced hepatotoxicity L. acidophilus reduced percentage of volume change of the rectum during prostate cancer radiation

Lactobacillus rhamnosus can be administered orally 1.5 g three times a day for a week safely

Probiotics found to reduce radiation-induced diarrhoea (grade 204) at the end of treatment for pelvic cancer

Bifilact® probiotics (L. acidophilus LAC-361 and B. longum BB-536): a standard dose twice a day (1.3 billion CFU) or a high dose three times a day (10 billion CFU)

MansouriTehrani HA, RabbaniKhorasgani M, Hosseini SM, et al. 2015[78] Kumar M et al. 2013[79] Sharma S et al. 2012[80] Ki Y, Kim W, Nam J, et al. 2013[81] Demers M, Dagnault A, Desjardins J 2014[82]

Results were not significant. However, a trend was seen in favour of probiotics in patients receiving pelvic radiotherapy

Rat study, no dose given Rat study, no dose given Probiotic capsule containing 1.0 × 108 colony-forming units of L. acidophilus

Glutamine Glutamine as an amino acid has been used for side effects for both chemotherapy and radiation. In a recent meta-analysis on glutamine for radiation-induced severe oral mucositis in head and neck patients,[83] glutamine was found to significantly reduce the risk and the severity of oral mucositis during radiotherapy from the five clinical studies included in the review. Melatonin Melatonin is well known for its mechanism of action for insomnia and sleep disturbances. However, melatonin has also been found to have other beneficial activities in relation to radiation. In a phase II, prospective, double-blind randomised trial, patients with radiationinduced dermatitis were treated with a melatonin-containing emulsion which was found to significantly reduce the dermatitis compared to placebo.[84] In addition, melatonin has also been found to be a potent stimulus for enhancing the efficacy of laser radiation on induction of apoptosis in tumour cells for ovarian cancer.[85] A literature review has found that melatonin can effectively protect animals against injury

to healthy tissues from ionising radiation, but no studies have been conducted on humans to date.[86] If human studies focus on healthy tissue protection from melatonin document similar protective effects, melatonin could provide a great adjunct in protection against radiation-induced side effects. Deglycyrrhizinated liquorice Studies examining the protective effects of liquorice for radiotherapy-induced side effects are limited. However, it is worth noting for its mucosal healing properties. One of the most common side effects of head and neck radiation is mucositis. One trial on Glycyrrhiza glabra protection for head and neck cancers found that the severity of radiation-induced mucositis for head and neck was reduced by a great extent. Therefore it was found beneficial for the prevention and treatment of radiation-induced mucositis, working in two ways: 1) there were no interruptions in the treatment; and 2) food intake was not severely affected, leading to maintenance of nutritional status and weight of patients.[87] Calendula Calendula officinalis is well known as a topical agent for skin conditions. It has been noted to increase skin healing and has been tested for oral mucositis as a mouthwash in hamsters[88] with positive effects. Similarly, in a randomised trial on 40 head and neck cancer patients receiving radiotherapy, those who were given the calendula mouthwash had a significantly lower intensity of oropharyngeal mucositis compared to placebo.[89] Calendula has also been assessed for the treatment of radiation-induced skin conditions such as radiation-induced dermatitis. A review examining calendula as a topical treatment and preventive agent of radiation-induced skin toxicity found that it was safe; however, the evidence for benefit remains weak.[90]

Support through chemotherapy The aim of using natural therapies during chemotherapy is to:

• reduce side effects, in particular long term • increase efficacy of medical treatment • increase the quality of life of the patient. There is a risk of interference or interaction with chemotherapy drugs during treatment with natural supplements. An overview of potential interactions from ingestive complementary medicines can be seen in Table 21.5.

TABLE 21.5

Ingestive complementary medicine interaction with chemotherapy Action

Complementary ingestive medicine

St John's wort[91,92] Ginkgo biloba[92,93] Kava[92,94] Black cohosh[94] Panax ginseng[95] Echinacea purpurea[96] Milk thistle[95] Evening primrose oil[92] Affect cellular protein P- Curcumin[97,98] glycoprotein Ginseng[99] Piperine[98] Ginger[98] Capsaicin[98] Resveratrol[98] Green tea catechins[98] Quercetin[98] Silymarin[100] Inhibit or induce cytochrome P450 enzymes

Suggestions Avoid during chemotherapy treatment

A majority of these natural components have chemo-sensitising ability, especially for multi-drug resistant tumours

In regards to introducing natural ingestive medicines or supplements during chemotherapy, there are some essential points that need to be taken into consideration. Some of the general principles include stopping the ingestive complementary medicine 1–2 days prior to chemotherapy administration and then recommencing 2–3 days post administration. This may vary depending on the half-life of the chemotherapy drugs, but this is a general rule to follow. Some natural vitamin supplements may be safe and efficacious to take through the chemotherapy cycle, but it may be easier for the patient to keep all supplements away from chemotherapy for ease of taking and remembering to take them and so they do not become confused. In addition, polypharmacy in cancer treatment is common, and precautions when adding ingestive complementary medicine is warranted. One of the major challenges for medical health professionals is the lack of awareness or understanding of natural health products. They may not have the time to research these products or may not have had heard of them. Therefore, it is important to consider dose, frequency, time of use and the administration of use. If a practitioner is in doubt about an ingestive supplement, do not prescribe it. Diet Diet or what people eat will vary greatly depending on the chemotherapy combination they

are undertaking and which stage they are at. Diet in general, or what people eat, is often a controversial and hotly debated topic. Medical professionals may recommend that they eat what they want or continue their normal diet; dietitians may recommend certain foods or breakdown of foods to keep on weight; natural health professionals debate among themselves about certain types or styles of diets. All of this can be very confusing for patients to know what is best for them. A general rule for people undergoing chemotherapy is to try to keep their diet as healthy as possible, limit highly processed foods, avoid delicatessen foods and ensure all foods are fully cooked (e.g. no raw eggs or fish, no leftovers that have been kept in the fridge for more than 1 day or any foods that are in a bain-marie). This is due to low neutrophils and the body's inability to fight normal bacteria and viruses. In addition, many patients undergoing chemotherapy experience taste and smell changes and have malaise, nausea and either of, or a combination of, constipation and diarrhoea. Some general rules for people undergoing chemotherapy include:

• If something does not taste or smell good, and makes them feel sick, even though they know it is good for them, it is best not to eat or drink it, the reason being that there is a memory that is triggered, and if they eat it and it makes them sick, when they try to eat it after the treatment is finished, they will find it difficult to eat. Chemotherapy is only for a short time in general, so it is beYer to keep good foods for later when they can eat them for maintenance. • Freeze foods and bring them out when needed. Having a range of frozen meals assists when they are not sure what they feel like, if they are served foods and then cannot eat them, and because of the fatigue they generally do not have energy at the end of the day, so this is a good way to ensure good nutrient intake. Note: do not freeze rice as it may harbour bacteria. • Include complex carbohydrates. Due to chemotherapy's effect on blood glucose, the malaise and the nausea, consuming complex carbohydrates with protein gives the person slow-release energy, which helps them feel beYer. • If the person is suffering from constipation, try pear juice or prune juice. • If the person has diarrhoea, try grated apple that needs to be eaten only when the apple flesh goes brown. • For nausea, eat every 2 hours and have crackers available if needed.

Hot chips (oven baked if possible) have been found to help a lot of people with chemotherapy nausea. There are many different dietary techniques that can assist people, but each person is different. Tailor the person's diet accordingly and be gentle with them as it is a very hard experience and they need assistance and compassion to get through it. Exercise Exercise during chemotherapy and post cancer treatment has received a lot of aYention within the past 5 years. Exercise during treatment and after treatment is highly recommended. There are many benefits that have been found. The term used now is ‘activity’ rather than exercise during chemotherapy treatment to assist people to understand that because of the fatigue and other side effects, they may not be able to participate in an organised exercise regimen, but can still do moderate activity. Exercise or activity has been found to mitigate several symptoms associated with chemotherapy treatment. This is because it influences biological pathways such as the inflammatory immune response, metabolic and neuroendocrine adaptations and genetic and epigenetic influences.[101] Moreover, a higher resting level of certain sympathetic hormones has been linked to fatigue, depression and pain, which exercise can decrease.[101] Thus, exercise has been found to positively influence immune, metabolic, neuroendocrine, genetic and epigenetic functions in individuals without cancer, and now with cancer.[101] Some specific studies addressing side effects of chemotherapy and exercise are listed below:

• Tai chi during chemotherapy has been found to be very beneficial. A randomised clinical trial assessing tai chi for lung cancer patients during chemotherapy found that it was an effective intervention for managing cancer-related fatigue.[102] • A study conducted on 417 older patients (>65 years) during and after cancer treatment found that almost half of the older and oldest cancer patients reported that using exercise (activity) during and post treatment assisted in reducing their side effects, including sleep and skin problems. [103]

• A meta-analysis of randomised controlled trials on aerobic exercise for cancer-related fatigue found that it was very effective for the management of fatigue for patients who completed adjuvant chemotherapy treatment.[104] • Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating

side effect of a number of chemotherapy agents. The Pathways study found that patients who engaged in more than 5 hours per week of moderate-to-vigorous physical activity had less CIPN.[105] Therefore, some basic advice for patients undergoing chemotherapy regarding exercise is:

• Adjust exercise depending on mobility and level of fatigue. • Exercise at least three times a week to their ability. • Walking in most cases is suggested as it is low cost, safe and can be conducted at their own pace. • Tai chi and Qigong have been found to be beneficial for sleep and fatigue. • Avoid public swimming pools due to risk of infection. • Consult an exercise physiologist if required. Meditation The diagnosis and treatment of cancer is considered to be a major life stress. Implementing ways of managing this stress has been found to be highly beneficial for patients. Meditation, brief psychological interventions, mindfulness and gratitude have been found to assist patients psychologically.[106] Mindfulness, siYing meditation in particular, has been found to be extremely beneficial for patients who have higher symptoms of distress.[107] Sleep Insomnia is a common problem for patients undergoing chemotherapy, especially due to steroid use. A number of options have been trialled that showed possible benefit. These include melatonin, cognitive behaviour therapy, Qigong/tai chi and acupuncture. One study in particular was a double-blind, placebo-controlled randomised controlled trial (RCT) which assessed 50 patients (aged 20–65 years old) who had primary insomnia during cancer treatment. The intervention was 3 mg of melatonin or placebo 2 hours before bed for 14 days. It was found that the daily intake of the melatonin improved sleep induction and quality of sleep for the cancer patients.[108] General support during chemotherapy As mentioned, undertaking chemotherapy treatment for cancer can be very stressful. Being prepared and understanding the chemotherapy regimen may help lessen some of the stress associated with the treatment. As there are many different types of chemotherapy or anticancer drugs, a general list of some combinations for more common cancers and natural therapies that have been trialled are listed below. Some general tips for chemotherapy include:

• ginger for acute nausea and vomiting[109] • vitamin D3 for all patients[110] • probiotics for chemotherapy-induced diarrhoea.[111] Specific chemotherapy and combination regimens Cisplatin is a platinum compound that is used to treat a number of cancers, including testicular, ovarian, breast, lung, bladder, oesophageal, brain, head and neck and cervical cancer, as well as mesothelioma and neuroblastoma. Natural therapies trialled for cisplatin can be seen in Table 21.6. TABLE 21.6

Natural therapies trialled for cisplatin Complementary agent

Main mechanism of action

Dose

Vitamin E – alphatocopherol[112–115] Vitamin B6[116]

Decrease ototoxicity and CIPN

Alpha-lipoic acid[117] Quercetin[118,119]

Sensitises cells to chemotherapy

400 mg per day (300–600 mg/day) Dose in the trial was 300 mg daily. Lower dose is recommended Cell work, no dose given. Recommended 600–800 mg daily No dose given. Recommended 500 mg administered orally twice a day No dose given. Recommended 5 mg at night 2 hours before bed.

Melatonin[120,121]

Prevented CIPN, but affected dose response

In animal studies, reduces renal and hepatic toxicity Rat study showed protection against ototoxicity and fertility through decreased follicle loss

Please review Tables 21.7–21.15 for specific medication regimens for specific cancers. TABLE 21.7

Colorectal cancer regimens Chemotherapy regimen FOLFOX Every 2 weeks for 12 cycles FOLFIRI Every 2 weeks for 12 cycles CapeOX Every 2 weeks for 12 cycles FOLFOXIRI Every 2 weeks for 12 cycles

Chemotherapy agents Oxaliplatin Leucovorin (folinic acid) Fluorouracil (5FU) Leucovorin (folinic acid) Irinotecan Capecitabine (Xeloda) Oxaliplatin Leucovorin (folinic acid) Oxaliplatin Irinotecan

TABLE 21.8 Supportive therapy for colorectal cancer Complementary agent Alpha-lipoic acid Vitamin B6[124]

[122,123]

PSK (Coriolus versicolor) [125,126]

Main mechanism of action

Dose

Reduced severity of CIPN Possible reduction in CIPN

800 mg daily 60 mg daily

Immune modulation during treatment and increased survival rate

3 g per day away from food

TABLE 21.9

Breast cancer regimens Chemotherapy regimen AC – T(H)

FEC – D(H) FEC – T(H) TAC TC(H) CMF

Chemotherapy agents and cycles Adriamycin, cyclophosphamide: every 3 weeks for 3–4 cycles Then paclitaxel weekly for 9–12 weeks If HER 2+, Herceptin and possibly pertuzumab (Perjeta) every 3 weeks 5-fluorouracil, epirubicin, cyclophosphamide than docetaxel for 3 or 4 rounds, then docetaxel 3 or 4 rounds every 3 weeks 5-fluorouracil, epirubicin, cyclophosphamide every 3 weeks for 3 or 4 cycles, then paclitaxel weekly for 9–12 weeks Docetaxel, Adriamycin, cyclophosphamide every 3 weeks for 6 cycles Docetaxel, cyclophosphamide plus Herceptin every 3 weeks for 4–6 cycles Cyclophosphamide, methotrexate, 5-fluorouracil every 3 weeks for 6 cycles

TABLE 21.10

Supportive therapies for breast cancer Complementary Main mechanism of action agent

Dose

Omega-3 faYy acids[127] Vitamin B12[128,129]

Reduces CIPN

640 mg t.d.s.

Reduces CIPN

1000 micrograms daily

PSK[130]

Increases the prognosis of operable breast cancer with vascular invasion 3 g per day away and patients positive for HLA-B40 from food Sensitises cells to chemotherapy agent No dose given – cell culture Recommended 600– 800 mg/day Increases chemotherapy into cells, reduces drug resistance, increases 1 sachet per 30 kg of natural killer cells, protects Peyer's patches in digestive tract body weight Has potential for assisting against cancer-related fatigue. Tested in an 2 g every 8 hours open-label non-RCT on 100 breast cancer patients undergoing chemo throughout course of with Taxotere, Adriamycin, cyclophosphamide, 5FU and epirubicin chemotherapy treatment Melatonin prevents mitochondrial damage induced by doxurubicin in No dose given due to mouse fibroblasts mice/rat study 2–5 mg 2 hours before bed

Lipoic acid[117]

Biobran (Ribraxx)[131] Withania somnifera[132]

Melatonin[133]

TABLE 21.11

Prostate cancer Chemotherapy agent

Trial

Mainsail trial[134] Multi-national trial, RCT, phase III study 1059 patients received docetaxel, prednisone and lenalidomide or docetaxel, prednisone or placebo Authors looked at optimal number of docetaxel cycles Results: 8 or more cycles increased survival benefit Same treatment support as breast cancer Now treated with docetaxel (Taxotere)

TABLE 21.12

Lymphoma regimens Chemotherapy regimen R-CHOP or CHOP Every 2–3 weeks for 6–8 cycles

CVP (R) Every 2–3 weeks for 4–8 cycles May have rituximab or doxorubicin added Hyper-CVAD Schedule A (cycles 1, 3, 5, 7) Schedule B (cycles 2, 4, 6, 8)

Chemotherapy agents Cyclophosphamide Doxorubicin Vincristine Prednisolone Rituximab (MabThera) Cyclophosphamide Vincristine Prednisolone Part A: Cyclophosphamide Vincristine Doxorubicin Dexamethasone Part B: Methotrexate Cytarabine

TABLE 21.13

Supportive therapy for lymphoma Complementary Main mechanism of action agent CoQ10[135]

Used in conjunction with Adriamycin or doxorubicin. Non-toxic, did not affect anti-tumour activity, decreased cardiac dysfunction, decreased cardiotoxicity

Lipoic acid[136]

Decreases cardiotoxicity associated with cyclophosphamide. Mice study, but reversed abnormal biochemical changes to near normalcy. Protective role

Melatonin[133,137] Melatonin prevents mitochondrial damage induced by doxorubicin in mouse fibroblasts

EPA/DHA[138,139] Distribution of plasma faYy acids has been associated with patients’ response to chemotherapy for non-Hodgkin's lymphoma. Poor response (not finishing due to death or toxicity) had significantly lower EPA/DHA, palmitoleic, linoleic acid, omega-3, omega-6. Cell lines showed omega-3 faYy acids to promote chemo-sensitivity for chemo for chronic lymphocytic leukaemia (vincristine, doxorubicin, fludarabine) Withania Animal study showed Withania somnifera to protect against [140] somnifera cyclophosphamide-induced urotoxicity

Dose 200 and 350 mg/m2. Continued daily dose of at least 50 mg of CoQ10 No dose given due to mice study. Recommended 600–800 mg a day No dose given due to mice/rat study. Recommended 2–5 mg 2 hours before bed No dose given. Recommended 3–4 g of EPA/DHA

No dose given. Recommended 2 g per day

TABLE 21.14 Lung cancer chemotherapy agents Chemotherapy agent – a combination of these can be utilised Cisplatin Carboplatin Paclitaxel/Abraxane Docetaxel Gemcitabine Vinorelbine Irinotecan Etoposide Vinblastine or vincristine Pemetrexed (Alimta)

TABLE 21.15

Supportive therapy for lung cancer Complementary Main mechanism of action agent Lipoic acid[117]

Sensitises cells to chemotherapy agent

Omega-3 faYy acids[127] Vitamin B12[128,129]

Reduces CIPN

PSK[141]

Found to improve immune function, reduce tumour-associated symptoms, extend survival in lung cancer patients

Melatonin[142]

Melatonin in reduction of chemotherapy-induced toxicity trial was a doubleblind, placebo-controlled RCT. Was found that it did not affect survival, did not interfere with chemotherapy, had no adverse events but helped quality of life for patients Increases chemotherapy into cells, reduces drug resistance, increases natural killer cells, protects Peyer's patches in digestive tract

Biobran (Ribraxx)[131]

Reduces CIPN

Discussion on fasting and evidence

Dose No dose given – cell culture Recommended 600–800 mg/day 640 mg t.d.s. 1000 micrograms daily 3 g per day away from food 10–20 mg 2 hours before bed 1 sachet per 30 kg of body weight

A new, novel way to assist people with cancer or who have had cancer is fasting overnight. A multi-site randomised trial on patients with breast cancer conducted a women's healthy eating and living study.[143] Data was collected from 2413 women with breast cancer, but without diabetes mellitus, aged 27–70 years at diagnosis. A dietary analysis was conducted at baseline, 1 year post and then 4 years. The major outcomes found that prolonged nightly fasting (13 hours or more) reduced the risk of breast cancer recurrence, reducing inflammation (lower C reactive protein), improved gluco-regulation (lower HbA1c) and assisted sleep.[143] Although this study was conducted on women who had breast cancer, it can be extrapolated for all cancers. The recommendation is no food consumption (including milk) after 8 pm, and fasting for at least 13 hours overnight. Water and herbal teas can still be consumed, but no food substance. This means that if the person finished their dinner around 7.30 pm, they do not eat again until 8.30 am the next day. This is an easy-to-incorporate approach to assist in decreasing the risk of cancer, decreasing systemic inflammation, managing blood glucose control, assisting sleep and decreasing the risk of recurrence. Moreover, it is a non-pharmaceutical approach anyone can incorporate.

Case studies of most common types of cancer to highlight approach Case study 1 Breast cancer Overview RA is a 42 year-old-woman who was diagnosed with breast cancer 3 weeks ago (2 weeks before Christmas). Biopsy indicated invasive ductal carcinoma HER2 negative, oestrogen and progesterone positive with three possible axillary lymph node involvement. Due to the time of year and size, commenced chemotherapy 14 days post diagnosis before surgery and 1 week before presentation to the clinic consultation. The chemotherapy regimen is AC – Adriamyocin and cyclophosphamide 4 cycles, every 3 weeks. A scan will be conducted post 4th cycle and a decision will be made to either have surgery then or continue 9 weeks of paclitaxel weekly before surgery. Side effects of the first round of chemotherapy were constipation, nausea, increased smell sensation and body fatigue, or ‘heaviness’. Only known allergy was penicillin. She had just commenced a ketogenic diet prior to diagnosis and was unsure what she should do diet-wise throughout treatment, and wanted to work together to assist treatment. She is married with one child who is 2 years old.

Clinical examination • Weight 80.7 kg, height 1.62 m • Temperature: 36.2°C • Emotionally stable but stressed with the diagnosis

Investigations Blood testing that precipitated medication prescription included: Test

Result

Haemoglobin Platelet count White cell count Neutrophils Lymphocytes Monocytes Mean cell volume Mean cell haemoglobin

122 (115–160) 198 5.2 (4.0–11.0) 4.1 (2.0–7.5) 1.9 (1.1–4.0) 0.4 (0.2–1.0) 85 (80–98) 29 (27–35)

Treatment protocol The treatment focused on assisting RA through this stage of treatment until she knew if she was going to have surgery first or further chemotherapy. The aim was to minimise side effects and provide a dietary plan that would work for her and her family during this first period of time. Herbal medicine

Due to her stress, a capsule formula of Withania somnifera, Eletherococcus senticosis and Rhodiola rosea was prescribed – two capsules a day but not on the day of and 2 days after chemotherapy administration. A majority of patients cannot tolerate liquid herbal mixtures due to smell and taste changes associated with chemotherapy administration. Capsules or tablets have a beYer compliance response in most cases. Nutritional medicine Dietary

Dietary suggestions were given in accordance with what the patient would consume and the chemotherapy regimen she is undergoing currently. This regimen generally makes the patient feel sick in the morning and fatigued in the evening. Constipation occurs within the first week after chemotherapy administration. Water also tastes terrible and can leave a metallic taste in the mouth. Mouth ulcers are very common and taste changes occur after the first round of chemotherapy in most people. The following suggestions were given: • Breakfast options may include: – Light rye or spelt toast with buYer with Vegemite (can add avocado)

– Cooked potatoes or hash browns – If she feels like it, scrambled eggs • Largest meal should be lunch in the middle of the day and consist of either salad or cooked vegetables with some form of protein: – Salmon paYies – Lentil paYies – Chicken/turkey – Eggs – quiche, scrambled, omeleYe – Pork rissoles homemade • For dinner, more cooked vegetables rather than raw due to fatigue and poor digestive ability (e.g. yellow Thai curry with small amount of basmati rice, slowcooked meals) – Avoid – high tomato-based foods or creamy based sauces, no delicatessen foods, no grapefruit, no citrus fruits, chilli or hot, spicy foods – If feeling nauseous, eat every 2–3 hours, have crackers if needed; hot ovenbaked chips can help manage and decrease the nausea – Consume a small cup of bone broth daily – Consume fresh ginger and/or peppermint tea – In water (drink cold) – put small amount of grated ginger, fresh mint, cut up apple or small amount of pomegranate or cranberry juice to change taste of water – Snacks if required: cut up vegetables such as carrot or celery with hummus Supplemental Nutrient Vitamin D3

Dose

1000 IU (1 capsule) after food Coriolus (medicinal 2 capsules twice a mushrooms) day Liposomal vitamin C 1 sachet per day

Justification To maintain or increase vitamin D levels to decrease risk of osteoporosis, fatigue and aches and pains To support the immune system To assist immune system and healing

Note: Not to be administered on chemotherapy day and 2 days post chemotherapy administration.

Lifestyle/education

Emphasis was placed on listening to herself and her body. Rest when needed, manage stress, refer to an exercise physiologist for correct exercise advice, ensure good sleep habits, engage in activities she enjoys and socialise and have fun with her daughter and husband. Avoid large areas of people from days 8 to 14 post chemotherapy administration as she will be at higher risk of infection. Take her temperature daily, and if over 38°C, go to the hospital. Conduct good hygiene, particularly 48 hours post chemotherapy administration, as a majority is excreted through urine.

Case study 2 Lymphoma Overview KB is a 56-year-old woman who has been diagnosed with follicular B cell lymphoma grade 3, stage 3. History includes atrial fibrillation, haemorrhoids and anal fissure, two bowel prolapse surgeries, hysterectomy (ovaries not taken), bone marrow and tumour biopsies. Medication includes Noten, Tambocor, rectogesic for the anal fissure, antibiotic (Bactrum) twice a week, and has currently just completed chemotherapy treatment, RCHOP six cycles every 2 weeks, 3 weeks ago at time of consultation. Currently taking magnesium capsules and has just taken Macu-Vision for her sight. She is walking briskly for about 3–4 km most days. Diet is very good, with a protein shake for breakfast (blueberries, pea protein powder, vital greens, almond milk, coconut yoghurt, spinach leaves, cinnamon, ginger and turmeric), lunch is a salad with spinach, tomato, avocado, olives with salmon. Dinner consists of cooked fish with cooked vegetables. Snacks include fruit, nuts, hummus with gluten-free crackers or falafel chips. She consumes water, herbal teas and, occasionally, almond decaf coffee. She is married with two children. Current status, she is due for a PET/CT in a month's time to see progress of tumours. Last tumour showed main tumours had reduced in size. Had been administered Xarelto but had ceased use 1 month ago. Currently, she is experiencing CIPN grade 2 (currently not painful but had been), eyes and eyesight affected – tear ducts blocked, dry and inflamed, and extreme fatigue, particularly in the legs, has dizzy spells, headaches, ectopic heart beats, sore mouth (had oral thrush and was prescribed oral Nilstat), tongue sore and persistent stinging sensation around mouth, bowels are currently working ‘OK’ and is taking a laxative daily due to anal fissure.

Clinical examination Weight 63 kg, height 1.56 m

Treatment protocol The treatment focused on decreasing the side effects from treatment. The CIPN, leg fatigue and nerve stinging sensations near the mouth are all from vincristine administration. The eye reactions are from the steroids, and the rest are from the chemotherapy combination. As she has only just finished her chemotherapy regimen, she is still experiencing acute and chronic side effects. Herbal medicine

A tablet of Ginkgo biloba was prescribed, two tablets a day (120 mg twice a day). This is to assist in reducing CIPN pain and in restoring nerve fibre damage. Also may assist with chemo brain symptoms.

For fatigue, an American ginseng tablet 1000 mg a day was prescribed to be taken in the morning. Nutritional medicine Dietary

Minimal dietary suggestions were given due to her diet, which she has worked on with an integrative doctor. • Increase protein for lunch such as salmon, small amounts of organic chicken (no skin), organic lamb or beef, egg or sheep's cheese (haloumi) or goat's feYa Supplemental Nutrient

Dose

Justification

Acetyl-L-carnitine

2000 g a day on an empty stomach 1000 micrograms of methylcobalamin daily 1–2 lozenges sucked daily

To restore nerve damage (CIPN) and assist with fatigue and chemotherapy brain To assist in reversing CIPN

Vitamin B12 Sublingual CoQ10 lozenges

To assist in healing the mouth and help with fatigue and heart complications

Lifestyle/education

For her mouth, try rubbing coconut oil around her mouth and tongue daily. For her eyes, try puYing wet tea bags on them daily, or an eye bath of Eyebright. Continue exercise and rest when needed.

Case study 3 Metastatic colorectal cancer Overview JL is a 73-year-old woman who has been diagnosed with metastatic colorectal cancer and adenocarcinoma. Six months prior to her first consultation, she thought she had a urinary tract infection, and went to an osteopath who thought it might be appendicitis, so sent her to the doctor. Upon seeing her general practitioner, she was sent straight to hospital where she was operated on immediately, and 27 cm of her large bowel was removed. She had 26 nodes removed, eight positive for cancer (n = 8/26). Staged T4a N2b, carcinoembryonic antigen (CEA) levels were 400, and received a PET scan a few days post surgery which identified lymphatic involvement. Was diagnosed stage 4 colorectal cancer and declined chemotherapy. History includes pleuroparenchymal scarring on both lungs, cysts on the liver, hay fever and haemochromatosis. Currently her CEA is 17.1. Allergies include intravenous dye and valerian. Currently, only medication is melatonin 3

mg per night. Complementary medicines include: • Five-mushroom extract 20 drops three times day • Citrus pectin 1 teaspoon three times a day • Vitamin C 1000 mg three times a day • Zinc 30 mg a day • Magnesium 400 mg a day • Vital greens • CoQ10 150 mg daily • Fish oil – two capsules daily • Curcumin – two capsules daily • Green-lipped muscle extract three capsules daily • Gelatine • Silica • Fibergy • Olive leaf extract. Diet consisted of: Breakfast: chia seeds soaked with almonds, magnesium powder, vital greens, Fibergy, silica, kefir yoghurt, goji berries, cranberries and ½ banana Lunch: greens from garden (home grown), leYuce, garlic chives, kale, steamed beetroot, sundried tomatoes, avocado, apple cider vinegar, boiled egg (from her own chickens), cashew cheese and 1 dessertspoon of sauerkraut Dinner: fish/chicken, vegetable burger paYies (homemade) or egg-omeleYe with steamed vegetables Snacks: brazil nuts Beverages: 4 cups of water with apple cider vinegar in all of it, herbal teas – Jason Winters (3 cups a day), green tea (1–2 cups), ginger and lemon

Clinical examination Weight: 60 kg, height: 1.65 m

Treatment protocol The treatment focused on working with her diet, improving her immune system, decreasing her diarrhoea, and trying to prevent further metastasis and reduce or stabilise cancer growth. Herbal medicine

A liquid herbal mixture was prescribed:

Herb

Amount

Cat's claw (Uncaria tomentosa) Astragalus membranaceus Artemisia annua Withania somnifera

80 mL 60 mL 20 mL 40 mL 200 mL

TOTAL Dose: 8 mL to be taken twice daily.

Nutritional medicine Dietary

• Remove magnesium powder from the shake and take at night time before bed • Consume plain filtered water with no apple cider vinegar in it • Continue diet ensuring 2 cups of cooked vegetables at night • Consume only 2 serves of fruit a day • Consume lamb once a fortnight in a slow cooker • Organic cheese in small amounts Supplemental

Change vitamin C oral to liposomal vitamin C. Nutrient

Dose

Justification

PSK

2 capsules three times a day away from food 1 sachet twice a day

To assist with immune system

Liposomal vitamin C Biobran (Ribraxx) 1 sachet twice a day

To support the immune system, act as an anticancer agent To assist immune system, healing, increase natural killer cells

Lifestyle/education

Emphasis was placed on listening to herself and her body. Recommended she try tai chi as an exercise, engage in activities she enjoys particularly gardening and bridge, and develop good sleep hygiene habits.

References [1] Sonnenschein C, Soto AM. Somatic mutation theory of carcinogenesis: why it should be dropped and replaced. Mol Carcinog. 2000;29:205–211. [2] Cahill DP, Kinzler KW, Vogelstein B, et al. Genetic instability and darwinian selection in tumours. Trends Cell Biol. 1999;9(12):M57–60. [3] Mally A, Chipman JK. Non-genotoxic carcinogens: early effects on gap junctions, cell proliferation and apoptosis in the rat. Toxicology. 2002;180:233– 248.

[4] Thomas F, Fisher D, Fort P, et al. Applying ecological and evolutionary theory to cancer: a long and winding road. Evol Appl. 2012;6:1–10. [5] Soto AM, Sonnenschein C. The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory. Bioessays. 2011;33(5):332– 340. [6] Mazzocca A, Ferraro G, Miciagna G, et al. A systemic evolutionary approach to cancer: hepatocarcinogenesis as a paradigm. Med Hypotheses. 2016;93:132– 137. [7] National Cancer Institute. Understanding cancer prognosis. [Available from] hYps://www.cancer.gov/about-cancer/diagnosis-staging/prognosis; 2016. [8] Sunkara V, Woo H, Cho YK. Emerging techniques in the isolation and characterization of extracellular vesicles and their role in cancer diagnostics and prognostics. Analyst. 2016;141:371. [9] Sutherland AM. Technology for single cell protein analysis in immunology and cancer prognosis. [PhD dissertation] 2016 [California Institute of Technology]. [10] Juodzbalys G, Kasradze D, Cicciu M, et al. Modern molecular biomarkers of head and neck cancer. Part 1. Epigenetic diagnostics and prognostics: systematic review. Cancer Biomark. 2016;17(4):487–502. [11] Ma S, Ren J, Fenyo D. Breast cancer prognostics using multi-omics data. AMIA Jt Summits Transl Sci Proc. 2016;2016:52–59. [12] Bartošík M, Ondroušková E. Novel approaches in DNA methylation studies – MS-HRM analysis and electrochemistry. Klin Onkol. 2016;29(Suppl. 4):64–71. [13] Zogopoulos P, Korkolopoulous P, Patsouris E, et al. The antitumour action of cannabinoids on glioma tumorigenesis. Histol Histopathol. 2015;30:629–645. [14] Pinkas J, Jablonski P, Kidawa M, et al. Use of marijuana for medical purposes. Ann Agric Environ Med. 2016;23(3):525–528. [15] Velasco G, Galve-Roperh I, Sánchez C, et al. Hypothesis: cannabinoid therapy for the treatment of gliomas? Neuropharmacology. 2004;47:315–323. [16] Shelef A, Barak Y, Berger U, et al. Safety and efficacy of medical cannabis oil for behavioural and psychological symptoms of dementia: an-open label, add-on, pilot study. J Alzheimers Dis. 2016;51:15–19. [17] Munson AE, Harris LS, Friedman MA, et al. Antineoplastic activity of cannabinoids. J Natl Cancer Inst. 1975;55(3):597–602. [18] Various. World Health Organization Cancer Guideline publications. [Available from] hYp://www.who.int/cancer/publications/en/; 2016. [19] Ko YS, Lee W, Panchanathan R, et al. Polyphenols from Artemisia annua L inhibit adhesion and EMT of highly metastatic breast cancer cells MDA-MB231. Phytother Res. 2016;30(7):1180–1188. [20] Yuan H, Lu X, Ma Q, et al. Flavonoids from Artemisia sacrorum Ledeb. and

their cytotoxic activities against human cancer cell lines. Exp Ther Med. 2016;12(3):1873–1878. [21] Michaelsen FW, Saeed M, Schwarzkopf J, et al. Activity of Artemisia annua and artemisinin derivatives, in prostate carcinoma. Phytomedicine. 2015;22(14):1223– 1231. [22] Dozmorov MG, Yang Q, Wu W, et al. Differential effects of selective frankincense (Ru Xiang) essential oil versus non-selective sandalwood (Tan Xiang) essential oil on cultured bladder cancer cells: a microarray and bioinformatics study. Chin Med. 2014;9:18. [23] Ni X, Suhail M, Yang Q, et al. Frankincense essential oil prepared from hydrodistillation of Boswellia sacra gum resins induces human pancreatic cancer cell death in cultures and in a xenograft murine model. BMC Complement Altern Med. 2012;12:253. [24] Suhail MM, Wu W, Cao A, et al. Boswellia sacra essential oil induces tumor cell-specific apoptosis and suppresses tumor aggressiveness in cultured human breast cancer cells. BMC Complement Altern Med. 2011;11:129. [25] Cappiello G, McGinley B, Elahi MA, et al. Differential evolution optimization of the SAR distribution for head and neck hyperthermia. IEEE Trans Biomed Eng. 2016;64(8):1875–1885. [26] DaYa NR, Krishnan S, Speiser DE, et al. Magnetic nanoparticle-induced hyperthermia with appropriate payloads: Paul Ehrlich's ‘magic (nano)bullet’ for cancer theranostics? Cancer Treat Rev. 2016;50:217–227. [27] Bar-Sela G, Wollner M, Hammer L, et al. Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatinbased combinations: a randomised phase II study. Eur J Cancer. 2013;49(5):1058–1064. [28] Büssing A, Raak C, Ostermann T. Quality of life and related dimensions in cancer patients treated with mistletoe extract (iscador): a meta-analysis. Evid Based Complement Alternat Med. 2012;2012:219402. [29] Dole M, Wilson F, Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science. 1975;190(4210):152–154. [30] Moen I, Stuhr L. Hyperbaric oxygen therapy and cancer – a review. Targ Oncol. 2012;7:233–242. [31] Beard J. The enzyme treatment of cancer and its scientific basis. ChaYo & Windus: London, UK; 1911. [32] Leipner J, Saller R. Systematic enzyme therapy in oncology: effect and mode of action. Drugs. 2000;59:769–780. [33] Beuth J. Proteolytic Enzyme therapy in evidence-based complementary oncology: fact or fiction? Integr Cancer Ther. 2008;7(4):311–316.

[34] Pauling L. Effect of ascorbic acid on incidence of spontaneous mammary tumors and UV-light-induced skin tumors in mice. Am J Clin Nutr. 1991;54(6 Suppl.):1252S–1255S. [35] Creagan ET, Moertel C, O'Fallon JR, et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer – a controlled trial. N Engl J Med. 1979;301:687–690. [36] PadayaYy SJ, Riordan H, HewiY SM, et al. Intravenously administered vitamin C as cancer therapy: three cases. Research. 2006;174(7):937–942. [37] Riordan HD, Casciari J, González MJ, et al. A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. P R Health Sci J. 2005;24(4):269–276. [38] Eastman KL, McFarland L, Raugi GJ. A review of topical corrosive black salve. J Altern Complement Med. 2014;20(4):284–289. [39] Clark JJ, Woodcock A, Cipriano SD, et al. Community perceptions about the use of black salve. J Am Acad Dermatol. 2016;74(5):1021–1023. [40] López-Lázaro M. Dual role of hydrogen peroxide in cancer: possible relevance to cancer chemoprevention and therapy. Cancer LeU. 2007;252(1):1–8. [41] PritcheY S, Green D, Rossos P. Accidental ingestion of 35% hydrogen peroxide. Can J Gastroenterol. 2007;21(10):665–667. [42] PDQ Integrative. Alternative, and complementary therapies editorial board. Laetrile/Amygdalin (PDQ®): health professional version. National Cancer Institute: Bethesda, MD; 2017. [43] Milazzo S, Horneber M. Laetrile treatment for cancer. Cochrane Database Syst Rev. 2015;(4) [CD005476]. [44] Cancer Research UK. Rife machine and cancer. [Available from] hYp://www.cancerresearchuk.org/about-cancer/cancers-in-general/cancerquestions/rife-machine-and-cancer; 2016. [45] Jain NK, Gupta VB, Garg R, et al. Efficacy of cow urine therapy on various cancer patients in Mandsaur District, India – a survey. Int J Green Pharm. 2010;4(1). [46] Koltai T. Cancer: fundamentals behind pH targeting and the double-edged approach. Onco Targets Ther. 2016;9:6343–6360. [47] Pavlova NN, Thompson C. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23(1):27–47. [48] Fenton TR, Huang T. Systematic review of the association between dietary acid load, alkaline water and cancer. BMJ Open. 2016;6(6):e010438. [49] Wright ME, Michaud D, Pietinen P, et al. Estimated urine pH and bladder cancer risk in a cohort of male smokers (Finland). Cancer Causes Control. 2005;16(9):1117–1123.

[50] Bellavia A, Stilling F, Wolk A. High red meat intake and all-cause cardiovascular and cancer mortality: is the risk modified by fruit and vegetable intake? Am J Clin Nutr. 2016;10(4):1137–1143. [51] Marin-Valencia I, Yang C, Mashimo T, et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab. 2012;15:827–837. [52] Maher EA, Marin-Valencia I, Bachoo RM. Metabolism of [U-13 C]glucose in human brain tumors in vivo. NMR Biomed. 2012;25:1234–1244. [53] Altmann DM. A Nobel prize-worthy pursuit: cancer immunology and harnessing immunity to tumour neoantigens. Immunology. 2018;155(3):283–284. [54] Voena C, Chiarle R. Advances in cancer immunology and cancer immunotherapy. Discov Med. 2016;21(114):125–133. [55] SchmiY MW, Loeb L, Salk JJ. The influence of subclonal resistance mutations on targeted cancer therapy. Nat Rev Clin Oncol. 2016;13(6):335–347. [56] Garofalo A, Sholl L, Reardon B, et al. The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine. Genome Med. 2016;8:79. [57] Park P, Dhupal M, Kim CS, et al. Implication of immunokine profiling for cancer staging. Med Hypotheses. 2016;88:46–48. [58] The Cancer Institute. Impact of cancer genomics on precision medicine for the treatment of cancer. [The Cancer Cengome Atlas; Available from] hYps://cancergenome.nih.gov/cancergenomics/impact; 2016. [59] Teitelbaum A, Spencer D, Bollu VK, et al. Monitoring response and treatment outcome in patients with chronic phase chronic myeloid leukemia (CML) treated with imatinib. J Clin Oncol. 2011;29(15_Suppl.):e16612. [60] Olson EM, Najita J, Sohl J, et al. Predictors of survival in patients with HER2+ metastatic breast cancer (MBC) treated with trastuzumab. J Clin Oncol. 2016;29(15_Suppl.):e11100. [61] Wanebo HJ, Sanikommu S, Taneja C, et al. Hepatic artery infusion for recurrent or chemotherapy-resistant hepatic malignancy. J Clin Oncol. 2016;29(15_Suppl.):e14151. [62] Hongo F, Mikami K, Nakanouchi T, et al. Intra-arterial chemotherapy for local invasive bladder cancer. J Clin Oncol. 2016;29(15_Suppl.):e15063. [63] Yu B, Ma Z, Guan C, et al. Clinical introtumoral chemoimmunotherapy for late stages of lung cancer. J Clin Oncol. 2016;29(15_Suppl.):e21001. [64] Maciver AH, Lee N, SkiÖki JJ, et al. Cytoreduction and hyperthermic intraperitoneal chemotherapy (CS/HIPEC) in colorectal cancer: evidence-based review of patient selection and treatment algorithms. Eur J Surg Oncol. 2017;43(6):1028–1039.

[65] Zhao J, Zhou M, Li C. Synthetic nanoparticles for delivery of radioisotopes and radiosensitizers in cancer therapy. Cancer Nanotechnol. 2016;7(1):9. [66] Martinov MP, Thomson R. Heterogeneous multiscale Monte Carlo simulations for gold nanoparticle radiosensitization. Med Phys. 2017;44(2):644–653. [67] Su XX, Liu P, Hao W, et al. Enhancement of radiosensitization by metal-based nanoparticles in cancer radiation therapy. Cancer Biol Med. 2014;11(2):86–91. [68] Van de Wiele C, Maes A, Brugman E, et al. SIRT of liver metastases: physiological and pathophysiological considerations. Eur J Nucl Med Mol Imaging. 2012;39(10):1646–1655. [69] Citrin D, Cotrim A, Hyodo F, et al. Radioprotectors and mitigators of radiationinduced normal tissue injury. Oncologist. 2010;15(4):360–371. [70] Hasan I, Rashid T. Clinical communication, cancer patients & considerations to minimize the challenges. J Cancer Ther. 2016;7:107–113. [71] Shim E-J, Park JE, Yi M, et al. Tailoring communications to the evolving needs of patients throughout the cancer care trajectory: a qualitative exploration with breast cancer patients. BMC Womens Health. 2016;16:65. [72] Kerridge IH, McPhee J. Ethical and legal issues at the interface of complementary and conventional medicine. Med J Aust. 2004;181(3):164–166. [73] Ghorbanzadeh-Moghaddam A, Gholamrezaei A, Hemati S. Vitamin D deficiency is associated with the severity of radiation-induced proctitis in cancer patients. Int J Radiat Oncol Biol Phys. 2015;92(3):613–618. [74] Akinci MB, Sendur MA, Aksoy S, et al. Serum 25-hydroxy vitamin D status is not related to osteopenia/osteoporosis risk in colorectal cancer survivors. Asian Pac J Cancer Prev. 2014;15(8):3377–3381. [75] Alco G, Igdem S, Dincer M, et al. Vitamin D levels in patients with breast cancer: importance of dressing style. Asian Pac J Cancer Prev. 2014;15(3):1357– 1362. [76] Mego M, et al. Probiotic bacteria in cancer patients undergoing chemotherapy and radiation therapy. Complement Ther Med. 2013;21(6):712–723. [77] Frazzoni L, Marca M, Guido A, et al. Pelvic radiation disease: updates on treatment options. World J Clin Oncol. 2015;6(6):272–280. [78] Mansouri-Tehrani HA, Rabbani-Khorasgani M, Hosseini SM, et al. Effect of supplements: probiotics and probiotic plus honey on blood cell counts and serum IgA in patients receiving pelvic radiotherapy. J Res Med Sci. 2015;20(7):679–683. [79] Kumar M, et al. Probiotic Lactobacillus rhamnosus GG and Aloe vera gel improve lipid profiles in hypercholesterolemic rats. Nutrition. 2013;29(3):574– 579. [80] Sharma S, et al. Probiotic Enterococcus lactis IITRHR1 protects against

acetaminophen-induced hepatotoxicity. Nutrition. 2012;28(2):173–181. [81] Ki Y, Kim W, Nam J, et al. Probiotics for rectal volume variation during radiation therapy for prostate cancer. Int J Radiat Oncol. 2013;87(4):646–650. [82] Demers M, Dagnault A, Desjardins J. A randomized double-blind controlled trial: impact of probiotics on diarrhea in patients treated with pelvic radiation. Clin Nutr. 2014;33(5):761–767. [83] Leung HW, Chan AL. Glutamine in alleviation of radiation-induced severe oral mucositis: a meta-analysis. Nutr Cancer. 2016;68(5):734–742. [84] Ben-David MA, et al. Melatonin for prevention of breast radiation dermatitis: a phase II, prospective, double-blind randomized trial. Isr Med Assoc J. 2016;18(3– 4):188–192. [85] Akbarzadeh M, et al. Effects of combination of melatonin and laser irradiation on ovarian cancer cells and endothelial lineage viability. Lasers Med Sci. 2016;31(8):1565–1572. [86] Zetner D, Andersen LP, Rosenberg J. Melatonin as protection against radiation injury: a systematic review. Drug Res (StuUg). 2016;66(6):281–296. [87] Das D, Agarwal SK, Chandola HM. Protective effect of Yashtimadhu (Glycyrrhiza glabra) against side effects of radiation/chemotherapy in head and neck malignancies. Ayu. 2011;32(2):196–199. [88] Tanideh N, et al. Healing acceleration in hamsters of oral mucositis induced by 5-fluorouracil with topical Calendula officinalis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115(3):332–338. [89] Babaee N, et al. Antioxidant capacity of Calendula officinalis flowers extract and prevention of radiation induced oropharyngeal mucositis in patients with head and neck cancers: a randomized controlled clinical study. Daru. 2013;21(1):18. [90] Kodiyan J, Amber K. A review of the use of topical calendula in the prevention and treatment of radiotherapy-induced skin reactions. Antioxidants (Basel). 2015;4(2):293–303. [91] Goey AK, et al. The effect of St John's wort on the pharmacokinetics of docetaxel. Clin Pharmacokinet. 2014;53(1):103–110. [92] Zou L, Harkey MR, Henderson GL. Effects of herbal components on cDNAexpressed cytochrome P450 enzyme catalytic activity. Life Sci. 2002;71(13):1579– 1589. [93] Naccarato M, Yoong D, Gough K. A potential drug-herbal interaction between Ginkgo biloba and efavirenz. J Int Assoc Physicians AIDS Care (Chic). 2012;11(2):98–100. [94] Gurley BJ, et al. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes.

Clin Pharmacol Ther. 2005;77(5):415–426. [95] Goey AK, et al. Relevance of in vitro and clinical data for predicting CYP3A4mediated herb-drug interactions in cancer patients. Cancer Treat Rev. 2013;39(7):773–783. [96] Gorski JC, et al. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clin Pharmacol Ther. 2004;75(1):89–100. [97] Ooko E, et al. Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines. Toxicol Appl Pharmacol. 2016;305:216–233. [98] Khan M, et al. Enhancing activity of anticancer drugs in multidrug resistant tumors by modulating P-glycoprotein through dietary nutraceuticals. Asian Pac J Cancer Prev. 2015;16(16):6831–6839. [99] Jia W, et al. Aglycone Protopanaxadiol, a ginseng saponin inhibits Pglycoprotein and sensitizes chemotherapy drugs on multidrug resistant cancer cells. J Clin Oncol. 2004;22(14_Suppl.):9663. [100] Park JH, et al. Effects of silymarin and formulation on the oral bioavailability of paclitaxel in rats. Eur J Pharm Sci. 2012;45(3):296–301. [101] Mustian KM, Cole C, Lin PJ, et al. Exercise recommendations for the management of symptoms clusters resulting from cancer and cancer treatment. Semin Oncol Nurs. 2016;32(4):383–393. [102] Zhang LL, Wang S, Chen HL, et al. Tai chi exercise for cancer-related fatigue in patients with lung cancer undergoing chemotherapy: a randomized controlled trial. J Pain Symptom Manage. 2016;51(3):504–511. [103] Sprod L, et al. Exercise and side effects among 417 older patients with cancer during and after cancer treatment: a URCC CCOP study. J Clin Oncol. 2011;29(15_Suppl.):9036. [104] Tian L, et al. Effects of aerobic exercise on cancer-related fatigue: a metaanalysis of randomized controlled trials. Support Care Cancer. 2016;24(2):969– 983. [105] Leon-Ferre R, Ruddy K, Staff NP, et al. Fit for chemo: nerves may thank you. J Natl Cancer Inst. 2016;109(2). [106] Rush SE, Sharma M. Mindfulness-based stress reduction as a stress management intervention for cancer care: a systematic review. J Evid Based Complementary Altern Med. 2017;22(2):348–360. [107] Liu S, Qiu G, Louie W. Use of mindfulness siYing meditation in Chinese American women in treatment of cancer. Integr Cancer Ther. 2017;16(1):110–117. [108] Kurdi MS, Muthukalai SP. The efficacy of oral melatonin in improving sleep in cancer patients with insomnia: a randomized double-blind placebo-controlled study. Indian J Palliat Care. 2016;22(3):295–300.

[109] Marx W, et al. Ginger – mechanism of action in chemotherapy-induced nausea and vomiting: a review. Crit Rev Food Sci Nutr. 2017;57(1):141–146. [110] Trivanovic D, et al. An open-label randomized phase II trial of oral vitamin D3 supplementation in combination with standard chemotherapy or best supportive care compared with standard chemotherapy and best supportive care in patients with advanced solid tumors. J Clin Oncol. 2011;29(15_Suppl.):e19566. [111] Abd El-AYi S, et al. Use of probiotics in the management of chemotherapyinduced diarrhea: a case study. JPEN J Parenter Enteral Nutr. 2009;33(5):569–570. [112] Argyriou AA, et al. Preventing paclitaxel-induced peripheral neuropathy: a phase II trial of vitamin E supplementation. J Pain Symptom Manage. 2006;32(3):237–244. [113] Argyriou AA, et al. Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology. 2005;64(1):26–31. [114] Villani V, et al. Vitamin E neuroprotection against cisplatin ototoxicity: preliminary results from a randomized, placebo-controlled trial. Head Neck. 2016;38(Suppl. 1):E2118–21. [115] Pace A, Bove L, Jandolo B. Vitamin E for prophylaxis against chemotherapyinduced neuropathy: a randomized controlled trial. Neurology. 2005;65(3):501– 502. [116] Wiernik PH, et al. Hexamethylmelamine and low or moderate dose cisplatin with or without pyridoxine for treatment of advanced ovarian carcinoma: a study of the Eastern Cooperative Oncology Group. Cancer Invest. 1992;10(1):1–9. [117] Puchsaka P, Chaotham C, Chanvorachote P. Alpha-lipoic acid sensitizes lung cancer cells to chemotherapeutic agents and anoikis via integrin beta1/beta3 downregulation. Int J Oncol. 2016;49(4):1445–1456. [118] Dora CL, et al. Oral delivery of a high quercetin payload nanosized emulsion: in vitro and in vivo activity against B16-F10 melanoma. J Nanosci Nanotechnol. 2016;16(2):1275–1281. [119] Li QC, et al. Enhanced therapeutic efficacy and amelioration of cisplatininduced nephrotoxicity by quercetin in 1,2-dimethyl hydrazine-induced colon cancer in rats. Indian J Pharmacol. 2016;48(2):168–171. [120] Demir MG, et al. Effect of transtympanic injection of melatonin on cisplatininduced ototoxicity. J Int Adv Otol. 2015;11(3):202–206. [121] Jang H, et al. Melatonin prevents cisplatin-induced primordial follicle loss via suppression of PTEN/AKT/FOXO3a pathway activation in the mouse ovary. J Pineal Res. 2016;60(3):336–347. [122] Guo Y, et al. Oral alpha-lipoic acid to prevent chemotherapy-induced peripheral neuropathy: a randomized, double-blind, placebo-controlled trial.

Support Care Cancer. 2014;22(5):1223–1231. [123] Gedlicka C, et al. Amelioration of docetaxel/cisplatin induced polyneuropathy by alpha-lipoic acid. Ann Oncol. 2003;14(2):339–340. [124] Pachman DR, et al. The search for treatments to reduce chemotherapy-induced peripheral neuropathy. J Clin Invest. 2014;124(1):72–74. [125] Tomizawa K, et al. A retrospective study of UFT and oral leucovorin plus PSK combination adjuvant chemotherapy in patients with stage III colon cancer. Gan to Kagaku Ryoho. 2012;39(4):571–575. [126] Ohwada S, et al. Beneficial effects of protein-bound polysaccharide K plus tegafur/uracil in patients with stage II or III colorectal cancer: analysis of immunological parameters. Oncol Rep. 2006;15(4):861–868. [127] Ghoreishi Z, et al. Omega-3 faYy acids are protective against paclitaxelinduced peripheral neuropathy: a randomized double-blind placebo controlled trial. BMC Cancer. 2012;12:355. [128] Schloss JM, et al. A randomised, placebo-controlled trial assessing the efficacy of an oral B group vitamin in preventing the development of chemotherapyinduced peripheral neuropathy (CIPN). Support Care Cancer. 2017;25(1):195–204. [129] Schloss JM, et al. Chemotherapy-induced peripheral neuropathy (CIPN) and vitamin B12 deficiency. Support Care Cancer. 2015;23(7):1843–1850. [130] Kidd PM. The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev. 2000;5(1):4–27. [131] Badr El-Din NK, et al. Enhancing the apoptotic effect of a low dose of paclitaxel on tumor cells in mice by arabinoxylan rice bran (MGN-3/biobran). Nutr Cancer. 2016;68(6):1010–1020. [132] Biswal BM, et al. Effect of Withania somnifera (Ashwagandha) on the development of chemotherapy-induced fatigue and quality of life in breast cancer patients. Integr Cancer Ther. 2013;12(4):312–322. [133] Guven C, Taskin E, Akcakaya H. Melatonin prevents mitochondrial damage induced by doxorubicin in mouse fibroblasts through AMPK-PPAR gammadependent mechanisms. Med Sci Monit. 2016;22:438–446. [134] de Morree ES, et al. Association of survival benefit with docetaxel in prostate cancer and total number of cycles administered: a post hoc analysis of the Mainsail study. JAMA Oncol. 2017;3(1):68–75. [135] Cortes EP, et al. Adriamycin cardiotoxicity: early detection by systolic time interval and possible prevention by coenzyme Q10. Cancer Treat Rep. 1978;62(6):887–891. [136] Mythili Y, et al. Effect of DL-alpha-lipoic acid on cyclophosphamide induced lysosomal changes in oxidative cardiotoxicity. Life Sci. 2007;80(21):1993–1998. [137] Chua S, et al. The cardioprotective effect of melatonin and exendin-4 treatment

in a rat model of cardiorenal syndrome. J Pineal Res. 2016;61(4):438–456. [138] Cvetkovic Z, et al. Distribution of plasma faYy acids is associated with response to chemotherapy in non-Hodgkin's lymphoma patients. Med Oncol. 2013;30(4):741. [139] Fahrmann JF, Hardman WE. Omega 3 faYy acids increase the chemosensitivity of B-CLL-derived cell lines EHEB and MEC-2 and of B-PLL-derived cell line JVM-2 to anti-cancer drugs doxorubicin, vincristine and fludarabine. Lipids Health Dis. 2013;12:36. [140] Davis L, KuYan G. Effect of Withania somnifera on cyclophosphamideinduced urotoxicity. Cancer LeU. 2000;148(1):9–17. [141] FriÖ H, et al. Polysaccharide K and Coriolus versicolor extracts for lung cancer: a systematic review. Integr Cancer Ther. 2015;14(3):201–211. [142] Sookprasert A, et al. Melatonin in patients with cancer receiving chemotherapy: a randomized, double-blind, placebo-controlled trial. Anticancer Res. 2014;34(12):7327–7337. [143] Marinac CR, et al. Prolonged nightly fasting and breast cancer prognosis. JAMA Oncol. 2016;2(8):1049–1055.

22

Cancer – Advanced II Part A:, Manuela Boyle

Part B:, Teresa Mitchell-Paterson

Part A Recovery and restoration post cancer Survivorship Worldwide, the number of cancer survivors continues to increase due to both advances in early detection and treatment, and the ageing and growth of the population. It has been estimated that more than 15.5 million Americans with a history of cancer were alive on 1 January 2016, with this number projected to reach more than 20 million by 1 January 2026 (see Fig. 22.1).[1] Similar to the US, current data (2016) from the Australian population shows that the three most prevalent cancers among males are prostate, colorectal and melanoma. Among females, breast, uterine and colorectal cancers have been recorded to be the most prominent.

FIGURE 22.1

The estimated number of US cancer survivors Miller KD, Siegel RH, Lin CC et al. Cancer treatment and survivorship statistics, 2016. CA: A Cancer Journal for Clinicians 2016;66(4):271–89.

In clinical practice, it is widely recognised that cancer survivors have unique medical and psychosocial needs, requiring proactive assessment and management by primary care providers. In a longitudinal study conducted by Verdecchia et al.,[2] incidence and survival were modelled by cancer type, sex and age group from 1975 to 2012. Data

found that more than half (56%) of all survivors were diagnosed within the past 10 years.[3,4] Nearly half of all cancer survivors (47%) are aged 70 years or older, although age distribution varies by cancer type. For example, most of the prostate cancer survivors (64%) are aged 70 years or older, compared with only one-third of melanoma survivors (see Fig. 22.2).[1]

FIGURE 22.2

Age distribution of survivors for selected cancer types Miller KD, Siegel RH, Lin CC et al. Cancer treatment and survivorship statistics, 2016. CA: A Cancer Journal for Clinicians 2016;66(4):271–89.

Breast cancer (female) Recent data collection shows that there are an estimated 3.5 million women living in the US with a history of invasive breast cancer. Of these, 75 per cent of breast cancer survivors (more than 2.6 million women) are aged 60 years or older, while 7% are younger than 50 years (see Fig. 22.2).[1] Most of the surveyed cancer survivors had undergone surgical treatment for breast cancer either in the form of a breast-conserving surgery also known as lumpectomy, or in the form of mastectomy. Interestingly, survivorship has shown to be the same regardless of the choice of surgery – lumpectomy or mastectomy.[5,6] It is common for some breast cancer patients to undergo both a lumpectomy and a mastectomy, due to either tumour characteristics (i.e. locally advanced stage, large or multiple tumours) or to a pre-existing medical condition.[7] Furthermore, recent data have reported an increase in the proportion of women with non-metastatic disease undergoing contralateral preventive mastectomy.[8] Statistics show that most women diagnosed with stage I or II breast cancer generally prefer to undergo a breastconserving surgery, with only 36% choosing to receive a mastectomy to improve chances of survival[1] (see Fig. 22.3). This proportion has been shown to change for patients at stage III and stage IV, with a much smaller percentage opting for a lumpectomy and a clear majority preferring a mastectomy, followed by radiation and/or chemotherapy. Among women with hormone-receptor-positive breast cancer regardless of the stage, 79% receive hormonal therapy.[9] For survivors of breast cancer, reconstruction may involve the use of a saline or silicone implant, a tissue flap or a combination of both.[10,11]

FIGURE 22.3 Age distribution of new cases (%), median age at diagnosis, estimated number of new cases, and 5-year relative survival by cancer type Miller KD, Siegel RH, Lin CC et al. Cancer treatment and survivorship statistics, 2016. CA: A Cancer Journal for Clinicians 2016;66(4):271–89.

Paediatric cancers It is estimated that currently in the US alone, there are 65 190 children cancer survivors aged from birth to 14 years, and 47 180 adolescent survivors aged 15–19 years. The three most commonly diagnosed cancers are leukaemia (30%), brain and central nervous system tumours (26%) and soft tissue sarcomas (7%). Among adolescents, the most common cancers are brain and central nervous system tumours (20%), followed by leukaemia (14%) and Hodgkin lymphoma (HL) (13%).[12] Childhood cancer survivors may experience chronic long-term effects of chemotherapy, with some symptoms expected to occur months or years after diagnosis or treatment. It is noticeable that for those paediatric patients who received aggressive chemotherapy and radiation therapy treatment in the 1970s and 1980s, there is a demonstrated increased risk of secondary cancers and cardiomyopathies.[13] A study by Armstrong et al. reported that 50% of childhood cancer survivors are estimated to develop a significant chronic health condition by the time they reach the age of 50 years.[14] Furthermore, another investigation has demonstrated that the majority of childhood cancer survivors who were diagnosed and treated with common chemotherapy drugs between 1962 and 2001 experienced ongoing pulmonary dysfunction.[15] In the past two decades, the decline of side effects and cancer recurrence in children has been acributed to the reduced use of cranial and abdominal radiation.[14] However, it is well established that cognitive impairment secondary to chemotherapy still affects up to one-third of childhood cancer survivors.[16] Furthermore, childhood cancer survivors who were treated with surgery, radiation and some chemotherapies affecting the reproductive organs have been found to be infertile.[17] Colon and rectal cancers Current statistics estimate that in the US there are 1.4 million men and women with a previous diagnosis of colon and/or rectal cancers. Most colon cancer sufferers are aged 60 years and older, with a small minority aged 50 years and younger[1] (see Fig. 22.2). On the other hand, patients affected by rectal cancer tend to be younger at diagnosis

compared with those individuals diagnosed with colon cancer (median age, 63 vs 70 years, respectively).[10] Many survivors with a previous diagnosis of stage I and II colon cancer are given the choice to have either a partial or a total colectomy, depending on the position of the tumour mass. Approximately two-thirds of individuals diagnosed with stage III disease generally are scheduled to receive chemotherapy following a colectomy (see Fig. 22.4). For patients with rectal cancer, proctectomy or proctocolectomy is the most common treatment (61%) for stage I disease.[1] Chemotherapy is the general treatment for all stage IV rectal cancers.

FIGURE 22.4

Colon cancer treatment patterns (%) by stage, 2013 Miller KD, Siegel RH, Lin CC et al. Cancer treatment and survivorship statistics, 2016. CA: A Cancer Journal for Clinicians 2016;66(4):271–89.

Survivors of colon and/or rectal cancer who have been treated with chemotherapy often experience both chronic neuropathies[18] and chronic diarrhoea,[19] as well as chronic bowel dysfunction (including increased stool frequency, incontinence, radiation proctitis and perianal irritation), particularly among those treated with pelvic radiation.[20] Survivors may also suffer from bladder dysfunction, sexual dysfunction and negative body image following a colostomy.[21] However, research findings have shown that colorectal cancer survivors are often at risk of contracting secondary cancers arising from other organs of the gastrointestinal tract.[22] Leukaemias and lymphomas Although acute myeloid leukaemia (AML) is the most common type of cancer among children aged from birth to 14 years, the clear majority (92%) of patients with a blood-borne cancer are diagnosed at age 20 years and older with acute lymphocytic leukaemia. Adults diagnosed with leukaemia are affected by either acute myeloid leukaemia (AML) or chronic lymphocytic leukaemia.[23] The 5-year relative survival rate for children and adolescents is estimated to be 65%, rapidly declining to 50%, 32% and 6% for patients aged 20–49 years, 50–64 years and 65 years and older, respectively. Subdivision exists also among lymphomas, with HL and non-Hodgkin's lymphoma (NHL) identified as the two main types. NHLs can be further divided into indolent and aggressive categories, each of which includes many subtypes that progress and respond to treatment differently. Prognosis and treatment depends on the stage and type of lymphoma. Although both HL and NHL occur in children and adults, most HL cases (64%) are diagnosed before age 50 years, whereas most NHL cases (85%) occur in those aged 50 years and older. Chemotherapy is the standard treatment for the most common types of leukaemia and lymphoma, with most patients undergoing stem cell transplantation, often in combination with chemotherapy.[24] Survivors of leukaemia and lymphoma have been shown to experience several long-term and late effects. For example, documented health issues affecting those individuals who receive stem cell transplantation have been identified as being recurrent infections, infertility, serious anaemia requiring routine blood transfusions and chronic graft-versus-host disease, which can cause skin changes, dry mucous membranes (eyes, mouth, vagina), joint pain, weight loss, shortness of breath and fatigue. Furthermore, cancer survivors who were treated with anthracyclines commonly report cardiovascular problems.[25] Lung cancer Generally, the median age for a diagnosis of lung cancer is 70 years. Lung cancer is classified as small cell lung cancer (SCLC) (13% of cases) or non-small cell (NSCLC) (83%). SCLC survivors receive chemotherapy and thoracic radiation therapy. The treatment protocol for those individuals diagnosed with stage I and II NSCLC is surgery, with a minority of these cases also receiving chemotherapy and/or radiation therapy after the main intervention[1] (see Fig. 22.5). Recently, targeted therapy drugs, such as monoclonal antibodies, angiogenesis inhibitors, epidermal growth factor

receptor (EGFR) inhibitors and anaplastic lymphoma kinase inhibitors have become part of the treatment for NSCLC due to some recorded and consistent positive results. These types of drugs are growing to be a preferred option after research has demonstrated that many survivors of lung cancers who had received conventional oncological treatment showed impaired pulmonary function.[26] The recorded side effects of most targeted drugs, when administered in maximum doses, are: immune mediated toxicities, colitis, nephritis and endocrinopathy. Lung cancer survivors who are typically smokers and have chosen not to quit smoking after treatment have been found to be at an increased risk for subsequent smoking-related cancers, especially lung, head and neck, and oesophageal, as well as other smokingrelated health problems. It is interesting to note that, differently from other cancer survivors, these individuals commonly feel blame and low self-esteem due to the social perception that lung cancer is a self-inflicted disease.[27]

FIGURE 22.5

Non-small cell lung cancer treatment patterns (%) by stage, 2013 Miller KD, Siegel RH, Lin CC et al. Cancer treatment and survivorship statistics, 2016. CA: A Cancer Journal for Clinicians 2016;66(4):271–89.

Melanoma Melanoma is a cancer that has been linked to occupational and recreational exposure to ultraviolet radiation. As such, it is often detected in younger individuals who may have spent time in the outdoors.[10] Surgery is regarded as the primary conventional oncological treatment for most melanoma sufferers, and until a few years ago, these individuals were also treated with adjuvant immunotherapy such as ipilimumab, an anticytotoxic T-lymphocyte-associated protein. Following the mapping of the Human Genomic Project (2003), the identification of BRAF mutations has led to the creation of chemotherapeutic inhibitors, which have been shown to improve survival for melanoma patients.[28] Research data confirm that melanoma survivors treated with BRAF inhibitors have an increased risk of developing squamous cell skin carcinomas.[29] Although the 5-year and 10-year relative survival rates for people with melanoma are high, it is critical that these cancers are identified and diagnosed at a localised stage with regular medical check-ups, and that behavioural risk factors are correctly addressed.[30] Prostate cancer Typically, survivors of prostate cancer are over the age of 70 years, with a small minority identified under the age of 50 years[1] (see Fig. 22.2). Most men diagnosed with prostate cancers following a prostate-specific antigen (PSA) testing receive different types of treatment, depending on the extent of disease, age and pre-existing conditions. Most younger patients (55 000 20 000–55 000 7000–20 000 10% over 12 months • unintentional weight loss of >7.5% over 6 months • body cell mass (BCM) loss of >5% over 6 months • men: BCM for 14 days (14–21 days) – Early neurological Lyme/Lyme carditis: > ceftriaxone 2 g daily for 14 days (range 10–28 days). The conflict between the IDSA and the ILADS is reflected even in the acute antibiotic protocols each recommends. The ILADS has its own evidence-based treatment guidelines and ILADS the following position statements[12]:

• It is impossible to state a meaningful success rate for the prevention of Lyme disease by a single 200 mg dose of doxycycline because the sole trial of that regimen utilised an inadequate observation period and unvalidated surrogate end point. • Success rates for treatment of an erythema migrans rash were unacceptably low, ranging from 52.2% to 84.4% for regimens that used 20 or fewer days of azithromycin, cefuroxime, doxycycline or amoxicillin/phenoxymethylpenicillin (rates were based on patient-centred outcome definitions and conservative longitudinal data methodology). • In a well-designed trial of antibiotic retreatment in patients with severe fatigue, 64% in the treatment arm obtained a clinically significant and sustained benefit from additional antibiotic therapy. The philosophy behind ILADS’ statements and in its guidelines includes the following[13]:

• The optimal treatment regimen for the management of known tick bites, erythema migrans rashes and persistent disease has not yet been determined. Accordingly, it is too early to standardise restrictive protocols. • Given the number of clinical variables that must be managed and the heterogeneity within the patient population, clinical judgment is crucial to the provision of patientcentred care. • Based on the Grading of Recommendations Assessment, Development and

Evaluation model, ILADS recommends that patient goals and values regarding treatment options be identified and strongly considered during a shared decisionmaking process. In a nutshell, ILADS argues that the IDSA protocols may be too short, too restrictive, not have enough individualisation and not take into account the clinical judgment of the practitioner. It states that there is not enough evidence of the efficacy of the IDSA guidelines to make them universally accepted without any question or challenge. ILADS’ treatment guidelines suggest the following:

• Amoxicillin, cefuroxime or doxycycline as first-line agents for the treatment of erythema migrans. • Azithromycin is cited as an acceptable agent, particularly in Europe, based on trials showing it to either outperform or be as effective as other first-line agents.[47–50] • Initial antibiotic therapy should employ 4–6 weeks of: – amoxicillin 1500–2000 mg daily in divided doses – cefuroxime 500 mg twice daily – doxycycline 100 mg twice daily or a minimum of 21 days of azithromycin 250–500 mg daily. • Paediatric dosing for the individual agents is as follows: – amoxicillin 50 mg/kg/day in three divided doses, with a maximum daily dose of 1500 mg – cefuroxime 20–30 mg/kg/day in two divided doses, with a maximum daily dose of 1000 mg – azithromycin 10 mg/kg on day 1 then 5–10 mg/kg daily, with a maximum daily dose of 500 mg. For children 8 years and older, doxycycline is an additional option. Doxycycline is dosed at 4 mg/kg/day in two divided doses, with a maximum daily dose of 200 mg. Higher daily doses of the individual agents may be appropriate in adolescents.[12] Dr Richard Horowib treats acute Lyme disease with a 2-month regimen of the following[51]:

• First month: – doxycycline 200 mg – twice daily – hydroxychloroquine 200 mg – twice daily or – tinidazole 500 mg – twice daily. • Second month: – cefuroxime 500 mg – twice daily – azithromycin 500 mg – once daily or clarithromycin 500 mg – twice daily – hydroxychloroquine 200 mg – twice daily or tinidazole 500 mg – twice daily.

Antibiotic therapy for chronic Lyme disease

Antibiotic therapy for chronic Lyme disease is influenced by the morphology of the bacteria, which can morph back and forth between spirochaete, cell-wall-deficient form and cyst form. To adequately address chronic infection, medications must be given for all three forms. Borrelia tries to evade immune defences and antimicrobial therapy by morphing into the cyst form, where it is beEer protected. If medications are not included that address those cyst forms, the infection can be pushed into that state, which can bring symptom relief to the patient, as it is a more dormant state. Yet, when antibiotic therapy is ceased, the microbes can morph back to the spirochaetes and cell-wall-deficient forms, which are more active, pushing the patient into a relapsing state. According to Lyme-literate physician Joseph Burrascano, MD: It has been recognised that B. burgdorferi can exist in at least two, and possibly three different morphologic forms: spirochete, spheroplast (or l-form), and the recently discovered cystic form (presently, there is controversy whether the cyst is different from the l-form). L-forms and cystic forms do not contain cell walls, and thus beta lactam antibiotics will not affect them. Spheroplasts seem to be susceptible to tetracyclines and the advanced erythromycin derivatives. Apparently, Bb can shift among the three forms during the course of the infection. Because of this, it may be necessary to cycle different classes of antibiotics and/or prescribe a combination of dissimilar agents.[45]

A further note on cystic forms: When present in a hostile environment, such as growth medium lacking some nutrients, spinal fluid, or serum with certain antibiotics added, Bb can change into a cyst form. This cyst seems to be able to remain dormant, but when placed into an environment more favorable to its growth, the cyst can revert into the spirochete form. The conventional antibiotics used for Lyme, such as the penicillins, cephalosporins, etc do not kill the cystic form of Bb, yet there is laboratory evidence that metronidazole will kill it. Therefore, the trend now is to treat the chronically infected patient who has resistant disease by combining metronidazole with one or two other antibiotics to target all forms of Bb.[45]

Because antibiotic therapy for chronic Lyme can be long term and involve multiple medications, care must be taken to minimise side effects and offset any negative impact of antibiotics where possible. Liver and kidney function must be checked monthly to screen for any abnormalities. White blood cell counts, often low in chronic Lyme disease anyway, frequently drop further. Candida overgrowth is fairly common and is possibly the most problematic sequelae of long-term antibiotics. These three considerations will be discussed further in the section on naturopathic approaches to Lyme disease, but suffice it to say that naturopaths and integrative health practitioners are uniquely placed and well qualified to offer optimal support in these areas. Tables 24.1 and 24.2 are summaries of the medication classes used for different forms of Borrelia. The ultimate goal of therapy is to combine medications for spirochaete forms, cell-wall-deficient forms and cyst forms. Medication choices depend largely on the sensitivity of the patient, any medication allergies and prior therapy. Medications to address co-infections must be added also. TABLE 24.1 Medication summary Form of borrelia

Medication class

Commonly used examples

Spirochaetes

Penicillins Cephalosporins Macrolides Tetracyclines

Amoxicillin, bicillin LA Cefuroxime, ceftriaxone, cefdinir Azithromycin, clarithromycin Doxycycline, minocycline Tinidazole, metronidazole Hydroxychloroquine (Plaquenil) Nitazoxanide (Alinia)

Cell wall deficient Cyst forms

TABLE 24.2 Common dosages Penicillins Amoxicillin Augmentin XR Bicillin LA Cephalosporins Cefuroxime Ceftriaxone Cefdinir Macrolides Azithromycin Clarithromycin Telithromycin Tetracyclines Minocycline Doxycycline Tetracycline Cyst-form medications Metronidazole Tinidazole Plaquenil Babesia medications Mepron Malarone Lariam Alinia Bartonella, ehrlichia, anaplasma and ricke1sia medications Rifampicin Levaquin Bactrim DS

1000 mg 2000 mg 0.9 million units

3–6 daily 2 × daily 2 vials injected IM 3 × weekly

500 mg 2g 600 mg

3 × daily 2 g twice daily IV 4 days/week 2 × daily

500 mg 500 mg 800 mg

1 × daily 2 × daily 1 × daily

100 mg 100 mg 500 mg

3–4 × daily 2 twice daily 3–4 × daily

500 mg 500 mg 200 mg

2 × daily; 2 weeks on/2 weeks off 2 × daily; 2 weeks on/2 weeks off 2 × daily

750 mg/5 mL 250/100 mg 250 mg 500 mg

1–2 tsp twice daily 2 twice daily 1 every five days 2 × daily

300 mg 500 mg 800/160 mg

2 × daily 1 × daily 2 × daily

Antibiotic therapy during pregnancy and breastfeeding Starting in the early 1980s, the Lyme Disease Foundation in Hartford, Connecticut, kept a pregnancy registry over an 11-year period. It found that women who took adequate amounts of antibiotics during pregnancy showed a very low, in fact almost zero, transmission rate to their baby. Medications utilised in pregnancy include:

• amoxicillin – 1 g four times daily • bicillin LA – 1 injection three times weekly • cefuroxime – 1 g every 12 hours • azithromycin – 500 mg daily. At the ILADS annual conference in 2011, paediatric Lyme specialist Charles Ray Jones cited the following figures:

• Pregnant women with active Lyme disease who do not take antibiotics have a 50% chance of passing the infection to their child. • Women who take one antibiotic during pregnancy have a 25% chance of passing

Lyme disease to their child. • Women who take two antibiotics during pregnancy have less than a 5% chance of passing Lyme disease on to their child. Obviously, many women are reluctant to take antibiotics during pregnancy for fear of harming their baby. Certainly, there are specific medications that are not appropriate, such as the tetracycline class of antibiotics, metronidazole and tinidazole. The medications listed above are deemed safe in pregnancy. Although taking antibiotics during pregnancy is not ideal, it is a far beEer choice than risking the transmission of Lyme disease to a baby, which could then impact on their entire life. Since Borrelia spirochaetes have been detected in breast milk by PCR testing, the antibiotic regimens above should be continued if breastfeeding.

Antibiotic therapy for children Children can be treated with antibiotic therapy, but the medication choices and dosages will be adjusted for them. Tetracyclines are not used in children 8 years and younger because of their ability to cause a permanent discolouration of the teeth. Antibiotics considered safe and effective for children include:

• amoxicillin – 50 mg/kg/day divided into doses every 8 hours • cefuroxime axetil – 125–500 mg every 12 hours based on weight • azithromycin – 250–500 mg daily depending on their weight • tinidazole – 125–250 mg daily depending on weight. May be pulsed 2 days per week. Antibiotic therapy for co-infections Co-infections must be addressed concurrently with Borrelia for the best chance of recovery for the patient. Untreated co-infections are one of the biggest hindrances to recovery. The co-infection Babesia is a malaria-like protozoan parasite; therefore, the medications that treat Lyme are unlikely to help Babesia. Babesia requires malarial medications. Bartonella, Ehrlichia and Ricke?sia are bacteria, like Borrelia, so there is more crossover between medications for these co-infections (see Table 24.3).

TABLE 24.3 Commonly used medications for co-infections Babesia Atovaquone + proguanil (Malarone) Atovaquone (Wellvone) Nitazoxanide (Alinia) Artemether/lumefantrine (Riamet) Sulfamethoxazole/trimethoprim (Bactrim DS) Bartonella Rifampicin Doxycycline Azithromycin SMX/TMP Levofloxacin Ciprofloxacin Ehrlichia/ricke1sia Doxycycline Rifampicin

250/100 mg 750 mg/5 mL 500 mg 20/120 mg 800/160 mg

2 twice daily 5 mL twice daily 1 twice daily 4 tablets twice daily for 3 consecutive days per month 1 twice daily

300 mg b.i.d. 200 mg b.i.d. 500 mg q.d. 800/160 mg b.i.d. 750 mg b.i.d. 500 mg b.i.d. 200 mg b.i.d. 300 mg b.i.d.

Allopathic supportive therapy Another aspect in allopathic treatment of Lyme disease involves medications to provide symptomatic relief and supportive medications. These may be pain medications, sleep medications, cognitive enhancers, antidepressant medications and anxiety medications, to name just a few. Individuals suffering from chronic Lyme disease experience severe and unrelenting symptoms, so providing symptomatic relief can be necessary. Issues arise when those medications produce side effects of their own or when stopping them can provoke withdrawal reactions, such as with benzodiazepine withdrawal. Supportive medications can be life saving, but should not replace addressing the underlying cause of the symptoms.

Naturopathic approaches to Lyme disease and co-infections The following section discusses naturopathic approaches to Lyme disease treatment. There are several different treatment priorities in treating Lyme disease and co-infections, only part of which is eradicating the pathogens themselves. As previously stated, treatment must be holistic and address many of the secondary impacts of the illness. The following section is divided into the following modality classifications:

• Nutrition (dietary) • Nutrition (supplements) • Nutrition (micronutrients) • Herbal medicine • Amino acids • Lifestyle factors. Within each modality, you will find the information organised by treatment priority. Primary treatment priorities for Lyme patients include:

• antimicrobial therapy to kill pathogens

• inflammation reduction • immune system support • detoxification support. Secondary considerations and symptomatic support include:

• brain chemistry and mood balance • sleep support • energy/adrenal support • digestive support.

Nutritional therapy (dietary) Nutrition makes a profound difference in the outcomes of Lyme disease patients and should not be underestimated. For many patients, however, the dietary recommendations can be a whole new concept, and quite overwhelming and challenging. Encouraging gradual, step-by-step changes and providing consistent support and practical guidance, such as shopping lists and easy recipe ideas, will help with compliance. It is also useful to remind patients that in an illness in which they can feel so helpless and powerless, nutrition is one area that they have complete control over; they can feel empowered about that.

Reducing inflammation This is one of the key goals in nutritional therapy. Inflammation is a logical secondary effect of chronic infection and can produce a wide array of symptoms of its own. Lyme disease is primarily an infectious illness, and secondarily an inflammatory disorder. The key approach nutritionally is to avoid proinflammatory foods and eat anti-inflammatory foods. Pro-inflammatory foods Gluten

Gluten is one of the most inflammatory foods. It is found in oats, rye, barley and wheat, and is pervasive in processed foods today. It is thought that in the Australian population, 1 in 100 is gluten intolerant, 1 in 70 has coeliac disease and 56% carry the gene for gluten intolerance.[52] Gluten can create inflammation in a number of different ways. It can trigger an IgE food allergy, which is an immediate and usually obvious immune reaction – what we consider a food allergy. It can also cause an IgG immune response, also known as a type IV delayed hypersensitivity response. This reaction can take up to 72 hours to manifest, and the symptoms may be subtle and not always directly related to the immune system. Fatigue, brain fog and mood changes are common manifestations, especially in Lyme patients who are prone to those things anyway. The third way gluten can cause inflammation is by triggering an autoimmune response. Coeliac disease is the most extreme form of this; however, there are grades of gluten intolerance, which do not always fit the diagnostic criteria for coeliac. Testing may involve anti-gliadin and transglutaminase antibodies as well as genetic markers for gluten intolerance. Some patients who could tolerate gluten well in their past may find themselves becoming intolerant to it over the course of their Lyme illness, and even those who do not show laboratory markers in line with gluten intolerance may still feel beEer avoiding it, simply from an inflammatory standpoint. In one study, researchers assessed the likelihood of developing coeliac disease by observing gluten presentation on CD4 T cells. It states: In the presence of gluten, this could become a self-amplifying loop that could cause limited tissue damage locally.

This tissue damage would lead to the release of TG2 that will modify native gluten peptides into high affinity ligands for human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8, thereby expanding the gluten-specific CD4+ T cell responses and leading to additional tissue damage: the initiation of a second self-amplifying loop. Alternatively, infections occurring in the gastrointestinal tract would generate a proinflammatory milieu that might lead to loss of tolerance to native gluten peptides and generate tissue damage simultaneously and thus, initiate deamidation by TG2.[53]

Infections such as Borrelia and Bartonella can infect the gut; therefore, we see here the connection between Lyme disease and the onset of gluten intolerance. Any of these mechanisms (IgE, IgG and autoimmune) will create immune activation in the gut. Immune activation by nature leads to an inflammatory process that can impact on not only gut function, but systemic symptoms too. One of the things gluten can do is promote leaky gut, where the cell junctions of the intestinal wall open up and allow the passage of larger than normal food molecules to pass through, thus leading to even more immune activation and inflammation. Gluten does this by stimulating zonulin, a substance that regulates the permeability of the gut wall. Eating gluten triggers more zonulin, which makes the intestinal wall more permeable, which leads to food particle passage across the intestinal lining, which triggers an immune response (the immune system is trained that single amino acids, sugars and faEy acids are ‘normal’, whereas molecules containing groups of these are treated as ‘invaders’), which creates cytokines, chemokines and other chemical mediators of inflammation. These can then travel throughout the body and lead to inflammatory symptoms such as headache/migraine, joint pain, fatigue, myalgia and cognitive deficits, to name just a few.[54,55] Gluten has one other key negative impact. Zonulin regulates gut permeability, but it also regulates the permeability of the blood–brain barrier. So along with ‘leaky gut’, it promotes ‘leaky brain’. When the blood–brain barrier is compromised and rendered more permeable, it is more open to the influx of cytokines and chemokines, toxins including heavy metals and ammonia, and other harmful substances. This leads to a worsening of ‘Lyme brain’ – cognitive deficits such as brain fog, memory loss, word-finding difficulties, problems with focus and concentration, depression and anxiety. These are some of the symptoms that Lyme patients struggle with the most, so avoiding the gluten-containing foods that can make it worse is key. In one study, researchers observed how cereal grains affected human behaviour and mental health: In vitro, antibodies against gluten removed from human blood attack cerebellar proteins and components of the myelin sheath that insulate nerves. They also attack an enzyme involved in the production of GABA – our prime inhibitory neurotransmitter, whose dysregulation is implicated in both anxiety and depression.[54] Dairy

Dairy is the second food category that can be pro-inflammatory. Studies show that a diet containing A1 betacasein had pro-inflammatory effects in the gut, with increased levels of inflammatory markers and immunoglobulins, leukocyte infiltration and Toll-like receptor expression.[56] Cow dairy is the most inflammatory, followed by sheep dairy, and then goat dairy. Goat dairy is the closest in molecular structure to human dairy, has the smallest fat molecules and the lowest ratio of casein. Pasteurised dairy products are hard to digest because they are treated in a way that kills off naturally occurring enzymes and cultures. Raw dairy contains more of these beneficial ingredients, but can also contain bacteria that would normally be killed off in the pasteurisation process. In an immunosuppressed Lyme disease patient, this may present a further risk to their health. Dairy does not trigger autoimmune reactions in the same way that gluten does, but many patients have IgG sensitivities to dairy. IgG food sensitivity tests are so helpful in discerning the degree of sensitivity in patients, but they also give more of a detailed breakdown of dairy. Most tests will differentiate between casein, whey, different types of cheese, yoghurt, milk and goat's milk.

Casein and whey are the two key proteins in dairy. Of the two, casein is the more problematic: it comprises 80% of the proteins in dairy and the majority of proteins in cheese, and takes several hours to break down and digest as it coagulates and forms a gel in the stomach. Whey protein digests quickly and more easily, and has some helpful roles such as promoting glutathione production and providing a ready source of amino acids. For these reasons, there may be some patients who avoid dairy products in general but still tolerate a pure whey protein isolate. Still others cannot tolerate dairy, but fare well on kefir, which is fermented. Kefir has the added benefit of containing cultures and probiotics that can assist in maintaining healthy gut flora. Again, IgG food sensitivity testing can provide information that helps to guide these choices in different individuals. Food and symptom diaries can also help patients see correlations between certain food groups and flare-ups or improvements in their symptoms. Saturated fats

Saturated fats can be a source of inflammation in the body as they promote prostaglandins that fuel inflammation. Saturated fats are naturally occurring fats found in nature such as in red meat and dairy. Another source of inflammatory fats is trans faEy acids, which are found in processed foods. These fats may have originated as vegetable oils but have been treated with heat and pressure to make them more solid and give them a longer shelf life. They are often labelled as hydrogenated or partially hydrogenated oils and are found in chips, biscuits, lollies, cakes and crackers. Lyme patients are encouraged to eat a wholefoods diet low in processed foods of any kind. High-sugar, high-fat foods, such as fast foods and pastries, should be avoided, not only because of their unhealthy fat content, but many are made from gluten-containing grains, dairy and sugar, all of which are detrimental. Unhealthy fats such as these promote PG2 production – the prostaglandins that increase inflammation, constrict blood vessels and encourage blood cloEing. On the other hand, anti-inflammatory fats can help to reduce inflammation in the body and help with symptom control. Healthy fats promote PG1 and PG3 production. PG1 prostaglandins reduce inflammation and inhibit blood cloEing. PG3 prostaglandins have mixed function within the body, but are generally considered anti-inflammatory as they help to reduce the rate at which PG2 are formed. Anti-inflammatory fats are unsaturated fats – classified as omega-3, omega-6 and omega-9. Omega-3s have the greatest effect in reducing inflammation as they produce the lowest number of prostaglandins: they produce PG1 and PG3, which act to counter PG2 production, and they compete with omega-6 faEy acids on the binding sites of the COX1 enzyme, thus reducing omega-6's conversion to PG2. A review in the British Journal of Clinical Pharmacology looked at omega-3's anti-inflammatory properties. [57] It found substantial evidence that omega-3 faEy acids are able to inhibit a number of aspects of inflammation, including leukocyte chemotaxis, adhesion molecule expression and leukocyte–endothelial adhesive interactions, production of eicosanoids such as prostaglandins and leukotrienes from the omega-6 faEy acid arachidonic acid, production of inflammatory cytokines and T cell reactivity. Most people also get omega-6 and omega-9 faEy acids through their diet (prevalent in vegetable oils, nuts and seeds), whereas omega-3 faEy acids are less common. Fish and flax are the richest sources of omega-3, with fish oil having a much stronger effect. One study found flaxseed oil to inhibit the production of cytokines by 30% in 4 weeks, whereas 9 g of fish oil for another 4 weeks inhibited IL-1 by 80% and TNF-α by 74%.[58] Eating seafood and incorporating flax oil into a smoothie or as a salad dressing or food topping can be good ways to get more omega-3. Supplementation can be an important consideration in those with high levels of inflammation, as is frequently the case in Lyme disease. Cruciferous vegetables and carotenoids both exhibit anti-inflammatory activity in the body. One study of 1005 middle-aged Chinese women found that a higher intake of cruciferous vegetables was associated with significantly lower circulating concentrations of the pro-inflammatory markers TNF-α, IL-1β and IL-6, after accounting for a wide range of potential confounding variables, including socioeconomic status, dietary and non-dietary lifestyle factors, BMI, health conditions and medication use.[59]

The carotenoids, particularly lycopene and beta-carotene, concentrated in deeply coloured items such as carrots, tomatoes and dark green vegetables, are other dietary antioxidants that function to reduce oxidative stress in vivo and blood markers of inflammation.[60] Other inflammatory foods

Other foods that should be avoided are any foods that create immune activation for that person, regardless of what they are. Again, food sensitivity testing is a quick, easy way to assess these, but elimination diets can be a good tool to use too. One limitation of the elimination diet in Lyme patients is the time required to do the restriction phase and reintroduction phase. Since Lyme symptoms typically wax and wane, acting in a cyclical fashion, it can be hard for patients to differentiate what is a reaction to a reintroduced food versus what is a natural flare of their symptoms, which may happen every few days or every month regardless of dietary or treatment changes. Any food can cause inflammation in certain individuals. Garlic, bananas or blueberries may show high IgG reactions. These foods are generally regarded as healthy foods and not problematic for most. Some people may react to almond, which can be important because many people change their milk to almond milk, thinking that they are doing the right thing in avoiding dairy. This is where individuation of diet is important.

Supporting immune function A large part of dietary modification to support immune function means eradicating foods that cause immune activation, as discussed in the prior section on inflammation. The diet can also be tailored to promote healthy immune function. This mostly entails a diet that is high in fresh fruit and vegetables in order to provide the vitamins, minerals and enzymes needed to assist in the composition of cells, enhance cell-to-cell communication and provide catalysts for the thousands of biochemical reactions in our bodies, including those reactions necessary for our immune systems to function well. Deficiencies of particular nutrients can compromise the body's ability to create antibodies and elements of cell-mediated immunity. Malnutrition will decrease antibody production, so ensuring adequate kilojoule intake is important. Some Lyme patients have such compromised digestive function and such profound nausea that geEing adequate kilojoules can be challenging. Loss of appetite is also a common symptom of Lyme disease. Strategies must be employed to encourage small, frequent meals and utilise protein smoothies, broths and soups, which can be easier to digest, and light but nutrient-rich foods. Protein intake is important. Amino acids are the building blocks of cells and tissues, and are needed to create the antibodies that are needed to overcome infection. Lean, organic, high-quality proteins should be eaten with each meal to provide these amino acids. If not well tolerated, protein powders can be utilised once or twice daily. Another major element in dietary modification for Lyme disease is reducing overall sugar intake and eradicating any refined sugars. Naturally occurring sugars, such as in honey, maple syrup and fruit, do not have the immunosuppressive effects of refined sugars, but may still need to be restricted for reasons relating to digestive health and Candida. However, from an immune-support standpoint, the key is omiEing any refined sugars as they have a profoundly suppressive effect on the immune system. Eating or drinking 100 g of sugar, the equivalent of one medium boEle of soft drink, can reduce immune function by up to 40%. The immune-suppressing effects of sugar, including a reduction in the ability of neutrophils to engulf bacteria, start less than 30 minutes after ingestion and can last for up to 10 hours.[61] Secondarily, sugar causes the pancreas to secrete insulin, which can stay in the bloodstream long after the sugar has been metabolised. One of the things insulin does is suppress growth hormone production from the pituitary, and growth hormone is one of the key regulators of the immune system. Since refined sugar contains virtually no vitamins, minerals or other micronutrients, sugar consumption decreases overall micronutrient intake by an average of almost 20%.[61,62]

Finally, glucose competes with vitamin C for absorption into white blood cells. Vitamin C acts as an antioxidant and promotes healthy immune function. Reducing sugar ingestion to allow vitamin C uptake is going to have a more beneficial impact on overall immune function. Many patients with Lyme disease resort to sugar because of their profound fatigue. They try to get energy however they can, even if the boost is short term and followed by energy crashes. Others resort to highsugar foods for emotional reasons, to try to cheer themselves up during very trying times. Withdrawing from sugar can be very difficult for them but is crucial to their recovery.

Encouraging detoxification and elimination This is another significant consideration for Lyme patients – second only perhaps to reducing inflammation. As patients move through antimicrobial therapy, the toxins produced in the killing off of the bacteria (the Herx reaction), as well as the pre-existing toxic load that patients may be predisposed to due to HLA/methylation factors, such as heavy metals and ammonia, must be cleared from the body. Modalities such as nutrient supplementation, herbal medicine and homeopathy are crucial, but dietary choices can assist greatly in the process too. The first thing to think about in assisting the body in detoxification is to stop the influx of toxins. This means shifting the diet towards organic to reduce pesticides, fertilisers and other chemicals coming into the body. Meats and poultry should be grass fed, organic and hormone/antibiotic free. Seafood should be lowmercury types. Water should be filtered and free of pollutants such as heavy metals. Two litres of water should be drunk each day to help flush toxins out of the body. Caffeine and alcohol should be avoided, as they can place additional stress on the liver. Given that the liver is the key organ of detoxification in the body, foods to support liver function are useful. These include onions, garlic, broccoli, beetroot, spinach, asparagus, artichokes, Brazil nuts and walnuts. Cayenne pepper is both anti-inflammatory and supports detoxification. Lemon is a good cleansing agent. Green juices and smoothies are a good way to get concentrated nutrients to the cells in a way that does not stress the digestive system. Juices may be beEer for those who have highly inflamed GI systems, as sometimes the fibre content of blended smoothies can be irritating and hard to digest. For those who tend towards constipation, the fibre content of smoothies may be helpful. Juices are ideal, as the nutrients are easy to digest and assimilate, additional elements such as ginger, garlic and cayenne can be added, and they assist the liver and kidney in the detoxification process. Elimination is another consideration in supporting detoxification. Toxins have to be able to find their way out of the body. There are other ways to assist this, such as infra-red sauna and coffee enemas, but from a dietary standpoint, make sure that the kidneys are flushing well by drinking plenty of water and herbal teas made from ingredients such as dandelion, juniper berry, cranberry and tart cherry. Elimination through the bowel is especially important and can be challenging given that many Lyme patients experience either constipation or diarrhoea. Adequate dietary fibre intake to ensure at least once daily bowel movements can be helpful. High water intake is also important. As per the information on gluten and dairy as inflammatory foods, eliminating those often leads to healthier bowel function.

Supporting healthy digestion There are many different stressors on the digestive systems of Lyme patients. Overall, immune activation and inflammation can render them more reactive to various foods such as gluten and dairy (as discussed in the section on nutrition and inflammation). Those on antibiotic therapy can experience gastritis, oesophagitis and intestinal distress from the irritating effects of those medications. Borrelia and co-infections can inhabit the gut lining and cause symptoms of their own. Opportunistic infections, such as Blastocystis hominis, Cryptosporidium parvum, Giardia lamblia and Entamoeba histolytica, are not uncommon and should be screened for. Candida overgrowth and other changes in the gut microbiome can produce symptoms too.

Much of the naturopathic approach to these stressors rests on antimicrobial therapy and supplementation to reduce inflammation. Dietary modifications are largely geared around reducing any additional stress through inflammatory foods such as gluten, dairy and IgG food intolerances. Soothing, healing foods should be used: bone broth can help to heal leaky gut and provide high-level nutrition to those with compromised gut function; slippery elm powder can be added to smoothies and drinks; aloe vera juice can soothe and heal the gut mucosa; and deglycyrrhizinated liquorice can help with oesophagitis. Yeast also tend to grow in more inflamed and compromised environments, so identifying sources of inflammation and eradicating them also helps prevent yeast overgrowth. The second nutritional consideration in helping digestive function is the microbial balance, especially visà-vis Candida overgrowth, and maintaining healthy gut flora. This is especially important for those on antibiotics. Avoiding sugar and highly processed foods will reduce the overgrowth of yeast and unwanted bacteria. This is the most important thing patients can do in this area, and its importance must be stressed to them. For people with existing Candida issues, even restriction in fruit intake may be necessary for a period of time. For some, eating a grain-free diet is required and helps them to feel beEer. This can be hard to adhere to, but for those with severe digestive irritation, it might be necessary. Fermented foods can play a big role in promoting healthy gut flora. These include fermented vegetables such as kimchi, kefir and kombucha. It is important to caution patients about store-bought varieties, as they are often pasteurised, which takes away much of their benefit, and frequently have added sugars to make them more palatable. Suggest specific brands that are known to have the best health-giving benefits.

Supporting adrenal and thyroid function Lyme disease patients often have major hormonal irregularities impacting on adrenal and thyroid hormones. This is largely due to the impact of infections on the hypothalamic–pituitary axis, which then filter down the pathway to the endpoint hormones. Imbalances in these hormones can worsen typical Lyme symptoms such as fatigue, insomnia, brain fog, anxiety and depression. Diet can be used to support hormone balance. Adrenals Adrenal stress is profound in Lyme disease. With a chronic stressor on the body such as systemic infection, the adrenals will overcompensate by producing an excess of cortisol for a period of time, but ultimately, cortisol levels will fall and adrenal exhaustion will ensue. Poor nutrition is a stressor on the adrenals too, so people who are not conscious of their diet may be adding to the stress on their adrenals. Eating for adrenal health involves a few different principles. The first is to eat small amounts of food frequently. This helps to keep cortisol levels regulated, as cortisol will not be called in to help regulate fluctuating levels of blood sugar and insulin. It also tends to help people maintain sustained levels of energy, rather than have to endure the spikes and crashes involved with eating less frequently. The second principle is to eat a high-quality protein with every meal. Eating protein promotes glucagon, the opposing hormone to insulin. Since insulin can promote inflammation, weight gain through energy storage, high cholesterol and heart disease, it is important to produce glucagon to balance it. Highcarbohydrate, low-protein meals will produce mostly insulin in the body; high-protein and high-fat meals will produce a balance of insulin and glucagon. This is important for the regulation of blood sugar and management of inflammation in Lyme patients. Thyroid Thyroid function is frequently impacted on in Lyme patients and may need to be regulated through the use of herbs, nutrients or supplemental hormone therapy. Hypothyroidism is the prevalent condition seen.

Hashimoto's thyroiditis, involving a period of hyperthyroidism followed by a longer-term hypothyroidism, is also common. This is an autoimmune thyroid condition which has been associated with gluten intolerance (also autoimmune).[63] One study showed that 10 of 14 patients with Hashimoto's thyroiditis had genotypes compatible with coeliac disease (three patients had DQ heterodimer A1*0501, B1*0201, four had DRB1*04 and one had A1*0101, B1*0501). Six of these 14 patients showed an increased density of γδ+ T-cell-receptor-bearing intraepithelial lymphocytes and signs of mucosal T cell activation, both typical of coeliac disease.[64] Therefore, in thyroid dysfunction, gluten should be avoided, especially where autoimmune markers such as anti-thyroid peroxidase (TPO) and anti-thyroglobulin levels are elevated on blood work. One of the contributing factors to low thyroid function is low iodine levels, which is fairly common in Lyme patients. Eating iodine-rich foods, including asparagus, kelp, seafood, sesame seeds, Swiss chard, sea salt, spinach, turnip greens and seaweed, can help. Another factor can be a deficiency in tyrosine, an amino acid necessary for the production of T3 and T4. A high-protein diet will ensure that amino acids are available to the body for hormone production. There are some foods that block thyroid hormone production and thyroid function (termed goitrogens), and these should be avoided in people with low thyroid function. These include cabbage, broccoli, swede, cauliflower, kale, Brussels sprouts and peanuts. Cooking these foods can help limit the goitrogens associated with them; however, some need total avoidance.

Sample daily diet

BREAKFAST Chocolate chai smoothie: almond milk, cacao, chia, ginger, cardamom, cloves, cinnamon, banana and gluten-free oats.

LUNCH

DINNER

SNACK

Fatigue is a common complaint in Lyme disease; thus, foods rich in B vitamins such as oats, and foods rich in magnesium such as bananas, cacao and almonds are required for energy production as well as to help manage psychological symptoms such as depression. Notably, magnesium deficiency has been found in individuals with Lyme disease, and supporting healthy levels may function to stimulate impaired immunity.[65] Oats are high in fibre, which assists in maintaining stable blood sugar levels. In vivo studies reveal hyperglycaemia is associated with reduced ability of neutrophils to uptake and kill B. burgdorferi as well as impaired clearance of bacterial DNA in multiple tissues, including the brain, heart, liver, lung and knee joint.[66] Baked sweet potato Supporting the immune system is crucial in Lyme disease to assist in countering the filled with basil, rocket immune evasion mechanisms exhibited by Lyme disease spirochaetes and minimise and garlic pesto. effects of co-infections such as Candida. Marinated tofu. Foods with immune-boosting properties, including ample fruit, vegetables, herbs and Sauerkraut and side spices, are advocated. salad. To support antimicrobial properties to eradicate infection and resolve symptoms,[67] a diet that emphasises foods with anti-bacterial properties such as garlic, ginger, onion and basil would also be useful. Probiotic foods may be useful to enhance immunity and gut microbiome balance. Slow-cooked organic Centring the diet on potent anti-inflammatory agents and immune regulators is chicken, ginger, imperative. Systemic autoimmune joint diseases (i.e. RA, PsA, SpA) may follow Lyme turmeric, spring disease,[68] with 45–60% of individuals with Lyme disease manifesting some form of onions, shiitake arthritis[69]; thus, consumption of anti-inflammatory herbs and spices such as ginger mushroom and basmati and turmeric to downregulate inflammation and modulate the immune system is rice congee with tamari. suggested. Due to Lyme disease sharing many similar properties to autoimmune diseases, a gluten-free, dairy-free, anti-inflammatory diet should be followed. Blueberries and Foods chosen as snacks are reflective of their affinity for the neurological and walnuts cardiovascular system since both these systems are aEacked by B. Salsa and burgdorferi.Antioxidant constituents that are known to be able to cross the blood– guacamole with brain barrier, such as anthocyanins in blueberries and omega-3 faEy acids in walnuts, gluten-free crackers are recommended for their neuroprotective abilities where they counteract neuroinflammation that drives depression. Salsa is a source of lycopene. Although no studies exist examining its role as food as medicine in Lyme disease, lycopene displays cardioprotective properties. Thus, hypothetically, it may be useful counteract inflammation associated with Lyme carditis.

Nutritional therapy (supplements) Antimicrobial Colloidal silver Colloidal silver has a long history of use as an antimicrobial, including the World Health Organization's use of it to purify water in developing countries. True colloidal silver is nanoparticles of silver suspended in a liquid suspension. It works by binding to the cell wall, moving through the cell membrane and disabling essential metabolic functions of the cell. While human studies directly involving Lyme disease are limited, it appears that colloidal silver also impacts on the biofilm development of certain other bacteria, including Staphylococcus aureus, which also may have important implications for biofilm eradication in Lyme.[70] There are in vitro studies that demonstrate that colloidal silver does have potent antimicrobial activity against Borrelia, and many case reports back that up. Dr M. Paul Farber, author of The Micro-Silver Bullet: A Scientifically Documented Answer to the Three Largest Epidemics in the World: Lyme Disease, Aids Virus, Yeast Infection, and the Common Cold, cites[71]:

Two studies have been conducted with colloidal silver and its effectiveness against Borrelia burgdorferi. The first study conducted at Fox Chase Cancer Center, Philadelphia, Pennyslvania, showed growth inhibition in low concentrations (2–10 ppm) and much faster action in higher concentrations (15–75 ppm). The Department of Health and Human Services, Rocky Mountain Laboratories, tested cultured spirochetes of the Borrelia burgdorferi … using 150 ppm and 15 ppm colloidal silver … none of the treated cultures contained live spirochetes after 24 hours.

Safety of colloidal silver is an obvious consideration, as some colloidal silver products are simply specks of silver in suspension, which the body could have trouble clearing. High-quality silver used for medicinal purposes should be nanoparticles of silver, between 1 nanometer and 100 nanometers in size. Dose: up to 10 mL b.i.d. at 5–10 ppm.

Inflammation reduction Reducing inflammation is another high priority in the naturopathic treatment of Lyme disease. Inflammation is a byproduct of chronic inflammation and contributes significantly to many Lyme symptoms, ranging from joint pain to cognitive dysfunction. Proteolyic enzymes Proteolytic enzymes such as bromelain are significant regulators of the inflammatory response. They increase the activity of macrophages and increase the potency of natural killer cells. Most importantly, they have the ability to break down antigen–antibody complexes and even prevent their formation in the first place. These antigen–antibody complexes are an inherent part of the chronic infectious process, but if prolonged can contribute to a chronic inflammatory state. They also break down plasma proteins and inflammatory debris. One study demonstrated that bromelain has the ability to inhibit the expression of INF-γ and TNF-α, two distinctly inflammatory markers.[72] The other benefit of proteolytic enzymes is reducing fibrin, a fibrous mesh that forms in areas of tissue damage. Excessive fibrin can impede the flow of blood and can contribute to hypercoagulation, which is a common finding in Lyme patients. Hypercoagulation can lead to a reduction in oxygenation to the tissues and can impede the tissues’ ability to shuEle wastes and toxins out of the cells. Further, excess fibrin can contribute to the formation of biofilm which, as discussed, provides a polysaccharide matrix structure within which the bacteria themselves can hide and evade antimicrobial therapy. Therefore, proteolytic enzymes not only play a role in inflammation itself, but in the breaking down of biofilm. Dose: 100–300 mg b.i.d.–t.d.s. Lumbrokinase Lumbrokinase is an enzyme sourced from Lumbricus rubellus, a species of earthworm. It has been shown to contain six proteolytic enzymes that act to reduce blood clots, decrease fibrinogen levels, regulate hypercoagulation and dissolve biofilm.[73,74] Lumbrokinase is utilised in Lyme treatment to break down biofilm, which is the polysaccharide matrix created by the bacteria in the body and which houses and protects the bacteria. Breaking down biofilm to expose the bacteria to the antimicrobial effects of herbs and antibiotics is a vital part of the treatment process. NaEokinase is another biofilm agent, sourced from soybeans instead of earthworms. Consequently, it would be a beEer choice for vegans. However, lumbrokinase has demonstrated greater efficacy in clinical studies for Borrelia. NaEokinase has been shown to destroy biofilms of S. aureus and Bacillus subtilis.[75,76] Serrapeptase, which is from the digestive systems of silkworms, is yet another option. Dose: lumbrokinase 20 mg b.i.d. between meals.

Dose: serrapeptase 100 000–200 000 units q.d.

Immune system support Immune support is crucial in Lyme treatment because Lyme disease is immune suppressive. White blood cell counts are frequently low or on the low end of normal in this population, providing even more of a challenge for overcoming infection. Antibiotic therapy can also cause leukopenia, which is another reason why it is important for the patient to have monthly blood testing done that includes a full blood count with differential. Transfer factors Transfer factors are molecules that support and modulate immune function. They contain antigen-related information, helping the host immune system recognise, and beEer respond to, external threats. They help to train and sensitise the immune system. They also transfer recognition signals between immune cells, alerting naïve immune cells about a potential threat.[77] Transfer factors also boost natural killer cell activity, a vital part of immune defence. They work on the Th1 cellular immunity and help to balance Th1/Th2 balance. They can be general or antigen specific, and are available for Borrelia, mycoplasma, viruses and so on. They are generally derived from cow colostrum or chicken egg yolk. Dose: 500–1000 mg q.d. Beta-glucans Beta-glucans are polysaccharides that are naturally occurring in the cell walls of yeasts, bacteria, fungi and cereals. While beta-glucans can have diverse effects including helping with cardiovascular function, reducing blood levels of saturated fats and balancing blood sugar regulation, in Lyme treatment, they are chosen for their immune-balancing properties. Most of the ones used are sourced from medicinal mushrooms such as shiitake, maitake and reishi, or the yeast Saccromyces cerevisiae (although the final product is not yeast containing). Beta-glucans are immunomodulating, meaning they can strengthen immune function and also dampen detrimental immune hyperactivation. Beta-glucans can activate macrophages, neutrophils and T cells, seEing off a cascade of heightened cellular immune response.[78] Their ability to strengthen and activate macrophages is one of their key benefits in Lyme treatment, as it is postulated that Borrelia can actually invade macrophages and weaken their activity.[79] They also can assist in the phagocytosis of the Borrelia bacteria, through their influence on the complement receptor 3. Phagocytosis of Borrelia is dependent on complement receptor 3, which in turn requires an immune element called CD-14. In cases of deficient CD-14, beta-glucans were found to compensate and allow for greater phagocytosis.[80] Dose: 50–200 mg q.d. Colostrum Colostrum is a high-protein substance found in the milk of mammals. While naturally produced to protect offspring early in their lives as their immune system develops, bovine colostrum has been used in human supplements to confer similar immune-boosting properties. It is rich in antibodies, lactoferrin and other immune agents that provide bacteriostatic, bacteriocidal, antiviral, anti-inflammatory and immunomodulatory protection against infection.[81] It also modulates inflammation by binding and, hence, interfering with the bioactivity of TNF-α.[82] Studies also show that, along with IgG antibody protection, colostrum also contains IgA (albeit in lesser amounts), an anti-inflammatory antibody that plays a large role in immune protection in the mucosal membranes.[83] Given that Borrelia and related infections can invade gastrointestinal tissues, and given the

prevalence of intestinal bacterial and fungal imbalances, this provides significant benefit to Lyme patients. Dose: 500–1000 mg q.d.

Detoxification support Detoxification will make a tremendous difference to the outcomes of Lyme treatment. More sensitive patients may experience Herxheimer reactions at even low doses of antimicrobial therapy, but even those who are not highly sensitive can experience Herxes and will need additional detox support to help clear the toxins that were released from the killing off of the bacteria. Additionally, patients on antibiotic therapy will benefit from extra liver and kidney support as their systems are additionally taxed from the medications. It is helpful to look at a patient's methylation status as that can play such a pivotal role in immune health and detoxification capability. See Chapter 7 for detailed information. Glutathione Glutathione is a substance made up of three amino acids – glutamine, cysteine and glycine – and is produced in the liver. Glutathione is considered the ‘master antioxidant’ in the body; it plays a vital role in countering reactive oxidant species, especially in the brain, which consumes the greatest amount of oxygen and, therefore, creates the most oxidative stress. It is known to be neuroprotective, as it prevents neuronal death associated with amyloid plaque deposits. Glutathione production depletes with age, indicating a potential for supplementation especially in older populations.[84] Glutathione is also a major detoxification agent. It neutralises and clears heavy metals and other toxins from the body. While the body does produce its own supply of glutathione, excess toxic stress will deplete it, thus creating a higher need. If the body's production does not keep up with need, toxins will accumulate in the body. Glutathione supply can be boosted by moderate exercise, but many Lyme patients are not able to do even that. Supplementation with N-acetylcysteine or S-adenosyl methionine (SAMe) may provide precursors, and undenatured whey protein can also stimulate endogenous production. Glutathione is often given intravenously, which optimises absorption but can also produce significant detoxification responses in Lyme patients, especially when given at higher doses. Liposomal glutathione is the optimal form for oral supplementation as reduced glutathione is rapidly degraded in the gastrointestinal tract. Dose: 400–1000 mg q.d. PO (liposomal preferred); 500–2000 mg IV.

Energy/adrenal support Lyme disease can cause significant disturbances in hormone regulation, in particular, the hypothalamic– pituitary–adrenal axis. The chronic stressors of Lyme disease tax the adrenal glands, often resulting in imbalances in cortisol and DHEA levels. The first stage of the chronic stress response is elevated cortisol as the body tries to compensate for the additional need. This is more likely in the earlier stages of disease. In later stages of the chronic stress response, cortisol is likely to be depleted, and DHEA is often low too. This is a major contributor to the chronic fatigue in Lyme disease, and so adrenal support is a priority. Phosphatidylserine is a naturally occurring phospholipid that is produced in the body, and occurs in highest concentrations in the brain, lungs, liver, heart and skeletal muscle. It has been shown to lower excess cortisol levels by blunting the cortisol response – specifically, by altering the interactions with receptors to reduce the release of corticotropin releasing factor, which in turn would increase adrenocorticotropic hormone (ACTH), which would then reduce cortisol. Studies have shown this effect to occur using exercise as a short-term stressor on the body, but have also validated a similar response with mental and emotional stressors.[85] Low cortisol levels can also be balanced with adaptogenic herbs. DHEA supplementation may be indicated with patients with low levels of DHEA and also can act as a precursor to cortisol. Liquorice root is a herb known to have cortisol-boosting properties, but care must be taken because of its oestrogen-

promoting effects and also possible hypertensive side effects. Some patients with critically low cortisol benefit from hydrocortisone supplementation for a period of time; however, natural/ herbal remedies may be safer and more effective long term. Another aspect of energy support for Lyme disease patients is mitochondrial support. The mitochondria are the powerhouses of the cell where adenosine triphosphate (ATP) is produced. Nutrients such as NADH, co-enzyme Q10 (CoQ10) and acetyl-L-carnitine can enhance metabolic processes and energy production. Agents that help to repair the membranes of the mitochondrial wall have also been used to assist energy production in Lyme patients. Mitochondrial cell walls can become damaged over the course of chronic illness through prolonged inflammatory response and increase in free radical production and oxidative stress. Thus, repairing cell membranes and increasing membrane fluidity by providing phospholipid support can lead to increased nutrients entering the cells and greater mitochondrial output. NT factor is one variant of glycophospholipids that can be used for lipid replacement therapy. Another is phosphotidylcholine (PC). PC can be given orally or intravenously. Dose: phosphatidylserine 100–200 mg q.d. Dose: DHEA 5–25 mg q.d. Dose: NADH 5–10 mg q.d. Dose: CoQ10 100–400 mg q.d. Dose: acetyl-L-carnitine 500–2000 mg q.d. Dose: phosphatidylcholine 500–2000 mg q.d.

Digestive support Supporting the digestive systems of Lyme patients is important. First, because many of them suffer from digestive issues as part of their illness, but also because for those on antibiotic therapy, gastritis and overgrowth of Candida are two of the most common side effects they must overcome. Probiotics Top priority in all patients is a high-quality, high-potency probiotic to replenish any good flora that might be killed by antibiotics or other antimicrobials. Probiotics must be separated by any antimicrobials (pharmaceutical or herbal) by at least 2 hours to prevent it being adversely impacted itself. Probiotics will be the most important step in supporting digestive function and the top priority for those on antibiotics to prevent the overgrowth of Candida albicans. Strains that have been found to be most helpful include Lactobacillus acidophilus, L. casei, L. plantarum, Bifidobacterium lactis, B. longum, and B. bifidum. They are beneficial to the host by balancing the gastrointestinal microflora.[86] Key benefits of probiotics in Lyme treatment include that they:

• resist enteric pathogens • aid in lactose digestion • modulate the immune system • enhance nutrient value • reduce inflammation of the intestinal tract. Supplementation with kefir and kombucha can also help maintain healthy microbial balance in the gut. The main polysaccharide in kefir grains is kefiran. Kefiran is known to possess anti-inflammatory, antifungal and anti-bacterial properties.[87,88] Kombucha is a drink that is fermented from black tea by a symbiotic colony of bacteria and yeast, which results in a liquid that contains several species of beneficial flora, including lactic acid, acetic acid, bacteria and Saccharomyces boulardii (a yeast that has health-promoting properties and functions like a probiotic in the

body). Reducing irritation and inflammation of the gastrointestinal system can help patients to tolerate their antimicrobial treatments. Dietary modifications are obviously important here too to reduce any source of further inflammation. Dose: 50–200 billion CFUs q.d. at least 2 hours away from antimicrobials.

Sleep support Melatonin The pineal gland produces the hormone melatonin to regulate the body's internal time-keeping system, pubertal development and seasonal adaptation. When there are changes in melatonin production and melatonin receptor expression, circadian rhythm sleep disorders may arise.[89,90] Many Lyme patients have sleep disturbances, including sleep paEern reversal, where they cannot sleep at night but then sleep most of the day. Melatonin can help them to fall asleep at an appropriate hour. Sustained-release melatonin is more appropriate for people who wake during the night as melatonin has a short half-life and wears off quickly. Dose: 1–3 mg h.s.

Nutritional therapy (micronutrients) Lyme disease can cause nutrient depletion, and evaluations of vitamin and mineral status are important to identify specific ones in patients.

Vitamin C Because of its significance in immune function, vitamin C should be considered an important supplement. Liposomal vitamin C offers superior absorption without the risk of digestive distress caused by some forms of vitamin C. Some patients do very well with intravenous vitamin C as larger amounts can be given than oral forms – between 5 and 100 g, given by slow drip. Dose: 500–2000 mg PO; 5–100 g IV.

B vitamins B vitamins are important for energy production and to help the body manage the stress response associated with chronic disease. They can help neurological symptoms significantly too. Beyond the scope of this chapter, but worth stressing, is the importance of evaluating Lyme patients for methylation defects and treating them accordingly with methylated (or non-methylated) B vitamins. Methylfolate and methyl-B12 are

perhaps the most significant, but should be given with other B vitamins to prevent imbalance. Also of significance is the evaluation of pyroluria, a metabolic illness where abnormal porphyrins carry out zinc and B6 from the body. Supplementation with activated B6 (pyridoxal-5-phosphate) in combination with zinc and magnesium can help to restore healthy levels. Dose: methyl-folate 500–1000 micrograms; methyl-B12 1000–5000 micrograms daily, sublingual or IM preferred; pyridoxal-5-phosphate 50–100 mg.

Vitamin D Traditionally thought of as being most important for bone health, vitamin D is an important vitamin for immune modulation; it also functions as a hormone in the body. Deficiency of vitamin D is associated with increased autoimmunity as well as increased susceptibility to infection.[91] Vitamin D receptors and vitamin D metabolising enzymes are found in many immune cell types including antigen-presenting cells, T cells, B cells and monocytes. Research shows that vitamin D leads to a shift from a pro-inflammatory to a more antiinflammatory immune status. It inhibits the secretion of pro-inflammatory Th1 (IL-2, interferon-γ, TNF-α),

Th9 (IL-9) and Th22 (IL-22) cytokines while promoting the production of more anti-inflammatory Th2 cytokines (such as IL-3, IL-4, IL-5, IL-10).[92] Vitamin D is often depleted in chronic Lyme patients, so testing and possible supplementation should be considered. Dose: 1000–5000 IU q.d.

Zinc Zinc is a vital mineral, because of both its connection with pyroluria (which appears to be common in Lyme patients) and its general immune-enhancing properties. Zinc is crucial for the normal development and function of immune cells including neutrophils, macrophages and natural killer cells. Antibody production is also compromised in zinc deficiency.[93] Dose: 25–50 mg q.d.

Magnesium Perhaps the most depleted mineral in Lyme patients is magnesium. Borrelia and Bartonella both require magnesium to duplicate thus depleting the body's stores rapidly. While some practitioners argue that magnesium should not be supplemented so as not to ‘feed’ the pathogens, in reality, many patients benefit significantly from magnesium supplementation. This is particularly for its effects on muscle relaxation and relief from spasms, bowel function (offseEing constipation) and assistance with balancing mood and promoting beEer sleep. Dose: 300–1000 mg q.d. in divided doses. Can be taken h.s. to promote sleep.

Molybdenum Molybdenum is a trace mineral that can assist with detoxification in Lyme treatment. Molybdenum boosts the production of certain enzymes in the body known as molybdoenzymes. Sulfite oxidase helps to break down sulfites into sulfates, which can then be eliminated from the body. A subset of Lyme patients is sensitive to sulfites, so this can be a helpful mineral in those circumstances. Perhaps most importantly, molybdenum stimulates the production of aldehyde oxidase and aldehyde dehydrogenase – enzymes that are necessary to break down aldehydes such as formaldehyde and acetylaldehyde. Alcohol metabolism is one source of acetylaldehydes, but another important potential source for Lyme patients is Candida albicans. C. albicans produces aldehydes in the gastrointestinal tract by sugar fermentation. These aldehydes can have neurotoxic effects. Aldehydes can bind with the neurotransmiEers serotonin and dopamine, creating secondary metabolites that can cause neuronal cell death.[94,95] Aldehydes also damage cell membranes of red blood cells, compromising their function and impacting on haemoglobin levels and oxygenation to the brain.[96] Finally, aldehydes disable the formation of tubulin in the brain, which then undermines the structural support of dendrites, leading to dendritic atrophy and death.[97] Individuals with an overgrowth of Candida may benefit from supplementation of molybdenum to help metabolise those detrimental compounds.[98,99] Dose: 30–200 micrograms q.d.

Herbal medicine Antimicrobial therapy Herbal regimens for Lyme disease and co-infections can be very effective in eradicating the pathogens underlying the illness without the toxicity and side effects of antibiotics. The following herbs are just a sampling of what can be used in each category, but represent options that

are commonly used and have shown efficacy in the treatment of Lyme disease.

Herbal therapy for borrelia Uncaria tomentosa (cat's claw) Uncaria tomentosa (cat's claw) is a medicinal herb from the Amazon rainforest that has anti-inflammatory, anti-bacterial, anti-viral, immune-modulating and antioxidant properties. It is one of the more popular herbs for treating chronic Lyme disease. Cat's claw contains quinovic acid glycosides, which are natural precursors to quinolones, a class of pharmaceutical antibiotics (that includes Cipro and Levaquin). These compounds give it strong antimicrobial properties; however, the same side effect of tendon pain and damage that can come with the quinolone antibiotics can occur with cat's claw, so care must be taken. Cat's claw also has anti-inflammatory properties. An Austrian study published in the April 2002 Journal of Rheumatology showed that rheumatoid arthritis patients treated with 60 mg a day of a standardised extract of cat's claw for 1 year experienced a reduction in the number of painful and swollen joints.[100] The mechanisms for its anti-inflammatory properties are the inhibition of TNF-α production, as well as its ability to scavenge free radicals.[101] Dose: tincture 10–30 drops b.i.d. Dipsacus sylvestris (teasel root) Teasel root is considered a valuable antimicrobial herb in the treatment of Lyme disease. Some sources believe that it helps to bring spirochaetes into the bloodstream from the tissues, making them more vulnerable to antimicrobials.[102] One study looked at the expression of genes associated with the immune system in fibroblasts infected with Lyme disease after treatment with teasel root. The results suggested that the herb did indeed have antibacterial and anti-inflammatory effects in human cells infected with Lyme.[103] Dose: tincture 5–10 drops b.i.d. Olea europaea (olive leaf) Olive leaf extract has a wide variety of uses in Lyme treatment, but it is one of the stronger and more effective antimicrobials. Olive leaf contains high amounts of phenolics, in particular oleuropein. Its benefits include being anti-bacterial, anti-viral, anti-fungal and anti-protozoal. Olive leaf extract also has protective effects on the cardiovascular system, and has anti-inflammatory and antioxidant properties.[104] Of high priority for Lyme patients, olive leaf is neuroprotective and can help mitigate the cognitive impairment commonly experienced in Lyme. One of the ways it does that is by improving the permeability of the blood–brain barrier and reducing brain oedema.[105] Dose: capsules 500 mg t.d.s. Origanum vulgare (oil of oregano) Oil of oregano contains high concentrations of two substances called carvacrol and thymol, which are largely responsible for its strong anti-bacterial qualities.[106] The impact of oil of oregano appears to be dose and concentration dependent, and is equal between Gram-positive and Gram-negative bacteria. It is also a powerful anti-fungal. A study of several essential oils, including oregano, and three major antifungal medications (fluconazole, itroconazole and triclomazole) showed that yeast had higher sensitivity levels overall to the essential oils than the medications. The essential oils affected mainly the cell wall and membranes of the yeast.[107] Oil of oregano also has been shown to act in a synergistic fashion with certain other antimicrobials, notably the antibiotic doxycycline and biological silver nanoparticles, both of which are used in Lyme

treatment.[108,109] Georgetown University researchers found that oil of oregano appeared to be as effective as traditional antibiotics in reducing infection. Oil of oregano at relatively low doses was found to be efficacious against Staphylococcus bacteria and was comparable in its germ-killing properties to antibiotic drugs such as streptomycin, penicillin and vancomycin.[110] Oil of oregano is also a potent antimicrobial against Borrelia, Bartonella and Candida, and therefore is an important natural agent in Lyme treatment. Dose: capsules 50 mg b.i.d.–t.d.s. Citrus paradisi (grapefruit seed) Grapefruit seed extract is a good option for patients with Lyme disease, as it is a natural agent that has been shown to be effective against cystic forms of Borrelia. Grapefruit seed extract works by disrupting the bacterial membrane and liberating cytoplasmic contents.[111] One study showed that at low concentrations, grapefruit seed extract caused herniation and disruption of the cell membranes, with a leaking out of the contents of the cell, even just 15 minutes after contact. Then, at higher concentrations, grapefruit seed extract eradicated the bacteria and cysts completely.[112] The fact that grapefruit seed extract reduced the conversion of spirochaetes to cyst forms makes it a highly valuable part of Lyme treatment. Dose: capsules 250 mg b.i.d.

Herbal therapy for co-infections Artemisia annua (wormwood) Artemisia annua has been used in the treatment of malaria, mostly because of the anti-malarial compound it contains, known as artemisinin. Because Babesia is a malaria-like illness, artemisinin also has a place in its treatment. A. annua is the only known source of the sesquiterpene artemisinin (qinghaosu). Its biological activities relate to the presence of secondary metabolites such as sesquiterpenoids, aliphatic hydrocarbons, aromatic hydrocarbons, aromatic ketones, flavonoids, terpenoids and steroids.[113] Pharmaceutial companies have created synthetic versions of artemisinin, in the forms of artesunate and artemether. They are typically used in combination with other anti-parasitic agents to prevent resistance. Naturally occurring artemisinin has good blood–brain barrier penetration, lower toxicity levels and a moderate half-life in the body, so it is a credible choice for babesiosis. Unlike other antiprotozoal agents, artemisinin also appears to be effective against all stages of the life cycle, not just the mature parasites.[114] In a study by Kim et al., researchers evaluated the anti-inflammatory, antioxidant and antimicrobial effects of A. annua using the DPPH radical scavenging assay. The results demonstrated that artemisinin has anti-inflammatory, antioxidant and antimicrobial activities.[115] Dose: 200–400 mg q.d.; can pulse at higher doses up to 500 mg t.d.s. 4 days on/3 days off. Higher doses can be hard to tolerate. Cryptolepis sanguinolenta (cryptolepis root) The aqueous root extract of Cryptolepis sanguinolenta has been used as an anti-malarial agent for decades, and for this reason, it has benefit for patients with the Babesia co-infection. The major indoloquinoline alkaloid isolated from C. sanguinolenta is cryptolepine. Cryptolepine has been reported to have various biological activities such as anti-fungal and anti-bacterial activity against both Gram-positive and Gramnegative organisms.[116,117] Of further benefit to Lyme patients, cryptolepis has anti-inflammatory and analgesic effects on patients suffering from osteoarthritis.[118] Dose: tincture 60–120 drops b.i.d.

Houttuynia cordata (chameleon) Hou?uynia cordata is commonly used as a herbal tea in Japan to promote health. In one study, researchers demonstrated the anti-bacterial, bacteriostatic and antibiofilm effect of H. cordata poultice ethanol extract (eHCP) against S. aureus and MRSA. The findings support that eHCP has the ability to inhibit IL-8 and CCL20 productions from S. aureus without any cytotoxic effect.[119] The mechanisms of its action are not fully known, but preliminary studies demonstrate that houEuynia extracts can increase levels of hydrogen peroxide, which in turn, leads to bacterial cell death.[119] H. cordata is a herb that has been used in Lyme treatment, most specifically against the co-infection Bartonella. Clinical reports validate its use against Bartonella, although specific research is lacking for this use. HouEuynia has also been shown to help inhibit biofilm formation of C. albicans in the oral cavity, which further gives it relevance for Lyme patients.[120] Dose: capsules 250 mg t.d.s.

Immune support Astragalus membranaceus (astragalus) Astragalus has a long history of use as a tonic and immune strengthener, boosting the number and activity of immune cells. Astragalus works by stimulating several factors of the immune system, including enhancing phagocytic activity of monocytes and macrophages, increasing interferon production and natural killer cell activity, enhancing T cell activity and potentiating other anti-viral mechanisms. Astragalus has also been demonstrated to have anti-inflammatory activity. It is often used with other adaptogenic/tonic herbs such as liquorice and ginseng. There is some controversy as to whether astragalus should be avoided in late-stage Lyme because of its tendency to boost Th1 immune response; chronic, late-stage Lyme tends to be Th1 dominant. Herbalist Stephen Buhner cautions against its use and suggests that astragalus is a beEer herb for acute Lyme and early in infection. (See his website www.buhnerhealinglyme.com.)[121] Dose: 1000 mg q.d.

Inflammation reduction Curcuma longa (turmeric) Curcumin, a component of turmeric, is one of the most useful anti-inflammatory agents, and is widely used in Lyme treatment. It also has very strong antioxidant capabilities, and is immune supportive and immune balancing in autoimmune processes. Curcumin's anti-inflammatory actions come from its ability to reduce pro-inflammatory cytokines such as IL-1, IL-6, COX-2, MMP-9, NF-κB, CRP, TNF and others. Studies have shown multiple pathways and mechanisms by which curcumin reduces inflammation. Curcumin also has antioxidant properties. It increases levels of vitamins C and E in the body, and prevents lipid peroxidation and oxidative damage.[122] Curcumin can improve mitochondrial enzymes and boost glutathione levels, adding to its antioxidant, detoxification and ATP-producing benefits. Curcumin has been shown to be neuroprotective by reducing oxidative damage caused by D-galactose, a reducing sugar that can lead to mitochondrial dysfunction and death of neurons. It is also neuroregenerative – meaning it can promote the development of new, healthy neurons by increasing neuron stem cell growth in the brain by up to 80%.[123] Studies showed that it increased both the numbers of stem cells produced as well as the number of fully differentiated mature cells. It also helps reduce neuropathic pain by inhibiting TNF-α and nitric oxide release.[124] There are many human studies showing the efficacy of curcumin in reducing inflammation, while having

an excellent safety profile. Dose: capsules 500 mg t.d.s. Boswellia serrata (boswellia, frankincense) Boswellia is a herb that has long been used as an anti-inflammatory, with wide usage in arthritis and arthritic conditions. The main active constituents of boswellia are the boswellic acids, most importantly acetyl-11-keto-beta-boswellic acid (AKBA). AKBA has demonstrated many significant immunomodulatory and inflammation-modulating effects in preclinical research.[125] Boswellia works in a couple of different ways. It inhibits 5-lipoxygenase, an agent that promotes inflammatory leukotrienes. It can also reduce inflammation through the inhibition of the proinflammatory enzyme human leukocyte esterase. To date, boswellia is the only compound that has been found that works on both 5-lipoxygenase and human leukocyte esterase.[126] Because it works on the 5-lipoxygenase and not the COX-2 inhibition as non-steroidal anti-inflammatory drugs (NSAIDs) do, it can provide relief from pain and inflammation without the gastrointestinal side effects of the medications. NSAIDs, by default, block COX-1 enzymes too, which are necessary for a healthy gastrointestinal mucosal lining. In an animal study comparing the efficacy of 5-LOXIN™, a standardised extract from boswellia, to that of the anti-inflammatory drug ibuprofen, 5-LOXIN™ produced a 27% reduction in inflammation, compared to 35% for ibuprofen.[127] Another study comparing 5-LOXIN™ to the anti-inflammatory steroid drug prednisone found that 5LOXIN™ produced a 55% reduction in inflammation, similar to the effects of prednisone.[128] Thus, boswellia has a comparable benefit to anti-inflammatory medications, but with a much beEer side effect and safety profile. It is considered safe and well tolerated. Another way to utilise boswellia is the essential oil frankincense. The essential oil is a highly concentrated source of boswellic acids and can have profound anti-inflammatory benefits. The essential oil can be used topically on areas of pain and inflammation, often diluted in a carrier oil such as fractionated coconut oil. Dose: capsules 500 mg t.d.s. Polygonum cuspidatum (Japanese knotweed) The dried root of Japanese knotweed is a traditional Chinese medicinal herb, which has been widely distributed in the world. It can now be found in Asia and North America. Pharmacological and clinical studies have indicated that this herb has anti-viral, antimicrobial, anti-inflammatory, neuroprotective, antitumour, chemoprotective and cardioprotective functions. Main active compounds include anthraquinones, resveratrol and stilbenes.[129] Antimicrobial effects have seen in prevention of oral disease in relation to biofilms, as demonstrated by a study showing the inhibitory effects against ATP-ase and production of Streptococcus mutans in biofilms.[130] Anti-inflammatory properties have also been aEributed to Japanese knotweed as a potent agent for rheumatoid arthritis treatment. Research has shown ethyl acetate extract suppressed serotonin-induced swelling, as well as inhibiting positive responses of C-reactive protein and rheumatoid factor, when compared to untreated controls.[131] One of the most important aspects of Lyme treatment is to interrupt the pro-inflammatory cytokine cascade. Japanese knotweed is known to be a very strong inhibitor of cytokine cascades initiated by bacteria. In Lyme disease, there is a spirochaete-stimulated release of a number of matrix metalloproteinases (MMPs). Currently, this is the only herb that is known to specifically block MMP-1 and MMP-3 induction. Emodin, an anthraquinone, has been shown to inhibit the expression of inflammatory-associated genes including iNOS, TNF-α, interleukin-1, IκB kinase (IKK)-alpha, and IKK-gamma and to inhibit the nuclear translocation of NF-κB on LPS-induced inflammatory responses in RAW 264.7 macrophages.[132] There are many additional mechanisms responsible for the therapeutic properties of this herb. Its role as a

capillary stimulant is important in increasing blood flow to areas where Lyme spirochaetes reside, such as eyes, skin, heart and joints. According to Stephen Buhner,[121] this herb is an anti-spirochaetal, indicated for prevention and acute onset Lyme, as well as Bartonella co-infections. In addition, it has immune modulatory and protective properties against Lyme neurotoxins, Lyme arthritis, Lyme carditis, dermatoborreliosis, memory and cognitive decline, as well as reduction in Herxheimer reactions and headaches. Dose: capsules 500 mg up to 10 capsules q.d. in divided doses. Andrographis paniculata (andrographis) Andrographis is an important constituent of at least 26 Ayurvedic formulas in Indian pharmacopoeia. In traditional Chinese medicine, it is seen as a herb used to rid the body of heat and fever and to dispel toxins from the body.[133] Diterpenes, flavonoids, xanthones, noriridoides and other miscellaneous compounds have been isolated from this plant. Extract and pure compounds of the plant have been reported for their anti-microbial, cytotoxic, anti-protozoan, anti-inflammatory, antioxidant, immunostimulant, anti-diabetic, anti-infective, anti-angiogenic, hepato-renal protective, sex hormone/sexual function modulation and liver enzymes modulation.[134,135] The phytochemistry of this plant is quite complex, spanning many different body systems and mechanisms of action. Research has shown an alleviation in lipopolysaccharide-induced release of proinflammatory mediators, such as NO, IL-1β and IL-6, inflammatory mediators, such as PGE2 and TXB2, and allergic mediators. Additional anti-inflammatory effects can be aEributed to its interference with COXenzyme activity and downexpression of genes involved in the inflammatory cascade.[136] One of the reasons it may be helpful in treatment of Lyme is due to its ability to activate adenylate cyclase, increasing cAMP, which is important for preventing damage to cell membranes. In this way, symptoms of nerve cell irritation, such as headaches, tingling, burning, numbness, stabbing sensations, tremors and unexplained lactation, can be reduced.[137] Dose: capsules 400 mg b.i.d.

Detoxification support Smilax glabra (sarsaparilla) Smilax glabra is a herb that has detoxifying and anti-inflammatory properties. The polysaccharides contained in the rhizomes have been shown to reduce nitric oxide, TNF-α and IL-6, thus modulating inflammatory response.[138] Another study showed a reduction in COX-2 activity and COX expression.[139] The major benefit of S. glabra in terms of detoxification is its ability to cross the blood–brain barrier. Other species of smilax do not have that capability. S. glabra is able to neutralise neurotoxins and can play a significant role in mitigating Herxheimer reactions, particularly where they include the worsening of neurological symptoms. Research also shows that S. glabra can protect the brain against lead-induced oxidative stress. Administration of an extract from S. glabra reduced blood and tissue levels of lead significantly, while also increasing protective antioxidants such as superoxide dismutase and glutathione.[140] Given that many Lyme patients have methylation defects that may impair detoxification pathways and predispose them to accumulation of toxic metals, and given that metals such as lead and mercury have been found in biofilm, substances that support detoxification of these toxins play a significant role in treatment approaches. Dose: tincture 30–60 drops b.i.d. Liver support herbs Other than the specific detoxification agents discussed, there are many possibilities for liver support herbs,

including Taraxacum officinale (dandelion root), Cynara scolymus (artichoke), Glycyrrhiza spp. (liquorice root), Silybum marianum (milk thistle), Mahonia aquifolium (oregon grape root) and Schisandra chinensis (magnolia). Supporting liver function is one of the highest priorities in Lyme treatment for those who are on antibiotic therapy. Elevations in liver enzymes are always a possibility, especially in chronic cases where multiple antibiotics are being used on a long-term basis. Patients on antibiotics should have routine blood testing done on a monthly basis to monitor liver enzyme levels. Dose: tinctures 40–60 drops b.i.d. in combination.

Brain chemistry and mood balance Hypericum perforatum (St John's wort) St John's wort has been used successfully in mild to moderate depression. It works by inhibiting the reuptake of serotonin, dopamine and noradrenaline (norepinephrine) as well as the enzymes monoamine oxidase and catechol-O-methyltransferase, which allows more conversion of dopamine to noradrenaline. It also binds to GABA receptors.[141] St John's wort may also enhance memory properties due to the constituent hyperforin.[142] Dose: capsule 300 mg t.d.s.

Sleep support Valeriana officinalis (valerian) Numerous studies have demonstrated that valerian improves both the ability to fall asleep quickly and the quality and depth of sleep throughout the night. Valerian contains over 150 constituents that are calming to the nervous system, with valerenic acid as its main constituent. One review of data on valerian showed that 80% of patients experienced some improvement in sleep compared to placebo. Of six studies that measured ‘hangover effect’, valerian measured equally with placebo.[143] Other herbs that have been demonstrated to help with sleep include Humulus lupulus (hops), Passiflora incarnata (passionflower), Matricaria recutita and Chamomilla recutita (chamomile), and Scutellaria lateriflora (skullcap). Amino acids already discussed may also assist in sleep promotion, including 5-HTP, GABA and L-theanine. Assisting patients in geEing adequate sleep is a high priority as many experience significant insomnia and resort to prescription sleep medications and strong medications, such as benzodiazepines, both of which have significant side effect profiles and the potential for dependence. Dose: tincture 2–5 mL t.d.s.

Neuroprotectives Hericium erinaceus (lion's mane) Lion's mane is a traditional Chinese medicinal mushroom that was commonly prescribed for stomach ailments and cancer prevention, with additional medicinal properties emerging. Indications for lion's mane include aiding in digestion, stimulating nerve growth factor (NGF) in the central and peripheral nervous system, repairing neurological degradation from senility, improving cognitive function and memory loss, and improving reflexes. Memory and cognitive dysfunction from chronic Lyme disease and Lyme disease co-infections can be severe. Once the infections have invaded the brain and central nervous system, they are capable of causing numerous cognitive deficits, including short- and long-term memory loss, difficulty retaining new information, compromised ability to read and write, and an inability to make new memories.[144] Neurotrophic factors are important in promoting the growth and differentiation of neurons. NGF is

essential for the maintenance of the basal forebrain cholinergic system. Hericenones and erinacines isolated from the medicinal mushroom Hericium erinaceus can induce NGF synthesis in nerve cells.[145] The cognitive benefits of lion's mane stem from the potent neuroprotective properties of the mushroom and its ability to restore myelin along the axons in the brain – a process that is highly beneficial for those with Lyme disease and Lyme disease co-infections, as many of the cognitive deficits from these diseases result from the bacteria's affinity for breaking down myelin sheath in the brain. To date, lion's mane is the only mushroom that displays promising potential for nerve regeneration due to its ability to stimulate synthesis of NGF.[145,146] Dose: 2–3 mL b.i.d.

Amino acids Brain chemistry and mood balance Many patients with Lyme disease experience depression and anxiety, and many take pharmaceutical medications to try to relieve them. Amino acid therapy can provide significant relief, and could be considered as an alternative, providing the raw materials the body can use to produce more neurotransmiEers, thus supporting neurotransmiEer pathways without the side effects of medications. 5-HTP Used as a precursor to serotonin, the amino acid 5-HTP can bring significant relief from depression. In larger doses taken before bed, it can also be used as a sleep aid. 5-HTP crosses the blood–brain barrier and is freely converted to serotonin without biochemical feedback inhibition.[147] Studies have also shown 5-HTP to be beneficial for patients with migraines and symptoms of fibromyalgia, including tender points, pain intensity, sleep quality, morning stiffness, anxiety and fatigue. [148,149]

Dose: 50–100 mg q.d.; up to 200 mg h.s. for sleep promotion. GABA GABA is an inhibitory neurotransmiEer, just as serotonin is an inhibitory neurotransmiEer. Low GABA levels can lead to anxiety, noise sensitivity and aggressive behaviour; therefore, GABA supplementation can also calm the brain and balance mood. Interestingly, GABA can also promote gastric motility – low levels can lead to decreased bowel function – and can help reduce gastro-oesophageal reflux. This may be significant in the subset of Lyme patients who experience GORD and gastroparesis. GABA has shown profound benefit for those patients who struggle with anxiety.[150–152] Dose: 200–500 mg b.i.d. L-theanine L-theanine is another amino acid that has proven efficacy in states of anxiety and also insomnia. L-theanine comes from green tea leaves and blocks the binding of L-glutamic acid to glutamate receptors in the brain. It promotes GABA as well as the production of alpha brain waves, further inducing a relaxed state. Being a GABA agonist, it can also have benefits in promoting restful sleep and reducing the stress response.[153] Dose: 200–400 mg b.i.d. Tyrosine Tyrosine is the precursor to the catecholamine neurotransmiEers dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine), which make up more of the stimulatory, excitatory neurotransmiEers. Tyrosine can benefit depression and can also promote mental alertness.[154] Dose: 500–1000 mg b.i.d.

Lifestyle factors Patients benefit from undertaking additional measures at home that support detoxification.

Dry skin brushing Dry skin brushing can assist with lymphatic clearing by aiding in the manual return of toxins into the central blood stream from the periphery. This is especially important in patients who are mostly bedbound as they are not geEing the muscular contractions necessary to stimulate lymph flow.

Epsom salts baths Bathing in magnesium sulfate salts stimulates detoxification and can bring significant relief from Herxheimer reactions. Some patients are heat sensitive, so care must be taken to not overheat the bath water. The magnesium component of the Epsom salts can help ease muscle aches and spasms, while the sulfur component provides the detoxification effect.

Coffee enemas Coffee enemas can provide a rapid elimination of toxins via two key mechanisms. First, the palmitates of coffee stimulate glutathione-S-transferase, which helps to remove toxins from the blood. Second, the enema stimulates peristalsis within the intestines, which helps to move toxins through the intestines and out through the rectum. Many patients find that coffee enemas bring immediate and profound relief from Herxheimer reactions and general symptoms of pain, fatigue, depression, anxiety, headaches and migraines.

Conclusion Lyme is complex, multifactorial, multisystemic and challenging to treat. Simply addressing infection is clearly not enough; a truly holistic approach is necessary, with consideration of the many areas that are impacting on each individual. This can be very overwhelming for patient and practitioner alike, so sensitivity to that and a step-by-step, manageable approach will set up the patient for success. There are yet other areas that frequently impact on Lyme patients that were not covered in depth in this chapter, but are worth mentioning. Mould toxicity, methylation defects, pyroluria and heavy metal toxicity are co-stressors that are frequently present and can be closely related but hard to delineate, due to overlap of symptoms. Another consideration in treating Lyme patients is to be understanding of their illness experience to date. Lyme is frequently misdiagnosed and under-diagnosed; therefore, many patients have seen multiple doctors, often over many years, and failed to receive an accurate diagnosis or effective treatment. Many have been told that their illness is in their heads (because of the lack of medical findings to support any other diagnosis). Some have post-traumatic stress disorder in response to their experience. Many are angry, resentful and feel that the medical community has let them down. Friends and family often do not fully understand their illness, and patients are often told how well they look, when in reality they may be struggling to get out of bed each morning and in significant pain. The human side of the Lyme disease experience cannot be overlooked. Counselling can help patients to work through this, and addressing the emotional elements can in fact accelerate their physical healing. Children need modifications to their school and social schedules to help them adapt, and it is recommended that the family unit participate in support of some kind (therapy, counselling etc.) to be able to understand and support one another. There is a huge need for recognition of Lyme disease and practitioners who can recognise it and treat it. These patients are complex but also highly self-educated and motivated. An integrative approach is the usually the best approach, and a team of practitioners may need to be involved. Naturopathic and allied health practitioners are in a unique position to help patients manage this multisystem illness that frequently is missed in allopathic medical communities, and have the tools required to effect significant change in

patients. There is a clear need for more research into the mechanisms and therapeutics, especially with regards to chronic Lyme disease. Until more research is carried out, there will continue to be a lot of misunderstanding, misdiagnosis and mistreatment of this population.

Case study A 43-year old female presented with a diagnosis of Lyme disease, Babesia and Bartonella based on clinical presentation from a previous practitioner. Her Western blot had reported as indeterminate, so other doctors she had seen had been hesitant to treat her for Lyme based on the ambiguity of the lab work. Prior to seeing me, she had done some homeopathic treatments with a local practitioner with no positive response.

HPI Patient was working as a photographer and spent time in woodsy areas in a Lyme-endemic area doing photo shoots. She was also working in a colour photo lab, which was exposing her to chemicals daily, and she was studying full time. Her stress level was high, and gradually, health issues arose. Initial symptoms included a sore throat, sinus issues and feeling run down. She had been diagnosed with pernicious anaemia as a child and had some ongoing GI issues, but otherwise had enjoyed good health prior to the onset of these symptoms. After a couple of months, she experienced what she described as a ‘health crash’. She rested a lot, with moderate improvements. She saw another practitioner who started her on low doses of herbal medicines for Lyme, which triggered major anxiety, depression and panic aEacks. She started taking houEuynia in response (a herb for Bartonella), which alleviated those symptoms immediately. She added some essential oils, based on a lecture she had aEended, and was cycling oregano, thyme, clove and cassia in 2-week pulses. She felt more well on the 2 weeks on than the 2 weeks off. The patient presented to me after this with major symptoms of fatigue, always feeling like she was on the verge of the flu, cognitive issues such as short-term memory loss, and problems with focus and concentration. She was experiencing night sweats, air hunger and tightness in her chest. She had experienced pain in the soles of her feet, but that had resolved with the houEuynia. She also felt some dizziness and some mild anxiety and suffered from a low libido. She did not have severe joint or muscle pain, but did have more general aches with the flu-like episodes. She was supplementing with ozonated oils, allicin, houEuynia, essential oils, curcumin, B12, D, probiotic, CLO, NT factor, trace minerals, CoQ10, zinc and iron.

First treatment plan Patient was on a lot of good supportive supplements already. I wanted to support her detoxification further so I added the following: • Liposomal glutathione – start with ¼ teaspoon in water first thing in the morning on an empty stomach (can eat/drink 10 minutes later). Work up to 1 teaspoon daily. • Smilax – 30 drops twice daily in water. • Detox Support Formula – 30 drops twice daily in water. I also wanted to help her cognitive function and her energy levels, so I prescribed: • Frankincense – 2 drops twice daily under the tongue. • Energy Multiplex – 3 capsules in the morning.

This patient clearly had co-infections: Bartonella, based on severe anxiety, panic aEacks, pain in the soles of the feet (a hallmark symptom) and a positive response to houEuynia; and Babesia, based on night sweats, air hunger, low-grade fevers, chills and tightness in the chest. To try to get beEer discernment on these, I undertook a co-infection provocation in which I gave a herb that targets Borrelia for the first week, then added a herb that targets Babesia in the second week and a herb that targets Bartonella in the third week. This helped me to decipher what co-infection is playing what role based on symptom improvements and/or Herxheimer responses. Provocation: • Teasel root – 10 drops twice daily in water. Herb for Borrelia. Wait 1 week, then add: • Artemisinin SOD – 2 twice daily. Herb for Babesia. Wait 1 week, then add: • HH2 – 1 capsule three times daily. Herb for Bartonella. All other supplements were to remain the same so as not to create too many variables. Patient was to take notes on reactions and follow up with me in 6 weeks.

Visit two, 3 months later Patient reported results of the co-infection provocation: • Teasel had given her a sore throat, headaches, fevers and night sweats, from which she would wake up feeling more well than the day before. • Artemisinin gave her quite significant Herxing – severe anxiety, spliEing headache, head pressure and dizziness, but no sweats or fevers. That Herx was worse than any other she had experienced in treatment to date. • HH2 gave some head pressure, anxiety and tightness in the chest. Based on this provocation, it was clear that Babesia was playing a major role (provoked with the artemisinin). We added activated charcoal to help bind the toxins that had been released, and her Herxheimer reactions subsided. Patient was also doing infrared sauna and Epsom salts baths to help with detoxification. Concurrently, her primary care doctor gave her Nature Throid, based on blood work showing hypothyroidism, but the thyroid hormone made her sweat profusely, even at low doses, so she discontinued it. Patient was instructed to continue on current herbal protocol and supplements, increase her detox modalities and return in 2 months. Coffee enemas were suggested, but patient was not sure if she was going to do them.

Visit three, 2 months later Patient was feeling much beEer and more stable, with fewer ups and downs of symptoms. Herxheimer reactions had subsided, she was tolerating treatment well and feeling improvement. She wanted to get more aggressive with herbal antimicrobials. Herbal supplement plan:

• A-BAB – ½ drop twice daily. This is a combination formula from Byron White Herbs for Babesia. • Artemisinin – 2 twice daily. For Babesia. • Teasel root – had been at 5 drops twice daily. Advised that she could go up to 10 drops twice daily. • Lyme Support Formula – 10 drops twice daily. Blend of samento, guaiacum, andrographis, olive leaf extract and Japanese knotweed. • A-BART or houEuynia – 5 drops of each twice daily. • Grapefruit seed extract – 2 capsules twice daily; for cyst forms of Lyme and anti-fungal. • Anti-viral tincture – 40 drops twice daily (melissa and larrea). Patient had high titres of EBV and CMV on labwork. For immune boosting: • Transfer Factor Multi-immune – 2 at night. • Lauricidin – 1 scoop daily. • Low-dose naltrexone – 1.5 mg, working up to 4.5 mg. This is an immune modulator that also helps to boost endogenous endorphin production. It can help with mood, energy, sleep and pain.

Visit four, 2 months after visit three Low-dose naltrexone was helping her sleep, but she was still struggling a bit. She wakes feeling tired and often needs a nap mid-afternoon. She has added acupuncture to her plan and feels that is helping. She also started coffee enemas, which help dramatically calm her anxiety and relieve cognitive issues. Overall, patient is improving substantially – more good days now than bad, flu-like episodes resolved, body aches resolved and dizziness resolved. Biggest issues now are sleep quality and daytime fatigue. Patient feels fatigue is secondary to insomnia, more than a Lyme symptom of its own, as her energy is much beEer following nights of good sleep. Treatment plan focused on sleep: • PheniTropic (Biotics) – 2 before bed. This is a GABA derivative that crosses the blood–brain barrier beEer than regular GABA and assists sleep. • Serenity Restful Complex (doTERRA) – 2 before bed. This is a blend of lavender essential oil, Ltheanine, passionflower, chamomile and lemon balm. The only new thing added to her Lyme protocol was an enzyme to help break down biofilm to ensure that her antimicrobials were able to reach the pathogens: • Boluoke (lumbrokinase) – 1 twice daily on an empty stomach (at least 1 hour apart from foods, meds and supplements). Patient is feeling 80% improved by this stage. The focus is still on Babesia primarily, and Borrelia/Bartonella secondarily. Detoxification herbs and modalities were crucial in allowing her to tolerate quite an aggressive herbal antimicrobial protocol. Patient was highly self-motivated and was compliant with a gluten-free, sugar-free and dairy-free diet. Treatment will continue for 2 months beyond resolution of her symptoms, at which time antimicrobials will be gradually discontinued and a maintenance plan will be designed to support immune function and detoxification long term. I also anticipate more adrenal support being included at our next visit.

References [1] ScoE JD, Anderson JF, Durden LA, et al. Prevalence of the Lyme disease Spirochete, Borrelia burgdorferi, in blacklegged ticks, ixodes scapularis at Hamilton-Wentworth, Ontario. Int J Med Sci. 2016;13(5):316–324; 10.7150/ijms.14552. [2] Tawadros M. Borrelia burgdorferi. [n.d; Available from] hEp://web.uconn.edu/mcbstaff/graf/Student%20presentations/Bburgdorferi/bburgdorferi.html. [3] Stricker R, Johnson L. Lyme disease: the next decade. Infect Drug Resist. 2011;4:1–9; 10.2147/idr.s15653. [4] Domingue G, Woody H. Bacterial persistence and expression of disease. Clin Microbiol Rev. 1997;10:320–344. [5] Dienes L, Weinberger H. The L forms of bacteria. Bacteriol Rev. 1951;15:245–288. [6] Sapi E, Bastian SL, Mpoy CM, et al. Characterization of Biofilm formation by Borrelia burgdorferi in vitro. PLoS ONE. 2012;7(10); 10.1371/journal.pone.0048277. [7] Stricker RB, Lautin A. The Lyme wars: time to listen. Expert Opin Investig Drugs. 2003;12(10):1609–1614; 10.1517/eoid.12.10.1609.21835. [8] Gathany J. Erythema migrans – erythematous rash in Lyme disease. [Available from] hEps://en.wikipedia.org/wiki/Lyme_disease#/media/File:Erythema_migrans__erythematous_rash_in_Lyme_disease_-_PHIL_9875.jpg; 2006. [9] Burrascano J. Advanced topics in Lyme disease: diagnostic hints and treatment guidelines for Lyme and other tick-borne illness. [Available from; International Lyme and Associated Diseases] hEp://www.ilads.org/files/burrascano_0905.pdf; 2005. [10] Mayne P. Emerging incidence of Lyme borreliosis, babesiosis, bartonellosis, and granulocytic ehrlichiosis in Australia. Int J Gen Med. 2011;4:845–852; 10.2147/ijgm.s27336. [11] Brownstein JS, Holford TR, Fish D. A climate-based model predicts the spatial distribution of the Lyme disease vector Ixodes scapularis in the United States. Environ Health Perspect. 2003;111(9):1152–1157; 10.1289/ehp.6052. [12] International Lyme and Associated Diseases Society. Basic information about Lyme disease from ILADS. [Available from] hEp://www.ilads.org/lyme/about-lyme.php; 2016. [13] International Lyme and Associated Diseases Society. Treatment guidelines for Lyme disease from ILADS. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. [Available from] hEp://www.ilads.org/lyme/treatment-guideline.php#sthash.3BzAOGUa.dpuf; 2016. [14] Centers for Disease Control and Prevention. Data and statistics. [Available from] hEp://www.cdc.gov/lyme/stats; 2015. [15] Nelson CA, Saha S, Kugeler KJ, et al. Incidence of clinician-diagnosed Lyme disease, United States, 2005–2010. Emerg Infect Dis. 2015;21(9):1625–1631; 10.3201/eid2109.150417. [16] Lindgren E, Jaenson T. Lyme borreliosis in Europe: influences of climate and climate change, epidemiology, ecology and adaptation measures. [Available from; WHO Regional Office for Europe] hEp://www.euro.who.int/__data/assets/pdf_file/0006/96819/e89522.pdf; 2006. [17] European Centre for Disease Prevention and Control. Lyme Borreliosis in Europe. [Available from] hEp://ecdc.europa.eu/en/healthtopics/vectors/world-health-day2014/documents/factsheet-lyme-borreliosis.pdf; 2014. [18] Lyme Disease Association. Lyme in 80+ countries worldwide. [Available from] hEps://www.lymediseaseassociation.org/about-lyme/cases-stats-maps-a-graphs/940-lyme-inmore-than-80-countries-worldwide; 2013.

[19] Hudson B, Barry R, Shafren D, et al. Does Lyme borreliosis exist in Australia? Journal of Spirochetal and Tick Borne Diseases. 1994;1(2):46–51. [20] Luger S. Lyme disease transmiEed by a biting fly. N Engl J Med. 1990;322:1752. [21] Herzer P, Wilske B, Preac-Mursic V, et al. Lyme arthritis: clinical features, serological, and radiographic findings of cases in Germany. Klin Wochenschr. 1986;64(5):206–215; 10.1007/bf01711648. [22] Pokorný P. Incidence of the spirochete Borrelia burgdorferi in arthropods (Arthropoda) and antibodies in vertebrates (Vertebrata). Cesk Epidemiol Mikrobiol Imunol. 1989;38(1):52–60. [23] Hubálek Z, Halouzka J. Juřicová Z. Investigation of haematophagus arthropods for borreliae – summarized data, 1988–1996. Folia Parasitol (Praha). 1998;45:67–72. [24] Magnarelli L, Anderson J. Tick and biting insects infected with the etiologic agent of Lyme disease, Borrelia burgdorferi. J Clin Microbiol. 1988;26(8):1482. [25] Zákovská A, Capková L, Sery O, et al. Isolation of Borrelia afzelii from overwintering Culex piniens biotype molestus mosquitoes. Ann Agric Environ Med. 2006;13(2):345–348. [26] Middelveen MJ, Burke J, Sapi E, et al. Culture and identification of Borrelia spirochetes in human vaginal and seminal secretions. F1000Res. 2014;3:309; 10.12688/f1000research.5778.2. [27] MacDonald A. Gestational Lyme Borreliosis: implications for the fetus. Rheum Dis Clin North Am. 1989;15(4):657–677. [28] Schlesinger P, Duray P, Burke B, et al. Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Ann Intern Med. 1985;103(1):67–68. [29] MacDonald A, Benach J, Burgdorfer W. Stillbirth following maternal Lyme disease. N Y State J Med. 1987;87:615–616. [30] Lakos A, Solymosi N. Maternal Lyme borreliosis and pregnancy outcome. Int J Infect Dis. 2010;14(6):e494–8; 10.1016/j.ijid.2009.07.019. [31] Schmidt B, Aberer E, Stockenhuber C, et al. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis. Diagn Microbiol Infect Dis. 1995;21(3):121–128. [32] CanLyme. Symptoms. [n.d; Available from] hEps://canlyme.com/lyme-basics/symptoms/. [33] McFadzean N, Burrascano JJ. The beginner's guide to Lyme disease: diagnosis and treatment made simple. BioMed Publishing Group: San Diego, CA; 2012:76–78. [34] Aguero-Rosenfeld ME, Wang G, Schwarb I, et al. Diagnosis of Lyme borreliosis. Clin Microbiol Rev. 2005;18(3):484–509; 10.1128/CMR.18.3.484-509.2005. [35] Igenex.Com. Welcome to IGeneX, Inc. [n.d; Available from] hEp://search-id.com/d/igenex.com. [36] Sapi E, Pabbati N, Datar A, et al. Improved culture conditions for the growth and detection of Borrelia from human serum. Int J Med Sci. 2013;10(4):362–376; 10.7150/ijms.5698. [37] Bakken L, Callister S, Wand P, et al. Interlaboratory comparison of test results for detection of Lyme disease by 516 participants in the Wisconsin State Laboratory of Hygiene/College of American Pathologist proficiency testing program. J Clin Microbiol. 1997;35(3):537–543. [38] Stricker RB, Johnson L. Let's tackle the testing. BMJ. 2007;335(7628):1008; 10.1136/bmj.39394.676227.be. [39] Donta ST. Late and chronic Lyme disease. Med Clin North Am. 2002;86(2):341–349; 10.1016/s0025-7125(03)00090-7. [40] Steere A. Lyme disease. N Engl J Med. 2001;345:115–125. [41] Rossler D, Eiffert H, Jauris-Heipke S, et al. Molecular and immunological characterization of the p83/100 protein of various Borrelia burgdorferi sensu lato strains. Med Microbiol Immunol.

1995;184(1):23–32; 10.1007/bf00216786. [42] ArminLabs GmbH. Elispot. [Available from] hEp://www.arminlabs.com/en/tests/elispot; 2014. [43] Vidal V, Scragg IG, Cutler SJ, et al. Variable major lipoprotein is a principal TNF-inducing factor of louse-borne relapsing fever. Nat Med. 1998;4(12):1416–1420; 10.1038/4007. [44] Kaplanski G, Granel B, Vaz T, et al. Jarisch-Herxheimer reaction complicating the treatment of chronic Q fever endocarditis: elevated TNFα and IL-6 serum levels. J Infect. 1998;37(1):83–84; 10.1016/s0163-4453(98)91120-3. [45] Burrascano J. Advanced topic in Lyme disease. Diagnostic hints and treatment guidelines for Lyme and other tick borne illnesses. [16th ed; Available from] hEps://www.researchednutritionals.com/wp-content/uploads/2016/04/BurrascanosAdvanced-Topics-in-Lyme-Disease-_12_17_08.pdf; 2008. [46] Wormser GP, DaEwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and Babesiosis: clinical practice guidelines by the infectious diseases society of America. Clin Infect Dis. 2006;43(9):1089–1134; 10.1086/508667. [47] Strle F, Ružič E, Cimperman J. Erythema migrans: comparison of treatment with azithromycin, doxycycline and phenoxymethylpenicillin. J Antimicrob Chemother. 1992;30(4):543–550; 10.1093/jac/30.4.543. [48] Strle F, Cimperman J, Maraspin V, et al. Azithromycin versus doxycycline for treatment of erythema migrans: clinical and microbiological findings. Infection. 1993;21(2):83–88; 10.1007/bf01710737. [49] Weber K, Wilske B, Preac-Mursic V, et al. Azithromycin versus penicillin V for the treatment of early lyme borreliosis. Infection. 1993;21(6):367–372; 10.1007/bf01728915. [50] Barsic B, Maretic T, Majerus L, et al. Comparison of Azithromycin and Doxycycline in the treatment of Erythema migrans. Infection. 2000;28(3):153–156; 10.1007/s150100050069. [51] Horowib R. Lyme disease & babesiosis: updates on diagnosis and treatment 2011. [Available from] hEp://www.ilads.org/media/videos/videos_horowib.php; 2011. [52] Tye-Din J. The problem of coeliac disease in Australia. Australian Coeliac 2013. [Available from] hEp://search.informit.com.au/documentSummary;dn=792500089102977;res=IELHEA; Dec 2013. [53] Tjon JM-L, van Bergen J, Koning F. Celiac disease: how complicated can it get? Immunogenetics. 2010;62(10):641–651; 10.1007/s00251-010-0465-9. [54] Bressan P, Kramer P. Bread and other edible agents of mental disease. Front Hum Neurosci. 2016;10; 10.3389/fnhum.2016.00130. [55] Asmar RE, Panigrahi P, Bamford P, et al. Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology. 2002;123(5):1607–1615; 10.1053/gast.2002.36578. [56] Pal S, Woodford K, Kukuljan S, et al. Milk intolerance, beta-casein and lactose. Nutrients. 2015;7(9):7285–7297; 10.3390/nu7095339. [57] Calder PC. Omega-3 polyunsaturated faEy acids and inflammatory processes: nutrition or pharmacology? Br J Clin Pharmacol. 2013;75(3):645–662; 10.1111/j.1365-2125.2012.04374.x. [58] Caughey G, Manbioris E, Gibson R, et al. The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 faEy acids from vegetable oil or fish oil. Am J Clin Nutr. 1996;63:116–122. [59] Jiang Y, Wu S-H, Shu X-O, et al. Cruciferous vegetable intake is inversely correlated with

circulating levels of proinflammatory markers in women. J Acad Nutr Diet. 2014;114(5):700– 708.e2; 10.1016/j.jand.2013.12.019. [60] Johnston C. Functional foods as modifiers of cardiovascular disease. Am J Lifestyle Med. 2009;3(1 Suppl.):39S–43S; 10.1177/1559827609332320. [61] Sanchez A, Reeser J, Lau H, et al. Role of sugars in human neutrophilic phagocytosis. Am J Clin Nutr. 1973;26:1180–1184. [62] Ringsdorf WJ, Cheraskin E, Ramsay RJ. Sucrose, neutrophilic phagocytosis and resistance to disease. Dent Surv. 1976;52(12):46–48. [63] Collin P, Salmi J, Hällström O, et al. Autoimmune thyroid disorders and coeliac disease. Eur J Endocrinol. 1994;130:137–140. [64] Valentino R, Savastano S, Maglio M, et al. Markers of potential coeliac disease in patients with Hashimoto's thyroiditis. Eur J Endocrinol. 2002;146(4):479–483; 10.1530/eje.0.1460479. [65] Cristea V, Crişan M. Lyme disease with magnesium deficiency. Magnes Res. 2003;16(4):287– 289. [66] Javid A, Zlotnikov N, Pětrošová H, et al. Hyperglycemia impairs neutrophil-mediated bacterial clearance in mice infected with the Lyme disease pathogen. PLoS ONE. 2016;11(6). [67] Halperin JJ. Chronic Lyme disease: misconceptions and challenges for patient management. Infect Drug Resist. 2015;8:119–128. [68] Arvikar SL, Crowley JT, Sulka KB, et al. Autoimmune arthritides, rheumatoid arthritis, psoriatic arthritis, or peripheral spondyloarthritis following Lyme disease. Arthritis Rheumatol. 2017;69(1):194–202. [69] Borchers AT, Keen CL, Huntley AC, et al. Lyme disease: a rigorous review of diagnostic criteria and treatment. J Autoimmun. 2015;57:82–115. [70] Goggin R, Jardeleza C, Wormald P-J, et al. Colloidal silver: a novel treatment for staphylococcus aureus biofilms? Int Forum Allergy Rhinol. 2014;4(3):171–175; 10.1002/alr.21259. [71] Borwick S. Colloidal silver and Lyme disease. [Available from; The Silver Edge] hEp://thesilveredge.com/colloidal-silver-and-lyme-disease.shtml#.WBjbS3eZNm8; 2016. [72] Stopper H, Schinzel R, Sebekova K, et al. Genotoxicity of advanced glycation end products in mammalian cells. Cancer Le?. 2003;190(2):151–156; 10.1016/s0304-3835(02)00626-2. [73] Cooper E. New enzyme complex isolated from earthworms is potent fibrinolytic. ACAM Integrative Medicine Blog. [Available from] hEps://www.acam.org/blogpost/1092863/185721/NewEnzyme-Complex-Isolated-from-Earthworms-is-Potent-Fibrinolytic; 2009. [74] Cooper EL, Hirabayashi K. Origin of innate immune responses: revelation of food and medicinal applications. J Tradit Complement Med. 2013;3(4):204–212; 10.4103/2225-4110.119708. [75] Zapotoczna M, McCarthy H, Rudkin JK, et al. An essential role for coagulase in Staphylococcus aureus biofilm development reveals new therapeutic possibilities for devicerelated infections. J Infect Dis. 2015;212(12):1883–1893; 10.1093/infdis/jiv319. [76] Hsu R, Lee K, Wang J, et al. Amyloid-degrading ability of naEokinase from Bacillus subtilis naEo. J Agric Food Chem. 2009;57(2):503–508. [77] Lawrence HS, Borkowsky W. Transfer factor – current status and future prospects. Biotherapy. 1996;9(1–3):1–5; 10.1007/bf02628649. [78] Akramiene D, Kondrotas A, Didziapetriene J, et al. Effects of beta-glucans on the immune system. Medicina (Kaunas). 2007;43(8):597–606. [79] Chronic Lyme Disease. Beta glucan for treating Lyme disease. [n.d; Available from] hEp://www.chroniclymedisease.com.

[80] Hawley KL, Martín-Ruiz I, Iglesias-Pedraz JM, et al. CD14 targets complement receptor 3 to lipid rafts during phagocytosis of Borrelia burgdorferi. Int J Biol Sci. 2013;9(8):803–810; 10.7150/ijbs.7136. [81] Rodriguez NA, Miracle DJ, Meier PP. Sharing the science on human milk feedings with mothers of very-low-birth-weight infants. J Obstet Gynecol Neonatal Nurs. 2005;34(1):109–119; 10.1177/0884217504272807. [82] Buescher ES, McWilliams-Koeppen P. Soluble tumor necrosis factor-α (TNF-α) receptors in human colostrum and milk bind to TNF-α and neutralize TNF-α bioactivity. Pediatr Res. 1998;44(1):37–42; 10.1203/00006450-199807000-00006. [83] Cakebread JA, Humphrey R, Hodgkinson AJ. Immunoglobulin A in bovine milk: a potential functional food? J Agric Food Chem. 2015;63(33):7311–7316; 10.1021/acs.jafc.5b01836. [84] Kowalska K, Milnerowicz H. The influence of age and gender on the pro/antioxidant status in young healthy people. Ann Clin Lab Sci. 2016;46(5):480–488. [85] Starks MA, Starks SL, Kingsley M, et al. The effects of phosphatidylserine on endocrine response to moderate intensity exercise. J Int Soc Sports Nutr. 2008;5(1):11; 10.1186/1550-2783-511. [86] Kailasapathy K, Chin J. Survival and therapeutic potential of probiotic organisms with reference to Lactobacillus acidophilus and Bifidobacterium spp. Immunol Cell Biol. 2000;78(1):80–88; 10.1046/j.1440-1711.2000.00886.x. [87] Cevikbas A, Yemni E, Ezzedenn FW, et al. Antitumoural antibacterial and antifungal activities of kefir and kefir grain. Phytother Res. 1994;8(2):78–82; 10.1002/ptr.2650080205. [88] Rodrigues KL, Carvalho JC, Schneedorf JM. Anti-inflammatory properties of kefir and its polysaccharide extract. Inflammopharmacology. 2005;13(5–6):485–492; 10.1163/156856005774649395. [89] Claustrat B, et al. The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005;9:11–24. [90] Pandi-Perumal S, Trakht I, Srinivasan V, et al. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol. 2008;85(3):335–353. [91] Aranow C. Vitamin D and the immune system. J Investig Med. 2011;59(6):881–886. [92] Prietl B, Treiber G, Pieber TR, et al. Vitamin D and immune function. Nutrients. 2013;5(7):2502–2521; 10.3390/nu5072502. [93] Shankar A, Prasad A. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr. 1998;68(2):447S–463S. [94] Epp L, Mravec B. Chronic polysystemic candidiasis as a possible contributor to onset of idiopathic Parkinson's disease. Bratisl Lek Listy. 2006;107(6–7):227–230. [95] Maruyama W, Naoi M. Cell death in Parkinson's disease. J Neurol. 2002;249:183–189. [96] Tsuboi KK, Thompson DJ, Rush EM, et al. Acetaldehyde-dependent changes in hemoglobin and oxygen affinity of human erythrocytes. Hemoglobin. 1981;5(3):241–250; 10.3109/03630268108997548. [97] Tuma DJ, JenneE RB, Sorrell MF. The interaction of acetaldehyde with tubulin. Ann N Y Acad Sci. 1987;492(1):277–286; 10.1111/j.1749-6632.1987.tb48681.x. [98] Truss C. Metabolic abnormalities in patients with chronic candidiasis: the acetaldehyde hypothesis. J Orthomolecular Psychiatry. 1984;13(2):66–93. [99] SchmiE W, et al. Molybdenum for Candida albicans patients and other problems. The Digest of Chiropractic Economics. 1991;31(4):56–63.

[100] Mur E, Hartig F, Eibl G, et al. Randomized double blind trial of an extract from the pentacyclic alkaloid-chemotype of Uncaria tomentosa for the treatment of rheumatoid arthritis. J Rheumatol. 2002;29(4):678–681. [101] Sandoval M, Charbonnet RM, Okuhama NN, et al. Cat's claw inhibits TNF-α production and scavenges free radicals: role in cytoprotection. Free Radic Biol Med. 2000;29(1):71–78; 10.1016/s0891-5849(00)00327-0. [102] Lyme. Teasel root and Lyme disease treatment. [Available from] hEp://www.tiredoflyme.com/teasel-root.html/; 2011. [103] Stawonogi W. Zależności w układzie żywiciel-ektopasożyt-patogen. Koliber: Poland; 2016:207–215. [104] Stevenson L, et al. Oxygen radical absorbance capacity (ORAC) report on olive leaf. Australia's olive leaf extracts. Lismore, NSW: Southern Cross University. 2005. [105] Mohagheghi F, Bigdeli MR, Rasoulian B, et al. The neuroprotective effect of olive leaf extract is related to improved blood–brain barrier permeability and brain edema in rat with experimental focal cerebral ischemia. Phytomedicine. 2011;18(2–3):170–175; 10.1016/j.phymed.2010.06.007. [106] Lambert RJW, Skandamis PN, Coote PJ, et al. A study of the minimum inhibitory concentration and mode of action of oregano essential oil, thymol and carvacrol. J Appl Microbiol. 2001;91(3):453–462; 10.1046/j.1365-2672.2001.01428.x. [107] Bona E, Cantamessa S, Pavan M, et al. Sensitivity of Candida albicans to essential oils: are they an alternative to antifungal agents? J Appl Microbiol. 2016;121(6):1530–1545; 10.1111/jam.13282. [108] Valcourt C, Saulnier P, Umerska A, et al. Synergistic interactions between doxycycline and terpenic components of essential oils encapsulated within lipid nanocapsules against gram negative bacteria. Int J Pharm. 2016;498(1–2):23–31; 10.1016/j.ijpharm.2015.11.042. [109] Scandorieiro S, de Camargo LC, Lancheros CAC, et al. Synergistic and additive effect of oregano essential oil and biological silver nanoparticles against multidrug-resistant bacterial strains. Front Microbiol. 2016;7; 10.3389/fmicb.2016.00760. [110] Georgetown University Medical Center. Oregano oil may protect against drug-resistant bacteria, Georgetown researcher finds. [Available from; Science Daily] hEps://www.sciencedaily.com/releases/2001/10/011011065609.htm; 2001. [111] Heggers JP, CoEingham J, Gusman J, et al. The effectiveness of processed grapefruit-seed extract as an antibacterial agent: II. Mechanism of action and in vitro toxicity. J Altern Complement Med. 2002;8(3):333–340; 10.1089/10755530260128023. [112] Brorson Ø, Brorson S. Grapefruit seed extract is a powerful in vitro agent against motile and cystic forms of Borrelia burgdorferi sensu lato. Infection. 2007;35(3):206–208; 10.1007/s15010007-6105-0. [113] Brown GD. The biosynthesis of artemisinin (Qinghaosu) and the phytochemistry of artemisia annua L. (Qinghao). Molecules. 2010;15(11):7603–7698; 10.3390/molecules15117603. [114] Li J, Zhou B. Biological actions of Artemisinin: insights from medicinal chemistry studies. Molecules. 2010;15(3):1378–1397; 10.3390/molecules15031378. [115] Kim W-S, Choi WJ, Lee S, et al. Anti-inflammatory, antioxidant and antimicrobial effects of artemisinin extracts from Artemisia annua L. Korean J Physiol Pharmacol. 2014;19(1):21; 10.4196/kjpp.2015.19.1.21. [116] Sawer IK, Berry MI, Ford JL. The killing effect of cryptolepine on Staphylococcus aureus. Le? Appl Microbiol. 2005;40(1):24–29; 10.1111/j.1472-765x.2004.01625.x.

[117] Mills-Robertson FC, Tay SCK, Duker-Eshun G, et al. In vitro antimicrobial activity of ethanolic fractions of Cryptolepis sanguinolenta. Ann Clin Microbiol Antimicrob. 2012;11(1):16; 10.1186/1476-0711-11-16. [118] Hanprasertpong N, Teekachunhatean S, Chaiwongsa R, et al. Analgesic, anti-inflammatory, and chondroprotective activities of Cryptolepis buchanani extract: in vitro and in vivo studies. Biomed Res Int. 2014;2014:1–8; 10.1155/2014/978582. [119] Sekita Y, Murakami K, Yumoto H, et al. Anti-bacterial and anti-inflammatory effects of ethanol extract from HouEuynia cordata poultice. Biosci Biotechnol Biochem. 2016;80(6):1205– 1213; 10.1080/09168451.2016.1151339. [120] Sekita Y, Murakami K, Yumoto H, et al. Preventive effects of HouEuynia cordata extract for oral infectious diseases. Biomed Res Int. 2016;2016; 10.1155/2016/2581876. [121] Buhner S. Healing Lyme – natural healing of Lyme borelliosis and the coinfections Chlamydia and spo?ed fever ricke?sioses. 2nd ed. Raven Press: US; 2016. [122] Rai B, Jasdeep K, Reinhilde J, et al. Curcumin exhibits anti-pre-cancer activity by increasing levels of vitamin C and E, and preventing lipid peroxidation and oxidative damage. J Oral Sci. 2010;52(2). [123] Hucklenbroich J, Klein R, Neumaier B, et al. Aromatic-turmerone induces neural stem cell proliferation in vitro and in vivo. Stem Cell Res Ther. 2014;5(4):100; 10.1186/scrt500. [124] Sharma S, Kulkarni SK, Agrewala JN, et al. Curcumin aEenuates thermal hyperalgesia in a diabetic mouse model of neuropathic pain. Eur J Pharmacol. 2006;536(3):256–261; 10.1016/j.ejphar.2006.03.006. [125] Appleton J. Turmeric and frankincense in inflammation: an update. Natural Medicine Journal. 2013;3(9). [126] Safayhi H, Rall B, Sailer E, et al. Inhibition by boswellic acids of human leukocyte elastase. J Pharmacol Exp Ther. 1997;281(1):460–463. [127] Roy S, Khanna S, Shah H, et al. Human genome screen to identify the genetic basis of the anti-inflammatory effects of Boswellia in microvascular endothelial cells. DNA Cell Biol. 2005;24(4):244–255; 10.1089/dna.2005.24.244. [128] Roy S, Khanna S, Krishnaraju AV, et al. Regulation of vascular responses to inflammation: inducible matrix metalloproteinase-3 expression in human microvascular endothelial cells is sensitive to antiinflammatory boswellia. Antioxid Redox Signal. 2006;8(3–4):653–660; 10.1089/ars.2006.8.653. [129] Zhang H, Li C, Kwok S-T, et al. A review of the pharmacological effects of the dried root of Polygonum cuspidatum (Hu Zhang) and its constituents. Evid Based Complement Alternat Med. 2013;2013. [130] Pandit S, Kim HJ, Park SH, et al. Enhancement of fluoride activity against Streptococcus mutans biofilms by a substance separated from Polygonum cuspidatum. Biofouling. 2012;28(3):279–287. [131] Han JH, Koh W, Lee HJ, et al. Analgesic and anti-inflammatory effects of ethyl acetate fraction of Polygonum cuspidatum in experimental animals. Immunopharmacol Immunotoxicol. 2012;34(2):191–195. [132] Li HL, Chen HL, Li H, et al. Regulatory effects of emodin on NF-κB activation and inflammatory cytokine expression in RAW 264.7 macrophages. Int J Mol Med. 2005;16(1):41–47. [133] Deng WL. Preliminary studies on the pharmacology of the Andrographis product dihydroandrographolide sodium succinate. Newsle? Clin Herb Med. 1978;8:26–28.

[134] Singh PK, Roy S, Dey S. Antimicrobial activity of andrographis paniculata. Fitoterapia. 2003;74:692–694. [135] Chandrasekaran CV, Gupta A, Agarwal A. Effect of an extract of Andrographis paniculata leaves on inflammatory and allergic mediators in vitro. J Ethnopharmacol. 2010;129:203–207. [136] Parichatikanond W, Suthisisang C, Dhepakson P, et al. Study of anti-inflammatory activities of the pure compounds from Andrographis paniculata (Burm.f.) Nees and their effects on gene expression. Int Immunopharmacol. 2010;10:1361–1373. [137] Yang A-J, Li C-C, Lu C-Y, et al. Activation of the cAMP/CREB/inducible cAMP early repressor pathway suppresses andrographolide-induced gene expression of the π class of glutathione S-transferase in rat primary hepatocytes. J Agric Food Chem. 2010;58(93):1993–2000. [138] Chuan-li L, Wei Z, Min W, et al. Polysaccharides from Smilax glabra inhibit the proinflammatory mediators via ERK1/2 and JNK pathways in LPS-induced RAW264.7 cells. Carbohydr Polym. 2015;122:428–436; 10.1016/j.carbpol.2014.11.035. [139] Shu X-S, Gao Z-H, Yang X-L. Anti-inflammatory and anti-nociceptive activities of Smilax china L. Aqueous extract. J Ethnopharmacol. 2006;103(3):327–332; 10.1016/j.jep.2005.08.004. [140] Xia D, Yu X, Liao S, et al. Protective effect of Smilax glabra extract against lead-induced oxidative stress in rats. J Ethnopharmacol. 2010;130(2):414–420; 10.1016/j.jep.2010.05.025. [141] BuEerweck V. Mechanism of action of St John's wort in depression: what is known? CNS Drugs. 2003;17(8):539–562. [142] Klusa V, Germane S, Nöldner M, et al. Hypericum extract and hyperforin: memoryenhancing properties in rodents. Pharmacopsychiatry. 2001;34(Suppl. 1):61–69; 10.1055/s-200115451. [143] Bent S, Padula A, Moore D, et al. Valerian for sleep: a systematic review and meta-analysis. Am J Med. 2006;119(12):1005–1012; 10.1016/j.amjmed.2006.02.026. [144] White SM. Herbs and supplements for memory and cognitive support during lyme treatment. ProHealth. [Available from] hEps://www.prohealth.com/library/herbs-and-supplements-formemory-and-cognitive-support-during-lyme-treatment-7197; 2016. [145] Lai P-L, et al. Neurotrophic properties of the Lion's mane medicinal mushroom, Hericium erinaceus (higher basidiomycetes) from Malaysia. Int J Med Mushrooms. 2013;15(6). [146] Burke V. Lion's mane mushroom – unparalleled benefits for your brain and nervous system. GreenMedInfo. [Available from] hEps://rcf.fr/sites/default/static.rcf.fr/le_champignon_qui_protege_le_cerveau.pdf; 2016. [147] Hinz M, Stein A. 5-HTP efficacy and contraindications. Neuropsychiatr Dis Treat. 2012;8:323– 328; 10.2147/ndt.s33259. [148] De Giorgis G, MileEo R, Iannuccelli M, et al. Headache in association with sleep disorders in children: a psychodiagnostic evaluation and controlled clinical study–L-5-HTP versus placebo. Drugs Exp Clin Res. 1987;13:425–433. [149] PuEini P, Caruso I. Primary fibromyalgia syndrome and 5-hydroxy-L-tryptophan: a 90-day open study. J Int Med Res. 1992;20:182–189. [150] Yasko DA. Autism: pathways to recovery. 2004 [Bethel, ME: Neurological Research Institute, LLC]. [151] Yasko DA. Autism: pathways to recovery. 2007 [Bethel, ME: Neurological Research Institute, LLC]. [152] Yasko DA. Autism: pathways to recovery. 2009 [Bethel, ME: Neurological Research Institute, LLC].

[153] Juneja LR, Chu D-C, Okubo T, et al. L-theanine – a unique amino acid of green tea and its relaxation effect in humans. Trends Food Sci Technol. 1999;10(s 6–7):199–204; 10.1016/S09242244(99)00044-8. [154] Fernstrom J. Can nutrient supplements modify brain function? Am J Clin Nutr. 2000;71(6 Suppl.):1669S–1675S.

Index Page numbers followed by ‘f ’ indicate figures, ‘t’ indicate tables, and ‘b’ indicate boxes. A Abacavir hypersensitivity, 893 Aberrant Behaviour Checklist (ABC), 707 Abnormal gene transcription, 177 Academy of Breastfeeding Medicine (ABM), 486, 539–540 ACAT, AcylCoA-cholesterol acyl transferase (ACAT) ACE, Angiotensin-converting enzyme (ACE) Acetate, 122t–123t Acetylation, 78 Acetyl-CoA carboxylase β (ACC2) gene, 187–188 Acetyl L-carnitine, 170t–171t, 904–905 Down syndrome, 767 drug interactions, IT–76 non-Hodgkin lymphoma (NHL), 866

Acetylpenicillamine, 45 Acetyl serotonin, 160t Achalasia, 634, 746 Achillea millefolium, drug interactions, IT–1 Acid/alkaline diet, 825 Acquired thrombophilia, 349–350 ACSL1 gene, 188 Actaea racemosa (black cohosh), 285–286 drug interactions, IT–2 for female infertility, 300

as utero-ovarian tonic, 300

Actinic keratosis, 639 Activated charcoal, drug interactions, IT–76 Acute aluminium toxicity, 46–47 Acute iron toxicity, 50–51 Acute megakaryocyte-erythroid leukaemia (AMKL), 751 Acute onset, 888 Acute otitis media (AOM), 600–601 Acute otitis media with effusion (AOME), 600 Acute renal failure (ARF), polypharmacy, 652–653 Acyl carrier protein (ACP), 404 AcylCoA-cholesterol acyl transferase (ACAT), 180–182 Acyl CoA synthetase 1 (ACSL1), 188 Adaptogens, 299t, 315t for athletes, 239–241, 240t–241t herbal medicine, with aaention deficit (hyperactivity) disorder (AD(H)D), 716 in pregnancy, 432

AD(H)D, Aaention deficit (hyperactivity) disorder (AD(H)D) Additives, 102, 713 Adenine (A), 147 Adenoids, in Down syndrome, 740–741 Adenosine, drug interactions, IT–76 Adenosine triphosphate (ATP), 150 Adenosylcobalamin, 407 Adenosylhomocysteinase (AHCY), 166t Adipokines, 670 Adipose tissue, 670 melanoma of the skin, 861

Adolescence in Down syndrome behaviour, 732 developing life skills, 733 expectations, 732–733

nutritional health care, 591 phases, 590, 591t

Adoption, 285 Adoptive lactation, 497 Adrenal hormone profile, 281 Adrenal test, 925 Adrenal tonic, 240t–241t Adrenocorticotropic hormone (ACTH), 741 Adulthood in Down syndrome access to services and opportunities, 733 independent/supported living, 733 supported employment transition, 733 supporting carers, 734 support needs, 733–734

older atypical presentation of disease in, 642–644, 643t history-taking of, 642b

Advanced disease (AIDS), 889 Advanced glycation end (AGE) products, 287, 632 Advanced HIV infection, 885 Advanced maternal age, 344 Adverse drug reactions (ADRs) clinical presentation in older patients, 660, 661b medication errors, 658

Adverse drug withdrawal event (ADWE), 658 Adverse food reactions, 548, 549f Aerobic/oxidative system, 217, 218t–219t Aesculus hippocastanum, drug interactions, IT–3 2-AG, 798, 798f–799f Agaricus blazei, drug interactions, IT–3 Agaricus mushrooms, drug interactions, IT–76 Age and fertility, 262, 262t–263t miscarriage and, 347–348

Ageing, 627–640 cardiovascular system, 629–630, 630t dermatological system, 639 endocrine system, 637–638

gastrointestinal and hepatobiliary systems, 633–636 haematological system, 636 immune system, 636–637 metabolism and thermoregulatory changes, 640 musculoskeletal system, 638–639 nervous system, 628–629 physiology of, 628 renal system, 632–633 respiratory system, 630–632, 632t senses, 640 theories of, 628

Agricultural chemicals, 20 Agrimonia eupatoria, drug interactions, IT–3 AHCY, Adenosylhomocysteinase (AHCY) AIDS, Human immunodeficiency virus (HIV) definition, 885 pathogenesis, 890–891 statistics, 883 wasting syndrome, 890

Air particulate maaer (PM), 70–71 Air pollutants, 27 reduce exposure to, 20 sources of, 20

AIS’ ABCD classification system, 234, 234t–235t ALA, Alpha-linolenic acid (ALA) Alanine aminotransferase (ALT), 73 Albizia lebbeck, drug interactions, IT–3 Alchemilla vulgaris astringent properties, 298–299 drug interactions, IT–3 fertility, effects on, 298–299

Alcohol, 18, 71, 900 and breastfeeding, 514 female infertility and, 289, 301–302, 301t male infertility and, 304–305 miscarriage and, 352 renal cancer, 869

Aldosterone, antidiuretic hormone (ADH), 632 Aletris farinosa drug interactions, IT–3 for fertility, 286 for gynaecological conditions, 299 miscarriage prevention, 299

Alkaline phosphatase (ALP), 73 Alkaloids, 811 Allergen(s), 26–33 indoor, 26–27 pest, 29 sources of, 29–30

pet, 28–29 sources of, 29

plant, 30–31 avoiding, 31 sources of, 30 testing for, 31

Allergenic food, to infants, 26 Allergic diseases, 27 Allergy, 26, 28 cow's milk, 566–567, 594 gastrointestinal food, 559, 560t in infancy, 565 pet, reduction, 29

Allium cepa, drug interactions, IT–4 Allium sativum (garlic), 907–908 drug interactions, IT–4, IT–5 for miscarriage, 376 antioxidant enzymes, 376 antiplatelet and antithrombotic activity, 376 improved blood flow, 376

Alloimmune-mediated miscarriage, 349 Allopathic supportive therapy, 929 Allostasis, 200–201 Allostatic load, 201 Allyl isothiocyanate, bladder cancer, 872 Aloe barbadensis, drug interactions, IT–5, IT–6

Aloe vera (aloe vera), 908 Alopecia areata, 737, 754 α-pinene, 810–811 Alpha-casozepine milk protein, drug interactions, IT–77 Alpha-linolenic acid (ALA), 45–46, 501, 546, 588, 904 benefits, RDI and source, 238t–239t drug interactions, IT–77 female fertility, 291 for miscarriage, 359, 383t in pregnancy, 417

ALT, Alanine aminotransferase (ALT) Althea officinalis radix, 430, IT–6 Aluminium, 70 body load, 46 clinical manifestations, 46 diagnostic testing, 46–47 management/therapy, 47 sources, 46 toxicity, 46

Aluminium sulfate, 46 Alzheimer's disease, 180, 760–762 American Academy of Pediatrics (AAP) recommendations, 544–545 American Association of Naturopathic Medical Colleges (AANMC), 12–13 American Association of Naturopathic Physicians (AANP), 12–13 American Naturopathic Medical Association (ANMA), 12–13 Amino acids for female infertility, 290–291, 298t in Lyme disease, 943 for male infertility, 305–307, 314t for miscarriage management, 359–362

2-Amino-3-mercapto-3 methylbutyric acid, 45 Amish communities, 27 Ammi visnaga, drug interactions, IT–6 Amniocentesis, 423 trimester 1, 423

trimester 2, 429

Anaemia, ageing, 636 Anaerobic system, 217, 218t–219t Anandamide, 798, 798f Anatomical defects, miscarriage and, 345–346, 346t, 364t–372t Anchor, meditation, 206 Andrographis panniculata (andrographis), 908, 941, IT–6 Andrology assessment, 277t Androsten, 316 Anethum graveolens, drug interactions, IT–7 Anetoderma, 737 Aneuploidy, 347 prenatal testing for, 422–423

Angelica sinensis drug interactions, IT–7 female infertility, 299

Angiotensin-converting enzyme (ACE), 190 Angiotensinogen (AGT), 190 Aniseed, drug interactions, IT–77 ANMA, American Naturopathic Medical Association (ANMA) Anodyne, 240t–241t Anorexia, 263 of ageing, 669–670, 670–671, 671t

Antenatal care models, 392 Anthroquinone herbs, 593 Anti-β2-glycoprotein, 349 Antibiotic-associated diarrhoea (AAD), 568–569 Antibiotics, toddler, 587 Antibiotic therapy bacterial vaginosis, 364t–372t Lyme disease, 927–929, 928t–929t

Anticardiolipin antibodies (aCL), 349 Anti-galactagogues, 498t Antihypertensives, in pregnancy, 432

Antimicrobial herbs, in autism spectrum disorder (ASD), 708 Anti-miscarriage herbal medicines, 299t Anti-Müllerian hormone (AMH), 270b Antinuclear antibodies (ANA), 364t–372t Antioxidant(s), 45–46, 72, 81, 407–408, 483 dietary, 179 female fertility and, 291–293 lung cancer, 863 male fertility and, 304, 307–311 nutrients, 716 polyphenolic, 18

Antiphospholipid autoantibodies (aPLs), 349 Antiphospholipid syndrome (APS), 349–350, 364t–372t Anti-retroviral treatment (ART), 897 Anti-thrombotic formula, 378 Anxiety, 748 Anxiolytic activity, Gotu kola, 378 Apigenin, bladder cancer, 873 Apium graveolens, drug interactions, IT–7, IT–8 ApoA-5, 185 ApoB gene, 186 ApoB-100 gene, 186 ApoC3 gene, 185 APOE gene, 180, 184–185 Apolipoprotein (a), 186–187 Apolipoprotein E (APOE), 185 assessment, 184–185 genotyping, 180

Apoptosis, 54 Appendicitis, acute, 643t Apple cider vinegar, drug interactions, IT–77 Arachidonate 5-lipoxygenase, 378 Arachidonic acid (AA), 501, 581 Arctium lappa, drug interactions, IT–8

Arctostaphylos uva-ursi (UVA URSI), 908, IT–8 Arginine drug interactions, IT–78 female fertility and, 290 male fertility and, 305–306 trimester 2, pregnancy preeclampsia management, 432

Arm baths, 103 Armoracia rustica, drug interactions, IT–8 Arm rinses, 98 Arsenic (chelatable toxicants), 69t, 70 body load, 47 clinical manifestations, 47–48, 48f diagnostic testing, 48 management/therapy, 48 sources, 47 toxicity, 47

Artemisia, 826t Artemisia annua (wormwood), 939–940, IT–8 Artemisia herba-alba, drug interactions, IT–8 Arterial dysfunction, 97 Arthropathy, 754 Asanas, 211–213 Asherman's syndrome, Intrauterine adhesions Ashwagandha (Withania somnifera) exercise performance, 242 for female triathlete, 246t for male infertility, 317, 318t for male swimmer, 251t–252t for miscarriage, 377

Asia, AIDS statistics, 883 Asparagus racemosus (shatavari) cholinergic activity, 377 drug interactions, IT–8 female infertility, 299–300 luteal phase defect preconception formula, 378 for miscarriage, 377

steroidal saponins, 377

Asperger's syndrome (AS), 688–690 Aspermia definition, 276b semen analysis, 341t

Assisted insemination, 283–284 Assisted/instrumented birth, 392 Assisted-relaxation, 204 Assisted reproductive technology (ART), 258, 399, 539 Association for the Promotion of Preconceptual Care, 287 Asthenozoospermia carnitine for, 307 CoQ10 supplementation, 308–309 definition, 276b dietary nutrient intake and, 303–304 Mucuna pruriens treatment, 317t–318t Panax ginseng for, 314–316 semen analysis, 341t Withania somnifera, 318t zinc supplementation, 310

Asthma, 739 paediatrics and adolescence, 608–609

Astragalus membranaceus (astragalus), 246t, 867–868, 908 breast cancer, 859–860 drug interactions, IT–9 lung cancer, 863–864 for male infertility, 317 renal cancer, 870

Astringent herbs, 595 Asymptomatic infection, 889 Atherosclerosis, 737 Athletes adaptogens for, 239–241, 240t–241t considerations with, 243–244 dehydration, 228 energy requirements, 219–220

fluid intake during training, 229–230 nutrition female triathlete, 244b–249b male swimmer, 250b–253b

racing/competition considerations, 244

Atlantoaxial instability (AAI), 750 Atopic dermatitis (AD), paediatrics and adolescence, 606–607 breastfeeding, 606 case study, 607b–608b fish oil supplementation, 606 topical treatment, 607

Atopic (Allergic) March, 26 Atopy paediatrics and adolescence, 605–606 risk factors for, 605–606 sample daily diet, 610b

respiratory illness, in Down syndrome, 739

ATP binding casseae (ABC) transporters, 183, 186 Atractylodes macrocephalae rhizome (atractylodes), 862 Atrial natriuretic peptide (ANP), 632 Atrophy, vulvovaginal, 118 Aaention deficit (hyperactivity) disorder (AD(H)D) aetiology, 711–712 autoimmunity, 712 fetal exposure, 711–712

classification, 711 dietary factors, 713 DSM-5 criteria for, 711b–712b epidemiology, 711 investigations, 713 therapeutic application herbal medicine, 716 nutritional medicine, 713–715, 715–716

therapeutic considerations, 713

Aaention, stressed, 204 Atypical antipsychotics (AAPs), 755 Australian Bureau of Statistics (ABS), 688 Australian Health Survey, 582

Australian Institute of Health and Welfare, 539 Australian Institute of Sport (AIS), 233–234 Australian Longitudinal Study of Ageing (ALSA), 656 Australian Sports Anti-Doping Authority (ASADA), 234 Autism, 17 Autism spectrum disorder (ASD), 442–443 biomedical approach, 690–711 dietary intervention, 692–693 digestive tract healing, 693–694 inflammatory and immune factors, 695–699 investigations, 699–700 lifestyle recommendations, 709 principles, 690 therapeutic application, 700–702 therapeutic considerations, 700

case study, 710b classification, 688–690 diagnosis, 690, 691b environmental factors, 690 epidemiology, 688 immune factors involved with, 689t in people with Down syndrome, 748 pharmaceutical risk factors, 690 severity levels, 692t

Autogenic training, 204, 210 Autoimmune autoantibody formula, 378t Autoimmune diseases, 164, 349–350 Autoimmune pancreatitis, 164 Autoimmunity in aaention deficit (hyperactivity) disorder (AD(H)D), 712 in autism spectrum disorder (ASD), 695–696 in Down syndrome, 752

Autosomal trisomies, 347 Avena sativa drug interactions, IT–9 male fertility treatment, 313

Ayurvedic medicine, 4, 10 Ayurvedic Vata tea, 247t

Azadirachta indica, drug interactions, IT–9 Azoospermia definition, 276b semen analysis, 341t

B Babesia, 918, 923 Baby-Friendly Hospital Initiative (BFHI), 464, 464b, 489 Baby-led weaning (BLW), 547 BLISS approach, 551 choking, 551 nutritional adequacy, 551 principle of, 550

Bachelor of Naturopathy and Yogic Sciences (BNYS), 8, 10–11 Bacopa monniera, drug interactions, IT–10 Bacteria, breast milk as source of, 472 Bacterial vaginosis (BV), 116 definition, 350 management treatment approaches, 364t–372t

Bacteroides fragilis, in autism spectrum disorder (ASD), 704 Baking soda and black strap molasses, 826t BAL, British anti-Lewisite (BAL) Balneotherapy, 102, 105, 108 Baptisia tinctoria (wild indigo), 908–909 Barker hypothesis, 393 Barosma betulina, drug interactions, IT–10 Bartonella, 918, 923 Basal body temperature (BBT), 282 Basal metabolic rate (BMR), 640 Baths arm, 103 foot, 103 cold, 103 hot, 103

hyperthermia, 105–106 neutral full, 104

sim, 103 steam, Russia, 106 therapeutic, 102–104

Beers Criteria, 659, 660t Behavioural medicine biomedical approach, 198 SBM definition of, 198

Berberine extract, drug interactions, IT–11, IT–12 Berberis aquifolium, drug interactions, IT–10 Berberis vulgaris in autism spectrum disorder (ASD), 708 drug interactions, IT–10, IT–11

Beta-adrenergic receptors, 630 Beta-alanine, sports nutrition, 236t–237t β-caryophyllene, 811 3β-dehydrogenase, 292 Beta-carotene, 902 drug interactions, IT–79 female fertility, 292 male fertility, 308

β2-glycoprotein, 349 β-myrcene, 810 β-sitosterol, drug interactions, IT–79 Beta-glucan, drug interactions, IT–79 Betaine, 161, 170t–171t Betaine HCl, drug interactions, IT–804 Betaine-homocysteine methyltransferase (BHMT), 161, 166t Beta-thalassaemia, 43 Bicarbonate soda, 826t Bifidobacterium spp., 472 B. lactis, 554 B. longum, 81–82

Bile acid sequestrants, 82 Bilirubin levels, 74–75

Biochemical pregnancy, 343 Biofeedback, 200, 213–214 Biofilm, in autism spectrum disorder (ASD), 694 Bioflavonoids benefits, RDI and source, 238t–239t female fertility, 292 for miscarriage, 361, 383t, 385t–387t

Biological nurturing, 489 Biomarkers, 166–167, 167t Biomedical approach, 198 Biomedicine, 198–199 Biomolecules, 176 Biopsychosocial model, 198–199 Biosynthesis cannabinoid, 807f of lipids, 159–160 recycling of glutathione, 158–159

Biotin (B7) drug interactions, IT–80 in pregnancy, 411

Birth defects, 394 Birth weight, 392, 539–540 2-[2-[Bis(carboxymethyl)amino] ethyl-(carboxymethyl)amino] acetic acid (EDTA), 45, 45t Bisphenol A, 69t Biaer melon, 899–900 Biaer tonic, 240t–241t Blackcurrant oil, drug interactions, IT–80 Black salve (cansema), 826t Bladder cancer, 164 chemotherapy, 873 herbal medicine, 872 nutritional medicine, 872–873 prevention, 872 radiotherapy, 873

Blastocyst, 418

Bleeding and cramping, first trimester, 427 BLISS approach, baby-led weaning (BLW), 551 Blim guss, 98–99 BLLs, Blood lead levels (BLLs) Blocked ducts, 504–509 Blood–brain barrier, 22, 583 Blood lead levels (BLLs), 44, 69–70 Blood lipid profiles, 182–187 Blood movement, principles of, 93–94 Blood sugar regulation, 75, 76f Blood tests, in aaention deficit (hyperactivity) disorder (AD(H)D), 713 Blueberry, drug interactions, IT–80 BNYS, Bachelor of Naturopathy and Yogic Sciences (BNYS) Body energy systems, 217, 218f glycogen storage, 219f

Body ecology diet (BED), 714 Body mass index (BMI), 263, 264t, 590, 664–665 Bolan's clot retraction test (CRT), in autism spectrum disorder (ASD), 700 Bone mineral density (BMD), 589, 759–760 Borrelia, 918, 923 Boswellia serrata (boswellia, frankincense), 940–941, IT–12 Boaled coconut water, 231 Brain atrophy, ageing, 628 Brain-derived neurotrophic factor (BDNF), in autism spectrum disorder (ASD), 706 Branched chain amino acids (BCAAs), drug interactions, IT–80 Branched-chain DNA (b-DNA), 891 Brassica oleracea, drug interactions, IT–12 Breast abscess, 507 anatomy of, 484–485, 485f refusal, 509–510, 510t causes of, 510t

tissue damage, 507

Breast cancer, 16, 859–860 case study, 837b–838b chemotherapy, 860–861 herbal medicine, 859 nutritional medicine, 859–860 prevention, 858–859 radiotherapy, 860 regimens, 835t supportive therapies for, 836t

Breast crawl, 489 Breast-fed infants, 17 Breastfeeding, 130, 463 atopic dermatitis (AD), 606 barriers and enablers healthcare practices, 465, 467t skin-to-skin contact, 465 social-cultural and maternal factors, 465, 466t tailored interventions, 465

behaviour and infant feeding features, 490t challenges breast milk substitutes, 497–501 breast refusal, 509–510, 510t dysmorphic milk ejection reflex (DMER), 509 family planning, 511–512 herbal galactagogues, 492–493, 493t–497t inadequate feeding frequency and feeding duration, 490 lactation insufficiency, 489–490, 491f, 491t–492t milk stasis, blocked ducts and mastitis, 504–509 nipple pain, 501–502, 502t–504t poor latch and associated ineffective milk transfer, 491 relactation, 497 tongue tie, 504 weaning, 510–511

functions, 468–474, 469t allergy prevention, 474 breast milk as source of bacteria, 472 breast milk prebiotics, 472 entero-mammary pathway, 472 immune protection, 468–470 for infant, 470 infant microbiome, nourishment, 472 for mother–baby dyad, 471–472, 471t

good referral practice, 468 historical context, 464–465

and HIV, 516 infant care, Down syndrome, 730 initiation, 488–489 lactation breast, anatomy of, 484–485, 485f galactopoiesis, 488 infant feeding cues, 488, 488t mammogenesis, 485–486, 485f oxytocin and milk ejection reflex, 487–488, 488f prolactin in, 486–487, 486f storage capacity, 488

Lyme disease, 928–929 maternal–infant hybrid immune system, 468–470, 470f maternal infant sleep and, 516–517 medications/drugs and, 512–516, 512t alcohol, 514 environmental pollutants and contaminants, 515–516 herbal medicines, 514–515, 515t infant factors, 512–513 maternal antibiotics, 513–514, 513t recreational drugs, 514

naturopath roles, 465–468 nutritional considerations impact of maternal diet on macronutrients, 482 maternal dietary themes and outcomes in offspring, 482–483 for mother, 474–483, 474b, 475t–479t

premature cessation of, 467t risk reduction of otitis media (OM), 601 Rubin's puerperal change model, 465–466, 467b sample meal plan, 474, 474b self-efficacy, 465 suboptimal, risks associated with for infants, 471–472, 471t for mothers, 471t, 472

support, 489 teething, 566 WHO recommendations for, 463

Breast milk, 543 amylase, 543 bioactive components of, 473, 473t contaminants in, 515 factors influencing transfer of medications and drugs into, 513t faay acid, 546

infant microbiome, nourishment, 472 lactose in, 558 microbiome, 482–483, 483t–484t microbiota, 115 neonatal immune system, 468–470, 470f nutrients, 543 nutritional and herbal interventions via, 552–553, 553t prebiotics, 472 probiotic treatments through, 552–553, 552t relative infant dose (RID), 513, 513t as source of bacteria, 472 substitutes, 497–501

Breathing Buteyko, 213 exercises, 204 stressed, 203–204

Breathwork components of, 213 health impacts, 213

British anti-Lewisite (BAL), 43–44, 82–83 Bromelain, drug interactions, IT–80 Budwig protocol, 826t Bupleurum falcatum (bupleurum), 374, 909 in autism spectrum disorder (ASD), 708 drug interactions, IT–12 miscarriage management, 374–375 preconception formula, 378 pregnancy formula, 378

Butyrate, 122t–123t C Cachexia, 668–669, 669t Cadmium, 69t body load, 49 clinical manifestations, 49–50 diagnostic testing, 50 management/therapy, 50 sources, 49

toxicity, 48–49

CaEDTA, 53 Caesarean birth, 392–393 post-caesarean recovery, 443 risks for offspring, 442–443 vaginal seeding, 443

Caffeine, 900 drug interactions, IT–81, IT–82 female infertility and, 289 intake, 171 male infertility and, 304 metabolism, 190–191 miscarriage and, 352 in pregnancy, 401 sports nutrition, 236t–237t

Calcidiol, 633 Calcitriol, 409, 637 Calcium, 905 absorption, 589, 678 in autism spectrum disorder (ASD), 706 benefits, RDI and source, 238t–239t colorectal cancer (CRC), 857–858 daily intake for children, 589 drug interactions, IT–82, IT–83, IT–84 female fertility, 296, 298t for lactating women, 480t–482t male fertility, 312 in middle childhood, 36 months–10 years, 589 in pregnancy, 412–413 cautions, 413 dose, 413 supplementation, 412 trimester 3, 433 trimester 2, preeclampsia management, 431–432

Calcium D-glucarate, drug interactions, IT–85 Calcium-sensing receptor (CaSR), 857–858 Calendula, 833 Calendula officinalis, 601, 603, 833

in autism spectrum disorder (ASD), 708 drug interactions, IT–13

Calming oils, 709 CAM, Complementary and Alternative Medicine (CAM) Camellia sinensis (green tea), 247t, 909, IT–13, IT–14, IT–15 Canadian Association of Naturopathic Doctors (CAND), 5, 13 Cancer, 164 bladder, 164 (, Bladder cancer) breast, 16 (, Breast cancer) cervical, protect against, 118 chemotherapy, 868–869 colon, 164 (, Colon cancer) colorectal (, Colorectal cancer) herbal medicine, 867 language and communication, 830 legality, 830–831 medical system, 830 medicinal cannabis, 824–825 natural healthcare practitioners role, 829–830 nutritional medicine, 866–867, 867–868 oncology chemotherapy, 833–835 collaboration, 831 medical staff, 831 radiation, 831–833, 832t surgery, 831

pathogenesis scientific theories on, 823 systemic evolutionary theory of, 823–824

patients decline medical treatment, 830 prevention, 866–867 prognostics of, 824 prostate, 164 (, Prostate cancer) radiotherapy, 868 and treatment, 823–829 acid/alkaline diet, 825 alternative treatments for, 826t chemotherapy, 829 controversial treatments, 827t–828t genomics and impact on, 828–829 new developments in immunotherapies, 828

precision medicine, 829 profiling and staging, 829 radiation therapies, 829 sugar feeds cancer, 825–828 targeted therapies, 828

CAND, Canadian Association of Naturopathic Doctors (CAND) Candida spp., 561–562 Cannabinoids, 268 Cannabis controversies, 814–816 dosage forms, 813, 813t pharmacodynamic interactions, 814 phytochemistry, 806–810, 807f

Cannabis, 802–816 botany and morphology, 803–805, 804f CBC, 810, 810f CBD, 809, 809f CBG, 809–810, 810f cultivation and growth cycle, 806 delta-8-THC, 810 delta-9-THC, 807–809, 808f history of use, 803 monoterpene, 810–811, 810f phytochemistry, 806–810, 807f taxonomy and nomenclature, 805–806, 805t terpene, 810–811 THCV, 809, 809f

Cannabis spp., IT–15 Cannabis pharmacokinetic interactions, 813–814 absorption, 813 metabolism, 813–814

Cannabis sativa (marijuana), 805–806, 824, 909 Cannon's model, 201–202 Capsella bursa-pastoris, drug interactions, IT–15 Capsicum spp., drug interactions, IT–15, IT–16 Carbohydrate(s), 582 absorption of, 226f digestion, 543

in foods and drinks, 231–233, 231t–233t in human milk, 473t multiple transportable, 225–226, 226f pre-race intake, 248t sports nutrition, 220, 230t choice of, 222 intake guidelines, 220–223, 220t–222t sources of, 222, 223t wholefoods vs. fuelling, 222–223

Carbohydrate loading, 219, 221t–222t, 247–248 Carbohydrate-rich foods, 900–901 Carbon filters, 21 Cardiogenesis, 419 Cardiovascular disease, 164–165, 184, 186–187, 737 Cardiovascular health assessment protocol, 180–187, 181f Cardiovascular system (CVS), 629–630, 630t, 801 Caribbean, AIDS statistics, 883 Carica papaya, drug interactions, IT–16 Carnitine in autism spectrum disorder (ASD), 707 drug interactions, IT–85 female fertility and, 290–291 male fertility and, 306–307

Carnosine, with Down syndrome, 767 Carotenoids, 483 female fertility, 292 lung cancer, 863 male fertility, 308

Carotid intima-media thickness (CIMT), 55–56 Carum carvi, drug interactions, IT–16, IT–17 Caryophyllene oxide, 811 Casein, 692 Case study atopic dermatitis (AD), 607b–608b aaention deficit (hyperactivity) disorder (AD(H)D), 717b–718b autism spectrum disorder (ASD), 710b breast cancer, 837b–838b

Down syndrome, 738b–740b, 745b–746b, 776b–777b eczema, 448b–449b gastrointestinal dysbiosis, 136t, 136b gestational diabetes (GDM), 448b–449b human immunodeficiency virus (HIV), 912b–913b lymphoma, 839b mercury (chelatable toxicants), 59b metastatic colorectal cancer, 839b–840b methylation disorder due to SNPs, 167b–168b miscarriage, 379b–387b nausea and vomiting in pregnancy (NVP), 449b–450b nutrition, 244b–253b postnatal anxiety, 450b–452b postnatal depression (PND), 450b–452b sports patient vs. non-athlete patient, 242 teenage acne, 613b vaginal dysbiosis, 119b–120b

Casomorphin factor, in autism spectrum disorder (ASD), 692–693 Casual relaxation, 204 Catabolite activator protein (CAP), 359 Catechol-O-methyltransferase (COMT), 166t, 191–192 Cat scratch fever, 918 Catharanthus roseus, drug interactions, IT–15 Caulophyllum thalictroides (blue cohosh), 285 CB1 and CB2 cannabinoid receptors, 796 CBC, 810, 810f CBD, 809, 809f CBG, 809–810, 810f CBS, Cystathionine B synthase (CBS) CD4+, 891–892 CD8+, 892 CD-57, 925 CEFALO multicentre case-control study, 23 Celery, drug interactions, IT–85 Cell cycle, 149

Cell division, 149–150 Cell-free DNA (cfDNA), 422 Cell proliferation, 149 Cells, in human milk, 473t Cellular GGT metabolises, 73 Cellular imagery, 210 Centella asiatica (gotu kola) anxiolytic activity, 378 drug interactions, IT–17 for venous distension, 313 pharmacological actions, 377 pregnancy and, 377–378

Centers for Disease Control and Prevention (CDC), 515–516, 584 Central Asia, AIDS statistics, 883 Central nervous system (CNS), 125, 755 Ceramic filters, 21 CERENAT study, 23 Cervical cancer, protect against, 118 Cervical cerclage, 346, 364t–372t Cervical fluid assessment, 283 medications affecting, 303

Cervical incompetence, 345–346, 346t causes of, 345 cerclage, 346 management treatment approaches, 364t–372t

Cervical position assessment, 283 Cetraria islandica, drug interactions, IT–17 Chamaelirium luteum anti-abortive action, 286 drug interactions, IT–17 female infertility, 300

Cheilitis, 737 Chelatable toxicants aluminium

body load, 46 clinical manifestations, 46 diagnostic testing, 46–47 management/therapy, 47 sources, 46 toxicity, 46

arsenic body load, 47 clinical manifestations, 47–48, 48f diagnostic testing, 48 management/therapy, 48 sources, 47 toxicity, 47

cadmium body load, 49 clinical manifestations, 49–50 diagnostic testing, 50 management/therapy, 50 sources, 49 toxicity, 48–49

iron body load, 51 clinical manifestations, 51 diagnostic testing, 51 management/therapy, 51 sources, 50–51 toxicity, 50, 51t

lead body load, 52 clinical manifestations, 52–53 diagnostic testing, 53 management/therapy, 53–54 sources, 52 toxicity, 52

mercury body load, 54–55 clinical manifestations, 55–56 diagnostic testing, 56 management/therapy, 56, 57f sources, 54 toxicity, 54, 55b

Chelating agent, 42–46, 43t, 76 Chelation history, 42 therapy, 42, 82–83

Chelators, pharmaceutical, 42

Chelidonium majus, drug interactions, IT–17 Chemical effects, of water, 92 Chemical exposure, miscarriage and, 352 Chemokines, in human milk, 473t Chemotherapy bladder cancer, 873 breast cancer, 860–861 cancer, 868–869 colorectal cancer (CRC), 858 combination regimens, 835 diet, 833–834 exercise, 834 general support during, 835 interaction with, 833, 833t lung cancer, 864–865 meditation, 834 melanoma of the skin, 862–863 non-Hodgkin lymphoma (NHL), 866 pancreatic cancer, 872 prostate cancer, 856–857 renal cancer, 870 side effects of, 834 sleep, 834–835

Chemotherapy-induced peripheral neuropathy (CIPN), 834 Childhood food allergies, 26 obesity, 584–585

Childhood–school-age years, of Down syndrome adaptive functioning, 732 cognitive capacity, 731–732 cognitive development impact, 732 school choices, 732

Child-led weaning, 511 Children dosage calculations for, 579–580, 580t with Down syndrome, 730 zinc depletion with dehydrating diarrhoea in, 596

Chinese herbal medicine sales, 3 Chinese medicine, 4 Choking baby-led weaning (BLW), 551 hazards, 550

Cholecystitis, atypical presentations, 643t Cholecystokinin (CCK), 378, 539, 559–560 Cholesterol efflux regulatory protein, 186 Cholesteryl ester (CE), 180–182 Choline, 170t–171t drug interactions, IT–86 for lactating women, 475t–479t in pregnancy, 411–412

Cholinergic activity, Asparagus racemosus, 377 Chondroitin sulphate, drug interactions, IT–86 Chorionic villus sampling (CVS), 423 Chromatin, 149–150, 179 Chromatin remodelling, 179 Chromium, 905 in aaention deficit (hyperactivity) disorder (AD(H)D), 714 benefits, RDI and source, 238t–239t drug interactions, IT–86 female fertility, 296, 298t male fertility, 314t for miscarriage, 361 female, 383t male partner, 385t–387t

in pregnancy, 413

Chromosomal abnormalities, miscarriage and aneuploidy, 347 monosomy X, 347 morphologically abnormal, 347 prevalence of, 347 sex chromosomal polysomy, 347 trisomies, 347

Chromosomes, 148–149, 149f

Chronic aluminium toxicity, 46 Chronic constipation, 106 Chronic disease-related malnutrition, 667–668, 669f Chronic diseases, 15–16, 68 Chronic hepatic inflammation, 71 Chronic inflammation, 26, 188–189 Chronic inflammatory response syndrome (CIRS), 32 Chronic iron overload, 50 Chronic kidney disease (CKD), 652–653 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, 662 Chronic Lyme disease, 919–920 Chronic non-communicable diseases, 19 Chronic obstructive pulmonary disease (COPD), 162 Chronic pain, 108 Chronic rhinosinusitis, in Down syndrome, 740 Chronic suppurative otitis media (CSOM), 600 Cigareae smoking, Smoking Cimicifuga racemosa, miscarriage management, 378t CIMT, Carotid intima-media thickness (CIMT) Cinnamomum zeylanicum, drug interactions, IT–17 Ciona intestinalis, 795 CIRS, Chronic inflammatory response syndrome (CIRS) Cisplatin, 835 Citrus paradisi (grapefruit seed), 939 drug interactions, IT–17, IT–18, IT–19, IT–20, IT–21, IT–22

Clark's rule for otitis media (OM), 603 for teenage acne, 612

Cleavage, 417–418 Clinical Naturopathic Medicine (CNM), 565 Clomiphene citrate, 283, 309 Clostridia spp., 693 Clove, drug interactions, IT–86

Cluster feeding, 539 1C metabolism, 146 Cnicus benedictus, drug interactions, IT–22 CNME, Council on Naturopathic Medical Education (CNME) Cobalamin (vitamin B12), 120, 160 Cobalt, 57–58 Cocaine- and amphetamine-regulated transcript (CART), 670 Cockcroft-Gault (CG) equation, 662 for creatinine clearance (CrCl), 662

Cockroaches, pest allergens, 29–30 Cocoa, drug interactions, IT–88 Coconut oil, for otitis media (OM), 602 Coconut water, 230t, 231 Codex Alimentarius Commission, 500 Cod liver oil in autism spectrum disorder (ASD), 705 drug interactions, IT–88

Codonopsis pilosula (codonopsis), 867, IT–22 Codons, 150 Coeliac disease, 190, 550 in Down syndrome, 753

Coenzyme Q10 (CoQ10), 170t–171t, 869, 904 benefits, RDI and source, 238t–239t breast cancer, 860 drug interactions, IT–86, IT–87 female reproductive health, 292 lung cancer, 864 male fertility, 308–309 melanoma of the skin, 862 miscarriage treatment, 385t–387t in pregnancy, 417

Coffea arabica, drug interactions, IT–22, IT–23 Coffee enemas, 943 in pregnancy, 401

Cognitive assessment, geriatrics, 642 Cognitive capacity, childhood–school-age years, of Down syndrome, 731–732 Cola, 230t Cold foot baths, 103 Coleus forskohlii, drug interactions, IT–23 Colic, 556–557 Collagen, 639 Colloidal silver, drug interactions, IT–89 Colon cancer, 164 Colonic hydrotherapy, 106 Colonic irrigation, 106–107 Colonic transporters, 120 Colonisation resistance, gastrointestinal microbiota, 125–126 Colorectal cancer (CRC) chemotherapy, 858 exercise, 857 herbal medicine, 857 nutritional medicine, 857–858 radiotherapy, 858 regimens, 835t supportive therapy, 835t

Colostrum, 433, 486 Combination filters, 21 Combined first trimester screening (CFTS), 422–423 free-βhCG, 422 maternal age, 422 nuchal translucency (NT), 422 pregnancy-associated plasma protein-A (PAPP-A), 422

COMET assay, 277 Commensal microflora, 609 Commiphora mukul, drug interactions, IT–24 Commiphora myrrha/molmol, drug interactions, IT–24 Complementary and allopathic medicine (CAM), 893, 898 Complementary and alternative medicine (CAM), 3

Complementary healthcare practitioner, 830 Complementary medicine (CM), 830 and polypharmacy, 655–656 in pregnancy, 392, 394

Comprehensive Geriatric Assessment (CGA), 641 Compulsive behaviours, 748 COMT, Catechol-O-methyltransferase (COMT) Concentration meditation, 206 Conception, 260 Congenital abnormality, 345 Congenital cardiac abnormalities, 727 Congenital heart defects (CHD), newborn with Down syndrome, 734–737 Congenital hypoplasia, 345 Congenital hypothyroidism, with Down syndrome, 752 Congenital uterine anomaly, 346t Conjugated linoleic acid (CLA), drug interactions, IT–89 Constipation, 745 definition, 593 functional, 593 infantile, 566–568 herbal medicine for mothers with, 567 and safety, 568b signs and symptoms, 567 supplementation, 568 treatment of, 567

organic, 593 paediatrics and adolescence, 592–595 herbal formula, 595 supplementation, 594–595 treatment, 593–594

Constitutional hydrotherapy, 101–104 Contemporary Western herbal medicine, 11 Continuing professional development (CPD), 8 Continuing professional education (CPE), 8 Continuous positive airway pressure (CPAP), 755 Contrast full bath, 103–104 Contrast hydrotherapy, 83

Contrast showers, 99 Contrast sim baths, 103 Controlled ovarian stimulation, IVF, 339–340 Cooking methods, 171 COPD, Chronic obstructive pulmonary disease (COPD) Copper drug interactions, IT–89 HIV treatment, 904 for lactating women, 480t–482t

Coptic chinensis, drug interactions, IT–24 Copy number variant, 176 CoQ10, Coenzyme Q10 (CoQ10) Cordless phones, usage, 25–26 Cordyceps mushrooms, drug interactions, IT–89, IT–90 Cordyceps spp., drug interactions, IT–24, IT–25 Corn Laws, 26 Corticotropin-releasing hormone (CRH), 428 Council on Naturopathic Medical Education (CNME), 12–13 Counselling, for infertility, 302 CPD, Continuing professional development (CPD) CPE, Continuing professional education (CPE) CpG island, 179f Cradle cap, 565 signs and symptoms, 565 therapeutic treatment, 565

Crataegus spp., drug interactions, IT–25, IT–26 C-reactive protein (CRP), 74, 183, 188–189, 415 Creatine drug interactions, IT–90 sports nutrition, 236t–237t

Crocus sativus, drug interactions, IT–26 Crown-rump length (CRL), 419–420 CRP, C-reactive protein (CRP) CRP gene, 189

Crying, infants causes of, 560–561, 561t, 561b naturopathic treatments for, 562t–563t responsiveness, 556

Cryptolepis sanguinolenta (cryptolepis root), 940 Cryptorchidism, 266, 757 Cuddle therapy, 566 Culture test, 924 Cup feeding, 489–490, 499 Curcuma longa (turmeric), 81, 768–772, 867, 909 anti-thrombotic formula, 378 in autism spectrum disorder (ASD), 708 autoimmune autoantibody formula, 378 bladder cancer, 872 breast cancer, 860 colorectal cancer (CRC), 857–858 drug interactions, IT–26, IT–27, IT–90, IT–91 lung cancer, 863–864 Lyme disease, 940 male fertility and, 308 mechanisms of action, 375–376 melanoma of the skin, 862 for miscarriage, 375–376 non-Hodgkin lymphoma (NHL), 865–866 pancreatic cancer, 870–871 prostate cancer, 855–857 renal cancer, 869 safety, 376

Cutaneous microbiome, 110–111 Cyanocobalamin (B12), in pregnancy, 406–407 Cyclic adenosine monophosphate (cAMP), 401 Cynara scolymus, drug interactions, IT–27 CYP1A1, 193 CYP1A2 caffeine metabolism gene, 190–191 CYP1B1, 193–194 Cystathionine B synthase (CBS), 166t, 193

Cysteine, 155, 158, 162 with Down syndrome, 767 for miscarriage, 359

Cystic fibrosis, 264, 265t Cytochrome P450 2E1 (CYP2E1), 77 Cytochrome P450 (CYP450) enzymes, 77, 653 Cytokine, 473t, 636–637 Cytosine, 147 Cytotoxic T cells, 888 D Daily Spiritual Experience Scale, 209 Damp-building toxicity, 68–69 Darwinian theory, 823 DASH diet, 674 Decidua basalis, 418 Decidua capsularis, 418 Decidua parietalis, 418 Deep-breathing exercises, 200 Deferasirox, 50 Deferiprone, 50 Deferoxamine (DFO), 43, 47, 51, 82–83 Deglycyrrhizinated liquorice, 833 Dehydration, 228 exercise performance, 228, 229t heat risks, 228 maintaining adequate fluid intake, 228–230 nutritional assessment, geriatrics, 645, 645b signs and symptoms, 228, 229t sweat rate, 228

Dehydroepiandrosterone (DHEA), 637–638 Dehydroepiandrosterone sulphate (DHEAS), 428 Deioniser filters, 21 Delirium

vs. dementia, 649–650, 650t geriatric syndromes, 649–650, 650t

Delivery modes, pregnancy, 392–393 Delta-8-THC, 810 Delta-9-THC, 807–809, 808f Demethylation, 147, 179 Dental examination, trimester 2, 428–429 Dental problems, in Down syndrome, 737 Deoxyribonucleotide., 148 Depression, 747 atypical presentations, 643t geriatric syndromes, 648–649, 649t

Dermatological microbiota, 110–111, 112f Dermatological system, 639 Desferrioxamine, 43 Detoxification, 68, 80–83, 104–105, 193–194 in autism spectrum disorder (ASD), 696 bile sequestrants, 82 chelation therapy, 82–83 contrast hydrotherapy, 83 diet, 80–81 exercise, 83 fertility and, 299t genetics, 194b liver, 77 manual therapy, 83 mind-body, 83 nutritional factors botanicals, 82 nutraceuticals, 81–82

sauna therapy, 83 toxin avoidance, 80 of xenobiotics, 160

Developmental Origins of Adult Health and Disease (DOHaD), 17, 393 DFI threshold, 276 DFO, Deferoxamine (DFO)

DHA, Docosahexaenoic acid (DHA) Dharana, 212 Dhyana, 212 Diabetes atypical presentations, 643t miscarriage and, 351 risk, 748

Diacylglycerol lipase (DAGL), 796 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 443 Diaper dermatitis, Nappy rash Diarrhoea, 890 causes, 595 defined, 595 infantile antibiotic-associated diarrhoea (AAD), 568–569 and safety, 570b therapeutic considerations, 568 treatment of, 569

paediatrics and adolescence, 595–597 treatment, 595–597

persistent, 596

Diary, food, fluid and training, 242–243 Diet in aaention deficit (hyperactivity) disorder (AD(H)D), 713 in autism spectrum disorder (ASD), 692–693 bladder cancer, 872 breast cancer, 859 exclusions for female infertility, 289 for male infertility, 304–305

inflammation and ageing, 674–675 lung cancer, 864 melanoma of the skin, 862 miscarriage and, 362, 363t non-Hodgkin lymphoma (NHL), 865 and nutritional issues, geriatrics, 662–679 pancreatic cancer, 871 renal cancer, 869

Dietary AGEs, 287

Dietary antioxidants, 179 Dietary exclusions alcohol, 900 in aaention deficit (hyperactivity) disorder (AD(H)D), 715 in autism spectrum disorder (ASD), 701 caffeine, 900 carbohydrate-rich foods, 900–901 female infertility, 289 male infertility, 304–305 preservatives, colourings, additives, 901 sugar, 900 trans faay acids, 901

Dietary fat, 188, 582 Dietary folates, 155 Dietary inclusions in aaention deficit (hyperactivity) disorder (AD(H)D), 714 in autism spectrum disorder (ASD), 701 biaer melon, 899–900 macrobiotic foods, 900 Momordica charantia (biaer melon), 899–900 protein, 899 Spirulina platensis (blue-green algae), 900 wholefood diet, 899 whole lemon drink, 899, 899b

Dietary nutritional medicine in aaention deficit (hyperactivity) disorder (AD(H)D) additives, 713 body ecology diet, 714 exclusions, 715 gut and psychology syndrome diet, 714 inclusions, 714 paleo diet, 714 phenol/salicylate/glutamate sensitivity, 714 sugar, 714 wholefood principles, 714

in autism spectrum disorder (ASD) exclusions, 701 inclusions, 701 low-FODMAP diet, 701 therapeutic objectives, 700

breast cancer, 858–859

colorectal cancer (CRC), 857 in Down syndrome, 763–764, 764t exclusions, 764 inclusions, 764

human immunodeficiency virus (HIV), 898–901 dietary exclusions, 900–901 dietary inclusions, 899–900 therapeutic objectives, 898–899 vegetarian diet, 901

lung cancer, 863–865 in Lyme disease, 929–934 adrenal and thyroid function, 933–934 detoxification and elimination, 932–933 healthy digestion, 933 immune function, 932 inflammation reduce, 930–932

melanoma of the skin, 861 for paediatrics and adolescence for constipation, 594 for diarrhoea, 596–597 for otitis media (OM), 602 for teenage acne, 612

pancreatic cancer, 871–872

Diethylenetriaminepentaacetic acid (DTPA), 57–58 Diet modification, 598 Digestive enzymes, 78 Digestive physiology, 171–172 Digestive repair, in aaention deficit (hyperactivity) disorder (AD(H)D), 716 Digestive tract healing, in autism spectrum disorder (ASD), 693–694 Dihydrofolate reductase (DHFR) enzyme, 192–193 Dihydrogesterone, 351 Dihydrolipoic acid (DHLA), 417 Dihydrotestosterone, 316 1,25-Dihydroxycholecalciferol (active vitamin D), 161 1-25-Dihydroxyvitamin D3, 360 3-Diindolylmethane (DIM), drug interactions, IT–75 DILI, Idiosyncratic drug-induced liver injury (DILI) Dimercaprol, 43–44, 59, 82–83 Dimercaptopropane-1-sulfonate (DMPS), 44, 50, 56, 82–83, 352

Dimercaptosuccinic acid (DMSA), 44, 56, 82–83, 352 Dimethylglycine (DMG), 161, 707 Dioscorea villosa drug interactions, IT–27 for ovarian/uterine spasm, 300

Dipsacus sylvestris (teasel root), 939 Disability Inclusion Act 2014, 723–724 Disintegrative disorders, 747 DMG, Dimethylglycine (DMG) DMPS, Dimercaptopropane-1-sulfonate (DMPS) DMSA, Dimercaptosuccinic acid (DMSA) DNA, 148 demethylation of, 179 fragmentation, sperm, 353, 375t methylation, 146, 159, 178–179, 394, 824 epigenetic modification by, 179f functions and genetic significance of, 157t imprinting, 157t suppression of mobile elements, 157t X inactivation, 157t

purine and pyrimidine bases of, 148f replication, 178 SNPs in, 177

DNA fragmentation index, 280t DNA methyltransferases (DNMT), 178 Docosahexaenoic acid (DHA), 501, 546, 581–582, 588 for lactating women, 475t–479t sperm motility, 312–313

Docosapentaenoic acid (DPA), 402 DoHAD, Developmental Origins of Adult Health and Disease (DOHaD) Donor gametes, 285 Donor milk, 499 Dopamine agonists, 351, 364t–372t Dosage for children, 579–580, 580t herbal medicines, 580 nutrients, 580

supplemental nutrition female infertility, 297, 298t male infertility, 313, 314t

Dose window theory, 22

Down syndrome, 422 accelerated ageing, 738 achalasia, 746 adolescence behaviour, 732 developing life skills, 733 expectations, 732–733

adulthood access to services and opportunities, 733 independent/supported living, 733 supported employment transition, 733 supporting carers, 734 support needs, 733–734

bone mineral density, 759–760, 761t cardiac complications, 734–737 case study, 738b–740b, 745b–746b, 776b–777b childhood–school-age years adaptive functioning, 732 cognitive capacity, 731–732 cognitive development impact, 732 school choices, 732

dental problems, 737 dermatological conditions, 737–738 diagnosis at birth, 726–727 discrimination, 723 endocrine disorders, 741 end-of-life care, 734 enhanced pregnancy care, 727, 728t–729t epilepsy, 741–745, 743t–744t electrolyte disturbances, 745 late-onset epilepsy, 742–745

family, 727 gastrointestinal tract abnormalities, 745 gene triplication, 723 haematology, 746 health concerns, 734–762, 735t–736t health literacy, 758–759 hearing, 754–755 immunology, 750–754 alopecia areata, 754 arthropathy, 754 autoimmunity, 752 coeliac disease, 753

infection susceptibility, 751 insulin-dependent diabetes mellitus, 753–754 leukaemia, 751–752 malabsorption syndromes, 753 thyroid disorders, 752–753

infant care breastfeeding, 730 developmental milestones, 731 early intervention and environmental enrichment, 730–731 initial assessment, 727–730

life expectancy and quality of life, 760 medications, 755, 755t metabolic conditions, 748–749 diabetes risk, 748 obesity risk, 748 weight management, 748–749

naturopathic support goals, 724 methylation, 724–725 peri-conception supplementation, 724

neurological conditions, 746 neuropsychology, 746–748 orthopaedic conditions, 749–750 muscular strength, 750

oxidative stress, 759 pathogenesis, 724 premature ageing, 760–762 prenatal diagnosis, 725–726 prenatal screening impact, 725–726 prevalence, 725–726 respiratory illness, 738–741 atopy, 739 ear, nose and throat (ENT) health, 739 tonsils and adenoids, 740–741

screening, 725 sexual health and relationships, 756–758 female, 757–758 male, 757

sexual health resources disabilities, with the support of carers or family members, 791–793 for parents, carers and health professionals, 787–790

sleep apnoea, 755 speech and language acquisition, 754 therapeutic application

clinical examination and investigations, 763, 763t herbal medicine, 768–772, 772t–775t lifestyle, 776 nutritional medicine (dietary), 763–764, 764t nutritional medicine (supplemental), 765–768, 766t–771t

therapeutic considerations, 762–763

D-ribose, 170t–171t Drinking water inorganic arsenic in, 47–48 pollutants, sources of, 21

Drugs, in sport, 234 Dry skin brushing, Lyme disease, 943 Dutch famine study, 177 DUTCH hormone profile, 281–282 Dysbiosis, 559, 569 in autism, 692 in gastrointestinal tract (GIT), 693 microbial composition and, 111–113 nasopharyngeal factors associated with, 113 treatment of, 113

oral and consequences, 114 oral interventions for, 114–115 diet, 114 probiotics, 114–115 saliva, 114 smoking, 114

Dyslipidaemia, 71–72, 180, 183 genetic polymorphisms associated with, 185 nutritional management of, 184–185

Dysmenorrhoea, 757–758 Dysmorphic milk ejection reflex (DMER), 509 Dys-stress, 201 E Ear drops, for otitis media (OM), 602 Early disseminated Lyme, 919 Early intervention, in Down syndrome, 730–731

Early localised Lyme, 919, 919f Early miscarriage, 257–258 Early-onset GBS sepsis (EOGBS), 433–434 Ear, nose and throat (ENT) health, in Down syndrome, 739 East and southern Africa, AIDS statistics, 883 Eastern Europe, AIDS statistics, 883 Echinacea purpurea/angustifolia, drug interactions, IT–27, IT–28 Echinacea spp., 246t, 603 HIV, 909 miscarriage management, 377 preconception formula, 378 pregnancy formula, 378

Echium amoenum, drug interactions, IT–28 ECS, Endocannabinoid system (ECS) Eczema (atopic dermatitis), 737 case study, 448b–449b topical emollient for, 607

EDCs, Endocrine-disrupting compounds (EDCs) Edinburgh Postnatal Depression Scale (EPDS), 444 Egg retrieval, IVF, 340 Ehrlichia/anaplasma, 923 EHS, Electromagnetic hypersensitivity (EHS) Eicosapentaenoic acid (EPA), 182, 402, 482, 501, 546, 581–582 Elastin, 639 Elder abuse categories of, 651t geriatric syndromes, 650, 651t risk factors, 650 WHO definition, 650

Electrolyte capsules, 230 Electromagnetic energy, sources of RF, 25 Electromagnetic field, 21–26 AC magnetic fields sources, 25 cordless phones, 25–26 health effects adributed to, 23–24

mechanism of action, 22–23 mobile phones, 25–26 portable wireless devices, 26 reduce exposure to AC magnetic fields, 25 router (modem), 26 testing for, 24–25

Electromagnetic hypersensitivity (EHS), 24 Electromagnetic waves (EMWs), 267 Electron transport chain (ETC), 150, 629 Eleutherococcus senticosus (siberian ginseng), 910, IT–28, IT–29 Elevated sperm DNA fragmentation, 281 ALA treatment, 308 outcome of, 281b

Ellagic acid, Pomegranate Embryogenesis, 146 and pregnancy, 162–164

Embryonic development, timeline of, 335–338 Embryo transfer, IVF, 340 Emissions industrial, 20 vehicle, 20

Emotional and psychological wellbeing, pregnancy, 393 Emotional distress, fertility and, 302–303 Emotional freedom technique (EFT), 353 Emotional impact, infertility, 302 Emotional resilience challenge parameter, 201 commitment, 201 control parameter, 201

Emotion, stressed, 204 Endocannabinoid system (ECS), 797–798 alkaloids, 811 anatomy of, 796–800 2-AG, 798, 799f endogenous ligands, 797–798 enzymes, 798–800 receptors, 796–797, 797b

β-caryophyllene, 811 β-myrcene, 810 Cannabis, 802–816 botany and morphology, 803–805, 804f cannabis phytochemistry, 806–810, 807f CBC, 810, 810f CBD, 809, 809f CBG, 809–810, 810f clinical deficiency, 802 controversies, 814–816 cultivation and growth cycle, 806 delta-8-THC, 810 delta-9-THC, 807–809, 808f pharmacodynamic interactions, 814 pharmacokinetic interactions, 813–814 pharmacological classes, 811–812

caryophyllene oxide, 811 enzyme variability, 802 evolution of, 795–796 flavonoids, 811 genetic polymorphisms, 802 history of use, 803 limonene, 811 monoterpene, 810–811, 810f physiology of, 800–802 cardiovascular system, 801 gastrointestinal tract, 801 immune system, 802 neurological system, 800

phytochemical synergy, 812–813 α-pinene, 810–811 receptor expression, 802 sesquiterpenes, 811 taxonomy and nomenclature, 805–806, 805t terpene, 810–811 THCV, 809, 809f

Endocrine disorders, 741 diabetes, 351 female blood tests, 354t–356t hyperprolactinaemia, 351 hypothyroidism, 351 insulin resistance, 351 luteal phase defect, 350–351

management treatment approaches, 364t–372t obesity, 351 polycystic ovary syndrome, 350 thyroid antibodies, 351

Endocrine-disrupting compounds (EDCs), 15, 17, 163 Endocrine system, 637–638, 639t Endogenous glutathione, 158 Endogenous ligands, 797–798 Endogenous prostaglandins, 634 Endogenous toxins, 71 Endometrial biopsy, 357t Endometrial polyps, 346t Endometrium, 418, 440–441 Endorphins, 634–635 Endotoxaemia, metabolic, 126 Endotoxins, 71, 313 End-state imagery, 210 Endura, 230t Endurance exercise, carbohydrate fuelling, 221t–222t Enemas, 106–107, 709 Energetic imagery, 210 Energy, requirements ageing, 671, 672t athlete, 219–220 per trimester, 397, 397t

Energy systems, 217, 218f Enteric nervous system (ENS), 125, 634–635 Entero-mammary pathway, 472, 484 Environmental chemicals, and paediatric and adolescent health, 613–616 Environmental exposures fertility and, 265–267, 319–320 miscarriage and, 351 alcohol consumption, 352 caffeine, 352 chemicals, 352

chemotherapeutic agents, 351 radiation, 352 smoking, 352 X-ray irradiation, 351

Environmental medicine, 15–16 Environmental toxicants, 68 susceptibility to, 16–19 age and timing of exposure, 17 ethnicity, 18–19 gender, 17 genetic predisposition, 16–17 gut microbiome, 17–18 nutrition, 18

Environmental triggers of disease, 19, 19f Enzyme-linked immunosorbent assay (ELISA), 891, 924 Enzymes cytochrome P450 (CYP450), 77 of methylation, 157–158 methyltransferase, 150 polymorphic phase I, 77–78 RNA polymerase II (RNAPol II), 151 xenobiotic metabolising, 19

EPA, Eicosapentaenoic acid (EPA) Ephedra sinica, drug interactions, IT–29, IT–30 Epigallocatechin-3-gallate, Green tea Epigenetic(s), 152, 153f, 176–178 in autism spectrum disorder (ASD), 696 geriatrics, 655 pregnancy, 393–394

Epigenetic biomarkers, 824 Epigenetic control of gene expression, 177 mechanisms, 153f, 164, 178f disruption of, 152 including methylation, 163f

Epigenetic lesion, 157 Epigenetic modification, 177–178 by DNA methylation, 179f effect of nutrients on, 179

Epigenetic reprogramming, 393–394 Epigenetic traits, 152 Epigenome, of mtDNA, 150 Epilepsy, in Down syndrome, 741–745, 743t–744t electrolyte disturbances, 745 late-onset epilepsy, 742–745

Epsom salt baths in autism spectrum disorder (ASD), 709 for constipation, 594 Lyme disease, 943

Equisetum arvense, drug interactions, IT–30 Eriodictyon crassifolium, drug interactions, IT–30 Erythropoietin (EPO), 633, 636 Eschscholzia californica, drug interactions, IT–30 Essential fady acids (EFAs), 903 ageing, 673 in adention deficit (hyperactivity) disorder (AD(H)D), 715 female fertility, 297, 298t male fertility, 312–313, 314t in middle childhood, 36 months–10 years, 588–590 in pregnancy, 401–402 supplements for constipation, 594 in toddler, 12–36 months, 581–582

Essential oils in autism spectrum disorder (ASD), 709 for paediatrics and adolescence, 596

Essiac formula, 855 Ethanol intake, 171 Ethylenediaminetetraacetic acid (EDTA), 352 Eucalyptus globus, drug interactions, IT–30, IT–31 Euchromatin, 179 Eugenia caryophyllata, drug interactions, IT–31 Eupatorium perfoliatum, drug interactions, IT–31 Euphrasia spp., drug interactions, IT–31 Europe and the Toxic Substance Control Act, 15

European nature cure, 90 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), 544 European Union of Naturopathy, 11, 12t European water cure, 90 Eurycoma longifolia, drug interactions, IT–31 Eustress, 201 Evening primrose oil, drug interactions, IT–91, IT–92 Evidence-based supplements, sports nutrition, 234–242, 236t–237t herbal medicines, 239–242, 240t–241t non-sports specific supplements, 237 nutrients and foods, 237, 238t–239t

Executive function, 731 Exercise carbohydrate intake during, 226f and dehydration, 228, 229t detoxification strategies, 83 and fertility, 303 habits, 171 nutritional assessment, geriatrics, 645 physiology energy metabolism, 217 energy systems, 217, 218f–219f, 218t–219t fuel sources, 217–219, 219f

trimester 2, preeclampsia management, 432

Exhaustion, pregnancy, 442 Exogenous methyl groups, 147 Exogenous toxins, 68–71 Exons, 150 Expressive language, 754 Extracellular vesicles, isolation and characterisation of, 824 Extract of G. biloba (EGb), 376 F Facial expression, 754 Factor V Leiden, 348 FAD, Flavin adenine dinucleotide (FAD)

Fad diet, 242 FADS gene, 187 Fallen arches, Pes planus Fallopia japonica, for miscarriage, 385t–387t Falls, geriatric syndromes, 648, 649t Family planning, breastfeeding and, 511–512 Fast track and standard treatment (FASTT) trial, 291 Fat absorption, 187 Fatigue, first trimester, 426–427 Fat mass and obesity-associated (FTO) gene, 188 Fat, sports nutrition, 224 adaptation strategies, 224, 224t fuel source, 224

Fady acid, 71 monounsaturated, 182 polyunsaturated, 182 production, 121, 121t–123t profiling, 180–182 saturated, 182 trans, 182

Fady acid amide hydrolase (FAAH), 796 Fady acid-binding protein 2 (FABP2), 187 Fa?y acid desaturase (FADS) gene, 187 Fecundity calculation of, 260, 260t definition, 259–260

Feeding issues, 559–560 evidence of, 560b

reflexes, 542–543

Feel-state imagery, 210 Female infertility dietary nutritional medicine advanced glycation end (AGE) products, 287 dietary exclusions, 289 fertility diet, 287–288 Mediterranean diet, 288

modified diet, 288–289 oily fish, 288 protein, 288 therapeutic objectives, 287 wholefood diet, 288

herbal medicines Actaea racemosa, 300 Alchemilla vulgaris, 298–299 Aletris farinosa, 299 Angelica sinensis, 299 Asparagus racemosus, 299–300 Chamaelirium luteum, 300 classes, 298, 299t Dioscorea villosa, 300 Glycyrrhiza glabra, 300 Paeonia lactiflora, 300 Rehmannia glutinosa, 300 therapeutic objectives, 298 Tribulus terrestris, 300–301 Viburnum prunifolium, 301 Vitex agnus-castus, 301

lifestyle interventions counselling, 302 emotional impact, 302 factors association, 301–302, 301t general recommendations, 302 lubricants, 303 physical activity, 303 stress management, 302–303

sample daily diet, 290b supplemental nutritional medicine amino acids, 290–291 antioxidants, 291–293 B vitamins, 293–295 dosage requirements, 297, 298t therapeutic objectives, 289

Female, miscarriage and findings, 382 initial appointment, 379 investigations, 380–382 management treatment approaches, 364t–372t pathology, 380t–382t preconception care, 359 screen, 273t–274t blood tests, 353, 354t–356t ultrasounds and procedures, 353, 357t

second consultation, 380

sex hormone profile, 281–282 treatment plan, 383

Female triathlete flavour fatigue, 249 food, fluid and supplement diary, 245 general information, 244 herbal medicines, 246t investigations, 245 meal plan suggestions, 245t–246t nutrient requirements, 246t pre-race nutrition protocol, 247–248 race day, 245 race morning nutrition, 248–249 race nutrition plan, 249 stomach issues, 249 systems review, 244 training schedule, 244 treatment protocol, 245–249

Fermentative gut microorganisms, 123t Fermented vegetables, in autism spectrum disorder (ASD), 701 Fermented wheat extract drug interactions, IT–92 melanoma of the skin, 863

Ferritin, 51, 438 Fertile window, 262 Fertilisation, 417 Fertility, 258 adrenal hormone profile, 281 age and, 262, 262t–263t assisted insemination, 283–284 charting, 282, 333 cervical fluid, 283 cervical position assessment, 283 waking temperature, 282–283

clinical decision making and rationale, 283 conception requirements, 258 diet, 287–288 donor gametes, 285

female general investigations, 268, 271t–272t miscarriage screen, 269, 273t–274t, 274t–275t physical examination, 262, 262t–263t sex hormone profile, 281–282 stage one investigation, 268, 269t–271t, 270b stage two investigations, 269, 272t

genitourinary infection screening, 282 historical perspective, 285–286 intracytoplasmic sperm injection, 285 in vitro fertilisation, 284–285 male, 269–275 advanced assessments, 277t andrology assessment, 277t blood assessments, 277t general assessment, 276t–277t general health assessments, 277t miscarriage screen, 281, 281t–282t physical assessment, 276t reproductive history, 276t semen analysis, 278t–280t sex hormone profile, 282 sperm chromatin structure assay, 275–277 sperm DNA damage, 277–281 urinalysis, 277t

natural, optimisation, 260–268 nutrient and toxic element screening, 281 obesity, impact on, 263, 264t ovulation induction, 283 preconception treatment, 286–287 rate, definition, 257 sperm DNA fragmentation, 277–281, 280b surrogacy, 285

Fertility Society of Australia, 257 Fetal chromosomal abnormalities, 347 Fetal development trimester 1, 417–420 week 3, 418 week 4, 419 week 5, 419 week 6, 419 week 7, 419 week 8, 419 week 9, 420 week 10, 420

week 11, 420 week 12, 420 weeks 1–2, 417–418

trimester 2, 427 weeks 13–14, 427 weeks 15–16, 427 weeks 17–18, 427 weeks 19–21, 427 weeks 22–23, 427 weeks 24–25, 427 weeks 26–27, 427

trimester 3 week 28, 432 weeks 29–33, 432–433 weeks 34–40, 433

Fetal exposure, in adention deficit (hyperactivity) disorder (AD(H)D), 711–712 Fetal heart rate, miscarriage and, 345 Fetal programming, 163 Feto-placental unit, 401 Fever digital thermometer, 554 ibuprofen, 555 in infants, 554–555 management, 555

paediatrics and adolescence, 599–600 herbal medicine, 600 management, 600

paracetamol, 555 viral infections, 554

Fibre drug interactions, IT–92 lung cancer, 863 nutritional requirements, ageing, 674

Fight or flight response, 201–202 FIGLU, Formiminoglutamic acid (FIGLU) Filipendula ulmaria, drug interactions, IT–31 First-tier tests in adention deficit (hyperactivity) disorder (AD(H)D), 713 in autism spectrum disorder (ASD), 699, 699b

Fisetin, lung cancer, 865

Fish oil for miscarriage, 360 female, 383t male partner, 385t–387t

supplementation, 482–483

Fish test, 924 Five Facet Mindfulness Questionnaire, 207 Flat feet, Pes planus Flavin adenine dinucleotide (FAD), 160–161 Flavin adenine nucleotide (FAD), 404 Flavin mononucleotide (FMN), 160–161, 404 Flavonoids, 811 in autism spectrum disorder (ASD), 706 curcumin, 54

Flaxseed breast cancer, 859 drug interactions, IT–92

Fluid intake during exercise, 228–229 for male swimmer, 251 sports and, 225

FMN, Flavin mononucleotide (FMN) Foeniculum vulgare, drug interactions, IT–31 Folate, 160 in autism spectrum disorder (ASD), 703 of Down syndrome, 724 for lactating women, 480t–482t in pregnancy, 405–406 trimester 3, pregnancy, 433

Folate cycle, 155 Folic acid, 192–193 Folic acid fortification programs, 405 Folinic acid, 170t–171t Follicle-stimulating hormone (FSH), 637–638, 757 Follicular fluid, 291 Folliculitis, 737

Follitropin alfa/beta, 283 Food additives, 609 allergy in childhood, 26 and intolerance in infants, 547–550

carbohydrate content, 231t–233t diary, 242–243 fluid and supplement diary female triathlete, 245 male swimmer, 250

fluid and training diary, 242–243 nutrients and, 237, 238t–239t of older adults, 663–664, 664t

Food and Drug Administration (FDA), 4 Foodborne disease, in pregnancy, 425, 425b Food foundations in pregnancy, 400, 400t Food neophobia, 580–581 Food polyphenols, 234t–235t Food sensitivities, 189–191, 191b Food toxicants reduce exposure to, 21 sources of, 21

Foot baths, 103 cold, 103 hot, 103

Forced expiratory volume (FEV), 631 Forced vital capacity (FVC), 631 Foreign grass pollens, 26 Formiminoglutamic acid (FIGLU), 166–167 Formula-fed infants interventions for, 500–501 probiotics in 6-month-old, 553–554 reducing infection rates in, 555

FOS, Fructooligosaccharides (FOS) Frailty, geriatric syndromes, 646–647, 647t, 647b assessment criteria, 647

clinical scale, 647t consensus statement on, 647b

Frankincense, 826t Free fady acid (FFA), 435–436 Free fady acid receptor-2 (FFAR2), 126 Free fady acid receptor-3 (FFAR3), 126 Free T3 test, 354t–356t Free T4 test, 354t–356t Fried's rule, 554, 554f Fructooligosaccharides (FOS), 119, 501 Fructose, 226 Fruits carbohydrate content, 223t, 231–233, 231t–233t estimated serves for Australian adults, 663, 664t nutritional requirements ageing, 673–674

recommended daily serves by age, 582, 582t

FTO gene, 188 Fucus vesiculosis, drug interactions, IT–32 Fuel usage breakdown, 219, 219f Full baths contrast, 103–104 neutral, 104

Functional foods, 237, 237t Functional residual capacity (FRC), 631 G GABA drug interactions, IT–94 Lyme disease, 943

Gag reflex, 551 Galacto-oligosaccharides, 500–501 Galactopoiesis, 488 Galanin, 670 Galega officinalis, drug interactions, IT–32

Gall bladder, ageing, 635–636 Gamma-glutamyl transpeptidase (GGT), 73–74, 74f Gamma-linolenic acid (GLA), drug interactions, IT–94 Ganoderma lucidum (reishi), 910, IT–32, IT–33 Garcinia mangostana (mangosteen), drug interactions, IT–33, IT–111 Garlic, drug interactions, IT–95 Gas noxious, 20 radon, 20

Gastrointestinal and hepatobiliary systems, ageing, 633–636 Gastrointestinal dysbiosis, case study, 136t, 136b Gastrointestinal food allergy, 559 Gastrointestinal microbiota, 120–135 alterations in microbiota-dysbiosis, 132 causes of dysbiosis, 132, 133t clinical assessment techniques, 131–132 composition, 126–127, 128f–129f development, 127–131 antibiotics, 130–131 breastfeeding and development of microbiome, 130 formula feeding and development of microbiome, 130 hygiene hypothesis, 131 mode of delivery and infant microbiome, 128–130 placenta and uterine environment, 128 travelled frontiers of microbiome development, 131

functions, 120–126 colonisation resistance, 125–126 immunity, 121–124 mood management, 124–125 phytochemical metabolism, 125 short-chain fady acids production, 121, 121t–123t vitamins production, 120 weight and metabolism regulation, 126, 127f

interventions to improve health of ecosystem, 132–135 prebiotic-like foods, 134, 135t prebiotics, 134, 134t probiotics, 132–134 resistant starch, 134–135

Gastrointestinal pathologies, in autism spectrum disorder (ASD), 693–694 biofilm, 694 Clostridia spp., 693

dysbiosis in, 693 paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), 694 Streptococcus spp., 694 sulfate-reducing bacteria (SRB), 693–694 Yeasts, 693

Gastrointestinal tract (GIT), 633 Down syndrome, 745 endocannabinoid system (ECS), 801 microbiota development in toddlers, 587

Gastro-oesophageal reflux disease (GORD), 557, 634 atypical presentations, 643t diagnosis of, 557, 557b reflux and normal physiology, 557 trimester 2 aetiology, 429 management, 429–430

Gatorade, 230t GCKR, Glucokinase regulatory protein (GCKR) Gender, differences in toxicant exposure, 17 Gene methylation changes in, 149 regulation, 157t structure and function, 150

Gene expression changes in, 177–178 epigenetic control of, 177 methylation and, 152 regulation of, 178

Gene-nutrient interactions, 176 General adaptation syndrome adaptive response systems, 202 alarm phase, 202 exhaustion and burnout phase, 202 resistance phase, 202

Gene silencing, 178 Gene testing, cost of, 16–17 Genetic(s)

imprinting, 163 lipid metabolism, 187b metabolic function, 189b

Genetic code, 150 Genetic diseases, inheritance padern, 264, 265t Genetic polymorphisms, 166, 185, 802 Genetic screening, regulation of, 176–177 Genetic test, 177, 179–194 Genetic variants, 177 Gene transcription, abnormal, 177 Genistein, 869 colorectal cancer (CRC), 857 pancreatic cancer, 871 renal cancer, 870

Genitourinary infection screening, 282 Genome instability theory, 823 Genomic profiling, 828–829 Genomics, 176 Genotypes apolipoprotein E (APOE), 180 lipid metabolism, 183–187 metabolic function, 187–188 risk assessment, 176–177

Genotypic resistance assay, 893 Gentiana lutea, drug interactions, IT–33 Gentle gum massage, 566 Geomagnetic field, 21–22 Georgetown Male Factor Infertility Study, 276 Geriatric(s) ageing, 627–640 cardiovascular system, 629–630, 630t dermatological system, 639 endocrine system, 637–638 gastrointestinal and hepatobiliary systems, 633–636 haematological system, 636 immune system, 636–637 metabolism and thermoregulatory changes, 640

musculoskeletal system, 638–639 nervous system, 628–629 physiology of, 628 quality of life, 641 renal system, 632–633 respiratory system, 630–632, 632t senses, 640 theories of, 628

assessment, 640–645 atypical presentation of disease, 642–644, 643t cognitive, 642 functional, 642 nutritional, 644–645, 644b potential challenges, 642

case study, 679b–680b clinical naturopathic medicine, 662 clinical presentation of ADRs in older patients, 660, 661b clinical tools for appropriate prescribing, 659 clinical trials in elderly, 652 diet and nutritional issues, 662–679 food and nutrient intake of older adults, 663–664 malnutrition, 666–671, 667f, 668t–669t, 669f nutritional strategies, 671–679 weight, 664–666

epidemiology, 627 of medication use and potential issues, 650–652

epigenetics, 655 herbal medicines, 678 lifestyle, 678–679 medication errors and adverse events, 658–659, 658f pharmacodynamics, 654 pharmacogenetics/pharmacogenomics, 654–655 pharmacokinetics, 652–654, 653t polypharmacy, 655–657, 655f posology, 660–662, 661b reducing medication-related problems in elderly patients, 659–660 syndromes, 645–650 delirium, 649–650, 650t depression, 648–649, 649t elder abuse, 650, 651t falls, 648, 649t frailty, 646–647, 647t, 647b pain, 648 sarcopenia, 647–648

under-prescribing, 657–658, 658b

Geriatric assessment, 640–645 atypical presentation of disease, 642–644, 643t cognitive, 642 functional, 642 nutritional, 644–645, 644b potential challenges, 642

Geriatric Depression Scale, 648–649 Geriatric syndromes, 645–650 delirium, 649–650, 650t depression, 648–649, 649t elder abuse, 650, 651t falls, 648, 649t frailty, 646–647, 647t, 647b pain, 648 sarcopenia, 647–648

Germinated barley foodstuff, IT–96 Germline mutation, 176 Gestation, 392 Gestational diabetes mellitus (GDM), 408, 435–437 aetiology, 435–436 assessment, 436 case study, 448b–449b complications, 436 herbal medicine, 437 medical management, 436 naturopathic management, 436–437 pathogenesis, 435–436 risk factors, 436 threshold values for diagnosis of, 436, 436t

Gestational weight gain (GWG) excessive and inadequate, 398–399 excessive maternal preconception weight, 398 in pregnancy, 397–399 underweight preconception and/or inadequate, 399

Gestational weight loss (GWL), 397–398 GG homozygosity, 188 GGT, Gamma-glutamyl transpeptidase (GGT)

Ginger, in nausea and vomiting in pregnancy (NVP), 424–425 Ginger rhizome, 424 Ginkgo biloba, 768–772 in autism spectrum disorder (ASD), 708–709 drug interactions, IT–33, IT–34, IT–35 male fertility and, 314–316 miscarriage management, 376 preconception formula, 378 pregnancy formula, 378

Ginsenoside Re, 314–316 Glibenclamide, for gestational diabetes (GDM), 436 Glioma, 23 Global health governance actions at country level, 4 regulatory systems, 4 World Health Assembly (WHA), 4–5 World Health Organization (WHO), 3–5

Glomerular filtration rate (GFR), 632–633 Glucagon-like peptide 1 (GLP-1), 126, 670 Glucocorticoids, 202 Glucokinase regulatory protein (GCKR), 185 Glucooligosaccharides, 119 Glucosamine sulphate, drug interactions, IT–96 Glucose-derived pyruvate, 828 Glucose-6-phosphatase catalytic 2 (G6PC2), 188 Glucose transporter type 2 (GLUT2), 78 Glue ear, Otitis media with effusion (OME) GLUT2, Glucose transporter type 2 (GLUT2) Glutamine, 869 benefits, RDI and source, 238t–239t breast cancer, 861 drug interactions, IT–96, IT–97 for infantile diarrhoea, 569 for miscarriage, 359 radiation, 832

Glutathione (GSH), 170t–171t, 291, 631–632

biosynthesis and recycling of, 158–159 drug interactions, IT–97 endogenous, 158

Glutathione peroxidase, 359 Glutathione-S-transferase enzymes, 194 Glutathione-S-transferase Mu 1 (GSTM-1) gene, 16 Gluten, 692 Gluten- and casein-free (GFCF) diet, 692 Gluten exorphin, in autism spectrum disorder (ASD), 692–693 Gluten-free diet, 763–764 Glycine, drug interactions, IT–97 Glycine max, drug interactions, IT–35, IT–36 Glycogen, muscle, 217–219, 219f Glycolytic system, 217, 218t Glycyrrhetinic acid, 362 Glycyrrhiza glabra (liquorice), 601, 603, 910 cautions and contraindications, 363 drug interactions, IT–36, IT–37 fertility and, 300 melanoma of the skin, 862 for miscarriage, 362–363 sports nutrition, 246t, 251t–252t

Glycyrrhizin, 362 Good referral practice breastfeeding, 468 infancy, 532–538

GORD, Gastro-oesophageal reflux disease (GORD) G6PG2 gene, 188 G protein-coupled receptor 55 (GPR55), 796 G protein-coupled receptor 119 (GPR119), 796 G protein-coupled receptor(s), 18 Grapefruit, drug interactions, IT–98, IT–99, IT–100, IT–101, IT–102, IT–103 Grass pollens, 30 Graves’ disease, with Down syndrome, 752

Green tea epigallocatechin gallate (EGCG), 772, 867 bladder cancer, 872–873 breast cancer, 859 colorectal cancer (CRC), 857–858 drug interactions, IT–103, IT–104 lung cancer, 863–864 for mild acne, 611 non-Hodgkin lymphoma (NHL), 865–866 prostate cancer, 855–856 renal cancer, 869

Grifola frondosa, drug interactions, IT–38 Grommets, for otitis media with effusion (OME), 740 Group B Streptococcus (GBS) infection, trimester 3, 433–434 early-onset GBS sepsis (EOGBS), 433–434 management, 434 maternal complications of, 434 naturopathic support, 434

Growth and developmental nutrition adolescence, 10 years and older, 590 middle childhood, 36 months–10 years, 587–588 toddler, 12–36 months, 580–581

Growth hormone (GH), 637 Grubb equation, 662 GSH, Glutathione (GSH) Guaiacum officinale, drug interactions, IT–38 Guanidinoacetate, 160t Guanine (G), 147 Guar gum, drug interactions, IT–104 Guided imagery, 209–210 Gut and psychology syndrome diet (GAPS), in adention deficit (hyperactivity) disorder (AD(H)D), 714 Gut-associated lymphoid tissue (GALT), 540, 587 Gut microbes, 18 Gut microbiome, 17–18, 27 Gut microbiota, 27, 704 Gymnema leaf, 383t, 385t–387t

Gymnema sylvestre, drug interactions, IT–38 H HAART, 898, 906, 912 Haematological disorders, 364t–372t Haematological system, 636 Hair tissue analysis, 58 HAMLET, 471 Harpagophytum procumbens, drug interactions, IT–38, IT–39 Hashimoto's thyroiditis with Down syndrome, 752 selenomethionine for, 362

Hatha Yoga, 213 Hayflick theory, 628 Hazards, choking, 550 hCG, Human chorionic gonadotrophin (hCG) Hcy, Homocysteine (Hcy) HDMs, House dust mites (HDMs) Healthcare as breastfeeding barriers and enablers, 465, 467t genetic testing in, 179–194

Hearing aids, 740–741 Heartburn, trimester 2 aetiology, 429 management, 429–430

Heart failure, atypical presentations, 643t Heat-delivering wraps, 100 Heating, ventilation and air conditioning (HVAC) systems, 31–32, 32–33 Heat-producing wrap, 100–101 Heat-reducing wraps, 99 Heavy metals breastfeeding arsenic, 516 cadmium, 516 lead, 516

mercury, 516

fertility, 266, 352

Heilpraktiker, 1 Helicobacter pylori, 127 Helper T cells, 888 Hemidesmus indicus, miscarriage management, 375 preconception formula, 378 pregnancy formula, 378

Hepatic inflammation, chronic, 71 Hepatobiliary, in autism spectrum disorder (ASD), 708 Hepatocytes, 635 Hepcidin, 636 Herbal galactagogues, 492–493, 493t–497t Herbal medicine ageing, 678 prescribing principles, 662, 663b safe and ethical management, 662, 663b

in adention deficit (hyperactivity) disorder (AD(H)D) classes, 716 digestive repair, 716 neurological, 716 therapeutic objectives, 716

in autism spectrum disorder (ASD) classes, 708 hepatobiliary, 708 immune modulators, 708 inflammation, 708 neurological, 708–709 therapeutic objectives, 708

bladder cancer, 872 breast cancer, 859 and breastfeeding, 514–515 safety considerations, 514–515, 515t

colorectal cancer (CRC), 857 Contemporary Western, 11 dosage calculations for children, 580 in Down syndrome, 768–772 female fertility, 298–301, 299t for female triathlete, 246t gestational diabetes (GDM), 437

human immunodeficiency virus (HIV) Allium sativum (garlic), 907–908 Aloe vera (aloe vera), 908 Andrographis panniculata (andrographis), 908 Arctostaphylos uva-ursi (UVA URSI), 908 Astragalus membranaceus (astragalus), 908 Baptisia tinctoria (wild indigo), 908–909 Bupleurum falcatum (bupleurum), 909 Camellia sinensis (green tea), 909 Cannabis sativa (marijuana), 909 classes, 906, 907t Curcuma longa (turmeric), 909 Echinacea spp. (echinacea), 909 Eleutherococcus senticosus (Siberian ginseng), 910 Ganoderma lucidum (reishi), 910 Glycyrrhiza glabra (liquorice), 910 HAART, 906 Hydrastis canadensis (goldenseal), 910 Hypericum perforatum (St John's wort), 910 Lentinus edodes (shiitake), 910 Olea europaea (olive leaf), 910 Panax ginseng (Korean ginseng), 910–911 Phyllanthus amarus (phyllanthus), 911 Phytolacca decandra (poke root), 911 Scutellaria baicalensis (baical skullcap), 911 Silybum marianum (St Mary's thistle), 911 Tabebuia spp. (PAU D’ARCO), 911 therapeutic objectives, 906 Ulmus spp. (slippery elm), 911–912 Uncaria tomentosa (cat's claw), 912

infantile diarrhoea, treatment of, 569 intrahepatic cholestasis of pregnancy (ICP), 435 lung cancer, 863–864 Lyme disease antimicrobial therapy, 938–939 for Borrelia, 939 brain chemistry and mood balance, 942 for co-infections, 939–940 detoxification, 941–942 immune support, 940 inflammation reduction, 940–941 neuroprotectives, 942 sleep, 942

male fertility, 313–319, 315t for male swimmer, 251t–252t non-Hodgkin lymphoma (NHL), 865–866 for paediatrics and adolescence constipation, 593–594

diarrhoea, 595–596 fever, 600 otitis media (OM), 601–602 tonsillitis, 604 warts, 604

pancreatic cancer, 870–872 postnatal depression (PND), 444–445, 452 preeclampsia management, 432 in pregnancy, 395, 396b prostate cancer, 855–857 renal cancer, 869 sales, 3 and sports performance, 239–242, 240t–241t for teenage acne, 612 teething treatment, 566

Herbal teas, 247t, 514 Herbal tincture, 514, 738 Hericium erinaceus (lion's mane), 709, 942, IT–39 Heritable thrombophilias, 348 Herxheimer reactions, Jarisch–Herxheimer reaction Hesperidin, drug interactions, IT–105 HFCS, High-fructose corn syrup (HFCS) Hibiscus sabdariffa, drug interactions, IT–39 High-density lipoprotein (HDL) nutritional modulation of, 186 sub-fractions, 183, 184f

High-density lipoprotein cholesterol (HDL-C), 183 High-energy diets, male infertility and, 305 High-fat diet, 18, 287 High-fat, low-carbohydrate (HFLC) diet, 219 High-fructose corn syrup (HFCS), 71–72 High-functioning autism (HFA), 688–690 High intensity exercise, carbohydrate fuelling, 221t–222t Hippophae rhamnoides, drug interactions, IT–39 Histone, 149 acetylation, 179 methylation, 179

N-terminus of, 179

The History of Hot and Cold Bathing (Floyer), 90 HIV, Human immunodeficiency virus (HIV) HLA-G, 349 HLA markers, 190 Homemade formula, 499–500 Homemade sports drinks, 230–231 recipe for, 230–231

Homeopathy, 10 Homeostasis, 42, 200–201 Homeostenosis, 627 Homocysteine (Hcy), 75, 155, 164–165, 894 Hormone boosters, 234t–235t in human milk, 473t

Hospitalisation, for respiratory syncytial virus (RSV), 739 Hot foot bath, 103 Hot sin baths, 103 House dust mites (HDMs), 27–28 health concerns associated with, 28 reducing levels of, 28 sources of, 27–28 testing for, 28

Hou?uynia cordata (chameleon), 940 HPO modulation, 299t 5-HTP, Lyme disease, 943 Human chorionic gonadotrophin (hCG), 260, 408, 418 during pregnancy, 339, 339t testing, 339

Human chorionic somatomammotropin (hCS), 428 Human immunodeficiency virus (HIV), 162 aetiology, 885–887 breastfeeding and, 516 case study, 912b–913b classification, 883–885

dietary nutritional medicine, 898–901 dietary exclusions, 900–901 dietary inclusions, 899–900 therapeutic objectives, 898–899 vegetarian diet, 901

differential diagnosis, 891 herbal medicine Allium sativum (garlic), 907–908 Aloe vera (aloe vera), 908 Andrographis panniculata (andrographis), 908 Arctostaphylos uva-ursi (UVA URSI), 908 Astragalus membranaceus (astragalus), 908 Baptisia tinctoria (wild indigo), 908–909 Bupleurum falcatum (bupleurum), 909 Camellia sinensis (green tea), 909 Cannabis sativa (marijuana), 909 classes, 906, 907t Curcuma longa (turmeric), 909 Echinacea spp. (echinacea), 909 Eleutherococcus senticosus (Siberian ginseng), 910 Ganoderma lucidum (reishi), 910 Glycyrrhiza glabra (liquorice), 910 HAART, 906 Hydrastis canadensis (goldenseal), 910 Hypericum perforatum (St John's wort), 910 Lentinus edodes (shiitake), 910 Olea europaea (olive leaf), 910 Panax ginseng (Korean ginseng), 910–911 Phyllanthus amarus (phyllanthus), 911 Phytolacca decandra (poke root), 911 Scutellaria baicalensis (baical skullcap), 911 Silybum marianum (St Mary's thistle), 911 Tabebuia spp. (PAU D’ARCO), 911 therapeutic objectives, 906 Ulmus spp. (slippery elm), 911–912 Uncaria tomentosa (cat's claw), 912

historical perspective, 897 lifestyle recommendations, 912, 912t monitoring, 893, 893t–894t naturopathic diagnosis, 891–893 naturopathic perspective, 897–898 pathogenesis, 887–888 conditions associated with, 890–891 infection stages, 888–890 life cycle, 887–888

prevalence in, 884t risk, 887

statistics, 883 supplemental nutritional medicine acetyl-L-carnitine, 904–905 alpha-lipoic acid, 904 beta-carotene, 902 calcium, 905 chromium, 905 coenzyme Q10, 904 copper, 904 dosage requirements, 905–906 essential fady acids, 903 iron, 903–904 magnesium, 905 N-acetylcysteine (NAC), 905 niacin and lipodystrophy, 902 probiotics, 904 selenium, 903 therapeutic objectives, 902 vitamin A, 902 vitamin B complex, 902 vitamin C, 902 vitamin D, 902–903 vitamin E, 903 zinc, 903

therapeutic application allopathic perspective, 894–895 combination therapy, 895, 895t–896t current recommendations for medication, 895t medication breaks, 897 medications classes, 895 medication timing, 895–897

therapeutic considerations, 893–897 transmission, 885–887 treatment stages, 898

Human leukocyte antigen (HLA), 349 Human milk oligosaccharides (HMOs), 472–473, 500–501 Humulus lupulus, drug interactions, IT–39, IT–40 Huderite communities, vs. Amish communities, 27 Huderite farm children, vs. Amish children, 27 Huderite farm communities, 27 Hydrastis canadensis (goldenseal), 601, 910 in autism spectrum disorder (ASD), 708 drug interactions, IT–40, IT–41

Hydration

ageing, 671 improvement strategies, 675, 675b

nutritional assessment, geriatrics, 645

Hydrogen peroxide treatment, 826t Hydrolysed glucomannan oligosaccharides (HGO), 119 Hydrotherapy colonic, 106 constitutional, 101–102 contrast, 83 naturopathic (, Naturopathic hydrotherapy)

8-Hydroxy-2'-deoxyguanosine (8-OHdG), 47 Hydroxyhaemopyrrolin-2-one (HPL), 696, 697t 5-Hydroxytryptophan (5-HTP), drug interactions, IT–76 Hygiene hypothesis, 26–27, 549 Hyperactivation, sperm, 312 Hyperbaric chambers, 826t Hyperemesis gravidarum (HG), 423 Hyperglycaemia, atypical presentations, 643t Hypericum perforatum (St John's wort), 910 drug interactions, IT–41, IT–42, IT–43, IT–44 Lyme disease, 942

Hypermethylation, 157 Hypermobility, 750 Hyperprolactinaemia, 351 chaste tree extract, 377 management treatment approaches, 364t–372t

Hypertension, trimester 2, 430–432, 430t Hyperthermal rinses, 98 Hyperthermia, 107–108, 826t baths, 105–106 guidelines for, 105 indications for, 105 treatments, 104–106

Hyperthyroidism, atypical presentations, 643t Hypnosis

definition, 210 induction, 210

Hypogonadism, 312, 757 Hypomethylation, 156 of oncogenes, 164

Hyponatraemia, 228, 230 Hypospadias, 266 Hypothalamic pituitary adrenal (HPA) axis, 202, 638 Hypothyroidism, 741 atypical presentations, 643t iodine for, 312 male vs. female, 312 miscarriage and, 351

Hysterosalpingography, 357t I ICNM, International Congress on Naturopathic Medicine (ICNM) ICSI fertilisation, 340 Idiopathic environmental intolerance to electromagnetic fields (IEI-EMF), 24 Idiopathic oligoasthenoteratospermia CoQ10 supplementation, 308–309 omega-3 fady acids, 312–313 probiotic therapy, 313 Tribestan, 316

Idiosyncratic drug-induced liver injury (DILI), 72 IEI-EMF, Idiopathic environmental intolerance to electromagnetic fields (IEI-EMF) IL-6 gene, 189 Imagery, 204, 209–210 Immune aetiologies, miscarriage and alloimmune, 349 autoimmune diseases, 349–350 female blood tests, 354t–356t infections, 350, 350b natural killer cells, 350

Immune-modulating herbs, infertility, 299t

Immune response, methylation and, 159 Immune system ageing, 636–637 endocannabinoid system (ECS), 802 gastrointestinal microbiota, 121–124 stimulation, 104–105

Immunobead test (IBT), 277t, 279t–280t Immunoglobulin A (IgA), 540 Immunology, in Down syndrome, 750–754 alopecia areata, 754 arthropathy, 754 autoimmunity, 752 coeliac disease, 753 infection susceptibility, 751 insulin-dependent diabetes mellitus, 753–754 leukaemia, 751–752 malabsorption syndromes, 753 thyroid disorders, 752–753

Immunosenescence, 636 Impaired baroreceptor sensitivity, 630 Implantation, fetal development, 418 Incompetent cervix, 345 Indole-3-carbinol breast cancer, 860 drug interactions, IT–105

Indoor allergens, 26–27 Induction, 210 Industrial emissions, 20 Inevitable miscarriage, 345 Infancy arrival, 539 common infantile presentations allergy, 565 constipation, 566–568 cradle cap, 565 diarrhoea, 568–569 nappy rash, 564–565 naturopathic management of, 552–561

oral thrush, 561–564 teething, 565–566

early intestinal microbiota, 540–542, 541f–542f, 542t fourth trimester/newborn 0–3 months, 538–539 gastrointestinal development, 542–543 carbohydrate digestion, 543 lipid digestion, 543 protein digestion, 543 xenobiotic metabolism and renal function, 543

good referral practice, 532–538 growth and development, 539–540 naturopathic management, 552–561 nutritional requirements 0–12 months, 543–544 solids, 544–551 adverse food reactions, 548, 549f commencement, 547–551, 547f developmental needs, 546 foods to avoid for infants, 550, 550b general recommendations to parents for, 551, 552b iron requirements, 545–546 sample meal planner, 547, 548f sample staged, 549t timeline, 547f

Infant breast-fed, 17 breastfeeding functions for, 470 causes of crying at weeks 6 and 10–12, 555–556, 556t colicky, 559 crying causes of, 560–561, 561t, 561b naturopathic treatments for, 562t–563t responsiveness, 556

developmental milestones, 538, 538t feeding cues, 488, 488t food allergy and intolerance in, 547–550 gut microbiota development, 540–541, 541f intake assessment, 532–533, 533b iron deficiency in, 545, 545b maternal sleep and breastfeeding, 516–517 microbiome disrupting factors, 542, 542t influencing factors, 472 nourishment, 472 transmission, maturation and perturbation, 542, 542f

non-colicky, 559 sleep location and safety, 517 traffic light tool for assessment of fever, 532, 533t

Infant gastrointestinal tract (GIT), 540 Infantile autism, 688–690 Infantile constipation, 566–568 herbal medicine for mothers with, 567 and safety, 568b signs and symptoms, 567 supplementation, 568 treatment of, 567

Infantile diarrhoea antibiotic-associated diarrhoea (AAD), 568–569 and safety, 570b therapeutic considerations, 568 treatment of, 569 herbal medicine, 569 nutritional medicine, 569

Infection acute, atypical presentations, 643t miscarriage and, 350, 350b, 354t–356t pregnancy, 425–426

Infertility, 258–259 age and, 262t allopathic assessment for, 283–285, 284f definition, 257 evolution, 259b fecundity, 259–260 female factor, 260, 261b (, Female Infertility) male factor, 260, 261b normal pregnancy rates, 259 primary, 259 scope of, 257, 258f secondary, 259 unexplained, 259

Inflammation, 762 in autism spectrum disorder (ASD), 708 chronic, 26

genetics, 190b markers, 74, 188–189

Inflammation-reducing wraps, 99 Inflammatory, in autism spectrum disorder (ASD) allergic-type symptoms, 695 allergy, 695 autoimmunity, 695–696 cytokines and chemokines, 695 detoxification, 696 epigenetics, 696 GABA, 695 glutamate, 695 heavy and toxic metals, 697–699 mastocytosis, 695 maternal transfer, 695 metallothionein, 696–697 methylation, 696 mitochondrial dysfunction, 699, 699b neuroinflammation, 695 oxidation, 696 pyrroluria/HPL, 696, 697t

Inhalation, stream, 106 Inhaled soluble particles, 46

Inherited thrombophilias, 348 Inositol drug interactions, IT–105 for miscarriage, 361

Insect allergies, 30 Insemination, assisted, 283–284 Insidious onset, 888 Insomnia, 834–835 Insulin-dependent diabetes mellitus (IDDM), 753–754 Insulin-like growth factor-1 (IGF-1), 610–611, 637 Integrated science model, 199 Integrative practitioner, 830 Intellectual disability adults with, 759 women with, 758

Intelligence quotient (IQ), 815 International Classification of Diseases 10 (ICD-10), 443 International Congress on Naturopathic Medicine (ICNM), 5 International Society of Sports Nutrition, 220–222 Interpartum interval, pregnancy, 400 INTERPHONE study, 23 Intestinal microbiota, 540–542 Intestinal parasites, 894 Intracytoplasmic sperm injection (ICSI), 281, 285, 347 Intragenic region, 150 Intrahepatic cholestasis of pregnancy (ICP), 435 aetiology, 435 herbal medicine, 435 management, 435 outcomes, 435 pathogenesis, 435 presentation, 435

Intrauterine adhesions, 346t Intravenous vitamin C (IVC), 858, 868

breast cancer, 859–860

Introns, 150 Inula helenium, drug interactions, IT–44 In vitro fertilisation (IVF), 284–285 BMI and, 302 consequences, 284 controlled ovarian stimulation, 339–340 egg retrieval, 340 embryo transfer, 340 fertilisation, 340 ICSI fertilisation, 340 micromanipulation of gametes oocytes, 340 sperm, 340

physical activity and, 303 post-implantation endometrial support, 340 protocol, 284–285 sperm retrieval, 340 vitamin E supplementation, 309

Iodine, 508, 512 benefits, RDI and source, 238t–239t breast cancer, 860 drug interactions, IT–105, IT–106 female fertility, 296–297 for lactating women, 475t–479t male fertility, 312 miscarriage and, 361 preconception treatment, 298t in pregnancy, 413–414, 433 toddler, 12-36 months, 583–584

Iris versicolor, drug interactions, IT–44 Iron in adolescence, 10 years and older, 592 in a[ention deficit (hyperactivity) disorder (AD(H)D), 715 in autism spectrum disorder (ASD), 699 benefits, RDI and source, 238t–239t body load, 51 clinical manifestations, 51

deficiency, in children, 583 diagnostic testing, 51 of Down syndrome, 724 drug interactions, IT–106, IT–107 female fertility, 297, 298t for female triathlete, 246t fortification, 546 HIV, 903–904 for lactating women, 480t–482t male fertility, 312 management/therapy, 51 in pregnancy, 414–415, 433 requirements in infants, 545–546 sources, 50–51 in toddler, 12–36 months, 583 toxicity, 50, 51t

Iron-chelating agents, 50 Iron deficiency anaemia (IDA), 437–439, 545, 583 aetiology, 437 assessment, 438 clinical features, 438 consequences, 438 management, 438–439 perineal massage, 439 risk factors, 438 supplementation, 438–439, 438t

Iron deficiency in infancy, 545, 545b Iron-fortified foods, 546 Iscador (mistletoe), 826t Islamic medicine, 11 Isoflavones, 125 J Jacobson's protocol, 211 Japanese liverwort, 811 Jarisch–Herxheimer reaction, 926 Jnana Yoga, 213

Joint Commission on Accreditation of Healthcare Organizations (JCAHO), 208 Joint hypermobility, 724 Juglans cinerea, drug interactions, IT–44, IT–45 Juniperus communis, drug interactions, IT–45 K Karma Yoga, 213 Keap1-Nrf2-ARE signalling pathway, 376 Keihi, 300 Ketogenic diet, 742 Kitchen spices, 867 Knee rinses, 98 Kneipp hydrotherapy, 108 KOALA Birth Cohort Study, 71 Krill oil, Omega-3 fa[y acids K-selection, 259b L Labour and childbirth, 439 naturopathic support, 439 preparations, 439 stages of, 440t–441t

Lactate, 123t Lactation breastfeeding breast, anatomy of, 484–485, 485f galactopoiesis, 488 infant feeding cues, 488, 488t mammogenesis, 485–486, 485f oxytocin and milk ejection reflex, 487–488, 488f prolactin in, 486–487, 486f storage capacity, 488

prolactin in, 486–487, 486f

Lactational amenorrhoea method (LAM), 511 Lactation insufficiency, 489–490, 491f, 491t–492t

Lactobacilli-dominated ecosystem, 118–119 Lactobacilli-dominated microbiota, 117–118 cervical cancer, protect against, 118 enhance fertility, 117 prevent vulvovaginal atrophy, 118 reduce HIV transmission, 117–118 reduce STI risk, 118 urinary tract infections, protect against, 118

Lactobacilli, vaginal, 115b, 118b Lactobacillus fermentum CECT 5716, 554 Lactobacillus rhamnosus GG (LGG), 554 Lactobacillus salivarius CECT5713, 508 Lactocytes, 486 Lactoferrin, 473 Lactose, 499 intolerance, 557–558 types of, 558, 558t

malabsorption testing in breastfed infants, 558 overload, 558

Lactose intolerance, 190, 596 Lactulose, 119 for constipation, 594

Laetrile, 826t Laid back nursing, 489 L-ascorbic acid, 161 Late miscarriage, 257–258 Late-onset epilepsy, 742–745 Latin America, AIDS statistics, 883 Lavation, 101 neutral, 101 and simple compresses, 101

Lavendula officinalis, drug interactions, IT–45 Laxatives, 567 LCAT, Lecithin-cholesterol acyltransferase (LCAT) LDL-C, Low-density lipoprotein cholesterol (LDL-C)

LDL-R genes, 186 Lead, 69–70, 69t, 583 body load, 52 clinical manifestations, 52–53 diagnostic testing, 53 management/therapy, 53–54 sources, 52 toxicity, 52

Lecithin, 509 Lecithin-cholesterol acyltransferase (LCAT), 182 Legumes, 674 Lentinus edodes (shiitake), 910, IT–45 Leonurus cardiaca, drug interactions, IT–45 Lepidium meyenii, drug interactions, IT–45 Leptandra virginica, drug interactions, IT–46 Leptin, 670 Leptospermum scoparium, drug interactions, IT–46 Letrozole, 283 Leukaemia, 15, 751–752 Leukonychia, 584 Leydig cells, 420 L-glutamine,

596

Life stress, unse[led and unsoothable infant, 559 Lifestyle ageing, 678–679, 679t female infertility, 301–303 male infertility, 319–320

Limonene, 811 Linoleic acid, 501 Linum usitatissimum, drug interactions, IT–46 Lipid biosynthesis of, 159–160 digestion, 543 feeding issues, 559–560 in human milk, 473t

Lipid metabolism genetics, 187b genotyping, 183–187

Lipodystrophy/lipoatrophy, 890 Lipofuscin, 629 Lipophilic toxicants, 17 Lipopolysaccharide (LPS), 126 Lipoprotein LPL hydrolyses triglycerides in, 186 metabolism, 180, 181f profiling, 183 subclass phenotyping, 182–187 sub-fraction cholesterol measurements, 183

Lipoteichoic acids, 124 Lipotropic agents, 81 Liquid herbal formulae, miscarriage, 378 Listeria monocytogenes, 425 Listeriosis, pregnancy, 425–426 Live births, 391 Live blood analysis (LBA), 700 Liver ageing, 635–636 detoxification, 77

Liver function tests (LFTs), 635 L-5-MTHF, 170t–171t Lobelia inflata, drug interactions, IT–46, IT–47 Lochia alba, 440–441 Lochia rubra, 440–441 Lochia serosa, 440–441 Long-chain polyunsaturated fa[y acid (LCPUFA), 482, 501, 546 Low-carbohydrate high-fat diets, 224 Low-density lipoprotein (LDL), 186, 411 Low-density lipoprotein cholesterol (LDL-C), 182, 183f Lower oesophageal sphincter (LOS), 634

Low-FODMAP diet, 701 Low-grade chronic inflammation, 188–189 Lp(a), 186 LPA-Intron 25, 186–187 LPS, Lipopolysaccharide (LPS) L-theanine in a[ention deficit (hyperactivity) disorder (AD(H)D), 715–716 Lyme disease, 943

Lung cancer chemotherapy, 864–865 chemotherapy agents, 837t herbal medicine, 863–864 nutritional medicine, 864 prevention, 863 radiotherapy, 864 supportive therapy for, 837t

Lupus anticoagulant (LAC), 349, 364t–372t Luteal phase defect, 350–351 chaste tree extract, 376–377 management treatment approaches, 364t–372t preconception formula, Paeonia lactiflora, 378

Lutein, drug interactions, IT–107 Luteinising hormone (LH), 350, 637–638, 757 Luteolin, 706 Lycopene, 856 drug interactions, IT–107 male fertility, 311

Lycopus virginicus, drug interactions, IT–47 Lyme disease definition, 918–919 epidemiology, 920 naturopathic approaches, 929–943 amino acids, 943 herbal medicine, 938–942 lifestyle factors, 943 nutritional therapy (dietary), 929–934 nutritional therapy (micronutrients), 938 nutritional therapy (supplements), 935–938

signs and symptoms, 921–924 Babesia, 923 Bartonella, 923 Borrelia, 923 cognitive, 922 digestive and excretory systems, 922 ears/hearing, 922 Ehrlichia/anaplasma, 923 eyes/vision, 922 general wellbeing, 923 head, face, neck, 922 musculoskeletal system, 922 neurological system, 922 psychological/psychiatric, 922 reproduction and sexuality, 922 respiratory and circulatory systems, 922 RickeDsia, 923–924 skin, 922

stages, 919–920 testing for, 924–925 adrenal testing, 925 CD-57, 925 co-infections, 925 culture test, 924 ELISA test, 924 fish test, 924 PCR test, 924 T cell test, 925 thyroid testing, 925 Western blot test, 924–925

transmission, 920–921 treatment, 925–929 allopathic, 926–927 allopathic supportive therapy, 929 antibiotic therapy, 927–929, 928t–929t Jarisch–Herxheimer reaction, 926

Lymphatic herbs, 593 Lymphoma case study, 839b regimens, 836t supportive therapies for, 836t

Lysine, drug interactions, IT–107 Lysozymes, 473 M

Maca, drug interactions, IT–108 Macrobiotic foods, 900 Magnesium, 161, 170t–171t, 905 in a[ention deficit (hyperactivity) disorder (AD(H)D), 715 in autism spectrum disorder (ASD), 706 benefits, RDI and source, 238t–239t for constipation, 594 drug interactions, IT–108, IT–109, IT–110 female fertility, 297, 298t for female triathlete, 246t for lactating women, 480t–482t male fertility, 312 miscarriage and, 361 female, 383t male partner, 385t–387t

in pregnancy, 415, 431, 433

Magnesium sulfate, 415 Magnolia spp., drug interactions, IT–47 Maitake mushrooms, drug interactions, IT–111 Malabsorption syndromes, 753 Male infertility causes of, 286 dietary nutritional medicine antioxidants, 304 dietary exclusions, 304–305 oily fish, 303 phyto-oestrogens, 304 protein, 304 therapeutic objectives, 303 wholefood diet, 303–304

herbal medicines Astragalus membranaceus, 317 Avena sativa, 313 Centella asiatica, 313 classes, 313, 315t Ginkgo biloba, 314 Mucuna pruriens, 317 Nigella sativa, 319 Panax ginseng, 314–316 Serenoa serrulata, 316 therapeutic objectives, 313 Tribulus terrestris, 316

Turnera diffusa, 316–317 Withania somnifera, 317–319, 18t

lifestyle interventions, 319 sample daily diet, 306b supplemental nutritional medicine amino acids, 305–307 antioxidants, 307–311 dosage requirements, 313, 314t therapeutic objectives, 305

Male, miscarriage and, 385 investigations, 384–385 preconception care, 359 screen tests, 281, 281t–282t, 353, 357t–358t treatment plan, 385t–387t

Male swimmer carbohydrate intake, 251 fluid intake, 251 food, fluid and supplement diary, 250 general information, 250 herbal medicines, 251t–252t investigations, 250 meal plan suggestions, 252t–253t post-training smoothie recipe, 251, 251t protein intake, 250–251 race day, 250 supplement suggestions, 251t swim meet considerations, 253 systems review, 250 training schedule, 250 treatment protocol, 250–253

Malnutrition ageing acute disease or injury-related, 668, 669f anorexia, 669–670, 670–671, 671t cachexia, 668–669, 669t chronic disease-related, 667–668, 669f contributing factors, 668t ESPEN diagnostic criteria, 666, 667b hydration, 671 nutritional assessment, 668 risks and consequences of, 667, 667f starvation-related, 667, 669f

frailty, 647 nutritional screening for, 645 sarcopenic obesity, 648

Malnutrition Screening Tool (MST), 645, 646t Mammary defence system, 505 Mammary gland, 468, 484–485 Mammary inflammation, 508f Mammogenesis, 485–486, 485f secretory activation, 486 secretory differentiation, 486 stages of, 485

Manganese, drug interactions, IT–111 Manganese superoxide dismutase MnSOD (rs4880), 191 Mantra meditation, 206 Manual therapy, 83 Markers, inflammation, 188–189 Marketing in Australia of Infant Formulas (MAIF) Agreement, 464 Marrubium vulgare, drug interactions, IT–47 Mastitis, 504–509 acute, probiotics in, 505–507 complications breast abscess, 507 breast tissue damage, 507 lowered milk supply, 507 premature cessation of breastfeeding, 507 septicaemia, 507

core management strategies for, 506t engorgement, 509 follow-up and limits of therapy, 507 herbal cream for, 506b herbal formulas for, 506b herbal medicines as adjunctive for mastitis, 506t infective vs. non-infective, 507 management of, 505 practice guidelines for referral of women with, 507b predisposing factors for, 505, 505t prevalence, 504 recurrence, prevention, 507–509

signs and symptoms of, 504t types of, 505, 505t

MAT, Methionine adenosyltransferase (MAT) Maternal age and chromosomal abnormality in newborns, 263t miscarriage and, 263t, 344, 345t

Maternal antibiotics, and breastfeeding, 513–514, 513t Maternal changes, pregnancy trimester 1, 420 trimester 2, 428 trimester 3, 433 trimester 4, 439–445

Maternal depression, infants, 558 Maternal diet on macronutrients, 482 themes, 482–483

Maternal-infant hybrid immune system, 468–470, 470f Maternal infant sleep, and breastfeeding, 516–517 Maternal MTHFR, 348 Maternal protein synthesis, 401 Maternal vitamin D deficiency, 295–296 Matricaria recutita (chamomile), 247t drug interactions, IT–47, IT–48

Matrix metalloproteinases (MMPs), 22 5-MC, 5-Methylcytosine (5-MC) ME, Metabolic endotoxaemia (ME) Meal plan suggestions female triathlete, 245t–246t male swimmer, 252t–253t

Meat consumption, renal cancer, 869 Meat stocks/bone broths, in autism spectrum disorder (ASD), 701 Mechanical effects, of water, 92 Meconium, 540–541 Median urinary iodine concentration (MUIC), 413–414 Medical cannabis, 742

Medical supplements, 236t–237t Medicago sativa, drug interactions, IT–48 Medication ageing, safe and ethical management of, 650–654, 662, 663b in pregnancy, 394

Medication errors, 658–659 adverse drug reactions (ADR), 658–659 adverse drug withdrawal events (ADWE), 659 adverse outcomes, 658, 658f defined, 658 therapeutic failure (TF), 659

Medicines regulatory authorities (MRAs), 4 Meditation, 200, 204 components of, 205–206 definition, 205 types, 206

Mediterranean diet, 482–483, 674 female infertility, 288 gestational diabetes (GDM), 436

Medium chain fa[y acids (MCFAs), 482 Melanoma of the skin during active cancer, 861–862 chemotherapy, 862–863 prevention, 861 radiotherapy, 862

Melatonin, 638, 868–869 bladder cancer, 873 breast cancer, 860–861 chaste tree induced, 377 colorectal cancer (CRC), 858 drug interactions, IT–111, IT–112 lung cancer, 864 melanoma of the skin, 863 non-Hodgkin lymphoma (NHL), 866 pancreatic cancer, 871 prostate cancer, 856–857

Melissa officinalis, drug interactions, IT–48, IT–49

Menarche, 757 Menorrhagia, 757–758 Mentha spicata, drug interactions, IT–49 Mentha x piperita, drug interactions, IT–49 Menyanthes trifoliata, drug interactions, IT–50 Mercury (chelatable toxicants), 69 body load, 54–55 clinical manifestations, 55–56 diagnostic testing, 56 management/therapy, 56, 57f pregnancy, 400–401 sources, 54 toxicity, 54, 55b case study, 59b

Meso-2,3-dimercaptosuccinic acid (DMSA), 50 Messenger RNA (mRNA), 148 Metabolic activity, of gut microbiome, 17–18 Metabolic endotoxaemia (ME), 71, 126 Metabolic energy systems, 219f Metabolic function genetics, 189b genotyping, 187–188

Metabolic pathways, 154–156 Metabolism caffeine, 190–191 lipoprotein, 180, 181f omega-3 and omega fa[y acid, 187 one-carbon, 146 phytochemical, 125 regulation, 126 and thermoregulatory changes, 640

Metabolites, 74–75 microbial, 124 toxic, 69

Metal-ion homeostasis, 42 Metallic mercury, 69

Metallothionein (MT), in autism spectrum disorder (ASD), 696–697 Metals, toxic, 42 Metaphoric imagery, 210 Metastatic colorectal cancer, case study, 839b–840b Metformin for gestational diabetes (GDM), 436 for miscarriage, 364t–372t

Methionine, 147f, 154, 160t, 170t–171t, 406–407 cycle, 154–155 for miscarriage, 360

Methionine adenosyltransferase (MAT), 161 Methionine adenosyltransferase I alpha (MAT1A), 166t Methionine cycle, 164 Methionine synthase, 155, 161 Methionine synthase reductase (MTRR), 166t, 404 Methylated B12, in autism spectrum disorder (ASD), 706 Methylation, 145, 191–193 and adverse consequences, 191t in autism spectrum disorder (ASD), 696 biochemical structures, 147–148 changes in genes, 149 cycle, 154, 154f deficits and associated conditions, 162, 162f developmental and evolutionary origins, 146 DNA, 146, 159, 178–179 of Down syndrome, 724–725 enzymes of, 157–158 epigenetic mechanisms including, 163f and gene expression, 152 genetics, 193b and immune response, 159 importance of, 145 laboratory assessment of, 165–167 biomarkers, 166–167, 167t genetic testing, 165–166 routine pathology, 167, 168t

and mitochondria, 150

nervous system physiology, 158 protein, 151–152 therapeutics and prescriptions, 168–172 dietary modifications, 169, 169t lifestyle modifications, 171–172 medications, 172 supplementation, 169–171

Methylation disorder due to SNPs, 167b–168b precursor and supportive nutrients for, 170t–171t

Methylation genetic profiling, genetic SNPs associated with, 166t Methylation nutrients, food-based sources of, 169, 169t Methylcobalamin, 155, 160, 170t–171t, 406–407 in autism spectrum disorder (ASD), 706

5-Methylcytosine (5-MC), 178–179 Methyl donors, 156, 170t–171t Methylenetetrahydrofolate (MeTHF), 160 5,10-Methylenetetrahydrofolate reductase gene (MeTHFR), 160 Methylene tetrahydrofolate reductase gene (MTHFR), 348, 423 enzyme activity, 192t gene, 165, 191–192 mutation, 364t–372t polymorphisms, 165 biochemical impact of, 165t

Methyl group, 146 chemistry and biochemistry of, 146–147 exogenous, 147

Methylmalonic acid (MMA), 166–167 Methylmercury, pregnancy, 400–401 Methylome, 163 5-Methyl-tetrahydrofolate (5-MTHF), 155, 703 Methyltransferase, 150, 157–158 Microbes, 32 Microbial community, in gut, 127 Microbial contamination, 554 Microbial folate production, 120

Microbial metabolites, 124 Microbiome, 27, 110 breast milk, 115, 482–483, 483t–484t compositional diversity, 110, 112f cutaneous, 110–111 dermatological microbiota, 110–111 melanoma of the skin, 861 nasopharyngeal microbiota, 111–113 oral microbiota, 113–115 primer in taxonomics, 111b primer on, 111b vaginal microbiota, 115–119, 116f–117f

Microbiota ageing, 674 breastmilk, 115 dermatological, 110–111, 112f gastrointestinal, 120–135 gut-brain axis, 124f infant disrupting factors, 542, 542t transmission, maturation and perturbation, 542, 542f

nasopharyngeal, 111–113 oral, 113–115 vaginal, 115–119

Microflora hypothesis, 27 Micronutrients, 18 nutritional therapy, in Lyme disease magnesium, 938 molybdenum, 938 vitamin B, 938 vitamin C, 938 vitamin D, 938 zinc, 938

in pregnancy, 403

Microwave signals, wide-band, 24 Mid-trimester morphology scan, 429 Migraine, 559 Milk, carbohydrate content, 231–233, 231t–233t Milk ejection reflex (MER), 487–488, 488f

Milk-oriented microbiome (MOM), 472 Milk stasis, 504–509 prompt recognition of, 508

Mind-body medicine, 198 definition of, 199–200 emotional resilience, 201 mechanisms of action, 200 placebo effects, 204–205, 205t polyvagal theory, 202–203 self-stressing theory, 203–204, 204t stress response, 200–201 therapeutics autogenic training, 209–211 biofeedback, 213–214 breathwork, 213 guided imagery, 209–211 hypnosis, 209–211 meditation, 205–206 mindfulness, 206–208 progressive muscle relaxation, 211 spirituality, 208–209 yoga, 211–213

Mindfulness, 204 altered areas, brain, 207 concepts, 206–207 definition, 206 Five Facet Mindfulness Questionnaire, 207 meditation, 206

Mineral(s) hair analysis, 352 for miscarriage, 361–362 preconception treatment, dosage female, 298t male, 314t

Mineralocorticoids, 202 Mini-Nutritional Assessment (MNA), 645, 646t Mini-Nutritional Assessment Short Form (MNA-SF), 645 Miscarriage aetiology, 345, 345t age and, 347–348

Allium sativum, 376 anatomical aetiologies, 345–346, 345t–346t cervical incompetence, 345–346, 345t–346t

Asparagus racemosus, 377 Bupleurum falcatum, 374–375 case study, 379b–387b female, 379–383 male partner, 384–387

Centella asiatica, 377–378 chromosomal abnormalities aneuploidy, 347 monosomy X, 347 morphologically abnormal, 347 prevalence of, 347 sex chromosomal polysomy, 347 trisomies, 347

Curcuma longa, 375–376 definition, 257–258, 343 Echinacea spp., 377 endocrine aetiologies diabetes, 351 hyperprolactinaemia, 351 hypothyroidism, 351 insulin resistance, 351 luteal phase defect, 350–351 obesity, 351 polycystic ovary syndrome, 350 thyroid antibodies, 351

environmental exposures, 351 alcohol consumption, 352 caffeine, 352 chemicals, 352 chemotherapeutic agents, 351 radiation, 352 smoking, 352 X-ray irradiation, 351

factor V Leiden mutation and, 348 genetic factors, 345t, 346–347 Ginkgo biloba, 376 Glycyrrhiza glabra, 362–363 Hemidesmus indicus, 375 immune aetiologies alloimmune diseases, 349 autoimmune diseases, 349–350 infections, 350, 350b

natural killer cells, 350

implantation, placental formation and, 268, 269t inherited thrombophilias, 348 investigations female blood tests, 353, 354t–356t female ultrasounds and procedures, 353, 357t male, 353, 357t–358t

liquid herbal formulae, 378 male factors abnormality, 352–353 management treatment approaches, female, 364t–372t nutritional medicines amino acids, 359–362 minerals, 361–362 oily fish, 362 wholefood diet, 362, 363t

Paeonia lactiflora, 363–374 paternal genetic contribution, 348 prothrombin 2021GrA mutation and, 348 Rehmannia glutinosa, 363 risks fetal heart rate, 345 by maternal age, 344, 345t by weeks of pregnancy, 344, 344f, 344t

statistics, 343–344 treatment emotional support, 353 preconception care, 359 tender love, 353 therapeutic objectives, 353–359

Vitex agnus-castus, 376–377 Withania somnifera, 377 Zingiber officinale, 378

Mitchella repens (squaw vine), miscarriage prevention, 286 Mitochondrial disorders, 150 Mitochondrial DNA (mtDNA), 150, 629 Mitochondrial dysfunction, 699, 699b Mitochondrial functions, 159 Mitochondrial methylation, 159 Mitochondrial theory, of ageing, 629 Mitochondria, methylation and, 150 Mixed anti-globulin reaction (MAR) test, 278t–280t

MMA, Monomethylarsonous acid (MMA) MMPs, Matrix metalloproteinases (MMPs) Modification Diet in Renal Disease (MDRD) equation, 662 Moisture external sources of, 31 internal sources of, 31–32 solutions for water-damaged buildings, 33 subfloor, 31

Moisture-related problems, 31 Molluscum contagiosum, paediatrics and adolescence, 605 Momordica charantia (bi[er melon), 899–900, IT–50 Monoamine oxidase A and B (MAO-A and MAO-B), 166t Monoisoamyl dimercaptosuccinic acid (MiADMSA), 48 Monomethylarsonous acid (MMA), 47, 70 Monosome, 347 Monosomy X, 347 Monoterpene, 810–811, 810f Monounsaturated fa[y acids (MUFAs), 180–182 Monozygotic twins, 110 Mood management, gastrointestinal microbiota, 124–125 Moringa oleifera folia, drug interactions, IT–50 Morus alba, drug interactions, IT–50 Mother–baby dyad, breastfeeding for, 471–472 Mould, 31–33, 68–69 clinical testing, 32 health concerns associated with, 32 house testing, 32–33 sources of, 31–32

MRAs, Medicines regulatory authorities (MRAs) mRNA, Messenger RNA (mRNA) mtDNA, Mitochondrial DNA (mtDNA) MTHFR, Methylene tetrahydrofolate reductase gene (MTHFR) MTRR, Methionine synthase reductase (MTRR) Mucuna pruriens

drug interactions, IT–50, IT–51 male infertility treatment, 317 clinical parameters, 317t hormonal parameters, 318t

MUIC, Median urinary iodine concentration (MUIC) Müllerian anomalies, 346t Multi-omics data, 824 Multiple polymorphisms, 18 Multiple pregnancy weight guidelines, 399 Multiple transportable carbohydrates, 225–226, 226f Muscle glycogen, 217–219, 219f Muscle protein synthesis (MPS), 223, 227–228, 228f Muscle relaxation therapy, 211 Muscular hypotonia, 724 Musculoskeletal system, 638–639 Mushrooms (Lentinus edodes and Ganoderma lucidum), 868–870 Mutation, 158 germline, 176 somatic, 176

Mutational theory, 823 Myeloid leukaemia of Down syndrome (ML-DS), 751 Myenteric plexus, 634 Myocardial infarction, atypical presentations, 643t Myo-inositol, 361 Myrtilli fructus, drug interactions, IT–51 N N-acetylcysteine (NAC), 45, 83, 162, 170t–171t, 307, 905 in autism spectrum disorder (ASD), 707 benefits, RDI and source, 238t–239t drug interactions, IT–113 for miscarriage, 359

N-acetyl glucosamine (NAG), 82 N-acetyl-p-benzoquinone imine, 77 N-acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD), 796

N-acyltransferase, 796 Nadi shodhana, 213 Nappy rash, 564–565 guide to eruptions in nappy area, 564, 564t treatment, 564–565

N-arachidonoyl phosphatidylethanolamine (NAPE), 798 Nasopharyngeal dysbiosis factors associated with, 113 treatment of, 113

Nasopharyngeal microbiota, 111–113 factors associated with nasopharyngeal dysbiosis, 113 microbial composition and dysbiosis, 111–113 probiotics, 113 treatment of nasopharyngeal dysbiosis, 113

National Center for Complementary and Alternative Medicine (NCCAM) mind-body medicine, definition of, 199–200

National College of Natural Medicine (NCNM), 11 National Disability Insurance Scheme (NDIS), 688 National Fertility Study, 286 National Health and Medical Research Council (NHMRC) recommendations daily intake of calcium for children, 589 fibre intake for adolescent, 592 for children, 588

protein intake for adolescent, 592

National Health and Nutrition Examination Survey (NHANES), 647 National Human Adipose Tissue Survey (NHATS), 266 National Institute for Health and Care Excellence (NICE), 532 National Institute of Allergy and Infectious Diseases, 548 National Institutes of Health (NIH), mind-body medicine, definition of, 199–200 National University of Natural Medicine (NUNM), 12–13 Na[okinase, drug interactions, IT–113 Natural fertility, optimisation baby making, 262 conception, 260 environmental factors, 265–267

exposure route, 266 radiation, 267 toxins, 266–267

frequency of intercourse, 261–262 genetic factors, 264–265, 265t maturing fertility, 261 recreational drugs, 268 smoking, 267–268 sperm production, 260–261 weight balance, 263, 264t

Natural killer (NK) cells, 350, 598 Natural medicine doctor, 1 Nature of naturopathy, 13–14 Naturheilkuner, 1 Naturopath, 3 Naturopathic clinical theory, hydrotherapy and connection to modern, 91 Naturopathic doctor, 3 Naturopathic education areas of study, 7–8 courses, 10–11 education standards, 7, 7f and training, 6–8

Naturopathic hydrotherapy colonic irrigation, 106–107 commonly prescribed treatments, 97–107 arm rinses, 98 blim guss, 98–99 contrast showers, 99 hot compresses, 100 hyperthermal rinses, 98 knee and thigh rinses, 98 rinses and douches, 97–99 warming compresses, 99–100

conducting treatments, 95–96 general treatment rules, 96 post-treatment patient care, 96 preparing the patient for treatment, 95–96

and connection to modern naturopathic clinical theory, 91 constitutional hydrotherapy, 101–102 contraindications, cautions and dysfunctional reactions, 96–97

effects of water on tissues and systems, 91–94 blood movement, 93–94 physiological responses to thermal stimuli, 92–93, 93t stimulus-reaction-regulation, 91–92 thermal, mechanical and chemical effects of water, 92

enemas, 106–107 evidence supporting therapeutic uses of water, 107–108 evolution of, 90–91 factors influencing appropriate intensity, 95 guidelines for administering, 94–96 hyperthermia treatments, 104–106 hyperthermia baths, 105–106 saunas, 105 steam therapies, 106

lavations and simple compresses, 101 modern, 90–91 therapeutic baths, 102–104 contrast full bath, 103–104 foot and arm baths, 103 neutral full bath, 104 sim baths, 103

type and intensity of application, 94–95, 95t wraps, 99–101 heat-delivering wraps, 100 heat-producing wraps, 100–101 sweat-producing wraps, 100–101

Naturopathic institutions, 8 Naturopathic medicine, 9 global scope of, 1–3 scale of, 1

Naturopathic modalities, 8 Naturopathic perspective, in autism spectrum disorder (ASD), 700 Naturopathic Physicians Licensing Examinations (NPLEX), 12–13 Naturopathic practice, 8 by world region, 1–3

Naturopathic principles, 6 Naturopathic regulation, 8–10 professional representation, 9–10 regulatory models, 9 scope of practice, 9 use of title, 9

Naturopathic teaching institutions, 6–7, 6t Naturopathic therapies, 9t Naturopathy, 1 global impact, 3 modern, 1 nature of, 13–14 practice of, 6 by world region, 10–14 African region, 10, 10t Eastern Mediterranean region, 11, 11t European region, 11 Latin America and the Caribbean region, 12 North American region, 12, 13t South East Asia region, 10, 11t Western Pacific region, 13, 14t

Nausea and vomiting in pregnancy (NVP), 423–425 aetiology, 423–424 case study, 449b–450b consequences, 424 diagnosis, 424 management, 424–425 dietary and lifestyle strategies, 425, 425b ginger, 424–425 vitamin B6, 425

risk factors, 423

NCNM, National College of Natural Medicine (NCNM) Necrosis, proximal tubular, 55 Necrospermia, 276b Neonatal intensive care and special care units (NICUs), 464–465 Neonates gastric pH, 543 pancreatic amylase level, 543

Nepeta cataria, drug interactions, IT–51 Nervines fertility treatment, 315t in pregnancy, 432

Nervine tonic, 240t–241t Nervous system, 628–629 Neural tube, 419

Neural tube defects (NTDs), 405–406 Neurodevelopmental disorders, 17 Neuro-emotional technique (NET), 353 Neuro-endocrine model, unsoothable crying, 556 Neurological system, endocannabinoid system (ECS), 800 Neuropeptide-Y (NPY), 670 Neurotransmi[ers, 156 Neutral full bath, 104 duration of, 104 indications for, 104 temperature of, 104

Neutral lavation, 101 Newborn, stomach volume of, 539 New Zealand green-lipped mussel, IT–113 NHL, Non-Hodgkin lymphoma (NHL) Niacin (B3) drug interactions, IT–114, IT–115 and lipodystrophy, 902 in pregnancy, 404

Nicotinamide, 404 drug interactions, IT–115

Nicotinamide adenine dinucleotide (NAD), 404 Nicotinamide adenine dinucleotide phosphate (NADP), 404 Nigella sativa drug interactions, IT–51, IT–52 for male infertility, 319

Nigra alba, drug interactions, IT–52 Nipple pain, 501–502 differential diagnosis of, 502t–504t

Nitrate, sports nutrition, 236t–237t Nitric oxide synthase 3 (NOS3) gene, 185 Niyamas, 212 Non-autoimmune hypothyroidism, with Down syndrome, 752 Non-coeliac gluten sensitivity, 753

Non-communicable diseases, chronic, 19 Non-genotoxic theory, 823 Non-Hodgkin lymphoma (NHL) chemotherapy, 866 herbal medicine, 865 nutritional medicine, 865–866 prevention, 865 radiotherapy, 866

Non-ionising radiation, 22–23 Non-porous water-damaged contents, 33 Non-pregnant cervix, 345 Normal pregnancy rates, 259 Normal vaginal delivery (NVD), 392 Normozoospermia, 311 Mucuna pruriens treatment, 317t–318t semen analysis, 341t Withania somnifera, 318t

North Africa, AIDS statistics, 883 North America, AIDS statistics, 883 Noxious gases, 20 NPLEX, Naturopathic Physicians Licensing Examinations (NPLEX) Nuclear DNA (nDNA), 150 Nuclear factor-kappa beta (NF-kβ), 631 Nucleic acid, 147–148 Nucleic acid sequence-based amplification (NASBA), 891 Nucleosome, 179 Nucleotide, 148, 148f NUNM, National University of Natural Medicine (NUNM) Nurses’ Health Study II, 287–288 Nutraceuticals, 18 Nutrient(s) dosage calculations for children, 580 on epigenetic modification, 179 sports performance, 237, 238t–239t and toxic element screening, 281

Nutrigenetics, 176 Nutrigenomics, 176 Nutrition considerations for breastfeeding mother, 474–483, 474b, 475t–479t impact of maternal diet on macronutrients, 482 maternal dietary themes and outcomes in offspring, 482–483

female triathlete, general and race, 244b–249b male swimmer, 250b–253b trimester 3, pregnancy, 433–439

Nutritional adequacy, baby-led weaning (BLW), 551 Nutritional assessment geriatrics components, 644–645, 644b dehydration, 645, 645b exercise, 645 hydration, 645 screening for malnutrition, 645

in pregnancy aspects of, 397 objectives, 396

Nutritional interventions, 183 Nutritional medicine for a[ention deficit (hyperactivity) disorder (AD(H)D) dietary, 713 supplemental, 715–716

for autism spectrum disorder (ASD) dietary, 700–701 supplemental, 702–707

bladder cancer, 872–873 breast cancer, 859–860 diet, 858–859

colorectal cancer (CRC), 857–858 diet, 857

for Down syndrome dietary, 763–764, 764t supplemental, 765–768, 766t–767t

female infertility diet, 287–289 supplements, 289–297

for human immunodeficiency virus (HIV) dietary, 898–901 supplemental, 902–906

infantile diarrhoea, treatment of, 569

lung cancer, 864 diet, 863–865

male infertility diet, 303–305 supplements, 305–313

management, of dyslipidaemia, 184–185 melanoma of the skin diet, 861

for miscarriage amino acids, 359–362 minerals, 361–362 oily fish, 362 wholefood diet, 362, 363t

non-Hodgkin lymphoma (NHL), 865–866 for paediatrics and adolescence dietary, 594, 596–597, 602, 612 supplementation, 593–594, 596, 598–599, 603, 605, 612 topical, 605

pancreatic cancer, 871–872 diet, 871–872

pregnancy dietary, 399–403 supplementation, 403–417

prostate cancer, 855–857 renal cancer, 869–870

Nutritional modulation, of HDL, 186 Nutritional requirements adolescence, 10 years and older, 591–592 middle childhood, 36 months–10 years, 588–590 calcium, 589 essential fa[y acids, 588–589 vitamin D, 589–590

toddler, 12–36 months, 581–587 antibiotics, 587 childhood obesity, 584–585 essential fa[y acids, 581–582 growth monitoring, 584 iodine, 583–584 iron, 583 microbiota development of gastrointestinal tract (GIT), 587 paediatric microbiome, 587 zinc, 584

Nutritional status, ageing improvement strategies, 675–676

nutritional therapy plan, 675b supplementation, 676–679, 676t

Nutritional therapy, in Lyme disease dietary, 929–934 adrenal and thyroid function, 933–934 detoxification and elimination, 932–933 healthy digestion, 933 immune function, 932 inflammation reduce, 930–932

micronutrients magnesium, 938 molybdenum, 938 vitamin B, 938 vitamin C, 938 vitamin D, 938 zinc, 938

supplements antimicrobial, 935 detoxification, 936 digestive systems, 937 energy/adrenal, 936–937 immune system support, 935–936 inflammation reduction, 935 sleep, 937–938

Nuts, carbohydrate content, 231–233, 231t–233t O Obesity ageing, 664–666, 664t childhood, 584–585 defined, 584 definition of, 351 female infertility and, 301t, 302 fertility and, 263, 264t high-energy diets and, 305 miscarriage and, 351 risk, 748

Ocimum tenuiflorum, drug interactions, IT–52 OCPs, Organochlorine pesticides (OCPs) Oestradiol, 193 Oestrone, 193

8-OHdG, Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) Oily fish, 362 female infertility, 288 male infertility, 303

Olea europaea (olive leaf), 910, 939 drug interactions, IT–53

Oligoasthenoteratospermia, idiopathic CoQ10 supplementation, 308–309 omega-3 fa[y acids, 312–313 probiotic therapy, 313

Oligoasthenoteratozoospermia (OAT) definition, 276b semen analysis, 341t

Oligospermia, ashwagandha for, 317 Oligozoospermia, 276b Mucuna pruriens treatment, 317t–318t semen analysis, 341t Withania somnifera, 318t

Omega-3 fa[y acids, 401–402, 580–582, 589, 868–869 benefits, RDI and source, 238t–239t bladder cancer, 873 breast cancer, 859, 861 colorectal cancer (CRC), 858 drug interactions, IT–116 female fertility, 297, 298t lung cancer, 864–865 male fertility and, 305, 312 melanoma of the skin, 862–863 metabolism, 187 non-Hodgkin lymphoma (NHL), 865 pancreatic cancer, 871 postnatal depression (PND), 444 prostate cancer, 855 renal cancer, 870 trimester 2, 432

Omega-6 fa[y acids, 401 Omega-3s DHA (docosahexaenoic acid), 182

Omics-based medicine, 176 ‘Omics’ revolution, 176 Omics suffix, 176 Oncogenes, hypomethylation of, 164 One carbon atom, 147f One-carbon metabolism, 146 Onychomycosis, in Down syndrome, 738 Optimal lubricant, 303 Oral dysbiosis and consequences, 114 interventions for, 114–115 diet, 114 probiotics, 114–115 saliva, 114 smoking, 114

Oral glucose tolerance test (OGTT), 436 Oral microbiota, 113–115 composition, 113–114 interventions for oral dysbiosis, 114–115 diet, 114 probiotics, 114–115 saliva, 114 smoking, 114

oral dysbiosis and consequences, 114

Oral thrush, 561–564 clinical presentation, 563 treatment of, 564

Organic acids test (OAT), 700 Organic compounds, volatile, 20 Organic contaminants, ozone oxidises, 21 Organic foods, 615 Organochlorine pesticides (OCPs), 69t, 73 Organogenesis, 419 Organophosphate pesticides, 69t, 615 Origanum vulgare (oil of oregano), 939 drug interactions, IT–53

Orthophthalates, 319–320

Osmosis, reverse, 21 Otitis media (OM), paediatrics and adolescence, 600–603 ear drops, 602 example protocol for, 602–603 herbal formula, 602 herbal tea, 603 risk reduction, 601 treatment, 601–602

Otitis media with effusion (OME), 740 Otosclerosis, 640 Ovarian ageing, 258 Ovarian hyperstimulation syndrome (OHSS), 284 Ovarian reserve, 263t assessment of, 270b

Over-the-counter (OTC) medicines, in pregnancy, 394 Overweight, ageing, 664–666, 664t Ovulation induction, 283 secondary infertility and, 259

Oxidation, 191, 407 in autism spectrum disorder (ASD), 696

Oxidative stress, 19, 22, 191, 191b, 291, 431, 759, 762 oocyte quality and, 291 sperm DNA fragmentation, 353

8-oxodG, Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) Oxygen radical absorbance capacity (ORAC), 407 Oxygen therapy, 826t Oxytocin, 471, 487–488, 488f and milk ejection reflex, 487–488

Ozone oxidises organic contaminants, 21 P Pacemaker cells, 630 Packera aurea (life root), 285–286 Paediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS), 603

with a[ention deficit (hyperactivity) disorder (AD(H)D), 712 with autism spectrum disorder (ASD), 694

Paediatric microbiome, toddler, 12-36 months, 587 Paediatrics and adolescence asthma, 608–609 atopic dermatitis (AD), 606–607 atopy, 605–606 constipation, 592–595 diarrhoea, 595–597 dosage calculations herbal medicines, 580 nutrients, 580

environmental chemicals, 613–616 fever, 599–600 growth and developmental nutrition adolescence, 10 years and older, 590 middle childhood, 36 months–10 years, 587–588 toddler, 12–36 months, 580–581

molluscum contagiosum, 605 nutritional requirements adolescence, 10 years and older, 591–592 middle childhood, 36 months–10 years, 588–590 toddler, 12–36 months, 581–587

otitis media (OM), 600–603 recurrent and chronic infections, 597–599 rhinitis, 609 teenage acne, 610–612 tonsillitis, 603–604 warts, 604–605

Paeonia lactiflora (paeonia) drug interactions, IT–53 miscarriage management, 363–374 luteal phase defect preconception formula, 378 preconception formula, 378 pregnancy formula, 378

total glucosides of peony, 363–374

Paeoniflorin, 374 Pain atypical presentations, 643t geriatric syndromes, 648 people with Down syndrome, 746

Paleo diet, in a[ention deficit (hyperactivity) disorder (AD(H)D), 714 Panax ginseng (Korean ginseng), 385t–387t, 910–911 drug interactions, IT–53, IT–54 exercise performance, 241 male fertility and, 314–316

Panax notoginseng, drug interactions, IT–55 Panax quinquefolius, drug interactions, IT–55 Pancreatic cancer during active cancer herbal medicine, 870–871 nutritional medicine, 871–872

chemotherapy, 872 prevention, 870

Pancreatic glucagon, 427 Pancreatitis, autoimmune, 164 PANDAS, Paediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) Pantothenic acid (B5), in pregnancy, 404 Papain, drug interactions, IT–117 Paracetamol, 77 in autism spectrum disorder (ASD), 690

Parathyroid gland, 419 Parathyroid hormone, 637 Parenchymal atrophy, 635 Parental MTHFR, 348 Particulate ma[er (PM), air, 70–71 Particulates, 20 Passiflora incarnata, drug interactions, IT–55 Paternal carriage, 348 PCBs, Polychlorinated biphenyls (PCBs) PCR test, 713, 924 Peanut allergy, 549–550 Pelargonium sidoides, drug interactions, IT–55 D-Penicillamine, 45, 59, 82–83 Peptic ulcer disease, atypical presentations, 643t

Peptide YY (PYY), 126 Perineal care, pregnancy, 442 Peripheral natural killer (pNK), 350 Peripheral neuropathy, 890 Peripheral vascular tonics, 315t Pernicious anaemia, 634 Peroxidase-positive leucocytes, 279t–280t, 342t Peroxisome proliferator-activated receptors (PPARs), 188 Persistent diarrhoea, 596 Persistent furunculosis (boils), 737 Persistent organic pollutants (POPs), 70, 302 Persistent rhinitis, 738–739 Pes planus, 750 Pest allergens, 29–30 Pest allergies avoiding, 30 testing for, 30

Pesticides chronic exposure of, 73 organochlorine, 73

Pet allergens, 28–29 health concerns associated with, 29 sources of, 29

Pet allergies, reduction, 29 Peumus boldus, drug interactions, IT–56 P-glycoprotein (P-gp), 653 Pharmaceutical chelators, 42 Pharmaceutical medications, 72 Pharmacodynamics, geriatrics, 654 Pharmacogenetics/pharmacogenomics, geriatrics, 654–655 Pharmacokinetics, geriatrics, 652–654, 653t Phenol/salicylate/glutamate sensitivity, 714 Phenotypic assay, 893 Phenylethanolamine N-methyltransferase (PNMT), 158

Phosphate system, 217, 218t Phosphatidylcholine, 159–160, 412 drug interactions, IT–117 synthesis, 159f

Phosphatidylethanolamine-methyltransferase (PEMT), 191–192 Phosphatidylserine, drug interactions, IT–117 Phosphoethanolamine methyltransferase (PEMT), 159 Phospholipase C (PLC), 796 Phthalates, 69t, 319–320 Phyllanthus amarus (phyllanthus), 911 Physical activity carbohydrate intake suggestions, 220t and fertility, 303, 320

Physical investigations, fertility female, 262, 262t–263t male, 276t

Physical therapy, otitis media (OM), 602 Physiological imagery, 210 Phytochemical metabolism, 125 Phytolacca americana, 603 Phytolacca decandra (poke root), 246t, 911 Phytonutrients, 673–674 Phyto-oestrogens, male fertility and, 304 Pica, 583 Picrorhiza kurroa, drug interactions, IT–56 Pimpinella anisum, drug interactions, IT–56 Pinus pinaster, drug interactions, IT–56, IT–57 Piper longum, drug interactions, IT–57 Piper methysticum (kava-kava), 811–812, IT–57, IT–58 Piscidia erythrina/piscipula, drug interactions, IT–58 Placebo effects, mind-body medicine, 204–205, 205t Plantago ovata, drug interactions, IT–58 Plant allergens, 30–31 avoiding, 31

health concerns associated with, 30–31 sources of, 30 testing for, 31

Plasma retinol, 408 Plymouth dementia screening checklist, 794 Pneumocystis jirovecii, 897 Pneumonia, atypical presentations, 643t Pollens, 28, 30 foreign grass, 26 grass, 30 sensitisation, 26

Pollutants, See specific types of pollutants Polybrominated diphenyl ethers, 69t Polychlorinated biphenyls (PCBs), 69t, 73, 74f, 515, 589 Polychlorinated dibenzofurans (PCDFs), 515

Polychlorinated dibenzo-p-dioxins (PCDDs), 515 Polycystic ovary syndrome (PCOS), 350 Polyglutamate, dietary folates in, 155 Polygonum cuspidatum (Japanese knotweed), 941 Polygonum multiflorum, drug interactions, IT–58, IT–59 Polymorphic phase I enzymes, 77–78 Polymorphisms, 16, 18 Polypharmacy, in geriatrics, 655–657, 655f complementary medicines (CM) and, 655–656 definitions, 655 risk factors for receiving, 656–657 risks of, 657

Polyphenolic antioxidants, 18 Polyphenols, 125, 483 in autism spectrum disorder (ASD), 706–707

Polysomy, 347 Polyunsaturated faTy acids (PUFAs), 180–182, 411, 581, 588 Polyvagal theory, Porges, Porges polyvagal theory Pomegranate, drug interactions, IT–117, IT–118 Poor weighing technique, 533, 538b POPs, Persistent organic pollutants (POPs) Porges’ polyvagal theory, 202 phylogenetic stages, 203, 203t trauma research, 203

Portable wireless devices, usage, 26 Posology, 660–662, 661b assessments, 661–662 frailty and pharmacotherapy, 661

Possums approach, infants crying, 561 Post-exercise nutrition considerations in eating, 227 goals, 227 protein needs, 227–228 time between training sessions, 227

Post-implantation endometrial support, IVF, 340 Postnatal depression (PND), 443–445 aetiology, 443 assessment, 444 case study, 450b–452b clinical features, 444 herbal medicine, 444–445 naturopathic approach, 444 nutrition, 444–445 pathogenesis, 443 pharmaceutical treatment, 445 risk factors, 443–444 sample daily diet, 451b supplementation, 444 symptoms, 443

Postnatal maternal mood disorders, 558–559 Postpartum haemorrhage (PPH), 440–441 Postpartum thyroiditis (PPT) aetiology, 445 assessment considerations, 445 defined, 445 naturopathic management, 445 presentation, 445 risk factors, 445

Postprandial hypotension, 634 Post-training smoothie recipe, 251t Postural stress, 203 Potassium benefits, RDI and source, 238t–239t drug interactions, IT–118, IT–119 trimester 2, preeclampsia management, 432

Potentially inappropriate medications (PIMs), 659 Potentially pathogenic microorganisms (PPMs), 125–126 PowerAde, 230t PPARs, Peroxisome proliferator-activated receptors (PPARs) PPMs, Potentially pathogenic microorganisms (PPMs)

Practice of naturopathy, 6 Practitioners, working with sportspeople, 242–244 case history, 242 considerations with athletes, 243–244 food diary, 242–243 practitioner's limits, 244 racing/competition considerations, 244 scientific and naturopathic principles, 242 special needs, 244 systems review, 243

Pranayama, 212 Pratyahara, 212 Praying, 209 Prebiotics breast milk, 472

Precision medicine, 829 Preconception treatment, 286–287 foresight research, 287 supplementation dosage requirements female, 297, 298t male, 313, 314t

zinc treatment, 287

Preeclampsia, trimester 2 consequences, 431 herbal medicine, 432 management, 431–432 naturopathic treatment, 431–432 pathophysiology, 431 risk factors, 430–431

Pre-event fuelling, carbohydrate, 221t–222t Pregnancy antenatal care, models of, 392 breastfeeding through, 511–512 care plan, 445, 446t–448t case study eczema and GDM, 448b–449b postnatal anxiety and depression, 450b–452b weight management and NVP, 449b–450b

embryogenesis and, 162–164 emotional and psychological wellbeing, 393 epidemiology gestation and birth weight, 392 live births, 391 maternal age and parity, 391 overseas-born mothers, 391 stillbirths, 391

epigenetics, 393–394 gestational weight, 397–399 excessive and inadequate, 398–399 multiple pregnancy weight guidelines, 399

guidelines for prescribing, 395, 395b and human chorionic gonadotrophin (hCG), 339, 339t labour and childbirth, 395–397, 439 naturopathic support, 439, 440t–441t preparations, 439 stages, 439, 440t–441t

modes of delivery, 392–393 naturopath roles, 392 nutritional assessment, 395–397 nutritional medicine dietary, 399–403 supplementation, 403–417

origins of disease, 393–394 safety issues critical periods in human development, 395 herbal medicines, 395, 396b medication and CM use, 394 safety, 394

trimester 1 fetal development, 417–420 maternal changes, 420 screening and assessments, 420–427

trimester 2 fetal development, 427 investigations, 428–429 maternal changes, 428 maternal conditions, 429–432

trimester 3 assessments, 433 fetal development, 432–433 maternal changes, 433 nutrition, 433–439

trimester 4, maternal changes, 439–445

Pregnancy-associated plasma protein-A (PAPP-A), 422 Pregnancy care plan, 445, 446t–448t Pregnenolone, 638 Preimplantation genetic diagnosis (PGD), 265 Preimplantation genetic testing (PGT), 258 Pre-labour rupture of the membranes (PROM), 408 Premature cessation, of breastfeeding, 467t, 507 Premenstrual mood dysphoria, 757 Prenatal screening trimester 1, 422–423 trimester 2, 429

Prescribing Indicators in Elderly Australians (PIEA), 659 Pre-sediment filters, 21 Pre-term birth, 539, 542 Pre-training, food choices, 225 Prevention (Preventare), 199 Primary healthcare practitioner, 830 Primary infertility, 259 Primary urogenital infections, 282 Proanthocyanidins, 862 Probiotics, 501, 904 in aTention deficit (hyperactivity) disorder (AD(H)D), 716 in autism spectrum disorder (ASD), 704–705, 704t, 705f benefits, RDI and source, 238t–239t drug interactions, IT–119 female fertility, 297, 298t for female triathlete, 246t male fertility, 313, 314t miscarriage, 361, 385t–387t in 6-month-old formula-fed infants, 553–554 for paediatrics and adolescence atopic dermatitis (AD), 606–607 otitis media (OM), 602 recurrent and chronic infections, 599

in pregnancy, 417

radiation, 832, 832t supplementation with, 554 therapeutic treatment of infant via mother, 552–553, 552t

Progesterone, 351 Progressive cytopenias, 890 Progressive muscle relaxation, 204, 211 Jacobson's protocol, 211 steps in, 211 training schedule, 211, 212t

Prohormones, 234t–235t Prolactin, 428 in lactation, 486–487, 486f

Propionate, 122t–123t Propolis, drug interactions, IT–119 Prostaglandins, 438 Prostate cancer, 164, 836t chemotherapy herbal medicine, 856–857 nutritional medicine, 857

exercise, 855 herbal medicine, 855 nutritional medicine, 855–856 prevention, 854–855 radiotherapy herbal medicine, 856 nutritional medicine, 856

Protein, 899 ageing, 671–673 recommendations, 672, 672t supplements, 673

for athletes, 223–224 in common serving sizes, 228, 229t digestion, 543 in human milk, 473t infertility treatment, 288, 304 muscle, synthesis, 227–228, 228f pancreatic cancer, 871 during post-training, 227–228

in pregnancy, 401, 433

Protein methylation, and post-translational modification, 151–152 Protein synthesis, 151 Proteolytic enzyme therapy, 826t Prothrombin gene mutation test female, 354t–356t male, 357t–358t

Prothrombin 2021GrA mutation, 348 Protodioscin, 316 Provocative urine testing, 76 Proximal tubular necrosis, 55 Pruritic urticarial papules and plaques of pregnancy (PUPPP), 434–435 aetiology, 434 management, 434–435 naturopathic support, 434–435 pathogenesis, 434

Psychiatric disorders, 747 Psychological imagery, 210 Psychosis, 815 Psyllium husks, 594 PUFAs, Polyunsaturated faTy acids (PUFAs) Pulmonary hypertension, 739 Pulmonary oedema, atypical presentations, 643t Pumpkin seeds, drug interactions, IT–120 Punica granatum, drug interactions, IT–59, IT–60 Purines, 147 Purple cone flower, 811–812 Pycnogenol, drug interactions, IT–120 Pygeum africanum (pygeum), 855 Pyrethroid, 70 Pyridoxal phosphate (PLP), 160, 405, 705–706, 873 Pyridoxine (B6), in pregnancy, 404–405 Pyrroluria, 696, 697t

Q Qi gong, 206 Quadruple test, 429 Quantiplex, 891 Quantitative polymerase chain reaction (Q-PCR), 891 Queen of herbs, 377 Quercetin, 81, 868–869 benefits, RDI and source, 238t–239t bladder cancer, 873 breast cancer, 861 colorectal cancer (CRC), 858 drug interactions, IT–120, IT–121, IT–122 melanoma of the skin, 862–863 non-Hodgkin lymphoma (NHL), 866 prostate cancer, 856

Quinone, 78 R Radiation female infertility, 302 fertility and, 267, 267t male infertility, 319 miscarriage and, 352 non-ionising, 22–23 oncology, 831–833, 832t calendula, 833 deglycyrrhizinated liquorice, 833 glutamine, 832 melatonin, 832–833 probiotics, 832, 832t vitamin D3, 832, 832t

treatment, 829

Radiofrequency electromagnetic energy (RF EME), 17 reduce exposure to external source, 25–26 sources of, 25

Radiofrequency radiation (RFR), 22 Radiotherapy breast cancer, 860

cancer, 868 colorectal cancer (CRC), 858 lung cancer, 864 melanoma of the skin, 862 non-Hodgkin lymphoma (NHL), 866 prostate cancer, 856

Radon gas, 20 Radula perro:etii, 811 Rapid maxillary expansion (RME), 737 Raspberry leaf, 439 Reactive oxygen species (ROS), 19, 68, 629, 759 DNA damage, 278–280 physiological levels, 291 sperm, 281

Ready-made sports drinks, 230, 230t Receptor for vitamin D (VDR), 868 Recommended dietary intakes (RDIs), 237, 238t–239t, 543 Recreational drugs, 268 and breastfeeding, 514 female fertility and, 302 male fertility and, 319

Rectal infantile food protein-induced enterocolitis syndrome (FPIES), 560t Recurrent acute otitis media, 600 Recurrent and chronic infections, 598–599, 599t Recurrent miscarriages definition, 343 incidence of, 343

Recurrent pregnancy loss, 257 Reflex effect, spinal, 94 Reflexive treatment areas, 94, 94t Regressive autism, 688–690 Regular contrast baths, 103–104 Rehmannia glutinosa (rehmannia), 246t adjuvant therapy for females, 300 drug interactions, IT–60

miscarriage management, 363 preconception formula, 378 pregnancy formula, 378

in Western herbal medicine, 363

Reishi mushrooms, drug interactions, IT–122, IT–123 Relactation, 497 Relative infant dose (RID), 513 Relaxation methods, 204 Relaxin, 428 Renal atrophy, 632–633 Renal cancer during active cancer herbal medicine, 869 nutritional medicine, 869–870

chemotherapy, 870 prevention, 869

Renal system ageing, 632–633 kidney function, 633 lower urinary tract, 633

Renal tubules, 632 Renin, 630 Renin-angiotensin-aldosterone system (RAAS), 630 Repetitive behaviours, 748 Reproductive success, 259b Residual volume (RV), 631 Resistant starch (RS), 134–135 Respiratory illness, in Down syndrome, 738–741 atopy, 739 ear, nose and throat (ENT) health, 739 tonsils and adenoids, 740–741

Respiratory syncytial virus (RSV), 739 Respiratory system, 630–632, 632t Resveratrol, 48, 868 bladder cancer, 873 breast cancer, 860

colorectal cancer (CRC), 858 Down syndrome, 767–768 drug interactions, IT–120 melanoma of the skin, 862 non-Hodgkin lymphoma (NHL), 866

Retinoid-x-receptors (RXR), 188 Retrograde ejaculatory testing, 277t Reverse osmosis, 21 RF EME, Radiofrequency electromagnetic energy (RF EME) RFR, Radiofrequency radiation (RFR) Rhamnus purshiana, drug interactions, IT–60 Rh antigen test female, 354t–356t male, 357t–358t

Rheum palmatum, drug interactions, IT–60, IT–61 Rhinitis, paediatrics and adolescence, 609 Rhodiola rosea drug interactions, IT–61, IT–62 in sports nutrition, 241, 251t–252t

Riboflavin (B2), 160–161 for lactating women, 475t–479t in pregnancy, 404

Ribonucleotides, 148 Ribosomal RNA (rRNA), 148 Ricinus communis, drug interactions, IT–62 Ricke:sia, 918, 923–924 Rife machine, 826t Rinses and douches, naturopathic hydrotherapy, 97–99 arm rinses, 98 blii guss, 98–99 contrast showers, 99 hyperthermal rinses, 98 knee and thigh rinses, 98

Risk assessment genotypes, 176–177 RNA, 148

purine and pyrimidine bases of, 148f

RNA polymerase II (RNAPol II) enzyme, 151 Rodents, pest allergens, 29–30 ROS, Reactive oxygen species (ROS) Rosmarinus officinalis, 855 in autism spectrum disorder (ASD), 708 drug interactions, IT–62 melanoma of the skin, 861–862

Router (modem), usage, 26 Rowland Universal Dementia Assessment Scale (RUDAS), 642 Royal College of Pathologists of Australasia (RCPA), 662 Royal yoga, 211–213 rRNA, Ribosomal RNA (rRNA) RS, Resistant starch (RS) R-selection, 259b rs9939609 polymorphism, 188 rs1205 TT genotype, 189 Rubin's puerperal change model, 465–466, 467b Rubus idaeus, 400–402 Rumex acetosa, drug interactions, IT–62 Rumex crispus, drug interactions, IT–62 Run, race nutrition plan, 249 Russian steam bath, 106 indications for, 106

RXR, Retinoid-x-receptors (RXR) S Saccharomyces boulardii in autism spectrum disorder (ASD), 705 drug interactions, IT–123

S-adenosyl-homocysteine (SAH), 155, 191–192 S-adenosyl-l-homocysteine, 78 S-adenosyl methionine (SAMe), 150, 154–155, 161, 170t–171t, 179, 406–407 drug interactions, IT–123

Safe Sleep Seven, 517, 517b Safety issues, in pregnancy, 394 critical periods in human development, 395 herbal medicines, 395, 396b medication and CM use, 394 safety, 394

SAH, S-adenosyl-homocysteine (SAH) Saikosaponins, 374 Salix alba, drug interactions, IT–62 Salvia divinorum, 811 Salvia miltiorrhiza, drug interactions, IT–63 Salvia officinalis, drug interactions, IT–63, IT–64 Samadhi, 213 Sambucus nigra, drug interactions, IT–64 SAMe, S-adenosyl methionine (SAMe) Sample daily diet ageing, 677b for atopy, 610b in aTention deficit (hyperactivity) disorder (AD(H)D), 714b in autism spectrum disorder (ASD), 702b in Down syndrome, 765b eczema, 449b female infertility, 290b gestational diabetes (GDM), 449b HIV, 901b Lyme disease, 934b male infertility, 306b postnatal depression (PND), 451b for teenage acne, 612b

Sample meal plan, for breastfeeding mother, 474, 474b Sandalwood essential oil therapy, 826t Sanguinaria canadensis (‘black salve’), 861 Saponins, in Tribulus terrestris, 316 Sarcopenia, 638, 647–648 obesity, 648 prevalence, 647

Saturated faTy acids, 182 Saunas, 105 Sauna therapy, 83 Scabies, in Down syndrome, 738 Scar management, Gotu kola, 377–378 Sceletium tortuosum, drug interactions, IT–64 SCFA, Short-chain faTy acids (SCFA) Schisandra chinensis (schisandra), 251t–252t, IT–64 Schizophrenia, 800, 815 Scleroderma, 164 Sclerosis, systemic, 164 Screening Tool of Older Persons (STOPP), 659, 660t Screening Tool to Alert doctors to Right Treatments (START), 659 Scrotal (testicular) ultrasonography, 277t Scutellaria baicalensis (baical skullcap), 911, IT–65 Scutellaria lateriflora (skullcap) drug interactions, IT–65 sports nutrition, 251t–252t

Seborrhoeic dermatitis, 737 Secondary infertility causes, 259 definition, 259

Secondary urogenital infections, 282 Second-tier tests in aTention deficit (hyperactivity) disorder (AD(H)D), 713 in autism spectrum disorder (ASD), 700

Secretory immunoglobulin A (SIgA), 468–470 Sedative herbs, 716 Sedentary lifestyle, fertility and, 320 Seeds, carbohydrate content, 231–233, 231t–233t Selective serotonin reuptake inhibitors (SSRIs), 690, 755 Selenium, 161, 170t–171t, 508, 589, 868, 903 antioxidant properties, 293 bladder cancer, 873

colorectal cancer (CRC), 858 drug interactions, IT–124, IT–125 female fertility, 293 for lactating women, 475t–479t male fertility, 310 for miscarriage, 362 female, 383t male partner, 385t–387t

non-Hodgkin lymphoma (NHL), 866 pancreatic cancer, 871–872 in pregnancy, 415–416, 433 prostate cancer, 856 for recurrent and chronic infections, 599

Selenoenzyme, 415–416 Selenomethionine, 362 Selenoproteins, 362 Self-focus skill, 206 Self-hypnosis, 210 Self-relaxation, 204 Self-stressing theory, 203–204 aTention, 204 body focus, 204 breathing, 203–204 emotion, 204 mind-body practices, 204t posture and position, 203 relaxation methods, 204 skeletal muscles, 203

Self-talk, 204, 209 Semen analysis, WHO 5th criteria, 357t–358t, 384–385 fertility and, 278t–280t macroscopic characteristics, 341t in mobile phone use groups, 267, 267t motility, gradation of, 341t nomenclature, 341t parameters, 341t WHO guidelines, 342t

Seminal vitamin C, 309

Senile emphysema, 631 Senses, ageing ears and hearing, 640 eyes and vision, 640 taste and smell, 640

Sensitisation, pollen, 26 Sensitivity-related illnesses (SRIs), 19 Sensory hunger, 559 Septicaemia, 507 Serenoa repens (saw palmeTo), 856 drug interactions, IT–66 female sterility, 285–286 male fertility, 286

Serine, 160t, 170t–171t Seroconversion illness, 888 Serotonin, acetyl, 160t Serrapeptase, drug interactions, IT–125 Sertoli cell metabolism, 304 Serum uric acid, 75, 75f Sesquiterpenes, 811 Seven-day food, 242 Sex chromosomal polysomy, 347 Sex hormone-binding globulin (SHBG), 637–638 Sex hormone profile female, 281–282 male, 282

Sexual function, 259 Sexual maturation, 590 Shark cartilage drug interactions, IT–125 lung cancer, 864 renal cancer, 870

Shiitake mushrooms, drug interactions, IT–125 Short-chain faTy acids (SCFA), 18, 121, 121t–123t

Siberian ginseng, 241 Silence gene transcription, 178–179 Silica, benefits, 238t–239t Silybum marianum (St Mary's thistle), 911 in autism spectrum disorder (ASD), 708 drug interactions, IT–66, IT–67

Silymarin, 82 Simplified Nutrition Assessment Questionnaire for community-dwelling adults aged 65 years and older (SNAQ65+), 645, 646t Single cell protein analysis, 824 Single-nucleotide polymorphisms (SNPs), 16, 145, 160, 176, 396 associated with methylation genetic profiling, 166t in DNA, 177

Sii baths, 103 contrast, 103 hot, 103

Skin bacterial communities, 111 biogeography of, 110

SLC30A8 gene, 188 Sleep apnoea, 755 Sleep hygiene, 171 Slippery elm powder, 594–595 drug interactions, IT–125 for infantile constipation, 567

Slow-wave sleep (SWS), 516–517 Smilax glabra (sarsaparilla), 941–942 Smilax ornata, drug interactions, IT–67 Smoking female infertility and, 301–302, 301t fertility and, 266–268 male infertility and, 319 miscarriage and, 352

Smoking cessation, 171–172 SNPs, Single-nucleotide polymorphisms (SNPs)

Society of Behavioral Medicine (SBM), 198 Sodium benefits, RDI and source, 238t–239t drug interactions, IT–125 in sports drinks, 230, 230t

Sodium bicarbonate drug interactions, IT–126, IT–127 sports nutrition, 236t–237t

Sodium-dependent glucose transporter (SGLT1), 78 Sodium sensitivity genetics, 189–190 Solidago spp., drug interactions, IT–67 Solids, infancy, 544–551 adverse food reactions, 548, 549f commencement, 547–551, 547f developmental needs, 546 foods to avoid for infants, 550, 550b general recommendations to parents for, 551, 552b iron requirements, 545–546 sample meal planner, 547, 548f sample staged, 549t timeline, 547f

Somatic cells, 149–150 Somatic mutation, 176 Southern School of Natural Therapies (SSNT), 13 Soy isoflavones, 856 drug interactions, IT–127, IT–128

Soy protein, drug interactions, IT–127, IT–128 Special athletic populations, 244 Specific hormone binding globulin (SHBG), 270t, 277t Speedy refuelling, carbohydrates, 221t–222t Sperm lubricants, effect of, 303 metabolic syndrome and, 305 production, 260–261 role of zinc, 310 selenium effects on motility, 310

vitamin E treatment, 309

Spermatogenesis folate and, 311 selenium and, 310

Spermatozoa, 150 Sperm chromatin integrity test (SCIT), 352 Sperm chromatin structure assay (SCSA), 275–277, 277t, 352–353, 357t–358t Sperm DNA fragmentation, 277–281, 353 ALA treatment, 308 causes of, 280b elevated, 281, 281b management treatment approaches, 375t treatment, 281 vitamin C treatment, 309 vitamin E treatment, 309

Sperm function, 259 Sperm retrieval, IVF, 340 Spinal reflex effect, 94 Spin mucus, Spinnbarkeit Spinnbarkeit, 283 Spiritual imagery, 210 Spirituality components of, 208 Daily Spiritual Experience Scale, 209 definition of, 208 emotion and, 208–209 and health, 208 history, 209

Spirulina, drug interactions, IT–128 Spirulina platensis (blue-green algae), 46, 900 Spontaneous abortion, Miscarriage Sport, drugs in, 234 Sports Dietitians Australia, 233–234 Sports drinks, 230–231 homemade, 230–231 ready-made, 230, 230t

sodium, 230

Sports food evidence-based supplements, 236t–237t and supplement ingredients, 234, 234t–235t

Sports nutrition, 217 AIS’ ABCD classification system, 234, 234t–235t ashwagandha, 242 carbohydrates, 220 choice of, 222 intake guidelines, 220–223, 220t–222t sources of, 222, 223t wholefoods vs. fuelling, 222–223

competitions/race days, fuelling for, 233–234 eating during training, 225–227 energy requirements, 219–220 evidence-based supplements, 234–242, 236t–237t herbal medicines, 239–242, 240t–241t non-sports specific supplements, 237 nutrients and foods, 237, 238t–239t

exercise physiology, 217–219 fat, 224 adaptation strategies, 224, 224t fuel source, 224

female triathlete, general and race, 244b–249b Korean ginseng, 241 male swimmer, 250b–253b naturopathic perspective, 226 post-exercise considerations in eating, 227 goals, 227 protein needs, 227–228 time between training sessions, 227

pre-training, 225 protein, 223–224 rhodiola, 241 Siberian ginseng, 241 working with sportspeople, 242–244 case history, 242 considerations with athletes, 243–244 food diary, 242–243 practitioner's limits, 244 racing/competition considerations, 244 scientific and naturopathic principles, 242

special needs, 244 systems review, 243

Sports patient, 242–243 Sportspeople, 242 SREBP, Sterol regulatory element binding protein (SREBP) SRIs, Sensitivity-related illnesses (SRIs) SSNT, Southern School of Natural Therapies (SSNT) Staminade sport, 230t Stanford Hypnotic Susceptibility Scale, 210 Starvation-related malnutrition, 667, 669f Stasis dermatitis, 639 Steam therapies, 106 ST-elevation myocardial infarction (STEMI), 644 Steroidal saponins, 377 Sterol regulatory element binding protein (SREBP), 180–182 Stillbirth, 391 definition of, 343 incidence of, 257 iodine and, 296 microorganisms association, 350b

Stimulants, 234t–235t Stimulation, immune system, 104–105 Stimulus, 201 Stimulus-reaction-regulation, 91–92 Strategies for Management of Anti-Retroviral Therapy (SMART) trial, 897 Stream inhalation, 106 Streptococcus agalactiae, 433–434 Streptococcus spp., 694 Stress cognitive appraisal theory, 201 definition of, 200 and fertility, 302–303 management, 171 oxidative, 19, 22, 191, 191b

Stressor, 200

Stretching exercises, 204 Subclinical hyperthyroidism, 637 Subclinical hypothyroidism, 752–753 Subfertility, 288–289 Suboptimal breastfeeding risks associated with for infants, 471–472, 471t for mothers, 471t, 472

in US, 463

Sudarshan kriya, 213 Sudden infant death syndrome (SIDS), 517 Sugar in aTention deficit (hyperactivity) disorder (AD(H)D), 714 dietary exclusions, in HIV, 900 female infertility and, 289

Sugar feeds cancer, 825–828 Sulfation, in autism spectrum disorder (ASD), 690 Sulnydryl group, 44 Sulfur, 161 Sun protection, melanoma of the skin, 861 Superoxide dismutase (SOD), 631–632 Superoxide radical-eliminating ability (SREA), 407 Supplemental nutritional medicine ageing, 676–679, 676t prescribing principles, 662, 663b safe and ethical management, 662, 663b

in aTention deficit (hyperactivity) disorder (AD(H)D) antioxidant nutrients, 716 dosage requirements, 716 essential faTy acids, 715 iron, 715 L-theanine, 715–716 magnesium, 715 probiotics, 716 vitamin B6, 715 vitamin D, 715 zinc, 715

in autism spectrum disorder (ASD) calcium, 706 carnitine, 707

dimethylglycine and trimethylglycine, 707 dosage requirements, 707 folate, 703 magnesium, 706 methylated B12, 706 mineral deficiency prevalence, 702t N-acetylcysteine (NAC), 707 polyphenols, 706–707 probiotics, 704–705, 704t, 705f therapeutic objectives, 702 vitamin A, 705 vitamin B6, 705–706 vitamin C, 706 vitamin D, 705 zinc, 702–703, 703f

in Down syndrome, 765–768, 766t–767t female infertility, 289–297 human immunodeficiency virus (HIV) acetyl-L-carnitine, 904–905 alpha-lipoic acid, 904 beta-carotene, 902 calcium, 905 chromium, 905 coenzyme Q10, 904 copper, 904 dosage requirements, 905–906 essential faTy acids, 903 iron, 903–904 magnesium, 905 N-acetylcysteine (NAC), 905 niacin and lipodystrophy, 902 probiotics, 904 selenium, 903 therapeutic objectives, 902 vitamin A, 902 vitamin B complex, 902 vitamin C, 902 vitamin D, 902–903 vitamin E, 903 zinc, 903

in Lyme disease antimicrobial, 935 detoxification, 936 digestive systems, 937 energy/adrenal, 936–937 immune system support, 935–936 inflammation reduction, 935 sleep, 937–938

male infertility, 305–313

for paediatrics and adolescence for constipation, 593–594 for diarrhoea, 596 for otitis media (OM), 603 for recurrent and chronic infections, 598–599 for teenage acne, 612 for warts, 605

Supportive galactagogues, 497t Surrogacy, 285 Survey of Disability, Ageing and Carers (SDAC), 688 Sweat loss, 230 Sweat-producing wrap, 100–101 Sweat rate, factors affecting, 228 Swimming, in asthmatic children, 609 Sympathetic adrenal medullary (SAM) axis, 202 Sympathetic nervous system (SNS), 556, 559 Symptomatic illness, 889 Systemic sclerosis, 164 Systems review female triathlete, 244 male swimmer, 250 sportspeople, 243

Systolic Hypertension in the Elderly Program (SHEP), 665 T Tabebuia avellanedae, drug interactions, IT–67 Tabebuia spp. (PAU D’ARCO), 911 TAGs, Triglycerides (TAGs) Tai chi, 206 Tanacetum parthenium, drug interactions, IT–67 Taraxacum officinale, drug interactions, IT–67, IT–68 Taraxacum officinale radix, 708 Taraxacum officinale (dandelion), 247t Targeted nutrition, risk reduction with, 185 Target of rapamycin (mTOR), 706–707 Taurine, drug interactions, IT–129

T cell test, 925 TCF7L2 gene, 188 T&CM, Traditional and complementary medicine (T&CM) Teenage acne, 610–612 case study, 613b sample daily diet, 612b and self-esteem, 611 treatment, 612

Teenage mothers, in pregnancy, 399–400 Teething, 565–566 pharmaceutical gels, cautions, 566 treatment breastfeeding, 566 cuddle therapy, 566 gentle gum massage, 566 herbal medicines, 566 safe foods, 566 teething toys, 566

Temperature exercise and, 228 of neutral full bath, 104 waking, 282–283

Teratogens, 394 Teratozoospermia definition, 276b semen analysis, 341t

Teratozoospermia index (TZI), 278t Terminal ductal lobular units (TDLUs), 485 Terminalia arjuna, drug interactions, IT–68 Terpene, 810–811 Testes, 260–261 Testicular dysgenesis syndrome (TDS), 265–266 Testicular microlithiasis, 757 Testosterone, 637–638 TET enzymes (ten-eleven translocases), 178–179 2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD), 70 Tetrahydrobiopterin cycle, 156

Δ9-Tetrahydrocannabinol (THC), 795 Tetrahydrofolate (THF), 155, 160, 404 TGA, Therapeutic Goods Authority (TGA) Thallium, 56–57 THCV, 809, 809f Theanine, drug interactions, IT–129 Therapeutic baths, 102–104 Therapeutic drug monitoring (TDM), 892–893 Therapeutic failure (TF), 658 Therapeutic Goods Administration (TGA), 234, 662 Therapeutic Goods Authority (TGA), 4 Thermal effects, of water, 92 Thermal stimuli, physiological responses to, 92–93, 93t THF, Tetrahydrofolate (THF) Thiamine (B1), 120 deficiency, 403–404 for lactating women, 475t–479t in pregnancy, 403–404

Thiamine pyrophosphate (TPP), 403–404 Thigh rinses, 98 Third-tier tests, in autism spectrum disorder (ASD), 700 Thrombophilia acquired, 349–350 inherited, 364t–372t

Thuja occidentalis, drug interactions, IT–68 Thymine (T), 147 Thymus vulgaris, drug interactions, IT–68 Thyroid antibodies, 351 Thyroid autoimmunity, 296 Thyroid disorders, 741, 752–753 Thyroid-stimulating hormone (TSH), 413, 420, 637 Thyroid test, 925 Thyroxine (T4), 413, 637

Thyroxine-binding globulin (TBG), 420 Tilia spp., drug interactions, IT–68 Timber-framed homes, 31 Tinea, in Down syndrome, 738 Tinospora cordifolia, drug interactions, IT–68 Tissue organisation theory, 823 Tissues and systems, effects of water on, 91–94 TMG, Trimethylglycine (TMG) TNF-α gene, 189 Tobacco, 72, Smoking Tocopherols, 81 Toll-like receptor (TLR), 126 Tongue protrusion reflex, 542–543 Tongue tie, 504 Tonsillectomy, 604 Tonsillitis, paediatrics and adolescence, 603–604 acute, 603 herbal formula, 604 herbal medicine, 604 tonsillectomy, 604

Tonsils, in Down syndrome, 740–741 Topical cream, Down syndrome treatment, 738 Total fertility rate (TFR), 257 Total glucosides of peony (TGP), 363–374 Toxicant exposure diseases associated with, 19 sources of, 20–21 air, 20 food, 21 water, 21

Toxicity, damp-building, 69 Toxic load, and disease burden, 69t Toxic metabolites, 69 Toxic metals, 42 assessment of, 58

Toxin elimination, organs involved in, 77–80 gastrointestinal (GI) system, 78–79 kidneys, 79 liver, 77–78

Toxin exposure, through employment, 172 Toxins/toxicants, 15, 17, 19–21, 68–72 assessment of, 72–77 challenge testing, 76 conventional laboratory tests, 72–75 basophilic stippling, 73 blood sugar regulation, 75, 76f full blood count, 72–73 inflammatory markers, 74 lipids, 74 liver enzymes, 73–74 metabolites, 74 platelets, 73, 73f white blood cells (WBC), 73

direct measures of, 76 endogenous sources, 71 environmental, 16–19, 68 age and timing of exposure, 17 ethnicity, 18–19 gender, 17 genetic predisposition, 16–17 gut microbiome, 17–18 nutrition, 18

exogenous sources, 68–71 air particulate maTer (PM), 70–71 chloroalkenes, 70 mould, 68–69 persistent organic pollutants (POPs), 70 toxic metals, 69–70 volatile organic compound (VOC), 70

lipophilic, 17 non-conventional laboratory tests, 75–76 vulnerable, 17

Toxoplasma gondii, 426 Toxoplasmosis, pregnancy, 426 Traditional and complementary medicine (T&CM), 3 goals, 4 objectives, 4

Traditional Arabic medicine, 11

Traditional medicine, 3, 11 in Central America, 12 practitioners, 3 in South America, 12 strategy 2014-2023, 3–4

Training low diet, 220 Training schedule female triathlete, 244 male swimmer, 250

Transcription, 151 abnormal gene, 177 and translation, 151

Transcription factor 7-like 2 (TCF7L2), 188 Trans faTy acids, 182, 289, 901 Transfer RNA (tRNA), 148 Transient diabetes mellitus, 751 Transient leukaemia, 751 Transient receptor potential vanilloid 1 (TRPV1), 796 Transition to work (TTW) programs, 733 Translation, 151 Transmethylation, 159–160, 160t Transrectal ultrasonography, 277t Transsulfuration pathway, 155–156 Trastuzumab, 829 Tribestan, 301, 316 Tribulus terrestris drug interactions, IT–68, IT–69 female infertility, 300–301 FSH stimulating properties, 301 male fertility enhancement, 316 for miscarriage, 385t–387t saponins, 316

Trifolium pratense, drug interactions, IT–69, IT–70 Triglycerides (TAGs), 78–79 elevated, 185

Trigonella foenum-graecum, drug interactions, IT–70 Triiodothyronine (T3), 413, 637 Trimester 1 fetal development, 417–420 investigations, 422t maternal changes, 420 obstetric history, 420–421, 421t screening and assessments, 420–427

Trimester 2 fetal development, 427 investigations, 428–429 maternal changes, 428 maternal conditions, 429–432

Trimester 3 assessments, 433 fetal development, 432–433 maternal changes, 433 nutrition, 433–439

Trimester 4, maternal changes, 439–445 Trimethylglycine (TMG), 161, 707 Trisomies, 347 Trisomy 21, Down syndrome Triterpenoid saponins, 362, 374 tRNA, Transfer RNA (tRNA) Tryptophan, drug interactions, IT–129, IT–130 Tubal function, 259 Tumouricidal herbs, 867 TUNNEL assay, 277 Turnera diffusa (damiana) drug interactions, IT–70 male fertility, 286 as male tonic, 316–317

Type 2 diabetes, 75 Tyrosine drug interactions, IT–130 Lyme disease, 943

for miscarriage, 383t

U Ubiquinol/Ubidecarenone, Coenzyme Q10 Ulmus fulva, drug interactions, IT–70 Ulmus rubra, 430 Ulmus spp. (slippery elm), 911–912 Ultraendurance exercise, carbohydrate fuelling, 221t–222t Ultrasound trimester 3, pregnancy, 433 trimester 1, 6–8 weeks, 421–422

Umbilical cord, 419 Uncaria tomentosa (cat's claw), 601, 912, 939 drug interactions, IT–70, IT–71

Unexplained infertility, 259 Unkei-to, 300 Unnoticed miscarriage, 258 UnseTled and unsoothable infant causes of infant crying, 560–561 clinical approach, 559 diagnostic labels, 556–557 gastro-oesophageal reflex disease (GORD), 557, 557b lactose intolerance, 557–558, 558t lactose malabsorption testing, 558 lactose overload, 558 neuro-endocrine model, 556 potential causal factors, 558–559

Uracil (U), 147, 160t Uric acid, serum, 75, 75f Urinalysis, 277t trimester 3, 433

Urinary coproporphyrin levels, 56 Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), 75 Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), 75 Urinary pyrroles

in aTention deficit (hyperactivity) disorder (AD(H)D), 713 in autism spectrum disorder (ASD), 699–700

Urinary tract infections (UTIs) atypical presentations, 643t protect against, 118

Urine testing, 58 Urine therapy, 826t Urine toxic metal provocation test, 700 Urogenital infections, screening, 282 primary, 282 secondary, 282

Ursodeoxycholic acid (UDCA), 82 Urtica dioica (neTle), 855, IT–71 Uterine fibroids, 346t Uterine NK (uNK) cells, 350 Utero-ovarian tonic, 300 Utero-placental unit, 401 UTIs, Urinary tract infections (UTIs) V Vaccinium macrocarpon, drug interactions, IT–71, IT–72 Vaccinium myrtillus, drug interactions, IT–72 Vaginal birth after caesarean (VBAC), 392–393 Vaginal dysbiosis, case study, 119b–120b Vaginal ecosystem, 116–117 Vaginal lactobacilli, 115b, 118b Vaginal microbiota, 115–119, 116f–117f Vaginal seeding, 443 Vaginosis, bacterial, 116 Vagus nerve, 202 Valeriana officinalis (valerian), 942 drug interactions, IT–72

Varicocele-associated asthenospermia, 308–309 Vascular endothelial growth factor (VEGF) placental levels, 360

VCS, Visual contrast sensitivity (VCS) Vegans diet, in pregnancy, 399 Vegetables carbohydrate content, 223t, 231t–233t estimated serves for Australian adults, 663, 664t nutritional requirements, ageing, 673–674 recommended daily serves by age, 582, 582t renal cancer, 870

Vegetarian diet, 399, 901 Vehicle emissions, 20 Ventral vagal complex, 203 Verbascum thapsus, 601 Verbena officinalis, drug interactions, IT–73 VGCCs, Voltage-gated calcium channels (VGCCs) Viburnum prunifolium (black haw) for miscarriage and infertility, 301 nervine sedative and uterine tonic actions, 285–286

Vinclozolin, 266 Vinyl chloride (VC), 70 Viral load, 894 quantity, 891 test, 891

Virtual phenotype, 893 Visceral hypersensitivity, 559 Viscum album, drug interactions, IT–72 Vis Medicatrix Naturae, 91 Visual contrast sensitivity (VCS), 32 Vitamin(s) preconception treatment, dosage female, 298t male, 298t

production, 120

Vitamin A in autism spectrum disorder (ASD), 705 benefits, RDI and source, 238t–239t drug interactions, IT–130, IT–131

female fertility, 291 HIV, 902 for lactating women, 475t–479t male fertility, 308 for miscarriage, 360 for paediatrics and adolescence otitis media (OM), 602 for recurrent and chronic infections, 598

in pregnancy, 408–409 cautions, 409 dose, 409

Vitamin B, 599 female fertility and, 293–295 male fertility and, 311–312

Vitamin B1 (thiamine), 293–295 benefits, RDI and source, 238t–239t drug interactions, IT–131 female fertility, 294 male fertility, 311

Vitamin B2 (riboflavin) benefits, RDI and source, 238t–239t drug interactions, IT–132 female fertility, 294 trimester 2, preeclampsia management, 432

Vitamin B3 benefits, RDI and source, 238t–239t drug interactions, IT–114, IT–115 for female triathlete, 246t

Vitamin B5 (pantothenic acid) female fertility, 294 male fertility, 311

Vitamin B6 (pyridoxine) in aTention deficit (hyperactivity) disorder (AD(H)D), 715 in autism spectrum disorder (ASD), 705–706 benefits, RDI and source, 238t–239t bladder cancer, 873 drug interactions, IT–132, IT–133 female fertility, 294

for lactating women, 475t–479t male fertility, 311 nausea and vomiting in pregnancy (NVP), 425

Vitamin B9 (folic acid) benefits, RDI and source, 238t–239t drug interactions, IT–93, IT–94 female fertility, 294–295 male fertility, 311 and vitamin B12 combined therapy, 295b

Vitamin B12 ageing, 677 benefits, RDI and source, 238t–239t deficiency and infertility, 295 drug interactions, IT–134 for lactating women, 475t–479t for male infertility, 311–312

Vitamin B complex, 902 antioxidants, 407–408 cyanocobalamin (B12), 406–407 folate (B9), 405–406 niacin (B3), 404 pantothenic acid (B5), 404 pyridoxine (B6), 404–405 riboflavin (B2), 404 thiamine (B1), 403–404

Vitamin C in autism spectrum disorder (ASD), 706 benefits, RDI and source, 238t–239t breast cancer, 861 drug interactions, IT–135 female fertility, 292 for female triathlete, 246t HIV, 902 infusions, 826t for lactating women, 475t–479t male fertility, 309 for miscarriage, 361 female, 383t

male partner, 385t–387t

in pregnancy, 409 for recurrent and chronic infections, 599

Vitamin D, 360, 508, 751–752, 868 ageing, 677–678 in aTention deficit (hyperactivity) disorder (AD(H)D), 715 in autism spectrum disorder (ASD), 705 breast cancer, 859 cofactors, 868 colorectal cancer (CRC), 858 deficiency, 410, 598, 599t drug interactions, IT–136, IT–137 female fertility, 312 HIV, 902–903 kidney function, 633 for lactating women, 475t–479t lung cancer, 864 male fertility, 295–296 melanoma of the skin, 863 in middle childhood, 36 months–10 years, 589–590 non-Hodgkin lymphoma (NHL), 865–866 for paediatrics and adolescence atopic dermatitis (AD), 607 otitis media (OM), 602 recurrent and chronic infections, 598–599

pancreatic cancer, 871 in pregnancy, 409–410, 432–433 prostate cancer, 856 renal cancer, 870

Vitamin D3 benefits, RDI and source, 238t–239t for miscarriage, 360 female, 383t male partner, 385t–387t

radiation, 832, 832t

Vitamin E, 903 ageing, 678 benefits, RDI and source, 238t–239t breast cancer, 861 drug interactions, IT–137

female fertility, 292–293 for lactating women, 475t–479t male fertility, 309 for miscarriage, 360, 385t–387t in pregnancy, 411

Vitamin K drug interactions, IT–138 female fertility, 296, 298t male fertility, 314t in pregnancy, 411

Vitex agnus-castus (chaste tree), 487b dopaminergic activity, 377 drug interactions, IT–73 female fertility enhancement, 301 fruit, constituents of, 377 luteal phase defects, 376–377 preconception formula, 378

melatonin secretion, 377 for miscarriage, 376

Vitis vinifera drug interactions, IT–73 for miscarriage, 375t, 385t–387t

VOC, Volatile organic compound (VOC) Volatile oils, 424 Volatile organic compound (VOC), 20, 70 Voltage-gated calcium channels (VGCCs), 22 Vulnerable toxicants, 17 Vulvovaginal atrophy, 118 W Waking temperature, 282–283 Warming compresses, 99–100 Warts, paediatrics and adolescence herbal formula, 604 herbal medicine, 604 nutritional medicine, 604–605 topical treatment, 604

Wasting syndrome, 890 Water filters, 21 renal cancer, 869 thermal, mechanical and chemical effects of, 92

Water-dissolving (effervescent) tablets, 230 Water pollutants reduce exposure to, 21 sources of drinking, 21

Weaning, 510–511 and maternal emotional responses, 511

Weighing errors, causes of, 538b Weight, ageing, 664–666, 664t Weight gain and growth, assessment of length-for-age boys, 537f length-for-age girls, 536f weight-for-age boys, 535f weight-for-age girls, 534f

Weight Gain During Pregnancy: Reexamining the Guidelines, 397 Weight gain, for singleton pregnancies, 397, 397t Weight loss ageing, 665–666 cautions, 665–666

melanoma of the skin, 861

Western and central Africa, AIDS statistics, 883 Western and central Europe, AIDS statistics, 883 Western blot test, 924–925 Western diet, 580, 674–675 WFS1 gene, 188 Wholefood diet, 362, 363t, 899 female infertility, 288 male infertility, 303–304

Wholefood principles, in aTention deficit (hyperactivity) disorder (AD(H)D), 714 Wholefoods, for sport, 222–223 Wholegrains, renal cancer, 870

Whole lemon drink, 899, 899b Wide-band microwave signals, 24 Winter cherry, Ashwagandha (Withania somnifera) Wireless devices, portable, usage, 26 Withania somnifera (ashwagandha), 859, 867, IT–73, IT–74 WNF, World Naturopathic Federation (WNF) Wolff-Chaikoff effect, 414 Wolfram syndrome 1 (WFS1), 182, 188 World Anti-Doping Agency (WADA), 234 World health assembly (WHM), Geneva, 4–5 World Health Organization (WHO) actions at country level, 4 for breastfeeding, 463 cut-off values for iron-deficiency anaemia, 583 definition, healthy ageing, 627 global health governance, 3–5 guidelines median urinary iodine concentration (MUIC), 413–414, 413t semen analysis, 342t

International Code of Marketing of Breast milk Substitutes, 464 miscarriage, definition of, 257–258 traditional and complementary medicine benchmarks for training, 4 goals, 4 objectives, 4

traditional medicine strategy 2014–2023, 3–4

World Naturopathic Federation (WNF), 4–5, 5–6 history, 5 membership of, 5 vision of, 5

Wraps heat-delivering wraps, 100 heat-producing, 100–101 sweat-producing, 100–101

X Xenobiotics

detoxification of, 160 metabolising enzymes, 19 and renal function, 543

Xerosis (dry skin), 737 Xylitol in autism spectrum disorder (ASD), 701 for otitis media (OM), 602

Y Yamas, 212 Yeasts, 693 Yoga, 200, 206 health benefits, 213 history of, 211–213 parts of, 211–213

Yoga Sutras, 211–213 Yolk sac, 419 Z Zanthoxylum simulans, drug interactions, IT–74 Zanthoxylum spp., drug interactions, IT–74 Zea mays, drug interactions, IT–74 Zinc, 161, 170t–171t, 361 in aTention deficit (hyperactivity) disorder (AD(H)D), 715 in autism spectrum disorder (ASD), 699, 702–703, 703f benefits, RDI and source, 238t–239t deficiency, in middle childhood, 36 months–10 years, 588 depletion in children with dehydrating diarrhoea, 596 Down syndrome, 765–767 drug interactions, IT–139, IT–140 female fertility, 287, 293 HIV, 903 for lactating women, 480t–482t male fertility, 310–311 for miscarriage, 361 female, 383t male partner, 385t–387t

non-Hodgkin lymphoma (NHL), 865 in pregnancy, 416–417 deficiency, 416 dose, 416–417 supplementation, 416

for recurrent and chronic infections, 598 in toddler, 12–36 months, 584

Zinc citrate, 855 Zinc deficiency, 678 Zinc depletion, 569 Zinc supplementation, 569 Zingiber officinale (ginger), 601 drug interactions, IT–74, IT–75 miscarriage management, 378 preconception formula, 378 pregnancy formula, 378

Zizyphus jujube/spinosa, drug interactions, IT–75

Interactions table Herb/nutrient–drug interactions tables Compiled by Liesl Blott Potential herb–drug and nutrient–drug interactions are described in the following tables. These tables have been formulated to include information on interactions between herbal medicines, nutrients/nutritional medicines and drugs. They include a summary of the potential outcome, a graded recommendation and a comments section that explains the nature of each interaction in more detail. The recommendations are broadly divided into four categories: avoid, caution, monitor and benefi cial. Factors that were taken into account when determining these interaction categories include currently available evidence and safety data; potential severity and clinical consequences; the likelihood of an interaction; whether the interaction is based on clinical studies or extrapolated from case studies, laboratory or animal studies; and commonly applied integrative prescribing principles. However, new safety data and evidence are constantly emerging, and best practice regarding some of these interactions may change with time. The tables do not include information on possible contraindications, for example use in pregnancy, nor do they include herb– herb, herb–nutrient or nutrient–nutrient interactions. Practitioners are encouraged to use the interactions tables as a guide, but to apply professional judgment on the appropriateness of use of a combination of herb–drug or nutrient–drug for each individual patient. It is imperative that health practitioners investigate whether there are any known safety concerns or interactions when prescribing herbal or nutritional medicines for patients already taking pharmaceutical medicines. Health practitioners of all disciplines are encouraged to make use of available resources to allow for informed decisions, so as to optimise patient wellbeing without compromising patient safety. When recommending complementary medicines in combination with pharmaceutical medicines, both anticipated benefi ts and potential risks should be taken into consideration.

LEGEND Combination okay to use Use of combination should be monitored Use combination with caution Avoid combination

References Al-Jenoobi FI, Al-Thukair AA, Alam MA, et al. Effect of Curcuma longa on CYP2D6- and CYP3A4-mediated metabolism of dextromethorphan in human liver microsomes and healthy human subjects. Eur J Drug Metab Pharmacokinet. 2014 [online ahead of print]. Azadmehr A, Ziaee A, Ghanei L, et al. A Randomized Clinical Trial Study: anti-oxidant, anti-hyperglycemic and antihyperlipidemic effects of olibanum gum in Type 2 Diabetic Patients. Iran J Pharm Res. 2014;13(3):1003–1009. Baskaran K, Ahamath BK, Shanmugasundaram KR, et al. Antidiabetic effect of a leaf extract from Gymnema sylvestre in non-insulin dependent diabetes mellitus patients. J Ethnopharmacol. 1990;30:295–305. Biswal BM, Sulaiman SA, Ismail HC, et al. Effect of Withania somnifera (Ashwagandha) on the development of chemotherapy-induced fatigue and quality of life in breast cancer patients. Integr Cancer Ther. 2013;12(4):312–322. Blonk M, Colbers A, Poirters A, et al. Effect of ginkgo biloba on the pharmacokinetics of raltegravir in healthy volunteers. Antimicrob Agents Chemother. 2012;56(10):5070–5075. Bodinet C, Freundenstein J. Influence of Cimicifuga racemosa on the proliferation of estrogen receptor-positive human breast cancer cells. Breast Cancer Res. 2002;76:1–10. Bonego N, Santelli L, Bagistin L, et al. Serotonin syndrome and rhabdomyolysis induced by concomitant use of triptans, fluoxetine and hypericum. Cephalalgia. 2007;27(12):1421–1423 [Epub 2007 Sep 14]. Bossaer JB, Odle BL. Probable etoposide interaction with Echinacea. J Diet Suppl. 2012;9(2):90–95; 10.3109/19390211.2012.682643. Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Elsevier Churchill Livingston; 2015. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583–1593. Burgos RA, Hancke JL, Bertoglio JC, et al. Efficacy of an Andrographis paniculata composition for the relief of rheumatoid arthritis symptoms: a prospective randomized placebo-controlled trial. Clin Rheumatol. 2009;28(8):931– 946. Campbell NR, Kara M, Hasinoff BB, et al. Norfloxacin interaction with antacids and minerals. Br J Clin Pharmacol. 1992;33(1):115–116. Campbell N, Paddock V, Sundaram R. Alteration of methyldopa absorption, metabolism, and blood pressure control caused by ferrous sulfate and ferrous gluconate. Clin Pharmacol Ther. 1988;43(4):381–386. Chan TY. Drug interactions as a cause of overanticoagulation and bleedings in Chinese patients receiving warfarin. Int J Clin Pharmacol Ther. 1998;36(7):403–405.

Chedraui P, et al. Effect of Trifolium pratense-derived isoflavones on the lipid profile of postmenopausal women with increased body mass index. Gynecol Endocrinol. 2008;24(11):620–624. Chen HW, Lin IH, Chen YJ, et al. A novel infusible botanically-derived drug, PG2, for cancer-related fatigue: a phase II double-blind, randomized placebo-controlled study. Clin Invest Med. 2012;35(1):E1–11. Chen MF, Shimada F, Kato H, et al. Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone. Endocrinol Jpn. 1991;38(2):167–174. Chen M-F, Shimanda F, Kato H, et al. Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone. Endocrinol Jpn. 1991;38:167–175. Cui Y, Shu X-O, Gao Y-T, et al. Association of ginseng use with survival and quality of life among breast cancer patients. Am J Epidemiol. 2006;163:64553. Day E, Bentham P, Callaghan R, et al. Thiamine for prevention and treatment of Wernicke-Korsakoff Syndrome in people who abuse alcohol. Cochrane Database Syst Rev. 2013;(7) [CD004033]. de Maat MMR, Hoetelmans RMW, Mathot RAA, et al. Drug interaction between St John's wort and nevirapine. AIDS. 2001;15(3):420–421. Dhamija P, Malhotra S, Pandhi P. Effect of oral administration of crude aqueous extract of garlic on pharmacokinetic parameters of isoniazid and rifampicin in rabbits. Pharmacology. 2006;77:100–104. Ding Y, Jia Y, Li F, et al. The effect of staggered administration of zinc sulfate on the pharmacokinetics of oral cephalexin. Br J Clin Pharmacol. 2011; 10.1111/j.1365-2125.2011.04098.x. Enseleit F, Sudano I, Périat D, et al. Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: a double-blind, randomized, placebo-controlled, cross-over study. Eur Heart J. 2012;33(13):1589– 1597. Fan L, Zhang W, Guo D, et al. The effect of herbal medicine baicalin on pharmacokinetics of rosuvastatin, substrate of organic anion-transporting polypeptide 1B1. Clin Pharmacol Ther. 2008;83(3):471–476 [Epub 2007 Sep 12]. Golden EB, Lam PY, Kardosh A, et al. Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood. 2009;113(23):5927–5937. Guo L, Bai SP, Zhao L, et al. Astragalus polysaccharide injection integrated with vinorelbine and cisplatin for patients with advanced non-small cell lung cancer: effects on quality of life and survival. Med Oncol. 2012;29(3):1656–1662. Gupta I, et al. Effects of gum resin of Boswellia serrata in patients with chronic colitis. Planta Med. 2001;67(95):391– 395. Gupta A, Gupta R, Lal B. Effect of Trigonella foenum-graecum (Fenugreek) seeds on glycaemic control and insulin resistance in Type 2 Diabetes Mellitus: a double blind placebo controlled study. J Assoc Physicians India. 2001;49:1057–1061. Harada T, Ohtaki E, Misu K, et al. Congestive heart failure caused by digitalis toxicity in an elderly man taking a licorice-containing chinese herbal laxative. Cardiology. 2002;98(4):218. Heiss C, Jahn S, Taylor M, et al. Improvement of endothelial function with dietary flavanols is associated with mobilization of circulating angiogenic cells in patients with coronary artery disease. J Am Coll Cardiol. 2010;56(3):218–224. Hernandez-Munoz G, Pluchino S. Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer. Maturitas. 2003;44(Suppl. 1):S59–65. Hurrel RF, Reddy M, Cook JD. Inhibition of non-haem iron absorption in man by polyphenolic-containing beverages. Br J Nutr. 1999;81(4):289–295. Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol. 2001;19(10):2739–2745. JAMA 2004;291(2):216–21. Jiang X, Williams K, Liauw WS, et al. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2005. Isso AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs. 2009;69(13):1777–1798. Khalid Z, Osuagwu FC, Shah B, et al. Celery root extract as an inducer of mania induction in a patient on venlafaxine and St John's Wort. Postgrad Med. 2016;128(7):682–683. Kassi E, et al. Greek plant extracts exhibit selective estrogen receptor modulator (SERM)-like properties. J Agric Food Chem. 2004;52(23):6956–6961. Kenny FS, Pinder SE, Ellis IO, et al. Gamma linolenic acid with tamoxifen as primary therapy in breast cancer. Int J Cancer. 2000;85:643–648.

Krivoy N, Pavloqky E, Chrubasik S, et al. Effect of salicis cortex extract on human platelet aggregation. Planta Med. 2001;67:209–212. Kurnik D, Loebstein R, Rabinoviq H, et al. Over-the-counter vitamin K1-containing multivitamin supplements disrupt warfarin anticoagulation in vitamin K1-depleted patients. A prospective, controlled trial. Thromb Haemost. 2004;92(5):1018–1024. Lau WC, Carville DG, Guyer KE, et al. St John's Wort enhances the platelet inhibitory effect of clopidogrel in clopidogrel ‘resistant’ healthy volunteers. J Am Coll Cardiol. 2005;45:382A. Lau WC, Welch TD, Shields T, et al. The effect of St John's Wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity. J Cardiovasc Pharmacol. 2011;57(1):86–93. Li R, Guo W, Fu Z, et al. A study about drug combination therapy of Schisandra sphenanthera extract and Rapamycin in healthy subjects. Can J Physiol Pharmacol. 2012;90(7):941–945 [Epub 2012 Jun 12]. Li Y, Xue WJ, Tian PX, et al. Clinical application of Cordyceps sinensis on immunosuppressive therapy in renal transplantation. Transplant Proc. 2009;41(5):1565–1569. Lissoni P, Rovelli F, Brivio F, et al. A randomized study of chemotherapy versus biochemotherapy with chemotherapy plus Aloe arborescens in patients with metastatic cancer. In Vivo. 2009;23(1):171–175. Lydeking-Olsen E, Beck-Jensen JE, Setchell KD, et al. Soymilk or progesterone for prevention of bone loss–a 2 year randomized, placebo-controlled trial. Eur J Nutr. 2004;43(4):246–257. Maged AM, Elsawah H, Abdelhafez A, et al. The adjuvant effect of metformin and N-acetylcysteine to clomiphene citrate in induction of ovulation in patients with Polycystic Ovary Syndrome. Gynecol Endocrinol. 2015;31(8):635– 638. Malsch U, Kieser M. Efficacy of kava-kava in the treatment of non-psychotic anxiety, following pretreatment with benzodiazepines. Psychopharmacology (Berl). 2001;157:277–283. Mansour A, Mohajeri-Tehrani MR, Qorbani M, et al. Effect of glutamine supplementation on cardiovascular risk factors in patients with type 2 diabetes. Nutrition. 2015;31(1):119–126. Mathijssen RHJ, Loos WJ, Sparreboom A, et al. Effects of St. John's wort on irinotecan metabolism. J Natl Cancer Inst. 2002;94(16):1247–1249. McBride BF, et al. Electrocardiographic and hemodynamic effects of a multicomponent dietary supplement containing ephedra and caffeine: a randomized controlled trial. Mills S, Bone K. The essential guide to herbal safety. Churchill Livingstone: Elsevier; 2005. Moltó J, Valle M, Miranda C, et al. Effect of milk thistle on the pharmacokinetics of Darunavir-Ritonavir in HIVinfected patients. Antimicrob Agents Chemother. 2012;56(6):2837–2841. Mosby's Handbook of drug-herb and drug-supplement interactions. [Mosby] 2003. Natural Medicines databases. [Therapeutic Research Center] 2017. Neuvonen PJ. Interactions with the absorption of tetracyclines. Drugs. 1976;11(1):45–54. Persky VW, Turky ME, Wang L, et al. Effect of soy protein on endogenous hormones in postmenopausal women. Am J Clin Nutr. 2002;75:145–153. Piscitelli SC, Burstein AH, Welden N, et al. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis. 2002;34:234–238. Pryce R, Bernaitis N, Davey AK, et al. The use of fish oil with warfarin does not significantly affect either the international normalised ratio or incidence of adverse events in patients with atrial fibrillation and deep vein thrombosis: a retrospective study. Nutrients. 2016;8(9). Pyevich D, Bogenschuq MP. Herbal diuretics and lithium toxicity. Am J Psychiatry. 2001;158(8):1329. Qiu H, Fu P, Fan W, et al. Treatment of primary chronic glomerulonephritis with Rehmannia glutinosa acteosides in combination with the angiotensin receptor blocker irbesartan: a randomized controlled trial. Phytother Res. 2014;28(1):132–136. Rahimi R, et al. Induction of clinical response and remission of inflammatory bowel disease by use of herbal medicines: a meta-analysis. World J Gastroenterol. 2013;19(34):5738–5749. Rajnarayana K, Reddy MS, Vidyasagar J, et al. Study on the influence of silymarin pretreatment on metabolism and disposition of metronidazole. ArzneimiPelforschung. 2004;54(2):109–113. Raskin HN, Fishman RA. Pyridoxine-deficiency neuropathy due to hydralazine. N Engl J Med. 1965;273:1182–1185. Rockwell S, Liu Y, Higgins SA. Alteration of the effects of cancer therapy agents on breast cancer cells by the herbal medicine black cohosh. Breast Cancer Res Treat. 2005;90:233–239. Samman S, Sandström B, Toft MB, et al. Green tea or rosemary extract added to foods reduces nonheme-iron

absorption. Am J Clin Nutr. 2001;73(3):607–612. Sandborn WJ, Targan SR, Byers VS, et al. Andrographis paniculata extract (HMPL-004) for active ulcerative colitis. Am J Gastroenterol. 2013;108(1):90–98. Scambia G, De Vincenzo R, Ranellegi FO, et al. Antiproliferative effect of silybin on gynaelogical malignancies: synergism with cisplatin and doxorubicin. Eur J Cancer. 1996;32:877–882. Schelosky L, Raffauf C, Jendroska K, et al. Kava and dopamine antagonism. J Neurol Neurosurg Psychiatry. 1995;58(5):639–640. Segal R, Pilote L. Warfarin interaction with Matricaria chamomilla. CMAJ. 2006;174(9):1281–1282. Sharma RD, Sarkar A, Hazra DK, et al. Use of fenugreek seed powder in the management of non-insulin dependent diabetes mellitus. Nutr Res. 1996;16(8):1331–1339. Shi S, Kloq U. Drug interactions with herbal medicines. Clin Pharmacokinet. 2012;51(2):77–104. Sigurjónsdógir HA, Franzson L, Manhem K, et al. Liquorice-induced rise in blood pressure: a linear dose-response relationship. J Hum Hypertens. 2003;17(2):125–131. Sigurjonsdogir HA, Manhem K, Axelson M, et al. Subjects with essential hypertension are more sensitive to the inhibition of 11 beta-HSD by liquorice. J Hum Hypertens. 2003;17(2):125–131. Shanmugasundaram ERB, Rafeswari G, Baskaran K, et al. Use of Gymnema sylvestre leaf extract in the control of blood glucose in insulin-dependent diabetes mellitus. J Ethnopharmacol. 1990;30:281–294. Stargrove MB, Treasure J, McKee DL. Herb, nutrient and drug interactions. Clinical implications and therapeutic strategies. Elsevier: Mosby; 2008. Stoddard GJ, Archer M, Shane-McWhorter L, et al. Ginkgo and warfarin interaction in a large veterans administration population. AMIA Annu Symp Proc. 2015;2015:1174–1183. Terzic MM, Dotlic J, Maricic S, et al. Influence of red clover-derived isoflavones on serum lipid profile in postmenopausal women. J Obstet Gynaecol Res. 2009;35(6):1091–1095. Turkistani A, Abdullah KM, Al-Shaer AA, et al. Alkatheri K. Melatonin premedication and the induction dose of propofol. Eur J Anaesthesiol. 2007;24(5):399–402 [Epub 2006 Nov 10]. Uehleke B, Müller J, Stange R, et al. Willow bark extract STW 33-I in the long-term treatment of outpatients with rheumatic painmainly osteoarthritis or back pain. Phytomedicine. 2013;20(11):980–984. Ulbricht CE, Basch EM. Natural standard. Herb and supplement reference. Evidence-based clinical reviews. Elsevier: Mosby; 2005. Var C, Keller S, Tung R, et al. Supplementation with vitamin B6 reduces side effects in Cambodian women using oral contraception. Nutrients. 2014;6(9):3353–3362; 10.3390/nu6093353. Wainstein J, Ganz T, Boaz M, et al. Olive leaf extract as a hypoglycemic agent in both human diabetic subjects and in rats. J Med Food. 2012;15(7):605–610. Walker AF, Marakis G, Morris AP, et al. Promising hypotensive effect of hawthorn extract: a randomized doubleblind pilot study of mild, essential hypertension. Phytother Res. 2002;16(1):48–54. Xin HW, Wu XC, Li Q, et al. Effects of Schisandra sphenanthera extract on the pharmacokinetics of midazolam in healthy volunteers. Br J Clin Pharmacol. 2009;67(5):541–546. Xin HW, Wu XC, Li Q, et al. Effects of Schisandra sphenanthera extract on the pharmacokinetics of tacrolimus in healthy volunteers. Br J Clin Pharmacol. 2007;64:469–475. Yamamoto T, Hatanaka M, Matsuda J, et al. Clinical characteristics of five elderly patients with severe hypokalemia induced by glycyrrhizin derivatives. Nippon Jinzo Gakkai Shi. 2010;52(1):80–85. Yuan CS, Wei G, Dey L. American ginseng reduces warfarin's effect in healthy patients. A randomized, controlled trial. Ann Intern Med. 2004;141(1):123–126. Zemestani M, Rafraf M, Asghari-Jafarabadi M. Chamomile tea improves glycemic indices and antioxidants status in patients with type 2 diabetes mellitus. Nutrition. 2016;32(1):66–72.

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