Cannabis: Medical Aspects 9781536105100, 9781536105223

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HEALTH AND HUMAN DEVELOPMENT

CANNABIS MEDICAL ASPECTS

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HEALTH AND HUMAN DEVELOPMENT JOAV MERRICK - SERIES EDITOR NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT, MINISTRY OF SOCIAL AFFAIRS, JERUSALEM Adolescent Behavior Research: International Perspectives Joav Merrick and Hatim A. Omar (Editors) 2007. ISBN: 1-60021-649-8

Poverty and Children: A Public Health Concern Alexis Lieberman and Joav Merrick (Editors) 2009. ISBN: 978-1-60741-140-6

Complementary Medicine Systems: Comparison and Integration Karl W. Kratky 2008. ISBN: 978-1-60456-475-4 (Hardcover) 2008. ISBN: 978-1-61122-433-7 (E-book)

Living on the Edge: The Mythical, Spiritual, and Philosophical Roots of Social Marginality Joseph Goodbread 2009. ISBN: 978-1-60741-162-8

Pain in Children and Youth Patricia Schofield and Joav Merrick (Editors) 2008. ISBN: 978-1-60456-951-3

Alcohol-Related Cognitive Disorders: Research and Clinical Perspectives Leo Sher, Isack Kandel and Joav Merrick (Editors) 2009. ISBN: 978-1-60741-730-9 (Hardcover) 2009. ISBN: 978-1-60876-623-9 (E-book)

Challenges in Adolescent Health: An Australian Perspective David Bennett, Susan Towns, Elizabeth Elliott and Joav Merrick (Editors) 2009. ISBN: 978-1-60741-616-6 (Hardcover) 2009. ISBN: 978-1-61668-240-8 (E-book) Behavioral Pediatrics, 3rd Edition Donald E. Greydanus, Dilip R. Patel, Helen D. Pratt and Joseph L. Calles, Jr. (Editors) 2009. ISBN: 978-1-60692-702-1 (Hardcover) 2009. ISBN: 978-1-60876-630-7 (E-book) Obesity and Adolescence: A Public Health Concern Hatim A. Omar, Donald E. Greydanus, Dilip R. Patel and Joav Merrick (Editors) 2009. ISBN: 978-1-60456-821-9

Advances in Environmental Health Effects of Toxigenic Mold and Mycotoxins- Volume 1 Ebere Cyril Anyanwu 2010. ISBN: 978-1-60741-953-2 Children and Pain Patricia Schofield and Joav Merrick (Editors) 2009. ISBN: 978-1-60876-020-6 (Hardcover) 2009. ISBN: 978-1-61728-183-9 (E-book) Chance Action and Therapy. The Playful Way of Changing Uri Wernik 2010. ISBN: 978-1-60876-393-1 (Hardcover) 2011. ISBN: 978-1-61122-987-5 (Softcover)

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Rural Child Health: International Aspects Erica Bell and Joav Merrick (Editors) 2011. ISBN: 978-1-60876-357-3 (Hardcover) 2010. ISBN: 978-1-61324-005-2 (E-book) Understanding Eating Disorders: Integrating Culture, Psychology and Biology Yael Latzer, Joav Merrick and Daniel Stein (Editors) 2011. ISBN: 978-1-61728-298-0 Positive Youth Development: Evaluation and Future Directions in a Chinese Context Daniel T.L. Shek, Hing Keung Ma and Joav Merrick (Editors) 2011. ISBN: 978-1-60876-830-1 (Hardcover) 2010. ISBN: 978-1-61668-376-4 (E-book) Self-Management and the Health Care Consumer Peter William Harvey 2011. ISBN: 978-1-61761-796-6 (Hardcover) 2011. ISBN: 978-1-61122-214-2 (E-book) Sexology from a Holistic Point of View Soren Ventegodt and Joav Merrick 2011. ISBN: 978-1-61761-859-8 (Hardcover) 2011. ISBN: 978-1-61122-262-3 (E-book) Principles of Holistic Psychiatry: A Textbook on Holistic Medicine for Mental Disorders Soren Ventegodt and Joav Merrick 2011. ISBN: 978-1-61761-940-3 (Hardcover) 2011. ISBN: 978-1-61122-263-0 (E-book)

Clinical Aspects of Psychopharmacology in Childhood and Adolescence Donald E. Greydanus, Joseph L. Calles Jr., Dilip P. Patel, Ahsan Nazeer and Joav Merrick (Editors) 2011. ISBN: 978-1-61122-135-0 (Hardcover) 2011. ISBN: 978-1-61122-715-4 (E-book) Climate Change and Rural Child Health Erica Bell, Bastian M. Seidel and Joav Merrick (Editors) 2011. ISBN: 978-1-61122-640-9 (Hardcover) 2011. ISBN: 978-1-61209-014-6 (E-book) Rural Medical Education: Practical Strategies Erica Bell, Craig Zimitat and Joav Merrick (Editors) 2011. ISBN: 978-1-61122-649-2 (Hardcover) Advances in Environmental Health Effects of Toxigenic Mold and Mycotoxins Ebere Cyril Anyanwu 2011. ISBN: 978-1-60741-953-2 (Hardcover) Public Health Yearbook 2009 Joav Merrick 2011. ISBN: 978-1-61668-911-7 (Hardcover) Child Health and Human Development Yearbook 2009 Joav Merrick 2011. ISBN: 978-1-61668-912-4 (Hardcover) Alternative Medicine Yearbook 2009 Joav Merrick (Editor) 2011. ISBN: 978-1-61668-910-0 (Hardcover)

The Dance of Sleeping and Eating among Adolescents: Normal and Pathological Perspectives Yael Latzer and Orna Tzischinsky (Editors) 2011. ISBN: 978-1-61209-710-7 (Hardcover) Social and Cultural Psychiatry Experience from the Caribbean Region Hari D. Maharajh and Joav Merrick (Editors) 2011. ISBN: 978-1-61668-506-5 (Hardcover) 2011. ISBN: 978-1-61728-088-7 (E-book) Human Development: Biology from a Holistic Point of View Søren Ventegodt, Tyge Dahl Hermansen and Joav Merrick (Editors) 2011. ISBN: 978-1-61470-441-6 (Hardcover) Drug Abuse in Hong Kong: Development and Evaluation of a Prevention Program Daniel TL Shek, Rachel CF Sun and Joav Merrick (Editors) 2011. ISBN: 978-1-61324-491-3 (Hardcover) Building Community Capacity: Minority and Immigrant Populations Rosemary M Caron and Joav Merrick (Editors) 2012. ISBN: 978-1-62081-022-4 (Hardcover) Building Community Capacity: Skills and Principles Rosemary M Caron and Joav Merrick (Editors) 2012. ISBN: 978-1-61209-331-4 (Hardcover) Textbook on Evidence-Based Holistic Mind-Body Medicine: Basic Principles of Healing in Traditional Hippocratic Medicine Søren Ventegodt and Joav Merrick 2012. ISBN: 978-1-62257-094-2 (Hardcover)

Human Immunodeficiency Virus (HIV) Research: Social Science Aspects Hugh Klein and Joav Merrick (Editors) 2012. ISBN: 978-1-62081-293-8 (Hardcover) Adolescence and Chronic Illness. A Public Health Concern Hatim Omar, Donald E. Greydanus, Dilip R. Patel and Joav Merrick (Editors) 2012. ISBN: 978-1-60876-628-4 (Hardcover) 2012. ISBN: 978-1-61761-482-8 (E-book) Our Search for Meaning in Life: Quality of Life Philosophy Soren Ventegodt and Joav Merrick 2012. ISBN: 978-1-61470-494-2 (Hardcover) Child and Adolescent Health Yearbook 2009 Joav Merrick 2012. ISBN: 978-1-61668-913-1 (Hardcover) Applied Public Health: Examining Multifaceted Social or Ecological Problems and Child Maltreatment John R. Lutzker and Joav Merrick (Editors) 2012. ISBN: 978-1-62081-356-0 (Hardcover) Translational Research for Primary Healthcare Erica Bell, Gert P. Westert and Joav Merrick (Editors) 2012. ISBN: 978-1-61324-647-4 (Hardcover) Child and Adolescent Health Yearbook 2010 Joav Merrick (Editor) 2012. ISBN: 978-1-61209-788-6 (Hardcover)

Child Health and Human Development Yearbook 2010 Joav Merrick (Editor) 2012. ISBN: 978-1-61209-789-3 Public Health Yearbook 2010 Joav Merrick (Editor) 2012. ISBN: 978-1-61209-971-2 (Hardcover) The Astonishing Brain and Holistic Consciousness: Neuroscience and Vedanta Perspectives Vinod D. Deshmukh 2012. ISBN: 978-1-61324-295-7 (Hardcover) Randomized Clinical Trials and Placebo: Can You Trust the Drugs are Working and Safe? Søren Ventegodt and Joav Merrick 2012. ISBN: 978-1-61470-067-8 (Hardcover) Alternative Medicine Yearbook 2010 Joav Merrick (Editor) 2012. ISBN: 978-1-62100-132-4 (Hardcover) AIDS and Tuberculosis: Public Health Aspects Daniel Chemtob and Joav Merrick (Editors) 2012. ISBN: 978-1-62081-382-9 (Hardcover) Public Health Yearbook 2011 Joav Merrick (Editor) 2012. ISBN: 978-1-62081-433-8 (Hardcover) Alternative Medicine Research Yearbook 2011 Joav Merrick (Editor) 2012. ISBN: 978-1-62081-476-5 (Hardcover)

Textbook on Evidence-Based Holistic Mind-Body Medicine: Research, Philosophy, Economy and Politics of Traditional Hippocratic Medicine Søren Ventegodt and Joav Merrick 2012. ISBN: 978-1-62257-140-6 (Hardcover) Textbook on Evidence-Based Holistic Mind-Body Medicine: Basic Philosophy and Ethics of Traditional Hippocratic Medicine Søren Ventegodt and Joav Merrick 2012. ISBN: 978-1-62257-052-2 (Hardcover) Textbook on Evidence-Based Holistic Mind-Body Medicine: Holistic Practice of Traditional Hippocratic Medicine Søren Ventegodt and Joav Merrick 2013. ISBN: 978-1-62257-105-5 (Hardcover) Textbook on Evidence-Based Holistic Mind-Body Medicine: Healing the Mind in Traditional Hippocratic Medicine Søren Ventegodt and Joav Merrick 2013. ISBN: 978-1-62257-112-3 (Hardcover) Textbook on Evidence-Based Holistic Mind-Body Medicine: Sexology and Traditional Hippocratic Medicine Søren Ventegodt and Joav Merrick 2013. ISBN: 978-1-62257-130-7 (Hardcover) Health and Happiness from Meaningful Work: Research in Quality of Working Life Søren Ventegodt and Joav Merrick (Editors) 2013. ISBN: 978-1-60692-820-2 (Hardcover)

Conceptualizing Behavior in Health and Social Research: A Practical Guide to Data Analysis Said Shahtahmasebi and Damon Berridge 2013. ISBN: 978-1-60876-383-2 Adolescence and Sports Dilip R. Patel, Donald E. Greydanus, Hatim Omar and Joav Merrick (Editors) 2013. ISBN: 978-1-60876-702-1 (Hardcover) 2013. ISBN: 978-1-61761-483-5 (E-book) Pediatric and Adolescent Sexuality and Gynecology: Principles for the Primary Care Clinician Hatim A. Omar, Donald E. Greydanus, Artemis K. Tsitsika, Dilip R. Patel and Joav Merrick (Editors) 2013. ISBN: 978-1-60876-735-9 Living on the Edge: The Mythical, Spiritual, and Philosophical Roots of Social Marginality Joseph Goodbread 2013. ISBN: 978-1-61122-986-8 (Softcover) Health Risk Communication Marijke Lemal and Joav Merrick (Editors) 2013. ISBN: 978-1-62257-544-2 (Hardcover) Bedouin Health: Perspectives from Israel Joav Merrick, Alean Al-Krenami and Salman Elbedour (Editors) 2013. ISBN: 978-1-62948-271-2 (Hardcover) Building Community Capacity: Case Examples from Around the World Rosemary M. Caron and Joav Merrick (Editors) 2013. ISBN: 978-1-62417-175-8 (Hardcover)

Managed Care in a Public Setting Richard Evan Steele 2013. ISBN: 978-1-62417-970-9 (Softcover)

Pain Management Yearbook 2011 Joav Merrick (Editor) 2013. ISBN: 978-1-62808-970-7 (Hardcover)

Bullying: A Public Health Concern Jorge C. Srabstein and Joav Merrick (Editors) 2013. ISBN: 978-1-62618-564-7 (Hardcover)

Food, Nutrition and Eating Behavior Joav Merrick and Sigal Israeli (Editor) 2013. ISBN: 978-1-62948-233-0 (Hardcover)

Health Promotion: Community Singing as a Vehicle to Promote Health Jing Sun, Nicholas Buys and Joav Merrick (Editors) 2013. ISBN: 978-1-62618-908-9 (Softcover) Public Health Yearbook 2012 Joav Merrick (Editor) 2013. ISBN: 978-1-62808-078-0 (Hardcover) Alternative Medicine Research Yearbook 2012 Joav Merrick (Editor) 2013. ISBN: 978-1-62808-080-3 (Hardcover) Advanced Cancer: Managing Symptoms and Quality of Life Natalie Pulenzas, Breanne Lechner, Nemica Thavarajah, Edward Chow, and Joav Merrick (Editors) 2013. ISBN: 978-1-62808-239-5 (Hardcover) Treatment and Recovery of Eating Disorders Daniel Stein and Yael Latzer (Editors) 2012. ISBN: 978-1-61470-259-7 (Hardcover) 2013. ISBN: 978-1-62808-248-7 (Softcover) Health Promotion: Strengthening Positive Health and Preventing Disease Jing Sun, Nicholas Buys and Joav Merrick (Editors) 2013. ISBN: 978-1-62257-870-2 (Hardcover)

Pain Management Yearbook 2012 Joav Merrick (Editor) 2013. ISBN: 978-1-62808-973-8 (Hardcover) Public Health Concern: Smoking, Alcohol and Substance Use Joav Merrick and Ariel Tenenbaum (Editor) 2013. ISBN: 978-1-62948-424-2 (Hardcover) Mental Health from an International Perspective Joav Merrick, Shoshana Aspler and Mohammed Morad (Editor) 2013. ISBN: 978-1-62948-519-5 (Hardcover) Suicide from a Public Health Perspective Said Shahtahmasebi and Joav Merrick (Editor) 2014. ISBN: 978-1-62948-536-2 (Hardcover) India: Health and Human Development Aspects Joav Merrick (Editor) 2014. ISBN: 978-1-62948-784-7 (Hardcover) Alternative Medicine Research Yearbook 2013 Joav Merrick (Editor) 2014. ISBN: 978-1-63321-094-3 (Hardcover) Public Health Yearbook 2013 Joav Merrick (Editor) 2014. ISBN: 978-1-63321-095-0 (Hardcover)

Public Health: Improving Health via Inter-Professional Collaborations Rosemary M. Caron and Joav Merrick (Editors) 2014. ISBN: 978-1-63321-569-6 (Hardcover) Alternative Medicine Research Yearbook 2014 Joav Merrick (Editor) 2015. ISBN: 978-1-63482-161-2 (Hardcover) Pain Management Yearbook 2014 Joav Merrick (Editor) 2015. ISBN: 978-1-63482-164-3 (Hardcover) Public Health Yearbook 2014 Joav Merrick (Editor) 2015. ISBN: 978-1-63482-165-0 (Hardcover) Forensic Psychiatry: A Public Health Perspective Leo Sher and Joav Merrick (Editor) 2015. ISBN: 978-1-63483-339-4 (Hardcover) Leadership and Service Learning Education: Holistic Development for Chinese University Students Daniel TL Shek, Florence KY Wu and Joav Merrick (Editors) 2015. ISBN: 978-1-63483-340-0 (Hardcover) Mental and Holistic Health: Some International Perspectives Joseph L. Calles Jr., Donald E Greydanus, and Joav Merrick 2015. ISBN: 978-1-63483-589-3 (Hardcover) Cancer: Treatment, Decision Making and Quality of Life Breanne Lechner, Ronald Chow, Natalie Pulenzas, Marko Popovic, Na Zhang, Xiaojing Zhang, Edward Chow, and Joav Merrick (Editors) 2016. ISBN: 978-1-63483-863-4 (Hardcover)

Cancer: Bone Metastases, CNS Metastases and Pathological Fractures Breanne Lechner, Ronald Chow, Natalie Pulenzas, Marko Popovic, Na Zhang, Xiaojing Zhang, Edward Chow, and Joav Merrick (Editors) 2016. ISBN: 978-1-63483-949-5 (Hardcover) Cancer: Spinal Cord, Lung, Breast, Cervical, Prostate, Head and Neck Cancer Breanne Lechner, Ronald Chow, Natalie Pulenzas, Marko Popovic, Na Zhang, Xiaojing Zhang, Edward Chow, and Joav Merrick (Editors) 2016. ISBN: 978-1-63483-904-4 (Hardcover) Cancer: Survival, Quality of Life and Ethical Implications Breanne Lechner, Ronald Chow, Natalie Pulenzas, Marko Popovic, Na Zhang, Xiaojing Zhang, Edward Chow, and Joav Merrick (Editors) 2016. ISBN: 978-1-63483-905-1 (Hardcover) Cancer: Pain and Symptom Management Breanne Lechner, Ronald Chow, Natalie Pulenzas, Marko Popovic, Na Zhang, Xiaojing Zhang, Edward Chow, and Joav Merrick (Editors) 2016. ISBN: 978-1-63483-864-1 (Hardcover) Alternative Medicine Research Yearbook 2015 Joav Merrick (Editor) 2016. ISBN: 978-1-63484-511-3 (Hardcover) Public Health Yearbook 2015 Joav Merrick (Editor) 2016. ISBN: 978-1-63484-514-4 (Hardcover)

Quality, Mobility and Globalization in the Higher Education System: A Comparative Look at the Challenges of Academic Teaching Nitza Davidovitch, Zehavit Gross, Yuri Ribakov, and Anna Slobodianiuk (Editors) 2016. ISBN: 978-1-63484-986-9 (Hardcover) Cannabis: Medical Aspects Blair Henry, Arnav Agarwal, Edward Chow, Hatim A. Omar, and Joav Merrick (Editors) 2016. ISBN: 978-1-53610-510-0 (Hardcover)

HEALTH AND HUMAN DEVELOPMENT

CANNABIS MEDICAL ASPECTS

BLAIR HENRY ARNAV AGARWAL EDWARD CHOW HATIM A. OMAR AND

JOAV MERRICK EDITORS

New York

Copyright © 2017 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this publication. Simply navigate to this publication’s page on Nova’s website and locate the “Get Permission” button below the title description. This button is linked directly to the title’s permission page on copyright.com. Alternatively, you can visit copyright.com and search by title, ISBN, or ISSN. For further questions about using the service on copyright.com, please contact: Copyright Clearance Center Phone: +1-(978) 750-8400 Fax: +1-(978) 750-4470 E-mail: [email protected]. NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data Library of Congress Control Number: 2016958258 ISBN: 978-1-53610-522-3 (e-book)

Published by Nova Science Publishers, Inc. † New York

CONTENTS Foreword

xvii Blair Henry, Arnav Agarwal, Edward Chow, Hatim A Omar and Joav Merrick

Section one: Introduction

1

Chapter 1

Plants as medical tools Haleh Hashemi, Andrew Hand, Angelique Florentinus-Mefailoski, Paul Kerrigan, Phineas Samuel and Jeremy Friedberg

Chapter 2

History of medical cannabis Andrew Hand, Alexia Blake, Paul Kerrigan, Phineas Samuel and Jeremy Friedberg

17

Chapter 3

Cannabis or marijuana Donald E Greydanus and Joav Merrick

27

Section two: Plant pharmacology

3

63

Chapter 4

Pharmacology of cannabis Mandakini Sadhir

65

Chapter 5

The pharmacological properties of cannabis Istok Nahtigal, Alexia Blake, Andrew Hand, Angelique Florentinus-Mefailoski, Haleh Hashemi Sohi and Jeremy Friedberg

71

Section three: Clinical applications

83

Chapter 6

Medical cannabis use in an outpatient palliative care clinic Noah Spencer, Erynn Shaw and Marissa Slaven

85

Chapter 7

Four patient perspectives on medical cannabis Jeremy Friedberg

95

xiv

Contents

Chapter 8

Safety concerning medical cannabis Bonnie Cheung and Hance Clarke

Chapter 9

Medical cannabis in the treatment of chemotherapyinduced nausea and vomiting Jordan Stinson and Carlo DeAngelis

99

105

Chapter 10

Medical marijuana, cancer anorexia and cachexia Meiko Peng, Minhaz Khaiser, Michael Lam, Soha Ahrari, Mark Pasetka and Carlo DeAngelis

113

Chapter 11

Medical cannabis dosing strategies in pain related conditions Minhaz Khaiser, Meiko Peng, Michael Lam, Soha Ahrari, Mark Pasetka and Carlo DeAngelis

129

Chapter 12

How to administrate cannabis and efficacy Stephanie Stockburger

147

Chapter 13

Cannabis and pain Jonathan K Hwang and Hance Clarke

155

Chapter 14

Medical cannabis for pain in adolescence Barry Knishkowy

179

Section four: Policy, ethics and social commentary

187

Chapter 15

Medical cannabis from the pain physician’s perspective Ainsley M Sutherland, Judith Nicholls and Hance Clarke

189

Chapter 16

Ethical and policy implications concerning medical cannabis Sally Bean and Maxwell J Smith

199

Chapter 17

Adverse effects of cannabis use Amy L Burnett

207

Chapter 18

Cannabis and the role of our schools Venus Wong and Alissa Briggs

211

Chapter 19

Canada and medical marijuana Blair Henry, Rachel McDonald, Stephanie Chan, Edward Chow and Leigha Rowbottom

221

Chapter 20

Medical cannabis and palliative care Noah Spencer, Erynn Shaw and Marissa Slaven

227

Section five: Acknowledgments

233

Chapter 21

About the editors

235

Chapter 22

About the Rapid Response Radiotherapy Program at the Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada

237

Contents Chapter 23 Chapter 24

xv

About the National Institute of Child Health and Human Development in Israel

239

About the book series “Health and human development”

243

Section six: Index

247

Index

249

FOREWORD MEDICAL CANNABIS: TO USE OR NOT TO USE? Blair Henry, D(Bioethics)1,, Arnav Agarwal, MD(C)1, Edward Chow, MBBS1, Hatim A Omar, MD, FAAP2 and Joav Merrick, MD, MMedSc, DMSc2-6 Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada, 2 Division of Adolescent Medicine and Young Parents Program, Kentucky Children’s Hospital, UK Healthcare, Department of Pediatrics, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America, 3 National Institute of Child Health and Human Development, Jerusalem, 4 Office of the Medical Director, Health Services, Division for Intellectual and Developmental Disabilities, Ministry of Social Affairs and Social Services, Jerusalem, 5 Division of Pediatrics, Hadassah Hebrew University Medical Center, Mt Scopus Campus, Jerusalem, Israel and 6Center for Healthy Development, School of Public Health, Georgia State University, Atlanta, US

1

INTRODUCTION Cannabis has a long history of medicinal use, dating back thousands of years (1). However, with the discovery of morphine, hypodermic needles and other fast acting synthetic opioids in the ninetieth and the turn of the twentieth century- cannabis use declined as a medication (2). For most of the past six decades, cannabis has been considered a recreational drug, and was considered illegal in many jurisdictions. Yet in the past few years its association with medicine has made a dramatic comeback. As illustrated in figure 1, over the past six years (2010-2016) the terms “medical cannabis” and “medical marijuana” has seen a 4 to 5 fold increase in references based on a historical trend analysis of the terms noted in the PubMed database. It



Correspondence: Mr Blair Henry, Senior Ethicist, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON Canada. E-mail: [email protected].

xviii

Haleh Hashemi, Andrew Hand, Angelique Florentinus-Mefailoski et al.

would appear that the term medical cannabis is most often used over medical marijuana, in the emerging literature. 700 600

Frequency of citations

500 400 Term Medical Cannabis

300

Term Medical Marijuana

200 100

0 1960

1980

2000

2020

Year of Pulication Search Figure 1. Number of article titles using the terms: medical cannabis and medical marijuana in PubMed

In the past several years, claims on the potential for cannabis to treat, cure and prevent a number of diseases and conditions has led some to query whether these claims are overstated. A game changer for medical cannabis has been the ability to consume it without a need to actually inhale it along with other negative products of combustion. Newer technologies that allow for the vaporization of the full plant has made it less of a health concern (3). Noticeably the evidence on medical cannabis is lacking in both quality and quantity. To date most of the research has been conducted in Israel, however, with cannabis set to be legalized for use in Canada (4) and in a recent move in the United States, by the Obama administration (5), to remove barriers should allow researchers greater access to medical cannabis for testing in well-designed clinical trials. In Canada, the federal marijuana regulations were updated in the summer of 2016 with the introduction of the Access to Cannabis for Medical Purposes Regulations (ACMPR). The aim of this newly update regulation (ACMPR) is to treat marijuana like other psychoactive drugs used for medical purposes. Many of the Colleges (eight provincial) in Canada prohibit or at best strongly discourage its members from dispensing, providing or accepting delivery of marijuana for medical purposes (6). Of major concern for most Colleges has been a lack of good evidence on both medical risks and therapeutic benefits of marijuana- intimating that

Foreword

xix

physicians’ currently prescribing cannabis may be falling short of a fulsome informed consent process. The typical recommendation for Canadian physicians is that medical cannabis should not be a first line therapy and that documentation should outline that conventional therapies were attempted but were not successful (6). The legal defense organization for physicians practicing in Canada- the Canadian Medical Protective Association (CMPA), updated its guidance document following the passing of ACMPR regulations- a cursory read through this document quickly identifies a less than positive endorsement for physicians, highlighting mainly potential risks and limitations to physicians potentially interested in adding medical cannabis to their treatment recommendations. As the medical community has been slow to start- noticeable in the grey literature is the proliferation of website by patient and advocacy groups making claims that cannabis has the potential to treat ailments and symptoms ranging from AIDS related illness, Asperger’s, Bulimia, carpal tunnel syndrome to whiplash- making the differentiation between the miraculous and mere hype all the more challenging to identify (7-9).

REFERENCES [1] Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013;33(2):195–209. [2] Kritikos PG, Papadaki SP. The history of the poppy and of opium and their expansion in antiquity in the eastern Mediterranean area, 1967. URL: https://www.unodc.org/unodc/en/data-and-analysis/bulletin/ bulletin_1967-01-01_3_page004.html [3] Grant I, Atkinson JH, Gouaux B, Wilsey B. Medical marijuana: Clearing away the smoke. Open Neurol J 2012;6(1):18–25. [4] Philpott J. Plenary statement for the Honourable Jane Philpott, Minister of Health - UNGASS on the World Drug Problem. United Nations General Assembly Special Session on the World Drug Problem. URL: http://news.gc.ca/web/article-en.do?nid=1054489 [5] Saint Louis C, Apuzzo M. Obama administration set to remove barrier to marijuana research. New York Times 2016 Aug 16 August. [6] Canadian Medical Protective Association. Medical marijuana: Considerations for Canadian doctors, 2014. URL: https://www.cmpa-acpm.ca/en/legal-and-regulatory-proceedings/-/asset_publisher/ a9unChEc2NP9/content/medical-marijuana-new-regulations-new-college-guidance-for-canadiandoctors [7] United Patient’s Group. Illnessess treatable with medical cannabis, 2016. URL: https:// unitedpatientsgroup.com/ [8] Walia AQ. Twenty medical studies that show cannabis can be a potential cure for cancer, 2013. URL: http://www.collective-evolution.com/2013/08/23/20-medical-studies-that-prove-cannabis-can-curecancer/ [9] Harding A. Medical marijuana, 2013. URL: http://www.webmd.com/pain-management/features/medicalmarijuana-uses

SECTION ONE: INTRODUCTION

In: Cannabis: Medical Aspects Editors: B. Henry, A. Agarwal, E. Chow et al.

ISBN: 978-1-53610-510-0 © 2017 Nova Science Publishers, Inc.

Chapter 1

PLANTS AS MEDICAL TOOLS Haleh Hashemi, PhD, Andrew Hand, MSc, Angelique Florentinus-Mefailoski, MSc, Paul Kerrigan, BSc, Phineas Samuel, BSc and Jeremy Friedberg*, PhD MedReleaf Corp, Markham Industrial Park, Markham, Ontario, Canada Cannabis has been used for centuries for its fiber, food and as medicine. This review highlights the history of cannabis, its uses as a medical tool and the active ingredients found in this versatile plant. Many pain management pharmaceuticals widely accepted and used today, such as opioids and aspirin, contain plant derived extracts. The evolving cannabis story is paralleled to the history of current plant extracts used as pharmaceuticals. Usage, side effects and mortality rates of current pain medications are compared to cannabis and reveal great potential for cannabis as a safe and effective alternative in pain management.

INTRODUCTION One of the primary sources of difficulty for doctors to explore the use of cannabis as a medical tool stems from the idea that they are prescribing a “plant” and not an individual compound. Although this plant contains a predominant family of active ingredients, the cannabinoids, it is still a mixture of all the components in the plant tissue or plant extract. To compound this apprehension, this particular plant has had long and sorted cultural and social-political history in western civilization that is slowly, yet with difficulty, on the path to a resolution. However, in the annals of western medicine, the story of this plant’s journey is not new or unique and there is much to learn from the journey other plants have gone through from obscurity to common use. The purpose of this chapter is to chronicle two historical plant’s journeys in modern medicine and what comparisons and differences can be drawn to the story of cannabis.

*

Correspondence: Jeremy Friedberg, PhD, MedReleaf Corp, Markham Industrial Park, POBox 3040, Markham, Ontario, L3R 6C4, Canada. E-mail: [email protected].

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CURRENT PLANT EXTRACTS USED AS PHARMACEUTICALS AND USED IN PHARMACEUTICAL PRODUCTION Secondary metabolites, also referred to as natural products (NP), are organic compounds that are not directly involved in the natural growth, development, or reproduction of an organism, and typically result from the activities of biosynthetic pathways. The vast biodiversity of earth’s flora and fauna have been a tremendous and variable source of useful and medically relevant compounds and in many cases compounds that cannot be synthesized in vitro (1). The mechanism by which an organism synthesizes secondary metabolites is often found to be unique to each organism or it is an expression of the individuality of a species. They are produced for different reasons from a result of the organism’s adapting to its external environment, to acting as a possible defense mechanism against predators, or simply in assisting in the survival of the organism (2, 3).

Medicinal plants Plants and their extracts have been used as medicinal compounds for thousands of years. Their unique properties are the result of their evolution. This has resulted in the production of unique and structurally diverse secondary metabolites. These unique pharmacological properties and their application by different cultures and regions made them great candidates for new drug discovery research (4). According to the World Health Organization (WHO), 80% of people still rely on traditional plant-based medicine for primary health care and 80% of plant derived drugs were related to their historical application(5). In recent years, advancements in molecular biology in association with traditional medicine has promoted further investigations and yielded new drug candidates for the pharmaceutical market (6).

HISTORY OF PLANT EXTRACTS USED AS PHARMACEUTICALS The oldest records for the usage of medicinal plants dates back to 2400 BCE on clay tablets (Mesopotamia). The Greek physician Dioscorides (100 AD), recorded the collection, storage and the uses of medicinal herbs, whilst the Greek philosopher and natural scientist, Theophrastus (~300 BCE) collected similar information in a series of books available to this day. The monasteries in England, Ireland, France and Germany preserved this Western knowledge whilst scholars in the Middle East preserved the Greco-Roman knowledge and expanded the uses of their own resources, together with Chinese and Indian herbs unfamiliar to the Greco-Roman world during the Dark and Middle Ages. In the Middle East, Avicenna, a Persian pharmacist, physician and philosopher contributed much to the sciences of pharmacy and medicine through works such as the Canon Medicine book, which directly aided people in the middle east to establish privately owned pharmacies as early as the 8th century (7).

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CURRENT STATUS OF NATURAL PRODUCTS (NP) INCLUDING MEDICINAL PLANT EXTRACTS In 2014, the global market for plant-derived drugs was valued at $23.2 billion. It is expected that this market will reach $35.4 billion by 2020, representing a significant share of the global pharmaceutical market (8). This increase is a result of (1) the interest expressed by pharmaceutical companies in new and lower price drugs especially for psychosomatic, metabolic, and minor disorders and (2) the tendency of people to use modern traditional medicine. Traditional medicine has been widely used in different types of medication, dietary products and nutritional supplements since ancient times. Many of them currently are registered pharmaceuticals through regulatory offices such as the Food and Drug Agency (FDA) once they surpass clinical trials and demonstrate efficacy and safety (6, 8, 9). To date, 60,000 species of plants have been screened to yield the 135 known drugs. Considering the number of unscreened plant species, (approximately >300,000) there is a potential to find 540–653 new drug candidates in the years to come (10). Table 1. Plant-derived natural products approved for therapeutic use in the last thirty years (1984–2014) Generic name

Scientific name

Indication (mechanism of action)

Artemisia annua L.

Trade name (year of introduction) Artemisinin (1987)

Artemisinin

Arglabin

Artemisia glabella

Arglabin (1999)

Cancer Chemotherapy (farnesyl transferase inhibition)

Capsaicin

Capsicum Annum L.,

Qutenza (2010)

Post therapeutic neuralgia(TRPV1activator)

Colchicine

Colichicum SPP

Colcrys (2009)

Gout (tubulin binding)

Malaria Treatment (radical formation)

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Haleh Hashemi, Andrew Hand, Angelique Florentinus-Mefailoski et al. Table 1. (Continued) Generic name

Scientific name

Indication (mechanism of action)

Cannabis Sativa L,

Trade name (year of introduction) Sativex a (2005)

Delta -9Tetrahydrocannbinol (THC)

Galanthiamine

Galanthus Caucasicus

Razadyne (2001)

Dementia associated with Alzheimer’s disease (ligand of human Nicotinic acetyl choline receptors (nAChRs)

Ingenol mebutate

Euphorbia peplus L.

Picato (2012)

Actinic keratosis (inducer of cell death)

Masoprocol

Larrea tridentata

Actinex (1992)

Cancer chemotherapy (lipoxygenase inhibitor)

Omacetaxine mepesuccinate (Homoharringtonine)

Cephalotaxus harringtonia

Synribo (2012)

Oncology (protein translation inhibitor)

Chronic neuropathic pain (CB1 and CB 2Receptor activation)

Cannabidiol (CBD)

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Plants as medical tools Generic name

Scientific name

Paclitaxel

Taxus brevifolia Nutt.

Solamargine

Solanum spp

Trade name (year of introduction) Taxol (1993), Abraxanec b (2005), Nanoxelc (2007)

Indication (mechanism of action)

Curadermd (1989)

Cancer chemotherapy (apoptosis triggering)

Cancer chemotherapy (mitotic inhibitor)

Resources: (Ref 53), www.clinicaltrials.gov, and www.drugs.com. a Mixture of the two compounds b Paclitaxel nanoparticles. c Containing not just solamargine but also other solasodine glycosides

PLANT EXTRACTS WIDELY USED IN PHARMACEUTICAL PRODUCTION The plant extracts utilized as pharmaceutics vary greatly from country to country. Due to the rapid development in the understanding of plant chemistry, and the advancing ability to isolate and purify natural compounds, there are now a diversity of plant extracts on the market, either synthetic or directly derived from plants. Morphine, purified from opium by Serturner (1806), was the first alkaloid with high biological efficacy. This event was subsequently followed by the isolation of many other alkaloids including strychinine from Strychnos mux-vomica, and quinine from Cinchona spp. The most widely used breast cancer drug is paclitaxel (Taxol®), was isolated from the bark of Taxus brevifolia (Pacific Yew). It is now produced synthetically and is one of the main tools to treat breast cancer. Cannabis (Cannabis sativa) was traditionally used to alleviate severe headaches, a treatment for degenerative bone and joint diseases, ophthalmitis, general edema, infectious wounds, gout, and pelvic pain. Sativex, a titrated extract containing delta-9tetrahydrocannabinol (psychoactive) and cannabidiol (anti-inflammatory), has been approved in a few countries (e.g., Canada, The United Kingdom, Germany and New Zealand) since 2005. This botanical prescription drug is an oromucosal spray containing cannabinoid medicine for the treatment of spasticity due to multiple sclerosis and neuropathic pain of various origins. Marinol (dronabinol) and Cesamet (nabilone) are available in North-America for the treatment of vomiting and nausea associated with the use of chemotherapy to treat cancer (11). Several FDA approved botanicals currently are available in the global market like Veregen (Tea catechins) for the treatment of external genital and perianal warts (12) and Fulyzaq (extract from the red sap of Croton lechleri) for the treatment of diarrhea in HIV patients. In 2012 the Dutch Medicines Evaluation Board approved a dry extract of Dioscorea nipponica, a traditional Chinese botanical to relief headache, muscle pain and cramps (12). This was the first time that a Traditional Chinese Medicine (TCM) product was introduced into a European Union country. The list of plant species, which are processed in a relatively large scale, and their respective

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bioactive agents has been shown in table 1. A list of plant-derived products that has been used in clinical tials are shown in table 2. Table 2. Plant derived natural products in clinical trialsa Generic name and chemical structure Haplophragma adenophyllum

Curcumin

Curcuma longa L. (Turmeric)

Epigallocatechin-3-O-gallate

Camellia sinensis (L.)

Genistein

Genista tinctoria L.

Number of recruiting clinical trialsb: indications (potential mechanism of action) 1 trial: Solid tumors (E2F1 pathway activator)

26 trials: Cognitive impairment, different types of cancer, familial adenomatous polyposis, schizophrenia, cognition, psychosis, prostate cancer, radiation therapy, acute kidney injury, abdominal aortic aneurysm, inflammation, vascular aging, bipolar disorder, irritable bowel syndrome, neuropathic pain, depression, somatic neuropathy, autonomic dysfunction, Alzheimer's disease, plaque psoriasis, fibromyalgia, cardiovascular disease (NF-κB inhibition) 14 trials: Epstein-Barr virus reactivation in remission patients with nasopharyngeal carcinoma, multiple system atrophy, Alzheimer's disease, cardiac amyloid light-chain amyloidosis, Duchenne muscular dystrophy, cystic fibrosis, diabetic nephropathy, hypertension, fragile X syndrome, different types of cancer, obesity, influenza infection (cell growth arrest and apoptosis induction 5 trials: Colon cancer, rectal cancer, colorectal cancer, Alzheimer's disease, non-small cell lung cancer, adenocarcinoma, osteopenia, osteoporosis (protein-tyrosine kinase inhibitor, antioxidant)

Plants as medical tools Generic name and chemical structure Gossypol

Gossypium hirsutum L.

Picropodophyllotoxin

Podophyllum hexandrum Royle, replaced by Sinopodophyllum hexandrum

Quercetin

Allium cepa L.

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Number of recruiting clinical trialsb: indications (potential mechanism of action) 2 trials: B-cell chronic lymphocytic leukemia, refractory chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, nonsmall cell lung cancer (Bcl-2 inhibitor) 1 trial: Glioblastoma, glio sarcoma, anaplastic astrocytoma, anaplastic oligo dendroglioma, anaplastic oligo L.astrocytoma, anaplastic ependymoma (tubulin binding/IGF-1R Inhibitor)

9 trials: Chronic obstructive pulmonary disease, Fanconi anemia, different types of prostate cancer, diabetes mellitus, obesity diastolic heart failure, hypertensive heart disease, heart failure with preserved ejection fraction, hypertension, oxidative stress, Alzheimer's disease, pancreatic ductal adenocarcinoma, plaque psoriasis (NF-κB inhibition) Resveratrol Vitis vinifera L. 22 trials: Pre-diabetes, vascular system injuries, lipid metabolism disorders (including non-alcoholic fatty liver disease), endothelial dysfunction, gestational diabetes, cardiovascular disease, type 2 diabetes mellitus, inflammation, insulin resistance, disorders of bone density and structure, metabolic syndrome, coronary artery disease, obesity, memory impairment, mild cognitive impairment, diastolic heart failure, hypertensive heart disease, heart failure with preserved ejection fraction, hypertension, oxidative stress, polycystic ovary syndrome, Alzheimer's disease (NF-κB inhibition) a Resources: (Ref 53), www.clinicaltrials.gov, and www.drugs.com. b Determined from www.clinicaltrials.gov on 22nd of October, 2014, including trials in which the respective natural product is applied alone or as a mixture with other constituents, excluding studies with unknown status.

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THE OPIOIDS STORY Opiates have had a similar, long standing role to Cannabis in both management of disease and recreational use. The Greek word for juice “opos”was chosen due to the latex liquid that seeps from cuts in immature seed capsule. Modern usage of the word applies to all alkaloid and peptide compounds that can bind to opioid receptors (15). It is widely accepted that opium poppies were first cultivated in lower Mesopotamia, with the Sumerians referring to it as “hul gil,” which translates to “joy plant” (16). In the same geographical region, civilizations such as the Babylonians, Assyrians and Egyptians all have documented use of the plant for both pain management and ritualistic use (17). The Ebers Papyrus, an Egyptian medical document from ca. 1500 BCE also was mentioned about use of opium soaked sponges to manage pain during surgery, and for the prevention of excessive crying from children. From there, opium spread through the eastern world, with documented evidence of opium use by Greek culture in the third century BCE, and both India and China in the eighth century AD (18). With the introduction of opium came addiction and abuse, particularly in China during the seventeenth century after the banning of tobacco smoking led to an increased rate in the smoking of opium. Pharmacist Friedrich Sertürner first isolated morphine from opium poppies in 1806, the name being derived from Morpheus, the Greek GOD of dreams (19). Morphine saw regular use in the nineteenth century for pain, as well as other ailments such as respiratory problems and anxiety (20). With the invention of the hypodermic needle in 1853, use of morphine for minor surgical procedures, management of chronic pain and as an anesthesia during operations increased (16, 20). During the American Civil War, many soldiers were given morphine for injuries sustained during battle, and thus many suffered from opiate addiction after the war ended (21). To help combat morphine addiction, heroin was synthesized in 1898 as a more effective, less addictive and generally safer alternative. Saint James Society even provided free heroin through the mail to morphine addicts in an attempt to curb their usage. Between 1898 and 1910 Bayer marketed heroin as an analgesic and cough suppressant, before discovering that the drug did indeed induce considerable dependence in the user, and was very hazardous (22). All opioids act by interacting with opioid receptors, which are distributed throughout both the central and peripheral nervous systems, as well as some other organs such as the heart, liver and kidney (23). Multiple opioid receptors classifications exist- μ, κ, σ, nociception receptor, each with similar but different tissue location and function (24). Opioid receptors located on sensor nerves in the peripheral nervous system regulate analgesia and inflammation, the later due to cytokines produced during inflammation inducing the release of endogenous compounds that interact with opioid receptors. Similar to the endocannabinoids endogenously produced by the human body, endo-opioids such as endorphins and enkephalins interact with the same opioid receptors as plant derived opioids (25).

THE ASPIRIN STORY Humans have benefitted from the use of plant derived salicylates for millennia. Recommendations for treatment are described among the Ebers papyrus in Egypt (1500-3000 BCE) and also in Greece (500 BC) by the physicians Hippocrates and Galen (26). Patients

Plants as medical tools

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would be treated with a preparation including the leaves or bark of the willow tree, Salix alba, which alleviated inflammation, fever, and pain. To test historical observations, scientific validation is needed to confirm true relationships. In 1763, the first scientific description of Salix alba as a treatment for malarial fever in 50 patients is performed by Reverend Edward Stone (27). At the end of his account, Stone states his hopes; “that it (Salix alba bark powder) may have a fair and full trial in all its variety of circumstances and situations, and that the world may reap the benefits accruing from it” (27). Advances in organic chemistry in the 1820s allowed for the isolation of Salicin from willow bark (28). Salicin is used successfully to treat rheumatic fever, notably by TJ Maclagan and Sir William Osler until the end of the 19th century (29). In 1838, salicylic acid was derived from Salicin. Pharmaceutical chemists began to investigate the useful derivatives of salicylic acid which reduced such side effects as gastrointestinal irritation, resulting in over a dozen such compounds being synthesized by 1908 (26). In 1897, acetylsalicylic acid is synthesized in pure form and by 1899 is being sold worldwide as Aspirin by Bayer. Current worldwide production of acetylsalicylic acid is estimated to be 40,000 tons a year, and the number of clinical trials involving the drug is estimated to be 700-1000 annually (30). Certainly, the powdered bark of Salix alba has had its advantages and many people continue to reap benefit from its acetylated and pure cousin, acetylsalicylic acid.

THE EVOLVING CANNABIS STORY In the Western world cannabis was used only as a fiber source until the mid-1800s. However, once introduced for its pharmacological benefits, it quickly played an important role in medicine as early as the 20th century (31). Early in its introduction, cannabis was included in numerous over the counter and prescription drugs and referenced in many medical texts (32). However, in the mid-20th century, the use cannabis underwent a major cultural shift going from a medication to the status of being an illicit drug and its therapeutic applications were soon deterred by as a result of changes in the law (33). As a medication, cannabis had many strengths and potential applications, however, one of the main reasons of its initial decline was the growing use of alternative analgesics (33). Initially the decline in cannabis medicinal uses were practical: It was insoluble in water making it incompatible with hypodermic needles, and it’s delayed onset of at least an hour when consumed, posed a challenge for new quick acting analgesics (32). Another significant practical dilemma involved the sizable variation in effects both between different batches of cannabis and from person to person leading to inconsistent results. Ultimately, physicians found it difficult to work around these issues and analgesics such as aspirin, heroin and chloral hydrate, which were easily administered, fast acting and consistent, began to phase out cannabis (33). Though there where legitimate reasons for physicians to move towards other analgesics, cannabis had major advantages that were lost as a result: the reduced risks of developing physical dependence associated with cannabis, its low toxicity and that is had little to no disturbance in vegetative functions (32). These advantages over other analgesics warrant efforts to solve the practical obstacles to the medical uses of cannabis in modern day approaches. The main issue of inconsistency with Cannabis can be addressed far more effectively in modern day

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medicine than it could have been in the past. The main method used to determine the strength of a dose during the late 1800s was to administer cannabis to animals and observe the reaction (33). Today, laboratory analysis can be far more precise in measurement, using modern chemical analysis techniques to determine the exact chemical composition of the plant. By providing this information to physicians it is now possible for them to gauge the dose they are prescribing the patient (34). Another cause of inconsistency was that cannabis was most likely obtained from many sources growing different plants (32). Even if the source was the same, each plant would have a different potency due to genetic variation between seeds and as a results, acquiring a supply of cannabis that was consistent in composition was nearly impossible (35). Today this issue can be addressed through the application of clonal propagation and growing many daughter plants using prunings from a single mother plant. The advantage of this method is that all daughter plants will be genetically identical and so patients can continue to have access to consistent and identical medication (36). In light of these developments and based off growing evidence of the medical application of Cannabis, the perception of cannabis is once again changing. We are seeing a general trend towards cannabis once again becoming a part of western medicine as evidenced by its legal status for medicinal use in Canada (37). Use of Cannabis as a medicine should be re-evaluated using modern approaches of science and medicine to determine its true value as a therapeutic agent.

COMPARISON OF CURRENT PAIN MEDICATIONS The use of prescription pain medications such as opioids, corticosteroids and anticonvulsants has dramatically increased over the past decades. These prescription pain medications provide effective pain management but often come with risk of abuse, physical dependence, addiction and other serious side effects and are routinely used in combination with other medications (3844) (see table 3). Opioids, including morphine, codeine and oxycodone, are the most commonly used prescribed medication to treat acute or chronic moderate to severe pain. Opioids are used to control pain in cancer, neuropathy, fibromyalgia and other sources of pain. Patients taking prescription opioids need to be observed closely to monitor pain management and the physical reaction to the medication prescribed. Long term use brings adverse effects such as tolerance, risk of overdose, dependence and addiction and even death. Other side effects with short or long time use include brain damage, heart disease, liver disease, breathing problems and psychiatric effects (45).

Table 3. Comparison of current pain medications Medication

Utility

Common drugs

Target

Physical dependance

Side effects

Mortality rate

Cannabis

Cancer, HIV Neurological disorders Immunity Mood and behaviour Appetite and metabolism

Cannabis Sativa

Endocannabinoid receptor

Rare

Cognitive and memory impairment

Not reported

Pain (dental, injury, surgery) Cough, serious diarrhea Neuropathy Sickle cell disease Headache, migrane Fybromyalgia Anxiety Cancer

Morphine Codeine Oxycodone Tramadol

Cancer Arthritis

Dexamethasone

Seizures Neuropathy Personality disorders Mood Brain disorders (bipolar, mania, depression) Fybromyalgia Insomnia

Carbamazepine Ethosuximide Gabapentin

Opioids

Corticosteroids

Anti-convulsant

Increased heart rate, fluctuation in blood pressure. Rare: Stroke, heart infarct Anxiety, panic, depression Suppressed immune system, growth disorders, apathy, mood/personality changes, hormonal changes

Opioid receptor

Yes

Addiction, brain damage, death Weakened immune systetm, hallucinations, coma, breathing problems Sedation, anxiety, hormonal inbalance

30% reduction in pain from tolerance on baseline: greater with Day 1 cannabis versus placebo

AUTHOR CLINICAL STUDY AND PAIN DESIGN DATE CONDITION

Abrams et al. (2007) (22)

CoreyBloom et al. (2012) (31)

DURATION

POPULATION (N)

INTERVENTION (THC POTENCY %)

DOSING PAIN RELIEF FREQUENCY

HIV neuropathy

Prospective, randomized, double-blind, placebocontrolled

N = 55: 28 control, 27 21 day trial; 5 intervention - 25 3 inhalations Smoked cannabis day treatment completed trial daily for 5 cigarettes weighing periods for each category days 0.9g (3.56%) (M = 48, F = 7); Age: Mean 50 y

Multiple sclerosis and spasticity

Randomized, double-blind, placebocontrolled, crossover trial

17 day trial; intervention for 3 days total

SMOKED CANNABIS - Dronabinol vs Cannabis Randomized, Healthy placebo5, 6-hour Cooper et individuals controlled, outpatient al. (2013) (experimental doublesessions; 2-4 (26) ly-induced dummy, weeks trial pain) double-blind VAPORIZED CANNABIS Randomized, 3, 6-hour double-blind, sessions; 3 to Wilsey et al. placebo14 day NP (2013) (28) controlled, intervals crossover between study sessions

Decrease in daily pain with smoked cannabis >30% reduction in pain from baseline: 52% of intervention group; 24% in control group Median reduction on daily VAS: 34% in intervention group; 17% in placebo group Decrease in pain and spasticity with smoked cannabis Ashworth scale - smoked cannabis modified score by 2.74 points more than placebo Pain relief (VAS score) 5.28 points more than placebo

N = 30 (M = 11, F = 19); Age: Mean 21 y

Smoked cannabis cigarette weighing 0.8g (4%)

1 inhalation daily for 3 days

N = 30 (M = 15, F = 15) Age: 21-45 y (Mean 27 y)

Dronabinol (0mg, 10mg, 20mg) OR cannabis cigarettes (0.00, 1.98, 3.56% THC; ca. 800mg)

3-7 puffs (70% of cigarette pyrolyzed) per session

N = 39 (M = 28, F = 11); current or past cannabis users Age: Mean 50 y

Vaporized cannabis: placebo Decrease in neuropathic 8-12 puffs per (0%) medium dose pain; equivalent results for 6-hour session (3.53%); low dose low and medium doses (1.29%)

Decrease in experimentallyinduced pain with dronabinol and cannabis cigarettes; dronabinol produced longer-lasting decreases

PRIMARY OUTCOME MEASURE (PAIN ASSESSMENT)

100 mm VAS; daily diary

Ashworth Scale (spasticity assessment); VAS (Secondary Outcome)

McGill Pain Questionnaire (post CPT); 100-mm VAS

100-mm VAS & PGIC

Table 2. (Continued) AUTHOR CLINICAL STUDY AND PAIN DESIGN DATE CONDITION

DURATION

POPULATION (N)

INTERVENTION (THC POTENCY %)

Vaporized (aerosolized) Wallace et N = 16 (M = 9, F Diabetic 4 sessions; 2 cannabis: low dose al. (2015) = 7); neuropathy week intervals (1%); medium dose (29) Age: Mean 56.9 y (4%); high dose (7%); placebo (0%) Chronic pain N = 21 (M = 11, Vaporized (on twiceF = 10); cannabis: from Abrams et daily doses Not placeboAge: Mean 42.9 y cigarette 0.9g on al. (2011) of sustained controlled, not 5 days total (morphine cohort) average containing (25) release randomized and 47.1 y 3.56% THC (~96 morphine or (oxycodone mg THC/day) oxycodone) cohort) SMOKED, VAPORIZED, EDIBLE, TOPICAL Randomized, placebocontrolled, crossover study

Rhyne et al. (2016) (30)

Migraine headache

Retrospective, observational -chart review

Forms of cannabis used: vaporized (n N = 121 (M = 51, = 42), edible (n = F = 63); 66), topical (n = Age = 18-89 y 15), smoked (n = 55)

DOSING PAIN RELIEF FREQUENCY Single dosing session; 4 inhalations per session

Decrease in spontaneous pain scores most with high dose (7% THC); no 10-cm VAS; foam statistical difference between brush; von Frey medium and low dose (4 and 1%)

Inhaled on evening of Day 1, three Decrease in pain ratings on times daily on Day 5 compared to Day 1 days 2-4, morning of day 5

--

PRIMARY OUTCOME MEASURE (PAIN ASSESSMENT)

Decrease in monthly frequency of migraine headache

Drug Effects Questionnaire (subjective)

Primary: monthly frequency of migraine HA Secondary: Type and dose of medical cannabis used, previous and adjunctive migraine therapies, patient reported effects

Abbreviations: CPT = cold pressor test; DDS = descriptor differential scale; F = female; M = male; NP = neuropathic pain; PGIC = patient global impression of change; THC = delta-9-tetrahydrocannabinol; VAS = visual analog scale; VASPI = visual analog scale of pain intensity; y = years.

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Smoked cannabis In total, seven studies used smoked cannabis to manage pain associated with various conditions. Two trials were performed in healthy individuals with no pain history who received a painful stimulus (23, 26); four studies assessed neuropathic pain (NP) (24, 32), two of which explored HIV-related neuropathy (22, 27); and one trial assessed MS-associated pain and spasticity (31). All seven trials demonstrated a significant effect on pain relief compared to controls. The control in all studies was a placebo cigarette containing 0% THC content, while in one study smoked cannabis was also compared to an active control (dronabinol, a synthetic cannabinoid). The dosing frequency and THC content of the intervention drug varied between the studies (see Table 2). Relief of acute pain using smoked cannabis was studied in two trials. The first trial, by Wallace et al., used 15 healthy volunteers who received intradermal capsaicin-induced cutaneous pain after four standardized inhalations of smoked cannabis (23). When capsaicin was used 20 minutes after smoking cannabis (early time course), none of the cannabis potencies (low [2% THC], medium [4% THC], high [8% THC]), or placebo showed any difference in pain perception. However, at 55 minutes after smoking cannabis (late time course), capsaicininduced pain was decreased by the medium dose (4% THC), but increased by the high dose (8% THC). Plasma levels of THC and metabolites showed a correlation to the decrease in pain at the medium dose but this correlation did not exist with the high dose. The authors hypothesized that there may be another compound not accounted for in the high dose cannabis that may have contributed to the hyperalgesia. The high dose cannabis was also associated with increased mild to moderate side effects such as dizziness and somnolence compared to other doses. In another study of cannabis users (≥ 3 cannabis cigarettes at least 4 times per week), dronabinol was compared to smoked cannabis (26). Pain was experimentally induced using the Cold Pressor Test, where participants inserted their hands in a warm water bath (37°C) followed by a cold water bath (4°C) (26). Pain sensitivity (time taken to first report pain sensation), pain tolerance (time taken to withdraw hand from the cold water) and subjective pain ratings (Pain Intensity and Bothersomeness Scales) were assessed. As expected, peak effects of the drugs were seen 15 minutes after cannabis use and 180 minutes after dronabinol use. Compared to placebo, both smoked cannabis and dronabinol showed decreased pain sensitivity by increasing the time taken to report the pain sensation (p ≤ 0.01): 3.56% THC (13.1 ± 3.9s from baseline), 20 mg dronabinol (12.1 ± 5.6s from baseline) compared to placebo (0.3 ± 1.0s from baseline). Pain tolerance was improved (p ≤ 0.05) with low dose cannabis, 1.98% THC and both dronabinol doses (10mg and 20mg). Although the high dose cannabis (3.56%) increased pain tolerance in the first hour of administration (9.0 ± 3.0s from baseline), this decreased below baseline after the first hour and no significant change in tolerance was seen compared to placebo. In terms of subjective pain ratings of ‘pain intensity’ and ‘bothersomeness’, both cannabis doses (1.98%, 3.56% THC; p ≤ 0.001) produced a greater decrease compared to high dose dronabinol (20 mg; p ≤ 0.05). Thus, while smoked cannabis produced more subjective pain relief than dronabinol, the latter peaked later and produced longer lasting pain relief by increasing tolerance. Both drugs did not produce any negative subjective effects and cognitive effects were not assessed. There were four studies that looked at relief of neuropathic pain using smoked cannabis. In all four studies, patients had a mean age range of 45-50 years. They were randomized to

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smoked cannabis of varying potencies versus placebo (0% THC). Three of the studies had a crossover design with participant numbers ranging from 23-38 (24, 27, 32) while one had 25 participants in each arm of the study (22). To reduce risk of adverse psychoactive effects in cannabis naïve patients, two trials limited enrolment to previous cannabis users (22, 24), while others had no limitations. All studies excluded patients with any psychoactive issues or drug dependence. Even though neuropathic pain relief was the common outcome, each of the studies varied in the interventions and pain assessments used.

Pain relief outcomes A 2008 study conducted in central and peripheral neuropathic pain patients by Wilsey et al. reported an equianalgesic effect between high (7% THC) and low (3.5% THC) potencies of cannabis cigarettes compared to placebo (24). Pain relief was assessed using the Visual Analog Scale (VAS) and a 0.0035 reduction per minute in pain intensity was recorded for both doses (p = 0.016). Another study assessed neuropathic pain caused by trauma or surgery using three active cannabis potencies (2.5%, 6% and 9.4% THC) smoked for five days (32). An approximate 11% decrease in daily pain intensity was achieved with the high dose (9.4% THC) cannabis compared to placebo (p = 0.023). The other potencies (2.5%, 6%) resulted in nonsignificant, moderate decreases in pain. The higher dose was also associated with more drowsiness, better sleep with less periods of wakefulness (p < 0.05) there were no reports of confusion or disorientation which are serious cognitive effects. In the studies assessing HIV neuropathy, a decrease of > 30% in pain intensity measuring numeral rating scales (clinically significant decrease) (34) relative to placebo was reported with smoked cannabis use (22, 27). In both studies, a larger proportion of participants reported reduction in pain intensity when smoking cannabis (46%-52%) compared to the placebo groups (18%-24%) (22, 27).

Dosing frequency Three of the studies (HIV and post-traumatic neuropathy) had a range of 3-4 inhalations daily for five treatment days after which pain relief measures were taken (22, 27, 32). In one study of mixed neuropathic pain, the intervention had a significantly higher dose, with nine inhalations over a single 6-hour session (24). Some evidence exists for cannabis use in MS-related pain and spasticity. Corey-Bloom et al. reported reductions in patient reported scores with single inhalation of 4% THC cannabis for three treatment days (31). There was a decrease in the modified Ashworth scale of 2.74 points representing better spasticity compared to placebo (p < 0.0001). Pain measured using the VAS decreased by an average of 5.28 points compared to placebo (p = 0.008) (31). Five participants withdrew from the study due to treatment-related adverse effects in the intervention arm (feeling euphoria, dizziness, fatigue).

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Vaporized cannabis Of the three studies using vaporized cannabis, two were conducted to assess neuropathic pain relief (28, 29). Both were follow-up studies of previous work that had been conducted using smoked cannabis. In the 2013 follow-up study by Wilsey et al., lower THC concentrations were used compared to the 2008 study done with smoked cannabis (24, 28). Vaporized cannabis at a medium (3.53% THC) and low dose (1.29% THC) was inhaled through 8-12 inhalations in a 6-hour session. Even though both doses improved pain tolerance the effect was equianalgesic when compared to each other. Wallace et al. assessed vaporized cannabis use at three THC doses (1%, 4%, 7%) in diabetic neuropathy (29). This was a follow up study of one published in 2007, where similar doses of smoked cannabis were assessed in healthy individuals with experimentally-induced pain (23). Spontaneous pain scores were significantly decreased by the high dose (7% THC) compared to other interventions. No statistical difference was reported between low and medium doses (p = 0.92). Vaporized cannabis has also been studied in chronic pain patients currently using opioids. In one 2011 study, 21 participants with chronic pain on sustained-release morphine (average dose: 62 mg twice daily) or oxycodone (average dose: 53 mg twice daily) therapy were given vaporized cannabis (3.56% THC) to augment pain relief (25). Participants in both opioid groups reported a 27% average decrease in pain measures on Day 5 of treatment compared to Day 1 when they had no exposure to cannabis. Cannabis inhalation was associated to a subjective “high” that was not seen in opioid use alone.

Other dosage forms A recent study in migraine headache (HA) showed a decrease in frequency from 10.4 to 4.6 headaches per month (p < 0.0001) with chronic use of medical cannabis (30). The study was a retrospective, observational chart review of patients with a follow-up appointment post migraine diagnosis. In the study, 121 patients used different forms of cannabis, most of whom used edible (n = 66, 77.4 g monthly), smoked (n = 55, 45.1 monthly), vaporized (n = 42, 74.8 g monthly), and some used topical cannabis (n = 15, 73.4 g monthly). Most patients used cannabis for both prophylaxis and treatment (90%), though differences in doses have not been reported. Edible cannabis users were more likely to report negative outcomes including somnolence, increase headache and difficulty determining dosing and onset of action. While approximately 85% patients reported reduced frequency of migraine HAs monthly, about 10% patients who used inhaled forms of cannabis reported complete control of migraine HAs. This study concluded that cannabis has positive effects in migraine prophylaxis and treatment, and warrants further prospective studies to assess dose-response relationships in a controlled environment.

Other edible forms Though the following studies were not included in the final screened trials due to unmet inclusion criteria (case study; pain relief not assessed), it is worthwhile to explore the evidence that exists for edible forms of cannabis.

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Brownie No randomized trials have been conducted in any pain related indication using cannabis brownies. A 1988 study by Cone et al. used a double-blind crossover design to assess behavioral measures for five healthy, male subjects after consumption of cannabis-laced brownies (35). The participants had a history of cannabis use and the brownies contained 2.8% THC either at a dose of two 800mg cannabis cigarettes, one 800 mg cigarette or placebo (0% THC) (4, 35). The intervention group scored higher on behavioral measures assessed using subjective scales including the Single Dose Questionnaire, Addiction Research Center Inventory (ARCI), and VAS compared to placebo. However, the peak effects were slow to appear and variable at 2.53.5 hours after brownie consumption unlike smoking cannabis where effects are seen in minutes (35). Subjects were not restricted in terms of diet that may have contributed to differences in absorption and inter-subject variability. In another study by Watchel et al., peak plasma THC levels were analyzed upon consumption of brownies versus smoked cannabis (36). Brownies containing low dose of THC (9 mg THC/brownie) resulted in a mean peak plasma levels of 5 ng/mL and high dose brownies (13 mg THC/brownie) resulted in mean peak plasma levels of 6-9 ng/mL (whole plant material versus THC) (36). It is interesting to note that the level associated with euphoria ranges from 50 to 100 mcg/L (37). However, smoking equivalent THC amounts produced at least five times higher peak plasma THC levels. The dose-dependent plasma THC levels increased one hour after brownie ingestion, while smoking resulted in a rapid increase in THC plasma levels (36).

Cannabis oil No clinical trials were identified for cannabis oil use in pain management. A 1997 case study of a young male patient with chronic relapsing pain, gastric inflammation and familial Mediterranean fever symptoms, used cannabis oil as an intervention (38). A peripheral cannabinoid receptor (unnamed) was identified and localized to the immune system in the gastrointestinal tract. This investigation hoped to assess the role of cannabinoids in gastric inflammatory conditions. The patient was randomly assigned to olive or cannabis oil weekly over six weeks (1 washout week, 1 active week, 2 placebo weeks, 2 active weeks, 1 placebo week). The dose used was 50 g THC per day as 10 g THC in 5 doses in an effort to minimize psychotropic effects.(38) The patient continued oral sustained-release morphine (30 g twice daily) throughout the study and used 10 mg morphine for breakthrough pain management. During two consecutive placebo weeks, the patient experienced mood disorders due to possible withdrawal from previous THC use and during the final two weeks he was unable to differentiate between placebo and drug suggesting possible development of tolerance to the active medication with two weeks of continuous (38). The most interesting finding in this case is that the total amount of breakthrough pain medication requirement decreased with use of cannabis. The patient used 17 tablets of breakthrough morphine during the active weeks versus 41 tablets during placebo weeks. Cannabis oil did not show any anti-inflammatory effects but this case showed a significant reduction in additional analgesic requirements.

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DISCUSSION With implementation of new regulations in Canada, eligible individuals with an authorized prescription can access medical cannabis through licensed producers. A number of Canadians associate cannabis use with low risk of harm, and it is gaining popularity as a potential treatment option for unmanageable conditions (39, 40). However, the act of prescribing cannabis is complicated by the lack of strong evidence on dosing (41). Various professional governing bodies and researchers have published standards of practice and guidelines to help physicians navigate through this issue, but further research is warranted to solidify recommendations (20, 42, 43). The College of Family Physicians of Canada recommends physicians follow the strategy, “Start low, go slow” when prescribing cannabis (37). The recommendation is to prescribe an inhaled dose of 100-700 mg of no more than 9% THC cannabis daily, titrating to a maximum 3 g dried cannabis per day. No specific inhalation instructions have been provided except that patients should start with a single inhalation and appreciate the effects over 4 hours before increasing (37). One review article made preliminary recommendations to prescribe, “12g cannabis (9% THC) for 30 days, start with 1 inhalation/day to a maximum of 4 inhalations/day” after conducting a literature review in a chronic non-cancer pain setting (43). There is a growing body of evidence in support of synthetic THC capsules (dronabinol or nabilone) and plant extract oromucosal sprays (nabiximols), but less is known about herbal cannabis (17, 44). The current scoping review aimed to assess existing evidence on dosing and potency specifically for herbal cannabis in pain related conditions.

Limitations of clinical trials Even though nine out of 11 studies included in this review had a randomized, double-blind and placebo controlled design, common limitations across the studies reduced the quality of evidence. One issue that was recognized by most studies is the small participant size ranging from 16-27 participants in the intervention groups. With the exception of one study, where HIV neuropathy patients were all male, there is a fairly good representation of both genders in other trials (27). Thus, the generalizability of the data is limited. The crossover design of most studies makes blinding of cannabis versus placebo challenging. The psychoactive effect of THC (especially at high potencies) contributes in patients correctly guessing the intervention they receive. Ellis et al. tried to correct for this factor by asking participants to report what they think they received at several points during the study (27). In the first treatment week, guessing was no better than chance and cannabis was still shown to be better than the control group in providing pain relief. In other studies, treatment effects could have been enhanced due to unmasking of interventions. However, using more than one intervention group, for example 2.5% versus 6% versus 9.4% THC would increase the likelihood of blinding among intervention groups as participant may not be able to determine the exact potency (32).

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Oral administration versus inhalation This review mainly assessed herbal cannabis delivered through inhalation (smoking or vaporizing) and commentary has been included on cannabis brownies and oil. Evidence shows that oral administration has a slower onset, longer duration of action, and lower peak levels of medication in the blood when compared to inhalation (8). Peak plasma THC levels can be at least 5 times higher through smoking compared to oral routes (36). Even though some behavioral changes were noticed using 2.8% THC cannabis-laced brownies, these appeared 2.5-3.5 h after consumption (35). Thus, the typical side effect of THC, euphoria, and other positive reinforcement effects such as relaxation and enhanced sensory experiences occurs rapidly through inhaled forms (~15 minutes) compared to oral administration (45). Individual physiological differences such as rate of gastrointestinal absorption, degree of first-pass metabolism and genetic makeup of the participant may also contribute to inter-subject variability with oral cannabis. Since inhalation provides a direct and fast onset of pain relief, it is the more preferred route of administration. However, there is a proven relationship for THC dose-related adverse neurologic or psychoactive effects (e.g., dysphoria, sedation and poor concentration) with inhaled cannabis (16). In one study, the ratings for “feeling high” (p < 0.003) and “feeling stoned” (p < 0.004) were highest with the higher dose (3.53% THC) versus the lower dose (1.29% THC) (28). Since oral cannabis results in lower plasma levels of THC these may cause less psychoactive effects and may be designed to reduce the euphoric “high” that is experienced by inhaled cannabis. This is relevant for certain patient populations (e.g., older, work requiring high cognitive performance) who may opt for oral cannabis to avoid the “high” even if it means a delayed pain relief effect. Low THC potencies used in low doses have also shown to cause cognitive impairment in some patients that lasts up to 24 hours (4). Thus, even if oral cannabis or low THC potencies of inhaled cannabis are selected to prevent psychoactive effects, there is no guarantee of how a patient may respond.

Smoking versus vaporizing Smoking is the act of burning the plant material and inhaling the smoke while vaporizing is heating the herb below point of combustion (7). Taking into account the hazards of smoking, investigators of two follow-up studies chose to repeat their initial smoking studies using vaporized cannabis as this would reduce exposure to carcinogens (23, 24, 28, 29). Smoking is not an optimal delivery system as similar carcinogenic materials usually found in tobacco smoke are also present in cannabis smoke (9). Vaporizing cannabis can produce carbon monoxide as a by-product but it is comparably in much smaller amounts compared to smoking (7). Thus, in agreement with the recommendations by governing bodies, vaporizing should be the chosen mode of delivery (20, 43).

Standard inhalation protocol versus reality In most studies, the “Foltin Puff Procedure” was used which standardized the inhalation protocol. Participants mostly self-administered cannabis while being given verbal cues, but in one study were taught the inhalation method to be used at home (32). Participants in this study

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collected daily urine samples and returned all capsules (containing herbal cannabis to be used in a titanium pipe) at the end of each intervention period. Investigators concluded compliance was excellent as all dispensed capsules were returned, and urine and plasma THC assays were consistent with results (32). Participants in a clinical trial are under supervision and have regular follow-ups in a controlled environment, but this is not the case in clinical practice. Practitioners who choose to prescribe cannabis need to consider various methods to prevent or control substance abuse, such as prescribing small amounts at a time, or ordering regular urine testing to reduce risk of diversion or abuse.

Dose-response relationship Trials studying smoked cannabis for neuropathic and MS pain conditions had the shortest intervention periods, lasting 1-5 days. The dosing frequency ranged from one inhalation daily to nine inhalations in a 6-hour session, with majority of the studies ranging from 3-4 inhalations per day. A number of the studies defined low, medium, or high dose using THC percentage by weight. The wide variation in the design of the trials makes it challenging to compare them headto-head but some important conclusions can be highlighted. Overall, use of cannabis reduced participant reported pain measures compared to placebo. This was observed in studies using a single potency of THC (~4%) in HIV related neuropathy and MS related pain settings (22, 31) Similar studies of smoked and vaporized cannabis in neuropathic pain settings found equianalgesic effects between low, medium, and high THC potencies (24, 28). In other studies, decrease in spontaneous pain scores was most with the highest dose studied (25, 28). These results highlight the challenge that exists in selecting the best initial cannabis potency for treatment. One study avoided this dilemma by first titrating participants to a maximum tolerance ranging 1-8%, and then performed the intervention phase of the trial, which resulted in successful pain reduction from baseline (27). Therefore, titration by “starting low, going slow” is the best dosing strategy as 1) lower potencies have shown equivalent efficacy to higher doses; 2) all patients may not equally tolerate higher potencies of cannabis.

Dosing recommendation In neuropathic pain settings, controlled trials have shown efficacy of THC doses from 1% to 9%. The best dosing strategy in this group is to start at the lower THC doses based on patient history of cannabis use (e.g., 1-2% THC) up to 3-4 vaporized inhalations daily (separated by 45 seconds based on Foltin procedure) (33). For cannabis-naïve patients, it should be required for patients to start at the lowest THC dose (i.e., 1% THC) to avoid undesirable side effects and titrate up to pain relief (19). Cannabis-naïve patients should be counseled to separate inhalations by at least 30 minutes to assess side effect and prevent overdosing. For non-neuropathic pain the same recommendations may be followed as above. Cannabis oil may be dosed using dronabinol/Marinol® (oral capsules of synthetic THC in sesame oil) as a reference as no clinical trials exist (19). Average dose of Marinol® used is 20 mg THC per day and doses range from 2.5 mg to maximum 210 mg THC per day. Just as with the inhaled cannabis, oils should be prescribed at the lowest dose (e.g., 2.5 mg THC) and then titrated to effect (19). Patients

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should wait at least two hours between administrations of single oral doses as acute effects may last up to 4 hours (4). To start, dried cannabis should be prescribed at 1 g per day (30 g/month) to a maximum of 3 g per day (90 g/month) (4). The amount prescribed should follow the MMPR regulation: “30 times the daily quantity of dried marijuana indicated by your healthcare practitioner on your medical document, or 150 grams of dried marijuana, whichever is less” (18).

Limitations of the scoping review Due to the nature of this scoping review where MeSH terms were used in databases deemed most appropriate, it is not possible to ensure all relevant studies were gathered for inclusion. Cannabis dosing in pain settings has very limited evidence and clinical studies of cannabisbased edible products (e.g., oils, teas, brownies etc.) are non-existent. Case studies and animal studies were excluded and should be considered for inclusion moving forward as they may provide some perspective on novel dosing strategies that may be of clinical importance.

CONCLUSION Even though medical cannabis is not approved as a therapeutic agent in Canada, it is available for medical use by patients with an authorized prescription. Current literature on herbal cannabis mostly involves smoked and vaporized mode of delivery, and very little evidence exists regarding oral forms such as brownies and oils. Smoking is not an optimal delivery system due to toxic by-products and thus, vaporizing cannabis is preferred. The studies identified in this review are limited by large variability in dosing strategies, small sample sizes and short intervention periods. Standardized studies regarding orally consumed cannabis (oils, brownies etc.) are essentially non-existent and limit our ability to make substantial conclusions. It is best to choose a low potency to start treatment with and titrate to an optimal dose that provides pain relief, improves function with minimal adverse effects.

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In: Cannabis: Medical Aspects Editors: B. Henry, A. Agarwal, E. Chow et al.

ISBN: 978-1-53610-510-0 © 2017 Nova Science Publishers, Inc.

Chapter 12

HOW TO ADMINISTRATE CANNABIS AND EFFICACY Stephanie Stockburger*, MD Division of Adolescent Medicine, UK Healthcare, Department of Pediatrics, Lexington, Kentucky, US The legalization of marijuana for medical use is increasingly common in the United States. The marijuana plant contains a number of cannabinoids along with chemical delta-9tetrahydrocannabinol (THC) which is known to be psychoactive. In states where medical marijuana is legal, physicians may be trained to certify patients for medical marijuana use. Patients then take their certification and obtain medical marijuana from a dispensary. The dispensary provides advice on which marijuana species or strain to purchase as well as dosing and administration. Forms of medical marijuana are the same as recreational marijuana. Forms include dried leaves or buds for smoking or ingestion and hashish which may also be smoked or ingested. Marijuana concentrates are becoming more popular as they are easier to conceal and require a smaller amount to produce the desired effect. Types of concentrates include butane honey oil, CO2 honey oil, wax or budder, and shatter. Dabbing is a technique used for consuming concentrates that involves placing a “dab” of the concentrate on a heated surface and inhaling the vapors. As products are not regulated by the United States Food and Drug Administration, there is concern that potency and product-labeling of THC content varies widely among dispensaries and patients are at risk for under- and over-dosing. Overall, more research is needed about the effects of specific cannabinoids on individual body systems and health conditions in order to standardize forms of administration and their efficacy as well as dosing.

INTRODUCTION The legalization of marijuana for medical use is increasing in the United States. Marijuana is the dried leaves, flowers, stems, and seeds from the hemp plant, Cannabis sativa (1, 2). Marijuana contains numerous cannabinoids. The chemical delta-9-tetrahydrocannabinol (THC) is a known mind-altering chemical that is found within the plant. Currently, there are two *

Correspondence: Stephanie J Stockburger, MD, Division of Adolescent Medicine, UK Healthcare, Department of Pediatrics, KY Clinic Room J413, Lexington, KY 40536-0284, United States. E-mail: [email protected].

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United States Food and Drug Administration (FDA) approved cannabinoids: dronabinol and nabilone. The FDA-approved indications for these drugs are nausea and vomiting associated with chemotherapy and appetite stimulation in acquired immunodeficiency syndrome (AIDS) (1). Marijuana (as opposed to the isolated cannabinoids mentioned above) is classified as a schedule I drug which means it has no currently accepted medical use and has a high potential for abuse (1). However, our current law permits individual states to allow physicians to certify marijuana use for certain medical conditions (3). Many states agree that Alzheimer’s disease, amyotrophic lateral sclerosis, cachexia/wasting syndrome, cancer, Crohn’s disease, epilepsy and seizures, glaucoma, hepatitis C virus, human immunodeficiency virus/acquired immunodeficiency syndrome, multiple sclerosis and muscle spasticity, severe and chronic pain, and severe nausea are conditions that physicians can certify patients for medical marijuana use (3). Typically, it is recommended that the FDA-approved cannabinoids dronabinol and nabilone are tried initially. Then if patient has minimal or no improvement, therapy may be escalated to medical marijuana use that is certified by the physician. The patient then goes to a dispensary and receives advice on which marijuana species or strain to purchase as well as dosing and administration (1). The forms and administration of medical marijuana are identical to the use of recreational marijuana.

FDA-APPROVED CANNABINOIDS Currently, there are two isolated cannabinoids that are approved by the FDA. These are dronabinol and nabilone. They are approved for the treatment of chemotherapy-induced nausea and vomiting as well as appetite stimulation in patients with acquired immunodeficiency syndrome (AIDS) (4). Both drugs are available in capsule form. Dosing of dronabinol is 2.5 mg to 10 mg three or four times daily. Dronabinol is available in a 2.5 mg capsule, 5 mg capsule, and a 10 mg capsule (4). It is considered a controlled substance, category C-III. For appetite stimulation, the initial recommended dose is 2.5 mg twice daily (before lunch and dinner) or once daily if dose is not tolerated (4). Dose can be titrated up based on response and tolerability to a maximum of 20 mg per day (4). For chemotherapy-induced nausea and vomiting the recommended dose is 5 mg/m2 administered 1 to 3 hours before chemotherapy, then give 5mg/m2/dose every 2 to 4 hours after chemotherapy for a total of 4 to 6 doses/day (4). Dose can be increased in increments of 2.5 mg/m2 based on response and tolerability with a maximum dose of 15 mg/m2/dose. Off-label dosing of chemotherapy-induced nausea and vomiting that is refractory is 2.5 to 10 mg 3 or 4 times daily (4). Nabilone is FDA approved for treatment of nausea and vomiting associated with cancer chemotherapy (5). It also comes in a capsule form (5). Capsules are 1 mg. Dosing instructions are 1-2 mg twice daily with a maximum of 6 mg in 3 doses daily (5). It is recommended to begin with the lower dose and increase if needed. Nabilone is also considered a controlled substance and is category C-II (5). It is approved for treatment for adults but use in pediatric patients is considered off-label (5).

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MEDICAL MARIJUANA As mentioned previously, the use of medical marijuana can be certified by a physician for certain conditions within state laws. States that allow physicians to certify medical marijuana have their own list of approved conditions that may be managed with medical marijuana (1). Each state that has legalized medical marijuana also has a legal limit which may be something like “1-2 ounces every 30 days”. The legal limit varies widely by state (1). It is important to note that physicians are not prescribing marijuana but instead are certifying that the patient has a medical condition that may benefit from medical marijuana use and that the physician has discussed the risks and benefits (1). Certification must state the medical condition that the physician believes would be treated effectively with the medical marijuana (1). In some states, the recommended amount of marijuana needed to treat the condition must also be stated on the certification (1). Marijuana cannot be prescribed due to its status at the federal level of being a schedule I drug which makes it illegal (1). It is not regulated by the FDA or dispensed by pharmacies (1). Physicians must have training in prescribing medical marijuana which usually consists of continuing medical education (CME) activities prior to certifying patients for medical marijuana use (1). When physicians are treating patients for conditions that would otherwise be treated by marijuana itself, it is reasonable to start therapy with dronabinol or nabilone (1). If these medications are not successful, treatment may be escalated to marijuana itself (1). Marijuana contains a number of cannabinoids and it is currently not known how individual cannabinoids affect the various diseases that are currently managed with medical marijuana (1). Conditions which are permissible for treatment with medical marijuana vary by state. However, there are a number of conditions that states agree upon in which management with medical marijuana is permissible (3). These conditions include Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), cachexia/wasting syndrome, cancer, Crohn’s disease, epilepsy and seizures, glaucoma, hepatitis C virus, HIV/AIDS, multiple sclerosis and muscle spasticity, severe and chronic pain, and severe nausea (3). Once a patient begins medical marijuana treatment, close physician follow-up is very important as it is with any medication that could have significant adverse effects and abuse potential (1). It is recommended that the patient be seen for follow-up within 30 days with additional telephone contact as necessary (1). After this, the patient may be followed monthly for three months and then in intervals depending on the clinical situation (1). Medical marijuana is administered in the same way as recreational users use the drug. When a patient receives certification from a physician for treatment with medical marijuana, they take the certification to a dispensary (1). The dispensary provides advice on which marijuana species or strain to purchase as well as dosing and administration (1). Forms of marijuana include dried leaves and buds, resin from the flowers, and extracts. Only the leaves and buds of the female Cannabis Sativa and Cannabis indica plants contain psychoactive properties (6). The male plants do not contain THC and therefore do not have psychoactive properties (6).

SMOKING Smoking leaves and buds of the marijuana plant is a common way to use marijuana recreationally or medically. Joints (also called “spliffs or doobies” are hand-rolled cigarettes

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that contain marijuana leaves and buds (2). A blunt is an emptied cigar that is partly or completely refilled with marijuana (6). The lumpy texture of marijuana as well as the distinct odor of marijuana distinguishes it from tobacco (6). The marijuana may be sprayed with contaminants such as other psychoactive drugs to enhance effects of poor quality, stale, or male (not psychoactive) marijuana plants (6). Pipes and water pipes may also be used to smoke marijuana. Hashish (hash, for short) is made by shaking the buds of marijuana and dropping the resin glands onto silk screens (6, 7). The resin glands are then sieved through the silk screens to create kief. Kief has a loose powdery consistency. Kief is normally compressed to form a block of hash. Kief and hash may be smoked in pipes, water pipes, bongs or mixed with tobacco and smoked (6). The different names for hashish include black, goldseal black, redseal black, and Morrocan (Rocky for short) (6). Hashish is an oily, solid substance (6).

EDIBLES Marijuana can be mixed in food such as brownies, cookies or candy (2). It can also be brewed as a tea (2). It can also be used like a kitchen herb and added to many types of food (6). Hashish and hashish oil can also be dissolved into milk and consumed in drinks (6). Cannabis is an oilbased substance and the emulsive properties of milk allow it to be dissolved. When marijuana is ingested, compared to inhaling the smoke or vapors of marijuana, it has a delayed-onset of effect, and tends to last for a longer period of time (8). It is estimated that 16% to 26% of patients using medical cannabis consume edible products (9). Oral consumption does not have the harmful effects of smoking but users may have a more difficult time titrating their dose to desired effect (10).

CONCENTRATES Concentrates contain a higher percentage of THC than marijuana leaves or hash products (7). All concentrates must be made by using some type of solvent to extract the THC (7). Toward the end of the concentrate-making process, the solvents and plant matter are removed (7). Solvents used are either butane or carbon dioxide (CO2) (7). There is concern that it is difficult to completely remove the solvent from the concentrate. Health concerns exist about consuming concentrate that still contains butane (7). However, professional concentrate manufacturers have supposedly become extremely efficient at removing butane (7). In addition, because the process usually involves butane, which is lighter fluid, individuals who have attempted to create extracts at home have caused fires and explosions and have been seriously burned and injured (2). Concentrates may be in the form of oil, wax, or shatter. Hash oil or honey oil is a gooey liquid that is usually used in vape pens (7). As above, the extraction process either involves the use of butane (butane honey oil or BHO) or CO2 (CO2 honey oil). Wax or budder is a soft solid that has a texture like lip balm (2). It is created by whipping hash oil during the purging process and has a consistency that is comparable to earwax (7). The percentage of THC between oil and wax are similar (7). Shatter is a hard, amber-colored solid that is a refined version of butane

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honey oil (2, 7). It takes multiple steps to make in order to extract all the plant matter and solvents and is usually made in a pressure vacuum (7). It is usually a thin cake, is yellow or amber in color, and “shatters” when you break a piece off (7). Shatter is the most potent concentrate and can contain 90% THC (7).

DABBING Dabbing is a technique that is used for consuming concentrates (7). It involves placing a “dab” of concentrate onto a heated surface which vaporizes the concentrate. The concentrate is then inhaled (7). There is a recent increase in “dabbing” among recreational marijuana users as well as medical marijuana users (11). Users are recommended to start with a single inhalation of marijuana vapor and monitor for effect (1). If twenty minutes pass without effect, the patient may take two inhalations and monitor for another twenty minutes (1).

CANNABINOID (CBD) OIL Cannabinoid oil is not FDA-approved in the United States but is a product worth mentioning due to its likelihood of beneficial effects for several medical conditions. Cannabidiol (CBD) is a compound found in marijuana that is not psychoactive like THC (12, 13). Cannabidiol and THC levels vary among different plants and breeders have created strains of the marijuana plant that have high levels of CBD and very low, next to zero, levels of THC (12). CBD oil is thought to have antipsychotic, antihyperalgesic, anticonvulsant, neuroprotective, and antiemetic properties (13). The American Academy of Neurology published guidelines in 2014 that recommended an oral cannabis extract containing both THC and CBD as having the highest level of evidence-based support as treatment for spasticity as well as pain associated with multiple sclerosis (14). This product is not currently FDA-approved for use in the United States (14).

POTENCY AND LABELING CONCERNS The potency of THC and other cannabinoids is not regulated and varies widely among products with the exception of the FDA-approved and regulated cannabinoids dronabinol and nabilone. The mean potency of marijuana preparations appears to be increasing over the last two decades. A study by Mehmedic, et al. evaluated confiscated cannabis preparations from 1993 to 2008 (13). A total of 46,211 samples were seized and analyzed by gas chromatography-flame ionization detection. It was found that the mean Δ9-THC content increased from 3.4% in 1993 to 8.8% in 2008 (13). Hashish potencies were not noted to increase consistently during this period but were noted to vary widely from 2.5% to 9.2% (1993-2003) to 12.0-29.3% (20042008) (13). The study concluded that the increase in cannabis preparation potency was mainly due to an increase in the potency of nondomestic versus domestic samples (13). There is also a large concern about the consistency of cannabinoid dose and label accuracy. A study by Vandrey et al. (10) evaluated the package contents of edible medical cannabis

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products from three major metropolitan areas (10). Dispensaries were located by an internet directory and three dispensaries from each of the three major metropolitan areas were randomly identified (10). Individuals with physician certification for medical cannabis use purchased products from the dispensaries. The samples were tested with high-performance liquid chromatography. Researchers noted that the products failed to meet basic label accuracy standards for pharmaceuticals (10). They found that greater than 50% of products evaluated had significantly less cannabinoid content than labeled, with some products containing negligible amounts of THC (10). They noted that other products contained significantly more THC than labeled. If products are over-labeled, the medical benefits may be negligible (10). If products are under-labeled, the higher THC content puts patients at risk of experiencing increased adverse effects (10).

DOSING Dosing for the FDA-approved products dronabinol and nabilone is well-established. However, the dosing for medical marijuana is not standardized. According to the World Health Organization, a standard marijuana cigarette contains as little as 0.5 g of marijuana (1). As an example, in Massachusetts, state law allows a 60-day supply of 10 oz of medical marijuana (1). A 60-day supply of 10 oz is up to 560 marijuana cigarettes or about 10 per day (1). If a patient smokes 1 to 2 marijuana cigarettes a day, they would need about 0.5 to 1 oz of marijuana per month (1). It is estimated that ingesting marijuana requires about three to five times the smoked dosage (8). When cannabis is ingested, the effects are spread out over a longer period of time (8). This may be useful for patients who are having trouble with sleep or situations where smoking is impractical or impossible (8). However, ingested cannabis can be harder to titrate due to its delayed onset and an individual’s metabolic activity (8). It is recommended that medical marijuana users have an accurate scale to weight, measure, track and titrate their dosage and supply of cannabis (8). Patients tend to “stockpile” their marijuana as they cannot purchase it at the pharmacy (8). One author recommends a personal supply of three to six pounds (8). There is concern that potency diminishes a little with time but cannabis can be reportedly stored in a cool, dark, dry place for years without significant loss of effect (8).

CONCLUSION In conclusion, there are a number of different forms of administration of medical marijuana. At this time, medical marijuana is not regulated by the FDA and therefore dispensaries often have under- or over-labeled THC content of their products. Marijuana contains a number of different cannabinoids which may have different effects on different medical conditions. There may be a role for the non-psychoactive CBD oil in treatment for a number of medical conditions. More research is needed to safely recommend marijuana forms and route of administration as well as specific strains and species of the plant.

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REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]

Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems. JAMA 2015;313(24):2474-83. National Institute on Drug Abuse. DrugFacts: Marijuana. URL: https://www.drugabuse.gov/ publications/drugfacts/marijuana. Belendiuk KA, Baldini LL, Bonn-Miller MO. Narrative review of the safety and efficacy of marijuana for the treatment of commonly state-approved medical and psychiatric disorders. Addict Sci Clin Pract 2015;10:1-10. UpToDate. Dronabinol: Drug information. URL: http://www.uptodate.com/contents/dronabinol-druginformation?source=search_result&search=dronabinol&selectedTitle=1%7E25. UpToDate. Nabilone: Drug information. URL: http://www.uptodate.com/?source=search_ result&search=nabilone&selectedTitle=1%7E13. Hartney E. Types of marijuana: How to recognize the many different forms of marijuana. URL: https://www.verywell.com/types-of-marijuana-22323. PotGuide.com Colorado. Different types of marijuana concentrates available in Colorado. URL: https://www.coloradopotguide.com/colorado-marijuana-blog/2014/february/06/different-types-ofmarijuana-concentrates-available-in-colorado/ Conrad C. Cannabis yields and dosage. URL: http://www.safeaccessnow.net/yieldsdosage.htm. Grella CE, Rodriguez L, Kim T. Patterns of medical marijuana use among individuals sampled from medical marijuana dispensaries in Los Angeles. J Psychoactive Drugs 2014;46(4):267-75. Vandrey R, Raber JC, Raber ME, Douglass B, Miller C, Bonn-Miller MO. Cannabinoid dose and label accuracy in edible medical cannabis products. JAMA 2015;313(24):2491-3. Stogner JM, Miller BL. Assessing the dangers of “dabbing”: mere marijuana or harmful new trend? Pediatrics 2015;136(1):1-3. Leaf science. 5 must-know facts about cannabidiol (CBD). URL: http://www. leafscience.com/ 2014/02/23/5-must-know-facts-cannabidiol-cbd/ Mehmedic Z, Chandra S, Slade D, Denham H, Foster S, Patel A, et al. Potency trends of Δ9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J Forensic Sci 2010;55 (5):1209-17. Wright S, Yadav V, Bever C Jr, Bowen J, Bowling A, Weinstock-Guttman B, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2014;83 (16):1484-6.

In: Cannabis: Medical Aspects Editors: B. Henry, A. Agarwal, E. Chow et al.

ISBN: 978-1-53610-510-0 © 2017 Nova Science Publishers, Inc.

Chapter 13

CANNABIS AND PAIN Jonathan K Hwang, BSc(C) and Hance Clarke, MD, PhD* Pain Research Unit, Department of Anesthesia and Pain Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada Cannabis and cannabis derivatives are sometimes used to relieve pain. Objective: To conduct a scoping review to explore the extent of the literature on the efficacy, safety, and side effects of cannabis and cannabis derivatives as a treatment for pain. Methods: The English-language literature was searched using electronic databases for studies published from 1960 to August 15, 2016. All randomized controlled trials that compared cannabis to a control and that examined pain as an outcome were included. Data on demographic and clinical characteristics, study duration, intervention duration, and outcomes were abstracted. Results: Of 4,472 articles identified through the literature search, only 28 studies satisfied eligibility criteria. An additional five were identified through hand search Most studies had very small sample sizes. The primary methods of administration were oromucosal spray of nabiximol, oral ingestion of cannabis extract capsules, and inhalation of smoked cannabis. Overall, nabiximol oromucosal sprays resulted in reductions in pain that were statistically significant but of variable clinical relevance. Studies of oral cannabis extracts nabilone and dronabinol yielded mixed results, with some studies demonstrating effectiveness and others being negative. Studies of smoked cannabis consistently demonstrated statistically significant and clinically relevant reductions in neuropathic pain. Conclusions: Published research on the efficacy of cannabis as a treatment for pain is extremely limited. Evidence of effectiveness was strongest for smoked cannabis for neuropathic pain.

INTRODUCTION Cannabis and cannabis derivatives have been used since ancient times as an analgesic to relieve pain from a variety of conditions. Although long considered a natural remedy for

*

Corresponding author: Hance Clarke, MD, PhD, Staff Anesthesiologist, Director of Clinical Pain Services and Medical Director of Pain Research Unit, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON Canada. E-mail: [email protected].

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various conditions, the evidence for its use has not been systematically reviewed until relatively recently. This scoping review will explore the extent of the literature on the efficacy, safety, and side effects of cannabis and cannabis derivatives as a treatment for pain.

OUR REVIEW We searched the English-language literature for studies published from 1960 to August 15, 2016 using electronic databases such as MEDLINE, EMBASE, CINAHL, EBM Reviews and Cochrane Databases. Our search strategy includes the MESH terms: marijuana, cannabis, cannabinoids, and pain. We also searched the bibliographies of systematic reviews and all included studies by hand for additional relevant studies.

Eligibility criteria We included all randomized controlled trials that compared cannabis to a control and examined pain as an outcome; the control could be placebo or another analgesic. We excluded crosssectional studies, prospective and retrospective observational studies, case-control studies, case reports, case series and review articles. We also excluded studies that were published in abstract form only.

Selection process and data abstraction We reviewed titles and abstracts from the literature search to select articles that met our eligibility criteria. Then, one of the authors abstracted data from the selected articles, including demographic and clinical characteristics of the study, study duration, intervention duration, and outcomes. During our review, we further excluded studies that were not blinded and studies with sample size less than 10 when considering efficacy data. When considering long-term safety data, we did include open label studies as there was not much long-term safety data.

FINDINGS A total of 4,472 articles were identified through the literature search. Of these, there were only 28 studies that satisfied our eligibility criteria (see Figure 1). An additional 5 studies (1-5) were identified through hand search of bibliographies of review articles and included studies. After excluding 5 studies that were not blinded (6-10) and 1 with small sample size (11), we included a total of 27 articles (see Table 1). The majority of evidence on cannabis and pain comes from randomized controlled trials that use either a placebo or known analgesics as controls. As there is no standard dose for cannabinoids, the studies vary greatly in the amount of the cannabinoid administered. Specific studies covered conditions that caused pain such as cancer, multiple sclerosis (MS), HIVinduced neuropathy, fibromyalgia, or trauma-induced neuropathy. Other studies were more

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general and did not specify the primary cause of pain. Of particular interest is the use of cannabis for cancer pain and multiple sclerosis as cannabis is thought to have other positive anti-emetic and anti-spastic effects. The primary methods of administering the treatments included use of a nabiximol oromucosal spray, ingestion of cannabis extract capsules, and inhalation of smoked cannabis.

Figure 1. Scoping review flow diagram.

Table 1. Characteristics of included RCTs (n = 27) First author, year, country

No. of subjects

Male (%)

Abrams et al. (2007), USA

55

87

Berman et al. (2004), United Kingdom

48

96

Cooper et al. (2013), USA

30

Corey-Bloom et al. (2012), USA

30

Mean age* (SD) 48.5 (6.6)

Clinical condition

Type of pain

Duration of study

Treatment

Outcome

Results

Adverse events -Anxiety, Sedation, Disorientation, Paranoia, Confusion, Dizziness, and Nausea (all mild) -No dropouts due to adverse events Dizziness (n=9), Somnolescence (n =7), Dysgeusia (n =10), Nausea (n = 1), Feeling Drunk (n = 4) (all mild to moderate)

HIV

Neuropathy

3 weeks

Smoked Cannabis (3.56% THC) x 3/ day for 5 days vs placebo

Ratings of pain (VAS)

Pain Reduction by 34% using Cannabis vs. 17% by placebo (p= 0.03)

39 (10)

Brachial Plexus Avulsion

Neuropathy

6 weeks

27 (6)

Cold Pressor Test

Nociceptive

5 x 6-7 hour sessions

Pain on an 11 point box scale, Short-Form McGill Pain Questionnaire, Pain Disability Index Pain on an 11 item numeric scale

Pain Scores -Baseline: 7.5, After Placebo: 6.9, -After 1:1 THC:CBD: 6.1 (p = 0.005), -After THC only: 6.3 (p = 0.02)

50

Sativex Oromucosal Spray (2.7 mg THC + 2.5 mg CBD/ spray) vs placebo and THC Oromucosal Spray (2.7 mg THC/ spray) x 1-48 sprays vs placebo Smoked Cannabis (1.98% and 3.56% THC), Dronabinol 10 mg, 20 mg, placebo

37

51 (8)

Multiple Sclerosis

Spasticity (nociceptive)

17 days

Smoked Cannabis (4% THC) x 1/ day vs placebo

Pain (using VAS)

Effect (95% CI) = 5.28 (2.48 – 10.01) reduction in VAS scores in cannabis vs placebo group

Unable to abstract due to method of recording

Subjective Drug Effects: Smoked Cannabis (1.98% and 3.56% THC) and 20 mg Dronabinol produced increased “High” and “Good” Drug Effects relative to placebo Acute Cognitive Effects (Dizziness, Headache, Fatigue, feeling too “high”)

First author, year, country

No. of subjects

Male (%)

Ellis et al. (2012), USA

34

97

Frank et al. (2008), United Kingdom

96

52

Johnson et al. (2010), United Kingdom

177

54

Mean age* (SD) 49.1 (6.9)

Clinical condition

Type of pain

Duration of study

Treatment

Outcome

Results

Adverse events -Concentration Difficulties, Fatigue, Sleepiness, Sedation, Increased sleep duration, Reduced salivation and thirst; moderate to severe adverse events more common in treatment group -1 drop out due to Psychosis, 1 due to Intractable Cough Tiredness (n = 79), Sleeplessness (n = 46), Sickness (n=46), Tingling (n = 25), Strangeness (n = 27), Nightmares (n = 7), Shortness of Breath (n=18), Headaches (n = 20), Other (n = 66)

HIV

Neuropathy

7 weeks

Smoked Cannabis (1-8% THC) x 4/day vs placebo

Pain intensity on a Descriptor Differential Scale (DDS)

Median difference in DDS points for pain reduction of cannabis vs. placebo: 3.3 (p = 0.016)

50.2 (13.6)

Various

Neuropathy

6 weeks

250ug-2 mg Nabilone or 30240 mg dihydrocodeine per day

Pain (using VAS)

60.2 (12.3)

Cancer

Mixed

2 weeks

Oromucosal THC Extract Spray (2.7 mg THC per spray), Oromucosal THC:CBD Extract Spray,

Pain on an 11 item numeric scale

VAS Scores (mm): -Baseline: 69.6 (range 29.495.2), Nabilone: 59. 93 (SD = 24.42), Dihydrocodeine : 58. 58 (SD = 24.08) -3/64 in Nabilone group had a clinically significant drop in VAS (by 10 mm or more) Numeric Pain Scale Scores: -Baseline THC:CBD Group(SD): 5.68 (1. 24), -Baseline THC

-THC:CBD: Somnolescence (n = 8), Dizziness (n = 7), Confusion (n=4), Nausea (n=6), Vomiting (n = 3), Raised

Table 1. (Continued) First author, year, country

No. of subjects

Male (%)

Mean age* (SD)

Clinical condition

Type of pain

Duration of study

Treatment (2.7 mg THC + 2.5 mg CBD per spray) x 8-12 sprays according to individual response, placebo

Outcome

Results

Adverse events

Group (SD): 5.77 (1.33), -Baseline Placebo(SD): 6.05(1.32), -Median Reduction THC:CBD Group: 1.37(p=0.024), -Median Reduction THC Group: 1.01(p=0.204), -Median Reduction Placebo Group: -0.69 -Statistically significant reduction for THC:CBD group only, clinically significant (>30% pain Reduction) reduction observed in 43% of treatment patients vs. 21% of placebo patients

Gamma GT (n =2), Hypercalcemia (n = 0), Hypotension (n =3) -THC: Somnolescence (n = 8), Dizziness (n = 7), Confusion (n=1), Nausea (n = 4), Vomiting (n = 4), Raised Gamma GT (n = 5), -Mostly mild or moderate.

First author, year, country

No. of subjects

Male (%)

Kalliomaki et al. (2013), Sweden

30

100

Killestein et al. (2002), Netherlands

16

N/A

Kraft et al. (2008), Germany

18

0

Mean age* (SD) 29.3 (6.25)

Clinical condition

Type of pain

Duration of study

Treatment

Outcome

Results

Adverse events -Dizziness (n = 21), Postural Dizziness (n = 11), Fatigue (n = 10), Dry Mouth (n=10), Tachycardia (n = 9). Mostly mild to moderate. - 14 severe adverse events led to the withdrawal of four patients -Adverse events were more common with the C. sativa extract than the Dronabinol treatment. All were mild to moderate. -1 severe adverse effect (acute psychosis) with C. sativa extract. Drowsiness, Sedation, Dry Mouth, and Vertigo had significantly different self-report and observer reported VAS scores for the cannabis treatment compared to placebo

Healthy volunteers

Nociceptive using a heatpain model or intradermal capsaicin

3 treatment sessions

Nabilone Capsules (1 mg, 2 mg, and 3 mg), placebo. Single dose.

Pain (using a VAS)

No significant difference between nabilone doses and placebo for electronic VAS (maximal pain) or VAS (area under curve)

46 (7.9)

Multiple Sclerosis

Spasticity (nociceptive)

12 weeks

Dronabinol (THC) 2.5 mg, C. sativa extract (2.5 mg THC, CBD, other cannabinoids)

Pain (using VAS)

No abstractable pain data

23.5 (2.6)

Healthy volunteers

Nocioceptive-Sunburn Hyperalgesia, Electrical Pain, and Intradermal Capsaicin

8 hour sessions

Oral Cannabis Extract Capsules (2:1 THC:CBD Content) (20 mg THC) per session

Pain (using VAS)

No significant difference between cannabis extract capsules and placebo was found for any pain models

Table 1. (Continued) First author, year, country

No. of subjects

Male (%)

Langford (2013), 33 study sites globally

339

32

Lynch et al. (2014), United Kingdom

18

17/83

Mean age* (SD) 49.0 (10.5)

56 (10.8)

Clinical condition

Type of pain

Duration of study

Treatment

Outcome

Results

Adverse events 15 (9%) in the THC/CBD spray group and 12 (7 %) in the placebo group, stopped study medication due to AEs. Majority of AEs leading to permanent cessation of study medication were within the nervous system disorders and gastrointestinal disorders system organ classes Fatigue (n = 7), Dry Mouth (n = 5), Dizziness (n = 6), Nausea (n = 6), Increased Appetite (n = 2), Diarrhea (n = 2), Decreased Appetite (n = 1), Feeling “stoned” (n = 1), Anxiety (n = 1), Panic Attack (n = 1), Headache (n = 2), Confusion (n = 1), “Fuzzy Thinking” or “Foggy Brain” (n = 1)

Multiple sclerosis

Neuropathy

(Phase A) 4 weeks

Oral muscosa spray (2.7 mg of THC + 2.5 mg of CBD), x max 12 sprays/ day, placebo

Validated selfreported 0– 10 point numerical rating scale (NRS) assessing mean daily neuropathy

Responders at the 30 % improvement level in mean pain NRS score totaled 50 % in the THC/CBD spray group vs 45 % in the placebo group (p = 0.234)

Chemothera py induced pain

Neuropathy

6 months

Oromucosal THC Extract Spray (2.7 mg THC/spray), Oromucosal THC:CBD Extract Spray, (2.7 mg THC + 2.5 mg CBD/ spray) x 1-12 sprays according to individual response, placebo

Pain on an 11 item numeric scale

No significant difference was found between placebo and the nabiximol spray, however 5/16 participants experienced a clinically significant reduction in pain at the end of 6 months.

First author, year, country

No. of subjects

Male (%)

Narang (2008), USA

30

47

Nurmikko et al. (2007), United Kingdom

125

41

Mean age* (SD) Median (range): 43.5 (21-67)

53.3 (15.5)

Clinical condition

Type of pain

Duration of study

Treatment

Outcome

Results -Patients on Dronabinol had decreased pain intensity and increased satisfaction compared with placebo. -No difference in benefit were found between the 20 mg and 10 mg -Difference between Sativex and Placebo Decrease: -0.96 (p=0.004) -Statistically significant decrease in pain -26% of Sativex vs 15% placebo patients achieved a clinically significant decrease in pain (>30% pain reduction)

Non-cancer pain (taking opiods)

Chronic pain

Phase 1 ~4 weeks

10 mg or 20 mg of dronabinol (single dose), placebo

Total Pain Relief at 8 hours (TOTPAR)

Allodynia

Neuropathy

5 weeks

Sativex Oromucosal Spray (2.7 mg THC + 2.5 mg CBD/ spray) x 148 sprays according to individual response, placebo

Pain on an 11 item numeric scale, Neuropathi c Pain Scale

Adverse events 2 adverse events during the study, both related to anxiety (tremors, dizziness, inability to concentrate). Both occurred in subjects who received 20 mg of dronabinol. -Dizziness (n = 18), Nausea (n = 14), Fatigue (n = 13), Dry Mouth (n = 11), Vomiting (n = 8), Feeling Drunk (n = 6), Headache (n = 6), Diarrhea (n = 4), Nasopharyngitis (n = 4), Anorexia (n = 4), Somnolescence (n = 4), Abdominal Pain Upper (n=3), Disturbance in Attention (n=3), Memory Impairmnet (n = 3) -91% of patients experienced at least1 AE; most were mild

Table 1. (Continued) First author, year, country

Portenoy et al. (2012), US

No. of subjects

360

Male (%)

52

Mean age* (SD)

58 (12.2)

Clinical condition

Various

Type of pain

Various

Duration of study

24 months

Treatment

Sativex Oromucosal Spray (2.7 mg THC + 2.5 mg CBD/ spray) x 14,6-10,11-16 sprays according to individual response

Outcome

Pain on an 11 item numeric scale

Results

No statistical or clinical significant difference in pain relief between Sativex spray and placebo

Adverse events -11% on Sativex experienced a severe AE vs. 8% on placebo Neoplasm Progression (n = 47), Nausea (n = 59), Dizziness (n =51), Vomiting (n =42), Somnolescence (n=39), Disorientation (n = 18), Anorexia (n = 22), Constipation (n=20), Dry Mouth (n=22), Anemia (n=19), Diarrhea (n=17), Dysgeusia (n = 11), Headache (n =15), Asthenia (n =18), Hallucination (n = 8), Decreased Appetite (n = 11), Fatigue (n = 13), Pain (n = 11), Insomnia (n = 8), Stomatitis (n =11), Weight Decreased (n = 8) -29.5% of patients receiving Sativex had a severe adverse event

First author, year, country

No. of subjects

Male (%)

Rog et al. (2005), United Kingdom

66

21

Skrabek et al. (2008), Canada

40

7

Mean age* (SD) 49.2 (8.3)

Multiple Sclerosis

central pain

48.9 (7.6)

Fibromyalgi a

Nociceptive

Clinical condition

Type of pain

Duration of study

Treatment

Outcome

Results

Adverse events

4 weeks

Sativex Oromucosal Spray (2.7 mg THC + 2.5 mg CBD/ spray) x 148 sprays according to individual response, placebo

Pain on an 11 item numeric scale

Numeric Pain Scale Scores (SD) -Baseline Sativex: 6.5 (1.6), -Baseline Placebo: 6.4 (1.7),-Decrease in Pain Scale Score Sativex, Placebo: -2.7, 1.4 (between groups difference((p = 0.005)

8 weeks

Nabilone (THC) Capsules (0.5-1 mg)/day for one week?, placebo

Pain (using VAS)

-Decrease in Pain for 1 mg Nabilone BID from Baseline after 4 weeks: -2.04 (p < 0.02).

-Dizziness (n = 18), Somnolescence (n = 3), Disturbance in Attention (n = 2), Headache (n = 1), Dissociation (n = 3), Euphoria (n = 2), Dry Mouth (n = 4), Nausea (n = 3), Diarrhea (n = 2), Glossodynia (n = 1), Mouth Ulceration (n = 1), Vomiting (n = 1), Falls (n = 3), Weakness (n = 3), Fatigue (n = 2), Feeling Abnormal (n = 1), Feeling Drunk (n =1), Pharyngitis (n = 2), Hoarseness (n = 1), Throat Irritation (n = 1) - 88.2% of patients on Sativex developed one or more AE, -2 patients withdrew due to severe AEs After 4 weeks: -Drowsiness (n = 7), Dry Mouth (n = 5), Vertigo (n = 4), Ataxia (n = 3), Confusion (n = 2), Decreased

Table 1. (Continued) First author, year, country

Svendson et al. (2004), Denmark

No. of subjects

24

Male (%)

42

Mean age* (SD)

50 (8)

Clinical condition

Multiple Sclerosis

Type of pain

Spasticity (nociceptive)

Duration of study

6 weeks

Treatment

Dronabinol (THC) 10 mg/day for 3 weeks, placebo

Outcome

Pain on an 11 item numeric scale

Results

Adverse events

-No significant differences observed for 0.5 mg Nabilone PO at 2 or 4 weeks and no significant differences observed for 1 mg Nabilone BID at 2 weeks.

Concentration (n = 2), Dissociation (n = 2), Orthostatic Hypertension (n=2), Anorexia (n = 2), Headache (n = 1), Dysphoria (n = 1), Euphoria (n = 1), Sensory Disturbance (n = 1). Mostly mild. -No serious adverse events occurred -Adverse events were significantly more common in the treatment group at 2 and 4 weeks -Dizziness or Lightheadedness (n = 14), Tiredness or Drowsiness (n = 10), Fatigue (n = 1), Balance Difficulty (n = 2), Headache (n = 6), Migraine (n = 1), Speech Disorders (n = 1), Feeling of Drunkenness (n = 2), Sleep Difficulty (n = 1), Multiple Sclerosis Aggravated (n = 1), Myalgia (n = 6), Muscle Weakness

-Median spontaneous pain significantly lower for Dronabinol than for placebo (p=0.02) with 13 (54%) patients achieving clinically significant (>30% pain reduction) pain reduction on active treatment

First author, year, country

Toth (2012), Canada

No. of subjects

26

Male (%)

54

Mean age* (SD)

61.2 (14.7)

Clinical condition

Refractory human diabetic peripheral neuropathic pain

Type of pain

Neuropathy

Duration of study

5 weeks

Treatment

nabilone 1-4 mg/day, taken as 2/day, 12 hours apart

Outcome

Pain diaries

Results

Adverse events

versus 5 (21%) on placebo

(n = 3), Limb Heaviness (n = 1), Distortion of Wrist (n = 1), Mouth Dryness (n = 3), Nausea (n = 3), Palpitations (n = 4), Euphoria (n = 3), Hyperactivity (n = 1), Hot Flushes (n = 1), Anorexia (n = 1), Chills (n = 1), Upper Airway Infection (n = 1), Tenderness in Nose (n = 1) -Number of adverse events was high for the active treatment group than for the placebo group -No severe adverse events were reported; no withdrawals due to adverse events Treatment-emergent adverse events were reported by 6/13 (46%) subjects receiving placebo and by 7/13 (54%) subjects receiving nabilone (most were mild or moderate)

Improvement in the change in mean end-point neuropathic pain in nabilone vs placebo (mean treatment reduction of 1.27; 95% confidence interval 2.290.25)

Table 1. (Continued) First author, year, country

No. of subjects

Male (%)

Turcotte (2015), Canada

15

13

Wade et al. (2003), United Kingdom

24

50%

Mean age* (SD) 45.5 (10.8)

N/A

Clinical condition

Type of pain

Duration of study

Treatment

Outcome

Results After adjustment, a significant group x time2 interaction term was reported for both the VASpain and VASimpact score, demonstrating the adjusted rate of decrease for both outcomes was statistically greater in nabilone vs placebo group. - Statistically significant decrease in pain for THC and CBD treatments, but not THC:CBD treatment

Relapsingre mitting multiple sclerosis (MS) patients (on gabapentin)

MS-induced neuropathic pain

9 weeks

Nabilone 5-week maintenance of 1mg oral nabilone (placebo) twice daily

Pain (using VAS): pain intensity (VASpain), and impact of pain on daily activities (VAS impact)

Various

Various

8 weeks

Sativex Oromucosal Spray (2.7 mg THC + 2.5 mg CBD/ spray), THC Oromucosal Spray (2.7 mg THC), CBD Oromucosal Spray (2.5 mg CBD) x 1-44 (120 mg THC/120 mg CBD) sprays according to individual

Pain (using VAS)

Adverse events Nabilone was well tolerated, with dizziness/ drowsiness most frequently reported.

-THC:CBD only: “Drug Toxicity” (n = 1), Headache (n = 1), Nausea (n = 1), Vomiting (n = 1), Diarrhea (n = 1), Sleepiness (n = 2), Fall (n = 1), Cough (n = 1), Impaired Balance (n = 1), Fatigue (n = 1), Influenza-like Symptoms (n = 1), Thirst (n = 1) -Feeling Intoxicated led to 3 withdrawals

First author, year, country

Wallace et al. (2007), USA

No. of subjects

19

Male (%)

58

Mean age* (SD)

28.9 (10.9)

Clinical condition

Healthy volunteers

Type of pain

Nociceptive – pain induced by Capsaicin

Duration of study

1 day

Treatment response, placebo Smoked Cannabis (2%, 4%, 8% THC)

Outcome

Results

Adverse events

Pain (using VAS; Visual Analogue Spontaneous Pain Intensity VASPI)

Five minutes after cannabis exposure, there was no effect on capsaicininduced pain at any dose. By 45 min after cannabis exposure, however, there was a significant decrease in capsaicininduced pain with the medium dose and a significant increase in capsaicininduced pain with the high dose. There was no effect seen with the low dose, nor was there an effect on the area of hyperalgesia at any dose. Significant negative correlations

-Low Dose: Dizziness/Faintness (n = 1), Injection Side Effects (n = 2). -No Medium Dose Adverse Events reported. - High Dose: Dizziness/Faintness (n = 3), Somnolescence (n = 1), Feeling Cold (n = 1), Cognitive Impairment (n = 1), Dyspnea (n = 1), Dry Mouth (n = 1), Injection Side Effects (n = 1), Nausea and Vomiting (n = 1)

Table 1. (Continued) First author, year, country

Ware et al. (2010), Canada

No. of subjects

23

Male (%)

48

Mean age* (SD)

45.4 (12.3)

Clinical condition

PostTrauma/Surg ery

Type of pain

Neuropathy

Duration of study

8 weeks

Treatment

Smoked Cannabis (2.5%,6%, and 9.4% THC) x 3/ day, placebo

Outcome

Results

Pain on an 11 item numeric scale

between pain perception and plasma _-9tetrahydrocanna binol levels were found after adjusting for the overall dose effects. Difference between placebo and 9.4% THC: 0.7 (p=0.023) -Statistically significant pain relief for 9.4% THC cigarettes, but nonsignificant pain relief at other THC concentrations

Adverse events

-9.4% THC: Asthenia (n = 2), Decreased Motor Skill (n = 1), Dizziness (n = 4), Headache (n = 4), Heavy-headed (n = 1), Lightheaded (n = 1), Numbness (n = 2), Sleepiness (n = 2), Unbalanced (n = 1), Burning Sensation (n = 3), Fatigue (n = 1), Heaviness (n = 1), Hematoma (n = 1), Irritation of Oral Cavities (n = 1), Itchiness (n = 1), Itchiness in Face (n = 1), Itchiness of Nose (n = 1), Pain (n = 2), Tingling Nose (n = 1), Craving for Sweets (n = 1), Disinterest

First author, year, country

Wilsey et al. (2008), USA

No. of subjects

38

Male (%)

53

Mean age* (SD)

Median (range): 46 (21– 71)

Clinical condition

Unspecified

Type of pain

Neuropathy

Duration of study

3 x 6 hour sessions

Treatment

Smoked Cannabis (3.5% and 7% THC) x 9 puffs per session

Outcome

Pain (using VAS) and Neuropathic Pain Scale

Results

-Mean Difference VAS Pain Intensity per minute (7% THC vs. Placebo): 0.0035 (p = 0.04), -Mean

Adverse events in Surroundings (n = 1), Dysphoria (n = 2), Euphoria (n = 1), Fidgety Fingers (n = 1), Foggy Mental State (n = 1), Lack of Concentration (n = 2), Less Alert (n = 1), Paranoia (n = 1), Racing Thoughts (n = 1), Cough (n = 3), Short of Breathe (n = 1), Throat Irritation (n = 3), Dry Mouth (n = 1), Increased Appetite (n = 2), Nausea (n = 1), Dry Eyes (n = 1), Itchiness of Eyes (n = 1), Edema (n = 1), Injury to Right Knee (n = 1); all were mild to moderate. -No severe adverse events Adverse events were not mentioned individually, however a significant “good drug effect” was reported for both treatments when compared to the placebo and a

Table 1. (Continued) First author, year, country

Wilsey et al. (2013), USA

No. of subjects

39

Male (%)

72

Mean age* (SD)

50 (11)

Clinical condition

Unspecified

Type of pain

Neuropathy

Duration of study

3 x 6 hour sessions

Treatment

Smoked Cannabis (1.29% and 3.5% THC) x 8-12 puffs per session

Outcome

Pain (using VAS) and Neuropathi c Pain Scale

Results

Adverse events

Difference VAS Pain Intensity per minute (3.5% THC vs. Placebo): -0.0036 (p=0.03) -No significant difference between the two THC doses -Difference between both treatment groups and placebo observed at 120 mins (p = 0.0002), and evident at 240 mins (p = 0.0004), and 300 mins (p = 0.018). -10/38 patients had a clinically significant (>30% pain reduction) reduction in pain on placebo vs. 21/37 on the low dose THC and 22/ 36 on

significant “bad drug effect” was reported only for the 7% THC dose nearer to the end of the trial

Adverse events were not mentioned individually, however a significant “good drug effect” was noted with both treatments when compared to placebo and a significant “bad drug effect” was noted with the medium dose THC at 240 mins

First author, year, country

No. of subjects

Male (%)

Mean age* (SD)

Clinical condition

Type of pain

Duration of study

Treatment

Wissel et al. (2006), Austria

17

24

44.8 (14.4)

Multiple Sclerosis

Spasticity (Nociceptive)

9 weeks

Nabilone Capsules (1 mg per day)

Zajicek et al. (2012), United Kingdom

277

37

51.9 (7.8)

Multiple Sclerosis

Spasticity (nociceptive)

12 weeks

Dronabinol (THC) 2.5 mg taken up to 25 mg daily

Outcome

Pain on an 11 item numeric scale, Ashworth Score (Spasticity) Pain on an 11 item numeric Likert scale, Ashworth Score (Spasticity) Pain is a secondary outcome.

Results the medium dose THC. Nabilone treatment decreased by a median 2 points when compared to placebo (p < 0.05) -Mean Change in Body Pain from Baseline Dronabinol (SD): -1.2 (2.6) -Mean Change in Body Pain from Baseline Placebo(SD): -0.3 (2.4) -Statistically significant decrease in pain between THC and placebo (p 25%) and the ethics behind this practice. Several patients in our clinic have been victims of assault and there is a harm reduction component for individuals that will continue to consume recreational cannabis sought outside of the regulated licensed producers. According to the MMPR the health care professional must indicate the daily quantity of dried marihuana to be used by the person, expressed in grams (2). But what is an appropriate daily amount for a patient with pain? And what dose of phytocannabinoids with analgesic properties will the patient actually receive by inhaling dried marihuana? Table 1. Dosing and resultant serum concentrations of synthetic cannabinoids versus inhaled dried marihuana (20-24, 41) Cannabinoid

Components

Dose

Onset

Duration

Nabilone

Δ9-THC

2mg BID

8-12h

Dronabinol

Δ9-THC

2.5mg BID 5mg BID 10mg BID

6090min 3060min

Nabiximols

Δ9-THC + CBD

4 sprays (10.8mg Δ9THC and 10mg CBD) 1.75% (16mg Δ9-THC) 3.55% (34mg Δ9-THC)

1540min

2-4h

5min

2-4h

Dried Marihuana

4-6h

Serum [Δ9-THC] (range) 2ng/mL 1.3ng/mL (0.7 1.9ng/mL) 2.9ng/mL (1.2 – 4.7ng/mL) 7.9ng/mL (3.3 – 12.4ng/mL) 5.5ng/mL CBD: 3ng/mL 7.0 ± 8.1ng/mL 18.1 ± 12.0ng/mL

Table 2. Dose calculations and conversions (11) Smoked dose (mg) = %THC x mg dried cannabis Oral dose (mg) = smoked dose (mg) x 2.5

As physicians we are trained to prescribe medications at a specific dose in order to achieve a predictable response, and titrate to effect. In prescribing medical marihuana we must understand how many milligrams of Δ9-THC are in a “dose”. The World Health Organization describes a typical marihuana cigarette as being around 750mg of cannabis (25). The available Δ9-THC, or “smoked dose” can thus be calculated based on the percentage of Δ9-THC by weight in a standard 750mg joint (smoked dose = %THC x mg dried cannabis) (see Table 2) (11). In a 750mg joint with 1% THC, the THC dose would be 7.5mg (0.01 x 750mg). In a 750mg joint with 30% THC the THC dose would be 225mg (0.3 x 750mg) (11). It is important

194

Ainsley M Sutherland, Judith Nicholls and Hance Clarke

to remember that the smoked dose is the amount of Δ9-THC in milligrams that is available in the entire marihuana cigarette. The actual amount of Δ9-THC delivered to the patient is highly variable as it is dependent on smoking technique, effort, number of puffs, etc. Keeping in mind the variability in the dose actually received by the patient due to variability in inhalation, a reasonable smoked dose for analgesia may be around 30-150mg per day of THC. A study of smoked cannabis in neuropathic pain found patient’s visual analogue scores (VAS) decreased after inhalation of the equivalent of either 28mg or 56mg per day of THC compared to placebo, but there was no difference between the lower and higher doses (5). Another study in chronic post-surgical or post-traumatic pain found that patients receiving only the equivalent of 7mg per day of THC reduced pain and improved sleep (7). A smoked dose of 7mg a day appears to be very low however, in light of a titration study in HIV neuropathy that found most patients self-titrated to a smoked dose between 64-128mg THC per day (6). Only one patient out of 28 in this trial titrated to a lower smoked dose of 32mg per day of THC (6). Another study in HIV neuropathy found patients had decreased pain with a smoked dose of 96mg per day of THC versus placebo (4). This is in line with the finding that in patients on chronic opioids for a variety of pain conditions, a smoked dose of 96mg/day of THC decreased their pain scores by 27% with no change in the pharmacokinetics of the opioids (26). Based on these studies it would be reasonable to recommend a patient with a neuropathic pain condition begin with a smoked dose of 30mg of THC per day and titrate up or down according to the degree of analgesia they achieve while avoiding side effects and cognitive dysfunction. Surveys of medical marihuana patients show that the average consumption is 1-3g of dried marihuana per day (27-29). A reasonable starting prescription would be around 1-2g per day recognizing that content of Δ9-THC, and thus the smoked dose, in any given gram of dried marihuana is highly variable. According to Health Canada the average THC content in illicit marihuana is 10% (11). The dried marihuana provided by Health Canada has a THC content of 12.5  2% and less than 0.5% CBD (11). Licensed producers have a wide range of products with varying THC content (0.5-27% in one case), and CBD (0-18% in one case) (30). Cannabis naïve patients being initiated on medical marihuana therapy should be advised to start with low THC (i.e., less than 10-15%) content to avoid adverse psychotropic effects. Several cannabis naïve patents in our clinic have presented to emergency departments having acquired marihuana from dispensaries and licensed producers with THC content greater than 20% THC experiencing intolerable hallucinogenic effects of the strain. Patients without any prior experience need to be warned of this potential. Licensed producers list the THC and CBD percentages on their websites, so the patient can select a product with a low THC content. Patients in consultation with their medical practitioners can then titrate the amount of marihuana smoked, the THC and CBD content, to achieve a therapeutic effect with minimal adverse effects. Currently medical marihuana is not legal for oral consumption in edible form under the MMRP. There exists no solid evidence for converting a smoked dose to an oral dose of marihuana, however, Health Canada suggests using a conversion factor of 2.5 to account for differences in bioavailability between smoking (25% bioavailability) and orally ingesting (10% bioavailability) marihuana (11,31). Thus, if a patient has good therapeutic effect from smoking 1g of medical marihuana with 10% THC (0.1 x 1g = 100mg THC), they may need to ingest 2.5g of the same strain with 10% THC (250mg THC) to achieve the same therapeutic effect (smoked dose (mg) x 2.5 = oral dose (mg)) (see Table 2) (11). Health Canada provides a table for quick conversion from smoke to oral dose of marihuana (see Table 3) (11). As stated above,

Medical cannabis from the pain physician’s perspective

195

patients should be advised that marihuana in any form must be heated above 120°C in order to decarboxylate inactive THCA to the active form (THC) (32).

POPULATIONS THAT MAY BENEFIT FROM MEDICAL CANNABIS Cannabinoids administered in combination with opioids have been shown to result in superior analgesia in both rats and humans (26, 33, 34). As discussed previously, patients with complex co-morbidities may benefit from cannabinoids as adjuncts to reduce opioid requirements and avoid opioid-related adverse events. Other populations of patients that may benefit from cannabinoids are patients with diseases that cause intermittent flares of pain, such as rheumatoid arthritis, sickle cell disease, inflammatory bowel disease (IBD) or other abdominal visceral pains such as chronic pancreatitis. These patients often increase their opioid consumption acutely with a flare, which then becomes their new baseline dose. With multiple flares they may end up on opioid doses far beyond what is suggested as a watchful dose (200mg morphine equivalent/day) by the Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain (35). Inhaled or oral cannabinoids may be useful during these intermittent flares of pain so as to avoid ramping up patients’ daily opioid dose. One small study in patients with IBD and healthy volunteers did not find that 5 or 10mg of oral Δ9-THC improved symptoms of rectal sensitivity compared to placebo (36). Five to ten milligrams of oral Δ9-THC, however, is a low dose (