Forensic Chemistry of Substance Misuse. A Guide to Drug Control [2 ed.]

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Forensic Chemistry of Substance Misuse A Guide to Drug Control 2nd Edition

     

Forensic Chemistry of Substance Misuse A Guide to Drug Control 2nd Edition

By

Leslie A. King

Email: [email protected]

Print ISBN: 978-­1-­83916-­450-­7 PDF ISBN: 978-­1-­83916-­663-­1 EPUB ISBN: 978-­1-­83916-­664-­8 A catalogue record for this book is available from the British Library © Leslie A. King 2022 All rights reserved Apart from fair dealing for the purposes of research for non-­commercial purposes or for private study, criticism or review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry or the copyright owner, or in the case of reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page. Whilst this material has been produced with all due care, The Royal Society of Chemistry cannot be held responsible or liable for its accuracy and completeness, nor for any consequences arising from any errors or the use of the information contained in this publication. The publication of advertisements does not constitute any endorsement by The Royal Society of Chemistry or Authors of any products advertised. The views and opinions advanced by contributors do not necessarily reflect those of The Royal Society of Chemistry which shall not be liable for any resulting loss or damage arising as a result of reliance upon this material. The Royal Society of Chemistry is a charity, registered in England and Wales, Number 207890, and a company incorporated in England by Royal Charter (Registered No. RC000524), registered office: Burlington House, Piccadilly, London W1J 0BA, UK, Telephone: +44 (0) 20 7437 8656. Visit our website at www.rsc.org/books Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon, CR0 4YY, UK

Dedication The ‘Journey’ is one of the great themes of literature. It is said that a journey of exploration starts from the known and travels to the unknown, whereas a journey in science goes from the unknown to the known. My own journey has been an adventure in the exploration of science. This book is dedicated to my grandchildren: Jude, Toby, Tom and Emily. Whatever their chosen careers, I hope that their journeys through life are also good adventures.

  Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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Preface to the 2nd Edition Part of my work in the Home Office Forensic Science Service (FSS) involved the examination of drug-­related items submitted by law enforcement agencies to determine if there was evidence of an offence under the Misuse of Drugs Act, 1971 (MDAct). If that process required no more than a comparison of analytical results with a table of controlled drugs then there would be little need for this book. In reality, the chemistry of drug legislation has a complexity sufficient to challenge some chemists, let alone the lay person, while some areas of the drug laws are rarely explored. That Act came into force in 1973, and within a few years a substantial body of case-­law and scientific interpretation had rapidly accumulated. To keep up to date in those early days, my colleagues and I annotated our copies of the Act with a succession of Modification Orders as well as collecting an expanding folder of loose notes on reported cases, legal interpretation and other aspects. Some years later, this material found its way into a set of lectures. After retiring from the FSS, those notes were pulled together into a 2003 book (see Bibliography), the purpose of which was to set out those technical complexities in drugs legislation as seen from the viewpoint of a forensic chemist. That short monograph was superseded by the first edition of this book, published in 2009 (see Bibliography), which continued with those same objectives. Drug misuse continues to have a high political and public profile. Because of the large number of offenders regularly prosecuted, drugs legislation is subjected to regular scrutiny by the Courts. There is a need for all participants in the legal process of drug control – lawyers, criminologists, law enforcement officers and those involved in drug regulation – to have a basic familiarity with the underlying chemical principles. It is hoped that at least some of the content is accessible to non-­scientists. For chemists, the extensive use of molecular structures in the text allows a complete and easier comprehension   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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of the chemical background to the legislation, although some of the generic definitions can seem hard going. This book is intended to provide that background understanding and complements other publications that deal primarily with legal interpretation and the case law that has built up over the past 50 years. In the latter respect, the reader can do no better than refer to the comprehensive publication by Rudi Fortson QC (see Bibliography). All jurisdictions have to address the question of whether certain activities with certain substances should be penalised and if so whether some substances should attract heavier penalties than others, regardless of whether those penalties are defined in the criminal law or are civil penalties or merely administrative sanctions. The King James Bible (Proverbs 13 : 14) tells us that ‘The law of the wise is the fountain of life…’: an inscription in the Central Criminal Court in London. Most would accept that modern laws controlling harmful substances reflect our wisdom. Yet within that broad acceptance, there is continued debate about which substances should be included and what the penalties for offences should be. Part of that concern lies in the reasons for control. One might believe that restrictions on certain drugs are a rational response to the relative harm of substances, whether that means harm to the individual or to society. However, it is clear that drug legislation has been, and continues to be, guided more by moral imperatives. Thus, the preamble to the United Nations Single Convention on Narcotic Drugs (1961) sets the tone by referring to the ‘evil of drug addiction’. It is also apparent that controls on some substances reflect not just a moral viewpoint but some misguided measure of perceived harm. Thus, the relatively harmless hallucinogenic drugs (e.g., ‘magic mushrooms’) are treated as if they were as dangerous as heroin or cocaine. Unlike in most other areas of public health, the minimisation of harm from drugs does not appear to have a similar high priority. A growing body of academic work leads to the conclusion that the classification system in the MDAct and the International Treaties does not reflect the relative harmfulness of those substances. Extreme examples of this disconnect are alcohol and tobacco, particularly in many Western countries; both lie outside conventional drug control. While their sale and consumption is certainly restricted to varying degrees, penalties for transgression are minor compared to those that operate on often less harmful drugs. Such is the social acceptance of alcohol and tobacco that there is a general reluctance to even see them as psychoactive drugs, but together they cause far more damage to society and to individuals than all of the scheduled substances combined. An opportunity has been taken to rearrange, update and expand the material in the 1st Edition. Inevitably, this book will also become dated, but it is hoped that some of the content has lasting value. But, while it is still necessary to anchor much discussion around the domestic legal and epidemiological situation, attention is also paid to developments at the international level as illustrated by the various United Nations Conventions and supranational role of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).

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In the title of this book, ‘Substance Misuse’ refers strictly to offences such as possession, supply, importation and production; it does not include areas such as the administration of poisons to self or others, criminal damage caused by chemical substances or acts such as driving a vehicle while impaired through alcohol or other drugs. No detailed account is provided of epidemiology, pharmacology, toxicology, or the wider social aspects of drug abuse, but the interested reader is directed to the Bibliography. Selected references to specific legislation and research publications are included at the end of each Chapter, but these are not meant to provide an exhaustive review of the subject matter. Because they are mentioned so frequently in various Chapters, there are no text citations to the MDAct 1971 or the three United Conventions of 1961, 1971 and 1988. However, these are included in the Bibliography, together with links to much background information on the general chemistry of the substances described. Extensive background information on new psychoactive substances is available on the EMCDDA website and, for those in the European Union (EU) with access, the European Database on New Drugs (EDND). The United Kingdom is no longer a member of the EU; for this reason, certain information from EMCDDA is complete only up to December 2020. There is no discussion of the arguments for or against legalisation, depenalisation or decriminalisation of some or all drugs, or to what extent drug misuse is a health problem as opposed to a law enforcement issue. This book is not a guide to general aspects of the law, stated cases, sentencing policy or related legislation. It is also beyond the scope of this book to provide any recommendations on the presentation of evidence in Court or how results should be set out in reports and statements. Analytical properties of the major drugs are only provided where they have a bearing on interpretation. Some aspects of synthesis are covered in the sections concerned with precursor chemicals. Leslie A. King Hampshire

     

Preface “Gold is worse poison to a man’s soul, doing more murders in this loathsome world, than any mortal drug” William Shakespeare (Romeo and Juliet) An earlier publication† described the UK drugs legislation from the viewpoint of a forensic scientist. In the current book, an opportunity has been taken to rearrange and expand the material and improve clarity, to include the changes that have occurred in the past six years, and, more importantly, to widen the scope and the intended audience. Given the high political profile of drug misuse and the large number of offenders regularly prosecuted, drugs legislation is subjected to a high level of scrutiny by the Courts. The legislation is also technically complex with areas that are rarely explored. It follows that there is need for all participants in the legal process to have some familiarity with the underlying chemical principles. This book is intended to provide that background understanding and complements other publications that deal primarily with legal interpretation and the case law that has built up over the past three decades. This book is largely based on UK law and practice, and provides a description of the current legislation. However, this is placed into the context of the United Nations drug control conventions, and, where appropriate, compared with the US legislation. Sitting between national legislations and the international drug control treaties, the European Union (EU) has a supranational role. The EU is having an increasing impact on domestic law. Thus, apart from precursor legislation, which derives from the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances 1988, the EU has specific competence in the area of “new psychoactive substances”, formerly known as “new synthetic drugs”. †

L. A. King, The Misuse of Drugs Act: A Guide for Forensic Scientists – see Bibliography.

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While most countries have chosen to implement only the essential elements required in international law by the 1961 and 1971 United Nations Conventions, a few have extended the scope to a wider range of substances. Examples of other countries' approaches to drug control in regard to generic/ analogue controls and emergency legislation are provided. The structure-­ specific generic controls in the Misuse of Drugs Act are comprehensively covered with more examples. Yet other generic controls derive from the international drug control treaties, and are therefore common to the law of many countries. An unusual feature of UK drugs law, shared with that of the US and only a few other countries, is that it includes a large number of anabolic steroids. These substances not only lack psychoactivity, but even include testosterone: a steroid that occurs naturally in human and other mammalian tissues. Although many new substances have been brought under control in recent years, the list of potential candidates has increased even more. Throughout the 1990s most “new synthetic drugs” were either ringsubstituted phenethylamines or, less commonly, substituted tryptamines. In the last six years, clandestine drug manufacturers seem to have largely exhausted this chemical repertoire and have now diversified into a much more heterogeneous group of substances. Nevertheless, these psychoactive novelties continue to be mostly CNS stimulants or compounds with a pharmacology having some resemblance to that of the well-­established drug MDMA (3,4-­m ethylenedioxymethylamphetamine; ecstasy). As a subtheme to the arguments about relative harmfulness, considerable time and energy have been expended in the UK, particularly since 2002, on the specific classification of cannabis, and to a lesser extent of certain other substances. The irony is that, despite three major reviews and an intermediate period when its status was changed, cannabis will soon be back to where it was in late 2003 and had been since 1971. When it is recognised that few substances have been reclassified since 1971, many observers might conclude that the system is largely impervious to change and should be replaced for that reason alone. All States have to address the question of whether certain activities with certain substances should attract heavier penalties than others, regardless of whether those penalties are defined in the criminal law or are civil penalties or merely administrative sanctions. In recent years, many critical questions have been raised as to whether, after nearly 40 years, the UK drugs legislation is still fit for purpose. To a large extent such questions have centred on the classification of substances and their relative harmfulness. These concerns are relevant to all legislations, since it is a general principle of drug laws that there should be a correlation between harm, either to the individual or society, and the penalties associated with various offences. As part of the critical light that now shines on drug control, not only are concerns being raised about the substances that are scheduled, but anomalies with society's approach to nonscheduled substances are becoming clearer. The most obvious of these are alcohol and tobacco, which together cause far more damage to society and to individuals than all of the scheduled

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substances combined. Yet these substances are often not even regarded as drugs. But these “socially acceptable” substances are by no means free of controls. The law determines such matters as who may sell them, where, when and to whom. Furthermore, the social acceptance of alcohol has a strong cultural and religious link. If we take a strict line about relating legal control to harmfulness and by relating harmfulness largely to the pharmacological and toxicological properties of those substances then we must recognise that the social drugs lie on a continuum of harm with all other substances and do not belong in some different dimension. From here it is a short step to examine our attitude to all harmful substances and ask how they should fit into the scale. Such substances include simple poisons, drug and weapon precursors, industrial solvents, established medicines, harmful materials in the workplace, the social drugs and those, often innocuous, substances intended for use as cutting agents. This book is aimed not only at forensic scientists but also at police and customs officers, lawyers and all those with an interest in drugs legislation. There is coverage of the many problem areas that arise in the forensic interpretation of analytical results. For chemists, the extensive use of molecular structures in the text allows a complete and easier comprehension of the chemical background to the legislation. It is not a guide to general aspects of the law, stated cases, sentencing policy or related legislation although some of these are dealt with briefly in the Appendices. Also excluded is any comprehensive discussion of chemical analysis, but brief analytical properties of the major drugs are provided, and specific problem areas are mentioned where they have a bearing on interpretation. No account is provided of the wider social dimension to drug abuse, to epidemiology, pharmacology or toxicology, but the interested reader is directed to the Bibliography. Selected references to specific articles and research publications are included in the text as footnotes, but these are not meant to be exhaustive. There is no discussion of the arguments for or against legalisation or decriminalisation of some or all drugs, or to what extent drug misuse is a health problem as opposed to a law-­ enforcement issue. Finally, it is beyond the scope of this book to provide any recommendations on the presentation of evidence in Court or how analytical results should be set out in reports and statements. I particularly wish to thank Professor Geoffrey Phillips, Dr John Ramsey and Professor Les Iversen for supporting the concept of this book in early discussions with the Royal Society of Chemistry. Professor Geoffrey Phillips, Rudi Fortson and Ric Treble kindly reviewed a draft manuscript and offered valuable comments. Leslie A. King, Hampshire

     

Acknowledgements My formal scientific career started in the Wellcome Laboratories of Tropical Medicine, London, and the Biochemistry Department of C. H. Boehringer Sohn, Ingelheim, Germany. That was followed by postgraduate research in chemistry at Loughborough University. The inspiration for this book and its predecessors arose during my career in the former Forensic Science Service (FSS) in working with police, customs officers and lawyers, and in giving evidence in the criminal and coroner's courts. I spent fifteen years as a co-­opted member, and later a full member, in the position once known as the ‘Statutory Chemist’, of the Home Office Advisory Council on the Misuse of Drugs. After retiring from the FSS, I became an advisor to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) in Lisbon and UK co-­ordinator on new psychoactive substances for the EMCDDA-­REITOX Focal Point, initially in the former DrugScope and later, the Department of Health, London. That period coincided with the great expansion of scientific and political interest in new psychoactive substances. I have learnt so much from former colleagues over the past 60 years. I wish to thank the Royal Society of Chemistry for supporting the concept of this book series. I am especially grateful to István Ujváry for checking the entire text and apprising me of recent international developments. Rudi Fortson, Q.C. reviewed a draft manuscript and provided advice on UK legislation. I thank my wife, Diane, for her forbearance during the many lonely hours while I was writing this book and for guiding me through some of the more obscure corners of Microsoft Word and Excel.

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Coda: Beginnings When I was 11 years old, I gained a place at Wilson's Grammar School in South London. Many of my friends who also passed the 11 plus exam were given a bicycle by their parents; my parents bought me a ‘Lotts Chemistry Set’. That turned out to be a much better investment and provided such an inspiration that I was soon determined to become a scientist. By the time I was 14, my father had set up a laboratory for me in a corner of his large garden workshop. That had mains electricity, water and gas, and I was able to buy a generous amount of glassware and other equipment. Not only did I repeat the practical sessions from my school chemistry classes, but I could go much further. Sourcing chemicals presented no problems. My local pharmacy was able to sell me most of what I needed, whether that was nitric acid, benzene or all manner of what we would now recognise as harmful substances. The pharmacist was only concerned that I should not try to make fireworks. In those days, the notion of health and safety was not something to which any of us, either at home or school, paid much attention. Some of the school experiments and demonstrations stay with me as vivid memories such as when my chemistry teacher, a Mr Dash, dissolved white phosphorus in carbon disulfide and then poured it over a large mass of cotton wool held in a clamp stand. Within seconds, the whole mass caught fire – the self-­igniting Molotov cocktail. And no one gave a thought to the cloud of phosphorus pentoxide that hung over us. With GCE ‘O’ Levels looming, I was told that there would always be a question on the paper about how one would make various gases. I was soon making hydrogen and oxygen by electrolysis, chlorine and many more gases. In one of those sessions, the atmosphere in my garden laboratory was so damaging that some of my father's tools became corroded, but I don't recall that he was too annoyed. And in thinking of gases, Mr Dash assured me that a   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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true chemist could always distinguish the smell of hydrogen chloride from that of sulfur dioxide. I never could tell the difference and those attempts at sniffing such toxic substances may be why my sense of smell is now so poor. Even though I had the wherewithal in those early days to synthesise many organic compounds, the thought of creating psychoactive substances never crossed my mind. Indeed, an interest in drugs would not arise until much later when I joined the pharmaceutical industry. The only activity that came close to being illicit was the distillation of fermented fruit juice, but the fiery liquid produced was just a poor quality brandy. It is unlikely that what I did then could be done these days; and perhaps just as well. I was lucky to survive the many hazards from occasional fires, poisonous gases, electric shocks and other events, all without any protective equipment. A few years later, my youngest brother, Mike, gained a scholarship to read chemistry at Exeter College, Oxford. I like to think I might have inspired him. Eventually I met a girl who later became my wife. She was also a chemistry student, which I am sure was part of the attraction.

Glossary Terms in bold italics are themselves defined.

Active pharmaceutical The substance in a medicinal product that is biologically ingredient (API) active. Addiction For most purposes, addiction is synonymous with dependence. Adulterant Often synonymous with cutting agent. A substance added as a diluent to a drug. It may be inert or pharmacologically active. Such diluents can be found in illicit powders as well as tablets, in which case the term might also include tablet binders. Affinity constant The equilibrium dissociation constant, expressed as a Ki value, used in drug-­receptor binding to describe how tightly a ligand (drug) binds to a particular receptor. Ligand-­ receptor affinities are measured in molar units (M), which correspond to the concentration of ligand at which the binding site of a particular receptor is half occupied. The smaller the constant, the more tightly bound the ligand is, and the higher the affinity between ligand and receptor. Agonist A drug that mimics the effect of neurotransmitters or other endogenous molecules. It has the opposite effect to an antagonist. Alkali Usually, an inorganic base such as sodium hydroxide or sodium carbonate. By combining with the chemically-­ bound acid residue, an alkali is used, for example, to convert a salt into the free base. Alkaloid A naturally-­occurring nitrogenous base. Aluminium foil method A type of reductive amination that requires little equipment. A precursor ketone (e.g., P2P, PMK) is reacted in ethanol with aluminium metal pieces, an amine and a mercuric chloride catalyst. When the amine is methylamine and the ketone is PMK then the product is MDMA.   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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Amine A chemical group comprising a nitrogen atom attached to one or more carbon atoms and one or more hydrogen atoms. Amines are typically bases. Analgesic A substance that reduces the sensation of pain. Also known as an analgetic. See also narcotic analgesic. Analogue A substance whose structure is related to that of another, but whose chemical and biological properties may be quite different. Sometimes used to mean derivative. Analogue control The inclusion in legislation of a definition that covers a family of substances. It is less specific than generic control and may be based on the concept of ‘similarity in chemical structure’ as well as ‘similarity in pharmacological activity’ to the parent substance. Antagonist An agent that opposes the action of another (the opposite of agonist). Base A nitrogenous substance, sometimes known as an alkaloid when derived from plant material, which reacts with acids to form a salt. Many bases are insoluble in water but soluble in organic solvents. Bioisostere A compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. Cannabimimetic A synthetic substance that has similar properties to THC, i.e., it interacts with the CB1 receptor usually as an agonist. Also known as cannabinomimetic. The preferred term now is synthetic cannabinoid receptor agonist. CB1 receptor A cannabinoid receptor primarily located in the CNS. THC behaves as an agonist at the CB1 receptor, which is then responsible for the psychoactive effects. Other cannabinoid receptors, such as CB2, are found mainly in the immune system, and are partly involved in the perception of pain. CBD Cannabidiol (CBD) is one of several phytocannabinoids in Cannabis sativa. It has anti-­psychotic and anti-­convulsant effects and occurs at a higher concentration in cannabis resin than in herbal cannabis. In some strains of intensively produced cannabis, with a high THC content, the CBD level may be extremely low. CBN Cannabinol (CBN) is a phytocannabinoid and an oxidation product of THC. It is normally only found in aged samples of cannabis and cannabis resin. CNS Central nervous system. Cutting agent A substance added as a diluent to a drug. It may be inert or pharmacologically active. Such diluents can be found in illicit powders as well as tablets where the term might also include tablet binders. Often synonymous with adulterant.

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Dependence Drug dependence is a psychiatric disorder and a complex neurobiological phenomenon, whereby repeated use leads to increasing difficulty in stopping. The term has been used by the World Health Organization (WHO) in preference to addiction. Diastereoisomers In the simplest case, when a molecule contains two centres of asymmetry, it can form four diastereoisomers (i.e., two pairs of enantiomers). Thus ephedrine, for example, exists as four diastereoisomers, two of which are known as pseudoephedrine. Dopamine An example of a neurotransmitter, it is a naturally-­occurring substituted phenethylamine. Substances that interact with the dopamine receptor are said to be dopaminergic. Drug A substance presented for treating, curing or preventing disease in human beings or in animals. It may also be used for making a medical diagnosis or for restoring, correcting, or modifying physiological functions. Drug Abuse The use of a pharmacologically-­active substance for non-­ medicinal purposes. Drug Misuse For most purposes, drug misuse is synonymous with drug abuse, but it can also imply abuse of a substance which has a legitimate medicinal use, whereas drug abuse could be used more generally. Ecstasy Originally used to describe MDMA, but since generalised to describe a wide range of substituted phenethylamines and, less precisely, certain unrelated substances. Empathogen A substance that produces empathy with others, most often applied to MDMA and related drugs. See also entactogen. Enantiomer One of a pair of stereoisomers arising from the presence in a molecule of an asymmetric carbon atom. The two enantiomers are mirror images of each other, with left-­and right-­handed forms denoted S (sinister) and R (rectus) respectively. Enantiomeric pairs may be denoted by the symbols (+) and (−) or previously by the terms d and l. Entactogen A substance that produces a socialising effect and desire for contact, most often applied to MDMA and related drugs. See also empathogen. Ergoline A tetracyclic molecule ultimately derived from the ergot fungus. It contains a molecular sub-­unit that is effectively a rigidified tryptamine. The most common ergoline is lysergide (LSD). Euphoriant A substance that induces an emotional condition in which a person experiences intense feelings of well-­being, elation and happiness. Generic control The inclusion in legislation of a definition that covers a family of substances. At one level this includes esters or ethers of a parent molecule – an example that derives from the 1961 UN Single Convention on Narcotic Drugs. More elaborate generic definitions are based on substitution patterns in a parent molecule where the type, number and position of substituents may be precisely specified. A consequence of generic control is that it may subsume substances with varied pharmacological activity or even none at all. The generic approach should be contrasted with analogue control.

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Hallucinogen A substance that produces, as a main effect, perceptual distortions, especially visual and auditory. The term is somewhat misleading as some so-­called hallucinogenic substances do not cause true hallucinations (i.e., sensory perceptions in the absence of external stimuli). The term hallucinogen is often now used for substances that were once described as psychedelic, psychotomimetic or psychodysleptic. Homologue When a series of chemical compounds differ only by a constant structural element, they are said to form a homologous series. Hydrate Some salts contain water chemically bound within their crystalline structure; these are referred to as hydrates. Hypnotic A substance that induces sleep. Illicit drug Strictly refers to a substance that has not been formally licensed as a medicine. The term is widely used in a more general sense to mean a drug without therapeutic use or a drug that has been produced under clandestine circumstances. INN International Non-­Proprietary Name. Defined by the World Health Organization (WHO) for substances that have or have had therapeutic value. IUPAC International Union of Pure and Applied Chemistry. A body responsible for the systematic nomenclature of chemical entities. Leuckart route A popular method for converting ketones (e.g., P2P and PMK) to the corresponding amines using formic acid, ammonium formate or formamide/methylformamide as reagents. When the ketone is P2P, the result is amphetamine or methylamphetamine, while MDA and MDMA arise from the ketone PMK. Mass spectrum A pattern of charged molecular fragments produced by bombarding molecules with electrons. The fragmentation pattern is characteristic of the molecule. Narcotic In older literature (the ‘UN 1961 Single Convention on Narcotic Drugs’ and the ‘International Narcotics Control Board’ are prime examples), the term narcotic was once used to mean what would now be described as a psychoactive substance. Narcotic analgesic A type of analgesic acting on the central nervous system rather than on peripheral nerves. Many opioids and opiates (e.g., diamorphine) are typical narcotic analgesics. Neurotransmitter A chemical messenger involved in passing a signal from one neuron to adjacent neurons in the brain. These include serotonin, dopamine, glutamate and γ-­aminobutyric acid (GABA). Nitrogenous base A synthetic or naturally-­occurring substance containing one or more amine nitrogen atoms in its structure and acting as a base. Noradrenaline Also known as norepinephrine and an example of a neurotransmitter that is a naturally-­occurring substituted phenethylamine. Substances that interact with the noradrenaline receptor are said to be noradrenergic.

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Opiate An opiate is a substance derived from opium. Opium alkaloids include morphine, papaverine, thebaine etc, but it also includes the semi-­synthetic derivatives of those alkaloids such as diacetylmorphine and codeine. Opioid An opioid is a substance that has not been derived from opium, and may be structurally unrelated to morphine, but has similar properties, i.e., a narcotic analgesic. However, the term opioid is sometimes used to include opiates. Opium The dried latex of the seed capsule of the opium poppy (Papaver somniferum L.). P2P 1-­Phenyl-­2-­propanone: a ketone often used as a precursor to amphetamine and methylamphetamine. Also known as phenylacetone and benzylmethylketone (BMK). Phenethylamine Phenethylamine is 2-­phenylethylamine. The term is used less precisely to mean a derivative of phenethylamine, often by substitution in the side-­chain or in the aromatic ring or both. The phenethylamine family includes a range of substances that may be stimulants, entactogens or hallucinogens. Phytocannabinoid One of a group of compounds found only in Cannabis sativa including cannabidiol (CBD), cannabinol (CBN) and tetrahydrocannabinol (THC). Commonly abbreviated to cannabinoid and distinct from synthetic cannabinoid receptor agonist. PMK Piperonylmethylketone, a ketone often used as a precursor in the manufacture of MDMA. Also known as 3,4-­methylenedioxyp henyl-­2-­propanone. Potency A quantitative measure of the activity or strength of a drug: a different concept to purity, which is the proportion of active drug in a preparation. Primary amine A chemical group comprising a nitrogen atom attached to two hydrogen atoms and to a carbon atom. Psychoactive drug A substance that affects the mind or mental processes. The term is often used in a broad sense to include both psychotropic and narcotic drugs. This term is preferred to older, less common, expressions such as psychodysleptic and psychotomimetic. Psychotropic drug A generic term for substances that modify normal behaviour. It includes inter alia, stimulants, hallucinogens, tranquillisers, hypnotics. In the UK at least, the preferred term is psychoactive drug. Purity The proportion (%) of active drug in a preparation: a different concept to potency. Most laboratories determine purities with respect to the base because in a sample sent for analysis, the particular salt form cannot be determined without further, often unnecessary, investigation. For example, pure amphetamine base has a purity defined as 100%. When amphetamine base reacts with e.g., sulfuric acid to form the sulfate salt, then the purity of that salt, with respect to the base, is 73%; the remaining 27% is the sulfate residue. If the purity is expressed with respect to a specific salt form, then pure amphetamine sulfate has a purity of 100%. R-­Enantiomer See enantiomer

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Glossary

Racemate, also A 50 : 50 mixture of two enantiomers produced when a Racemic mixture synthesis is not stereoselective. Reclassification The process of moving a substance from one Class to another in the (UK) Misuse of Drugs Act, and the legislation of certain other countries. Reduction A chemical process involving removal of oxygen atoms and/or addition of hydrogen atoms. Reductive amination A chemical process involving removal of oxygen atoms and addition of amino groups. S-­Enantiomer See enantiomer Salt The product of reacting a base with an acid. Many salts are soluble in water but poorly soluble in organic solvents. Secondary Amine A chemical group comprising a nitrogen atom attached to a hydrogen atom and two carbon atoms. Serotonin Also known as 5-­hydroxytryptamine, it is an example of a neurotransmitter. It is a naturally-­occurring substance closely related to synthetic hallucinogenic tryptamines. Stereoisomer One of two or more forms of a molecule with the same sequence of atoms, which arises from the three-­ dimensional arrangement of those atoms. Stimulant A substance that increases psychomotor activity, often by increasing the production of certain neurotransmitters in brain synapses. Synthetic Cannabinoid  A synthetic substance that interacts with, for example, Receptor Agonist (SCRA) the CB1 receptor for the endogenous substance anandamide and produces similar effects to THC. Tautomerism Tautomers are isomers of organic compounds that readily interconvert by a chemical bond rearrangement called tautomerism. This commonly results in the migration of a hydrogen atom, accompanied by a switch of a single bond and an adjacent double bond. Tertiary amine A chemical group comprising a nitrogen atom attached to three carbon atoms but bearing no hydrogen atoms. THC Δ9-­Tetrahydrocannabinol, the major active principal in cannabis. The International Non-­Proprietary Name (INN) is dronabinol. Tryptamine Tryptamine itself is 1H-­indole-­3-­ethanamine, but the term is also used less precisely to mean a derivative of tryptamine, often by substitution at the side-­chain nitrogen atom or in the aromatic ring or both. The tryptamine family includes numerous hallucinogens and/or substances that interact with serotonin receptors.

Abbreviations In the abbreviations and acronyms listed below, only the more frequently-­ mentioned drugs are included. Acronyms for many phenethylamines and tryptamines can be found in the publications PiHKAL and TiHKAL respectively (see Bibliography). Some well-­known abbreviations, such as THC and MDMA will not be found in the Misuse of Drugs Act (MDAct) because they are subsumed by generic definitions. Thus, THC is ‘a tetrahydro derivative of cannabinol’, and MDMA is ‘a compound…structurally derived from … an N-­alkylphenethylamine…by substitution in the ring… with… alkylenedioxy… substituents’. LSD is listed specifically under the approved name lysergide. Although cannabis (herbal cannabis; marijuana) and cannabis resin (hashish) are distinct entities, it is sometimes convenient to describe them both under the collective term ‘cannabis’. Similarly, ‘cannabinols’ is used to mean cannabinol and cannabinol derivatives; a distinction is only made in the text where legal or chemical aspects need to be identified. The MDAct and other UK legislation uses the word ‘sulphate’, whereas the preferred international term is now ‘sulfate’. For sulfur-­containing compounds, this book uses that word as well as sulfate, sulfuric etc. except where the legislation is directly quoted. Although some texts use ‘MDA’ as an abbreviation for the Misuse of Drugs Act, ‘MDAct’ is used here to avoid confusion with 3,4-­methylenedioxyamphetamine (MDA). Expanded definitions of some abbreviations shown below can be found in the Glossary.

1,4-­BD 1,4-­Butanediol 2C-­I 2,5-­Dimethoxy-­4-­iodophenethylamine 2C-­T-­2 2,5-­Dimethoxy-­4-­ethylthioamphetamine 2C-­T-­7 2,5-­Dimethoxy-­4-­propylthiophenethylamine 4-­MTA 4-­Methylthioamphetamine 5-­HT 5-­Hydroxytryptamine (serotonin) ACMD UK Advisory Council on the Misuse of Drugs API Active Pharmaceutical Ingredient

  Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

xxv

xxvi

Abbreviations

BAN British Approved Name BZP 1-­Benzylpiperazine CBD Cannabidiol CBN Cannabinol CND Commission on Narcotic Drugs (a UN body) CNS Central Nervous System DEA Drug Enforcement Administration (US) DHEA Dehydroepiandrosterone DOB 4-­Bromo-­2,5-­dimethoxy-­α-­methylphenethylamine DPMA Drugs (Prevention of Misuse) Act 1964 ECDD Expert Committee on Drug Dependence (part of WHO) EMA European Medicines Agency EMCDDA European Monitoring Centre for Drugs and Drug Addiction EU European Union EWS Early Warning System GABA γ-­Aminobutyric acid, a neurotransmitter GBL γ-­Butyrolactone GC-­MS Gas chromatography-­mass spectrometry GHB γ-­Hydroxybutyrate; 4-­hydoxybutyric acid GHV γ-­Hydroxyvaleric acid GVL 4-­Hydroxypentanoic acid lactone HO The UK Home Office INN International Non-­proprietary Name IUPAC International Union of Pure and Applied Chemistry LSD Lysergide; Lysergic acid diethylamide MBDB N-­Methyl-­1-­(1,3-­benzodioxol-­5-­yl)-­2-­butanamine mCPP 1-­(3-­Chlorophenyl)piperazine MD Regulations The UK Misuse of Drugs Regulations 2001 (as amended) MDA 3,4-­Methylenedioxyamphetamine MDAct The UK Misuse of Drugs Act 1971 (as amended) MDEA 3,4-­Methylenedioxyethylamphetamine MDMA 3,4-­Methylenedioxymethylamphetamine MDPEA Methylenedioxyphenethylamine MHRA Medicines and Healthcare Products Regulatory Agency NBOMe N-­Benzylmethoxyphenethylamine NHS The UK National Health Service NPS New Psychoactive Substance (EMCDDA post 2005). Less commonly, Novel Psychoactive Substance NRG-­1 Naphthylpyrovalerone (naphyrone) NSD New Synthetic Drug (EMCDDA use before 2005) ONS Office for National Statistics P2P 1-­Phenyl-­2-­propanone PCP Phencyclidine PEA Phenethylamine PiHKAL Book: Phenethylamines I Have Known and Loved (see Bibliography) PMA 4-­Methoxyamphetamine PMK 3,4-­Methylenedioxyphenyl-­2-­propanone

Abbreviations

xxvii

PMMA 4-­Methoxymethylamphetamine PSA UK Psychoactive Substances Act 2016 R Rectus (stereochemical prefix) or (R) an unspecified substituent S Sinister (stereochemical prefix) S.I. Statutory Instrument SCRA Synthetic cannabinoid receptor agonist STP 2,5-­Dimethoxy-­α,4-­dimethylphenethylamine TCDO Temporary Class Drug Order THC Δ9 -Tetrahydrocannabinol THCA Δ9 -Tetrahydrocannabinolic acid TiHKAL Book: Tryptamines I Have Known and Loved (see Bibliography) TMA-­2 2,4,5-­Trimethoxyamphetamine UK United Kingdom UN 1961 United Nations Single Convention on Narcotic Drugs, 1961 (as amended) UN 1971 United Nations Convention on Psychotropic Substances, 1971 (as amended) UN 1988 United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988 (as amended) UN United Nations UNODC UN Office on Drugs and Crime US United States of America WADA World Anti-­Doping Agency WHO World Health Organization

     

Contents Chapter 1 D  rug Misuse  1.1 Introduction  1.2 Drug Misuse in England and Wales  1.2.1 Household Surveys of Drug Misuse  1.2.2 Drug-associated Deaths  1.2.3 Seizures by Law Enforcement Agencies  References 

1 1 2 2 3 4 5

Chapter 2 International Drugs Control  2.1 Introduction  2.2 United Nations Single Convention on Narcotic Drugs, 1961  2.3 United Nations Convention on Psychotropic Substances, 1971  2.4 United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988  2.5 The Role of the European Union  2.5.1 ‘Joint Action’: The Period 1997 to 2005  2.5.2 The EU Council Decision of 2005  2.5.3 The Period since 2018  2.6 Legislative Developments in Other Countries  References 

7 7

10 11 11 11 12 14 16

Chapter 3 Primary UK Drugs Legislation up to 1971  3.1 Drug Control in the UK before 1971  3.2 The Misuse of Drugs Act 1971 

18 18 19

 Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

xxix

9 9

Contents

xxx



3.3 O  ffences and Penalties under the MDAct  3.3.1 Cultivation of Cannabis  3.3.2 Production of a Controlled Drug  3.4 The Advisory Council on the Misuse of Drugs  3.5 Reviews of the MDAct  3.5.1 Review by the ACMD (1979)  3.5.2 The Independent Enquiry into the MDAct (2000)  3.5.3 Home Affairs Select Committee (2001–2)  3.5.4 Select Committee on Science and Technology (2006)  3.5.5 Royal Society of Arts Report (2007)  3.5.6 Demos Report ‘Taking Drugs Seriously’ (2011)  3.5.7 Home Affairs Select Committee (2012)  3.5.8 All-Party Parliamentary Group for Drug Policy Reform (2013)  3.5.9 Royal Society for Public Health (2016)  3.5.10 Royal Society of Arts (2017)  3.5.11 House of Commons Health and Social Care Committee: Drugs Policy (2019)  3.5.12 Independent Review of Drugs by Dame Carol Black (2021)  3.5.13 Problem Drugs Bill: A Private Members' Bill Tabled by Tommy Sheppard MP (2021)  3.6 Substances Removed and/or Reinstated  3.7 Cannabis: Classification and Reclassification  3.8 The Classification of MDMA  3.9 The Precautionary Principle  3.10 Conclusions  References 

21 22 22 23 25 25 25 26 26 27 27 27 28 28 28 28 28 29 29 30 33 34 35 37

Chapter 4 The Misuse of Drugs Regulations 2001  4.1 Introduction  4.2 Regulations Relevant to Forensic Science  4.2.1 Exceptions for Drugs in Schedules 4 and 5 and Poppy Straw  4.2.2 Exceptions for Drugs in Schedule 1  4.2.3 Exceptions for Gamma-butyrolactone and 1,4-Butanediol  4.3 The Impact of the MD Regulations on Scientific Research  References 

40 40 41

42 44

Chapter 5 UK Drugs Legislation since 1971  5.1 Drugs Act 2005  5.2 Temporary Class Drug Orders 

46 46 47

41 42 42

Contents





xxxi

5.3 Importation Controls  5.4 The Psychoactive Substances Act 2016  5.4.1 Alkyl Nitrites  5.4.2 Nitrous Oxide  5.4.3 Reviews of the Psychoactive Substances Act  5.5 Other Drug-related Legislation in the UK  5.5.1 Road Traffic Act 1972  5.5.2 The Customs and Excise Management Act 1979  5.5.3 The Drug Trafficking Act 1994  5.5.4 The Crime and Disorder Act 1998  5.5.5 The Criminal Justice and Police Act 2001  5.5.6 The Criminal Justice Act 2003  5.5.7 The Criminal Justice (International Cooperation) Act 1990; Controlled Drugs (Drug Precursors) (Intra-community Trade) Regulations 2008; Controlled Drugs (Drug Precursors) (Community External Trade) Regulations 2008  5.5.8 Serious Crime Act 2007  5.5.9 Crime and Courts Act 2013  References 

Chapter 6 N  omenclature  6.1 Introduction  6.2 B  ritish Approved Names and International Non-proprietary Names  6.3 Phenyl-substituted Alkanes  6.3.1 Amphetamine  6.3.2 Methylamphetamine  6.3.3 N-Hydroxy MDA  6.4 Code Names  6.5 Anabolic Steroids  6.6 Synonyms and Common Terms  6.7 The Meaning of ‘3,4-Methylenedioxy’  6.8 Dialkyl Derivatives  6.9 The Meaning of ‘Structurally Derived from’  6.10 Redundancy  References  Chapter 7 E  sters, Ethers, Salts, Homologues, Stereoisomers and Isotopes  7.1 Esters and/or Ethers: Introduction  7.2 Esters  7.3 Ethers  7.4 Salts  7.5 Homologues 

48 48 50 52 53 53 53 54 54 54 54 54

55 55 55 55 58 58 59 59 61 61 61 62 62 62 63 64 64 65 66 68 68 69 70 71 72

Contents

xxxii



7.6 Stereoisomers  7.7 Isotopes  References 

Chapter 8

Structure-specific Generic Legislation  8.1 Introduction  8.2 Generic Control in the UK before 1970  8.3 Generic Control in the UK after 1970  8.4 Anabolic/Androgenic Steroids  8.5 Barbiturates  8.6 Benzofurans and Related Structures  8.7 N-Benzylphenethylamines  8.8 Cannabinols  8.9 Cathinone Derivatives  8.10 Ecgonine Derivatives  8.11 Fentanyls  8.12 Lysergide and Derivatives of Lysergamide  8.13 Pentavalent Nitrogen Derivatives of Morphine  8.14 Pethidine and Prodine Derivatives  8.15 Ring-substituted Phenethylamines  8.16 Phenyl- and Benzylpiperazines  8.17 Phenyl and Other Arylcyclohexylamines  8.18 Pipradrol Derivatives  8.19 Synthetic Cannabinoid Receptor Agonists  8.20 Tryptamines  References 

79 79 80 80 81 84 86 86 88 88 92 94 99 99 99 105 111 116 121 124 124 124

Chapter 9

 eneric Control in Other Jurisdictions  G 9.1 Introduction  9.2 Generic Definitions in New Zealand  9.2.1 Amphetamine Derivatives  9.2.2 Methaqualone Derivatives  9.2.3 Dimethyltryptamine Derivatives  9.3 Generic Control in Other Countries  9.3.1 Israel  9.3.2 Switzerland  9.3.3 Germany  9.3.4 New South Wales, Australia  9.3.5 China  References 

127 127 128 128 129 129 130 130 131 131 133 134 134

Chapter 10 Generic Control: A Critique  10.1 Introduction  10.2 General Concerns with Generic Control  10.2.1 Effect on the Pharmaceutical Industry  10.2.2 Capture of Inactive Substances 

74 76 78

135 135 136 136 136

Contents



xxxiii

10.2.3 Difficulty in Comprehension  10.2.4 Obsolescence  10.2.5 Reference Materials  10.2.6 Other Criticisms of Generic Control  10.3 Specific Issues with Certain Generic Definitions  10.3.1 Cathinones  10.3.2 Benzofurans and Related Compounds  10.3.3 The Phenidate Group  10.3.4 Anabolic Steroids  10.3.5 Ring-substituted Phenethylamines  10.3.6 Synthetic Cannabinoid Receptor Agonists (SCRAs)  10.3.7 Cannabinol  10.4 The Future of Generic Legislation  References 

136 137 137 137 137 138 138 140 144 144

Chapter 11

Analogue Legislation  11.1 Introduction  11.2 Analogue Control in the United States  11.3 Analogue Control in Other Countries  11.3.1 Canada  11.3.2 South Africa  11.3.3 New Zealand  11.4 Problems with Analogue Control  References 

146 146 146 149 149 149 150 150 151

Chapter 12

What Is a Derivative?  12.1 Introduction  12.2 General Definitions of ‘Derivative’  12.3 The Term ‘Derivative’ in Legal Practice  12.4 Cocaine Precursors  12.5 2-Bromo-LSD and Other Ergolines  12.6 Conclusions  References 

153 153 155 156 157 158 160 160

Chapter 13

New Psychoactive Substances (NPS): An Old Problem  13.1 Introduction  13.2 Morphine Derivatives in the Period before 1932  13.3 Ring-substituted Phenethylamines from the 1960s  13.4 Fentanyl and Pethidine Derivatives in the 1980s  13.5 The Period after 1990  13.6 Chemical Aspects of New Psychoactive Substances  13.6.1 Fluorinated Compounds  13.6.2 Analytical Problems with NPS 

162 162 163





144 144 144 145

165 165 165 168 168 168

Contents

xxxiv



13.6.3 Structure–Activity Aspects of the Pharmacology and Toxicology of NPS  13.6.4 Anticipation of NPS  eferences  R

169 170 171

Chapter 14 S  ubstances Not Listed in the International Conventions  14.1 Introduction  14.2 P  henethylamines  14.2.1 N-Substituted 2-Phenethylamines  14.2.2 Phenylalkylamines Other than 2-Phenylethylamines  14.2.3 Arylalkylamines  14.2.4 Conformationally-restricted Phenethylamines  14.2.5 Ephedrine and Derivatives  14.3 Methylhexaneamine  14.4 Cognitive and Other Enhancers  14.5 Carisoprodol  14.6 Benzydamine  14.7 Analogues of Methaqualone  14.8 ‘Isocathinones’  14.9 1-Ethynylcyclohexanol  14.10 Camfetamine  14.11 Selective Androgen Receptor Modulators (SARMs)  14.12 Bioisosteres of Tryptamine  14.13 Phenyloxazoline Derivatives  14.14 Amfonelic Acid  14.15 Substances Banned by WADA  14.16 Alkyl Nitrites  14.17 Substances Reviewed by the WHO/ECDD in 2020  14.18 Salvinorin  14.19 4-Benzylpiperidine  14.20 Bromantane  14.21 Cyclohexylbenzamide Opioids  14.22 RH-34  14.23 Benzylbenzimidazole Opioids  14.24 Other Atypical Opioids  14.25 Hyoscine  14.26 Other Psychoactive Plant Products  References 

173 173 174 174

Chapter 15 Amphetamine, Methylamphetamine and MDMA  15.1 Introduction  15.2 Amphetamine  15.2.1 Amphetamine: Pharmacology  15.2.2 Amphetamine: Synthesis 

204 204 205 205 206

176 178 182 182 184 185 187 187 188 188 190 191 191 191 192 193 193 193 194 194 194 194 197 199 199 200 201 201 201

Contents



xxxv

15.3 Methylamphetamine  15.3.1 Introduction  15.3.2 Methylamphetamine: Pharmacology  15.3.3 Methylamphetamine: Synthesis  15.4 MDMA (3,4-Methylenedioxymethylamphetamine)  15.4.1 Introduction  15.4.2 MDMA: Pharmacology  15.4.3 MDMA: Synthesis  References 

206 206 208 208 209 209 210 210 210

Chapter 16 B  enzodiazepines  16.1 Introduction  16.2 ‘New’ Benzodiazepines  References 

212 212 213 219

Chapter 17

Cannabis and Phytocannabinoids  17.1 Introduction  17.2 Definitions of Cannabis and Cannabis Resin  17.3 Cannabis Seeds  17.4 Phytocannabinoids  17.5 Control of Cannabinols  17.6 Hash Oil  17.7 ‘High Potency’ Cannabis  17.8 Medicinal Cannabis  17.8.1 The Period before 2018  17.8.2 Recent Developments  17.9 Miscellaneous Issues with Cannabis  References 

220 220 221 222 222 224 226 227 228 228 229 232 232

Chapter 18

Synthetic Cannabinoid Receptor Agonists (SCRAs)  18.1 Introduction  18.2 Nomenclature of SCRAs  18.3 Control Status  18.3.1 Introduction  18.3.2 Generic Control of SCRAs in the UK  18.3.3 Continuing Problems with the Generic Definition of SCRAs  18.3.4 Non-controlled SCRAs  18.3.5 Barriers to Research with SCRAs  18.3.6 Conclusions  References 

234 234 235 239 239 239

Cocaine, Crack and Synthetic Analogues  19.1 Cocaine  19.2 Crack Cocaine  19.3 Coca Leaf and Coca Tea 

251 251 253 253

Chapter 19

244 246 248 248 249

Contents

xxxvi



19.4 Analogues of Cocaine  References 

254 255

Chapter 20

Tryptamines and Lysergamides  20.1 Introduction  20.2 TiHKAL Substances  20.3 Generic Control of Tryptamines in the UK  20.4 Lysergide and Derivatives of Lysergamide  20.4.1 Lysergide  20.4.2 Lysergamide  References 

257 257 257 260 263 263 264 267

Chapter 21 G  amma-hydroxybutyrate and Related Substances  21.1 GHB  21.2 Other Substances Based on n-Butyric Acid  References 

269 269 270 272

Chapter 22

Morphine, Heroin and Other Opiates  22.1 Introduction  22.2 Heroin  22.3 Miscellaneous Opiates and Opioids  22.3.1 Codeine, Dihydrocodeine and Pholcodine  22.3.2 Oxycodone  22.3.3 Nalbuphine  22.3.4 Dextromethorphan  22.3.5 Glaucine  22.3.6 Desomorphine  22.3.7 Butorphanol  22.3.8 Apomorphine  22.3.9 Naloxone  22.3.10 Buprenorphine  References 

273 273 274 275 275 275 276 276 276 277 277 278 278 278 279

Chapter 23

Purity, Potency, Drug Content and Prices  23.1 Introduction  23.2 The Measured Purities of Powdered Drugs  23.3 The Potency of Cannabis  23.4 Statistical Analysis of Purity Data  23.5 Drug Content  23.6 Wrap Sizes  23.7 Adulterants in Powdered Drugs  23.8 Drug Prices  References 

281 281 282 285 285 287 287 288 288 290

Chapter 24 Measuring Drug Harm  24.1 Introduction  24.2 ACMD: Developing a Scale of Harm (2000–2007) 

291 291 292

Contents



xxxvii

24.3 The Netherlands Study (2010)  24.4 A Multi-criteria Decision Analysis of Drug Harms in the UK (2010)  24.5 The UK Survey by Morgan et al. (2009)  24.6 A Scale of Harm Produced by Drug Users (2011)  24.7 The International Survey by Morgan et al. (2013)  24.8 New Zealand Drug Harm Index  24.9 Index Measures of Lethal Toxicity  24.9.1 Fatal Poisonings and Prescriptions  24.9.2 Fatal Poisonings and Other Measures of Availability  24.9.3 The Safety Ratio  24.9.4 ‘Sole’ and ‘All Mentions’ on Death Certificates  References 

294

Chapter 25 Miscellaneous Issues  25.1 Diagnostic Kits  25.2 Low Dosage Preparations  25.2.1 Low Dosage Preparations Containing Cocaine  25.2.2 Low Dosage Preparations Containing Dihydrocodeine and Other Opiates  25.2.3 Low Dosage Preparations Containing Morphine  25.3 Cutting Agents and Adulterants  25.4 Preparations Designed for Administration by Injection  25.5 Supply of Meat Products  25.6 Medicinal Products  25.6.1 Medicinal Products and the Psychoactive Substances Act 2016  25.6.2 Psychoactive Substances ‘Not for Human Consumption’  25.6.3 1-Benzylpiperazine as a Medicinal Product  25.6.4 Historical Issues with Benzodiazepines  25.6.5 Nitrous Oxide  25.6.6 Medicinal Products and the EU Early Warning System  References 

307 307 307

Chapter 26

315 315 315 317 318 319



Natural Products  26.1 Introduction  26.2 Opium  26.3 Poppy Straw and Concentrate of Poppy Straw  26.4 Fungi Containing Psilocin or an Ester of Psilocin  26.5 Peyote and Other Cacti 

295 296 299 299 300 300 300 301 303 303 305

309 309 309 310 310 311 311 312 312 313 313 313 313 314

Contents

xxxviii



26.6 ‘Morning Glory’ Seeds  26.7 Plants Containing Tryptamines  26.8 Non-controlled Natural Products  References 

319 319 320 321

Chapter 27 Drug Precursors and Intermediates  27.1 United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988  27.2 Precursor Controls in the EU and UK  27.3 Precursor Chemicals and the US Controlled Substances Act  27.4 Production of Drugs from Listed and Unlisted Precursors  27.5 Drug ‘Intermediates’ Listed in the UN 1961 Convention or the Misuse of Drugs Act  References 

323

Chapter 28

Other Harmful Substances  28.1 Introduction  28.2 Poisons  28.3 Chemical Weapons and Their Precursors  28.4 Volatile Solvents and Gases  28.5 Other Dangerous Substances  28.6 Other Controls  References 

331 331 333 334 335 336 336 337

Chapter 29

Social Drugs  29.1 Introduction  29.2 Alcohol  29.3 Tobacco  29.4 Caffeine  29.5 Khat  29.5.1 Introduction  29.5.2 Control Status of Khat  29.6 Areca Nut and Betel Leaf  References 

339 339 339 340 341 342 342 343 343 344

323 324 325 326 329 329

Bibliography 

346

Appendix 1: EMCDDA Risk Assessments 

349

Appendix 2: Modification and Amendment Orders to the Misuse of Drugs Act (1973–2021)

351

Appendix 3: Substances Added Specifically to the Misuse of Drugs Act (1973–2021)

359

Contents

xxxix

Appendix 4: Significant Drug Case Judgments

362

Appendix 5: Selected Reports of the Advisory Council on the Misuse of Drugs (2002–2021)

365

Appendix 6: Anabolic/Androgenic Steroids Controlled under the Misuse of Drugs Act

368

Appendix 7: The 34 PiHKAL Substances and 4-MTA Added to the Misuse of Drugs Act as Class A Drugs in 2001

370

Appendix 8: An Unusual Case of MDMA Manufacture

374

Appendix 9: Presumptive Tests for Drugs

376

Appendix 10:  Useful Websites

378

Appendix 11:  Fentanyl Derivatives Reported to EMCDDA

380

Subject Index 

383

Chapter 1

Drug Misuse 1.1  Introduction Drugs whose possession or supply is restricted by law are known as scheduled or, in the UK, as controlled substances. They comprise both licit materials (i.e., those manufactured under licence for clinical use) and the illicit products of clandestine factories. Although many plant-­based drugs have been self-­administered for thousands of years (e.g., coca leaf, cannabis, opium, and peyote cactus), the imposition of criminal sanctions is mostly a product of the 20th century. Many of the drugs currently misused were once not only on open sale, but often promoted as beneficial products by the food and pharmaceutical industries. A pattern developed whereby initial misuse of pharmaceutical products such as heroin, cocaine and amphetamine led to increasing legal restrictions and the consequent rise of an illicit industry. The word ‘misuse’ signifies the non-­authorised use of medicines that can, in appropriate circumstances, be legally used. That word has carried over into the title of the UK primary drug legislation, i.e., the Misuse of Drugs Act (MDAct), and to the corresponding legislation in a number of Anglophone countries. This was a departure from the earlier use in UK legislation of the title ‘Dangerous Drugs’. According to the WHO,1 scheduled drugs are ‘abused’. In this book, the term drug misuse is used since it is considered to be less judgemental. However, even the word ‘misuse’ is somewhat misleading since many controlled drugs are not and never have been used therapeutically. This is particularly true of the huge range of, mostly synthetic, psychoactive substances that have appeared in the past 30 years. In many cases, it is appropriate to say that such substances are merely ‘used’. It is equally correct to say that medicinal products both licit and illicit, such as the benzodiazepine tranquillisers and certain analgesic drugs, are ‘misused’. In the following text, and for convenience, the word ‘misuse’ applies to both situations.   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

1

Chapter 1

2

1.2  Drug Misuse in England and Wales Overall drug use in England and Wales has remained fairly stable in the past 20 years but is still predominantly associated with younger members of the population. Data for England and Wales are published, where appropriate, by the HO,2 the ONS,3 and the NHS.4 Separate arrangements operate in the devolved administrations in Scotland and Northern Ireland. To a certain extent many of these data collections are limited by various factors. Thus, household surveys can only reach those who live in normal circumstances; some problem drug users are homeless. Drug seizures also depend partly on the level of enforcement. Furthermore, the total quantity of drugs seized can be distorted in any period by unusually large seizures. For this reason, ‘number of seizures’ is a more reliable statistic, and particularly when relative seizures of closely related drugs are examined.

1.2.1  Household Surveys of Drug Misuse Figure 1.1 shows estimates of the numbers of illicit drug users (16-­ to 59-­year-­olds) in England and Wales2 in the period 2001/02 to 2017/18 for any drug broken down by those who have ‘ever taken in lifetime’ and ‘taken in the last year’. On both measures, the number of users has remained fairly stable in the period shown. About 20% of the adult population in England and Wales admits to having used a controlled drug at least once in their lives. Table 1.1 shows data for the same age group in 2017/2018 by drug type and when taken. The most common drug was cannabis while around a third had taken a Class

Figure 1.1  Estimates  of the numbers (thousands) of illicit drug users, 16-­ to

59-­year-­olds, in the period 2001/02 to 2017/18 (England and Wales) for any drug ‘ever taken in lifetime’ (black bars) and ‘taken in the last year’ (grey bars).

Drug Misuse

3

Table 1.1  Estimates  of the numbers (thousands) of illicit drug users (16-­ to 59-­year-­olds) in 2017/2018 (England and Wales) by drug type and period when taken.

Substance

Last month

Last year

Ever

Last month/Ever

Powder cocaine Crack cocaine Ecstasy LSD ‘Magic mushrooms’ Heroin Methadone Amphetamine Methylamphetamine Cannabis Ketamine Mephedrone Anabolic steroids NPS

331 8 172 18 10 13 5 32 5 1109 103 3 35 n/a

895 23 559 134 142 23 19 173 16 2420 266 30 62 127

3576 273 3386 1755 2466 215 150 3284 212 10 125 941 629 316 834

0.09 0.03 0.05 0.01 0.004 0.06 0.03 0.01 0.02 0.10 0.10 0.004 0.11 n/a

A drug. Apart from cannabis and amphetamine, use of other Class B drugs was much lower. Cocaine in any form, ‘ecstasy’ (probably mostly MDMA) and ‘magic mushrooms’ were the most commonly-­used Class A drugs. Heroin and other opiates were far less common. Despite the high level of public interest in new psychoactive substances (NPS), in 2017/2018 they represented only 7% of all users and, furthermore, apart from mephedrone, no data on NPS were collected before 2016. The final column in Table 1.1 gives an estimate of whether use of certain substances is declining/increasing relative to others. ‘Magic mushrooms’ and mephedrone show the lowest value of this index (i.e., greatest negative change) while cannabis, powder cocaine, ketamine and anabolic steroids show the highest values of the index (i.e., greatest increase).

1.2.2  Drug-­associated Deaths Table 1.2 shows deaths in 2020 in England and Wales associated with specific substances, where those substance were mentioned on the death certificate.3 Some of these deaths involved more than one substance. These data include all substances, but two-­thirds involved ‘drug misuse’ which is defined as deaths associated with drug abuse, drug-­dependence or those that involved a controlled drug (i.e., listed in the MDAct). Figure 1.2 shows the trend in drug-­associated deaths in England and Wales for the period 2001 to 2020. In 2020, heroin and morphine accounted for around 30%, and all opiates/ opioids combined accounted for nearly 60%. The total number of deaths in 2020 (4561) was the highest number since recording started in 1993 and represents a rate of 79.5 deaths per million people. Males accounted for two-­ thirds of those deaths. Long delays can occur in recording some deaths; the data show deaths recorded in the year stated rather than occurring in that year. In 2020, drug-­associated deaths in Scotland5 reached an all-­time high

Chapter 1

4

Table 1.2  Deaths  in 2020 in England and Wales associated with specific substances. Substance(s) (opiates/opioids) Heroin and morphine Methadone Tramadol Codeinea Dihydrocodeinea Oxycodone Fentanyl

Number of deaths

Substance(s) (others)

Number of deaths

1337

Cocaine

777

516 203 212 96 102 57

Amphetamine Ecstasy/MDMA Cannabis NPS Benzodiazepines Zopiclone/ Zolpidem Pregabalin Gabapentin Barbiturates

99 82 36 137 476 146

Fentanyl analogues 2 Buprenorphine 43 Unspecified opiate 150

344 118 26

a

Codeine and dihydrocodeine deaths exclude compound formulations.

Figure 1.2  Drug-­  associated deaths in England and Wales (2001–2020). (1339 cases). On a per capita basis, this is over three times the rate in England and Wales. It also the highest rate in Europe although there are some differences in the definition of drug-­related deaths used by the Scottish Records Office, the ONS and the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).

1.2.3  Seizures by Law Enforcement Agencies Table 1.3 lists the number of drug seizures by Police in England and Wales in 2018/19.6 The data exclude those made by the Border Force. A large proportion of those arrested for drugs offences are drug users, rather than

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Table 1.3  Drug  seizures by Police in England and Wales in 2018/19. The classification of each substance (A, B or C) under the MDAct is shown.

Substance

Number of seizures Substance

Number of seizures

Cocaine (A) Crack cocaine (A) Ecstasy (A) Heroin (A) LSD (A) Methadone (A)

16 653 6556 2687 8338 166 407

3456 15 862 58 463 2249

Amphetamine (B) Barbiturates (B) Ketamine (B) Mephedrone (B) Anabolic steroids (C) Benzodiazepines (C)

Figure 1.3  Police  drug seizures in England and Wales in the period 2006/07 to

2018/19. Class A = dark grey bars; Class B = hatched bars; Class A = black bars.

suppliers, manufacturers, or importers, and most of those are for the offence of possession. Cannabis in its various forms represented 74% of all seizures. The trend in police drug seizures since 2006/07 is set out in Figure 1.3.

References 1. WHO, Lexicon of Alcohol and Drug Terms, https://apps.who.int/iris/ bitstream/handle/10665/39461/9241544686_eng.pdf?sequence=1&isAllowed=y, accessed October 2021. 2. Home Office, Drug Misuse: Findings from the 2018 to 2019 CSEW, https:// www.gov.uk/government/statistics/drug-­misuse-­findings-­from-­the-­2018-­ to-­2019-­csew, accessed October 2021.

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3. Office for National Statistics, Deaths related to drug poisoning in England and Wales: 2020 registrations, https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsrelatedtodrugpoisoninginenglandandwales/2020, accessed October 2021. 4. National Health Service Digital, Statistics on Drug Misuse, England, 2019, https://digital.nhs.uk/data-­a nd-­information/publications/statistical/ statistics-­on-­drug-­misuse/2019, accessed October 2021. 5. National Records of Scotland, Drug-­related deaths in Scotland in 2020, https://www.nrscotland.gov.uk/files//statistics/drug-­related-­deaths/20/ drug-­related-­deaths-­20-­pub.pdf, accessed October 2021. 6. Home Office, Seizures of drugs in England and Wales, financial year ending 2020, https://www.gov.uk/government/statistics/seizures-­of-­drugs-­ in-­england-­and-­wales-­financial-­year-­ending-­2020, accessed October 2021.

Chapter 2

International Drugs Control 2.1  Introduction Some features of the international legislation before 1961 are covered in Chapter 13, particularly the early controls on morphine derivatives. In current international law, controls on drugs of abuse are set out in three UN Treaties: The Single Convention on Narcotic Drugs, 1961 (UN 1961 Convention1), the Convention on Psychotropic Substances, 1971 (UN 1971 Convention2) and the Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988 (UN 1988 Convention3); they are described below. The international treaties are implemented in domestic laws by signatories and have been considerably extended in some States. In the UK, the corresponding legislation is the Misuse of Drugs Act 1971 (MDAct)4 and the Misuse of Drugs Regulations 2001 (MD Regulations)5 as amended. Since the inception of the UN Conventions, numerous substances have been added to the Schedules, particularly those of the 1971 Treaty. The organisation of chemical entities into various schedules in the UN Conventions is partly based on whether the substances have any therapeutic value and partly on their harmfulness. However, national legislatures have often incorporated the UN scheduling scheme as a basis for determining penalties associated with various offences such as possession, supply, production, importation etc. As discussed in Chapter 3, a notable exception to this rule is the UK. Here, the Schedules of the MD Regulations largely reflect the UN classification, but the separate MDAct sets out the same substances (known as controlled drugs) in three Classes (A, B and C). The administrative procedures involved in adding a substance to national drug laws show considerable variation. For example, they may require approval of Parliament, the Government or simply a Minister. Depending on which process occurs, the speed of the process can vary   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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Chapter 2

from a few weeks to years. Detailed information on the methods used in individual EU countries, the substances concerned and the penalties for specific offences are detailed by the EMCDDA.6 While most countries originally chose to implement only the essential elements required in international law by the 1961 and 1971 UN Conventions, a few have extended the scope to a wider range of substances. The problem of whether and how to control new and often widely-­available substances is being tackled in many different ways by different countries. The substances concerned are available everywhere, often via internet retail sites. Between 1997, when the EU monitoring system began, and late 2020, 830 new substances were reported to the EMCDDA and Europol as part of the EU-­wide early-­ warning system (EWS), and it is likely that more have been found when other countries are included. The appearance of novel substances has continued to cause problems for drug control authorities in many countries. Following the lead of the UN Treaties, it has been an accepted part of drug legislation that a substance should only be scheduled if it can be shown to be harmful, either to individuals, to society or both. And therein lies the central difficulty; almost nothing is known about the pharmacology of new substances or their potential for abuse. Some were developed by academic laboratories or the pharmaceutical industry as potential medicines, but never succeeded to market authorisation. The synthesis and basic chemical properties of these ‘failed pharmaceuticals’ will often have been described in the scientific or patent literature, yet apart from in vitro studies and occasional limited animal testing, their pharmacodynamic and pharmacokinetic properties in humans remain largely unexplored. Some limited information comes from occasional fatal poisonings in humans and clinical observations of intoxicated patients. Anecdotal reports from users, such as may be found on internet ‘chat rooms’, must be treated with caution since the exact identity of the substances concerned may be unknown, often being described by street terms or product names, the composition of which often changes with time. While the basic properties of new substances could be investigated by research programmes, perhaps using in vitro receptor binding, metabolic studies and other methods, that takes time and resources, and governments often wish to act at an early stage of misuse. The precautionary principle (Chapter 3) requires that it is better to control a substance immediately because of the severe consequences of permitting open sale of a substance that later turns out to be harmful. On the other hand, restricting a substance that is later shown to be harmless has far fewer negative consequences. The problem is made worse by the number of compounds involved and the rapid replacement of controlled substances by non-­controlled analogues. Thus, even those substances that remain uncontrolled often have a short lifetime on the illicit market. Furthermore, reliable population surveys and information on prevalence may not become available until a substance is well-­ established, if at all.

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2.2  U  nited Nations Single Convention on Narcotic Drugs, 1961 In the 1961 Convention, there is a strong emphasis on plant-­based drugs, with rules for their cultivation, manufacture and trade. The drugs are set out in four Schedules, the principal objectives of which are to provide proportionate levels of restriction on legitimate trade in the drugs. Those restrictions follow the order I > II > III. The substances in Schedule I (by far the largest group) include cannabis, opium and cocaine. In addition, there are around 100 synthetic narcotic analgesics, but only a few of these are now used clinically or ever reported to be abused. Schedule II includes, for example, codeine and dihydrocodeine. Schedule III includes preparations of certain narcotic drugs with rules on the maximum concentrations or amounts that may be present. An example here is codeine, which falls into Schedule III if it is ‘compounded with one or more other ingredients and containing not more than 100 milligrams of the drug per dosage unit and with a concentration of not more than 2.5 per cent in undivided preparations’. Schedule IV is somewhat paradoxical in that it is not less restrictive than Schedule III. It includes a small group of substances (e.g., cannabis, cannabis resin and heroin) that are already listed in Schedule I, but which are considered to be particularly dangerous, and to which special provisions should apply. In modern usage, the word narcotic is usually confined to the naturally-­occurring and synthetic opioids such as morphine and methadone and related compounds. Both cannabis and cocaine would now be described as psychotropic drugs, or simply psychoactive substances, rather than narcotics. All signatories to the Convention have incorporated the listed substances and general principles of control into their domestic law, but most have chosen to realign and expand the Schedules such that those controls are listed in a more logical order. For example, in the UK MD Regulations 2001 and the US Controlled Substances Act there are five Schedules where controls decrease in the order I to V.

2.3  U  nited Nations Convention on Psychotropic Substances, 1971 More than 100 psychotropic substances are listed in the 1971 Convention, but again only a small fraction are regularly abused. The term ‘psychotropic’ is not defined in the Convention. There are four Schedules of controlled substances, ranging from Schedule I (most restrictive) to Schedule IV (least restrictive). Schedule I includes drugs which are considered to be the most dangerous and whose therapeutic value is doubtful, e.g., LSD, N,N-­dimethyltryptamine and tetrahydrocannabinol (THC). In Schedule II are drugs such as amphetamine, where some limited therapeutic value is recognised. Schedule III includes, for example, cathine and buprenorphine, while Schedule IV includes pemoline, aminorex and benzodiazepines. Thus,

10

Chapter 2

Schedule I largely comprises illicit substances, whereas Schedules II, III and IV include legitimate active pharmaceutical agents (APIs). A notable feature is that barbiturates are spread across Schedules II, III and IV. Part of the reason is that secobarbital (quinalbarbitone), the only example in Schedule II, was identified as having a particularly high fatal toxicity,7 whereas phenobarbital (Schedule IV) not only has a much lower toxicity and is not a hypnotic but is used in the treatment of epilepsy. The inclusion of THC and its isomers in Schedule I has led to some confusion since cannabis, cannabis resin and extracts of cannabis are listed in the 1961 Convention. Further confusion is caused by the placement of dronabinol, i.e., (−)-­trans-­Δ9-­THC, in Schedule II of the 1971 Convention. Unlike the Treaty of 1961, there was originally no overarching control of the stereoisomers of psychotropic drugs (see Chapter 7 for a discussion of stereoisomerism). Thus, in Schedule I, amfetamine (meaning both enantiomers) is listed together with dexamfetamine (the S-­enantiomer of amfetamine) and levamfetamine (the R-­enantiomer) while metamfetamine (meaning the S-­enantiomer) is listed alongside metamfetamine racemate (a mixture of the two enantiomers). These examples, and the situation whereby the stereochemical configuration of many other substances was left unspecified, lead to some confusion. The UN has since clarified the status of stereochemical variants in the 1971 Convention. These problems were avoided in the MDAct by the inclusion of the stereoisomers of almost all controlled drugs (Chapter 7).

2.4  U  nited Nations Convention against Illicit   Traffic in Narcotic Drugs and Psychotropic Substances, 1988 The purpose of the 1988 Convention was to provide additional legal mechanisms for enforcing the 1961 and 1971 Conventions. The treaty is concerned with tackling organised crime by co-­operation in tracing and seizing drug-­related assets. To limit money laundering, it allows signatories to empower their courts to seize bank and commercial records. Whereas there had hitherto been no clear requirement for signatories to criminalise drug possession, this Convention is more explicit on the need for this. According to the text of Article 3 of the 1988 Convention: ‘Subject to its constitutional principles and the basic concepts of its legal system, each Party shall adopt such measures as may be necessary to establish as a criminal offence under its domestic law, when committed intentionally, the possession, purchase or cultivation of narcotic drugs or psychotropic substances for personal consumption contrary to the provisions of the 1961 Convention, the 1961 Convention as amended or the 1971 Convention’. There has been some debate about the precise interpretation of Article 3. Another purpose of this Convention was to introduce controls on precursor chemicals. This is described in Chapter 27.

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2.5  The Role of the European Union Sitting between national legislations and the international drug control treaties, the EU has a supranational role. Apart from precursor legislation, which derives from the United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988, the EU has specific competence in the area of what are now termed new psychoactive substances, the original abbreviation for which was NPAS, but is now NPS.8

2.5.1  ‘Joint Action’: The Period 1997 to 2005 From the early 1990s, many ‘designer drugs’ were regularly detected in the EU. They were often psychotropic substances related to MDMA, i.e., ring-­ substituted phenethylamines. Throughout this period, illicit drugs were manufactured in clandestine laboratories, mostly located in Europe, and produced as tablets bearing characteristic logos. They were often marketed through criminal networks as ‘Ecstasy’, a term which initially meant MDMA or one of its homologues, but later became much broader. This raised questions about possible health risks and the problems that could arise if such substances were arbitrarily controlled in some Member States but not in others. It was agreed that progress could be made by sharing information and by establishing a risk assessment procedure and a mechanism for their eventual control across the EU. This led, in 1997, to the ‘Joint Action concerning the information exchange, risk assessment and control of new synthetic drugs’. These ‘new synthetic drugs’ (NSD) were defined as those that had a limited therapeutic value and were not at that time listed in the 1971 UN Convention on Psychotropic Substances yet posed as serious a threat to public health as the substances listed in Schedules I and II of that Convention. The term ‘new’ did not refer to newly-­invented, but rather ‘newly-­misused’; most of the drugs in question were first created many years ago. Thus, well-­ established drugs such as amphetamine, MDMA and its ethyl homologue (MDEA) were excluded since they were already controlled in international law. The ‘Joint Action’ took place against a political background whereby Europe had become a leading producer of synthetic drugs.

2.5.2  The EU Council Decision of 2005 In 2002, a review of the Joint Action was carried out under the terms of the EU Action Plan on Drugs 2000–2004. Suggestions for improvements led to a process that, in 2005, culminated in Council Decision 2005/387/JHA.9 This broadened the scope of, and replaced, the 1997 ‘Joint Action’, while maintaining a three-­step approach. The term NSD was replaced with ‘new psychoactive substance’ (NPS), which included not only substances that might qualify for inclusion in the UN 1971 Convention, but also narcotic substances that would normally be listed in the UN 1961 Convention. Furthermore, there was no restriction to synthetic drugs, so that naturally-­occurring products

12

Chapter 2

would also qualify for investigation. To a large extent, these new compounds can be distinguished from the classical drugs of misuse (e.g., amphetamine, cocaine, heroin and cannabis) because they have had little or no history of medicinal use. In the information exchange/early-­warning stage, once a NPS is detected on the European market, Member States ensure that information on the manufacture, traffic and use of the drug is transmitted to the EMCDDA and Europol. If a risk assessment is carried out then the Council may decide that the drug should be controlled. Appendix 1 lists those risk-­assessments that have been carried out by EMCDDA. Appropriate measures and criminal penalties in the EU Member States are decided in line with national laws, which in turn comply with the UN Conventions. The Council decision does not prevent individual Member States from unilaterally introducing national control measures at an earlier stage if they consider it appropriate. Alongside the EU EWS, a parallel system of monitoring new substances is maintained by the UN. Known, initially, as the Global Smart (Synthetics Monitoring: Analyses, Reporting and Trends) Programme, set up in 2008, it now incorporates the UNODC Early Warning Advisory (EWA) on New Psychoactive Substances. The programme publishes a number of research reports, available on their website.10 These include detailed information on the detection and pharmacology of NPS, a database of national legal responses and a large number of other publications.

2.5.3  The Period since 2018 As of 23 November 2018, the EU EWS operates under an updated Regulation,11 a Directive12 and revised guidelines.13,14

2.5.3.1 Formal Notification Most new substances are identified for the first time following the chemical analysis of a seizure made by national law enforcement agencies. When a substance is suspected of being a NPS, the national EWS reports this to the EMCDDA. This includes chemical information, as well as the circumstances of the event. The submission of analytical data is also required; and such data are temporary substitutes for analytical reference standards, which are often not available when an NPS is first detected. Following a review of the reported information, the EMCDDA identifies other relevant information that may be available in the literature. If confirmed as a new substance, then a formal notification is issued on behalf of the reporting Member State. The notification includes the names and identifiers of the substance, chemical and physical properties, analytical methodologies used for its identification, pharmacology and toxicology if known, circumstances of the detection, and any other relevant information. At this stage, the EMCDDA begins to formally monitor the substance.

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The formal notification process is one of the foundations of a successful EWS as it ensures that members of the network are alerted as soon as possible to the detection of a new substance in Europe. This allows the network to identify and analyse any potential threats as well as to identify and implement any response measures that might be needed. This process also lets forensic and toxicology laboratories include the substance in their analytical screening, thereby allowing it to be detected and therefore monitored.

2.5.3.2 Monitoring and Responses Once an NPS has been formally notified, it is monitored through the EWS for signals of harm. In doing so, the EMCDDA uses a range of interconnected systems that make up the EWS, including event-­based data, toxicovigilance, signal management, and open source information. Depending on the signal, responses include placing the NPS under intensive monitoring, issuing risk communications including public health-­related alerts, and the production of an initial report which may lead to a risk assessment. As of late 2020, the EMCDDA was monitoring 830 NPS that have been formally notified since 1997.

2.5.3.3 Initial Report Under the previous legal framework setup by Council Decision 2005/387/ JHA, the initial report was known as a Joint Report that was prepared in conjunction with Europol. The EMCDDA and Europol prepared 25 Joint Reports on NPS between 2005 and 2018.15 Based on the information reported to the EWS, if the EMCDDA considers that an NPS may pose health or social risks at EU level, it produces, what is currently called, an initial report on the substance. This report includes information on:    ●● the nature, number and scale of incidents showing health and social problems in which the NPS may potentially be involved, and the patterns of use of the substance; ●● the chemical and physical description of the NPS and the methods and precursors used for its manufacture; ●● the pharmacological and toxicological description of the NPS; ●● the involvement of criminal groups in the manufacture or distribution of the NPS; ●● information on the human and veterinary medical use of the NPS, including as an active ingredient in a medicinal product for human or veterinary use; ●● information on the commercial and industrial use of the NPS, the extent of such use, as well as its use for scientific research and development purposes; ●● information on whether the NPS is subject to any restrictive measures in the Member States;

Chapter 2

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information on whether the NPS is currently or has been under assessment within the system established by the 1961 Single Convention on Narcotic Drugs, as amended by the 1972 Protocol, and the 1971 Convention on Psychotropic Substances (‘United Nations system’); ●● other relevant information, where available.    For the initial report, the European Medicines Agency provides information on whether the NPS is used in human or veterinary medicine. Europol provides information on the involvement of criminal groups in the manufacture, distribution, trafficking and use of the NPS. The European Chemicals Agency, the European Centre for Disease Prevention and Control and the European Food Safety Authority also provide information and data, where available, on the NPS. Based on the initial report, the European Commission may request the EMCDDA to formally assess the potential risks posed by the NPS and to draw up a risk assessment report, where there are indications in the initial report to believe that the substance may pose severe public health risks and, where applicable, severe social risks. A recent review16 describes the evolution of information exchange and legal responses to NPS in the European Union. ●●

2.6  Legislative Developments in Other Countries The UNODC provides a comprehensive analysis of drug control in Member States with emphasis on NPS; it covers the use of analogue and generic legislation, temporary listing and other rapid responses, and the use of consumer protection or medicines law.17 Generic legislation is described in Chapter 8, while analogue control is covered in Chapter 11. In its reaction to the designer drugs of the day, the first response of the US government, in 1984, was to introduce emergency scheduling provisions. Emergency scheduling, otherwise known as temporary control, was a scheme whereby a substance could be added to Schedule 1 of the Controlled Substances Act 1970 18 for a period of one year. The conditions that had to be satisfied were that the substance presented an imminent hazard to the public safety, and that it was not already listed in another Schedule of the Act. This temporary measure could be extended by six months provided, by then, procedures had been initiated to control the substance permanently. There was still a requirement on the authorities to provide some evaluation of the abuse potential of the substance, even if these had to be inferred from structure–activity relationships and comparison with similar compounds. One advantage of temporary control was that it provided a partial solution to the question: ‘How should a State treat a substance that is believed to have a very low level of harm but sufficient data are not available?’ This is another situation where a jurisdiction might rely on the precautionary principle (Chapter 3). A good example was provided by the piperazine derivatives BZP and TFMPP (3-­trifluoromethylphenylpiperazine). These were placed under temporary control for one year in 2002, but when no further information

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came to light on the harmful properties of TFMPP it was removed, although BZP was subsequently made subject to permanent control (Schedule I). Within a few years, it was recognised that, while a valuable tool, emergency scheduling was not in itself enough to limit the illicit manufacture of designer drugs. This need for a more proactive stance gave rise to the Controlled Substances Analogue Enforcement Act (Chapter 11). To a certain extent, analogue control reduced the need for emergency action, but temporary scheduling continued to be used in the US. The initial responses to NPS in other countries were varied. Some used medicines legislation, but a later decision by the European Court of Justice decided that it was not appropriate to control substances as medicines if they were never intended to act as medicines. In Germany in late 2008, the German government acted to bring several synthetic cannabinoid receptor agonists under temporary control for a period of one year. These and many others were subsequently incorporated into substantive legislation (Betäubungsmittelgesetz). Several other countries used temporary control measures, including Hungary, New Zealand and the Netherlands. In New Zealand, a somewhat different approach to emergency legislation was originally used.19,20 From around 2000, BZP was sold as a ‘safer’ alternative to methamphetamine but without restriction from either the Misuse of Drugs Act 1975 or the Medicines Act 1981. Dosage units, known as ‘party pills’, were widely available and often contained a 1 : 1 mixture of BZP and TFMPP, which was thought to mimic some of the effects of MDMA. In 2004, the Expert Advisory Committee on Drugs (EACD) stated that ‘After considering the evidence, … there is no current schedule under the MDAct 1975 under which BZP could reasonably be placed’. The Ministry of Health therefore created a new schedule of ‘Restricted Substances’, informally referred to as ‘Class D’, with BZP as the first example of this new class of substance. Unlike in the UK, this was not necessarily seen as a temporary measure. From 2005, ‘Restricted Substances’ attracted no penalty for possession, but were regulated through control of manufacture, advertising and sale, rather than prohibition. However, this experiment ended when, a few years later, BZP was added to Part 1 of Schedule 3 of the Misuse of Drugs Act 1975. The Criminal Justice (Psychoactive Substances) Act was introduced in Ireland in 2010 and predated broadly similar legislation in the UK (Chapter 5). It was designed specifically to deal with the problem caused by novel substances and stands as a piece of legislation quite separate from the existing Misuse of Drugs Act 1977 of the Republic of Ireland. It makes it a criminal offence, with a maximum penalty of five years in prison, to advertise, sell or supply, for human consumption, psychoactive substances not specifically controlled under existing legislation. They are defined as ‘substances which have the capacity to stimulate or depress the central nervous system, resulting in hallucinations, dependence or significant changes to motor function, thinking or behaviour’. The Act excludes medicinal and food products, animal remedies, alcohol and tobacco. There is no personal possession offence.

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References 1. Single Convention on Narcotic Drugs, https://www.unodc.org/unodc/en/ treaties/single-convention.html, accessed April 2022. 2. Convention on Psychotropic Substances, https://www.unodc.org/unodc/ en/treaties/psychotropics.html, accessed April 2022. 3. Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, International Narcotics Control Board, 1988, https://www.incb. org/documents/PRECURSORS/1988_CONVENTION/1988Convention_E. pdf, accessed October 2021. 4. The Misuse of Drugs Act 1971, https://www.legislation.gov.uk/ukpga/ 1971/38/contents, accessed October 2021. 5. The Misuse of Drugs Regulations 2001, https://www.legislation.gov.uk/ uksi/2001/3998/contents, accessed October 2021. 6. European Monitoring Centre for Drugs and Drug Addiction, Law topics page, https://www.emcdda.europa.eu/topics/law_en, accessed October 2021. 7. L. A. King and A. C. Moffat, Lancet, 1981, i, 387. 8. European Monitoring Centre for Drugs and Drug Addiction, Early Warning System on NPS, https://www.emcdda.europa.eu/publications/topic-­ overviews/eu-­early-­warning-­system_en, accessed October 2021. 9. EU Council Decision 2005/387/JHA, Official Journal of the European Union, https://eur-­lex.europa.eu/eli/dec/2005/387/oj, accessed October 2021. 10. UNODC Early Warning Advisory (EWA) on New Psychoactive Substances (NPS), https://www.unodc.org/LSS/Home/NPS, accessed October 2021. 11. European Commission, Regulation (EC) 1920/2006, https://www.emcdda. europa.eu/drugs-­library/regulation-­ec-­no-­19202006_en#:∼, accessed October 2021. 12. European Parliament and Council, Directive (EU) 2017/2101, https://www. legislation.gov.uk/eudr/2017/2103/introduction/2017-­11-­15, accessed October 2021. 13. European Monitoring Centre for Drugs and Drug Addiction, Operating Guidelines for the European Union Early Warning System on New Psychoactive Substances, 2019, https://www.emcdda.europa.eu/system/files/publications/12213/EWS%20guidelines_final.pdf, accessed October 2021. 14. European Monitoring Centre for Drugs and Drug Addiction, EMCDDA Operating Guidelines for the Risk Assessment of New Psychoactive Substances, 2020, https://www.emcdda.europa.eu/publications/manuals-­and-­guidelines/ emcdda-­risk-­assessment-­guidelines_en, accessed October 2021. 15. European Monitoring Centre for Drugs and Drug Addiction, Early Warning System on NPS, 2019, https://www.emcdda.europa.eu/publications/ topic-­overviews/eu-­early-­warning-­system, accessed October 2021. 16. M. R. Varì, G. Mannocchi and R. Tittarelli, et al., Int. J. Environ. Res. Public Health, 2020, 17(22), 8704.

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17. United Nations Office on Drugs and Crime, Early Warning Advisory on New Psychoactive Substances, https://www.unodc.org/LSS/Country/List, accessed October 2021. 18. United States Controlled Substances Act 1970, https://www.dea.gov/ drug-­information/csa, accessed October 2021. 19. M. Bowden and P. Trevorrow, Drug Test. Anal., 2011, 3(7–8), 426. 20. T. Bassindale, Drug Test. Anal., 2011, 3(7–8), 428.

Chapter 3

Primary UK Drugs Legislation up to 1971 3.1  Drug Control in the UK before 1971 Apart from the Pharmacy Act of 1868, which restricted the sale of opium, the modern period of drug control started in the early 20th century. Following the Poisons and Pharmacy Act 1908 and the Shanghai Opium Commission in 1909, further restrictions were introduced on cocaine, morphine and opium. More controls on a wider range of substances were introduced in the UK by successive Dangerous Drugs Acts. The distribution and use of morphine and cocaine, and later cannabis, were criminalised, but these drugs were available to addicts through doctors; this arrangement became known as the ‘British system’ and was confirmed by the report of the Departmental Committee on Morphine and Heroin Addiction (Rolleston Committee) in 1926.1 Following that report, the medical profession regulated the distribution of licit opioid supplies and the provisions of the Dangerous Drugs Acts of 1920 and 1925 controlled illicit supplies. The medical treatment of dependent drug users was separated from the punishment of unregulated use and supply. This policy on drugs was maintained in Britain until the 1960s. During this era, drug use remained low; there was relatively little recreational use and dependent users were prescribed drugs as part of their treatment. By 1951, there was a simple list of ‘traditionally abused drugs’ that included opium, opiates, cocaine and cannabis (known as ‘Indian Hemp’ in the legislation). However, the UN Single Convention of 1961 required that this short list be expanded to cover a large group of substances. These were mostly semi-­synthetic opiates and other narcotic analgesics, but many were, and remain to this day, little more than chemical curiosities. Inclusion of substances listed in the UN 1961 Convention into UK legislation led to the   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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19

2

Dangerous Drugs Act of 1964. An opportunity was then taken to redefine cannabis as no longer just the flowering tops of female plants and, for the first time, to create an offence of cannabis cultivation. These changes were consolidated in the Dangerous Drugs Act of 1965.2 In the meantime, new problems appeared that had not been anticipated by the UN 1961 Convention. Stimulants such as amphetamine and related compounds and other psychotropic drugs rapidly became more prevalent, and special legislation was needed for their control. This became the Drugs (Prevention of Misuse) Act 1964 (DPMA).3 Following legal difficulties that arose in a 1964 prosecution under the Pharmacy and Poisons Act of 1933 (Chapters 7 and 28), which concerned the supply of LSD, a Modification Order to the DPMA was made in 1966.4 This introduced specific controls to mescaline and lysergamide and extended control to N-­alkyl derivatives of lysergamide and ring-­hydroxy derivatives of N,N-­dimethyltryptamine. Problems arising from the meaning of ‘derivative’ first arose at this time. This issue, which was discussed by Phillips5 is further expanded in Chapter 12. An early, and ultimately unsuccessful, attempt to control phenethylamines by generic definitions is described in Chapter 8.

3.2  The Misuse of Drugs Act 1971 The MDAct replaced the Dangerous Drugs Act 1965 and the DPMA. The purpose of the MDAct was to incorporate the provisions of the UN 1971 Convention into UK law. The MDAct introduced the concept of ‘controlled drugs’, which are defined as those substances or products set out in Parts I, II and III of Schedule 2. For the sake of clarity and when the context is clear, ‘controlled drugs’ are often described herein simply as ‘drugs’ or ‘substances’. The full text of Schedule 2, as of 2008, was shown in the 1st Edition of this book,6 but it has now become too unwieldy for inclusion here, largely because of the many generic definitions. A list of (named) controlled drugs can be found on the UK Government website,7 and the full text of the latest version of the MDAct is published on the UK legislation website.8 The meaning of certain terms, as set out in Part IV of Schedule 2, is shown in Table 3.1. An independent web-­based system that claims to provide an index of controlled substances is available.9 The MDAct incorporated the changes introduced by the UN 1971 Convention on Psychotropic Substances. The MDAct prohibits certain activities with respect to controlled drugs (e.g., possession, possession with intent to supply and production) without a licence. With the exception of opium, there is no illegality in using or consuming a controlled drug. The great majority of arrests for offences under the MDAct involve possession of relatively small amounts of a controlled drug. This led John Lennon to coin the aphorism: ‘Possession is not nine-­tenths of the law it is nine-­tenths of the problem’. The controlled drugs listed in Schedule 2 of the MDAct are divided into three groups: Class A (Part I of Schedule 2), Class B (Part II) and Class C (Part III). In principle, these groups represent, in decreasing order A to C, the

20

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Table 3.1  The  full text of Part IV of Schedule 2 to the MDAct. Meaning of certain expressions used in this schedule For the purposes of this schedule the following expressions (which are not among those defined in Section 37 (1) of this Act) have the meanings hereby assigned to them respectively, that is to say– ‘Cannabinol derivatives’ means the following substances, except where contained in cannabis or cannabis resin, namely tetrahydro derivatives of cannabinol and 3-­alkyl homologues of cannabinol or its tetrahydro derivatives; ‘Coca leaf’ means the leaf of any plant of the genus Erythroxylon from whose leaves cocaine can be extracted either directly or by chemical transformation; ‘Concentrate of poppy-­straw’ means the material produced when poppy-­straw has entered into a process for the concentration of its alkaloids; ‘Khat’ means the leaves, stems or shoots of the plant of the species ‘Catha edulis’; ‘Medicinal opium’ means raw opium which has undergone the process necessary to adapt it for medicinal use in accordance with the requirements of the British Pharmacopoeia, whether it is in the form of powder or is granulated or is in any other form, and whether it is or is not mixed with neutral substances; ‘Opium poppy’ means the plant of the species Papaver somniferum L; ‘Poppy-­straw’ means all parts, except the seeds, of the opium poppy, after mowing; ‘Raw opium’ includes powdered or granulated opium but does not include medicinal opium.

propensity of the substances to cause social harm. The list of substances in Schedule 2 may be varied by a Statutory Instrument (S.I.) known as a Modification or Amendment Order. There have been 42 such Orders since 1973 when the MDAct came into force (Appendix 2). Some of the named substances listed in the MDAct, numerous definitions and a few generic controls derive directly from the UN Conventions. However, the Act goes beyond the minimum in many areas. Not only are there more substances, but an important feature of the Act is the extensive use of structure-­specific generic terms (Chapter 8). In 1973, there were 124 substances listed by name. Since then, 204 more have been added specifically to the MDAct; Appendix 3 shows their original classification and status in the UN 1961 or 1971 Conventions. Substances that were once under temporary control are shown in Chapter 5. Inspection of the list in Appendix 3 of named drugs added to the MDAct since 1973 shows that the majority are listed in the UN Conventions, with most of those in the 1971 Convention reflecting the greater number of psychotropic as opposed to narcotic drugs. The main exceptions are anabolic steroids as well as zeranol and zilpaterol (both non-­steroidal anabolic substances), a group of phenidate derivatives, certain substances related to 4-­hydroxy-­n-­butyric acid (GHB), certain ‘Z-­drugs’ (e.g., zolpidem), LSD analogues and the recently added gabapentin and pregabalin. Fortson10 has argued that the MDAct is being misused in the sense that it has become a pre-­emptive device rather than a reactive measure to a significant proven risk to a person's health or to the wellbeing of society. This is an example of the precautionary principle (see below). Of the over 300 substances listed by name in the MDAct, let alone the huge number

Primary UK Drugs Legislation up to 1971

21

defined generically since then, around 20 substances account for nearly all use, deaths and law enforcement seizures. In other words, over 90% of just the named controlled drugs are, at least currently, an insignificant issue for individuals or society.

3.3  Offences and Penalties under the MDAct The maximum penalties for the offences of possession and supply or production involving controlled drugs are set out in Table 3.2; they mostly decrease in the order A > B > C. These maximum sentences are only used in the most serious cases. In practice, the Sentencing Council produces guidelines for the benefit of Magistrates and Crown Courts. The most recent revision of the guidelines was published in early 2021. More details can be found on the website of the Sentencing Council.11 In their statement, the Council noted that:    ●● ‘New and more powerful drugs have also been brought onto the market over recent years, including various kinds of “Spice”, and synthetic opioids such as fentanyl and carfentanil. The new MDA guidelines provide for such drugs. In the assessment of harm, the quantity of some drugs has been updated to reflect the change in purity (ecstasy) and yield (cannabis) of the drugs since the 2012 guidelines’.    The changes to the 2012 list of relevant drugs include:    ●● ‘The addition of MDMA, separate from ecstasy. This has been added as MDMA is now just as commonly used in forms such as powder rather than just tablet form. ●● The addition of Synthetic Cannabinoid Receptor Agonists (SCRAs), in the list of relevant drugs. These drugs, commonly referred to as SPICE, are becoming increasingly common. Table 3.2  Maximum  penalties on indictment for offences under the MDAct. Class A

Possession

Up to 7 years in prison, an unlimited fine or both B Up to 5 years in prison, an unlimited fine or both C Up to 2 years in prison, an unlimited fine or both (except anabolic steroids – it is not an offence to possess them for personal use) Temporary None, but police can take away a susclass pected temporary class drug

Supply/Production Up to life in prison, an unlimited fine or both Up to 14 years in prison, an unlimited fine or both Up to 14 years in prison, an unlimited fine or both Up to 14 years in prison, an unlimited fine or both

Chapter 3

22 ●●

Amendments to the quantities of ecstasy within the guidelines. For example, in the importation, supply and production guidelines an offender had to have at least 10 000 tablets of ecstasy to be in the highest category of harm, this has been reduced to 7000 tablets as evidence has shown that the average purity of ecstasy has increased. The current guideline was based on an average purity of 100 mg of MDMA per ecstasy tablet, but evidence shows that purity has increased to 150 mg per tablet’.

3.3.1  Cultivation of Cannabis The MDAct makes cultivation of cannabis an offence. Thus Section 6 reads:    Restriction of cultivation of cannabis plant.    (1) Subject to any regulations under section 7 of this Act for the time being in force, it shall not be lawful for a person to cultivate any plant of the genus Cannabis. (2) Subject to section 28 of this Act, it is an offence to cultivate any such plant in contravention subsection (1) above.    The reference to section 7 of the Act refers to situations where the Secretary of State may deem such cultivation lawful. The reference to section 28 of the Act refers to the defence of lack of knowledge. In Schedule 4 of the Act (Prosecution and punishment of offences), the maximum penalty on indictment for the offence of cultivation is 14 years imprisonment or a fine or both. Although the cultivation of any other plant under the MDAct is not listed specifically, even when such a plant contains a controlled drug, an offence could arise if it was deemed that an act of production by cultivation had taken place. With opium poppies, an offence only arises if opium is extracted from the ripe capsules.

3.3.2  Production of a Controlled Drug The MDAct makes production of controlled drugs an offence. Thus, part of Section 4(1) of the Act reads:    … it shall not be lawful for a person-­    (a)  to produce a controlled drug; or (b)  to supply or offer to supply a controlled drug to another.    The following definition is found in Section 37(1) of the Act (Interpretation):    ‘“produce”, where the reference is to producing a controlled drug, means producing it by manufacture, cultivation or any other method, and “production” has a corresponding meaning’.   

Primary UK Drugs Legislation up to 1971

23

Since the inception of the MDAct, and despite the above definition, much legal effort has been spent on examining what the term ‘production’ means, and in the event, the original definition has been much expanded. Even though cocaine and its salts are all treated equally as Class A drugs, in R-­v-­ Russell (Appendix 4), the production of crack (i.e., cocaine base) from cocaine hydrochloride was deemed to be an offence of production. By extension this would seem to apply to any salt-­base interconversion. More recently the Court of Appeal made a number of related decisions. Firstly, it was considered that to mix, for example, benzocaine with cocaine is to produce cocaine. The Courts made this construction on the basis that the definition of a controlled drug includes a mixture of substances of which one is a controlled drug. Thus, a powder containing 1% cocaine and 99% cutting agent (diluent) is itself a controlled drug that was produced by the addition of that cutting agent. In another context, the preparation of a ‘tea’ from a plant that naturally contains dimethyltryptamine (DMT) is to produce DMT. Those legal interpretations have to be accepted, but they sit uneasily with other definitions of ‘produce’. Thus, the synthesis of amphetamine from its precursors is clearly an act of production, but the extraction of sugar from sugar cane is arguably not production but an act of refining. The distinction here lies in the concept that production means creating something that was not already present. Amphetamine is not present in its precursor chemicals, but sugar is already present in sugar cane. By extension, a ‘tea’ containing DMT made from plant material is an act of refining rather than production. To make matters worse, the recording of offences by some police forces has changed the meaning of production to a level that is little short of absurd. Monaghan12 reported that the crime database of the Metropolitan Police recorded far more offences of production than can be reasonably expected. Further investigation showed that the offence of production was recorded even when, for example, the police officer noted that the suspect ‘readily produced’ a drug from his pocket. The offence of ‘production’ is also a criminal lifestyle offence for the purposes of the Proceeds of Crime Act 2002 and thus the characterisation is important.

3.4  The Advisory Council on the Misuse of Drugs The MDAct, which came into effect in 1973, set up an Advisory Council on the Misuse of Drugs (ACMD) whose terms of reference include a definition of what should constitute a controlled drug. This is set out in Section 1(2) of the MDAct as:    ‘It shall be the duty of the Advisory Council to keep under review the situation in the United Kingdom with respect to drugs which are being or appear to them likely to be misused and of which the misuse is having or appears to them capable of having harmful effects sufficient to constitute a social problem’.   

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The ACMD succeeded an earlier body: The Advisory Committee on Drug Dependence. The constitution of the ACMD was originally set out in Schedule 1 of the MDAct, part of which follows:    ‘The members of the Advisory Council, of whom there shall be not less than twenty, shall be appointed by the Secretary of State after consultation with such organisations as he considers appropriate, and shall include—    (a) in relation to each of the activities specified in sub-­paragraph (2) below, at least one person appearing to the Secretary of State to have wide and recent experience of that activity; and (b) persons appearing to the Secretary of State to have wide and recent experience of social problems connected with the misuse of drugs. (2)  The activities referred to in sub-­paragraph (1)(a) above are— (a)  the practice of medicine (other than veterinary medicine); (b)  the practice of dentistry; (c)  the practice of veterinary medicine; (d)  the practice of pharmacy; (e)  the pharmaceutical industry; (f)  chemistry other than pharmaceutical chemistry’.    A substantial body of reports on drugs has been produced by the ACMD. Those published since 2002 are set out in Appendix 5. In late 2009, David Nutt, the Chairman of the ACMD was dismissed by the Home Secretary. The background to this is described by Nutt13 but, as far as the Home Office was concerned, a presentation by Nutt to the Centre for Crime and Justice Studies on ‘Estimating Drug Harms: A Risky Business’ was a step too far. That talk was based on work done by the ACMD, which is described in detail in Chapter 24. Within the following days and weeks, several other members, including this author, resigned from the ACMD. The ACMD now had less than the required 20 members as well as losing some specified positions, including my own as the Statutory Chemist. In the middle of this upheaval, the ACMD had started to produce recommendations on the control of mephedrone and other cathinones. It was debatable whether, in the light of the reduced membership of the ACMD, the advice given to Ministers at that time was constitutionally acceptable. However, control of those substances went ahead. It was somewhat ironic that the Amendment Order to the MDAct (S.I. 1207) in 2010 was so badly drafted that it had to be replaced in the following year, as described in Chapter 10. Since the Home Office was unable to recruit sufficient new members in the time available, it was decided that the constitution of the ACMD should be changed to avoid any future problems. This came into effect by means of Section 152 of the Police Reform and Social Responsibility Act, 2011.14 Contrary to what some thought at the time, this did not remove the need for scientists on the ACMD, but rather removed the statutory requirement that specific types of scientist (chemist, pharmacist, etc.) were required.

Primary UK Drugs Legislation up to 1971

25

3.5  Reviews of the MDAct 3.5.1  Review by the ACMD (1979) In the first review of drug classification in the MDAct in 1979,15 the ACMD was broadly satisfied with the overall classification system since few recommendations for change were made. Reclassification of methaqualone from Class C to Class B was accepted by the Government, but moving cannabis and cannabis resin from Class B to Class C was not.

3.5.2  The Independent Enquiry into the MDAct (2000) In the 20 years that followed the 1979 review, many more substances were added to the MDAct and the generic controls were extended. But few questions were raised about classification. In the absence of any further scrutiny by the ACMD, the Police Foundation, a body independent of the Government, decided to commission its own review of the MDAct in the late 1990s. This became the Independent Enquiry into the MDAct (The Runciman Committee) with a remit to examine the changes that had taken place in society in the 30 years since the MDAct appeared and to ask whether the legislation needed to be revised to make it both more effective and more responsive to those changes. Their report16 was published in 2000; it made many recommendations covering enforcement, offences, treatment and research. For the classification system, it recommended that the three-­Class approach should be retained and that there should be clear criteria for additions to and transfers between the classes. Apart from cannabis and cannabis resin, which should be transferred from Class B to Class C, the Independent Enquiry also recommended that a number of other controlled drugs should be reclassified. It proposed that ecstasy and related compounds should be moved from Class A to B, LSD from Class A to B, and buprenorphine from Class C to B. However, the Government of the day did not accept any of the recommendations concerning drug reclassification. Although it would be included in risk assessment exercises carried out by the ACMD after 2000, there has been little subsequent debate about the status of LSD. This may be partly a reflection that its use has become less common. Buprenorphine is an opioid analgesic used clinically as a pre-­medication and an adjunct to anaesthesia as well as in the treatment of drug dependence. It was considered by the ACMD in 2002 and again in 2005, and reclassification (to Class B) was supported. In the light of a review by the ACMD in 2006, information emerged that buprenorphine was increasingly used as an alternative to methadone in treating drug dependence, as well as an analgesic in veterinary medicine. In the meantime, buprenorphine had also been considered by the Expert Committee on Drug Dependence (ECDD), part of the WHO, whereby no change had been recommended in its status under the UN 1971 Convention. There was little evidence that it was being more widely abused in the UK, and therefore the original proposal for reclassification was abandoned. Thus, buprenorphine remains in Class C.

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Chapter 3

3.5.3  Home Affairs Select Committee (2001–2) The Home Affairs Select Committee is appointed by the House of Commons to examine the expenditure, administration and policy of the Home Office and the Lord Chancellor's Department (now part of the Ministry of Justice) and certain other public bodies. The Committee chooses its own areas of investigation. For its third report of the session 2001–2, it investigated drugs policy.17 This wide-­ranging inquiry made two recommendations about drugs classification. Firstly, it supported the Home Secretary's proposal of 2001 to reclassify cannabis from Class B to Class C. Secondly, and echoing the findings of the Independent Enquiry into the MDAct, it recommended that ecstasy (MDMA) should move from Class A to Class B. The latter was again rejected by the Government largely on the alleged fatal toxicity of MDMA. As would be repeated on later occasions, it was stated that: ‘The Government has no intention of reclassifying ecstasy. Ecstasy can and does kill unpredictably; there is no such thing as a “safe dose”. The Government firmly believes that ecstasy should remain a Class A drug.’ This focus on the toxicity of ecstasy reflected public concern following a number of high profile deaths, most notably that of a young woman named Leah Betts. It later transpired that this death had been caused by hyponatraemia from drinking too much water. As would be later demonstrated, the fatal toxicity of MDMA was similar to that of amphetamine.18 As controversially expressed by Nutt,19 the use of MDMA led to fewer deaths than horse riding, causing the Home Secretary of the day (Jacqui Smith) to state, equally controversially, that deaths from legal activities cannot be compared to illegal activities.

3.5.4  Select Committee on Science and Technology (2006) As part of a wider investigation into the provision of expert advice to the Government, the Parliamentary Select Committee on Science and Technology examined the drug classification system and the role played by the ACMD. In their report,20 a number of deficiencies were identified. There was specific criticism of the activities of the ACMD including a lack of transparency and apparently muddled thinking in its decision to reclassify methylamphetamine from Class B to Class A so soon after its own report recommended that no change of status was required. The classification of drugs was considered to be generally inconsistent, and the Government was criticised for using the ABC system to send a signal to users and society at large that was at odds with the stated objective of classifying drugs on the basis of harm. The Government was criticised for using the Drugs Act 2005 to make fresh ‘magic mushrooms’ a Class A drug: a mechanism that contravened the spirit of the MDAct by giving the ACMD no formal opportunity to consider the matter. There was little evidence that classification had a deterrent effect, and the system was described as ‘not fit for purpose’. In the view of the Committee, it should be replaced with a science-­based scale of harm decoupled from penalties. The report concluded that there should be a thorough review of the

Primary UK Drugs Legislation up to 1971

27

current system as proposed by the former Home Secretary in early 2006. As an annex to their report, the Committee included an early version of a publication on a scale of drug harm, which is described in more detail in Chapter 24. Among specific points, the Select Committee recommended that there should be an urgent review of the legal status of ecstasy.

3.5.5  Royal Society of Arts Report (2007) Although making no specific suggestions regarding reclassification, the report of the Royal Society of Arts Commission on Illegal Drugs, Communities and Public Policy21 provided a critique of the MDAct, arguments for and against legalisation and options for change. However, the latter were largely influenced by the recently-­completed report from the Parliamentary Select Committee on Science and Technology and the subsequently-­published Scale of Drug Harm (Chapter 24). But even without anything particularly novel arising from this review, it says much about the state of drug policy in the UK in the early years of the 21st century that the Royal Society of Arts felt there was a need to add yet a further voice to a debate already crowded with reviews.

3.5.6  Demos Report ‘Taking Drugs Seriously’ (2011) This report22 was strongly influenced by the rapid appearance of new psychoactive substances (NPS) in the UK and predated the use of Temporary Class Drug Orders and the Psychoactive Substances Act 2016. It was considered that the traditional approaches to drug control were not working. The report recognised how attitudes to drug misuse were entrenched among policymakers and the wider population with differing views on what the objectives of drug control should be. It was noted that there is no clear evidence that classifying a substance through the MDAct reduces overall harms. This bias may unintentionally increase harms, in addition to leading to substantial financial costs in the criminal justice system. The report recommended that alternative methods of drug control should be investigated.

3.5.7  Home Affairs Select Committee (2012) Some of the recommendations of this review23 related specifically to the MDAct. It was suggested that ‘…there is now, more than ever, a case for a fundamental review of all UK drugs policy in the international context, to establish a package of measures that will be effective in combating the harm caused by drugs, both at home and abroad. We recommend the establishment of a Royal Commission to consider the best ways of reducing the harm caused by drugs in an increasingly globalised world’. However, no such Royal Commission was instituted.

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Chapter 3

3.5.8  A  ll-­Party Parliamentary Group for Drug Policy   Reform (2013) As with the Demos report noted above, this was again focussed on NPS. In the conclusions of their report (Toward a Safer Drug Policy: Challenges and Opportunities arising from ‘legal highs’),24 the Group stated ‘The aim of the 1971 Misuse of Drugs Act, as explained by the Home Secretary at that time, was to divide drugs according to their accepted dangers, in the light of current knowledge, and to provide for classification changes to be made in the light of new scientific knowledge. This aspiration has not been fulfilled. Politicians of any political persuasion are reluctant to downgrade the classification of any drug as new evidence emerges which would support such a decision. The result is that relatively less harmful drugs like ecstasy and cannabis are inappropriately classified (Class A and Class B respectively). … Inevitably, the classification system has therefore fallen into disrepute’.

3.5.9  Royal Society for Public Health (2016) In the recommendations of their report (‘Taking a new line on drugs’), the Royal Society for Public Health25 concluded that: illegal drugs strategy should be transferred to the Department of Health; that evidence-­based drug harm profiles and rankings should inform strategies and enforcement priorities rather than the current A, B, C legal classification; and the personal possession and use of illegal substances should be decriminalised.

3.5.10  Royal Society of Arts (2017) In this short personal report by R. Cowan, MP (‘High Time for Changing Drug Policy’),26 it was noted that ‘the Misuse of Drugs Act was signed in 1971 when there were estimated to be 1,300 people who had a problem with drugs. After 46 years of coming down hard on users and jailing people for possession that number has risen to 380,000’.

3.5.11  H  ouse of Commons Health and Social Care Committee: Drugs Policy (2019) Among a number of conclusions,27 it was recommended that there was a clear need for evidence-­led policy on drugs. The Committee supported a consultation on the decriminalisation of drug possession for personal use by changing it from a criminal offence to a civil matter.

3.5.12  Independent Review of Drugs by Dame Carol Black (2021) The objective of this review was to examine the harm that drugs cause and look at prevention, treatment and recovery.28 There was no specific requirement to examine the classification system within the MDAct.

Primary UK Drugs Legislation up to 1971

29

3.5.13  P  roblem Drugs Bill: A Private Members' Bill Tabled by Tommy Sheppard MP (2021) This was tabled in March 2021 29 and proposed a review of the MDAct. Some of the key points were    ●● to transfer lead responsibility from the Home Office to the Department for Health and Social Care in England; ●● review the ‘structure and utility’ of the drug classification system; ●● decriminalisation of the possession of small quantities of drugs; ●● safer drug consumption facilities.    However, the Bill failed to complete its passage through Parliament before the end of the session and will therefore make no further progress.

3.6  Substances Removed and/or Reinstated In the past 40 years, the scope of the MDAct has increased to encompass many new substances. Indeed, the generic definitions discussed in Chapter 8 theoretically cover an infinite number. Yet in all this time, only five drugs have been removed from control, three of which were later reinstated. Only prolintane and propylhexedrine have been permanently removed from control (Table 3.3). Dexamphetamine (Class B) was also removed as a named substance in 1985 (S.I. 1995), but only because by then it fell to control as a stereoisomer of amphetamine. Of the hundreds of named substances in the MDAct, most are never misused. One reason for their retention is that they are still listed in the UN 1961 or 1971 Conventions and no substance has ever been removed from international control. A second reason lies closer to home and is well-­ illustrated by the history of pemoline. This anorectic drug was controlled by the MDAct (and was originally included in the DPMA of 1964) because of its potential for abuse, but licensed products containing pemoline were no longer available by the early 1970s in the UK. Pemoline was therefore Table 3.3  Substances  that have been removed or reinstated since 1971. Substance

Original control

Removed

Reinstated

Fencamfamin

1971 Act Class C 1971 Act Class C 1971 Act Class C 1971 Act Class C 1986 (S.I. 2230) Class C

1973 (S.I. 771)

1973 (S.I. 771)

1986 (S.I. 2230) Class C 1989 (S.I. 1340) Class C 1985 (S.I. 1995) Class C N/A

1995 (S.I. 1966)

N/A

Pemoline Phentermine Prolintane Propylhexedrine

1973 (S.I. 771) 1973 (S.I. 771)

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Chapter 3

removed from the MDAct in 1973. Within a few years, illicit manufacturers began to produce pemoline tablets. Eventually, pemoline was brought under the scope of Schedule IV of the UN 1971 Convention and pemoline was reintroduced into the MDAct in 1989. Apart from pemoline, phentermine and fencamfamin (both of which had been listed in the DPMA of 1964) were also removed only to be later reinstated. The moral of this episode is that it is probably safer to leave substances under control even when they cease to be an immediate social problem. Unless the pharmaceutical industry should wish to reactivate ‘old’ drugs, their retention causes no problems. Because of commitments to the UN, there is in any case only limited scope to remove further substances. Two obvious candidates stand out in the MDAct, namely chlorphentermine and mephentermine. They are both in Class C and were originally brought under UK control in the DPMA of 1964. Neither is listed in the UN 1971 Convention and both have long ceased to be available in medicinal products in the UK. However, as with pemoline, their removal could send a signal to clandestine manufacturers.

3.7  Cannabis: Classification and Reclassification Before the MDAct came into force, the UK Advisory Committee on Drug Dependence, a body that preceded the current ACMD, produced a report in 1969 (The Wootton Report)30 that was entirely focussed on cannabis. One of the conclusions in the report was:    ‘The long term consumption of cannabis in moderate doses has no harmful effects (…) Cannabis is less dangerous than the opiates, amphetamines and barbiturates, and also less dangerous than alcohol. (…) An increasing number of people, mainly young, in all classes of society are experimenting with this drug, and substantial numbers use it regularly for social pleasure. There is no evidence that this activity is causing violent crime, or is producing in otherwise normal people conditions of dependence or psychosis requiring medical treatment (…) there are indications that (cannabis) may become a functional equivalent of alcohol’.    As will be seen later, this assessment of the relatively minor harms of cannabis has been reiterated many times by successive reviews. Yet that 1969 report was largely rejected by the Government of the day. There appear to be few documentary records of how the UK came to adopt the two-­dimensional approach to drug control, i.e., the concept that the legal status of every controlled substance was defined by both a Schedule in the Misuse of Drugs Regulations and a Class in the MDAct. In a statement by the Home Secretary (James Callaghan) in 1970, the purpose of introducing drug Classes was: ‘… to make, so far as is possible, a more sensible differentiation between drugs. It will divide them according to their dangers and harmfulness in the light of current knowledge and it will provide for changes to be made in the classification in the light of new scientific knowledge’. There is no clear reason why a three-­Class

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31

system was adopted. Anecdotal accounts from the late 1960s and early 1970s, when the Misuse of Drugs Bill was being debated, suggest that the Government's plan was to have a two-­Class approach. Although the terms are now largely obsolete, the idea may have arisen because, at the time, there was a commonly held view that drugs of abuse could be divided into ‘hard drugs’ and ‘soft drugs’. These terms are in any case ambiguous, since in medicinal chemistry ‘hard drug’ can refer to a substance that is not metabolised, while a ‘soft drug’ is a substance that is degraded in vivo to non-­toxic, inactive metabolites. However, the question of where to place cannabis and cannabis resin in this structure is said to have caused so much debate that a compromise was reached whereby cannabis became Class B such that ‘hard drugs’ were placed in Class A and the ‘soft’ substances were distributed between Class B and a new Class C. At that time, the question of cannabis was often associated with the aphorism that ‘Everything starts and finishes with cannabis’. Whatever the truth, when the MDAct came into force, Class B contained only 14 named entries and Class C contained ten. By contrast, there were over 90 named substances in Class A. There is some suggestion that the classification was based on ad hoc rules such as ‘all narcotic analgesics and hallucinogens belong in Class A, but amphetamine-­ type stimulants should be in Classes B and C’. It should be noted that the classification system is entirely independent of scheduling under the 1961 and 1971 United Nations Conventions; movements between classes is a purely domestic issue. However, during the ACMD review of MDMA in 2009 31 that did not prevent the late Hamid Ghodse, an official from the United Nations, writing to the Home Office disapproving of any attempt to reclassify MDMA. In late 2001, the Home Secretary (David Blunkett), giving evidence to the Parliamentary Home Affairs Committee, announced that the Government was proposing that cannabis and cannabis resin should be reclassified as Class C drugs. In large measure, this proposal was prompted by the amount of police time spent processing relatively minor cannabis offences, when they were expected to focus enforcement efforts on Class A drugs. It was also recognised that police activity against cannabis users was antagonising many young people. As would happen again in later years, the political proposal often appeared to pre-­empt a recommendation by the ACMD. But reclassification of cannabis, cannabis resin and the ‘cannabinols’ was supported by the ACMD.32 There was no intention that cannabis, cannabis resin or the ‘cannabinols’ should be rescheduled with respect to the Regulations; they would remain in Schedule 1 which contains substances with no recognised medicinal value. In his speech in 2001, David Blunkett had stressed that reclassification would not amount to legalisation or decriminalisation, but later events showed that large sections of the public or the media had difficulty in distinguishing these concepts from reclassification. It is apparent that the initial enthusiasm for reclassification became tempered in 2003. Firstly, following the ACMD report of March 2002, a Modification Order was not published until 2003 33 and did not come into force until 29 January 2004. Secondly, and much more significantly, the penalties for

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certain offences involving Class C drugs were changed on the same day by the Criminal Justice Act 2003.34 This allowed the power of arrest to be used for the possession of cannabis, whereas before reclassification, the possession of a Class C drug was not an arrestable offence. The maximum prison sentence for supplying any Class C drug was increased from five years to 14 years, i.e., similar to the penalty associated with Class B drugs. These measures were seen as immediately negating part of the impact of reclassification. Although the maximum prison sentence for possessing cannabis was simultaneously reduced from five years (as a Class B) drug to that of a Class C drug, i.e., two years, there had never been many instances of imprisonment for simple possession of any Class C drug. In early 2005, the Home Secretary (Charles Clarke) asked the ACMD to consider whether it had changed its position from that set out in its March 2002 report in the light of new evidence that associated cannabis with mental health problems and the prevalence of new varieties of cannabis with high levels of THC. Following a further review by the ACMD in 2005, its report in 2006 35 supported the retention of cannabis and ‘cannabinols’ in Class C. The Government's somewhat reluctant decision to accept the recommendations of the 2005 report on cannabis gave rise in January 2006 to a proposal by the Home Secretary (Charles Clarke) that there should be a review of the entire drug classification system. It was felt that the system had been in operation for 35 years, had never been fully reviewed and was not completely understood by the public. It was believed, at the time, that the Government favoured a two-­Class system, an idea that had been originally advocated in the late 1960s. However, later that same year, Charles Clarke left his post as Home Secretary. His replacement as Home Secretary (John Reid) quickly abandoned the proposed review of drug classifications citing lack of evidence amongst the major stakeholders that this was a high priority issue. The year 2007 brought a new Home Secretary (Jacqui Smith) and yet another call for the ACMD to re-­investigate the status of cannabis. As has happened before with initiatives in the drug control field, this latest move was not entirely unconnected with wider political imperatives. On this occasion, it was the Prime Minister (Gordon Brown) who chose to announce the need for the review, and again pre-­empted the outcome of a 2008 review36 by claiming that cannabis should be moved to Class B. There was a growing concern about the harmfulness of cannabis. This was based on: the apparently strengthening evidence that cannabis was a causative agent for chronic psychosis, particularly schizophrenia; the fact that high potency forms (sinsemilla/skunk) were now the dominant market product (Chapter 17); and increasing evidence of dependence and the social harms caused by the recent and rapid proliferation of large indoor cannabis farms and their association with organised crime. The recommendation of the ACMD36 was that cannabis should stay in Class C, but in May 2008 the Government decided that ‘cannabis products’ should be reclassified to Class B. This took effect in 2009 (Appendix 2). In ignoring the advice of the ACMD, the Home Secretary used the precautionary principle and admitted ‘erring on the side of caution’ in

Primary UK Drugs Legislation up to 1971

33

Table 3.4  Classification  of cannabis (1971–2008). Statute/Enquiry/Review body Year

Recommendation Government response

MDAct ACMD The independent enquiry into the MDAct ACMD Home affairs select committee ACMD ACMD

1971 1979 2000

Place in class B Move to class C Move to class C

Rejected Rejected

2002 2002

Move to class C Move to class C

Accepted Accepted

2006 2008

Retain in class C Retain in class C

Accepted Rejected – moved to class B

relation to the possible harmful effects of cannabis on the mental health of future generations. Together with reclassification, the Home Secretary also announced other measures to tackle cannabis misuse which included: more robust enforcement against cannabis supply and possession, for example, those repeatedly caught with the drug will not just receive warnings; a new strategic and targeted approach to tackling cannabis farms and the organised criminals behind them; introducing additional aggravating sentencing factors for those caught supplying cannabis and other illegal substances near further and higher educational establishments, mental health institutions and prisons; and working with the Association of Chief Police Officers to look at how existing legislation and powers can be used to curtail the sale and promotion of cannabis paraphernalia. That re-­examination of cannabis is likely to be the last for some time. Although one of the recommendations of the 2008 ACMD report36 was that there should be a further review in 2010, it was doubtful that there would be any political will for this to happen. Furthermore, it seems that high potency cannabis will remain the dominant product for some time. It is also improbable that our understanding of the harms caused by cannabis, particularly harms to mental health, will be further increased by yet more epidemiological studies. Since 1979, when the ACMD first recommended that cannabis should be moved to Class C, a period when our knowledge about the effects of and use of cannabis have increased dramatically, the ACMD has been remarkably consistent in its view on classification. Table 3.4 summarises the various recommendations for the classification of cannabis that have been made over nearly 40 years. In that table, the term cannabis is used as a shorthand for herbal cannabis, cannabis resin, and from 2002, cannabinol and cannabinol derivatives.

3.8  The Classification of MDMA Certain amphetamine derivatives including MDMA (ecstasy) were added to the MDAct in 1977 as part of a wider generic control of ring-­substituted phenethylamines (Chapter 8). At the time, the inclusion of these substituted

34

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phenethylamines in Class A was a not unreasonable precautionary measure since little was known about their harmful effects, and misuse, at least in the UK, was almost unknown. Although ecstasy would not become common in the UK for another ten years, and much later in some European countries, MDMA is now viewed by many as much less harmful than most of the substances in Class A. In the light of 20 years' experience, and despite animal studies which showed that MDMA acutely depleted serotonin levels and caused pruning of axons, it is probably safe to conclude that there are now fewer concerns about long-­term neurotoxicity. In their 2006 report,20 the Select Committee on Science and Technology recommended that the ACMD should review the status of ecstasy. This was carried out in 2009 by the ACMD, with the recommendation that MDMA should move from Class A to Class B.31 However, that was not accepted by the Government. Until that time, the classification of LSD, some or all benzodiazepines and ‘magic mushrooms’/ psilocin were considered as likely possibilities for more detailed investigation by the ACMD. However, following the MDMA review, there was little enthusiasm for these systematic reviews to take place.

3.9  The Precautionary Principle In the United Nations system, drug scheduling requires that the substance to be controlled has been shown to be harmful. Since this is not always possible to demonstrate, one solution would simply be to allow the substance to remain outside legal control. Yet for many governments that course of action seems unacceptable; there is a belief that the precautionary principle should be invoked. In other words, if there is doubt, then the safest option is to introduce some form of control. This is sometimes guided by the proposition that if harms are unknown, then if the substance cannot be shown to be safe it should be restricted. In reality, demonstrating that a substance is safe can be an impossible task. In other words, new substances are guilty until proven otherwise. That was the position taken during the EMCDDA risk assessment of BZP in 2007. A persuasive argument leading to its ultimate EU-­wide control was based on the fact that there was no evidence that BZP was safe. The precautionary principle has its origins in environmental protection and food safety and became a means of protecting the public from the activities of commercial and industrial concerns. As discussed by Nutt,37 the precautionary principle when applied to drug control suffers from a number of weaknesses. These include: the risk of causing more harm by criminalising users than is caused by the substance itself; distorting markets; entrenchment of a moral attitude to drug use; and encouraging other drug use. In the latter respect, Nutt gave the example of mephedrone. Before it became controlled, there was evidence that it was being used by those who would otherwise have used cocaine. Once mephedrone became a Class B drug that displacement effect ceased. Yet there is little doubt that cocaine is a much more harmful substance than mephedrone. There is the danger that the precautionary principle can also override the scientific risk assessment process.

Primary UK Drugs Legislation up to 1971

35

The European Commission counselled against the overuse of the principle and has stated that: ‘the implementation of an approach based on the precautionary principle should start with a scientific evaluation, as complete as possible, and where possible, identifying at each stage the degree of scientific uncertainty’.38 It could be argued that the proper use of the precautionary principle is in situations where little information on risk is available, and the proper course of action is to err on the side of caution. That might describe, for example, the situation with MDMA and other ring-­substituted phenethylamines in 1977, long before they were widely used, when they were placed in Class A. But in the case of cannabis, and despite the large amount of published data, there is still no certain answer to basic questions such as does cannabis use lead to chronic psychosis or is high potency cannabis necessarily more harmful. With this continued lack of knowledge, it is not entirely surprising that political reaction might be guided by caution. It might also be said that the ACMD itself has not been fully consistent in its arguments. Thus, it invoked the precautionary principle when proposing that methylamphetamine should move to Class A in 2006 (Chapter 15). One could say that if it was right to move methylamphetamine to Class A on the basis of caution, as they proposed, and at a time when there was hardly any misuse of that drug in the UK, then the same precautionary approach should have been used for cannabis in 2008. In other words, to be consistent, the ACMD should have recommended that cannabis should move from Class C to Class B. Instead, the ACMD ignored the precautionary principle on that occasion.

3.10  Conclusions Considerable time and energy have been expended in the UK, particularly since 2002, on the classification of cannabis, and to a lesser extent MDMA. Despite three major reviews and an intermediate period when its status was changed, cannabis is now back to where it was in late 2003 and had been since 1971. The irony of this situation is exposed by the way in which cannabis offenders are treated. There is a clear disconnect between de jure and de facto; while cannabis is a Class B drug in the statute, when it comes to the less serious offence of possession, it is often seen as a Class C drug. This anomaly has increased in recent years with cannabis offenders often dealt with by an ‘Out of Court Disposal’ such as a caution or a ‘community resolution’,39 actions which are far less common with other controlled drugs. Whatever one's views on cannabis, this situation is unsatisfactory; justice is not best served by allowing law enforcement agencies to determine penalties when there is a wide geographical disparity, particularly in the use of community resolutions. The placing of substances into three classes was a fairly arbitrary process since no formal risk assessment was conducted. Not only have few substances been reclassified, but almost all that have changed their status have been moved to a higher Class. This effect has been described as the ‘drugs ratchet’.40 Table 3.5 shows substances that have been reclassified since 1971.

Chapter 3

36

Table 3.5  Substances  that have been reclassified (1971–2020). Substance Nicodicodine Methaqualone Methylamphetamine Pipradrol Cannabinol and cannabinol derivatives Cannabis and cannabis resin Ketamine

Original class

Reclassified Date (modification order)

A C B C A C B C C

B B A B C B C B B

1973 (S.I. 771) 1984 (S.I. 859) 2006 (S.I. 3331) 2012 (S.I. 1390) 2003 (S.I. 3201) 2008 (S.I. 3130) 2003 (S.I. 3201) 2008 (S.I. 3130) 2014 (S.I. 1106)

The only substances to have been permanently moved down in that time are nicodicodine, cannabinol and cannabinol derivatives, none of which could be described as commonly misused. The final words of James Callaghan's 1970 statement concerning changes to be made in the classification in the light of new scientific knowledge may now have a hollow ring; the passage of time has led to a great increase in scientific knowledge of drugs matched only by a corresponding ossification of their classification. This inertia against change has not been helped by the absence of any procedure for monitoring the impact of modifications to the MDAct. Part of the problem is that the classification system is a blunt weapon, and many other factors influence drug misuse beyond the potential legal consequences for offenders. Many observers have concluded that the system is largely impervious to change and should be replaced for that reason alone, although another argument would say that the system has not needed to change because the architects of the classification scheme got it almost right all those years ago. The classification system has clearly been used by different stakeholders for different purposes. The original intention was to create a scale of penalties. In principle, this should have been based on the relative harmfulness of controlled drugs, but later work would show that the correlation between Class and either social or individual harm was weak. For politicians, classification has been a means of showing that they are ‘tough on drugs’ and a convenient tool to spread messages about drug harm, some of which may not always have been based on sound scientific evidence. More cynical observers would say that reclassification has become a political football, which often comes into play shortly before elections or is used as a distraction from other events. For the police and customs, particularly after the appearance of a drug strategy in the late 1990s, it became a means of prioritising law enforcement activity against those drugs associated with the greatest social harm, i.e., certain Class A drugs. It is clear that members of the public have only a limited concept of which drugs are in which classes, and it has been suggested that most drug users are either

Primary UK Drugs Legislation up to 1971

37

unaware or are unconcerned about a drug's classification. In the popular mind, the concept of reclassification has either meant reclassification to a lower Class or, more commonly, has been totally confused with declassification or even legalisation. There is little doubt that the reclassification of cannabis in 2004 led to at least an initial confusion about its legal status. This was not helped by the way in which the reclassification was bundled with a realignment of the penalties associated with Class C drugs. These events together led to a common view amongst criminal lawyers that the system had degenerated into a two-­Class system, i.e., Class A drugs and everything else. Given that heroin and cocaine account for almost all of the social harm associated with drug misuse, the emerging de facto two-­Class system could even be described as cocaine and heroin versus the rest. As noted earlier, a two-­Class system was probably the original intention in the late 1960's and was allegedly the favoured solution in the Government's aborted 2006 review.

References 1. Departmental Committee on Morphine and Heroin Addiction (Rolleston Committee), 1926, https://en.wikipedia.org/wiki/Rolleston_Committee, accessed October 2021. 2. Drugwise, UK Drug Scene Timeline 1960–1994, https://www.drugwise. org.uk/wp-­content/uploads/druglinktimeline-­1.pdf, accessed October 2021. 3. The Drugs (Prevention of Misuse) Act 1964, https://www.parliament.uk/ about/living-­heritage/transformingsociety/private-­lives/relationships/ collections1/parliament-­a nd-­t he-­1 960s/dangerous-­drugs-­a ct-­1 964/, accessed October 2021. 4. The Drugs (Prevention of Misuse) Act 1964, Modification Order 1970, https://www.legislation.gov.uk/uksi/1970/1796/pdfs/uksi_19701796_ en.pdf, accessed October 2021. 5. G. F. Phillips, Chem. Br., 1972, 123. 6. L. A. King. Forensic Chemistry of Substance Misuse: A Guide to Drug Control, Royal Society of Chemistry, London, 2009, ISBN 978-­0-­85404-­178-­7. 7. Home Office, Controlled drugs list, https://www.gov.uk/government/ publications/controlled-­drugs-­list–2, accessed October 2021. 8. United Kingdom Government, https://www.legislation.gov.uk/, accessed October 2021. 9. Scitegrity, https://www.scitegrity.co.uk/index.php?page=cs2, accessed October 2021. 10. R. Fortson, Crim. Law Today, 2011, Issue 2. 11. Sentencing Council, https://www.sentencingcouncil.org.uk/, accessed October 2021. 12. G. Monaghan, personal communication. 13. D. Nutt, Nutt Uncut, Waterside Press, Sherfield on Loddon, Hampshire, UK, 2020, ISBN 978-­1-­909976-­85-­6.

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14. Police Reform and Social Responsibility Act 2011, https://www. legislation.gov.uk/ukpga/2011/13/contents, accessed October 2021. 15. Advisory Council on the Misuse of Drugs, 1979, Report on a Review of the Classification of Controlled Drugs and of Penalties under Schedule 2 and 4 of the Misuse of Drugs Act 1971. 16. Drugs and the Law: Report of the Independent Inquiry into the Misuse of Drugs Act 1971, The Police Foundation, London, 2000, https://www. police-­foundation.org.uk/publication/inquiry-­into-­drugs-­and-­the-­law, accessed October 2021. 17. House of Commons Select Committee on Home Affairs, 2002, The Government’s Drugs Policy: Is it Working?, https://publications.parliament.uk/ pa/cm200102/cmselect/cmhaff/318/31804.htm, accessed October 2021. 18. L. A. King and J. M. Corkery, Hum. Psychopharmacol., 2010, 25, 162. 19. D. J. Nutt, J. Psychopharmacol., 2009, 23(1), 3. 20. House of Commons Select Committee on Science and Technology, 2006, Drug classification: making a hash of it?, https://publications. parliament.uk/pa/cm200506/cmselect/cmsctech/1031/1031.pdf, accessed October 2021. 21. Drugs: Facing Facts: The Report of the RSA Commission on Illegal Drugs, Communities and Public Policy, Royal Society of Arts, London, 2007, ISBN 978-­0-­901469-­60-­1. 22. Demos, 2011, Taking Drugs Seriously, https://demos.co.uk/project/ taking-­drugs-­seriously/, accessed October 2021. 23. House of Commons Select Committee on Home Affairs, 2012, Drugs: Breaking the Cycle, https://publications.parliament.uk/pa/cm201213/ cmselect/cmhaff/184/18402.htm, accessed October 2021. 24. All-­Party Parliamentary Group for Drug Policy Reform, 2013, Report of an Inquiry into new psychoactive substances, https://docs.google. com/file/d/0B0c_8hkDJu0DODg3UXpfa2U0SFk/edit?resourcekey=0-­ v8mQJu0bCklmSVxdvevjlw, accessed October 2021. 25. Royal Society for Public Health, 2016, Taking a new line on drugs, https://w w w.rsph.org.uk/static/uploaded/36dfae8b-­7 b10-­4 b28-­ 9f6776743003e1a1.pdf, accessed October 2021. 26. High Time for Changing Drug Policy, Royal Society of Arts, 2017, https:// www.thersa.org/comment/2017/07/high-­time-­for-­changing-­drug-­policy, accessed October 2021. 27. House of Commons Health and Social Care Committee, Drugs Policy, 2019, https://publications.parliament.uk/pa/cm201919/cmselect/ cmhealth/143/143.pdf, accessed October 2021. 28. C. Black, 2021, Review of drugs part two: prevention, treatment and recovery, https://www.gov.uk/government/publications/review-­of-­drugs-­ phase-­t wo-­report, accessed October 2021. 29. Transform, 2021, Problem Drugs Bill: A private members Bill tabled by Tommy Sheppard MP, https://transformdrugs.org/blog/new-­drug-­ reform-­bill-­tabled-­in-­parliament, accessed October 2021.

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30. The Wootton Report, 1969, https://en.wikipedia.org/wiki/Wootton_, accessed October 2021. 31. Advisory Council on the Misuse of Drugs, 2009 MDMA ('ecstasy') review, https://www.gov.uk/government/publications/mdma-­ecstasy-­review, accessed October 2021. 32. Advisory Council on the Misuse of Drugs, 2002, The Classification of Cannabis under the Misuse of Drugs Act 1971, https://assets.publishing. service.gov.uk/government/uploads/system/uploads/attachment_data/ file/119126/cannabis-­class-­m isuse-­drugs-­a ct.pdf, accessed October 2021. 33. The Misuse of Drugs Act 1971 (Modification) (No. 2) Order 2003, S.I. 3201, https://www.legislation.gov.uk/uksi/2003/3201/contents, accessed October 2021. 34. The Criminal Justice Act 2003, https://www.legislation.gov.uk/ukpga/ 2003/44/contents, accessed October 2021. 35. Advisory Council on the Misuse of Drugs, 2006, Further consideration of the classification of cannabis under the Misuse of Drugs Act 1971, https://assets.publishing.service.gov.uk/government/uploads/system/ uploads/attachment_data/file/119124/cannabis-­r eclass-­2 005.pdf, accessed October 2021. 36. Advisory Council on the Misuse of Drugs, 2008, Cannabis: Classification and Public Health, https://assets.publishing.service.gov.uk/government/ uploads/system/uploads/attachment_data/file/119174/acmd-­cannabis-­ report-­2008.pdf, accessed October 2021. 37. D. Nutt, Precaution or perversion: eight harms of the precautionary principle, https://profdavidnutt.wordpress.com/2010/06/23/precaution-­ or-­perversion-­eight-­harms-­of-­the-­precautionary-­principle/, accessed October 2021. 38. European Commission, The precautionary principle, https://eur-­lex. europa.eu/legal-­c ontent/EN/TXT/HTML/?uri=LEGISSUM:l32042&from=EN, accessed October 2021. 39. Home Office, Reforms to the adult out of court disposals framework in the Police, Crime, Sentencing and Courts Bill: Equalities Impact Assessment, https://www.gov.uk/government/publications/ police-­c rime-­s entencing-­a nd-­c ourts-­b ill-­2 021-­e quality-­s tatements/ reforms-­to-­the-­adult-­out-­of-­court-­disposals-­framework-­in-­the-­police-­ crime-­sentencing-­courts-­bill-­equalities-­impact-­assessment, accessed October 2021. 40. A. Stevens and F. Measham, Addiction, 2014, 109(8), 1226, https://online­ library.wiley.com/doi/10.1111/add.12406, accessed October 2021.

Chapter 4

The Misuse of Drugs Regulations 2001 4.1  Introduction In the MD Regulations, which came into force on 1st February 2002 1 and replaced the previous Regulations of 1985, controlled drugs are divided into five Schedules based on a balance between their value as medicines and their hazards as drugs of abuse. In simple terms, the MD Regulations set out what should be done with controlled drugs whereas the MDAct sets out what should not be done. In broad terms, at least for psychotropic drugs, the Schedules in the MD Regulations correspond to the respective Schedules of the 1971 UN Convention. Whereas it is permitted for a substance listed in the UN 1971 Convention to be placed in a higher Schedule in the Regulations, it is generally accepted that it should not be placed in a lower Schedule. To a large extent, there is agreement between Schedule in the MD Regulations compared to the UN 1971 Convention; only a few are placed in a higher Schedule in the MD Regulations. The connection between the Schedules in the MD Regulations and the Schedules of the UN 1961 Convention is less precise, although the principle still holds that national governments should not permit less stringent controls on substances than those set out in the 1961 Convention. Under the MD Regulations 2001, limits are placed on the manufacture, prescription, storage and record-­keeping of the substances in decreasing order Schedule 1 to Schedule 5. Drugs in Schedule 1 may not be prescribed but can be used under licence in medical and scientific research. Table 4.1 gives examples of the two-­dimensional matrix of UK drug control. Most Class C drugs are found in Schedule 4 and most Class A drugs are found in   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

40

The Misuse of Drugs Regulations 2001

41

Table 4.1  Relationship  between Class in the Misuse of Drugs Act and Schedule in the Regulations for selected substances.

Regulations Class A Schedule 1 Schedule 2 Schedule 3 Schedule 4 Schedule 5

Class B

Class C

Lysergide, MDMA Cannabis, methcathinone Cathinone Diamorphine, Amphetamine, codeine Dextropropoxyphene cocaine — Barbiturates (most) Temazepam, flunitrazepam — — Other benzodiazepines, anabolic steroids ‘Low dose’ ‘Low dose’ codeine ‘Low dose’ dextromorphine propoxyphene

Schedules 1 and 2 of the MD Regulations, but there is otherwise little correlation between the Class of a substance in the MDAct and its Schedule in the Regulations.

4.2  Regulations Relevant to Forensic Science To a large extent, the provisions of the MD Regulations are of most concern to the medical, veterinary and pharmaceutical professions. There are a few instances, detailed below, that are of some interest to a forensic scientist. Here ‘Regulation’ refers to the relevant part of the MD Regulations.

4.2.1  E  xceptions for Drugs in Schedules 4 and 5 and Poppy Straw Regulation 4 reads:    ‘(1) Section 3(1) of the Act (which prohibits the importation and exportation of controlled drugs) shall not have effect in relation to the drugs specified in Schedule 5. (2) The application of section 3(1) of the Act, in so far as it creates an offence, and the application of sections 50(1) to (4), 68(2) and (3) or 170 of the Customs and Excise Management Act 1979, in so far as they apply in relation to a prohibition or restriction on importation or exportation having effect by virtue of section 3 of the Act, are hereby excluded in the case of importation or exportation which is carried out in person for administration to that person of any drug specified in Part II of Schedule 4. (3) Section 5(1) of the Act (which prohibits the possession of controlled drugs) shall not have effect in relation to— (a)  any drug specified in Part II of Schedule 4; (b)  the drugs specified in Schedule 5. (4) Sections 4(1) (which prohibits the production and supply of controlled drugs) and 5(1) of the Act shall not have effect in relation to poppy-­straw.

42

Chapter 4

(5) Sections 3(1), 4(1) and 5(1) of the Act shall not have effect in relation to any exempt product’.    In relation to (3)(a), the drugs in Part II of Schedule 4 comprise mostly anabolic steroids. Before a 2012 Amendment, the text at (3)(a) read: ‘any drug specified in Part II of Schedule 4 which is contained in a medicinal product’. In relation to (3)(b), the drugs specified in Schedule 5, which relates to low-­ dosage preparations, are described in Chapter 25. In relation to (4), poppy straw is discussed in Chapter 26.

4.2.2  Exceptions for Drugs in Schedule 1 Regulation 4A is concerned with exceptions for possession of fungi which contain psilocin or an ester of psilocin (Chapter 26).

4.2.3  E  xceptions for Gamma-­butyrolactone and   1,4-Butanediol Regulation 4B was concerned with exceptions for certain offences involving these substances, but those exceptions will be removed in 2022 (see Chapter 21).

4.3  T  he Impact of the MD Regulations on Scientific Research The restrictive nature of Schedule 1 of the Regulations, and more generally, Schedules I of the UN 1961 and 1971 Conventions, impact on the ability to carry out clinical research with these substances. It is often stated, but not expressly in the legislation, that substances are placed into those Schedules because they have no medical value, or at least have none at the time of scheduling. This becomes a circular problem, because if a substance is in one of those Schedules, then, by definition, it is deemed to have no therapeutic value, rendering any clinical research difficult. A small number of psychoactive drugs, including opiates such as diamorphine, are placed in Schedule 2 of the MD Regulations. This allows them to be used as treatments for medical conditions such as pain. Others, such as cannabis, 3,4-­methylenedioxy-­N-­methylamphetamine (MDMA) and psychedelics, are in Schedule 1, meaning they are controlled more stringently and are therefore not generally available for therapeutic use. This distinction is not based on the relative harms of these drugs; it is simply a reflection of scientific and legal norms of the time. Nutt et al.2–4 have argued that the legal approach to drug control has hindered research into the therapeutic potential of cannabis, stimulants and psychedelic drugs. The UN Conventions make it clear that use of Schedule I substances, such as MDMA, psilocybin and lysergic acid diethylamide (LSD; lysergide), is to be

The Misuse of Drugs Regulations 2001

43

severely restricted. Parties to the Conventions are to ‘prohibit all use except for scientific and very limited medical purposes by duly authorized persons, in medical or scientific establishments which are directly under the control of their Governments or specifically approved by them’. In the United States, this agency is the Drug Enforcement Administration (DEA),5 whose mission it is, in part, to prevent the diversion of controlled substances. In the UK, this control is exercised by the Home Office. Production or use of controlled drugs without such a licence is illegal and can bring severe penalties of up to life imprisonment. The decisions that were made about which drugs should be controlled under this legislation seem to be unclear and inconsistent and may have been made for political rather than health-­related reasons. This is because for many drugs those decisions were made before modern scientific methods allowed a proper understanding of their pharmacology and toxicology. As a result, the listing of MDMA, psilocybin and LSD as UN Schedule I drugs was not based on any consideration of their mental or physical harms but on the assumption that there were no medical benefits. Indeed, analyses (Chapter 24) have suggested that there is little relation between the harms of a range of psychoactive drugs and their current legal status in the UK. In the US, a substance is classified as Schedule I if it meets three criteria. First, the drug or other substance has a high potential for abuse; second, it has no currently accepted medical use; and third, there is a lack of accepted safety for use of the drug or other substance under medical supervision. With regard to the first criterion, the term ‘abuse’ is undefined; it does not mean that the substance must possess the ability to foster dependence or addiction. This criterion could apply to many prescription drugs. In any case, there is no evidence that psychedelics have addictive properties and, in fact, LSD was once recommended to treat other addictions. MDMA similarly has low dependence potential, although some chronic cannabis users can develop dependence. The widespread perception that because a substance is classified as Schedule I, it must pose a significant danger to humans still exists among the general public, and possibly also among neuroscientists. However, this perception is generally incorrect. Importantly, the current regulations are based on this misperception and make research, both basic and clinical, hugely difficult. For example, in the United Kingdom, it is much harder to study MDMA and psilocybin than it is to study heroin, even though heroin is a more dangerous drug in terms of its medical and societal harms than those other drugs. However, the recognised therapeutic properties of heroin allow its medical use in the United Kingdom and hence it is placed in the less restrictive Schedule 2. Current UK regulations permit all hospitals to hold heroin and other opioids but require each individual hospital to obtain a licence for Schedule 1 drugs. Few UK hospitals have such a licence. Applying for a licence takes about a year, costs many thousands of pounds and once granted is subject to regular police reviews. As a consequence, many researchers who would like to work on these pharmacologically-­fascinating substances cannot afford to do so.

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Chapter 4

The regulations apply to any quantity of a drug, so even basic researchers who use only sub-­milligram quantities must comply with them. In addition, if researchers do obtain approval to use the drugs, the rules regarding the storage of the drug in the laboratory are stringent. For example, in a trial of psilocybin for patients with cancer in the United States,6 the researchers were required to ensure that the few milligrams of substance were weighed daily by two people to protect against theft. As far as is known, there are no examples of a significant diversion of research drugs (Schedule I or otherwise) into recreational use. If the investigator can obtain all the necessary approvals and licences for a research study, the problem then becomes how and where to obtain the pharmaceutical substance, as these drugs are not available from standard chemical manufacturers. The cost of custom synthesis is usually prohibitively high and beyond the means of an investigator with a small grant. Furthermore, contract synthesis companies are generally reluctant to prepare Schedule I substances because they in turn require extensive documentation, such as a controlled substance manufacturer's licence and secure storage. What is more, the illegal and presumed dangerous perception of Schedule I drugs appears to be a powerful deterrent to grant-­giving bodies. University and hospital ethics committees are similarly hesitant and obtaining approvals for studies into these drugs is often protracted and difficult. The justification for the continued illegal status of cannabis includes claims of harms such as lung disease associated with smoking the substance, schizophrenia and addiction. Such harms undoubtedly exist, but they are frequently exaggerated. Overall, cannabis is less harmful than other popular drugs, such as alcohol (Chapter 24). In the UK, MDMA and related compounds are in Schedule I. However, a recent analysis challenged the publicly held view that MDMA has a relatively high fatal toxicity.7 Recently, it has been found that psilocin has therapeutic value in the treatment of depression.8 The above concerns were published in 2013,3 since when the regulatory system in the UK has not changed. However, in February 2020, the ACMD called for evidence on whether research involving 3rd generation synthetic cannabinoids may have been impeded by regulatory controls. That report was published in July 2021.9 The recommendations of that report are discussed in Chapter 18. In March 2021, the ACMD announced it was collecting written evidence from researchers regarding barriers to legitimate research with controlled drugs, other than synthetic cannabinoids, for its second report on barriers to research.10

References 1. The Misuse of Drugs Regulations 2001, https://www.legislation.gov.uk/ uksi/2001/3998/contents, accessed October 2021. 2. D. Nutt and L. A. King, How the drug laws impede advances in health and science, in Reframing Addiction: Policies, Processes and Pressures, ed. P. Anderson, G. Bühringer and J. Colom, The ALICE RAP project, 2014, ch. 9, pp. 91–102, ISBN: 978-­84-­697-­1647-­2. www.alicerap.eu, accessed October 2021.

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3. D. J. Nutt, L. A. King and D. E. Nichols, Nat. Rev. Neurosci., 2013, 14, 577. 4. D. J. Nutt, L. A. King and D. E. Nichols, Nat. Rev. Neurosci., 2013, 14, 877. 5. Drug Enforcement Administration, https://www.dea.gov/, accessed October 2021. 6. S. Ross, personal communication. 7. L. A. King and J. M. Corkery, Hum. Psychopharmacol. Clin. Exptl., 2010, 25, 162. 8. R. L. Carhart-­Harris, M. Bolstridge and J. Rucker, et al., Lancet Psychiatry, 2016, 3(7), 619. 9. Advisory Council on the Misuse of Drugs, Consideration of barriers to research. Part 1. Synthetic cannabinoid receptor agonists (SCRA), 2021, https://www.gov.uk/government/publications/consideration-­of-­barriers-­ to-­research-­part-­1, accessed October 2021. 10. Advisory Council on the Misuse of Drugs, Call for Evidence – Barriers to research for controlled drugs (excluding synthetic cannabinoids), 2021, https://www.gov.uk/government/publications/barriers-­t o-­r esearch-­ beyond-­cannabinoids-­call-­for-­evidence, accessed October 2021.

Chapter 5

UK Drugs Legislation since 1971 5.1  Drugs Act 2005 The Drugs Act 2005 1 had several objectives. One of these (Section 21 of that Act) was intended to clarify the law regarding ‘magic mushrooms’ (see Chapter 26). But Section 2 was a more controversial part of the Act. This created a new presumption of intent to supply where a defendant is found to be in possession of more than a certain quantity of controlled drugs. The controversy largely centred on what was tantamount to the idea that a defendant might be guilty of a certain offence unless proved otherwise. For Section 2 to operate, threshold amounts would have to be set for the main drugs of misuse. In the event, and following much consultation, it proved to be difficult to reach any consensus on what those thresholds should be. Arguments ranged from how the Courts would not be able to use their discretion and take other facts into consideration and fundamental legal issues raised by the reverse burden of proof, to the fact that amounts of drug for personal use might vary both geographically and in time. It was also felt that the thresholds would be seen as acceptable levels for personal use and would encourage drug dealers to carry just below the thresholds. No solution was proposed to the problem of how drug purity might be factored into the threshold amounts. It was later announced that Section 2 of the Act would not be introduced for the present time. It was later repealed by the Policing and Crime Act 2009. It may be noted that such thresholds operate in other jurisdictions. Schedule 1 of the Drug Misuse and Trafficking Act 1985 of New South Wales2 lists prohibited substances. Alongside each is identified a ‘Trafficable quantity’, a ‘Small quantity’, an ‘Indictable quantity’, a ‘Commercial quantity’, a ‘Large commercial quantity’ and, where appropriate, a ‘Discrete dosage unit’. As an   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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47

example, with cannabis resin, these amounts for the first five levels are 30 g, 5 g, 90 g, 2.5 kg and 10 kg, respectively. The remaining Sections of the Drugs Act were concerned with issues such as testing of arrestees for Class A drugs, and consequent assessment of those testing positive, providing additional powers to law enforcement agencies to tackle dealers who swallow or hide drugs in body cavities, and requiring Courts to take account of aggravating factors, such as dealing near a school, when sentencing.

5.2  Temporary Class Drug Orders In early 2010, I gave an interview on the BBC Radio 4 Today programme that was concerned with the problem of new drugs. I suggested that temporary control, as used in the US and elsewhere, might be one such solution. Following that interview, in March 2010, I attended a meeting of the Angelus Foundation3 to discuss approaches to the control of NPS. The outcome of that meeting, including the suggestion of temporary control, was passed to the late James Brokenshire MP. Within a short period, the possibility of introducing temporary controls was included in the manifesto of the Conservative Party4 ahead of the General Election in 2010. This stated: ‘We will introduce a system of temporary bans on new ‘legal highs’ while health issues are considered by independent experts’. Temporary Class Drug Orders (TCDOs) were then introduced into legislation by the Police Reform and Social Responsibility Act (2011) Act,5 and the provisions are set out in Section 151, which came into force on 15 November 2011. Following consultation with the ACMD, new substances may be added to a new Class under the MDAct for a period of one year. There will be no possession offence, but in some circumstances law enforcement officers will have powers to seize and destroy a ‘Temporary Class Drug’. Unlike the arrangements in the US where the DEA, as an executive agency, can determine which substances are added to the temporary list, in the UK this will require Parliamentary approval. But as with those other emergency scheduling procedures, there must be a decision at the end of the one-­year period on whether the substance should be substantively controlled or removed from the Act entirely. Table 5.1 shows substances that were later brought under temporary control. All were subsequently placed under permanent control, although a caveat Table 5.1  Substances  that were brought under temporary control. All were subsequently placed under permanent control.

Substance

Initial control

Methoxetamine N-­Benzylphenethylamines, benzo-­and dihydrobenzofurans, and indolylmethylethylamines Substances related to methylphenidate Methiopropamine

2012 2013 2014 2015

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regarding the legislation controlling benzofurans and related substances is described in Chapter 10. It will be seen that the provisions for temporary control have not been used since 2015. Although it might have been assumed that such measures were made redundant by the Psychoactive Substances Act, 2016, that was not the view of the ACMD. In 2017, the Home Secretary requested that the ACMD should investigate the future use and purpose of TCDOs. In their 2019 report,6 the ACMD advised that TCDOs remain a useful tool that can enable immediate action to be taken on substances of severe harm. A TCDO can be recommended by the ACMD, or the HO, at any time and initiated within a week. The ACMD further suggested that TCDOs could be used in conjunction with the PSA to offer a flexible model of substance control and provide a useful stepping-­stone between the PSA and the MDAct.

5.3  Importation Controls Insofar as most new substances are imported, often from countries in Asia, then one means of restricting their supply would be to prohibit their importation. In the UK, this power was first used in 2010 for the substance 2-­diphenylmethylpiperidine, or desoxypipradrol, (2-­DPMP). This is a designer drug based on the now obsolete anorectic drug pipradrol, a Schedule IV substance in the UN 1971 Convention. The Import of Goods (Control) Order 1954 bans the importation of all goods except those permitted to be imported under licence.7 In practice, most goods can be imported freely by an ‘Open General Import Licence’ (OGIL) except those listed in the schedule. In October 2011, the ACMD8 recommended to the Government that 2-­DPMP, which was being marketed at that time as Ivory Wave, should be subject to an immediate ban under the OGIL. That advice was accepted and a ban was implemented on 4 November 2011. Subsequently, phenazepam was likewise made the subject of an import ban. In both cases, and shortly after the bans had been announced, the ACMD recommended that 2-­DPMP and a group of generically-­defined analogues9 as well as phenazepam should become controlled drugs under the Misuse of Drugs Act. This advice was enacted in 2012.10 Import bans have not since been used as a means of drug control, possibly as a consequence of the Psychoactive Substances Act 2016.

5.4  The Psychoactive Substances Act 2016 Following the perceived success of TCDOs discussed above, the UK Government needed a more robust means of controlling NPS. Until around 2005, the annual appearance of new substances reported to the EMCDDA was stable and, by later standards, relatively modest. But, as will be seen from Figure 13.1 in Chapter 13, after 2008, that number increased rapidly each year, reaching a peak in around 2014. The major response in the UK had been to enact ever more controls on named substances or groups of substances. These controls would be set out in Modification Orders to the MDAct (Appendix 2),

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and their rising number can be seen in Figure 13.2 in Chapter 13. Despite the apparent efficiency of generic controls, a better legal instrument was needed. The purpose of the Psychoactive Substances Act 2016 (PSA)11 was to control psychoactive substances, not by name and not by ever more structure-­ specific generic controls, but rather by effectively trying to control all of them by their pharmacology. Certain substances would be exempted, for example alcohol, tobacco or nicotine-­based products, caffeine, food and drink, medicinal products and any drug that is already regulated under the MDAct. Those exemptions are listed in Schedule 1 to the PSA. Among other matters, the PSA makes it an offence to produce, supply, offer to supply, possess with intent to supply, possess on custodial premises, import or export psychoactive substances; that is, any substance intended for human consumption that is capable of producing a psychoactive effect. Unlike the MDAct, the premise of the PSA was not based on the harm to individuals or society of substances nor their potential for dependence, but the mere fact that they were psychoactive. Noteworthy was that the Act, like TCDOs, did not include a possession offence, although importation even for personal use would be an offence. The maximum sentence is seven years’ imprisonment. Certain healthcare activities and approved scientific research would be exempted. The Act was widely condemned as an attack on pleasure and an infringement of civil liberties. However, the major concern about the Act was that the law was unworkable as the psychoactivity of a substance cannot be unequivocally proven at the time of its appearance. Many discussions took place within the ACMD, one outcome of which was an attempt to define psychoactivity by how putative substances interacted in a range of receptor assays.12 While that bioassay approach has some merit, it is certainly not possible to predict the psychoactivity in humans of a substance by inspection of its molecular structure or any of its physico-­chemical properties. Equally implausible is to accept anecdotal reports from users about the effects of a given substance. The only reliable method of assessing psychoactivity is to conduct clinical trials using recognised methodology, but that not only raises ethical issues, but assumes that research can be facilitated with putative agents when it is recognised how difficult that can be with existing substances in Schedule I of the MD Regulations. More general concerns about the PSA focussed on the poor evidence that the law is an effective means of communicating with the public, i.e., sending messages about the harm of psychoactive substances in general. In 2015, Stevens et al.,13 described the pending legislation as ‘Legally flawed, scientifically problematic, potentially harmful’. At a time when drug-­related deaths in the UK have risen to an all-­time high (Chapter 1), it is often forgotten that almost all of those deaths are the result of using established, controlled drugs, particularly heroin and cocaine. NPS, whether or not controlled by the MDAct, make up a minute fraction of all such cases.14 The PSA may be seen as a form of ‘reduced analogue’ control, i.e., there is a requirement to show psychoactivity, which by general implication means a pharmacological effect substantially similar to that of existing novel substances, but there is no

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requirement for the test substance to be substantially similar in a chemical-­ structural sense. Two such substances, namely alkyl nitrites and nitrous oxide, have led to major problems as described in the following sections.

5.4.1  Alkyl Nitrites There are three important homologous members of this group as shown in Schemes 5.1–5.3, namely isopropyl, isobutyl and 3-­methylbutyl nitrite (commonly called amyl nitrite). Alkyl nitrites are widely known by euphemisms such as ‘poppers’ or ‘room odourisers’. Amyl nitrite (Scheme 5.3) was once used as an antidote to cyanide poisoning and as a coronary vasodilator for treating angina pain, but it has now been superseded. Illicit products containing amyl nitrite were once widely available. In 1994, the Royal Pharmaceutical Society of Great Britain (RPSGB) brought a successful prosecution under the Medicines Act against a retailer selling poppers containing amyl nitrite.15 This resulted in a UK-­wide ban and the disappearance of amyl nitrite from sale. However, manufacturers of poppers simply replaced amyl nitrite with n-­butyl nitrite or isobutyl nitrite (Scheme 5.2). A later prosecution by the RPSGB in 2001 against a supplier of poppers containing isobutyl nitrite was unsuccessful because the defence

Scheme 5.1  Isopropyl  nitrite.

Scheme 5.2  2-­  Methylpropyl nitrite; isobutyl nitrite.

Scheme 5.3  3-­  Methylbutyl nitrite.

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was able to show that these products did not cause significant harm. Unlike amyl nitrite, other alkyl nitrites had not been used as licensed medicinal products. The Dangerous Substances and Preparations (Safety) Regulations 2006 16 (now revoked) prohibited the sale of isobutyl nitrite, largely because it has been shown to be a human carcinogen.17 Manufacturers of poppers therefore switched to isopropyl nitrite (Scheme 5.1), which has similar physiological effects to its homologues. Among other features, the Intoxicating Substances (Supply) Act 1985 was intended to control the supply of alkyl nitrites. It was generally considered to have been ineffective, and it was repealed in 2016 when it was succeeded by the PSA. During the formulation of the PSA, debate arose as to how alkyl nitrites should be treated. An intended ban was difficult to reconcile with how relatively safe these substances are in practice, and it was claimed control would be specifically aimed at gay men. Alkyl nitrites exert their effects following conversion to nitric oxide (NO). In their report18 on alkyl nitrites in early 2016, the ACMD noted that following inhalation of alkyl nitrites, the brain perceives a transient ‘rush’ or ‘high’ as an indirect effect caused by the dilation of blood vessels in the brain and the periphery. The effects of ‘poppers’ on blood vessels in the brain was considered to be ‘peripheral’ as these lie outside the blood–brain barrier. It was recognised that the definition of psychoactivity is not explicit with respect to direct or indirect effects on the central nervous system. Thus, Section 2.(1) of the PSA states:    ‘In this Act ‘psychoactive substance’ means any substance which—    (a) is capable of producing a psychoactive effect in a person who consumes it, and (b)  is not an exempted substance (see Section 3)’.    Section 2.(2) states:    ‘For the purposes of this Act a substance produces a psychoactive effect in a person if, by stimulating or depressing the person's central nervous system, it affects the person's mental functioning or emotional state; and references to a substance's psychoactive effects are to be read accordingly’.    Section 2.(3) states:    ‘For the purposes of this Act a person consumes a substance if the person causes or allows the substance, or fumes given off by the substance, to enter the person's body in any way’.    The conclusion of the ACMD was that a psychoactive substance has a direct action on the brain and that substances having peripheral effects, such as those caused by alkyl nitrites, do not directly stimulate or depress the central

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nervous system. Thus, alkyl nitrites do not fall within the scope of the current definition of a psychoactive substance in the PSA. This view of the status of alkyl nitrites was generally accepted at least until the question of nitrous oxide arose as discussed below.

5.4.2  Nitrous Oxide First described in 1772 by Joseph Priestley, nitrous oxide (N2O) was known widely as laughing gas because of its effects on users. Later its anaesthetic and analgesic properties were discovered, and it is still used to this day as a short-­acting agent in childbirth and for minor medical procedures. Nitrous oxide is also used to create whipping cream in devices where the gas is stored in a small aluminium container known as a ‘whippet’. In the last twenty years, interest has been resurrected in exploring the recreational effects of nitrous oxide. The gas in the ‘whippet’ is typically discharged into a balloon, inhalation of which produces a short-­lived ‘high’ or ‘head rush’. The ACMD had reported19 on nitrous oxide in 2015, but did not recommend that it should be controlled under the MDAct. It was noted that the sale of nitrous oxide to under-­18 year olds was already illegal through the Intoxicating Substances (Supply) Act 1985.20 Evidence indicated that by 2015, the recreational misuse of nitrous oxide had increased rapidly and it became the second most popular recreational drug after cannabis. Deaths linked to nitrous oxide are rare and are usually caused by hypoxia rather than the direct effect of nitrous oxide. A number of criminal cases were subsequently brought under the PSA for offences involving nitrous oxide. The initial prosecutions were successful, but later the defence would argue successfully that nitrous oxide is not subject to the Act. For example, it was contended that nitrous oxide is a medicine and medicines were excluded. A counter-­argument would claim that when nitrous oxide was used for recreational purposes it was not a medicine. Secondly, nitrous oxide should be excluded since, like alkyl nitrites, its effects were primarily on blood vessels and blood flow to the brain, not directly on the brain itself. However, it had been shown many years ago21 that in experimental animals, nitrous oxide did penetrate the brain. Eventually, the arguments were taken to the Court of Appeal. In the case of R-­v-­Rochester (Appendix 4), the court decided that it was irrelevant whether the psychoactivity of a drug was via a direct or indirect mode of action on the brain. This judgment not only ran against the earlier statement from the ACMD mentioned above, but now left a difficult situation in regard to alkyl nitrites. A feature of that ACMD report on alkyl nitrites18 was the statement: ‘Consequently, the ACMD does not see a need for an exemption under the Psychoactive Substances Act 2016’. This was accepted by the HO Minister, but now placed alkyl nitrites in a somewhat curious legal position insofar as they were not specifically exempted, like alcohol and caffeine for example, but there was an expectation that no prosecutions would be brought. If such a specific exemption had been recommended and accepted by the Government, then

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this anomalous legal situation could have been avoided. It must now be concluded that unless Parliament makes an exemption, alkyl nitrites, when produced, supplied, imported or exported for recreational use, are now subject to the PSA. There has so far been no attempt to prosecute offences involving these substances. In September 2021, the Home Secretary (Priti Patel) asked the ACMD to again review the status of nitrous oxide under the MDAct.22

5.4.3  Reviews of the Psychoactive Substances Act The HO published a review23 of the PSA in November 2018. Some of the main findings were:    ● The PSA reduced the need for TCDOs. ● Many ‘head shops’ had closed, but it was accepted that the supply of psychoactive substances has continued by other routes. ● The emergence of new NPS has not ceased. ● The use of synthetic cannabinoid receptor agonists in prisons had not changed. ● There is some evidence that use of NPS has fallen, although this was happening before 2016. ● The use of nitrous oxide had not been affected by the Act. ● While a number of cases involving synthetic cannabinoids have challenged whether the testing process for the PSA provides sufficient evidence that synthetic cannabinoids are capable of producing a psychoactive effect, and therefore whether they are within scope of the Act, a number of Crown Court judgments have determined that synthetic cannabinoids considered in those cases fell within the scope of the PSA.    A number of criticisms of the review were made by the ACMD24 which claimed that it should have been carried out by an independent body, not the HO. They also refuted the suggestion that TCDOs were now less useful. It was also clear that there was insufficient evidence to quantify the extent to which NPS users have substituted other existing drugs so it is not possible to identify whether the Act has led to an overall reduction in drug use.

5.5  Other Drug-­related Legislation in the UK Parts of the following statutes either modify some Sections of the MDAct or have some relevance to other offences involving controlled drugs. Not all necessarily refer to all countries of the UK.

5.5.1  Road Traffic Act 1972 The Road Traffic Act 1972 makes it an offence to be in charge of a motor vehicle while unfit to drive through drink or drugs (controlled or otherwise).25

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5.5.2  The Customs and Excise Management Act 1979 The Customs and Excise Management Act 1979 extends the limited powers in the MDAct against importation and exportation of controlled drugs. It provides the means for prosecuting drug offenders involved in these activities.26

5.5.3  The Drug Trafficking Act 1994 The Drug Trafficking Act 1994 enables the UK to meet further obligations under the UN 1988 Convention. It replaced the Drug Trafficking Offences Act 1986 and gives police the power to seize assets and income of anyone who is found guilty of drugs trafficking, even if that income is not related to the trafficking of drugs. The Act applies to England and Wales only.27

5.5.4  The Crime and Disorder Act 1998 The Crime and Disorder Act 1998 requires offenders, who are convicted of crime committed in order to fund their drug habit, to be tested for drug misuse and to undertake drug treatment. The Drug Testing and Treatment Orders (DTTOs) were later consolidated by the Powers of Criminal Courts (Sentencing) Act 2000. However, many of the provisions of the latter Act, including the DTTOs, are in the process of being repealed.28

5.5.5  The Criminal Justice and Police Act 2001 Among other powers, the Criminal Justice and Police Act 2001 amends Section 8(d) of the MDAct 1971 to read ‘administering or using a controlled drug in any person's possession at or immediately before the time when it is administered or used’. Section 8(d) was previously only concerned with ‘smoking cannabis, cannabis resin or prepared opium’. Although primarily designed to give police additional powers to close ‘crack houses’ the proposed amendment proved controversial and has been abandoned.29

5.5.6  The Criminal Justice Act 2003 Among other provisions, the Criminal Justice Act 2003 amends sentences for Class C drugs. An amendment to the Police and Evidence Act 1984 allows the power of arrest to be used for the possession of cannabis and any other Class C drug. Before the reclassification of cannabis in 2004, the possession of a Class C drug had not been an arrestable offence. The maximum prison sentence for supplying any Class C drug was increased from 5 years to 14 years, i.e., similar to the penalty associated with Class B drugs.30

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5.5.7  T  he Criminal Justice (International Cooperation) Act 1990; Controlled Drugs (Drug Precursors) (Intra-­ community Trade) Regulations 2008; Controlled Drugs (Drug Precursors) (Community External Trade) Regulations 2008 The Criminal Justice (International Cooperation) Act 1990, the Controlled Drugs (Drug Precursors) (Intra-­Community Trade) Regulations 2008 and the Controlled Drugs (Drug Precursors) (Community External Trade) Regulations 2008 are part of a group of statutes created to discharge UK responsibilities to the UN 1988 Convention and the corresponding EU legislation. They regulate the licensing, manufacture and distribution of substances (precursors) useful for the production of illicit drugs.31–33

5.5.8  Serious Crime Act 2007 Sections 44 to 46 in Part 2 of the Serious Crime Act 2007 deal with the inchoate offences of encouraging or assisting crime. An example is given in Chapter 25 whereby a supplier of a cutting agent might be held liable even if the anticipated offence was not committed. This Act was amended by the Serious Crime Act 2015.34

5.5.9  Crime and Courts Act 2013 Section 56 of the Crime and Courts Act 2013 inserted a new Section into the Road Traffic Act 1988 (Section 5A Drugs and Driving). To secure a conviction of driving while exceeding the legal limit of a specified drug under Section 5A, no proof of impairment is necessary. Proof that the level of drug in a defendant's body at the time of the offence exceeded the legal limit is sufficient. Legislation has specified seventeen drugs, including controlled and medicinal drugs, alongside the maximum legal drug driving limit of each drug.35

References 1. The Drugs Act 2005, https://www.legislation.gov.uk/ukpga/2005/17/ contents, accessed October 2021. 2. New South Wales, Australia, Drug Misuse and Trafficking Act 1985, http://www6.austlii.edu.au/cgi-­bin/viewdoc/au/legis/nsw/consol_act/ dmata1985256/sch1.html, accessed October 2021. 3. Angelus Foundation, https://en.wikipedia.org/wiki/Angelus_Foundation, accessed October 2021. 4. Manifesto of the Conservative Party 2010, https://general-­election-­2010. co.uk/conservative-­party-­manifesto-­2010-­general-­election/, accessed October 2021.

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5. Police Reform and Social Responsibility Act 2011, https://www. legislation.gov.uk/ukpga/2011/13/contents, accessed October 2021. 6. Advisory Council on the Misuse of Drugs, 2019, Future use and purpose of Temporary Class Drug Orders (TCDOs), https://www.gov.uk/government/publications/acmd-­advice-­future-­use-­and-­purpose-­of-­temporary-­ class-­drug-­orders, accessed October 2021. 7. The Import of Goods (Control) Order 1954, https://www.legislation.gov. uk/uksi/1954/23/contents/made, accessed October 2021. 8. Advisory Council on the Misuse of Drugs, 2011, Desoxypipradrol (2-DPMP) advice, https://assets.publishing.service.gov.uk/government/ uploads/system/uploads/attachment_data/file/119114/desoxypipradrol-­ report.pdf, accessed October 2021. 9. Home Office 2011, Press release: Import ban of new 'legal high' phenazepam introduced, https://www.gov.uk/government/news/import-­ban-­of-­ new-­legal-­high-­phenazepam-­introduced, accessed October 2021. 10. The Misuse of Drugs Act 1971 (Amendment) Order 2012 (S.I.1390), https://www.legislation.gov.uk/uksi/2012/1390/contents/made, accessed October 2021. 11. Psychoactive Substances Act 2016, https://www.legislation.gov.uk/ ukpga/2016/2/contents, accessed October 2021. 12. L. Iversen, S. Gibbons and R. Treble, et al., Eur. J. Pharmacol., 2013, 700(1– 3), 147. 13. A. Stevens, R. Fortson, F. Measham and H. Sumnall, Int. J. Drug Policy, 2015, 26, 1167. 14. L. A. King and J. M. Corkery, J. Psychopharmacol., 2018, 32(7), 793. 15. Sigma Research, Making it Count Briefing Sheet: Poppers, 2011, https:// sigmaresearch.org.uk/files/MiC-­briefing-­7-­Poppers.pdf, accessed October 2021. 16. The Dangerous Substances and Preparations (Safety) Regulations 2006 (revoked), https://www.legislation.gov.uk/uksi/2006/2916/contents, accessed October 2021. 17. H. Kromhout, M. Friesen and M. M. Marques, et al., Lancet Oncol., 2018, 19(8), 1020. 18. Advisory Council on the Misuse of Drugs 2016, ACMD review of alkyl nitrites (“poppers”), https://www.gov.uk/government/publications/acmd-­ review-­of-­alkyl-­nitrites-­poppers, accessed October 2021. 19. Advisory Council on the Misuse of Drugs, 2015, ACMD advice on nitrous oxide abuse, https://www.gov.uk/government/publications/acmd-­advice-­ on-­nitrous-­oxide-­abuse, accessed October 2021. 20. Intoxicating Substances (Supply) Act 1985, https://www.legislation.gov. uk/ukpga/1985/26/contents, accessed October 2021. 21. S. S. Kety, M. H. Harmel, H. T. Broomell and C. B. Rhode, J. Biol. Chem., 1948, 173(2), 487. 22. Nitrous Oxide: Home Secretary's letter to the ACMD, https://www.gov.uk/ government/publications/nitrous-­oxide-­home-­secretarys-­letter-­to-­the-­ acmd, accessed October 2021.

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23. Home Office, 2018. Review of the Psychoactive Substances Act 2016, https://www.gov.uk/government/publications/review-­of-­the-­psychoactive-­ substances-­act-­2016, accessed October 2021. 24. Advisory Council on the Misuse of Drugs, 2019, ACMD contribution to the Impact Review of the Psychoactive Substances Act 2016, https://www. gov.uk/government/publications/review-­of-­psychoactive-­substances-­act-­ 2016-­acmd-­contribution, accessed October 2021. 25. Road Traffic Act 1972, https://www.legislation.gov.uk/ukpga/1972/20/ contents/enacted, accessed October 2021. 26. Customs and Excise Management Act 1979, https://www.legislation.gov. uk/ukpga/1979/2/contents, accessed October 2021. 27. Drug Trafficking Act 1994, https://www.legislation.gov.uk/ukpga/1994/37/ contents, accessed October 2021. 28. Crime and Disorder Act 1998, https://www.legislation.gov.uk/ukpga/1998/ 37/contents, accessed October 2021. 29. The Criminal Justice and Police Act 2001, https://www.legislation.gov. uk/ukpga/2001/16/contents, accessed October 2021. 30. Criminal Justice Act 2003, https://www.legislation.gov.uk/ukpga/2003/44/ contents, accessed October 2021. 31. The Criminal Justice (International Cooperation) Act 1990, https://www. legislation.gov.uk/ukpga/1990/5#:∼:text, accessed October 2021. 32. Controlled Drugs (Drug Precursors)(Intra-­Community Trade) Regulations 2008, https://www.legislation.gov.uk/uksi/2008/295/contents, accessed October 2021. 33. Controlled Drugs (Drug Precursors)(Intra-­Community and Community External Trade) Regulations 2010, https://www.legislation.gov.uk/ uksi/2010/2564/contents/made, accessed October 2021. 34. Serious Crime Act 2007, https://www.legislation.gov.uk/ukpga/2007/27/ contents, accessed October 2021. 35. Crime and Courts Act 2013, https://www.legislation.gov.uk/ukpga/ 2013/22/contents, accessed October 2021.

Chapter 6

Nomenclature 6.1  Introduction From a casual reading of the MDAct, one might not realise that certain ‘unnamed’ substances are in fact controlled. However, the absence of common terms has been a feature of legislation for many years. As an example, one will search the MDAct in vain for specific mention of ‘heroin’, ‘LSD’ or ‘THC’. The first two are known as diamorphine and lysergide, respectively, whereas THC was embedded in a generic definition (as a cannabinol derivative) fifty years ago without any apparent problem. Thus, the well-­known controlled drug MDMA, a member of the ‘ecstasy’ group of so-­called entactogenic stimulants, is more formally known as 3,4-­methylenedioxy-­methylamphetamine or fully systematically as N-­methyl-­1-­(3,4-­methylenedioxy-­phenyl)propan-­2-­amine or, according to the rules of the International Union of Pure and Applied Chemistry (IUPAC), 1-­(2H-­1,3-­benzodioxol-­5-­yl)-­N-­methylpropan-­ 2-­amine. Yet none of these terms or any other direct synonym will be found in the Act. Similarly, when mephedrone (4-­methylmethcathinone) was first brought under control in the UK in 2010, the opportunity was taken to embed this substance in a generic definition. But, apart from an initial legislative error (Chapter 10), neither mephedrone nor any direct synonym is mentioned explicitly. In this book, the names of drugs correspond, where appropriate, with the names in the MDAct, but not all are formal (IUPAC) names. The situation is further confused since more than one formal may be in common use. For example, the EMCDDA shows 3-­fluoromethoxyacetylfentanyl as having the IUPAC name N-­(3-­fluorophenyl)-­2-­methoxy-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]acetamide, but it is also known as N-­(3-­fluorophenyl)-­2-­ methoxy-­N-­[1-­(2-­phenylethyl)-­4-­piperidyl]acetamide and 2-­methoxy-­N-­(1-­ phenethylpiperidin-­4-­yl)-­N-­(3-­fluorophenyl)acetamide.

  Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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For the non-­chemist, and even some professional chemists, the names of drugs and related substances provide numerous pitfalls. For example, the cathinone derivatives mephedrone, methedrone and methylone are distinct entities, but the first two are easily confused with one another and with the almost homophonic, yet unrelated substance, methadone. Alternatively, what is one to make of the following name: 2-­( 5-­methoxy-­2 ,2-­d imethyl-­2 ,3-­d ihydrobenzo-­[ b]furan-­6 -­y l)-­1 -­m ethylethylamine? Even an experienced chemist might struggle to recognise this immediately as a relative of MDMA. The nomenclature of synthetic cannabinoid receptor agonists (SCRAs) is an equally difficult issue, and is covered in Chapter 18.

6.2  B  ritish Approved Names and International   Non-­proprietary Names In common with most chemical substances, a given drug may have a number of synonyms. The MDAct originally used British Approved Names (BAN), which were defined by the British Pharmacopoeia Commission. However, in 2003, a decision was made to abandon most BANs and use International Non-­proprietary Names in the British Pharmacopoeia. In general, a BAN only existed for drugs, which have or have had clinical value. In the absence of a BAN, the formal chemical name was used, i.e., a name in agreement with the IUPAC rules.1 European Law (Directives 65/65 and 92/27/EEC)2 required the use of an International Non-­proprietary Name (INN) for the labelling of medicinal products. The assignment of an INN to a substance is decided by the WHO. In many cases, the differences between a BAN and an INN are minor. Table 6.1 sets out those controlled drugs where the name still used in the MDAct differs from the INN. Metamfetamine is strictly the INN for the d-­isomer only. Clorazepate is a salt of clorazepic acid. There is no intention to ensure that BANs in the MDAct should be changed to correspond with International Non-­ proprietary Names. Apart from the administrative burden, several difficulties would arise. For example, there are many occasions where the INN refers to a specific stereoisomer, even though the names in the MDAct must necessarily include all stereoisomers.

6.3  Phenyl-­substituted Alkanes Phenethylamine is a contraction of 2-­phenylethylamine, also known as β-­phenylethylamine (Scheme 6.1); it should not be confused with the isomeric 1-­phenylethylamine also known as α-­phenylethylamine (Scheme 6.2). The implications of this distinction for the generic control of phenethylamines are covered in Chapter 8. Many 2-­phenethylamines of interest are α-­methyl-­substituted (Scheme 6.3) and it is common practice to refer to them in a non-­IUPAC approved shorthand form as ‘amphetamines’ (viz.

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Table 6.1  Controlled  drugs where the name used in the MDAct differs from the International Non-­proprietary Name (INN).

Name in Act

Class

INN

4-­Bromo-­2,5-­dimethoxy­α-­methylphenethylamine Dimenoxadole N-­Hydroxy-­tenamphetamine Methadyl acetate Tilidate Amphetamine Methylamphetamine Methylphenobarbitone Quinalbarbitone Benzphetamine Clorazepic acid Diethylpropion N-­Ethylamphetamine Ethyloestrenol Fenethylline Methandienone Methenolone Methyprylone Stanolone

A

Brolamfetamine

A A A A B B B B C C C C C C C C C C

Dimenoxadol N-­Hydroxy MDA Acetylmethadol Tilidine Amfetamine Metamfetamine Methylphenobarbital Secobarbital Benzfetamine Clorazepate Amfepramone Etilamfetamine Ethylestrenol Fenetylline Metandienone Metenolone Methyprylon Androstanolone

Scheme 6.1  2-­  Phenylethylamine.

Scheme 6.2  1-­  Phenylethylamine.

Scheme 6.3  An  α-­methyl-­substituted 2-­phenethylamine. α-­methylphenethylamine) derivatives. Similarly, N,α-­dimethyl-­substituted phenethylamines are often named as methylamphetamine derivatives. Phenylalkylamine is a more general term for substances where a phenyl group is attached to a carbon atom in an alkylamino group, where the alkyl moiety contains any number of carbon atoms.

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6.3.1  Amphetamine Caution is needed in the use of the plural form ‘amphetamines’. This is commonly found in the general drugs literature, often without clear definition. It may be used to mean amphetamine plus methylamphetamine or it may include ring-­substituted amphetamines such as MDMA as well. When describing the legal status of ‘amphetamines’ it can be even more problematic, particularly in the UK. Here, methylamphetamine and many ring-­substituted amphetamines are Class A drugs, but amphetamine itself is Class B, whereas N-­ethylamphetamine and benzphetamine, for example, are in Class C. The IUPAC name for amphetamine is (RS)-­1-­phenylpropan-­2-­amine, but the alternative formal name α-­methylbenzene-­ethanamine is often seen. The INN term amfetamine refers to a racemic mixture of the two enantiomers. The R and S-­enantiomers as well as the racemate (a 50 : 50 mixture of the R and S-­stereoisomers) are listed in Schedule II of the UN 1971 Convention. In the MDAct, amphetamine is a Class B controlled drug. Amfetamine is also the spelling required by Directives 65/65 and 92/27/EEC2 for the labelling of medicinal products within the EU. Dexamfetamine, the INN for the S-­ enantiomer, is also known as (+)-­α-­methylphenethylamine. Levamfetamine, the R-­enantiomer, is also known as (−)-­α-­methylphenethylamine. Other commonly-­used chemical names include: 1-­phenyl-­2-­aminopropane and phenylisopropylamine. Hundreds of other synonyms and proprietary names exist. ‘Street’ terms include speed, base and whizz.

6.3.2  Methylamphetamine The S-­enantiomer of methylamphetamine is listed as metamfetamine in Schedule II of the UN 1971 Convention. In the UK and some other countries, the name used in drugs legislation is methylamphetamine. The racemate is listed separately in Schedule II of the UN 1971 Convention as metamfetamine racemate, but the R-­enantiomer is not separately identified in the Convention. In the MDAct, methylamphetamine (both enantiomers) was a Class B controlled drug until 2006 when it was moved to Class A. Metamfetamine is also the name required by Directives 65/65 and 92/27/EEC for the labelling of medicinal products within the EU. Other commonly-­used chemical names include N-­methylamphetamine, 1-­phenyl-­2-­methylaminopropane, phenylisopropylmethylamine, and desoxyephedrine. Many other synonyms and proprietary names exist. ‘Street’ terms include speed, crank and meth. In Central Europe, the names pervitin and piko are used (the former name derived from an earlier medicinal product) as well as yaba and shabu in certain countries in the Far East. The terms crystal meth and ice usually refer to the S-­enantiomer.

6.3.3  N-­Hydroxy MDA In Schedule I of the UN 1971 Convention, a substance, sometimes known as MDOH, is listed as N-­hydroxy MDA, (±)-­N-­[alpha-­methyl-­3,4-­(methylenedioxy)phenethyl]hydroxylamine. This was added to the MDAct in 1990 as

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N-­hydroxy-­tenamphetamine. However, the latter is not a BAN, an INN or an acceptable IUPAC name. Even the core word ‘Tenamphetamine’ itself is an anglicised version of ‘Tenamfetamine’, the INN for one of the ecstasy drugs commonly called 3,4-­methylenedioxyamphetamine (MDA). In hindsight, since MDA is almost never referred to as Tenamfetamine, it would have been clearer if it had been listed in the MDAct simply as N-­hydroxy MDA.

6.4  Code Names A large number of controlled phenethylamines and tryptamines (mainly the PiHKAL3 and TiHKAL4 compounds) are commonly known by their acronyms (e.g., 2C-­T-­7, 4-­MTA, 2C-­B, DALT and DMT). However, unlike some jurisdictions and the UN Conventions, until recently the MDAct was reluctant to use acronyms and code names for drugs. In recent years, code names have started to appear largely because some of the IUPAC names, which are usually given alongside those code names, have become unwieldy. Examples in the MDAct now include U-­47,700, MT-­45, AH-­7921, 4,4′-­DMAR, ETH-­LAD and ALD-­52. Meanwhile, the large number of synthetic cannabinoid receptor agonists reported to EMCDDA are generally known by structure-­related code names (Chapter 18).

6.5  Anabolic Steroids Most anabolic steroids in the MDAct are listed by common names (Appendix 6). However, steroid nomenclature has changed over the years. IUPAC recommendations define steroids and sterols as: ‘Steroids are compounds possessing the skeleton of cyclopenta[a]phenanthrene or a skeleton derived therefrom by one or more bond scissions or ring expansions or contractions. Methyl groups are normally present at C-­10 and C-­13. An alkyl side chain may also be present at C-­17. Sterols are steroids carrying a hydroxyl group at C-­3 and most of the skeleton of cholestane. Additional carbon atoms may be present in the side chain’. Nevertheless, there is still some confusion in the literature between a steroid and a sterol.

6.6  Synonyms and Common Terms Table 6.2 gives examples of drug names which either do not occur in the MDAct as such because of generic definitions or there is a better-­known abbreviation or the trivial name is more widely used. In other cases, US English offers alternative spellings or there are acceptable chemical synonyms. An extensive list of drug synonyms in different languages is published by the UN.5 A large number of slang terms for drugs are in use although their popularity varies from place to place and in time; a few are shown in Table 6.2. A large collection of ‘street names’ used in the US is published on the website6 of the US Drug Enforcement Administration. It should be noted that heroin and diamorphine are not strictly synonymous. The former is a crude preparation obtained by the acetylation of crude morphine, in which diamorphine (diacetylmorphine) is usually the major component.

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Table 6.2  Synonyms  and other names for certain controlled drugs. Common name Name in MDAct

Alternative names

Slang terms

Bromo-­STP, DOB

4-­Bromo-­2,5-­dimeth- Brolamfetamine; 4-­bromo-­ oxy-­α-­methyl-­ 2,5-­dimethoxyamphetphenethylamine amine Cannabis Cannabis Marijuana/marihuana Pot, dope, (US), hemp blow, weed Cannabis resin Cannabis resin Hashish (US) Hash, ganja, charas Heroin Diamorphine Diacetylmorphine ‘H’, horse, skag, smack N-­Hydroxy MDA N-­Hydroxy-­ N-­Hydroxytenamfetamine tenamphetamine LSD Lysergide Lysergic acid diethylamide LSD-­25, acid MDEA (Generically 3,4-­Methylenedioxyethyl- ‘E’, Eve, ecstasy subsumed) amphetamine MDMA (Generically 3,4-­Methylenedioxymethyl- ‘E’, Adam, subsumed) amphetamine ecstasy, XTC Mephedrone (Generically 4-­Methylmethcathinone, MCAT, meow subsumed) 4-­MMC meow Methcathinone Methcathinone Ephedrone Crank Methylamphet- Methylamphetamine Methamphetamine (US), Meth, speed, amine metamfetamine (INN ice, crystal for the d-­isomer) meth Pethidine Pethidine Meperidine (US) STP 2,5-­Dimethoxy-­α,4-­ 2,5-­Dimethoxy-­4-­methylamdimethyl-­phenethylphetamine, DOM amine

A further example of synonymy occurs in the generic definitions where halide and halogeno in the MDAct should be interpreted as having the same meaning. As discussed earlier, mephedrone and methadone are distinct, unrelated compounds. In early 2010, two young men died in Scunthorpe, UK. The local police immediately announced that they had died from the effects of mephedrone, although immediate evidence for this was lacking. Sometime later, following toxicological testing, it transpired that the cause of death had been the narcotic analgesic methadone.7 The incident achieved notoriety because of the impact these alleged mephedrone deaths had on an increased interest in this so-­called legal high8 as well as on a media and public that was already in the throes of a moral panic about the alleged dangers of mephedrone. The event probably had some impact on the decision to control mephedrone a few weeks later.

6.7  The Meaning of ‘3,4-­Methylenedioxy’ Many derivatives of amphetamine and cathinone feature a five-­membered dioxo-­heterocyclic structural subunit fused to the phenyl ring. Scheme 6.4 shows the example of MDMA (3,4-­methylenedioxy-­N-­methylamphetamine,

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Scheme 6.4  3,4-­  Methylenedioxy-­N-­methyl-­amphetamine; MDMA.

Scheme 6.5  An  isomeric peroxy form of methylone.

aka N-­methyl-­1-­(1,3-­benzodioxol-­5-­yl)-­2-­propanamine). The prefix ‘3,4-­ methylenedioxy’ refers to a sub-­structure containing O–CH2–O; it does not include peroxy forms where the sub-­structure is CH2–O–O. Thus, the structure shown in Scheme 6.5 is not a 3,4-­methylenedioxy compound.

6.8  Dialkyl Derivatives Among a number of phenethylamine derivatives that were added by name to the MDAct in 2001 (Appendix 7), two represented compounds where the nitrogen atom is disubstituted with alkyl groups. This was necessary because some doubt resided in whether N,N-­disubstitution on the amine is currently subsumed by the generic definition in paragraph 1(c) of Part I of Schedule 2 (viz. ‘…an N-­alkylphenethylamine…’). However, another instance of ‘N-­alkyl’ substitution arises in paragraph 1(a) of Part I of Schedule 2. But here the explicit use of the phrase ‘Lysergide and other N-­alkyl derivatives of lysergamide’, by focussing on lysergide (a dialkyl derivative), was therefore intended to mean that ‘N-­alkyl’ subsumes N,N-­dialkyl.

6.9  The Meaning of ‘Structurally Derived from’ The concept of ‘derivative’ is discussed in Chapter 12. A specific example of that word occurs in some of the group-­generic definitions discussed in Chapter 8. For example, in ring-­substituted phenethylamines, reference is made to ‘a compound… structurally derived from phenethylamine’. In the judgment in the case of R-­v-­Couzens and Frankel in 1992 (Appendix 4), it was accepted that to say that compound A is structurally derived from B does not necessarily mean that B can be chemically converted to A in one or even several reaction stages. What is meant in the example of

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phenethylamines is that A still contains the carbon skeleton of phenethylamine (i.e., B), but that additional atoms (carbon, oxygen or other as defined) are now attached without implying that such an attachment is chemically possible. In practical terms, it will almost always be the case that A and B are produced from quite separate precursor chemicals which, in this example, may not in themselves be phenethylamines. This is an example of a situation where the word ‘derivative’ is used unambiguously. However, in other parts of the legislation, both national and international, ‘derivative’ is often not well-­defined. This matter is taken up in Chapter 12.

6.10  Redundancy The widespread introduction into the MDAct, from the late 1970s, of generic definitions based on chemical substitution patterns (Chapter 8) led to a certain amount of duplication. In other words, some controlled drugs continued to be named specifically, but also fell within the scope of generic control. However, this situation was not new; several examples of redundancy can be traced back to the Geneva Convention of 1931 (Chapter 13). This extended controls to include the esters or ethers of substances in Schedule I of that Convention. The best example of added redundancy is that both morphine and heroin (diamorphine) continue to be listed by name in the UN 1961 Convention and the UK MDAct. Other examples of redundancy include other morphine esters such as nicomorphine, and morphine ethers such as benzylmorphine. It can be argued that no harm is caused by this duplication. Removal of the word ‘diamorphine’ and others, while having no legal significance, might be misunderstood and lead to unnecessary debate. A further level of duplication is caused by the retention in Schedule I of the UN 1961 Convention and in Part I of Schedule 2 to the MDAct, of three racemic forms. Thus racemoramide, racemethorphan and racemorphan could be deleted because they each contain 50% of an existing controlled drug, namely dextromoramide, levomethorphan and levorphanol, respectively. Table 6.3 shows examples of Class A substances where effective double entry occurs in the MDAct. Thebacon is an ester and an ether of hydromorphone and is therefore not covered directly by paragraph 3 of Part I of Schedule 2 of the MDAct. In other words, hydrocodone and thebacon are not both redundant, but either could be listed without the other. As discussed in Chapter 18, the synthetic cannabinoid receptor agonist nabilone is listed by that name and by its formal name. The Drugs Act 2005 9 caused the following text to be added to Part I of Schedule 2 to the MDAct ‘Fungus (of any kind) which contains psilocin or an ester of psilocin’. Since esters of psilocin, and of all other Class A drugs, were already controlled, this was more added redundancy.

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Table 6.3  ‘Double  entry’ of Class A controlled drugs in the MDAct. Specific name in part I of schedule 2

Generic control in part I of schedule 2

Bufotenine N,N-­Diethyltryptamine N,N-­Dimethyltryptamine Psilocin Etryptamine

Tryptamines

4-­Bromo-­2,5-­dimethoxy-­α-­methylphenethylamine 2,5-­Dimethoxy-­α,4-­dimethylphenethylamine Mescaline

Phenethylamines

Alfentanil Carfentanil Lofentanil Sufentanil

Fentanyls (aka Fentanils)

Allylprodine Alphameprodine Alphaprodine Anileridine Benzethidine Properidine Trimeperidine Benzylmorphine Diamorphine Hydrocodone Levomethorphan Methadyl acetate Nicomorphine Oxycodone Thebacon

Pethidines/Prodines

An ether of morphine An ester of morphine An ether of hydromorphone An ether of levorphanol An ester of methadol (dimepheptanol) An ester of morphine An ether of oxymorphone An ester of hydrocodone (enol form)

References 1. International Union of Pure and Applied Chemistry (IUPAC), https://iupac. org/, accessed October 2021. 2. European Union Directives 65/65 and 92/27/EEC, https://en.wikipedia.org/ wiki/Directive_65/65/EEC and https://www.legislation.gov.uk/eudr/1992/27/ adopted, accessed October 2021. 3. A. Shulgin and A. Shulgin, PiHKAL: A Chemical Love Story, Transform Press, Berkeley, California, 1991, ISBN 0-­9630096-­0-­5. 4. A. Shulgin and A. Shulgin, TiHKAL, The Continuation, Transform Press, Berkeley, California, 1997, ISBN 0-­9630096-­9-­9.

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5. United Nations Multilingual Dictionary of Narcotic Drugs and Psychotropic Substances under International Control, https://www.unodc.org/unodc/ en/scientists/multilingual-­dictionary-­of-­narcotic-­drugs-­and-­psychotropic-­ substances-­under-­international-­control.html, accessed October 2021. 6. US Drug Enforcement Administration, https://www.deadiversion.usdoj. gov/drug_chem_info/index.html, accessed October 2021. 7. Guardian, Banned Mephedrone Cleared of Blame for Two Deaths, 2010, https://www.theguardian.com/society/2010/may/28/mephedrone-­cleared-­ teenage-­uk-­deaths, accessed October 2021. 8. A. J. M. Forsyth, Int. J. Drug Policy, 2011, 23(3), 198. 9. Drugs Act 2005, https://www.legislation.gov.uk/ukpga/2005/17/contents, accessed October 2021.

Chapter 7

Esters, Ethers, Salts, Homologues, Stereoisomers and Isotopes 7.1  Esters and/or Ethers: Introduction Esters and ethers are defined by the International Union of Pure and Applied Chemistry (IUPAC).1 Esters of both organic and inorganic acids occur; an example of the latter is psilocybin, the phosphate ester of psilocin. The esters or ethers of Class A substances, certain substances in Class B (i.e., cannabinol and cannabinol derivatives; phenylcyclohexylamine derivatives; pipradrol derivatives; and synthetic cannabinoid receptor agonists) are subject to the same controls as their unmodified parents unless that ester or ether is already specified elsewhere in Schedule 2 of the MDAct. Only structures with a hydroxyl (–OH), sulfhydryl (–SH) or a suitable acid such as carboxylic (CO2H) group commonly form esters, and only hydroxyl and sulfydryl groups form ethers. Amongst those basic drugs listed in the Act, which are able to form an ester or an ether, only the hydroxyl function is found. Schedule 2 of the MDAct refers specifically to control of ‘Any ester or ether’. This was deliberately designed. In other words, a substance that is both an ester and an ether is not controlled. An example here is thebacon, which, as an ester and an ether of hydromorphone, is listed by name as a Class A drug. However, for the Class C anabolic/androgenic steroids and 1,4-­butanediol, control is extended to esters and ethers where more than one hydroxyl function is available.

  Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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7.2  Esters An example of ester formation is the conversion of morphine to diamorphine (the diacetyl ester of morphine), as shown in Scheme 7.1. This process is used, for example, in the illicit production of heroin (crude diamorphine) from opium (Chapter 22). Diamorphine slowly hydrolyses in damp conditions or rapidly in aqueous alkaline solutions to produce 6-­O-­monoacetylmorphine (Scheme 7.2). Monoacetylmorphine is still an ester of morphine and therefore remains a Class A controlled drug. Another example of an ester is psilocybin, the naturally-­occurring phosphate of psilocin (Scheme 7.3). Both psilocin and psilocybin are found in certain fungi of the Psilocybe genus (so-­called ‘magic mushrooms’; Chapter 26). The illicit production of the acetyl ester of tetrahydrocannabinol (THC) has been recorded in clandestine laboratories. It was claimed that the resulting THC acetate was a more potent drug, but after the appearance of synthetic

Scheme 7.1  The  esterification of morphine [(4R,4aR,7S,7aR,12bS)-­3-­methyl-­ 2,3,4,4a,7,7a-­h exahydro-­1 H-­4 ,12-­m ethano[1]benzofuro[3,2-­e ]isoquinoline-­7,9-­diol] to diamorphine (Ac2O is acetic anhydride).

Scheme 7.2  The  hydrolysis of diamorphine to form 6-­O-­monoacetylmorphine.

Scheme 7.3  3-­  [2-­(Dimethylamino)ethyl]-­1H-­indol-­4-­ol; psilocin.

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cannabinoid receptor agonists around 2008, there has been little interest in producing ‘designer drugs’ closely related to phytocannabinoids. Esters of the Class C anabolic steroids are quite common in commercial formulations. Schemes 7.4 and 7.5 show testosterone and its 17β-­propanoate ester respectively. Other common esters of testosterone are the 17β-­ cyclopentanepropionate (cypionate) and the 17β-­undecanoate (undecyclate).

7.3  Ethers A number of controlled drugs, principally certain opioids, are ethers. Neither codeine (the 3-­methyl ether of morphine; Scheme 7.6), dihydrocodeine (the 3-­methyl ether of dihydromorphine; Scheme 7.7), pholcodine (the 3-­[morpholinoethyl]ether of morphine; Scheme 7.8) nor ethylmorphine (the 3-­ethyl ether of morphine; Scheme 7.9) are Class A drugs because they are

Scheme 7.4  [(8R,9S,10R,13S,14S,17S)-­  1 7-­H ydrox y-­1 0,13-­d imethyl-­1 ,2,6,7,-

8,9,11,12,14,15,16,17-­dodecahydrocyclopenta[a]phenanthren-­3-­one; 17β-­hydroxyandrost-­4-­en-­3-­one; testosterone], an androgenic anabolic steroid. Ring hydrogen atoms are omitted for clarity.

Scheme 7.5  The  17β-­propanoate ester of testosterone. Ring hydrogen atoms are omitted for clarity.

Scheme 7.6  Codeine,  the 3-­methyl ether of morphine.

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Scheme 7.7  Dihydrocodeine,  the 3-­methyl ether of dihydromorphine.

Scheme 7.8  Pholcodine,  the 3-­[morpholinoethyl]ether of morphine.

Scheme 7.9  Ethylmorphine,  the 3-­ethyl ether of morphine. already listed under Class B. However, other ethers of morphine or dihydromorphine or of another Class A drug would be controlled under Class A.

7.4  Salts The salts of all controlled drugs containing acidic or basic (amino) groups are controlled to the same degree as the parent. A salt is the product of reacting a base with an acid. Like many physiologically active chemicals, controlled drugs are mostly bases, often described as nitrogenous bases or, in some cases, alkaloids. For various reasons, including stability and ease of handling, the salts, especially hydrochlorides and sulfates, less commonly tartrates and phosphates, are more often seen in both commercial and illicit products than the parent substances. Schemes 7.10 and 7.11 show two examples of the formation of salts.

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Scheme 7.10  The  conversion of amphetamine to amphetamine sulfate.

Scheme 7.11  The  conversion of methylamphetamine to methylamphetamine hydrochloride.

Scheme 7.12  The  conversion of a 5,5-­disubstituted barbituric acid to form the di-­anion.

Acidic drugs are uncommon; the best examples amongst controlled drugs are the barbiturates. The reaction of a 5,5-­disubstituted barbituric acid with alkali (pH > 10) produces the di-­anion (Scheme 7.12). Unless a prosecution wishes to bring a charge of production of a base from a salt (e.g., crack cocaine from cocaine hydrochloride), then it is not necessary for the forensic chemist to identify whether a questioned substance is in its free form (base or acid) or a particular salt. However, an understanding of the relationship between bases, acids and salts is necessary to comprehend the two different methods of expressing the purity of substances that form salts (Chapter 23).

7.5  Homologues A particular type of derivative is known as a homologue. This term is used to describe a compound belonging to a series of compounds differing from each other by a standard repeating unit, such as a methylene group, a peptide residue, etc. The simplest example occurs with the straight chain alkanes. Thus methane, ethane, propane, n-­butane, etc., are part of a homologous series where the constant difference between adjacent members is a methylene

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(CH2) moiety. It is therefore correct to say, for example, that ethane, propane, n-­butane, etc., are the higher homologues of methane and that methane and ethane are the lower homologues of propane. A clear homologous series is represented by alkyl nitrites (e.g., isopropyl nitrite, isobutyl nitrite and amyl nitrite; see Chapter 5), and by the series cathinone, methcathinone and ethcathinone (Chapter 8). Some synthetic cannabinoid receptor agonists (SCRAs) form homologous series (Chapter 18). The compound CP 47,497 provides a good example. This hydroxycyclohexylphenol has a methyloctan-­2-­yl substituent at the 5-­position of the phenolic ring, but the homologous dimethyloctyl – and dimethylheptyl – substituted forms are also known. As a first response to the problem of SCRAs, the Austrian government modified the Pharmaceutical Law in March 2009 to prohibit the importation or marketing of, inter alia, CP 47,497 and its homologues. However, some other definitions of homologue are far less inclusive; they require that functional groups do not change across the series. As an example of this stricter interpretation, 3,4-­methylendioxymethylamphetamine (MDMA) would not be regarded as a homologue of 3,4-­methylendioxyamphetamine (MDA). Although the two compounds differ by CH2, the former is a secondary amine, but the latter is a primary amine. However, in all systems 3,4-­methylenedioxyethylamphetamine (MDEA) is a homologue of MDMA. A more subtle role of functional groups is illustrated when they may be separated by successive CH2 groups. Tolperisone (Scheme 7.13) is a β-­aminoketone related to the α-­aminoketone cathinone derivative shown in Scheme 7.14. However, the additional CH2 group which separates the keto function from the amino group brings about major changes in the pharmacological properties. Thus, tolperisone is a centrally-­acting muscle relaxant,2 but the corresponding (i.e., desmethylene) cathinone derivative in Scheme 7.14 is expected to be a CNS stimulant. In this situation, some would modify the

Scheme 7.13  2-­  M ethyl-­1 -­( 4-­m ethylphenyl)-­3 -­( 1-­p iperidinyl)propan-­1 -­o ne; tolperisone.

Scheme 7.14  2-­  Methyl-­1-­(4-­methylphenyl)-­3-­(1-­piperidinyl)ethan-­1-­one; a cathinone derivative.

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definition of a homologous series such that no major change in pharmacological properties should occur across the series. In that case, tolperisone would not be a homologue of a cathinone derivative. A further example of this is illustrated by the cyclohexylbenzamide opioids shown in Chapter 14. Thus, the substance U-­47700 is listed in the UN 1961 Convention but U-­51754 has been reported as an NPS. The latter compound, a benzeneacetamide derivative, differs from U-­47700, a benzamide, in that it contains a methylene bridge. It could be argued that the pair are homologues but it is unclear if they have a similar pharmacology. The definition of a homologue has a long history of proving a troublesome concept in legislation. The Pharmacy and Poisons Act 1933, referred to ‘Ergot, alkaloids of; their homologues’, but it was never established what was meant by ‘homologue’ and in particular whether it included LSD (see also Chapter 28). In the current UK legislation, the term homologue can be found in respect of cannabinol and its tetrahydro derivatives. This is discussed in detail in Chapter 17 where the meaning of homologue has again been contentious.

7.6  Stereoisomers While isomers are compounds with the same chemical formula, stereoisomers are particular isomers with identical constitution, but with different spatial arrangements of their atoms in the molecule; this may lead to different physical and pharmacological properties. They are a particular type of geometrical isomerism, where the molecule contains one or more chiral centres. Different spatial arrangements at the chiral centre give rise to molecules that are related as mirror images and are called enantiomers. Such molecules are normally optically active (they rotate the plane of polarised light) and were formerly designated (d) [from dexter] or (+) or were designated (l) [from laevus] or (−). The (+) and (−) forms cause rotation to the right and left, respectively. They may also form an optically neutral racemate, i.e., a mixture of equal numbers of (+) and (−) molecules, shown as (dl) or ‘(±)’. However, these terms are now obsolete; the present standard designation for steric configuration (the Cahn–Ingold–Prelog or CIP rule) is the R (rectus) and S (sinister) notation. It is related to the absolute steric configuration of substituents at chiral centres. The CIP rule replaced an earlier absolute system that used the designation d (derived from Dextrose) and l (derived from Laevulose, i.e., fructose). Neither the CIP system (R or S) nor the d/l systems bear any correlation with the direction of optical rotation. Stereoisomerism is not uncommon amongst controlled drugs. In all cases, the chiral centre involves an asymmetric carbon atom, that is to say, one having four different substituents. With a few named exceptions, discussed later, all stereoisomers of controlled drugs are controlled. As with salts, in a criminal trial there is no need for the prosecution to name a particular stereoisomeric form. Scheme 7.15 shows the two enantiomers of amphetamine, where each is a mirror image of the other such that neither is superimposable on the other.

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Scheme 7.15  The  two enantiomers of amphetamine; (S) left and (R) right. Whereas enantiomeric pairs are common, there are far fewer instances of controlled drugs with two or more chiral centres. A good example occurs in 2-­amino-­1-­phenylpropan-­1-­ol. Here there are two asymmetric carbon atoms giving rise to four stereoisomers as set out in Schemes 7.16 and 7.17. The 1S,2S enantiomer, also known as (+)-­norpseudoephedrine, is cathine (Class C). This is a mirror image of its 1R,2R enantiomer, i.e., (−)-­norpseudoephedrine. The 1S,2R and 1R,2S enantiomers are known as (+)-­ and (−)-­norephedrine, respectively. Each of the four stereoisomers is optically active; aqueous solutions of enantiomers at the same concentration will rotate the plane of polarised light to an equal extent, but in opposite directions. However, opposite pairs, e.g., (+)-­norephedrine and (+)-­norpseudoephedrine, known as diastereoisomers, will not produce an equal rotation. Thus, in this example, there are two pairs of enantiomers and four diastereoisomers. The two stereoisomers of norephedrine, when present as a racemic mixture, are known as phenylpropanolamine, although, confusingly, this term has sometimes been used to refer only to the 1R,2S isomer. Cathine can be distinguished from its non-­controlled diastereoisomers, i.e., (+)-­and (−)-­norephedrine using chiral chromatography. Phenylpropanolamine, as a decongestant drug, is excluded from control in Part III of Schedule 2 of the MDAct. It has been withdrawn from use in many countries because of fears that it increases the risk of haemorrhagic stroke. Norephedrine can be used as a precursor to amphetamine; it is now included in Table I of the UN 1988 Convention and the corresponding EU and UK legislation (Chapter 27). A less common illicit use of norephedrine is as a precursor3 to the stimulant drug 4-­methylaminorex, a Class A drug in the UK and Schedule I in the UN 1971 Convention. Ephedrine and pseudoephedrine form an exactly similar group of four stereoisomers. An extreme case of stereoisomeric complexity amongst controlled drugs occurs with pentazocine, for example, which has three chiral centres and therefore, at least in theory, there could be eight diastereoisomers. Further exceptions for certain stereoisomers are made in the MDAct for dextromethorphan and dextrorphan. These are both of clinical value although dextromethorphan is occasionally misused. Their enantiomers (i.e., levomethorphan and levorphanol respectively) have much greater abuse potential and are both Class A controlled drugs. But apart from these exceptions, the stereoisomers of all other controlled drugs are themselves controlled. In 1998, following a proposal from the Spanish government, the WHO considered extending control of substances listed in the UN 1971 Convention to isomers, esters, ethers and ‘analogues’. Although some of these proposals

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Scheme 7.16  (1S,2S)-­  2-­Amino-­1-­phenylpropan-­1-­ol (left) and (1R,2R)-2-­amino-­ 1-­phenylpropan-­1-­ol (right).

Scheme 7.17  (1R,2S)-­  2-­Amino-­1-­phenylpropan-­1-­ol (left) and (1S,2R)-2-­amino-­ 1-­phenylpropan-­1-­ol (right).

would have brought the 1971 Convention into line with current UK practice, the proposals were rejected. Despite the positive experience of the UK with generic controls, the WHO considered that the changes might have a negative impact on legitimate industry. It also stated that control of ‘analogues’ would contradict its mandate of evaluating individual substances. The proposed control of isomers, as opposed to stereoisomers, was widely regarded as being too vague.

7.7  Isotopes The chemical elements (e.g., hydrogen, carbon, oxygen) each exist in a number of isotopic forms. These isotopes may be stable or unstable (radioactive). The isotopes of an element arise from the presence of different numbers of neutrons in their atomic nucleus. Their electronic structure and qualitative chemical properties are unchanged, but because they differ in mass, slight differences exist between the quantitative properties of the isotopes of a given element. Both stable and radioactive isotopes are widely used in analytical-­chemical, diagnostic and other medical procedures. The lightest element is hydrogen and it has three isotopes. The most abundant form (99.985%) is known simply as hydrogen or protium (1H). The nucleus contains one proton. Deuterium (2H or D) is also a stable isotope of hydrogen; it contains a proton and a neutron. The natural abundance of deuterium is 0.015%. A third isotope, known as tritium (3H or T), contains two neutrons and is radioactive. Tritium has an extremely low abundance and is normally manufactured in nuclear reactors. The enrichment of a chemical compound so as to increase the proportion of D is called deuteration. In certain cases, deuterium-­enriched molecules may have different physicochemical and pharmacokinetic properties. Ordinary carbon consists of two stable isotopes: 98.9% of mass twelve (12C) and 1.1% of mass thirteen (13C).

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Apart from hydrogen, isotopes of other elements do not have unique names or symbols. In a criminal trial in Sweden in the late 1990s, the defendants were charged with the unlawful manufacture of amphetamine. Their defence was that they intended to produce deuterated amphetamine, which was not a scheduled substance. After much debate and conflicting expert advice, the Supreme Court in Stockholm decided by a majority verdict on 5 July 1999 that deuterated amphetamine was to be considered as a substance under the Swedish Penal Law on Narcotics. There is now an almost unanimous view that the specification of a particular isotope which forms part of a controlled substance does not influence the fact that the substance is subject to control. If practical matters are ignored, i.e., whether suitable precursors are available and if the process is economically attractive, then the main arguments in favour of this view are as follows:    ●● Isotopically-­pure substances do not exist. In the case of normal amphetamine, where there are nine carbon and thirteen hydrogen atoms, 0.2% of molecules will have at least one hydrogen replaced by deuterium and 10% of molecules will have at least one 13C atom. An extreme example of this is afforded by the Class A controlled drug 4-­bromo-­2,5-­dimetho xy-­α-­methylphenethylamine (DOB). Considering the bromine atom in this molecule and ignoring isotopic variation in other atoms, then DOB exists in two almost equally abundant forms, i.e., a form containing 79Br (50.6%) and a form containing 81Br (49.4%). It can hardly be argued that one is controlled and the other not; the Act must cover both. If DOB were to be enriched or depleted in either bromine isotope, the product would still be controlled. By extension, the same argument applies to all isotopes. ●● As mentioned above, the biological properties of isotopic variants of controlled drugs differ only slightly from the normal compounds. There is no evidence that they cause any less social harm. ●● Isotopic variants are not distinct chemical entities.    A dissenting view is based on a conservative interpretation of the UN Conventions, namely there is no explicit mention of these variants in the international drug control treaties. There remains a possibility that any future case involving isotopic variants could again lead to lengthy technical and legal arguments in a Court. If it were felt that, despite the above arguments, the status of isotopic variants should be clarified unambiguously in the Act, then new paragraphs could be added to Parts I, II and III of Schedule 2 referring to ‘Any isotopic variants of a substance for the time being specified in paragraphs 1 or 2 (etc.) of this Part of this Schedule’. Regardless of the control status of isotopic variants, it should be recognised that deuterated drugs could cause analytical confusion when examined by mass spectrometry.

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References 1. IUPAC, Compendium of Chemical Terminology, https://goldbook.iupac.org/, accessed October 2021. 2. Tolperisone, https://en.wikipedia.org/wiki/Tolperisone, accessed October 2021. 3. W. R. Rodriguez and R. A. Allred, Microgram J., 2005, 3(3–4), 154, https:// www.erowid.org/library/periodicals/microgram/microgram_journal_ 2005-­2.pdf, accessed October 2021.

Chapter 8

Structure-­specific Generic Legislation 8.1  Introduction In a world where new substances do not appear too often then it is unsurprising that the standard method of control would be to name them as individual chemical entities or plant products. Specific listing has the advantage that there is no ambiguity about whether or not a substance is covered by the legislation. In other words, it satisfies the legal principle of certainty in criminal law. The major drawback is that, when new substances arise in quick succession, the legislative process of adding them one-­by-­one can prove increasingly burdensome. Ignoring salts, esters, ethers and generically-­defined substances, by 2020 over 600 named substances were listed in the UK MDAct. Generic control offers two useful possibilities. First, a group of known substances may be summarised by a few sentences of structure-­specific definition. Secondly, and perhaps more importantly, other substances that have not yet been seen in the illicit trade may be anticipated. A good example of the second point is shown by phenethylamines, which are discussed in more detail below. When the generic control of this family was introduced into UK law in 1977, it had no immediate impact. The few ring-­substituted phenethylamines that had appeared at that time had been listed specifically for some years, for example, mescaline (3,4,5-­trimethoxyphenethylamine), 4-­bromo-­ 2,5-­dimethoxy-­α-­methylphenethylamine (DOB) and 2,5-­dimethoxy-­α,4-­ dimethylphenethylamine (STP). What the legislation did achieve was to anticipate the appearance of MDMA some ten years later and then subsequently capture a large number of phenethylamines that appeared throughout the 1990s, none of which was well-­known, at least in Europe, in 1977.   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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The essence of a generic definition is that it starts with a core molecular structure. This may not in itself be liable to misuse, but the definition goes on to set out particular substituent groups at specified positions in that core molecule that do lead to controlled substances. In later sections, the definitions forming the generic controls on a wide range of chemical families are described in detail.

8.2  Generic Control in the UK before 1970 In 1964,1 an attempt was made to group a large number of CNS stimulants into a single definition. The Drugs (Prevention of Misuse) Act 1964 contained the following definition (with certain named exceptions): ‘Any synthetic compound structurally derived from either α-­methylphenethylamine or β-­methylphenethylamine by substitution in the side chain, or by ring closure therein, or by both such substitution and such closure…’. However, although this did indeed include compounds such as phentermine, methylphenidate and other prescription anorectics common in those days, it soon became clear that a refined interpretation included many drugs that were not stimulants. It was even argued that some barbiturates such as phenobarbitone were also captured. Difficulties then arose with interpretation when multiple bonds were present in the side chain or substitution by oxidation occurred in the side chain.2 This generic control was repealed in 1970.3 Following this early failure, it would be some years before generic control of phenethylamines again entered the legislation. But this time (1977), the focus would be on ring-­substituted phenethylamines, it would be much more robust and, as discussed below, would be followed by generic controls for many other groups.

8.3  Generic Control in the UK after 1970 When the MDAct appeared in 1971, it contained a few generic definitions that were intended to bring the legislation into agreement with the UN 1961 and 1971 Conventions. These limited definitions covered derivatives of cannabinol, ecgonine and lysergamide as well as pentavalent derivatives of morphine. Thus, under ‘Ecgonine’, the 1961 Convention included ‘its esters and derivatives which are convertible to ecgonine and cocaine’. Under ‘Morphine methobromide’ were listed ‘and other pentavalent nitrogen morphine derivatives, including in particular the morphine-­N-­oxide derivatives, one of which is codeine-­N-­oxide’. As discussed in Chapter 17, the generic definition of controlled cannabinols was intended to avoid the separate listing of the eight substances, including tetrahydrocannabinol (THC), in the 1971 Convention. The generic definition of ‘…other N-­alkyl derivatives of lysergamide’ (Chapter 20) controlled substances closely related to lysergide (LSD), although, like the cannabinols, it too had no generic ancestry in the UN Conventions.

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Table 8.1  Chemical  groups for which permanent generic controls operate under the MDAct, showing their year of first introduction and classification. Substances shown as (*) had been subject to earlier temporary control. The original definition of tryptamines was introduced in 1977 but revised in 2014. Synthetic cannabinoid receptor agonists were first brought under generic control in 2009. That definition was revised in 2013, again in 2016 and again in 2019. Cannabinols and cannabinol derivatives were originally in Class A, but later moved to Class C and finally Class B in 2008. The definition of cathinone derivatives was revised in 2011.

Group

Year

Class

Anabolic/Androgenic steroids Barbiturates Benzofurans and related compounds (*) N-­Benzylphenethylamines (*) Cannabinols Cathinones and related compounds Ecgonine derivatives Fentanyls Lysergide and derivatives of lysergamide Pentavalent derivatives of morphine Pethidines and alphaprodine derivatives Phenethylamines Phenyl-­and benzylpiperazines Phenylcyclohexylamine derivatives Pipradrol derivatives Synthetic cannabinoid receptor agonists Tryptamines

1996 1984 2014 2014 1971 2010 1971 1986 1971 1971 1986 1977 2009 2013 2012 2009 1977

C B B A B B A A A A A A C B B B A

Table 8.1 lists the groups for which generic control now exists in the UK under the MDAct, showing their year of introduction and classification. In the following definitions, substituents that lead to controlled substances are defined precisely. Thus ‘alkyl’ means a straight or branched chain saturated hydrocarbon (e.g., ethyl, isobutyl, etc.), but it does not include cycloalkyl or unsaturated carbon hydrocarbon chains (i.e., alkenyl and alkynyl, either linear or cyclic) and nor does it include any chain with atoms other than carbon or hydrogen. Because of the complexity of the substances controlled, discussion of generic definitions of synthetic cannabinoid receptor agonists (SCRAs) and tryptamines/lysergamides are dealt with separately in Chapters 18 and 20, respectively.

8.4  Anabolic/Androgenic Steroids An unusual feature of UK drugs law, shared with that of the US, is that it includes a large number of anabolic steroids. These substances not only lack psychoactivity but even include testosterone: an endogenous steroid that occurs naturally in human and other mammalian tissues. Anabolic/androgenic

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steroids are used illicitly by body builders to increase muscle mass and for cosmetic purposes. In the UK, these steroids, together with certain other anabolic substances, including polypeptide hormones, first entered the MDAct in 1996 as Class C controlled drugs (Appendix 6). That event had a contentious history since the wish to control such steroids came from the Home Office, but the ACMD was for some time reluctant to consider such control. The original intention was to focus on those substances the use of which was restricted in sporting events as determined by the International Olympic Committee. However, after the World Anti-­Doping Agency (WADA) assumed responsibility for the misuse of drugs in sport, other steroids were added to the MDAct that were not principally anabolic (e.g., danazol). A number of ‘designer steroids’ intended to evade legislation were associated with the BALCO company4 in San Francisco. The MDAct 1971 (Modification) Order 1996 (S.I. 1300)5 also included a generic definition of further anabolic steroids as follows:    ‘any compound (not being Trilostane or a compound for the time being specified in sub-­paragraph (b) above) structurally derived from 17-­hydroxyandrostan-­3-­one or from 17-­hydroxyestran-­3-­one by modification in any of the following ways, that is to say,    (i) by further substitution at position 17 by a methyl or ethyl group; (ii) by substitution to any extent at one or more of the positions 1,2,4,6,7,9,11 or 16, but at no other position; (iii) by unsaturation in the carbocyclic ring system to any extent, provided that there are no more than two ethylenic bonds in any one carbocyclic ring; (iv) by fusion of ring A with a heterocyclic system’.    Scheme 8.1 shows the steroid ring-­labelling and partial ring-­substituent numbering system. Schemes 8.2 and 8.3 show the general structure of the two steroids (i.e., 17-­hydroxyandrostan-­3-­one and 17-­hydroxyestran-­3-­one) upon which the above rules operate. Testosterone, a substance listed specifically, is shown in Scheme 8.4. Trilostane (Scheme 8.5), which would otherwise be captured by the generic definition, is specifically excluded since it has clinical value as an adrenocortical suppressant used in the treatment of breast cancer.

Scheme 8.1  The  ring-­labelling and partial ring-­substituent numbering system in steroids.

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Scheme 8.2  17-­Hydroxyandrostan-­  3-one, upon which part of the generic definition of a controlled steroid operates. Ring hydrogen atoms are omitted for clarity.

Scheme 8.3  17-­Hydroxyestran-­  3-one, upon which part of the generic definition of a controlled steroid operates. Ring hydrogen atoms are omitted for clarity.

Scheme 8.4  Testosterone,  a steroid listed specifically in the MDAct. Ring hydrogen atoms are omitted for clarity.

Scheme 8.5  Trilostane,  specifically excluded from control. Ring hydrogen atoms are omitted for clarity.

The MDAct 1971 (Modification) Order 2003 (S.I. 1243)6 added four more anabolic steroids, namely 4-­androstene-­3,17-­dione, 5-­androstene-­3,17-­diol, 19-­nor-­4-­androstene-­3,17-­dione and 19-­nor-­5-­androstene-­3,17-­diol, again as Class C drugs (Appendix 6). Scheme 8.6 shows 4-­androstene-­3,17-­dione: a steroid that fails the generic test because the substitution at position 17 is not by a methyl or ethyl group.

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Scheme 8.6  4-­  Androstene-­3,17-­dione, a steroid not covered by the generic definition, but added by name to the MDAct in 2003. Ring hydrogen atoms are omitted for clarity.

The MDAct 1971 (Amendment) Order 2009 (S.I. 3209)7 brought more anabolic steroids under control. A full list of named steroids now controlled in the UK is set out in Appendix 6. However, the control of anabolic steroids has not been without its problems. Thus, in November 2011, the Chairman of the ACMD wrote to the Minister recommending that two steroids (7-­hydroxy DHEA and 7-­keto DHEA) should be added to the MDAct. That advice was accepted and subsequently included in a Modification Order. However, the Statutory Instrument was never published. In February 2012, the previous advice was withdrawn since the ACMD had belatedly learnt that neither steroid was anabolic and both were used in dietary supplements. A Revocation Order came into force in March 2012.8 Since most countries take their lead on drug control from the UN Conventions, it is not surprising that few have controlled anabolic steroids. These substances are neither narcotics nor psychotropics and fall beyond the current scope of the international treaties. In the US Controlled Substances Act, over 50 anabolic substances are named. In both countries, esters or ethers of the controlled substances are subsumed, but only the UK has extended the list to include generic definitions as well as related products such as growth hormones, clenbuterol (a β2-­adrenergic agonist) and non-­steroidal anabolic agents (zeranol and zilpaterol).

8.5  Barbiturates The barbiturate drugs were once commonly-­used as hypnotics and were associated with many fatal poisonings. They are now rarely prescribed having been succeeded by much safer alternatives such as the benzodiazepines. Thiobarbiturates such as thiopentone (sodium pentothal) have found limited use as intravenous anaesthetics. The barbiturates are unusual in being acidic drugs whereas most psychoactive substances are bases. Control of barbiturates was introduced by The MDAct 1971 (Modification) Order 1984 (S.I. 859).9 Class B barbiturates are defined as: ‘any 5,5 disubstituted barbituric acid’. Scheme 8.7 shows a 5,5 disubstituted barbituric acid. In practice, all clinically useful barbiturates have alkyl, alkenyl or aryl at the R5a and

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Scheme 8.7  The  general form of a 5,5-­disubstituted oxo-­barbituric acid.

Scheme 8.8  5-­  Phenyl-­5-­ethyl-­3-­methylbarbituric acid; methylphenobarbitone.

Scheme 8.9  5-­  Ethyl-­4,6-­dioxo-­5-­(pentan-­2-­yl)-­1,4,5,6-­tetrahydropyrimidin-­2-­yl sulfanide; thiopentone.

R5b positions, and nearly all are not N-­substituted. Methylphenobarbitone (5-­phenyl-­5-­ethyl-­1-­methylbarbituric acid; Scheme 8.8), does not comply with this rule (because of the N-­methyl substituent) and is therefore listed specifically as a Class B drug. The term ‘barbituric acid’ is rather ambiguous; it can be interpreted to mean both oxo-­barbituric acid and thiobarbituric acid such that thiopentone (Scheme 8.9) is also a controlled drug; however, oxo-­ barbituric acid itself, having no 5,5-­disubstitution, is excluded from control. The 12 barbiturates listed in the UN 1971 Convention are shown in Table 8.2; this illustrates the economy of the UK generic definition. In the UN 1971 Convention, secobarbital is listed in Schedule II, amobarbital, butalbital, cyclobarbital and pentobarbital are in Schedule III; the remainder are in Schedule IV. The generic definition of barbituric acids enables an unknown substance to be uniquely assigned to a group of 5,5 disubstituted compounds by measuring its UV absorption spectra at pH values corresponding to the formation of a di-­anion, a mono-­anion and a neutral species. However, methylphenobarbitone and other 1,5,5-­trisubstituted barbituric acids only form neutral species and mono-­anions.

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Table 8.2  The  12 barbiturates listed in the UN Convention on Psychotropic Substances, 1971 – see Scheme 8.7.

Name

R

R5a

R5b

Allobarbital Amobarbital Barbital Butalbital Butobarbital Cyclobarbital Methylphenobarbital Pentobarbital Phenobarbital Secbutabarbital Secobarbital Vinylbital

H H H H H H Methyl H H H H H

Allyl Ethyl Ethyl Allyl Ethyl Ethyl Ethyl Ethyl Ethyl Ethyl Allyl Vinyl

Allyl Iso-­pentyl Ethyl Iso-­butyl n-­Butyl 1-­Cyclohexen-­1-­yl Phenyl 1-­Methylbutyl Phenyl s-­Butyl 1-­Methylbutyl 1-­Methylbutyl

Most barbiturates are covered by Schedule 3 of the MD Regulations, but quinalbarbitone (secobarbital) is named specifically in Schedule 2 of the Regulations. This is partly because of its higher intrinsic toxicity.10,11 Barbitone (5,5-­diethylbarbituric acid), a substance often used in buffering solutions, clearly qualifies as a Class B drug. But the MD Regulations exempt ‘a person in charge of a laboratory when acting in his capacity as such’ from the restrictions on possession and supply of barbitone (and any other Schedule 3 drug) when in the form of buffering solutions. The definition of a 5,5-­disubstituted barbituric acid also captures substances that are not listed in the UN 1971 Convention (e.g., 5,5-­diphenylbarbituric acid). A profile of barbiturates is available on the EMCDDA website.12

8.6  Benzofurans and Related Structures The generic definition of 1-­benzofurans and related compounds presents technical problems; a detailed discussion can be found in Chapter 10.

8.7  N-­Benzylphenethylamines Although it had been found many years ago that the introduction of alkyl substituents at the amine group in various phenethylamines led to a decrease in psychoactivity as the size of the alkyl groups increased, benzyl groups led to a marked increase in hallucinogenic activity.13,14 To a certain extent, these substances might also be described, not as phenethylamines derivatives, but rather as substituted benzylamines, although benzylamine and its simple derivatives are not substances of misuse. The MDAct 1971 (Ketamine etc.) (Amendment) Order 2014 (S.I. 1106)15 brought a number of so-­called NBOMe compounds under permanent control as Class A drugs, some of which had been subject to earlier

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temporary control. The abbreviation NBOMe (N-­Benzyl-­O-­Methyl) refers to N-­benzylphenethylamines where the benzyl moiety is substituted in the ring with a methoxy group. One of the most potent substances in the group is 25I-­NBOMe. A common dose of the hydrochloride salt is 600–1200 micrograms. Dosage forms are typically small pieces of impregnated paper (blotters). The generic definition reads as follows:    ‘any compound (not being benzyl(α-­methyl-­3,4-­methylenedioxyphenethyl)amine) structurally derived from mescaline, 4-­bromo-­2,5-­dimethoxy-­α-­ methylphenethyl-­amine, 2,5-­dimethoxy-­α,4-­dimethylphenethylamine, N-­ hydroxytenamphetamine, or a compound specified in sub-­paragraph (ba) or (c) above, by substitution at the nitrogen atom of the amino group with a benzyl substituent, whether or not substituted in the phenyl ring of the benzyl group to any extent’.    The excluded substance in the definition, i.e., benzyl(α-­methyl-­3,4-­ methylenedioxy-­phenethyl)amine, is one of the PiHKAL substances added to the MDAct in 2001 (Appendix 7). In some ways it is a prototype of the NBOMe compounds that would appear many years later. Some examples of compounds that fall within the definition are shown in Schemes 8.10 and 8.11. Many other members of this group have been reported to EMCDDA, for example 25I-­NB4OMe, 25C-­NBOH, 25I-­NBOH, 25B-­NBOH, 25I-­NBF, 25C-­ NBF, 25H-­NBOMe, 25iP-­NBOMe, 25D-­NBOMe 25E-­NBOMe as well as more

Scheme 8.10  2-­  (4-­Chloro-­2,5-­dimethoxyphenyl)-­N-­[(2-­methoxyphenyl)methyl]-

ethanamine; 25C-­NBOMe; 25C, a controlled N-­benzylphenethylamine.

Scheme 8.11  2-­  (4-­Iodo-­2,5-­dimethoxyphenyl)-­N-­[(2-­methoxyphenyl)methyl]ethanamine; 25I-­NBOMe; 25I; Cimbi-­5, a controlled N-­benzylphenethylamine.

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complex forms such as 25I-­NBMD, C30-­NBOMe, 5-­APB-­NBOMe 4MMA-­ NBOMe, 4-­EA-­NBOMe and 3,4-­DMA-­NBOMe. An extensive list of these compounds is available.16 The carbon-­11 labelled version of 25I-­NBOMe, also known as [11C]Cimbi-­5, has been used as a radiotracer for positron emission tomography. As a 5-­HT2A receptor full agonist [11C]Cimbi-­5 shows promise as a functional marker of this receptor.17 Despite this application, all NBOMe compounds controlled by the above definition were placed in Schedule I of the MD Regulations (i.e., they are regarded as having no recognised medicinal use).

8.8  Cannabinols The generic control of cannabinols in the MDAct presents a number of complexities, and a detailed discussion is provided in Chapter 17.

8.9  Cathinone Derivatives The potential of 3,4-­methylenedioxycathinone derivatives as potential drugs of misuse was recognised by Dal Casson18 at the DEA laboratory in Chicago in 1997. By around 2006, it became clear that manufacturers of new substances were now trawling the world's scientific and patent literature in search of failed pharmaceuticals or, as they also became known, ‘designer medicines’. Illicit cathinone derivatives started to appear around 2008. At first, the most common substance in Europe was 4-­methylmethcathinone (mephedrone). The chemistry, pharmacology and toxicology of synthetic cathinone derivatives was reviewed by Kelly19 and a drug profile is available on the EMCDDA website.12 By late 2020, 156 cathinone family members have been seen in law enforcement seizures and collected samples in the EU. Several cathinone derivatives have long been listed as named compounds in the MDAct (i.e., diethylpropion, methcathinone and pyrovalerone). In 2010, an ACMD report20 proposed a generic definition for a wide range of substituted cathinone derivatives; legislation was subsequently introduced.21 Some early problems with the drafting of that Modification Order21 are described in Chapter 10. A few months later, an additional generic definition was created to bring a further group of cathinone derivatives including naphthylpyrovalerone under control.22,23 Cathinone derivatives make up the second largest group of substances reported to EMCDDA. There are 12 cathinones listed in the UN 1971 Convention as of 2020 (Table 8.3). All are in Schedule II apart from cathinone itself and methcathinone, which are in Schedule I. All are covered by the updated UK generic definition. Contrary to the statement on the Home Office/ACMD website,22 naphthylpyrovalerone is not listed in the UN 1971 Convention. The MDAct 1971 (Amendment No. 2) Order 2010 (S.I. 1833) was later amended by the MDAct 1971 (Amendment) Order 2011 (S.I. 744), which removed specific reference to 4-­methylmethcathinone. This drafting error is

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Table 8.3  Cathinone  and derivatives listed in the UN 1971 Convention. Common name

Name in the UN 1971 convention

Cathinone Methcathinone Clephedrone Ethylone MDPV

(−)-­(S)-­2-­Aminopropiophenone 2-­(Methylamino)-­1-­phenylpropan-­1-­one 1-­(4-­Chlorophenyl)-­2-­(methylamino)-­1-­propanone (RS)-­1-­(1,3-­Benzodioxol-­5-­yl)-­2-­(ethylamino)propan-­1-­one (RS)-­1-­(Benzo[d][1,3] dioxol-­5-­yl)-­2-­(pyrrolidin-­1-­yl)pentan-­1-­one (RS)-­2-­Methylamino-­1-­(4-­methylphenyl)propan-­1-­one (RS)-­2-­Methylamino-­1-­(3,4-­methylenedioxyphenyl)propan-­1-­one 2-­(Ethylamino)-­1-­(4-­methylphenyl)propan-­1-­one 1-­(2H-­1,3-­Benzodioxol-­5-­yl)-­2-­(ethylamino)pentan-­1-­one 2-­(Ethylamino)-­1-­phenyl-­1-­hexanone α-­Pyrrolidinovalerophenone (±)-­2-­(Methylamino)-­1-­phenylpentan-­1-­one

Mephedrone Methylone 4-­Methylethcathinone N-­Ethylnorpentylone N-­Ethylhexedrone α-­PVP Pentedrone

Scheme 8.12  2-Amino-1-phenyl-1-propanone  upon which the original generic definition operates.

described in more detail in Chapter 10. The final definition of Class B cathinone derivatives reads:    ‘Any compound (not being bupropion, cathinone, diethylpropion, pyrovalerone or a compound for the time being specified in sub-­paragraph (a) above) structurally derived from 2-amino-1-phenyl-1-propanone by modification in any of the following ways, that is to say,      (i) by substitution in the phenyl ring to any extent with alkyl, alkoxy, alkylenedioxy, haloalkyl or halide substituents, whether or not further substituted in the phenyl ring by one or more other univalent substituents; (ii)  by substitution at the 3-­position with an alkyl substituent; (iii) by substitution at the nitrogen atom with alkyl or dialkyl groups, or by inclusion of the nitrogen atom in a cyclic structure’.    Scheme 8.12 shows the general form of a substituted cathinone. To qualify as a Class B drug, the following criteria must be satisfied: R1 = H or alkyl; R2 = H or alkyl;

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2

3

R = H or alkyl or R and R are part of a cyclic structure; R4 = alkyl, alkoxy, alkylenedioxy or halogen (either singly or in any combination) with or without any other univalent substituents in the ring. The later definition reads as follows:    ‘Any compound structurally derived from 2-­aminopropan-­1-­one by substitution at the 1-­position with any monocyclic, or fused polycyclic ring system (not being a phenyl ring or alkylenedioxyphenyl ring system), whether or not the compound is further modified in any of the following ways, that is to say,    (i) by substitution in the ring system to any extent with alkyl, alkoxy, haloalkyl or halide substituents, whether or not further substituted in the ring system by one or more other univalent substituents; (ii) by substitution at the 3-­position with an alkyl substituent; (iii) by substitution at the 2-­amino nitrogen atom with alkyl or dialkyl groups, or by inclusion of the 2-­amino nitrogen atom in a cyclic structure’.    Scheme 8.13 shows the general form of an aryl-­substituted cathinone. To qualify as a Class B drug, the following criteria must now be satisfied: R5 = any monocyclic, or fused polycyclic ring system (not being a phenyl ring or alkylenedioxyphenyl ring system); R1 = H or alkyl; R2 = H or alkyl; R3 = H or alkyl or R2 and R3 are part of a cyclic structure; R4 = alkyl, alkoxy, alkylenedioxy or halogen (either singly or in any combination) with or without any other univalent substituents in the ring. The two definitions of cathinones need to be read in conjunction. Scheme 8.14 shows 4-­methylmethcathinone.

Scheme 8.13  Substitution  patterns in the structure of 2-amino-1-aryl-1propanone (R5 = aryl and R4 is a substituent in R5).

Scheme 8.14  2-­  Methylamino-­1-­(4-­methylphenyl) propan-­1-­one; 4-­methylmeth-

cathinone, controlled under the MDAct as a Class B drug by the definition of a substituted 2-amino-1-phenyl-1-propanone.

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Scheme 8.15 shows cathinone, which is controlled under the MDAct as a named Class C drug. Scheme 8.16 shows 4-­methyl-­N-­benzylcathinone, a compound encountered in illicit products, but which is not covered by either of the above definitions since the N-­benzyl substituent is not mentioned in the definitions. Scheme 8.17 shows 1-­naphthalen-­2-­yl-­2-­pyrrolidin-­1-­ylpentan-­ 1-­one, commonly known as naphyrone (a term also used to describe the 1-­naphthalen-­2-­yl positional isomer). Naphyrone is controlled as a Class B drug by the second definition above. Scheme 8.18 shows bupropion, which is specifically excluded from control since it is an active pharmaceutical ingredient in medicinal products (e.g., Wellbutrin®, Zyban®) where it is used as an antidepressant and an aid for the cessation of smoking. Scheme 8.19 shows pyrovalerone, a substance excluded from either generic definition, but which remains controlled as a named Class C drug. Scheme 8.20 shows a phthalimidopropiophenone, a substance that is believed to act as a metabolic precursor to cathinone. It is covered by the generic definition, as would phthalimido analogues of many other cathinone derivatives.

Scheme 8.15  (S)-­  2-­Amino-­1-­phenyl-­1-­propanone; cathinone, controlled under the MDAct as a named Class C drug.

Scheme 8.16  4-­  Methyl-­N-­benzylcathinone; benzedrone; 4-­MBC, an illicit product

that is not covered by either of the generic definitions of a substituted 2-amino-1-phenyl-1-propanone.

Scheme 8.17  1-­  (Naphthalen-­2-­yl)-­2-­(pyrrolidin-­1-­yl)pentan-­1-­one; naphyrone; NRG-­1;

naphthylpyrovalerone, controlled under the MDAct as a Class B drug by the updated definition of a substituted 2-amino-1-aryl1-propanone.

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Scheme 8.18  2-­  (tert-­Butylamino)-­1-­(3-­chlorophenyl)propan-­1-­one; bupropion, a substance specifically excluded from control.

Scheme 8.19  1-­  (4-­Methylphenyl)-­2-­(1-­pyrrolidinyl)pentan-­1-­one; pyrovalerone, a substance not covered by the generic definitions, but which remains as a named Class C drug.

Scheme 8.20  Phthalimidopropiophenone,  a substance covered by the generic definition of a controlled cathinone derivative.

8.10  Ecgonine Derivatives Ecgonine was listed in 1971 as a Class A drug in Part I of Schedule 2 to the MDAct. It is not an abusable substance per se, but one of several drug intermediates (i.e., precursors) that occur in the MDAct (Chapter 27). The full entry, which derives directly from the UN 1961 Convention, reads ‘Ecgonine, and any derivative of ecgonine which is convertible to ecgonine or to cocaine’. The relationship between ecgonine and cocaine is shown in Schemes 8.21 and 8.22. It will be seen that they differ at both the 2-­ and 3-­positions of the tropane ring. A more detailed treatment of cocaine can be found in Chapter 19, and a discussion of what ‘…convertible to ecgonine or to cocaine’ might mean is covered in Chapter 12. Scheme 8.23 shows benzoylecgonine: a substance which would qualify as a controlled derivative of ecgonine because it can be converted to cocaine by esterification and converted to ecgonine by hydrolysis. Scheme 8.24 shows cocaethylene, the ethyl ester of benzoylecgonine and the higher homologue of cocaine. It is a metabolic product of the concurrent consumption of cocaine and ethanol. Since it is readily converted to ecgonine, it qualifies as a Class A controlled drug.

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Scheme 8.21  3-­Hydroxy-­  8-­methyl-­8-­azabicyclo[3.2.1]octane-­2-­carboxylic acid; ecgonine, showing the ring-­numbering system.

Scheme 8.22  Methyl  (1R,2R,3S,5S)-­3-­(benzoyloxy)-­8-­methyl-­8-­azabicyclo-­[3.2.1]octane-­2-­carboxylate; cocaine, the methyl ester of benzoylecgonine.

Scheme 8.23  (1R,2R,3S,5S)-­  3-­Benzoyloxy-­8-­methyl-­8-­azabicyclo[3.2.1]octane-­2-­ carboxylic acid; benzoylecgonine, a controlled derivative of ecgonine.

Scheme 8.24  Cocaethylene,  the ethyl ester of benzoylecgonine.

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8.11  Fentanyls Fentanyl (Scheme 8.25) is a widely-­used potent narcotic analgesic. It was first produced in 1960 and is available as injection solutions, nasal spray, tablets and skin patches. It is listed as a Class A drug in the UK and as Schedule I in the UN 1961 Convention. As noted in Chapter 13, a number of illicit fentanyl derivatives (aka fentanils) were manufactured during the 1980s as heroin substitutes. In response to this problem, the UK Government decided to introduce generic controls on fentanyl analogues. This was enacted by the MDAct 1971 (Modification) Order 1986 (S.I. 2230).24 A profile of fentanyls is available on the EMCDDA website.12 Class A fentanyls are defined as:    ‘any compound (not being a compound for the time being specified in sub-­ paragraph (a) above) structurally derived from fentanyl by modification in any of the following ways, that is to say,    (i) by replacement of the phenyl portion of the phenethyl group by any heteromonocycle whether or not further substituted in the heterocycle; (ii) by substitution in the phenethyl group with alkyl, alkenyl, alkoxy, hydroxy, halogeno, haloalkyl, amino or nitro groups; (iii) by substitution in the piperidine ring with alkyl or alkenyl groups; (iv) by substitution in the aniline ring with alkyl, alkoxy, alkylenedioxy, halogeno or haloalkyl groups; (v) by substitution at the 4-­position of the piperidine ring with any alkoxycarbonyl or alkoxyalkyl or acyloxy group; (vi) by replacement of the N-­propionyl group by another acyl group’.    There are four named fentanyl derivatives in the MDAct as Class A drugs (alfentanil, carfentanil, lofentanil and sufentanil). They were added in 1986 at the same time as the above generic definition was introduced. Since all four are covered by the above definition, the reason for this effective double listing is unclear. As examples of controlled fentanyl analogues, lofentanil (Scheme 8.26) passes the generic test because the 3-­methyl substituent in

Scheme 8.25  N-­  Phenyl-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]propanamide; fentanyl.

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the piperidine ring and the 4-­methoxycarbonyl substituent are both permitted. In sufentanil (Scheme 8.27), the replacement of the phenethyl group by thiophenylethyl as well as the 4-­methoxymethyl substituent in the piperidine ring are both permitted. In the following structures, the reason for capture by the definition is shown by reference to the subsections (i to vi) in the above definition. Remifentanil (Scheme 8.28) fails to meet

Scheme 8.26  Methyl  (3S,4R)-­3-­methyl-­1-­(2-­phenylethyl)-­4-­(phenylpropanoylamino)-­ 3-­piperidine-­4-­carboxylate; lofentanil, a Class A substance controlled by the generic definition of a substituted fentanyl (subsections iii and v).

Scheme 8.27  N-­  [ 4-­( Methoxymethyl)-­1 -­( 2-­t hiophen-­2 -­y lethyl)-­4 -­p iperidyl]-­N -­ phenylpropanamide; sufentanil, a Class A substance controlled by the generic definition of a substituted fentanyl (subsections i and v).

Scheme 8.28  Methyl  1-­(3-­methoxy-­3-­oxopropyl)-­4-­(N-­phenylpropanamido)-­piperidine-­ 4-­carboxylate; remifentanil, a Class A substance which is not covered by the generic definition of a substituted fentanyl but is listed specifically.

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the fentanyl derivatives generic description because the phenethyl group has been replaced with a group not specified in the definition. Remifentanil (Schedule I in the UN 1961 Convention) was added to the MDAct as a named Class A drug in 2003. Two of the most commonly-­reported illicit fentanyl derivatives in earlier years, namely α-­methylfentanyl and 3-­methylfentanyl, are shown in Schemes 8.29 and 8.30 respectively; they are both captured by the generic definition. Ojanperä et al.25 described an epidemic of fatal 3-­methylfentanyl poisoning in Estonia in 2008. In the past decade, there has been a sharp increase in overdose deaths involving illicitly manufactured fentanyl and related substances in the US.26 Illicit interest in fentanyl and its analogues then remained low for many years, but by 2012 many novel fentanyl derivatives started to appear in Europe, and these are described below and in Appendix 11. Seven fentanyl derivatives were risk assessed by the EMCDDA (Appendix 1), namely acryloylfentanyl, carfentanil, cyclopropylfentanyl, 4F-­iBF, furanylfentanyl, methoxyacetylfentanyl and THF-­F; their structures and relationship to the existing generic controls are described below (Schemes 8.31–8.37).

Scheme 8.29  N-­  Phenyl-­N-­[1-­(1-­phenylpropan-­2-­yl)piperidin-­4-­yl]propenamide; α-­ methylfentanyl, a Class A substance captured by the generic definition of a substituted fentanyl (subsection ii).

Scheme 8.30  (RS)-­  N-­(3-­Methyl-­1-­phenethyl-­4-­piperidyl)-­N-­phenyl-­propanamide; 3-­methylfentanyl, a Class A substance captured by the generic definition of a substituted fentanyl (subsection iii).

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Scheme 8.31  N-­  Phenyl-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]prop-­2-­enamide;

acryloylfentanyl, a Class A substance captured by the generic definition of a substituted fentanyl (subsection vi).

Scheme 8.32  Methyl  1-­(2-­phenylethyl)-­4-­[phenyl(propanoyl)amino]piperidine-­4-­ carboxylate; carfentanil, a Class A substance listed specifically and captured by the generic definition of a substituted fentanyl (subsection v).

Scheme 8.33  N-­  Phenyl-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]cyclopropane carboxamide; cyclopropylfentanyl, a Class A substance captured by the generic definition of a substituted fentanyl (subsection vi).

Scheme 8.34  4F-­  iBF; N-­(4-­Fluorophenyl)-­N-­[1-­(2-­phenylethyl)-­4-­piperidinyl]-­isobutana­

mide; 4-­fluoroisobutyrylfentanyl, a Class A substance captured by the generic definition of a substituted fentanyl (subsections iv and vi).

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Scheme 8.35  N-­  Phenyl-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]furan-­2-­carboxamide; furanylfentanyl, a Class A substance captured by the generic definition of a substituted fentanyl (subsection vi).

Scheme 8.36  2-­  M ethoxy-­N -­( 1-­p henethylpiperidin-­4 -­y l)-­N -­p henylacetamide;

methoxyacetylfentanyl, a Class A substance captured by the generic definition of a substituted fentanyl (subsection vi).

Scheme 8.37  N-­  Phenyl-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]oxolane-­2-­carboxamide;

tetrahydrofuranylfentanyl; THF-­F, a Class A substance captured by the generic definition of a substituted fentanyl (subsection vi).

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Scheme 8.38  (4R,4aR,7S,7aR,12bS)-­  3-­M ethyl-­2,3,4,4a,7,7a-­h exahydro-­1H-­4,12-­ methano[1]benzofuro[3,2-­e]isoquinoline-­7,9-­diol 3-­oxide; morphine N-­oxide, a pentavalent derivative of morphine.

8.12  Lysergide and Derivatives of Lysergamide The generic control of these substances is included with tryptamines in Chapter 20.

8.13  Pentavalent Nitrogen Derivatives of Morphine In Part I of Schedule 2 of the MDAct, control is extended to ‘morphine methobromide, morphine N-­oxide and other pentavalent nitrogen morphine derivatives’. This text is a modification of the original generic definition in the UN 1961 Convention, i.e., ‘Morphine methobromide and other pentavalent nitrogen morphine derivatives, including in particular the morphine-­N-­oxide derivatives, one of which is codeine-­N-­oxide’. Curiously, the Convention then lists morphine-­N-­ oxide as a separate item in Schedule I. However, these substances are rarely used or misused. Scheme 8.38 shows morphine N-­oxide in the alternative dipolar form as opposed to a pentavalent structure with a N=O bond.

8.14  Pethidine and Prodine Derivatives Pethidine (meperidine; Scheme 8.39) is an opioid analgesic and was first synthesised in the 1930s. It is the prototype of a large family of phenylpiperidines many of which are under international control. A medical disaster caused by a synthetic contaminant (MPTP) in the illicit synthesis of desmethylprodine is described in Chapter 13. Alongside the fentanyl derivatives (see above), generic legislation was also introduced into the UK in 1986 to control illicit derivatives of pethidine. This was enacted by The MDAct 1971 (Modification) Order 1986 (S.I. 2230).24 Class A derivatives of pethidine are defined as:    ‘any compound (not being a compound for the time being specified in sub-­ paragraph (a) above) structurally derived from pethidine by modification in any of the following ways, that is to say,   

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Scheme 8.39  Ethyl  1-­methyl-­4-­phenylpiperidine-­4-­carboxylate; pethidine, a named Class A controlled drug under the MDAct.

Scheme 8.40  4-­  Cyano-­1-­methyl-­4-­phenylpiperidine; pethidine intermediate A, which is not covered by the generic definition of a substituted pethidine, but listed by name as a Class A controlled drug.

(i) by replacement of the 1-­methyl group by an acyl, alkyl whether or not unsaturated, benzyl or phenethyl group, whether or not further substituted; (ii) by substitution in the piperidine ring with alkyl or alkenyl groups or with a propano bridge, whether or not further substituted; (iii) by substitution in the 4-­phenyl ring with alkyl, alkoxy, aryloxy, halogeno or haloalkyl groups; (iv) by replacement of the 4-­ethoxycarbonyl by any other alkoxycarbonyl or any alkoxyalkyl or acyloxy group; (v) by formation of an N-­oxide or of a quaternary base’.    A number of Class A drugs are closely related to pethidine. Thus, three pethidine intermediates (Chapter 27) were listed by name in the MDAct many years before the generic definition was introduced. None complies with the above definition; all three had originally been listed in the Dangerous Drugs Act 1964 and all derive from the UN 1961 Convention. They are 4-­cyano-­1-­methyl-­4-­phenylpiperidine (Pethidine Intermediate A; Scheme 8.40), 4-­phenylpiperidine-­4-­carboxylic acid ethyl ester (Pethidine Intermediate B; Scheme 8.41) and 1-­methyl-­4-­phenylpiperidine-­4-­carboxylic acid (Pethidine Intermediate C; Scheme 8.42). In the case of 4-­cyano-­1-­methyl-­4-­phenylpiperidine, the 4-­cyano group is unspecified in the generic definition, for 4-­phenylpiperidine-­4-­carboxylic acid ethyl ester, the 1-­methyl group has been replaced with hydrogen which is unspecified, for 1-­methyl-­4-­phenylpiperidine-­4-­carboxylic acid the 4-­ethoxycarbonyl is now the unspecified 4-­carboxylic acid.

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Scheme 8.41  4-­  Phenylpiperidine-­4-­carboxylic acid ethyl ester; pethidine intermediate B; norpethidine, which is not covered by the generic definition of a substituted pethidine, but listed by name as a Class A controlled drug.

Scheme 8.42  1-­  Methyl-­4-­phenylpiperidine-­4-­carboxylic acid; pethidine intermediate C, which is not covered by the generic definition of a substituted pethidine, but listed by name as a Class A controlled drug.

Scheme 8.43  1-­  Methyl-­4-­phenyl-­3-­(prop-­2-­en-­1-­yl)piperidin-­4-­yl propanoate; allylprodine, a Class A controlled drug listed by name in the MDAct and covered by the generic definition of a substituted pethidine/prodine (subsections ii and iv).

Several other substances are built on the same 1-­phenylpiperidine skeleton as pethidine. All are named Class A drugs under the MDAct and Schedule I in the UN 1961 Convention. Desmethylprodine, the reverse ester of pethidine, is covered by the generic definition as a Class A controlled drug (replacement of the 4-­ethoxycarbonyl group by an acyloxy group). These other 1-­phenylpiperidines are shown in Schemes 8.43–8.55.

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Scheme 8.44  (1,3-­  Dimethyl-­4-­phenylpiperidin-­4-­yl) propanoate; alphaprodine, a Class A controlled drug listed by name in the MDAct and covered by the generic definition of a substituted pethidine/prodine (subsections ii and iv).

Scheme 8.45  Ethyl  1-­[2-­(4-­aminophenyl)ethyl]-­4-­phenylpiperidine-­4-­carboxylate;

anileridine, a Class A controlled drug listed by name in the MDAct and covered by the generic definition of a substituted pethidine/prodine (subsection i).

Scheme 8.46  Ethyl  1-­[2-­(benzyloxy)ethyl]-­4-­phenylpiperidine-­4-­carboxylate; benzethi-

dine, a Class A controlled drug listed by name in the MDAct and covered by the generic definition of a substituted pethidine/prodine. In this interpretation of subsection (i), it is assumed that the benzyloxyethyl substituent on the piperidine ring represents the replacement of the 1-­methyl group by ethyl which is then further substituted with a benzyloxy group.

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Scheme 8.47  (1-­  Methyl-­4-­phenylpiperidin-­4-­yl) propanoate; desmethylprodine; MPPP, a Class A controlled drug not listed by name, but covered by the generic definition of a substituted pethidine/prodine in the MDAct as a Class A drug (subsection iv).

Scheme 8.48  1-­  (3-­Cyano-­3,3-­diphenylpropyl)-­4-­phenylpiperidine-­4-­carboxylic

acid; difenoxin, a Class A controlled drug listed by name in the MDAct and not covered by the generic definition of a substituted pethidine/prodine (N-­substituent not specified).

Scheme 8.49  Ethyl  1-­(3-­cyano-­3,3-­diphenylpropyl)-­4-­phenylpiperidine-­4-­carboxylate;

diphenoxylate, a Class A controlled drug listed by name in the MDAct and not covered by the generic definition of a substituted pethidine/prodine (N-­substituent not specified).

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Scheme 8.50  Ethyl  4-­( 3-­h ydroxyphenyl)-­1 -­m ethyl-­p iperidine-­4 -­c arboxylate;

hydroxypethidine, a Class A controlled drug listed by name in the MDAct and not covered by the generic definition of a substituted pethidine/prodine (Hydroxyl in phenyl ring not specified).

Scheme 8.51  Ethyl  1-­(3-­hydroxy-­3-­phenylpropyl)-­4-­phenylpiperidine-­4-­carboxylate;

phenoperidine, a Class A controlled drug listed by name in the MDAct and not covered by the generic definition of a substituted pethidine/ prodine (N-­substituent not specified).

Scheme 8.52  (3S,4R)-­  3-­Ethyl-­1-­methyl-­4-­phenylpiperidin-­4-­yl propanoate; alpha­ meprodine, a Class A controlled drug listed by name in the MDAct and covered by the generic definition of a substituted pethidine/prodine (subsections ii and iv).

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Scheme 8.53  Isopropyl  1-­methyl-­4-­phenylpiperidine-­4-­carboxylate; properidine, a

Class A controlled drug listed by name in the MDAct and covered by the generic definition of a substituted pethidine/prodine (subsection iv).

Scheme 8.54  (2S,5R)-­  1,2,5-­Trimethyl-­4-­phenylpiperidin-­4-­yl propanoate; trimeperidine; promedol, a Class A controlled drug listed by name in the MDAct and covered by the generic definition of a substituted pethidine/prodine (subsections ii and iv).

Scheme 8.55  1-­  [4-­(3-­Hydroxyphenyl)-­1-­methyl-­4-­piperidyl]propan-­1-­one; ketobemidone, a Class A controlled drug listed by name in the MDAct and not covered by the generic definition of a substituted pethidine/prodine (Hydroxyl in phenyl ring and 4-­propan-­1-­one substituent not specified).

8.15  Ring-­substituted Phenethylamines Just two ring-­substituted phenethylamine were originally listed by name in the MDAct in 1971, i.e., 2,5-­dimethoxy-­α,4-­dimethylphenethylamine (DOM) and mescaline, although a third, namely 4-­bromo-­2,5-­dimethoxy-­α-­methylphenethylamine (DOB), was added in 1975. Class A phenethylamines were brought under generic control by the MDAct 1971 (Modification) Order 1977 (S.I. 1243).27 The definition reads:    ‘any compound (not being methoxyphenamine or a compound for the time being specified in sub-­paragraph (a) above) structurally derived from

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phenethylamine, an N-­alkylphenethylamine, α-­methylphenethylamine, an N-­alkyl-­α-­methyl-­phenethylamine, α-­ethylphenethylamine, or an N-­alkyl-­α-­ ethylphenethylamine by substitution in the ring to any extent with alkyl, alkoxy, alkylenedioxy or halide substituents, whether or not further substituted in the ring by one or more other univalent substituents (Scheme 8.56)’.    To qualify as a Class A drug, the following criteria must be satisfied: R5 = H or alkyl; R6 = R1 = R2 = R3 = H; R4 = H, methyl or ethyl; Rx = alkyl, alkoxy, alkylenedioxy or halogen (either singly or in any combination) with or without any other univalent substituents in the ring. The focus of this definition is ring-­substitution in amphetamine-­like molecules. The reasoning is that the attachment of other atoms (especially oxygen, sulfur or halogen) to one or more of the carbon atoms (commonly the 2-­,4-­ or 5-­positions) in the aromatic ring of phenethylamine leads to major changes in pharmacological properties. While amphetamine and many of its side chain isomers and other simple derivatives (e.g., methylamphetamine, methcathinone, benzphetamine) are all central nervous system stimulants, suitable substitution in the ring can create hallucinogens (e.g., mescaline) or empathogenic/entactogenic agents which may or may not retain some stimulant activity. In the early to mid-­1990s, a number of seizures were made in Europe of 3,4-­methyledioxy-­amphetamine (MDA) and 3,4-­methyledioxy-­N-­ethylamphetamine (MDEA). Most of the MDA originated from a large illicit factory in Latvia. When this was closed down, MDA disappeared. The lifetime of MDEA was also brief; within a short time of its first appearance, it was added to the UN 1971 Convention. Another homologue of MDMA, namely N-­methyl-­1-­ (1,3-­benzodioxol-­5-­yl)-­2-­butanamine (MBDB), made a similarly short appearance on the European illicit market in the late 1990s. EMCDDA published a risk assessment report on MBDB in 1999 (Appendix 1). That report did not recommend EU-­wide control of MBDB, although it was already covered by the generic definition of a controlled ring-­substituted phenethylamine in the UK. As a less potent alternative to MDMA, the demise of MBDB was probably unrelated to its legal status. Some 4-­substituted phenethylamines appear to be particularly toxic for example PMA (para-­methoxyamphetamine) and PMMA (para-­methoxymethylamphetamine).28 The generic definition refers to certain substitution patterns in phenethylamine. The term ‘phenethylamine’ is a contraction for 2-­phenylethylamine

Scheme 8.56  Phenethylamine  (2-­phenylethylamine) showing substitution patterns.

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(also known as β-­phenylethylamine; Scheme 8.57); it does not refer to the isomeric 1-­phenylethylamine (also known as α-­phenethylamine; Scheme 8.58). Because of this distinction, derivatives of 1-­phenylethylamine (Chapter 14), even when they otherwise satisfy the substitution pattern set out in paragraph 1(c) of Part I of Schedule 2, are therefore not controlled drugs. The specific exception of methoxyphenamine (Scheme 8.59) was made because this drug, a prescription bronchodilator, would have fallen to control under the subsequent definition. However, methoxyphenamine was withdrawn from general use in the UK in 1986. Between 2009 and 2010, a number of illicit powders seized by the police in the UK were found to contain methoxyphenamine, some of which were mixed with mephedrone and some with BZP. Thus, the continued exemption of methoxyphenamine would now seem to be redundant. The generic definition deliberately excludes from control ring-­hydroxy phenethylamines, a group which includes naturally-­ occurring products such as dopamine, tyramine and adrenaline as well as clinically useful substances such as 4-­hydroxyamphetamine. However, substances with ring hydroxyl substitution and one or more of the specified ring-­ substituents would qualify for control. Schemes 8.60–8.67 show examples of phenethylamines, which either do or do not represent controlled drugs under the generic definition. Scheme 8.60 depicts the well-­known example of MDMA (3,4-­methylenedioxymethylamphetamine) which qualifies as a Class A controlled drug. The substance in Scheme 8.61, one of the ‘PiHKAL’ drugs,29 fails the generic test because of the α-­methoxy substituent, but is listed by name in Part I of Schedule 2 as 4-­bromo-­α,2,5-­trimethoxyphenethylamine (Appendix 7).

Scheme 8.57  2-­  Phenylethylamine.

Scheme 8.58  1-­  Phenylethylamine.

Scheme 8.59  Methoxyphenamine,  specifically excluded from control.

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Scheme 8.60  3,4-­  Methylenedioxymethylamphetamine; MDMA, a Class A substance controlled by the generic definition of a substituted phenethylamine.

Scheme 8.61  A  phenethylamine derivative from the ‘PiHKAL’ list (4-­bromo-­α,2,5-­ trimethoxyphenethylamine), not covered by the generic definition of a substituted phenethylamine, but listed by name as a Class A drug.

Scheme 8.62  2-­  (4,7-­Dimethoxy-­2,3-­dihydro-­1H-­indan-­5-­yl)ethylamine, a substance not covered by the generic definition of a substituted phenethylamine, but listed by name as a Class A drug.

Another PiHKAL substance is shown in Scheme 8.62 [2-­(4,7-­dimethoxy-­2,3-­ dihydro-­1H-­indan-­5-­yl)ethylamine]. This is not covered by the generic definition of a substituted phenethylamine but was listed by name as a Class A drug in 2001 (Appendix 7). It fails the generic test because the fused dihydroindan ring is not a univalent substituent. Scheme 8.63 shows an example of a non-­controlled phenethylamine (N,α-­dimethyl-­4-­nitrophenethylamine); it has been described as having pharmacological properties similar to those of analogous phenethylamines.30 It is not listed specifically and fails the generic test because of the 4-­nitro substituent and the absence of other defined ring-­substituents. Scheme 8.64 shows mebeverine, an antispasmodic drug, which does not qualify as a controlled phenethylamine. It too is not listed specifically and is not captured by the generic test because of the complex substituent on the nitrogen atom. Scheme 8.65 shows the p-­isomer (PMMA) of methoxyphenamine: a substance that falls within the generic definition. PMMA (para-­methoxymethylamphetamine) has been seen in drug seizures

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Scheme 8.63  A  non-­controlled phenethylamine (N,α-­dimethyl-­4-­nitrophene­

thylamine), not covered by the generic definition of a substituted phenethylamine and not listed by name in the MDAct.

Scheme 8.64  Mebeverine,  a phenethylamine derivative not covered by the generic definition of a substituted phenethylamine and not listed by name in the MDAct.

Scheme 8.65  para-­  Methoxymethylamphetamine (PMMA), the p-­isomer of methoxy­ phenamine and covered by the generic definition.

in Europe and was subjected to risk assessment by the EMCDDA in late 2001 (Appendix 1). Although their mass spectra, for example, do show some small differences, the forensic analyst would need to ensure that methoxyphenamine and PMMA are clearly distinguished from each other. Fenfluramine [(RS)-­N-­ethyl-­1-­[3-­(trifluoromethyl)phenyl]propan-­2-­amine; Scheme 8.66], an anorectic drug, is also excluded from control; it has a haloalkyl ring-­ substitution which is neither halide nor alkyl. The endogenous substance 3-­iodothyronamine (Scheme 8.67) that forms part of the endogenous thyroid system is captured by the generic definition because there is an allowed iodo-­ substituent and the ring is further substituted by another univalent substituent, i.e., the 4-­hydroxyphenoxy group. The generic controls on phenethylamines were remarkably far-­sighted and comprehensive. Not only did they successfully anticipate the major ecstasy drugs such as MDMA and its congeners, but the generic definition subsumed nearly all of the many ring-­substituted amphetamine-­t ype compounds which would appear in UK drug seizures over the next 25 years. PiHKAL29 provides

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Scheme 8.66  (RS)-­  N-­Ethyl-­1-­[3-­(trifluoromethyl)phenyl]propan-­2-­amine; fenfluramine, an anorectic drug excluded by the generic definition and not listed specifically.

Scheme 8.67  4-­  [4-­(2-­Aminoethyl)-­2-­iodophenoxy]phenol; 3-­iodothyronamine, an

endogenous substance that is captured by the definition of a ring-­ substituted phenethylamine.

synthetic methods for over 170 substances with notes on their effects and doses. Of these, over 30 were not covered by the generic definition of 1977. Since many of the PiHKAL drugs were broadly similar to the well-­known ecstasy compounds and related hallucinogens, the UK Government recognised that they presented a potential social problem. Although consideration had been given to extending the generic definition of phenethylamines, two arguments worked against this approach. Firstly, the non-­controlled substances formed a heterogeneous set of chemical structures, the inclusion of which would have needed an elaborate definition. This then risked including substances of current or future interest to the pharmaceutical industry. Secondly, the generic control of 1977 has worked remarkably well with no forensic difficulty, but its enlargement could pose a danger not just of incomprehension but of creating loopholes by virtue of its complexity. In 2001, 34 PiHKAL substances were added to the MDAct where they are listed by name as Class A controlled drugs. Although some of these substances were probably inactive or had other properties which would have made them undesirable to users, it was considered a safe precaution to include them all. The list does not include the parent compound, phenethylamine itself, nor, through an apparent oversight, 2-­methoxy-­4,5-­methylenethio-­ oxy-­amphetamine (PiHKAL #167). Another ring-­substituted phenethylamine (4-­methylthioamphetamine: 4-­MTA) that had not been listed in PiHKAL, but was risk assessed by EMCDDA in 1999 (Appendix 1), was also included. Yet further substances are mentioned in PiHKAL, albeit buried in monographs devoted to other substances. It was reasoned that having a lower profile they would be less likely to appear as substances of misuse. Appendix 7 lists the 34 ‘PiHKAL’ compounds and 4-­MTA firstly as they appear in the MDAct under their IUPAC names, then as their less formal

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names and acronyms. Where appropriate, the IUPAC name has been based on the more common root ‘3,4-­methylenedioxyphenyl-­Z’, where Z is some substituent or other part of the molecule, rather than the alternative root ‘1-­(1,3-­benzodioxol-­5-­yl)-­Z’. The 35 compounds fall into several structural groups. Groups 1–3 are divided into those (a) where, according to PiHKAL, positive psychoactive effects may be expected, and those (b), where no effect was detected, the effect was unpleasant or the dose was unacceptably high. Although the term ‘acronym’ is used for convenience both here and elsewhere, many of the code names for compounds described in PiHKAL are rarely pronounceable and bear a rather obscure relationship to the molecular structure. The phenethylamine period lasted until well into the 21st century. In this time, over 100 illicit phenethylamine derivatives would be found in police and customs seizures in Europe, but they are now less common. Apart from the occasional reappearance of PMA and PMMA, most had a short lifespan. The hallucinogenic members were rarely regarded as superior to established indole alkaloids such as LSD and psilocybin (‘magic mushrooms’), and the demand for such psychedelics was in any case limited. None of the other phenethylamines displaced MDMA as the entactogen of choice. A review of phenethylamines reported in Europe was published in 2014.31

8.16  Phenyl-­ and Benzylpiperazines Some piperazine derivatives could be described as ‘failed pharmaceuticals’, that is to say compounds that had been evaluated by the pharmaceutical industry as potential therapeutic agents, but which had never succeeded to market authorisation. The prototypical member of the piperazine family is 1-­benzylpiperazine (BZP), with numerous ring-­substituted phenylpiperazines eventually being seen. Evaluated by Burroughs Wellcome in the early 1970s as a potential antidepressant, BZP was soon found to have a similar pharmacology to amphetamine, albeit with less potency.32 There had been some illicit interest in BZP in the USA during the 1990s, but it became firmly established in New Zealand in the early part of this century. As a CNS stimulant, it was promoted as a safer alternative to methamphetamine. The piperazine derivatives arrived in Europe in around 2004; they came under EU-­wide control after 2007. A profile of piperazine derivatives is available on the EMCDDA website.12 In a rather curious consequence of the illicit interest in BZP, there was a widely held view by non-­chemists that it contained piperazine as the active ingredient, a non-­psychoactive anthelmintic drug for the treatment of intestinal roundworms. It seems that this was the basis upon which the Medicines and Healthcare Products Regulatory Agency (MHRA) decided that BZP was a medicinal product, even though it had no therapeutic use. As was pointed out by King and Nutt,33 BZP no more contains piperazine than amphetamine (α-­methylbenzene-­ethanamine) contains benzene. This error arose from

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ignoring a fundamental concept in elementary chemistry, namely the difference between a compound and a mixture. The piperazines occupied a transition state in the marketing of NPS. Some were found as tablets bearing the usual markings that signalled ecstasy, although later they would be in the form of loose powders. More importantly, the source was no longer a clandestine laboratory, but legitimate chemical supply companies, some of which were located in Asian countries. Since, by definition, the substances concerned were not initially controlled under drugs legislation, their production and distribution became far more overt. Alongside more traditional retail outlets (head shops), the growth of the internet opened up new channels for their sale, and for online ‘chat-­rooms’, where their properties could be openly discussed. Piperazine is shown in Scheme 8.68. Many derivatives of piperazine have been developed as pharmaceutical agents or intermediates. As far as illicit drugs are concerned, they fall into two main structural groups: the 1-­benzylpiperazines and the 1-­phenylpiperazines, both of which may be further substituted. Among the phenylpiperazines, at least one (1-­(3-­chlorophenyl)piperazine: mCPP) is used as a starting product for the manufacture of several antidepressant drugs, e.g., trazodone and nefazodone. Both benzyl-­ and phenylpiperazines were at one time widely reported as drugs of misuse in Europe and elsewhere; their general structures are shown in Schemes 8.69 and 8.70. Around 16 years ago, mCPP, occurring in fake ecstasy tablets, became one of the most common new substances of misuse in Europe.34 The group included mCPP and its positional isomer pCPP, MeOPP (1-­(4-­methoxyphenyl)piperazine), MPP (4-­methylphenylpiperazine), FPP (1-­(4-­fluorophenyl)piperazine), TFMPP (1-­(3-­trifluoromethylphenyl)piperazine), 1-­benzyl-­4-­methylpiperazine, MDBP (1-­(3,4-­methylenedioxybenzyl)piperazine) as well as BZP.

Scheme 8.68  Piperazine. 

Scheme 8.69  The  general form of a substituted benzylpiperazine.

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Scheme 8.70  The  general form of a substituted phenylpiperazine.

A generic control of Class C controlled derivatives of piperazine was introduced by the MDAct 1971 (Amendment) Order 2009 (S.I. 3209).6 The definition reads:    ‘1-­benzylpiperazine or any compound structurally derived from 1-­benzylpiperazine or 1-­phenylpiperazine by modification in any of the following ways—    (i) by substitution at the second nitrogen atom of the piperazine ring with alkyl, benzyl, haloalkyl or phenyl groups; (ii) by substitution in the aromatic ring to any extent with alkyl, alkoxy, alkylenedioxy, halide or haloalkyl groups’.    To qualify as a Class C controlled piperazine, the following conditions in Schemes 8.69 or 8.70 must be satisfied:    R1, R2 and R3 = any combination of alkyl, alkoxy, alkylenedioxy, halide or haloalkyl groups; R4 = alkyl, benzyl, haloalkyl or phenyl. Schemes 8.71–8.73 show, respectively, 1-­benzylpiperazine, 1-­(3-­trifluoro­methylphenyl)piperazine and 2C-­B-­BZP all of which were once reported in drug seizures but, like so many NPS, are now rarely seen. All three are controlled by the generic definition. However, the numerous diphenylmethylpiperazines, which have found use as antihistaminic and anti-­emetic drugs, for example cyclizine (1-­diphenylmethyl-­4-­methylpiperazine; Scheme 8.74), are deliberately excluded by the generic definition. Similarly, although the antipsychotic agent aripiprazole (7-­[4-­[4-­(2,3-­dichlorophenyl)piperazin-­1-­yl]butoxy]-­3,4-­dihydroquinolin-­ 2(1H)-­one; Scheme 8.75) is not covered by the generic definition, one of its metabolites (and synthetic precursor) is 1-­(2,3-­dichlorophenyl)piperazine, which would be controlled. Recently, pharmacologically-­distinct cinnamylpiperazine derivatives have appeared as NPS.35–37 Neither 1-­butyral-­4-­cinnamylpiperazine (bucinnazine,

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Scheme 8.71  1-­  Benzylpiperazine; BZP, controlled by the definition of a piperazine derivative.

Scheme 8.72  1-­  (3-­Trifluoromethylphenyl)piperazine; TFMPP, controlled by the definition of a piperazine derivative.

Scheme 8.73  4-­  Bromo-­2,5-­dimethoxybenzylpiperazine; 2C-­B-­BZP, controlled by the definition of a piperazine derivative.

Scheme 8.74  1-­  Diphenylmethyl-­4-­methylpiperazine; cyclizine, excluded from the definition of a piperazine derivative.

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Scheme 8.75  7-­  ( 4-­[ 4-­( 2,3-­D ichlorophenyl)piperazin-­1 -­y l]butoxy)-­3 ,4-­d ihydro­

quinolin-­2(1H)-­one; aripiprazole, excluded from the definition of a piperazine derivative.

Scheme 8.76  1-­  (5-­Amino-­2-­methoxyphenyl)-­4-­methylpiperazine, excluded from the definition of a piperazine derivative.

AP-­237), which is used as an analgesic medicine in Asia, nor its ring-­ methylated homologues, such as 2-­methyl-­AP-­237 and 2,6-­dimethyl-­AP-­237 (AP-­238), are covered by the generic legislation. Finally, 1-­(5-­amino-­2-­methoxyphenyl)-­4-­methylpiperazine (Scheme 8.76), a commercially available synthetic intermediate, would also be excluded from control. The 5-­amino group is an undefined substituent. Thus, in order for the compound to be controlled, the generic definition above would need to have the form ‘(ii) by substitution in the aromatic ring to any extent with alkyl, alkoxy, alkylenedioxy, halide or haloalkyl groups, whether or not substituted by other univalent groups’. The substance 2-­methylpiperazine (Scheme 8.77) is commercially available. Just as piperazine is the precursor to numerous piperazine derivatives such as BZP and mCPP, 2-­methylpiperazine could make an entirely analogous series of derivatives with a 2-­methyl group in the heterocyclic ring. It is not certain that they would be psychoactive, and they would fail to be covered by the above generic definition.

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Scheme 8.77  2-­  Methylpiperazine.

Scheme 8.78  1-­  (1-­Phenylcyclohexyl)piperidine; phencyclidine.

Scheme 8.79  N-­  Ethyl-­1-­phenylcyclohexylamine; eticyclidine, a named Class A substance in the MDAct.

8.17  Phenyl and Other Arylcyclohexylamines Although they are also based on the phenylpiperidine skeleton, the arylcyclohexylpiperidines have a quite different pharmacology to the pethidine family of opioid analgesics described earlier. Phencyclidine [1-­(1-­phenylcyclohexyl)piperidine; PCP; Scheme 8.78], once known as ‘angel dust’, is a hallucinogen and dissociative anaesthetic. No longer in use as a therapeutic agent, phencyclidine was succeeded by ketamine. Phencyclidine is listed in Schedule II of the UN 1971 Convention. It was added to the MDAct in 1979. However, although misuse of phencyclidine was once well-­known in the US, it has always been extremely rare in Europe. In 1984, three analogues of phencyclidine were added to the MDAct as named Class A substances: eticyclidine, rolicyclidine and tenocyclidine (Schemes 8.79–8.81). All three are in Schedule I of the UN 1971 Convention. Ketamine [2-­(2-­chlorophenyl)-­2-­methylamino-­cyclohexan-­1-­one; Scheme 8.82], which is not listed in the UN 1971 Convention, is also based on the phenylcyclohexylamine skeleton. It is a dissociative anaesthetic drug used in animal and emergency human surgery and, more recently as a potential, rapidly acting antidepressant.38 The S-­enantiomer (esketamine) is said to be more active in this respect. It is not strictly hallucinogenic but

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Scheme 8.80  1-­  (1-­Phenylcyclohexyl)pyrrolidine; rolicyclidine, a named Class A substance in the MDAct.

Scheme 8.81  1-­  (1-­(2-­Thienyl)cyclohexyl)piperidine; tenocyclidine, a named Class A substance in the MDAct.

Scheme 8.82  2-­  (2-­Chlorophenyl)-­2-­methylamino-­cyclohexan-­1-­one; ketamine. causes catalepsis (muscle rigidity) and leaves users feeling detached from their immediate environment. In the UK, ketamine is available for hospital use as injection solutions, but there are no preparations licensed for oral use. Misuse of ketamine was recognised almost 40 years ago in the US, but it did not come to notice until around 1990 in the UK.39 At that time, seizures often comprised ampoules of the proprietary preparations Ketalar and Vetalar or loose powders that had probably been produced by evaporation of these injection liquids. Illicit ketamine was later found in the form of well-­ made tablets, visually similar to, and often sold as, ecstasy tablets. Ketamine was originally listed in the MDAct as a Class C drug in 2005, but following increased reports of misuse it was moved to Class B in 2014. Ketamine is closely related to the veterinary anaesthetic tiletamine (Scheme 8.83). This is not controlled in the UK or internationally. In the 1990s, tiletamine appeared in the UK for a short time as illicit tablets. They were later found to have originated in the theft of material from a pharmaceutical company.39 By 2012, methoxetamine (MXE; Scheme 8.84) was reported as an illicit alternative to ketamine. Following temporary listing in 2012, methoxetamine was brought under permanent control as a Class B drug in 2013. It is listed

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Scheme 8.83  2-­  Ethylamino-­2-­(2-­thienyl)cyclohexanone; tiletamine, a substance specifically excluded from control in the UK.

Scheme 8.84  (R/S)-­  2-­(3-­Methoxyphenyl)-­2-­(ethylamino)cyclohexanone; methoxetamine; MXE, a named Class B substance in the MDAct.

in Schedule II of the UN 1971 Convention. The opportunity was taken by the ACMD in 2013 to develop a generic control40 to cover methoxetamine and other phenylcyclohexylamines as Class B drugs. The definition in the MDAct 1971 (Amendment) Order 2013 (S.I. 239)41 reads:    ‘1-­Phenylcyclohexylamine or any compound (not being ketamine, tiletamine or a compound for the time being specified in paragraph 1(a) of Part 1 of this Schedule) structurally derived from 1-­phenylcyclohexylamine or 2-­amino-­2-­phenylcyclohexanone by modification in any of the following ways, that is to say,    (i) by substitution at the nitrogen atom to any extent by alkyl, alkenyl or hydroxyalkyl groups, or replacement of the amino group with a 1-­piperidyl, 1-­pyrrolidyl or 1-­azepyl group, whether or not the nitrogen containing ring is further substituted by one or more alkyl groups; (ii) by substitution in the phenyl ring to any extent by amino, alkyl, hydroxy, alkoxy or halide substituents, whether or not further substituted in the phenyl ring to any extent; (iii) by substitution in the cyclohexyl or cyclohexanone ring by one or more alkyl substituents; (iv) by replacement of the phenyl ring with a thienyl ring’.    Because sub-­paragraph (ii) allowed, among others, substitution in the phenyl ring by hydroxy, it was necessary to amend the legislation to allow ethers and esters of these Class B drugs to be controlled. As discussed in Chapter 7, the control of esters and ethers previously only extended to Class A drugs and

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Scheme 8.85  1-­  Phenylcyclohexylamine, showing substitution patterns.

Scheme 8.86  2-­  Amino-­2-­phenylcyclohexanone, showing substitution patterns.

Scheme 8.87  N-­  Ethyl-­1-­(3-­methoxyphenyl)cyclohexan-­1-­amine; 3-­MeO-­PCE, a Class B substance controlled by the generic definition of a substituted 1-­phenylcyclohexylamine (subsections i and ii).

Class C anabolic/androgenic steroids. Schemes 8.85 and 8.86 show the basic skeletons of 1-­phenylcyclohexylamine and 2-­amino-­2-­phenylcyclohexanone upon which the above rules operate. A Class B drug arises if in Schemes 8.85 and 8.86, any of the following apply: R1 = one or more alkyl, alkenyl, hydroxyalkyl or the N atom is part of a saturated heterocyclic structure with 4, 5 or 6 carbon atoms, whether or not further substituted in that ring with one or more alkyl groups; R2 = one or more amino, alkyl, hydroxy, alkoxy, or halide groups whether or not further substituted in the ring to any extent; R3 = one or more alkyl groups; or: Replacement of the phenyl group with a thienyl group. Schemes 8.87–8.91 show other 1-­phenylcyclohexylamine and 2-­amino­2-­phenylcyclohexanone derivatives that are captured by this definition; all

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Scheme 8.88  2-­  (2-­Methoxyphenyl)-­2-­(methylamino)cyclohexanone; 2-­methoxy­ketamine

or 2-­MeO-­2-­deschloroketamine, a Class B substance controlled by the generic definition of a substituted 2-­amino-­2-­phenylcyclohexanone (subsections i and ii).

Scheme 8.89  1-­  [1-­(3-­Methoxyphenyl)cyclohexyl]-­piperidine; 3-­MeO-­phencyclidine,

a Class B substance controlled by the generic definition of a substituted 1-­phenylcyclohexylamine (subsections i and ii).

Scheme 8.90  1-­  [1-­(4-­Methoxyphenyl)cyclohexyl]-­piperidine; 4-­MeO-­phencyclidine, a Class B substance controlled by the generic definition of a substituted 1-­phenylcyclohexylamine (subsections i and ii).

have been reported as substances of misuse in Europe. None of the examples examined by the ACMD and shown in Schemes 8.87–8.91 gives rise to control by means of sub-­paragraph (iii) in the above definition, i.e., substitution in the cyclohexyl or cyclohexanone ring by one or more alkyl substituents. Although most arylcyclohexylamines are based on phenylcyclohexylamine, a few have other aryl-­substituents. Tiletamine (Scheme 8.83) has a thienyl substituent while benocyclidine (Scheme 8.92), a compound reported to EMCDDA by France in 2016, has a benzothiophenyl substituent. Benocyclidine is not captured by the above generic definition.

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Scheme 8.91  2-­  (2-­Chlorophenyl)-­2-­(ethylamino)cyclohexan-­1-­one; N-­ethyl-norketa­

mine, a Class B substance controlled by the generic definition of a substituted 2-­amino-­2-­phenylcyclohexanone (subsections i and ii).

Scheme 8.92  1-­  [1-­(1-­Benzothiophen-­2-­yl)cyclohexyl]piperidine; benocyclidine.

8.18  Pipradrol Derivatives Pipradrol, which acts as a relatively mild stimulant, was developed in the 1940s and found use initially for treating obesity and certain other conditions such as narcolepsy. Because of its potential for misuse, pipradrol was added to Schedule IV of the UN 1961 Convention. Control of pipradrol derivatives as Class B drugs was enacted by the MDAct 1971 (Amendment) Order 2012 (S.I.1390).42 The definition reads:    ‘Any compound (not being pipradrol) structurally derived from piperidine, pyrrolidine, azepane, morpholine or pyridine by substitution on a ring carbon atom with a diphenylmethyl group, whether or not the compound is further modified in any of the following ways, that is to say,    (i) by substitution in any of the phenyl rings to any extent with alkyl, alkoxy, haloalkyl or halide groups; (ii) by substitution on the methyl carbon atom with an alkyl, hydroxyalkyl or hydroxy group; (iii) by substitution on the ring nitrogen atom with an alkyl, alkenyl, haloalkyl or hydroxyalkyl group’.    Pipradrol (1,1-­diphenyl-­2-­piperidinemethanol; Scheme 8.93) remains as a Class C drug in the MDAct, and is listed in Schedule IV of the UN 1971 Convention and is effectively an obsolete anorectic drug. The first substance related to pipradrol to be found in illicit products was 1,1-­diphenyl-­2-­pyrrolidinylmethanol (diphenylprolinol, D2PM;

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Scheme 8.94); it is thought to have similar CNS stimulant properties to pipradrol. Subsequently, two more related substances appeared: desoxypipradrol (2-­(1,1-­diphenylmethyl)piperidine; 2-­DPMP; Scheme 8.95) and 2-­(1,1-­diphenylmethyl)pyrrolidine; desoxy-­D2PM; Scheme 8.96. All of the substances shown in Schemes 8.94–8.96 (i.e., D2PM, 2-­DPMP and desoxy-­ D2PM) are covered by the above definition. Neither D2PM nor desoxy-­D2PM are strictly designer drugs since both have been used as reagents. Thus (S)-­ D2PM, when condensed with borane, is used as an enantioselective catalyst in certain organic syntheses, while (S)-­desoxy-­D2PM has been used as chiral solvating agent in NMR analysis.43 The widely-­used antihistamine drug fexofenadine ([(RS)-­2-­[4-­[1-­hydroxy-­4-­ [4-­(hydroxy-­diphenyl-­methyl)-­1-­piperidyl]butyl]phenyl]-­2-­methyl-­propanoic

Scheme 8.93  1,1-­  Diphenyl-­2-­piperidinemethanol; pipradrol, a Class C drug in the MDAct and listed in Schedule IV of the United Nations 1971 Convention.

Scheme 8.94  1,1-­  Diphenyl-­2-­pyrrolidinylmethanol; D2PM, controlled under the MDAct by the generic definition of a pipradrol derivative.

Scheme 8.95  2-­  (1,1-­Diphenylmethyl)piperidine; desoxypipradrol; 2-­DPMP, con-

trolled under the MDAct by the generic definition of a pipradrol derivative.

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acid]; Scheme 8.97), like the closely related antihistamine terfenadine, fails the generic definition since the bulky substituent on the nitrogen atom of the piperidine ring is neither an alkyl, alkenyl, haloalkyl nor a hydroxyalkyl group. However, azacyclonol [diphenyl(piperidin-­4-­yl)methanol; Scheme 8.98], a positional isomer of pipradrol would be controlled. Although azacyclonol is now rarely used as a therapeutic agent, it is a precursor and metabolite of fexofenadine and terfenadine, but unlike pipradrol, azacyclonol has antidepressant properties and does not act as a stimulant.

Scheme 8.96  2-­  (1,1-­Diphenylmethyl)pyrrolidine; desoxy-­D2PM, controlled under the MDAct by the generic definition of a pipradrol derivative.

Scheme 8.97  (RS)-­  2-­[4-­[1-­Hydroxy-­4-­[4-­(hydroxy-­diphenyl-­methyl)-­1-­piperidyl]butyl]phenyl]-­2-­methyl-­propanoic acid; fexofenadine, a substance that is not covered by the generic definition of a controlled pipradrol derivative.

Scheme 8.98  Diphenyl(piperidin-­  4-­yl)methanol; azacyclonol, a discontinued antidepressant that is controlled under the MDAct by the generic definition of a pipradrol derivative.

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8.19  Synthetic Cannabinoid Receptor Agonists The generic definition of synthetic cannabinoid receptor agonists (cannabimimetics) presents a number of complexities; a detailed discussion can be found in Chapter 18.

8.20  Tryptamines The generic definition of tryptamines is described in Chapter 20.

References 1. The Drugs (Prevention of Misuse) Act 1964, https://www.parliament.uk/ about/living-­heritage/transformingsociety/private-­lives/relationships/ collections1/parliament-­a nd-­t he-­1 960s/dangerous-­drugs-­a ct-­1 964/, accessed October 2021. 2. G. F. Phillips, Chem. Br., 1972, 8(3), 123. 3. The Drugs (Prevention of Misuse) Act 1964 Modification Order 1970, https:// www.legislation.gov.uk/uksi/1970/1796/pdfs/uksi_19701796_en.pdf, accessed October 2021. 4. BALCO scandal, https://en.wikipedia.org/wiki/BALCO_scandal, accessed October 2021. 5. The Misuse of Drugs Act 1971 (Modification) Order 1996 (S.I. 1300), https://www.legislation.gov.uk/uksi/1996/1300/contents/made, accessed October 2021. 6. The Misuse of Drugs Act 1971 (Modification) Order 2003 (S.I. 1243), https://www.legislation.gov.uk/uksi/2003/1243/contents/made, accessed October 2021. 7. The Misuse of Drugs Act 1971 (Amendment) Order 2009 (S.I. 3209), https://www.legislation.gov.uk/uksi/2009/3209/contents/made, accessed October 2021. 8. The Misuse of Drugs Act 1971 (Designation) (Amendment) (England, Wales and Scotland), (Revocation) Order 2012, http://www.legislation.gov. uk/uksi/2012/384/pdfs/uksi_20120384_en.pdf, accessed October 2021. 9. The Misuse of Drugs Act 1971 (Modification) Order 1984 (S.I. 859), https://www.legislation.gov.uk/uksi/1984/859/contents/made, accessed October 2021. 10. L. A. King and A. C. Moffat, Lancet, 1981, (i), 387. 11. L. A. King and A. C. Moffat, Med., Sci. Law, 1983, 23(3), 193. 12. European Monitoring Centre for Drugs and Drug Addiction, Drug Profiles, https://www.emcdda.europa.eu/publications/drug-­profiles_en, accessed October 2021. 13. R. Heim, thesis, Frei Universität, Berlin, 2004, http://dx.doi.org/10.17169/ refubium-­16193, accessed October 2021. 14. A. L. Halberstadt, Curr. Top. Behav. Neurosci., 2017, 32, 283.

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15. The Misuse of Drugs Act 1971 (Ketamine etc.) (Amendment) Order 2014 (S.I. 1106), https://www.legislation.gov.uk/uksi/2014/1106/contents/ made, accessed October 2021. 16. 25-­NB, https://en.wikipedia.org/wiki/25-­NB, accessed October 2021. 17. A. Ettrup, M. Palner and N. Gillings, et al., J. Nucl. Med., 2010, 51(11), 1763. 18. T. A. Dal Cason, Forensic Sci. Int., 1997, 87(1), 9. 19. J. Kelly, Drug Test. Anal., 2011, 3(7–8), 439. 20. Advisory Council on the Misuse of Drugs, Consideration of the Cathinones, 2010, https://assets.publishing.service.gov.uk/government/uploads/system/ uploads/attachment_data/file/119173/acmd-­cathinodes-­report-­2010.pdf, accessed October 2021. 21. The Misuse of Drugs Act 1971 (Amendment) Order 2010 (S.I. 1207), https://www.legislation.gov.uk/uksi/2010/1207/made, accessed October 2021. 22. Home Office, Advisory Council on the Misuse of Drugs Naphyrone Report, 2010, https://www.gov.uk/government/publications/advisory-­council-­on-­ the-­misuse-­of-­drugs-­naphyrone-­report-­2010, accessed October 2021. 23. The Misuse of Drugs Act 1971 (Amendment No. 2) Order 2010 (S.I. 1833), https://www.legislation.gov.uk/uksi/2010/1833/contents/made, accessed October 2021. 24. The Misuse of Drugs Act 1971 (Modification) Order 1986 (S.I. 2230), https://www.legislation.gov.uk/uksi/1986/2230/contents/made, accessed October 2021. 25. I. Ojanperä, M. Gergov and M. Liiv, et al., Int. J. Leg. Med., 2008, 122, 115. 26. J. K. O'Donnell, J. Halpin and C. L. Mattson, et al., Centers for Disease Control and Prevention, MMWR Early Release, 2017, 66(43), 1197. 27. The Misuse of Drugs Act 1971 (Modification) Order 1977 (S.I. 1243), https://www.legislation.gov.uk/uksi/1977/1243/made, accessed October 2021. 28. L. A. King, Pharm. J., 2015, 294, 176. 29. A. Shulgin and A. Shulgin, PiHKAL: A Chemical Love Story, Transform Press, Berkeley, California, 1991, ISBN 0-­9630096-­0-­5. 30. J. Knoll, E. S. Vizi and Z. Ecseri, Arch. Int. Pharmacodyn. Ther., 1966, 159(2), 442. 31. L. A. King, Drug Test. Anal., 2014, 6(7–8), 808. 32. L. A. King and S. Elliott, Review of the pharmacotoxicological data on 1-­benzylpiperazine (BZP), in Report on the risk assessment of BZP in the framework of the Council Decision on new psychoactive substances, EMCDDA, 37–55, 2009. ISBN: 978-­92-­9168-­345-­1, https://www.emcdda.europa.eu/ publications/risk-­assessments/bzp_en, accessed October 2021. 33. L. A. King and D. Nutt, Lancet, 2007, 370, 220. 34. L. A. King, Review of the Pharmacotoxicological Data on m-­ chlorophenylpiperazine (mCPP In: Europol–EMCDDA Active Monitoring Report on a new psychoactive substance: 1-­(3-­chlorophenyl)piperazine (mCPP), EMCDDA, 2005, https://www.emcdda.europa.eu/publications/ joint-­reports/mcpp_en, accessed October 2021.

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35. NMS Labs, 2300 Stratford Ave Willow Grove, PA 19090, https:// w w w.npsdiscover y.org/wp-­c ontent/uploads/2020/04/para-­M ethyl-­ AP-­237_041320_NMSLabs_Report.pdf, accessed October 2021. 36. National Forensic Laboratory, Slovenia, Analytical Report: 2-­methyl AP-­237, https://www.policija.si/apps/nfl_response_web/0_Analytical_Reports_ final/2-­Methyl-­AP-­237-­ID-­2053-­19_report.pdf, accessed October 2021. 37. Bucinnazine, https://en.wikipedia.org/wiki/Bucinnazine, accessed October 2021. 38. D. Matveychuk, R. K. Thomas and J. Swainson, et al., Ther. Adv. Psychopharmacol., 2020, 10. 39. L. A. King, K. Clarke and A. J. Orpet, Ketamine and Tiletamine Abuse in the UK, Home Office Central Research Establishment, Technical Note No. 792, 1993, https://www.researchgate.net/publication/270760826_Ketamine_ and_Tiletamine_Abuse_in_the_UK, accessed October 2021. 40. Advisory Council on the Misuse of Drugs, An Untitled Report that Refers to Control of Analogues of Ketamine, Methoxetamine and Phencyclidine, 2012, https://assets.publishing.service.gov.uk/government/uploads/system/ uploads/attachment_data/file/119087/methoxetamine2012.pdf, accessed October 2021. 41. The Misuse of Drugs Act 1971 (Amendment) Order 2013 (S.I. 239), https:// www.legislation.gov.uk/uksi/2013/239/made, accessed October 2021. 42. The Misuse of Drugs Act 1971 (Amendment) Order 2012 (S.I.1390), https://www.legislation.gov.uk/uksi/2012/1390/contents/made, accessed October 2021. 43. D. J. Bailey, D. O'Hagan and M. Tavasli, Tetrahedron: Asymmetry, 1997, 8(1), 149.

Chapter 9

Generic Control in Other Jurisdictions 9.1  Introduction While most countries have chosen to implement only the essential elements required in international law by the 1961 and 1971 UN Conventions, a few have extended the scope of their legislation to a wider range of substances or have introduced generic or analogue control. One example is the Irish Republic, where the Misuse of Drugs Act 1975 closely follows the UK approach. For many years, most European countries only listed controlled substances individually. However, as the number of new substances increased, more countries have sought to control groups of substances. Most countries have defined the groups by chemical structure though a few have defined the groups by their effects. Those that have taken the generic approach have added the group definitions to existing drug laws, but some have only included such groups in specific NPS legislation. The EMCDDA annual report for 20181 shows that until 2010 there were only two countries in Europe that used generic control, but by 2017 this had increased to 16. According to the UNODC,2 there are 22 member states of the UN, mostly in Europe, that have generic control in their drug legislation. The UNODC list does not include New Zealand, where generic definitions are set out in Schedule 3, Part 7 of the Misuse of Drugs Act 19753 as amended by section 10 of the Misuse of Drugs Amendment Act (No 2) 1987 and the Misuse of Drugs Amendment Act (No 2) 2011. The omission of New Zealand from the UNODC list has arisen probably because it also has analogue legislation as discussed in Chapter 11. Some confusion may also be caused by the preamble to the structure-­specific definitions in the New Zealand legislation. Thus, these definitions cover ‘analogues’   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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of amphetamine, pethidine, phencyclidine, fentanyl, methaqualone and dimethyltryptamine. These six families were considered to be the primary focus of designer drugs in the 1980s. These definitions differ considerably from those in the UK MDAct, and in general have a wider scope. Three of them: amphetamine, methaqualone, and dimethyltryptamine derivatives are described below. This is followed by a brief overview of generic control in selected countries.

9.2  Generic Definitions in New Zealand 9.2.1  Amphetamine Derivatives The full definition reads as follows:    ‘Amphetamine analogues, in which the 1-­amino-­2-­phenylethane nucleus carries any of the following radicals, either alone or in combination:    (a) 1 or 2 alkyl radicals, each with up to 6 carbon atoms, attached to the nitrogen atom; (b) 1 or 2 methyl radicals, or an ethyl radical, attached to the carbon atom adjacent to the nitrogen atom; (c) a hydroxy radical, attached to the carbon atom adjacent to the benzene ring; (d) any combination of up to 5 alkyl radicals and/or alkoxy radicals and/or alkylamino radicals and/or alkylthio radicals (each with up to 6 carbon atoms, including cyclic radicals) and/or halogen radicals and/or nitro radicals and/or amino radicals, attached to the benzene ring’.    To qualify as a Class C controlled amphetamine derivative in New Zealand, the following criteria in Scheme 9.1 must be satisfied: R5 = H or alkyl (not more than six carbon atoms); R6 = H or alkyl (not more than six carbon atoms); R3 = H or methyl; R4 = H, methyl or ethyl; R1 = H or OH; R2 = H; Rx = alkyl, alkoxy, alkylamino, halogen, nitro or amino (either singly or in any combination) or a cyclic group, where no substituent has more than six carbon atoms.

Scheme 9.1  Phenethylamine  (β-­phenylethylamine) showing substitution patterns.

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Scheme 9.2  The  methaqualone nucleus showing substitution patterns.

9.2.2  Methaqualone Derivatives The UK MDAct has not set up a generic control of methaqualone derivatives, possibly because they were never commonly misused and are now rarely seen. However, as shown in Chapter 14, a number of such compounds have been reported in Europe, all of which are captured by the following New Zealand definition. This reads as follows:    ‘Methaqualone analogues, in which the 3-­arylquinazolin-­4-­one nucleus has additional radicals, either alone or in combination, attached as follows:    (a)  an alkyl radical, with up to 6 carbon atoms, attached at the 2 position; (b) any combination of up to 5 alkyl radicals and/or alkoxy radicals (each with up to 6 carbon atoms, including cyclic radicals) and/or halogen radicals, attached to each of the aryl rings’.    To qualify as a Class C controlled methaqualone derivative in New Zealand, the following criteria in Scheme 9.2 must be satisfied: R1 = alkyl (not more than six carbon atoms); R2 = any combination of up to five substituents that include alkyl, alkoxy, halogen or a cyclic group, where no substituent has more than six carbon atoms.

9.2.3  Dimethyltryptamine Derivatives The full definition reads as follows:    ‘DMT (dimethyltryptamine) analogues, in which the 3-­(2-­aminoethyl)indole nucleus has additional radicals, either alone or in combination, attached as follows:    (a) 1 or 2 alkyl radicals, each with up to 6 carbon atoms, including cyclic radicals, attached to the amino nitrogen atom; (b) 1 or 2 methyl groups, or an ethyl group, attached to the carbon atom adjacent to the amino nitrogen atom;

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Scheme 9.3  The  structure of tryptamine showing substitution patterns.

(c) any combination of up to 5 alkyl radicals and/or alkoxy radicals (each with up to 6 carbon atoms, including cyclic radicals) and/or halogen radicals, attached to the benzene ring’.    To qualify as a Class C controlled DMT derivative in New Zealand, the following criteria in Scheme 9.3 must be satisfied: R1 = methyl or other alkyl including [R1 to R2] cyclic groups; R2 = methyl or other alkyl. For R1 and R2, not more than six carbon atoms; R3 = H or methyl; R4 = H, methyl or ethyl; R5 = R6 = H; Rx = any combination of up to five substituents that include alkyl, alkoxy, halogen or a cyclic group, where no substituent has more than six carbon atoms.

9.3  Generic Control in Other Countries 9.3.1  Israel The Dangerous Drugs Ordinance [New Version], 5733-­1973 4 defines a number of structural derivatives of controlled substances as ‘A substance in which there is a transformation (by substitution or replacement) or subtraction of one or more chemical groups on/from a chemical structure of a given substance’. The legislation then sets out control of such derivatives to include, among others:    ● ● 2-­a mino-­indane, including its isomers and structural derivatives, unless expressly excluded and excluding Rasagiline (R)-­N-­(prop-­2-­ynyl)-­ 2,3-­dihydro-­1H-­inden-­1-­amine; ●● cathinone, including its isomers and structural derivatives, unless expressly excluded; ●● naphthylmethylindoles provided that on the nitrogen in the indole ring or the indane ring one of the following groups also exists: alkyl, haloalkyl, alkenyl, cycloalkyl, N-­1(-­methyl-­2-­piperidinyl)methyl or 2-­(4-­morpholinyl)ethyl as well as structural derivatives of these substances;

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α-­pyrrolidinopropiophenone, including structural derivatives of these substances; ●● 2-­amino-­1-­phenylpropanum, including the isomers and structural derivatives of this substance, unless expressly excluded’.    The text in the example above of ‘Naphthylmethylindoles’ is reproduced for many other groups of synthetic cannabinoid agonists. By UK standards, these definitions are extremely broad. ●●

9.3.2  Switzerland In the Ordonnance du DFI sur les tableaux des stupéfiants, des substances psychotropes, des précurseurs et des adjuvants chimiques (Ordonnance sur les tableaux des stupéfiants, OTStup-­DFI)5 of 2011, there is a list (schedule e) of raw materials and products with a supposed effect similar to controlled drugs. This includes generic definitions of synthetic cathinones, naphthylpyrovalerones and related compounds, and five groups of synthetic cannabinoids. As an example, the generic definition of cathinones reads as follows:    ‘Toute substance (autre que le bupropione, la cathinone, l'amfépramone, la pyrovalérone ou qu'une des substances soumises à contrôle figurant dans les tableaux a, b, d, f et g), dont la structure est dérivée du 2-­amino-­1-­phényl-­1-­propanone suite à l'une des modifications suivantes: – Substitution au niveau du cycle phényl, à n'importe quelle extension, avec des substituants alkyl, alkoxy, alkyléndioxy, haloalkyl ou halide, encore substitués ou non dans le cycle phényl par un ou plusieurs autres substituants univalents; – Substitution en position 3 avec un substituant alkyl; – Substitution au niveau de l'atome d'azote avec des groupes alkyl ou dialkyl, ou en incluant l'atome d'azote dans une structure cyclique’.

9.3.3  Germany The New Psychoactive Substances Act (Neue-­psychoaktive-­Stoffe-­Gesetz; NpSG)6 entered into force in 2016. This law prohibits the acquisition, possession and sale of NPS. The NpSG does not apply to substances already controlled under the Medicines Law or the Narcotic Law and explicitly allows accepted use for commercial, industrial and research purposes. In particular, the NpSG introduces generic controls over two NPS groups, i.e., phenethylamines and synthetic cannabinoids. The generic definition of phenethylamines is extremely comprehensive. It reads in part as follows:    ‘Eine von 2-­Phenethylamin abgeleitete Verbindung ist jede chemische Verbindung, die von einer 2-­Phenylethan-­1-­amin-­Grundstruktur abgeleitet werden kann (ausgenommen 2-­Phenethylamin selbst), eine maximale

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Molekülmasse von 500u hat und dem nachfolgend beschriebenen modularen Aufbau aus Strukturelement A und Strukturelement B entspricht’.    This is followed by diagrams showing Strukturelement A and Strukturelement B, which refer respectively to the phenyl ring and the side chain with all substituent positions marked. The text then continues and gives possibilities for alternative Strukturelement A, namely naphthyl, tetralinyl, methylenedioxyphenyl, ethylenedioxyphenyl, furyl, pyrrolyl, thienyl, pyridyl, benzofuranyl, dihydrobenzofuranyl, indanyl, indenyl, tetrahydrobenzodifuranyl, benzodifuranyltetra-­hydrobenzodipyranyl, cyclopentyl and cyclohexyl. These ring systems can then be substituted as follows:    ‘Diese Ringsysteme können an jeder Position mit folgenden Atomen oder Atomgruppen (Rn) substituiert sein: Wasserstoff, Fluor, Chlor, Brom, Iod, Alkyl-­(bis C6), Alkenyl-­(bis C6), Alkinyl-­(bis C6), Alkoxy-­(bis C6), Carboxy-­, Alkylsulfanyl-­(bis C6) und Nitrogruppen’.    There then follows a comprehensive description of what may be substituted in the side-­chain (Strukturelement B):    ‘Die 2-­Aminoethyl-­Seitenkette des Strukturelements B kann mit folgenden Atomen, Atomgruppen oder Ringsystemen substituiert sein:    a) R1 und R2 am Stickstoffatom:Wasserstoff, Alkyl-­(bis C6), Cycloalkyl-­(bis C6), Benzyl-­, Alkenyl-­ (bis C6), Alkylcarbonyl-­ (bis C6), Hydroxy-­ und Aminogruppen. Ferner sind Stoffe eingeschlossen, bei denen das Stickstoffatom Bestandteil eines cyclischen Systems ist (beispielsweise Pyrrolidinyl-­, Piperidinyl-­). Ein Ringschluss des Stickstoffatoms unter Einbeziehung von Teilen des Strukturelements B (Reste R3 bis R6) ist dabei möglich. Die dabei entstehenden Ringsysteme können die Elemente Kohlenstoff, Sauerstoff, Schwefel, Stickstoff und Wasserstoff enthalten. Diese Ringsysteme dürfen fünf bis sieben Atome umfassen.    Ausgenommen von den erfassten Stoffen der Stoffgruppe der von 2-­Phenethylamin abgeleiteten Verbindungen sind Verbindungen, bei denen das Stickstoffatom direkt in ein cyclisches System integriert ist, das an das Strukturelement A anelliert ist.    Die Substituenten R1 und R2 können weiterhin mit beliebigen, chemisch möglichen Kombinationen der Elemente Kohlenstoff, Wasserstoff, Stickstoff, Sauerstoff, Schwefel, Fluor, Chlor, Brom und Iod substituiert sein. Die auf diese Weise entstehenden Substituenten dürfen dabei eine durchgehende Kettenlänge von maximal zehn Atomen aufweisen (ohne Mitzählung von Wasserstoffatomen). Atome von Ringstrukturen werden dabei nicht in die Zählung einbezogen.

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b) R3 und R4 am C1-­Atom sowie R5 und R6 am C2-­Atom: Wasserstoff, Fluor, Chlor, Brom, Iod, Alkyl-­ (bis C10), Cycloalkyl-­ (bis C10), Benzyl-­, Phenyl-­, Alkenyl-­ (bis C10), Alkinyl-­ (bis C10), Hydroxy-­, Alkoxy-­ (bis C10), Alkylsulfanyl-­ (bis C10), Alkyloxycarbonyl-­gruppen (bis C10), einschließlich der chemischen Verbindungen, bei denen Substitutionen zu einem Ringschluss mit dem Strukturelement A oder zu Ringsystemen, die die Reste R3 bis R6 enthalten, führen. Diese Ringsysteme dürfen vier bis sechs Atome umfassen. Die aufgeführten Atomgruppen und Ringsysteme können weiterhin mit beliebigen, chemisch möglichen Kombinationen der Elemente Kohlenstoff, Wasserstoff, Stickstoff, Sauerstoff, Schwefel, Fluor, Chlor, Brom und Iod substituiert sein. Die auf diese Weise entstehenden Substituenten dürfen dabei eine durchgehende Kettenlänge von maximal zehn Atomen aufweisen (ohne Mitzählung von Wasserstoffatomen). Atome von Ringstrukturen werden dabei nicht in die Zählung einbezogen    Sofern die Reste R3 bis R6 Bestandteil eines Ringsystems sind, das das Stickstoffatom des Strukturelements B enthält, gelten für weitere Substituenten die Beschränkungen aus Buchstabe a.    c) Carbonylgruppe in beta-­Stellung zum Stickstoffatom (sogenannte bk-­ Derivate, siehe Abbildung der Cathinon-­Grundstruktur unter Nummer 1: R5 und R6 am C2-­Atom: Carbonylgruppe (C=O))’.  

9.3.4  New South Wales, Australia In Schedule 1 of the Drug Misuse and Trafficking Act 1985, which refers to prohibited plants and prohibited drugs,7 a large number of substances are listed. A far reaching generic control is then introduced, which applies to all substances in Schedule 1. Although the preamble refers to ‘analogue’, it is not analogue control. It reads as follows:    ‘Any substance that is an analogue of a drug prescribed in this Schedule is not separately specified in this Schedule and is, in relation to the drug, any of the following: (a) a structural isomer having the same constituent groups as the drug, (b) a structural modification obtained in one or more of the following ways—(i) the replacement of up to 2 carbocyclic or heterocyclic ring structures with different carbocyclic or heterocyclic ring structures, (ii) the addition of hydrogen atoms to 1 or more unsaturated bonds, (iii) the addition of 1 or more of the following groups having up to 6 carbon atoms in any alkyl residue, namely, alkoxy, cyclic diether, acyl, acyloxy, monoalkylamino and dialkylamino groups, (iv) the addition of 1 or more of the following groups having up to 6 carbon atoms in the group and being attached to oxygen, namely, alkyl, alkenyl and alkynyl groups (for example, ester groups and ether groups), (v) the addition of 1 or more of the following groups having up to 6 carbon atoms in the group and being attached to nitrogen, sulphur or carbon, namely, alkyl, alkenyl

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and alkynyl groups, (vi) the addition of 1 or more of the following groups, namely, halogen, hydroxy, nitro and amino groups, (vii) the replacement of 1 or more of the groups specified in subparagraphs (iii)–(vi) with 1 or more other groups so specified, (viii) the conversion of a carboxyl or an ester group into an amide group’.  

9.3.5  China The People's Republic of China introduced a generic regulation in May 2019 for fentanyl-­related substances that have:    1. Other acyl groups to substitute for propionyl; 2. Any substituted and unsubstituted mono-­aromatic groups to substitute for phenyl directly connected to the nitrogen atom; 3. A piperidine ring having substituent groups such as alkyl, alkenyl, alkoxy, ester, ether, hydroxy, halogen, haloalkyl, amino and nitro; 4. Having any other groups (except hydrogen) to substitute for phenethyl.8    In addition, generic regulation was introduced for several structural groups of synthetic cannabinoid receptor agonists in May 2021.8

References 1. European Monitoring Centre for Drugs and Drug Addiction, Annual report for 2018, https://www.emcdda.europa.eu/system/files/publications/8585/20181816_TDAT18001ENN_PDF.pdf, accessed October 2021. 2. United Nations Office on Drugs and Crime, Early Warning Advisory on New Psychoactive Substances, https://www.unodc.org/LSS/Country/List, accessed October 2021. 3. New Zealand Government, Misuse of Drugs Act 1975, https://www. legislation.govt.nz/act/public/1975/0116/latest/DLM436101.html, accessed October 2021. 4. State of Israel, Ministry of Health, https://www.health.gov.il/LegislationLibrary/Samim_01_EN.pdf, accessed October 2021. 5. Switzerland, Federal Department of the Interior, Ordonnance sur les tableaux des stupéfiants, OTStup-­DFI, https://fedlex.data.admin.ch/filestore/fedlex.data.admin.ch/eli/cc/2011/363/20110701/fr/pdf-­a/fedlex-­data-­admin-­ ch-­eli-­cc-­2011-­363-­20110701-­fr-­pdf-­a.pdf, accessed October 2021. 6. Federal Republic of Germany, Neue-­psychoaktive-­Stoffe-­Gesetz, https:// de.wikipedia.org/wiki/Neue-­psychoaktive-­Stoffe-­Gesetz, accessed October 2021. 7. New South Wales Government, Drug Misuse and Trafficking Act 1985, http://www6.austlii.edu.au/cgi-­b in/viewdoc/au/legis/nsw/consol_act/ dmata1985256/sch1.html, accessed October 2021. 8. The People's Republic of China, National Narcotics Control Commission, https://www.unodc.org/LSS/Announcement/Details/f2adea68-­fbed-­4292-­ a4cc-­63771c943318, accessed October 2021.

Chapter 10

Generic Control: A Critique 10.1  Introduction The structure-­specific generic controls as described in Chapter 8 were created to provide an efficient way of capturing large groups of substances. For example, when the book PiHKAL1 was published in 1991, almost 80% of the substances shown in the principal monographs were covered by the 1977 definition of ring-­substituted phenethylamines in the MDAct. Of the many phenethylamines notified to EMCDDA in the following years, only a few fell outside the generic definition of 1977. Many of these ‘outlaws’ were captured by the specific controls of phenethylamines introduced in 2001 (Appendix 7). A further set of N-­benzyl-­substituted phenethylamines were defined by the generic controls of 2014.2 As of 2020, over 140 cathinone derivatives had been reported to EMCDDA, making them the second largest group of NPS. Most are subsumed by the UK generic definition; the only notable exceptions being those with anomalous N-­substitution, particularly N-­benzyl-­substituted compounds. However, the definitions of many other groups have hardly been tested in a criminal trial. This is the case with some older definitions such as the fentanyls, but is particularly true with controls aimed at more recent groups of NPS, for example, phenylcyclohexylamine derivatives and piperazines where the substances in question had already started to disappear from the drug scene by the time controls had been introduced. That may either be seen as the impact of the legislation or simply a reflection that most NPS have a short lifetime. Nevertheless, some of the definitions drafted in the past ten years, were not well-­ constructed, and these specific problems are discussed in Section 10.3. In the meantime, many general concerns have been raised about the use of generic drug control.

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10.2  General Concerns with Generic Control 10.2.1  Effect on the Pharmaceutical Industry As far as is known, most generic controls have not greatly hindered the development in the pharmaceutical industry of novel compounds for legitimate clinical use. This may not be true for substances that act as synthetic cannabinoid receptor agonist as discussed in Chapter 18, where an earlier form of the generic controls did inadvertently capture a number of medicinal substances. It could be said that if the pharmaceutical industry did wish to develop substances that were covered by generic controls, it should be a simple matter to either issue licences or modify the legislation. Unfortunately, experience shows that changing the legislation, particularly the restrictions posed by the MD Regulations, is less easy. Following a consultation exercise in 2020, the ACMD reported in 2021 on problems, related to the legal status of SCRAs, faced by academia, the pharmaceutical industry and contract research organisations. This is discussed in Chapter 18.

10.2.2  Capture of Inactive Substances Because the MDAct relies on the concept of actual or potential social harm, rather than the specific pharmacological or toxicological properties of a controlled drug, no great difficulty arises from the introduction of generic control. This would be more of concern in those jurisdictions (and the UN itself ) where there is an a priori need to review the pharmacological and toxicological properties of every substance considered for control. It is quite certain that amongst the essentially infinite number of generically defined substances, there will be compounds that have little abuse potential and some may have no physiological effect of any sort. Without these effects, a substance will not be marketed by the pharmaceutical industry and neither will it be produced as a drug of misuse. However, it cannot be denied that this further blurs the principle that penalties associated with a drug offence should correlate with the harmful properties of that drug.

10.2.3  Difficulty in Comprehension One of the most complex definitions in the MDAct involves ring-­substituted phenethylamines, but in the past 30 years many thousands of witness statements, involving the identification of MDMA in seized samples, have been submitted in evidence by UK forensic science laboratories. These statements have incorporated the definition without any apparent problems. Nevertheless, it is still perceived as a weakness that certain common substances, e.g., MDMA, and mephedrone (4-­methylmethcathinone), are not named specifically but rather are hidden within a definition that may be accessible only to forensic chemists.

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10.2.4  Obsolescence Many of the substances controlled by generic legislation, particularly in the past ten years, are no longer misused in significant amounts. Indeed, many of the substances in question were already in decline before the legislation had been completed. This is not directly a criticism of generic control since specific listing would have fared no better. On the other hand, that is not a reason to revoke such controls since experience has shown that simply provides drug manufacturers with an opportunity to re-­establish the substances.

10.2.5  Reference Materials Good laboratory practice requires that analytical findings on questioned substances should be compared with results obtained using pure reference compounds. In a defined list system, it is possible, at least in principle, to synthesise samples of every controlled drug. But when generic control theoretically covers an infinite number of compounds, reference samples may not always be available. In the early 1990s, the forensic science laboratory at Aldermaston, UK, encountered an unknown substance. Analysis showed that it was not included in any mass-­spectral or chromatographic library. Recourse was therefore made to NMR spectroscopy, which enabled the chemical structure to be identified as MBDB (N-­methyl-­1-­(1,3-­benzodioxol-­5-­yl)-­2-­butanamine), a close relative of MDMA (ecstasy). At the time, MBDB had not been seen anywhere else. Yet it was important that it was identified since it was a Class A controlled drug by virtue of the generic definition of phenethylamines set up in 1977. The same difficulty can still happen today, prompting forensic laboratories to routinely use sophisticated analytical techniques and exchange relevant information.

10.2.6  Other Criticisms of Generic Control van Amsterdam et al.3 suggested that substances defined via generic legislation will contain useful medications, as noted above. However, those authors gave the example of GBL (γ-­butyrolactone), which is a useful solvent, but neither GBL nor any related compounds fall within the scope of generic control, at least within the UK. van Amsterdam et al.3 suggested that ‘The introduction of generic legislation violates the principle of legality, the rule that nothing is punishable without penalty provision and the associated accountability to citizens. Citizens need to understand what exactly is punishable according to law’. However, the principle of generic control, as an application of the precautionary principle, causes no legal difficulties in the UK and, furthermore, unlike analogue control (Chapter 11), the generic definitions set out precisely what is controlled.

10.3  Specific Issues with Certain Generic Definitions There are numerous problems with the control of synthetic cannabinoid receptor agonists; they are discussed in detail Chapter 18. Drafting problems with definitions of cathinones and benzofurans (and related compounds) are

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described below in Sections 10.3.1 and 10.3.2 respectively. The absence of any generic definition of phenidates is covered in Section 10.3.3.

10.3.1  Cathinones Mephedrone (4-­methylmethcathinone) and certain other cathinone derivatives were first controlled in 2010 under the MDAct (Amendment) Order 2010 (S.I. 1207).4 This added 4-­methylmethcathinone and a group of generically defined cathinone (2-aminopropan-1-one) derivatives to Part II of Schedule 2. However, this generated confusion for forensic scientists and legal practitioners. In creating the legislation, a decision had been made to specifically mention mephedrone, perhaps to make it clear that this substance was being controlled. But, as shown in Chapter 8, a normal feature of generic definitions is that they do not mention any specific controlled substance by name, although substitution patterns in an uncontrolled nucleus might be used. Thus, in 2010, one isomer of mephedrone was listed in one sub-­paragraph, while all isomers of mephedrone (i.e., the 2-­, 3-­ and 4-­positional isomers) were absorbed within a generic definition in another sub-­paragraph. This amounted to another example of double entry. To distinguish those different isomers is a challenging task for a laboratory. Yet without that absolute identification, it would not be clear under which sub-­paragraph of the Act 4-­methylmethcathinone was controlled. Eventually, following many discussions between the forensic science community and the Crown Prosecution Service, a legally acceptable, but temporary, work-­around was concocted. The problem was formally addressed in the following year with a subsequent amendment (The MDAct 1971 (Amendment) Order 2011 (S.I. 744)),5 which removed specific reference to 4-­methylmethcathinone, such that all three isomers (2-­, 3-­and 4-­methylmethcathinone) were covered by the generic definition, which meant that there was no longer a requirement to identify which isomer was in question.

10.3.2  Benzofurans and Related Compounds A number of compounds structurally derived from 1-­benzofuran, 2,3-­dihydro-­1-­benzofuran, 1H-­indole, indoline, 1H-­indene or indane, some of which were previously subject to temporary control in 2013, were placed under permanent control as Class B drugs by the MDAct 1971 (Ketamine etc.) (Amendment) Order 2014 (S.I. 1106).2 The generic definition reads as follows:    ‘Any compound (not being a compound for the time being specified in paragraph 1(ba) of Part 1 of this Schedule) structurally derived from 1-­benzofuran, 2,3-­dihydro-­1-­benzofuran, 1H-­indole, indoline, 1H-­indene, or indane by substitution in the 6-­membered ring with a 2-­ethylamino substituent whether or not further substituted in the ring system to any extent with alkyl, alkoxy, halide or haloalkyl substituents and whether or not substituted in the ethylamino side-­chain with one or more alkyl substituents’.   

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The definition refers to ‘the ethylamino side-­chain’. While that term is not ambiguous, it cannot mean what was intended; an ethylamino substituent in a ring would have the nitrogen atom directly attached to the ring. An example of that situation (6-­ethylamino-­1-­benzofuran) is shown in Scheme 10.1. One of the substances that the ACMD considered should be covered was 6-­(2-­aminopropyl)-­1-­benzofuran, often called 6-­APB or ‘Benzofury’, shown in Scheme 10.2. In the legislation of the Bailiwick of Guernsey (The Misuse of Drugs (Modification) Order, 2014) (Guernsey S.I. 2014 No. 79),6 the more precise term ‘2-­aminoeth-­1-­yl’ is used for the ring substituent. Thus, a substance such as 6-­(2-­aminopropyl)-­1-­benzofuran would only be captured by the UK definition if it had read:    ‘Any compound (not being a compound for the time being specified in paragraph 1(ba) of Part 1 of this Schedule) structurally derived from 1-­benzofuran, 2,3-­dihydro-­1-­benzofuran, 1H-­indole, indoline, 1H-­indene, or indane by substitution in the 6-­membered ring with an 2-­aminoeth-­1-­yl substituent whether or not further substituted in the ring system to any extent with alkyl, alkoxy, halide or haloalkyl substituents and whether or not substituted in the 2-­aminoeth-­1-­yl side-­chain with one or more alkyl substituents’.    The same situation arises with the other core structures in the definition, namely 2,3-­dihydro-­1-­benzofuran, 1H-­indole, indoline, 1H-­indene, and indane. It follows that the intention to control substances such as 6-­APB, aminoindanes and the so-­called isotryptamines (Chapter 14), among others, has failed. None of the benzofuran derivatives or other compounds which were intended for control in the UK is listed in the UN 1971 Convention.

Scheme 10.1  6-­  Ethylamino-­1-­benzofuran.

Scheme 10.2  6-­  (2-­Aminopropyl)-­1-­benzofuran.

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A further anomaly arose with these substances. Thus, two benzofurans were already listed as Class A drugs, i.e., 2-­(5-­methoxy-­2-­methyl-­2,3-­dihydrobenzo[b]furan-­6-­yl)-­1-­methylethylamine and 2-­(5-­methoxy-­2,2-­dimethyl-­2,3-­ dihydro-­benzo[b]furan-­6-­yl)-­1-­methylethylamine. For reasons that are unconnected with their relative harm, and in the light of the above error in the definition, benzofurans would have been split between Class A and Class B.

10.3.3  The Phenidate Group Aside from errors of commission, it can be argued that the ACMD has been inconsistent in the use of generic legislation. In 2017, alongside the existing Class B methylphenidate (Scheme 10.3), 12 analogues (Schemes 10.4–10.15) were added by name to the MDAct as Class B drugs.7 All were reported to be

Scheme 10.3  Methyl  phenyl(piperidin-­2-­yl)acetate; methylphenidate, an existing Class B drug.

Scheme 10.4  Ethyl  (1-­benzylpiperidin-­2-­yl)(phenyl)acetate; N-­benzylethylphenidate.

Scheme 10.5  Ethyl  (naphthalen-­2-­yl)(piperidin-­2-­yl)acetate; ethylnaphthidate; HDEP-­28.

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Scheme 10.6  Ethyl  2-­phenyl-­2-­piperidin-­2-­ylacetate; ethylphenidate.

Scheme 10.7  Propan-­  2-­yl 2-­phenyl-­2-­(piperidin-­2-­yl)acetate; isopropylphenidate; IPP or IPPD.

Scheme 10.8  Methylmorphenate. 

Scheme 10.9  Methyl  (naphthalen-­2-­yl)(piperidin-­2-­yl)acetate; methylnaphthidate; HDMP-­28.

misused in the UK in the period 2011–2015. Methylphenidate (Ritalin) is a licensed medicine; it acts as a reuptake inhibitor for dopamine and norepinephrine and has found use in the treatment of attention deficit hyperactivity disorder.

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Scheme 10.10  Propyl  2-­phenyl-­2-­(piperidin-­2-­yl)acetate; propylphenidate.

Scheme 10.11  Ethyl  2-­(3,4-­dichlorophenyl)-­2-­(piperidin-­2-­yl)acetate; 3,4-­dichloro­ethylphenidate.

Scheme 10.12  Methyl  2-­(3,4-­dichlorophenyl)-­2-­(piperidin-­2-­yl)acetate; 3,4-­dichloromethylphenidate; 3,4-­DCMP.

Scheme 10.13  Ethyl  2-­(4-­fluorophenyl)-­2-­(piperidin-­2-­yl)acetate; 4-­fluoroethylphenidate.

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Scheme 10.14  Methyl  2-­(4-­fluorophenyl)-­2-­(piperidin-­2-­yl)acetate; 4-­fluoromethylphenidate.

Scheme 10.15  Methyl  2-­(4-­methylphenyl)-­2-­(piperidin-­2-­yl)acetate; 4-­methylmethylphenidate.

It is not clear why the 12 analogues were not incorporated into a generic definition since they are all phenidates based on the core structure methyl(piperidin-­2-­yl)acetate. Although the original ACMD report8 expressed some uncertainty about the possible legitimate use of these drugs, and thus a possible reason for the lack of generic control, a subsequent circular from the Home Office8 noted that they would all be added to Schedule 1 of the MD Regulations ‘…since they have no recognised medicinal use outside of research in the United Kingdom’. All have a chiral carbon atom at position 2 in the piperidine ring but, for clarity, that is ignored in the structures shown here. A suggested generic definition could read as follows:    ‘Any compound, not being methylphenidate, structurally derived from methyl(piperidin-­2-­yl)acetate by modification in one of the following ways:    (a)  replacement of the phenyl group by a naphthyl group; (b)  substitution in the phenyl group with one or more alkyl or halide groups; (c)  replacement of the ester methyl group with another alkyl group; (d) replacement of the piperidine ring with a pyrrolidine, azepane, morpholine or piperazine ring; (e) substitution at the nitrogen atom of the piperidine ring with a benzyl group whether or not further substituted in the benzyl group to any extent’.

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10.3.4  Anabolic Steroids The generic definition described in Chapter 8 clearly erred on the side of caution and can be criticised for being insufficiently comprehensive; none of the four further anabolic steroids added to the MDAct in 2003 nor the 15 added in 2009 as named Class C drugs were covered by the above definition.

10.3.5  Ring-­substituted Phenethylamines The definition of ring-­substituted phenethylamines described in Chapter 8 has proved to be one of the most robust of all generic controls. Set up in 1977 because it was believed that substances, such as MDMA, that were beginning to circulate in the US might become more widespread, it would be more than ten years before those phenethylamines surfaced in the UK. It would then be several more years before the publication of PiHKAL1 and the beginning of a new phase in the designer drugs story (Chapter 13). Of the 179 phenethylamines described in the primary sections of PiHKAL, around 80% were captured by the 1977 definition. The 34 phenethylamines that fell outside the definition were added to the MDAct as named compounds (Appendix 7). It was recognised that any expansion of the original definition to include such ‘outlaws’ risked either producing a text that was too difficult to comprehend or, worse, of damaging the whole structure. At the time, there was debate as to whether the term ‘N-­alkyl’ in the definition also included ‘N,N-­dialkyl’. Thus, it was unclear if the definition included compounds such as dimethyl(α-­methyl-­ 3,4-­methylenedioxyphenethyl)amine. It was therefore decided to include N,N-­ dimethyl compounds by name in that list. Although it might still be argued that the 1977 definition of ring-­substituted phenethylamines was too conservative, in reality few of the substances shown in Appendix 7 have ever appeared.

10.3.6  Synthetic Cannabinoid Receptor Agonists (SCRAs) There are numerous problems with the generic definition of SCRAs; these are described in detail in Chapter 18.

10.3.7  Cannabinol This phytocannabinoid is a named Class B controlled drug in the MDAct, but its inclusion is an anomaly since at the time it was not believed to be psychoactive, nor is it ever misused. It was suggested by the late Geoffrey Phillips, the author of the generic definition of cannabinoids, that it was inadvertently included because of the intention to capture certain cannabinol derivatives. More recently, some evidence has accumulated that cannabinol may have a weak psychoactivity.9

10.4  The Future of Generic Legislation Following the marked decline in the appearance of NPS, as shown in Chapter 13, there appears to be little incentive in the UK to introduce new generic definitions. Apart from the structure-­specific definition of synthetic cannabinoid

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receptor agonists, which has continued to dominate the agenda of the ACMD in this area, no new generic definitions have been created since 2014 when the existing definition of controlled tryptamine derivatives was revised. Although novel substances continue to appear, they often have diverse structures which do not fall into clear families. A possible exception might be the 2-­benzylbenzimidazole opioids, i.e., etonitazene analogues (Chapter 14). Many differ from each other by small variations in the ring-­substituents, allowing a generic definition to be readily crafted. It might also be concluded that NPS remain a minor interest among drug users and have never displaced the traditional drugs of misuse. Furthermore, with over 800 such new compounds now recognised, drug manufacturers might be faced with diminishing returns.

References 1. A. Shulgin and A. Shulgin, PiHKAL: A Chemical Love Story, Transform Press, Berkeley, California, 1991, ISBN 0-­9630096-­0-­5. 2. The Misuse of Drugs Act 1971 (Ketamine etc.) (Amendment) Order 2014 (S.I.1106), https://www.legislation.gov.uk/uksi/2014/1106/contents/made, accessed October 2021. 3. J. van Amsterdam, D. Nutt and W. van den Brink, J. Psychopharmacol., 2013, 27(3), 317. 4. The Misuse of Drugs Act 1971 (Amendment) Order 2010 (S.I. 1207), https:// www.legislation.gov.uk/uksi/2010/1207/contents/made, accessed October 2021. 5. The Misuse of Drugs Act 1971 (Amendment) Order 2011 (S.I. 744), https:// www.legislation.gov.uk/uksi/2011/744/contents/made, accessed October 2021. 6. Guernsey (The Misuse of Drugs (Modification) Order, 2014 (Guernsey S.I. 2014 No. 79). 7. Advisory Council on the Misuse of Drugs, Further advice on methylphenidate-­related NPS, 2017, https://assets.publishing.service.gov. uk/government/uploads/system/uploads/attachment_data/file/598494/ ACMD_s_further_advice_on_methylphenidate-­related_NPS_Mar_17.pdf, accessed October 2021. 8. Home Office Circular 008/2017: A change to the Misuse of Drugs Act 1971 to control U-­47,700, twelve methylphenidate related substances and sixteen ‘designer’ benzodiazepines, https://assets.publishing.service.gov. uk/government/uploads/system/uploads/attachment_data/file/616781/ misuse_of_drugs_act_circular_008_2017.pdf, accessed October 2021. 9. Advisory Council on the Misuse of Drugs, Phytocannabinoids: A review of the generic definition, 2016, https://assets.publishing.service.gov. uk/government/uploads/system/uploads/attachment_data/file/578089/ Plant_Cannabinoid_Working_Group_Final_16_December.pdf, accessed October 2021.

Chapter 11

Analogue Legislation 11.1  Introduction In medicinal chemistry, an ‘analogue’ is generally defined as a drug whose structure is related to that of another drug but whose chemical and biological properties may be quite different. This may be contrasted with the various uses of the word ‘derivative’ (Chapter 12). Analogue legislation differs from generic (structure-­specific) control insofar as it asks the question whether a given substance is ‘substantially similar’ to an existing controlled substance both in terms of general chemical structure and pharmacological properties. It therefore has a much broader scope than generic legislation. By contrast, generic control sets out precisely-­defined chemical similarities, but does not usually suggest that pharmacological properties should be similar. According to the UNODC,1 there are seven member states of the UN that have analogue control in their drug legislation: Canada, Italy, Latvia, Luxembourg, New Zealand, South Africa and the US.

11.2  Analogue Control in the United States The US was the first country to adopt analogue controls. The Controlled Substances Analogue Enforcement Act 1986 (sometimes called the Federal Analogue Act)2 defines analogues in the following way:    ‘Controlled substance analogue means a substance:    (i) the chemical structure of which is substantially similar to the chemical structure of a controlled substance in schedule I or II. (ii) which has a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in schedule I or II; or (iii) with respect to a particular person, a substance which such person represents or intends to have a stimulant, depressant, or hallucinogenic effect on the central nervous system substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect of a controlled substance in schedule I or II’.    The main appeal of the analogue concept is that it provides a means of avoiding a full risk assessment, particularly when little scientific information may be available on which to base such an assessment. However, as will be described later, lengthy arguments in US courts about whether or not a substance is an analogue of an existing controlled drug controlled tended to vitiate this advantage. Although analogue control would normally be used substance-­by-­ substance, it has the further advantage that a group of substances might be considered en bloc. Thus, according to Wong et al.3 in the case of US-­v-­ Niemoeller,4 it was decided that the phenethylamine 2C-­T-­7 (Scheme 11.1; R = 4-­(n)-­propyl) was substantially similar to the controlled drug 2C-­B (Scheme 11.1; R = Br). It would then be a short step to consider that almost any 4-­substituted-­2,5-­dimethoxy-­phenethylamine, for example, 2C-­H (R = H), 2C-­I (R = I), 2C-­Cl (R = Cl), 2C-­E (R = ethyl), 2C-­D (R = methyl) would be an analogue of 2C-­B and hence controlled. In other words, this has the effect of dissuading suppliers of such non-­controlled substances from entering the market. Thus, what starts as an analogue approach becomes almost equivalent to a tacit generic control of 4-­substituted-­2,5-­dimethoxy-­phenethylamines. In an appeal heard in 1996 (US-­v-­Allen McKinney),5 the Federal Analogue Act was deemed not to be constitutionally vague.6 The case concerned the sale of aminorex (5-­phenyl-­4,5-­dihydro-­1,3-­oxazol-­2-­amine) before it became explicitly controlled, and the sale of phenethylamine as a substitute for methamphetamine. Some of the limits of what was meant by ‘substantially similar’ were argued in the case of US-­v-­Damon S. Forbes et al.,7 where it was decided that α-­ethyltryptamine (AET; Scheme 11.2) was not an analogue of either N,N-­dimethyltryptamine (DMT; Scheme 11.3) or N,N-­diethyltryptamine (DET; Scheme 11.4).

Scheme 11.1  A  4-­substituted-­2,5-­dimethoxyphenethylamine.

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Scheme 11.2  α-­  Ethyltryptamine; AET.

Scheme 11.3  N,N-­  Dimethyltryptamine; DMT.

Scheme 11.4  N,N-­  Diethyltryptamine; DET.

The reasons for this decision were: AET is a primary amine, but DMT and DET are tertiary amines; AET cannot be synthesised from DMT or DET; and the effects of AET are not substantially similar to those of DMT or DET. By contrast, it has been accepted that 5-­methoxy-­DMT (5-­MeO-­DMT; Scheme 11.5) is an analogue of DMT even though it cannot readily be synthesised from it. A further example is provided by US-­v-­T.W. Washam,8 where it was determined that 1,4-­butanediol (1,4-­BD) was substantially similar to GHB. Nevertheless, there is a view in Europe that analogue controls are less satisfactory from a legal viewpoint. Whereas with explicit listing of substances in a schedule or even a generic definition, the status of a substance is clear from the outset, the use of analogue legislation requires that a court process should determine whether the substance is or is not controlled. It has been argued that such a retrospective process undermines the right of a defendant to know from the outset whether an offence has been committed. Case-­by-­case decisions on whether a substance is or is not an analogue might be seen as cumbersome, requiring as they do expert chemical and pharmacological testimony on each occasion but, from a US perspective, it appears that the Controlled Substances Analogue Enforcement Act was successful in curtailing the proliferation of an earlier generation of designer drugs. The US

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Scheme 11.5  5-­  Methoxy-­N,N-­dimethyltryptamine; 5-­MeO-­DMT. government prosecuted a substantial number of individuals for the manufacture and distribution of analogues of MDMA, amphetamine, pethidine (meperidine), fentanyl and others. In a presentation by the DEA to the Home Office and the ACMD in 2010, the Federal Analogue Act was described as ‘An Imperfect Law’.3 In the last two years, the US has sidestepped the option of analogue control by placing a number of new substances such as cathinone derivatives and synthetic cannabinoid receptor agonists under conventional drugs legislation.

11.3  Analogue Control in Other Countries 11.3.1  Canada The Controlled Drugs and Substances Act (CDSA), 1996 9 contains not only a list of substances individually listed for purposes of control, but in some cases a salt, derivative, isomer or analogue of a substance already listed in one of the Schedules. This is determined on a case-­by-­case basis via a process which assesses the chemical structure and/or pharmacological activity of the substance against that of existing controlled substances. For example, methylone is considered to be an analogue of amphetamine. Schedule II to the CDSA, which deals with cannabis, allows the Minister of Health to deem any similar synthetic preparation of cannabis to be a controlled substance. The challenge, however, is that in order for a substance to be deemed a similar synthetic preparation, there has to be scientific data showing that the substance has a similar pharmacological activity profile to THC, and often that is not available. A unique feature of the Act is that, in some cases, it also applies to precursor analogues.

11.3.2  South Africa Controlled substances in South Africa are regulated in the Drugs and Drug Trafficking Act, 1992 (Act No. 140 of 1992).10 In 2014, this Act was amended to extend the control of individual substances listed in Schedule II to ‘all homologues of the listed substances (being any chemically related substances that incorporate a structural fragment into their structures that is similar to the structure of a listed substance or exhibit pharmacodynamic properties similar to the listed substances in this Part of the Schedule), unless listed separately in any Part

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of Schedule 2’. With this provision, it is possible to control substances not explicitly mentioned in the legislation via analogue controls.

11.3.3  New Zealand As noted in Chapter 9, a system of generic controls operates in New Zealand. The Misuse of Drugs Amendment Act (No. 2) 1987 11 introduced the definition of a “Controlled Drug Analogue” as “any substance, such as the substances specified or described in Part VII of the Third Schedule to this Act, that has a structure substantially similar to that of any controlled drug”. The Amendment goes on to exclude any substance listed elsewhere in the Misuse of Drugs Act or as a pharmacy-­only medicine, restricted medicine or prescription medicine under the Medicines Act and Regulations. To a certain extent, this Amendment was inspired by, and modelled on, the US analogue controls. The application of the analogue provisions of the Amendment Act is not limited to the families of substances listed in Part VII of the Third Schedule (i.e., amphetamine, pethidine, phencyclidine, fentanyl, methaqualone and dimethyltryptamine) for which generic controls also operate.

11.4  Problems with Analogue Control The ACMD once suggested that the UK Government should consider analogue legislation. It could be used in conjunction with generic controls in situations where a set of related substances are not sufficiently similar to merit a concise generic definition. An example might be to consider 4-­fluorotropacocaine and dimethocaine as analogues of cocaine. Because the structures have common features, yet are rather diverse, this group would be less easy to render generically. A comprehensive critique of the Federal Analogue Act, and by implication other analogue controls, has been provided by Kau.12 A more recent discussion has been provided by King et al.13 In addition to the constitutional validity of retrospective control, Kau pointed out several main problems, namely: the difficulty of determining what is meant by ‘substantially similar’; that no court has ever given guidelines on what is ‘not substantially similar’; that decisions can be founded more on opinion than scientific evidence; decisions about which analogue is a controlled substance may not be binding on other Courts and the related possibility that different Courts might come to different conclusions about the same chemical entity. Another fact emerges when the US case law is examined: most of it is quite old. An ACMD report14 in 2011, on what it then called novel psychoactive substances, proposed a means of avoiding some of the problems of analogue control by suggesting that it should be the task of a statutory agency to determine what qualifies as a controlled analogue. This could still lead to problems if the decisions of that agency were to be challenged in a criminal trial.

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Scheme 11.6  Methyl  (2S,4aR,6aR,7R,9S,10aS,10bR)-­9-­(acetyloxy)-­2-­(furan-­3-­yl)-­6a,-

10b-­dimethyl-­4,10-­dioxo-­dodecahydro-­2H-­naphtho[2,1-­c]pyran-­7-­ carboxylate; salvinorin-­A.

Finally, it is clear that some new substances will be beyond the current scope of the analogue definitions. The US Courts have interpreted the separate parts of the analogue definition as being additive. In other words, the substance in question must be substantially similar in both chemical structure and pharmacological effect, i.e., (i) and (ii) or (i) and (iii) must apply. From this we can conclude that salvinorin-­A (Scheme 11.6) the active principle of the hallucinogenic herb Salvia divinorum, being chemically distinct from any other controlled substance, would immediately fail the test. The same argument applies to the structurally-­unique active constituents in many other herbal materials such as kawain, mitragynine, arecoline and ibogaine. The plant products containing these alkaloids have all been reported to EMCDDA in the past few years as NPS. It should also be recognised that analogue control is likely to impact on legitimate pharmaceutical research and development. Although this criticism is sometimes levelled at generic controls (see Chapter 10), unlike analogue control it is open to all to determine a priori if a new compound is covered by a generic definition. An example of this uncertainty is discussed earlier, where it would be a simple matter to extend the existing analogue controls in the US to almost any 4-­ substituted-­2,5-­dimethoxyphenethylamine. While most of the substances that are closely related to a ‘target’ substance in a chemical sense often have a similar physiological activity, this is not always true. And such exceptions may be difficult to predict.

References 1. United Nations Office on Drugs and Crime, https://www.unodc.org/LSS/ Country/List, accessed October 2021. 2. United States Federal Analogue Act 1986, https://en.wikipedia.org/wiki/ Federal_Analogue_Act, accessed October 2021.

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3. L. Wong, D. Dormont and H. J. Matz, United States Controlled Substance Analogue Act: Legal and Scientific Overview of an Imperfect Law, Presentation to the Advisory Council on the Misuse of Drugs, 2010. 4. United States v Niemoeller, https://casetext.com/case/usa-­v-­niemoeller-­2, 2003, accessed October 2021. 5. United States of America, Appellee, v. Allen Mckinney, Appellant, 79 F.3d 105 (8th Cir. 1996), https://law.justia.com/cases/federal/appellate-­courts/ F3/79/105/555999/, accessed October 2021. 6. Anon, U.S. Analogue statute ruled not constitutionally vague, J. Clandest. Lab. Invest. Chem. Assoc., 1996, 6(4), 5–6. 7. United States v. Forbes, 806 F. Supp. 232 (D. Colo. 1992), https://law.justia.com/cases/federal/district-­courts/FSupp/806/232/1747696/. accessed October 2021. 8. United States v. Washam, 2002, https://caselaw.findlaw.com/us-­8th-­circuit/ 1262827.html, accessed October 2021. 9. Government of Canada, Controlled Drugs and Substances Act, https://laws. justice.gc.ca/eng/acts/C-­38.8/index.html, accessed October 2021. 10. Republic of South Africa, Drugs and Drug Trafficking Act, 1992. https:// www.gov.za/sites/default/files/gcis_document/201409/a1401992.pdf, accessed October 2021. 11. New Zealand Government, The Misuse of Drugs Amendment Act (No. 2), 1987, http://www6.austlii.edu.au/nz/legis/hist_act/modaa219871987n193318.pdf, accessed October 2021. 12. G. Kau, Univ. Pa. Law Rev., 2008, 156(4), 1077. 13. L. A. King, D. Nutt, N. Singleton and R. Howard, United Kingdom Drug Policy Commission, 2012, https://www.ukdpc.org.uk/wp-­content/uploads/ Analogue-­control-­19.06.12.pdf, accessed October 2021. 14. Advisory Council on the Misuse of Drugs, Consideration of the Novel Psychoactive Substances (‘Legal Highs’), 2011, https://assets.publishing. service.gov.uk/government/uploads/system/uploads/attachment_data/ file/119139/acmdnps2011.pdf, accessed October 2021.

Chapter 12

What Is a Derivative? 12.1  Introduction This Chapter is an abridged version of an article1 that was published in 2014. The term ‘derivative’ is widely used in chemistry and related disciplines, and its actual meaning depends on the topic and context. Thus, some uses might suit particular situations in chemistry better than others. The term is also widely used in drugs legislation, but it is rarely defined. This leads to a situation where the legal status of some substances is unclear. The problem of how the law should be interpreted is illustrated by certain derivatives of ecgonine (e.g., cocaine precursors) and certain ergolines (e.g., 2-­bromo-­LSD). An early use of the term ‘derivative’ appears in Article 14 of the International Opium Convention of 1912, signed at The Hague (Chapter 13). The objective of the Convention was ‘to bring about the gradual suppression of the abuse of opium, morphine, and cocaine as also of the drugs prepared or derived from these substances…’, and regulations were meant to apply ‘to all new derivatives of morphine, of cocaine, or of their respective salts, and to every other alkaloid of opium’.2 The current Yellow List3 of internationally controlled drugs under the UN Single Convention on Narcotic Drugs still mentions, but does not define, the term ‘derivative’. In addition to heroin and nicomorphine that are ester derivatives of morphine obtained by simple acylation of the natural product, other semi-­synthetic opioids can only be made by multistep processes. For example, both etorphine and its 3-­acetyl derivative (acetorphine) are considered to be thebaine derivatives. Likewise, desomorphine (Chapter 22), the infamous active ingredient of ‘crocodile’, which has been produced clandestinely from codeine-­containing medicines in Russia, is mentioned as a ‘derivative of morphine’. In these cases, the controlled substances are semi-­synthetic opioids

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and are indeed prepared, albeit in several stages, from the respective natural alkaloid. Schedule I of the UN 1961 Convention lists ‘Ecgonine, its esters and derivatives which are convertible to ecgonine and cocaine’. While the term ‘esters’ is unambiguous, there is no explanation either in the Convention or in the Commentary on the Single Convention of what is meant by ‘derivatives’. When the MDAct was created in the UK, a similar control was included. Thus Part I of Schedule 2 to the Act (i.e., Class A) lists ‘Ecgonine, and any derivative of ecgonine which is convertible to ecgonine or to cocaine’. Furthermore, the MDAct went on to include several other generic definitions based on the concept of ‘derivative’. Thus, among the Class A drugs are included ‘Lysergide and other N-­alkyl derivatives of lysergamide’ as well as ‘morphine methobromide, morphine N-­oxide and other pentavalent nitrogen morphine derivatives’. Among Class B drugs are included ‘cannabinol derivatives’, which are defined as ‘…the following substances, except where contained in cannabis or cannabis resin, namely tetrahydro derivatives of cannabinol and 3-­alkyl homologues of cannabinol or of its tetrahydro derivatives’. Apart from this definition of cannabinol derivatives, no other explanation is provided in the MDAct. In the CSA of the United States,4 under section 802 Definitions (9)(A), derivatives of barbituric acid are controlled, although these are at least qualified as being substances that are later designated as habit forming. Thus: ‘a drug which contains any quantity of (i) barbituric acid or any of the salts of barbituric acid; or (ii) any derivative of barbituric acid which has been designated by the Secretary as habit forming under section 352(d) of this title’. However, other uses of ‘derivative’ in the CSA are less clear. Under subsection (16), marihuana (cannabis) derivatives are controlled as: ‘The term “marihuana” means all parts of the plant Cannabis sativa L., whether growing or not; the seeds thereof; the resin extracted from any part of such plant; and every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds or resin’. Under subsection (17)(A), opium derivatives are controlled. Thus: ‘Opium, opiates, derivatives of opium and opiates, including their isomers, esters, ethers, salts, and salts of isomers, esters, and ethers, whenever the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation. Such term does not include the isoquinoline alkaloids of opium’. Although a list of opiate derivatives is subsequently provided, it is not clear if this is exhaustive. Remarkably, despite resting in the legislation for 50 years, and until the recent emergence of legitimate uses for 2-­bromo-­LSD, the concept of a derivative caused almost no forensic-­chemical or legal problems. There has been no Court trial that could have provided specific guidelines on what was and what was not a derivative. Part of the reason is that few potential derivatives are of any public concern. Thus, controlling ecgonine derivatives makes sense if clandestine synthesis of cocaine were a common activity. In practice, synthetic cocaine is almost never encountered, probably because extraction and production of the natural alkaloid is economically much more favourable. Pentavalent derivatives of morphine are rarely used in a clinical setting and have never been reported as drugs of misuse. Although

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9

Δ -­tetrahydrocannabinol (THC) is not commonly found in a pure state, its definition as a tetrahydro derivative of cannabinol causes no contention.

12.2  General Definitions of ‘Derivative’ In general, chemists use the word ‘derivative’ in a broader sense without problem. Webster's dictionary5 provides a chemical definition of ‘derivative’ as: ‘a compound derived or obtained from known or hypothetical substances and containing essential elements of the parent substance’. The same dictionary defines ‘derive’, as used in chemistry, as: ‘to produce or obtain (a compound) from another substance by chemical reaction’. The Oxford Dictionary of Chemistry,6 though partly relying on tautology, provides the following definition for ‘derivative’: ‘a compound that is derived from some other compound and usually maintains its general structure, e.g., trichloromethane (chloroform) is a derivative of methane’. This latter definition seems to have been adopted by editors of online dictionaries7 by typically defining the term as a compound derived or obtained from another on one hand and containing essential elements of the parent substance on the other. Both the process and the structural similarity are prerequisites. In spite of its common use in organic, analytical and medicinal chemistry, IUPAC provides no definition for ‘derivative’ in its 2019 Glossary, although the term ‘analogue’ is defined.8 There are many situations in the literature where ‘analogue’ and ‘derivative’ are used inter-­changeably. Examples here are papers on a series of ‘dihydrobenzofuran analogues of hallucinogens’ prepared for the investigation of structure–activity relationship of compounds with structural features of DOB [2,5-­dimethoxy-­4-­bromoamphetamine] and mescaline.9,10 The dihydrobenzofurans, such as 2C-­B-­Fly [2-­(8-­methoxy-­2,3,5,6-­tetrahydrofuro[3,2-­f][1]benzofuran-­4-­yl)ethanamine] and the benzofuran bromo-­dragonfly [1-­(8-­bromofuro[2,3-­f][1]benzofuran-­4-­yl)propan-­2-­amine] are considered to be ‘derivatives’ of mescaline [2-­(3,4,5-­trimethoxyphenyl)ethanamine], but it is only the phenylethylamine core that is common in all of their structures. In other words, such benzofurans can only be hypothetically, but not economically prepared (that is, chemically derived) from mescaline. In analytical chemistry, derivatisation of alcohols, amines or carboxylic acids, in particular, is frequently applied to aid the separation or the physicochemical characterisation of a substance. It is in this sense that the term ‘derivative’ is generally used in forensic and analytical toxicology. Derivatisation is mentioned in a standard organic chemistry textbook11 as: ‘We generally convert the unknown by a chemical reaction into a new compound called a derivative, and show that this derivative is identical with the product derived in the same way from the previously reported [and well-­defined] compound’. The term ‘derivative’ can also refer to biochemically related substances that are transformed into each other by metabolic processes.12 A relevant example is the case of the semi-­synthetic diacetylmorphine (diamorphine), i.e., heroin, the diacetyl derivative of morphine: In the body, it is hydrolysed to 6-­monoacetylmorphine, which is then further converted to morphine,

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thus rendering, in a biochemical sense, morphine as a ‘derivative’ of heroin. Subsequent biotransformations of morphine yield the 3-­ and 6-­glucuronide or 3-­O-­sulfate conjugates, which are thus also ‘derivatives’. In some general technical usage of the term derivative, chemical transformations, as opposed to physical processes, are not always involved. Thus, kerosene (paraffin) may be considered to be a crude oil derivative, and morphine is an opium derivative.

12.3  The Term ‘Derivative’ in Legal Practice In the view of Phillips,13,14 a substance B could be described as a derivative of A if A could be converted into B in a single reaction. If more reaction stages were needed to effect the conversion of A to B then B was a ‘derivative of a derivative’ and therefore excluded from control. Part of the thinking behind this was that any looser use of ‘derivative’ would lead to the situation where every chemical compound could ultimately be seen as a derivative of everything else: an absurdity that would render the law meaningless. However, as mentioned earlier, the inclusion in the UN Yellow List of a number of substances which are indirect derivatives of a named parent suggests that B is a derivative of A even if B can only be produced from A in a multistep reaction. A similar view on multistep derivatives was expressed a decade later in connection with the rescheduling of buprenorphine as a narcotic in the USA.15,16 The manufacturer of this semi-­synthetic analgesic contested the regulation claiming that buprenorphine (Scheme 12.1) cannot be considered to be a ‘derivative’ of thebaine, a scheduled narcotic. It was argued that the preparation of the drug from thebaine required considerable chemical modifications to provide the distinct structure of buprenorphine that is thus too chemically remote from thebaine to be termed a derivative. It was nevertheless agreed that the thebaine ring skeleton is contained within

Scheme 12.1  Following  a 1986 case in the US, the Drug Enforcement Adminis-

tration successfully argued that buprenorphine is a derivative of thebaine even though the conversion may involve several synthetic stages.

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that of buprenorphine. While the US CSA does not define the term ‘derivative’, the DEA cited the 1976 edition of the Van Nostrand's Scientific Encyclopaedia,17 which defines ‘derivative’ as ‘[a] term used in organic chemistry to express the relation between certain known or hypothetical substances and the compound formed from them by simple chemical processes in which the nucleus or skeleton of the parent substance exists. Usually, the term applies to those compounds where the resulting compound is formed in one step, although a chain of steps may be involved in some cases depending essentially upon how easy it is to identify the “derivative” within the parent substance’. The DEA also noted that attributing great significance to the actual number of reactions would be misleading. At the time, and depending on the method chosen, the conversion of thebaine to buprenorphine required six or eight separate steps. However, a shortened synthetic route has recently been developed.18 In support of the decision to classify buprenorphine as a narcotic, reference was also made to its ‘opiate-­like actions’. Finally, the arguments of the DEA were accepted and the petition for de-­scheduling was denied. In the UK MDAct, a different use of the word derivative occurs in some later generic definitions. For example, in ring-­substituted phenethylamines, reference is made to ‘a compound… structurally derived from phenethylamine’. In the judgment in the case of R-­v-­Couzens and Frankel in 1992 (Appendix 4), it was accepted that to say that compound A is ‘structurally derived from’ from B does not necessarily mean that B can be chemically converted to A in one or even several reaction stages. What is meant in the example of phenethylamines is that A still contains the carbon skeleton of phenethylamine (i.e., B), but that additional atoms (carbon, oxygen or other as defined) are now attached without implying that such an attachment is chemically possible. In practical terms, it will almost always be the case that A and B are produced from quite separate precursor chemicals which, in this example, may not in themselves be phenethylamines. This refined, albeit restricted, use of ‘derivative’ has caused no forensic problems.

12.4  Cocaine Precursors A number of synthetic routes to cocaine use 2-­carbomethoxytropinone as a starting point. However, 2-­carbomethoxytropinone cannot be converted to cocaine in a single step. Typically, a reduction stage converts it to methylecgonine, which is then esterified with, e.g., benzoic anhydride to yield cocaine (Scheme 12.2). If required, the intermediate methylecgonine can also be hydrolysed to yield ecgonine. Despite being a derivative of a derivative, many chemists would accept that 2-­carbomethoxytropinone is a ‘…derivative of ecgonine which is convertible to ecgonine or to cocaine’. It could be argued that the word ‘convertible’ is the real stumbling block. Yet to regard 2-­carbomethoxytropinone as a controlled drug would be perverse. Not only is it not an abusable substance in its own right, but modern domestic legislation, deriving from the UN 1988 Convention, deals with precursor chemicals in a way that is quite distinct from drugs.

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Scheme 12.2  The  conversion of 2-­carbomethoxytropinone to cocaine via methylecgonine: (1) stereoselective reduction; (2) benzoylation.

12.5  2-­Bromo-­LSD and Other Ergolines While lysergide (lysergic acid diethylamide, LSD; Chapter 20) was once a common drug of misuse and a substance that might still have therapeutic potential, there has been little clinical or illicit use of other ‘N-­alkyl derivatives of lysergamide’. That situation changed when it was found that 2-­bromo-­LSD (aka BOL-­148; Scheme 12.3) had value in the treatment of cluster headaches, a condition that often fails to respond to any conventional means of control. Because of the ambiguity of the above definition, there is no straightforward answer to the question ‘Is 2-­bromo-­LSD a controlled drug?’ For example, it might mean any derivative of N-­alkyl lysergamide, in which case 2-­bromo-­LSD is a controlled drug. In other words, 2-­bromo-­LSD is covered by the UK generic definition since that definition does not specifically exclude substitution in the ring system. On the other hand, it could be argued that the definition refers only to N-­alkyl homologues of lysergamide in which case 2-­bromo-­LSD is not controlled. A further complication is whether it should be accepted that ‘N-­alkyl’ includes N,N-­dialkyl. If it does not then 2-­bromo-­LSD, an N,N-­dialkyl compound, is not controlled. As discussed in Chapter 8, in the generic control of ring-­substituted phenethylamines introduced into the UK in 1977, some doubt resided in whether N,N-­disubstitution on the amine is currently subsumed by phrases such as ‘N-­alkylphenethylamine’. Another way of looking at this problem is to note that, in the language of Phillips,13,14 2-­bromo-­LSD might be seen as a ‘derivative of a derivative’, and therefore excluded. But it cannot be assumed that every ‘derivative of a derivative’ is automatically excluded, particularly in the light of the case regarding the derivative status of buprenorphine as discussed above. In conclusion, it cannot be predicted which view a Court might take. Those who wish to manufacture, supply or use this substance are then placed in a position where they could risk prosecution. The irony is that 2-­bromo-­LSD is not hallucinogenic and poses no threat of misuse. Further uncertainty occurs with other ergolines. It is believed that the legislation was not intended to control 1-­alkyl lysergamide alkanolamide derivatives such as methysergide (1-­methyl-­d-­lysergic acid-­(1-­hydroxybut-­2-­yl) amide; Scheme 12.4), a drug used to treat migraine. Similarly, ergometrine (ergonovine; Scheme 12.5), a drug used in obstetrics, is not normally regarded as a controlled drug in the UK. However,

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159

Scheme 12.3  (6aR,9R)-­  5 -­B romo-­N ,N-­d iethyl-­7 -­m ethyl-­4 ,6,6a,7,8,9-­h exahydro­

indolo[4,3-­fg]quinoline-­9-­carboxamide; 2-­bromo-­LSD; BOL (R′ = R″ = ethyl). Ring hydrogen atoms are omitted for clarity.

Scheme 12.4  1-­  Methyl-­d-­lysergic acid-­(1-­hydroxybut-­2-­yl) amide; methysergide. Ring hydrogen atoms are omitted for clarity.

Scheme 12.5  (6aR,9R)-­  N -­( (S)-­1 -­H ydrox ypropan-­2 -­y l)-­7 -­m ethyl-­4 ,6,6a,7,8,9-­ hexahydroindolo[4,3-­f g]quinoline-­9-­c arboxamide; ergometrine; ergonovine.

bearing in mind the various interpretations of the definition ‘N-­alkyl derivatives of lysergamide’ as discussed above, then just as with 2-­bromo-­LSD, the status of methysergide and ergometrine is also unclear. If the definition does refer to any derivative of N-­alkyl lysergamide, then both would

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therefore qualify as controlled drugs. This same view in respect of ergometrine is taken by the anonymous author of an article in an online encyclopaedia.19 In summary, there is considerable confusion regarding the status of certain ergolines under the MDAct. It would seem that the only options open to those who wish to develop clinical use of 2-­bromo-­LSD in the UK are either to provoke a test case, with potentially serious consequences for those involved, or to modify the law. The control of N-­alkyl derivatives of lysergamide is a purely UK domestic matter; apart from lysergide, no other ergoline, including lysergamide, is listed in the Schedules of either the 1961 or 1971 UN Conventions. It is considered possible that the law could be changed without increasing drug misuse. Although a revised generic definition could be developed, a simpler solution might be to exclude 2-­bromo-­LSD as a named substance from the scope of the definition.

12.6  Conclusions The concept of a ‘derivative’ is used widely in chemistry, where its precise meaning depends on the circumstances. In some cases, it is synonymous with ‘analogue’, yet this usage is rarely problematic. However, numerous examples of ‘derivative’ also occur in drugs legislation. Yet because it is rarely defined, a situation is created where the legal status of some substances is uncertain. It would appear that there is no single definition of ‘derivative’ that would suit all legal purposes, and it is therefore suggested that some existing legislation should be rewritten and all future legislation drafted such that the term is avoided unless unambiguously defined.

References 1. L. A. King, I. Ujváry and S. D. Brandt, Drug Test. Anal., 2014, 6(7–8), 879. 2. League of Nations, Publications of Treaties and International Engagements Registered with the Secretariat of the League of Nations, No. 222, International Opium Convention, signed at The Hague, 23 January 1912, http://treaties.un.org/doc/Publication/UNTS/LON/Volume%208/v8.pdf, accessed October 2021. 3. International Narcotics Control Board, List of Narcotic Drugs under International Control, 50th edn, https://www.incb.org/documents/ Narcotic-­Drugs/Yellow_List/60th_edition/YL_60th_edition_EN-­1.pdf, accessed October 2021. 4. United State Controlled Substances Act 1970, https://www.dea.gov/drug-­ information/csa, accessed October 2021. 5. American Heritage, Webster’s II New College Dictionary, Houghton Mifflin, Boston, 2005. 6. Oxford Dictionary of Chemistry, ed, R. Rennie and J. Law, Oxford University Press, Oxford, 7th edn, 2016, https://www.oxfordreference. com/view/10.1093/acref/9780198722823.001.0001/acref-­9780198722823, accessed October 2021.

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7. The Free Dictionary, http://www.thefreedictionary.com/derivative, accessed October 2021. 8. IUPAC Compendium of Chemical Terminology, https://goldbook.iupac. org/, accessed October 2021. 9. A. P. Monte, D. Marona-­Lewicka and M. A. Parker, et al., J. Med. Chem., 1996, 39(15), 2953. 10. A. P. Monte, S. R. Waldman and D. Marona-­Lewicka, et al., J. Med. Chem., 1997, 40(19), 2997, DOI: https://doi.org/10.1021/jm970219x. 11. R. T. Morrison and R. N. Boyd, Organic Chemistry, Allyn and Bacon Inc., Boston, 4th edn, 1983. 12. D. E. Metzler. Biochemistry – The Chemical Reactions of Living Cells, Harcourt/Academic Press, Burlington, MA, 2nd edn, 2001. 13. G. F. Phillips, Med. Sci. Law, 1973, 13(3), 216. 14. G. F. Phillips, personal communication, 2001. 15. Office of the Federal Register and National Archives and Records Administration, Schedules of controlled substances; rescheduling of buprenorphine from Schedule II to Schedule V of the Controlled Substances Act, Fed. Regist., 1985, 50, 8104. 16. Reckitt & Colman Ltd vs. Drug Enforcement Administration, 1986, 788 F.2d 22 (252 U.S. App. D.C. 120), https://law.resource.org/pub/us/case/ reporter/F2/788/788.F2d.22.85-­1193.html, accessed October 2021. 17. Van Nostrand, Van Nostrand's Scientific Encyclopaedia, 5th edn, 1976, ISBN: 0442216297. 18. A. Machara, L. Werner and M. A. Endoma-­Arias, et al., Adv. Synth. Catal., 2012, 354(4), 613. 19. Ergometrine, http://en.wikipedia.org/wiki/Ergometrine, accessed October 2021.

Chapter 13

New Psychoactive Substances (NPS): An Old Problem 13.1  Introduction The phenomenon of what are now most commonly called new psychoactive substances (NPS) can be divided into four main historical periods:    ●● morphine derivatives in the period before 1932 ●● ring-­substituted amphetamines from the 1960s ●● fentanyl and pethidine derivatives in the 1980s ●● the period after 1990    At different times and in different places, these substances have been known, amongst others, as designer drugs, designer medicines, research chemicals, party pills, plant food, bath salts, new synthetic drugs, novel psychoactive substances, recreational drugs and legal highs. The latter was originally a term used by Brown and Malone1 in the 1970s to describe herbal products. Most of these expressions have their drawbacks. Thus ‘legal high’ may refer to a substance that is not legal in some jurisdictions, ‘new synthetic drug’ excludes natural products, and NPS do not necessarily mean newly synthesised: many were first produced years ago. Here ‘new’ is more accurately interpreted to mean newly-­misused. The term new psychoactive substances (NPS) can also be problematic in that it raises the question of how one determines that the latest substance to be misused is actually psychoactive when controlled scientific studies in humans may be lacking. This topic is a central issue in questions about the UK Psychoactive Substances Act, 2016 (Chapter 5).   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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To a large extent these variants were, and continue to be, synthetic products; their production was intended to circumvent national and international controls yet lead to substances with a similar pharmacology to established drugs of misuse. ‘New’ substances also offered the advantage that they might not be detected by existing analytical techniques because suitable reference materials were not available to testing laboratories. In the case of synthetic cannabinoid receptor agonists (SCRAs), they have been found in complex mixtures that appeared to be designed to disrupt analytical identification. Many were ‘failed pharmaceuticals’, that is to say potential medicines that were evaluated by academic laboratories or the pharmaceutical industry but which never received a marketing authorisation usually because they had undesirable side effects or were no better than existing agents. Their synthesis and, occasionally, limited biological properties had usually been described in the open scientific literature or in patents. By contrast, the clandestine manufacture of truly novel compounds is less common. Non-­ synthetic drugs, most of which are plant-­based, have also appeared; they are described later, but represent a relatively minor position amongst drugs of misuse. These activities mirror a common legitimate activity in the pharmaceutical industry whereby competitors strive to develop useful medicines that may mimic established products but which can be created without infringing patents. Several reviews of new substances have been published2–4 and more can be found on the EMCDDA website.5 Despite the clear definition of NPS as originally provided by the EU Council Decision of 2005,6 nomenclatural problems have persisted.7

13.2  Morphine Derivatives in the Period before 1932 Morphine and its derivatives are covered in Chapter 22. Although the term itself would not be coined for another 50 years, the first ‘designer drugs’, were certain esters of morphine; and they appeared in the early years of the 20th century. Following the Shanghai Opium Commission in 1909, the International Opium Convention of 1912, signed at The Hague, attempted to control trade in opium, morphine and cocaine. However, heroin, the diacetyl ester of morphine (Scheme 13.1) continued to be diverted into the illicit trade. A second International Opium Convention was signed in

Scheme 13.1  Diamorphine. 

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Geneva in 1925, which came into force in 1928; it included specific control of morphine and diacetylmorphine. Within a short time, other, non-­ controlled, esters of morphine started to appear.8 They were intended as direct substitutes for heroin without any specific medical advantage. The most commonly manufactured were dibenzoylmorphine (Scheme 13.2) and acetylpropionylmorphine (Scheme 13.3); both could be easily converted back into morphine, and both could be used as drugs of misuse in their own right. In the UK, morphine esters and a number of related substances were subsequently added to the Dangerous Drugs Act 1920.9 International efforts to control these illicit esters of morphine came into effect with the League of Nations ‘Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs’,10 that was signed in Geneva in 1931. Article 1, Group I (sub-­group a) of that Convention includes, inter alia, the phrase ‘Diacetylmorphine and the other esters of morphine and their salts’. Control was also extended (in sub-­group b) to ethers of morphine with the exception of methylmorphine (codeine) and ethylmorphine, which were placed in Group II. It seems that those controls were sufficient to stop the production of morphine variants, and the widespread misuse of diamorphine did not become a major issue in Western countries until around 1980 when illicit diamorphine (heroin) started to appear from production sites in the Middle East. Further information on morphine and related opiates can be found in Chapter 22.

Scheme 13.2  Dibenzoylmorphine. 

Scheme 13.3  Acetylpropionylmorphine. 

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13.3  R  ing-­substituted Phenethylamines from   the 1960s Although it had been patented by the Merck Company in 1914, 3,4-­methylenedioxymethamphetamine (MDMA) was never formally marketed. Together with a few related phenethylamine derivatives, it remained largely forgotten until the 1960s, when it came into use as an aid in psychiatric counselling. Whereas amphetamine and its side-­chain derivatives are essentially central nervous system (CNS) stimulants, ring-­substitution, especially with alkoxy, alkyl and halogens leads to compounds with a novel pharmacology. Some may be hallucinogens, but many are better described as entactogens and empathogens. Isolated examples of other ring-­substituted amphetamines occurred in the 1960s with, for example, the appearance in the UK11 of DOM (2,5-­dimethoxy-­α,4­dimethylphenethylamine) and DOB (4-­bromo-­2,5-­dimethoxy-­α-­methylphenethylamine); this led to their early control as named substances in the MDAct.

13.4  Fentanyl and Pethidine Derivatives in the 1980s The next phase in the creation of illicit substitutes for controlled substances was inspired by the great expansion of the pharmaceutical industry and the rise of synthetic medicines after the Second World War. Just as in the pre-­war years, the main focus was again on narcotic analgesics. This brief period occurred mostly in the US. Clandestine chemists produced a number of fentanyl derivatives, for example, α-­methylfentanyl and 3-­methylfentanyl, together with certain derivatives of pethidine (meperidine), for example desmethylprodine (MPPP), its reverse ester. The term ‘designer drug’ was first coined by Gary Henderson in 1984.12 They were defined as ‘analogues, or chemical cousins, of controlled substances that are designed to produce effects similar to the controlled substances they mimic’. These highly potent substitutes for heroin caused a number of accidental deaths. Furthermore, a synthetic contaminant (MPTP) in the synthesis of desmethylprodine13 led to a chemically-­induced Parkinson's disease in a number of injecting drug users. Desmethylprodine provides an early example of a group of substances that, while originally described as a ‘designer drug’, were in fact ‘failed pharmaceuticals’. Thus, desmethylprodine had been synthesised in the 1940s as a potential analgesic.14 Derivatives of fentanyl and derivatives of pethidine were controlled in 1986 by generic definitions in the UK. Examples of fentanyl derivatives continued to arise sporadically, but in the past ten years a large group of fentanyl derivatives and other new narcotic analgesics have been reported (Chapter 8 and Appendix 11).

13.5  The Period after 1990 The past 30 years have seen a huge chemical diversification into new drug families. Throughout the 1990s most ‘new synthetic drugs’ were either ring-­ substituted phenethylamines or, less commonly, substituted tryptamines,

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many of which were undoubtedly inspired by the books PiHKAL15 and TiHKAL.16 In the past 20 years, manufacturers of NPS seem to have largely exhausted the chemical repertoire typified by these compounds and have diversified into a much more heterogeneous group of substances. Thus, in the early part of the 21st century, several new groups appeared, including piperazine and cathinone derivatives as well as synthetic cannabinoid receptor agonists (SCRAs; cannabimimetics). Some of these psychoactive novelties continued to be CNS stimulants, that is to say compounds with a pharmacology having some resemblance to that of the well-­established drugs amphetamine and MDMA (3,4-­methylenedioxy-­methylamphetamine; ecstasy) or they were hallucinogens or opioids. But SCRAs soon became by far the largest group. This might be a continuation of a historical process, whereby restrictions on a substance or its precursor chemicals stimulate clandestine chemists to explore new compounds, which in turn lead to further controls. However, the appearance of novel substances is also likely to reflect advances in organic and medicinal chemistry. Such developments will almost certainly continue to generate new legislative and analytical challenges. The role of the EMCDDA in monitoring NPS is described in Chapter 2. Table 13.1 shows the classification of substances reported to EMCDDA between 1997 and 2020,17 46 of which were reported in 2020. Each year, around 400 previously reported NPS are detected in Europe. Most are the subject of generic definitions in the UK legislation. Around two-­thirds are CNS stimulants. Figure 13.1 shows the annual number of new substances reported to EMCDDA for the first time under the terms of the EWS (Chapter 2). Figure 13.2 shows the number of Modification/Amendment Orders to the MDAct over the period 2007 to 2020 (Appendix 2). The steep rise in those Orders from early in the 21st century is almost entirely a reflection of attempts to control new substances. Reflecting the decline in reports of new Table 13.1  Classification  of substances reported to EMCDDA between 1997 and 2020.

Group

Number

Synthetic cannabinoids Cathinones Other substances Phenethylamines Opioids Tryptamines Arylalkylamines Benzodiazepines Arylcyclohexylamines Piperazines Piperidines and Pyrrolidines Plants and extracts Aminoindanes

209 156 106 102 67 53 41 30 22 18 15 9 6

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Figure 13.1  New  psychoactive substances reported annually to EMCDDA.

Figure 13.2  The  number of Modification/Amendment Orders to the MDAct over the period 1973 to 2020.

substances shown in Figure 13.1, it may be noted that there were no Modification/Amendment Orders to the MDAct in 2020 and just one in 2021. More detailed information on new substances can be found in Chapter 8. However, synthetic cannabinoid receptor agonists form an important and complex group: they are described in Chapter 18.

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13.6  C  hemical Aspects of New Psychoactive Substances The following sections highlight selected areas of the chemistry of NPS. They are followed by a discussion of whether NPS might be anticipated. Legislative responses to NPS are covered in Chapter 2.

13.6.1  Fluorinated Compounds A particularly interesting development has been the exploitation of fluorinated forms. At the simplest level, the substitution of a non-­facile hydrogen atom by a fluorine atom will rarely cause major changes in the pharmacological properties of the molecule, but if appropriately placed will often lead to a non-­controlled designer drug. Examples of fluorinated analogues include: 4-­fluorofentanyl, 2-­, 3-­and 4-­fluoroamphetamine; 4-­fluoromethamphetamine (and the precursor 4-­fluoro-­P2P); p-­fluorophenylpiperazine ( pFPP); 3-­ and 4-­fluoromethcathinone; the fluoropentyl derivatives of the synthetic cannabinoid receptor agonists JWH-­018 and JWH-­122; 3-­( p-­fluorobenzoyloxy)tropane ( pFBT); 4-­fluoroephedrine, several fluorinated benzodiazepines (such as flubromazolam) as well as forms where the non-­fluorinated molecule is uncommon such as trifluoromethylphenylpiperazine and 4-­fluorotropacocaine. Meanwhile, 3-­fluorophenmetrazine, a non-­controlled derivative of phenmetrazine which is a Class B controlled drug in the UK was critically reviewed by WHO/ECDD in 2020.

13.6.2  Analytical Problems with NPS The fast growth and diversification of novel structures has created further problems at both the analytical and legislative level. The initial absence of reference standards for both parent drugs and their metabolites has been a long-­standing problem and has led to increasing challenges to forensic and clinical laboratories in both the identification and quantification of NPS. Archer et al.18 discussed the challenges facing producers of reference materials. Not only has there been an increase in the number of novel structures being encountered, but in the absence of those reference standards, further difficulties are caused by the complexity of some analytes particularly when mixtures or difficult matrices are present or when positional as well as stereoisomer may exist. Good examples here are the synthetic cannabinoid receptor agonists, where the active constituents consist of a few milligrams among several grams of unknown vegetable matter. In this situation, recourse must be made to high resolution chromatography-­mass spectrometry since NMR analysis is almost impossible due to its reliance on homogeneous, that is to say, high purity analytes. While the identification of solid samples may often be difficult, the analysis of NPS in biological matrices is even more so.

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13.6.3  S  tructure–Activity Aspects of the Pharmacology and Toxicology of NPS Most substances reported to EMCDDA are CNS stimulants, and their chemical structures are now quite diverse; they range from several derivatives of pipradrol to arecoline, aminopropylbenzofuran, ring-­substituted aminoindans, the thiophenyl bioisostere of methamphetamine, as well as compounds structurally related to cocaine. Despite the various chemical groups involved, certain trends can be identified. Thus, not only is there a continuing effort to find novel, non-­scheduled stimulants, but the structures involved so far continue to explore the arylalkylamine theme. The amino group, which may be substituted, is separated from the ring by one or, more usually, two carbon atoms, and the side-­chain may be free or cyclic (i.e., part of a second ring). This structural pattern is not unique to stimulants, but it was originally exploited by chemists when creating the phenethylamine and tryptamine family. It can be seen in aminorex and pemoline as well as derivatives of piperazine, cathinone, indan, indene, tetralin, pipradrol, 1-­benzofuran, 5-­aminopropylindole, methylphenidate and many others. Some phenethylamines seem to be far more toxic than others, and this toxicity is largely associated with amphetamines that are ring-­substituted at the 4-­position. Thus 4-­methylthioamphetamine (4-­MTA) was associated with several fatal poisonings in the UK in the late 1990s despite being uncommon in seized material. Both 4-­methoxyamphetamine (PMA) and 4-­methoxymethamphetamine (PMMA) have been associated with many fatalities.19 The former has long been listed in the UN 1971 Convention, while PMMA was risk-­assessed under the terms of the EU Joint Action in 2003 (Appendix 1) and subsequently recommended for EU-­wide control. Finally, there was sufficient concern about 4-­methylamphetamine to warrant its risk assessment in late 2012 (Appendix 1) under the terms of the 2005 EU Council Decision. The presence of hydrophobic 4-­substituents (e.g., short-­chain alkyl and thioalkyl) may have several biological effects including increased potency caused by better partitioning into the CNS as well as reduced liability for metabolic attack. In phenethylamines not substituted at the 4-­position, including amphetamine itself, a major metabolic pathway proceeds via 4-­hydroxylation. This is not available in those compounds with a 4-­substituent. The risk to health of most NPS is unknown, a major ethical consideration that makes it difficult to justify human studies that would help underpin interpretation of cases in analytical toxicology. In such circumstances, in vitro metabolic investigations, employing preparations containing human liver enzymes, are an indispensable aid to the identification and characterisation of metabolites, as reviewed by Peters.20 What little we do know about the harmful properties of new substances comes from occasional work in animal toxicology, fatal poisonings in humans, or clinical observations of intoxicated patients. Some of the substances discovered so far may be less

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harmful than the controlled drugs they seek to replace, but their acute, and particularly chronic, toxicological properties are difficult to predict. While phytocannabinoids, including THC, possess low acute toxicity, by contrast, preliminary data suggest that at least some synthetic cannabinoid receptor agonists have a high fatal toxicity.21 Also, the adulteration of, for example, heroin with highly potent synthetic opioids, such as analogues of fentanyl and etonitazene, exacerbate the risks of overdose. While there has been no repeat of the problems posed 30 years ago by MPTP, a major public health crisis in the future cannot be ruled out so long as there is uncontrolled experimentation with novel substances.

13.6.4  Anticipation of NPS The historical sequence of NPS begs the question: ‘Could any of this have been predicted?’ In unpublished work by the author nearly 20 years ago and discussed as a potential research project by EMCDDA, it was suggested that within the ring-­substituted phenethylamines some guidelines could be established. Examination of the substances described in PiHKAL, for example, showed that not all were likely candidates for wider use. Thus, for a drug to be of interest the following criteria were suggested:    ●● CNS stimulants and empathogens (MDMA-­like) are more popular than hallucinogens; ●● the synthesis must have been described in the scientific literature or can be adapted from the preparation of analogous compounds; ●● precursor chemicals or essential reagents should be readily available; ●● the method of synthesis or extraction should not be too difficult; ●● the substance should not already be controlled in most countries; ●● the substance should be active orally at a dose of no more than 100 mg; ●● potentially toxic substances (e.g., alkoxy and alkylthiophenethylamines) or those with other unpleasant side effects are unlikely candidates.    However, some substances available today as ‘legal highs’ were well-­ anticipated. The best examples are the cathinone derivatives. When, in the mid-­1990s, methcathinone was added to Schedule I of the UN 1971 Convention, it was realised that the way was open for further compounds to appear. Within a few years, some ring-­substituted cathinone derivatives were being synthesised and studied as potential drugs of misuse. Thus Dal Cason et al.22 at the DEA laboratory in Chicago examined the properties of some 3,4-­methylenedioxycathinone homologues. By 2003, it was noted that ‘“Ring-­ substituted cathinones” represent an almost totally unexplored family of compounds and their pharmacology is unknown’.23 By contrast, the synthetic cannabinoid receptor agonists were not only unanticipated, but there was a general view that since cannabis was so cheap, there would be little commercial incentive to produce synthetic variants of THC. This mistaken view ignored the economics of chemical synthesis: it is

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only necessary to produce a few milligrams of active material per dose, and much less for agonists with a high affinity for the CB1 receptor. Secondly, the fact that the SCRAs were not at the time controlled drugs, and many would successfully evade drug testing regimes, would be attractive to users. An alternative approach to predict new substances would be to review the medicinal chemistry literature, both old and new, for likely candidates, but this would be an onerous task. While many likely substances would be found, it then becomes a separate task to suggest those which might be synthesised by clandestine chemists even given the above criteria. The downside of trying to anticipate new substances, especially if that is then published, is that the predictions could become self-­fulfilling. Finally, the time has now passed when anticipation might be a useful tool. As seen from Figure 13.1, the appearance of new substances in Europe seems to have peaked around 2014. It is unclear if this is because there are now sufficient substances available, users have less interest and are returning to more established drugs, there is less scope to create more novelties or it is due to successful regulations, including generic legislations introduced in response to this new phenomenon.

References 1. J. K. Brown and M. H. Malone, Clin. Toxicol., 1978, 12(1), 1. 2. S. D. Brandt, L. A. King and M. Evans-­Brown, Drug Test. Anal., 2014, 6(7–8), 587. 3. L. A. King and A. T. Kicman, Drug Test. Anal., 2011, 3(7–8), 401. 4. Novel Psychoactive Substances: Classification Pharmacology and Toxicology, ed. P. I. Dargan and D. M. Wood, Academic Press, London, 2nd edn, 2021, ISBN 978-­0-­12818788-­3. 5. European Monitoring Centre for Drugs and Drug Addiction, The EU Ear­ ly Warning System, https://www.emcdda.europa.eu/publications/topic­overviews/eu-­early-­warning-­system_en, Accessed October 2021. 6. European Union Council Decision 2005/387/JHA of 10 May 2005 on the information exchange, risk-­assessment and control of new psychoactive substances, https://eur-­lex.europa.eu/legal-­content/EN/ALL/?uri=CELEX%3A32005D0387, accessed October 2021. 7. L. A. King and D. J. Nutt, Lancet, 2014, 383, 952. 8. M. Delavingne, Br. J. Inebriety (Alcoholism and Drug Addiction), 1935, 32(3), 125. 9. Dangerous Drugs Act 1920, https://navigator.health.org.uk/theme/ dangerous-­drugs-­act-­1920-­criminalising-­opium-­and-­cocaine-­possession, accessed October 2021. 10. League of Nations. Publications of Treaties and International Engagements registered with the Secretariat of the League of Nations, No. 3219. Convention for limiting the manufacture and regulating the distribution of narcotic drugs. Signed at Geneva, 13 July 1931, http://treaties.un.org/doc/ Publication/UNTS/LON/Volume%20139/v139.pdf, accessed October 2021.

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11. G. F. Phillips and R. J. Mesley, J. Pharm. Pharmacol., 1969, 21(1), 9. 12. R. M. Baum, Chem. Eng. News, 1985, 63(36), 7. 13. MPTP, https://en.wikipedia.org/wiki/MPTP, accessed October 2021. 14. Desmethylprodine, https://en.wikipedia.org/wiki/Desmethylprodine, Accessed October 2021. 15. A. Shulgin and A. Shulgin, PiHKAL: A Chemical Love Story, Transform Press, Berkeley, California, 1991, ISBN 0-­9630096-­0-­5. 16. A. Shulgin and A. Shulgin, TiHKAL, The Continuation, Transform Press, Berkeley, California, 1997, ISBN 0-­9630096-­9-­9. 17. European Monitoring Centre for Drugs and Drug Addiction, European Drug Report: Trends and Developments, 2021, https://www.emcdda. europa.eu/system/files/publications/13838/TDAT21001ENN.pdf, accessed October 2021. 18. R. P. Archer, R. Treble and K. Williams, Drug Test. Anal., 2011, 3(7–8), 505. 19. L. A. King, Pharm. J., 2015, 294(7849), 176. 20. F. T. Peters and M. R. Meyer, Drug Test. Anal., 2011, 3(7–8), 483. 21. L. A. King and J. M. Corkery, J. Psychopharmacol., 2018, 32(7), 793. 22. T. A. Dal Cason, Forensic Sci. Int., 1997, 87(1), 9. 23. L. A. King, The Misuse of Drugs Act: A Guide for Forensic Scientists, Royal Society of Chemistry, London, 2003, ISBN 0-­85404-­625-­9.

Chapter 14

Substances Not Listed in the International Conventions 14.1  Introduction This Chapter is focussed on synthetic substances, or groups of substances that are not listed in the UN 1961 or 1971 Conventions. None is covered specifically or by generic definitions in the MDAct, but most would, in principle, be subject to the UK Psychoactive Substances Act, 2016 (Chapter 5). This review is mostly concerned with substances having more novel structures, and does not include non-­controlled members of established groups such as certain ring-­substituted phenethylamines, fentanyl derivatives, synthetic cannabinoid receptor agonists, cathinone derivatives and others. Many have been found in isolated drug seizures or have been offered for sale on websites. A few represent potential substances of misuse, although in reality the scope for novel psychoactivity is huge. The detailed pharmacological properties of many novel substances are unknown, but in terms of general effects it is clear that users continue to seek out substances which are primarily CNS stimulants like amphetamine or behave as entactogens and empathogens like MDMA. The following sections on phenethylamine side-­chain derivatives are followed by a heterogeneous group of compounds. The substances have usually come to notice in drugs seizures by law enforcement agencies in Europe, the US or other countries, or they are the result of test purchases from headshops or internet websites, anonymous depositions in amnesty bins or, less commonly, have been identified in ante-­mortem or post-­mortem tissues. A few others have been described on websites as potential psychoactive drugs. Many of those described below have represented a short-­lived experimentation by drug users and had limited circulation. Nevertheless, experience   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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shows that what we might think are yesterday's drugs can be rediscovered by later generations.

14.2  Phenethylamines The phenethylamine nucleus provides much scope for new molecular variations. Apart from the well-­known ring-­substituted members (e.g., MDMA), variations in the side-­chain have given rise to five main series:    ●● N-­substituted 2-­phenethylamines ●● phenylalkylamines other than 2-­phenylethylamines ●● arylalkylamines ●● conformationally-­restricted phenethylamines ●● ephedrine derivatives  

14.2.1  N-­Substituted 2-­Phenethylamines The N-­substituted phenethylamines make up a rather mixed group. Some are well-­known as established drugs of abuse while others have value in medicine with little abuse potential. Many of the latter are still of forensic interest because they metabolise to either amphetamine or methylamphetamine and may be detected in the urine.1 Nearly all of these compounds are N-­substituted α-­methylphenethylamines (i.e., N-­ substituted amphetamines). Scheme 14.1 shows the general form of a N-­ substituted 2-­phenethylamine. Table 14.1 lists some of the better-­known non-­controlled substances and a few examples of compounds which have been found in seizures. For comparison, Table 14.2 lists those N-­ substituted 2-­phenethylamines that are controlled in the UK. Many are rarely encountered, although Captagon® tablets, which originally contained fenethylline, but now contain amphetamine or other CNS stimulants have been common in the Middle East for several decades. Although it is a Class C drug, mesocarb is excluded from Table 14.2 because it is not a simple N-­substituted phenethylamine; the amine nitrogen is part of an oxadiazolium ring. The attraction of certain N-­substituents to an illicit chemist is that a non-­ controlled drug can be made which is sufficiently labile that it can be converted metabolically or by other simple means into an active substance: in other words, it is a proxy for a controlled drug. A good example here is

Scheme 14.1  The  general form of a N-­substituted 2-­phenethylamine.

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175

Table 14.1  Non-­  controlled N-­substituted 2-­phenethylamines – see Scheme 14.1. Compound

R1

R2

N-­Acetylamphetamine Amphetaminil

H H

Acetyl 1-­Phenyl-­1-­ cyanomethyl

Clobenzorex

H

N,N-­Dimethylamphetamine N,N-­Dimethylphenethyamine N-­Propylamphetamine Famprofazone

Methyl Methyl H Methyl

Fencamine

Methyl

N-­Ethyl-­1-­phenylbutan-­2-­ amine

H

R3

Comment

Methyl Illicit product Methyl Medicinal product (not UK) o-­Chlorobenzyl Methyl Medicinal product (not UK) Methyl Methyl Illicit product Methyl H Illicit product Propyl Methyl Illicit product 3-­(1-­Phenyl-­2-­methyl-­4-­ Methyl Medicinal isopropylpyrazolin-­ product 5-­one)methyl (not UK) 2-­(3,7-­Dihydro-­1,3,Methyl Medicinal 7-­trimethyl-­1H-­ product purine-­2,6-­dione-­ (not UK) 8-­amino)ethyl Ethyl Ethyl Illicit product

Table 14.2  Controlled  N-­substituted 2-­phenethylamines – see Scheme 14.1.

Compound

R 1 R2

R3

Amphetamine Benzphetamine N-­Ethylamphetamine Fenethylline Fenproporex Mefenorex Methylamphetamine α-­Methylphenethylhydroxylamine

H H H H H H H H

Methyl Methyl Methyl Methyl Methyl Methyl Methyl Methyl

Lisdexamphetamine

H Benzyl Ethyl 7-­Theophyllinylethyl 2-­Cyanoethyl 3-­Chloropropyl Methyl Hydroxy

Class under the MDAct; UN 1971 Convention Schedule

Class B; Sch. II Class C; Sch. IV Class C; Sch. IV Class C; Sch. II Class C; Sch. IV Class C; Sch. IV Class A; Sch. II Class B; (not listed) H Diaminohexanecar- Methyl Class B; (not bonyl listed)

α-­methylphenethyl-­hydroxylamine (the N-­hydroxy derivative of amphetamine), now listed as a Class B drug in the UK. However, a downside of N-­ substitution is that non-­alkyl groups are often labile and especially prone to hydrolysis. It occurs, for example, with N-­hydroxyamphetamine, where the parent compound (amphetamine) may be present in detectable amounts, thereby vitiating any advantage offered by a non-­controlled derivative. More recent examples are the N-­tert-­butoxycarbonyl (t-­BOC) derivatives of

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methamphetamine and MDMA recently seized in several countries. These ‘masked’ and uncontrolled phenethylamines undergo hydrolysis in acidic conditions and produce the parent compound.2

14.2.2  Phenylalkylamines Other than 2-­Phenylethylamines In 2-­phenethylamine, the amino group is separated from the phenyl ring by two saturated carbon atoms. This configuration, exemplified by amphetamine (α-­methylphenethylamine) and its numerous derivatives, appears to be optimal for pharmacological, that is CNS stimulant activity. The substance β-­methylphenethylamine (Scheme 14.2), a structural isomer of amphetamine, was reported to EMCDDA by Norway in 2010. However, illicit chemists have experimented with other arrangements, where the amino group is separated from the phenyl ring by one or three saturated carbon atoms. Scheme 14.3 shows a substituted α-­methylbenzylamine. In the mid-­ 1990s, 1-­phenylethylamine (α-­methylbenzylamine; Table 14.3) and, less

Scheme 14.2  β-­  Methylphenethylamine; 2-­phenylpropan-­1-­amine; BMPEA.

Scheme 14.3  The  general form of a substituted 1-­phenylethylamine (α-­methyl­ benzylamine).

Table 14.3  Miscellaneous  phenylalkylamines other than 2-­phenethylamines – see Scheme 14.3.

Name

R1

R2

R3

N-­Methyl-­1-­phenylethylamine 1-­Phenylethylamine (α-­methylbenzylamine) 1-­Phenyl-­1-­propanamine 1-­Amino-­1-­(3,4-­methylenedioxyphenyl)propane N-­Benzylmethylamine N-­Benzylethylamine

Methyl H H Methyl Methyl Ethyl

H H H 3,4-­MDOa H H

Methyl Methyl Ethyl H H H

a

3,4-­MDO = 3,4-­methylenedioxy.

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commonly, two isomeric analogues (4,α-­dimethylbenzylamine and N,α-­ dimethylbenzylamine) first appeared in drug seizures in Europe.3 In the same period a further ring-­substituted compound was found in the Netherlands and Germany. Although not described in detail, the latter is mentioned in PiHKAL4 under the code name ALPHA. More recently, 1-­phenylpropan-­ 1-­amine(α-­ethylbenzylamine) has been reported in Europe (Table 14.3). The dimeric substance N,N-­di-­(2-­phenylisopropyl)amine (DPIA) is also known as an illicit substance. Although it is a side-­product of amphetamine synthesis, it has sometimes occurred at high concentration suggesting deliberate synthesis. Two related compounds, N-­benzylmethylamine (Scheme 14.4) and N-­ benzylethylamine, both lacking psychoactivity, have been reported in the US as mimics for crystalline methylamphetamine.5 As far as is known, the other examples listed in Table 14.3 behave as weak stimulants, but the pharmacology of the ring-­substituted derivatives (e.g., ALPHA; Scheme 14.5) might be closer to MDMA. None of the phenylalkylamines listed in Table 14.3 is controlled in the UK or listed in the UN Conventions. A single example (1-­phenyl-­3-­butanamine, aka homoamphetamine; Scheme 14.6) has been encountered in the UK where the amino group is more distant from the phenyl group.

Scheme 14.4  N-­  Benzylmethylamine.

Scheme 14.5  1-­  Amino-­1-­(3,4-­methylenedioxyphenyl)propane; ALPHA.

Scheme 14.6  1-­  Phenyl-­3-­butanamine.

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14.2.3  Arylalkylamines Numerous substances related to the phenethylamines are known6 where the phenyl group has been replaced with some other aryl or polycyclic structure. The following sections consider thiophenylalkylamines, naphthylalkylamines, indanylalkylamines, 1-­benzofurans, 2,3-­dihydro-­1-­benzofurans, 1H-­indoles, indolines, and 1H-­indenes. Certain members of these groups have been recommended for control as Class B drugs by the ACMD in the UK.7,8 However, apart from the specific listing of 1-­(thiophen-­2-­yl)-­2-­methylaminopropane (see below), attempts to create generic definitions for the other substances in the MDAct have foundered on the precise definition of the aminoalkyl substituent; this is discussed in Chapter 10. The indans make up another sub-­group, although they have so far not been considered for control in the UK. They are also not listed in the UN 1971 Convention. Much less is known about the illicit use of aminotetralins.

14.2.3.1 Thiophenylalkylamines Derivatives of amphetamine have been found in illicit products, where the phenyl group has been replaced with a thiophenyl group such as thiophenylamphetamine and 1-­(thiophen-­2-­yl)-­2-­methylaminopropane. The latter is also known as methylthienyl-­propamine; (MPA; Scheme 14.7) and is the thiophene analogue of methylamphetamine; it is listed in Schedule II of the UN 1971 Convention and is a Class B drug in the MDAct. It was originally synthesised in 1942.9 However, the lower homologue, namely thiophenylamphetamine (1-­(thiophen-­2-­yl)-­2-­aminopropane), which was reported to EMCDDA by the Czech Republic in 2012, remains outside control.

14.2.3.2 Naphthylalkylamines A naphthyl group occurs in some synthetic cannabinoid receptor agonists (e.g., naphthoylindoles; Chapter 18) and a few cathinone derivatives (e.g., naphyrone; see Chapter 8). Two naphthylalkylamines are listed in PiHKAL,3 namely 2-­(1,4-­dimethoxy-­2-­naphthyl)-­1-­methylethylamine and 2-­(1,4-­dimethoxy-­2-­naphthyl)ethylamine (Appendix 7), but neither has so far been reported in drug seizures. There is evidence that a naphthyl group may bring with it undesirable properties, particularly the risk of carcinogenicity, possibly caused by metabolism of the naphthyl ring to a highly reactive naphthalene epoxide.10 The clinical development of the beta-­blocker pronethanol

Scheme 14.7  1-­  (Thiophen-­2-­yl)propan-­2-­methylamine; methylthienylpropamine; MPA.

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(1-­(naphthalen-­2-­yl)-­2-­(propan-­2-­ylamino)ethanol; Scheme 14.8), which bears some close structural resemblance to both naphthylalkylamines and naphyrone, was abandoned because of its carcinogenicity in mice.11

14.2.3.3 Indanylalkylamines Otherwise known as the indanyl analogue of MDA, 1-­(5-­indanyl)-­2­aminopropane (5-­IAP; Scheme 14.9) was first reported in the US as suspected ecstasy.12 On a structural basis, it is possible that 5-­IAP acts as a CNS stimulant. It was later offered on European websites under the alternative name 5-­(2-­aminopropyl)-­2,3-­dihydro-­1H-­indene (5-­APDI).

14.2.3.4 Aminoalkyl-­1-­benzofurans Few 1-­benzofurans have been reported as illicit products and none is listed in the UN 1971 Convention. The most commonly-­mentioned compound is 6-­(2-­aminopropyl)benzofuran, commonly known as 6-­APB or Benzofury, as shown in Scheme 14.10. More complex derivatives of 1-­benzofuran are known where the aminoalkyl group is located on the heterocyclic ring. These are essentially bioisosteres of tryptamine and are described in Section 14.12

Scheme 14.8  1-­  (Naphthalen-­2-­yl)-­2-­(propan-­2-­ylamino)ethanol; pronethanol.

Scheme 14.9  1-­  (5-­Indanyl)-­2-­aminopropane; 5-­IAP or 5-­APDI.

Scheme 14.10  6-­  (2-­Aminopropyl)benzofuran; 6-­APB.

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below. Problems with the generic control of 1-­benzofurans in the UK are described in Chapter 10.

14.2.3.5 Aminoalkyl-­2,3-­dihydro-­1-­benzofurans A typical member of this sub-­group is 6-­(2-­aminopropyl)dihydrobenzofuran (Scheme 14.11), commonly known as 6-­APDB.

14.2.3.6 Aminoalkyl-­1H-­indoles Aminoalkyl indoles are structural isomers of the better-­known tryptamine drugs. The substance 5-­(2-­aminopropyl)indole (5-­API or 5-­IT; Scheme 14.12) has been of sufficient interest that it was risk-­assessed by EMCDDA in 2014 (Appendix 1) and recommended for control across the EU but is not under international control. The corresponding 6-­isomer (6-­API) is also known.

14.2.3.7 Aminoalkylindolines Scheme 14.13 shows 5-­(2-­aminopropyl)indoline. This is the dihydro analogue of 5-­IT.

14.2.3.8 2-­Aminoindans and 2-­Aminoindenes In Europe, 2-­aminoindan (2-­AI; Scheme 14.14), 5,6-­methylenedioxy-­ 2-­aminoindan (MDAI; Scheme 14.15); and 5-­iodo-­2-­aminoindan (5-­IAI; Scheme 14.16) have all been reported in illicit products.13 From a structural aspect,

Scheme 14.11  6-­  (2-­Aminopropyl)dihydrobenzofuran; 6-­APDB.

Scheme 14.12  5-­  (2-­Aminopropyl)indole; 5-­API or 5-­IT.

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Scheme 14.13  5-­  (2-­Aminopropyl)indoline.

Scheme 14.14  2-­  Aminoindan.

Scheme 14.15  5,6-­  Methylenedioxy-­2-­aminoindan; MDAI.

Scheme 14.16  5-­  Iodo-­2-­aminoindan; 5-­IAI. 2-­aminoindane can be seen as a rigidified amphetamine, where the α-­methyl substituent has been tethered to the aromatic ring. It is a short acting stimulant with analgesic properties and has been compared to 1-­benzylpiperazine and methylamphetamine. Closely related to the 2-­aminoandans is the substance 5,6-­methylenedioxy-­ 2-­aminoindene (Scheme 14.17). Some years ago, illicit interest was shown in its synthesis, but it does not appear to have been recorded in seizures or other notifications. By contrast, 1-­aminoindans have a different pharmacological profile.

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Scheme 14.17  5,6-­  Methylenedioxy-­2-­aminoindene. Thus, rasagiline ((R)-­N-­2-­propynyl-­1-­indanamine) has been used in the treatment of Parkinson's disease.14

14.2.3.9 Aminoalkyltetralins As with the 2-­aminoindene noted above (Scheme 14.17), the same individuals were also interested in the illicit synthesis of 5,6-­methylenedioxy-­2-­ aminotetralin (Scheme 14.18). This substance is effectively the ring-­closed analogue of BDB (1-­[1,3-­benzodioxol-­5-­yl]-­2-­butanamine), a phenethylamine listed in PiHKAL.4

14.2.4  Conformationally-­restricted Phenethylamines Apart from 2C-­B-­Fly (Scheme 14.19) and bromodragonFly (Scheme 14.20), other conformationally-­restricted phenethylamine analogues have been evaluated15 as 5-­HT receptor agonists where the aminoalkyl side-­chain has been partly converted to a cyclic structure. It was predicted that the R-­enantiomer of the benzocyclobutene analogue of 2C-­B, also known as TCB-­2, (Scheme 14.21) would be the most potent. These substances are all potential candidates for illicit production.

14.2.5  Ephedrine and Derivatives Ephedrine, which exists in two enantiomeric forms (Scheme 14.22), can be a synthetic substance or extracted from Ephedra vulgaris (known as Ma Huang in Chinese medicine). It is used and abused in several different ways. As a medicine it finds wide application as a bronchodilator to treat bronchospasm associated with asthma, bronchitis and emphysema. It is abused for its stimulant properties, but l-­ephedrine, now known as (1R,2S)-­ephedrine, is five times less potent than amphetamine, although somewhat more potent than diethylpropion (amfepramone). Pseudoephedrine is used as a decongestant. Both ephedrine and pseudoephedrine are precursors in the clandestine synthesis of methylamphetamine and, less commonly, methcathinone; they are subject to certain trade controls under the provisions of the UN 1988 Convention and subsequent domestic legislation (Chapter 27). Ephedrine is

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Scheme 14.18  5,6-­  Methylenedioxy-­2-­aminotetralin.

Scheme 14.19  2-­  (4-­Bromo-­2,3,6,7-­tetrahydrofuro[2,3-­f][1]benzofuran-­8-­yl)ethanamine; 2C-­B-­Fly.

Scheme 14.20  1-­  ( 4-­B romofuro[2,3-­f ][1]benzofuran-­8 -­y l)propan-­2 -­a mine; bromodragonFly.

Scheme 14.21  The  benzocyclobutene analogue of 2C-­B [[(7R)-­3-­bromo-­2,5-­di­ methoxy-­bicyclo[4.2.0]octa-­1,3,5-­trien-­7-­yl]methanamine; TCB-­2].

also found in certain illicit products, either alone or added to other powdered or tabletted drugs such as amphetamine or ketamine as an active diluent. Ephedrine and pseudoephedrine form part of a stereoisomeric quartet (Chapter 7). In 1998, the WHO proposed that (1R,2S)-­ephedrine and its racemate should be brought within the scope of the UN 1971 Convention. The d-­isomer, now

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Scheme 14.22  Ephedrine  enantiomers [(−)-­(1R,2S)-­ephedrine (top) and (+)-­(1S,2R)-­ephedrine (bottom)]. Some hydrogen atoms are omitted for clarity.

Scheme 14.23  1-­  (4-­Fluorophenyl)-­2-­(methylamino)propan-­1-­ol; 4-­fluoroephedrine. known as (1S,2R)-­ephedrine, was not recommended for control as it is much less potent than the l-­isomer. However, at a subsequent meeting of CND, the proposal was not accepted by the majority of UN signatories and was therefore not adopted. More recently, with continued concern about the potential diversion of these substances towards methylamphetamine manufacture, products containing more than 180 mg ephedrine or 720 mg pseudoephedrine became Prescription Only Medicines in the UK from 2008. The MHRA proposed that both drugs should be controlled under the MDAct. However, there is little evidence that these substances are intrinsically harmful; control would be seen as another way of restricting their use as precursors. Both ephedrine and pseudoephedrine are listed in the precursor chemical legislation (Chapter 27). The compound 4-­fluoroephedrine (Scheme 14.23) is a novel derivative of ephedrine that had been found in the urine of an intoxicated patient and in an unconnected post-­mortem sample; these findings were reported to EMCDDA by the UK in 2012. Because of the quantities involved, it did not appear to be a metabolite. The alpha-­methyl derivative of ephedrine (i.e., 3-­(methylamino)-­2-­phenyl-­butan-­2-­ol) was reported to the EMCDDA by The Netherlands in 2018.

14.3  Methylhexaneamine Methylhexaneamine (4-­methylhexan-­2-­amine; Scheme 14.24), also known as 1,3-­dimethylamylamine (DMAA) and dimethylpentylamine, was once a fairly obscure stimulant that was patented in 1944 and considered as an inhalant

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Scheme 14.24  Methylhexaneamine;  DMAA.

Scheme 14.25  Heptane-­  2-­amine; tuaminoheptane. for nasal decongestion.16 In recent times, it has been marketed as a dietary supplement for athletes under the unlicensed name ‘Geranamine’ or as ‘geranium extract’. DMAA has been found in the form of tablets and capsules in ‘legal high’ products. The 2010 report from the World Anti-­Doping Agency (WADA) on adverse analytical findings17 for all sports, noted that methylhexanamine was the most commonly-­reported stimulant representing 21.4% of all cases and ahead of amphetamine, the next most common (19.5%). In early 2012, the US Food and Drug Administration issued warnings to manufacturers and distributors that no evidence had been submitted that dietary supplements containing DMAA were safe, and that therefore such products were considered as being ‘adulterated’. DMAA is closely related to the isomeric tuaminoheptane (heptane-­2-­amine; Scheme 14.25), a substance that also acts as a sympathomimetic stimulant and is prohibited by WADA.18 Another homologue, octodrine, (6-­methylheptan-­2-­amine) was reported to EMCDDA by Belgium in 2017.

14.4  Cognitive and Other Enhancers Although hallucinogenic and psychedelic drugs are sometimes thought to ‘expand the mind’, the search for substances that truly improve mental functions has proved more elusive. Sometimes known as nootropics or simply ‘smart drugs’, early candidates represented a diverse group of substances that included cholinergic drugs such as piracetam and its analogues, acetyl cholinesterase inhibitors, vitamins, amino acids, monoamine oxidase inhibitors, vasodilators and numerous herbal products. Such drugs are claimed to change the availability of neurochemicals in the brain, to improve the oxygen supply to the brain, or to stimulate nerve growth. However, the efficacy of alleged nootropic substances in most cases has not been conclusively determined.

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In the ‘Foresight Project on Brain Science, Addiction and Drugs: Drug Futures 2025’, launched in 2005 by the former Department of Trade and Industry,19 one component was focussed on cognition enhancers. It was believed that such substances would find use in the treatment of dementia, for those with specific cognitive impairment and those affected by the normal ageing process. A fourth group of users would be those who wished to use cognitive enhancers for non-­ therapeutic purposes. This in turn would raise social and ethical issues about whether and how such substances should be controlled by the criminal law. It is recognised that there are similarities in the potential use of cognitive enhancers with the current use of performance enhancing drugs in sport. Modafinil (2-­(diphenylmethyl)sulfinylacetamide; Scheme 14.26) is listed in the US Controlled Substances Act, Schedule IV, but is not currently under international control. Claimed not to be a typical stimulant, but more a ‘wakefulness promoting agent’ (eugeroic), modafinil has been used in the treatment of narcolepsy, idiopathic hypersomnia and Attention Deficit Hyperactivity Disorder. There have been few reports of its abuse. It has been suggested that it has cognitive enhancing and neuroprotective effects. Modafinil is available through similar internet channels to other novel substances. The European Medicines Agency announced in November 2011 that the use of modafinil should be restricted to the treatment of narcolepsy. The review by the Agency's Committee for Medicinal Products for Human Use (CHMP) was initiated because of a number of safety concerns, relating to psychiatric disorders, skin and subcutaneous tissue reactions as well as significant off-­label use and potential for abuse. Four analogues of modafinil have been reported to EMCDDA, namely adrafinil ((±)-­2-­benzhydrylsulfinylethanehydroxamic acid) by Sweden in 2014; modafiendz (N-­methyl-­4,4′-­ difluoromodafinil) by Luxembourg in 2014; fladrafinil (2-­[bis(4-­fluorophenyl)methylsulfinyl]-­N-­hydroxyacetamide) by Slovenia in 2016; and fluoromodafinil (2-­([bis(4-­fluorophenyl)-­methyl]sulfinyl)acetamide) by Sweden in 2018. In 2021, the ACMD20 considered Sunosi® [solriamfetol; (R)-­2-­amino-­3-­ phenylpropylcarbamate], a proprietary wakefulness agent. It was concluded that it had a low risk of misuse and should not be added to the MDAct. A number of drugs are used for physical enhancement. Apart from anabolic steroids, which are described elsewhere, these include substances to improve: weight loss (e.g., rimonabant and sibutramine to reduce the appetite and dinitrophenol to ‘burn fat’); cosmetic appearance (e.g.,

Scheme 14.26  2-­  (Diphenylmethanesulfinyl)acetamide; modafinil.

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mercury-­containing creams to lighten the skin colour or melanotan II for an artificial suntan); sexual function (e.g., sildenafil and bremelanotide) as well as mood enhancers (e.g., paroxetine). While many are unlikely candidates for control under drug legislation, the use of some is almost entirely unregulated. They have been described as human enhancement drugs.21

14.5  Carisoprodol Carisoprodol (Scheme 14.27) is a centrally-­acting skeletal muscle relaxant. It was developed to create a drug with less abuse potential than meprobamate (Scheme 14.28), a metabolite of carisoprodol that is already a controlled substance (UN 1971 Convention Schedule IV, and Class C in the UK). There have been a number of case reports showing that carisoprodol also has abuse potential,22 and is listed in Schedule IV of the US Controlled Substances Act. In late 2007, the European Medicines Agency recommended suspension of marketing authorisations for carisoprodol-­containing medicinal products throughout the EU.

14.6  Benzydamine Misuse of benzydamine (Scheme 14.29) has been reported in Poland.23 This substance is a non-­steroidal anti-­inflammatory drug with local anaesthetic properties. Normally intended for external use, it can produce hallucinations when large amounts are used orally.

Scheme 14.27  2-­  [[(Aminocarbonyl)oxy]methyl]-­2-­methylpentyl(1-­methylethyl)carbamate; carisoprodol.

Scheme 14.28  [2-­  (Carbamoyloxymethyl)-­2-­methyl-­pentyl]carbamate; meprobamate, a controlled metabolite of carisoprodol.

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Scheme 14.29  3-­  ( 1-­B enzyl-­1 H-­indazol-­3 -­y loxy)-­N ,N-­d imethylpropan-­1 -­a mine; benzydamine.

14.7  Analogues of Methaqualone Methaqualone (Scheme 14.30), sometimes known by the proprietary names Quaaludes® and Mandrax®, as well as the chlorinated derivative mecloqualone (Scheme 14.31) were added to Schedule II of the UN 1971 Convention many years ago. Although they are now uncommon hypnotic drugs, several derivatives of methaqualone have since appeared in isolated cases. Methylmethaqualone (Scheme 14.32) and the brominated analogue mebroqualone (Scheme 14.33) were found in Germany in 1997. Etaqualone (Scheme 14.34) was first reported to EMCDDA by Denmark in 2009. Afloqualone (6-­amino-­ 2-­(fluoromethyl)-­3-­(2-­methylphenyl)-­quinazolin-­4-­one) was reported by Sweden in 2014. As noted in Chapter 9, generic control of certain methaqualone operates in New Zealand, where all five substances shown below would be captured.

14.8  ‘Isocathinones’ A number of so-­called ‘isocathinones’ have been reported in illicit products. These include isoethcathinone (Scheme 14.35), which was reported to EMCDDA by Ireland in 2010, and isopentedrone. It is possible that they may have been synthesised deliberately, but they can also arise by the rearrangements that occur with cathinone derivatives. Scheme 14.36 shows the rearrangements that can occur with cathinone derivatives. Structures (1) and (2) show the keto–enol tautomeric forms of cathinone. The extent and conditions under which the equilibrium is displaced towards the enol form may depend on a number of factors including pH and the presence of particular substituents. One consequence of the equilibrium is that it would compromise the chiral character of the alpha-­carbon atom and hence lead to racemisation. The dimer in structure (3) arises by the condensation of two enol forms with elimination of water. This dimer can then undergo aromatisation to form the diphenylpyrazine (4). The latter is known to arise in khat and provides one of the mechanisms for reducing the cathinone

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Scheme 14.30  2-­  Methyl-­3-­o-­tolyl-­4(3H)-­quinazolinone; methaqualone.

Scheme 14.31  3-­  (2-­Chlorophenyl)-­2-­methylquinazolin-­4(3H)-­one; mecloqualone.

Scheme 14.32  3-­  (2,4-­Dimethylphenyl)-­2-­methylquinazolin-­4(3H)-­one; methyl­ methaqualone.

Scheme 14.33  3-­  (2-­Bromophenyl)-­2-­methylquinazolin-­4-­one; mebroqualone.

Scheme 14.34  3-­  (2-­Ethylphenyl)-­2-­methylquinazolin-­4-­one; etaqualone.

Scheme 14.35  1-­  Ethylamino-­1-­phenyl-­propan-­2-­one; isoethcathinone.

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Scheme 14.36  Rearrangements  of cathinone.

content in aged plant material. The dimer (3) can dissociate in two ways: either to reform the cathinone tautomers (1) and (2) or to form the two keto–enol tautomers in structures (5) and (6). The keto form in (5) is described informally as isocathinone. These rearrangements are also possible in N-­alkyl cathinones with or without ring-­substitution, but in those cases, the diphenylpyrazine (4) does not occur. If this is the mechanism for the formation of isocathinones, then it is surprising that some have been found in a relatively pure state in illicit material suggesting that the equilibrium between structure (6) and structure (5) is displaced strongly in favour of (5).

14.9  1-­Ethynylcyclohexanol The substance 1-­ethynyl-­cyclohexanol (ECX; Scheme 14.37) has been advertised as a ‘legal high’. It is a precursor and metabolite of ethinamate (1­ethynylcyclohexanolcarbamate; Scheme 14.38), which has short acting mild

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Scheme 14.37  1-­  Ethynylcyclohexanol.

Scheme 14.38  1-­  Ethynylcyclohexanolcarbamate; ethinamate. sedative and hypnotic properties. Although ethinamate is under international control (Schedule IV of the 1971 UN Convention), it is not clear if 1-­ethynyl-­cyclohexanol has psychoactive properties, particularly as it is a non-­nitrogenous neutral compound.

14.10  Camfetamine Camfetamine (Scheme 14.39) which has appeared for sale on ‘research chemicals’ websites, is the N-­methyl analogue of fencamfamin, a substance listed in Schedule IV of the 1971 Convention. Camfetamine is presumed to have similar properties to fencamfamin, i.e., a central nervous system stimulant which acts as a dopamine uptake inhibitor and increases locomotor activity. It was reported to EMCDDA by the UK in 2011.

14.11  S  elective Androgen Receptor Modulators (SARMs) A number of tissue-­selective androgen receptor modulators (SARMs) are under development for the prevention and treatment of certain cancers. One such substance (ostarine; Scheme 14.40) was reported to the EMCDDA by Sweden in 2011. Although they are not psychoactive, SARMs possess anabolic as well as androgenic effects, and could be misused in a similar manner to anabolic steroids.

14.12  Bioisosteres of Tryptamine It has long been recognised in medicinal chemistry that replacement of a ring hetero atom with another of similar valency may change the potency of a substance without radically altering the qualitative aspects of its pharmacology. Thus, replacement of the ring-­nitrogen in N,N-­dimethyltryptamine (DMT) by sulfur, methylene or oxygen would lead to bioisosteres of DMT.

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Scheme 14.39  N-­  Methyl-­3-­phenylbicyclo[2.2.1]heptan-­2-­amine; camfetamine.

Scheme 14.40  3-­  ( 4-­C yanophenoxy)-­N -­[ 4-­c yano-­3 -­( trifluoromethyl)phenyl]-­2 -­ hydroxy-­2-­methyl-­propanamide; ostarine.

Scheme 14.41  The  general form of a dimethyltryptamine bioisostere where the original R = N is replaced such that R may be S, CH2 or O.

Scheme 14.41 shows the generalised form of the DMT core. The benzothiophene (R = S) and 3-­indenalkylamine (R = CH2) analogues have a similar activity to dimethyltryptamine as agonists at the 5-­HT2 receptor in rat fundus and could therefore be potential hallucinogens. Other bioisosteres of DMT have been evaluated, including thienopyrrole analogues and certain benzofurans, for example 2-­(5-­methoxy-­1-­benzofuran-­3-­yl)-­N,N-­dimethylethanamine (5-­MeO-­BFE) where R = O.

14.13  Phenyloxazoline Derivatives Pemoline (Scheme 14.42) and aminorex (Scheme 14.43) are both Class C controlled drugs (and both Schedule IV in the UN 1971 Convention) while 4-­methylaminorex (Scheme 14.43) is a Class A controlled drug (Schedule I of the UN 1971 Convention). To a certain extent, the first two at least may be cautiously termed ‘obsolete stimulants’. However, just as with phenethylamines and cathinones, there are various possibilities for ring-­substituted derivatives to appear. A good example here is 2C-­B-­aminorex (2-­amino-­5-­(4-­bromo-­2,5-­dimethoxyphenyl)-­2-­oxazoline), which was reported to EMCDDA by Sweden in 2019.

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Scheme 14.42  (RS)-­  2-­Amino-­5-­phenyl-­1,3-­oxazol-­4(5H)-­one; pemoline. A Class C controlled drug.

Scheme 14.43  The  general form of a 5-­phenyl-­4,5-­dihydro-­1,3-­oxazol-­2-­amine. Aminorex (R = H) and 4-­methylaminorex (R = CH3).

This compound is another example of how the oxazoline substituent (i.e., 4-­bromo-­2,5-­dimethoxyphenyl) originally found in the phenethylamine 2C-­B has appeared in a number of other manifestations including the NBOMe compounds and in substituted piperazines (Chapter 8).

14.14  Amfonelic Acid Amfonelic acid (Scheme 14.44) is a potent and highly selective dopamine reuptake inhibitor.24 It has been offered for sale on the internet and has received a number of user-­reports describing it as a stimulant.

14.15  Substances Banned by WADA A number of psychoactive substances not listed in the schedules of the UN Conventions are banned in sporting events by WADA. In the 2010 report on adverse analytical findings in all sporting events,17 the following stimulants were found: 4-­phenylpiracetam, cropamide, crotetamide, etamivan, heptaminol, isometheptene, methylephedrine, nikethamide, oxilofrine, pholedrine, selegiline and sibutramine. However, in all cases their use was uncommon, amounting to no more than a few percent of all stimulants detected. Many other psychoactive compounds are banned by WADA; some were once used as therapeutic agents, but few are still available and most are unlikely candidates for more widespread use as recreational drugs.

14.16  Alkyl Nitrites These substances, and their relationship to the UK Psychoactive Substances Act, are covered in Chapter 5.

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Scheme 14.44  1-­  Ethyl-­4-­oxo-­7-­(phenylmethyl)-­1,8-­naphthyridine-­3-­carboxylic acid; amfonelic acid; AFA; WIN 25,978.

14.17  S  ubstances Reviewed by the WHO/ECDD   in 2020 At its 43rd meeting in October 2020, the WHO/ECDD25 carried out critical reviews on the following 11 substances (Schemes 14.45–14.55). At the 64th Session of the Commission on Narcotic Drugs (December 2020 and April 2021), it was decided to control eight of the substances as follows: isonitazene to Schedule I of the UN 1961 Convention; CUMYL-­ PEGACLONE, MDMB-­4en-­PINACA, 3-­methoxyphencyclidine and diphenidine to Schedule II, and clonazolam, diclazepam and flubromazolam to Schedule IV of the UN 1971 Convention. It follows that 2-­MeO-­diphenidine, 5-­MeO-­DALT and 3-­fluorophenmetrazine remain uncontrolled by the UN Conventions.

14.18  Salvinorin The plant Salvia divinorum is described in Chapter 26. The active constituent is salvinorin-­A (Scheme 14.56), a non-­nitrogenous substance. The methoxymethyl and ethoxymethyl ethers of salvinorin-­A are synthetic derivatives both known as salvinorin-­B and ‘symmetry’. They are claimed to be more potent than the parent compound.26

14.19  4-­Benzylpiperidine It is known that 4-­benzylpiperidine (Scheme 14.57) acts as a monoamine dopamine-­selective releaser and is expected to exhibit stimulant effects.27

14.20  Bromantane Bromantane (Scheme 14.58) has been used therapeutically in Russia as a psychostimulant and anxiolytic. It was reported to EMCDDA by Sweden in 2015.

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Scheme 14.45  N,N-­  Diethyl-­2-­[2-­[(4-­isopropoxyphenyl)methyl]-­5-­nitro-­benzimidazol-­ 1-­yl]ethanamine; isotonitazene. A synthetic opioid.

Scheme 14.46  Methyl  (S)-­3,3-­dimethyl-­2-­(1-­(pent-­4-­en-­1-­yl)-­1H-­indazole-­3-­carbox­ amido)butanoate; MDMB-­4en-­PINACA. A synthetic cannabinoid receptor agonist.

Scheme 14.47  2,5-­  Dihydro-­2-­(1-­methyl-­1-­phenylethyl)-­5-­pentyl-­1H-­pyrido[4,3-­b]indol-­1-­one; CUMYL-­PEGACLONE. A synthetic cannabinoid receptor agonist.

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Scheme 14.48  8-­  Bromo-­6-­(2-­fluorophenyl)-­1-­methyl-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepine; flubromazolam. A benzodiazepine.

Scheme 14.49  6-­  (2-­Chlorophenyl)-­1-­methyl-­8-­nitro-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepine; clonazolam. A benzodiazepine.

Scheme 14.50  7-­  Chloro-­5-­(2-­chlorophenyl)-­1-­methyl-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­one; diclazepam. A benzodiazepine.

Scheme 14.51  1-­  [1-­(3-­Methoxyphenyl)cyclohexyl]-­piperidine; 3-­MeO-­PCP. A phencyclidine analogue.

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Scheme 14.52  1-­  (1,2-­Diphenylethyl)piperidine; diphenidine. A phencyclidine analogue.

Scheme 14.53  1-­  [1-­(2-­Methoxyphenyl)-­2-­phenylethyl]piperidine; 2-­MeO-­di­pheni­dine. A phencyclidine analogue.

Scheme 14.54  N-­  [2-­(5-­Methoxy-­1H-­indol-­3-­yl)ethyl]-­N-­(prop-­2-­en-­1-­yl)prop-­2-­en-­1-­ amine; 5-­MeO-­DALT. A tryptamine.

Scheme 14.55  2-­  (3-­Fluorophenyl)-­3-­methylmorpholine; 3-­fluorophenmetrazine. A synthetic stimulant.

14.21  Cyclohexylbenzamide Opioids The substance U-­47700 (Scheme 14.59) is listed in the UN 1961 Convention. Two closely related compounds were reported to EMCDDA by Sweden in 2017, namely U-­51754 (Scheme 14.60) and U-­48800 (Scheme 14.61). They are believed to be narcotic analgesics, but little is known about their

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Scheme 14.56  Methyl(2S,4aR,6aR,7R,9S,10aS,10bR)-­  9-­(acetyloxy)-­2-­(furan-­3-­yl)-­ 6a,10b-­dimethyl-­4,10-­dioxo-­dodecahydro-­2H-­naphtho[2,1-­c]pyran-­ 7-­carboxylate; salvinorin-­A.

Scheme 14.57  4-­  Benzylpiperidine.

Scheme 14.58  N-­  (4-­Bromophenyl)adamantan-­2-­amine; bromantane.

Scheme 14.59  3,4-­  D ichloro-­N -­[ -­( 2-­( dimethylamino)cyclohex yl)-­] -­N -­m ethyl-­ benzamide; U-­47700.

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Scheme 14.60  2-­  (3,4-­Dichlorophenyl)-­N-­[2-­(dimethylamino)cyclohexyl]-­N-­methyl-­ acetamide; U-­51754.

Scheme 14.61  2-­  (2,4-­Dichlorophenyl)-­N-­[2-­(dimethylamino)cyclohexyl]-­N-­methyl-­ acetamide; U-­48800.

pharmacology or whether the addition of the methylene bridge changes their properties.

14.22  RH-­34 This selective partial agonist (Scheme 14.62) for the 5-­HT2A serotonin receptor was reported to the EMCDDA by France in 2013, but little is known about its potential for misuse.

14.23  Benzylbenzimidazole Opioids The opioid etonitazene (1-­diethylaminoethyl-­2-­p-­ethoxybenzyl-­5-­nitrobenzimidazole) is listed in Schedule I of the UN 1961 Convention. Isotonitazene (Scheme 14.45), which was risk-­assessed by EMCDDA in 2020, is described in Section 14.17 above (Substances Reviewed by the WHO/ECDD in 2020). Since then, further 2-­benzylbenzimidazoles have been detected in Europe, namely etazene (Scheme 14.63), fluonitazene (Scheme 14.64), metonitazene, the lower homologue of etonitazene, and metodesnitazene (Scheme 14.65) as well as the n-­propyl isomer of isotonitazene (proponitazene), the n-­butyl homologue (butonitazene) and the N-­p yrrolidino analogue etonitazepyne. These substances, which are many times more potent than morphine,28 are offered for sale on various websites. A report from Public Health England29 in October 2021 described the detection of isotonitazene and etonitazepyne in samples of heroin.

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Scheme 14.62  3-­  [ 2-­( 2-­M ethoxybenzylamino)ethyl]-­1 H-­quinazoline-­2 ,4-­d ione; RH-­34.

Scheme 14.63  2-­  [ 2-­[ (4-­E thoxyphenyl)methyl]benzimidazol-­1 -­y l]-­N ,N-­d iethyl­ ethanamine; etazene; etodesnitazene.

Scheme 14.64  N,N-­  Diethyl-­2-­(2-­(4-­fluorobenzyl)-­5-­nitro-­1H-­benzo[d]imidazole-­ 1-­yl)ethan-­1-­amine; fluonitazene.

14.24  Other Atypical Opioids As with many pharmacological groups, a particular activity can arise in a diverse range of chemical structures, often with no common features. This is equally true of narcotic analgesics, and examples of opiates, fentanyls, pethidines are described elsewhere. A number of unusual opiates were reported to EMCDDA in 2020 including:    ●● 1-­[1-­[1-­(4-­Bromophenyl)ethyl]-­4-­piperidinyl]-­1,3-­dihydro-­2H-­benzimidazol-­ 2-­one; brorphine

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201

Scheme 14.65  N,N-­  D iethyl-­2 -­[ (4-­m ethoxyphenyl)methyl]-­1 H-­b enzimidazole-­1 -­ ethanamine; metodesnitazene.

●● ●●

Ethyl 2-­methylamino-­1-­phenylcyclohex-­3-­ene-­1-­carboxylate; nortilidine 1-­[2,6-­Dimethyl-­4-­(3-­phenylprop-­2-­enyl)piperazin-­1-­yl]propan-­1-­one; AP-­238

14.25  Hyoscine This non-­selective muscarinic antagonist is a licensed medicine used to treat motion sickness. Although it is an unlikely substance for recreational use, hyoscine (scopolamine), as an extract of plants in the genus Brugmanisa, is used for ritual purposes in Colombia, but accounts of its ability to act as an incapacitant for criminal purposes may be exaggerated.30

14.26  Other Psychoactive Plant Products A number of plants that contain psychoactive constituents, but are not under international control, are listed in Chapter 26.

References 1. J. T. Cody, Forensic Sci. Rev., 1993, 5(2), 109–127. 2. K. Sugie, D. Kurakami, M. Akutsu and K. Saito, Forensic Toxicol., 2018, 36(2), 261. 3. L. A. King, A. J. Poortman-­van-­der Meer and H. Huizer, Forensic Sci. Int., 1996, 77(3), 141. 4. A. Shulgin and A. Shulgin, PiHKAL: A Chemical Love Story, Transform Press, Berkeley, California,1991, ISBN 0-­9630096-­0-­5. 5. Anon, Microgram Bull., 2007, 40(8), 79. 6. A. P. Monte, D. Marona-­Lewicka, N. V. Cozzi and D. E. Nichols, J. Med. Chem., 1993, 36(23), 3700.

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7. Advisory Council on the Misuse of Drugs, 2017. Further advice on Methiopropamine https://assets.publishing.service.gov.uk/government/ uploads/system/uploads/attachment_data/file/619755/ACMD_s_ further_advice_on_methiopropamine_June_2017.pdf 0, accessed October 2021. 8. Advisory Council on the Misuse of Drugs, 2013, Benzofurans: A review of the evidence of use and harm https://assets.publishing.service.gov. uk/government/uploads/system/uploads/attachment_data/file/261783/ Benzofuran_compounds_report.pdf, accessed October 2021. 9. F. F. Blicke and J. H. Burckhalter, J. Am. Chem. Soc., 1942, 64(3), 477. 10. D. B. Clayson, J. W. Jull and G. M. Bonser, Br. J. Cancer, 1958, 12(2), 222. 11. R. Howe, Nature, 1965, 207, 594. 12. J. F. Casale, T. D. McKibben, J. S. Bozenko and P. A. Hays, Microgram J., 2005, 3(1–2), 3. 13. P. D. Sainsbury, A. T. Kicman and R. P. Archer, et al., Drug Test. Anal., 2011, 3(7–8), 479. 14. National Institute for Health and Care Excellence (NICE), Rasagiline, https://bnf.nice.org.uk/drug/rasagiline.html, accessed October 2021. 15. T. H. McLean, J. C. Parrish and M. R. Braden, et al., J. Med. Chem., 2006, 49(19), 5794. 16. Methylhexanamine, https://en.wikipedia.org/wiki/Methylhexanamine, accessed October 2021. 17. World Anti-­Doping Agency, 2010. Adverse Analytical Findings and Atypical Findings Reported by Accredited Laboratories, https:// www.wada-­a ma.org/sites/default/files/resources/files/WADA_2010_ Laboratory_Statistics_Report.pdf, accessed October 2021. 18. Tuaminoheptane, https://en.wikipedia.org/wiki/Tuaminoheptane, ac­cessed October 2021. 19. UK Government, 2005, Foresight project: Brain science, addiction and drugs, https://www.gov.uk/government/collections/brain-­science-­ addiction-­and-­drugs, accessed October 2021. 20. Advisory Council on the Misuse of Drugs, 2021. Sunosi, https://assets. publishing.ser vice.gov.uk/government/uploads/system/uploads/ attachment_data/file/979830/ACMD_advice_on_Sunosi.pdf, accessed October 2021. 21. M. Evans-­Brown, J. McVeigh, C. Perkins and M. A. Bellis, Human Enhancement Drugs, North West Public Health Observatory and John Moore’s University Centre for Public Health, Liverpool, 2012, ISBN 978-­1-­908929-­01-­3. 22. Carisoprodol, https://en.wikipedia.org/wiki/Carisoprodol, accessed Oct­ ober 2021. 23. J. S. Anand, M. Lukasik-­Glebocka and R. P. Korolkiewicz, Clin. Toxicol., 2007, 45(2), 198. 24. Amfonelic acid, http://en.wikipedia.org/wiki/Amfonelic_acid, accessed October 2021.

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25. World Health Organization, 43rd ECDD, list of substances under review, https://www.who.int/publications/m/item/43rd-­ecdd-­list-­of-­substances-­ under-­review, accessed October 2021. 26. Salvinorin B methoxymethyl ether, https://en.wikipedia.org/wiki/ Salvinorin_B_methoxymethyl_ether, accessed October 2021. 27. S. S. Negus, M. H. Baumann and R. B. Rothman, et al., J. Pharmacol. Exp. Ther., 2009, 329(1), 272. 28. I. Ujváry, R. Christie and M. Evans-­Brown, et al., ACS Chem. Neurosci., 2021, 2(7), 1072. 29. Public Health England, National Intelligence Network on drug health harms briefing: October 2021, https://khub.net/web/phe-­national/ public-­% 20librar y/-­/ document_librar y/v2WsRK3ZlEig/vie w_ file/546620794, accessed October 2021. 30. L. A. King, R. Fortson, I. Ujváry, J. Ramsey and D. J. Nutt, Sci. Justice, 2014, 54(4), 321.

Chapter 15

Amphetamine, Methylamphetamine and MDMA 15.1  Introduction The following sections are firstly concerned with two important phenethyl­amines that are not ring-­substituted, namely amphetamine [(RS)-­1-­phenylpropan-­ 2-­amine; Scheme 15.1] and its N-­methyl derivative methylamphetamine [(RS)-­ N-­methyl-­1-­phenylpropan-­2-­amine also known as methamphetamine; Scheme 15.2]. This is followed by a description of MDMA (3,4-­methylenedioxymethylamphetamine), by far the most important of the ring-­substituted phenethylamines. The control status of these three substances is set out in Table 15.1. Before 2006, methylamphetamine was a Class B drug in the MDAct, but was moved to Class A in the light of increased concerns about its use and particularly more harmful properties when smoked. However, in the intervening years, methylamphetamine has remained a rarity in Europe and smoking methylamphetamine, requiring pure material such as ‘Ice’, is even less common. The worldwide production and consumption of illicit amphetamine and the closely-­related methylamphetamine show clear geographical trends. In Europe, particularly Western Europe, amphetamine is much more common than methylamphetamine1 but in North America and the Far East this situation is reversed.

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Scheme 15.1  1-­Phenylpropan-­  2-­amine; α-­methylbenzene-­ethanamine; amphetamine.

Scheme 15.2  N-­  Methyl-­1-­phenylpropan-­2-­amine; methylamphetamine. Table 15.1  The  status of amphetamine, methylamphetamine and MDMA in the MDAct and the UN 1971 Convention.

Substance

MDAct

UN 1971 convention

Amphetamine Methylamphetamine MDMA

Class B Class A Class A

Schedule II Schedule II Schedule I

15.2  Amphetamine A profile of amphetamine is available on the EMCDDA website.2 The first synthesis of amphetamine (then known as phenylisopropylamin) was described by Edeleano in 1887.3 The frequently-­used manufacturing method was developed in the in the 1880s by the German chemist Leuckart. His publications do not mention amphetamine, but do establish the process which bears his name, that is to say the reductive amination of a ketone with formamide or ammonium formate. Like methylamphetamine, it appears that systematic studies of its chemistry and pharmacology did not come about until the early 20th century. Amphetamine has had some limited therapeutic use in the treatment of narcolepsy and attention deficit hyperactivity disorder. Illicit material is often manufactured in clandestine laboratories in Europe. The asymmetric α-­carbon atom gives rise to two enantiomers. These two forms were previously called the (−) or l-­stereoisomer and the (+) or d-­stereoisomer, but in modern usage are defined as the R and S stereoisomers. Amphetamine base is a colourless volatile oil insoluble in water. The most common salt is the sulfate: a white or off-­white powder soluble in water. Illicit products mostly consist of powders. Tablets containing amphetamine may carry logos similar to those seen on MDMA and other ‘ecstasy’ tablets.

15.2.1  Amphetamine: Pharmacology Amphetamine is a CNS stimulant that causes hypertension and tachycardia with feelings of increased confidence, sociability and energy. It suppresses appetite and fatigue and leads to insomnia. Following oral use, the effects

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usually start within 30 minutes and last for many hours. Later, users may feel irritable, restless, anxious, depressed and lethargic. It stimulates the noradrenaline and dopamine neurotransmitter systems. Amphetamine is less potent than methylamphetamine, its N-­methyl derivative, but in uncontrolled situations, the effects are almost indistinguishable. The S-­enantiomer has greater activity than the R-­enantiomer. It is rapidly absorbed after oral administration. After a single oral dose of 10 mg, maximum plasma levels are around 0.02 mg L−1. The plasma half-­life varies from 4 to 12 hours and is dependent on the urinary pH; alkaline urine decreases the rate of elimination. A major metabolite is 1-­phenyl-­2-­propanone with smaller amounts of 4-­hydroxyamphetamine. Interpretation of amphetamine in urine is confounded because it is a metabolite of methylamphetamine and certain medicinal products.4 Acute intoxication causes serious cardiovascular disturbances as well as behavioural problems that include agitation, confusion, paranoia, impulsivity and violence. Chronic use of amphetamine causes neurochemical and neuroanatomical changes, and dependence, as shown by increased tolerance, deficits in memory and in decision-­making and verbal reasoning. Some of the symptoms resemble paranoid schizophrenia. These effects may outlast drug use, although often resolve eventually. Injection of amphetamine carries the same viral infection hazards (e.g., HIV and hepatitis) that are found with other injectable drugs. Fatalities directly attributed to amphetamine are rare. The estimated minimum oral lethal dose in non-­addicted adults is 200 mg.

15.2.2  Amphetamine: Synthesis The most common route of synthesis (Leuckart method) uses 1-phenyl-2-­ propanone (P2P, BMK, phenylacetone) and reagents such as formic acid, ammonium formate or formamide to yield a racemic mixture of the R-­ and S-­enantiomers. A much less common, but stereoselective, method is by reduction of the appropriate diastereoisomers of norephedrine or norpseudoephedrine. Norephedrine and 1-­phenyl-­2-­propanone are listed in Table I of the UN 1988 Convention concerned with precursor chemicals ­(Chapter 27). Many other synthetic routes to amphetamine are known based on ­precursors such as benzaldehyde, benzyl chloride, phenylacetic acid, etc. Caffeine is added to amphetamine at source, but glucose, other sugars and other usually inert substances may be used as subsequent cutting agents.

15.3  Methylamphetamine 15.3.1  Introduction A profile of methylamphetamine is available on the EMCDDA website.2 As with amphetamine, the asymmetric α-­carbon atom gives rise to two enantiomers: the R-­and S-­enantiomers. Methylamphetamine (Scheme 15.2) is (RS)-­N-­methyl-­ 1-­phenylpropan-­2-­amine or alternatively, N,α-­dimethylbenzene-­ethanamine or N,α-­dimethylphenethylamine.

Amphetamine, Methylamphetamine and MDMA 5

207

First manufactured in Japan in 1919, methylamphetamine has some limited therapeutic use, but most is made in clandestine laboratories. It is the most widely abused synthetic psychotropic drug, particularly in North America and countries of the Far East. Methylamphetamine is also commonly reported in Eastern Europe but is much less widespread in countries where illicit amphetamine is the established stimulant. The pharmacological properties of methylamphetamine are similar to those of amphetamine.6 The base is a colourless volatile oil insoluble in water. The most common salt is the hydrochloride: a white or off-­white powder or crystals soluble in water. Illicit products mostly consist of powders, but the crystalline hydrochloride, typically the pure S-­enantiomer known as ‘Ice’, is rarely seen outside the Far East. Tablets containing methylamphetamine may carry logos similar to those seen on MDMA and other ecstasy tablets. What little drug is seized by law enforcement agencies in Europe is nearly always in the form of powders or tablets, both of which would normally be ingested. It is sometimes the case that material claimed to be ‘crystal meth’ is found, on analysis, to be crystalline MDMA. Methylamphetamine hydrochloride is sufficiently volatile that it can be smoked, although this practice would normally only occur with the pure material to avoid the undesirable combustion of cutting agents. There is little doubt that smoking this drug is a much more harmful activity than ingestion. Drugs that are smoked (e.g., tobacco/nicotine, heroin, crack cocaine, cannabis/THC) reach the brain far more quickly than when ingested. As a consequence, their addictive potential is higher. The much higher prevalence of the drug in the US has encouraged numerous commentators over many years to suggest that Europe is overdue for a rapid rise in consumption, rather as occurred with crack cocaine over twenty years ago. There are good reasons for thinking that methylamphetamine will not become more widespread as long as amphetamine is readily and cheaply available: a situation that is not true in the US. Methylamphetamine had not been included in the original ACMD risk assessment survey (Chapter 24). However, following a later review carried out by the ACMD, and using the same parameters of harm in a risk assessment exercise, methylamphetamine scored 2.12 out of a possible 3. This was higher than had been given to amphetamine (score = 1.66), and the third highest score of twenty-­t wo substances. Following pressure from law enforcement agencies, a recommendation for reclassification was made by the ACMD.7 Methylamphetamine became a Class A drug in 2006. The new evidence presented largely revolved around an apparent increase in attempts to manufacture the drug. In reality, to this day, little has changed and there have been no significant seizures of clandestine laboratories in the UK. Surveys continue to show that not only does it account for less than 1% of amphetamine seizures in the UK, but that it is extremely rare in urine samples tested under employee drug testing regimes and rarely features in calls for advice to poison control centres.

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15.3.2  Methylamphetamine: Pharmacology Methylamphetamine is a CNS stimulant that causes hypertension and tachycardia with feelings of increased confidence, sociability and energy. It suppresses appetite and fatigue and leads to insomnia.8 The pharmacological properties of methylamphetamine are similar to those of amphetamine. Following oral use, the effects usually start within 30 minutes and last for many hours. Later, users may feel irritable, restless, anxious, depressed and lethargic. It increases the activity of the noradrenaline and dopamine neurotransmitter systems. Methylamphetamine is more potent than amphetamine, but in uncontrolled situations, the effects are almost indistinguishable. The S-­stereoisomer has greater activity than the R-­stereoisomer. The therapeutic dose of the S-­stereoisomer is up to 25 mg orally. It is rapidly absorbed after oral administration, and maximum plasma levels are in the range 0.001 to 0.005 mg L−1. The plasma half-­life is about 9 hours. The major metabolites include 4-­hydroxymethylamphetamine and amphetamine. Fatalities directly attributed to methylamphetamine are rare. In most fatal poisonings the blood concentration is above 0.5 mg L−1. As with amphetamine, the interpretation of methylamphetamine in urine is confounded because it is a metabolite4 of certain medicinal products (e.g., selegiline). Acute intoxication causes serious cardiovascular disturbances as well as behavioural problems that include agitation, confusion, paranoia, impulsivity and violence. Chronic use of methylamphetamine causes neurochemical and neuroanatomical changes, dependence (as shown by increased tolerance), deficits in memory and in decision-­making and verbal reasoning. Some of the symptoms resemble paranoid schizophrenia. These effects may outlast drug use, although they often resolve eventually. Injection of methylamphetamine carries the same viral infection hazards (e.g., HIV and hepatitis) as are found with other injectable drugs such as heroin. When methylamphetamine is smoked it reaches the brain much more quickly.

15.3.3  Methylamphetamine: Synthesis The S-­enantiomer is most commonly produced by reduction of l-­ephedrine, i.e., (1R,2S)-­2-­methylamino-­1-­phenylpropan-­1-­ol, or by reduction of pseudoephedrine, i.e., (1S,2S)-­2-­methylamino-­1-­phenylpropan-­1-­ol. Both ephedrine and pseudoephedrine are commercially available and are used in certain medicinal products. Ephedrine may also be extracted from the plant Ephedra vulgaris L. (used in Chinese medicine as Ma Huang). Both the Leuckart route and other reductive aminations such as the aluminium foil method which use 1-­phenyl-­2-­propanone (P2P, BMK, phenylacetone) yield a racemic mixture of the R-­ and S-­enantiomers. Recently, illicit laboratories in Europe have started to produce methylamphetaminer enriched in the S-­isomer using resolution of racemic methamphetamine.9 The synthetic route used may be identified by impurity profiling. Ephedrine, pseudoephedrine and 1-­phenyl-­2-­propanone are listed in Table I of the UN 1988 Convention (Chapter 27).

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15.4  MDMA (3,4-­Methylenedioxymethylamphetamine) 15.4.1  Introduction A profile of MDMA is available on the EMCDDA website.2 The term MDMA (Scheme 15.3) is an abbreviation for MethyleneDioxyMethylAmphetamine. It is a synthetic substance commonly known as ecstasy, although the latter term has now been generalised to cover a wide range of other substances. Originally patented in 1914 by the Merck chemical company, MDMA was not seen as a potential medicine in it is own right but rather as an intermediate in the preparation of therapeutically-­useful compounds. Although once proposed as an aid to psychiatric counselling, that was effectively ended by legal controls in the US, and later, other jurisdictions. However, there has been a rekindled interest in MDMA as a potential treatment of post-­traumatic stress disorder.10 Illicit MDMA is normally seen as tablets with a characteristic impression (logo), many of which are manufactured in Europe, but MDMA can also occur as a powder. It acts as a CNS stimulant and has a weak hallucinogenic property more accurately described as increased sensory and social awareness (entactogenicity or empathogenicity). MDMA, shown as (+/−)-­N,α-­dimethyl-­3,4-­(methylenedioxy)phenethylamine, is listed in Schedule I of the UN 1971 Convention. In the MDAct, MDMA is covered by the generic definition of a substituted phenethylamine as a Class A controlled drug. MDMA is formally named as N-­methyl-­1-­(3,4-­methylenedioxyphenyl)propan-­2-­amine, but it is commonly known as 3,4-­methylenedioxymethamphetamine or methylenedioxymethylamfetamine. Other names include N,α-­dimethyl-­3,4-­methylenedioxyphenethylamine or, more formally, 1-­(2H-­ 1,3-­benzodioxol-­5-­yl)-­N-­methylpropan-­2-­amine. A number of closely-­related compounds with broadly similar effects have appeared but have proved less popular. That group includes MDA (MethyleneDioxyAmphetamine), MDEA (MethyleneDioxyEthylAmphetamine) and MBDB (N-­Methyl-­1-­(1,3-­ BenzoDioxol-­5-­yl)-­2-­Butanamine). As with many other phenethylamines, MDMA exists in two enantiomeric forms (R and S) although racemic mixtures are commonly encountered. The most common salt is the hydrochloride, a white or off-­white powder or crystals soluble in water. The phosphate salt is also seen.

Scheme 15.3  3,4-­  Methylenedioxymethylamphetamine; MDMA.

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15.4.2  MDMA: Pharmacology Whereas phenethylamines without ring substitution usually behave as stimulants, ring substitution (as in MDMA) leads to a modification in the pharmacological properties. MDMA is a serotonergic drug that inhibits the synaptic reuptake of serotonin, although the dopamine and noradrenaline systems are also affected. Ingestion of MDMA causes euphoria, increased sensory awareness and mild central stimulation. It is less hallucinogenic than its lower homologue, 3,4-­methylenedioxyamphetamine (MDA). Following ingestion, most MDMA is excreted in the urine unchanged. Major metabolites are MDA and O-­demethylated compounds. Using a dose of 75 mg, the maximum plasma concentration of around 0.13 mg L−1 is reached within 2 hours. The plasma half-­life is 6–7 hours. In animals, MDMA shows neurotoxicity as evidenced by anatomical changes in axon structure and a persisting reduction in brain serotonin levels. The significance of these findings to human users is still unclear, although cognitive impairment is associated with MDMA use. Some of the pharmacodynamic and toxic effects of MDMA, which include hyperthermia, vary depending on which enantiomer is used. However, almost all illicit MDMA exists as a racemic mixture. Fatalities following a dose of 300 mg have been noted, but toxicity depends on many factors including individual susceptibility and the circumstances in which MDMA is used.

15.4.3  MDMA: Synthesis There are four principal precursors, which can be used in the manufacture of MDMA and related drugs: safrole, isosafrole, piperonal and 3,4-­methylenedioxyphenyl-­2-­propanone (MDP2P or PMK). For decades, safrole has been the key starting material. In the original Merck patent of 1914, safrole was reacted with hydrobromic acid to form bromosafrole (shown as bromodihydrosafrole in the patent), which was converted to MDMA using methylamine. Many illicit syntheses start with PMK and use either the Leuckart route or various reductive aminations including the aluminium foil method. All of these methods produce racemic MDMA. The four precursors noted above as well as the two glycidic acid derivative pre-­precursors of PMK are listed in Table I of the UN 1988 Convention (Chapter 27).

References 1. P. Griffiths, V. Mravcik, D. Lopez and D. Klempova, Drug Alcohol Rev., 2008, 27(3), 236. 2. European Monitoring Centre for Drugs and Drug Addiction, Drug Profiles, https://www.emcdda.europa.eu/publications/drug-­profiles_en, accessed October 2021. 3. L. Edeleano, Ber. Dtsch. Chem. Ges., 1887, 20(1), 616. 4. J. T. Cody, Forensic Sci. Rev., 1993, 5(2), 109–127.

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5. L. A. King, Drug Test. Anal., 2014, 6(7–8), 808. 6. M. R. Hammer, A Key to Methamphetamine-­Related Literature, New York State Department of Health, 2006, https://www.health.ny.gov/diseases/ aids/consumers/prevention/crystalmeth/docs/meth_literature_index. pdf, accessed October 2021. 7. Advisory Council on the Misuse of Drugs, 2005, Methylamphetamine https://assets.publishing.service.gov.uk/government/uploads/system/ uploads/attachment_data/file/119145/ACMDFurtherMethylamphetamine.pdf, accessed October 2021. 8. C. E. Cook, A. R. Jeffcoat and J. M. Hill, et al., Drug Metab. Dispos., 1993, 21(4), 717. 9. INCB, Precursors and chemicals frequently used in the illicit manufacture of narcotic drugs and psychotropic substances, 2020, https://www. incb.org/documents/PRECURSORS/TECHNICAL_REPORTS/2020/AR_ with_Annexes/Precursors_with_annex_E_eBook_final_rev.pdf, accessed October 2021. 10. US National Library of Medicine, https://clinicaltrials.gov/ct2/results? cond=PTSD&term=MDMA, accessed October 2021.

Chapter 16

Benzodiazepines 16.1  Introduction A profile of benzodiazepines is available on the EMCDDA website.1 They are synthetic substances normally seen as pharmaceutically-­manufactured tablets, capsules and occasionally as injectable solutions. They are widely used in medicine to treat anxiety and insomnia, and act as depressants of the central nervous system. Benzodiazepines facilitate the binding of the inhibitory neurotransmitter γ-­aminobutyric acid (GABA) at various receptors in the CNS. Some benzodiazepines are used as anxiolytics and some as hypnotics, but there is no clear distinction since the former will induce sleep if taken at night and the latter will sedate during the day. They are far safer than other hypnotics such as barbiturates, which they eventually replaced, and old drugs such as clomethiazole and chloral hydrate. Different benzodiazepines vary in their half-­lives. On average, short-­acting drugs have a half-­life of less than 24 hours, e.g., midazolam; intermediate-­ acting compounds such as nitrazepam have half-­lives greater than 24 hours, whereas long-­acting compounds such as diazepam have half-­lives greater than 48 hours. The side-­effects include drowsiness, ataxia, mental confusion, impaired judgment, diminished cognitive function, driving impairment and anterograde amnesia. Many of these effects are potentiated by concomitant alcohol consumption. A similar fatal interaction can occur when opiates are taken with benzodiazepines as part of a pattern of polydrug use. The combined use of benzodiazepines and opiates is a major risk factor in drug-­related deaths. Benzodiazepines also potentiate the effect of tricyclic antidepressants such as amitriptyline since median fatal blood levels of the latter are significantly lower when benzodiazepines are also present.2 Chlordiazepoxide (Librium®) was the first to be synthesised in 1957 and introduced into medicine in 1961. Diazepam (Valium®; Scheme 16.1)   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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Scheme 16.1  9-­  C hloro-­2 -­m ethyl-­6 -­p henyl-­2 ,5-­d iazabicyclo[5.4.0]undeca-­5 ,8,-

10,12-­tetraen-­3-­one, also known as 7-­chloro-­1,3-­dihydro-­1-­methyl-­5-­ phenyl-­2H-­1,4-­benzodiazepine-­2-­one; diazepam.

is one of the most widely-­prescribed benzodiazepines. The various benzodiazepines differ in their substitution pattern on the basic molecular skeleton (3H-­1,4-­benzodiazepine). Following concern about their potential for misuse, benzodiazepines were included in the UN 1971 Convention. Most were listed in Schedule IV of that Convention, but because of increased potential for misuse, flunitrazepam was in Schedule III. Thirty-­three compounds were then added to the MDAct as Class C drugs in 1985; all were in Schedule 4 of the MD Regulations, but flunitrazepam was in Schedule 3. Subsequently, brotizolam, midazolam and phenazepam were added to the MDAct in the period 1990 to 2012. Midazolam3 was later transferred from Schedule 4 to Schedule 3. This move was partly prompted by evidence of abuse of midazolam by a medical practitioner.

16.2  ‘New’ Benzodiazepines By 2021 there were 41 benzodiazepines in the UN 1971 Convention as shown in Table 16.1. In the past 10–15 years, many other novel benzodiazepines have been reported to EMCDDA under the Early Warning System. Some are, or have been, used as medicinal products. For example, phenazepam (Scheme 16.2), also listed as fenazepam, was produced in Russia, and appears to have a similar use and misuse profile to many other benzodiazepines. As with many new substances, novel benzodiazepines present analytical challenges.4 A recent review5 of designer benzodiazepines was published by Greenblatt and Greenblatt. A further 16 benzodiazepines were added to the MDAct as Class C drugs in 2017. They are listed in Table 16.2. As of late 2020, none of those 16 in the MDAct had been added to the UN 1971 Convention. The Medicines and Healthcare Products Regulatory Agency (MHRA) confirmed that none of them had a UK marketing authorisation. They are therefore placed in Schedule I of the MD Regulations (i.e., no medicinal use). At its 63rd Session in March 2020, The UN Commission on Narcotic Drugs added flualprazolam and etizolam to Schedule IV of the UN 1971 Convention.6

Schedule III. The Table also shows when they were added to the MDAct as Class C controlled drugs.

1985 1985 1998 1985 1985 1985 1985 2017 1985 (as clorazepic acid) 1985 1985 1985 1985 2017 1985

Chapter 16

ALPRAZOLAM 8-­Chloro-­1-­methyl-­6-­phenyl-­4H-­s-­triazolo[4,3-­a][1,4]benzodiazepine BROMAZEPAM 7-­Bromo-­1,3-­dihydro-­5-­(2-­pyridyl)-­2H-­1,4-­benzodiazepin-­2-­one BROTIZOLAM 2-­Bromo-­4-­(o-­chlorophenyl)-­9-­methyl-­6H-­thieno[3,2-­f]-­s-­triazolo[4,3-­a][1,4]diazepine CAMAZEPAM 7-­Chloro-­1,3-­dihydro-­3-­hydroxy-­1-­methyl-­5-­phenyl-­2H-­1,4-­benzodiazepin-­2-­one dimethylcarbamate CHLORDIAZEPOXIDE 7-­Chloro-­2-­(methylamino)-­5-­phenyl-­3H-­1,4-­benzodiazepine-­4-­oxide CLOBAZAM 7-­Chloro-­1-­methyl-­5-­phenyl-­1H-­1,5-­benzodiazepine-­2,4(3H,5H)-­dione CLONAZEPAM 5-­(o-­Chlorophenyl)-­1,3-­dihydro-­7-­nitro-­2H-­1,4-­benzodiazepin-­2-­one CLONAZOLAM 6-­(2-­Chlorophenyl)-­1-­methyl-­8-­nitro-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepine CLORAZEPATE 7-­Chloro-­2,3-­dihydro-­2-­oxo-­5-­phenyl-­1H-­1,4-­benzodiazepine-­3-­carboxylic acid CLOTIAZEPAM 5-­(o-­Chlorophenyl)-­7-­ethyl-­1,3-­dihydro-­1-­methyl-­2H-­thieno[2,3-­e]-­1,4-­diazepin-­2-­one CLOXAZOLAM 10-­Chloro-­11b-­(o-­chlorophenyl)-­2,3,7,11b-­tetrahydro-­oxazolo-­[3,2-­d][1,4]benzodiazepin-­6(5H)-­one DELORAZEPAM 7-­Chloro-­5-­(o-­chlorophenyl)-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­one DIAZEPAM 7-­Chloro-­1,3-­dihydro-­1-­methyl-­5-­phenyl-­2H-­1,4-­benzodiazepin-­2-­one DICLAZEPAM (Chlorodiazepam) 7-­Chloro-­5-­(2-­chlorophenyl)-­1-­methyl-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­one ESTAZOLAM 8-­Chloro-­6-­phenyl-­4H-­s-­triazolo[4,3-­a][1,4]benzodiazepine

214

Table 16.1  The  41 benzodiazepines listed in the UN 1971 Convention as of 2021. All are in Schedule IV except flunitrazepam which is in

1985 2017 1985 2021

Benzodiazepines

ETHYL LOFLAZEPATE Ethyl 7-­chloro-­5-­(o-­fluorophenyl)-­2,3-­dihydro-­2-­oxo-­1H-­1,4-­benzodiazepine-­3-­carboxylate ETIZOLAM 4-­(2-­Chlorophenyl)-­2-­ethyl-­9-­methyl-­6H-­thieno[3,2-­f][1,2,4]triazolo[4,3a][1,4]diazepine FLUDIAZEPAM 7-­Chloro-­5-­(o-­fluorophenyl)-­1,3-­dihydro-­1-­methyl-­2H-­1,4-­benzodiazepin-­2-­one FLUALPRAZOLAM 8-­Chloro-­6-­(2-­fluoro-­phenyl)-­1-­methyl-­4H-­benzo[f][1,2,4]triazolo[4,3-­a][1,4]diazepine FLUBROMAZOLAM 8-­Bromo-­6-­(2-­fluorophenyl)-­1-­methyl-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepine FLUNITRAZEPAM 5-­(o-­Fluorophenyl)-­1,3-­dihydro-­1-­methyl-­7-­nitro-­2H-­1,4-­benzodiazepin-­2-­one FLURAZEPAM 7-­Chloro-­1-­[2-­(diethylamino)ethyl]-­5-­(o-­fluorophenyl)-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­one HALAZEPAM 7-­Chloro-­1,3-­dihydro-­5-­phenyl-­1-­(2,2,2-­trifluoroethyl)-­2H-­1,4-­benzodiazepin-­2-­one HALOXAZOLAM 10-­Bromo-­11b-­(o-­fluorophenyl)-­2,3,7,11b-­tetrahydrooxazolo[3,2-­d][1,4]benzodiazepin-­6(5H)-­one KETAZOLAM 11-­Chloro-­8,12b-­dihydro-­2,8-­dimethyl-­12b-­phenyl-­4H-­[1,3]oxazino[3,2-­d][1,4]benzodiazepin-­4,7(6H)-­dione LOPRAZOLAM 6-­(o-­Chlorophenyl)-­2,4-­dihydro-­2-­[(4-­methyl-­1-­piperazinyl)methylene]-­8-­nitro-­1H-­imidazo[1,2-­a][1,4]benzodiazepin-­1-­one LORAZEPAM 7-­Chloro-­5-­(o-­chlorophenyl)-­1,3-­dihydro-­3-­hydroxy-­2H-­1,4-­benzodiazepin-­2-­one LORMETAZEPAM 7-­Chloro-­5-­(o-­chlorophenyl)-­1,3-­dihydro-­3-­hydroxy-­1-­methyl-­2H-­1,4-­benzodiazepin-­2-­one MEDAZEPAM 7-­Chloro-­2,3-­dihydro-­1-­methyl-­5-­phenyl-­1H-­1,4-­benzodiazepine MIDAZOLAM 8-­Chloro-­6-­(o-­fluorophenyl)-­1-­methyl-­4H-­imidazo[1,5-­a][1,4]benzodiazepine NIMETAZEPAM 1,3-­Dihydro-­1-­methyl-­7-­nitro-­5-­phenyl-­2H-­1,4-­benzodiazepin-­2-­one

2017 1985 1985 1985 1985 1985 1985 1985 1985 1985 1990 1985 215

(continued)

NITRAZEPAM 1,3-­Dihydro-­7-­nitro-­5-­phenyl-­2H-­1,4-­benzodiazepin-­2-­one NORDAZEPAM 7-­Chloro-­1,3-­dihydro-­5-­phenyl-­2H-­1,4-­benzodiazepin-­2-­one OXAZEPAM 7-­Chloro-­1,3-­dihydro-­3-­hydroxy-­5-­phenyl-­2H-­1,4-­benzodiazepin-­2-­one OXAZOLAM 10-­Chloro-­2,3,7,11b-­tetrahydro-­2-­methyl-­11b-­phenyloxazolo[3,2-­d][1,4]benzodiazepin-­6(5H)-­one PHENAZEPAM 7-­Bromo-­5-­(2-­chlorophenyl)-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­one PINAZEPAM 7-­Chloro-­1,3-­dihydro-­5-­phenyl-­1-­(2-­propynyl)-­2H-­1,4-­benzodiazepin-­2-­one PRAZEPAM 7-­Chloro-­1-­(cyclopropylmethyl)-­1,3-­dihydro-­5-­phenyl-­2H-­1,4-­benzodiazepin-­2-­one TEMAZEPAM 7-­Chloro-­1,3-­dihydro-­3-­hydroxy-­1-­methyl-­5-­phenyl-­2H-­1,4-­benzodiazepin-­2-­one TETRAZEPAM 7-­Chloro-­5-­(1-­cyclohexen-­1-­yl)-­1,3-­dihydro-­1-­methyl-­2H-­1,4-­benzodiazepin-­2-­one TRIAZOLAM 8-­Chloro-­6-­(o-­chlorophenyl)-­1-­methyl-­4H-­s-­triazolo[4,3-­a][1,4]benzodiazepine

216

Table 16.1  (continued) 1985 1985 1985 1985 2012 1985 1985 1985 1985 1985

Chapter 16

Benzodiazepines

217

Scheme 16.2  Phenazepam.  Table 16.2  The  16 benzodiazepines added to the MDAct in 2017 as Class C drugs. ADINAZOLAM 1-­(8-­Chloro-­6-­phenyl-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepin-­1-­yl)-­ N,N-­dimethylmethanamine BROMAZOLAM 8-­Bromo-­1-­methyl-­6-­phenyl-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepine 4-­CHLORODIAZEPAM 7-­Chloro-­5-­(4-­chlorophenyl)-­1-­methyl-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­one CLONAZOLAM 6-­(2-­Chlorophenyl)-­1-­methyl-­8-­nitro-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepine DESCHLOROETIZOLAM 2-­Ethyl-­9-­methyl-­4-­phenyl-­6H-­thieno[3,2-­f][1,2,4]triazolo[4,3-­a][1,4]diazepine DICLAZEPAM 7-­Chloro-­5-­(2-­chlorophenyl)-­1-­methyl-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­one ETIZOLAM 4-­(2-­Chlorophenyl)-­2-­ethyl-­9-­methyl-­6H-­thieno[3,2-­f][1,2,4]triazolo[4,3a][1,4]diazepine FLUBROMAZEPAM 7-­Bromo-­5-­(2-­fluorophenyl)-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­one FLUBROMAZOLAM 8-­Bromo-­6-­(2-­fluorophenyl)-­1-­methyl-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepine FONAZEPAM 5-­(2-­Fluorophenyl)-­7-­nitro-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­one 3-­HYDROXYPHENAZEPAM 7-­Bromo-­5-­(2-­chlorophenyl)-­3-­hydroxy-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­one MECLONAZEPAM 5-­(2-­Chlorophenyl)-­3-­methyl-­7-­nitro-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­one METIZOLAM 4-­(2-­Chlorophenyl)-­2-­ethyl-­6H-­thieno[3,2-­f][1,2,4]triazolo[4,3-­a][1,4]diazepine NIFOXIPAM 5-­(2-­Fluorophenyl)-­3-­hydroxy-­7-­nitro-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­one NITRAZOLAM 1-­Methyl-­8-­nitro-­6-­phenyl-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepine PYRAZOLAM 8-­Bromo-­1-­methyl-­6-­(2-­pyridinyl)-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepine

In 2020, the ACMD recommended7 that three more benzodiazepines should be added to the MDAct as Class C drugs (Table 16.3). This was enacted in 2021.8 One of these (flualprazolam) was already listed in the UN 1971 Convention (Table 16.1). There are no current plans in the UK to create generic controls for the benzodiazepines. Although they have some structural

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Table 16.3  Three  benzodiazepines added to the MDAct in 2021 as Class C drugs. FLUALPRAZOLAM 8-­Chloro-­6-­(2-­fluorophenyl)-­1-­methyl-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepine FLUNITRAZOLAM 6-­(2-­Fluorophenyl)-­1-­methyl-­8-­nitro-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepine NORFLUDIAZEPAM 7-­Chloro-­5-­(2-­fluorophenyl)-­1,3-­dihydro-­1,4-­benzodiazepin-­2-­one

Table 16.4  Further  benzodiazepines reported to EMCDDA. CLONIPRAZEPAM Sweden, 2016 5-­(2-­Chlorophenyl)-­1-­(cyclopropylmethyl)-­7-­nitro-­1,3-­dihydro-­2H-­ [1,4]-­benzodiazepin-­2-­one 3-­HYDROXYPHENAZEPAM Germany, 2016 7-­Bromo-­5-­(2-­chlorophenyl)-­3-­hydroxy-­1,3-­dihydro-­2H-­1,4-­ benzodiazepin-­2-­one FONAZEPAM (Desmethylflunitrazepam) Sweden, 2016 5-­(2-­Fluorophenyl)-­1,3-­dihydro-­7-­nitro-­2H-­1,4-­benzodiazepin-­ 2-­one THIONORDAZEPAM Sweden, 2017 7-­Chloro-­5-­phenyl-­1,3-­dihydro-­2H-­1,4-­benzodiazepin-­2-­thione Ro 07-­4065 (Difludiazepam) Sweden, 2017 7-­Chloro-­5-­(2,6-­difluorophenyl)-­1-­methyl-­2H-­1,4-­benzodiazepin-­ 2-­one CLOBROMAZOLAM (Phenazolam) Sweden, 2018 8-­Bromo-­6-­(2-­chlorophenyl)-­1-­methyl-­4H-­[1,2,4]triazolo[4,3-­a][1,4]benzodiazepine BENTAZEPAM Sweden, 2019 5-­Phenyl-­1,3,6,7,8,9-­hexahydro-­2H-­[1]benzothieno[2,3-­e][1,4]diazepin-­2-­one CINAZEPAM Sweden, 2019 4-­([7-­Bromo-­5-­(2-­chlorophenyl)-­2-­oxo-­1,3-­dihydro-­2H-­1,4-­ benzodiazepin-­3-­yl]oxy)-­4-­oxobutanoic acid CLOZAPINE UK, 2020 3-­Chloro-­6-­(4-­methylpiperazin-­1-­yl)-­11H-­benzo[b][1,4]benzodiazepine

similarity, even when certain members such as brotizolam (a thienotriazolo-­ diazepine and not strictly a benzodiazepine) and clotiazepam (a thienodiazepine) are excluded, the remaining benzodiazepines still do not form a sufficiently homogeneous group amenable to a readily-­comprehensible group definition. Other ‘designer benzodiazepines’ have been reported to EMCDDA as shown in Table 16.4. All remain outside control in the UK and in the UN 1971 Convention. It should be assumed that yet more unusual benzodiazepines will appear in the future. A review9 of new benzodiazepines in Europe was produced by the EMCDDA in 2021.

Benzodiazepines

219

References 1. European Monitoring Centre for Drugs and Drug Addiction, Drug Profiles, https://www.emcdda.europa.eu/publications/drug-­profiles_en, accessed October 2021. 2. L. A. King, Lancet, 1982, ii, 982. 3. The Misuse of Drugs and Misuse of Drugs (Safe Custody) (Amendment) Regulations 2007 (S.I. 2154), https://www.legislation.gov.uk/uksi/2007/2154/ contents/made, accessed October 2021. 4. B. Moosmann, L. A. King and V. Auwärter, World Psychiatry, 2015, 14(2), 248. 5. D. H. Karl Greenblatt and D. J. Greenblatt, Clin. Pharmacol. Drug Dev., 2019, 8(3), 266. 6. United Nations Laboratory and Scientific Service Portals, Recently scheduled benzodiazepines Flualprazolam and Etizolam associated with multiple post-­mortem and DUID cases in UNODC EWA, 2020, https://www.unodc.org/ LSS/Announcement/Details/ad0c279b-­b4d4-­49f3-­b638-­cd87755d2d42, accessed October 2021. 7. Advisory Council on the Misuse of Drugs, Novel Benzodiazepines A review of the evidence of use and harms of Novel Benzodiazepines, 2020, https://assets. publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/881969/ACMD_report_-­a_review_of_the_evidence_of_ use_and_harms_of_novel_benzodiazepines.pdf, accessed October 2021. 8. The Misuse of Drugs Act 1971 (Amendment) Order 2021 (S.I. 868), https:// www.legislation.gov.uk/uksi/2021/868/contents/made, accessed October 2021. 9. European Monitoring Centre for Drugs and Drug Addiction, New benzodiazepines in Europe – a review, https://www.emcdda.europa.eu/­system/ files/publications/13759/TD0221596ENN_002.pdf, accessed October 2021.

Chapter 17

Cannabis and Phytocannabinoids 17.1  Introduction A profile of cannabis is available on the EMCDDA website.1 The cannabis plant (Cannabis sativa) is broadly distributed and grows in temperate and tropical areas. Together with tobacco, alcohol, betel and caffeine, it is one of the most widely consumed drugs throughout the world and has been used as a drug and a source of fibre since historical times. Herbal cannabis consists of the dried flowering tops and leaves. Cannabis resin is a compressed solid made from the resinous parts of the plant, and cannabis (hash) oil is a solvent extract of cannabis or cannabis resin. Cannabis sativa is dioecious: there are separate male and female plants. The major active principal, THC (Δ9-­tetrahydrocannabinol), is largely concentrated around the flowering parts of the female plant. The leaves and male plants have less THC, while the stalks and seeds contain almost none. Plants have characteristic compound leaves with up to 11 separate serrated lobes. Imported herbal cannabis occurs as compressed blocks of dried brown vegetable matter comprising the flowering tops, leaves, stalks and seeds of Cannabis sativa. Cannabis resin is usually produced in 250 g blocks (i.e., 9 ounce bars), many of which carry a brandmark impression. Hash oil (cannabis oil) is a dark brown viscous liquid when produced from cannabis resin but may be dark green when produced from herbal cannabis. Herbal cannabis imported into Europe may originate from West Africa, the West Balkans, the Caribbean or South-­East Asia, but cannabis resin often comes from North Africa or Afghanistan. Cannabis is usually smoked and may be mixed with tobacco either in a cigarette or in a smoking device (bong). Because THC has a low water solubility,   Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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221

ingestion of cannabis leads to poor absorption. Cannabis cigarettes are now rarely examined but old data showed that the average cigarette contained around 200 mg of herbal cannabis or cannabis resin.2 In some US jurisdictions where ‘adult use’ has recently become legalised, concentrated cannabis extracts for vaping in electronic cigarettes have become available. In many countries, herbal cannabis and cannabis resin are formally known as marihuana and hashish (or just ‘hash’) respectively. Cannabis cigarettes may be termed reefers, joints or spliffs. Street terms for cannabis and cannabis resin include bhang, charas, pot, dope, ganja, hemp, weed, blow, grass and many others. Although the leaves of C. sativa are reasonably characteristic, cannabis and cannabis resin can both be positively identified by low power microscopy, where the appearance of glandular trichomes and cystolithic hairs is diagnostic. The Duquenois test is considered to be specific for cannabinols. It is based on the reaction of cannabis extracts with p-­dimethylbenzaldehyde (Ehrlich's reagent). This produces a violet blue colouration that is extractable into chloroform. As with other naturally-­occurring drugs of misuse (e.g., heroin and cocaine), total synthesis is not currently an economic proposition. No precursors to THC are listed in the UN 1988 Convention.

17.2  Definitions of Cannabis and Cannabis Resin In many ways, cannabis is central to drug control. It is the most widely consumed illegal substance in most countries. It has been used since antiquity, yet its pharmacology and harmful effects have only come into clear focus in recent years. This in turn has led to several recent shifts in its legal status. Overlaid on this has been the major problem of defining cannabis. Following the League of Nations Convention of 1931,3 control of cannabis (at that time commonly called Indian Hemp) had been restricted to the female plant. In the UK Dangerous Drugs Act, 1951, cannabis was defined as ‘Indian hemp is the dried flowering and fruiting tops of the pistillate plant known as Cannabis sativa [alt. indica] from which the resin has not been extracted’. Cannabis and cannabis resin are both listed in Schedules I and IV of the UN 1961 Convention. This removed the exclusion of male plants and the restriction to a particular species of Cannabis, thereby avoiding taxonomic debate on whether or not that genus is monospecific. In Article 1, Paragraph 1 of that Convention, cannabis is defined as: ‘The flowering or fruiting tops of the cannabis plant (excluding the seeds and leaves when not accompanied by the tops) from which the resin has not been extracted, by whatever name they may be designated’. Cannabis resin is defined as: ‘The separated resin, whether crude or purified, obtained from the cannabis plant’. In 1971, the MDAct defined cannabis (Section 37) as: ‘“cannabis” (except in the expression “cannabis resin”) means the flowering or fruiting tops of any plant of the genus Cannabis from which the resin has not been extracted, by whatever name they may be designated’. But, as discussed by Phillips,4 problems soon arose and led to a number of challenges. For example, the lower

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leaves are not part of the inflorescence, so presumably were not controlled, even though they may contain identifiable resin glands and THC. This caused difficulties in identifying finely divided material and smoking residues. A new definition was introduced by Section 52 of the Criminal Law Act (1977) as follows:    ‘“cannabis” (except in the expression “cannabis resin”) means any plant of the genus Cannabis or any part of any such plant (by whatever name designated) except that it does not include cannabis resin or any of the following products after separation from the rest of the plant, namely–    (a)  mature stalk of any such plant; (b) fibre produced from mature stalk of any such plant, and seed of any such plant’.    Even today, questions can still arise from the 1977 definition when herbal cannabis is examined. For example, what fraction of non-­controlled stalk and seeds should a sample of cannabis contain before it is no longer considered to be controlled? Even if a sample comprising largely stalk and seeds is deemed to be controlled then, in calculating the weight, should some of the non-­controlled material be removed? This situation is reminiscent of the pre-­1977 definition, described above, which excluded lower leaves.

17.3  Cannabis Seeds Cannabis seeds are excluded from control, but despite ‘sterilisation’, even seeds intended for use as bird food or fishing bait will often germinate. It is conceivable that cannabis seeds could be regarded as precursors to cannabis and therefore incorporated into the appropriate legislation. But apart from the uses noted above, cannabis seeds of approved type are produced on a large scale for the licensed cultivation of ‘low-­THC’ crops. These are intended for the manufacture of rope, paper and animal bedding; controls on seed would impact on that industry. Although small amounts of cannabis (e.g., bracts and other flowering parts) may be found adhering to cannabis seeds, there are insignificant quantities of THC in clean seeds or in cannabis seed oil used for culinary or cosmetic purposes.

17.4  Phytocannabinoids Naturally-­occurring tetrahydrocannabinol (THC) is the R,R-­trans-­stereo­ isomer of Δ9-­THC, the main psychoactive constituent of cannabis (Scheme 17.1). The substituent R, at position 3, is a n-­pentyl group (C5H11). Along with a number of its isomers and stereochemical variants, Δ9-­THC is listed in Schedule I of the UN 1971 Convention.

Cannabis and Phytocannabinoids

223

Scheme 17.1  Δ  9-­Tetrahydrocannabinol showing the partial ring-­numbering in the

dibenzopyran system (left) and in the monoterpenoid system (right). R = C5H11.

Scheme 17.2  Tetrahydrocannabinol-­  2-­oic acid (THC-­A). R = C5H11.

The unsaturated bond in the cyclohexene ring is located between C9 and C10 in the more common dibenzopyran ring-­numbering system. According to the older monoterpenoid ring-­numbering system, that double bond is between C1 and C2. There are four stereoisomers of THC, but only the (−)-­trans isomer occurs naturally. The systematic name for this THC isomer is (−)-­(6aR,10aR)-­ 6,6,9-­trimethyl-­3-­pentyl-­6a,7,8,10a-­tetrahydro-­6H-­benzo[c]chromen-­1-­ol, but it is also known as (6aR,10aR)-­6a,7,8,10a-­tetrahydro-­6,6,9-­trimethyl-­3-­ pentyl-­6H-­dibenzo[b,d]pyran-­1-­ol. Two precursor substances, Δ9-­tetrahydro-­ cannabinol-­2-­oic acid (Scheme 17.2) and Δ9-­tetrahydrocannabinol-­4-­oic acid (THC-­A and THC-­B respectively) are also present in fresh cannabis, sometimes in large amounts. During smoking, THCA is converted to THC although other substances are also formed. Quantitative analysis of THC in cannabis is usually achieved by gas chromatography; the precursor acids are pyrolysed in the injection port thereby enabling total THC to be estimated. The concentration of THC in imported herbal cannabis and resin is typically 5% but may be as high as 15% in cannabis grown under intensive conditions.5 Other closely-­related phytocannabinoids that occur in cannabis include cannabidiol (CBD; Scheme 17.3) and, in aged samples, cannabinol (CBN; Scheme 17.4), both of which have quite different pharmacological effects to THC. Like THC, CBD occurs naturally in the form of a precursor cannabidiolic acid. The active isomer Δ8-­THC, where the unsaturated bond is located between C8 and C9, is found

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Scheme 17.3  Cannabidiol.  R = C5H11.

Scheme 17.4  Cannabinol.  R = C5H11. in cannabis in smaller amounts. Unlike many psychoactive substances, phytocannabinoids are not nitrogenous bases. Other compounds found in cannabis include the cannabivarins, cannabigerols and cannabichromenes. One of these, namely Δ9-­tetrahydrocannabivarin (THCV), is of particular interest, and is discussed later.

17.5  Control of Cannabinols In the UN 1971 Convention, six specific isomers and stereochemical variants of THC are listed by name together with two related synthetic substances (DMHP and parahexyl) as shown in Table 17.1. However, the generic clause in Part IV of Schedule 2 of the MDAct defines cannabinol derivatives as ‘…the following substances, except where contained in cannabis or cannabis resin, namely tetrahydro derivatives of cannabinol and 3-­alkyl homologues of cannabinol or of its tetrahydro derivatives’. The first part of the definition, i.e., ‘tetrahydro derivatives of cannabinol’ is straightforward. It is generally accepted that tetrahydro means the addition of four hydrogen atoms to the carbocyclic ring, and therefore includes both Δ9-­THC and Δ8-­THC. The definition excludes, for example, CBD, which is not a simple derivative of cannabinol or tetrahydrocannabinol. CBD is widely sold as a health food in the UK, but in early 2021 the UK Food Standards Agency6 required manufacturers to apply for ‘novel food’ status in order to improve quality and prevent mislabelling. Epidyolex® is a preparation of CBD that was approved as a medicine by the European Commission in 2019;

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Table 17.1  Six  isomers and stereochemical variants of THC and two related substances (DMHP and Parahexyl) as listed in the UN Convention on Psychotropic Substances 1971.

7,8,9,10-­Tetrahydro-­6,6,9-­trimethyl-­3-­pentyl-­6H-­dibenzo[b,d]pyran-­1-­ol (9R,10aR)-­8,9,10,10a-­Tetrahydro-­6,6,9-­trimethyl-­3-­pentyl-­6H-­dibenzo[b,d]pyran-­1-­ol (6aR,9R,10aR)-­6a,9,10,10a-­Tetrahydro-­6,6,9-­trimethyl-­3-­pentyl-­6H-­dibenzo[b,d]pyran-­1-­ol (6aR,10aR)-­6a,7,10,10a-­Tetrahydro-­6,6,9-­trimethyl-­3-­pentyl-­6H-­dibenzo[b,d]pyran-­1-­ol 6a,7,8,9-­Tetrahydro-­6,6,9-­trimethyl-­3-­pentyl-­6H-­dibenzo[b,d]pyran-­1-­ol (6aR,10aR)-­6a,7,8,9,10,10a-­Hexahydro-­6,6-­dimethyl-­9-­methylene3-­pentyl-­6H-­ dibenzo[b,d]pyran-­1-­ol 3-­(1,2-­Dimethylheptyl)-­7,8,9,10-­tetrahydro-­6,6,9-­trimethyl-­6H-­dibenzo[b,d]pyran-­ 1-­ol (DMHP) 3-­Hexyl-­7,8,9,10-­tetrahydro-­6,6,9-­trimethyl-­6H-­dibenzo[b,d]pyran-­1-­ol (Parahexyl)

it is discussed later. In the US, CBD is presently deemed to be a Schedule I controlled substance by the US Drug Enforcement Administration.7 Also excluded from control in the UK are the natural carboxylic acid precursors (THCA) and the metabolite 11-­hydroxy-­Δ9-­THC (Scheme 17.5). However, the second part of the above definition, i.e., ‘3-­alkyl homologues of cannabinol or of its tetrahydro derivatives’ is more problematic. It was the intention of the late Geoffrey Phillips, the author of this and many other early generic definitions in the MDAct, that ‘homologue’ should mean only higher homologues. In other words, a controlled substance arises if, in Schemes 17.3 and 17.4, the substituent R contains six or more linear or branched carbon atoms. Unfortunately, the Act does not define ‘homologues’. If it is maintained that only the higher homologues are included, then cannabivarins, such as 6,6,9-­trimethyl-­3-­propyl-­6a,7,8,10a-­tetrahydro-­6H-­benzo[c]chromen-­ 1-­ol (tetrahydrocannabivarin; THCV; Scheme 17.6) with a 3-­propyl group, are not covered by the definition of a controlled cannabinol derivative. However, it is generally accepted that ‘homologue’ means both lower and higher homologues as discussed in Chapter 7 in which case THCV is a controlled drug. The significance of this debate arises because it has been suggested that THCV might have some therapeutic value. In 2016, the ACMD issued a report8 on 97 phytocannabinoids. In respect of THCV, evidence for psychoactivity was equivocal and it was concluded that, in the view of the ACMD, it was a controlled drug, but that its status in respect of the MD Regulations needs to be reviewed in the light of further research. The separate inclusion of cannabinol in the MDAct in 1971 is an anomaly; it was not at that time believed to be psychoactive, is not an obvious precursor

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Scheme 17.5  11-­  Hydroxy-­Δ9-­THC, a non-­controlled metabolite of Δ9-­THC. R = C5H11.

Scheme 17.6  6,6,9-­  Trimethyl-­3 -­p ropyl-­6 a,7,8,10a-­t etrahydro-­6 H-­b enzo[c]chromen-­1-­ol; tetrahydrocannabivarin; THCV. R = C3H7.

to THC and is not listed in the UN 1971 Convention. A final complexity in the definition of controlled phytocannabinoids is the word ‘derivatives’, which occurs twice, but is otherwise not defined. This matter is taken up in Chapter 12.

17.6  Hash Oil Cannabis (hash) oil has traditionally been made by solvent extraction of cannabis resin followed by removal of the excess solvent to leave a dark viscous liquid. It may contain a high concentration of THC. Before 2003, the legal status of hash oil had developed into a notorious problem caused by the separate classification of vegetable matter (i.e., cannabis and cannabis resin) in Class B with (pure) cannabinol derivatives in Class A. That distinction arose from the separate inclusion of the substances in the UN 1961 and 1971 Conventions. Preparations or products of Class B drugs are also controlled by virtue of paragraph 4 of Part II of Schedule 2, namely ‘Any preparation or other product containing a substance or product for the time being specified in any of paragraphs 1 to 3 of this Part of this Schedule, not being a preparation falling within paragraph 6 of Part I of this Schedule’. Hash oil (cannabis oil) is not considered to fall within this definition because it cannot be said to contain cannabis or cannabis resin as such. However, Section 37 of the MDAct defines cannabis resin as ‘…the separated resin, whether crude or purified, obtained from any

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plant of the genus Cannabis’. It had been accepted for many years that hash oil is a purified form of cannabis resin and therefore a Class B drug. This situation was brought into confusion after 1990 when it became clear that some hash oil was being produced, not from cannabis resin, but from herbal cannabis. In R-­v-­Carter (Oxford Crown Court, Judgment of 16 December 1992) it was successfully argued that such hash oil could no longer be deemed to be a purified form of cannabis resin; the only option open to the Court was to regard it as a preparation of cannabinol and therefore a Class A drug. It is sometimes possible to distinguish the two types of hash oil insofar as cannabidiol is present in much greater amounts in cannabis resin than it is in herbal cannabis.4 Thus, if CBD is found in hash oil, then it has probably not originated from herbal cannabis. Furthermore, hash oil made from fresh herbal cannabis may also appear to have a dark green colour because of the presence of the pigment chlorophyll. But from the user's viewpoint, there is little distinction between the two types of hash oil; it is anomalous that it could be treated as either Class A or Class B solely on the basis of its manufacturing route. Following this judgment, there arose a general scientific agreement that one solution to the problem would be to define hash oil as a Class B drug by including it as a named substance in Part II of Schedule 2 to the MDAct. Unfortunately, unlike chemically-­defined substances, hash oil as an entity cannot be added to the MDAct by a simple Modification Order. The reason for this is that firstly a definition of hash oil would be needed in Part IV of Schedule 2 to the MDAct if not also in Section 37. Secondly, the definition of the Class A ‘cannabinols’ in Part IV of Schedule 2 would have to be re-­worded to say: ‘cannabinol derivatives means the following substances, except where contained in cannabis, cannabis resin or liquid cannabis…’. These changes would have required primary legislation, but a suitable definition might have been ‘Liquid cannabis is a solvent extract of cannabis or cannabis resin’. It is interesting to note that the UN 1961 Convention included the concept of liquid cannabis but defined it as ‘…extracts and tinctures of cannabis’. This was intended as a reference to the medicinal products once found in Pharmacopoeias, but now long obsolete. The original separation in the MDAct between the Class A ‘cannabinols’ and the corresponding Class B plant material was a rare instance where the classification of a pharmacologically-­active substance (i.e., THC) was effectively based on the potency of different products or preparations. Hash oil formed an awkward bridge between these two groups. These problems were resolved in 2004 by placing cannabis and ‘cannabinols’ into Class C (and Class B from 2009). This saga is now only of historical interest.

17.7  ‘High Potency’ Cannabis The concept of potency as opposed to purity is described in Chapter 23. In the past 20 years, intensive indoor cultivation has become widespread in Europe and elsewhere.9–11 This is based on improved seed varieties and

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procedures such as artificial heating and lighting, hydroponic cultivation in nutrient solutions and propagation of cuttings of female plants. It leads to a high production of flowering material (sometimes known as ‘sinsemilla’ or ‘skunk’) where the THC content may be in excess of 20%. The increasing THC content (potency) of certain types of cannabis was a major factor in both of the 2005 and 2008 UK reviews of the classification of cannabis.12,13 From the point of view of a drug chemist, higher potency in itself causes no more difficulties than are already inherent in the analysis of cannabis, i.e., inhomogeneous samples, especially herbal cannabis. Although it has been suggested from time to time that higher potency cannabis might have a different legal classification, this would be a sure route to legal problems. Not only is the precision (reproducibility) of quantitative cannabis assay often worse than that for most other drugs of misuse, but such an approach could not target a particular type of cannabis since there is considerable overlap in the potencies of ‘traditional’ (i.e., imported) herbal cannabis, cannabis resin and intensively cultivated herbal cannabis. In the Netherlands, high potency cannabis (15% or more THC content) is now a so-­ called ‘hard drug’ according to the ‘Opium Law’.14

17.8  Medicinal Cannabis 17.8.1  The Period before 2018 Cannabis has been used since historical times for various medicinal purposes. However, in the modern era the attitude has been taken that cannabis has limited value. In the MDAct, cannabis and its products were placed in Schedule I of the MD Regulations alongside other drugs that were deemed not to be used as therapeutic agents. Nevertheless, two substances were regarded as having medicinal use. The first of these is nabilone (Scheme 17.7), a constituent of the proprietary preparation Cesamet®, and a synthetic analogue of THC. Under the MDAct,

Scheme 17.7  9-­  (Hydroxymethyl)-­6,6-­dimethyl-­3-­(2-­methyloctan-­2-­yl)-­6a,7,10,10a-­ tetrahydrobenzo[c]chromen-­1-­ol; nabilone.

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it is a Class B controlled drug (Schedule 2 of the MD Regulations) licensed for hospital use in the UK as a treatment for the nausea arising from cancer chemotherapy, but not for other conditions. Nabilone is listed in the MDAct alongside other synthetic cannabinoid receptor agonists (Chapter 18). Dronabinol, the INN for (−)-­trans-­THC, is not licensed for use in the UK, but may be imported on a ‘named patient basis’, again for the same indications as nabilone; it is marketed as ‘Marinol®’ in the US. Dronabinol, including its stereoisomers, is listed in Schedule II of the UN 1971 Convention and the MD Regulations. A decision by WHO in 2006 to move dronabinol from Schedule II to Schedule III of the UN 1971 Convention was not supported by the UN Commission on Narcotic Drugs. Subsequently, a preparation of cannabinoids, known as Sativex® containing THC and CBD in a 1 : 1 ratio, and produced by GW Pharmaceuticals, was approved for use in the UK and some other countries for the treatment of muscle spasms associated with multiple sclerosis. It is also approved in some countries for managing pain. Originally it had been thought that Sativex® should be treated in the same way as dronabinol, i.e., placed in Schedule 2 of the Regulations. However, it was argued that as an extract of cannabis, it falls within the scope of the UN 1961 Convention under ‘Extracts and Tinctures of Cannabis’. It was therefore listed in Schedule 4 of the MD Regulations in generic terms without the proprietary name by The Misuse of Drugs (Amendment No. 2) (England, Wales and Scotland) Regulations 2013.15 The entry reads:    ‘A liquid formulation—    (a)  containing a botanical extract of cannabis— (i) with a concentration of not more than 30 milligrams of cannabidiol per millilitre, and not more than 30 milligrams of delta-­9-­ tetrahydrocannabinol per millilitre, and (ii) where the ratio of cannabidiol to delta-­9-­tetrahydrocannabinol is between 0.7 and 1.3, (b) which is dispensed through a metered dose pump as a mucosal mouth spray, and (c) which was approved for marketing by the Medicines and Healthcare Products’ Regulatory Agency on 16th June 2010.’

17.8.2  Recent Developments The illicit use of cannabis products for treating various medical problems has continued for many years. This self-­medication was strictly an offence under the MDAct. It had been recognised that cannabis products have some efficacy in the treatment of certain types of epilepsy, particularly those refractory cases where established drugs were ineffective. There was considerable public concern about a few patients, often children, whose parents travelled outside the UK to obtain cannabis products such as those manufactured by the Bedrocan company in the Netherlands. This publicity led the Home

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Office to ask the ACMD to investigate whether the legal status of cannabis-­ derived medicinal products should be changed. In their initial report, the ACMD advised that these products should no longer be subject to the requirements of Schedule 1 of the MD Regulations. However, the ACMD noted that there was no clear definition of what constituted a cannabis-­derived medicinal product; some were oils containing unspecified amounts of THC or other phytocannabinoids. They also recommended that such products should not contain synthetic cannabinoid receptor agonists. In a subsequent report, the ACMD set out proposals for assessing a suitable definition, prescribing practice, route of administration, clinical trials and marketing authorisation. Cannabis-­derived medicines were inserted into Schedule 2 of the MD Regulations by The Misuse of Drugs (Amendments) (Cannabis and Licence Fees) (England, Wales and Scotland) Regulations 2018 (S.I. 1055).16 The text reads:    ‘“cannabis-­based product for medicinal use in humans” means a preparation or other product, other than one to which paragraph 5 of part 1 of Schedule 4 applies, which—    (a) is or contains cannabis, cannabis resin, cannabinol or a cannabinol derivative (not being dronabinol or its stereoisomers); (b)  is produced for medicinal use in humans; and— (c)  is— (i)  a medicinal product, or (ii) a substance or preparation for use as an ingredient of, or in the production of an ingredient of, a medicinal product’.    ‘“clinical trial” has the same meaning as in the Medicines for Human Use (Clinical Trials) Regulations 2004;’    ‘“dronabinol” does not include any substance which—    (a) has the international non-­proprietary name dronabinol (recommended by the World Health Organisation); and (b)  is derived from cannabis, cannabis resin or their constituents,    and stereoisomers of dronabinol are to be construed accordingly; and’    ‘“medicinal product” has the same meaning as in the Human Medicines Regulations 2012’.    Yet, despite the relaxation of legal controls on the medicinal use of cannabis, few prescriptions have been written since 2018. There are several reasons for this:    ●● lack of confidence by the medical profession insofar as there are few clinical trials that demonstrate the efficacy of cannabis-­derived medicines and whether it is not just a placebo effect;

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no clear definition, both qualitative and quantitative, of what constitutes a cannabis-­based medicine; ●● no marketing authorisation by MHRA; ●● no clarity on what treatments benefit from cannabis-­based medicines; ●● lack of enthusiasm by the pharmaceutical industry in what would probably be a poor financial investment.    The situation may change now that the charity DrugScience has started a project17 known as TWENTY21 to have 20 000 patients enrolled in a trial. In the meantime, Epidyolex® is approved for use as an adjunctive therapy for seizures associated with Lennox–­Gastaut and Dravet syndromes, in conjunction with clobazam, for patients from 2 years of age. Epidyolex is essentially a pure preparation of plant-­based CBD, which is not a controlled drug. Since THC may be present as an impurity, the marketing authorisation states that this should be x, then it suggests that sequential cutting is occurring as the drug is passed down a distribution chain and fragmented into smaller aliquots. The mode is a more useful measure when the population is skewed. An example here is the distribution of amphetamine purity in the UK (Figure 23.3); the population has a long positive tail with a large number of low purity values and a small number of high purity values. Closer examination of the low purity samples (i.e., expansion of the abscissa in Figure 23.3) shows that the modal purity is less than 4%. By contrast, the mean purity is close to 10%. This pattern has been observed with amphetamine for many years, although heroin (Figure 23.4) has always shown a more symmetrical distribution, where the mode, mean and median are around 40%. In the case of cocaine and crack cocaine, determining the purity of the material, i.e., the percentage of cocaine base causes no problems at the individual sample level. But if the frequency histogram of a number of purity determinations of cocaine is then studied, it is sometimes found that the

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Figure 23.3  Distribution  of amphetamine purity in street seizures in the UK between April 2009 and March 2010. These data were obtained in the Forensic Science Service. The distribution illustrates the significance of different measures of central tendency; the mean is 10.1%, but the mode and median are ≪ 10%.

Figure 23.4  Distribution  of heroin purity (% diamorphine content) in street

seizures in the UK between April 2009 and March 2010. These data were obtained in the Forensic Science Service. The mean, mode and median are all close to 40%.

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distribution curve is bimodal, i.e., a lower maximum closely relating to the modal purity of cocaine hydrochloride and a higher maximum probably caused by the presence in the sample population of crack cocaine. This almost certainly arises because some samples of crack cocaine will be in powdered form and will have been described as cocaine. For the powdered drugs considered here, it had been a general observation over many years that their mean purity in Scotland and Northern Ireland is below that seen in England. This effect probably arose because those countries are situated at some distance from the main seaports and airports of importation, most of which are located in the South of the UK, thereby giving greater opportunity for dilution to occur. Almost all of the drugs considered here are imported. Although illicit laboratories attempting to produce amphetamine, MDMA or related substances are occasionally uncovered in the UK, almost all are small-­scale operations; none has ever made a significant impact on the national supply. Examination of the purities of large seizures at the importation level shows that both amphetamine and cocaine are diluted before reaching users. However, the similarity between the mean street level and importation purities of heroin over many years showed that little dilution occurred. This is supported by the finding that when they were sorted by weight, the mean purity of heroin samples of less than 1 g was the same as samples with weights between 100 g and 1 kg. Because of their physical state, tablets and other dosage forms are not susceptible to dilution.

23.5  Drug Content The term ‘drug content’, while meaning either purity or potency in a fairly broad sense, is best used sparingly. It is ideally suited to the specific case of dosage units, particularly in a toxicological investigation. Thus, it is more helpful to say that a 300 mg tablet contains 150 mg of MDMA rather than that tablet has a purity of 50%. This is because a tablet is usually consumed as a single entity, and the dose (i.e., 150 mg) is a useful measure of what has been ingested.

23.6  Wrap Sizes The wrap (i.e., street deal) sizes of cannabis products and commonly-­used powdered drugs and their typical adulterants, as recorded by Forensic Science Service in 2006 in the UK, are shown in Table 23.3. More recent data have not been published, but a broadly similar pattern had existed for many years. There is a wide range in the amounts of drug present in street deals. An examination of test purchases carried out by the Metropolitan Police from 1992 to 2003 4 provided an extreme example of how the drug content of wraps may vary. Thus, for cocaine, crack cocaine and heroin, the respective ranges were 90–1860 mg, 12–1620 mg and 7–3500 mg.

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Table 23.3  Wrap  sizes and common adulterants for powdered drugs and cannabis in 2006; n/a = not available or not applicable.

Substance

Wrap size (2006)

Common adulterants

Amphetamine

0.5–1.0 g

Cannabis (herbal) Cannabis (resin) Cocaine Crack cocaine

1–4 g 1–4 g 0.2–0.4 g 0.1–0.2 g

Heroin

0.1–0.3 g

Caffeine, glucose, lactose, mannitol, benzocaine, lignocaine n/a n/a Benzocaine, phenacetin, lignocaine, caffeine, diltiazem, paracetamol, procaine, boric acid, dimethylterephthalate Caffeine, paracetamol, diazepam, phenacetin, phenobarbitone

Illicit tablets are often marked with a characteristic logo. They are typically around 8–10 mm in diameter and weigh around 250–300 mg. LSD microdots are 2 mm in diameter, and LSD paper squares are typically 8 mm square. However, LSD is now uncommon in any form and even less commonly quantified; the drug content of paper squares has not been measured in recent times. The only published data for the UK were made over 20 years ago.5

23.7  Adulterants in Powdered Drugs Adulterants are rarely examined in detail in forensic science laboratories. Those that are reported are often found fortuitously and merely reflect the method of analysis (typically GC-­MS). Thus, inorganic moieties, such as sodium bicarbonate and magnesium sulfate, which will not elute from a gas-­ chromatograph are under-­reported. Little quantitative data on adulterants have been published.

23.8  Drug Prices Table 23.4 shows the average prices6 of street drugs in the UK in 2016. Prices are per gram except for ‘Ecstasy’ (tablets, essentially MDMA) and SCRAs where a bag is typically 3.5 g. Crack cocaine prices were based on price per ‘rock’, which was assumed to be 0.2 g, while a typical bag of heroin was 0.1 g; these have been recalculated here as £ per g. Source data were provided to the nearest £. From Table 23.4, and bearing in mind general inflation in the economy, most prices have remained largely constant over nearly 20 years. However, for the earlier period 1992 to 2003 there was a long-­term decline in drug prices in the UK. Figure 23.5 shows the mean price of heroin and crack cocaine from 1992 to 2010. Those data derived from test purchases by the London Metropolitan Police.4 Since the UK retail price index rose by 61% in the period 1992 to 2010, the real cost of heroin in 1992 expressed in 2010 values was over £600 per g.

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Table 23.4  Mean  or range of street prices (£) per gram or tablet of drugs in the UK in 2016; n/a = not available.

Substance

Price (£)

Amphetamine Cannabis (herbal) Cannabis (resin) Cannabis (high strength) Cocaine Crack cocaine Heroin Ketamine LSD MDMA (tablet) MDMA (powder) Methylamphetamine SCRAs (Spice, etc.)

5 upwards 5–6 n/a 8 30–40 50–100 100 200 n/a 5–15 40 200 20–60

Figure 23.5  The  mean price (£) per gram of heroin and crack cocaine in London from 1992 to 2010.

The EMCDDA publishes data on drug prices for the European Union.7 Drug prices are often used by law enforcement agencies to express the value of large drug seizures. However, it is doubtful if drug prices say much about the size or shape of drug markets. Despite attempts to create a more

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sophisticated analysis of price and purity data, it appears that these two variables have little correlation. Furthermore, both may be influenced by complicating factors such as the availability of and demand for that drug and the availability, price and quality of alternative substances.

References 1. United Kingdom Drug Situation 2019, Focal Point Annual Report, https:// www.gov.uk/government/publications/united-­kingdom-­drug-­situation-­ focal-­point-­annual-­report/united-­kingdom-­drug-­situation-­focal-­point-­ annual-­report-­2019, accessed October 2021. 2. International Narcotics Control Board, List of Narcotic Drugs under International Control, https://www.incb.org/incb/en/psychotropics/green-­list. html, accessed October 2021. 3. International Narcotics Control Board, List of Psychotropic Substances under International Control, https://www.incb.org/incb/en/narcotic-­drugs/ Yellowlist/yellow-­list.html, accessed October 2021. 4. L. A. King Metropolitan Police Service, Specialist Crime Department Test-­ Purchase Database: Drug Type, Unit Prices and Purities in the Period 1992 to 2003, Internal Report for Home Office, 2004. 5. L. A. King, Forensic Sci. Int., 1997, 85(2), 135. 6. DrugWise, https://www.drugwise.org.uk/how-­much-­do-­drugs-­cost/, accessed October 2021. 7. European Monitoring Centre for Drugs and Drug Addiction, Statistical Bulletin 2020 – Price, Purity and Potency, https://www.emcdda.europa.eu/ data/stats2021/ppp_en, accessed October 2021.

Chapter 24

Measuring Drug Harm 24.1  Introduction A central principle of the international drug control treaties is that they should only include in their schedules those substances that can be shown to be harmful. Guidelines for assessing the harms of substances have been used by the WHO/ECDD for a number of years. Until the mid-­1990s in the UK, there was little systematic evaluation of evidence when the ACMD debated the classification of substances under the MDAct. A checklist of issues was eventually created to guide discussion about a substance. This included: chemistry with general information on synthesis, preparation and properties; pharmacology and toxicology; dependence potential; therapeutic applications; law enforcement seizures; industrial use; illicit manufacture, etc. Since drug control policy in most member states of the UN followed the requirements of the UN 1961 and later Conventions, there had been little need to introduce parallel domestic risk assessments. This began to change as NPS became more widespread. By 1999, the EMCDDA had produced a comprehensive scheme for assessing the harms of what at that time were called new synthetic drugs. The most recent version1 of the procedure was updated in 2020. In the Netherlands, a committee had been set up in the 1990s to carry out risk assessments using numerical scoring at the national level. This system was described in 1998 at a meeting of the EMCDDA in Lisbon where a pre-­assessment was made of the need to control the novel phenethylamine 4-­MTA. In the UK, in 1999, an objective framework for risk assessment was made by the Police Foundation Independent Enquiry2 into the MDAct.

  Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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24.2  A  CMD: Developing a Scale of Harm   (2000–2007) It was against this background that the ACMD started work in 2000 on risk assessments of what would eventually amount to 22 substances, spanning all three Classes in the MDAct (i.e., A, B and C) and including some that were non-­controlled. They were ranked on a scale of harm, based on a nine-­ parameter matrix that included both personal and social harms3 as set out in Table 24.1. Each of the nine parameters was scored for each substance by members of ACMD using a scale of 0 to 3, where a score of 0 indicated no concern and a score of 3 indicated the highest concern. Figure 24.1 shows the overall mean scores for the original 20 substances3 together with methylamphetamine and 1-­benzylpiperazine, which were assessed subsequently. The current classification (A, B or C) of the substances under the MDAct is also shown in Figure 24.1. It will be seen that there is little correlation between the harm score and the legal status. Of the 22 substances, 14 had been previously scored by a panel of psychiatrists on a similar matrix during the Independent Inquiry into the MDAct.2 The analysis by the psychiatrists referred to temazepam, whereas the ACMD analysis covered all benzodiazepines. Good agreement was reached between the ranking obtained by the ACMD members and the psychiatrists (Pearson's correlation coefficient: r = 0.892; n = 14; P < 0.001; Figure 24.2). Alcohol (score = 1.85 out of a possible 3) was ranked highest of non-­ controlled drugs. Although there is no suggestion that it could ever be controlled by the MDAct, alcohol was deemed to be as harmful as many substances in Class A. The next highest non-­controlled drug was ketamine (score = 1.75 out of a possible 3). This led to a review of ketamine by the ACMD, following which a recommendation was made that it should be controlled; and in 2005 it was listed in Class C. It could be argued from its score that ketamine should have been placed in Class B, but to a large extent the decision to choose Class C was precipitated by a need to control importation Table 24.1  Assessment  parameters used to determine a scale of harm.3 Adapted from ref. 3 with permission from Elsevier, Copyright 2007.

Category of harm

Parameter

Physical harm

1 2 3 4 5 6 7 8 9

Dependence Social harms

Acute Chronic i.v. harm Intensity of pleasure Psychological dependence Physical dependence Intoxication Other social harms Healthcare costs

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Figure 24.1  Overall  mean harm scores of 22 substances examined by the ACMD. The current classification (A, B or C) under the MDAct (X = unclassified) is shown against each bar.

of non-­medicinal products containing ketamine; there was little enthusiasm for wishing to criminalise users. Although it had first come to notice as a problem in the UK as early as 1992,4 no convincing evidence emerged in the intervening years that it should have been controlled sooner. Thus, despite the high score achieved by ketamine, it might have seemed illogical for it to be immediately classified higher than Class C. However, over the following years, there was increasing concern about ketamine, particularly its association with damage to the urinary bladder. Ketamine was therefore reclassified to Class B in 2014.5 Khat achieved the lowest score (0.80 out of a possible 3). In line with this finding, a subsequent review by the ACMD6 recommended that khat should remain outside the MDAct. Many years later, khat was reviewed again by the ACMD7 and again it was recommended that it should not be controlled. However, this advice was not accepted by the Government, and khat became a Class C drug in 2014. The alkyl nitrites (score = 0.92) are also unlikely substances for control under the MDAct, but in the last few years, their status under the Psychoactive Substances Act 2016 has come into question. As mentioned in Chapter 5, the status of nitrous oxide under the MDAct is to be

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Figure 24.2  Overall  harm scores of 14 substances as assessed by the ACMD and an

independent group of psychiatrists. Key: 1 = heroin; 2 = cocaine; 3 = alcohol; 4 = barbiturates; 5 = amphetamine; 6 = methadone; 7 = benzodiazepines; 8 = solvents; 9 = buprenorphine; 10 = tobacco; 11 = ecstasy; 12 = cannabis; 13 = LSD; 14 = steroids.

reviewed again by ACMD. Amongst the controlled drugs in Figure 24.1, the placement of heroin and cocaine in the first and second places was of little surprise. However, the ranking of some seems misplaced. In particular, it was argued that ecstasy (essentially MDMA) and LSD should be reclassified from Class A to Class B. The debate about the status of MDMA would surface in a major review by the ACMD in 2009 (Chapter 3).

24.3  The Netherlands Study (2010) Although the study by Nutt et al.3 was based on UK experience, it recommended that international comparisons should be made. A subsequent report by van Amsterdam et al.8 took a similar approach. It evaluated the legal classification of drugs in the Netherlands and how this corresponded with the ranking of the drugs according to their harm. It had a similar scope to the 2007 study3 being based on 19 substances (17 illicit drugs plus alcohol

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Figure 24.3  The  correlation between the mean harm scores obtained by Nutt

et al.3 and by van Amsterdam et al.8 Key: 1 = LSD; 2 = khat; 3 = anabolic steroids; 4 = methylphenidate; 5 = ketamine; 6 = ecstasy; 7 = buprenorphine; 8 = cannabis; 9 = benzodiazepines; 10 = GHB; 11 = amphetamine; 12 = methadone; 13 = methylamphetamine; 14 = tobacco; 15 = alcohol; 16 = cocaine/crack; 17 = heroin. The straight line is the least squares fit.

and tobacco) and was assessed by 19 Dutch experts from various fields. The harm indicators scored were acute and chronic toxicity, addictive potency and social harm. Physical and social harms were further sub-­divided into harm at the individual and the population levels. The four most harmful substances were crack cocaine, heroin, alcohol and tobacco. The four least harmful substances were khat, anabolic steroids, LSD and ‘magic mushrooms’. Figure 24.3 shows the correlation between the mean scores obtained by van Amsterdam et al.8 and those reported in the UK.3 The correlation coefficient is r = 0.81. The main differences in scores were found for heroin and ketamine (both scored more highly by Nutt et al.3) and khat, GHB and tobacco (scored more highly by van Amsterdam et al.).8

24.4  A  Multi-­criteria Decision Analysis of Drug Harms in the UK (2010) One of the major weaknesses of the UK 2007 study3 was that the nine measures of harm were treated equally, and no allowance was made for the possibility that some harms are more important than others. To address the question of weighting, attention turned to the use of Multi-­criteria Decision Analysis.9 This has been used in resolving other policy problems where some

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method was needed to synthesise numerous pieces of evidence and at the same time assess the importance that should be attached to each. An initial panel of experts comprised members of the ACMD. Their task was to assemble a set of criteria against which substances could be tested. Sixteen evaluation criteria were selected, and their definitions are shown in Table 24.2. The criteria are divided into nine that are associated with ‘Users’ and seven that relate to harm to ‘Others’. A further panel was set up in 2010 by the organisation now known as DrugScience10 comprising 15 experts. In the first stage, they assessed the harms of each of 20 substances against those 16 criteria. The next stage was to examine substances which had the highest scores on each of the 16 criteria. These were then considered pair wise in an exercise to determine which of the pair the expert panel believed was the most important, that is to say which should be weighted more. While this remains a subjective judgment, subsequent sensitivity analysis showed that the final rankings were sufficiently robust to be mostly unaffected by large changes in the weightings. The results of this analysis11 are shown in Table 24.3 and Figure 24.4. The overall harm ranking was similar to that of the previous studies.3,8 The four most harmful substances to users were alcohol, heroin, crack cocaine and methylamphetamine. The six substances with the least harm were khat, anabolic steroids, MDMA, LSD, buprenorphine and ‘magic mushrooms’. Alcohol was the most harmful substance to others, followed by heroin, crack cocaine and tobacco.

24.5  The UK Survey by Morgan et al. (2009) This study12 extended the earlier work3 by requesting 1501 drug users resident in the UK to complete a similar scoring of 20 substances. The survey was hosted on the internet. Using the same unweighted matrix of harms as before, a remarkably high overall correlation was found between that of Nutt et al.3 and the users (r = 0.896; P < 0.001). As before, there was no correlation between the classification of the 20 drugs under the MDAct and their harm ranking (Kendall's rank correlation = 0.234; P = 0.18). Some drugs had consistently high ratings across all harm categories (e.g., heroin, cocaine and alcohol), while some had consistently low scores (e.g., alkyl nitrites, cannabis, khat and methylphenidate). Some minor differences between the scores of experts and users were noticed. Thus, the correlations for ‘pleasure’ and for ‘intoxication’ were less obvious. The survey results imply that users are relatively well informed about the harms associated with the drugs they use and suggest that the current UK legal classification system is not acting to inform users of the harms of psychoactive substances. A second part of this study asked users about the benefits of the different substances. Thus ecstasy, cannabis and LSD were ranked highest by users on both acute and chronic benefits, whereas the lowest benefits were recorded for solvents, alkyl nitrites and anabolic steroids.

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Table 24.2  Evaluation  criteria and their definitions as used in a Multi-­criteria Decision Analysis.

Evaluation criterion

Description

To users Drug specific mortality

Intrinsic lethality of the drug expressed as ratio of lethal dose and standard dose (for adults) Drug related mortality The extent to which life is shortened by the use of this drug (excludes drug specific mortality), e.g., road traffic accidents, lung cancer, HIV, suicide Drug specific damage Drug specific damage to physical health e.g., cirrhosis, seizures, strokes, cardiomyopathy, stomach ulcers Drug related damage Drug related damage to physical health, including consequences of e.g., self-­harm, blood-­borne viruses, emphysema, damage from cutting agents. Dependence The extent to which this drug creates a propensity or urge to continue to use despite adverse consequences (ICD10 or DSM4). Drug specific impairment Drug specific impairment of mental functioning, of mental functioning e.g., amphetamine induced psychosis, ketamine intoxication Drug related impairment Drug related impairment of mental functioning, e.g., of mental functioning mood disorders secondary to drug users' lifestyle or drug use Loss of tangibles Extent of loss of tangible things (e.g., income, housing, job, educational achievements, criminal record, imprisonment) Loss of relationships Extent of loss of relationship with family and friends To others Injury

Crime Environmental damage Family adversities

International damage

Economic cost

Community

The extent to which the use of this drug increases the chance of injuries to others both directly and indirectly, e.g., violence (including domestic violence), traffic accident, foetal harm, drug waste, secondary transmission of blood-­borne viruses The extent to which the use of this drug involves or leads to an increase in volume of acquisitive crime directly or indirectly (at the population level, not the individual) The extent to which the use and production of this drug causes environmental damage locally, e.g., toxic waste from amphetamine factories, discarded needles The extent to which the use of this drug causes family adversities, e.g., family breakdown, economic well-­ being, emotional well-­being, future prospects of children, child neglect The extent to which the use of this drug in the UK contributes to damage at an international level, e.g., deforestation, destabilisation of countries, international crime and new markets The extent to which the use of this drug causes direct costs to the country (e.g., healthcare, police, prisons, social services, customs, insurance, crime) and indirect cost (e.g., loss of productivity, absenteeism) The extent to which the use of this drug creates decline in social cohesion and decline in the reputation of the community

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Table 24.3  The  harm to users and to others according to an MCDA analysis.11 Substance

Harm to users

Harm to others

Alcohol Heroin Crack cocaine Methylamphetamine Cocaine Tobacco Amphetamine Cannabis GHB Benzodiazepines Ketamine Methadone Mephedrone Butane Khat Anabolic steroids Ecstasy (MDMA) LSD Buprenorphine Psilocybe mushrooms

56.4 73.4 79.8 69.1 42.6 37.5 41.0 25.4 38.1 27.6 29.0 25.0 26.1 21.8 18.0 18.3 18.6 15.0 11.8 12.0

84.9 39.8 32.3 2.2 14.4 17.0 8.1 15.4 2.3 5.1 3.3 4.7 1.5 1.4 1.3 2.3 1.0 0.3 2.3 0.1

Figure 24.4  The  20 drugs shown for their harm to users and harm to others.11 For the sake of clarity only the highest nine are labelled. 1 = alcohol; 2 = heroin; 3 = crack cocaine; 4 = methylamphetamine; 5 = cocaine; 6 = tobacco; 7 = amphetamine; 8 = cannabis; 9 = GHB.

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Table 24.4  The  ranking of harms produced by 1006 respondents to an online survey, all of whom had used mephedrone.

Substance

Harm rank

Heroin Alcohol Tobacco Cocaine Amphetamines GHB Ketamine Benzodiazepines Mephedrone LSD MDMA ‘Magic mushrooms’ Cannabis

1 2 3 4 5 6 7 8 9 10 11 12 13

24.6  A Scale of Harm Produced by Drug Users (2011) Apart from questions specifically about mephedrone use, an online survey conducted by Carhart-­Harris et al.13 took the opportunity to ask all 1506 respondents to rank 13 substances according to their overall harmful properties. The results are shown in Table 24.4. The ranking of harms agreed closely with the earlier studies.3,8 The four most harmful substances were alcohol, tobacco, cocaine and heroin. The four least harmful substances were ‘magic mushrooms’, LSD, cannabis and MDMA.

24.7  T  he International Survey by Morgan et al. (2013) The Morgan et al. study14 was a continuation of earlier work by these authors and was aimed to assess the perceived benefits as well as harms of widely used recreational drugs, both licit and illicit, in an international sample of drug users. The survey was hosted on the internet and was available in three languages. Respondents reported their experience of 15 commonly used drugs or drug classes; regular users then rated their harms and benefits. Because of its international basis, some changes were made to the previously-­used set of substances. In all, 5791 individuals from over 40 countries completed the survey, although most were from English-­speaking countries. Skunk and herbal cannabis were ranked consistently of high benefit while alcohol and tobacco fell below many controlled drugs. There was no correlation between users’ harm ranking of drugs and their classification in the Schedules of the USA legislation or the ABC system in the UK. Prescription pain killers, alcohol and tobacco were ranked within the top ten most harmful drugs. These findings suggest that health campaigns should consider the need for a more

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credible, balanced communication of both harms and benefits to young people.

24.8  New Zealand Drug Harm Index A study15 carried out by the New Zealand Ministry of Health, and published in 2016, arrived at broadly similar conclusions to earlier research. It was found that when ranked for personal and community harms both for dependent users and, separately, for casual users, the most harmful substances were methamphetamine, heroin/‘homebake’, pharmaceutical opioids, cocaine and synthetic cannabinoids. The least harmful substances were cannabis, LSD and ecstasy. The study also included the estimates of the financial cost of drug misuse.

24.9  Index Measures of Lethal Toxicity In parallel with measures of overall harm, a number of independent measures have been described for evaluating the fatal toxicity of drugs. Although fatal toxicity is but one of the many parameters of harm considered in the studies described above, it is usually weighted strongly and is found to correlate well with overall harm. Unlike some aspects of harm, fatal toxicity is amenable to direct measurement since it is usually well recorded in official statistics. However, although counting the total number of deaths associated with a particular substance provides useful information for public health interventions it is of little value for assessing the intrinsic toxicity of substances. For this, a suitable denominator is required, and the methods described below show the various attempts to use such denominators. The first two examples relate the number of fatal poisonings in a given period to various measures of availability. The third method relies on the therapeutic index, i.e., the ratio of the mean or median fatal dose to the therapeutic dose. The fourth method is based entirely on the information on death certificates, namely the ratio of those cases where a certain drug was mentioned, but no other, to the total number of cases where that drug was mentioned.

24.9.1  Fatal Poisonings and Prescriptions Forty years ago, the barbiturate hypnotics were widely prescribed yet were well-­recognised as toxic drugs. The barbiturates act as respiratory depressants and many accidental and deliberate poisonings occurred. When consumed with alcohol, they were particularly toxic. Many barbiturates were brought under international control in the early 1980s. Thereafter, prescriptions for barbiturates started to fall dramatically as they were gradually replaced by the much safer benzodiazepine hypnotics. During this period, it became clear that the number of deaths caused by barbiturates showed

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Figure 24.5  The  relation between the index of fatal toxicity (T) and the n-­octanol/

water partition coefficient (P) for five barbiturates.16 The straight line shows the least squares fit, (r = 0.992; p < 0.001). Key: 1 = phenobarbitone; 2 = butobarbitone; 3 = pentobarbitone; 4 = amylobarbitone; 5 = quinalbarbitone.

a close correlation with the number of prescriptions issued. This suggested that the ratio of deaths to prescriptions (defined as the index T) might provide a measure of the intrinsic toxicity of individual barbiturates. Figure 24.5 shows the results of this analysis, where values of T are plotted against the n-­octanol/water partition coefficient (P) for five barbiturates.16,17 The coefficient P is a measure of how effectively a substance penetrates the blood– brain barrier and is known to correlate with other measures of toxicity for a wide range of substances. The finding that quinalbarbitone (secobarbitone) had the highest toxicity not just among barbiturates, but of all substances commonly reported in fatal poisonings at that time, was one of the factors that led to quinalbarbitone being moved from Schedule 3 to Schedule 2 by The Misuse of Drugs (Amendment) Regulations 1988 (S.I. 916).

24.9.2  Fatal Poisonings and Other Measures of Availability In order to measure the intrinsic toxicity of illicit substances, it is clearly not possible to use prescription data. However, other data may be used as proxy measures of availability including: national household surveys; seizures by law enforcement agencies; and estimates of market size. Five illicit substances were chosen (heroin, cocaine, amphetamine, MDMA and cannabis). Figure 24.6 shows the correlation between three index values, namely the ratio of the number of deaths associated with each substance to the

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Figure 24.6  Correlation  between three measures of the index of fatal toxicity based

on all mentions on death certificates.18 The abscissa shows deaths/ users (D/U) and the ordinate shows both deaths/seizures (D/S) and deaths/market quantity (D/Q), all as logarithmic transforms.

Table 24.5  The  mean index of toxicity of five illicit substances based on three measures of availability.

Substance

Overall index of fatal toxicity

Heroin Cocaine + crack cocaine Amphetamine MDMA Cannabis

1000 42 32 41 1000 1000 1000 >150 38 30 20 20 16 15 10 10 8 6

24.9.3  The Safety Ratio A different index of toxicity was constructed by Gable.19 A safety ratio for a number of substances was defined as the acute lethal dose divided by the dose most commonly used for non-­medicinal purposes, where the higher the ratio the safer the drug. The safety ratios for selected substances are shown in Table 24.6. For the five substances examined by King and Corkery18 as described above, and assuming that methylamphetamine in Gable's study can be equated to amphetamine, then the safety ratios are well-­correlated with the inverse of the index of fatal toxicity.

24.9.4  ‘Sole’ and ‘All Mentions’ on Death Certificates The previously mentioned methods of establishing the intrinsic toxicity of substances can only be used if there are sufficient data on either availability or therapeutic and toxic doses. With NPS, particularly in the early stages, such information is completely lacking. However, a further index of fatal toxicity can still be constructed.20 It relies entirely on the information on death certificates, and is based on the relative frequency of mentions of a substance on death certificates. If it is imagined that a substance has an extremely low toxicity, then amongst a population of suspected fatal poisonings it will occur rarely and will mostly be associated with other more toxic substances that are the direct cause of death. If the number of cases where it is the sole mention (S) and those where it is mentioned alongside other substances (A) is determined, then the ratio S/A will be low. On the other hand, if a substance has a high toxicity, then its presence will often be associated with the direct cause of death, and the ratio S/A will be higher. Thus S/A should be a measure of the intrinsic toxicity of a substance. Figure 24.7 shows the correlation between

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Figure 24.7  Correlation  (r = 0.92) between the mean value of S/A (ratio of sole to all mentions of a substance implicated in a death, 2003–2009) and an index of toxicity (natural logarithmic transform) based on the ratio of sole mentions of a substance on a death certificate to availability.20 The straight line is the least squares fit [Ln = m(S/A) + c, where m = 30.9 and c = −4.78].

the index of fatal toxicity of seven substances and the ratio S/A. A check on the validity of S/A as a measure of fatal toxicity can be made by examining S/A values for established medicinal drugs. The highest values occurred with barbiturates, followed by tricyclic antidepressants (e.g., amitriptyline, dothiepin), then a broad group of narcotic analgesics (e.g., fentanyl, methadone), followed by a miscellaneous group (e.g., zopiclone, pregabalin). Diazepam had the lowest value of S/A. This order is entirely consistent with those studies based on medicinal drugs described earlier and therefore supports the validity of S/A as a measure of fatal toxicity. Using values of S/A for a wide range of other substances involved in fatal poisonings where no prevalence data were available, Figure 24.7 can be interpolated to give estimates of the index of fatal toxicity, Ln(Tf ), as shown in Figure 24.8. Because of the relatively few numbers of deaths associated with these substances, Figure 24.8 should not be over-­interpreted; the difference between adjacent substances is probably not significant. However, it is useful to comment on the most and least fatally toxic substances. Thus, the appearance of γ-­hydroxybutyrate/γ-­ butyrolactone (GHB/GBL) and p-­methoxyamphetamine/p-­methoxy-­N-­ methylamphetamine (PMA/PMMA) near the top is consistent with what we know about these substances. The high score for synthetic cannabinoid receptor agonists (SCRAs) is a much more original finding, but it fits with the many anecdotal reports and publications that have described

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Figure 24.8  The  index of fatal toxicity [Ln(Tf)] shown on the abscissa for substances calculated from the ratio of ‘Sole’ to ‘All’ mentions (S/A) on death certificates.

the dangerous properties of these cannabis substitutes, particularly those most recently encountered. It is therefore ironic that cannabis itself scores so low. Benzodiazepine analogues represent a further group with low scores. That finding is consistent with the well-­known low toxicity of established benzodiazepines such as diazepam.

References 1. European Monitoring Centre for Drugs and Drug Addiction, EMCDDA operating guidelines for the risk assessment of new psychoactive substances, https://www.emcdda.europa.eu/publications/manuals-­and-­guidelines/ emcdda-­risk-­assessment-­guidelines_en, accessed October 2021. 2. The Police Foundation, Drugs and the Law: Report of the Independent Inquiry into the Misuse of Drugs Act 1971, London, 2000, https://www. police-­foundation.org.uk/publication/inquiry-­into-­drugs-­and-­the-­law, accessed October 2021. 3. D. Nutt, L. A. King, W. Saulsbury and C. Blakemore, Lancet, 2007, 369, 1047.

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4. L. A. King, K. Clarke and A. J. Orpet, Ketamine and Tiletamine Abuse in the UK, Home Office Central Research Establishment, Technical Note No. 792, 1–18 https://www.researchgate.net/publication/270760826_Ketamine_and_Tiletamine_Abuse_in_the_UK, accessed October 2021. 5. The Misuse of Drugs Act 1971 (Ketamine etc.) (Amendment) Order 2014 (S.I. 1106), https://www.legislation.gov.uk/uksi/2014/1106/contents/made, accessed October 2021. 6. Advisory Council on the Misuse of Drugs, 2005. Khat (Qat): Assessment of risk to the individual and communities in the UK, https://assets. publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/119095/Khat_Report_.pdf, accessed October 2021. 7. Advisory Council on the Misuse of Drugs, 2013, Khat: A review of its potential harms to the individual and communities in the UK, https:// assets.publishing.service.gov.uk/government/uploads/system/uploads/ attachment_data/file/144120/report-­2013.pdf, accessed October 2021. 8. J. van Amsterdam, A. Opperhuizen, M. Koeter and W. van den Brink, Eur. Addict. Res., 2010, 16(4), 202. 9. V. Belton and T. Stewart, Multiple Criteria Decision Analysis: An Integrated Approach, Springer Science + Business Media B.V. Dordrecht, Netherlands, 2002, ISBN 978-­1-­4613-­5582-­3. 10. Drug Science, The Truth about Drugs, https://www.drugscience.org.uk/, accessed October 2021. 11. D. J. Nutt, L. A. King and L. D. Phillips, Lancet, 2010, 376, 1558. 12. C. J. A. Morgan, L. Muetzelfeldt and M. Muetzelfeldt, et al., J. Psychopharmacol., 2009, 24(2), 147. 13. R. L. Carhart-­Harris, L. A. King and D. J. Nutt, Drug Alcohol Depend., 2011, 118(1), 19. 14. C. J. A. Morgan, L. A. Noronha and M. Muetzelfeldt, et al., J. Psychopharmacol., 2013, 27(6), 497. 15. New Zealand Ministry of Health, Research Report: The New Zealand Drug Harm Index 2016, https://www.health.govt.nz/publication/research-­ report-­new-­zealand-­drug-­harm-­index-­2016, accessed October 2021. 16. L. A. King and A. C. Moffat, Lancet, 1981, (i), 387. 17. L. A. King and A. C. Moffat, Med. Sci. Law, 1983, 23(3), 193. 18. L. A. King and J. M. Corkery, Hum. Psychopharmacol. Clin. Exp., 2010, 25, 162. 19. R. S. Gable, Addiction, 2004, 99(6), 686. 20. L. A. King and J. M. Corkery, J. Psychopharmacol., 2018, 32(7), 793.

Chapter 25

Miscellaneous Issues 25.1  Diagnostic Kits In the MD Regulations of the UK1 (Regulation 2), certain products are exempted from controls. This includes ‘diagnostic kits’, which are commercial products used as calibrators in automatic drug-­detection systems such as those for workplace drug testing. These may contain small amounts of controlled drugs. Such kits must first satisfy the requirements that they are not designed for administration of the drugs to a human or animal and that the drugs are not readily recoverable in a yield which constitutes a risk to health. They are then exempt provided that no one component part contains more than 1 mg of a controlled drug or 1 µg in the case of lysergide or any other N-­alkyl derivative of lysergamide. These threshold levels were designed to reduce the regulatory burden on manufacturers without opening an avenue for drug diversion. However, in framing the Regulation, some compromises were necessary. There are several substances where the required human dose is less than 1 mg (e.g., certain narcotic analgesics), such that a kit containing these drugs could be misused.

25.2  Low Dosage Preparations The purpose of Schedule 5 of the 2001 MD Regulations1 is to except a number of defined ‘low-­dose’ preparations from certain controls. Apart from these exceptions, there are no lower limits to the quantities of controlled drug required to create a possession offence. It is only necessary for the analyst to show unequivocally that the controlled drug is present. Legal arguments

  Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

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about what constitutes a usable amount of drug have largely been replaced by a need for the prosecution to show that the defendant was aware that he or she had possession of the drug. The full text Schedule 5 of the 2001 MD Regulations is set out in Table 25.1. Table 25.1  Schedule  5 of the Misuse of Drugs Regulations. Controlled Drugs Excepted from the Prohibition on Importation, Exportation and Possession and Subject to the Requirements of Regulations 24 and 26. 1.(1) Any preparation of one or more of the substances to which this paragraph applies, not being a preparation designed for administration by injection, when compounded with one or more other active or inert ingredients and containing a total of not more than 100 milligrams of the substance or substances (calculated as base) per dosage unit or with a total concentration of not more than 2.5% (calculated as base) in undivided preparations 1.(2) The substances to which this paragraph applies are acetyldihydrocodeine, codeine, dihydrocodeine, ethylmorphine, nicocodine, nicodicodine (6-­nicotinoyldihydrocodeine), norcodeine, pholcodine and their respective salts (Paragraph 2 was revoked in 2005) 3. Any preparation of medicinal opium or of morphine containing (in either case) not more than 0.2% of morphine calculated as anhydrous morphine base, being a preparation compounded with one or more other active or inert ingredients in such a way that the opium or, as the case may be, the morphine cannot be recovered by readily applicable means or in a yield which would constitute a risk to health 4. Any preparation of dextropropoxyphene, being a preparation designed for oral administration, containing not more than 135 milligrams of dextropropoxyphene (calculated as base) per dosage unit or with a total concentration of not more than 2.5% (calculated as base) in undivided preparations 5. Any preparation of difenoxin containing, per dosage unit, not more than 0.5 milligrams of difenoxin and a quantity of atropine sulphate equivalent to at least 5% of the dose of difenoxin 6. Any preparation of diphenoxylate containing, per dosage unit, not more than 2.5 milligrams of diphenoxylate calculated as base, and a quantity of atropine sulphate equivalent to at least 1% of the dose of diphenoxylate 7. Any preparation of propiram containing, per dosage unit, not more than 100 milligrams of propiram calculated as base and compounded with at least the same amount (by weight) of methylcellulose 8. Any powder of ipecacuanha and opium comprising – 10% opium, in powder, 10% ipecacuanha root, in powder, well mixed with 80% of any other powdered ingredient containing no controlled drug 9. Any mixture containing one or more of the preparations specified in paragraphs 1 to 8, being a mixture of which none of the other ingredients is a controlled drug 10.  A liquid formulation— (a)  containing cannabidiol obtained by extraction and purification from cannabis; (b)  where the concentration of— (i)  delta-­9-­tetrahydrocannabinol is not more than 0.1 milligram per millilitre; and (ii)  cannabidiol is 95–105 milligrams per millilitre; (c)  which is presented in a bottle, as an oral solution for oral administration; and (d) which was approved for marketing by the European Commission on 19th September 2019

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25.2.1  Low Dosage Preparations Containing Cocaine Schedule 5 of the MD Regulations had its origins in the UN 1961 Convention. It was intended to ease the regulatory burden on those using certain substances for therapeutic use. That Convention still includes the following text:    ‘Any preparation of cocaine containing not more than 0.1% of cocaine calculated as cocaine base, being a preparation compounded with one or more other active or inert ingredients in such a way that the cocaine cannot be recovered by readily applicable means or in a yield which would constitute a risk to health’.    While that may have once helped the medical profession, it became a burden for forensic scientists since every sample of cocaine examined had to be shown to contain more than 0.1% cocaine. If that were not done then the defence could argue that in the absence of such quantitative analysis, it was possible that the sample could be exempted by the Regulations. Since almost all illicit cocaine has a purity far in excess of 0.1%, the cost of such analysis became difficult to justify. Furthermore, by the 1990s it was clear that not only was therapeutic use of cocaine limited, but physicians and hospital staff usually kept cocaine in more concentrated solutions to which the MD Regulations in Schedule 3 applied. The entry for cocaine was removed in 2005.2

25.2.2  L  ow Dosage Preparations Containing Dihydrocodeine and Other Opiates In the UK, proprietary tabletted preparations containing dihydrocodeine are available. Because the dihydrocodeine is present as the bitartrate salt, each tablet only contains 40 mg or less of base; these tablets are therefore excepted by the provisions of paragraph 1.(1). But other dihydrocodeine tablets may be encountered where it is not necessarily obvious that the drug is present as the tartrate or any other specific salt. However, it is unlikely that manufacturers outside the UK would wish to market preparations containing more than 100 mg base of dihydrocodeine or the other opiates specified in paragraph 1.(2), but if in doubt a quantitative analysis would have to be carried out.

25.2.3  Low Dosage Preparations Containing Morphine The exemption of morphine and opium preparations containing less than 0.2% morphine base is not usually problematical. Apart from proprietary morphine–kaolin mixtures, which always have less than 0.2% morphine, the only other common preparations are morphine sulfate tablets. These always contain much more than 0.2% morphine and are therefore not exempt. ‘Oromorph®’ is a liquid preparation containing 10 mg morphine sulfate per 5 ml (i.e., reaction

MDMA > purple to black Amphetamine > light orange Opiates > purple Most benzodiazepines > orange Flunitrazepam > pink Vanillin, acetaldehyde, ethanol, Cannabis > violet (in chloroform CHCl3 layer) p-­Dimethylaminobenzaldehyde, Lysergide > violet ethanol, sulfuric acid Sodium carbonate, acetaldeSecondary amines > blue hyde, sodium nitroprusside Alkaline solution of Most benzodiazepines > m-­dinitrobenzene red/purple Methanol, sulfuric acid, heated Cocaine > odour of methylsalicylate Cobalt thiocyanate, hydrochloric Cocaine > blue acid, glycerol

References 1. R. Braithwaite, Metals and Anions, in Clarke's Analysis of Drugs and Poisons in Pharmaceuticals, Body fluids, and Postmortem Material, ed. A. C. Moffat, M. D. Osselton, B. Widdop and J. Watts, The Pharmaceutical Press, London, 4th edn, 2011, p. 288. ISBN 978-­0-­85369-­711-­4. 2. B. Widdop, Colour Tests, in Clarke's Analysis of Drugs and Poisons in Pharmaceuticals, Body fluids, and Postmortem Material, ed. A. C. Moffat, M. D. Osselton, B. Widdop and J. Watts, The Pharmaceutical Press, London, 4th edn, 2011, p. 471. ISBN 978-­0-­85369-­711-­4. 3. M. Philp and S. Fu, Drug Test. Anal., 2018, 10(1), 95. 4. Home Office Circular 015/2012, The testing of substances suspected to be drugs controlled under the Misuse of Drugs Act 1971, https:// w w w.gov.uk/government/publications/the-­t esting-­o f-­s ubstances-­ suspected-­to-­be-­drugs-­controlled-­under-­the-­misuse-­of-­drugs-­act-­1971/ circular-­0 152012-­t he-­t esting-­o f-­s ubstances-­s uspected-­t o-­b e-­d rugs-­ controlled-­under-­the-­misuse-­of-­drugs-­act-­1971, accessed October 2021.

Appendix 10

Useful Websites Table A10.1 provides a limited list of major agencies concerned with drug control, public policy, drug information or related areas. Some of these organisations provide a considerable amount of information and online publications relating, where appropriate, to chemistry, toxicology, legislation, addiction, household surveys, drug seizures, annual reports on drug situations in various countries and many other aspects of drugs. Table A10.1 Useful websites.a URL

Host organisation

https://www.emcdda.europa.eu/topics/law European Legal Database on Drugs http://www.ema.europa.eu European Medicines Agency http://www.drugabuse.gov National Institute on Drug Abuse (NIDA) http://www.emcdda.europa.eu/ European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) https://www.who.int/groups/who-­expert-­ World Health Organization (ECDD) committee-­on-­drug-­dependence https://www.unodc.org/unodc/en/comUnited Nations Commission on Narmissions/CND/Mandate_Functions/ cotic Drugs (CND) Mandate-­and-­Functions_Scheduling. html http://www.opsi.gov.uk/legislation/about_ All UK legislation since 1988 legislation.htm http://www.homeoffice.gov.uk Home Office http://www.rpsgb.org.uk The Royal Pharmaceutical Society of Great Britain

  Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

378

Useful Websites

379

Table A10.1  (continued) URL

Host organisation

http://www.incb.org

UN International Narcotics Control Board Medicines and Healthcare Products Regulatory Agency (MHRA) DrugScience Sentencing Council (UK) Reports of NPS in the US

http://www.mhra.gov.uk/index.htm https://www.drugscience.org.uk https://www.sentencingcouncil.org.uk https://www.npsdiscovery.org/reports/ monographs/ a

All above Accessed October 2021.

Appendix 11

Fentanyl Derivatives Reported to EMCDDA Table A11.1 includes those fentanyl derivatives shown in Chapter 8 that were risk-­assessed by EMCDDA (see also Appendix 1), viz. acryloylfentanyl, carfentanil, cyclopropylfentanyl, 4F-­iBF, furanylfentanyl, methoxyacetylfentanyl and THF-­F. Table A11.1 Fentanyl derivatives reported to EMCDDA. Short name

IUPAC name

2-­Methyl-­N-­phenyl-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]propanamidea (Iso)butyryl-­F-­fentanyl N-­benzyl N-­(1-­Benzylpiperidin-­4-­yl)-­N-­(N-­ analogue fluorophenyl)-­butanamideb Alpha-­Methylfentanyl butana2-­Methyl-­N-­phenyl-­N-­[1-­(1-­phenmide analogue ylpropan-­2-­yl)piperidin-­4-­yl]propanamide Ocfentanil N-­(2-­Fluorophenyl)-­2-­methoxy-­N-­ [1-­(2-­phenylethyl)-­4-­piperidinyl]acetamide Carfentanil 4-­[(1-­Oxopropyl)phenylamino]-­ 1-­(2-­phenylethyl)-­4piperidinecarboxylic acid methyl ester (Iso)butyrylfentanyl (IBF)

Reported Finland, 2012 Italy, 2020 Finland, 2012 Finland, 2012 Netherlands, 2013 Latvia, 2013

  Forensic Chemistry of Substance Misuse: A Guide to Drug Control, 2nd Edition By Leslie A. King © Leslie A. King 2022 Published by the Royal Society of Chemistry, www.rsc.org

380

Fentanyl Derivatives Reported to EMCDDA

381

Table A11.1  (continued) Short name

IUPAC name

N-­(4-­Fluorophenyl)-­N-­[(1-­(2-­ phenylethyl)-­4-­piperidinyl)]butanamide Fentanyl butanamide analogue, N-­Phenyl-­N-­[1-­(2-­phenylethyl)-­4-­ butyrylfentanyl piperidinyl]butanamide 4-­Fluoro butyrlfentanyl

Acetylfentanyl/ desmethylfentanyl Despropionyl-­2-­fluoro fentanyl 4-­MeO-­BF or 4-­methoxybutyrylfentanyl Furanylfentanyl Valerylfentanyl Acryloylfentanyl 4-­Chloro-­isobutyrylfentanyl (4Cl-­iBF) 4-­Fluoro-­isobutyrylfentanyl (4F-­iBF) 2-­Fluorofentanyl 3-­Fluorofentanyl Methoxyacetylfentanyl Tetrahydrofuranylfentanyl (THF-­F) Cyclopentylfentanyl Benzodioxolefentanyl Benzoylfentanyl 3-­Phenylpropanoylfentanyl

N-­Phenyl-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]-­N-­ phenylacetamide N-­(2-­Fluorophenyl)-­1-­(2-­ phenylethyl)piperidin-­4-­amine N-­(4-­Methoxyphenyl)-­N-­[1-­(2-­ phenylethyl) piperidin-­4-­yl]butanamide N-­Phenyl-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]-­furan-­2-­ carboxamide N-­Phenyl-­N-­[1-­(2-­phenylethyl)-­4-­ piperidyl]pentanamide N-­(1-­Phenethylpiperidin-­4-­yl)-­N-­ phenylacrylamide N-­(4-­Chlorophenyl)-­2-­methyl-­N-­[1-­ (2-­phenylethyl)piperidin-­4-­yl]propanamide N-­(4-­Fluorophenyl)-­2-­methyl-­N-­[1-­ (2-­phenylethyl)piperidin-­4-­yl]propanamide N-­(2-­Fluorophenyl)-­N-­[1-­(2-­ phenylethyl)-­4-­piperidinyl]propanamide N-­(3-­Fluorophenyl)-­N-­[1-­(2-­ phenylethyl)-­4-­piperidyl]propanamide 2-­Methoxy-­N-­phenyl-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]acetamide N-­Phenyl-­N-­[1-­(2-­ phenylethyl)piperidin-­4-­yl]tetrahydrofuran-­2-­carboxamide N-­Phenyl-­N-­[1-­(2-­ phenylethyl)-­4-­piperidyl]cyclopentanecarboxamide N-­Phenyl-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]-­2H-­1,3-­ benzodioxole-­5-­carboxamide N-­Phenyl-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]benzamide N-­Phenyl-­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]-­3-­ phenylpropanamide

Reported Poland, 2014 Poland and Sweden, 2014 Poland, 2014 Germany and France, 2015 Sweden, 2015 Finland, 2015 France, 2016 Denmark, 2016 Slovenia, 2016 Slovenia, 2016 Ireland, 2016 France, 2016 Slovenia, 2016 Sweden, 2016 Sweden, 2017 Slovenia, 2017 Sweden, 2017 Sweden, 2017 (continued)

Appendix 11

382

Table A11.1  (continued) Short name

IUPAC name

Reported

Tetramethylcyclopropanefentanyl

2,2,3,3-­Tetramethyl-­N-­phenyl-­N-­ [1-­(2-­phenylethyl)-­4-­piperidyl]cyclopropane carboxamide N-­Phenyl-­N-­[1-­(2-­ phenylethyl)-­4-­piperidyl]cyclopropanecarboxamide N-­Phenyl-­N-­[1-­ (phenylethyl)piperidin-­4-­yl]thiophene-­2-­carboxamide N-­Phenyl-­N-­[1-­(phenylmethyl)-­4-­ piperidinyl]-­propanamide N-­(1-­Benzyl-­4-­piperidyl)-­N-­phenyl-­ benzamide N-­(1-­Benzyl-­4-­piperidyl)-­N-­phenyl-­ acetamide N-­(2-­Methylphenyl)-­N-­[1-­(2-­ phenylethyl)-­4-­piperidinyl]acetamide N-­(1-­Benzyl-­4-­piperidyl)-­N-­phenyl-­ furan-­2-­carboxamide N-­Phenyl-­N-­[1-­(2-­phenylethyl)-­ 4-­piperidyl]-­3-­methylbut-­2enamide N-­(1-­Benzylpiperidin-­4-­ yl)-­N-­(4-­fluorophenyl)cyclopropanecarboxamide N-­(4-­Hydroxyphenyl)­N-­[1-­(2-­phenylethyl)piperidin-­4-­yl]-­butanamide N-­(3-­Fluorophenyl)-­2-­methoxy-­N-­ [1-­(2-­phenylethyl)piperidin-­4-­yl]acetamide N-­Phenyl-­N-­[1-­(2-­phenylethyl)-­4-­ piperidinyl]-­2-­butenamide N-­(4-­Fluorophenyl)-­N-­(1-­ phenylethylpiperidin-­4-­yl)furan-­2-­carboxamide

Sweden, 2017

Cyclopropylfentanyl Thiophenefentanyl Benzylfentanyl Benzoylbenzylfentanyl Acetylbenzylfentanyl 2-­Methylacetylfentanyl Furanylbenzylfentanyl 3-­Methylcrotonylfentanyl 4-­Fluorocyclopropylbenzylfentanyl 4-­Hydroxybutyrylfentanyl 3-­Fluoromethoxyacetylfentanyl Crotonylfentanyl 4F-­Furanylfentanyl

a

Latvia, 2017 Poland, 2017 Slovenia, 2017 Poland, 2017 Poland, 2017 Poland, 2018 Germany, 2018 Germany, 2018 Germany, 2018 Sweden, 2018 Czech Republic, 2018 The Netherlands, 2019 Italy, 2019

In (iso)butyrylfentanyl, originally reported by Finland, the actual C4-­acyl isomer was not determined; in a subsequent independent seizure in Italy, the isobutyroyl moiety was assigned. b In this (iso)butyryl-­F-­fentanyl N-­benzyl analogue, the position of the fluorine substituent was undetermined.

Subject Index Charts and tables in bold. Abyssinian tea, 342. see also khat academic laboratories, 8, 163 acetaminophen, 241, 243 acetic anhydride, 69, 275, 324, 326, 328 acetone, 252, 325, 332, 374 acetorphine, 153 acetylamphetamine, 175 acetylanthranilic acid, 324, 325 acetylbenzylfentanyl, 382 acetylcodeine, 274 acetyldihydrocodeine, 308 acetylephedrine, 328 acetylfentanyl, 381 acetylmethadol, 60 acetyloxyethyl acetate, 328 acetylpropionylmorphine, 164 Acorus calamus, 321 acryloylfentanyl, 96–97, 350, 380–381 Adam, 63 adinazolam, 217 adulterants, 232, 253, 274, 284, 287– 288, 310, 364 Afghanistan, 220 afloqualone, 188 air freshener, 374 alcohol, 339–340 analysis, 294–295 caffeine, 341–342 cannabis classifications, 30 cocaine, 252

controls, 336 derivatives defined, 155 drug harm in UK, 296 GHB, 269 international survey, 299–300 khat, 339, 343 legislative developments, 15 lethal toxicity, 303 methadone, 339 Psychoactive Substances Act 2016, 49, 52 risk assessment, 339 scale of harm ACMD, 292, 294 scale of harm by users, 299–300 scientific research, 44 tobacco, 341 UK survey, 296, 298–299 alfentanil, 66, 94, 352, 359 alkyl nitrite, 50–52, 73, 193, 293, 296, 364, 366 alkylphenethylamine, 64, 106, 158 allobarbital, 86 allylprodine, 66, 101 alphameprodine, 66, 104 alphaprodine, 66, 81, 102 alprazolam, 214 aluminium foil method, 208, 210, 374 Amanita sp., 321 amfepramone, 60, 131, 182 amfetamine, 10, 60, 61 383

384

amfonelic acid, 193–194 amineptine, 355, 360, 367 aminobenzoic acid, 255 aminobutyric acid (GABA), 212, 269–271, 320 aminoindanes, 139, 166, 180–181 aminopropane, 61, 178–179 aminopropylbenzofuran, 169 aminorex, 9, 147, 169, 192–193, 353, 360 methylaminorex, 75, 192–193, 353, 360 aminotetralin, 178, 182–183 aminotetralins, 178 amitriptyline, 212, 304 ammonium formate, 205–206, 325 amobarbital, 85, 86 amphetamines acetylamphetamine, 175 benzylamphetamine, 371 bromoamphetamine, 155 dexamphetamine, 29, 352, 362 dimethoxyamphetamine, 63 ecstasy, 205 ethylamphetamine, 60, 61, 106, 175, 353 fluoroamphetamine, 168,328 fluoromethamphetamine, 168 homoamphetamine, 177 hydroxyamphetamine, 107, 175, 206 hydroxytenamphetamine, 87 iodoamphetamine, 372 lisdexamphetamine, 175, 356, 361, 366 methoxyamphetamine (PMA), 106, 111, 169, 304 methoxymethylamphetamine, 106, 108–109 methylenedioxyamphetamine, 73 methylenedioxyethylamphetamine, 63, 73, 209 methylenedioxymethylamphetamine, 63, 107–108, 204, 209, 374

Subject Index

methylthioamphetamine, 110, 169 propylamphetamine, 175 tenamphetamine, 60, 62, 63, 87, 353, 360 thiophenylamphetamine, 178 UN Conventions 1988, 206 amphetaminil, 175 amyl nitrite, 50–51, 73 amylobarbitone, 301 anabolic steroids, 62, 81–84, 336, 353–354, 360, 362, 366–367, 368 androgen receptors, 191 arylcyclohexylamine, 119 drug harm in UK, 294–295, 296 drug misuse in England and Wales, 3, 5 enhancers, 186 esters, 70 forensic science, 42 penalties under MDAct, 21 specific issues, 144 UK survey, 298 Anadenanthera sp., 319 analysis alcohol, 294–295 diamorphine, 286 ecstasy, 295 importation, 287 analytical reference standards, 12 androgen receptors, 191 androgenic steroids, 68, 70, 81, 82–84, 119, 311, 368 androstanolone, 60 androstene, 83–84, 354, 360, 369 androstenedione, 369 Angelus Foundation, 47 angina, 50 anileridine, 66, 102 anthelmintic drug, 111 anthranilic acid, 324, 325 antidepressant, 91, 111–112, 116, 123, 212, 304 antihistamine, 122–123 apomorphine, 276, 278–279 Arabian tea, 342. see also khat

Subject Index

Areca catechu, 320, 343 areca nut, 343–344 arecaidine, 344 arecoline, 151, 169, 320, 344 Argyreia nervosa, 320 aripiprazole, 113, 115 arsenic, 333 arylalkylamine, 166, 169, 174, 178 arylcyclohexylamines, 116–120 arylcyclohexylpiperidine, 116 asarone, 321 atamestane, 368 atorvastatin, 241, 243 Atropa belladonna, 321 atropine, 251–252, 254, 308, 321 Attention Deficit Hyperactive Disorder (ADHD), 141, 186, 205 Australia, 55, 326, 333 New South Wales, 46, 133–134 Austria, 73 axons, 34, 210 ayahuasca, 260 azacyclonol, 123 Aztec people, 264 baclofen, 271 BALCO company, 82 Banisteriopsis caapi, 321, 364 barbitals allobarbital, 86 amobarbital, 85, 86 butobarbital, 86, 301 cyclobarbital, 85, 86 methylphenobarbital, 60, 86 pentobarbital, 85, 86 phenobarbital, 10, 86 secbutabarbital, 86 secobarbital, 10, 60, 85–86 barbiturates, 4–5, 10, 30, 72, 80, 81, 84–86, 294, 300–304 barbituric acid, 72, 84–85, 86, 154, 352 diethylbarbituric acid, 86 diphenylbarbituric acid, 86 methylbarbituric acid, 85 thiobarbituric acid, 85

385

barium, 333 base purity rule, 282 bath salts, 162, 312 bazedoxifene, 241, 243 Bedrocan company, 229 Belgium, 185 benocyclidine, 120–121 bentazepam, 218 benzaldehyde, 206, 325, 328 dimethylbenzaldehyde, 221, 253 benzethidine, 66, 102 benzfetamine, 60 benzocaine, 23, 288 benzocyclobutene, 182–183 benzodioxolefentanyl, 381 benzoylbenzylfentanyl, 382 benzoylecgonine, 92–93, 251–252 benzoylfentanyl, 381 benzphetamine, 60, 61, 106, 175 benzydamine, 187–188 benzyl chloride, 206, 328 benzyl methyl ketone (BMK), 206, 208, 324, 325–326 benzylamphetamine, 371 benzylbenzimidazole, 199 benzylcathinone, 91 benzylethylphenidate, 140 benzylfentanyl, 382 benzylmorphine, 65, 66 benzylphenethylamines, 47, 81, 86–88 benzylpiperazine (BZP), 34, 81, 107, 111–115, 181, 292, 313, 349, 367 benzylpiperidine, 194, 198 betel, 220, 320, 339, 343–344 bhang, 221 biak, 321 Blood Alcohol Concentration (BAC), 340 blood–brain barrier, 51, 274, 301 blotters, 87, 263 blow, 63, 221 body builders, 82, 269, 276 body cavities, 47

386

bolandiol, 368 bolasterone, 368 bolazine, 368 boldenone, 368 bolenol, 368 bolmantalate, 368 bong, 220 bremelanotide, 187 British Approved Names (BAN), 59, 62 brolamfetamine, 60, 63, 352 bromantane, 194, 198 bromazepam, 214 bromazolam, 217 bromoamphetamine, 155 bromobenzene, 325 bromodihydrosafrole, 210 bromodragonFly, 182–183 bromosafrole, 210 bronchitis, 182 broom, 321 brotizolam, 213, 214, 218, 353, 360 Brugmanisa,sp., 201 bucinnazine, 113 bufotenine, 66, 258, 260, 321 Bulgaria, 276 buprenorphine, 4, 9, 25, 156–158, 278–279, 294–295, 296, 298, 353, 360 butanamine, 106, 137, 177, 182, 209, 327 butane, 72, 298, 335 butanediol, 42, 68, 148, 270–271, 335, 354, 360, 367 butobarbital, 86, 301 butorphanol, 277–278 butyl nitrite, 50 butyric acids aminobutyric acid (GABA), 212, 269–271, 320 GHB, 270–271 phenylbutyric acid, 271–272 butyrolactone (GBL), 137, 270–271, 304, 325, 354, 360, 365, 367 butyrylfentanyl (IBF), 380–382

Subject Index

Caapi, 321 caffeine, 49, 52, 106, 288, 339, 341– 342, 364 Cahn–Ingold–Prelog (CIP) rule, 74 calamus root, 321 calusterone, 368 camazepam, 214 camfetamine, 191–192 Canada, 146, 149 cancer, 44, 51, 82, 178–179, 191, 229, 297, 336 cannabimimetics, 124, 166, 234– 235, 239, 248 cannabis controls, 224–226 cannabis cultivation, 19, 22, 222, 227–228, 232, 315 cannabis medicinal, 229–232 cannabis potency, 33, 35, 227–228 cannabis resin, 9,10,25,47,354, 363, 376 cannabis classifications, 31, 33 cannabis controls, 224 cannabis medicinal, 230–232 cannabis potency, 228 common terms, 63 definitions, 221–222 Drugs Act 2005, 47 hash oil, 226–227 legislation in the UK, 54 opium, 316 Cannabis sativa, 154, 220–221, 316 cannabis seeds, 222 cannabivarins, 224–225 Captagon tablets, 174 carbomethoxytropinone, 157–158, 252 carbonyldiimidazole, 263 carboxylic acid, 93, 100–103, 155, 194, 214, 225, 324, 329, 344 oxiranecarboxylic acid, 326 piperidinecarboxylic acid, 380 carfentanil, 21, 66, 94, 96–97, 350, 353, 360, 380 carisoprodol, 187 catalepsis, 117 Catha edulis. see khat

Subject Index

cathine, 9, 75, 342–343, 353, 360 cathinone derivatives, 88, 89 cathinones, 81,137–138, 367 benzylcathinone, 91 chemical aspects, 170 derivatives, 88, 90 ethcathinone, 73 ethynylcyclohexanol, 190 fluoromethcathinone, 168 isocathinones, 188–190 methcathinone, 41, 63, 73, 88, 89, 106, 170, 182, 353, 360 methylenedioxycathinone, 88, 170 methylmethcathinone, 58, 63, 88, 90, 136, 138, 312, 354–355 phenyloxazoline derivatives, 192-193 Switzerland, 131 central nervous system (CNS), 73, 80, 111, 122, 165–176, 179, 205, 208–209, 212, 251 Cesamet, 228 charas, 63, 221 chat, 342 chat rooms, 8, 112 chavibetol, 344 chavicol, 344 hydroxychavicol, 344 chemical aspects, 169–171 chemical weapons, 331–332, 334–335 Chemical Weapons Act 1996, 334 childbirth, 52 China, 134, 182 Chinese medicine, 182, 208, 320 chloral hydrate, 212 chlordiazepoxide, 212, 214 chlorodiazepam, 214, 217 chloroephedrine, 324 chloroform, 155, 221, 377 chloromethandienone, 368 chlorophenylpiperazine, 313 chlorophyll, 227 chloropseudoephedrine, 324

387

chlorphentermine, 30 cholestane, 62 chromatography, 75, 168, 223, 264 cinazepam, 218 cinnamoylcocaine, 252 cinnamylpiperazine, 113 clandestine laboratories, 11, 69, 112, 205, 207, 252, 263, 374 Claviceps paspali, 333 Claviceps purpurea, 263, 333 clenbuterol, 84, 353, 368 clephedrone, 89 clobazam, 214, 231 clobenzorex, 175 clobromazolam, 218 clomethiazole, 212 clonazepam, 214 clonazolam, 194, 196, 214, 217 cloniprazepam, 218 clonitazene, 241, 243 clorazepate, 59, 60, 214 clorazepic acid, 59, 60 clostebol, 368 clotiazepam, 214, 218, 218 cloxazolam, 214 clozapine, 218 cobalt thiocyanate, 253, 377 coca, 1, 20, 251, 253–254, 315 coca tea, 253 cocaethylene, 92–93, 252 cocaine hydrochloride, 23, 72, 251– 253, 287, 363 codeine, 9, 80, 351 acetylcodeine, 274 acetyldihydrocodeine, 308 dihydrocodeine, 4, 9, 70–71, 275, 309, 351 drug misuse in England and Wales, 4 ethers, 70 lethal toxicity, 303 morphine derivatives, 99, 164 nicotinoyldihydrocodeine, 308 norcodeine, 351 opiates, 275, 277, 316–317 coffee, 339, 341–342

388

Colombia, 201 commercial quantity defined, 46 Communities and Public Policy, 27, 331 Consumer Protection Act 1987, 335 control status, 239,240,249 Controlled Substances Analogue Enforcement Act, 15, 146, 148 controlling natural products, 320, 321 Corydalis sp., 320 Corynanthe johimbe, 321 Cozart cocaine test, 376 crack houses, 54 crank, 61, 63 Crime and Courts Act 2013, 55 Crime and Disorder Act 1998, 54 Criminal Justice (International Cooperation) Act 1990, 55, 325 Criminal Justice Act 2003, 32, 54 Criminal Justice and Police Act 2001, 54 Criminal Law Act (1977), 222 crocodile, 153 cropamide, 193 crotetamide, 193 crotonylfentanyl, 382 crude oil, 156 crystal meth, 61, 63, 207 cultivation, 9–10, 22 cannabis, 19, 22, 222, 227–228, 232, 315 magic mushrooms, 318 Customs and Excise Management Act 1979, 41, 54 cutting agents, 23, 55, 206–207, 252, 297, 310, 333 cyanide, 50 cyclidines benocyclidine, 120–121 eticyclidine, 116, 259, 352 methoxyphencyclidine, 194 phencyclidine, 116, 120, 126, 128, 196–197, 325, 326, 352, 355, 359 rolicyclidine, 116–117, 359

Subject Index

tenocyclidine, 116–117, 352, 359 cyclizine, 113–114 cyclobarbital, 85, 86 cyclohexylbenzamide, 197 cyclohexylphenols, 234 cyclopentanepropionate, 70 cyclopropane, 97 cyclopropylfentanyl, 96–97, 350, 381–382 cypionate, 70 cystolithic hairs, 221 cytisine, 321 Cytisus scoparius, 321 danazol, 69, 369 Dangerous Drugs Acts, 18–19, 100, 164, 221, 333 Datura stramonium, 321 DEA laboratories, 88, 170 dehydroepiandrosterone (DHEA), 84 delorazepam, 214 Denmark, 188, 278, 381 deschloroetizolam, 217 designer drugs, 11, 14–15, 48, 70, 122, 144, 148, 165, 168, 311 desmethylfentanyl, 381 desmethylflunitrazepam, 218 desmethylprodine, 99, 101, 103, 165 desmethyltramadol, 355, 361, 366 desomorphine, 153, 277–278 desoxyephedrine, 61 desoxymethyltestosterone, 369 desoxypipradrol, 48, 122, 367 deuterium, 76–77 dexamfetamine, 10, 61 dexamphetamine, 29, 352, 362 dextrorphan, 75 dextromethorphan, 75, 276–277 dextropropoxyphene, 41, 352, 359 dextrose, 74 diacetylmorphine, 63, 155, 164, 274–275, 620 diagnostic kits, 307 dialkyl derivatives, 64

Subject Index

diamorphine, 41, 58, 62, 63, 65, 66, 163-164 analysis, 286 derivatives, 155 esters, 69 forensic science, 42 heroin, 274 low dosages, 310 purity, 283 diazepam, 212–213, 214, 288, 304–305 dibenzopyrans, 223, 234 dibenzoylmorphine, 164 dichloroethylphenidate, 142, 357, 361 dichloromethylphenidate, 142, 356–357, 361 dichloropane, 254 diclazepam, 194, 196, 214, 217 diethylamine, 263, 325 diethylbarbituric acid, 86 diethylethanamine, 200 diethylpropion, 60, 88–89, 182, 352, 359 diethyltryptamine, 66, 147–148, 260 difenoxin, 103, 308, 352, 359 difludiazepam, 218 difluoromodafinil, 186 dihydrocodeine, 4, 9, 70–71, 245, 275, 308, 309, 351 dihydrodesoxymorphine, 277 dihydroetorphine, 354, 360 dihydrofuranone, 270 dihydromorphine, 70–71, 275 diltiazem, 252, 288 dimenoxadole, 60 dimethocaine, 150, 254–255 dimethoxyamphetamine, 63 dimethoxybenzylpiperazine, 114 dimethoxyphenethylamine, 147, 151 dimethylamphetamine, 175, 328, 372 dimethylbenzaldehyde, 221, 253 dimethylmethanamine, 217 dimethylterephthalate, 288

389

dimethyltryptamine, 9, 19, 23, 66, 128–130, 147–150, 191–192, 260– 263, 318–319, 364 dimethyltryptamine (DMT), 191– 192, 364 analogues in USA, 147–149 code names, 62 lysergide derivatives, 263 New Zealand, 129–130 penalties under MDAct, 23 plant tryptamines, 319 TiHKAL substance, 258–259, 260 dinitrophenol, 186, 334 diphenylbarbituric acid, 86 diphenylmethylpiperazine, 48, 113 diphenylmethylpiperidine, 48 diphenylpyrazine, 188, 190 Diplopterys cabrerana, 320 discrete dosage unit defined, 46 dopamine, 107, 141, 191, 193–194, 206, 208, 210, 320, 341 dopaminergic, 252, 277, 341 dope, 63, 221 dothiepin, 304 Dravet syndrome, 231 dronabinol, 10, 229–232, 240, 240 drostanolone, 368 drotebanol, 351, 359 drug harm in UK, 295–296 drug intermediates, 329 Drug Misuse and Trafficking Act 1985, 46, 55, 133–134 Drug Misuse in England and Wales, 2-5 drug prices, 288–290 drug production ecstasy, 326 methadone, 329 UN Conventions 1971, 327–328 UN Conventions 1988, 326–328 drug seizures, 2–5, 108, 113, 173, 177–178, 289, 378 Drug Testing and Treatment Orders (DTTOs), 54

390

Drug Trafficking Act 1994, 54 drug-detection systems, 307 Drugs (Prevention of Misuse) Act 1964 (DPMA), 19, 29–30 Drugs Act 2005, 26, 46, 65, 315, 316, 318–319, 362 drugs ratchet, 35 Drugs, Poisons and Controlled Substances Act 1981, 333 DrugScience, 231, 296, 379 Duquenois test, 221, 377 Early Warning System (EWS), 8, 12–13, 166, 213, 260, 311–314, 320 ecgonine, 80, 81, 92–93, 153–154, 157, 252–253, 329 benzoylecgonine, 92–93, 251–252 methylecgonine, 157–158 Echinopsis peruviana, 319 ecstasy, 3–5, 63, 137, 166 amphetamines, 205 analysis, 295 arylcyclohexylamines, 117 benzylpiperazines, 112 drug prices, 288 drug production, 326 European Union, 11 GHB, 269 MDAct reviews, 25–28 MDMA, 33–34, 209 methylamphetamine, 207 New Zealand drug harm, 300 penalties under MDAct, 21–23 phenethylamines, 109–110, 179 phenyl-substituted alkanes, 62 scale of harm ACMD, 294 tobacco, 340 UK survey, 296, 298 Edgewood Arsenal, USA, 334 Ehrlich's reagent, 221, 253, 264 electronic cigarettes, 221, 232 empathogens, 106, 165, 170, 173, 209

Subject Index

endocannabinoid reuptake, 246 enestebol, 368 entactogens, 58, 106, 111, 165, 209, 260 Ephedra distachyia, 328 Ephedra vulgaris, 182, 208, 328 ephedrines, 174, 324 acetylephedrine, 328 chloroephedrine, 324 chloropseudoephedrine, 324 desoxyephedrine, 61 fluoroephedrine, 168, 184 methylephedrine, 193, 328 norephedrine, 75, 206, 324, 342 norpseudoephedrine, 75, 206, 343 pseudoephedrine, 75, 182–184, 208, 324, 325, 328 Epidyolex, 224, 231, 366 epilepsy, 10, 229 epitiostanol, 368 Epsom salts, 282 ergolines, 158–160 ergometrine, 158–160, 263, 265, 324 ergonovine, 158–159 ergot fungus, 74, 263–264, 333 ergotamine, 263, 324, 332 Erythroxylon coca, 20, 251, 253, 316 Erythroxylum coca. see Erythroxylon coca esketamine, 117 estazolam, 214 esters, 69–70 estragole, 344 etamivan, 193 etaqualone, 188–189 etazene, 199–200 ethanamine, 61, 87, 111, 155, 183, 195, 201, 205–206 ethane, 73 phenylethane, 128 ethcathinone, 73 ethchlorvynol, 352, 359 ethers, 70–71 ethinamate, 190–191, 352, 359

Subject Index

Ethiopia, 342 ethyl ether, 70–71, 325 ethylamphetamine, 60, 61, 106, 175, 353, 360 ethylhexedrone, 89 ethylidene diacetate, 328 ethylmorphine, 70–71, 164, 308, 351 ethylnaphthidate, 140, 357, 361 ethylnorpentylone, 89 ethyloestrenol, 60, 368 ethylone, 89 ethynylcyclohexanol, 190–191 ethynylcyclohexanolcarbamate, 191–192 ethynylcyclohexaol, 191 eticyclidine, 116, 259, 352 etilamfetamine, 60 etizolam, 213, 215, 217, 366 etodesnitazene, 200 etonitazene, 145, 170, 199, 241, 243 etorphine, 153, 275, 329 etryptamine, 66, 258, 260, 353, 360 EU Action Plan on Drugs, 11 EU Member States, 12 eugenol, 344 European Centre for Disease Prevention and Control, 14 European Chemicals Agency, 14 European Food Safety Authority, 14 European Union, 11–14 Eve, 63 Expert Advisory Committee on Drugs (EACD), 15 Expert Committee on Drug Dependence (ECDD), 25, 168, 199, 239, 277, 291, 341, 343 exportation, 41, 54, 308, 316 failed pharmaceuticals, 8, 88, 111, 163, 165 fatal poisoning, 8, 84, 169, 208, 300– 301–304, 335 fatal toxicity, 10, 26, 44, 170, 235, 300–305, 301, 302–303, 305 Federal Analogue Act, 146–147, 149–150

391

fenazepam, 213 fencamfamin, 29, 30, 191, 351, 353, 360 fencamine, 175 fenethylline, 60, 174, 175, 353, 360 fenetylline. see fenethylline fenproporex, 175, 353, 360 fentanils alfentanil, 66, 94, 352, 359 carfentanil, 21, 66, 94, 96–97, 350, 353, 360, 380 lofentanil, 66, 94–95, 353, 360 ocfentanil, 380 remifentanil, 95–96, 354, 360 sufentanil, 66, 94–95, 352, 359 fentanyls, 94–99, 149, 170, 324, 353, 366, 380, 381 acetylbenzylfentanyl, 382 acetylfentanyl, 381 acryloylfentanyl, 96–97, 350, 380–381 benzodioxolefentanyl, 381 benzoylbenzylfentanyl, 382 benzoylfentanyl, 381 butyrylfentanyl (IBF), 380– 382 China, 134 crotonylfentanyl, 382 cyclopropylfentanyl, 96–97, 350, 380, 382 derivatives from the 80's, 165 desmethylfentanyl, 381 drug misuse in England and Wales, 4 fluorofentanyl, 168, 381 fluoroisobutyrylfentanyl, 97 fluoromethoxyacetylfentanyl, 58, 382 furanylfentanyl, 96, 98, 350, 380, 381–382 hydroxybutyrylfentanyl, 382 isobutyrylfentanyl, 381 lethal toxicity, 304 methoxyacetylfentanyl, 96, 98, 350, 380–381 methylcrotonylfentanyl, 382

392

methylfentanyl, 96, 165, 380–381 New Zealand, 150 opium, 277 penalties under MDAct, 21 phenylpropanoylfentanyl, 381 tetrahydrofuranylfentanyl, 98, 381 tetramethylcyclopropanefentanyl, 382 thiophenefentanyl, 382 valerylfentanyl, 381 fexofenadine, 122–123 field test, 253, 275, 376 fladrafinil, 186 flualprazolam, 213, 215, 217, 218, 358, 361 flubromazepam, 217 flubromazolam, 168, 194, 196, 215, 217 fludiazepam, 215 flunitrazepam, 41, 213, 214–215, 303, 377 desmethylflunitrazepam, 218 flunitrazolam, 218, 358 fluonitazene, 199–200 fluoroamphetamine, 168, 328 fluorobenzoic acid, 254 fluorococaine, 254 fluoroephedrine, 168, 184 fluoroethylphenidate, 143, 357, 361 fluorofentanyl, 168, 381 fluoroisobutyrylfentanyl, 97 fluoromethamphetamine, 168 fluoromethcathinone, 168 fluoromethoxyacetylfentanyl, 58, 382 fluoromethylphenidate, 143, 357, 361 fluoromodafinil, 186 fluorophenmetrazine, 168, 194, 197 fluorophenylpiperazine, 168 fluorotropacocain, 150, 168, 254 fluoxymesterone, 368 flurazepam, 214–215 fly agaric, 321

Subject Index

fonazepam, 217–218 forensic laboratories, 13, 136–137, 241, 246, 282, 288, 376 forensic science, 41–42 Forensic Science Service, 283, 284, 286, 287 formamide, 205–206, 325 methylformamide, 325 formic acid, 206, 332–333, 374 fructose, 74 fungi, 42, 69, 315, 316, 318–320 furanylfentanyl, 96, 98, 350, 380, 381–382 furazabol, 368 gabapentin, 4, 20, 358, 361, 366 gamma-OH, 269 ganja, 63, 221 gas chromatography, 223 Geneva Convention of 1931, 65 geranium extract, 185 Germany, 15, 131–133, 177, 188, 205, 218, 234, 375, 381–382 gestrinone, 369 GHB, 269–270, 349–360, 365–366 alcohol, 269 analogues in the USA, 148 butyric acid, 270–271 ecstasy, 269 lethal toxicity, 303, 304 misuse of Drug Act 1971, 20 Netherlands study, 295 UK survey, 298–299 glandular trichomes, 221 glaucine, 276–277 Glaucium flavum, 276 Glauvent, 276 Global Smart Programme, 12 glucocorticosteroids, 336 glucose, 206, 252, 288, 310 glutethimide, 352, 359 glycidic acid, 210, 324, 326 grass, 221 Green List of Controlled drugs, 282 growth hormones, 84, 368 guvacine, 344

Subject Index

GW Pharmaceuticals, 229 Gymnopilus sp., 318 halazepam, 215 hallucinations, 15, 187, 260 halothane, 336 haloxazolam, 215 hard drugs, 31, 228 harmaline, 260, 321 Harmful Substances Act, 331 harmine, 260, 321 hash, 63, 220–221, 226–227, 232 hash oil, 220, 226–227, 232 Hawaiian baby woodrose, 320 head shops, 53, 112, 234 Healthcare Products Regulatory Agency (MHRA), 111, 213, 229, 311–312, 321, 379 Hebrew University, Jerusalem, 235 helium, 336 hemp, 18, 63, 221, 232 henbane, 321 heptaminol, 193 high potency cannabis, 33, 35, 227–228 Hofmann, Albert, 263–264 Home Affairs Select Committee, 26–27 homoamphetamine, 177 horse, 63, 274 Huffman, J. W., 235 hydrochloric acid, 252, 324, 325, 332, 375, 377 hydrocodone, 65, 66 hydrogen peroxide, 374 hydromorphone, 65, 66, 68 hydroxyamphetamine, 107, 175, 206 hydroxybutyric acid, 269, 271 hydroxybutyrylfentanyl, 382 hydroxychavicol, 344 hydroxycocaine, 254 hydroxymitragynine, 320 hydroxypentanoic acid, 271–272 hydroxypethidine, 104 hydroxyphenazepam, 217–218 hydroxytenamfetamine, 63

393

hydroxytenamphetamine, 87 hydroxyvaleric acid, 271 hyoscine, 201, 251, 254, 321 hyoscyamine, 251, 321 Hyoscyamus niger, 321 hypothermia, 274 hypoxia, 52 iboga, 321 ibogaine, 151, 257, 260, 320, 321 ice, 61, 63, 63, 204, 204, 207 illicit laboratories, 208, 287 importation, 48, 336 analysis, 287 coca leaf, 254 cutting agents, 310 forensic science, 41 homologues, 73 legislation in UK, 54 low dosages, 308 opium, 316 penalties under MDAct, 22 psilocin, 318 Psychoactive Substances Act 2016, 49 purity, 283–284 scale of harm ACMD, 292 inactive metabolites, 31, 264 incense, 234 indanylalkylamines, 178–179 Indian hemp. see hemp indictable quantity defined, 46 indometacin, 241, 243 Inocybe sp., 318 insecticidal poisons, 332 International Cooperation Act 1990, 55, 325 International Non-proprietary Name (INN), 59, 60, 61, 63, 229 International Opium Convention of 1912, 153, 163 international surveys, 299–300 Intoxicating Substances (Supply) Act 1985, 51–52, 335 intrinsic toxicity, 86, 300–301, 303 iodoamphetamine, 372

394

iodothyronamine, 109–110 ipecacuanha root, 308, 316 Ipomoea sp., 319 Ireland, 2, 15, 127, 188, 287, 381 isobutyl nitrite, 50–51, 73 isocathinones, 188–190 isometheptene, 193 isopentedrone, 188 isopropyl nitrite, 50–51, 73 isopropylphenidate, 141, 356–357, 361 isopropyltryptamine, 261 isosafrole, 210, 324, 326, 374–375 isotonitazene, 195, 199, 350 isotopes, 68–77 isotryptamine, 139 Israel, 130–131 Hebrew University, Jerusalem, 235 Italy, 146, 246, 380, 382 Ivory Wave, 48, 367 Japan, 207 Jerusalem Hebrew University, 235 jet lag, 261 jimson weed, 321 Jin Bu Huan, 320 joint action, 11, 169 kaolin, 309 kava kava, 320, 321 kavalactones, 320, 321 kawain, 151, 320 Kendall's rank correlation, 296 Kenya, 342 kerosene, 156, 252 Ketalar, 117 ketamine, 138, 249, 354, 356, 360, 366–367 arylcyclohexylamines, 116–118 benzylphenethylamines, 86 drug misuse in England and Wales, 3, 5 drug prices, 289 lethal toxicity, 303 Netherlands study, 297

Subject Index

phenethylamines, 183 scale of harm ACMD, 292–293 UK survey, 297–299 ketazolam, 215 ketobemidone, 105 ketum, 321 khat, 342–343, 356, 361, 366, 373 alcohol, 339, 343 isocathinones, 188 Misuse of Drugs Act 1971, 20 Netherlands study, 295 opium, 316 scale of harm ACMD, 293 UK survey, 296, 298 World Health Organization (WHO), 343 krathom, 321 kratom, 320, 321 laboratories, 44, 86, 137–138, 163, 168, 309, 328 academic, 8, 163 clandestine, 11, 69, 112, 205, 207, 252, 263, 374 DEA, 88, 170 forensic, 13, 136–137, 241, 246, 282, 288, 376 illicit, 208, 287 Sandoz, 263 toxicology, 13 lactose, 288 laevulose, 74 large commercial quantity defined, 46 larocaine, 255 Latvia, 106, 146, 380, 382 lefetamine, 352, 359 legal highs, 28, 47, 63, 162, 170, 185, 254, 344 Lennon, John, 19 Lennox–Gastaut syndrome, 231 lethal toxicity, 301 alcohol, 303 codeine, 303 fentanyl, 304 GHB, 303, 304

Subject Index

ketamine, 303 methadone, 303, 304 synthetic cannabinoid receptor agonists (SCRAs), 304 Leuckart method, 205–206, 208, 210 levamfetamine, 10, 61 levamisole, 252 levomethorphan, 65, 66, 75, 276 levonantradol, 243, 245 levorphanol, 65, 66, 75 lewisites, 334 liberty cap mushroom, 318 Librium, 212 lignocaine, 288 liquid ecstasy, 269 lisdexamphetamine, 175, 356, 361, 366 lofentanil, 66, 94–95, 353, 360 loflazepate, 215 Lophophora williamsii, 319 lorazepam, 215 lormetazepam, 215 losartan, 241, 243 low dosages, 308, 309–310 Luxembourg, 14, 186 lysergamide, 19, 80–81, 257–267 derivatives, 99 diagnostic kits, 307 dialkyl derivatives, 64 drug intermediates, 329 ergolines, 158–160 morning glory seeds, 319 poisons, 333 lysergic acid methylpropylamide (LAMPA), 264 lysergide derivatives, 263–264 Ma Huang, 182, 208 magic mushrooms, 3, 26, 34, 46, 69, 111, 295–296, 299, 318–319 magnesium sulfate, 282, 288 Mandragora officinarum, 321 mandrake, 321 Mandrax, 188 mannitol, 288 Marquis field test, 253, 275

395

mass spectrometry, 77, 109, 137, 168 mazindol, 352, 359 MDEA, 11, 63, 73, 106, 209 mebolazine, 368 meclonazepam, 217 mecloqualone, 188–189, 352, 359 medazepam, 215 mefenorex, 175, 353, 360 melanotan, 187 melatonin, 258, 261 meow meow, 63 meperidines, 63, 99, 149, 165 trimeperidine, 66, 105 mephedrone, 24, 63, 136, 138, 349, 354, 367 cathinone derivatives, 88, 89 drug misuse in England and Wales, 3, 5 medicines, 312–313 phenethylamines, 107 precautionary principle, 34 scale of harm by users, 299 UK survey, 298, 299 mephentermine, 30, 371 mepitiostane, 368 meprobamate, 187, 352, 360 Merck Chemical Company, 165, 209–210 mercuric chloride, 374 mercury, 333187 mesabolone, 368 mescal beans, 321 mescaline, 19, 66, 79, 87, 105–106, 155, 319 mesocarb, 174, 353, 360 mestanolone, 369 mesterolone, 369 metamfetamine, 10, 59, 60, 63 metandienone, 60 metenolone, 60 methadone, 9, 63 alcohol, 339 drug misuse in England and Wales, 3, 4, 5 drug production, 329 lethal toxicity, 303, 304

396

MDAct reviews, 25 Netherlands Study, 295 opium, 278 scale of harm ACMD, 294 UK survey, 298 methadyl acetate, 60, 66 methanamine, 183 methanandamide, 235 methandienone, 60, 369 methandriol, 369 methane, 73, 155, 241–242 trichloromethane, 155 methaqualone, 25, 36, 128–129, 150, 188–189, 324–325, 352, 359 methylmethaqualone, 188–189 methcathinone, 41, 63, 73, 88, 89, 106, 170, 182, 353, 360 Methedrine, 311 methenolone, 60, 369 methiopropamine, 47, 47, 357–358, 361, 366 methoxetamine, 47, 117–118, 350, 355, 360, 366 methoxyacetylfentanyl, 96, 98, 350, 380–381 methoxyamphetamine (PMA), 106, 111, 169, 304 methoxymethylamphetamine, 106, 108–109 methoxyphenamine, 105, 107–109 methoxyphencyclidine, 194 methyl alpha-phenylacetoacetate (MAPA), 324, 328 methylaminopropane, 61, 178 methylaminorex, 75, 192–193, 353, 360 methylbarbituric acid, 85 methylbenzoate, 248, 253 methylbutyl nitrite, 50 methylcellulose, 308 methylcrotonylfentanyl, 382 methylcyclopropanamine, 363 methylecgonine, 157–158 methylenedioxyamphetamine, 62, 73, 209–210, 326 methylenedioxycathinone, 88, 170

Subject Index

methylenedioxyethylamphetamine, 63, 73, 209 methylenedioxymethylamfetamine, 209 methylenedioxymethylamphetamine, 63, 107–108, 204, 209, 374 methylephedrine, 193, 328 methylfentanyl, 96, 165, 380–381 methylformamide, 325 methylmethaqualone, 188–189 methylmethcathinone, 58, 63, 88, 90, 136, 138, 312, 354–355 methylmethylphenidate, 143, 357, 361 methylmorphenate, 141, 357, 361, 382 methylmorphine, 164 methylnaphthidate, 141, 356–357, 361 methylone, 59, 64, 89, 149 methylphenethylamine, 60–61, 66, 77–80, 105–106, 165, 176, 352, 359, 372 methylphenidate, 47, 80, 140–143, 169, 295, 296, 356–357, 366 dichloromethylphenidate, 142, 356–357 fluoromethylphenidate, 357, 361 methylmethylphenidate, 143, 357, 361 methylphenobarbital, 60, 86 methylphenobarbitone, 60, 85, 352 methylphenylpiperazine, 112 methylpiperazine, 112–116 methylpropyl nitrite, 50 methyltestosterone, 369 methylthienylpropamine, 178 methylthioamphetamine, 110, 169 methyprylone, 60, 352, 360 methysergide, 158–159, 265 metizolam, 217 metodesnitazene, 199, 201 metonitazene, 199 metribolone, 369 Mexican sage, 321 mibolerone, 369 microdots, 263, 288

Subject Index

microwave method, 253 midazolam, 212–213, 215, 353, 369 Mimosa hostilis, 319 miraa, 342 Misuse of Drugs Act 1971, 15, 19–21, 127, 134 Mitragyna speciosa, 320, 321 mitragynine, 151, 320, 321 hydroxymitragynine, 320 modafinil, 186 difluoromodafinil, 186 fluoromodafinil, 186 Molipaxin, 314 money laundering, 10 monoacetylmorphine, 69, 155, 274 monoamine oxidase inhibitor (MAOI), 185, 260 moramide, 329 morning glory seeds, 319 morphine sulfate, 273, 308 morphines. see also diamorphine benzylmorphine, 65, 66 diacetylmorphine, 63, 155, 164, 274–275, 620 dihydromorphine, 70–71, 275 ethylmorphine, 70–71, 164, 308, 351 methylmorphine, 164 monoacetylmorphine, 69, 155, 274 nicomorphine, 65, 66, 153 motor function, 15 Multi-criteria Decision Analysis, 295, 297, 339–340 multiple sclerosis, 229 murungu, 342 muscimol, 321 mustards, 334 mutagens, 336 Myristica fragrans, 321 myristicin, 321 nabilone, 65, 228–229, 242, 244–245 nalbuphine, 276 naloxone, 278–279, 366 nandrolone, 369

397

naphthoylindoles, 178, 234 naphthoylpyrroles, 234 naphthylalkylamines, 178–179 naphthylmethylindenes, 234 naphthylpyrovalerone, 88, 91, 131, 355, 367 naphyrone, 91, 178–179, 366–367 narcolepsy, 121, 186, 205, 270 nefazodone, 112 Netherlands, 15, 177, 184, 228–229, 291, 294, 380, 382 Netherlands study, 294–296, 297 neuromodulator, 269 neuroscientists, 43 neurotoxicity, 34, 210 new benzodiazepines, 214, 217, 218 New South Wales, 46, 133–134 new synthetic drugs (NSD), 11, 162, 165, 291 New Zealand, 15, 111, 127–130, 134, 146, 150, 188 New Zealand drug harm, 300 nicocodine, 308 nicodicodine, 36, 308, 351 nicomorphine, 65, 66, 153 Nicorette, 341 nicotine, 119, 207, 332–333, 341 nicotinoyldihydrocodeine, 308 nifoxipam, 217 nightshade, 321 nikethamide, 193 nimetazepam, 215 nitracaine, 255 nitrazepam, 212, 216 nitrazolam, 217 nitric oxide, 51 nitrogen mustards, 334 nitrous oxide, 50, 52–53, 293, 303, 313, 335, 364, 366 NMR analysis, 122, 137, 168 non-steroidal agents, 20, 187 nootropics, 185 noradrenaline, 206, 208, 210, 341 norandrostenedione, 369 norboletone, 369 norclostebol, 369

398

norcodeine, 308, 351 nordazepam, 216 norephedrine, 75, 206, 324, 342 norepinephrine, 141, 341 norethandrolone, 369 noretiocholanolone, 369 norfludiazepam, 218, 358 norpethidine, 101 norpseudoephedrine, 75, 206, 343 nortilidine, 201 noscapine, 274 Nubain, 276 nuclear reactors, 76 nutmeg, 321 obesity, 121 ocfentanil, 380 oleamide, 235 olmesartan, 241, 243 Open General Import Licence (OGIL), 48 open source information, 13 opiates, 275–277, 278 codeine, 275, 277 fentanyl, 277 methadone, 278 World Health Organization (WHO), 277 opium cannabis resin, 316 codeine, 316–317 importation, 316 khat, 316 psilocin, 316 opium granulated, 20, 316 opium medicinal, 20, 308, 315–316 opium poppy, 20, 22, 273, 315–317, 363–364 opium raw, 20, 315–316 Oramorph, 273 organophosphorus, 333 oripavine, 275, 329, 354, 360, 367 ostarine, 191–192 ovandrotone, 369 oxabolone, 369 oxazepam, 216

Subject Index

oxazolam, 216 oxilofrine, 193 oxiranecarboxylic acid, 326 oxybate, 269 oxycodone, 4, 66, 275, 276 Oxycontin, 275 oxymesterone, 369 oxymetholone, 369 palm tree, 320, 343 Panaeolus sp., 318 Papaver somniferum. see opium poppy papaverine, 274 paracetamol, 288, 364 paraffin, 156, 252 parahexyl, 224–225, 240 paraquat, 333 Parkinson's disease, 165, 182, 278 Parliamentary Select Committee on Science and Technology, 26–27 paroxetine, 187 party pills, 15, 162 Passiflora incarnata, 321 passion flower, 321 patterns of use, 13, 251, 342 Pearson's correlation coefficient, 292 pemoline, 9, 29–30, 169, 192–193, 351, 353, 360 penalties under MDAct anabolic steroids, 21 dimethyltryptamine (DMT), 23 ecstasy, 21–23 fentanyl, 21 importation, 22 synthetic cannabinoid receptor agonists (SCRAs), 21 pentazocine, 75, 352, 359 pentedrone, 89 pentobarbital, 85, 86 pentobarbitone, 301 Perdue University, 265 Peruvian torch cactus, 319 pervitin, 61

Subject Index

pethidines, 63, 81, 99–105, 116, 149– 150, 165, 200, 329, 353 anileridine, 66, 102 benzethidine, 66, 102 hydroxypethidine, 104 norpethidine, 101 properidine, 66, 105 trimperidine, 66, 105 peyote cactus, 1, 319 Pfizer, Charles, 236 Phalaris sp., 319 pharmacodynamic properties, 8, 149, 210 pharmacokinetic properties, 8, 76 Pharmacy Act of 1868, 18 Pharmacy and Poisons Act 1933, 74, 333 phenacetin, 288 phenazepam, 48, 213, 216–218, 355, 360, 367 phenazolam, 218 phencyclidine, 116, 120, 126, 128, 196–197, 325, 326, 352, 355, 359 phenethylamines, 106, 175, 177, 178–179, 182, 183 ecstasy, 109–110, 179 ketamine, 183 mephedrone, 107 risk assessment, 106, 109 World Health Organization (WHO), 183 phenibut, 271–272 phenobarbital, 10, 86 phenobarbitone, 288, 301 phentermines, 29, 30, 80, 351–352, 360, 371 chlorphentermine, 30 mephentermine, 30, 371 phenyl-substituted alkanes, 59–62 phenylacetic acid, 206, 323, 324, 328 phenylacetone, 206, 208, 325–326, 375 phenylacetylcarbinol, 328 phenylacetylindoles, 234 phenylbutyric acid, 271–272

399

phenylcyclohexylamine, 68, 81, 116, 118–120, 135, 326, 355 phenylcyclohexanone, 119–121 phenylethane, 128 phenylisopropylamine, 61, 205 phenylmethylpiperidine, 324 phenyloxazoline derivatives, 192 phenylpiperazine, 112–113 phenylpiperidine, 99, 329 phenylpiracetam, 193 phenylpropanoylfentanyl, 381 pholcodine, 70–71, 275, 308, 351 pholedrine, 193 phosphonofluoridates, 334 phosphonothiolates, 334 phosphoramidocyanidates, 334 phthalimidopropiophenone, 91–92 phytocannabinoids, 70, 144, 170, 220–232, 234, 366 PiHKAL substances, 87, 107–111, 144, 170, 178, 182, 257, 370–373, 375 piko, 61 pinazepam, 216 Piper betle, 320, 343 Piper methysticum, 320, 321 piperazines, 14, 111–116, 143, 166, 169, 313, 354 benzylpiperazine (BZP), 14–15, 34, 81, 107, 111–115, 181, 292, 313, 349, 367 chlorophenylpiperazine, 313 cinnamylpiperazine, 113 dimethoxybenzylpiperazine, 114 diphenylmethylpiperazine, 48, 113 fluorophenylpiperazine, 168 methylphenylpiperazine, 112 methylpiperazine, 112–116 phenylpiperazine, 113 trifluoromethylphenylpiperazine (TFMPP), 14–15, 112, 114, 168 piperidine, 94–97, 100–104, 116– 117, 120–123, 134, 143, 196–197, 325

400

piperidinecarboxylic acid, 380 piperidines arylcyclohexylpiperidine, 116 benzylpiperidine, 194, 198 diphenylmethylpiperidine, 48 methanol, 121–122 phenylmethylpiperidine, 324 phenylpiperidine, 99, 329 piperonal, 210, 324 piperonylmethylketone, 326, 374 pipradrol, 36, 48, 68, 81, 121–124, 169 desoxypipradrol, 48, 122, 367 piracetam, 185 placebo, 230 plant growth stimulators, 312 plant tryptamines, 319 poisons, 333–334 Poisons and Pharmacy Act 1908, 18 Poland, 187, 381–382 Police Foundation Independent Enquiry, 291 Police Reform and Social Responsibility Act 2011, 24, 47 Policing and Crime Act 2009, 46 poppers, 50–51, 364. see also alkyl nitrite; amyl nitrite poppy straw, 20, 41–42, 315, 316, 317, 363 yellow horned, 276 positron emission tomography, 88 pot, 63, 221 potassium dichromate, 325 potassium permanganate, 252, 323, 324 Powers of Criminal Courts (Sentencing) Act 2000, 54 prasterone, 369 prazepam, 216 precautionary principle, 8, 14, 20, 32, 34–35, 137 pregabalin, 4, 20, 304, 358, 361, 366 prescription pain killers, 299 procaine, 252, 255, 288 Proceeds of Crime Act 2002, 23

Subject Index

prodines, 99–105 allylprodine, 66, 101 alphameprodine, 66, 104 alphaprodine, 66, 81, 102 desmethylprodine, 99, 101, 103, 165 proglumetacin, 241, 243 prolintane, 29, 29, 351 pronethanol, 178–179 propane, 73, 176, 177 aminopropane, 61, 178–179 cyclopropane, 97 methylaminopropane, 61, 178 propellants, 335 properidine, 66, 105 propetandrol, 369 propiram, 351, 359 propylamphetamine, 175 propylhexedrine, 29, 353, 360–361 propylphenidate, 142, 356–357, 361 protium, 76 pseudoephedrine, 75, 182–184, 208, 324, 325, 328 psilocin, 65, 66, 318–319, 362 esters, 69 forensic science, 42 importation, 318 opium, 316 peyote, 319 precautionary principle, 34 scientific research, 44 TiHKAL substances, 258 tryptamines, 260 Psilocybe cubensis, 318 Psilocybe semilanceata, 318 Psilocybe sp., 69, 298, 316 psilocybin, 42–44, 68–69, 111, 260, 263, 303, 318 Psychoactive Substances Act 2016, 15, 27, 48–53, 131, 193, 248, 293, 312, 364–365 Psychotria viridis, 319, 364 public health, 11, 13–14, 28, 170, 199, 300 purity, 282–284 pyrazolam, 217

Subject Index

pyrovalerone, 88–89, 91–92, 353, 360 pyrrolidinylmethanol, 121–122 qat, 342 quinalbarbitone, 10, 60, 86, 301 quinbolone, 369 radiotracer, 88 rasagiline, 130, 182 rat fundus, 192 REACH project, 336 remifentanil, 95–96, 354, 360 reproductive toxicity, 336 RH-34, 199–200 rimonabant, 186 risk assessment, 147, 169, 239, 349–350 alcohol, 339 caffeine, 342 European Union, 11–14 MDAct reviews, 25 medicines, 313 methylamphetamine, 207 phenethylamines, 106, 109 precautionary principle, 34–35 scale of harm ACMD, 292 ritalin. see methylphenidate Rivea corymbosa, 264 Road Traffic Act 1988, 55, 340 rolicyclidine, 116–117, 359 Rolleston Committee, 18 room odorisers, 234 rotundine, 320 roxibolone, 369 Royal Commission, 27 Royal Pharmaceutical Society of Great Britain (RPSGB), 50, 378 Royal Society for Public Health, 28 Royal Society of Arts, 27–28 RSA Commission on Illegal Drugs, 331 Runciman Committee, 25 Russia, 153, 194, 213, 277, 336 safety ratio, 303 safroles, 210, 324, 326, 374–375 bromodihydrosafrole, 210

401

bromosafrole, 210 isosafrole, 210, 324, 326, 374–375 Salvia divinorum, 151, 194, 320, 321 salvinorin, 151, 194, 198, 320, 321 Sandoz laboratory, 263 Sativex, 229, 231, 366 scale of harm ACMD, 299–300 alcohol, 292, 294 ecstasy, 294 importation, 292 ketamine, 292–293 khat, 293 methadone, 294 risk assessment, 292 schizophrenia, 32, 44, 206, 208 scientific research, 42–44 scopolamine, 201, 251, 254 Scotland, 2–3, 229–230, 270, 287, 351 Scottish Records Office, 4 secbutabarbital, 86 secobarbital, 10, 60, 85–86 Second World War, 165 selegiline, 193, 208 semi-synthetic opiates, 18, 153 Serious Crime Act 2007, 55, 310 Serious Crime Act 2015, 55, 310 serotonin, 34, 199, 210, 261–263 shabu, 61 Shanghai Opium Commission, 18, 163 sibutramine, 186, 193, 208 Sigma-Aldrich, 246 signal management, 13 silandrone, 369 sildenafil, 187, 311 Simon test, 377 sinsemilla, 32, 228 skag, 63 skin patch, 94 skunk, 32, 228, 299 Slovenia, 186, 381–382 smack, 63, 274 small quantity defined, 46 sodium bicarbonate, 253, 288

402

sodium hydroxide, 253, 270 sodium pentothal, 84 soft drugs, 31 Somalia, 342 somatomax, 269 Sophora secundiflora, 321 South Africa, 146, 149–150 Spain, 75 sparteine, 321 specific issues with definitions, 139 anabolic steroids, 144 cathinones, 137–138 ketamine, 138 mephedrone, 138 synthetic cannabinoid receptor agonists (SCRAs), 144 speed, 61, 63 Spice, 21, 234, 249, 289, 344 spot test, 375 spray paint, 335 stanolone, 60, 369 androstanolone, 60 drostanolone, 368 mestanolone, 369 stanozolol, 362, 369 steep dose–response curve, 269 stenbolone, 369 Stephania sp., 320 stereoisomers, 75–76 steroids. see also anabolic steroids androgenic, 68, 70, 81, 82–84, 119, 311, 368 glucocorticosteroids, 336 non-steroidal agents, 20, 187 sufentanil, 66, 94–95, 352, 359 sugar cane, 23 sulfur mustards, 334 sulfuric acid, 252, 324, 325, 377 Sunosi, 186, 365 Sweden, 77, 186, 188, 191–2, 194, 197, 218, 255, 267, 381–382 Switzerland, 131 synthetic cannabinoid receptor agonists (SCRAs), 81, 136, 144, 166, 171, 234–249, 360, 365 drug prices, 288, 289

Subject Index

homologues, 73 lethal toxicity, 304 penalties under MDAct, 21 Tabernanthe iboga, 320, 321 tachycardia, 205, 208, 252 tapentadol, 355, 360, 367 tar, 341 tea, 23, 341–342 Abyssinian, 342 Arabian, 342 coca, 253 telmisartan, 241, 243 temazepam, 41, 216, 292 Temporary Class Drug Orders (TCDO), 27, 47–49, 53, 357, 365 tenamfetamine, 62, 63 tenamphetamine, 60, 62, 63, 87, 353, 360 tenocyclidine, 116–117, 352, 359 terfenadine, 123 testes, 311 testosterone, 70, 81–83, 311, 369 desoxymethyltestosterone, 369 methyltestosterone, 369 tetrahydrocannabinol (THC), 9–10, 32, 69, 80, 149, 155, 170, 207, 220–232, 285 tetrahydrocannabinolic acid (THCA), 223, 225 tetrahydrocannabivarin (THCV), 224–226 tetrahydrofuranylfentanyl, 98, 381 tetrahydrogestrinone, 369 tetrahydropalmatine, 320 tetramethylcyclopropanefentanyl, 382 tetramisole, 252 tetrazepam, 216 thebacon, 65, 66, 68 thebaine, 153, 156–157 theobromine, 341 therapeutic index, 300 therapeutic value, 7, 9, 11, 42, 44, 225, 263, 275 thienotriazolodiazepine, 218

Subject Index

thiobarbiturates, 84 thiobarbituric acid, 85 thiomesterone, 369 thionordazepam, 218 thiopentone, 84–85 thiophenefentanyl, 382 thiophenylalkylamines, 178 thiophenylamphetamine, 178 thorn apple, 321 TiHKAL substances, 166, 257–261, 264–265 tiletamine, 117–118, 120, 126 tilidate, 60, 352, 359 tilidine, 60, 352, 359 nortilidine, 201 tocopheryl, 232, 234 tolperisone, 73–74 toluene, 325, 335 toluidine, 325 toxic doses, 303 toxicology laboratories, 13 toxicovigilance, 13 trafficable quantity, 46 tramadol, 4, 356, 361, 366 trazodone, 112, 314 trenbolone, 369 triazolam, 216 trichloromethane, 155 Trichocereus peruvianus, 319 trifluoromethylphenylpiperazine (TFMPP), 14–15, 112, 114, 168 trilostane, 82–83 trimeperidine, 66, 105 tritium, 76 troparil, 254 tropinone, 252 carbomethoxytropinone, 157–158, 252 tryptophan, 257 tuaminoheptane, 185 TWENTY21 Project, 231 UK Food Standards Agency, 224 UK survey alcohol, 296, 298–299 anabolic steroids, 298

403

ecstasy, 296, 298 GHB, 298–299 ketamine, 297–299 khat, 296, 298 mephedrone, 298, 299 methadone, 298 ultraviolet light (UV), 264 UN Commission on Narcotic Drugs, 213, 229, 329 UN Conventions, 62, 80 barbituates, 85, 86 controlling natural products, 320, 321 isotopes, 77 Misuse of Drugs Act 1971, 20 phenethylamines, 177 scientific research, 42 steroids, 84 TiHKAL substances, 260 tobacco, 341 WADA banned, 193 UN Conventions 1961, 9–10, 18–19 cannabis resin, 9 coca leaf, 253 cocaine, 251 codeine, 9 cyclohexylbenzamide, 197 definitions, 221 drug intermediates, 329 ergoline derivatives, 92 fentanyls, 94, 96 hash oil, 227 homologues, 74 low dosages, 309 methadone, 9 morphine derivatives, 99 opium, 275–277 pethidine and prodine, 100–101 pipradrol, 121 redundancy, 65 under review, 194 RH-34, 199

404

UN Conventions 1971, 10–11, 30, 139, 194, 350, 361 arylcyclohexylamines, 116, 118 cannabis controls, 224, 226 cannabis medicinal, 229, 231 carisoprodol, 187 cathinone derivative, 89 chemical aspects, 169–170 control status, 239, 240, 249 drug production, 327–328 ergolines, 160 ethynylcyclohexanol, 191 heroin, 271 importation, 48 khat, 373 lysergide derivatives, 263–264 MDAct reviews, 25 MDMA, 209 methaqualone, 188 Misuse of Drugs Act 1971, 19 new benzodiazepines, 214, 217, 218 nomenclature of SCRAs, 238 opium, 278 phenethylamines, 106, 175, 178–179, 183 phenyl-substituted alkanes, 61 phenyloxazoline derivatives, 192 phytocannabinoids, 222 pipradrol, 121 purity, 282 stereoisomers, 75 tryptamines, 260 UN Conventions 1988, 10, 323, 324, 325 amphetamines, 206 cocaine, 252 cocaine precursors, 157 drug production, 326–328 European Union, 11 fentanyl, 324 heroin, 275 legislation in UK, 54–55 lethal toxicity, 301 MDMA, 210

Subject Index

medicines, 314 methylamphetamine, 208–209 phenethylamines, 182 stereoisomers, 75 University Hebrew University, Jerusalem, 235 Perdue, 265 urine, 174, 184, 206–210, 252, 264, 274, 340 US Controlled Substances Act, 9, 84, 186–187, 239, 249, 260, 325 US Drug Enforcement Administration (DEA), 43, 47, 62, 149, 157, 325 US Synthetic Drug Abuse Prevention Act, 239 usability test, 362 valerolactone, 271–272 valerone naphthylpyrovalerone, 88, 91, 131, 355, 367 pyrovalerone, 88–89, 91–92, 353, 360 valerylfentanyl, 381 Valium, 212 vaping, 221, 232 vasodilators, 185 veterinary use, 13–14, 24–25, 41, 117 viminol, 241, 243 vinylbital, 86 violent crime, 30 vitamin E, 232, 234 Wales, 2–4, 5, 54, 229–230, 270, 282, 283, 351, 363–364 weed, 63, 221 weighted average, 285 Wellbutrin, 91 whippets, 313 whipping cream, 52, 313 wintergreen oil test, 377 Wootton Report, 30 World Anti-Doping Agency (WADA), 82, 185, 193, 336

Subject Index

World Health Organization (WHO), 59, 168, 194, 239 benzylbenzimidazole, 199 cannabis medicinal, 229 khat, 343 MDAct reviews, 25 opium, 277 phenethyamines, 183 stereoisomers, 75–76 tobacco, 341 wrap, 287 Xyrem, 270 yaba, 61 yage, 321

405

yellow horned poppy, 276 Yellow List of controlled drugs, 153, 156, 282 Yemen, 342 yohimbe, 321 yohimbine, 321 zafirlukast, 241, 243 zaleplon, 356, 366 zeranol, 20, 84, 354, 360, 368 zilpaterol, 20, 84, 354, 360, 368 Zimmermann test, 377 zipeprol, 353, 360 zolpidem, 4, 20, 354, 360, 366 zopiclone, 4, 304, 356, 361, 366 Zyban, 91