Introduction

INTRODUCTION This publication was prepared because of the increasing concern that is felt in many responsible quarters about the self-administration of a number of psychoactive substances in order to experience their psychic effects. It presents technical data on 253 psychoactive drugs and herbs considered to have an actual or potential capacity to produce central nervous system stimulation, depression, or hallucina- tions or to produce distortions in perception, thinking or judgement and that may induce drug dependence. Substances of the types already under international "narcotics " control (opioids, coca leaves, cocaine and cannabis plants) are not included in this review. In choosing the substances for review, the authors have compiled lists of (1) drugs already subjected to some national controls because of their dependence- producing properties, (2) compounds that are close chemical or pharmacological congeners of controlled drugs, and (3) other substances that have been abused, or might have such a potential because of their close chemical or pharmacological similarity. A few precursors of some hallucinogens are also considered. TERMINOLOGY The following four definitions, formulated by the WHO Expert Committee on Drug Dependence,70 have been adopted in this publication. Drug: " Any substance that, when taken into the living organism, may modify one or more of its functions." Drug abuse: " Persistent or sporadic excessive drug use inconsistent with or unrelated to acceptable medical practice." Drug dependence: "A state, psychic and sometimes also physical, resulting from the interaction between a living organism and a drug, characterized by behavioural and other responses that always include a compulsion to take the drug on a continuous or periodic basis in order to experience its psychic effects, and sometimes to avoid the discomfort of its absence. Tolerance may or may not be present. A person may be dependent on more than one drug." Physical dependence capacity: " The ability of a drug to act as a substitute for another upon which an organism has been made physically dependent, i.e., to suppress abstinence phenomena that would otherwise develop after abrupt withdrawal of the original dependence- producing drug." For purposes of greater clarity the following additional descriptions are offered. Psychic dependence: A compulsion that requires periodic or continuous administration of a drug to produce pleasure or avoid discomfort. This compulsion is the most powerful factor in chronic intoxication with psychotropic drugs, and with certain types of drugs may be the only factor involved in the perpetuation of abuse even in the case of most intense craving. Psychic de- pendence, therefore, is the universal characteristic of drug dependence. Operationally, it is recognized by the fact that the dependent continues to take the drug in spite of conscious admission that it is causing harm to his health and to his social and familial adjustment, and that he takes great risks to obtain and maintain his supply of the drug. Physical dependence: A pathological state brought about by repeated administration of a drug and that leads to the appearance of a characteristic and specific group of symptoms, termed an abstinence syndrome, when the administration of the drug is discontinued or- in the case of certain drugs-significantly reduced. In order to prevent the appearance of an abstinence syn- drome the continuous taking of the drug is required. Physical dependence is a powerful factor in reinforcing psychic dependence upon continuing drug use or in relapse to drug use after withdrawal. Tolerance: The state in which repetition of the same dose of a drug has progressively less effect, or in which the dose needs to be increased to obtain the same degree of pharmacological effect as was caused by the original dose. Cross-tolerance: The state in which tolerance to one drug has the effect of causing tolerance to another drug of the same or a different chemical type. It should be borne in mind that the fact that a substance is termed a drug of dependence does not necessarily mean that it should be controlled, nationally or internationally, and, in addition, listing a substance as a drug of dependence does not indicate the type or degree of control which should be applied to a particular substance. The need for and the degree of control must be determined individually for each substance and must be based on the degree of risk to public health and the usefulness of the drug in medical practice.70 -S5 H. ISBELL & T. L. CHRU§CIEL CLASSIFICATION In order to facilitate the search for individual drugs a classification was developed which is partly pharmacological and partly chemical. This classifica- tion is followed in the tables. The compounds have been divided into five main categories: 1. Central nervous system depressants Tables I-XI 2. Central nervous system stimulants Tables XII-XV 3. Hallucinogens TablesXVI-XIX 4. Crude plant drugs Table XX 5. Precursors Table XXI The categories of central nervous system de- pressants, central stimulants and hallucinogens have been further subdivided into chemical classes: for example, the general category of central nervous system depressants was split into 13 chemical types: the diureides (barbiturates), the monoureides, etc. In the various chemical subgroups, each individual compound has been listed and assigned a number within that subgroup. Where only one chemical was found in a particular group (bromide, paraldehyde, phencyclidine) no table has been prepared but the substance and its dependence potential are described in the text. It is important to note that the central nervous system depressants do not include the reserpine, phenothiazine and butyrophenone groups of anti- psychotic drugs. These groups do not appear to cause dependence or abuse (except, possibly, in so far as they may contribute in combinations). The antihistamines have also not been included, since there has been little abuse of these drugs. Alcohol has also been omitted because, although it is the most important central nervous system depressant causing dependence of the barbiturate-alcohol type, the problem of alcohol is so huge and so different in sociological, cultural and legal respects from dependence on other depressant drugs. The central nervous system stimulants do not include the antidepressant dibenzazepines, such as imipramine or amitryptiline and the monoamine oxidase inhibitors, such as iproniazid or tranyl- cypromine, since neither of these two kinds of drugs has been widely abused. MATERIAL INCLUDED After the classification was settled, the literature was searched and the lists of individual substances compiled. The source material included compilations of drugs already subjected to special national con- trols; 6, 17, 22-37, 57 the manuals for physicians and pharmacists listing drugs available in particular coun- tries;'9 15, 40, 42, 45, 48, 51, 59, 66 the International Phar- macopoeia I' and national formularies; 16, 50, 69 text- books of pharmacology from various countries; 1, 5 7, 11-12, 19-21, 38, 39, 41, 49, 56, 62, 64, 71 and some general articles dealing with problems of drug dependence in various countries.2-4" 8, 10, 14, 18, 42, 44, 46, 47, 52-55, 61, 68, 65, 67, 68 No attempt has been made to list all compounds that have been synthesized in a particular chemical class. In categories 1 and 2, central nervous system depressants and stimulants that are, have been, or are likely to be available for therapeutic use have been selected. In many instances the drugs are obsolete, have been used very little. or are not yet on the market so that information is incomplete, but these substances have been included because of close chemical and pharmacological similarity to other drugs listed. There is also a large number of com- pounds for which it was difficult or impossible to find definite documentation regarding abuse or de- pendence. Such drugs have been categorized on the basis of analogies of chemical structure, pharmaco- dynamic properties and stated therapeutic indica- tions. In the case of the hallucinogens it was manifestly impossible to include all the congeners of LSD that have been synthesized, all the hallucino- genic amphetamines and all the tetrahydrocanna- binols. Those hallucinogens that have been included comprise substances that (1) have been shown to be hallucinogenic in man, and (2) have appeared in the illicit market somewhere in the world. USE OF THE TABLES The titles of Tables I to XIX indicate the chemical and pharmacological classification of the pure compounds. The subcodings of the tables are largely self-explanatory and further clarified by the footnotes. Column 1 shows the chemical formula and/or the commonly accepted short chemical name. Each compound or crude plant drug is assigned a numeral with the prefix S. The numbers are carried forward consecutively through the tables; that is, the last compound in Table I is No. S 66, the first compound in Table II is No. S 67, etc. In some cases the longer and more exact names according to the system of Chemical Abstracts are used. Column 2 lists the name of the substance as a drug. Whenever an International Nonproprietary Name (INN) is available, it is the name used. When no INN is available the fact is indicated by the entry " None ", 6 DEPENDENCE LIABILITY OF " NON-NARCOTIC " DRUGS 7 and the name used is, if possible, another non- proprietary name with the source of the name being identified by initials explained in a footnote. If no nonpropnetary name is available, the leading name listed in the Subsidia Pharmaceutica IndexNominum 59 or the Merck Index 60 has been chosen. Column 3 tabulates some important symptoms of intoxication. Column 4 indicates whether or not tolerance develops (or lack of information). Column 5 states whether psychic dependence develops and sometimes gives a rough, non-quantitative descriptive rating of the degree of psychic dependence that can develop. Column 6 states whether physical dependence occurs and, where appropriate, lists the major manifesta- tions of abstinence. Column 7 shows the therapeutic indications for the drug and, in some instances, the duration and onset of action after oral ingestion. Column 8 gives the major dangers of abuse. Col- umn 9 shows an abuse-potential rating. A rating of " high " in column 9 indicates that the substance can create strong psychic dependence and that extensive abuse has occurred or is judged likely to occur if the drug was readily available. A rating of " moderate " indicates that the drug creates a less intense degree of psychic dependence and that some degree of abuse has occurred or is judged likely to occur if the drug was readily available. A rating of " low " indicates that the drug creates only mild psychic dependence and that only little or no abuse has occurred or is deemed likely to occur. If "None" appears in column 9, the compound is judged not to be a drug of dependence. Column 10 gives the bibliographical references on which the ratings were based. The references pertinent to a particular table appear at the end of the text relevant to that table. References have been numbered consecutively through the various reference lists, that is, the last number in " General References " below is No. 71, making the first number in the next reference list-under " Central nervous system depressants, Diureides (barbiturates) "-No. 72. GENERAL REFERENCES 1. Bacq, Z. M., Cheymol, J. & Dallemagne, M. J. (1961) Pharmacodynamie biochimique, Masson et Cie, Paris 2. -Backhouse, C. I. & James, I. P. (1969) Brit. J. Addict., 64, 75-79 (The relationship and prevalence of smoking, drinking and drug taking in (delin- quent) adolescent boys) 3. Balduzzi, E. (1965) Rass. Neuropsichiat., 19, 137-146 (La tossicomania. Situazione e condizione) 4. Bewley, T. H. (1969) Bull. Narcot., 21, 13-30 (Drug dependence in the USA) 5. Bowman, W. C., Rand, M. J. & West, G. B. (1968) Textbook of pharmacology, Blackwell Scientific Publications, Oxford 6. Bull. eidg. Gesundh.-Amt. (1967) p. 37 (Verzeichnisse der Stoffe und Praparate gemass Art. 2, lit. a-e, der Vollziehungsverordnung vom 4 Marz 1952/1. Mai 1953 (V) zum Bundesgesetz uber die Betaubungsmittel vom 3 Oktober 1951 (BG) Beilage A, Nr 3) 7. Burger, A. (1968) Drugs affecting the central nervous system, Edward Arnold Ltd., London 8. Cohen, -H. (1968) T. soc. Geneesk., 46, 714-719 (Clandestien drug-gebruik en maat-schappij) 9. World Health Organization (1967) Cumulative list of proposed international non-proprietary names for pharmaceutical preparations, Geneva 10. Deniker, P. (1969) Ann. med.-psycholog., 1, 193-211 (Sur les abus des drogues psychodysleptiques: toxicomanies modernes et pharmaco-psychoses) 11. DiPalma, J. R., ed. (1965) Drill's pharmacology in medicine, 3rd ed., McGraw-Hill Book Co., New York 12. Efron, D. H., Cole, J. O., Levine, J. & Wittenborn, J. R. (1968) Psychopharmacology. A review ofpro- gress 1957-1967 (US Public Health Service Pub- lication No. 1836) Washington, D.C. 13. Ehrhart, G. & Rushig, H. (1968) Arzneimittel Ent- wicklung Wirkung Darstellung, Verlag Chemie, Weinheim, vol. 1 and 2 14. Evang, K. (1969) T. norske Lageforen., 89, 454-549 (Narkoticaproblemer-narcotics) 15. Falconer, M. W., Patterson, H. R. & Gustafson, E. A. (1968) Current drug handbook 1968-70, W. B. Saunders Co., Philadelphia 16. FASS (1968) Farmacevtiska specialiteter i Sverige, Almquist & Wiksell, Stockholm 17. Federal Register, 33, No. 193, part II (Narcotic and dangerous drug enforcement regulations 1968) 18. Fraletti, P. (1965) Arch. Dep. Assist. Psicop. S. Paulo, 31, 5-27 (Uso e abuso de psicotropicos leis e etica) 19. Goldstein, A., Aronow, L. & Kalman, S. M. (1968) Principles of drug action, Harper & Row, New York 20. Goodman, L. S. & Gilman, A., ed. (1965) The phar- macological basis of therapeutics, 3rd ed., Mac- millan Co., New York 21. Gordon, M. (1964, 1967) Psychopharmacological agents, vols. 1 and 2, Academic Press, New York 22. Government of Canada (1967) Drug Schedules ofthe Food and Drug Act and Regulations issued by the Food and Drug Directorate, Ottawa 23. Government of Denmark (1955) Law No. 169 of 24 May 1955, concerning psychoactive drugs, Copenhagen 8 H. ISBELL & T. L. CHRU§CIEL 24. Government of Federal Republic of Germany (1929) Gesetz uiber den Verkehr mit Betaubungsmitteln, RBGI I, 215, Berlin 25. Government of Federal Republic of Germany (1967) Vierte Verordnung uiber die den Betdubungsmitteln gleichgestellten Stoffe, 21.2.1967, BGBI I, p. 197, Berlin 26. Government of Japan (1951) Law No. 252 of30 June 1951, Tokyo (Awakening drug control law) 27. Government of Norway (1965) Norwegian Act of 20 June 1964 relating to medicinal goods and poi- sons, etc. (Lov om legemidler og gifter m.v.), Norges Apotekerforening, Oslo 28. Government of Norway (1965) Forskrifter og be- stemmelser om narkotika av 6 januar og 13 mars, Gr0ndahl & S0n, Oslo 29. 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