Bull. Org. mond. Sante 1965, 32, 721-733 Bull. Wld Hlth Org.

Drug Dependence: its Significance and Characteristics

NATHAN B. EDDY, M.D.,1 H. HALBACH, Dr. med. Dr.-Ing.,2 , M.D.3 & MAURICE H. SEEVERS, M.D.4

It has become impossible in practice, and is scientifically unsound, to maintain a single definition for all forms of and/or habituation. A feature common to these conditions as well as to drug abuse in general is dependence, psychic or physical or both, of the individual on a chemical agent. Therefore, better understanding should be attained by substitution of the term drug dependence of this or that type, according to the agent or class of agents involved, in discussions of these conditions, especially inter-disciplinary. Short descriptions, followed by concise listings of their characteristics, are formulated for the various types ofdependence on atpresent widely abused major groups ofsubstances.

CONTENTS Page Introduction ...... 721 The term " drug dependence " ...... 722 Characteristics of drug dependence ...... 724 Type ...... 724 - Type ...... 725 Type ...... 727 (Marihuana) Type ...... 728 Type ...... 729 Khat Type ...... 730

Hallucinogen (LSD) Type ...... 731 Resume...... 731 References ...... 733

INTRODUCTION notification from a government, the Committee come Among the functions of the World Health Organ- to a finding as to whether or not the substance in ization is the taking of decisions on the status of question is or is convertible into one with addiction- individual under the relevant international producing or addiction-sustaining properties similar treaties for narcotics control. This function has been to those of morphine or cocaine or cannabis. A posi- established by international conventions and depends tive finding by the Committee is followed by a recom- upon the competence of the WHO Expert Com- mendation for appropriate international narcotics mittee on Addiction-Producing Drugs. The con- control. Pertinent to any conclusion or decision is ventions specifically direct that, in response to a the consideration of specific therapeutic effects, the liability of substances having such effects to 1 Consultant, National Institutes of Health, Bethesda, produce drug dependence, and the evaluation of Md., USA. the risk to public health if such substances are 2 Chief, Pharmacology and Toxicology, World Health used for medical Organization, Geneva, Switzerland. purposes or abused. Obviously, ' Professor of Medicine and Head, Section of Clinical such considerations depend upon the availability Pharmacology, Department of Medicine, University of of dependable methods and critical evaluation of Kentucky, Lexington, Ky., USA. their application to the determination of both useful 'Professor of Pharmacology and Chairman of the Department, The University of Michigan, Ann Arbor, therapeutic properties and the kind and degree of Mich., USA. dependence that may accompany drug use. WHO

1604 -721 722 N. B. EDDY AND OTHERS has already published a series of reports on these individuals will not get a reaction satisfactory or requirements (Braenden, Eddy & Halbach, 1955; pleasurable to them, persuading them to continue Eddy, Halbach & Braenden, 1956, 1957; Halbach its use even to the point of abuse-that is, to exces- & Eddy, 1963; WHO Scientific Group on the sive or persistent use beyond medical need. Probably Evaluation of Dependence-Producing Drugs, 1964). the only exceptions are agents that have incidental As a partial guide to its own deliberations and or side effects that prevent such use-for example, those of others, the WHO Expert Committee on cumulative or early toxic effects, to which the Addiction-Producing Drugs (1952) attempted to individual does not become tolerant. formulate a definition of addiction that would be to applicable drugs under international control. THE TERM " DRUG DEPENDENCE" A revised definition 1 was proposed by the Com- mittee several years later, in its seventh report In order to try to clarify this situation, much (WHO Expert Committee on Addiction-Producing thought and discussion have been devoted to finding Drugs, 1957). a term that will cover all kinds of drug abuse. The In its seventh report the Committee sought also component in common appears to be dependence, to differentiate addiction from habituation and whether psychic or physical or both. Hence, use of wrote a definition of the latter 2 which, however, the term " drug dependence " with a modifying failed in practice to make a clear distinction. These phrase linking it to a particular type of drug in order definitions gained some acceptance, but confusion to differentiate the characteristics associated with in the use of the terms addiction and habituation, one class of drugs or another has been given most and particularly misuse of the former, continue. careful consideration. In its thirteenth report, the Both terms are frequently used interchangeably and WHO Expert Committee on Addiction-Producing often inappropriately. It is not uncommon to apply Drugs (1964) has, in fact, recommended substitution the term addiction to any misuse of drugs outside of of the term " drug dependence " for both of the medical practice, with a connotation of serious terms drug addiction and drug habituation. This harm to the individual and to society, and often recommendation has been endorsed by the WHO with a demand that something be done about it. Scientific Group on Evaluation of Dependence- Such broad use can only create confusion and Producing Drugs (1964) and has been concurred in misunderstanding when abuse of drugs is discussed and supported, inter alia, by the Committee on from different viewpoints. Drug Addiction and Narcotics of the National The difficulties in terminology become increas- Academy of Sciences-National Research Council ingly apparent with the continuous appearance of (USA).8 new agents with various and perhaps unique phar- Drug dependence is a state of psychic or physical macological profiles, and with changing patterns dependence, or both, on a drug, arising in a person of use of drugs already well known. These develop- following administration of that drug on a periodic ments must be considered in their relation to, but or continuous basis. The characteristics of such a may not be adequately characterized by, current state will vary with the agent involved, and these definitions of addiction. There is scarcely any agent characteristics must always be made clear by desig- which can be taken into the body to which some nating the particular type of drug dependence in each specific case; for example, drug dependence of 1 " Drug addiction is a state of periodic or chronic intoxication produced by the repeated consumption of a morphine type, of barbiturate type, of amphetamine drug (natural or synthetic). Its characteristics include: type, etc. (1) an overpowering desire or need (compulsion) to continue The specification of the type of dependence is taking the drug and to obtain it by any means; (2) a tendency to increase the dose; (3) a psychic (psychological) and essential and should form an integral part of the generally a on the effects of the drug; new terminology, since it is neither possible nor (4) detrimental effect on the individual and on society." even desirable to delineate or define the term " Drug habituation (habit) is a condition resulting from drug the repeated consumption of a drug. Its characteristics dependence independently of the agent involved. include: (1) a desire (but not a compulsion) to continue It should also be remembered that it was the desire taking the drug for the sense of improved well-being which it engenders; (2) little or no tendency to increase the dose; to achieve the impossible and define a complex (3) some degree of psychic dependence on the effect of the situation by a single term (" addiction " or " habiA drug, but absence of physical dependence and hence of an abstinence syndrome; (4) detrimental effects, if any, primarily, on the individual." 3Twenty-sixth Meeting, Washington, D.C., 1964. DRUG DEPENDENCE: ITS SIGNIFICANCE AND CHARACTERISTICS 723 tuation ", respectively) which has given rise to In this situation, there is a feeling of satisfaction and confusion in many cases. Therefore, the description a psychic drive that require periodic or continuous of drug dependence as a state is a concept for administration of the drug to produce pleasure or clarification and not, in any sense, a specific defini- to avoid discomfort. Indeed, this mental state is tion. the most powerful of all of the factors involved in It must be emphasized that drug dependence is a chronic intoxication with psychotropic drugs, and general term that has been selected for its applicabil- with certain types of drugs it may be the only factor ity to all types of drug abuse and thus carries no involved, even in the case of most intense craving connotation of the degree of risk to public health and perpetuation of compulsive abuse. or need for any or a particular type of drug control. Some drugs also induce physical dependence, The agents controlled by international treaties and which is an adaptive state that manifests itself by by national narcotics laws continue to be those that intense physical disturbances when the administra- are morphine-like, cocaine-like, or cannabis-like, tion of the drug is suspended or when its action is the use of which may result, respectively, in drug affected by the administration of a specific antag- dependence of morphine type, of cocaine type, or of onist. These disturbances, i.e., the withdrawal or cannabis type. Other types of drug dependence, abstinence syndromes, are made up of specific such as those of the barbiturate and amphetamine arrays of symptoms and signs of psychic and phy- types, continue to present problems, and their sical nature that are characteristic for each drug description under the general term of drug de- type. These conditions are relieved by re-administra- pendence, while it may help to delineate those tion of the same drug or of another drug of similar problems, in no way suggests or affects the measures pharmacological action within the same generic to be taken to solve them. Use of the general term type. No overt manifestation of physical dependence will help to indicate a relationship by drawing is evident if an adequate dosage is maintained. attention to a common feature associated with drug Physical dependence is a powerful factor in reinfor- abuse, but at the same time will differentiate, by cing the influence of psychic dependence upon more exact description, specific characteristics continuing drug use or to drug use after according to the nature of the agent involved. attempted withdrawal. Further to clarify our meaning, the nature and To reiterate, psychic dependence can and does significance of drug abuse may be considered from develop, especially with -type drugs, two points of view: one relates to the interaction without any evidence of physical dependence and, between the drug and the individual, the other to therefore, without an abstinence syndrome develop- the interaction between drug abuse and society. ing after . Physical dependence, The first viewpoint is concerned with drug depen- too, can be induced without notable psychic dence and the interplay between the pharmaco- dependence; indeed, physical dependence is an dynamic actions of the drug and the psychological inevitable result of the pharmacological action of status of the individual. The second-the inter- some drugs with sufficient amount and time of action between drug abuse and society-is con- administration. Psychic dependence, while also cerned with the interplay of a wide range of con- related to pharmacological action, is more particu- ditions, environmental, sociological, and economic. larly a manifestation of the individual's reaction The Committee tried to encompass both points of to the effects of a specific drug and varies with the view when, in its definition of addiction, it listed individual as well as with the drug. characteristics of which some were pharmaco- Many of the drugs that induce dependence, dynamic and others psychological and socio- especially those that create physical dependence, economic, perhaps thereby compounding some of also induce tolerance, which is an adaptive state the existing confusion. characterized by diminished response to the same As already noted, individuals may become quantity of drug or by the fact that a larger dose is dependent upon a wide variety of chemical sub- required to produce the same degree of pharmaco- stances that produce central nervous system effects dynamic effect. Both drug dependence and drug ranging from stimulation to depression. All of these abuse may occur without the development of drugs have one effect in common: they are capable demonstrable tolerance. of creating, in certain individuals, a particular state Drugs that are capable of inducing dependence of mind that is termed " psychic dependence ". may also be associated with psychotoxic effects 724 N. B. EDDY AND OTHERS that are manifested by profound alterations in (c) Development of tolerance that requires an behaviour. These effects may occur with a single increase in dosage to obtain the initial pharmaco- large dose or during the course of continued dynamic effects. administration, or they may be precipitated by With morphine, the abstinence syndrome appears withdrawal of the drug following continued ad- within a few hours of the last dose, reaches peak ministration. The pattern of abnormal behaviour intensity in 24 to 48 hours, and subsides spontaneous- is, within limits, characteristic for each drug type, ly. The most severe symptoms usually disappear but wide variation occurs in individual responses within ten days, although a residuum persists for a depending, among other things, upon the pre- much longer period. The time of onset, peak existing mental state of the person involved. intensity, and duration of abstinence phenomena The characteristics of drug dependence show vary with the degree of dependence on the drug significant differences from one generic type to (Andrews & Himmelsbach, 1944) and with the another, a situation that makes it mandatory to characteristics of the specific agent involved. establish clearly the pattern for each type of drug Administration of a specific antagonist during dependence. Even though some variations occur continuing administration of morphine-like drugs among individual members of each generic group, promptly precipitates a more rapid and intense the consistency of the pattern of pharmacodynamic abstinence syndrome that lasts only a few hours. actions and responses is sufficiently uniform to The unique feature of the morphine abstinence permit, at this time, the delineation of each of the syndrome is that it represents changes in all major principal types. areas of nervous activity, including alteration in behaviour, excitation of both divisions of the autonomic system simultaneously, and dysfunction CHARACTERISTICS OF DRUG DEPENDENCE of the somatic nervous system. The complex of symptoms and signs include anxiety, restlessness, Drug Dependence of Morphine Type generalized body aches, , yawning, lacrima- The outstanding and distinctive characteristic tion, rhinorrhoea, perspiration, , pilo- of dependence on morphine and morphine-like erection (gooseflesh), hot flushes, nausea, emesis, agents is that the major elements-psychic and diarrhoea, elevation of body temperature, of physical dependence, as well as tolerance-can be respiratory rate and of systolic blood pressure, initiated by the repeated administration of small abdominal and other muscle cramps, dehydration, doses and increase in intensity in direct relationship anorexia, and loss of body weight (Isbell & White, to an increase in dosage. This characteristic implies 1953). that dependence on drugs of this generic type may The generic type of morphine-like compounds for be created within the dosage range generally used which morphine is used as the standard of reference for therapeutic purposes, and that its mechanism comprises substances with different chemical constitu- may be set in motion by the first dose administered. tions but similar pharmacological profiles. They vary The characteristics of dependence of the morphine in potency from substances with low activity to others type are: that are several thousand times as potent as morphine. These agents are alike in their ability to produce and (a) Strong psychic dependence, which manifests maintain some degree of physical dependence, to itself as an overpowering drive or compulsion to maintain tolerance and physical dependence and continue taking the drug and to obtain it by any to prevent the appearance of abstinence phenomena. means, for pleasure or to avoid discomfort. These agents are mutually interchangeable by sub- (b) An early development of physical dependence stitution, although not on a milligram-for-milligram which increases in intensity, paralleling increase in basis. Variations exist in the capacity of potent dosage. This requires a continuation of administra- morphine-like substances to induce psychic de- tion of the same drug, or an allied one, to maintain pendence and to produce psychic satisfaction on a semblance of homeostasis and to prevent the substitution for one another. appearance of the symptoms and signs of with- Within the generic class of agents with pharmaco- drawal. Withdrawal of the drug or administration dynamic features similar to those of morphine, of a specific antagonist precipitates a definite, making them capable of inducing physical depend- characteristic and self-limited abstinence syndrome. ence with sufficient dosage, there are some with a DRUG DEPENDENCE: ITS SIGNIFICANCE AND CHARACTERISTICS 725 high degree of usefulness which, in therapeutic doses, turate on a continuous basis, generally in amounts are generally inadequate substitutes for morphine. that exceed the usual therapeutic dose levels. There Even in higher doses, these compounds are not is a strong desire or need to continue taking the completely satisfactory in sustaining an established drug, a need that can be satisfied by the drug taken morphine dependence; their effects are not usually initially or by another with barbiturate-like pro- sufficiently satisfying subjectively to induce signifi- perties. There is a psychic dependence on the effects cant psychic dependence. is generally of the drug that is related to subjective and individual recognized as a reference standard for this group. appreciation of those effects, and there is physical A relationship between dose, pharmacodynamic dependence requiring the presence of the drug for properties and intensity of physical dependence has the maintenance of homeostatis and resulting in a been mentioned. Regularity of administration at characteristic and self-limited abstinence syndrome intervals well within the duration of action of the when the drug is withdrawn. drug also hastens development of physical de- Tolerance to does develop and, with pendence. The time from the beginning of admi- relatively low doses, it will become evident within nistration to the appearance of demonstrable phy- seven days. There is, in contrast with tolerance to sical dependence also varies with the agent. With morphine-like drugs, a limit to the dose to which morphine, this interval under clinical conditions of a person can become tolerant. This limit is a administration is two or three weeks; it is shorter characteristic of the individual patient and varies for ketobemidone, probably longer for phenazocine widely. Following withdrawal of barbiturates, and definitely longer for codeine, especially when tolerance is rapidly lost, and some patients may this is administered orally. become more sensitive to barbiturates than they Finally, with drug dependence of the morphine had been prior to chronic intoxication with these type, harm to the individual is, in the main, indirect, drugs (Belleville & Fraser, 1957). arising from preoccupation with drug-taking; During the chronic intoxication of continuing personal neglect, malnutrition and infection are administration, there is some persistence of frequent consequences. For society also, the action, ataxia, etc. through the incomplete develop- resultant harm is chiefly related to the preoccupa- ment of tolerance, which makes the individual tion of the individual with drug-taking; disruption accident-prone. There is also impairment of mental of interpersonal relationships, economic loss, and ability, confusion, increased emotional instability, crimes against property are frequent consequences. and risk of sudden overdosage through delayed onset of action and perceptional distortion of time. Drug Dependence of Barbiturate-Alcohol Type The clinical manifestations of chronic barbiturism The signs and symptoms of barbiturate and of are similar to those of chronic (Isbell are similar, as are the signs and et al., 1950). symptoms of abstinence from these drugs. Barbi- The abstinence syndrome is the most character- turates will suppress alcohol abstinence phenomena, istic and distinguishing feature of drug dependence and alcohol will suppress, at least partially, the of the barbiturate type. It begins to appear within symptoms of barbiturate withdrawal. The two drugs the first 24 hours of cessation of drug-taking, reaches are essentially additive and interchangeable in peak intensity in two or three days, and subsides chronic intoxications; these similarities justify the slowly. At present there is no agent which is known term " dependence of barbiturate-alcohol type ", to precipitate the barbiturate abstinence syndrome but there are psychological and sociological differ- during continuation of drug administration. The ences, so that barbiturate and complex of symptoms constituting the abstinence will be described separately. syndrome, in approximate order of appearance includes: anxiety, involuntary twitching of muscles, Drug dependence of barbiturate type. While tremor of hands and fingers, progressive weakness, dependence on drugs of the barbiturate type pre- dizziness, distortion in visual preception, nausea, sents certain similarities to dependence on drugs vomiting, insomnia, weight loss, a precipitous drop of the morphine type, in detail there is a charac- in blood pressure on standing, convulsions of a teristically different picture both during the course of grand-mal type, and a resembling alcoholic intoxication and during withdrawal. It is a state or a major psychotic episode. arising from repeated administration of a barbi- Convulsions and delirium do not usually occur at 726 N. B. EDDY AND OTHERS the same time; generally, a patient may have one and paraldehyde, but there may be or two convulsions during the first 48 hours of with- exceptions. drawal and then become psychotic during the second Drug dependence ofalcohol type. Drug dependence or third night. With respect to the psychotic of the alcohol type may be said to exist when the episodes, paranoid reactions, reactions resembling consumption of alcohol by an individual exceeds with and , the limits that are accepted by his culture, if he withdrawn semi-stuporous state, and disorganized consumes alcohol at times that are deemed inap- panic have been seen. propriate within that culture, or if his intake of One would expect that the mechanism of physical alcohol becomes so great as to injure his health or dependence of the barbiturate type, as of that of the impair his social relationships. Since the use of morphine type, would be set in motion by the first alcoholic beverages is a normal, or almost normal, dose, but there is no evidence that this is the case. part of the cultures of many countries, dependence There is, indeed, no evidence that physical depend- on alcohol is usually apparent as an exaggeration ence develops to a detectable degree with continua- of culturally accepted drinking patterns, and the tion of the therapeutic doses usual for the production manifestations of dependence vary accordingly in a of sedation or hypnosis; the daily dose must be characteristic fashion with the cultural mode of increased appreciably above the usual therapeutic alcohol use. Thus, in the USA. alcohol is frequently level before abstinence signs will appear on abrupt taken in concentrated forms as an aid to socia' withdrawal. Some degree of psychic dependence intercourse, so that dependence on alcohol in the facilitating continuance of administration may USA is usually characterized by heavy consumption occur with therapeutic doses, but such doses can of strong spirits during short periods of the day, usually be discontinued without serious subjective by a tendency to periodic drinking, and by overt disturbance. Factors that may lead to increasing drunkenness. In some other countries, on the other consumption and eventual overt physical dependence hand, alcohol is customarily consumed in wine, include, in addition to tolerance, the incomplete usually with meals. In these countries, dependence relief of emotional problems and tension, and on alcohol is characterized by the drinking of wine impairment of judgement, so that larger doses are throughout the day, by a relatively continuous taken without regard to need. intake of alcohol in this manner, and by relatively In drug dependence of the barbiturate type, the little overt drunkenness. A similar pattern applies detrimental effect on the individual stems in part where beer is the common beverage. from his preoccupation with drug-taking, but more Psychic dependence on alcohol occurs in all particularly from the untoward effects of large doses degrees. In the mildest grade, alcohol is missed or of the drug: ataxia; dysarthria; impairment of desired if not available at meals or at social functions. mental function, with confusion, loss of emotional A moderate degree of psychic dependence exists control, poor judgement and, occasionally, a toxic when the individual feels compelled to drink in ; coma and death. The harm to society order to work or to participate socially and takes is also related to both the individual's preoccupa- steps to ensure a supply of alcohol for these purposes. tion with drug-taking and the persistence of the Strong dependence is present if the individual uses effects of these drugs on motor functioning, emo- alcohol in amounts far exceeding the cultural norm, tional stability and interpersonal relationships, drinks in situations that culturally do not call for with proneness to accidents and to assaults on other drinking and is obsessed with maintaining a supply persons as frequent consequences. By analogy, all of alcohol even to the extent of drinking unusual agents which produce barbiturate-like sedation, or poisonous mixtures. because of the relief of anxiety, mental stress, etc., As with other drugs, psychic dependence on should produce some psychic dependence and, for alcohol results from an interplay between the the reasons enumerated for dosage increase, physical pharmacodynamic effects of the drug and the dependence when a sufficient concentration in the personality problems of the user. The consciously organism has been attained. This possibility has verbalized reasons for the use of alcohol cover a been confirmed for many sedative agents of different wide gamut and may include a need to stimulate types, including barbiturates and the so-called non- the appetite, to alleviate anxiety or fatigue, to barbiturate such as , methy- remove boredom or to induce sleep. Other reasons, prylon, , , bromisoval, not consciously verbalized, may include needs to DRUG DEPENDENCE: ITS SIGNICANCE AND CHARACTERISTICS 727 express masculinity, to remove behavioural controls property damage and injury to others. The economic so that aggressive impulses may be expressed, and burden of dependence on alcohol is enormous; to blot out completely a hostile, threatening world. even more important is the tremendous amount of Tolerance to alcohol does develop. During human suffering endured by the alcoholic and all continuous drinking there is a slight but definite who are close to him. increase in the amount of ingested alcohol required The characteristics of drug dependence of the to maintain a given blood level. In addition, some barbiturate-alcohol type are: sort of physiological and psychological adaptation occurs so that the alcoholic appears less intoxicated (a) Psychic dependence of varying degree that and is less impaired in performance tests at a given may lead to periodic rather than continuous abuse, concentration of blood alcohol than is a non- especially with alcohol. alcoholic. Tolerance to alcohol, however, is in- (b) The definite development of a physical complete and never reaches the degree seen with dependence that generally, however, can be detected morphine-like agents. only after the consumption of amounts considerably Physical dependence on alcohol definitely occurs, above the usual therapeutic or usual socially and the abstinence syndrome resulting when the acceptable levels. Upon the reduction of intake intake of alcohol is reduced below a critical level below a critical level, a characteristic self-limited is manifested by tremors, sweating, nausea, tachy- abstinence syndrome ensues, the symptoms of which, cardia, rise in temperature, hyper-reflexia, postural in the case of barbiturates, can be suppressed not hypotension and, in severe grades, convulsions and only by a barbiturate-like agent but also, at least delirium. The last-mentioned condition is charac- partially, by alcohol. The reverse situation exists in terized by confusion, disorientation, delusions and the case of alcohol. vivid visual hallucinations. The intensity of the (c) The development of tolerance which is alcohol abstinence syndrome probably varies with irregular and incomplete, so that there is consider- the duration and amount of alcohol intake, but as able persistence of behavioural disturbance de- yet little quantitative information on this point is pendent upon the pharmacodynamic effects of the available. The mortality rate, when the alcohol drugs. There is a mutual, but incomplete, cross abstinence syndrome is severe, averages at least 8 %. tolerance of some degree between alcohol and the The harm to the individual resulting from barbiturates. dependence on alcohol can be quantitatively greater than that caused by any other type of drug depend- (d) A frequent consequence of alcoholism is overt ence. Alcohol impairs efficiency of thinking and pathology in tissues, whereas a similar development psychomotor co-ordination, leading to deterioration with the barbiturates has not been demonstrated. in work performance and to accidents. Judgement Drug Dependence of Cocaine Type deteriorates, leading to all sorts of errors in business and to disturbances of relations with other people. Cocaine is the prototype of the stimulant drugs Conscious controls of behaviour are " dissolved ", that are capable, in high dosage, ofinducing euphoric with resulting exhibitionism, aggressiveness and excitement and hallucinatory experiences. These assaultiveness. In addition, dependence on alcohol properties rank it high in the esteem of experienced predisposes to and causes serious physical disease. drug abusers and lead to the highest degree of The physical damage may be indirect, due to neglect psychic dependence. of hygiene or to inadequate dietary intake and Abuse of cocaine takes several forms. The most utilization, with resultant deficiencies, for example, in common is the centuries-old custom of coca-leaf vitamins, minerals and proteins. The most common chewing, which is practised habitually by certain serious complication ofprotracted alcoholism is fatty Indians of the high Andes. The leaf, mixed with portal cirrhosis. Alcoholics are frequently injured lime, ostensibly to release the alkaloid, is used because of impaired co-ordination and judgement. almost continuously to reduce sensations of cold, Damage to society is great. The alcoholic squand- fatigue and hunger. With this form of abuse, release ers his resources to obtain his beverage, his pro- of the alkaloid and its absorption generally are too ductivity declines, and his family may be neglected slow or quantitatively too small to induce mental to the extent that it has to be supported by society. changes that would lead to abnormal behaviour, as Alcoholics are frequently involved in accidents, with described below.

9 728 N. B. EDDY AND OTHERS

Despite its vasoconstrictive properties, cocaine is led to the belief that tolerance to cocaine develops, readily absorbed through mucous membranes. At a conclusion that is warranted neither by the facts one time, the application of cocaine solutions to nor by analogy with animal experiments. The criteria oral and nasal lesions was a very popular form of for tolerance (diminution in objective effects and treatment, especially with those patients who appre- elevation of the lethal dose) are not observed in ciated the euphoric stimulation induced by the ab- animals even though it may be possible to administer sorbed drug. Closely allied to such use or abuse is several lethal doses within 24 hours, the total quan- another form of absorption through the mucous tity varying with the detoxification capacity of the membranes that is now less common than it was- individual species. Although the acute lethal dose namely, the snuffing of cocaine crystals. This for man is unknown, it is clear that, given a constant is a concentrated form of administration that blood level,no diminution ofits subjective or objective induces such great psychic effects as to border on effects is noted. These effects, in fact, become those which may be obtained with intravenous enhanced, a phenomenon that is also administration. seen in animals. It is safe to conclude that man, Diminished need for cocaine as a local anaesthetic like animals, does not develop tolerance to cocaine. and control of the world supply has reduced the In summary, then, the characteristics of drug total illicit use of this drug, but coincidentally there dependence of the cocaine type are: has developed a most dangerous type of abuse- (a) Strong psychic dependence. intravenous injection. In the most advanced form, (b) No development of physical dependence and, this type of abuse involves administration at frequent therefore, absence of a characteristic abstinence intervals, as short as 10 minutes, the user desiring syndrome when the drug is withdrawn. the ecstatic thrills associated with this practice. This type of abuse appeals particularly to persons (c) Absence of tolerance; rather, there is sensitiza- with psychopathic tendencies, which are often tion to the drug's effects in some instances. unmasked by the drug. The induced feeling of great (d) A strong tendency to continuation of adminis- muscular and mental strength leads the individual tration, as in coca-leaf chewing, or rapid repetition to overestimate his capabilities. This, associated of the dose, as in the current practice of intravenous with paranoid delusions and auditory, visual and administration. Quantitatively, the effects are tactile hallucinations, often makes the user a very strikingly different, according to the mode of abuse. dangerous individual, capable of serious antisocial Cocaine is probably the best example of a sub- acts. Digestive disorders, nausea, loss of appetite, stance to which neither tolerance nor physical emaciation, sleeplessness, and occasional convulsions dependence develops and with which psychic de- are commonly experienced by cocaine abusers of pendence can lead to a profound and dangerous this type. Long-standing, continuing misuse of type of drug abuse. cocaine alone at a high level is rare, however. The user reaches such a state of excitement that he Drug Dependence of Cannabis (Marihuana) Type voluntarily seeks sedation. A frequent current It is not known with absolute certainty which of practice is to antagonize the exciting effects by the the chemical structures that have been isolated from alternate administration of morphine or some other L. is responsible for the typical drug, or by the injection of the two types cannabis effects, but these can nevertheless be of drug in combination, the cocaine- mixture described as constituting an entity that varies in ("speedball ") being particularly popular. degree according to the concentration of the active No physical dependence on cocaine develops and, principle or principles in the plant and the prepara- consequently, no characteristic abstinence syndrome tions obtained therefrom, and to the mode ofapplica- is noted on abrupt withdrawal. But severe de- tion. These effects are also producible by certain pression may occur and delusions may persist for synthetic substances of similar chemical structure. some time after withdrawal. Among the more prominent subjective effects of Since cocaine undergoes rapid destruction in the cannabis, for which it is taken occasionally, perio- organism, large quantities can be given during a dically or chronically, are: hilarity, often without 24-hour period. Indeed, in man as much as 10 gm apparent motivation; carelessness; loquacious daily may be used when the drug is administered in , with increased sociability as a result; relatively small doses at short intervals. This has distortion of sensation and perception, especially DRUG DEPENDENCE: ITS SIGNIFICANCE AND CHARACTERISTICS 729 of space and time, with the latter reinforcing psychic dangerous drugs, such as or barbiturates. dependence and being valued under special circum- Transition to the use of such drugs would be a stances; impairment of judgement and memory; consequence of this association rather than an inhe- distortion of emotional responsiveness; irritability; rent effect of cannabis. The harm to society derived and confusion. Other effects, which appear es- from abuse of cannabis rests in the economic con- pecially after repeated administration and as more sequences ofthe impairment ofthe individual's social experience is acquired by the user include: lowering functions and his enhanced proneness to asocial and of the sensory threshold, especially for optical and antisocial behaviour. acoustical stimuli, thereby resulting in an intensified appreciation of works of art, paintings and music; Drug Dependence of Amphetamine Type hallucinations, illusions, and delusions that pre- The capacity of the and drugs dispose to antisocial behaviour; anxiety and aggres- with similar pharmacological properties to elevate siveness as a possible result of the various intellectual mood and induce a state of well-being is probably and sensory derangements; and sleep disturbances. largely the basis for their value and widespread use In the psychomotor sphere, hypermotility occurs as and anorexiants. Since such therapy without impairment of co-ordination. Among commonly involves continuous and prolonged somatic effects, often persistent, are injection of the administration, the users of these drugs may develop ciliary vessels and oropharyngitis, chronic bron- varying degrees of psychic dependence upon them. chitis and asthma; these conditions and hypogly- This fact establishes the basis for abuse, where the caemia, with ensuing bulimia, are symptoms of dosage may be increased in both quantity and intoxication, not of withdrawal. frequency of administration in order to attain a Typically, the abuse of cannabis is periodic but, continuing stimulation and state of elation. When even during long and continuous administration, carried to an extreme, the psychotoxic effects of no evidence of the development of physical de- large amounts of drugs of the amphetamine type pendence can be detected. There is, in consequence may lead to aggressive and dangerous antisocial no characteristic abstinence syndrome when use of behaviour. the drug is discontinued. The abuse of this class of drugs originates in and Whether administration of the drug is periodic is perpetuated by the psychic drive to attain or continuous, tolerance to its subjective and psycho- maximum euphoria; no physical dependence is motor effects has not been demonstrated. created. Qualitatively, the psychological effects are Whereas cannabis often attracts the mentally in many respects similar to those produced by unstable and may precipitate temporary psychoses cocaine. in predisposed individuals, no unequivocal evidence A unique feature of the amphetamines is their is available that lasting mental changes are produced. capacity to induce tolerance, a quality possessed by Drug dependence of the cannabis type is a state few central nervous system stimulants. Although arising from chronic or periodic administration of tolerance develops slowly, a progressive increase in cannabis or cannabis substances (natural or syn- dosage permits the eventual ingestion of amounts thetic). Its characteristics are: that are several hundredfold greater than the (a) Moderate to strong psychic dependence on original therapeutic dose. Apparently, all parts of account of the desired subjective effects. the central nervous system do not become tolerant (b) Absence of physical dependence, so that at the same rate, so that the user will continue to there is no characteristic abstinence syndrome when experience increased nervousness and insomnia as the drug is discontinued. the dose is increased. Although an individual may survive the oral administration of very large quanti- (c) Little tendency to increase the dose and no ties, such ingestion may produce profound be- evidence of tolerance. havioural changes that are often of a psychotic For the individual, harm resulting from abuse of nature, including hallucinations, delusions, etc. cannabis may include inertia, lethargy, self-neglect, These latter effects are much more likely to occur feeling of increased capability, with corresponding after intravenous injection than after ingestion. failure, and precipitation of psychotic episodes. Indeed, the intravenous route is employed for the Abuse of cannabis facilitates the association with express purpose of obtaining bizarre mental effects, social groups and sub-cultures involved with more often associated with sexual functions, even to the 730 N. B. EDDY AND OTHERS point of orgasm. This type of abuse has been through and manifest itself at an inopportune time. increasingly frequent in recent years with the chang- Abuse by intravenous administration, with its ing patterns of drug abuse in various countries. concomitant bizarre mental effects, may result in Although the amphetamines do not induce serious antisocial behaviour. physical dependence, as measured by the criterion Drug Dependence ofKhat Type of a characteristic and reproducible abstinence syndrome, it would be inaccurate to state that with- Khat (Catha edulis Forssk.) is cultivated and drawal from very large dosages is symptomless. The consumed in circumscribed areas of East Africa and sudden withdrawal of the stimulant drug which has the Arabian peninsula. The common, and quanti- masked chronic fatigue and the need for sleep now tatively most profitable, mode of application is by permits these conditions to appear in an exaggerated way of chewing the tender parts of the plant in as fashion. Thus, the withdrawal period is character- fresh a state as possible. istically a state of depression, both psychic and The active principle of the khat leaf is chemically physical, which probably reinforces the drive to and pharmacologically related to the amphetamine resume the drug. In this regard, it is much less impor- group of substances so closely that its effects are tant and does not compare in magnitude with those to be considered qualitatively identical with those that occur with morphine, barbiturates, alcohol of the latter group and quantitatively equal to their and other drugs that create physical dependence. weaker members. These resemblances extend to the Withdrawal of drugs of the amphetamine type is somatic as well as to the psychic effects, among never threatening to life and requires psychological which a usually moderate degree of central stimula- rather than somatic therapy. tion, with ensuing elation and removal of fatigue, is the effect most sought for by The use of amphetamines by self-administration khat users, besides has increased consistently in recent years, ostensibly suppression of hunger and, sometimes, of libido. as anti-fatigue agents in situations in which it is The quantitative difference between the effects of desired to remain mentally alert for long periods khat and those of the commonly abused ampheta- without sleep or rest or to permit increased physical mine substances is enhanced by the limitation of performance. The use of amphetamines as stimu- the ingestion and absorption of khat due to its lants has also increased markedly in persons who particular mode of application. The naturally in such limited dose of khat is assumed to prevent the abuse alcohol and/or barbiturates; many occurrence of tolerance, of rebound phenomena instances there is dependence on more than one after cessation, and of psychotoxic effects typical drug. In such cases, the prognosis is poor, the ofthe relapse rate is high, and continued dependence on amphetamines when the latter are administered one or more drugs is the rule, especially in pre- in pure form and in high dosage. There is no or individuals with latent evidence ofthe development ofa physical dependence psychotics schizophrenia. on khat during chronic use. Thus, the characteristics of drug dependence of Nevertheless, the pleasurable effects afforded by the amphetamine type are: khat are a strong inducement for many to procure (a) A variable psychic dependence. by any means the necessary supplies at least once a (b) No physical dependence and, consequently, day or to repeat or prolong the periods of chewing, no characteristic abstinence syndrome, though often at the expense of vital needs such as food. withdrawal will be followed by a state of mental Such behaviour is a manifestation of psychic and physical depression as the organism escapes dependence. from the persistent stimulation. Drug dependence of the khat type is, under the (c) The slow development of a considerable degree circumstances of its traditional consumption by of tolerance to many effects, but not participated chewing, characterized by: in equally by all components of the cerebral system, (a) Moderate but often persistent psychic de- so that nervousness and sleeplessness persist and pendence as long as its maintenance is at all psychotoxic effects such as hallucinations and practicable. delusions may occur. (b) Lack of physical dependence. Abusers of amphetamines are prone to accidents (c) Absence of tolerance. because of both the excitation produced by these The habitual and, in particular, the exaggerated agents and the excessive fatigue which may break consumption of khat may also, on account of its DRUG DEPENDENCE: ITS SIGNIFICANCE AND CHARACTERISTICS 731

non-amphetamine ingredients (tannins) damage of a single dose or of several doses over a period of the individual's health. The social and economic two or three days is the customary pattern; pro- consequences of dependence on khat consist, in the longed or continuous use is unusual. Periodic, rather main, of the alienation of the user's funds and the than continuous, use is favoured by difficulty in erosion of his working capacity and concern both obtaining the drugs, rapid development and dis- the individual and his environment as well as the appearance of tolerance, and lack of physical community. dependence on these drugs. Drugs of the LSD type induce a state of excitation Drug Dependence of (LSD) Type of the central nervous system and central autonomic hyperactivity manifested by changes in mood Drugs of this type include lysergic acid diethyl- (usually euphoric, sometimes depressive), anxiety, aamide (LSD), a semisynthetic derivative of ergo- distortion in sensory perception (chiefly visual), novine; , an found in a mushroom visual hallucinations, delusions, depersonalization, (" teonanacatl ", Psilocybe mexicana); , the dilatation of the pupils, and increases in body most active alkaloid present in the buttons of a temperature and blood pressure. small cactus (" mescal ", " ", Lophophora Psychic dependence on drugs of the LSD type williamsii), and in the seeds of some morning glory varies greatly, but it usually is not intense. The varieties (" ololiuqui ", Rivea corymbosa L. Hall f.; thrill-seekers and non-conformists may enjoy the Ipomoea violacea L.), the active principle of which is effects of these agents and may wish to repeat them, closely related to LSD. The mushrooms, cactus but if such agents are not readily available, these buttons and the morning glory seeds are used by persons will either do without them or substitute certain American Indian tribes in religious ceremo- another substance. A minority of users may develop nies or are employed by medicine men or women such strong psychic dependence on those substances of these tribes in treating illness, usually in ritualistic that they wreck their careers by persisting in using fashion. Such religious and ritualistic use does not the drugs despite strong social condemnation. seem to lead frequently to drug dependence. The No evidence of physical dependence can be drugs have received wide publicity, however, and detected when the drugs are withdrawn abruptly. they possess a particular attraction for certain A high degree of tolerance to LSD (Isbell et al., psychologically and socially maladjusted persons 1956) and to psilocybin (Wolbach, Isbell & Miner, who have difficulty in conforming to usual social 1962) develops rapidly and disappears rapidly. norms. These include " arty " people such as Tolerance to mescaline develops more slowly. struggling writers, painters and musicians; frustrated Persons who are tolerant to any of these three non-conformists; and curious thrill-seeking ado- drugs are cross-tolerant to the other two (Wolbach, lescents and young adults. The drugs are taken for Isbell & Miner, 1962). thrills (" kicks "), to alter mood, to change and The chief dangers to the individual arise from the clarify perception, to induce reveries, and to obtain psychological effects. Impairment of judgement "s psychological insight " into the personality prob- could lead to dangerous decisions or accidents. lems of the user. Generally, the drugs are taken Occasional persons may become depressed, so that orally and in the company of other users. Ingestion suicide is a possibility in users of these drugs.

UMI!

L'element commun aux differentes formes de la toxico- nature du contr6le eventuel a envisager. L'utilisation manie etant un etat de dependance, qu'il soit psychique generale de ce terme contribuera a faire ressortir l'exis- ou physique ou qu'il ait ce double caractere, le Comite tence d'une relation entre certaines substances, en appe- OMS d'experts des Drogues engendrant la Toxicomanie lant l'attention sur une caracteristique commune de leur a recommande de substituer le terme e dependance * aux emploi abusif, et elle permet de mieux decrire et de mieux termes 4 toxicomanie * et e accoutumance a. diff6rencier certaines particularites specifiques des sub- e Dependance . est un terme de portee gen6rale, qui a stances en cause. l'avantage d'etre applicable a tous les types d'emploi La dependance se definit comme un etat qui resulte abusif de drogues et de ne prejuger en rien l'ampleur du de l'absorption periodiquement ou continuellement risque qui resulte de ces abus pour la sante publique, ni la repetee d'une certaine drogue. Ses caracteristiques varient 732 N. B. EDDY AND OTHERS suivant les drogues, ce qui doit etre bien precise par l'in- c) apparition d'une tolerance, dont le caractere incons- dication, dans chaque cas, du type particulier dont il tant et partiel d6termine la persistance, a un 'degr6 s'agit. consid6rable, d'un trouble du comportement tributaire Les descriptions ont ete limitees aux aspects medicaux des effets pharmacodynamiques des drogues. On observe de la dependance, mais les caracteristiques et repercus- une certaine tolerance croisee et reciproque, mais incom- sions sociales et 6conomiques du phenomene ne doivent plete, a l'alcool et aux barbituriques; pas etre perdues de vue. Elles varient suivant le type d) l'alcoolisme entraine frequemment des lesions de drogue et, de meme, le prejudice cause a l'individu pathologiques evidentes au niveau de certains tissus; et a la societe differe selon le type de dependance. une action analogue n'a pu etre mise en evidence concer- Dans I'article qui precede, sept types de dependance nant les barbituriques. ont ete d6crits, c'est-a-dire la dependance de type mor- phinique, barbiturique-alcool, cocainique, cannabique, Caracteristiques de la dependance de type cocatnique: amphetaminique ainsi que des types du khat et des sub- a) forte dependance psychique; stances hallucinogenes (LSD). Pour les differents b) absence d'apparition d'une d6pendance physique et, types de dependance, les caract6ristiques medicales sont par suite, absence d'un syndrome d'abstinence caract6- resumees dans une formule breve et precise comme suit: ristique lors du sevrage; c) absence de tolerance; on note plut6t une sensibili- Caracte'ristiques de la dJpendance de type morphinique: sation aux effets de la drogue, dans certains cas. a) forte dependance psychique, qui se manifeste par une tendance ou impulsion irr6sistible a continuer a Caracte'ristiques de la d4pendance de type cannabique: prendre la drogue et A se la procurer par tous les moyens, a) d6pendance psychique mod6r6e ou forte, suivant soit pour en obtenir des jouissances, soit pour pallier des les effets subjectifs recherches; sensations desagreables; b) absence de d6pendance physique, de sorte qu'il b) apparition precoce d'une d6pendance physique qui n'existe pas de syndrome d'abstinence caracteristique s'accroit parallelement a l'augmentation des doses. Ce lorsque l'administration de la drogue est suspendue; fait oblige a continuer l'administration de la drogue c) peu de tendance A augmenter les doses; aucune initiale, ou d'une substance ayant des proprietes analo- tol6rance n'a pu etre demontree. gues, afin de maintenir un semblant d'homeostase et de prevenir l'apparition de symptomes et d'indices resul- Caracteristiques de la dependance de type amphiftaminique: tant du sevrage. Celui-ci, de meme que l'administration a) d6pendance psychique variable; d'un antagoniste, precipite l'apparition d'un syndrome d'abstinence bien defini, caracteristique et limite dans le b) pas de dependance physique et, par suite, pas de temps; syndrome d'abstinence caract6ristique, bien que le sevrage provoque un etat de depression mentale et phy- c) apparition d'une tolerance, d'oLu la n6cessite d'aug- sique lorsque l'organisme n'est plus soumis a l'excitation menter les doses pour obtenir les effets pharmacodyna- permanente de la drogue; miques initiaux. c) developpement lent d'une tolerance marqu&e vis-a-vis de beaucoup des effets de la drogue, mais avec Caracteristiques de la dependance de type barbiturique- participation inegale des differentes composantes du alcool: systeme cerebral, si bien que l'etat d'agitation et l'in- a) dependance psychique d'intensite variable qui peut somnie persistent et que des phenomenes psychotoxiques, conduire a l'abus periodique plut6t qu'a l'abus continuel, comme des hallucinations ou des illusions, peuvent notamment dans le cas de l'alcool; apparaitre. b) nette apparition d'une d6pendance physique qui, La dependance de type khat, dans l'eventualite de la cependant, ne peut generalement etre d6cel6e qu'apres consommation traditionnelle par mastication, se consommation de quantit6s tres superieures aux normes caracte¶rise par: habituellement admises selon les criteres th6rapeutiques a) une d6pendance psychique mod6ree, mais souvent et sociaux. Si la consommation est abaiss6e au-dessous persistante, pour autant qu'elle puisse etre entretenue; d'un seuil critique, on note I'apparition d'un syndrome b) l'absence de d6pendance physique; d'abstinence caract6ristique et limite dans le temps. En c) l'absence de tolerance. ce qui concerne les barbituriques, la suppression des sympt6mes peut etre obtenue non seulement par l'admi- La d6pendance psychique vis-a-vis des drogues du type nistration d'un agent possedant une action analogue, des substances hallucinogenes est tres variable, mais mais egalement, en partie du moins, par l'administration generalement peu accentu6e. d'alcool. Pour ce dernier, c'est le ph6nomene inverse Aucun indice de d6pendance physique n'est observe qui se produit; en cas de sevrage brusque. DRUG DEPENDENCE: ITS SIGNICANCE AND CHARACTERISTICS 733

Une tol6rance marqu6e it la LSD et a la psilocybine ment. Les personnes qui sont tolerantes a l'une de ces se manifeste rapidement et disparait egalement rapide- trois substances presentent une tol6rance croisee aux ment. La tolerance i la mescaline apparait plus lente- deux autres.

REFERENCES

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