Drug Dependence: its Significance and Characteristics

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

Drug Dependence: its Significance and CharacteristicsNATHAN B. EDDY, M.D.,1 H. HALBACH, Dr. med. Dr.-Ing.,2HARRIS ISBELL, M.D.3 & MAURICE H. SEEVERS, M.D.4

It has become impossible in practice, and is scientifically unsound, to maintain a singledefinition for all forms of drug addiction and/or habituation. A feature common to theseconditions 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 attainedby substitution of the term drug dependence of this or that type, according to the agent orclass of agents involved, in discussions of these conditions, especially inter-disciplinary.Short descriptions, followed by concise listings of their characteristics, are formulated forthe various types ofdependence on at present widely abused major groups ofsubstances.

CONTENTSPage

Introduction ......... .. .. .. .. . . 721The term " drug dependence " . . . . . . . . . . . . 722Characteristics of drug dependence . . . . . . . . . . 724

Morphine Type . . . . . . . . . . . . . . . . . 724Barbiturate-Alcohol Type . . . . . . . . . . . . . 725Cocaine Type . . . . . . . . . . . . . . . . . . 727Cannabis (Marihuana) Type . . . . . . . . . . . . 728Amphetamine Type . . . . . . . . . . . . . . . 729Khat Type . . . . . . . . . . . . . . . . . . . 730Hallucinogen (LSD) Type ......... 731

Resume. . . . . . . . . . . . . . . . . . . . . . 731References .................... 733

INTRODUCTION

Among the functions of the World Health Organ-ization is the taking of decisions on the status ofindividual drugs under the relevant internationaltreaties for narcotics control. This function has beenestablished by international conventions and dependsupon the competence of the WHO Expert Com-mittee on Addiction-Producing Drugs. The con-ventions specifically direct that, in response to a

1 Consultant, National Institutes of Health, Bethesda,Md., USA.

2 Chief, Pharmacology and Toxicology, World HealthOrganization, Geneva, Switzerland.

' Professor of Medicine and Head, Section of ClinicalPharmacology, Department of Medicine, University ofKentucky, Lexington, Ky., USA.

'Professor of Pharmacology and Chairman of theDepartment, The University of Michigan, Ann Arbor,Mich., USA.

notification from a government, the Committee cometo a finding as to whether or not the substance inquestion is or is convertible into one with addiction-producing or addiction-sustaining properties similarto those of morphine or cocaine or cannabis. A posi-tive finding by the Committee is followed by a recom-mendation for appropriate international narcoticscontrol. Pertinent to any conclusion or decision isthe consideration of specific therapeutic effects,the liability of substances having such effects toproduce drug dependence, and the evaluation ofthe risk to public health if such substances areused for medical purposes or abused. Obviously,such considerations depend upon the availabilityof dependable methods and critical evaluation oftheir application to the determination of both usefultherapeutic properties and the kind and degree ofdependence that may accompany drug use. WHO

1604 -721

722 N. B. EDDY AND OTHERS

has already published a series of reports on theserequirements (Braenden, Eddy & Halbach, 1955;Eddy, Halbach & Braenden, 1956, 1957; Halbach& Eddy, 1963; WHO Scientific Group on theEvaluation of Dependence-Producing Drugs, 1964).As a partial guide to its own deliberations and

those of others, the WHO Expert Committee onAddiction-Producing Drugs (1952) attempted toformulate a definition of addiction that would beapplicable to drugs under international control.A revised definition 1 was proposed by the Com-mittee several years later, in its seventh report(WHO Expert Committee on Addiction-ProducingDrugs, 1957).

In its seventh report the Committee sought alsoto differentiate addiction from habituation andwrote a definition of the latter 2 which, however,failed in practice to make a clear distinction. Thesedefinitions gained some acceptance, but confusionin the use of the terms addiction and habituation,and particularly misuse of the former, continue.Both terms are frequently used interchangeably andoften inappropriately. It is not uncommon to applythe term addiction to any misuse of drugs outside ofmedical practice, with a connotation of seriousharm to the individual and to society, and oftenwith a demand that something be done about it.Such broad use can only create confusion andmisunderstanding when abuse of drugs is discussedfrom different viewpoints.The difficulties in terminology become increas-

ingly apparent with the continuous appearance ofnew agents with various and perhaps unique phar-macological profiles, and with changing patternsof use of drugs already well known. These develop-ments must be considered in their relation to, butmay not be adequately characterized by, currentdefinitions of addiction. There is scarcely any agentwhich can be taken into the body to which some

1 " Drug addiction is a state of periodic or chronicintoxication produced by the repeated consumption of adrug (natural or synthetic). Its characteristics include:(1) an overpowering desire or need (compulsion) to continuetaking the drug and to obtain it by any means; (2) a tendencyto increase the dose; (3) a psychic (psychological) andgenerally a physical dependence on the effects of the drug;(4) detrimental effect on the individual and on society."

" Drug habituation (habit) is a condition resulting fromthe repeated consumption of a drug. Its characteristicsinclude: (1) a desire (but not a compulsion) to continuetaking the drug for the sense of improved well-being whichit engenders; (2) little or no tendency to increase the dose;(3) some degree of psychic dependence on the effect of thedrug, but absence of physical dependence and hence of anabstinence syndrome; (4) detrimental effects, if any, primarily,on the individual."

individuals will not get a reaction satisfactory orpleasurable to them, persuading them to continueits use even to the point of abuse-that is, to exces-sive or persistent use beyond medical need. Probablythe only exceptions are agents that have incidentalor side effects that prevent such use-for example,cumulative or early toxic effects, to which theindividual does not become tolerant.

THE TERM " DRUG DEPENDENCE"

In order to try to clarify this situation, muchthought and discussion have been devoted to findinga term that will cover all kinds of drug abuse. Thecomponent in common appears to be dependence,whether psychic or physical or both. Hence, use ofthe term " drug dependence " with a modifyingphrase linking it to a particular type of drug in orderto differentiate the characteristics associated withone class of drugs or another has been given mostcareful consideration. In its thirteenth report, theWHO Expert Committee on Addiction-ProducingDrugs (1964) has, in fact, recommended substitutionof the term " drug dependence " for both of theterms drug addiction and drug habituation. Thisrecommendation has been endorsed by the WHOScientific Group on Evaluation of Dependence-Producing Drugs (1964) and has been concurred inand supported, inter alia, by the Committee onDrug Addiction and Narcotics of the NationalAcademy of Sciences-National Research Council(USA).8Drug dependence is a state of psychic or physical

dependence, or both, on a drug, arising in a personfollowing administration of that drug on a periodicor continuous basis. The characteristics of such astate will vary with the agent involved, and thesecharacteristics must always be made clear by desig-nating the particular type of drug dependence ineach specific case; for example, drug dependence ofmorphine type, of barbiturate type, of amphetaminetype, etc.The specification of the type of dependence is

essential and should form an integral part of thenew terminology, since it is neither possible noreven desirable to delineate or define the term drugdependence independently of the agent involved.It should also be remembered that it was the desireto achieve the impossible and define a complexsituation by a single term (" addiction " or " habiA

3Twenty-sixth Meeting, Washington, D.C., 1964.

DRUG DEPENDENCE: ITS SIGNIFICANCE AND CHARACTERISTICS

tuation ", respectively) which has given rise toconfusion in many cases. Therefore, the descriptionof drug dependence as a state is a concept forclarification and not, in any sense, a specific defini-tion.

It must be emphasized that drug dependence is ageneral term that has been selected for its applicabil-ity to all types of drug abuse and thus carries noconnotation of the degree of risk to public healthor need for any or a particular type of drug control.The agents controlled by international treaties andby national narcotics laws continue to be those thatare morphine-like, cocaine-like, or cannabis-like,the use of which may result, respectively, in drugdependence of morphine type, of cocaine type, or ofcannabis type. Other types of drug dependence,such as those of the barbiturate and amphetaminetypes, continue to present problems, and theirdescription under the general term of drug de-pendence, while it may help to delineate thoseproblems, in no way suggests or affects the measuresto be taken to solve them. Use of the general termwill help to indicate a relationship by drawingattention to a common feature associated with drugabuse, but at the same time will differentiate, bymore exact description, specific characteristicsaccording to the nature of the agent involved.

Further to clarify our meaning, the nature andsignificance of drug abuse may be considered fromtwo points of view: one relates to the interactionbetween the drug and the individual, the other tothe interaction between drug abuse and society.The first viewpoint is concerned with drug depen-dence and the interplay between the pharmaco-dynamic actions of the drug and the psychologicalstatus of the individual. The second-the inter-action between drug abuse and society-is con-cerned with the interplay of a wide range of con-ditions, environmental, sociological, and economic.The Committee tried to encompass both points ofview when, in its definition of addiction, it listedcharacteristics of which some were pharmaco-dynamic and others psychological and socio-economic, perhaps thereby compounding some ofthe existing confusion.As already noted, individuals may become

dependent upon a wide variety of chemical sub-stances that produce central nervous system effectsranging from stimulation to depression. All of thesedrugs have one effect in common: they are capableof creating, in certain individuals, a particular stateof mind that is termed " psychic dependence ".

In this situation, there is a feeling of satisfaction anda psychic drive that require periodic or continuousadministration of the drug to produce pleasure orto avoid discomfort. Indeed, this mental state isthe most powerful of all of the factors involved inchronic intoxication with psychotropic drugs, andwith certain types of drugs it may be the only factorinvolved, even in the case of most intense cravingand perpetuation of compulsive abuse.Some drugs also induce physical dependence,

which is an adaptive state that manifests itself byintense physical disturbances when the administra-tion of the drug is suspended or when its action isaffected by the administration of a specific antag-onist. These disturbances, i.e., the withdrawal orabstinence syndromes, are made up of specificarrays of symptoms and signs of psychic and phy-sical nature that are characteristic for each drugtype. These conditions are relieved by re-administra-tion of the same drug or of another drug of similarpharmacological action within the same generictype. No overt manifestation of physical dependenceis evident if an adequate dosage is maintained.Physical dependence is a powerful factor in reinfor-cing the influence of psychic dependence uponcontinuing drug use or relapse to drug use afterattempted withdrawal.To reiterate, psychic dependence can and does

develop, especially with stimulant-type drugs,without any evidence of physical dependence and,therefore, without an abstinence syndrome develop-ing after drug withdrawal. Physical dependence,too, can be induced without notable psychicdependence; indeed, physical dependence is aninevitable result of the pharmacological action ofsome drugs with sufficient amount and time ofadministration. Psychic dependence, while alsorelated to pharmacological action, is more particu-larly a manifestation of the individual's reactionto the effects of a specific drug and varies with theindividual as well as with the drug.Many of the drugs that induce dependence,

especially those that create physical dependence,also induce tolerance, which is an adaptive statecharacterized by diminished response to the samequantity of drug or by the fact that a larger dose isrequired to produce the same degree of pharmaco-dynamic effect. Both drug dependence and drugabuse may occur without the development ofdemonstrable tolerance.Drugs that are capable of inducing dependence

may also be associated with psychotoxic effects

723

N. B. EDDY AND OTHERS

that are manifested by profound alterations inbehaviour. These effects may occur with a singlelarge dose or during the course of continuedadministration, or they may be precipitated bywithdrawal of the drug following continued ad-ministration. The pattern of abnormal behaviouris, within limits, characteristic for each drug type,but wide variation occurs in individual responsesdepending, among other things, upon the pre-existing mental state of the person involved.The characteristics of drug dependence show

significant differences from one generic type toanother, a situation that makes it mandatory toestablish clearly the pattern for each type of drugdependence. Even though some variations occuramong individual members of each generic group,the consistency of the pattern of pharmacodynamicactions and responses is sufficiently uniform topermit, at this time, the delineation of each of theprincipal types.

CHARACTERISTICS OF DRUG DEPENDENCE

Drug Dependence of Morphine Type

The outstanding and distinctive characteristicof dependence on morphine and morphine-likeagents is that the major elements-psychic andphysical dependence, as well as tolerance-can beinitiated by the repeated administration of smalldoses and increase in intensity in direct relationshipto an increase in dosage. This characteristic impliesthat dependence on drugs of this generic type maybe created within the dosage range generally usedfor therapeutic purposes, and that its mechanismmay be set in motion by the first dose administered.The characteristics of dependence of the morphine

type are:

(a) Strong psychic dependence, which manifestsitself as an overpowering drive or compulsion tocontinue taking the drug and to obtain it by anymeans, for pleasure or to avoid discomfort.

(b) An early development of physical dependencewhich increases in intensity, paralleling increase indosage. This requires a continuation of administra-tion of the same drug, or an allied one, to maintaina semblance of homeostasis and to prevent theappearance of the symptoms and signs of with-drawal. Withdrawal of the drug or administrationof a specific antagonist precipitates a definite,characteristic and self-limited abstinence syndrome.

(c) Development of tolerance that requires anincrease in dosage to obtain the initial pharmaco-dynamic effects.With morphine, the abstinence syndrome appears

within a few hours of the last dose, reaches peakintensity in 24 to 48 hours, and subsides spontaneous-ly. The most severe symptoms usually disappearwithin ten days, although a residuum persists for amuch longer period. The time of onset, peakintensity, and duration of abstinence phenomenavary with the degree of dependence on the drug(Andrews & Himmelsbach, 1944) and with thecharacteristics of the specific agent involved.Administration of a specific antagonist duringcontinuing administration of morphine-like drugspromptly precipitates a more rapid and intenseabstinence syndrome that lasts only a few hours.The unique feature of the morphine abstinence

syndrome is that it represents changes in all majorareas of nervous activity, including alteration inbehaviour, excitation of both divisions of theautonomic system simultaneously, and dysfunctionof the somatic nervous system. The complex ofsymptoms and signs include anxiety, restlessness,generalized body aches, insomnia, yawning, lacrima-tion, rhinorrhoea, perspiration, mydriasis, pilo-erection (gooseflesh), hot flushes, nausea, emesis,diarrhoea, elevation of body temperature, ofrespiratory rate and of systolic blood pressure,abdominal and other muscle cramps, dehydration,anorexia, and loss of body weight (Isbell & White,1953).The generic type of morphine-like compounds for

which morphine is used as the standard of referencecomprises substances with different chemical constitu-tions but similar pharmacological profiles. They varyin potency from substances with low activity to othersthat are several thousand times as potent as morphine.These agents are alike in their ability to produce andmaintain some degree of physical dependence, tomaintain tolerance and physical dependence andto prevent the appearance of abstinence phenomena.These agents are mutually interchangeable by sub-stitution, although not on a milligram-for-milligrambasis. Variations exist in the capacity of potentmorphine-like substances to induce psychic de-pendence and to produce psychic satisfaction onsubstitution for one another.Within the generic class of agents with pharmaco-

dynamic features similar to those of morphine,making them capable of inducing physical depend-ence with sufficient dosage, there are some with a

724


high degree of usefulness which, in therapeutic doses,are generally inadequate substitutes for morphine.Even in higher doses, these compounds are notcompletely satisfactory in sustaining an establishedmorphine dependence; their effects are not usuallysufficiently satisfying subjectively to induce signifi-cant psychic dependence. Codeine is generallyrecognized as a reference standard for this group.A relationship between dose, pharmacodynamic

properties and intensity of physical dependence hasbeen mentioned. Regularity of administration atintervals well within the duration of action of thedrug also hastens development of physical de-pendence. The time from the beginning of admi-nistration to the appearance of demonstrable phy-sical dependence also varies with the agent. Withmorphine, this interval under clinical conditions ofadministration is two or three weeks; it is shorterfor ketobemidone, probably longer for phenazocineand definitely longer for codeine, especially whenthis is administered orally.

Finally, with drug dependence of the morphinetype, harm to the individual is, in the main, indirect,arising from preoccupation with drug-taking;personal neglect, malnutrition and infection arefrequent consequences. For society also, theresultant harm is chiefly related to the preoccupa-tion of the individual with drug-taking; disruptionof interpersonal relationships, economic loss, andcrimes against property are frequent consequences.

Drug Dependence of Barbiturate-Alcohol Type

The signs and symptoms of barbiturate and ofalcohol intoxication are similar, as are the signs andsymptoms of abstinence from these drugs. Barbi-turates will suppress alcohol abstinence phenomena,and alcohol will suppress, at least partially, thesymptoms of barbiturate withdrawal. The two drugsare essentially additive and interchangeable inchronic intoxications; these similarities justify theterm " dependence of barbiturate-alcohol type ",but there are psychological and sociological differ-ences, so that barbiturate and alcohol dependencewill be described separately.

Drug dependence of barbiturate type. Whiledependence on drugs of the barbiturate type pre-sents certain similarities to dependence on drugsof the morphine type, in detail there is a charac-teristically different picture both during the course ofintoxication and during withdrawal. It is a statearising from repeated administration of a barbi-

turate on a continuous basis, generally in amountsthat exceed the usual therapeutic dose levels. Thereis a strong desire or need to continue taking thedrug, a need that can be satisfied by the drug takeninitially or by another with barbiturate-like pro-perties. There is a psychic dependence on the effectsof the drug that is related to subjective and individualappreciation of those effects, and there is physicaldependence requiring the presence of the drug forthe maintenance of homeostatis and resulting in acharacteristic and self-limited abstinence syndromewhen the drug is withdrawn.

Tolerance to barbiturates does develop and, withrelatively low doses, it will become evident withinseven days. There is, in contrast with tolerance tomorphine-like drugs, a limit to the dose to whicha person can become tolerant. This limit is acharacteristic of the individual patient and varieswidely. Following withdrawal of barbiturates,tolerance is rapidly lost, and some patients maybecome more sensitive to barbiturates than theyhad been prior to chronic intoxication with thesedrugs (Belleville & Fraser, 1957).During the chronic intoxication of continuing

administration, there is some persistence of sedativeaction, ataxia, etc. through the incomplete develop-ment of tolerance, which makes the individualaccident-prone. There is also impairment of mentalability, confusion, increased emotional instability,and risk of sudden overdosage through delayedonset of action and perceptional distortion of time.The clinical manifestations of chronic barbiturismare similar to those of chronic alcoholism (Isbellet al., 1950).The abstinence syndrome is the most character-

istic and distinguishing feature of drug dependenceof the barbiturate type. It begins to appear withinthe first 24 hours of cessation of drug-taking, reachespeak intensity in two or three days, and subsidesslowly. At present there is no agent which is knownto precipitate the barbiturate abstinence syndromeduring continuation of drug administration. Thecomplex of symptoms constituting the abstinencesyndrome, in approximate order of appearanceincludes: anxiety, involuntary twitching of muscles,tremor of hands and fingers, progressive weakness,dizziness, distortion in visual preception, nausea,vomiting, insomnia, weight loss, a precipitous dropin blood pressure on standing, convulsions of agrand-mal type, and a delirium resembling alcoholicdelirium tremens or a major psychotic episode.Convulsions and delirium do not usually occur at

725


the same time; generally, a patient may have oneor two convulsions during the first 48 hours of with-drawal and then become psychotic during the secondor third night. With respect to the psychoticepisodes, paranoid reactions, reactions resemblingschizophrenia with delusions and hallucinations,withdrawn semi-stuporous state, and disorganizedpanic have been seen.One would expect that the mechanism of physical

dependence of the barbiturate type, as of that of themorphine type, would be set in motion by the firstdose, but there is no evidence that this is the case.There is, indeed, no evidence that physical depend-ence develops to a detectable degree with continua-tion of the therapeutic doses usual for the productionof sedation or hypnosis; the daily dose must beincreased appreciably above the usual therapeuticlevel before abstinence signs will appear on abruptwithdrawal. Some degree of psychic dependencefacilitating continuance of administration mayoccur with therapeutic doses, but such doses canusually be discontinued without serious subjectivedisturbance. Factors that may lead to increasingconsumption and eventual overt physical dependenceinclude, in addition to tolerance, the incompleterelief of emotional problems and tension, andimpairment of judgement, so that larger doses aretaken without regard to need.

In drug dependence of the barbiturate type, thedetrimental effect on the individual stems in partfrom his preoccupation with drug-taking, but moreparticularly from the untoward effects of large dosesof the drug: ataxia; dysarthria; impairment ofmental function, with confusion, loss of emotionalcontrol, poor judgement and, occasionally, a toxicpsychosis; coma and death. The harm to societyis also related to both the individual's preoccupa-tion with drug-taking and the persistence of theeffects of these drugs on motor functioning, emo-tional stability and interpersonal relationships,with proneness to accidents and to assaults on otherpersons as frequent consequences. By analogy, allagents which produce barbiturate-like sedation,because of the relief of anxiety, mental stress, etc.,should produce some psychic dependence and, forthe reasons enumerated for dosage increase, physicaldependence when a sufficient concentration in theorganism has been attained. This possibility hasbeen confirmed for many sedative agents of differenttypes, including barbiturates and the so-called non-barbiturate sedatives such as glutethimide, methy-prylon, meprobamate, chlordiazepoxide, bromisoval,

chloral hydrate and paraldehyde, but there may beexceptions.Drug dependence ofalcohol type. Drug dependence

of the alcohol type may be said to exist when theconsumption of alcohol by an individual exceedsthe limits that are accepted by his culture, if heconsumes alcohol at times that are deemed inap-propriate within that culture, or if his intake ofalcohol becomes so great as to injure his health orimpair his social relationships. Since the use ofalcoholic beverages is a normal, or almost normal,part of the cultures of many countries, dependenceon alcohol is usually apparent as an exaggerationof culturally accepted drinking patterns, and themanifestations of dependence vary accordingly in acharacteristic fashion with the cultural mode ofalcohol use. Thus, in the USA. alcohol is frequentlytaken in concentrated forms as an aid to socia'intercourse, so that dependence on alcohol in theUSA is usually characterized by heavy consumptionof strong spirits during short periods of the day,by a tendency to periodic drinking, and by overtdrunkenness. In some other countries, on the otherhand, alcohol is customarily consumed in wine,usually with meals. In these countries, dependenceon alcohol is characterized by the drinking of winethroughout the day, by a relatively continuousintake of alcohol in this manner, and by relativelylittle overt drunkenness. A similar pattern applieswhere beer is the common beverage.

Psychic dependence on alcohol occurs in alldegrees. In the mildest grade, alcohol is missed ordesired if not available at meals or at social functions.A moderate degree of psychic dependence existswhen the individual feels compelled to drink inorder to work or to participate socially and takessteps to ensure a supply of alcohol for these purposes.Strong dependence is present if the individual usesalcohol in amounts far exceeding the cultural norm,drinks in situations that culturally do not call fordrinking and is obsessed with maintaining a supplyof alcohol even to the extent of drinking unusualor poisonous mixtures.As with other drugs, psychic dependence on

alcohol results from an interplay between thepharmacodynamic effects of the drug and thepersonality problems of the user. The consciouslyverbalized reasons for the use of alcohol cover awide gamut and may include a need to stimulatethe appetite, to alleviate anxiety or fatigue, toremove boredom or to induce sleep. Other reasons,not consciously verbalized, may include needs to

726

DRUG DEPENDENCE: ITS SIGNICANCE AND CHARACTERISTICS

express masculinity, to remove behavioural controlsso that aggressive impulses may be expressed, andto blot out completely a hostile, threatening world.

Tolerance to alcohol does develop. Duringcontinuous drinking there is a slight but definiteincrease in the amount of ingested alcohol requiredto maintain a given blood level. In addition, somesort of physiological and psychological adaptationoccurs so that the alcoholic appears less intoxicatedand is less impaired in performance tests at a givenconcentration of blood alcohol than is a non-alcoholic. Tolerance to alcohol, however, is in-complete and never reaches the degree seen withmorphine-like agents.

Physical dependence on alcohol definitely occurs,and the abstinence syndrome resulting when theintake of alcohol is reduced below a critical levelis manifested by tremors, sweating, nausea, tachy-cardia, rise in temperature, hyper-reflexia, posturalhypotension and, in severe grades, convulsions anddelirium. The last-mentioned condition is charac-terized by confusion, disorientation, delusions andvivid visual hallucinations. The intensity of thealcohol abstinence syndrome probably varies withthe duration and amount of alcohol intake, but asyet little quantitative information on this point isavailable. The mortality rate, when the alcoholabstinence syndrome is severe, averages at least 8 %.The harm to the individual resulting from

dependence on alcohol can be quantitatively greaterthan that caused by any other type of drug depend-ence. Alcohol impairs efficiency of thinking andpsychomotor co-ordination, leading to deteriorationin work performance and to accidents. Judgementdeteriorates, leading to all sorts of errors in businessand to disturbances of relations with other people.Conscious controls of behaviour are " dissolved ",with resulting exhibitionism, aggressiveness andassaultiveness. In addition, dependence on alcoholpredisposes to and causes serious physical disease.The physical damage may be indirect, due to neglectof hygiene or to inadequate dietary intake andutilization, with resultant deficiencies, for example, invitamins, minerals and proteins. The most commonserious complication of protracted alcoholism is fattyportal cirrhosis. Alcoholics are frequently injuredbecause of impaired co-ordination and judgement.Damage to society is great. The alcoholic squand-

ers his resources to obtain his beverage, his pro-ductivity declines, and his family may be neglectedto the extent that it has to be supported by society.Alcoholics are frequently involved in accidents, with

property damage and injury to others. The economicburden of dependence on alcohol is enormous;even more important is the tremendous amount ofhuman suffering endured by the alcoholic and allwho are close to him.The characteristics of drug dependence of the

barbiturate-alcohol type are:(a) Psychic dependence of varying degree that

may lead to periodic rather than continuous abuse,especially with alcohol.

(b) The definite development of a physicaldependence that generally, however, can be detectedonly after the consumption of amounts considerablyabove the usual therapeutic or usual sociallyacceptable levels. Upon the reduction of intakebelow a critical level, a characteristic self-limitedabstinence syndrome ensues, the symptoms of which,in the case of barbiturates, can be suppressed notonly by a barbiturate-like agent but also, at leastpartially, by alcohol. The reverse situation exists inthe case of alcohol.

(c) The development of tolerance which isirregular and incomplete, so that there is consider-able persistence of behavioural disturbance de-pendent upon the pharmacodynamic effects of thedrugs. There is a mutual, but incomplete, crosstolerance of some degree between alcohol and thebarbiturates.

(d) A frequent consequence of alcoholism is overtpathology in tissues, whereas a similar developmentwith the barbiturates has not been demonstrated.

Drug Dependence of Cocaine Type

Cocaine is the prototype of the stimulant drugsthat are capable, in high dosage, of inducing euphoricexcitement and hallucinatory experiences. Theseproperties rank it high in the esteem of experienceddrug abusers and lead to the highest degree ofpsychic dependence.Abuse of cocaine takes several forms. The most

common is the centuries-old custom of coca-leafchewing, which is practised habitually by certainIndians of the high Andes. The leaf, mixed withlime, ostensibly to release the alkaloid, is usedalmost continuously to reduce sensations of cold,fatigue and hunger. With this form of abuse, releaseof the alkaloid and its absorption generally are tooslow or quantitatively too small to induce mentalchanges that would lead to abnormal behaviour, asdescribed below.

9

727


Despite its vasoconstrictive properties, cocaine isreadily absorbed through mucous membranes. Atone time, the application of cocaine solutions tooral and nasal lesions was a very popular form oftreatment, especially with those patients who appre-ciated the euphoric stimulation induced by the ab-sorbed drug. Closely allied to such use or abuse isanother form of absorption through the mucousmembranes that is now less common than it was-namely, the snuffing of cocaine crystals. Thisis a concentrated form of administration thatinduces such great psychic effects as to border onthose which may be obtained with intravenousadministration.Diminished need for cocaine as a local anaesthetic

and control of the world supply has reduced thetotal illicit use of this drug, but coincidentally therehas developed a most dangerous type of abuse-intravenous injection. In the most advanced form,this type of abuse involves administration at frequentintervals, as short as 10 minutes, the user desiringthe ecstatic thrills associated with this practice.This type of abuse appeals particularly to personswith psychopathic tendencies, which are oftenunmasked by the drug. The induced feeling of greatmuscular and mental strength leads the individualto overestimate his capabilities. This, associatedwith paranoid delusions and auditory, visual andtactile hallucinations, often makes the user a verydangerous individual, capable of serious antisocialacts. Digestive disorders, nausea, loss of appetite,emaciation, sleeplessness, and occasional convulsionsare commonly experienced by cocaine abusers ofthis type. Long-standing, continuing misuse ofcocaine alone at a high level is rare, however. Theuser reaches such a state of excitement that hevoluntarily seeks sedation. A frequent currentpractice is to antagonize the exciting effects by thealternate administration of morphine or some otherdepressant drug, or by the injection of the two typesof drug in combination, the cocaine-heroin mixture("speedball ") being particularly popular.No physical dependence on cocaine develops and,

consequently, no characteristic abstinence syndromeis noted on abrupt withdrawal. But severe de-pression may occur and delusions may persist forsome time after withdrawal.

Since cocaine undergoes rapid destruction in theorganism, large quantities can be given during a24-hour period. Indeed, in man as much as 10 gmdaily may be used when the drug is administered inrelatively small doses at short intervals. This has

led to the belief that tolerance to cocaine develops,a conclusion that is warranted neither by the factsnor by analogy with animal experiments. The criteriafor tolerance (diminution in objective effects andelevation of the lethal dose) are not observed inanimals even though it may be possible to administerseveral lethal doses within 24 hours, the total quan-tity varying with the detoxification capacity of theindividual species. Although the acute lethal dosefor man is unknown, it is clear that, given a constantblood level,no diminution ofits subjective or objectiveeffects is noted. These effects, in fact, becomeenhanced, a sensitization phenomenon that is alsoseen in animals. It is safe to conclude that man,like animals, does not develop tolerance to cocaine.

In summary, then, the characteristics of drugdependence of the cocaine type are:

(a) Strong psychic dependence.(b) No development of physical dependence and,

therefore, absence of a characteristic abstinencesyndrome when the drug is withdrawn.

(c) Absence of tolerance; rather, there is sensitiza-tion to the drug's effects in some instances.

(d) A strong tendency to continuation of adminis-tration, as in coca-leaf chewing, or rapid repetitionof the dose, as in the current practice of intravenousadministration. Quantitatively, the effects arestrikingly different, according to the mode of abuse.

Cocaine is probably the best example of a sub-stance to which neither tolerance nor physicaldependence develops and with which psychic de-pendence can lead to a profound and dangeroustype of drug abuse.

Drug Dependence of Cannabis (Marihuana) Type

It is not known with absolute certainty which ofthe chemical structures that have been isolated fromCannabis sativa L. is responsible for the typicalcannabis effects, but these can nevertheless bedescribed as constituting an entity that varies indegree according to the concentration of the activeprinciple or principles in the plant and the prepara-tions obtained therefrom, and to the mode of applica-tion. These effects are also producible by certainsynthetic substances of similar chemical structure.Among the more prominent subjective effects of

cannabis, for which it is taken occasionally, perio-dically or chronically, are: hilarity, often withoutapparent motivation; carelessness; loquaciouseuphoria, with increased sociability as a result;distortion of sensation and perception, especially

728


of space and time, with the latter reinforcing psychicdependence and being valued under special circum-stances; impairment of judgement and memory;distortion of emotional responsiveness; irritability;and confusion. Other effects, which appear es-pecially after repeated administration and as moreexperience is acquired by the user include: loweringof the sensory threshold, especially for optical andacoustical stimuli, thereby resulting in an intensifiedappreciation of works of art, paintings and music;hallucinations, illusions, and delusions that pre-dispose to antisocial behaviour; anxiety and aggres-siveness as a possible result of the various intellectualand sensory derangements; and sleep disturbances.

In the psychomotor sphere, hypermotility occurswithout impairment of co-ordination. Amongsomatic effects, often persistent, are injection of theciliary vessels and oropharyngitis, chronic bron-chitis and asthma; these conditions and hypogly-caemia, with ensuing bulimia, are symptoms ofintoxication, not of withdrawal.

Typically, the abuse of cannabis is periodic but,even during long and continuous administration,no evidence of the development of physical de-pendence can be detected. There is, in consequenceno characteristic abstinence syndrome when use ofthe drug is discontinued.Whether administration of the drug is periodic

or continuous, tolerance to its subjective and psycho-motor effects has not been demonstrated.Whereas cannabis often attracts the mentally

unstable and may precipitate temporary psychosesin predisposed individuals, no unequivocal evidenceis available that lasting mental changes are produced.Drug dependence of the cannabis type is a state

arising from chronic or periodic administration ofcannabis or cannabis substances (natural or syn-thetic). Its characteristics are:

(a) Moderate to strong psychic dependence onaccount of the desired subjective effects.

(b) Absence of physical dependence, so thatthere is no characteristic abstinence syndrome whenthe drug is discontinued.

(c) Little tendency to increase the dose and noevidence of tolerance.

For the individual, harm resulting from abuse ofcannabis may include inertia, lethargy, self-neglect,feeling of increased capability, with correspondingfailure, and precipitation of psychotic episodes.Abuse of cannabis facilitates the association withsocial groups and sub-cultures involved with more

dangerous drugs, such as opiates or barbiturates.Transition to the use of such drugs would be aconsequence of this association rather than an inhe-rent effect of cannabis. The harm to society derivedfrom abuse of cannabis rests in the economic con-sequences of the impairment of the individual's socialfunctions and his enhanced proneness to asocial andantisocial behaviour.

Drug Dependence of Amphetamine Type

The capacity of the amphetamines and drugswith similar pharmacological properties to elevatemood and induce a state of well-being is probablylargely the basis for their value and widespread useas stimulants and anorexiants. Since such therapycommonly involves continuous and prolongedadministration, the users of these drugs may developvarying degrees of psychic dependence upon them.This fact establishes the basis for abuse, where thedosage may be increased in both quantity andfrequency of administration in order to attain acontinuing stimulation and state of elation. Whencarried to an extreme, the psychotoxic effects oflarge amounts of drugs of the amphetamine typemay lead to aggressive and dangerous antisocialbehaviour.The abuse of this class of drugs originates in and

is perpetuated by the psychic drive to attainmaximum euphoria; no physical dependence iscreated. Qualitatively, the psychological effects arein many respects similar to those produced bycocaine.A unique feature of the amphetamines is their

capacity to induce tolerance, a quality possessed byfew central nervous system stimulants. Althoughtolerance develops slowly, a progressive increase indosage permits the eventual ingestion of amountsthat are several hundredfold greater than theoriginal therapeutic dose. Apparently, all parts ofthe central nervous system do not become tolerantat the same rate, so that the user will continue toexperience increased nervousness and insomnia asthe dose is increased. Although an individual maysurvive the oral administration of very large quanti-ties, such ingestion may produce profound be-havioural changes that are often of a psychoticnature, including hallucinations, delusions, etc.These latter effects are much more likely to occurafter intravenous injection than after ingestion.Indeed, the intravenous route is employed for theexpress purpose of obtaining bizarre mental effects,often associated with sexual functions, even to the

729


point of orgasm. This type of abuse has beenincreasingly frequent in recent years with the chang-ing patterns of drug abuse in various countries.Although the amphetamines do not induce

physical dependence, as measured by the criterionof a characteristic and reproducible abstinencesyndrome, it would be inaccurate to state that with-drawal from very large dosages is symptomless. Thesudden withdrawal of the stimulant drug which hasmasked chronic fatigue and the need for sleep nowpermits these conditions to appear in an exaggeratedfashion. Thus, the withdrawal period is character-istically a state of depression, both psychic andphysical, which probably reinforces the drive toresume the drug. In this regard, it is much less impor-tant and does not compare in magnitude with thosethat occur with morphine, barbiturates, alcoholand other drugs that create physical dependence.Withdrawal of drugs of the amphetamine type isnever threatening to life and requires psychologicalrather than somatic therapy.The use of amphetamines by self-administration

has increased consistently in recent years, ostensiblyas anti-fatigue agents in situations in which it isdesired to remain mentally alert for long periodswithout sleep or rest or to permit increased physicalperformance. The use of amphetamines as stimu-lants has also increased markedly in persons whoabuse alcohol and/or barbiturates; in many suchinstances there is dependence on more than onedrug. In such cases, the prognosis is poor, therelapse rate is high, and continued dependence onone or more drugs is the rule, especially in pre-psychotics or individuals with latent schizophrenia.

Thus, the characteristics of drug dependence ofthe amphetamine type are:

(a) A variable psychic dependence.(b) No physical dependence and, consequently,

no characteristic abstinence syndrome, thoughwithdrawal will be followed by a state of mentaland physical depression as the organism escapesfrom the persistent stimulation.

(c) The slow development of a considerable degreeof tolerance to many effects, but not participatedin equally by all components of the cerebral system,so that nervousness and sleeplessness persist andpsychotoxic effects such as hallucinations anddelusions may occur.

Abusers of amphetamines are prone to accidentsbecause of both the excitation produced by theseagents and the excessive fatigue which may break

through and manifest itself at an inopportune time.Abuse by intravenous administration, with itsconcomitant bizarre mental effects, may result inserious antisocial behaviour.

Drug Dependence ofKhat TypeKhat (Catha edulis Forssk.) is cultivated and

consumed in circumscribed areas of East Africa andthe Arabian peninsula. The common, and quanti-tatively most profitable, mode of application is byway of chewing the tender parts of the plant in asfresh a state as possible.The active principle of the khat leaf is chemically

and pharmacologically related to the amphetaminegroup of substances so closely that its effects areto be considered qualitatively identical with thoseof the latter group and quantitatively equal to theirweaker members. These resemblances extend to thesomatic as well as to the psychic effects, amongwhich a usually moderate degree of central stimula-tion, with ensuing elation and removal of fatigue, isthe effect most sought for by khat users, besidessuppression of hunger and, sometimes, of libido.The quantitative difference between the effects ofkhat and those of the commonly abused ampheta-mine substances is enhanced by the limitation ofthe ingestion and absorption of khat due to itsparticular mode of application. The naturallylimited dose of khat is assumed to prevent theoccurrence of tolerance, of rebound phenomenaafter cessation, and of psychotoxic effects typicalof the amphetamines when the latter are administeredin pure form and in high dosage. There is noevidence of the development ofa physical dependenceon khat during chronic use.

Nevertheless, the pleasurable effects afforded bykhat are a strong inducement for many to procureby any means the necessary supplies at least once aday or to repeat or prolong the periods of chewing,often at the expense of vital needs such as food.Such behaviour is a manifestation of psychicdependence.Drug dependence of the khat type is, under the

circumstances of its traditional consumption bychewing, characterized by:

(a) Moderate but often persistent psychic de-pendence as long as its maintenance is at allpracticable.

(b) Lack of physical dependence.(c) Absence of tolerance.The habitual and, in particular, the exaggerated

consumption of khat may also, on account of its

730


non-amphetamine ingredients (tannins) damagethe individual's health. The social and economicconsequences of dependence on khat consist, in themain, of the alienation of the user's funds and theerosion of his working capacity and concern boththe individual and his environment as well as thecommunity.

Drug Dependence of Hallucinogen (LSD) Type

Drugs of this type include lysergic acid diethyl-aamide (LSD), a semisynthetic derivative of ergo-novine; psilocybin, an indole found in a mushroom(" teonanacatl ", Psilocybe mexicana); mescaline, themost active alkaloid present in the buttons of asmall cactus (" mescal ", "peyote ", Lophophorawilliamsii), and in the seeds of some morning gloryvarieties (" ololiuqui ", Rivea corymbosa L. Hall f.;Ipomoea violacea L.), the active principle of which isclosely related to LSD. The mushrooms, cactusbuttons and the morning glory seeds are used bycertain American Indian tribes in religious ceremo-nies or are employed by medicine men or womenof these tribes in treating illness, usually in ritualisticfashion. Such religious and ritualistic use does notseem to lead frequently to drug dependence. Thedrugs have received wide publicity, however, andthey possess a particular attraction for certainpsychologically and socially maladjusted personswho have difficulty in conforming to usual socialnorms. These include " arty " people such asstruggling writers, painters and musicians; frustratednon-conformists; and curious thrill-seeking ado-lescents and young adults. The drugs are taken forthrills (" kicks "), to alter mood, to change andclarify perception, to induce reveries, and to obtain"s psychological insight " into the personality prob-lems of the user. Generally, the drugs are takenorally and in the company of other users. Ingestion

L'element commun aux differentes formes de la toxico-manie etant un etat de dependance, qu'il soit psychiqueou physique ou qu'il ait ce double caractere, le ComiteOMS d'experts des Drogues engendrant la Toxicomaniea recommande de substituer le terme e dependance * auxtermes 4 toxicomanie * et e accoutumance a.

e Dependance . est un terme de portee gen6rale, qui al'avantage d'etre applicable a tous les types d'emploiabusif de drogues et de ne prejuger en rien l'ampleur durisque qui resulte de ces abus pour la sante publique, ni la

of a single dose or of several doses over a period oftwo or three days is the customary pattern; pro-longed or continuous use is unusual. Periodic, ratherthan continuous, use is favoured by difficulty inobtaining the drugs, rapid development and dis-appearance of tolerance, and lack of physicaldependence on these drugs.Drugs of the LSD type induce a state of excitation

of the central nervous system and central autonomichyperactivity manifested by changes in mood(usually euphoric, sometimes depressive), anxiety,distortion in sensory perception (chiefly visual),visual hallucinations, delusions, depersonalization,dilatation of the pupils, and increases in bodytemperature and blood pressure.

Psychic dependence on drugs of the LSD typevaries greatly, but it usually is not intense. Thethrill-seekers and non-conformists may enjoy theeffects of these agents and may wish to repeat them,but if such agents are not readily available, thesepersons will either do without them or substituteanother substance. A minority of users may developsuch strong psychic dependence on those substancesthat they wreck their careers by persisting in usingthe drugs despite strong social condemnation.No evidence of physical dependence can be

detected when the drugs are withdrawn abruptly.A high degree of tolerance to LSD (Isbell et al.,

1956) and to psilocybin (Wolbach, Isbell & Miner,1962) develops rapidly and disappears rapidly.Tolerance to mescaline develops more slowly.Persons who are tolerant to any of these threedrugs are cross-tolerant to the other two (Wolbach,Isbell & Miner, 1962).The chief dangers to the individual arise from the

psychological effects. Impairment of judgementcould lead to dangerous decisions or accidents.Occasional persons may become depressed, so thatsuicide is a possibility in users of these drugs.

UMI!

nature du contr6le eventuel a envisager. L'utilisationgenerale de ce terme contribuera a faire ressortir l'exis-tence d'une relation entre certaines substances, en appe-lant l'attention sur une caracteristique commune de leuremploi abusif, et elle permet de mieux decrire et de mieuxdiff6rencier certaines particularites specifiques des sub-stances en cause.La dependance se definit comme un etat qui resulte

de l'absorption periodiquement ou continuellementrepetee d'une certaine drogue. Ses caracteristiques varient

731


suivant les drogues, ce qui doit etre bien precise par l'in-dication, dans chaque cas, du type particulier dont ils'agit.

Les descriptions ont ete limitees aux aspects medicauxde la dependance, mais les caracteristiques et repercus-sions sociales et 6conomiques du phenomene ne doiventpas etre perdues de vue. Elles varient suivant le typede drogue et, de meme, le prejudice cause a l'individuet a la societe differe selon le type de dependance.Dans I'article qui precede, sept types de dependance

ont ete d6crits, c'est-a-dire la dependance de type mor-phinique, barbiturique-alcool, cocainique, cannabique,amphetaminique ainsi que des types du khat et des sub-stances hallucinogenes (LSD). Pour les differentstypes de dependance, les caract6ristiques medicales sontresumees dans une formule breve et precise comme suit:

Caracte'ristiques de la dJpendance de type morphinique:

a) forte dependance psychique, qui se manifeste parune tendance ou impulsion irr6sistible a continuer aprendre la drogue et A se la procurer par tous les moyens,soit pour en obtenir des jouissances, soit pour pallier dessensations desagreables;

b) apparition precoce d'une d6pendance physique quis'accroit parallelement a l'augmentation des doses. Cefait oblige a continuer l'administration de la drogueinitiale, ou d'une substance ayant des proprietes analo-gues, afin de maintenir un semblant d'homeostase et deprevenir l'apparition de symptomes et d'indices resul-tant du sevrage. Celui-ci, de meme que l'administrationd'un antagoniste, precipite l'apparition d'un syndromed'abstinence bien defini, caracteristique et limite dans letemps;

c) apparition d'une tolerance, d'oLu la n6cessite d'aug-menter les doses pour obtenir les effets pharmacodyna-miques initiaux.

Caracteristiques de la dependance de type barbiturique-alcool:

a) dependance psychique d'intensite variable qui peutconduire a l'abus periodique plut6t qu'a l'abus continuel,notamment dans le cas de l'alcool;

b) nette apparition d'une d6pendance physique qui,cependant, ne peut generalement etre d6cel6e qu'apresconsommation de quantit6s tres superieures aux normeshabituellement admises selon les criteres th6rapeutiqueset sociaux. Si la consommation est abaiss6e au-dessousd'un seuil critique, on note I'apparition d'un syndromed'abstinence caract6ristique et limite dans le temps. Ence qui concerne les barbituriques, la suppression dessympt6mes peut etre obtenue non seulement par l'admi-nistration d'un agent possedant une action analogue,mais egalement, en partie du moins, par l'administrationd'alcool. Pour ce dernier, c'est le ph6nomene inversequi se produit;

c) apparition d'une tolerance, dont le caractere incons-tant et partiel d6termine la persistance, a un 'degr6consid6rable, d'un trouble du comportement tributairedes effets pharmacodynamiques des drogues. On observeune certaine tolerance croisee et reciproque, mais incom-plete, a l'alcool et aux barbituriques;

d) l'alcoolisme entraine frequemment des lesionspathologiques evidentes au niveau de certains tissus;une action analogue n'a pu etre mise en evidence concer-nant les barbituriques.

Caracteristiques de la dependance de type cocatnique:a) forte dependance psychique;b) absence d'apparition d'une d6pendance physique et,

par suite, absence d'un syndrome d'abstinence caract6-ristique lors du sevrage;

c) absence de tolerance; on note plut6t une sensibili-sation aux effets de la drogue, dans certains cas.

Caracte'ristiques de la d4pendance de type cannabique:a) d6pendance psychique mod6r6e ou forte, suivant

les effets subjectifs recherches;b) absence de d6pendance physique, de sorte qu'il

n'existe pas de syndrome d'abstinence caracteristiquelorsque l'administration de la drogue est suspendue;

c) peu de tendance A augmenter les doses; aucunetol6rance n'a pu etre demontree.

Caracteristiques de la dependance de type amphiftaminique:

a) d6pendance psychique variable;b) pas de dependance physique et, par suite, pas de

syndrome d'abstinence caract6ristique, bien que lesevrage provoque un etat de depression mentale et phy-sique lorsque l'organisme n'est plus soumis a l'excitationpermanente de la drogue;

c) developpement lent d'une tolerance marqu&evis-a-vis de beaucoup des effets de la drogue, mais avecparticipation inegale des differentes composantes dusysteme cerebral, si bien que l'etat d'agitation et l'in-somnie persistent et que des phenomenes psychotoxiques,comme des hallucinations ou des illusions, peuventapparaitre.La dependance de type khat, dans l'eventualite de laconsommation traditionnelle par mastication, secaracte¶rise par:a) une d6pendance psychique mod6ree, mais souvent

persistante, pour autant qu'elle puisse etre entretenue;b) l'absence de d6pendance physique;c) l'absence de tolerance.

La d6pendance psychique vis-a-vis des drogues du typedes substances hallucinogenes est tres variable, maisgeneralement peu accentu6e.Aucun indice de d6pendance physique n'est observe

en cas de sevrage brusque.

732

DRUG DEPENDENCE: ITS SIGNICANCE AND CHARACTERISTICS 733

Une tol6rance marqu6e it la LSD et a la psilocybinese manifeste rapidement et disparait egalement rapide-ment. La tolerance i la mescaline apparait plus lente-

ment. Les personnes qui sont tolerantes a l'une de cestrois substances presentent une tol6rance croisee auxdeux autres.

REFERENCES

Andrews, H. L. & Himmelsbach, C. K. (1944) J. Pharma-coL. exp. Ther., 81, 228

Belleville, R. E. & Fraser, H. F. (1957) J. Pharmacol.exp. Ther., 120, 469

Braenden, 0. J., Eddy, N. B. & Halbach, H. (1955)Bull. Wld Hlth Org., 13, 937

Eddy, N. B., Halbach, H. & Braenden, 0. J. (1956)Bull. Wid Hlth Org., 14, 353

Eddy, N. B., Halbach, H. & Braenden, 0. J. (1957)Bull. Wld Hlth Org., 17, 569

Halbach, H. & Eddy, N. B. (1963) Bull. Wld Hlth Org.,28, 139

Isbell, H. & White, W. M. (1953) Amer. J. Med., 14,558

Isbell, H., Altschul, S., Kornetsky, C. H., Eisenman, A. J,Flanary, H. G. & Fraser, H. F. (1950) Arch. Neurol.Psychiat. (Chic.), 64, 1

Isbell, H., Belleville, R. E., Fraser, H. F., Wikler, A. &Logan, C. R. (1956) Arch. Neurol. Psychiat. (Chic.),76, 468

Wolbach, A. B., Jr, Isbell, H. & Miner, E. J. (1962)Psychopharmacologia (Berl.), 3, 1

WHO Expert Committee on Addiction-Producing Drugs.Third Report (1952) Wld Hlth Org. techn. Rep. Ser.,57, 9

WHO Expert Committee on Addiction-Producing Drugs.Seventh Report (1957) Wld Hlth Org. techn. Rep. Ser.,116, 9

WHO Expert Committee on Addiction-Producing Drugs.Thirteenth Report (1964) Wld Hlth Org. techn. Rep.Ser., 273, 9

WHO Scientific Group on the Evaluation of Dependence-Producing Drugs (1964) Wld Hlth Org. techn. Rep.Ser., 287

Drug Dependence: its Significance and Characteristics

Documents

Transcript of Drug Dependence: its Significance and Characteristics