CHAPTER TWO : THE DRUGS AND THEIR EFFECTS

INTRODUCTION

20. The primary purpose of this chapter is to review in preliminary fashion the current scientific knowledge of certain psychotropic drugs used non-medically in Canada. In addition, this section will introduce a few basic concepts which may be helpful to the understanding of some of the potentials and limitations of the scientific method as applied to the study of human behaviour and drugs.* Psychopharmacology, the branch of science specifically concerned with these issues, can be defined as the study of the interaction of drugs with ongoing psychological and behavioural activity.

A certain amount of the current controversy and lack of communication regarding the 'drug problem' has been attributed to the multitude of meanings that the term 'drug' has to different people, and to the often arbitrary way in which our society defines, and endeavours to solve, the problems arising from man's persistent use of chemical substances to alter his existence. To some people the word 'drug' means a medicine used in the prevention, diagnosis, of treatment of an abnormal or pathological condition. In other situations, it is often used to refer only to illegal or socially disapproved substances. Some individuals employ the word in a manner suggesting dependence or addiction, regardless of whether it refers to some chemical substance or to other preoccupations such as television, music, books, or sports and games. Some consider alcohol, tea and coffee as drugs, while to others these are simply normal beverages not to be confused with the more foreign and unfamiliar substances viewed as drugs. Furthermore, the terms 'drug' and 'narcotic' are given special meanings in legal areas.

* A glossary of technical terms, as used in this report, is presented at the end of this volume.

Even scientists frequently disagree as to the precise definition of the term 'drug'.

Modell164 has suggested a comprehensive pharmacological definition of drugs which the Commission has adopted. As noted in Chapter One, a drug is considered to be any substance that by its chemical nature alters structure or function in the living organism. Modell observed that:

Drug action is therefore a general biological phenomenon ... pharmacologic effects are exerted by foods, vitamins, hormones, microbial metabolites, plants, snake venoms, stings, products of decay, air pollutants, pesticides, minerals, synthetic chemicals, virtually all foreign materials (very few are completely inert) and many materials normally in the body.

While this interpretation may be too broad for certain practical purposes, it provides some perspective into the ubiquitous nature of our internal and external chemical environment, and the complexity of the question of human drug use. The Commission's primary concern is focused on the use and effects of drugs taken for their psychotropic or psychoactive properties as defined by their capacity to alter sensation, mood, consciousness or other psychological or behavioural functions.

21. The use of psychoactive drugs seems to be an almost universal phenomenon and has apparently occurred throughout recorded history, in almost all societies. Some scholars have suggested that this use of drugs may have been among the earliest behavioural characteristics distinguishing man from the other animals. Blum, in the United States Task Force Report (1967), has stated:27

Mind-altering drug use is common to mankind. Such drugs have been employed for millennia in almost all cultures. In our work we have been able to identify only a few societies in the world today where no mind-altering drugs are used; these are small and isolated cultures. Our own society puts great stress on mind-altering drugs as desirable products which are used in many acceptable ways (under medical supervision, as part of the family home remedies, in self-medication, in social use [alcohol, tea parties, coffee klatches, etc.] and in private use [cigarettes, etc.] ). In terms of drug use, 'the rarest or most abnormal form of behaviour is not to take any mind-altering drugs at all.... If one is to use the term 'drug user', it applies to nearly all of us.

The Role of Science

22. It has been suggested that the potential role of science in the solution of the 'drug problem' is to provide information to better enable individuals and society to make informed and discriminating decisions regarding the availability and use of particular drugs. Unfortunately, considerable disparity often exists between the need for such information and the capacity of science to acquire and communicate it.

Helen Nowlis has noted: 172

There are many reasons why the 'facts' invoked in non-scientific discussions of drugs are often not facts at all. They may be second or third-hand quotations of statements attributed to scientists. There is a readiness on the part of many to accept as 'scientific fact' any statement made by, or attributed to, someone labelled as scientist, whether it is a statement based on research, on uncontrolled observation, or merely on personal opinion.

While science may be able to serve as a useful guideline and source of information, science itself is not a policy-making process, but merely a practical system designed to explore and test notions of a certain abstract nature. Even though the aim of science is to maximize objectivity, the interpretation and application of scientific data is usually a subjective venture regardless of the controls maintained in the formal analyses. The practical use of such information in the social sphere often entails economic, legal, philosophical and moral issues which are not amenable to scientific analysis as we know it today.

Even though considerable progress has been made in advancing our knowledge of biology, science has provided only a minimal understanding of the essential nature of psychological and behavioural functions and their relationship to underlying physiological processes. Consequently, psychopharmacology today must be content with exploring the interaction of chemicals (often with certain identified physical characteristics) with a largely unknown largely unknown human psychobiological system of enormous complexity.

The Classification of Drugs

23. Drug classifications, based on a variety of different considerations have been developed and there appears to be little general agreement as to the optimal scheme for ordering the universe of biologically active substances. For example, drugs might be organized according to chemical structure, clinical-therapeutic use, potential health hazards, liability to non-medical use, public availability and legality, effects on specific neural or other physiological systems, or influence on certain psychological and behavioural processes. The classification systems developed from these different approaches may show considerable overlap, although there are often striking incongruities. For example, some drugs which appear very similar in chemical structure may be quite different in pharmacological activity and vice-versa. The most useful organization depends on the intended use of the classifications.

Since our major concern here is with the effects of psychologically active substances, our interim drug classification system is based primarily on general psychological and pharmacological considerations. In Table I eight major classes are presented along with some examples of drugs from each group. While the categories are not considered to be exhaustive, the general system is applicable to the majority of drugs used for their psychological effects. Since the effects of drugs depend on a vast number of psychological and physiological components, many of which seem unpredictable, these categories are to some extent based on a typical reaction by an average subject to a common dose. Large variations in any of various factors can greatly alter the effects and may reduce the reliability of the descriptions.

CLASSIFICATION OF MAJOR PSYCHOACTIVE DRUGS

I - Sedatives and Hypnotics (a)

Barbiturates - e.g.,

Verpnal* (barbital)

Seconal* (secobarbital)

Nembutal* (pentobarbital)

Minor tranquilizers - e.g.,

Librium* (chlordiazepoxide)

Valium* (diazepam)

Doriden* (glutethimide)

Mittown* (meprobamate)

Others - e.g.,

bromides, alcohol (ethanol), paraldehyde, chloral hydrate, antihistamines (e.g., Gravol*),

anticholinergics (e.g., datura stramonium, atropine, scopolamine [Sominex* and Compoz*])

II - Stimulants (a)

Amphetamines - e.g.,

Benzedrine* (amphetamine)

Dexedrine* (dextroamphetamine)

Methedrine* (methamphetamine)

Others - e.g.,

Ritalin* (methylphenidate), Meratran* (pipradol), Preludin* (phenmetrazine), cocaine, ephedrine, caffeine (coffee, tea and cola drinks), nicotine (tobacco), khat

III - Psychedelics and Hallucinogens (b)

LSD (lysergic acid diethylamide-25, lysergide)

Cannabis (marijuana, hashish)

THC (tetrahydrocannabinol)

Mescaline (peyote)

Psilocybin

DMT (dimethyltryptamine)

DET (diethyltryptamine)

DOM (STP, dimethoxymethamphetamine),

MDA (methylenedioxyamphetamine )

MMDA (methoxymethylenedioxyamphetamine )

LBJ (methylipiperidylbenzilate)

PCP (Sernyl*, phencyclidine)

IV - Opiate Narcotics (a)

Opium (e.g. Paregoric*, Pantopon*)

Heroin (diacetylmorphine)

Morphine

Codeine (methoxymorphine)

Synthetics -e.g.,

Deremol* (pethidine)

Alvodine* (piminodine)

Dolophine* (methadone)

V - Volatile Solvents (b)

Sources: Glue, gasoline, paint thinner, nail polish, nail polish remover, lighter and cleaning fluid, spray cans, etc.

Active agents: Toluene, acetone, benzene, naphtha, trichloroethylene, ether, chloroform, amyl nitrate, nitrous oxide, freon, etc.

VI - Non-Narcotic Analgesics (a)

Aspirin* (acetylsacylic acid)

Phenacetin* (acetophenetidin)

VII - Clinical Anti-Depressants (c)

Monoamine oxidase (MAO) inhibitors - e.g.,

Nardil* (Phenezine)

Tricyclics - e.g.,

Trofanil* (Imipramine)

VIII - Major Tranquillizers (c)

Phenothiazines - e.g.,

Largactil * (chlopromazine)

Rauwolfia alkaloids, (snake root) - e.g.,

Serpasil* (reserpine)

Butyrophenones - e.g.,

Haldol* (haloperidol)

Thioxanthenes - e.g.,

Taractan* (chlorprothixene)

(a) Used medically and non-medically.

(b) Little or no medical use.

(c) Wide medical use, and little or no non-medical use

* Registered Trade Name

24. The sedatives and hypnotics (e.g., alcohol, barbiturates, 'sleeping pills' and minor tranquillizers) generally decrease central nervous system (CNS) arousal (although some psychological stimulation may result at low doses). Most of these drugs are used medically to reduce anxiety and tension, to produce general sedation and, at higher doses, sleep. The anticholinergic substances (e.g., belladonna alkaloids) are often used as sedatives at low doses although larger amounts may produce excitation and delirium.

25. The stimulants (e.g., amphetamines or 'speed', 'diet' and 'pep pills', caffeine, and cocaine) generally suppress appetite, increase activity, alertness, tension and general CNS arousal, and, at higher doses, block sleep. Tobacco (nicotine and coal tars) is usually considered a physiological stimulant although a variety of other effects are not uncommon.

26. The third group includes drugs described as psychedelic (mind-manifesting), hallucinogenic (hallucination-producing), psychotomimetic (psychosis-imitating), illusinogenic (illusion-producing), and psychodysleptic (mind-disrupting). While these terms refer to somewhat overlapping effects alleged to occur with the drugs in this class, the various labels emphasize different characteristics which are neither synonymous nor necessarily mutually exclusive. Probably none are entirely adequate as descriptive terms. These drugs may produce profound alteration in sensation, mood and consciousness at doses which result in comparatively light physiological activity . LSD and marijuana are examples from this group. The medical value of these drugs is the subject of considerable current controversy.

27. The drugs in the fourth category have, traditionally been referred to as narcotics or opiates, and are derivatives of, or pharmacologically related to, products of the opium plant. The best known examples are heroin, morphine and codeine. The word 'narcotic' has been used inconsistently in scientific as well as lay language and has been the subject of considerable disagreement in legal matters (for example, marijuana, cocaine, and other non-opiates are frequently controlled under laws regulating narcotics, in spite of the fact that they are pharmacologically different from this group). The use of the term 'opiates' is generally more specific, although its application has not always been limited to these drugs. Consequently, the specific term opiate narcotics is suggested to reduce ambiguity. These drugs are used medically mainly for their pain-relieving effects.

28. The fifth group is an aggregate of chemically diverse substances perhaps best described on a physical basis as volatile solvents. They are usually inhaled and include the vapour of such common materials as glue, gasoline and lacquer thinner. Some of these drugs have been called deliriants although delirium is only one of many potential effects and is clearly not restricted to these substances. Many are quite similar in effect to the sedative group and might be considered in a sub-class of that category. Others may have slight psychedelic or hallucinogenic effects. Most of these substances have no known medical use although several have been employed as clinical anaesthetics.

29. The non-narcotic analgesics (e.g., Aspirin* and Phenacetin*) are primarily used to reduce aching pain and to lower fever. In some instances they may also serve as mild sedatives.

30. The clinical anti-depressants (e.g., Tofranil* and Nardil*) are used medically to improve mood in severely depressed patients. These drugs are rarely used for non-medical purposes since they have little effect on normal mood states.

31. The final group, the major tranquillizers, are primarily used to reduce the symptoms of severe psychosis (e.g., schizophrenia). Largactil* and reserpine are examples. While these have initiated a widespread revolution in chemo-therapy in psychiatry, they are rarely involved in non-medical use.

* Throughout this chapter an asterisk indicates a registered drug trade name.

Psychological Considerations

32. The general effect of most drugs is greatly influenced by a variety of psychological and environmental factors. Unique qualities of an individual's personality, his past history of drug experience, his attitudes towards the drug, his expectations of its effects and his motivation for taking it are extremely important and in some instances may completely obscure the typical pharmacological response to a drug. These factors are often referred to collectively as the person's mental 'set'. 'The 'setting' or total environment in which the drug is taken may also be a factor of major significance.

A few drinks of alcohol may produce drowsiness and fatigue in some situations, while the same individual under different circumstances may be psychologically stimulated and aroused by the same dose. It appears that the set and setting may be of greater significance with the psychedelic-hallucinogenic substances than with the other drugs, and it has been suggested that psychological factors may often be the primary components in determining the quality or character of the psychedelic drug experience.

The so-called placebo effect is a striking example of the importance of set and setting in determining the drug response. A placebo, in this context, refers to a pharmacologically inactive substance which elicits a significant reaction, entirely because of what the individual expects or desires to happen. In certain individuals in some settings a placebo substance may have surprisingly powerful consequences. The placebo effect is specific to the individual and the setting, and not to any chemical properties of the substance involved. Therefore, in spite of an apparent 'drug effect', the placebo is not considered a drug since it does not alter function 'by its chemical nature'.

Placebos have been reported in therapeutic situations to significantly relieve such symptoms as headache and a variety of other pains, hay fever, colds, seasickness, neuroses, and a number of gastrointestinal complaints.97 Some scientists have suggested that the bulk of medical history may actually have been a history of the placebo, since many 'effective cures' of the past have been shown to be without relevant direct pharmacological action, and are today of no value as therapeutic agents.

To control for the influence of such psychological factors in drug research, testing is usually done under at least two conditions: an assessment is made using the actual drug of interest, and a separate measurement is taken after a placebo is given under identical circumstances. By comparing these two conditions some of the effects of set and setting can often be controlled and the actual drug effect uncovered.

Pharmacological Considerations

33. In studying how drugs affect the body, pharmacologists generally divide the analysis into several processes:

1. Administration: how does the drug enter the body?

2. Absorption: how does the drug get from the site of administration into the physiological system of the body?

3. Distribution: how is the drug distributed to various areas in the body?

4. Action: how and where does the drug produce what effects?

5. Physiological Fate: how is the drug inactivated, metabolized, and/or eliminated from the body?

Different routes or modes of administration can have considerable influence on the latency, duration, intensity and the general nature of the drug effect. Many drugs are well absorbed from the stomach and intestines after ingestion while others are poorly taken up or may be destroyed by the gastric juices. Certain drugs may be injected, with a hypodermic syringe for example, just under the skin (subcutaneous or S.C,), into the muscle (intramuscular or I.M.), or into a blood vein (intravenous or I.V.). The effects are generally most rapid and intense after intravenous injection and, consequently, this mode of administration can be quite dangerous in inexperienced hands. In addition, certain volatile substances can be rapidly and efficiently absorbed from the lungs by inhalation.

34. The action of a drug is in many cases terminated by chemical changes which it undergoes in the body, Certain organs (often the liver) metabolize or 'break down' the original substance into other chemicals which are usually (but not always) less active and more easily eliminated from the body. Some drugs may be excreted unchanged in the urine, faeces, or breath. Action is not always terminated by excretion, however, and the effects of some drugs greatly outlast the actual presence of the chemical in the body. Numerous physiological factors alter absorption, distribution, action and fate, and must therefore be taken into consideration in the study of drug effects.

The details of cellular physiology are largely unknown and with rare exceptions there is little information as to the mechanism by which any particular drug changes the activity of the nervous system. At the simplest level, it appears that a drug alters the functioning of the living cell by entering into some sort of chemical combination with substances already present. Even if this molecular process were well understood, it would not provide a straightforward basis for predicting the overall effects of the drug on a group of interacting cells, or, at higher level, on the total nervous system (comprising billions of cells) and associated psychological and behavioural processes.

35. The importance of dose. One of the basic principles of pharmacology is that specific statements about drug effects can not be made without consideration of the quantity or dose of the drug involved. With all drugs, the response differs both in the intensity and the character of the reaction, according to the amount of the drug administered. The relation between the dose and the intensity of an effect is often referred to by scientists as the dose-response or dose-effect relationship.

Although the magnitude of the effects of some drugs may increase in a rather uniform (monotonic) fashion as dose is increased, other drugs, particularly the sedatives, may show a bi-phasic response and actually produce behaviourally opposite effects at some doses compared to others. Low doses of alcohol may, in certain instances, be somewhat stimulating, while higher doses generally have a strong sedating effect. Scopolamine (a belladonna alkaloid) may produce sedation at low doses, and excitation, delirium and hallucinations with larger quantities. Very toxic doses of this drug can again produce sedation, coma and even death.

For every drug there is a dose low enough so as to produce no noticeable reaction, and at the opposite extreme, some degree of toxicity or poisoning can be produced by any substance if enough is taken. The concept of a poison, in fact, really refers to the quantity of a drug which exceeds the body's capacity to cope with it without damage. No drug can be designated either safe, beneficial, or harmful without consideration of the dose likely to be consumed. Chlorine, for example, which is present in most urban drinking water in concentration so low as to have little or no pharmacological effect on humans, is intended to poison harmful bacteria. The same substance, highly concentrated in gaseous form, was developed during World War I as an extremely potent respiratory poison. Even the concept of a psychotropic drug implies some notion of the range of doses likely to be consumed, since almost any drug can, in high quantities, affect psychological function. In many instances, however, considerable physical toxicity or poisoning develops before significant psychological effects occur.

It is usually essential to study a drug's effect over a range of doses in order to obtain an adequate understanding of the nature of the response. It is also important to consider doses which have some relevance to existing or potential patterns of use if social implications are to be inferred from experimental findings.

36. The importance of time. Another important pharmacological concept is the time-response relationship or the relation between the time which has elapsed since administration and the effect produced. Such a temporal analysis may be restricted to immediate or short-term (acute) effects of a single dose, or on the other extreme, may involve the long-term effects of persistently repeated (chronic) use of a drug.

The intensity and often the character or quality of the overall drug effect may change substantially within a short period of time. For example, the main intoxicating effects of a large dose of alcohol generally reach a peak in less than an hour, then gradually taper off. An initially stimulating effect may later change to one of sedation. With some drugs, an initial state of tension or anxiety may later turn into one of relaxation and sense of well-being, or vice-versa, as a function of time.

It may also be important with some drugs to consider the long-term consequences of chronic use. Usually such effects can not be readily predicted from what is known of the immediate response. For instance, while there is little doubt that the smoking of a few tobacco cigarettes has no lasting detrimental effect on lung or cardiac function, there is increasing scientific evidence that long-term heavy use of this substance has serious consequences. As another example, the clinical picture of the chronic alcoholic involves psychological and physiological disturbances which do not develop with moderate drinking. In simple terms, it is essential to ask: 'How much?'; 'How often?'; and 'For how long?' (as well as 'By whom?') when discussing the long-term reaction to repeated drug use.

37. Main effects and side effects. It is highly unlikely that any drug has only a single action on a particular behavioural or physiological function. Most drugs can produce an almost unlimited number of effects on the body, each with a somewhat unique dose-response and time-response relationship. The relative strength of the different responses to a drug generally varies with the amount taken, and a particular effect which is prominent at one dosage level may be quite secondary at another.

In a therapeutic or clinical setting, one is usually interested in a single or perhaps a small number of the many possible effects. Those which are desired are generally considered 'main effects' whilst the other unwanted but concurrent drug responses are labelled 'side effects'. This distinction between main and side effects is a relative one and depends on the purpose or the anticipated use of the drug. A response which is considered unnecessary or undesirable in one application may, in fact, be the main or desired effect in another. For example, in the clinical treatment of severe pain, the analgesic (pain-reducing) properties of morphine are considered the main effect, and the psychological euphoria and the intestinal constipation also produced are undesirable side effects. To the 'street addict', however, the euphoric properties are the main effects, and the analgesic and constipating effects may be irrelevant or undesired. Certain opiate compounds such as paregoric are used in treatment of diarrhoea and, in this instance, the constipating effect of the drug is desired and the other responses are considered side effects. It is universal that drugs have undesirable and toxic side effects if the dose is sufficiently increased.

38. Drug interaction. Even in cases where the individual effects of different drugs are well known and reliable, if several substances are taken at the same time, tile interaction may produce a response which is quite unpredictable on the basis of the knowledge of the individual drugs alone. Less commonly, a particular interaction effect may be anticipated. If the drugs normally have similar properties, they may often have an additive effect if taken together, resulting in a general increase in responses similar to that produced by a larger single dose of either one. There are also instances in which one drug may potentiate the action of another, and the two together produce a greater effect than would be expected by merely adding the individual reactions. Furthermore, some drugs have antagonistic effects, and one may counteract or inhibit certain normal responses to the other.

Tolerance and Dependence

38a. Tolerance is said to develop when the response to the same dose of a drug decreases with repeated use. With most tolerance-producing drugs, effects of original intensity can be retained. to a certain extent, if the dose is increased. The extent of tolerance, and the rate at which it is acquired, depend on the drug, the individual using it, and the magnitude and frequency of administration. The body does not lose sensitivity to all aspects of the reaction to a particular drug with equal rapidity, or to the same degree. Some of the effects of a drug may 'drop out' sooner than others with repeated use. Tolerance to the effects which are reinforcing or rewarding drug use (i.e., 'main effects') is usually reflected by a tendency for users to increase dose. Most aspects of tolerance dissipate with abstinence from the drug.

A moderate degree of tolerance to most effects of alcohol and barbiturates develops and a heavy drinker may be able to consume two to three times the alcohol tolerated by a novice. Little tolerance develops to the lethal toxicity of these drugs, however, and a heavy user of sedatives is just as susceptible to death by overdose as is a non-tolerant individual. Opiate narcotics, such as morphine, are capable of producing profound tolerance, and heavy users have been known to take up to ten times the amount which would normally produce death. By contrast, no noticeable tolerance develops to cocaine (a short-acting stimulant).

The exact mechanisms by which the body adapts, or becomes tolerant, to different drug effects are not completely understood, although several processes have been suggested. Certain drugs (e.g., barbiturates) stimulate the body's production of the metabolic enzymes which inactivate them. In addition, there is evidence that a considerable degree of central nervous system (CNS) tolerance may develop to certain drugs independent of changes in the rate of absorption, metabolism or excretion. An individual tolerant to alcohol, for example, can be relatively unaffected by a large dose even though the resulting high level of alcohol in his blood may accurately reflect the magnitude of his intake. It is uncertain as to whether this represents some general molecular adaptation to the drug at the level of the individual nerve cell, or perhaps a specific response by the central nervous system to counteract the sedating effects and maintain normal function. Learning factors often appear to play an important role in changing the individual's response to a drug after experience with it. Effects which initially may be strange or frightening may later be accepted without reaction or concern, or perhaps, even be desired. There is evidence that people may learn to control some drug effects, or otherwise come to function normally in the presence of certain responses which might originally have been distracting, or otherwise disrupting of behaviour.

A phenomenon often referred to as 'reverse tolerance' has been noted with some drugs (notably the psychedelics) in which the desired effects may be achieved with smaller doses after experience with the drug. Both learning and pharmacological mechanisms have been suggested to underly this process.

In many instances, after an individual becomes tolerant to the effects of one drug, he will also show tolerance to others with similar action. This is called cross-tolerance. For example, a heavy drinker will normally show a reduced response to barbiturates, tranquillizers and anaesthetics, as well as to alcohol.

39. Physical dependence is a physiological state of adaptation to a drug, normally following the development of tolerance, which results in a characteristic set of withdrawal symptoms (often called the 'abstinence syndrome'), when administration of the drug is stopped. These symptoms may be of an intense nature after persistent heavy use, and with some sedatives and opiate narcotics, may include tremors, vomiting, delirium, cramps and, in severe cases with some drugs, convulsions and death. There are generally no overt signs of physical dependence if the drug level is kept high enough to avoid the withdrawal syndrome. In a sense, the body comes to depend on the drug for 'normal' functioning after adapting to its presence, and when the drug is absent, considerable disruption of essential physiological processes occurs until readjustment develops. The withdrawal syndrome may also he elicited without abstinence, by the administration of a substance which specifically antagonizes or blocks certain effects of the original drug.

Withdrawal symptoms can be prevented or promptly relieved by the administration of a sufficient quantity of the original drug or one with similar pharmacological activity. The latter case, in which different drugs can be used interchangeably in preventing withdrawal symptoms, is called cross-dependence. As an example, barbiturates and tranquillizers can be used in treating the abstinence syndrome associated with chronic alcoholism.

Often the recovery phase associated with different drugs is characterized by a rebound phenomenon dominated by activity opposite to that produced by the drug. For instance, withdrawal from the sedatives generally results in symptoms of acute and toxic hyperactivation and physiological arousal, while the pattern following intense stimulant (e.g. 'speed') use usually involves sedation, depression and sleep.

Although physical dependence can develop with such common drugs as alcohol and barbiturates, it is not a factor in the drug-taking behaviour of the vast majority of regular users. In the few individuals who become physically dependent on these particular drugs, serious social, personal and physiological consequences of drug use usually precede the physical dependence. Therefore, although physical dependence is a serious medical problem in a minority of sedative users, the abstinence syndrome itself is not the cause of major public health problems. The potent opiate narcotics, by contrast, tend to produce very pronounced tolerance and physical dependence early in the history of regular use. These features then soon become an integral part of the particular drug problem presented by the opiate narcotics. However, with these and other drugs, psychological factors in the dependence are often more significant in the long run.

40. Psychological dependence (also often called behavioural, psychic or emotional dependence, and habituation) is a much more elusive concept and is difficult to define in a satisfactory manner. A World Health Organization paper69 defines psychic dependence thus: 'In this situation there is a feeling of satisfaction and a psychic drive that require periodic or continuous administration of the drug to produce a desired effect or to avoid discomfort.' A major problem with this definition is the difficulty in operationally defining and objectively identifying the characteristics of the dependence in a practical situation.

By contrast, some scientists224 have identified behavioural dependence as repeated self-administration of a drug. This approach seems far too broad for most purposes since it only indicates that the drug is in some way reinforcing or rewarding to the user, and merely restates the observation that he takes the drug.

Extreme instances of psychological dependence are easier to identify and may be characterized by an intense craving for, or compulsion to continue the use of, a drug with obvious behavioural manifestations. In many instances, psychological aspects may be considerably more important than physical dependence in maintaining chronic drug use. The major problem with opiate dependence is not the physical aspects, since withdrawal can be successfully achieved in a few weeks, but the great likelihood that the individual will later return to chronic use due to psychological dependence.

In most instances of even regular non-medical use of drugs, such intense psychological dependence probably does not occur. However, more subtle psychological and social factors usually have persisting effects in maintaining the behaviour of drug consumption.

In talking about dependency in any context, whether dealing with drugs or not, it would seem useful to specify what it is that is being depended upon and for what reasons, and to identify the consequences of its presence or its absence. The significance of dependency changes considerably if the entity is relied upon, for example, for the maintenance of life (e.g., insulin for the diabetic) or for the escape from an unpleasant or intolerable situation (e.g., privacy), or perhaps for a feeling of well-being or satisfaction with life. In one sense psychological dependence may be said to exist with respect to anything which is part of one's preferred way of life. In our society, this kind of dependency occurs regularly with respect to such things as television, music, books, religion, sex, money, favourite foods, certain drugs, hobbies, sports or games and, often, other persons. Some degree of psychological dependence is, in this sense, a general and normal psychological condition.

A statement in the preliminary brief of the Addiction Research Foundation of Ontario reflects the complexity of interpreting the question of dependency:4

It should be recognized, however, that dependence is not necessarily bad in itself, either for the individual or for society. The question to he evaluated, therefore, is not whether dependence can occur, but whether dependence in a given case results in physical, psychological or social harm.

41. The concept of addiction. The term 'addiction' has had a variety of meanings, and a consensus as to the proper definition seems unlikely, even in scientific circles. Often it has been used interchangeably with dependence (psychological and/or physiological), while at other times it appears to be synonymous with the term 'drug abuse'. The classical model of the addiction- producing drug was based on the opiate narcotics, and has traditionally required the presence of tolerance, and physical and psychological dependence. However, this approach has not been generally satisfactory since only a few commonly used drugs (e.g., alcohol and other sedatives), in addition to the opiates, seem to fit the model at all. It is clearly inappropriate for many other drugs which can cause serious dependency problems. For example, amphetamines can produce considerable tolerance and strong psychological dependence with little or no physical dependence, and cocaine can produce psychological dependence without tolerance or physical dependence. Furthermore, in certain medical applications, morphine has been reported to produce tolerance and physical dependence without a significant psychological component.

Recognizing the problems with the concept of addiction, the World Health Organization (WHO) proposed the following:69

It has become impossible in practice, and is scientifically unsound, to maintain a single definition for all forms of drug addiction 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.... It must be emphasized that drug dependence is a general term that has been selected for its applicability to all types of drug abuse and thus carries no connotation of the degree of risk to public health or need for any or a particular type of drug control.

The WHO committee presented short descriptions of various different types of drug dependence which may occur in some individuals and situations. The list identifies drug dependence of the morphine type, the barbiturate - alcohol type, the cocaine type, the cannabis (marijuana) type, the amphetamine type, the khat type, and the hallucinogen (LSD) type. Details of these various kinds of drug dependence are discussed separately later in this chapter.

For reasons analogous to those presented above, it is further suggested here that the term dependent rather than the ambiguous description 'addict' be used to refer to aft individual who has developed drug dependence of either the physical or psychological forms.

Scientific Methods

42. The role of statistics. Statistics can be helpful in collecting and handling numerical or quantified information, interpreting data, and making inferences or generalizations from it. The simplest use of statistics is to describe or summarize certain abstract characteristics of a group or sample. For example, the average height of players on a basketball team provides a shorthand description of the group. The numerical mean is a common index of the average. Considerably more information could be communicated if some idea of the variability of heights within the team were known. The range of measures, for example, is a crude index of the variance of 'spread' in the distribution within a group.

A second function of statistics is to provide a system for inference about some population on the basis of a smaller group or sample selected from that population. For example, the mean I.Q. of a group of 50 students randomly selected from a school with 500 individuals might provide a reasonable estimate of the average intelligence of the entire student population of that school. The success of such generalization or extrapolation depends on the relative size of the sample and the accuracy or fidelity with which the group studied represents the overall population of interest. Any bias in sampling which reduces the similarity between the selected group and the population to which the results are to be generalized reduces the validity of such extrapolation.

Statistics may also assist in distinguishing between the differences in measurements resulting from random variation and the variance due to the factor which is being studied. By obtaining an estimate of the natural variability in a population, it may be possible to distinguish, with some confidence, between a 'real effect' associated with a particular condition or treatment, and the difference which might be expected by chance alone. The phrase 'statistically significant' is used to indicate an effect considered significantly greater than that likely due to chance.

However, statistical techniques alone can only indicate an association between different variables and can not actually identify cause and effect. Such causal inferences must be based on an overall consideration of the research design. In many laboratory experiments, the stimulus and its response may be readily identified, but in less tightly controlled social studies (e.g., surveys) and clinical observations, it is often very difficult or impossible to positively identify the causal variable in a complex pattern of associations among different characteristics of the sample. For example, the demonstration that persons who are heavy users of tranquillizers also tend to be regular alcohol drinkers does not necessarily indicate that one causes the other. It may well be that a third factor (e.g., the desire to avoid or escape anxiety and tension) may be responsible for both behaviours. Interpretation of the data generally requires considerations beyond that involved in the statistical analysis.

43. Experimental methods. Details of research design would not be appropriate here, although some simple notions as to elementary requirements for adequate experimental techniques in psychopharmacology may be worthwhile. A major goal of scientific research is to eliminate or control all factors, other than those to be studied, which can influence or bias measurement.

As discussed above, the subjects of the study must be sufficiently similar to the general population of ultimate interest to allow generalization from the data. Extrapolation from one animal species to another, from one human society to another, or from one social group to another is often quite tenuous and must be viewed with extreme caution. Variables such as age, sex, and social class often exert considerable influence on psychological measures, and must be taken into careful consideration.

Unless there is some reason why a particular dose level is of singular significance, more than one dose should be studied. If the purpose of the experiment is to allow inferences of a general social nature, then the dose, mode of administration and the general circumstances of the study must be relevant to the pattern of use in the general population.

In order to determine the effect of a particular treatment, it is necessary to have a reference or control condition for comparison, which has been treated identically to the experimental condition except for the factor under analysis. These data may be obtained from a separate group of control subjects, which is sufficiently similar to the experimental group, or from the same subjects studied at a different time. Due to the great variation between individuals in response to drugs, the latter approach is often most efficient, although it is sometimes inappropriate or impractical. Using subjects as their own controls requires special statistical techniques for handling the data, since repeated experience in the situation will affect the subject's subsequent performance through such mechanisms as general adaptation, practice and other learning variables, and often fatigue.

Care must be taken to control or eliminate the possible effects of the subject's and researcher's expectations and biases. Since set and setting play an important role in determining drug effects, an inactive placebo substance should be tested in a control situation under conditions which are identical to those present when the drug is studied. Sometimes, however, if the subject has had previous experience with the experimental drug, he may soon realize whether he was given the active drug or an inactive substance despite his initial lack of information, and consequently the placebo control may not be complete. An experimental design in which the subject is not informed as to which treatment is being investigated is called a single-blind study.

Since the scientist's bias and expectations can also influence the subject's performance and the interpretation of his behaviour (as well as the later data analysis), the validity of the measurements can often be further increased it the researcher is also unaware of which treatment condition is in effect at the time of the experiment. A study in which neither the subject nor the researcher knows which of the experimental treatment variables are operating is called a double-blind design. There are certain circumstances where a double-blind is inappropriate or impossible, although it is often the most efficient way to acquire specific information about drug effects in an experimental situation.

A Review of Selected Drugs

44. The remainder of this chapter is devoted to a short critical review of the scientific literature pertaining to the effects of certain psychoactive drugs. Barbiturates, alcohol, minor tranquillizers, amphetamines, LSD, cannabis, opiate narcotics, and volatile solvents are discussed. In these interim reviews an attempt has been made to concentrate on human psychopharmacological studies rather than on animal experiments or general social reports. Although original scientific sources were sought and used as often as possible, it was frequently necessary at this interim stage to rely on reviews prepared by others.

There has been no attempt to be exhaustive in the references presented in the text. These citations often indicate a typical example chosen from among numerous sources which would have been appropriate. The bibliography at the end of this chapter contains a broader representation of some of the materials used in preparing the summaries.