Drug Abuse

Appendix A

The Drugs and Their Effects

A.1 INTRODUCTION

OVERVIEW
The primary purpose of this appendix is to provide a critical review of the current scientific knowledge concerning the effects of the major psycho-tropic drugs used non-medically in Canada. Separate sections are devoted to
the following topics: Opiate narcotics; Amphetamines and amphetamine-like
drugs; Cocaine; Hallucinogens; Alcohol; Barbiturates; Minor tranquilizers and
non-barbiturate sedative-hypnotics; Volatile substances; and Tobacco. Each
section summarizes the history of the drugs and their medical and non-medical use, the chemical characteristics of illicit samples in Canada, how the drugs are taken and the physiological processes by which they are distributed in the body and finally eliminated, the major physiological, behavioural and psychological effects, including tolerance and dependence-producing potential, and interaction with other drugs. As well, much information bearing on motivation and causal factors and various epidemiological aspects of non-medical drug use is discussed, which can be considered supplementary to the separate appendicies of this Report devoted specifically to these topics.

This appendix is the result of re-examination and more comprehensive study of topics discussed in Chapter Two The Drugs and Their Effects of the Commission's Interim Report. Since the Interim Report, we have kept abreast of new scientific developments and have had the opportunity to examine the past literature in greater depth. These data were integrated with the findings of the Commission's own research program. Because the Commission has devoted a separate final report to the topic of Cannabis, discussion of marijuana, hashish, THC and related cannabinoids is included here only to the extent to which it is important to the examination of the other drugs and general issues. This review is based primarily on information available to the Commission up to January 1973, although progress in certain areas of principal concern was further monitored and assessed through to March 15, and any major new findings were incorporated. In this appendix, footnotes are indicated in the text by superior letters within brackets and are presented in a single general list at the back, followed by a separate reference list and selected bibliography for each drug section.

The remainder of this introductory section is primarily based on the Introduction to Chapter Two of the Interim Report. In addition to defining some technical terms, certain general concepts are introduced here 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 drug use.

THE DEFINITION OF PSYCHOTROPIC DRUGS

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

Modell has suggested a comprehensive pharmacological definition of drugs which the Commission has adopted.22 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. In the context of this report, substances which are typically required for normal functioning (such as food) are excluded from the definition. The Commission's primary concern is focussed 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. As noted earlier, the Commission considers non-medical drug use to be use which is not indicated or justified for generally accepted medical reasons, whether or not under medical supervision.

The use of psychotropic 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:

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 klatchs, etc.] and in private use [cigarettes, etc.]) In terms of drug use, the rarest or most abnornial 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

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:

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 easily amenable to scientific analysis as we know it today.

Pharmacology is the scientific study of the effects of drugs on the living organism; psychopharmacology is the branch of this discipline specifically concerned with the interaction of drugs with behavioural and psychological activity. 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, psycho-pharmacology today must be content with exploring the interaction of chemicals with a largely unknown human psychobiological system of enormous complexity.

THE CLASSIFICATION OF DRUGS

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 biological active substances. For example, drugs might be organized according to chemical structure, clinicaltherapeutic 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 classification system is based primarily on general psychopharmacological considerations. In Table A.1 eight major classes are presented along with some examples of drugs from each group. (Throughout this report the symbol "Cr is used to indicate a registered drug trade name.) 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 numerous factors can greatly alter the effects and may reduce the reliability of the descriptions.

TABLE A.1

CLASSIFICATION OF MAJOR PSYCHOTROPIC DRUGS

I Sedative-Hypnotics*
Alcohol (ethanol)
beer, wine and liquor
Barbiturates
amobarbital (Amytal®) pentobarbital (Nembutal®) phenobarbital (Luminal®) secobarbital (Seconal®)
Minor tranquilizers
chlordiazepoxide (Librium()) diazepam (Valium®)
meprobamate (Equanil®)
Others
anticholinergics (scopolamine§)
antihistamines (hydroxyzine [Atarax®]) bromides (Nytol®)
chloral hydrate (Noctec®)
ethchlorvynol (Placidyl®)
glutethimide (Doriden®)
methaqualone (Mandrax®)
methyprylon (Nodular())
II Stimulants*
Amphetamines
amphetamine (Benzedrine®) dextroamphetamine (Dexedrine®) methamphetamine (Methedrine®)
Amphetamine-like compounds cocaine (Erythroxylon coca)
diethylpropion (Tenuate®)
ephedrine (Ephedra vulgaris, Ma Huang)
methylphenidate (Ritalin®) pipradrol (Meratran®)
phenmetrazine (Preludin®)
Others
caffeine (coffee, tea and cola; Wake-Ups®)
khat (Catha edulis) strychnine (nux vomica) nicotine (tobacco) §
III Psychedelic-Hallucinogenst
Cannabinoids
cannabis (marijuana, hashish) § THC (tetrahydrocannabinol) Pyrahexyl (Synhexyl), DMHP
Datura-Belladonna alkaloids
atropine (hyoscyamine)
scopolamine (hyoscine)
Indole tryptophan derivatives
DMT (dimethyltryptamine)
harmine (Banisteriopsis caapi)
LSD (lysergic acid diethylamide-25, lysergide) psilocybin (Psilocybe mushrooms)
Phenethylamines
MDA (methylenedioxyamphetamine) mescaline (peyote cactus)
nutmeg (mace, myristicine)
PMA (4 - [or para-] methoxyamphetamine) STP (DOM, dimethoxymethylamphetamine)
Others
Amanita muscaria (`fly agaric' mushroom)
LBJ (methylpiperidyl benzilate)
PCP (phencyclidine, Sernyl())§
1V Opiate Narcotics*
Natural
codeine (methylmorphine) morphine
opium (paregoric, Pantopon®)
Semi-synthetic
heroin (diacetylmorphine) hydromorphone (Dilaudid®)
Synthetic
methadone (Dolphin())
pentazocine (Talwin())
pethidine (meperidine, Demerol()) propoxyphene (Darvon®)§
V Volatile Substances: Solvents and Gases* Active compounds
acetone, amyl nitrite, benzene, carbon tetrachloride, chloroform, ether, freon, naphtha, nitrous oxide, toluene (toluol), trichloroethylene.
Common sources
fast-drying glue, cement and paint; paint and polish thinner and remover; lighter and dry cleaning fluid; gasoline; aerosol cans.
VI Non-Narcotic Analgesicst Salicylates
acetylsalicylic acid (A.S.A., Aspirin®) sodium salicylate
Para-aminophenol derivatives
acetaminophen (Tempra®) phenacetin (acetophenetidin)
VII Anti-Depressants t
Monoamine oxidase (MAO) inhibitors
phenelzine (Nardil®) tranylcypromine (Parnate®)
Tricyclics
amitriptyline (Elavil®) imipramine (Tofranil®)
VIII Major Tranguilizerst Butyrophenones
haloperidol (Haldol®)
Phenothiazines
chlorpromazine (Largactil®)
Rauwolfia alkaloids
reserpine (Serpasil®)
Thioxanthenes
chlorprothixene (Taracton®)
* Used both medically and non-medically.
t Significant non-medical use, but little or no medical use. t Wide medical use, but little or no non-medical use.
§ Classification equivocal.
® Registered drug trade name as an example.

I. The sedative-hypnotics (e.g., alcohol, barbiturates, 'sleeping pills' and minor tranquilizers) generally decrease central nervous system (CNS) activity, although some psychological stimulation may result at low doses. These drugs are used medically primarily to reduce anxiety and tension, to produce general sedation and, at higher doses, sleep. Barbiturates are often considered the prototype of the sedative drugs.

II. 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. Amphetamine may be considered the prototype of the stimulant drugs. Nicotine (tobacco) is often categorized as a physiological stimulant although a variety of mixed effects are common, and there is some ambiguity as to the appropriate classification of tobacco.

III. These drugs are often described as psychedelic (mind-manifesting), hallucinogenic, (hallucination-producing), psychotomimetic (psychosis-imitating), illusinogenic (illusion-producing), or 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 slight peripheral physiological activity. LSD is often considered the prototype of this drug group. The Commission has classified cannabis with the hallucinogens. The medical value of these drugs is the subject of considerable current controversy.

IV. The drugs in this category have traditionally been referred to as narcotics or opiates, and include the natural psychotropic alkaloids of the opium poppy, the semi-synthetic derivatives of these substances, and the wholly synthetic compounds with similar pharmacological properties. Examples of these three types are morphine, heroin and methadone. 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 term 'opiate' is usually more specific, although its application has not always been limited to these drugs. Consequently, the specific term opiate narcotic is generally used in this report to reduce ambiguity. These drugs are used medically mainly for their pain-relieving effects.

V. This is an aggregate of chemically diverse substances perhaps best described on a physical basis as volatile solvents and gases. They are usually inhaled and include the vapours of such common materials as airplane glue, nail polish remover and gasoline. 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. Some have certain psychedelic or hallucinogenic effects. Most of these substances are not used medically, although several have been employed as surgical anesthetics.

VI. The non-narcotic analgesics (e.g., Aspirin® and phenacetin) are primarily used to reduce aching pain and to lower fever. They have little, if any, direct pleasurable effect and are, consequently, rarely used non-medically for their psychotropic properties.

VII. The anti-depressants (e.g., Tofranil® and Elavil®) are used medically to improve mood in severely depressed patients, but are rarely used for non-medical purposes since they have little immediate pleasurable effect on normal mood states. Some of the stimulants have been employed medically as anti-depressants, but their effects in this regard are inconsistent.

VIII. The major tranquilizers or neuroleptics (e.g., chlorpromazine and reserpine) are primarily used to reduce the symptoms of psychosis (as in schizophrenia) and certain other severe psychiatric disorders. While these drugs have initiated a widespread revolution in chemotherapy in psychiatry, they are rarely involved in non-medical use since they lack euphoric properties and generally produce some unpleasant side effects.

THE IDENTITY OF ILLICIT DRUGS

In order for controlled laboratory research to have practical relevance to the social situation of ultimate interest, it is necessary to acquire an adequate picture of the present (and likely future) patterns of use, and accurate information regarding the identity, purity and potency of the drugs being consumed from illicit sources. Furthermore, detailed knowledge of the chemical characteristics of the drugs actually being used is necessary for public health purposes. Although much non-medical drug use involves legally manufactured pharmaceutical compounds, often diverted at some level from legitimate channels, completely clandestine production and distribution of certain drugs is common Drugs obtained from the illicit market are often incorrectly identified, of inconsistent and unknown quality and strength, may be diluted or contaminated, and occasionally mixed with other drugs. Consequently, it is often difficult to generalize from controlled experimental studies employing known quantities of clinically pure compounds to situations involving the use of illicit drugs. Because of the uncertain identity of some of the drugs used, epidemiological data based on self-reports of illicit drug use may contain errors of considerable proportions. As well, drug identification in medical reports is nearly always based on the verbal report of the user, rather than on chemical analysis of the drugs involved, and erroneous classification of such cases frequently occurs. Samples of the drugs taken are not usually available for chemical analysis, and accurate detection of these drugs in body fluids is often beyond the capacity of the clinical laboratory.

Police drug seizures, although in some respects a biased sample because of the selective nature of law enforcement, are probably more representative of typical 'street drugs' than are the substances brought in to special health or analytic facilities for identification. Unless a specific attempt is made to obtain a random sample of drugs from the 'street', the unsolicited materials brought for analysis (for example, to the laboratories of the Addiction Research Foundation of Ontario or to the Commission) by outside individuals are often submitted because of suspected oddities, and, consequently, as a group, probably contain a disproportionate number of deviant samples. In one Commission study of illicit drugs, special effort was made to obtain analysis and identification of alleged rare or unusual drugs or combinations. General police seizures are not selected on any pharmacological basis, but data obtained from them provides a basis for direct generalization only to those sectors of the population which are the primary subjects of police attention. The Health Protection Branch of the Department of National Health and Welfare has conducted further analysis of police seizures suspected of adulteration. Data from these studies are presented in the specific drug sections below.[N• rei

PSYCHOLOGICAL CONSIDERATIONS

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 feel 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 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 and 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.12 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

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 its 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 addition, certain volatile substances can be rapidly and efficiently absorbed from the lungs by inhalation.

Often certain consequences or health problems associated with drug use can be traced directly or indirectly to the mode of administration employed by the user. Such factors may operate independently of the pharmacological properties of the drug or may interact in some way with specific drug effects. Examples include respiratory disorders associated with tobacco smoking, nasal damage due to chronic cocaine sniffing, gastrointestinal dysfunction from heavy alcohol drinking, plastic bag suffocation during solvent inhalation, skin absesses and infections such as tetanus and hepatitis due to unsterile injection, and cardiovascular or pulmonary damage arising from improper intravenous. or infra-arterial injection. A drug's potential for producing tolerance and dependence may vary considerably with the mode of administration. For example, ingestion of opium typically entails considerable less risk of physical dependence than intravenous morphine use.

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. This process may also be called biotransformation. Some drugs may be excreted unchanged in the urine, feces 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 few exceptions there is little information as to the specific mechanisms by which any particular drug changes the activity of the central 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. It is thought that this interaction typically takes place at a specific receptor site in the tissue. 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.

Age may be an important factor influencing drug distribution, physiological fate and action. Effects which are significant at one stage of maturation may be inconsequential or non-existent at another level of development. As examples, in recent years there has been particular concern over drug effects on the fetus in pregnant women, and the possible psychological effects of heavy drug use on adolescent maturation. Furthermore, certain drugs may have differential effects on old people.

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 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 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 high 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 produce coma and 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 a quantity of a drug which exceeds the body's capacity to cope with it without harm. 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.

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. Studies of shorter periods of repeated administration are often referred to as sub-chronic.

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 wellbeing, or vice-versa, as a function of time. Consequently, it is often essential to obtain measures at several points in time.

It is generally important to consider the long-term consequences of chronic use (especially at higher doses). 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?", and "Under what conditions?" when discussing the long-term reaction to repeated drug use.

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 effects, and the psychological euphoria and the intestinal constipation also produced are undesirable side effects. To certain non-medical users, 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 diarrhea 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.

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, the interaction may produce a response which is quite unpredictable on the basis of the knowledge of the individual drugs alone. Sometimes 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 response similar to that produced by a proportionately 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. Some drugs have antagonistic effects, and one may counteract or inhibit certain normal responses to the other.

TOLERANCE, DEPENDENCE AND ADDICTION

Tolerance

Tolerance is said to develop when the response to the same dose of a drug decreases with repeated use. With many tolerance-producing drugs, the intensity of the effects can, to a certain extent, be retained on continued use 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, frequency and mode of administration. It should be noted that the concepts of tolerance and dose increase are often mistakenly used interchangeably, when one does not necessarily imply the other. Tolerance may develop to various effects of a drug at different rates and to different degrees. Self-administration of increased doses might be expected if tolerance had developed to those specific aspects of the drug reaction which were reinforcing or rewarding its use. Tolerance or adaptation to some effects of a drug might occur independently from those responses which are sought by the user. Increased usage might also result if tolerance developed to unpleasant side effects. Most, but not all, 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. Less tolerance develops to the lethal toxicity of these drugs, however, and a heavy user of sedatives is still very susceptible to death by overdose. Opiate narcotics, such as morphine, are capable of producing profound tolerance, and heavy users have been known to take many 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" or sensitization has been noted with some drugs (notably the psychedelics) in which the desired effects may reportedly 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, minor tranquilizers and anesthetics, as well as to alcohol.

Physical Dependence

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 certain sedatives, 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 opiate narcotic withdrawal syndrome may also be elicited without abstinence in dependent users, by the administration of a substance which specifically antagonizes or blocks the 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, often, 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 minor tranquilizers 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 those 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 tend to produce pronounced tolerance and physical dependence early in the history of regular frequent use, in part because of the tendency of users to take large doses by injection. These features then soon become an integral part of the particular drug problem typically presented by the chronic use of the opiate narcotics. However, with these and other drugs, psychological factors in the dependence are often more significant in the long run.

Psychological Dependence

Psychological dependence, often called behavioural, psychic or emotional dependence, or habituation, is a much more elusive concept and is difficult to define in a satisfactory manner. A report in the Bulletin of the World Health Organization defined psychic dependence as follows: "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." 8 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 scientists have identified behavioural dependence as repeated self-administration of a drug.27 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. It has also been suggested that psychological dependence might be defined in terms of acute "behavioural withdrawal symptoms" (for example, anxiety, restlessness, or irritability) in a fashion analogous to the classical definition of physical dependence.26 This, of course, has the disadvantage of not allowing identification of the condition until drug use is terminated.

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

Generally, even regular use of most drugs does not result in such intense psychological dependence. However, more subtle psychological and social factors usually have persistent 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., the need for 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 brief to the Commission from the Addiction Research Foundation of Ontario reflects the complexity of interpreting the question of dependence:

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

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 useful since only a few commonly used drugs (e.g., alcohol and other sedatives), in addition to the opiates, seem to fit the model satisfactorily. 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 relatively limited physical dependence, and cocaine can produce psychological dependence without tolerance or significant physical dependence. Furthermore, in certain medical applications, morphine has been reported to produce tolerance and physical dependence without a significant psychological component. A review of the history of the concept of addiction and its various components was prepared for the Commission by Amit and Corcoran.2

Recognizing the problems with the concept of addiction, Eddy and associates, in the Bulletin of the World Health Organization (WHO), proposed the following:

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 type, the amphetamine type, the khat type, and the hallucinogen type. However, identifying discrete categories of dependence is often difficult in practice due to the growing prevalence of multiple drug use by drug-dependent persons.
In this report the word dependent is typically used rather than the descriptive term 'addict', to refer to an individual who has developed significant dependence on one or more drugs.

SCIENTIFIC METHODS

The Role of Statistics and the Problem of Sampling

Statistical techniques 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. The median is also frequently employed. 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 or 'spread' in the distribution. The standard deviation from the mean provides additional descriptive information on variability.

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 patterns of tobacco use in a group of 50 students randomly selected from a school with 500 individuals might provide a reasonable approximation to the smoking behaviour 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" may be used to indicate a change or difference in some measure which is considered significantly greater than that likely due to chance.

However, statistical techniques, at best, can only indicate the presence or absence of 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 tranquilizers 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.

It is important to realize that an adequate demonstration of the absence of a relationship between two variables is an extremely difficult scientific task. Simply not finding a significant effect or correlation in a study is not necessarily equivalent to demonstrating that no such relationship actually exists, but might be indicative of the methodological limitations of the research instead. The investigators may have asked the wrong questions, employed inappropriate or insensitive measures, failed to adequately control for confounding extraneous factors, used inadequate analytic and statistical techniques, or committed other errors in their research. Many factors must be taken into consideration in interpreting negative findings.

Experimental Methods

Details of research design would not be appropriate here, although some further review of basic experimental techniques in psychopharmacology may be worthwhile. A major methodological goal of scientific research is to eliminate or control for 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, genetic background, education, socio-economic status, nutritional and hygienic conditions, patterns of drug use, and a variety of other ethnic and cultural factors often exert considerable influence on psychological and physiological measures, and must be taken into careful consideration.

Animal studies of drug effects have often focussed on species, doses and measures of questionable applicability to humans. The assumption is often made in toxicology studies that one can accurately estimate the effects of long-term use of moderate amounts of a drug on the basis of sub-chronic administration of massive doses to lower species. The predictive validity of such procedures has not been clearly established and is the subject of much controversy. In many situations, one has little choice but to experiment on animals; such studies have often led to significant advances in human pharmacology, but in most behavioural areas this has been the exception rather than the rule.

It may be important to note that the vast majority of general human and animal pharmacological studies have employed only male subjects. With few exceptions, when general information about the effects of a drug is sought, males are used—females have not commonly been studied scientifically except when some specifically female characteristic was under consideration. To be sure, there are often justifiable biological, social and practical reasons for excluding female subjects in certain studies, but the information gap which exists in some areas is significant. Many studies have employed only prison inmates or psychiatric patients, and generalizations must be limited accordingly.

In order to determine the effect of a particular condition or treatment, it is necessary to have a reference or control condition for comparison, which has been treated identically to the experimental situation 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 in experimental studies 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 if 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.

Clinical Observations and Adverse Reactions

The term adverse reaction, as traditionally applied to the medical use of drugs, refers to significant undesirable or negative side effects of the drug. Drug adverse reactions in traditional medical treatment are not at all unusual. In one study in Montreal, a total of 524 psychiatric patients experienced 730 physiological and/or psychological adverse reactions to therapeutic drugs.'° This represents an overall incidence of close to 10% of the more than 5,000 patients studied over a one-year period.

In the area of the non-medical use of drugs, defining adverse reactions becomes considerably more complicated. With many drugs, personal and social attitudes and norms often dominate in the interpretation of psychological effects. What may be a desirable or pleasurable effect to one individual in a certain situation may be considered an adverse response in another situation or to another individual. For example, drug effects that are subjectively considered "psychedelic" or "peak" by certain persons are often defined as "psychotic" by others. Feelings of "increased sensitivity to humour" with a drug, may be viewed as "unnatural hilarity" or "loquacious euphoria" by other individuals. A "conscious rejection of the materialistic work ethic" may be seen as an indication of an "amotivational syndrome". What some would consider "exploration of inner consciousness" might alternatively be called "escape from reality". Clearly, the labelling of certain aspects of a drug experience as adverse, neutral or positive is often a function of individual and social constructs and concepts of normality, morality and reality, and generally implies a definite value judgment beyond the objective reporting of behaviour and experience.'°

Even if agreement is reached as to whether a particular drug-associated condition is positive or negative, in practice one is often left with the difficult task of determining whether the behaviour or condition under consideration is in fact a response to the drug, whether the drug use is the result of the condition, whether the two are merely randomly coincident, or if a combination or interaction of these possible situations might exist. For example, some observers contend that only individuals with serious psychiatric disorders become heavily involved in non-medical drug use, while others might argue from the same data that drugs are primarily responsible for the pathology. Alternatively, some investigators have suggested that the psychoses attributed to certain drugs in the literature are actually endogenous schizophrenia occurring in the drug-using population, independent of drug use. Furthermore, it is often very difficult to isolate the alleged effects of any single drug from the possible influence of others, since heavy drug users are almost invariably multi-drug consumers.

Surveys of clinicians and treatment services have generally inquired vaguely about instances of drug use which have come to professional attention, and typically encompass a range of undifferentiated cases covering a variety of social, psychological and physiological conditions. They often include non-medical involvement in cases rising, for example, from parental concern over adolescent usage, rather than from any direct drug effect per se. In general, little information can be gained about the 'normal' user of drugs through patient or treatment service sampling, since the subject population is defined a priori as pathological. Treatment facilities make contact with relatively few people who are not patients, and their resulting experiences and attitudes are generally biased accordingly.

With few exceptions, hospital records are not kept in a form which enables an efficient search of treatment cases, and ethical considerations regarding the patients' right to privacy often impose further restrictions on easy access to data. Furthermore, the reliability and validity of psychiatric diagnosis, especially in drug-related cases, is often not adequate for survey purposes. Polling individual clinicians and simply counting cases seen medically in a community can be misleading since many such patients are referrals, seen by different doctors, and consequently, may appear several times in the final totals. In addition, many clinicians are not well informed in the area of non-medical drug use, and surveys of such individuals often reflect personal attitudes as much as the epidemiological aspects of the situation.

Since most cases of adverse reaction are probably not brought to medical attention, accurate diagnostic and treatment statistics must be considered underestimates of the overall incidence of the less severe conditions. Most negative effects are handled by the user, his friends or other non-professionals. Fear of legal and social repercussions undoubtedly prevents many from seeking formal assistance. In any event, the number of drug-related clinical cases must ultimately be interpreted in terms of the overall patient population, and more importantly, in terms of the extent and patterns of drug use in the general population from which the patients were drawn.

Psychological problems often emerge in adolescence, which is also the period of greatest drug experimentation. Consequently, a variety of forms of psychological disorder would be expected to occur by chance in the youthful drug-using population. Some observers estimate that 10-30% of adolescents experience temporary or long-lasting psychological disorders or adjustment problems. Consequently, one would expect to see on a chance basis alone, a significant number of young people who were psychologically disturbed and using various drugs at the same time. In a small number of these individuals, the onset of both acute psychological problems and drug use would be expected to coincide.

The clinician, in treating cases of concomitant drug use and psychological disorder, is left in a very perplexing position. Armed with diagnostic and therapeutic concepts and techniques which are of questionable reliability and validity in even traditional non-drug cases, he must attempt to untangle the undoubtedly intricate and multi-dimensional causal and predisposing factors. It is clear that highly systematic and carefully controlled clinical research is necessary to parcel out causal variables, since most drugs do not typically produce easily identifiable chronic conditions of psychopathology. When such conditions are described, they often appear to be shaped as much by the prior personality of the individual as by the specific pharmacological effects of the drug. It is unlikely that important etiological questions will be answered by anecdotal clinical reports of psychopathology or personality change coincident with drug use in ill-defined sub-groups of patients. How ever, accurate clinical reports, put into proper population context, can provide valuable clues for subsequent systematic study. (Further discussion of theoretical and methodological issues relevant to the study of drug adverse reactions appears in the various drug sections which follow and, in particular, in Chapter Two of the Cannabis Report.)