2. Cannabis and Its Effects

TOLERANCE AND DEPENDENCE

Tolerance

Tolerance is said to develop when the response to the same dose of a drug decreases with repeated use. Gross tolerance to the major effects of cannabis does not ordinarily occur in humans with moderate or intermittent use, but there are many subtle aspects of this topic which have yet to be clarified. Although there is little tendency for intermittent users to increase dose, certain cannabis effects may be modified by repeated experience with the drug. and there is growing evidence that some tolerance develops with chronic use. 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 the various effects of a drug at different rates and to different degrees. Self-administration of increased doses would not ordinarily be expected unless 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.

Many investigators have observed that in some individuals there appears to be a "reverse tolerance", or "sensitization" after initial use.41,248,314,358,576,578,661 In other words, smaller doses may produce the desired effects after the person has become familiar with the use of the drug. Many individuals reportedly experience little or no effect the first time they smoke cannabis. On the other hand, some persons appear to be extremely sensitive to the effects of cannabis from the first exposure, and may initially experience intense, ornate, and perhaps frightening reactions which are rarely, if ever, equalled with subsequent use. It is uncertain whether the alleged sensitization effect often reported is due to an initially poor smoking technique, some learning, conditioning, or psychological adaptation process (see previous discussion of Becker's work39,42), the induction of enzymes producing an active metabolite, an accumulation of cannabinoids in the body over time, some molecular pharmacological receptor sensitization, or perhaps a combination of these. The actual nature of the change in response to cannabis which apparently occurs early after initial use has not been well documented or studied under controlled laboratory conditions.

As noted in an earlier section, the production of a psychoactive metabolite from a small quantity of injected THC has been demonstrated in humans. Mechoulam has suggested that THC metabolites may be responsible for the major effects of cannabis in humans. and that the efficiency of enzymatic formation of the active compounds from THC in the body may be enhanced by a cannabis-induced increase in production of the appropriate enzymes. 420 Such an effect might result in a subsequent increase in response to THC or, alternatively, it might also increase the rate of further metabolism and subsequent de-activation of primary active metabolites and reduce the overall reaction.

It has recently been demonstrated, using radio-active tracer techniques, that certain metabolites of THC may remain in the body in significant quantities for several days, or longer, after use.360,361 The possible role of this retention and possible accumulation of metabolites in the development of either sensitization or tolerance is unclear.

Several experiments have shown that experienced or heavy cannabis users may exhibit smaller reactions on certain physiological, behavioural and psychological measures than do novices or light users with standard doses;305,407,430,431,436,660 but others have not found such a difference.519 There is evidence in Commission experiments of a complex relationship between the frequency of cannabis use and the overall response to marijuana, THC and placebo in the laboratory. Preliminary analysis suggests that drug reactions on some measures are significantly negatively correlated with frequency of use, while other variables exhibit no relationship and, in a few instances, greater responses occurred in the more frequent users. Further detailed analyses of these relationships are underway.

Some investigators have reported that regular users learn to direct or control some of the psychological and behavioural effects of cannabis while subjectively 'high'. and may be able to perform a variety of behavioural or psychological tasks better than non-users given the same dose. Experience with the task while 'high' also apparently reduces drug-induced impairment. This would suggest that some sort of differential selective adaptation or tolerance may develop to some of the initially disrupting effects. Such an occurrence might reflect, in part, a behavioural adaptation to initially novel, distracting or disturbing stimulus aspects, rather than a direct physical tolerance. This notion is supported by the observation that the differential response to the drug by experienced users has been noted even after long periods of abstinence . 407 An alteration in response which persists long after drug use is not a characteristic of "classical tolerance" and suggests that some learning factor is involved. Some users report that if they stay 'high' for several days in a row, the drug experience loses much of its freshness and clarity and, consequently, they prefer occasional use. Also, some regular users claim that certain subjective aspects of their typical 'high' have changed over several years of use.243,248,438 Intermittent users apparently remain sensitive to the reinforcing or rewarding effects of the drug, since there is generally no marked inclination for them to increase dosage. On the other hand. Jones reported that chronic users show a reduced response on subjective ratings, as well as on some physiological measures, when compared to infrequent users. 305 Other investigators have not found evidence of a diminished 'high' in regular users.430,660

Only a few direct experimental studies of chronic cannabis use and tolerance in humans have been conducted. Williams and associates observed marijuna consumption in a group of prisoners given free access to the drug in a laboratory for over a month. Generally, large amounts were taken from the beginning and there was a small but gradual increase in the amount of marijuana consumed over time, and some change in the characteristic subjective and physiological effects were noted.670 Since no control group was included, certain aspects of this study are difficult to interpret. In a study in progress, Dornbush has found preliminary evidence of a reduced heart pulse rate response and perhaps some adaptation in cognitive function with daily use of a standard dose of marijuana, as compared to the initial acute reaction.160 By contrast, in another continuing experiment, Hollister found no change in oral THC effects on several physiological, biochemical and psychological 281 measures over a five-day period of daily oral THC consumption.281   Several other chronic or sub chronic experimental studies are underway in North America. 428,626

Data presented in the preliminary summary of the Addiction Research Foundation's experimental cannabis program provide evidence that certain kinds of tolerance to some marijuana effects may develop.436 A tendency was noted for a reduced acute pulse-rate response to marijuana doses given daily for more than a month. The work-output analysis discussed earlier suggests some adaptation or tolerance to the initial behaviour-disrupting or modifying effects of mandatory high dose use, as well. However, the question of tolerance to the rewarding or reinforcing aspects of the drug, which might lead to increased self-administration, cannot be clearly answered from the data provided. No attempt was made to quantify the magnitude or quality of the acute subjective response or 'high' obtained from the drug over repeated administration. In certain parts of the study, subjects were allowed to purchase and smoke additional marijuana. The data on free-purchase consumption, which is potentially most directly relevant, does not provide a complete picture. Under the mandatory smoking conditions studied, little additional marijuana was purchased and consumed by the subjects at any time, and in the completely optional, free-purchase periods, no suggestion of increased marijuana use over time occurred. In fact, subjects typically consumed less cannabis per day during free-purchase periods toward the end of the experiment than they did at the beginning. Tolerance to the reinforcing effects of the drug, and a subsequent increase in quantity or frequency of use, might occur with some individuals in other situations, but it does not appear to be a predominant characteristic of marijuana under conditions so far studied in the laboratory.

Recently a number of animal experiments have demonstrated definite tolerance to certain cannabis effects. Pigeons, dogs, rats and mice seem to be especially responsive, while rabbits are not.372,376,418 Tolerance to near-lethal toxic doses apparently develops quite quickly in some species. In dogs, tolerance to certain effects can be blocked by an enzyme inhibitor.419 There is some indication that tolerance to THC may develop in response to other cannabis constituents independent of THC administration.222 Monkeys and chimpanzees have also shown some behavioural adaptation to chronic cannabis administration, which cannot be entirely attributed to "classical Physical tolerance". 186,417,605 Even in instances where considerable tolerance to massive behaviour-disrupting and/or previously near-lethal doses have been demonstrated, no withdrawal symptoms have been noted in the animals when the drug was discontinued.418,419 Increased sensitivity, rather than tolerance, to repeated massive doses of cannabis in mice has also been recently demonstrated.192,225 The above experiments provide little information regarding tolerance to the potentially rewarding or reinforcing effects of the drug, and may not predict increased self-administration, even in the same species. The lack of suitable techniques for standard delivery of cannabinoids in animals has hampered self-administration studies.

There are reports of chronic, heavy cannabis users from the East who consume what would seem to be incredibly large quantities of the drug by Western standards. 45,71,125,126,295,414,560,583 McGlothlin estimates that several hundred milligrams of THC are smoked per day by some of these individuals, although typical use is much lower.414 Recently, the daily consumption of well over 100 mg of THC was noted in a group of chronic hashish smokers in Greece; acute smoked doses of 100 mg THC have been given these individuals without adverse reactions. 443,444,445 Massive cannabis consumption by a few American soldiers has also been reported.139,601 In a Commission field study of regular cannabis users in Ontario, the median consumption per person over one hundred sessions (averaging several hours in duration) was approximately 6 mg THC, but in a few instances over 50 mg THC was apparently smoked.238 A comparable range of figures was reported by Jones in San Francisco.305 As noted in an earlier section, under controlled laboratory condition, it is often difficult to give more than 10 - 15 mg THC to light users, in an acute dose, efficiently smoked, without inducing some untoward reactions. Because of vastly varying styles of smoking, which affect the quantity of THC delivered to and absorbed by the user, these figures must be treated only as general estimates for comparison purposes. Even with this qualification, however, it is clear that considerable individual differences exist in capacity for cannabis consumption, even among regular users. On the basis of these data one cannot be certain to what extent this reflects a major degree of tolerance with heavy use in some individuals, natural variation in drug sensitivity or responsiveness, differences in desired effects or general drugusing norms, or a combination of these factors. It seems unlikely, however, that some of the higher acute doses noted here could be consumed without significant prior tolerance development. Consequently, until evidence appears to the contrary, experimental studies of cannabis-using standard doses should specify in detail the past drug-use history of the subjects tested.

Smith has suggested a "J-shaped" function relating cannabis tolerance to use. Light to moderate users may be able to reach a preferred level of effect at lower doses than novices. However, chronic frequent users appear to consume considerably larger acute doses than other individuals.576

Physical Dependence

Physical dependence is a physiological state of adaptation to a drug. normally following the development of tolerance, which gives rise to 3 characteristic set of acute physiological withdrawal symptoms (often called the "abstinence syndrome"), when administration of the drug is stopped.

Opiate narcotics, alcohol and barbiturates are examples of drugs which can produce severe physical dependence with heavy chronic use. Significant physical dependence on cannabis has not been demonstrated in humans or animals, and it would appear that there are normally no serious adverse physiological effects or withdrawal symptoms resulting from abstinence from the drug, even after long periods of uninterrupted use. Many investigators have noted that when chronic cannabis users are deprived of their drug, either by legal arrest or hospitalization, no severe effects occur and there are few complaints or demands for drug treatment.14,38,86,170,248,560 This is in sharp contrast to comparable conditions involving opiate narcotic dependents, alcoholics, etc. (See also the section on for comments regarding cannabis dependence in the United States armed forces.)

On the other hand, there have been a few isolated reports of rather severe reactions occurring after withdrawal of the drug in some chronic heavy users. 47,200,651 While the great majority of reports of chronic users indicate little withdrawal response, acute abstinence symptoms that have occasionally been attributed to long-term heavy use in the literature include irritability, loss of appetite, restlessness and insomnia, sweating, mild gastrointestinal upset and headaches.69,124,131,295,401,560  Since hashish is smoked with large quantities of tobacco and other drugs in many countries, these mixtures may complicate the reactions noted in some reports. Recently, indications of tolerance and minor withdrawal symptoms have been noted among some chronic users in North America. 305,582

In Williams' experimental study of daily cannabis use, generally large quantities were consumed for a period of over a month. No significant withdrawal symptoms were seen with marijuana at the end of the experiment, but some abstinence signs occurred when the synthetic THC homologue, Pyrahexyl, was withdrawn.670 In the Addiction Research Foundation's experimental cannabis program no evidence of a withdrawal syndrome or other signs of dependence were seen, even after weeks of high daily doses which were considered subjectively aversive by the subjects.436

There is still some gap in our knowledge of the possibility of symptoms of dependence in individuals who might consume (either in the laboratory or on the street) even larger quantities of marijuana, throughout the day, for longer periods of time. There is little indication, however, that physical dependence on cannabis is a likely phenomenon under natural conditions.

Psychological Dependence

Psychological dependence, 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 report in the World Health Organization Bulletin defined psychic dependence as follows: "In this situation there is a reeling of satisfaction and a psychic drive that require periodic or continuous administration of the drug to produce a desired effect or to avoid discomfort."170 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.606 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. 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.

A statement in the brief to the Commission from the Addiction Research Foundation of Ontario reflects the complexity of interpreting the question of dependency:

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.7

The presence or absence of psychological dependence in a given situation depends on one's definition of the term. While many cannabis users in North America seem to take the drug once or twice a week, in a social context similar to that in which alcohol is normally consumed, and readily abstain for weeks or months with no ill effects, there is a small minority of users who smoke it daily, as a regular habit, and whose preferred routine and sense of well being are disrupted if they are unable to obtain the drug. There are reports from the East that considerable psychological dependence occurs in a minority of individuals in whom the acquisition and use of the drug have become a major component of their existence. Such habits are reportedly often difficult to discontinue. 23,71,124,125,295,347,583

Many users in North America apparently find cannabis pleasant and desirable, and often will go out of their way to acquire it-even at the risk of severe criminal penalty. In addition, there are several clinical reports of subtle adverse aspects of cannabis dependence in some chronic users on this continent. 305,439543,582 However. the craving and urgency associated with opiate narcotic, barbiturate, alcohol or tobacco dependence does not seem to develop.

A small study of regular daily users of both tobacco and marijuana suggests some differences in the type of dependence which can develop with these two drugs at least with present North American conditions. Subjects were asked which one drug they would prefer to use if they had to abstain from either marijuana or tobacco for different periods of time. All subjects indicated that in the long run they would prefer marijuana, and would choose to quit tobacco: when the required "abstinence time" was reduced to a day or less, almost all chose to use tobacco, since they felt it would be easier to do without marijuana  for short periods than to go through the acute discomfort of tobacco withdrawal. Generally similar results were obtained from a Commission study of adult users of cannabis, tobacco and alcohol.239 Whether or not behaviour would actually coincide with these attitudes was not demonstrated. Furthermore, if marijuana were as freely available as tobacco, the patterns of preference or dependence might be altered.