Drug Abuse

13. Some Suggested Cannabis Research Priorities

R. D. Miller, Former Research Director, Commission of Inquiry into, the Non-medical Use of Drugs, Ottawa.

PAST RESEARCH *

* Specific references have not been included in this overview. Thorough bibliographic documentation and further discussion of some of the issues dealt with here in summary form are presented in a detailed review of the literature on 'Cannabis and Its Effects', prepared by the author for the Commission of Inquiry into the Non-Medical Use of Drugs (published in the Commission's Cannabis Report, Ottawa: Information Canada, 1972). The present assessment of research priorities is based primarily on that review, with more recent information from the literature and current research taken into consideration.

In the mid-1960s, the cannabis controversy seemed to reach its peak. Many alleged authorities had taken diametrically opposed positions, not only on moral and social policy issues, but on the supposedly hard scientific facts as well. The world literature on cannabis numbered several thousand publications, but few of the papers met modern standards of scientific investigation. The majority of the reports were poorly documented and ambiguous, emotion-laden and sometimes incredibly biased, and could, in general, be relied upon for little verified information. Expertise in the area of cannabis was limited by the fact that there was little clearly established scientific information, and preconceived notions often dominated the interpretation of ambiguous data.

The lack of modern scientific knowledge of cannabis at that time could be attributed to several factors. To begin with, until recently, governmental restrictions on the medical and scientific use of cannabis have been so strict that the majority of would-be researchers have found it more attractive to work in other areas. Secondly, since the widespread and middle-class use of cannabis in North America, Europe and many other areas is a relatively recent phenomenon, it was not considered a particularly high priority research area. Observations made during centuries of relatively unrestricted cannabis use in regions of the East have rarely been scientifically documented, partly because most of what we consider modern science has been, until recently, a Western phenomenon. In addition, these countries have generally had considerably more pressing public health problems demanding the devotion of limited scientific and medical resources. Thirdly, until the last few years, there was little possibility of properly specifying, standardizing or comparing the cannabis substances studied since the relevant aspects of cannabis chemistry were unknown. Consequently, there was little basis for comparing reports, and generalizations from one study to another were limited. Much of the inconsistent data previously reported may well have resulted from widely varying cannabis doses being studied under different social and experimental conditions.

On the other hand, it is worth noting that a number of the earlier reports on cannabis, in retrospect, seem remarkably well done and are deserving of careful critical consideration today. Interestingly, in certain areas, recent formally designed and elaborately instrumented
studies have done little more than confirm the observations of some of the well documented, but technologically limited, investigations of the past.

In spite of strong disagreement over the years among extremists on many aspects of cannabis, more than a dozen major governmental and international reports by independent commissions and other groups of widely varying backgrounds and orientations, covering three-quarters of a century, have come to remarkably similar conclusions regarding the use and effects of cannabis and its relative potential for personal and social harm. In addition, generally similar conclusions were reached regarding the inappropriateness
of a heavy reliance on the criminal law to control the use of the drug. It has frequently been observed that the impact on government policy of these reports, and of scientific inquiry in general, has been disappointingly limited over the years.

In less than a decade, cannabis has emerged as one of the most widely studied drugs in history - perhaps surpassed only by alcohol. Accordingly, much of the past scientific controversy has diminished, although considerable disagreement still exists in some areas. The past five years have witnessed major advances in our knowledge of cannabis, its use and effects: systematic botanical studies are underway; the primary chemical constituents of cannabis have been identified and isolated, and many synthesized; some of the basic factors of cannabinoid absorption, distribution, metabolism and excretion have been elucidated; prominent short-term physiological, behavioural and psychological effects have been documented; many basic animal toxicology studies have been completed and, in some countries, restrictions on human experimental research have been relaxed accordingly; recent advances in cannabis chemistry and basic pharmacology have stimulated a re-interest in the possible use of natural and synthetic cannabinoids in the medical treatment of a variety of disorders; a number of systematic studies of possible social, psychological and physiological effects of long-term use are underway, and the preliminary findings of several laboratory and field investigations into chronic and sub-chronic use are available; and surveys and various behavioural studies have identified the major dimensions of the extent and patterns of cannabis use in certain countries.

In spite of this impressive progress, many important questions are as yet unanswered and must be resolved before a full picture can be presented of the etiology, general characteristics and consequences of the nonmedical use of cannabis in various societies. This is
not to say, however, that changes in the legal status or in other aspects of public policy regarding cannabis must necessarily await 'the full picture'. All the answers will never be in. Hopefully, the sophistication of both scientific knowledge and public policy can evolve simultaneously, as a flexible, continuing process.*

The following discussion provides some indication of areas where further research is needed. Some suggestions are addressed directly to issues of immediate social concern which urgently need clarification. Others are focussed more on the acquisition of basic scientific information, perhaps of direct and immediate interest primarily to researchers, but which is likely, in the long run, to contribute significantly to our general scientific knowledge of cannabis and, ultimately, to the better understanding of those aspects of its nonmedical use which are of potential concern to society.

* A potential role for science with respect to 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. While scientific enquiry may be able to provide 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, much of the actual process, including the original definition of the problem to be investigated and the particular research design adopted, on through to the interpretation and application of data, is often a rather subjective venture regardless of the controls maintained in the formal analyses. The practical use of scientific information in the social sphere often entails economic, political, legal, philosophical and moral issues which are not easily amenable to scientific analysis as we know it today. Input from many disciplines is clearly essential.

DRUG USING BEHAVIOUR

Some of the major dimensions of the extent and patterns of cannabis use in various countries have been identified in recent years. However, research coverage has been quite uneven, both with respect to geographic area and to the particular focus within the societies studied. Students in North America and Europe have been most frequently investigated groups. The epidemiology of cannabis use among adults and other populations in most parts of the world is much less well understood.

In some instances, when the number of users in the general population is relatively small, geographically clustered, or otherwise inaccessible to general survey, anthropological approaches may provide information unobtainable by other means. Much can be gained by ethnographic study of the patterns of cannabis use under natural conditions. Participant observation methods and procedures in which users record their own daily activities, including drug use, can provide much-needed information on the role that cannabis plays in the life of the user as well as its personal and social meanings and functions.

We need much more information, from a variety of different cultures, regarding the factors influencing what has been called the 'social career' of cannabis use. This refers to the sequence followed from initial experimental use on, in some cases, to higher levels of regular use through, more rarely, to heavy chronic use. While there is a fair amount known about the variables involved in initial use (e.g., easy availability, curiosity, peer group pressure, etc.), there is a relative paucity of data available on the factors which predispose different individuals to progress through different levels of use, to stabilize use at various plateaux, or to reduce or terminate cannabis use. Further research is nedded regarding the possible roles of such variables as: opportunity and availability; relative cost; other drug use (past and present); legal status and penalties; likelihood of detection; general social and specific peer group acceptability; information and attitudes regarding potential for harm; general pharmacological factors (including tolerance and dependence); individual differences in response; and a variety of other personal psychological and physiological factors under varying degrees of environmental and genetic control.

Available evidence suggests that the distribution of levels of use of a drug (i.e., dose and frequency of use) in a population takes the form of a continuous, positively-skewed, unimodal curve, approximating a log-normal function. The most common levels of use occur at the lower end of the scale, with relatively fewer individuals involved in increasingly heavier use. Some researchers have argued, on theoretical grounds, that in order to decrease the total number of users consuming higher (and potentially more dangerous) quantities of a drug, a mean shift towards lower levels of use would have to occur in the entire population of users. On the other hand, it may be possible to reduce the variance of such a distribution (and, therefore, the number of heavy users) to some degree, independently of
the mean. Some inventive research methodology is clearly needed here.

Many studies have failed to discriminate adequately among various levels of use. Simple dichotomous categories such as 'user' and 'non-user' provide little useful information regarding the full continuum of use patterns and associated personal and social correlates of concern. Social scientists might usefully explore the possibility of gathering and presenting data in a form analogous to the dose-response function in pharmacology.

Significant controversy exists regarding the relationships between the use of cannabis and the patterns of use of a variety of other drugs, including alcohol, tobacco, opiate narcotics, amphetamines and LSD. It appears that dynamic and changing personal, social, legal and economic factors are the primary determinants of patterns of sequential or concurrent multiple drug use, and that the specific pharmacology of the substances involved is often secondary. The relative roles of the various factors predisposing to multiple drug use should be further investigated.

We have little adequate information on the effects of cannabis use on levels of alcohol use within a population. It is not clear from the apparently contradictory data available whether, on a large scale, cannabis would tend to replace alcohol as an intoxicant in the user population, or whether the use of these drugs, at various levels, would be additive without significant interaction, or if the use of one might potentiate or increase the consumption of the other. In North America and Europe, cross-sectional surveys indicate that those who use alcohol are much more likely than 'teetotallers' to use cannabis, and that most cannabis users still drink alcohol. However, certain primarily retrospective data suggest that the use of cannabis may reduce or interchange with (but not totally replace) alcohol consumption over time in certain populations. In interpreting or designing studies, it is essential to distinguish cross-sectional between-subject correlations, at a single point in time, from within-subject co-variation over time, the latter being the relationship of ultimate interest here.

In addition to the alcohol-cannabis controversy, other questions which have received considerable attention in recent years include the role of tobacco smoking in the subsequent use of cannabis and the influence of cannabis use on later opiate narcotic consumption. Neither issue has been really adequately resolved. Systematic retrospective studies would be helpful, but careful prospective investigation of the relationships among the patterns of use of different drugs in various populations over time would be most likely to provide the needed information.

There is a general need for retrospective and prospective study of the changing patterns in drug use on a world-wide basis. Not enough is known as to how and why various forms of drug-using behaviour emerge and flow among geographic areas, from one culture to another and among subcultures within societies. Cross-cultural and historical investigation would enable a better understanding of those aspects of the patterns, functions and consequences of cannabis use which transcend cultural change, and those which are relatively
amenable to social manipulation or control. It is already clear that substantial drug-culture interaction occurs in many areas of interest and social concern.

CHEMICAL AND BOTANICAL ASPECTS

While much is known regarding agricultural aspects of hemp fibre production, until recently, little modern botanical research had been conducted on the psychotropic aspects of cannabis. Recent advances in the study of cannabinoid chemistry have enabled considerable progress in this area. Several basic projects are underway in various parts of the world and continued research could be valuable.

The relative and absolute levels of the neutral and acid forms of the major cannabinoids, tetrahydrocannabinol (Δ9 THC), cannabidiol (CBD) and cannabinol (CBN) in cannabis samples depends on a variety of genetic, environmental and post- harvest treatment and storage factors. In North America and England, at least, hashish is not simply a concentrated form of the marijuana available. On the average, hashish contains a much higher percentage of the total cannabinoids in the form of CBD and CBN. The pharmacological significance of this difference, with respect to acute and chronic use, has not yet been established.

Variables affecting the shelf-life (i.e., stability and degradation) of different forms of cannabis are not yet adequately understood. Standard storage procedures have been developed for most immediate research purposes, but additional inquiry is needed.

Almost all recent human experimental research has been conducted with marijuana or synthetic THC. While there are obvious advantages to the use of uniform substance in experimental work, because of the unusual heterogeneous nature of the various preparations of Cannabis sativa in use around the world, different strains of marijuana and varieties of hashish samples and liquid concentrates should be given chemical and experimental evaluation. Standard supplies of other primary cannabinoids and their metabolites should also be developed and made available to researchers for human and animal studies. Further development of water soluble cannabinoids would greatly facilitate experimental studies of effects relevant to both the medical and non-medical use of cannabis.

Accurate information as to the identity, purity and potency of drugs being consumed from illicit sources is essential for meaningful administrative control and regulation, as well as for socially relevant laboratory research and appropriate field studies. Existing data indicate that illicit cannabis around the world varies over a wide range in cannabinoid content. Cannabis is usually smoked with tobacco in most areas (North America being the only significant exception), and, although it is occasionally 'cut' or diluted with inactive materials on the illicit market, there is little evidence that adulteration with other active drugs, unbeknownst to the user, is a significant occurrence. Serious questions have been raised regarding possible contamination with herbicides, pesticides and toxic fungi in certain localities. Appropriate analyses have not been done in these areas.

No general systematic 'street drug' data have been collected on an international or national scale. Up-to-date, continuing qualitative and quantitative analyses of randomly selected samples of police seizures, supplemented with data from other sources, such as treatment-oriented laboratories and special field studies, would seem to provide an adequate system for monitoring the purity and potency of illicit cannabis in most countries. Information on the age and original geographic source of the samples would add to the value of such efforts. The uniform collection and analysis of these data on an international scale would seem worthwhile.

In the past two years, significant improvements have reportedly been made in chemical analytic techniques for quantifying the major cannabinoids in crude cannabis preparations. Reliable standard methods should be communicated on an international basis, with subsequent follow-up evaluation involving standard test materials submitted to participating analysts. The reliability and validity of the quantitative methods in current use in many laboratories are not adequate, and consequently some recent cannabis studies which have attempted to specify doses can only be interpreted in a general quantitative sense because of questions regarding the chemical assessment of the potency of the samples involved.

There is urgent need for simple and convenient techniques for identifying and quantifying the primary cannabinoids and their metabolites in the body. The development of such methods would enable much greater specificity and sophistication in many important areas of cannabis research and should be given high priority. For example, a quantitative chemical test, analogous to the alcohol BreathaZyzer, which could provide evidence of recent cannabis use and a reasonable estimate of the intensity of certain drug effects, would be invaluable to researchers in many fields. Although certain qualitative methods exist which can provide evidence of use in certain circumstances (e.g., finger swabs, mouth washes and dental scrapings), these techniques are often not appropriate and, in any event, cannot provide information regarding current effect levels.

Compared to the relatively simple case of alcohol, cannabis poses significant practical difficulties. Instead of a single primary active molecule, as is the case with ethanol, it appears that 9THC and perhaps several metabolites account for the major effects of cannabis. In addition, other cannabinoids and their metabolites, such as CBD and CBN, are also likely to be present in body tissue and fluid and would likely confound the analysis and perhaps alter the basic pharmacology of THC, as well. After specific analytic methods become available, the relationship between tissue levels of these various cannabinoids and the effects of interest must be established. Available evidence, based primarily on the relatively simple case of isolated THC administration, suggests that blood sample analysis is the most practical approach to estimating effects from levels of active cannabinoids in the body.

Although considerable progress is being made towards refining quantitative tests, even those methods which are likely to be developed in the near future may have limited applicability outside of the research laboratory. Several gas-liquid chromatography (GLC)-based methods (usually linked with other tests), which are currently being investigated, may be very sensitive and precise, but are relatively slow and expensive, and they require a high degree of specialised training and delicate laboratory equipment. In addition, venous blood samples are generally needed. Potentially, radioimmunoassay or spin immunoassay techniques could provide very rapid analysis of minute samples (e.g., a finger pin prick of blood), but at present such methods are not adequately specific. Even if simple and efficient blood sample methods were developed, significant practical and legal problems surrounding the acquisition of such samples would likely preclude their use for general control purposes in any way similar to the use of the alcohol Breathalyzer.

EFFECTS

CHRONIC USE STUDIES

Although some important questions regarding the acute effects of cannabis remain unanswered, the possible personal and social consequences of long-term heavy use are of primary immediate concern. Multi-disciplinary longitudinal studies of various populations, including groups of light and heavy users and non-users, would be invaluable and should be initiated. However, further clarification of certain issues is needed and cannot await the completion of such long-term investigations.

Cross-sectional studies of persons with varying histories of cannabis use are likely to provide a reasonable short-term pay off. Since the common use of the drug is a relatively recent phenomenon in North America and Europe, it might be rather difficult to locate an adequate number of suitable subjects for extensive epidemiological study in these geographic areas, although certain relevant projects could be conducted. It will be necessary to turn to those nonindustrial countries which have had a longer history of cannabis use for large-scale investigations of this type. Several studies of chronic users in various cultures are currently underway, and some significant reports have recently been published. Considerable additional effort is warranted. Cross-cultural generalizations must be made with caution, however, since many conditions of non-industrial countries may have limited applicability to other social situations.

Research into chronic effects must take into consideration the possible influence of such variables as age, sex, education, socio-economic status, nutritional and hygienic conditions, multiple-drug use and a variety of other ethnic and cultural factors. Appropriate control groups must be compared with experimental subjects for whom reasonable information is available on the frequency and duration of cannabis use and the quantities consumed. Quantitative analysis of the cannabinoid content of typical cannabis samples from the field would enhance such studies. In order to discriminate acute and chronic effects, it is essential to ensure that subjects are, indeed, drug-free at the time of testing. (A simple chemical test for recent use would be invaluable here.)

Correlational data of this nature, of course, cannot establish causal factors, but may suggest links and provide clues for further research. If an association were found between cannabis use and other variables, in many instances it would be difficult, if not impossible, to distinguish drug effects from predisposing personal and environmental factors without considerable concentrated follow-up effort.

Several sub-chronic studies have recently been conducted involving the daily administration of cannabis to humans under controlled laboratory conditions over periods of weeks and months. Such experiments can provide certain clues regarding the consequences of chronic use, but cannot detect possible effects which might develop only after more prolonged periods of exposure.

In some areas of interest, basic information can be obtained from studies of chronic cannabis administration to animals. The significance of such experiments, however, must ultimately be interpreted in the context of human conditions of drug use. Further effort should be made to develop animal tests which parallel pharmacological processes and effects relevant to humans. Because of often substantial inter-species differences, findings involving lower species should be verified in primates. Animal studies have traditionally employed enormous doses, administered under conditions of questionable pertinence to human situations. It is important to explore the acute and chronic effects of cannabis on animals employing dosage ranges and modes
of administration which are more comparable to those likely to be used by humans. The assumption is often implied in toxicity studies that one can usefully estimate the effects in humans of long term use of a drug on the basis of information obtained from sub-chronic administration of massive doses to lower species. The predictive validity of such procedures is uncertain, and results must be interpreted with caution.

SOME GENERAL EXPERIMENTAL AND PHARMACOLOGICAL CONSIDERATIONS

Quantitative information on major cannabinoids in experimental samples administered should be provided in laboratory research reports. Until convenient methods are available for assessing the levels of active cannabinoids in the body, researchers should provide estimates of the actual cannabinoid dose delivered to and absorbed by the subjects under the smoking conditions employed. Specifying doses on a body-weight basis would further aid interpretation of experimental results.

In some respects, it would appear advantageous for researchers to adopt more uniform modes of cannabis administration for experimental study. However, the variety of styles and techniques of cannabis consumption around the world requires that different modes of administration be investigated. The pyrolysis and delivery of cannabinoids smoked in cigarettes, conventional pipes, water pipes, or chillums may not be directly comparable, and possible differences in the acute and chronic effects of these methods of cannabis smoking, as well as ingestion, should be examined. Factors which affect the rate and extent of absorption of cannabinoids in the lung and gastro-intestinal tract have not been adequately delineated.

In North America and Europe, there is typically very little cannabis lost during the process of smoking, and users usually consume all of the material in a cannabis cigarette, including the butt. The common deep inhalation and retention procedure is similarly parsimonious. This style of smoking results in a much greater proportion of the THC in the cannabis being delivered to and absorbed by the user, in comparison to the more casual puffing style (with prompt exhalation) commonly seen in countries with
a longer history of cannabis use and ready availability - Jamaica or India, for example. These factors, along with probable differences in the efficiency of THC delivery among the various forms of pipes and cigarettes mentioned above, greatly complicate cross-cultural dose comparisons.

A clear understanding of the present, and likely future, conditions of cannabis use is essential for optimal laboratory efforts. socially relevant experimental conditions including appropriate drug doses and modes of administration require accurate information from sophisticated socio-pharmacological field studies. In addition, the influence of social attitudes and norms regarding cannabis use on the ultimate social, psychological and physiological effects of the drug needs further study in the laboratory as well as under natural field conditions.

Significant advances have been made in our knowledge of the metabolism and distribution of THC in the body, but considerable further research is needed. Since, as noted earlier, CBD and CBN are present in large quantities in some forms of cannabis, the pharmacokinetics of these cannabinoids should be thoroughly investigated, as well.

The molecular mechanisms involved in the various central and peripheral effects of cannabis are poorly understood. Structure-activity relationships of the various primary cannabinoids and metabolites should be established. Although it is now clear that L THC is the principal active constituent in cannabis (at least in part via metabolites), it appears that other cannabinoids may alter the pharmacology of THC and its metabolites. For example, CBD and CBN may compete for binding or receptor sites or alter THC metabolism and excretion. They do play a significant role in cannabis tolerance or sensitization and interaction with other drugs. There is evidence that primary cannabinoids or their metabolites may accumulate in the body for prolonged periods with chronic use; possible physiological consequences should be carefully explored. Most laboratory research of this nature has focussed on THC to the relative exclusion of CBD and CBN, even though certain hashish smokers, for example, likely consume a greater amount of these latter cannabinoids than of THC. The possible long-term effects of other, non-cannabinoid, components of marijuana and hashish should also be examined.

The vast majority of both human and animal pharmacological studies of cannabis have employed only male subjects. With very few exceptions, when general information about the effects of the drug is sought, males are used; females are rarely studied scientifically except when some specifically female characteristic is under consideration. Recent research has focussed on healthy, young adult males of middle class background (primarily college students), while earlier studies often employed male gaol prisoners as subjects. Other populations need to be investigated, especially females and older persons of both sexes. Acute and chronic effects of the drug in persons suffering from certain physical disabilities (e.g., diabetes, epilepsy,liver dysfunction, asthma or migraine headaches) should be explored as well.

Cannabis effects in persons with varying histories of other chronic drug use should be investigated. Alcohol is perhaps most important in this regard. Tobacco might also be significant. Experimental reports should specify, in detail, the subjects' past and current patterns of medical and non-medical drug use. Unless characteristics of the initial reaction to cannabis, or the adaptation to its effects early in the career of use, are of central concern to the study, the use of cannabis-naive subjects may not be advantageous. In most areas, information on regular users, who have developed a more consistent and stabilized general response, would be of considerably greater immediate social significance.

PHYSIOLOGICAL ASPECTS

Cannabis produces few prominent short-term physiological effects in normal users. Increased heart rate, a slight reddening of the eye and decreased salivation are the most commonly reported acute responses. Acute and chronic effects in persons suffering from certain prior physical disabilities may be more significant and should be investigated. Minor respiratory, gastrointestinal, cardiovascular and neurological dysfunction has been inconsistently noted in studies of heavy, long-term users of cannabis in non-industrial countries. In most of these reports, likely confounding variables have not been taken into account or controlled. Few cannabis-related disorders have been found in more recent controlled studies, but some significant areas of potential concern exist. Large scale epidemiological studies may be needed to investigate potential problems which might occur relatively infrequently in the user population. It is worth noting here that the major alcohol-and tobacco-related physical disorders which have come to light in recent years (such as liver cirrhosis and lung cancer) are prominent in only a small proportion of regular users of these drugs.

Recent evidence suggests that chronic smoking of large quantities of cannabis may have effects on the respiratory system similar to those produced by tobacco. Straightforward inquiry into chronic cannabis use is complicated by the fact that regular cannabis smokers typically also use tobacco, and the two drugs are mixed together for smoking in most countries. In North America, where they are more apt to be used separately, differences in typical patterns and methods of smoking, as well as quantities consumed, make simple comparisons between the substances difficult. The possibility that cannabis (either alone or in combination with tobacco) might produce or complicate respiratory disorders, including cancer, must be investi_ gated further and possible toxic factors identified.

Considerable effort must be concentrated on rectifying conflicting data on possible neuro-toxic effects of chronic cannabis use. Several recent controlled studies have found no electrophysiological or psychometric evidence of neurological disorders in persons with long histories of heavy use, but some clinical reports have suggested chronic effects (including brain damage) in certain users. Even though major methodological problems exist in these latter reports, the seriousness of the conditions implied requires that further systematic investigation be given high priority.

Reports of the acute and chronic effects of cannabis on sleep are inconsistent. The existence and ultimate neurological and behavioural significance of any cannabis-induced changes in sleep patterns need to be established.

Available human data have not indicated that cannabis-induced chromosome abnormalities are a likely occurrence, nor have adverse drug effects on the developing foetus been demonstrated in humans. However, some studies have detected such effects at extreme doses in certain animal species, and there are some preliminary suggestions that cannabis may affect DNA under certain circumstances. Because of the potentially serious consequences of any such effects in humans, further research is required. For example, prospective investigation of young women who are heavy cannabis users, studied through pregnancy with subsequent post-natal follow-up of the mothers and children, would be appropriate. Carefully chosen control groups would be necessary to isolate the influence of likely confounding variables. Although an apparently remote possibility, potential effects on the child of cannabis use by the father should also be considered.

Existing research reports of the acute effects of cannabis on muscle strength and physical work output are not conclusive, although some deficit in efficiency is suggested. On the other hand, it has been reported that cannabis is used in certain countries by labourers to reduce fatigue and increase work energy. Several relevant studies are in progress, but the effects of acute and chronic cannabis use on physical labour and athletic performance, under various laboratory and natural conditions, have not been clarified.

PSYCHOLOGICAL AND BEHAVIOURAL ASPECTS

Cannabis users typically report substantial acute alterations in sensory, perceptual and cognitive processes as a result of taking the drug. Attempts to verify most such subjective effects in the laboratory have net with surprisingly little success, in part because of the insensitivity of standard tests to the more psychedelic aspects of the experience. Since many of the prominent psychological effects reported by users are intensely personal, the laboratory scientist often has little opportunity to make objective measurements, and must rely on subjective, introspective reports communicated verbally through a language system which is frequently inadequate. It would be worthwhile, in order to better understand the growing popularity of the drug, to experimentally investigate, in more sensitive fashion, some of the effects which users claim provide the reinforcement or motivation for continued use at various levels. Of particular interest are those aspects of the response which reinforce chronic heavy use in certain users.

There are considerable differences among individuals in reaction to cannabis and in the degree to which various aspects of the response and patterns of use are considered desirable. More thorough investigation is needed of the relative importance of personality, past drug experiences, set and setting of use, and other cultural or genetic factors in determining various cannabis effects and their subjective valence and meaning to the user.

Experimental evidence indicates that under some conditions cannabis can produce short-term deficits in certain perceptual, attentional, cognitive and psychomotor abilities. Impairment is most consistently found on complex tasks requiring sustained or divided attention and short-term memory. Alterations in time perception and increased visual imagery are also highly predictable. The overall significance of the effects found in the laboratory to personal, social, scholastic, and occupational functioning under natural conditions has not yet been established. Further research, employing both laboratory and field approaches, should be undertaken and the practical predictive value of the experimental tests empirically evaluated.

Under certain experimental conditions, cannabis has been shown to have detrimental effects on automobile driving performance. A detailed analysis of such effects, and possible consequences for traffic safety, is needed. Although certain basic parameters can be established experimentally, such studies can provide only a limited basis for predicting the likely effects under natural conditions of drug use and driving. Once appropriate biochemical tests have been developed for the detection and quantification
of active cannabinoids in the body, epidemiological studies can be initiated to establish the extent to which cannabis and other drugs are associated with traffic accidents in the general driving population. Studies comparing drug levels in persons involved in accidents, with drug levels in suitable control subjects (who have not been associated with accidents) have been of primary importance in clarifying the traffic hazards of alcohol. Since epidemiological investigations of this nature can yield reliable information only if the incidence of the use of the drug in the driver population is fairly substantial, such studies are most likely to be fruitful in those geographic areas of industrial countries where cannabis use is most prevalent.

Acute anxiety or panic reactions to cannabis (generally of little clinical significance) have been reliably reported. Systematic information on contributing factors is scarce, but it appears that such occurrences are infrequent and typically involve higher doses and less experienced users. Only a small proportion of these are ever seen at treatment facilities. However, since such reactions do occasionally occur in laboratory studies of cannabis, valuable information might be obtained if detailed data regarding these incidents were collected from researchers. A prospective study could be undertaken employing standardized report forms outlining potential contributing factors.

A considerable body of clinical literature from certain Eastern and other non-industrial countries suggests that the heavy chronic use of cannabis may be associated with a variety of psychological and behavioural disorders. Certain investigators claim that a specific 'cannabis psychosis' exists, while others deny that such a separate clinical entity can be established. Some argue that preexisting psychopathology leads to heavy drug use. Methodological limitations in the reports preclude a comprehensive evaluation of these claims or the identification of causal variables. Modern systematic studies of these populations should be initiated.

The view that cannabis may precipitate a significant psychotic reaction in certain predisposed individuals has also been noted in the North American clinical literature. There is no consensus as to the nature of possible predisposing factors or their prevalence in the general population. Prolonged psychological correlates of chronic use of a more subtle nature (including difficulties in concentration and thinking, personality changes and an 'amotivational syndrome') have also been given considerable notice in the clinical literature. Of particular concern are possible adverse effects of heavy cannabis use in adolescents. It is not yet clear what role cannabis might play in the behavioural syndromes described.

Recurrences or 'flashbacks' of some cannabis effects in the absence of the drug are occasionally reported, but the concept has not been clearly delineated. We have little knowledge regarding the frequency, intensity and consequences of such experiences. More information is needed.

Additional anecdotal reports of individual adverse reaction cases from poorly defined patient groups would be of little value, but accurate clinical reports, put in a proper population context may provide valuable clues for subsequent systematic study. Clinical investigations, involving appropriate control groups, should focus particular attention on pre-morbid social, psychological and physical conditions, previous and concomitant use of other drugs (including detailed information on the quantities involved and the duration and frequency of use), static and dynamic symptom patterns, and long-term follow-up. It would be of interest, for example, to compare past patterns of drug use in patients presenting similar psychiatric symptoms. Detailed longitudinal study of symptom change in various groups of cannabis-using and non-using patients might prove fruitful. Studies of factors involved in more subtle behavioural syndromes would be considerably more perplexing. It may be extremely difficult to establish cause and effect relationships with present methods of investigation.

Given that certain adverse psychological conditions may be associated with heavy cannabis use, it is important to determine the frequency and severity of such reactions in the general population of users. Studies of patient populations alone cannot provide appropriate information for this purpose. There is currently little evidence that serious cannabis-induced disorders occur in a significant proportion of the user population, but adequate data are not available.

TOLERANCE AND DEPENDENCE

Gross tolerance to the major effects of cannabis does not develop under natural conditions of intermittant or moderate use, but more subtle changes in response to repeated cannabis administration have been noted. 'Reverse tolerance' or 'sensitization' ( where some individuals reportedly experience an increased subjective response after the first few experiences with cannabis) is frequently cited in the literature, but has not been adequately examined under controlled laboratory conditions. Furthermore, there is increasing evidence that, with intermittent or moderate use, some tolerance or behavioural adaptation develops to some of the initial performance-disrupting effects of the drug. The mechanism for such changes in response are uncertain. Available information suggests that learning and other psychological processes may play a more important role in these phenomena than do basic molecular pharmacological factors.

There is growing evidence that certain chronic heavy users, who likely maintain a continuously high tissue level of cannabinoids, develop a significant degree of tolerance to the general physiological and psychological effects of cannabis, including those subjective effects which apparently reinforce its use. Such individuals may consume much greater quantities of the drug than are desired or tolerated by the vast majority of users. Evidence of varying degrees of tolerance to certain effects of cannabis in sustained high doses has been observed in some animal species, but not in others. The ultimate epidemiological significance of cannabis tolerance in humans, under various cultural conditions, is as yet undetermined, but the possibility that it might occasion very high levels of use (and, therefore, increase the likelihood of dose-dependent adverse effects) in a small but significant proportion of regular users dictates that the subject be given considerable further study in both laboratory and natural field situations.

There is little evidence that even prolonged use of high doses of cannabis produces significant signs of 'classical' physical dependence, although more subtle undesirable physiological and behavioural symptoms may occur on withdrawal in some apparently rare situations. Possible effects in this regard should be characterized and their influence on sustained patterns of use, under natural conditions, explored. Further effort should be made to define the general concept of behavioural or psychological dependence in an adequate operational fashion, if possible, and the existence and consequences of the phenomenon in various populations of cannabis users investigated. Overreliance on drug dependence concepts may inappropriately focus attention on very extreme, statistically uncommon, patterns of use to the relative exclusion of the wider range of drug using behaviour of basic concern. It would appear that, in practice, drug dependence labels generally provide little verified information about the user which would not be more usefully conveyed by an accurate description of the level (i.e., dose and frequency) of the individual's drug use. Unless adequately defined in each situation in which it is employed, the concept of drug dependence is unlikely to contribute to progress in cannabis research.

INTERACTION WITH OTHER DRUGS

Interaction between the effects of cannabis and a full spectrum of other drugs commonly in use (both medically and non-medically ) should be explored, and likely physiological, psychological and social components and consequences of such interaction examined. Available evidence suggests that cannabis and alcohol can produce additive detrimental effects on certain psychomotor skills and may enhance common physiological reactions. The characteristics and mechanisms of alcohol-cannabis interaction should be fully investigated, with implications for automobile driving and the operation of complex machinery given special attention. Possible interactions with tobacco, minor tranquilizers, anti-depressants and various popular over-the-counter allergy and cold remedies also seem of likely importance. Although cannabis has exceptionally low lethal toxicity itself, the possibility that it might enhance the toxic effects of an overdose of other drugs, such as alcohol, barbiturates or opiate narcotics, should be thoroughly explored. Cross-tolerance between certain drugs, such as alcohol, and cannabis has been suggested in the literature and should be elucidated.

MEDICAL RESEARCH

Although the medical use of cannabis is not of primary concern to this paper, related research is likely to advance our general knowledge of cannabinoids and their effects, and may well result in significant medical progress. Any generally accepted use of cannabis, in modern Western medicine, would likely result in significant changes in attitudes regarding its non-medical use, as well. While cannabinoids have, over the centuries, been reported to produce a wide array of possibly useful medicinal effects, the majority of these claims have either not been adequately investigated using modern scientific methods, or the effects can be duplicated by other more readily available and more convenient drugs. The potential medical uses of natural or synthetic cannabinoids which are currently under investigation include the treatment of anxiety, loss of appetite, insomnia, severe fever, pain, epilepsy, migraine headaches, high blood pressure, glaucoma, sexual unresponsiveness and the secondary symptoms of the common cold and flu. Cannabis is also being studied, alone and in combination with other drugs, as an anesthetic and as a pre-anesthetic agent. In addition, certain cannabinoids have been shown to have significant antibiotic properties.

Acknowledgements

The valuable assistance of Judith Blackwell, throughout the preparation of this paper, is gratefully acknowledged.

DISCUSSION

PATTERNS OF USE

Dr Connell started this final discussion by asking whether the types of studies mentioned by Dr Miller would be important in the event that levels of use decreased. Dr Cameron said that in his opinion, given the existing levels of use throughout the world, an increase in use was not necessary to make the studies worthwhile. Dr Miller suggested that cannabis was still filtering to wider social groups in the West, and that there were few signs of any downturn. Cannabis had gone beyond the point where one could expect it to disappear - it was no longer just used by fad groups.

Ms Blackwell drew attention to the distinction between ever-use and current use, and said that whilst current use of some drugs may be stabilising, there still are increases in the number of those who have ever used.

It was agreed that a monitoring of the changing patterns of use in a range of populations was important. This should go beyond headcounting and investigate the patterns and frequencies and circumstances of use of cannabis and of other non-medical drugs.

TOLERANCE AND REINFORCEMENT

Dr Tinklenberg pointed out that much of the North American work on tolerance had used very weak preparations of cannabis. 'Recent experimental laboratory data strongly suggests that with more potent preparations tolerance very rapidly develops on a number of different dimensions, such as the cardiovascular, tachychardia, cognitive and so forth (personal communications with Reece-Jones, Frank and Miles). The reason why I bring this up is because Americans often think of the effects of cannabis in terms of what is available in our country - perhaps if only very weak alcohol preparations were available we would have few alcoholic problems. My observation is that when more potent preparations are available, in the Bay Area, cannabis connoisseurs seek those out. When they have the choice of weak local marijuana and some potent imported hashish, they'll pick the more potent preparation.'

Dr Miles stressed the need to separate out the physiological aspects from the cognitive aspects. In spite of some physiological tolerance, a group of his subjects did not have significant cognitive tolerance, and were stoned all the time.

Dr Miller said that you may get tolerance to certain kinds of effects, but not to those effects that reinforce use, so it may not lead to increased use except possibly by reducing some of the adverse effects. 'Then there's the question of whether all people are reinforced by the same effects. Some like the change between the stoned and the unstoned state, whilst others may find the continuously stoned state reinforcing.'

Mr Hasleton suggested that cannabis may achieve secondary reinforcing qualities by being used in pleasurable social, recreational or sexual contexts. 'Its these circumstances in which the stuff is used that provide the reinforcement, it seems to me. An inert substance (like putting a pencil in your ear) under these circumstances, would become a highly likely activity. I think that there is a tendency to see the reinforcement in the pharmacological effects.'

Dr Tinklenberg suggested that there are individuals who, given the choice of putting low-concentration or high concentration pencils in their ears, would opt for the higher concentration. 'This suggests to me that the pharmacological properties, such as concentration of THC, is important. It's not just the social factors that provide additional reinforcement.'

Mr.. Dorn suggested that in Dr Tinklenberg's 'hash is a rarity; its for the connoisseurs. In resin or hash is more common. People over here, are connoisseurs or real heads often try to get grass.' So heavier users do not always seek the centrated preparation. Dr Miller suggested that the English and Canadian experiences provide a control for the American situation. 'In Eastern Canada, imported marijuana is the rarity and people prefer to roll a joint with it than to use the more common resin.'

Dr Cameron suggested that with a more potent preparation it is easier to achieve a high dose. 'If you use enough beer, you can become intoxicated. The same is true of a relatively weak preparation of cannabis, you just have to use more. If you are not seeking to become intoxicated, then you may not persevere.'

It was agreed that research was needed to isolate the degree of tolerance and reverse tolerance in the whole spread of physiological and cognitive effects. There is no real evidence of any general tolerance or reverse tolerance: one must speak of tolerance to specific effects, isolated by specific objective tests.

CANNABIS AS A THERAPEUTIC AGENT

Ms Blackwell and Dr Rubin stressed the need to look at the function of the drug for the user. It is known that in some cultures, India and Jamaica for instance, it is used medicinally. The Czechoslavakians have been doing research into folk plants for over 20 years, and selected hemp as the most promising antibiotic out of hundreds of species, and it is now used for a whole range of diseases. Dr Miller mentioned ongoing work in raising seizure thresholds in epileptics, lowering interocular pressure
in glaucoma. In Canada there are reports of people taking cannabis to reduce secondary symptoms of flu or colds. Judith Blackwell and Dr Miller had done a small pilot study into possible use of cannabis in reducing discomfort associated with the menstrual cycle. Other possible uses reported by participants are as a pre-operative medication, and as a substitute drug in alcoholism.

Professor Paton pointed out that cannabis extract had been given a full clinical trial when O'Shameny introduced it in the 1940s. It might be worthwhile to collect all these reports, since although it was all uncontrolled clinical trial, one should remember that it was by this procedure that many of the currently used major drugs were identified as useful.

Dr Edwards suggested that the question was not whether cannabis has medical potential, but whether its balance of main therapeutic effect to side effects was more favourable than that of other drugs.

THE USER'S EXPERIENCE

Professor Paton said that it would be worthwhile to know what cannabis offered, and to ask how this could be offered by something else. Perhaps cannabis was just plain fun. 'I do think that the question of what cannabis offers is satisfactorily answered by saying that it's associated with this and that. I think that it's something to do with the drug effect: perhaps the cannabis user himself can tell us.' Dr Miller spoke of the possibility that the immediate powerful reward offered by
some drugs may be more strong than the other reinforcers available.

Mr Woodcock: 'The fact one form or another of psychoactive drug use is almost universal among human beings suggests that it has a functional purpose about which we really know very little. We should try to find out what it is that people gain from drug use. In much of what is said there is an implied comparison with some kind of human being who is totally healthy and who always
works at maximum potential, and this is quite unlike life. If one knew more of what to the individual were not deficits but operational benefits of drug use, one might be able to construct a social policy that could offer this in an alternative way.'

Dr Rathod said that there was insufficient talk about the effects as the consumer perceives them. 'How can we talk of what is an abnormal effect, if we don't know the 'normal'? We don't know if the Egyptian smoker experiences the same as the Canadian or English smoker. Unless we have comparable, reliable data then it is very difficult to compare qualitative and quantitative differences.' Professor Soueif stressed the present lack of evidence of reliability of interviews.

Dr Miller agreed with the points put by Dr Rathod and Mr Woodcock, saying that he had encompassed the question of the consumer's perspective by referring to factors that reinforce various levels of use. 'I'd like to see why this has become the first new drug to become widely used in several hundred years. There obviously is something important going on here. But I think that if I were talking to a politician or a funder with a limited amount of money then I would have a hard time persuading him to spend a lot of money on asking 'why?' rather than on the effects.'

Dr Miller mentioned a scale developed by the Commission on which users can report subjective cannabis effects. Visual imagery is particularly sensitive to dose. While the amount of imagery seems to increase with dose irrespective of culture, the content of the imagery may be culturally determined.

Dr Edwards suggested that the degree to which a drug effect is culture-free depends on the dose, with high dose, the effect transcends culture. Participants agreed that
how one reacted to one's drug experience was largely culture- specific, and that one's reaction influenced the effect.

Dr Rubin took up Mr Woodcock's point, saying that we should ask why human beings, over the millenia, have used drugs. 'Some of the most creative thinking of the adolescent deviant is directed towards the discovery of new psychoactive substances. I think that we ought to
use that energy for positive purposes - maybe that's where our major research energies should lie.'

EFFECTS ON DEVELOPMENT

Dr Hawks said that 'if we are right in assuming that in future there will be more widespread use of
cannabis in the UK, then younger age groups will be using the drug. In which case, we have to ask what the likely effect of the use of such a drug by organisms in state of incomplete physiological and psychological maturation.' Ms Berntsen suggested that this problem was dealt with satisfactorily by other cultures, in which adult patterns of use were not imitated by children.

Mr Woodcock suggested that if cannabis ceased to be regarded as 'a drug', then the situation with respect to use by younger age groups might be quite different. 'I don't think that there is a very great tendency for caffeine to be consumed by children. It's not regarded
as a drug at all. To see an eight year old child drinking coffee is unusual - yet here is something with no restriction on it at all.' Professor Paton pointed out that children sniff solvents, and Mr Woodcock responded that solvents-sniffing was a secret, non-adult activity.

RESEARCH PRIORITIES

Dr Hawks asked about the highest priorities out of those discussed in Dr Miller's paper. Dr Miller suggested that in terms of acute effects, effects on driving was a high priority. 'If I were in the position of government
I would not spend money on the sort of acute effects experiments that I personally would enjoy doing. I'd look more at the chronic physiological effects. The possibility of respiratory disorder is bothersome. Also, we can no longer attribute all adverse or unusual reactions to bad dope, since we know that they can be produced with pure materials, so we need some work into their causes.'

Dr Cameron stressed the need to encourage research into chronic as opposed to acute effects, given a more difficult nature of chronic effects research. Secondly, he stressed the importance of studies of drug interactions. Thirdly, he mentioned the need to relate the patterns of use in a particular area to the nature of the preparation used in that area. These, he suggested, were the priorities.

IMPACT ON POLICY

Dr Smart pointed out that although the LeDain Commission might be said to have had a liberating effect on court sentencing policy, more people were being convicted. So now there was in fact more criminalisation, but at a lower level: police felt more able to prosecute, and courts to convict. Dr Rubin asked 'I'm not clear whether you feel that public policy should await the outcome of the research that seems necessary.'

Dr Miller said that the LeDain Commission was probably a result as much as a cause of change in public attitudes to cannabis. Research is a part of the totality of public decision-making, rather than a separate activity that can be fully completed in advance of social change.

LIMITS OF SCIENCE

'Most people', said Dr Miller 'have a funny idea about science being very magical, very objective, and don't realise that defining the problem, choosing tools, interpreting results is incredibly subjective. People could be made much more sophisticated and able to evaluate media reports of science without much difficulty.'

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