ANNEX C
SOME DIRECTIONS FOR FUTURE RESEARCH ON THE PHARMACOLOGICAL AND CHEMICAL ASPECTS OF THE NON-MEDICAL USE OF CANNABIS

In the past few years we have witnessed a significant advance in our knowledge of cannabis and its effects: systematic botanical studies have begun; 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; many prominent short-term physiological, behavioural and psychological effects have been documented; many basic animal toxicology studies have been completed, and previous restrictions on human experimental research are being relaxed accordingly; recent advances in cannabis chemistry and pharmacology have stimulated a re-interest in the possible use of natural and synthetic cannabinoids in the medical treatment of a variety of disorders; and a number of systematic studies of possible social, psychological and physio-logical effects of long-term use are underway and the preliminary findings of several investigations into chronic and sub-chronic use are available. In spite of this impressive advance, many important questions are as yet unanswered and must be resolved before a full picture of the etiology, general characteris-tics and consequences of the non-medical use of cannabis can be presented.

The following discussion provides some indication of areas of cannabis chemistry and pharmacology where further research is needed. Specific atten-tion has not been given here to research into other aspects of the non-medical use of cannabis (such as the social history and context, extent and patterns of use, causes and motivation, education and prevention, and legal and eco-nomic implications) except as they pertain to the topics discussed in Chapter 2, Cannabis and Its Effects. 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 non-medical use which are of potential concern to society. Further discussion of general topics pertaining to scientific investigation, in the broader frame-work of non-medical drug use, will be presented in a later report, in a section primarily concerned with the role of government in this area.

Although a number of important questions regarding the acute effects of cannabis are unanswered, the possible personal and social consequences of long-term use are of primary concern. Multi-disciplinary longitudinal studies of various sectors of the general population, including groups of users and non-users, would be invaluable and should be initiated. However, at least tentative answers to certain questions are urgently needed and cannot await the completion of such long-term investigation. The possible consequences of chronic use on cognitive and intellectual ability, psychomotor skills, personal-ity, social behaviour and general physical condition (for example, brain, respiratory, heart, liver, kidney and endocrine function) are subjects of much immediate concern. Of special importance are possible effects of regular use on the maturation process in adolescents.

Large-scale cross-sectional studies of persons with varying histories of cannabis use are likely to provide a reasonable short-term payoff. Since the common use of cannabis is a relatively recent phenomenon in North Amer-ica, it will be difficult to locate an adequate number of suitable subjects for extensive epidemiological study, although certain more restricted projects could be conducted on this continent. It will be necessary to turn to other countries, which have had a longer history of widespread cannabis use, for large-scale epidemiological investigation. Several studies of chronic users in other cultures are currently underway, but considerable additional effort is warranted. Cross-cultural generalizations must be made with caution, and many conditions of non-industrial countries may have limited applicability to the North American situation.

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. Accurate correlational data of this nature 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 predis-posing personal and environmental factors.

Several sub-chronic studies are in progress which involve the daily admin-istration of cannabis to humans under controlled laboratory conditions, over periods of weeks and months. Such experiments can provide certain informa-tion regarding the consequences of chronic use, but cannot detect possible effects which might develop only after more prolonged periods of exposure.

In some areas basic information can be obtained from studies of chronic cannabis administration to animals. However, the significance of such studies must ultimately be interpreted in the context of human conditions of drug use. Further effort should be made to develop animal tests which will parallel pharmacological processes and effects in humans. Because of often substantial inter-species differences, findings involving lower species should be verified in primates. Since animal studies have traditionally employed massive doses (administered under conditions of questionable relevance to human situa-tions) it is important to explore the acute and chronic effects of cannabis on animals at doses which are more comparable to the quantities likely to be consumed by humans.

Over the past few years, almost all experimental research has been con-ducted on healthy, young adult males. Earlier cannabis experiments often employed male prisoners as subjects. Other populations need to be investi-gated, especially females, and adolescents and older persons of both sexes.

Cannabis effects in persons with varying histories of other chronic drug use should be investigated. Alcohol is perhaps most important in this regard. 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.

Although this discussion is not directly concerned with general social aspects of the extent and patterns of cannabis use in society, a clear under-standing of the present, and likely future, conditions of use is essential for optimal laboratory efforts. Information on multiple-drug use provides useful leads for drug interaction studies. Socially relevant experimental conditions, including appropriate drug doses, require accurate information from socio-pharmacological field studies. Factors associated with the initiation, increase, stabilization, reduction or cessation of cannabis use may provide valuable leads as to effects. In addition, the influence of social attitudes regarding cannabis use on the ultimate social, psychological and physiological effects of the drug needs further study.

It is also necessary to maintain accurate information as to the identity, purity and potency of drugs being consumed from illicit sources. Existing limited data suggest that, in Canada, cannabis is rarely adulterated with other active drugs, but that it is sometimes diluted or 'cut' with inactive materials, and that illicit cannabis varies in cannabinoid content over a wide range. However, no really adequate, systematic, national data have been collected. Serious questions have been raised regarding possible contamination with herbicides, pesticides and toxic fungi. Appropriate analyses have not been done in these areas. Up-to-date, continuing qualitative and quantitative analyses of randomly selected sub-samples of police seizures (supplemented with samples from other sources) might be the best method of monitoring the purity and potency of illicit cannabis in Canada. Information on the age and original geographic source of the samples would add to the value of the program. The comparison of such data with similar information from sources in other countries would be of further interest.

Considerable controversy exists regarding the appropriate chemical no-menclature for cannabinoids. A final decision should be made on an interna-tional basis to establish an acceptable uniform cannabis nomenclature system.Isi

Reliable standard analytic techniques for quantifying the major can-nabinoids in various cannabis preparations should be developed and commu-nicated on an international basis, and the effectiveness of such a program should be evaluated with follow-up research involving standard test materi-als. The reliability and validity of present methods of cannabis quantitative analysis are disappointing, and even recent experimental cannabis studies which have attempted to specify THC dose can only be interpreted in a general quantitative sense. Facilities for adequate analysis (and re-analysis) of research materials should be made available to all investigators.

In a closely related area, there is a definite need for simple and convenient techniques for identifying and quantifying primary cannabinoids and their metabolites in the body. When such methods become available, the relation-ship between body levels of biologically active compounds and primary effects should be established. A convenient quantitative chemical test, similar to the alcohol Breathalyzer, which might ultimately enable a reasonable estimate of the intensity of certain drug effects would be invaluable, and must be given high priority. Although considerable progress is being made in this area, even those methods which are likely to be refined in the near future may have limited practical application outside of the research laboratory.

While much is known regarding the agriculture of hemp fibre production, until recently, little systematic modern botanical research had been conducted on psychotropic aspects. Several important projects are in progress in Canada and other parts of the world, and further research in this area would be of value.

Variables affecting the stability, degradation and shelf-life of different forms of cannabis are not adequately understood. Effective standard storage procedures should be developed and communicated to researchers.

Almost all of the recent human experimental research has been conducted with marijuana or synthetic A' THC. While there are obvious advantages to the use of uniform substances 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 should be available for chemical and experimental evaluation. Sup-plies of other primary cannabinoids and their metabolites, in relatively pure form, should also be developed and made available to researchers for human and animal studies. The development of water soluble cannabinoids would greatly facilitate experimental studies of effects relevant to both the medical and non-medical use of cannabis.

Quantitative information on major cannabinoids in experimental materials should be provided in research reports. The pyrolysis and delivery of can-nabinoids smoked in cigarettes, conventional pipes or water pipes may not be directly comparable and further investigation is warranted. 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 the subject in the smoke under the experimental conditions employed. Specifying doses on a body-weight basis would further aid the 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 investi-gated. Possible differences in the acute and chronic effects of various methods of cannabis smoking and ingestion should be examined. Furthermore, factors which affect the rate and extent of absorption of cannabinoids in the lung and gastro-intestinal tract have not been adequately delineated.

Advances are being made in our knowledge of the metabolism and distri-bution of THC in the body, but considerable further research is needed. Since CBD and CBN are present in large quantities in some forms of cannabis, these cannabinoids should be thoroughly investigated, as well. The possibility that primary cannabinoids or their metabolites may accumulate in the body for prolonged periods with chronic use should be carefully explored and any physiological consequences elucidated.

The mechanisms involved in the various central and peripheral effects of cannabis are poorly understood. Studies in this area should be encouraged, and structure-activity relationships of the various primary cannabinoids and metabolites should be established.

Although it is now clear that A' THC is the principal active constituent in cannabis (at least in part via metabolites) the possibility remains, and must be explored, that other cannabinoids (particularly CBN and CBD) may in some way alter the pharmacology of THC and its metabolites. CBD and CBN might alter the function of primary organs of metabolism and excretion, for example, or perhaps play a significant role in cannabis tolerance or sensi-tization, or interaction with other drugs. Competition for binding or receptor sites might also exist among the cannaboids. The possible long-term effects of other, non-cannabinoid, components of marijuana and hashish should also be examined.

Cannabis seems to produce few significant short-term physiological effects in normal users. Both acute and chronic effects, however, should be investi-gated in persons suffering from certain physical disabilities as well. Of particular concern are the effects of cannabis on persons suffering disorders of the respiratory system, gastro-intestinal tract, cardiovascular system, liver, kidney, reproductive organs, endocrine system (including diabetes), and the central and autonomic nervous systems. Since cannabinoids are primarily metabolized in the liver, potential effects on hepatic function should be given special attention.

Available evidence suggests that chronic smoking of large quantities of cannabis may have effects on the respiratory system which are in some respects similar to those produced by tobacco. Differences in typical patterns and methods of smoking, as well as quantities consumed, complicate simple comparisons between the substances, however. The possibility that cannabis (either alone or in combination with tobacco) might complicate or produce respiratory disorders, including cancer, must be thoroughly investigated and possible toxic components identified.

Considerable effort must be concentrated on rectifying conflicting data on possible neuro-toxic effects of chronic cannabis use. Although several recent controlled studies have found no evidence of neurological disorders in per-sons with long histories of heavy use, other clinical reports have suggested chronic effects (including brain damage) in certain users. The seriousness of the conditions implied in these latter papers requires that immediate system-atic investigation be given high priority. Additional human and animal studies on chronic and sub-chronic use are needed.

Reports of the acute and chronic effects of cannabis on sleep are conflict-ing, and the existence and ultimate neurological and behavioural significance of any changes need to be established.

Present data does not indicate that cannabis produces chromosome abnor-malities or has adverse consequences on the developing foetus in humans, but some studies of certain lower species have detected adverse effects at extreme doses. Because of the seriousness of any such possible effects in humans, further research is required.

Existing research reports of the acute effects of cannabis on muscle strength and physical work output are not conclusive, although some deficit is sug-gested. 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 laboratory and natural conditions, have not been defined.

Recent advances in cannabis chemistry and pharmacology have stimulated a re-interest in the possible use of natural and synthetic cannabinoids in the treatment of a variety of disorders. Research of this nature is likely to result in a significant advancement in our basic knowledge of cannabinoids and their effects on the human body, as well as possible medical progress.

There are considerable differences among individuals in the general re-sponse to cannabis. The importance of an individual's personality, physical characteristics, past drug experiences, and the set and setting of use, in determining various cannabis effects should be systematically investigated.

Experimental evidence indicates that under some conditions cannabis can produce short-term deficits in certain perceptual, attentional, cognitive and psychomotor abilities. The overall significance of the effects found in the laboratory, to personal, social and occupational functioning under natural conditions has not been fully established. Further research, under more natural conditions, should be undertaken and the predictive validity of laboratory tests empirically evaluated. Data relating cannabis use to scholastic performance are contradictory, and many factors in such correlations require study.

Cannabis users typically claim substantial acute subjective alteration in sensory and perceptual processes as a result of taking the drug. Attempts to verify such effects in the laboratory have met with surprisingly little success. Although it is appropriate to concentrate initially on possible adverse effects of cannabis, it would be worthwhile, in order to better understand the growing popularity of the drug, to experimentally investigate, in more sensi-tive fashion, some of the subjective effects which users claim provide the reinforcement or motivation for continued use. Additional research, espe-cially in the areas of visual perception (under various conditions of illumina-tion), and attention and vigilance should be conducted, employing signal detection techniques where applicable.

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. After basic parameters have been established, however, experimental studies can provide only a limited basis for predicting the ultimate effects of natural drug use on traffic safety. Once appropriate biochemical tests have been developed for the detection and quantification of active cannabinoids in the body, epidemiolog-ical studies should be initiated to establish the extent to which cannabis and other drugs are associated with traffic accidents in the general population. Comparisons of drug levels in persons who had been involved in accidents, with drug levels in suitable control subjects (who had not been associated with accidents) have been of primary importance in clarifying the traffic hazards of alcohol. Since epidemiological studies of this nature can yield reliable information on a drug's effects on traffic safety only if the incidence of the use of the drug in the driver population is fairly substantial, such a study is most likely to be fruitful in those geographic areas where cannabis use is most prevalent.

Acute anxiety or panic reactions to cannnabis (generally of little signifi-cance) have been reliably reported. Little systematic information on contrib-uting factors is available, although it appears that such occurrences are infrequent and typically involve higher doses and less experienced users. Apparently only a small proportion of such occurrences are ever seen at treatment facilities. Since acute anxiety or panic reactions occasionally occur in laboratory studies of cannabis, valuable information might be obtained if detailed data regarding such 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 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. Some investigators claim that a specific "cannabis psychosis" exists, while others deny that such a separate clinical entity can be established. There have also been reports of chronic dementia in certain long-term users. Methodological limitations in the reports preclude a comprehensive evaluation of these claims. Modern systematic studies of these populations have not been con-ducted and 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, but such claims have yet to be systematically evaluated. Furthermore, there is no consensus as to the nature of posssible predisposing factors in such conditions or their prevalence in the general population. Prolonged psychological correlates of chronic use of a more subtle nature (including personality changes and an "amotivational syndrome") have also been given considerable notice in the clincial literature. It is not yet clear what role cannabis might play in the behavioural syndromes described.

While anecdotal reports of individual cases selected from poorly defined patient groups are of very limited value, accurate clinical reports, put in a proper population context, can provide valuable clues for subsequent system-atic 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 fre-quency 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 also prove fruitful. Studies of predisposing factors involved in more subtle behavioural syndromes would be considerably more perplexing, and it may be extremely difficult to establish cause and effect relationships with present methods of investigation. Of special concern are possible adverse effects of chronic cannabis use in young adolescents.

Given that a variety of adverse psychological reactions may be associated with cannabis use, it is important to investigate and thoroughly document reported cases and 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 disorders occur in a significant proportion of the user population, but adequate data are not available. Significant changes in the extent and patterns of cannabis use in Canada would undoubtedly alter the treatment picture, and the effects of such changes should be carefully and systematically monitored.

Recurrences or "flashbacks" of some cannabis effects in the absence of the drug are occasionally reported, but the concept has not been clearly defined, and we have little knowledge regarding the frequency, intensity and conse-quences of such experiences. More information is needed.

Although gross tolerance to the major effects of cannabis does not develop under conditions of moderate or intermittent use, many aspects of this phenomenon have not been adequately investigated. The often-mentioned "sensitization" or "reverse tolerance", reportedly occurring with the first few experiences with cannabis, has not been examined in the laboratory. Further-more, there is increasing evidence that with intermittent or moderate use, some tolerance or behavioural adaptation develops to some of the initially disrupting effects of the drug. The mechanism for such a change in response is uncertain. There is growing evidence that chronic heavy users in some countries have developed a significant degree of tolerance to the general effects of cannabis, including those that reinforce use, and may consume much greater quantities than are tolerated or desired by other users. Contrib-uting pharmacological, psychological and social factors in this complex pic-ture remain to be documented.

There is little evidence that cannabis, even with prolonged use at high doses, produces significant signs of "classical" physical dependence, although more subtle, undesirable, physiological and behavioural symptoms may occur on withdrawal in some situations. Possible effects in this regard should be characterized and their influence on sustained patterns of use, under natural conditions, explored. The general concept of behavioural or psychological dependence should be defined in an adequate operational fashion, if possible, and the existence and consequences of the phenomenon in various popula-tions of cannabis users investigated.

The possible 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 certain common physiological reactions. The mechanisms and characteristics of these interactions should be fully investigated, and implications for automobile driving and the operation of complex machinery given special attention. Although cannabis has exception-ally low lethal toxicity, 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.

Significant controversy exists regarding the relationship between the use of cannabis and the use of a variety of other drugs, including alcohol, heroin, tobacco, amphetamines and LSD. Social, economic and criminal-legal, as well as pharmacological factors predisposing to multiple-drug use, should be further investigated. Careful prospective studies would be helpful, although even with considerable effort it may not be possible to establish causal links among the various factors with any degree of certainty.

A centralized (perhaps international) documentation, information-gather-ing and alerting system would greatly facilitate effective communication among researchers in this rapidly expanding field. Because of the accelerating nature of scientific information on cannabis, existing modes of publication and communication are hardly adequate.

International co-operation and co-ordination in some of the areas discussed above might be effectively conducted through the World Health Organization, as suggested in their recent cannabis report. 678