ANNEX B

THE ADDICTION RESEARCH FOUNDATION EXPERIMENTAL STUDIES OF THE CHRONIC EFFECTS OF MARIJUANA: A DISCUSSION OF THE PRELIMINARY SUMMARY

C. G. Miles and associates' (G. Congreve, P. Devanyi, R. Gibbons, J. Marshman and J. Rankin) at the Addiction Research Foundation of Ontario are two-thirds of the way through a one and one-half year experimental program investigating some possible chronic effects of daily marijuana smok-ing in the laboratory. This series of studies was designed primarily to explore effects on behaviour—both social and personal. Secondarily, parallel investi-gations of other psychological, physiological and pharmacological aspects of cannabis use were organized around this central aim. A pilot study (lasting 70 days) and two phases of the main study (each taking 98 days) have been completed and a third phase is now in progress. Subjects were required to live in an experimental hospital ward for the duration of each study. All experiments contained a pre-cannabis period, followed by the administration of marijuana or placebo cigarettes, and then a second cannabis-free period.

The analysis and interpretation of the data from these experiments are incomplete and the researchers do not expect to publish a final assessment for at least another year. They have, however, shared some of their preliminary observations with the Commission, but stress that any statements made at this point must be accepted with caution and should in no way be construed as the final interpretation of the data. They state: "Our conclusions are little more than impressions which should be treated conservatively until the appropriate statistical analysis and logical evaluation have been completed."

These experiments provide significant information on the effects of re-peated cannabis administration in "normal" users which is not available from earlier studies. Details of the program's progress have not been pre-viously published. Consequently, in spite of the tentative nature of the discussion, an extended preliminary summary of the program was considered appropriate for presentation in this report. Commission staff have been in close contact with the Foundation researchers throughout most of this project, and the design of the Commission's own experimental program was influ-enced by the anticipation of certain information regarding chronic and sub-chronic effects of cannabis from the Foundation's studies. The two programs provide complimentary information on the effects of cannabis.

PROCEDURE

Each of the various Foundation program sub-studies will not be described in particular detail. Instead, some general features of the research will be discussed and some aspects of the various phases of the program will be outlined. The project was organized around a model "micro-economy" sys-tem which approximated some aspects of normal socio-economic behaviour. Subjects were given the opportunity to engage in productive behaviour in the ward for which they were ',aid in the form of cash value tokens which could be exchanged for everyday needs or desires. Certain minimal life-maintain-ing conditions were provided without charge; the bed and cleaning services, heat and light were free. All other items were paid for by the subjects with the cash-equivalent tokens. These tokens could be exchanged, for example, for food, candy, cigarettes, beverage alcohol, newspapers, records, baths, medical information about themselves, access to a gymnasium, to films and other recreational facilities, trips outside in the company of staff members and, in some conditions, marijuana cigarettes.

The costs of goods and services purchased in the ward were generally matched to realistic prices and, in turn, the subjects' earning potential was comparable to that which might occur with similar work in the outside world. In the pilot experiment, tokens were earned for constructing pre-cut wooden furniture and, in the main study, by weaving woollen belts. The work area was open at all hours. Subjects were paid on a piecework basis for completed items which met strict quality standards. A subject might typically earn several hundred dollars per week. Unspent tokens could be saved and ex-changed at the end of the experiment for the cash equivalent. Some subjects accumulated several thousand dollars during the period of the study. Com-plete records were kept of the work output and the savings and expenditures of each subject.

Subjects were healthy young adult volunteers who were regular cannabis smokers and had typically been using cannabis for about two years. (Details as to the frequency of use and quantities usually consumed by these subjects are not yet available.) Persons who showed significant psychological or physiological disorder were not selected. In the pilot study and the first two phases of the main study, males were used as subjects, but in the current third phase, females are being investigated. In the main experiment subjects were assigned, in pairs, to "semi-private" rooms in the ward.

All marijuana or placebo cigarettes used in this program consisted of 1 gm of plant material, although the THC content varied among different condi-tions. (In terms of total weight, these cigarettes were more than twice as large as 'joints' typically used on the street in Canada, but are comparable in size to regular tobacco cigarettes.) The marijuana used in the main studies originally contained 1.5% A' THC and approximately 0.2% CBD and CBN combined. Extracted marijuana, essentially containing no cannabinoids, was used in placebo conditions. The studies were run single-blind and subjects were given no information regarding the various drug doses or placebo administered, except that it was marijuana. When marijuana cigarettes were made available to the subjects, they were sold for the equivalent of fifty cents apiece, regardless of the THC content involved. Alcohol and tobacco could be pur-chased and consumed at any time during these studies.

Subjects in the mandatory dose conditions in all of these experiments smoked the minimum required marijuana or placebo dose over a one hour period each evening, but were allowed to smoke any extra marijuana which they had purchased whenever they wished. The actual smoking technique was not closely controlled, but subjects typically used a deep inhalation style and were asked to smoke essentially all of each required cigarette. In these respects the Foundation program is significantly different from the Commission studies of acute effects. In Commission research, subjects were required to smoke rapidly following a tightly controlled program of inhalation and breath retention, which maximized delivery and absorption of the active compounds, and also resulted in a much more rapid rate of drug administra-tion. Acute effects are likely to be maximized under these latter conditions. The more flexible and leisurely smoking procedure employed in the Founda-tion studies is clearly more natural, but allows considerable variability in smoking styles among individuals and allows the subject to control or "ti-trate" his dose, to some degree, by smoking less vigourously and efficiently after having reached a preferred level of effect. Since such details of adminis-tration are likely significant factors in determining effects, the doses used in the two programs cannot be directly compared on a quantitative basis.

Throughout the experiments (including the pre- and post-marijuana condi-tions) general medical physical and psychiatric examinations were adminis-tered at regular intervals. Particular attention was given to electroencephalo-grams (EEG); heart, liver and kidney function tests; and haematology, blood sugar and other blood chemistry measures. Subjects' behaviour was logged by research staff every half hour. Psychological assessments made at various stages in the experiments included general intelligence tests, psychiatric per-sonality inventories and a self-rating general mood scale. No specific attempt was made to quantify any other subjective or phenomenological effects of the marijuana-induced 'high' in this program. Typically, only heart pulse rate measurements were taken in the evenings after the mandatory smoking period. All other specific tests and examinations were conducted during the day. In most instances, tests were made when the subject was no longer experiencing the major acute effects of the drug, although with the larger doses, some individuals were 'high' essentially all of the time.

Subjects were comprehensively debriefed at the end of the experiments and given psychiatric and physical examinations before discharge. They were instructed that they would be aided in resettlement if necessary, and were asked to report any social, physical or psychological problems they experi-enced as a result of the experiment. In any case, they were instructed to return after six months for a follow-up investigation.

Pilot Experiment

Six subjects were selected and trained in making pre-cut wood and grass-weave stools. After two weeks without access to cannabis, subjects were allowed to buy as many marijuana cigarettes (each containing 8 mg of THC) as they wished. This one-week "free-purchase" period was followed by four weeks during which the subjects were required to smoke two such cigarettes (containing a total of 16 mg of THC) each evening and, in addition, were able to buy more of these 'joints' if they wished. After this mandatory smoking period, subjects were given a second free-purchase period of one week, and during the final two weeks, no cannabis was available.

Main Experiment—Phase 1

Twenty subjects were employed in the first phase of the main study-10 each in experimental and placebo groups. The two groups were separately housed in identical wards. The experimental group was required to smoke marijuana cigarettes, while the control group was initially scheduled to smoke inactive placebo cigarettes only. The final experimental treatment regime was as follows: (a) Experimental group. For the first eighteen days no cannabis was allowed. For the next week marijuana cigarettes (containing 8 mg of THC) were available for purchase. For the following fifty-one days a manda-tory minimum dose was given, plus whatever marijuana subjects wished to purchase. During this period the mandatory dose of THC was increased in stages from 16 mg (two cigarettes) per day for 27 days, to 24 mg (three cigarettes) for fifteen days, and then finally to 30 mg (two cigarettes) for nine days. Then followed a twelve-day period when cannabis was again available only on purchase—no minimum dose was required. In the remaining ten days of the experiment, cannabis use was not allowed. (b) Control group. After an initial base-line period, inactive placebo cigarettes were administered to the control group. After forty-three days of placebo, a small daily dose of 4 mg of THC was given (for six days) increasing abruptly to a high dose of 30 mg on each of two days. A twelve-day free-purchase period ensued, during which marijuana cigarettes containing 15 mg of THC were available. A final cannabis-free period followed.

Main Experiment—Phase 2

The second phase of the main study was conducted under conditions generally similar to those described in phase 1, but, in addition, was designed to explore the effects of cannabis when it is freely available for purchase and consumed in quantities determined only by the individual's own desires. After an initial base-line cannabis-free period, the ten subjects in the first group were given a mandatory dose of 16 mg of THC (two cigarettes) each evening during the drug period (52 days) and were allowed to purchase more if desired. This was followed by a free-purchase only (non-mandatory) period of 21 days and, finally, one week when no cannabis was consumed. The ten subjects in a second simultaneously-run group were allowed to buy and consume whatever quantity of marijuana cigarettes they desired (each pur-chased cigarette contained 2 mg of THC, resulting in joints', in some respects, more like those available outside). For 52 days, no mandatory lower limits of consumption were required for the second group and they were allowed to smoke at any time. For the next 3 weeks, these subjects were required to smoke a dose of 16 mg of THC (two cigarettes) each evening. A one-week no-cannabis period followed.

SUMMARY OF PRELIMINARY FINDINGS AND PROGRESS TO DATE

The following tentative observations are based on information obtained from the experimental program as a whole. The individual sub-projects are not distinguished in this general discussion.

No evidence of gross physiological damage or medical complications from marijuana smoking was detected in these studies. Analysis based on visual examination of EEG records did not yield evidence of any significant change in brain wave patterns, but more comprehensive analyses are still in progress. Electrocardiogram (ECG) records showed some transitory changes in heart function, but chronic effects were not considered likely. Many aspects of the physiological data are still undergoing analysis. There were strong indications that the acute rise in pulse rate, which is a characteristic short-term effect of cannabis use, tends to be progressively less pronounced over several weeks of testing, even when doses are increased over time. Alcohol-like 'hangover' effects were not seen with marijuana. Blood and urine samples were obtained in some situations and attempts to detect cannabinoids and their metabolites in these body fluids are in progress.

No gross behavioural changes appeared during the experiments. The drug did not seem to induce hostility or aggression, and no evidence was found of social deterioration, or a decline in concern over personal hygiene or general physical condition. No major changes in general sleep patterns were obs-erved. Chronic mood modification was not reflected in either staff ratings or the subjects' self-reports. No significant alterations in intellectual functioning were detected by the methods employed in these studies. Psychiatric examina-tions found no adverse effects as a result of cannabis use in the experiments.

In general, subjects reported that mandatory consumption of large doses of marijuana for long periods of time was subjectively unpleasant. In the highest dose condition, most subjects requested to stop marijuana use. Some even insisted that they would leave the experiment if forced to continue smoking high doses. (This would have resulted in a loss of 75% of their earnings and, for many subjects, this would have been a substantial sum of money.) The mandatory high dose was subsequently stopped. Almost none of these sub-jects expressed a desire for cannabis after this experience.

When a free-purchase situation was allowed, with cigarettes approximating the THC quantity of those available on the 'black market', the average daily consumption was less than one cigarette (containing 2 mg of THC). On days in which subjects did smoke they typically consumed between 2 and 4 mg of THC to get 'high'.

The data regarding the relationship between the use of marijuana, alcohol and tobacco under the experimental conditions have not yet been completely analysed and no statement of results in this area has been made.

When large mandatory doses of parijuana were introduced after long periods of abstinence in the laboratory, work productivity tended to be depressed. Discontinuation of marijuana use after a prolonged period of forced daily smoking of high doses resulted in an increase in productivity. When the work output of subjects on a mandatory high dose was compared to that of subjects who consumed only the amounts they desired (which were, in fact, relatively small quantities) the forced-dose group showed dramatically lower average productivity, which was most pronounced in the first few weeks. Some behavioural adaptation or tolerance to this effect of the drug seemed to develop over the course of the experiment and differences between the mandatory and free-purchase groups were minimal towards the end of the experimental period. The researchers suspect that this productivity decre-ment is due more to a reduction in time spent working, rather than to inefficient performance.

The investigators have been unable to detect any clear evidence of depen-dence on cannabis, or the presence of a withdrawal syndrome when the use of the drug is stopped.

Follow-up investigations, to date, have found no persistent effects of the experimental procedures except for a tendency for subjects in the high dose condition to report a decrease in cannabis consumption compared to a similar period before the study.

DISCUSSION

It should be restated that these studies provide tentative information on the effects of daily administration of various doses of marijuana for periods of weeks or months. To this extent, chronic effects have been investigated, but the program was not intended to provide a simple basis for predicting possible consequences of many years of regular cannabis use. There may be some long-term effects which are not detectable until after a more prolonged period of heavy use than was studied here. In addition, it must be stressed that non-behavioural measures were given only secondary attention in this program, and in some areas the evaluation battery employed was rather limited. Subject to these limitations, the major impression of the program's progress, to date, is of the paucity of chronic changes in physiological, behavioural and psychological functioning detected in these studies, even at daily doses well beyond the subject's normal and preferred levels of use.

The problem of bringing natural behaviour into the laboratory for control-led study, without significant disruption or artificial alteration of the phenom-enon of interest, is a perpetual issue in science. Interpretation of the behavio-ural aspects of the Foundation's program are, of course, subject to considera-ble limitations appropriate to the conditions of the experiment. It is clear that living under almost continuous observation in an experimental hospital ward is far from normal conditions of life and marijuana use. Behaviour under such a situation can be expected to be modified accordingly. Subject's conduct, for example, might be more controlled and socially acceptable than would occur in private. Also, the effects of the boredom or stress of institutional living would likely have significant influences on many aspects of the data. The overall importance of the unique setting provided in these experiments cannot be easily determined, and many observations made here will clearly have to be re-examined under different conditions.

Although the data on socio-economic behaviour cannot be interpreted in a simple, straightforward fashion, the program does provide evidence of at least temporarily reduced work output in the laboratory when the consump-tion of high doses of marijuana is required. The relationship between this effect and the so-called "amotivational syndrome" sometimes noted in clinical reports of chronic heavy users is not clear, but the data do lend support to the notion that cannabis, in certain circumstances, may reduce motivation for performing certain normally conducted tasks. Some characteristics of data of this type are very likely determined to a significant degree by the nature of the tasks involved. In this program, labour was of a repetitive, handicraft nature. Effects on work of a more intellectual or artistic variety, or on tasks of the subjects' own choosing, might yield different results, and should be explored.

These studies suggest that certain kinds of tolerance to some marijuana effects may develop. Evidence of reduced acute pulserate response to repeated marijuana doses (or to a single dose in heavy users) has been noted in several laboratories, and the data presented here provide additional support to these observations. The work output analysis suggests some adaptation or tolerance to the initial behaviour-disrupting or modifying effects of 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 here. No attempt was made to quantify the magnitude or quality of the acute subjective response or 'high' obtained from the drug over repeated use. The data on free-purchase con-sumption, 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 con-sumed less cannabis per day during free-purchase periods towards 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, or with present typical use in North America.

The lack of evidence for a withdrawal syndrome or other significant signs of dependence, even after apparently very high daily doses, is in agreement with the bulk of the scientific literature. But there is still a 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 any natural conditions.

It is also interesting to note that the intermittent patterns of marijuana use and the quantities consumed during the optional free-purchase periods in the laboratory were quite similar to that commonly observed in users under natural conditions in Canada. Daily use of high doses was generally consid-ered undesirable from the subject's point of view. Many aspects of these data are undoubtedly influenced significantly by the individual's previous history and normal patterns of cannabis use. Consequently, the final analysis and interpretation, in some areas, will require a detailed consideration of the subjects' past levels of use.

Some objection might be made regarding the possible confounding effects of generally open access to alcohol and tobacco throughout the study. This option does potentially permit, however, some evaluation of the interrelation-ships among the use patterns of the various drugs in the experimental setting.

Although these data are not yet fully analysed, it appears that alcohol consumption during the experiment was probably not great enough to have contributed significantly to the few effects observed, nor does it seem very likely that the intermittent drinking which occurred has masked other poten-tially detectable cannabis effects. However, these possibilities cannot yet be completely ruled out. Ongoing data analysis will clarify some of these issues.

A different pattern of response might have emerged on some parameters if subjects were required to smoke in the morning, for example, or at various times during the day, rather than just at night. However, even with such variations in procedure, major differences in the picture of chronic effects observed here would seem unlikely for most variables. It would also be of interest to study subjects of different age groups, with differing past histories of drug use.

The program provides an interesting and valuable exploration of the application of a micro-economy model in the study of drugs. The investiga-tors feel that the methodology employed in these studies is an experimentally useful technique and may have broad therapeutic possibilities as well. The Foundations' final report on the program (to be available in 1973) should contain a substantial amount of significant information on the effects of the repeated use of cannabis.