Physiological Effects

Cannabis

The Report of the Canadian Government Commission of Inquiry into the Non-Medical Use of Drugs - 1972

2. Cannabis and Its Effects

PHYSIOLOGICAL EFFECTS

Acute Effects

The short-term physiological effects of a typical cannabis dose on normal persons are generally quite benign, and are apparently of little clinical significance. Perhaps the most commonly reported physiological response to cannabis is a dose-related increase in heart pulse rate. In Commission experiments, a dose producing effects generally within the range of the subjects' past experience reliably increased pulse rate by more than one-third. A slight increase in systolic blood pressure was also seen at the higher dose. These cardiovascular effects disappeared within a few hours. Other studies in the literature have been inconsistent with respect to blood pressure effectssome investigators report an increase with cannabis, while others found no change or a slight decrease.284,296,301,407,564,670 Synthetic THC-like compounds have been shown to produce major reductions in blood pressure in some species.252 Changes in the electrocardiogram are reportedly minimal for normal subjects 284,301,436 Subjects with cardiac abnormalities have not been studied, however. Marijuana may reduce the typical heart rate response to breath inhalation or coughing. 519

Cannabis reliably induces a swelling of the minor conjunctival blood vessels in the membranes around the eye, producing a slight 'blood-shot' appearance (termed conjunctival congestion) similar to that seen with alcohol.399 This finding was confirmed in Commission studies. (This effect may be, at least in part, a secondary consequence of local irritation resulting from an inhibition of tear glands and subsequent drying of the eye, but is not caused by direct smoke irritation.) No corresponding retinal vascular change has been observed within the eye14,263 and the clinical significance of the conjunctival effect is probably minimal. A significant decrease in finger temperature in a Commission experiment suggests a slight constriction of minor blood vessels in the skin,440 although this latter vascular response has not been directly verified. Slight edema or puffing around the eyes sometimes occurs.16,155 Contrary to popular belief, there is no evidence of pupil dilation with cannabis, and recent controlled studies have detected no change or a slight pupillary constriction. 155,265,297,661 A reduction in intraocular (within the eye) fluid pressure has been reported with marijuana and may have therapeutic significance. 264

Salivation was significantly decreased by cannabis in a Commission experiment, even with low doses.440 There are occasional reports by users of initially stimulated saliva secretion, followed by a drying of the mouth, throat and nasal passages, but this bi-phasic response has not been verified in the laboratory. Minor effects on skin conductance and sweat gland activity were inconsistent both in Commission experiments,251,440,518 and other studies. 204,431,522 Cannabis may stimulate urination16,407 but such an effect has not been clarified. No consistent changes in blood sugar functions have been reported.161,279,397,407,505,661 Appetite is usually stimulated, but perhaps not as universally as commonly believed,3,16,248,279,407 and changes in hunger with the drug seem unrelated to blood glucose. Cannabis has not been reported to produce any significant changes in general hormone or blood biochemistry in man, except indirectly by eliciting general signs of arousal or activation in some instances.283,397,407,670 Acute use of cannabis does not seem to affect kidney or liver function or alter basal metabolism.407 No substantial changes in respiration have been noted with acute use, 407,564,661,670 nor have significant alterations in deep tendon reflex and other simple nerve functions been observed in humans.284,297,527 High doses in rats may increase DNA content in brain tissues.112 THC may lower body temperature slightly in humans,655 and large doses produce significant temperature reduction in animals.225,252,489

The acute effects of cannabis administration on the electroencephalogram (EEG) are slight at "social" doses and are generally considered to be of little clinical significance.189,308,527,641 Changes in sleeping EEG's (including REM phases) have not been clearly established, and existing reports are contradictory.32,285,522,574 Cannabis slightly alters the electrocortical visual evoked response in a way which suggests some increased reactivity or arousal effect.611 in a Commission experiment, enhanced two-flash visual discrimination also suggests some neuro-physiological (perhaps cortical) activation with the drug.440 Much higher doses in monkeys, however, produce changes which seem to reflect an ultimate depressant action.76

The effects of cannabis on neurohumoral transmitters is unclear. Existing studies are conflicting, but it appears that there is some alteration in brain concentration of catecholamines, serotonin and other neurochernicals in most of the animals studied. 67,90,140,207,280,409,446,565,579,619 The significance of these changes is ambiguous, but information in this area is increasing at a considerable rate.

Ling and associates reported that daily administration of THC to rats (for four days) failed to produce significant effects on general adrenal and gonadal activity, except at very high doses. However, an involution of the thymus gland was observed, which was similar to that produced by stress.370

Muscle strength seems to decrease with higher doses of cannabis. In Commission research the upper dose produced no change in maximum momentary strength of hand grip, but a one-minute sustained finger grip task showed a decrement, even five hours after smoking.440 Similar effects have been observed by others at higher doses. 284,407,507 Singh recently found no effect on acute muscle strength. but reported some evidence of reduced efficiency of work on a bicycle ergometer after marijuana,564 thus supporting the results of a 1901 study.183 Paradoxically, the use of cannabis to reduce fatigue during hard physical labour has been noted in several non-industrial countries.16,38,73,124,125,295,534,651 The effects of the drug under normal labour conditions have not been systematically studied.

Recently declassified United States Army research (with synthetic forms of THC and related analogues) has shown that some cannabinoids possess significant hypnotic, anaesthetic, anti-convulsant, anti-hypertensive and temperature-reducing effects of possible therapeutic potential.16,249,259,284,407 Controlled clinical trials in humans have yet to be completed, however.

Severe acute gastrointestinal disturbances rarely occur with smoked cannabis, although nausea is not uncommon when inordinately high doses are taken, especially orally, or when anxiety is associated with use.16,249,259,284,407 Headache, numbing, vomiting, cramps, diarrhoea or constipation have also been noted in the clinical literature. In some instances, lack of co-ordination, ataxia and tremors have been observed, and chest pains. dizziness and fainting have occasionally been noted, usually with large doses.243,548 High doses can also induce sleep, and drowsiness a few hours after administration is not uncommon, even with smaller quantities. Physiological hangover effects analogous to those produced by alcohol have been described in some persons, but are apparently rare, even after considerable intoxication. Some persons report that they feel more refreshed than usual the next day. More commonly, either no effects or a slight feeling of heaviness and lack of energy may be present the 'morning after'.126,232.243,248,249,407,415,436,438,440,670

Individual case reports of cannabis-precipitated diabetes and epileptic reaction have appeared. 292,318,384 These suggestions seem somewhat paradoxical in light of the numerous reports of the anti-convulsant properties of cannabinoids, and the lack of consistent effects on the blood-sugar functions with the drug.

In the past few years, there have been conflicting reports that large quantities of cannabis extract injected into pregnant females of certain strains of rodents can affect litter size or may cause abnormalities in the offspring.63,217,218,498 These disparate results cannot be easily generalized to other species and give little information regarding human effects. At this time, there is no scientific evidence that cannabis adversely affects the human foetus, although it may cross the placental barrier in pregnant women, as it does in the animals studied. Existing studies have not found cannabis-induced chromosome abnormalities in vitro, 356,404,468 in human cannabis users162,226 or in monkeys treated with cannabinoids. 375

Cannabis has exceptionally low lethal toxicity. Few, if any, human deaths have been caused directly by cannabis overdose. Although several isolated deaths were attributed to cannabis in the older literature, 651 these cases were not clearly documented, and the actual role of cannabis in the fatalities is ambiguous and has been questioned .243,573,576,633 Recently, a death was attributed to cannabis overdose in an individual in Belgium.266 Cannabinoids were reportedly found in the body on autopsy, and no other cause of death could be determined. Even this one case has been challenged 210,243 and given the international attention it has received, it may, if valid, be considered "the exception which proves the rule". A near-fatal case in which a young man attempted to commit suicide by ingesting massive quantities of hashish has also recently received wide publicity.234 In spite of his considerable effort, he was unsuccessful and has fully recovered. Lewis has reported a fatality allegedly caused by distention of the bowel during a prolonged bout of gross overeating under the acute influence of cannabis.367

Recently, there have been several reports of non-fatal acute physiological reaction to intravenous self-injection of 'home-made' marijuana extract. Severe body tremors, chills, fever, tachycardia, nausea, cramps, vomiting, diarrhoea. muscle aches and a variety of temporary systemic disruptions were noted.212,261,334,335,382 These effects are probably not specific to cannabinoids, but likely reflect a general response to a variety of insoluble foreign compounds in the crude concoctions. Fortunately, instances of such use appear to be few, and only one case has been reported in Canada.463

From the point of view of lethal toxicity, cannabis must be considered one of the safest drugs in either medical or non-medical use today. It is possible, however, that cannabis may interact with other drugs taken concomitantly (for example. alcohol, barbiturates or opiate narcotics) and enhance their toxicity. (See later section on Cannabis and Other Drugs.)

In summary, at typical doses of cannabis use, few acute physiological effects have been detected. Those which have been identified generally seem to have little clinical significance. Even at relatively high doses, few substantial physiological changes occur. Overall, it would appear that increased heart rate, a slight reddening of the eye, and decreased salivation are the most consistent and reliable objective physiological measures of acute THC, marijuana and hashish use. A statistical combination of just these three variables was extremely efficient in differentiating various THC doses administered in Commission research. 440

Chronic Physical Effects

There is little reliable information on the long-term physiological effects of cannabis use. There are numerous reports from Eastern countries of chronic ill health among very heavy long-term users of hashish. 126,295,442,583 Most commonly reported are minor bronchial, respiratory and gastrointestinal ailments. A chronic dementia has been alluded to in some heavy hashish users in the East. As discussed in more detail in the section on psychological adverse reactions, the majority of the Eastern studies have no control group of comparable non-users for a reference standard, and clinical findings are usually confounded with a variety of social, economic, nutritional, hygienic and cultural factors, which are not easily separated. Reports are rarely documented with clectrophysiological or autopsy data. The 1971 WHO technical report on cannabis notes:

It is questionable whether weight loss, emaciation. anaemia, constipation, etc.. which have been reported to be associated with cannabis smoking in India, are due to the drug or to poverty, poor nutritional status, and intercurrent infections. Studies in the USA, have. by and large, failed to show any significant physical deterioration after an average of 7-8 years of marihuana use.678 [P. 26]

Furthermore. in most non-industrial societies, cannabis is almost invariably smoked with large amounts of crude tobacco, and occasionally other drugs. and the separate effects of the various substances cannot be easily isolated, Perhaps the only chronic physical effect of cannabis use which has been established from these reports is a condition of persistent conjunctival congestion in some users, analogous to the swelling of the minor conjunctival blood vessels around the eye seen in acute use. Both the etiology and clinical significance of this effect are as yet unclear.

Considerable concern has been expressed that the chronic smoking of cannabis might have cancer-producing effects similar to those now attributed to tobacco. Although considerable variability exists among samples, it appears that the tar yield front crude marijuana may be comparable to that of commercial tobacco cigarettes.179,191,388 One study with mice indicated that tobacco and cannabis tar condensates had similar deleterious effects on mouse skin. The investigators stressed, however, that the findings do not indicate that marijuana is carcinogenic in the mouse or in man.388 In another mouse experiment, adverse effects of marijuana smoke were demonstrated on the cells of the respiratory tract.364 In a recent human study, microscopic analysis of the lining of the lung detected cellular changes in a sample of eight daily marijuana users somewhat similar to those seen in a group of subjects who only smoked tobacco.395,396 Epithelial abnormalities were found in the trachea of six heavy hashish smokers in another report.601

Even if tobacco and cannabis were shown to be equally carcinogenic on a weight basis, significant differences in patterns of use would prevent clear comparisons of the cancer-producing potential of these drugs. The present common pattern of regular cannabis use in North America is more analogous to intermittent social alcohol use than to the picture of chronic daily smoking presented by regular tobacco users. Clear exceptions to this pattern exist, of course, and may become more common in North America in the future. Regular tobacco smokers generally consume much greater quantities of plant material than do chronic cannabis users. The deep inhalation and long retention smoking techniques usually used with cannabis in North America may add complications, since this practice usually results in almost complete retention of all smoke particles in the lungs, as well as the absorption of the desired active compounds. The adverse effects of the various (mostly nonpsychotropic) substances in the smoke are not clear. In non-industrial countries the technique of cannabis inhalation is more similar to that regularly used with tobacco, and exaggerated inhalation and retention is not so common.

Tennant and associates reported on 31 military patients who smoked "enormous quantities" of hashish. Irritation of the respiratory tract appeared to be responsible for frequent ailments including bronchitis, sinusitis, asthma, rhinopharyngitis and uvular edema. There was also a high incidence of acne reported and some gastrointestinal disorders in a few patients.602 Later, "below normal" vital lung capacity was also seen in similar patients. Although most of the individuals observed smoked tobacco as well as cannabis, the authors submit that the excessive use of hashish was primarily responsible for the conditions described.601 Similar observations have been made with respect to chronic hashish smokers in Greece. 442

Various isolated studies have suggested other possible physiological problems associated with chronic cannabis use. Although the role of cannabis in producing the effects has not been well-established in these reports. they Indicate important areas for future research attention. One Moroccan paper reported arteritis in a number of cannabis smokers who consumed 10 to 15 pipe-fulls per day.587 Miras has made similar clinical observations in Greece.442 Bowman found no evidence of altered tonic or phasic heart rate in chronic cannabis users in Jamaica.74

Kew reported eight marijuana users who showed some liver dysfunction. Although these subjects had used other drugs, they "had not taken intravenous drugs or used alcohol to excess".332 Hochman and Brill studied 50 regular marijuana users in California with a mean duration of use of seven years. None of these subjects had a clinical history suggesting liver dysfunction. In the ten showing evidence of disturbed liver function in laboratory tests, the abnormalities were related to concurrent heavy alcohol use and were minimized by alcohol abstinence. There was no relationship between length of marijuana use and liver function.274 Tennant and associates found no abnormalities in liver-function studies of 31 patients who were extremely heavy users of hashish.602

Oki and Sisson have released some preliminary figures from the Addiction Research Foundation multi-disciplinary study of 200 regular cannabis users in Ontario. The average age of the subjects was 22 (range: 15-42) and average duration of marijuana use was 2.7 years (range: 1 20). Almost all of the subjects used alcohol and tobacco; more than one-half had tried LSD and "speed" and one-third had tried opiate narcotics. This frequent use of other drugs, as well as the absence of a comparable matched control group limits some of the conclusions that can be drawn from the study. Certain of the findings are relatively straightforward, others are not so easy to interpret. Compared to what might be expected in a similar non-cannabis using population, these subjects showed no indication of significantly increased incidence of disorders of the gastrointestinal tract, liver, kidney, spleen, or gall bladder; no dysfunction of the thyroid, parathyroid or other endocrine glands; and no blood cell abnormalities. Peripheral vascular disorders were rare and there was little evidence of cardiac conditions with the exception of some tachycardia and elevated blood pressure in a few subjects. Most had no bronchial, respiratory or asthmatic disorders, but 15% had some difficulties in this area. About one-fifth had acne, but this may not be too unusual for this age group. About one-half showed some conjunctival congestion (slight reddening of the eyes). The data on central nervous system function are somewhat ambiguous, but no clear indication of cannabis-related pathology appears. In this study, some subjects had not been abstinent for more than a few hours when the physical examination was carried out. Therefore. some of the conditions observed (especially cardiovascular and conjunctival) may have been residual reactions to acute intoxication. 481

In the continuing Addiction Research Foundation experimental cannabis program discussed earlier (see also Annex B) a variety of specific physiological measures were taken at regular intervals over a several-month period during which subjects (living on the hospital ward) smoked various doses of marijuana daily.436 In addition to general physical examinations, particular attention was given to EEG, to heart, liver and kidney function. and to a number of blood chemistry measures. Although these studies are not yet complete, some preliminary and tentative observations have been made. No evidence of physiological damage or medical complications from marijuana smoking has been detected in the program. 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. 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. No rnajor changes in general sleep patterns were observed. Many aspects of the physiological data are still undergoing analysis. It should be restated that this program provides 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.

Reports of the effects of chronic cannabis use on the electroencephalogram (EEG) have been inconsistent. In the La Guardia report some abnormal EFGs were noted in regular users, but no overall consistent pattern was seen. The investigators concluded that these and other subjects examined "had suffered no mental or physical deterioration as a result of the use of the drug."407 Freedman and Rockmore came to a similar conclusion after examining over 300 long-term users in the army.201,202 Williams and associates' study of sub-chronic high dose daily cannabis use indicated little significant EEG change. The minor alterations seen in some cases disappeared after the drug was discontinued.670 Miras has reported several isolated cases of abnormal EEGs in heavy chronic hashish users in Greece, although no systematic controlled studies were done.442

Lundell has examined a number of multi-drug-using youths, and reports having found psychometric evidence of an organic brain syndrome in some of these individuals.383 Ebel studied 100 "hard core" multiple-drug-using adolescents in Germany. Three took only hashish and sixty-eight used hashish and LSD. The remainder used a variety of drugs intravenously, mostly opiate narcotics. In eighty subjects, abnormal EEGs were found which the investigators felt were the result of "direct drug damage". 167

In a recent British study, some signs of brain atrophy were reported in a small group of chronic users of cannabis and, often, 'speed' and LSD.100 As the journal editors indicate, causal factors in this study are undetermined and many important variables remain to be explored.348 This paper has already stimulated considerable controversy in scientific and clinical circles. 90,100,101,348,466,492,538,577,592,668 Although many researchers have been critical of certain aspects of the report's general methodology and conclusions, because of the serious nature of the neurological conditions suggested, careful controlled exploration of these possible drug effects should be given high priority, both in studies of human chronic users and primate animals.

In Alberta, Campbell found more abnormal EEGs in 22 cannabis users than in schizophrenic and neurological patients. Some of the cannabis smokers had used other psychotropic drugs, but this apparently did not correlate with the EEG readings.102 While in certain cases the EEG patterns observed in this study may have been a transient result of acute intoxication, it is unlikely that such effects could provide a complete explanation.

In a recent preliminary report of a controlled study of 31 chronic daily hashish smokers in Greece, researchers found no indication of cannabis related EEG abnormalities. These subjects had been using several grams of hashish per day for an average of 27 years. They were all employed and displayed no gross behaviour disorders. The study is continuing and final conclusions have not been drawn.189 In a controlled study of behavioural functioning. Bowman found no psychometric evidence of neurological disorder in 30 long-term heavy marijuana users in Jamaica .74 Another study of chronic gania users in Jamaica is nearing completion, but no data have yet been released.535 A systematic study of a variety of measures, including EEG, is currently being carried out on a group of cannabis-using young people in Texas.31,32 No conclusive data are yet available from this study.

As noted earlier, chronic dementia, possibly reflecting an organic brain syndrome, has been described in a small proportion of chronic heavy hashish users in the East. although such reports have not been accompanied by adequate neurological or EEG data, or post mortern examinations, and no control groups have been employed. We have not yet been able to find any such cases scientifically documented in the Western literature. There are, however, a number of clinicians in North America who have suggested an organic quality in certain behavioural syndromes which seem to be associated with chronic cannabis use in some individuals. 383,664

The physiological and behavioural significance of the EEG patterns suggested in some of the above studies has yet to be determined. Controlled neurological research with chronic cannabis users is clearly indicated as a high priority research area. On balance, the existing evidence suggests that cannabis use does not generally result in serious neurological disorder.

Neurotoxicity to enormous daily quantities of cannabis, administered for weeks, has been demonstrated in animals, with rats being more sensitive than monkeys in this respect.386,605 The lowest of the doses used in these studies was approximately one hundred times the typical acute human dose. A cat study employing even larger doses showed EEG changes which persisted for weeks after discontinuation of the drug.33 The usual difficulties with generalizing from animal experiments to humans are complicated further by the massive doses involved in these studies. This work should be extended to primates with more relevant drug quantities.

As noted earlier, there is no evidence that chronic cannabis consumption damages chromosomes or has other genetic effects in humans.162,226 Further evidence from a major study in Jamaica will soon be released.38

In summary, the evidence as to the physiological effects of chronic use of cannabis is limited. varied, and conflicting. Modern, controlled studies are relatively recent and several are now in progress. Although no major effects have been established, existing information provides cause for concern if, several areas. Respiratory and bronchial disorders will probably result from heavy chronic smoking of many crude substances and cannabis seems to be no exception. Whether or not carcinogenic effects might be involved has not been determined. The evidence on neurotoxicity is conflicting: while there appears to be no indication of neurological dysfunction with moderate use, the effects of heavy chronic cannabis consumption have not been clarified. Liver dysfunction has been suggested in some reports, but the bulk of the evidence indicates that this is probably not a major risk. Effects on foetal development have been demonstrated in some strains of rodents but not in others, and there is currently no evidence that cannabis damages chromosomes or produces teratogenic effects in humans. Until further information is available, however, the use of cannabis, and most other drugs, should be avoided by pregnant women. Chronic cannabis use may produce a resistant 'blood-shot' eye appearance in some users, but this effect may be of aesthetic importance only.

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