The health and psychological consequences of cannabis use chapter 6
6. The chronic effects of cannabis use on health Cellular and immunological effects The possible effects of chronic cannabis use on cellular processes and the immune system are considered together because both effects may influence a cannabis user's susceptibility to diseases. If cannabis use affects cellular processes then users may be at increased risk of developing various types of cancer, and if it affects the immune system then cannabis users may be at increased risk of contracting infectious diseases and developing cancer. 6.1 Mutagenicity and carcinogenicity A major reason for research into the effects of cannabinoids on cellular processes is to discover whether cannabinoids are mutagenic, i.e. whether they may produce mutations in the genetic material in the somatic and germ cells of users. If cannabinoid exposure affects the genetic material of a user's somatic or bodily cells (such as those of the lung, for example) then chronic cannabis use may cause cancer. If it affects the genetic material of germ cells (the sperm and ova), then genetic mutations could be transmitted to the children of cannabis users. There is experimental evidence from in vitro studies of animal cells that some cannabinoids, including THC, can produce a variety of changes in cellular processes in vitro (i.e. in the test tube). These include alterations to cell metabolism, DNA synthesis, and cell division (Nahas, 1984). The potential for cannabinoids to produce genetic change in humans or animals is unclear. There is, at most, mixed evidence that THC and other cannabinoids are mutagenic in standard microbial assays, such as the Ames test, and there is contradictory evidence on whether the cannabinoids are clastogenic, i.e. produce breaks in chromosomes. According to Bloch (1983) who reviewed the literature for the World Health Organisation: "in vivo and in vitro exposure to purified cannabinoids or cannabis resin failed to increase the frequency of chromosomal damage or mutagenesis" (p412). Nahas (1984) reviewed the same evidence and concluded that "cannabinoids and marihuana may exert a weak mutagenic effect" (p117). More recently, Zimmerman and Zimmerman (1990/1991) concluded that "cannabis mutagenicity remains unclear", but argued that there was evidence that "cannabinoids induce chromosome aberrations in both in vivo and in vitro studies" (p19). There is stronger and more consistent evidence that cannabis smoke, like smoke produced by most burning plant material, is mutagenic in vitro, and hence, is potentially carcinogenic (Leuchtenberger, 1983). According to Bloch (1983) "marijuana smoke exposure has been reported to be associated with chromosomal aberrations ... [such as] hypoploidy, mutagenicity in the Ames test ... " (Bloch, 1983, p413). This is consistent with research indicating that cannabis smoke contains many of the same carcinogens as cigarette smoke (Institute of Medicine, 1982; Leuchtenberger, 1983), suggesting that if cannabis smoke is carcinogenic it is more likely to be because of the carcinogens it shares with cigarette smoke rather than because of the cannabinoids it contains. If it is the non-cannabinoid components of cannabis smoke that are mutagenic, then any cancers caused by cannabis smoking are most likely to develop after long-term exposure to cannabis smoke, and they are most likely to develop at sites which have had the maximum exposure to that smoke, namely, the upper aerodigestive tract and lung. This possibility is considered in more detail below (see pp49-50). 6.2 Immunological effects The possibility that cannabis reduces immune system function is important for several reasons. First, tobacco smoking suppresses both the humoral and cell-mediated immune systems. Given the similarities between the constituents of cigarette and cannabis smoke (Institute of Medicine, 1982; Leuchtenberger, 1983) it is reasonable to suspect that cannabis may also be an immunosuppressant (Nahas, 1984). Second, even a modest reduction in immunity caused by cannabis use could have public health significance because of the relatively large number of young adults who have used the drug (Munson and Fehr, 1983). Third, if cannabinoids have immunosuppressive effects, then this would have mixed implications for their therapeutic use. On the one hand, they could be therapeutically useful as immunosuppressant drugs in patients undergoing organ transplants. On the other hand, their therapeutic use for other purposes would be limited in patients with impaired immune systems, a restriction which would potentially preclude their use as anti-emetic agents in cancer chemotherapy, or as appetite stimulants and mood enhancers in patients with AIDS. There are a number of difficulties in deciding whether cannabis impairs the functioning of the immune system. First, the majority of studies that have been conducted have been either in vitro studies in which animal and human cell cultures have been exposed to cannabis smoke or cannabinoids, or in vivo animal studies in which the effects of cannabis and cannabinoid exposure on immune system function have been assessed in live animals. The usual problems of extrapolation from in vivo and in vitro studies to human users are complicated by the fact that many of the effects of cannabinoids on the immune system of animals are only obtained at very high doses which are rarely taken by human beings. Second, the difficulties in interpreting these studies are exacerbated because the results of the small number of human in vivo studies have been conflicting. Third, there have been very few epidemiological studies of immune system functioning and disease susceptibility in heavy chronic cannabis users. Given that the majority of the in vitro and in vivo animal work was undertaken in the 1970s, we have relied upon the summary of findings provided in the authoritative reviews of this literature undertaken by the Addiction Research Foundation and World Health Organization (Leuchtenberger, 1983; Munson and Fehr, 1983). This enables the present review to focus upon on the clinical and public health significance of the immunological effects observed in the experimental studies. Before doing so, a brief and schematic review will be provided of the components of the human immune system. 6.2.1 The immune system The immune system in mammals is "an adaptive and a protective mechanism against noxious foreign materials including pathogens and cancer cells" (Munson and Fehr, 1983). Its multiple components include: lymphoid tissues such as the spleen and lymph nodes; the bone marrow and thymus, where lymphocytes and other important cells in the immune system are manufactured; and the recirculating lymphocytes that mediate cellular and humoral immunity (see Grossman and Wilson, 1992; and Nossal, 1993). Immunity may be either innate or acquired. Innate immunity consists of those responses to foreign substances that do not require sensitisation from previous exposure, such as the ingestion of bacteria by macrophages, and the killing of tumour cells by natural killer cells. Acquired immunity is that form of immunity in which the recognition and destruction of foreign material depends upon processes produced by a previous exposure to the material. It is mediated by the cooperative functioning of two major systems of lymphocyte cells: the B-cells (Thymus-independent lymphocytes) which control humoral immunity, and T-cells (Thymus-dependent lymphocytes) the activity of which controls cell-mediated immunity. Humoral immunity involves the production of antibodies in response to antigens, usually proteins, which are attached to the surface of foreign cells. Antigens are recognised by the B-cells which proliferate and differentiate into two types of cells, the first of which synthesises and releases antibody, and the second of which remains as antigen-sensitised cells that are able to respond to subsequent exposure to the antigen by rapidly releasing large amounts of antibody. The antibodies can act directly to inactivate the pathogens or toxins by damaging cell membranes, or they can work cooperatively with the cell-mediated immune system by enabling cells called macrophages to recognise and destroy the foreign cells, either by ingesting those cells which have antibodies attached, or by releasing toxins which kill the cells. Cell-mediated immunity is directed against foreign cells including many bacteria, viruses and fungi. Macrophages are intimately involved in the early removal of foreign materials directly by ingestion, or indirectly by altering their antigens and presenting them to the T- and B-cells for the further development of the immune response. They work in concert with the humoral immune system to protect the organism from all pathogens in its environment. 6.2.2 Effects of cannabinoids on lymphoid organs A non-specific indication of an effect of cannabinoids on the immune system would be a reduction in the weight of lymphoid organs, such as the thymus and spleen, or a decrease in the number of circulating lymphocytes. A substantial body of anatomical and histological studies in animals bearing upon this possibility has been reviewed by Munson and Fehr (1983). These studies reveal that cannabinoids in high doses can affect the function of the stem cells which produce lymphocytes, and can reduce the size of the spleen in rodents. It is uncertain what the implications are for immune system competence because these effects all occur after acute exposure, typically in response to very high doses of cannabinoids. It is also unknown whether these effects occur as the direct result of cannabinoids acting upon the lymphoid cells, or whether they are an indirect effect of cannabinoids acting on the adrenal-pituitary axis to increase the release of corticosteroids which in turn shrink the spleen. 6.2.3 Effects of cannabinoids on humoral immunity The effect of cannabinoids on humoral immunity has been assessed in vitro by measuring the effect of cannabinoids on the number and functioning of animal and human B-cells produced in response to the presence of sheep red blood cells. Cannabinoids do not consistently alter the number or percentage of B-cells (Munson and Fehr, 1983). B-cell function has also been assessed in vitro by measuring the proliferation of B-cells in response to chemicals which stimulate the cells to divide, and by assessing antibody production in B-cells that have previously been exposed to cannabinoids. While cannabinoids have been consistently shown to impair the B-cell responses in mice, no such effects have been consistently observed in humans, and the few positive studies have produced results which are still within the normal range (Munson and Fehr, 1983). Antibody formation to THC has been demonstrated in animals. There are also clinical reports in humans that cannabinoids can exacerbate existing allergies, and there are several reports of demonstrated allergy to cannabinoids in humans (e.g. Freeman, 1983). Munson and Fehr (1983) concluded that: "it appears that cannabinoids can elicit the formation of specific antibodies ... [and that THC] or a metabolite is probably acting as a hapten, combining with a protein to form an antigenic complex" (p289). Hollister (1992), however, has questioned the clinical significance of this evidence, arguing that: While it is possible that a few persons may become truly allergic to cannabinoids, it is far more likely that allergic reactions, which have been extremely rare following the use of marijuana, are due to contaminants .. (e.g. bacteria, fungi, molds, parasites, worms, chemicals) that may be found in such field plants. That such impure material, when smoked and inhaled into the lungs, causes so little trouble is really a marvel (p163). 6.2.4 Effects of cannabinoids on cell-mediated immunity Researchers have examined the effects of cannabinoids on both the numbers and functioning of T-cells and macrophages. There are considerable inconsistencies in the results of studies on the effects of cannabinoids on T-cell numbers in humans, with some studies showing reductions (e.g. Nahas et al, 1974) while others have not (e.g. Dax et al, 1989). There is also mixed evidence on the effect of cannabinoids on T-cell functioning as assessed by response to allogenic cells and mitogens, chemicals which stimulate the cells to divide. A number of the earliest studies suggested that T-cells from chronic cannabis users showed a decreased responsiveness to such stimulation, but later studies, including laboratory studies of chronic heavy dosing in humans (e.g. Lau et al, 1976), have failed to replicate these results. Studies of in vitro exposure of T-cells to cannabinoids have also produced mixed results, while animal studies have showed a decreased T-cell response to mitogens (Munson and Fehr, 1983). Interpretations of this literature differ. Munson and Fehr (1983) concluded that the fact that cannabinoids can affect T-cell function in several species of animals "suggests that the same effects could occur in humans given exposure to these substances" (pp306-307). Nahas (1984) concluded that "there is only suggestive" evidence that cannabinoids "exert an immunodepressive effect" (p156). Hollister (1986) argued that even if there were such effects, they were of limited clinical significance because they were probably transient effects in healthy young adults, and there was no evidence of increased susceptibility to disease in cannabis smokers. More recently, Hollister (1992) has concluded that "... the effects of cannabinoids on cell-mediated immunity are contradictory. Such evidence as has been obtained to support such an effect has usually involved doses and concentrations that are orders of magnitude greater than those obtained when marijuana is used by human subjects. (p161)" 6.2.5 Effects of cannabinoids on host resistance It is one thing to decide that in vitro exposure of the immune system to high doses of cannabinoids impairs its functioning in various ways; it is much more difficult to decide whether the small impairments in immunity predicted by in vitro studies is likely to impair host resistance to pathogens and infection with micro-organisms among human cannabis users. There is a very small animal, and almost no human, literature on which to make such a decision. A small number of studies in rodents (mice and guinea pigs) has suggested that high doses (200mg/kg) of cannabinoids decrease resistance to infection (Friedman, 1991), e.g. with Lysteria monocytogenes (Morahan et al, 1979), and herpes simplex type 2 virus (Cabral et al, 1986; Mishkin and Cabral, 1985; Morahan et al, 1979). A reasonably consistent finding in humans has been that exposure to cannabis smoke adversely affects alveolar macrophages, cells in the respiratory system that constitute a first line of bodily defence against many pathogens and micro-organisms which enter the body via the lungs (Leuchtenberger, 1983). Studies of these cells obtained from cannabis smokers have demonstrated ultrastructural abnormalities (Tennant, 1980), and studies of the in vitro exposure of alveolar macrophages to cannabis smoke have demonstrated that their ability to inactivate Staphylococcus aureus (Leuchtenberger, 1983; Munson and Fehr, 1983), and more recently the fungus Candida albicans (Sherman et al, 1991) has been impaired. In this case, however, it seems to be the non-cannabinoid components of cannabis smoke that produce the effect (Leuchtenbeger, 1983). 6.2.6 Human significance of immunological effects of cannabinoids The animal evidence is reasonably consistent that cannabinoids produce impairments of the cell-mediated and humoral immune systems, and in several studies these changes have been reflected in decreased resistance to bacteria and viruses. There is also evidence that the non-cannabinoid components of cannabis smoke can impair the functioning of alveolar macrophages, the first line of the body's defence system. However, the doses required to produce these immunological effects have varied from the behaviourally relevant to very high doses. This raises the issue of whether their findings can be extrapolated to the doses used by humans. The possibility of tolerance developing to any immunological effects of cannabinoids also makes the human significance of the results of in vitro studies uncertain. If immunological tolerance develops with chronic use, then the possibility of observing even the small effects projected from the in vitro studies would be substantially reduced. There have been no demonstrations that such tolerance occurs in animals, in part because most studies have used short duration, high dosing schedules rather than chronic high dosing required for tolerance to be demonstrated. Given the large number of cannabinoid effects to which tolerance has been shown to develop, it would not be surprising if this were also true of its immunological effects. The very limited human evidence from experimental studies of immune function is mixed, with a small number of studies suggesting immunosuppressant effects that have not been replicated by others. As Munson and Fehr (1983) concluded: "At present, there is no conclusive evidence that consumption of cannabinoids predisposes man to immune dysfunction" (p338), as measured by reduced numbers or impaired functioning of T-lymphocytes, B-lymphocytes or macrophages, or reduced immunoglobulin levels. There was "suggestive evidence" of impaired T-lymphocyte functioning reflected in an impaired reaction to mitogens and allogenic lymphocytes (Munson and Fehr, 1983). More recently, Wallace et al (1988, 1993 in press) have failed to find any impairment of lymphocyte function in alveolar macrophages in marijuana smokers, although they did find such impairment in tobacco smokers. The clinical significance of these possible immunological impairments in chronic cannabis users is uncertain. There have been sporadic reports of ill health, including decreased resistance to disease, among chronic heavy cannabis users in Asia and Africa (Munson and Fehr, 1983). These reports are difficult to evaluate because of the confounding effects of poor living conditions and nutritional status, although it may be that the small human immunological impairment predicted from the animal literature is most likely to be seen among such populations (Munson and Fehr, 1983). Three field studies of the effects of chronic cannabis use in Costa Rica (Carter et al, 1980), Greece (Stefanis et al, 1977), and Jamaica (Rubin and Costas, 1975), have failed to demonstrate any evidence of increased susceptibility to infectious diseases among chronic cannabis users. However, these negative findings are not very convincing. Less than 100 users were studied overall, which is too small a sample in which to detect a small increase in the incidence of common infectious and bacterial diseases. While it is difficult to detect a small increase in the incidence of infections in an individual or among a small sample of people, such an increase may have great public health significance. The type of large-scale epidemiological studies that are needed to explore this issue have not been conducted until very recently. A recent study by Polen et al (1993) compared health service utilisation by non-smokers and daily cannabis only smokers enrolled in a health maintenance organisation. Their results provided the first suggestive evidence of an increased rate of presentation for respiratory conditions among cannabis-only smokers, although its significance remains uncertain because infectious and non-infectious respiratory conditions were aggregated. Nevertheless, further studies of this type may enable a more informed decision to be made about the seriousness of the risk that chronic heavy cannabis smoking poses to the immune and respiratory systems. Hollister (1992) has expressed a sceptical attitude towards the human health implications of the literature on the immunological effects of cannabis, arguing that: ... Clinically, one might assume that sustained impairment of cell-mediated immunity might lead to an increased prevalence of malignancy. No such clinical evidence has been discovered or has any direct epidemiological data incriminated marijuana use with the acquisition of human immunodeficiency virus or the clinical development of AIDS. (p161) Given the duration of large-scale cannabis use by young adults in Western societies, the absence of an epidemic of infectious disease is arguably sufficient to rule out the hypothesis that cannabis smoking produces major impairments in the immune systems of users comparable to those caused by AIDS. The absence of such epidemics among cannabis users does not, however, exclude the possibility that chronic heavy use may produce minor impairments in immunity, since this would produce small increases in the rate of occurrence of common bacterial and viral illnesses (Munson and Fehr, 1983) that would have escaped the notice of clinical observers. Such an increase could nonetheless be of public health significance because of the increased expenditure on health services, and the loss of productivity among the young adults who are the heaviest users of cannabis. Clinical studies of patients with immune systems compromised by AIDS may provide one of the best ways of detecting any adverse immunological effects of cannabinoids. AIDS patients and gay advocacy groups have proposed that cannabinoids should be used therapeutically to improve appetite and well-being in AIDS patients (see below p195). If it was ethical to conduct trials of the therapeutic use of cannabinoids in AIDS patients, then monitoring the impact on immune functioning would provide one way of evaluating the seriousness of the immunological effects of cannabinoids, not only for AIDS patients, but also for other immunologically compromised patients using cannabinoids for therapeutic purposes. If there were no effects in patients with compromised immune systems, it would also be a reasonable to infer that there was little risk of immunological effects in long-term recreational users. An epidemiological study of predictors of progression to AIDS among HIV positive homosexual men suggests that the risks may be sufficiently small in the case of HIV positive patients to warrant further research. Kaslow et al (1989) conducted a prospective study of progression to AIDS among HIV positive men in a cohort of 4,954 homosexual and bisexual men. Among the predictor variables studied were licit and illicit drug use, including cannabis use. Illicit drug use predicted an increased risk of infection with HIV, as has been consistently found in studies of risk factors for HIV infection. However, neither cannabis use, nor any other psychoactive drug use, predicted an increased rate of progression to AIDS among men who were HIV positive. Nor was cannabis use related to changes in a limited number of measures of immunological functioning. 6.2.7 Conclusions There is reasonable evidence that cannabis smoke is mutagenic, and hence, potentially carcinogenic, because of the many mutagenic and carcinogenic substances it shares with tobacco smoke. THC is at most weakly mutagenic. This suggests that the major cancer risk from cannabis use is the development of cancers of the respiratory tract arising from smoking as a route of administration, rather than from the mutagenicity of the psychoactive components of cannabis. There is reasonably consistent animal evidence that THC can impair both the cell-mediated and humoral immune systems, producing decreased resistance to infection by bacteria and viruses. The relevance of these findings to human health is uncertain: the doses required to produce these effects are often very high, and the problem of extrapolating from the effects of these doses to those used by humans is complicated by the possibility that tolerance develops to the effects on the immune system. The limited experimental evidence on immune effects in humans is conflicting, with the small number of studies producing adverse effects not being replicated. Even studies that have produced evidence of adverse effects observe small changes that are still within the normal range. The clinical and biological significance of even the small positive effects in chronic cannabis users is uncertain. There has not been any evidence of increased rates of disease among chronic heavy cannabis users analogous to that seen among homosexual men in the early 1980s. Given the duration of large-scale cannabis use by young adults in Western societies, the absence of such epidemics makes it unlikely that cannabis smoking produces major impairments in the immune system. It is more difficult to exclude the possibility that chronic heavy cannabis use produces minor impairments in immunity. Such effects would produce small increases in the rates of infectious diseases of public health significance, because of the increased expenditure on health services, and the loss of productivity among the young adults who are the heaviest users. There is one large prospective study of HIV-positive homosexual men which indicates that continued cannabis use did not increase the risk of progression to AIDS (Kaslow et al, 1989). A recent epidemiological study by Polen et al (1993) which compared health service utilisation by non-smokers and daily cannabis-only smokers provided the first suggestive evidence of an increased rate of medical care utilisation for respiratory conditions among cannabis smokers. This remains suggestive, however, because infectious and non-infectious respiratory conditions were not distinguished. The most sensitive assay of any small immunological effects of cannabis may come from studies of the therapeutic usefulness of cannabinoids in immunologically compromised patients, such as those undergoing cancer chemotherapy, or those with AIDS. 6.3 Cardiovascular effects Both the inhalation of marijuana smoke and the ingestion of THC reliably produces an increase in heart rate of 20 per cent to 50 per cent over baseline (Huber et al, 1988; Jones, 1984). When cannabis is smoked, the heart rate increases within two to three minutes, peaks within 15 to 30 minutes, and may remain elevated for up to two hours. When ingested, these effects are delayed for several hours, and last for four to five hours (Maykut, 1984). There are also complex changes in blood pressure which depend upon posture: blood pressure is increased while the person is sitting or lying, but decreases on standing, so that a sudden change from a recumbent to an upright position may produce postural hypotension and, in extreme cases, fainting (Maykut, 1984). Young, healthy hearts are likely to be only mildly stressed by these acute effects of cannabis (Tennant, 1983). The clinical significance of the repeated occurrence of these effects in chronic heavy cannabis users remains uncertain, because there is evidence from clinical and experimental studies (Benowitz and Jones, 1975; Jones and Benowitz, 1976; Nowlan and Cohen, 1977) that tolerance develops to the acute cardiovascular effects of cannabis. Clinical studies employing chronic dosing over periods of up to nine weeks show that the increased heart rate all but disappears, while the blood pressure increase is much attenuated. Tolerance to the cardiovascular effects develops within seven to 10 days in persons receiving high daily doses by the oral route (Jones, 1984). The field studies of chronic heavy users in Costa Rica (Carter et al, 1980), Greece (Stefanis et al, 1977), and Jamaica (Rubin and Costas, 1975) failed to disclose any evidence of cardiac toxicity, even in those subjects with heart disease that was unrelated to their cannabis use. The findings of the field studies have been supported by the fact that electrocardiographic studies in conditions of both acute and prolonged administration have rarely revealed pathological changes (Benowitz and Jones, 1975; Jones, 1984). It seems reasonable to conclude then that among healthy young adults who use cannabis intermittently, cannabis use is not a major risk factor for life-threatening cardiovascular events in the way that the use of cocaine and other psychostimulants can be (Gawin and Ellinwood, 1988). There is suggestive evidence of a small risk, however, since there have been a number of case reports of myocardial infarction in young men who were heavy cannabis smokers and had no personal history of heart disease (Tennant, 1983; Choi and Pearl, 1989; Pearl and Choi, 1992; Podczeck et al, 1990). Such cases deserve close investigation to exclude the role of other cardiotoxic drugs. The possibility remains that chronic heavy cannabis smoking may have more subtle effects on the cardiovascular system. Jones (1984) has suggested, for example, that there is a possibility that "after years of repeated exposure" there may be "lasting, perhaps even permanent, alterations of the cardiovascular system function" (p331). Arguing by analogy with the long-term cardiotoxic effects of tobacco smoking, he suggests that there are "enough similarities between THC and nicotine cardiovascular effects to make the possibility plausible" (p331). Moreover, since many cannabis smokers are also cigarette smokers, there is the possibility that there may be adverse interactions between nicotine and cannabinoids in their effects on the cardiovascular system. 6.3.1 Effects on patients with cardiovascular disease The cardiovascular effects of cannabis may adversely affect patients with pre-existing cardiovascular disease. As the Institute of Medicine observed: the possibility is great that the abnormal heart and circulation will not be as tolerant of an agent that speeds up the heart, sometimes unpredictably raises or drops blood pressure, and modifies the activities of the autonomic nervous system (pp69-70). There are a number of concerns about the potentially deleterious effects of cannabis use on patients with ischaemic heart disease, hypertension, and cerebrovascular disease (Jones, 1984; National Academy of Science, 1982). First, THC appears to increase the production of catecholamines which stimulate the activity of the heart, thereby increasing the risk of cardiac arrhythmias in susceptible patients. Second, THC increases heart rate, thereby producing chest pain (angina pectoris) in patients with ischaemic heart disease, and perhaps increasing the risk of a myocardial infarction. Third, THC also has analgesic properties (see below p194) which may attenuate chest pain, delaying treatment seeking, and thereby perhaps increasing the risk of fatal arrhythmias. Fourth, marijuana smoking increases the level of carboxyhaemoglobin, thereby decreasing oxygen delivery to the heart, increasing the work of the heart and, perhaps, the risk of atheroma formation. Moreover, the reduced delivery of oxygen to the heart is compounded by a concomitant increase in the work of the heart - and therefore its oxygen requirements - because of the tachycardia induced by THC. Fifth, patients with cerebrovascular disease may be put at risk of experiencing strokes by unpredictable changes in blood pressure, and patients with hypertension may experience exacerbations of their disease for the same reason. After considering the known cardiovascular effects of THC, and their likely interactions with cardiovascular disease, the Institute of Medicine (1982) concluded that it: " ... seems inescapable that this increased work, coupled with stimulation by catecholamines, may tax the heart to the point of clinical hazard" (p70). Despite the plausibility of the reasoning, there is very little direct evidence of the adverse effects of cannabis on persons with heart disease (Jones, 1984). Among the few relevant pieces of research evidence are two laboratory studies of the acute cardiovascular effects of smoking marijuana cigarettes on patients with occlusive heart disease. Aronow and Cassidy (1974) conducted a double blind placebo control study comparing the effect on heart rate and the time required to induce chest pain during an exercise tolerance test, of smoking a single marijuana cigarette containing 20mg of THC, with the effect of a placebo marijuana cigarette. Heart rate increased by 43 per cent, and the time taken to produce chest pain was approximately halved, after smoking a marijuana cigarette. It appeared that cannabis increased the myocardial oxygen demand while reducing the amount of oxygen delivered to the heart (Aronow and Cassidy, 1974). Aronow and Cassidy (1975) compared the effects of smoking a single marijuana cigarette and a high nicotine cigarette in 10 men with occlusive heart disease, all of whom were 20 a day cigarette smokers. A 42 per cent increase in heart rate was observed after smoking the marijuana cigarette compared with a 21 per cent increase after smoking the tobacco cigarette. Exercise tolerance time was halved (49 per cent) after smoking a marijuana cigarette by comparison with a 23 per cent decline after smoking a tobacco cigarette. Apart from these studies, there is very little direct evidence on the risks of cannabis use by persons with cardiovascular disease. The reasons for the absence of adverse effects of chronic cannabis use on diseased cardiovascular systems are unclear. It should not be assumed in the absence of evidence, however, that such effects do not exist. The absence of evidence may simply reflect the lack of systematic study. It may be that the development of tolerance to the cardiovascular effects with chronic heavy dosing has protected the heaviest users from experiencing such effects: it may be that there has been an insufficient exposure to cannabis smoking of a sufficiently large number of vulnerable individuals (National Academy of Science, 1982); or it may be that cardiologists have missed any such evidence because they have not inquired about cannabis use among their patients. On the face of it, the possibility of cannabis smokers developing heart disease may seem "theoretical". Most cannabis users are healthy young adults who smoke intermittently, most discontinue their use by their late 20s, and very few of the minority who become heavy cannabis users are likely to have clinical occlusive heart disease or other atherosclerotic disease. But the possibility of such adverse effects is not entirely theoretical. First, any such effects would contraindicate the therapeutic uses of cannabinoids among older patients, such as those with cancer and glaucoma, who are at higher risk, because they are older, of having significant heart disease (Jones, 1984). Second, the chronic heavy cannabis users who were inducted into cannabis use in the late 1960s and early 1970s are now entering the period in which that minority who have continued to smoke cannabis are at risk of experiencing symptoms of clinical heart disease. Among this group cannabis use may contribute to an earlier expression of heart disease, especially, if they have also been heavy cigarette smokers. Because of the high rates of cessation of cannabis use with age, however, this may be such a small number of persons that the effect is difficult to detect clinically, especially if cannabis use is not considered to be a risk factor about which cardiologists systematically inquire. It may be worth exploring this possibility by including questions on cannabis use in case-control studies of cardiovascular disease among middle-aged adults. 6.3.2 Conclusions On the available evidence, it is still appropriate to endorse the conclusions reached by the expert committee appointed by the National Academy of Science in 1982 that, although the smoking of marijuana "causes changes to the heart and circulation that are characteristic of stress ... there is no evidence ... that it exerts a permanently deleterious effect on the normal cardiovascular system..." (p72). The situation may be less benign for those with "abnormal heart or circulation" since there is evidence that marijuana poses "a threat to patients with hypertension, cerebrovascular disease and coronary atherosclerosis" (p72) by increasing the work of the heart. The "magnitude and incidence" of the threat remains to be determined as the cohort of chronic cannabis users of the late 1960s enters the age of maximum risk for complications of atherosclerosis of the cardiac, brain and peripheral vessels. In the interim, because any such effects could be life threatening in patients with significant occlusion of the coronary arteries or other cerebrovascular disease, such persons should be advised not to smoke cannabis (Tennant, 1983). 6.4 Effects on the respiratory system The most reliable acute effect of exposure to cannabis smoke is bronchodilation (National Academy of Science, 1982), which has principally been of interest because of its possible therapeutic effect upon asthma (see below pp193-194). Other than bronchodilation, it has proved difficult to demonstrate any effects of acute cannabis smoking on breathing "as measured by conventional pulmonary tests" (National Academy of Science, 1982, p58). The major concerns about the respiratory effects of cannabis use have been the possible adverse effects of chronic, heavy cannabis smoking (Tashkin, 1993). The two largest issues of concern have been the production of chronic bronchitis as a precursor of irreversible obstructive lung disease, and the possible causation of cancers of the aerodigestive tract (including the lungs, mouth, pharynx, larynx, and trachea) after 20 to 30 years of regular cannabis smoking. These risks are the primary focus of this section of the review. There is good reason to expect that chronic heavy cannabis smoking may have adverse effects upon the respiratory system (Tashkin, 1993). Cannabis smoke is similar in constitution to tobacco smoke, and contains a substantially higher proportion of particulate matter and of some carcinogens (e.g. benzpyrene) than does tobacco smoke (Leuchtenberger, 1983; National Academy of Science, 1982). Hence, the inhalation of cannabis smoke deposits irritating and potentially carcinogenic particulate matter onto lung surfaces. Cigarette smoking is known to cause diseases of the respiratory system, such as bronchitis, emphysema, and various forms of cancer affecting the lung, oral cavity, trachea, and oesophagus (Holman et al, 1988). Although tobacco smokers smoke many more cigarettes than cannabis smokers, cannabis smoke is typically inhaled more deeply, and the breath held for longer, than tobacco smoke, thereby permitting greater deposition of particulate matter on the lung surface (Hollister, 1986). It therefore seems a reasonable inference that chronic daily cannabis smoking may cause diseases of the respiratory system. Despite the reasonableness of this hypothesis, it has nonetheless been difficult to investigate the contribution of chronic heavy cannabis smoking to diseases of the respiratory system (Huber et al, 1988; National Academy of Science, 1982). A major problem is that most marijuana smokers also smoke tobacco, which makes it difficult to disentangle the effects of cannabis from those of tobacco smoking. The problems in quantifying current and lifetime exposure to cannabis, because of variations in quality and potency, make it difficult to examine dose-response relationships between cannabis use and the risk of developing various respiratory diseases. There is also likely to be a long latency period between exposure and the development of these diseases, especially in the case of cancers of the aerodigestive tract. This period is approximately the length of time since cannabis smoking became widespread in Western societies. There are also technical difficulties in designing studies which are sufficiently sensitive to detect increased risks of diseases arising from relatively rare exposures, such as chronic daily cannabis use. 6.4.1 Bronchitis and airways obstruction There is a small clinical literature containing case reports of acute lung diseases among heavy cannabis smokers in the US military stationed in West Germany during the early 1970s, when hashish was cheap and freely available (Henderson et al, 1972; Tennant et al, 1971). Tennant et al studied 31 soldiers who had smoked 100g or more of hashish monthly for six to 21 months, 21 of whom were also tobacco smokers. Nine complained of bronchitis which had its onset three to four months after they began to smoke hashish. Pulmonary function tests of five cases (two of whom did not smoke tobacco) revealed mild airflow obstruction that partially remitted after a reduction or cessation of hashish use. Tennant (1980) also reported histopathological studies of 23 of these patients in which all patients were found to have atypical cells of the type (squamous metaplasia in 21 cases) associated with chronic bronchitis and carcinoma of the lung. Henderson et al (1972) reported on 200 servicemen who sought treatment for problems related to hashish use, 90 per cent of whom were also cigarette smokers. Twenty men who smoked large doses of hashish on a weekly basis presented with symptoms of chronic bronchitis, and on testing had vital capacity that was 15-40 per cent below normal. Six had a bronchoscopic examination which showed epithelial abnormalities. The interpretation of these findings was complicated by the fact that the majority of these hashish smokers were also tobacco smokers, as were Tennant et al's subjects, and there was no adequate comparison group. The field studies of chronic cannabis smokers in Costa Rica (Carter et al, 1980) and Jamaica (Rubin and Comitas, 1975), which included comparison groups, have failed to support the clinical findings of Henderson et al, and Tennant et al. Neither of these studies found any statistically significant differences in lung function, or in the prevalence of respiratory symptoms, between chronic cannabis users and non-cannabis smoking controls. In both studies, however, the measures of respiratory function were relatively unsophisticated, the sample sizes were small, making it difficult to detect all but very large differences, and the comparisons were often confounded by a failure to control for tobacco smoking. The most convincing evidence that chronic cannabis use may be a contributory cause of impaired lung function and symptoms of respiratory disease comes from a series of controlled studies which have been conducted by Tashkin and his colleagues since the mid-1970s. One of their early studies evaluated the subacute effects of heavy daily marijuana smoking on respiratory function. The subjects were young male marijuana smokers who were studied in a closed hospital ward where they were allowed ad libitum access to marijuana for 47 to 59 days. The results of lung function tests showed a statistically significant decrease in the function of large and medium-sized airways over the course of the study. The degree of impairment was positively correlated with the number of marijuana cigarettes smoked, suggesting that the quantity of inhaled irritants was the important factor, perhaps by producing an inflammatory reaction in the tracheobronchial epithelium. Although the impairment was apparently small and values were still within the normal range, these changes were of clinical significance. If continued over a year, for example, the rate of decline in lung function would be several times greater than the normal rate. Tashkin and his colleagues (1987) subsequently recruited a volunteer sample of marijuana only smokers (MS, n=144), marijuana and tobacco smokers (MTS, n=135), tobacco only smokers (TS, n=70), and non-smoking controls (NS, n=97). A subset of these subjects were followed to examine changes in lung function, signs and symptoms of respiratory disease, and the occurrence of histopathological changes that may precede the development of carcinoma. In the baseline observations of their cohort, Tashkin et al (1987) found significant differences in the prevalence of symptoms of bronchitis (such as cough, bronchitic sputum production, wheeze and shortness of breath) between all types of smokers (MS, MTS, TS) and controls. There were no differences between cannabis and tobacco smokers in the prevalence of these symptoms. Lung function tests showed significantly poorer functioning and significantly greater abnormalities in small airways among tobacco smokers (regardless of concomitant cannabis use) while marijuana smokers showed poorer large airways functioning than non-marijuana smokers (regardless of concomitant tobacco use). These findings suggest that "habitual smoking of marijuana or tobacco causes functional alterations at different sites in the respiratory tract, with marijuana affecting mainly the large airways and tobacco predominantly the peripheral airways and alveolated regions of the lung" (Tashkin et al, 1990, p67). Follow-up studies of a subsample of this cohort have broadly supported the results of the cross-sectional baseline study, while providing more detail on some differences between marijuana and tobacco smoking in their effects on lung function (Tashkin et al, 1990). The first follow-up study was conducted two to three years after the baseline study. Approximately half of these subjects were retested and most remained in the same smoking categories as at baseline, namely, 40 of the 54 MTS, 60 of the 71 MS, 30 of the 32 TS, and 56 of 58 NS, respectively of those who were followed up. The prevalence of bronchitic symptoms of cough, sputum, and wheeze was higher in all smoking groups than among non-smokers at both time one and time two, and there was no significant change in the respiratory status of any of the smoking groups from time one to time two when those individuals who ceased smoking were excluded. Substantially the same results were obtained when the subjects were followed up three to four years after initial assessment. In addition, there was evidence of an additive adverse effect of marijuana and cigarette smoking, in that the MTS group showed effects of both types of damage attributable to marijuana and tobacco smoking alone. Tashkin and his colleagues (Fligiel et al, 1988; Gong et al, 1987) undertook histopathological studies of the lungs of a subsample of their cohort. Fligiel et al (1988) compared the bronchial morphology of males aged 25 to 49 years who were heavy smokers of marijuana only (n=30), marijuana and tobacco (n=17), tobacco only (n=15) and non-smoking controls (n=11). Bronchial biopsies were examined by pathologists who were "blind" as to their smoking status, and analyses were made of cellular inflammation. All subjects who smoked (whether cannabis, tobacco or both) showed more prevalent and severe histopathological abnormalities than non-smokers. Many of these abnormalities were more prevalent in marijuana smokers, and they were most marked in those who smoked both marijuana and tobacco. These findings were especially striking because they were observed in young adults who did not have respiratory symptoms, and they occurred at a younger age on average in marijuana than tobacco smokers, despite the fact that the marijuana smokers smoked less than a quarter as many "joints" as the tobacco smokers smoked cigarettes. Fliegel et al concluded that "marijuana smoking may be as damaging or perhaps even more damaging to the respiratory epithelium than smoking of tobacco" (p46), and there was "a very good possibility ... that marijuana smoking combined with smoking of tobacco, leads to a more significant mucosal alteration than either of these substances smoked alone" (p47). Evidence of inflammation was sought by examining the presence of alveolar macrophages, lymphocytes, neutrophils and eosinophils in the bronchial lavage of the same subjects. This examination revealed that marijuana and tobacco smoking induced an inflammatory cellular response in the alveoli, and that the combination of marijuana and tobacco smoking produced the largest inflammatory response, "implying an adverse effect of marijuana smoking on the lung that is independent of and additive to that of tobacco" (Tashkin et al, 1990, p74). Additional research by Tashkin and his colleagues (Tashkin et al, 1988; Wu et al, 1988) suggests that the most likely explanations of the apparently greater toxicity of marijuana smoking are major differences in the topography of marijuana and tobacco smoking. Laboratory studies of the volume of inhaled smoke from tobacco and marijuana, and analyses of its particulate content, indicated that marijuana smokers inhaled a larger volume of smoke (40-54 per cent more), inhaled more deeply, took in more particulate matter per puff, and held their breath about four to five times longer, thereby retaining more particulate matter, and absorbing three times more carbon monoxide, than cigarette smokers (Wu et al, 1988). Bloom et al (1987) have recently reported findings that broadly confirm those of Tashkin and his colleagues. Bloom et al conducted a cross-sectional study in a general population of the relationship between smoking "non-tobacco" cigarettes and respiratory symptoms and respiratory function. Their study sample was a community sample of 990 individuals aged under 40 years who were being followed as part of a prospective community study of obstructive airways disease. Subjects were asked about symptoms of cough, phlegm, wheeze and shortness of breath, and they were also measured on a number of indicators of respiratory function, including forced expiratory volume and forced vital capacity. The prevalence of ever having smoked a "non-tobacco" cigarette was 14 per cent (the same as the prevalence of marijuana smoking in general population surveys), with 9 per cent being current smokers and 5 per cent ex-smokers. Non-tobacco smokers were younger and more likely to be male than non-smokers of non-tobacco. The mean frequency of current non-tobacco smoking was seven times per week, and the average duration of use was nine years. Non-tobacco smokers were more likely than non-tobacco non-smokers to have smoked tobacco, and more likely to inhale deeply than tobacco smokers. Non-tobacco smoking was related to the prevalence of the self-reported respiratory symptoms of cough, phlegm, and wheeze, regardless of whether the person smoked tobacco or not. There were also mean differences in forced expiratory volume and forced vital capacity, with those who had never smoked having the best functioning, followed in decreasing order of function by current cigarette smokers, current non-tobacco smokers, and current smokers of both tobacco and non-tobacco cigarettes. Non-tobacco smoking alone had a larger effect on all flow indices than tobacco smoking alone, and the effect of both types of smoking was additive. Although there were some inconsistencies between the studies of Tashkin and colleagues and those of Bloom and colleagues, there is reasonable coherence in the available evidence on the respiratory effects of cannabis use. Taken as a whole, it suggests that chronic cannabis smoking increases the prevalence of bronchitic symptoms, reduces respiratory function, and in very heavy smokers produces histopathological changes that may portend the subsequent development of bronchogenic carcinoma, a well known consequence of heavy tobacco smoking. Although, "there is still no conclusive evidence in man of clinically important pulmonary dysfunction produced by smoking marihuana" (Huber et al, 1988; p8), it is nonetheless a reasonable inference that chronic heavy cannabis smoking probably increases the risk of developing respiratory tract cancer, and possibly influences the development of irreversible obstructive pulmonary disease. Persons who wish to reduce their risks of developing these diseases would be wise to desist from cannabis smoking (Tashkin, 1993). 6.4.2 Cancers of the aerodigestive tract Although "not a single case of bronchogenic carcinoma in man has been directly attributable to marijuana" (Tashkin, 1988), it would be unwise to infer from the absence of such cases that there is no such an effect (Huber et al, 1988; National Academy of Science, 1982). There is a 20 to 30-year latency period between the initiation of regular smoking and the development of cancer, and cannabis smoking only became widespread in Western societies in the early 1970s (National Academy of Science, 1982). There has also been a lack of clinical and epidemiological research on this question. Patients with lung or of other types of cancer, for example, have rarely been asked about their cannabis use as part of the clinical history-taking. No cohort or case-control studies of cancers among cannabis smokers have been reported, because the illegality of cannabis has made it difficult to obtain reliable information on habits of the large samples required, while the proportion of cannabis users who become long-term heavy users is likely to be small (Huber et al, 1988). Despite the absence of such evidence, there are good reasons for suspecting that cannabis may contribute to the development of lung cancer and cancers of the aerodigestive tract (the oropharynx, nasal and sinus epithelium, and the larynx). A major reason is the similarity between the constituents of cannabis and tobacco smoke, an accepted cause of cancers in these organs (Doll and Peto, 1980; International Agency for Research on Cancer, 1990). The major qualitative differences between tobacco and cannabis smoke are the presence of cannabinoids in cannabis smoke and of nicotine in tobacco. There are also some quantitative differences in the amount of various carcinogens with cannabis smoke typically containing higher levels than tobacco smoke (Leuchtenberger, 1983; National Academy of Science, 1982). The work of Fligiel et al (1988) has indicated that histopathological changes of the type that are believed to be precursors of carcinoma can be observed in the lung tissue of chronic marijuana smokers. These results confirmed the earlier finding of Tennant (1980), who performed bronchoscopies on 30 US servicemen stationed in Europe who had smoked large quantities of hashish and experienced symptoms of bronchitis. He found that 23 of these who also smoked tobacco had one or more pathological changes "identical to those associated with the later development of carcinoma of the lung when it occurs in tobacco smokers" (Tennant, 1983, p78). The results of these clinical and laboratory studies have recently received suggestive support from case reports of cancers of the upper aerodigestive tract in young adults who have been chronic cannabis smokers. Donald (1991a, b) reported 13 cases of advanced head and neck cancer occurring in young adults under 40 years of age among 3,000 of his cancer patients. Their average age was 26 years (range 19-38 years), compared with an average age of 65 years among his other patients. Eleven of the 13 had been daily cannabis smokers. Interpretation is complicated by the fact that at least five of these patients also smoked tobacco, and at least three were heavy alcohol consumers, both known risk factors for cancers of the upper aerodigestive tract (Holman et al, 1988; Vokes et al, 1993). Donald acknowledged these facts, but emphasised that half of his cases neither smoked tobacco nor consumed alcohol. Moreover, he argued, the implication of marijuana as a cause of cancers of the upper aerodigestive tract was strengthened by the observation that such cancers are rare under the age of 40 years, even among tobacco smokers who consume alcohol. Similar findings have been reported by Taylor (1988) in a retrospective analysis of cases of upper respiratory tract cancer occurring in adults under the age of 40 years over a four-year period. Because the medical records did not routinely report the patients' use of cannabis, Taylor asked the attending clinicians to make judgments about their patients' cannabis and other drug use. He found 10 cases among the 887 cases of cancer that were treated over the study period. They consisted of six males and four females with an average age of 33.5 years. Nine were cases of squamous cell carcinomas (of the tongue, the larynx, and the lung). Five cases had a documented history of heavy cannabis smoking, two patients were described as "regular" cannabis users, one was classified as a "possible" cannabis user because he was known to abuse other drugs, and two were judged not to be cannabis users. As with Donald's case series, interpretation was complicated by the fact that six out of 10 were heavy alcohol consumers, and six were cigarette smokers (four out of the five heavy cannabis users in each case). Taylor argued "that the regular use of marijuana is a potent etiologic factor, particularly in the presence of other risk factors, in hastening the development of respiratory tract carcinomas" (p1216). While he allowed that alcohol and tobacco use may have contributed to the development of these cancer, he discounted their importance, arguing like Donald, that the patients were well under 40 years of age, while the peak incidence of such cancers in drinkers and smokers is in the seventh decade of life. Other investigators (e.g. Caplan and Brigham, 1989; Endicott and Skipper, 1991, cited by Nahas and Latour, 1992) have also reported cases of upper respiratory tract cancers in young adults with histories of heavy cannabis use. Caplan and Brigham's (1989) report of two cases of squamous cell carcinoma of the tongue in men aged 37 and 52 years was especially noteworthy because neither of their cases smoked tobacco or consumed alcohol; a history of long-term daily cannabis use was their only shared risk factor. These case reports provide limited support for the hypothesis that cannabis use is a cause of upper respiratory tract cancers. They did not compare the prevalence of cannabis use in cases with that in a control sample, and cannabis exposure was not assessed in a standardised way or in ignorance of the case or control status, all of which are standard controls to minimise bias in case-control studies of cancer aetiology. Nonetheless, there is a worrying consistency about the reports that should be addressed by case-control studies which compare the proportions of cannabis smokers among patients with cancers of the upper aerodigestive tract and appropriate controls (National Academy of Science, 1982). Now may be the time to conduct such studies, since chronic cannabis smokers who began their use in early 1970s are now entering the period of risk for such cancers. If carcinomatous changes occur earlier in heavy cannabis smokers, it may be better to restrict attention to early onset cases (e.g. cases occurring in individuals under 50 years of age). Information on cannabis use should also be obtained prospectively in newly diagnosed cases, because of the problems with retrospective assessment of cannabis and other drug use from either clinical records or the relatives of those who have died. 6.4.3 Conclusions Chronic heavy cannabis smoking probably causes chronic bronchitis, and impairs functioning of the large airways. Given the documented adverse effects of cigarette smoking, it is likely that chronic cannabis use predisposes individuals to develop irreversible obstructive lung diseases. There is suggestive evidence that chronic cannabis smoking produces histopathogical changes in lung tissues that are precursors of lung cancer. Case studies raise a strong suspicion that cannabis may cause cancers of the aerodigestive tract. The conduct of case-control studies of these cancers is a high priority for research into the possible adverse health effects of chronic cannabis smoking. 6.5 Reproductive effects of cannabis In the mid-1970s there seemed to be good reason to suspect that cannabis use had adverse effects on the human reproductive system. There was some animal experimentation which suggested that cannabis adversely affected the secretion of gonadal hormones in both sexes, and the foetal development of animals administered crude marijuana extract or THC during pregnancy (Bloch, 1983; Institute of Medicine, 1982; Nahas, 1984; Nahas and Frick, 1987; Wenger et al, 1992). Cannabis was being widely used by adolescents who were undergoing sexual maturation, and by young adults who were entering the peak age for reproduction (Linn et al, 1983). The suspicion that cannabinoids had adverse effects on the human reproductive system was first raised by case reports of breast development (gynecomastia) in young men aged 23 to 26 years of age, all of whom had a history of heavy cannabis use (Harman and Aliapoulios, 1972). The suspicion seemed confirmed by human observations published shortly after by Kolodny et al (1974), who reported that males who were chronic cannabis users had reduced plasma testosterone, reduced sperm count and motility, and an increased prevalence of abnormal sperm. In the light of these observations, the widespread use of cannabis among young adults which began in the early 1970s and continued well into the mid-1980s raised understandable fears that fertility would be impaired in men, and the rates of unfavourable pregnancy outcomes would increase among women using cannabis during in their reproductive years. These outcomes could possibly include greater foetal loss, lower birth weight, and an increased risk of birth defects and perinatal deaths. Later, concerns were also raised about the possibility of adverse effects upon the subsequent behavioural development and health of children exposed to marijuana in utero. Evidence relevant to each of these concerns will be reviewed in this section. 6.5.1 Effects on the male reproductive system In animals, marijuana, crude marijuana extracts, THC and certain other purified cannabinoids have been shown to "depress the functioning of the male reproductive endocrine system" (Bloch, 1983, p355). If used chronically, cannabis reduces plasma testosterone levels, retards sperm maturation, reducing the sperm count and sperm motility, and increasing the rate of abnormal sperm (Bloch, 1983, National Academy of Science, 1982; Wenger et al, 1992). Although the mechanisms by which cannabis produces these effects are uncertain, it is likely that they occur both directly as a result of action of THC on the testis, and indirectly via effects on the hypothalamic secretion of the hormones that stimulate the testis to produce testosterone (Wenger et al, 1992). The small number of human studies on the effects of cannabis on male reproductive function have produced mixed results. The findings of the early study by Kolodny et al (1974) which reported reduced testosterone, sperm production, and sperm motility and increased abnormalities in sperm were contradicted shortly thereafter by the results of a larger, well controlled study of chronic heavy users, which failed to find any difference in plasma testosterone at study entry, or after three weeks of heavy daily cannabis use (Mendelson et al, 1974). Other studies have produced both positive and negative evidence of an effect of cannabinoids on testosterone, for reasons that are not well understood (Institute of Medicine, 1982). Hollister (1986) has conjectured that reductions in testosterone and spermatogenesis probably require long-term exposure. Even if there are such effects of cannabis on male reproductive functioning, their clinical significance in humans is uncertain (Institute of Medicine, 1982) since testosterone levels in the studies which have found effects have generally remained within the normal range (Hollister, 1986). The putative relationship between cannabis use and gynecomastia now seems very doubtful. The magnitude of reductions observed in the positive studies are too small to explain the case reports of gynecomastia among heavy male cannabis smokers (Harman and Aliapoulios, 1972), and a small case-control study failed to find any relationship between cannabis use and gynecomastia in 11 cases and controls (Cates and Pope, 1977). Altho 6. The chronic effects o this study did not exclude a four-fold higher risk of gynecomastia among cannabis smokers, studies in humans and animals have not shown any increased secretion of the hormone prolactin, the most likely mechanism of such effects in males. As Mendelson et al (1984) have argued, if chronic cannabis use caused gynecomastia, one would expect many more cases to have been reported in the clinical literature, given the widespread use of cannabis among young males during the past few decades. Hollister has argued that the reductions in testosterone and spermatogenesis observed in the positive studies are probably of "little consequence in adults", although he conceded that they could be of "major importance in the prepubertal male who may use cannabis" (p10). He cited a case of growth arrest in a 16-year-old male who began heavy cannabis use at the age of 11, and who experienced a retardation of growth and the development of secondary sexual characteristics which partially remitted after three months abstinence from cannabis (Copeland, Underwood and Van Wyck, 1980). The possible effects of cannabis use on testosterone and spermatogenesis may therefore be most relevant to males whose fertility is already impaired for other reasons, e.g. a low sperm count. 6.5.2 Effects on the female reproductive system The experimental animal studies suggests that cannabis use has similar effects on female reproductive system to those found in males. The acute effects of cannabis or THC exposure in the non-pregnant female animal is to transiently interfere with the hypothalamic-pituitary-gonadal axis (Bloch, 1983). Chronic cannabis exposure delays oestrous and ovulation by reducing leutinising hormone and increasing prolactin secretion. There have been very few human studies of the effects of cannabis on the female reproductive system because of fears that cannabis use may produce teratogenic and genotoxic effects in women of childbearing age who would be the experimental subjects in such studies (Rosenkrantz, 1985). Two studies have been reported with conflicting results. In an unpublished study, Bauman (1980 cited by Nahas, 1984) compared the menstrual cycles of 26 cannabis smokers with those of 17 controls, and found a higher rate of anovulatory cycles among the cannabis users. Mendelson and Mello (1984) observed hormonal levels in a group of female cannabis users (all of whom had undergone a tubal ligation) under controlled laboratory conditions. They failed to find any evidence that sub-chronic cannabis use affected the cycling of the sex hormones, or the duration of the cycle. In the absence of any other human evidence, both Bloch (1983) and the Institute of Medicine (1982) argued on the basis of the animal literature that cannabis use probably had an inhibitory effect on human female reproductive function which was similar to that which occurs in males. 6.5.3 Foetal development and birth defects Given evidence that THC affects female reproductive function, one might expect it to have a potentially adverse effect on the outcome of pregnancy. The possibility of adverse pregnancy outcomes is increased by evidence that THC crosses the placenta in animals (Bloch, 1983) and humans (Blackard and Tennes, 1984). This raises the possibility that THC, and possibly other cannabinoids, are teratogens, i.e. substances that may interfere with the normal development of the foetus in utero. The animal evidence indicates that in sufficient dosage cannabis can "produce resorption, growth retardation, and malformations" in mice, rats, rabbits, and hamsters (Bloch, 1983, p406). Growth resorption and growth retardation have been more consistently reported than birth malformations (Abel, 1985). There are also several caveats on the evidence that cannabis increases rates of malformations. The doses required to reliably produce malformations have been very high (Abel, 1985), and such effects have been observed more often after the administration of crude marijuana extract than pure THC, suggesting that other cannabinoids may be involved in producing any teratogenic effects. There have also been doubts expressed about whether these teratogenic effects can be directly attributed to THC. Some have argued, for example, that the malformations may be a consequence of reduced nutrition caused by the aversive properties of the large doses of cannabis used in these studies (Abel, 1985; Bloch, 1983). Hollister (1986) has also discounted the animal research data, arguing that "virtually every drug that has ever been studied for dysmorphogenic effects has been found to have them if the doses are high enough, if enough species are tested, or if treatment is prolonged" (p4). Similar views have been expressed by Abel (1985) and by Bloch (1983), who concluded that THC was unlikely to be teratogenic in humans because "the few reports of teratogenicity in rodents and rabbits indicate that cannabinoids are, at most, weakly teratogenic in these species" (p416). 188.8.131.52 Human studies The findings from the small number of epidemiological studies of the effects of cannabis use on human foetal development have been mixed for a number of reasons. First, both the adverse reproductive outcomes and the prevalence of heavy cannabis use during pregnancy are relatively rare events. Hence, unless cannabis use produces a large increase in the risk of abnormalities, very large sample sizes will be required to detect adverse effects of cannabis use on foetal development. Many of the studies that have been conducted to date have been too small to detect effects of this size (e.g. Greenland et al, 1982 a,b; Fried, 1980). There are also likely to be difficulties in identifying cannabis users among pregnant women. The stigma associated with illicit drug use, especially during pregnancy, may discourage honest reporting, compounding the usual problem of women accurately recalling drug use in early pregnancy, when they are asked about it late in their pregnancy, or after the birth (Day et al, 1985). If, as seems likely, a substantial proportion of cannabis users are misclassified as non-users, any relationship between cannabis use and adverse outcomes will be attenuated, requiring even larger samples to detect it (Zuckerman, 1985). Even when large sample sizes have been obtained, there are difficulties in interpreting any associations found between adverse pregnancy outcomes and cannabis use. Cannabis users are more likely to use tobacco, alcohol and other illicit drugs during their pregnancy. They also differ from non-users in social class, education, nutrition, and other factors which predict an increased risk of experiencing an adverse outcome of pregnancy (Fried, 1980, 1982; National Academy of Science, 1982; Tennes et al, 1985). These sources of confounding make it difficult to unequivocally attribute any relationship between reproductive outcomes and cannabis use to cannabis use per se, rather than to other drug use, or other variables correlated with cannabis use, such as poor maternal nutrition, and lack of prenatal care. Sophisticated forms of statistical control provide the only way of assessing to what degree this may be the case, but its application is limited by the small number of cannabis smokers identified in most studies. Given these difficulties, and the marked variation between studies in the proportion of women who report cannabis use during pregnancy, the degree of agreement between the small number of studies is more impressive than the disagreement that seems at first sight to such be a feature of this literature. There is reasonable consistency (although not unanimity) in the finding that cannabis use in pregnancy is associated with foetal growth retardation, as shown by reduced birth weight (e.g. Gibson et al, 1983; Hatch and Bracken, 1986; Zuckerman et al, 1989), and length at birth (Tennes et al, 1985). This relationship has been found in the best controlled studies, and it has persisted after statistically controlling for potential confounding variables by sophisticated forms of statistical analysis (e.g. Hatch and Bracken, 1986; Zuckerman et al, 1989). Uncertainty remains about the interpretation of this finding. Is it because the "marijuana products were toxic to foetal development", as argued by Nahas and Latour (1992)? Is it because THC interferes with the hormonal control of pregnancy shortening the gestation period, as has been reported by Gibson et al (1983) and Zuckerman et al (1989)? The fact that the lower birth weight among the children of women who used cannabis disappears after controlling for gestation length is supportive of the latter hypothesis. Is it because cannabis is primarily smoked, since tobacco smoking has been consistently shown to be associated with reduced birth weight (Fried, 1993)? The findings on the relationship between cannabis use and birth abnormalities are more mixed, and conclusions accordingly less certain. Early case reports of children with features akin to the Foetal Alcohol Syndrome born to women who had smoked cannabis but not used alcohol during pregnancy (e.g. Milman, 1982, p42) suggested that cannabis may increase the risk of birth defects. Subsequent controlled studies have produced mixed results. Four studies have reported no increased rate of major congenital abnormalities among children born to women who use cannabis (Gibson et al, 1983; Hingson et al, 1982; Tennes et al, 1985; Zuckerman et al, 1989). One study has reported a five-fold increased risk of children with foetal alcohol like features being born to women who reported using cannabis (Hingson et al, 1982). The significance of this finding is uncertain because the same study also found no relationship between self-reported alcohol use and "foetal alcohol syndrome" features. This is doubly surprising because of other evidence on the adverse effects of alcohol, and because the epidemiological data indicates that cannabis and alcohol use are associated (Norton and Colliver, 1988). An additional study reported an increase in the crude rate of birth abnormalities among children born to women who reported using cannabis. This result was no longer statistically significant after adjustment for confounders (Linn et al, 1983), although the confidence interval around this adjusted risk (OR=1.36) only narrowly included the null value (95 per cent CI: 0.97, 1.91). The study by Zuckerman et al provides the most convincing failure to find an increased risk of birth defects among women who used cannabis during pregnancy. A large sample of women was obtained, among which there was a substantial prevalence of cannabis use that was verified by urinalysis. There was a low rate of birth abnormalities among the cannabis users, and no suggestion of an increase by comparison with the controls. On this finding, one might be tempted to attribute the small increased risk in the positive study (Linn et al, 1983) to recall bias, since the report of cannabis use during pregnancy was obtained retrospectively after birth, when women who had given birth to children with malformations may have been more likely to recall cannabis use than those who did not. However, given the uncertainty about the validity of self-reported cannabis use in many of the null studies, it would be unwise to exonerate cannabis as a cause of birth defects until larger, better controlled studies have been conducted. 6.5.4 Chromosomal abnormalities and genetic effects Teratogenesis - interference with normal foetal development - is not the only way in which cannabis use might adversely affect human reproduction. Cannabis use could conceivably produce chromosomal abnormalities or genetic change in either parent which could be transmitted to their progeny. Although possible, there is no animal or human evidence that such events occur. The experimental evidence indicates that "in vivo and in vitro exposure to purified cannabinoids or cannabis resin failed to increase the frequency of chromosomal damage or mutagenesis" (Bloch, 1983, p412). Marijuana smoke exposure, by contrast, "has been ... associated with chromosomal aberrations ... [such as] hypoploidy, mutagenicity in the Ames test ... " (Bloch, 1983, p413). The latter fact is more relevant to an appraisal of the risk of cannabis users developing cancers from exposure to cannabis smoke rather than to the risks of transmissible genetic defects in their offspring. Hollister (1986) discounted the evidence from cytogenetic studies that cannabinoids may be mutagenic, as did the Institute of Medicine (1982). He also argued that assessing chromosomal damage was "more of an art than a science", as indicated by poor inter-observer agreement, and that the clinical significance remained unclear because "similar types and degrees of chromosomal changes have been reported in association with other drugs commonly used in medical practice without any clinical evidence of harm ..." (p4). Hollister concluded that "even if a small increase in chromosomal abnormalities is produced by cannabis, the clinical significance is doubtful" (p4). 6.5.5 Post-natal development A further possibility which needs to be considered is that cannabis use by the mother during pregnancy and breast feeding may affect the post-natal development of the child. This could occur either because of the enduring effects of developmental impairment arising from in utero exposure, or because the infant continued to be exposed to cannabinoids via breast milk. These are not well investigated possibilities, although there are a small number of animal studies which provide suggestive evidence of such effects (Nahas, 1984; Nahas and Frick, 1987). The most extensive research evidence in humans comes from the Ottawa Prospective Prenatal Study (OPPS), which studied developmental and behavioural abnormalities in children born to women who reported using cannabis during pregnancy (Fried and colleagues, 1980, 1982, 1983, 1985, 1986, 1989, 1990, 1992). In this study, mothers were assessed about their drug use during pregnancy and their children were measured on the Brazelton scales after birth, neurologically assessed at one month, and assessed again by standardised scales of ability at six and 12 months. The results indicated that there was some developmental delay shortly after birth in the infants' visual system, and there was also an increased rate of tremors and startle among the children of cannabis users. The behavioural effects discernible after birth had faded by one month, and no effects were detectable in performance on standardised ability tests at six and 12 months. Effects were subsequently reported at 36 and 48-month follow-ups (Fried and Watkinson, 1990) but these did not persist in a more recent follow-up at 60 and 72 months (Fried, O'Connell, and Watkinson, 1992). These results are suggestive of a transient developmental impairment occurring among children who had experienced a shorter gestation and prematurity. There is a possibility that the tests used in later follow-ups are insufficiently sensitive to the subtle effects of prenatal cannabis exposure, although they were able to detect effects of maternal tobacco smoking during pregnancy on behavioural development at 60 and 72 months (Fried and Watkins, 1990, 1992). Attempts to replicate the OPPS findings have been mixed. Tennes et al (1985) conducted a prospective study of the relationship between cannabis use during pregnancy and postnatal development in 756 women, a third of whom reported using cannabis during pregnancy. The children were assessed shortly after birth using the same measurement instruments as Fried (1980), and a subset were followed up and assessed at one year of age. The findings failed to detect any differences in behavioural development between the children of users and non-users after birth; i.e. there was no evidence of impaired development of the visual system, and no increased risk of tremor or startle among the children of users. There was also no evidence of any differences at one year. More recently, Day et al (in press), have followed up children at age three born to 655 women who were questioned about their substance use during pregnancy. They found a relationship between the mothers' cannabis use during pregnancy and the children's performances on memory and verbal scales of the Stanford-Binet Intelligence Scale. There is suggestive evidence that cannabis use during pregnancy may have a more serious and life threatening effect on post-natal development. This emerged from a case-control study of Acute Nonlymphoblastic Leukemia (ANLL), a rare form of childhood cancer (Neglia et al, 1991; Robinson et al, 1989). The study was not designed as a test of relationship between cannabis use and ANLL; it was designed to examine the possible aetiological role of maternal and paternal environmental exposures to petrochemicals, pesticides and radiation. Maternal drug use, including marijuana use before and during pregnancy, were assessed as possible covariates to be statistically controlled in any relationships observed between ANLL and environmental exposures. An unexpected but strong association was observed between maternal cannabis use and ANLL. The mothers of cases were 11 times more likely to have used cannabis before and during their pregnancy than were the mothers of controls. The relationship persisted after statistical adjustment for many other risk factors. Comparisons of cases whose mothers did and did not use cannabis during their pregnancies showed that cases with cannabis exposure were younger, and had a higher frequency of ANLL with cell types of a specific pathological origin than did the cases without such exposure. The authors argued that these differences made it unlikely that the relationship was due to chance. Reporting bias on the part of the mothers of cases is an alternative explanation of the finding that is harder to discount. The reports of cannabis use were obtained retrospectively after diagnosis of the ANLL, so it is possible that the mothers of children who developed ANLL were more likely to seek an explanation in something they did during their pregnancies, and hence, may have been more likely to report cannabis use than were mothers of controls. The authors investigated this possibility by comparing the rates of cannabis use reported in this study with the rates reported in several earlier case-control studies of other childhood cancers that they had conducted using the same methods. The rate was lower among controls in the ANLL study, but even when the rate of cannabis use among the controls in these other studies was used the odds ratio was still greater than three and statistically significant. Nonetheless, since this was an unexpected finding which emerged from a large number of exploratory analyses conducted in a single study, it should be replicated as a matter of some urgency. 6.5.6 Conclusions On the balance of probabilities, high doses of THC probably disrupt the male and female reproductive systems in animals by interfering with hypothalamo-pituitary-gonadal system, reducing secretion of testosterone, and hence reducing sperm production, motility, and viability in males, and interfering with the ovulatory cycle in females. It is uncertain whether these effects also occur in humans, given the dose differences, the inconsistency in the literature on human males and the absence of research on human females. Even if cannabinoids have such effects in humans, their clinical significance in normal healthy young adults is unclear. They may be of greater concern among young adolescents who are now more likely to use, and among males with fertility impaired for other reasons. Cannabis use during pregnancy probably impairs foetal development, leading to smaller birthweight, perhaps as a consequence of a shorter period of gestation. It is possible although far from certain that cannabis use during pregnancy produces a small increase in the risk of birth defects as a result of exposure of the foetus in utero. Prudence suggests that until this issue is resolved, we should err in the conservative direction by recommending that women not use cannabis during pregnancy, or when attempting to conceive (Hollister, 1986). There is not a great deal of evidence that cannabis use can produce chromosomal or genetic abnormalities in either parent which could be transmitted to offspring. The available animal and in vitro evidence suggests that the mutagenic properties of cannabis smoke are greater than those of THC, and are probably of greater relevance to the risk of users developing cancer than to the transmission of genetic defects to children. 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