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6. The chronic effects of cannabis use on health
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.
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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).
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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.
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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.