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The health and psychological consequences of cannabis use chapter 6

National Drug Strategy
Monograph Series No. 25

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).



6.5.3.1 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. There is suggestive evidence that infants exposed in
utero to cannabis may experience transient behavioural and
developmental effects during the first few months after birth. There
is also a single study which raises concern about an increased risk of
childhood leukemia occurring among the children born to women who used
cannabis during their pregnancies.



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