SEMINAR

National Drug and Alcohol Research Centre,
University of New South Wales, Sydney 2052, Australia

(part 1)
Cannabis The Drug
Patterns Of Cannabis Use
Acute Effects Of Cannabis
Effects Of Chronic Cannabis Use

(Part 2)
References
Further Reading

ADVERSE EFFECTS OF CANNABIS

Cannabis is the most widely used illicit drug in many developed societies.
Its health and psychological effects are not well understood and remain the
subject of much debate, with opinions on its risks polarised along the
lines of proponents' views on what its legal status should be. An
unfortunate consequence of this polarisation of opinion has been the
absence of any consensus on what health information the medical profession
should give to patients who are users or potential users of cannabis. There
is conflicting evidence about many of the effects of cannabis use, so we
summarise the evidence on the most probable adverse health and
psychological consequences of acute and chronic use. This uncertainty,
however, should not prevent medical practitioners from advising patients
about the most likely ill-effects of their cannabis use. Here we make some
suggestions about the advice doctors can give to patients who use, or are
contemplating the use, of this drug.

In many western societies, cannabis has been used by a substantial
minority, and in some a majority, of young adults, even though its use is
prohibited by law.1 Debate about the justification for continuing to
prohibit cannabis use has polarised opinion about the seriousness of its
adverse health effects.2 In addition, the possible therapeutic effects of
cannabinoids have become entangled in the debate about prohibition of
recreational cannabis use (see Further reading). The health effects of
cannabis use, especially of long-term use, remain uncertain because there
is very little epidemiological research and because of disagreements about
the interpretation of the limited epidemiological and laboratory evidence.2
Here we summarise the evidence on the most probable adverse health effects
of cannabis use acknowledging where appropriate the uncertainty that
remains.

CANNABIS THE DRUG

Cannabis preparations are largely derived from the female plant of Cannabis
sativa. The primary psychoactive constituent is -9-tetrahydrocannabinol
(THC).3 The THC content is highest in the flowering tops, declining in the
leaves, lower leaves, stems, and seeds of the plant. Marijuana (THC content
0B75-5B70%) is prepared from the dried flowering tops and leaves; hashish
(THC content 2-20%) consists of dried cannabis resin and compressed
flowers; and hashish oil may contain between 15% and 50% THC.3 Sinsemilla
and Netherwood varieties of cannabis may have a THC content of up to 20%.3
Cannabis may be smoked in a "joint", which is the size of a cigarette, or
in a water pipe. Tobacco may be added to assist burning. Smokers typically
inhale deeply and hold their breath to maximise absorption of THC by the
lungs. Marijuana and hashish may also be eaten, but cannabis is mostly
smoked because this is the easiest way to achieve the desired psychoactive
effects.2

A typical joint contains between 0B75 g and 1B70 g of cannabis. The THC
delivered varies between 20% and 70%,2 its bioavailability ranging from 5%
to 24%.3 As little as 2-3 mg of available THC will produce a "high" in
occasional users, but regular users may smoke five or more joints a day.

Cannabinoids act on a specific receptor that is widely distributed in the
brain regions involved in cognition, memory reward, pain perception, and
motor coordination.3 These receptors respond to an endogenous ligand,
anandamide, which is much less potent and has a shorter duration than THC.3
The identification of a specific cannabinoid antagonist promises to improve
our understanding of the role of cannabinoids in normal brain function.3

PATTERNS OF CANNABIS USE

Cannabis has been tried by many European young adults and by most young
adults in the USA and Australia.1 Most cannabis use is intermittent and
time-limited: most users stop in their mid to late 20s, and very few engage
in daily cannabis use over a period of years.4 In the USA and Australia,
about 10% of those who ever use cannabis become daily users, and another
20-30% use the drug weekly.1,4

Because of uncertainties about THC content, heavy cannabis use is generally
defined as daily or near daily use.2 This pattern of use over years places
users at greatest risk of adverse health and psychological consequences.2
Daily cannabis users are more likely to be male, to be less well educated,
to use alcohol and tobacco regularly, and to use amphetamines,
hallucinogens, psychostimulants, sedatives, and opioids.5

ACUTE EFFECTS OF CANNABIS

Cannabis produces euphoria and relaxation, perceptual alterations, time
distortion, and the intensification of ordinary sensory experiences, such
as eating, watching films, and listening to music.2 When used in a social
setting it may produce infectious laughter and talkativeness. Short-term
memory and attention, motor skills, reaction time, and skilled activities
are impaired while a person is intoxicated.2

The most common unpleasant side-effects of occasional cannabis use are
anxiety and panic reactions.2 These effects may be reported by naEFve
users, and they are a common reason for discontinuation of use; more
experienced users may occasionally report these effects after receiving a
much larger than usual dose of THC.2

Cannabis smoking or ingestion of THC increases heart rate by 20-50% within
a few minutes to a quarter of an hour; this effect lasts for up to 3 h.2
Blood pressure is increased while the person is sitting, and decreased
while standing.2 These effects are of negligible clinical significance in
healthy young users because tolerance develops to them.2

The acute toxicity of cannabinoids is very low.2 There are no confirmed
published cases worldwide of human deaths from cannabis poisoning, and the
dose of THC required to produce 50% mortality in rodents is extremely high
compared with other commonly used drugs.2

Psychomotor effects and driving

Cannabis produces dose-related impairments in cognitive and behavioural
functions that may potentially impair driving a motor vehicle or operating
machinery.6 These impairments are larger and more persistent for difficult
tasks that depend on sustained attention.6 The most serious possible
consequence of acute cannabis use is a road-traffic accident if a user
drives while intoxicated.2

The effects of recreational doses of cannabis on driving performance in
laboratory simulators and standardised driving courses have been reported
by some researchers as being similar to the effects when blood alcohol
concentrations are between 0B707% and 0B710%.2 However, studies of the
effects of cannabis on driving under more realistic conditions on roads
have shown much more modest impairments,7,8 probably because cannabis users
are more aware of their impairment and less inclined to take risks than
alcohol users.7,8

Results of epidemiological studies of road-traffic accidents are equivocal
because most drivers who have cannabinoids in their blood also have high
blood alcohol concentrations.2 In two studies with reasonable numbers of
individuals who had only used cannabis, there was no clear evidence of
increased culpability in these drivers.9 The separate effects of alcohol
and cannabis on psychomotor impairment and driving performance in
laboratory tasks are roughly additive,9 so the main effect of cannabis use
on driving may be in amplifying the impairments caused by alcohol, which is
often used with the drug.2

EFFECTS OF CHRONIC CANNABIS USE

Cellular effects and the immune system Cannabis smoke may be carcinogenic;
it is mutagenic in vitro and in vivo.10 Cannabinoids impair cell-mediated
and humoral immunity in rodents, decreasing resistance to infection, and
non-cannabinoids in cannabis smoke impair alveolar macrophages.11 The
relevance of these findings to human health is uncertain because the doses
of THC used in animal studies have been very high, and tolerance may
develop to the effects on immunity in human beings.12

A few studies that have pointed to the adverse effects of cannabis on human
immunity have not been replicated.12 There is no conclusive evidence that
consumption of cannabinoids impairs human immune function, as measured by
numbers of T lymphocytes, B lymphocytes, or macrophages, or immunoglobulin
concentrations.12 Two prospective studies of HIV-positive homosexual men
have shown that cannabis use is not associated with an increased risk of
progression to AIDS concentrations.13,14David

Summary of adverse effects of cannabis

Acute effects

* Anxiety and panic, especially in naEFve users.

* Impaired attention, memory, and psychomotor performance while intoxicated.

* Possibly an increased risk of accident if a person drives a motor vehicle
while intoxicated with cannabis, especially if cannabis is used with
alcohol.

* Increased risk of psychotic symptoms among those who are vulnerable
because of personal or family history of psychosis.

Chronic effects (uncertain but most probable)

* Chronic bronchitis and histopathological changes that may be precursors
to the developmentof malignant disease.

* A cannabis dependence syndrome characterised by an inability to abstain
from or to control cannabis use.

* Subtle impairments of attention and memory that persist while the user
remains chronically intoxicated, and that may or may not be reversible
after prolonged abstinence.

Possible adverse effects (to be confirmed)

* Increased risk of cancers of the oral cavity, pharynx, and oesophagus;
leukaemia among offspring exposed in utero.

* Impaired educational attainment in adolescents and underachievement in
adults in occupations requiring high-level cognitive skills.

Groups at higher risk of experiencing these adverse effects

* Adolescents with a history of poor school performance, who initiate
cannabis use in the early teens, are at increased risk of using other
illicit drugs and of becoming dependent on cannabis.

* Women who continue to smoke cannabis during pregnancy may increase their
risk of having a low-birthweight baby.

* People with asthma, bronchitis, emphysema, schizophrenia, and alcohol and
other drug dependence, whose illnesses may be exacerbated by cannabis use.

Respiratory system

Chronic heavy cannabis smoking is associated with increased symptoms of
chronic bronchitis, such as coughing, production of sputum, and
wheezing.15,16 Lung function is significantly poorer and there are
significantly greater abnormalities in the large airways of marijuana
smokers than in non-smokers. Tashkin and colleagues16,17 have reported
evidence of an additive effect of marijuana and tobacco smoking on
histopathological abnormalities in lung tissue.

Bloom and colleagues15 reported similar additive effects on bronchitic
symptoms in an epidemiological study of the respiratory effects of smoking
"non-tobacco" cigarettes in 990 individuals aged under 40 years in Tucson,
Arizona, USA. Non-tobacco smokers reported more coughing, phlegm
production, and wheeze than non-smokers, irrespective of whether they also
smoked tobacco. Those who had never smoked any substance had the best
respiratory functioning, followed in order of decreasing function by
current tobacco smokers, current non-tobacco smokers, and current smokers
of both tobacco and non-tobacco cigarettes. Non-tobacco smoking alone had a
larger effect on respiratory function than tobacco smoking alone, and the
effect of both types of smoking was additive.15

In 1997, Tashkin and colleagues18 reported that the rate of decline in
respiratory function over 8 years among marijuana smokers did not differ
from that in non-smokers. This finding contrasted with that of a follow-up
of the Tucson cohort,19 in which there was a greater rate of decline in
respiratory function among marijuana-only smokers than in tobacco-only
smokers and additive effects of tobacco and marijuana smoking. Both studies
showed that long-term cannabis smoking increased bronchitic symptoms.

In view of the adverse effects of tobacco smoking, the similarity between
tobacco and cannabis smoke, and the evidence that cannabis smoking produces
histopathological changes that precede lung cancer,17 long-term cannabis
smoking may also increase the risks of respiratory cancer.20 There have
been reports of cancers in the aerodigestive tract in young adults with a
history of heavy cannabis use.21,22 These reports are worrying since such
cancers are rare among adults under the age of 60, even those who smoke
tobacco and drink alcohol.20 Case-control studies of the role of cannabis
smoking in these cancers are urgently needed.

Reproductive effects

Chronic administration of high doses of THC to animals lowers testosterone
secretion, impairs sperm production, motility, and viability, and disrupts
the ovulatory cycle.23 Whether cannabis smoking has these effects in human
beings is uncertain because the published evidence is small and
inconsistent.2

Cannabis administration during pregnancy reduces birthweight in animals.24
The results of human epidemiological studies have been more equivocal.2 The
stigma of using illicit drugs during pregnancy discourages honest
reporting,25 and when associations are found, they are difficult to
interpret because cannabis users are more likely than non-users to smoke
tobacco, drink alcohol, and use other illicit drugs during pregnancy, and
they differ in social class, education, and nutrition.26 Several studies
have suggested that cannabis smoking in pregnancy may reduce birthweight.2
In the best controlled of these studies, this relation has persisted after
statistical control for potential confounding variables,27 but other
studies28 have not shown any such association. The effect of cannabis on
birthweight in the studies that have found an association has been small
compared with that of tobacco smoking.26

That cannabis use during pregnancy increases the risk of birth defects is
unlikely. Early case reports have not been supported by large
well-controlled epidemiological studies. For example, the study by
Zuckerman et al27 included a large sample of women with a substantial
prevalence of cannabis use that was verified by urine analysis, and there
was no increase in birth defects.

There is suggestive evidence that infants exposed in utero to cannabis have
behavioural and developmental effects during the first few months after
birth.26 Between the ages of 4 and 9 years, children who were exposed in
utero have shown deficits in sustained attention, memory, and higher
cognitive functioning.29 The clinical significance of these effects remains
unclear since they are small compared with the effects of maternal tobacco
use.29

Three studies have shown an increased risk of non-lymphoblastic
leukaemia,30 rhabdomyosarcoma,31 and astrocytoma32 in children whose
mothers reported using cannabis during their pregnancies. None of these was
a planned study of the association; cannabis use was one of many potential
confounders included in statistical analyses of the relation between the
exposure of interest and childhood cancer. Their replication is a priority.
Behavioural effects in adolescence

There is a cross-sectional association between heavy cannabis use in
adolescence and the risk of leaving high-school education and of
experiencing job instability in young adulthood.33 However, the strength of
this association is reduced in longitudinal studies when statistical
adjustments are made for the fact that, compared with their peers, heavy
cannabis users have poor high-school performance before using
cannabis.33,34 There is some evidence that heavy use has adverse effects on
family formation, mental health, and involvement in drug-related crime.33
In each case, the strong associations in cross-sectional studies are more
modest in longitudinal studies after statistical control for associations
between cannabis use and other pre-existing characteristics that
independently predict these adverse outcomes.34

A consistent finding in the USA has been the regular sequence of initiation
into drug use in which cannabis use has typically preceded involvement with
"harder" illicit drugs such as stimulants and opioids.5,33,35 The
interpretation of this sequence remains controversial. The less compelling
hypothesis is that cannabis use directly increases the use of other drugs
in the sequence. There is better support for two other hypotheses--namely,
that there is a selective recruitment into cannabis use of non-conforming
adolescents who have a propensity to use other illicit drugs, and that once
recruited to cannabis use, social interaction with drug-using peers, and
greater access to illicit-drug markets, they are more likely to use other
illicit drugs.2,34

Dependence syndrome

Animals develop tolerance to the effects of repeated doses of THC,36 and
studies suggest that cannabinoids may affect the same reward systems as
alcohol, cocaine, and opioids.37 Heavy smokers of cannabis also develop
tolerance to its subjective and cardiovascular effects,36 and some report
withdrawal symptoms on the abrupt cessation of cannabis use.36,38

There is evidence that a cannabis dependence syndrome occurs with heavy
chronic use in individuals who report problems in controlling their use and
who continue to use the drug despite experiencing adverse personal
consequences.2,39 There is some clinical evidence of a dependence syndrome
analogous to that for alcohol.2 In the USA, cannabis dependence is among
the most common forms of illicit-drug dependence in the population.40 About
one in ten of those who ever use cannabis become dependent on it at some
time during their 4 or 5 years of heaviest use.40 This risk is more like
the equivalent risk for alcohol (15%) than for nicotine (32%) or opioids
(23%).40

Cognitive effects

The long-term heavy use of cannabis does not produce the severe or grossly
debilitating impairment of memory, attention, and cognitive function that
is found with chronic heavy alcohol use.2 Electrophysiological and
neuropsychological studies show that it may produce more subtle impairment
of memory, attention, and the organisation and integration of complex
information.41-43 The longer cannabis has been used, the more pronounced
the cognitive impairment.41 These impairments are subtle, so it remains
unclear how important they are for everyday functioning, and whether they
are reversed after an extended period of abstinence.2 Early studies that
suggested gross structural brain damage with heavy use have not been
supported by better controlled studies with better methods.41 Research in
animals has shown that chronic cannabinoid administration may compromise
the endogenous cannabinoid system3,41 (its function is unclear, but it has
roles in memory, emotion, and cognitive functioning, as mentioned above).
These results are consistent with the subtlety of the cognitive effects of
chronic cannabis use in human beings.41

Psychosis

Large doses of THC produce confusion, amnesia, delusions, hallucinations,
anxiety, and agitation.44 Such reactions are rare, occurring after
unusually heavy cannabis use; in most cases they remit rapidly after
abstinence from cannabis.2

There is an association between cannabis use and schizophrenia. A
prospective study of 50 000 Swedish conscripts45 found a dose-response
relation between the frequency of cannabis use by age 18 and the risk of a
diagnosis of schizophrenia over the subsequent 15 years. A plausible
explanation is that cannabis use can exacerbate the symptoms of
schizophrenia,2,46 and there is prospective evidence that continued use
predicts more psychotic symptoms in people with schizophrenia.47 A
declining incidence of treated cases of schizophrenia over the period when
cannabis use has increased suggests, however, that cannabis use is unlikely
to have caused cases of schizophrenia that would not otherwise have
occurred.48 This observation suggests that chronic use may precipitate
schizophrenia in vulnerable individuals, an effect that would not be
expected to change incidence.45

Premature mortality

There have been two prospective epidemiological studies of mortality among
cannabis users. A Swedish study of mortality during 15 years among male
military conscripts showed an increased risk of premature death among men
who had smoked cannabis 50 or more times by age 18.49 Violent and
accidental death was the main contributor to this excess. However, the
association between mortality and cannabis use disappeared after
multivariate statistical adjustment for alcohol and other drug use.49

Sydney and colleagues50 reported a 10-year study of mortality in cannabis
users aged between 15 and 49 years among 65171 members of the Kaiser
Permanente Medical Care Program. The sample consisted of 38% who had never
used cannabis, 20% who had used fewer than six times, 20% who were former
users, and 22% who were current users. Regular cannabis use had a small
association with premature mortality (RR 1B733), which was wholly
explained by increased deaths from AIDS in men, probably because marijuana
use was a marker for male homosexual behaviour in this cohort. It is too
early to conclude from the study that marijuana use does not increase
mortality because the average age at follow-up was only 43 years, and
cigarette smoking and alcohol use were only modestly associated with
premature mortality.50

Possible effects of increased THC content of cannabis The average THC
content of cannabis has probably increased over the past several decades,
but without good data by how much is unclear.2 This situation probably
reflects a combination of an increased market for more potent cannabis
products among regular users,2 and improved methods of growing
high-THC-content.3 The net health consequences of any increase in potency
are uncertain.2 Among naEFve users, higher THC content may increase
adverse psychological effects, including psychotic symptoms, thereby
discouraging some from continuing to use. Among those who continue to use
cannabis, increased potency may increase the risks of developing
dependence, having accidents if driving while intoxicated, and experiencing
psychotic symptoms. If experienced users can regulate their dose of THC,
the respiratory risks of cannabis smoking may be marginally reduced.

Health advice for cannabis users

Uncertainty about the adverse health effects of acute, and especially
chronic, cannabis use, should not prevent medical practitioners from
advising patients who use cannabis about the most probable ill-effects of
their cannabis use with emphasis on the uncertainty. In the absence of
other risk factors, this should include advice about the possibility of
being involved in a motor-vehicle accident if patients drive while
intoxicated by cannabis; the higher risk of an accident if they drive when
intoxicated by both alcohol and cannabis; the respiratory risks of
long-term cannabis smoking, which are substantially increased if they also
smoke tobacco; an increased risk of developing dependence if they are daily
users of cannabis; and the possibility of subtle cognitive impairment if
they use regularly over several years.

We thank Greg Chesher for comments on an earlier version of this manuscript.