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UK: Lancet: Editorial: Dangerous Habits Sat, 14 Nov 1998 Editorial: Dangerous Habits 3 years ago, a Lancet editorial began, "The smoking of cannabis, even long term, is not harmful to health" (Nov 11, 1995); an assertion criticised by many readers as encouraging an indulgence that is illegal in many countries. Predictably, the legalise-cannabis lobby seized on The Lancet's apparent endorsement of this substance's safety. This week we publish a seminar on the adverse effects of cannabis (p 1611) . Wayne Hall and Nadia Solowij conclude that the most likely adverse effects of smoking cannabis are bronchial irritation, the risk of accidents when intoxicated, dependence, and possible cognitive impairment with heavy, long-term use. The evidence summarised in this seminar was considered by a committee of the UK House of Lords which reported on Nov 11 . The committee recommended that clinical trials be done on the effects of cannabis in multiple sclerosis and in chronic pain, and that the UK Government should reclassify cannabis so that it can be prescribed by doctors under certain circumstances. The debate about whether or not cannabis, taken for recreational rather than medical reasons, should be legalised in countries where it is banned will rumble on, and further complicate scientific assessment of the therapeutic effects of cannabinoids. The arguments advanced by each side are well-rehearsed, but usually fail to consider the problems presented by cannabis in a wider perspective. We would, perhaps, have been wiser to have begun our editorial 3 years ago with a less provocative statement; but, on the evidence summarised by Hall and Solowij, it would be reasonable to judge cannabis less of a threat to health than alcohol or tobacco, products that it many countries are not only tolerated and advertised but are also a useful source of tax revenue. The desire to take mood-altering substances is an enduring feature of human societies worldwide and even the most draconian legislation has failed to extinguish this desire--for every substance banned another will be discovered, and all are likely to have some ill-effect on health. This should be borne in mind by social legislators who, disapproving of other people's indulgences, seek to make them illegal. Such legislation does not get rid of the problem; it merely shifts it elsewhere. One aspect of taking mood-altering substances may require legislation: the protection of others from annoyance and harm. Whether or not a person's indulgence poses a threat to others has been used as a guide to define the limits of socially acceptable behaviour; although to do so begs the question of people's responsibility for themselves. Should it be, for example, permissible for people deliberately to put their lives or health at risk through participating in dangerous sports such as boxing or motor racing? Do people have the right to decide for themselves what risks to take, irrespective of any expense and inconvenience to others when the risks come home? Is it reasonable to say "It is my life, I shall do as I choose", when almost everyone shares their lives with friends or family who would be damaged by their illness or death? Whatever the answers to these questions, there is one aspect that is indisputable: people have the right to know what are the risks to themselves and to others. 2 weeks ago, we published evidence that the sustained use of 3,4-methylenedioxymethamphetamine ("Ecstasy") was associated with a decrease in serotonin neurons in the brain (Oct 31, p 1433) . This is information that any user of Ecstasy has a right to know; just as users of cannabis should be aware of its possible hazards. Because the debate about use of cannabis arouses strong emotions, there is, as Hall and Solowij note, no "consensus on what health information the medical profession should give to patients who are users or potential users of cannabis." Doctors called upon for advice about use of cannabis will find the authors' last paragraph a useful source of dispassionate information. The advice is little different from that appropiate for many other mood-altering substances: do not drive motor vehicles whilst intoxicated and do not overindulge. We will qualify our opinion of 3 years ago and say that, on
the medical evidence available, moderate indulgence in cannabis
has little ill-effect on health, and that decisions to ban or to
legalise cannabis should be based on other considerations. The Lancet **************** UK: Lancet: Adverse Effects Of Cannabis (part
1) Pubdate: Sat, 14 Nov 1998 Source: Lancet, The (UK) SEMINAR National Drug and Alcohol Research Centre, University of New
South Wales, Sydney 2052, Australia
Part 1 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. ********* UK: Lancet: Adverse Effects Of Cannabis (part
2) Sat, 14 Nov 1998 SEMINAR: ADVERSE EFFECTS OF CANNABIS (part 1) Cannabis The Drug Patterns Of Cannabis Use Acute
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