CHAPTER 4 TOXIC EFFECTS OF
CANNABIS AND CANNABINOIDS: REVIEW OF THE EVIDENCE
4.1 The prohibition
of the recreational use of cannabis, and some of the doubts about
medical use, are based on the presumption that cannabis is harmful
to individual and public health. We have tested the strength of
that presumption, and this Chapter records what we have found.
New research on this subject is constantly coming forward, so
this cannot be said to be the last word on it. Although cannabis
is not in the premier league of dangerous substances, new research
tends to suggest that it may be more hazardous to health than
might have been thought only a few years ago (Edwards QQ 21,
27).
4.2 In assessing the
adverse effects associated with cannabis use, we have been assisted
by a number of detailed recent reviews, including the recent WHO
report Cannabis: a health perspective and research agenda
(WHO/MSA/PSA/97.4); the Australian National Drug Strategy report
The health and psychological consequences of cannabis use
(1994) and other documents[9]
submitted by Professor Wayne Hall, Executive Director
of the Australian National Drug and Alcohol Research Centre in
Sydney, and his colleagues; and the recent reviews noted above
commissioned by the Department of Health. The evidence submitted
to us by the Royal Society and the Royal College of Psychiatrists
is also particularly relevant.
Acute
(short-term) effects of cannabis
4.3 The acute toxicity
of cannabis and the cannabinoids is very low; no-one has ever
died as a direct and immediate consequence of recreational or
medical use (DH QQ 219223). Official statistics record two
deaths involving cannabis (and no other drug) in 1993, two in
1994 and one in 1995 (HC WA 533, 21 January 1998);
but these were due to inhalation of vomit. Animal studies have
shown a very large separation (by a factor of more than 10,000)
between pharmacologically effective and lethal doses.
4.4 One minor toxic
side-effect of taking cannabis which merits attention is the short-term
effect on the heart and vascular system. This can lead to significant
increases in heart rate and a lowering of the blood pressure (Pertwee
Q 299). For this reason patients with a history of angina or other
cardiovascular disease could be at risk and should probably be
excluded from any clinical trials of cannabis-based medicines.
4.5 The most familiar
short-term effect of cannabis is to give a "high" —
a state of euphoric intoxication. This is, of course, precisely
the effect sought by the recreational user, analogous to the effect
of alcohol and sought for similar reasons. We have been told,
however, that people who use cannabis for medical purposes regard
it as an unwelcome side-effect (Hodges Q 97).
4.6 Intoxication with
cannabis leads to a slight impairment of psychomotor and cognitive
function, which is important for those driving a vehicle, flying
an aircraft or operating machinery (DH Q 197). The Department
of Health rate this as "the major concern from a public health
perspective" raised by recreational use (p 46), and
Professor Hall considers it the most serious possible short-term
consequence of cannabis use, both for the user and for the public
(p 222).
4.7 There is some disagreement
about how long such impairments persist after taking cannabis:
most assume that they last for only a few hours (e.g. Kendall
p 266); but Professor Heather Ashton of the University
of Newcastle-upon-Tyne, principal author of the BMA report, suggested
that subtle cognitive impairments could persist for 24 or
even 48 hours or more (Q 72), whereas the DETR say "probably
.... 24 hours at most" (Press Notice 94/Transport,
11 February 1998). On the other hand the impairment in driving
skills does not appear to be severe, even immediately after taking
cannabis, when subjects are tested in a driving simulator. This
may be because people intoxicated by cannabis appear to compensate
for their impairment by taking fewer risks and driving more slowly,
whereas alcohol tends to encourage people to take greater risks
and drive more aggressively (POST note 113; cp DH p 240).
4.8 Analysis of blood
samples from road traffic fatalities in 1996-97 (the results of
the first 15 months of a three year DETR study—Press
Notice 94/Transport, 11 February 1998) showed that 8 per
cent of the victims were positive for cannabis, including 10 per
cent of the victims who were driving. However, it is not clear
what figures would have been obtained from a random sample of
road users not involved in accidents (DH Q 211); and some
of those who tested positive may have taken the cannabis as much
as 30 days before, so that the effects would have worn off
long since (DH p 240). The interpretation of traffic
accident data is further confounded by the fact that 22 per
cent of the drivers found to be cannabispositive also had
evidence of alcohol intake; proportions of alcoholpositives
among cannabispositive drivers as high as 75 per cent
have been reported in other countries in similar studies. Professor Hall
considers cannabis's contribution to danger on the roads to be
very small; in his view the major effect of cannabis use on driving
may be in amplifying the impairments caused by alcohol (cp Keen
Q 42). According to a survey of 1,333 regular cannabis users
by the Independent Drug Monitoring Unit (IDMU) in 1994, users
who drove reported a level of accidents no higher than the general
population; those with the highest accident rates were more likely
to be heavier poly-drug users.
4.9 It is difficult
to see how cannabis intoxication could be monitored, if its use
were permitted. There could be no equivalent of the breathalyser
for alcohol, since small amounts of cannabis continue to be released
from fat into the blood long after any short-term impairment has
worn off (see paragraph 3.5 above).
4.10 A single dose
of cannabis for an inexperienced user, or an overdose for
an habitual user, can sometimes induce a variety of intensely
unpleasant psychic effects including anxiety, panic, paranoia
and feelings of impending doom (BMA p 9, RCPsych p 282).
These adverse reactions are sometimes referred to as a "whitey"
as the subject may become unusually pallid (Montgomery Q 577).
These effects usually persist for only a few hours.
4.11 In some instances
cannabis use may lead to a longer-lasting toxic psychosis involving
delusions and hallucinations that can be misdiagnosed as schizophrenic
illness (Strang Q 239, van der Laan Q 512). This is transient
and clears up within a few days on termination of drug use; but
the habitual user risks developing a more persistent psychosis,
and potentially serious consequences (such as action under the
Mental Health Acts and complications resulting from the administration
of powerful neuroleptic drugs) may follow if an erroneous diagnosis
of schizophrenia is made. It is also well established that cannabis
can exacerbate the symptoms of those already suffering from schizophrenic
illness (Q 239) and may worsen the course of the illness;
but there is little evidence that cannabis use can precipitate
schizophrenia or other mental illness in those not already predisposed
to it (RCPsych p 283).
4.12 These relatively
rare adverse psychological effects of cannabis are not considered
to represent a serious limitation on the potential medical use
of the drug (Strang Q 244), save that patients suffering
from schizophrenic illness or other psychoses should be excluded.
However they do constitute an issue for public health. According
to the Department of Health, cannabis contributes to the extra
cost of acute psychiatric services imposed by drug misuse, though
this cannot be separately costed (p 46; cp RCPsych p 282).
The Royal College of Psychiatrists (p 284) believe that the
proportion of users who experience acute adverse mental effects
is "significant".
Chronic
(long-term) toxicity
4.13 Cannabis can have
untoward long-term effects on cognitive performance, i.e. the
performance of the brain, particularly in heavy users. These have
been reviewed for us by the Royal College of Psychiatrists and
the Royal Society. While users may show little or no impairment
in simple tests of short-term memory, they show significant impairments
in tasks that require more complex manipulation of learned material
(so-called "executive" brain functions) (Edwards Q 21).
There is some evidence that some impairment in complex cognitive
function may persist even after cannabis use is discontinued[10];
but such residual deficits if present are small, and their presence
controversial (van Amsterdam Q 494, Hall Q 741). Dr Jan
van Amsterdam of the Netherlands National Institute of Public
Health and the Environment, who has reviewed the literature on
long-term cognitive effects of prolonged heavy use and kindly
came to Westminster to tell us his findings, pointed out the practical
difficulties of assessing possible residual effects (Q 487). These
include the impossibility of obtaining predrug baseline
values (i.e. measures of the cognitive functioning of the subject
before their first use of cannabis), the difficulty of estimating
the drug dose taken, the need for a lengthy "washout"
period after termination of use to allow for the slow elimination
of residual cannabis from the body, and the possibility of confusing
long-term deficits with withdrawal effects. He felt that many
of the published reports on this subject had not taken adequate
account of these problems.
4.14 The occurrence
of an "amotivational syndrome" in long-term heavy cannabis
users, with loss of energy and the will to work, has been postulated.
However it is now generally discounted (van Amsterdam Q 503);
it is thought to represent nothing more than ongoing intoxication
in frequent users of the drug (RCPsych p 283).
4.15 Animal experiments
have shown that cannabinoids cause alterations in both male and
female sexual hormones; but there is no evidence that cannabis
adversely affects human fertility, or that it causes chromosomal
or genetic damage (WHO report ch.7). The consumption of cannabis
by pregnant women may, however, lead to significantly shorter
gestation and lower birth-weight babies in mothers smoking cannabis
six or more times a week (WHO report ch.8; DH p 47). These
effects may be due to the inhalation of carbon monoxide in cannabis
smoke, which lowers the ability of the blood to carry oxygen to
the foetus, rather to any direct effect of cannabinoids. If so,
they are comparable with the effects of smoking tobacco.
4.16 The NHS National
Teratology [i.e. foetal abnormality] Information Service advise,
"There are a few case reports of malformations following
marijuana use in pregnancy. However, there is no conclusive evidence
to suggest either an increase in the overall malformation rate
or any specific pattern of malformations". Nevertheless,
they warn: "We would not recommend the legalisation of cannabis
because of the potential fetotoxicity that may occur if it is
used in pregnancy" (p 280).
4.17 Most of our witnesses
regard the consequences of smoking cannabis as the most important
long-term risk associated with cannabis use[11].
Cannabis smoke contains all of the toxic chemicals present in
tobacco smoke (apart from nicotine), with greater concentrations
of carcinogenic benzanthracenes and benzpyrenes It has been estimated
(BMA p 11) that smoking a cannabis cigarette (containing
only herbal cannabis) results in approximately a fivefold
greater increase in carboxyhaemoglobin concentration[12],
a threefold greater increase in the amount of tar inhaled,
and a retention in the respiratory tract of one third more tar,
than smoking a tobacco cigarette. Cannabis resin, the most commonly
used form of cannabis in the United Kingdom, is often smoked mixed
with tobacco, thus adding the well-documented risks of exposure
to tobacco smoke, while complicating the picture for the researcher.
4.18 Regular cannabis
smokers suffer from an increased incidence of respiratory disorders,
including cough, bronchitis and asthma. Microscopic examination
of the cells lining the airways of cannabis smokers has revealed
the presence of an inflammatory response and some evidence for
what may be pre-cancerous changes. There is as yet no epidemiological
evidence for an increased risk of lung cancer (DH p 46, Q 205);
but, by analogy with tobacco smoking, such a link may take 25-30 years
or more before it becomes evident, and the widespread use of smoked
cannabis in Western societies dates only from the 1970s. There
are some reports of an increased incidence of cancers of the mouth
and throat in young cannabis users[13],
but so far these involve only small numbers and no cause and effect
relationship has been established. Nevertheless, Professor Hall
considers it a "pretty reasonable bet" that heavy users
incur a risk of cancer (Q 741); and the risk is considered by
some of our witnesses to be sufficiently serious to rule out any
approval of long-term medical use of smoked cannabis, and to justify
the present prohibition on recreational use.
Tolerance
to cannabis
4.19 Tolerance is the
phenomenon whereby a regular user of a drug requires more each
time to achieve the same effect. It is not an adverse effect in
itself; but it may make medical use more difficult, and recreational
use more damaging as the user's demand for the drug increases.
4.20 Dr Pertwee
told us that both animal and human data show that tolerance can
develop on repeated administration of high doses of cannabinoids;
tolerance may develop more readily to some effects in animals
(e.g. lowering of body temperature) than to others (Q 304). However
Clare Hodges[14],
a sufferer from MS, said that she had not experienced tolerance
to the palliative effects of low doses of cannabis, and had been
taking the same dose (9g of herbal cannabis per week, costing
about £30 per week, usually smoked) for six years; neither
had other medical users reported tolerance in their experience
(QQ 117-119; cp LMMSG p 269).
4.21 Whether tolerance
develops may therefore depend on how much drug is consumed, and
how often. Neil Montgomery, a research journalist currently
studying cannabis users through the Department of Social Anthropology
at the University of Edinburgh, said that his observations of
heavy cannabis users (using more than 28g of cannabis resin per
week) suggested that they needed as much as eight times higher
doses to achieve the same psychoactive effects as regular users
consuming smaller doses of the drug (Q 570). Clear evidence
of tolerance has also been reported in volunteers given large
doses of THC under laboratory conditions (Pertwee Q 304).
4.22 This conforms
with the evidence of Professor Wall, who compared the experience
with morphine and related opiate pain-relieving agents during
the past 20-30 years, pioneered by Dame Cicely Saunders and
the Hospice movement. This has shown that tolerance (and addiction—see
below) are not major problems in the medical use of these drugs,
although in recreational use they may pose severe problems (Q 120).
Dependence
on cannabis
4.23 The repeated use
of cannabis or cannabinoids does not result in severe physical
withdrawal symptoms when the drug is withdrawn; so many have argued
that these drugs are not capable of inducing dependence. Dr Pertwee,
and Dr David Kendall of the University of Nottingham (p 267),
however, described new evidence from animal studies showing marked
signs of withdrawal in animals treated repeatedly with large doses
of cannabinoids and then challenged with a newly developed cannabinoid
CB1 receptor antagonist (see Box 1) called SR141716A. This has
provided the first real evidence for physical dependence and withdrawal
symptoms in animals (QQ 308-310).
4.24 The BMA report
says that withdrawal symptoms from cannabis in man are mild and
shortlived; but in the light of the newer definitions of
dependence noted in Box 2 this evidence is inconclusive. Professor
Ashton indicated that she felt cannabis to be potentially addictive,
and compared the withdrawal symptoms—tremor, restlessness
and insomnia—to those experienced by users of alcohol, sleeping
pills or tranquillisers. She had talked to students with quite
severe cannabis withdrawal problems (Q 73).
| BOX 2: DEFINITIONS OF DEPENDENCE
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| The consumption of any psychoactive drug, legal or illegal, can be thought of as comprising three stages: use, abuse, and addiction. Each stage is marked by higher levels of drug use and increasingly serious consequences.
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| Abuse and addiction have been defined and redefined by various organisations over the years. The most influential current system of diagnosis is that published by the American Psychiatric Association (DSM-IV, 1994). This uses the term substance dependence instead of addiction, and defines this as a cluster of symptoms indicating that the individual continues to use the substance despite significant substance-related problems. The symptoms may include tolerance (the need to take larger and larger doses of the substance to achieve the desired effect), and physical dependence (an altered physical state induced by the substance which produces physical withdrawal symptoms, such as nausea, vomiting, seizures and headache, when substance use is terminated); but neither of these is necessary or sufficient for the diagnosis of substance dependence. Using DSM-IV, dependence can be defined in some instances entirely in terms of psychological dependence; this differs from earlier thinking on these concepts, which tended to equate addiction with physical dependence.
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| The DSM-IV system also defines substance abuse as a less severe diagnosis, involving a pattern of repeated drug use with adverse consequences but falling short of the criteria for substance dependence.
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4.25 Professor Griffith
Edwards, a member of the Advisory Council on the Misuse of Drugs[15]
(Q 27), said that, using internationally agreed criteria
(DSM-IV—see Box 2), there seemed no doubt that some
regular cannabis users become dependent, and that they suffer
withdrawal symptoms on terminating drug use. According to the
WHO report, cannabis dependence is characterised by a loss of
control over drug use, cognitive and motivational impairments
that interfere with work performance, lowered self-esteem and
often depression. Professor Hall wrote, "By popular
repute, cannabis is not a drug of dependence because it does not
have a clearly defined withdrawal syndrome. There is, however,
little doubt that some users who want to stop or cut down their
cannabis use find it very difficult to do so, and continue to
use cannabis despite the adverse effects that it has on their
lives." In oral evidence he added that users who sought treatment
for cannabis dependence had typically taken large amounts of cannabis
every day for perhaps 15 years or more (Q 745).
4.26 The Institute
for the Study of Drug Dependence likewise conclude that, while
physical dependence is rare, "Regular users can come to feel
a psychological need for the drug or may rely on it as a "social
lubricant": it is not unknown for people to use cannabis
so frequently that they are almost constantly under the influence"
(p 263).
4.27 One measure of
the significance of cannabis dependence is the proportion of users
who become dependent. Since cannabis dependence is poorly defined,
and the total number of users is unknown, this figure is elusive.
Data from a recent study of 200 regular users in Australia[16]
suggest that more than 50 per cent of such users may be classified
as dependent, although many of these do not consider themselves
as dependent. This corresponds with the finding of an American
study of 1991, cited by the WHO report, that "about half
of those who use cannabis daily will become dependent". According
to Professor Hall, "Epidemiological studies suggest that
cannabis dependence in the sense of impaired control over use
is the most common form of drug dependence after tobacco and alcohol,
affecting as many as one in ten of those who ever use the drug"
(p 221).
4.28 Neil Montgomery
estimates that approximately 5 per cent of regular cannabis
users are heavy users, consuming as much as 28g of cannabis resin
per week. "These are people who have become dependent on
cannabis; they are psychologically addicted to the almost constant
consumption of cannabis...Becoming stoned and remaining stoned
throughout the day is their prime directive" (Q 554).
4.29 Another measure
of the extent of cannabis dependence is the number of people who
seek treatment for it. Department of Health figures (1996) show
that in 6 per cent of all contacts with regional drug clinics
cannabis was the main drug of misuse (Q 27). A similar figure,
that cannabis users constitute 7 per cent of all new admissions
to drug treatment centres in Australia, was reported recently.
Dr Philip Robson[17],
who runs a Regional Drug Dependence Unit in Oxford, said that
4.9 per cent of those admitted to his unit cited cannabis
as their main drug (Q 462). However he did not regard cannabis
as an important drug of addiction: "The drug falls well below
the threshold of what would be expected for a dependencyproducing
drug which has clinical significance...I do not meet people who
are prepared to knock over old ladies in the street or burglarise
houses or commit other crimes to obtain cannabis". Professor
Robbins estimated that at least 2 per cent of regular cannabis
users (whom he defined as those using cannabis more than once
a week) in the USA are dependent, on the basis of an estimate
of 5m users and an official figure of 100,000 on specific treatment
for cannabis dependency syndrome (Q 623).
4.30 It has been suggested
that US figures may be inflated by people on compulsory treatment,
for instance after testing positive at work, who may not in fact
be dependent. According to Professor Hall, however, "In Australia
... drug testing is uncommon and there is no cannabis treatment
industry. Yet treatment services...have seen an increase in the
number of persons seeking help for cannabis" (p 221).
He even suggests that the figures may be kept down by the widespread
belief that it is not possible to be dependent on cannabis (Q
748).
4.31 Giving up cannabis
is widely believed to be relatively easy: according to the Department
of Health, "studies report that of those who had ever been
daily users only 15 per cent persisted with daily use in
their late twenties" (p 45). Most epidemiological studies
in Britain and the United States have shown that the illicit use
of cannabis mainly involves people in their late teens and twenties,
with relatively few users over the age of 30.
4.32 It has been assumed
that young cannabis users give up the habit when they enter their
thirties; IDMU (p 236), however, suggest that this pattern
may be changing. The British Crime Survey (1996) shows that although
the prevalence of cannabis use falls after the age of 30, the
greatest proportional increases in the period 1991-1996 were in
older age groups, with incidence of past use doubling in the 40-44
age group (from 15 per cent to 30 per cent) and trebling in the
45-59 age group (from 3 per cent to 10 per cent). IDMU conclude
that the current relatively low levels of cannabis use in the
over-30 age group may reflect a generational and cultural divide,
rather than substantial numbers of users giving up.
4.33 It is therefore
clear that cannabis causes psychological dependence in some users,
and may cause physical dependence in a few. The Department of
Health sum up the position thus (p 45, cp Edwards Q 28):
"Cannabis is a weakly addictive drug but does induce dependence
in a significant minority of regular cannabis users."
9 Including Hall W, Room R and Bondy S, A comparison
of the health effects of alcohol, cannabis, tobacco and opiates,
in Kallant H, Corrigal W, Hall W and Smart R eds The Health
Effects of Cannabis, Addiction Research Foundation, Toronto,
1998; and articles awaiting publication in Addiction (Respiratory
risks of cannabis smoking, 1998, 93, 1461), Drug and Alcohol
Review, and the Lancet Seminar series (14 November
1998). Back
10
N Solowij, Cannabis and Cognitive Functioning, Cambridge
University Press, 1998. Back
11
See in particular DH p 46; papers kindly supplied by Professor
Donald Tashkin, University of California Los Angeles School of
Medicine, and Professor Hall; and Appendix 3, paragraph 8. Back
12
Carboxy-haemoglobin is formed by the action of carbon monoxide
on haemoglobin in the blood. It interferes with the transport
of oxygen around the body. Back
13
E.g. Taylor FM III, Marijuana as a potential respiratory carcinogen:
a retrospective analysis of a community hospital population,
South. Med. J. 1988, 81, 1213. Back
14
Miss Hodges is the founder-Director of the UK Alliance for Cannabis
Therapeutics (ACT). "Clare Hodges" is a nom de guerre. Back
15
Professor Edwards is Professor Emeritus of Addiction Behaviour
at the Institute of Psychiatry, University of London; past Chairman
of the National Addiction Centre; and editor-in-chief of the journal
Addiction. The ACMD is established under the Misuse of
Drugs Act 1971, to advise the Government. Back
16
By Dr Wendy Swift, Australian National Drug and Alcohol Research
Centre. Back
17
Consultant psychiatrist, Warneford Hospital; senior clinical lecturer,
University of Oxford; author of one of the reviews for the Department
of Health referred to in paragraph 1.4. Back
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