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

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.

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.

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.

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).

10 N Solowij, Cannabis and Cognitive Functioning, Cambridge University
Press, 1998.

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.

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.

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.

14 Miss Hodges is the founder-Director of the UK Alliance for Cannabis
Therapeutics (ACT). "Clare Hodges" is a nom de guerre.

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.

16 By Dr Wendy Swift, Australian National Drug and Alcohol Research Centre.

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.

Checked-by: Richard Lake