CHAPTER 3 PHARMACOLOGY OF
CANNABIS AND THE CANNABINOIDS
3.1 The plant Cannabis
sativa is also known as hemp; it is related to the nettle
and the hop. It grows readily in a warm climate, and may be grown
in more temperate regions. As a drug of abuse, it usually takes
the form of herbal cannabis (marijuana), consisting of the dried
leaves and female flower heads, or cannabis resin (hashish), the
resin secreted by the leaves and flower heads, which may be compressed
into blocks.
3.2 The family of chemically
related 21carbon alkaloids found uniquely in the cannabis
plant are known as cannabinoids. There are more than 60 different
cannabinoids; one of these, D9tetrahydrocannabinol
(THC), is the most abundant and accounts for the intoxicating
properties of cannabis. Other cannabinoids which occur in some
abundance (e.g. cannabidiol and cannabinol) are not psychoactive,
but it is thought that they may modify the effects of THC. The
amounts and proportions of the various cannabinoids in each plant
vary from strain to strain, and can be adjusted by breeding. By
coincidence, the chemistry and pharmacology of cannabis were among
the principal interests of the late Lord Todd, when he worked
at Manchester University in the 1930s; he went on to become, among
other things, the first Chairman of the House of Lords Select
Committee on Science and Technology on its establishment in 1979.
3.3 THC and other cannabinoids
dissolve readily in fat but not in water. This limits the possible
formulations of cannabis and cannabinoid preparations, and slows
down their absorption from the gut. On the other hand, when cannabis
is smoked (in a "joint" or "reefer", or in
a pipe), THC is absorbed very quickly into the bloodstream, through
the large surface area of the pharynx and the lungs. After smoking,
the psychoactive effects of THC are perceptible within seconds,
and peak effects are achieved within minutes. When cannabis or
cannabinoids are taken by mouth, peak effects may not occur for
several hours, but they last longer. After smoking or oral ingestion,
the drug persists in the brain longer than in the blood; so the
psychological effects persist for some time after the level of
THC in the blood has begun to decline.
3.4 Smoking delivers
30 per cent or more of the total THC in a cannabis cigarette to
the blood stream. The proportion of THC absorbed after taking
cannabis by mouth is 2-3 times less, because after absorption
in the gut the drug is largely degraded by metabolism in the liver
before it reaches the general circulation. Preliminary reports
indicate that absorption into the circulation can be increased
if THC is administered by rectal suppository, as this route delivers
the drug directly into the circulation, avoiding the liver.
3.5 Once THC has entered
the bloodstream, it is widely distributed in the body, especially
in fatty tissues. The slow release of THC from these tissues produces
low levels of drug in the blood for several days after a single
dose, but there is little evidence that any significant pharmacological
effects persist for more than 4-6 hours after smoking or 6-8 after
oral ingestion. The persistence of the drug in the body, and the
continuous excretion of degradation products in the urine, can
however give rise to cannabispositive forensic tests days
or even weeks after the most recent dose. (The implications of
this for roadside testing of drivers are considered below, at
paragraph 4.9.)
3.6 According to Professor
Trevor Robbins, speaking for the Medical Research Council (MRC),
"Cannabinoid pharmacology has exploded in the last decade¼,
opening up¼all
sorts of exciting possibilities" (Q 628). These advances
are reviewed in evidence to this Committee by the Royal Society
and by Dr Roger Pertwee of the University of Aberdeen[5].
It is now recognised that THC interacts with a naturally occurring
system in the body, known as the cannabinoid system. THC takes
effect by acting upon cannabinoid receptors (see Box 1). Two types
of cannabinoid receptor have been identified: the CB1 receptor
and the CB2 receptor. CB1 receptors are present on nerve cells
in the brain and spinal cord as well as in some peripheral tissues
(i.e. tissues outside the brain); CB2 receptors are found mainly
on cells of the immune system and are not present in the brain.
3.7 The roles played
by CB1 and CB2 receptors in determining the various effects of
cannabis in the whole organism remain to be established. Among
the effects of cannabinoids known from animal experiments to be
mediated by CB1 receptors are pain relief, impairments in memory
and in the control of movements, lowering of body temperature
and reductions in the activity of the gut. As CB1 receptors are
the only ones known to exist in the brain, it is assumed that
they mediate the intoxicant effects of THC. Little is known about
the physiological role of the more recently discovered CB2 receptor,
but it seems to be involved in the modulation of the function
of the immune system.
| BOX 1: CANNABIS PHARMACOLOGY—TERMINOLOGY
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| In common with many other drugs, the effects of THC result from its ability to activate special proteins known as receptors found on the surface of certain cells. The drug binds specifically to these proteins and activates a series of processes within the cells, leading to alterations in the cell's activity. Drugs, such as THC, that are able to "switch on" a receptor are known as agonists at that receptor. Other substances, however, bind to the receptor and, rather than activating it, prevent its activation by agonists; such substances are known as receptor antagonists.
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| The term cannabinoid was originally used to describe the family of naturally occurring chemicals found in cannabis, of which THC is the principal member. It is now also taken to encompass all those substances capable of activating cannabinoid receptors. These include the naturally occurring plant cannabinoids, certain synthetic substances (e.g. nabilone—see Box 4 below), and the recently discovered endogenous cannabinoids (see paragraph 3.8 below).
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3.8 Another important
recent discovery has been that the body contains naturally occurring
("endogenous") compounds that can activate cannabinoid
receptors. The most important of these "endogenous cannabinoids"
are the fatlike materials arichidonylethanolamide ("anandamide")
and 2arichidonylglycerol (2AG).
3.9 These discoveries
have transformed the character of scientific research on cannabis,
from an attempt to understand the mode of action of a psychoactive
drug to the investigation of a hitherto unrecognised physiological
control system in the brain and other organs. Although the physiological
significance of this system is still largely unknown, one of the
principal actions of THC and the endogenous cannabinoids seems
to be to regulate the amounts of chemical messenger substances
released from nerves in the brain, thus modulating neural activity.
3.10 The discovery
of the endogenous cannabinoid system has significant implications
for future pharmaceutical research in this area. Drugs that selectively
activate CB1 or CB2 receptors (agonists), or selectively block
one or other of these receptor types (antagonists), have already
been developed by some pharmaceutical companies (Lambert p 109
and Q 438; Pertwee Q 285). Agonists to the CB2 receptor
may have beneficial effects in modulating immune responses, and
would not be expected to possess any psychoactive properties as
the CB2 receptor is not found in the brain. Antagonists to the
CB1 receptor are also being investigated, as novel therapeutic
agents with the potential of reducing memory deficits associated
with ageing or neurological disease, as novel treatments for schizophrenia
or other psychoses, and as appetite suppressants.
3.11 It seems likely
that most of the putative medical indications proposed for cannabis
involve actions of the drug on CB1 receptors in the central nervous
system. Extensive attempts were made by academic and pharmaceutical
industry researchers during the 1970s to develop new chemically
modified cannabinoid molecules that separated the desired therapeutic
effects from the psychoactive properties of these substances;
but so far no such compound has been discovered.
3.12 Research continues
apace. Professor Patrick Wall of St Thomas' Hospital[6]
reports "intense activity in universities and pharmaceutical
companies" in this field; "Large numbers of cannabinoids
are being synthesised and investigated particularly by US companies"
(p 31); "It is an exciting period" (Q 101,
cp Q 125, Pertwee QQ 281-298 and Notcutt Q 411).
According to Dr Lambert, "The pharmaceutical industry
has now provided the researcher with a wide range of tools to
probe the cannabinoid system"[7].
3.13 Recent data from
animal studies reveal that, in common with various drugs of addiction
(heroin, cocaine, nicotine and amphetamines), THC activates the
release of the chemical messenger dopamine in some regions of
the brain of rats (Pertwee Q 311, Wall Q 126). This
is considered important as this pattern of dopamine release is
thought to be associated with the rewarding properties of these
drugs and hence may be related to their ability to cause dependence.
3.14 Other recent scientific
findings indicate a relationship between the cannabinoid system
in the brain and the naturally occurring opioid system[8].
The ability of THC to trigger dopamine release in the rat brain
is blocked by prior administration of naloxone, a drug that selectively
blocks the actions of opiates in the brain. This suggests that
some of the psychoactive effects of THC and other cannabinoids
may be mediated indirectly through an ability to activate the
opioid system (Pertwee Q 311). Recent studies have also shown
that the administration of THC to animals enhances the pain-relieving
effects of morphine and related opiates. Furthermore, administration
of naloxone (the opiate-blocker) to animals previously treated
repeatedly with a cannabinoid produced some physical withdrawal
signs; conversely, administration of a cannabinoid antagonist
to animals previously dependent on heroin elicited some (but not
all) of the signs of opiate withdrawal (see Appendix 4, paragraph
8). On the other hand, although some of the actions of THC may
involve activation of the opioid system, THC does not mimic morphine
or heroin either in its effects on animals or in the subjective
experience of human users.
3.15 This new information
may or may not be relevant to the debate as to whether cannabis
induces physical dependence. We discuss the degree to which cannabis
may induce dependence in man below, in Chapter 4.
5 Dr Pertwee is a world expert on the cannabinoids,
and current President of the International Cannabinoid Research
Society. At the University of Aberdeen, he heads a research team
of eight scientists engaged in research in this area. He was
a contributing author to the BMA report. Back
6
Professor Wall is editor-in-chief of the medical journal Pain;
he was a contributing author to the BMA report, and appeared before
us on behalf of the ACT. Back
7
Hirst R A, Lambert D G and Notcutt W G, Pharmacology and potential
therapeutic uses of cannabis. Br. J. Anaesthesia, July 1998. Back
8
The opioid system consists of receptors normally activated by
the enkephalins and endorphins, normally released in response
to pain and stress. They are also activated by morphine, heroin
and other opiates. Back
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