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 |
|
| 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.
|
|
| 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). |
|
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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