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
decade opening up all 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.

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.

7 Hirst R A, Lambert D G and Notcutt W G, Pharmacology and potential
therapeutic uses of cannabis. Br. J. Anaesthesia, July 1998.

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.

Checked-by: Richard Lake