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. 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.
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 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".
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. 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