Cannabis and the cannabinoids

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The hemp plant, Cannabis sativa, has been known for its commercial use as a source of hemp for the manufacture of rope, sacking and so on for well over 2000 years. The hemp seeds have also been used as a source of oil, as an animal feed and as a form of soap, while the leaves were first used in China because of the psychoactive ingredients they contained. From China, the use of hemp spread first to India and then to Europe via the Middle East in the 16th century.

All parts of the hemp plant contain psychoactive substances; some 60 active ingredients, the cannabinoids, have been isolated from the plant to date. In addition, over 300 non-cannabinoid compounds have been identified which do not appear to contribute to the psychoactive properties of the plant. The highest cannabinoid concentrations are found in the flowering heads.

There are three main types of cannabis preparation in use. Herbal cannabis, known variously as ''grass'', ''pot'', ''joint'' or ''marijuana'', is prepared by collecting the flowering heads or the upper leaves of the plant, allowing them to dry, and then removing the stems and stalks by rubbing the dried material. The resultant material is then rolled into cigarettes, or placed in a pipe, and smoked. The cannabinoid content of herbal cannabis varies according to the climate and growing conditions, but it comprises up to 8% cannabinoids.

Cannabis resin, an exudate secreted from the hairs on the leaves of the plant, is also collected from the upper leaves, and comprises up to 14% cannabinoids. The resinous material is powdered and usually compressed into a hard, brownish mass, which darkens in the air as a result of oxidation. This form of the drug is known as ''hash'', ''resin'' or ''charas''.

The purest form of the drug produced for illicit use is cannabis oil. This is prepared by solvent extraction of the resin followed by further purification to produce an oil that comprises up to 60% cannabinoids. Cannabis oil is generally added in small quantities to tobacco and smoked.

Cannabis in its various forms is still the most commonly used illicit drug in most countries. In the US, more than 50% of young adults report the use of this drug on some occasion, but it would appear that its casual use has declined among young people in that country from 37% in 1978 to about 18% 10 years later. Despite statements from the advocates for its decriminalization, there is evidence that the smoke from the dried leaves contains potential carcinogens, together with carbon monoxide, and is therefore liable to affect the respiratory and cardiovascular systems adversely, in a similar manner to tobacco.

The main active ingredients of cannabis are cannabinol, cannabidiol and several isomers of tetrahydrocannabinol, of which delta-9-tetrahydro-cannabinol (THC) is probably responsible for most of the psychoactive effects of the various preparations. It is of interest to note that THC does not contain nitrogen in its three-membered ring system. The structure of THC is shown in Figure 15.8.

Tetrahydrocannabinol and related compounds are very lipophilic and therefore readily absorbed from the lung and gastrointestinal tract. The bioavailability of oral THC varies from 4% to 12%, depending on the way in which it is delivered, whereas the availability of THC when smoked can be

Figure 15.8. Structure of tetrahydrocannabinol (delta-9-THC), the main psychoactive ingredient of the cannabis plant.

as high as 50%. Under optimal conditions, this could mean that a cigarette containing 1g could lead to the delivery of up to 10 mg of THC to the circulation. The plasma concentration peaks after about 10 minutes, and the psychoactive effects reach a maximum after 20-30 minutes and last for about 2-3 hours. The time of peak effect and the duration of the pharmacological response is slower after oral administration.

Tetrahydrocannabinol is metabolized in the liver to form active metabolites which are further metabolized to inactive polar compounds; these are excreted in the urine. Some metabolites are excreted into the bile and then recycled via the enterohepatic circulation. Because of their high lipophilicity, most active metabolites are widely distributed in fat deposits and the brain, from which sources they are only slowly eliminated. The half-life of elimination for many of the active metabolites has been calculated to be approximately 30 hours. Accordingly, accumulation occurs with regular, chronic dosing. Traces of the cannabinoids can be detected in the blood and urine of users for many days after the last administration. There is some evidence of metabolic tolerance occurring after chronic use of the drug. THC and related cannabinoids readily penetrate the placental barrier and may possibly detrimentally affect foetal development.

Mechanisms of action

The high lipophilicity of THC and related compounds implies that these drugs are widely distributed throughout the brain, particularly in the grey matter; they appear to be taken up into neurons rather than the glia.

Understanding the pharmacological properties of the cannabinoids has been greatly increased by the recent discovery and cloning of specific cannabinoid receptors in the mammalian brain, spleen and macrophages. In addition, possible endogenous candidates which act on these receptors have also been identified. In the brain, the cannabinoids act on the CB1 type of receptor. These are distributed in regions of the brain concerned with motor activity and postural control, such as the basal ganglia and cerebellum, with emotion (for example the amygdala and hippocampus), sensory perception

(thalamus) and autonomic and endocrine functions (hypothalamus, pons and medulla). The distribution of the CB1 receptors in the brain is similar to the distribution of tetrahydrocannabinol and other cannabinoids so it is not unreasonable to assume that they exert their pharmacological effects by activating the CB1 receptors. A second type of cannabinoid receptor, the CB2 receptor, has been detected on the surface of immune cells in the spleen and probably mediates the immunological effects of these drugs. Both types of receptor are present in peripheral tissues.

The first endogenous substance which was shown to interact with cannabinoid receptors was anandamide (from the Sanskrit word for bliss, ananda). This is a derivative of the polyunsaturated fatty acid arachidonic acid, namely arachidonyl ethanolamide. It appears that several other endogenous ligands also exist which include 2-arachidonylglycol. Stimulation of neurotransmitter receptors appears to play a determinant role in initiating the synthesis of these ligands. Thus it has been shown that anandamide release in the striatum is strongly enhanced by activation of dopamine D2 receptors. Once released, anandamide activates CB1 or 2 receptors or is accumulated in the adjacent cells by an energy and sodium-dependent transport mechanism. Thus anandamide and 2-arachidonylglycerol can be released from neuronal and non-neuronal cells when the need arises, utilizing distinct receptor-mediated pathways from those used by conventional neurotransmitters. The non-synaptic release mechanisms and short half-lives of these endogenous cannabinoids suggests that they act near the sites of their synthesis to regulate the effects of primary neurotransmitters and hormones. A major implication of the discovery of the cannabinoid receptors is that it should be possible to develop selective cannabinoid agonists and antagonists for use either as therapeutic agents or as tools to unravel the precise physiological function of the cannabinoid system.

As the endogenous cannabinoids might serve important regulatory functions, it is not unreasonable to assume that they may have important therapeutic applications. The following account summarizes such possibilities.

Modulation of pain. Cannabinoids strongly reduce pain responses by interacting with CB1 receptors in the brain, spinal cord and peripheral sensory neurons. In the case of neuropathic pain, these drugs have been shown to be potent inhibitors of allodynia (pain from non-noxious stimuli) and hyperalgesia (increased sensitivity to noxious stimuli). In a rat model of neuropathic pain, the CB1 receptor agonist WIN 552122 has been shown to attenuate such responses at doses that do not cause overt side effects. These beneficial effects were antagonized by the CB1 antagonist SR 141716A. In addition, CB1 receptor agonists have been shown to alleviate peripherally mediated pain, possibly by affecting the gating mechanism by enhancing the opioid peptides. The clinical impact of these advances is still modest but the development of novel cannabinoid receptor agonists may lead to the discovery of novel drugs to treat these often intractable conditions.

Neuroprotection. CB1 receptor agonists inhibit both glutamatergic transmission and long-term potentiation which suggests that the endogenous cannabinoids may play an important role in the regulation of excitatory transmission. In cultures of rat hippocampal neurons, the stimulation of glutamate release causes neuronal death. CB1 receptor agonists prevent this response but do not protect the neurons against the effects of exogenous glutamate. Similar protective effects of CB1 agonists have been shown to occur in in vivo models of cerebral ischaemia, these effects being blocked by CB1 receptor antagonists. Thus it seems possible that cannabinoids may be of potential value as neuroprotective agents.

Dopamine transmission, movement disorders and psychosis. CB1 receptors are densely expressed in the basal ganglia and cortex, a distribution which provides an anatomical substrate for the functional interaction between the cannabinoid system and ascending dopaminergic pathways. There is experimental evidence to show that anandamide modulates the dopamine-induced facilitation of psychomotor activity. In support of this hypothesis, ''knock-out'' mice lacking the CB1 receptor show a profound decrease in locomotor activity. The therapeutic implications of this discovery have been shown by the discovery that CB1 receptor agonists alleviate the spasticity in various conditions, and tics in Tourette's syndrome. With regard to psychosis, there is consensus that heavy cannabis abuse can precipitate psychotic episodes in those with an underlying schizophrenic condition. It is possible that CB1 antagonists may therefore be of some therapeutic value in the treatment of psychotic disorders. CB1 agonists such as tetrahy-drocannabinol have however been shown to inhibit amphetamine-induced stereotypy, a drug used in rodent models of psychosis. However, it has been shown that the chronic administration of cannabinoids causes an increase in the stimulant effects of amphetamine which suggests that CB1 receptor desensitization can exacerbate psychosis. Thus there is a need to investigate a wide variety of drugs which modulate the cannabinoid system.

In CONCLUSION, it would be surprising if the cannabinoid system which appears to serve such an important function in the brain and peripheral system, did not facilitate the development of novel drugs in the near future.

Tolerance and dependence

Regular use of cannabis can lead to an intake of THC which would be toxic to the naive user. This suggests that tolerance develops. While there is some evidence that metabolic tolerance may arise, it would appear that tissue tolerance is the most likely explanation for the effects observed. Tolerance develops to the drug-induced changes in mood, tachycardia, hyperthermia and decrease in intraocular pressure. Tolerance also develops to the effects of THC on psychomotor performance and changes on electroencephalography.

Cross-tolerance occurs between THC and alcohol, at least in animal studies, but this does not appear to occur between the cannabinoids and the psychotomimetics.

The abrupt withdrawal of very high doses of THC from volunteers has been associated with some withdrawal effects (irritability, insomnia, weight loss, tremor, changed sleep profile, anorexia), suggesting that both physical and psychological dependence may occasionally arise.

Pharmacological effects

Smoking a cigarette comprising 2% THC causes changes in memory, motor coordination, cognition and sense of time, all of which are adversely affected. There is an enhanced sense of well-being and euphoria, accompanied by a feeling of relaxation and sleepiness. The intensity of these effects depends to some extent upon the environment in which the drug is taken. The effect upon short-term memory and the impairment of the ability to undertake memory-dependent, goal-directed behaviour is called temporal disintegration. This process is correlated with a tendency to confuse the past, present and future, and to feel depersonalized. Such effects may last for several hours and may be intensified should the subject also consume alcohol.

Higher doses of THC are associated with hallucinations, delusions and paranoid ideas; the sense of depersonalization also becomes more intense. The possibility that high doses of THC can trigger a schizophrenic episode in predisposed people is well recognized. ''Flashbacks'' have been reported in those who have been exposed to high doses of the drug.

Chronic cannabis users frequently exhibit the ''amotivational syndrome'', characterized by apathy, impaired judgement, memory defects and loss of interest in normal social pursuits. Whether chronic cannabis abuse leads to more permanent changes in brain function is uncertain, but it is known that chronic administration to animals results in permanent damage to the hippocampus. Regular use of cannabis by adolescents frequently predisposes them to other types of drug abuse later. This may reflect the social pressures placed upon them rather than the pharmacological consequences of abusing cannabis.

The most consistent effects of THC upon the cardiovascular system are tachycardia, increased systolic blood pressure and a reddening of the conjunctivae. As myocardial oxygen demand is increased, the chances of angina are enhanced in those who may be predisposed to this condition.

Pulmonary function is impaired in chronic cannabis smokers, despite the clear evidence that the acute use of the drug results in a significant and long-lasting bronchodilatation. However, it should be noted that the tar produced by cannabis cigarettes is more carcinogenic than that obtained from normal cigarettes, so that the risks of lung cancer and heart disease are increased in chronic cannabis smokers.

There are conflicting reports on the effects of chronic high doses of THC on human sexual function, but there is some evidence that spermatogenesis and testosterone levels are decreased. In women, a single cannabis cigarette can suppress release of luteinizing hormone, so that lack of ovulation frequently occurs in women who abuse this drug. Lowered birth weight and increased chances of malformations have also been reported in the offspring of women who abuse THC during pregnancy. It is also possible that in utero exposure to this drug causes behavioural abnormalities in childhood.

There are two features of the cannabinoids which may ultimately be of therapeutic importance. THC lowers intraocular pressure, which may be of benefit in the treatment of glaucoma. There is also evidence that THC is a moderately effective antiemetic agent. Such a discovery has led to the development of nabilone, a synthetic cannabinoid, as an antiemetic agent, but its use is limited because of the dysphoria, depersonalization, memory disturbance and other effects which are associated with the cannabinoids. Whether the bronchodilator action of THC will ever find therapeutic application in the treatment of asthma remains an open question.

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