Hallucinogens

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Clinical effects

Many different classes of drugs can produce hallucinations when given in toxic doses (e.g. the anticholinergics, such as atropine and scopolamine), but such symptoms are generally associated with confusion and lack of sensory clarity. As such, hallucinations are a component of a toxic psychosis.

True hallucinogens, also called psychedelics or psychotomimetics, produce their effects without causing changes in the level of consciousness. Such effects are usually associated with a heightened sensory awareness but a diminished control of the incoming sensory impressions. Thus the individual frequently finds it impossible to differentiate between one sensory impression and another, thereby leading to a feeling of being ''in union with mankind or the universe'', a chemically induced equivalent of a religious experience.

The drugs usually included among the hallucinogens are of the indolealk-ylamine type (like lysergic acid diethylamide, LSD), the phenylethylamine (mescaline-like) or phenylisopropranolamine (amphetamine-like) types. Figure 15.6 gives the structures of some of the more common hallucinogens.

Another method of classification has been based on such criteria as their subjective effects, the neurophysiological changes they produce, and their ability to cause cross-tolerance with members of the same or different chemical series. This has led to the classification into:

1. LSD-like (e.g. LSD, psilocybin and psilocin).

2. Dimethoxyamphetamine (DMA), dimethoxymethylamphetamine (DOM), dimethyltryptamine (DMT) and related drugs.

3. Drugs which lack the effects of LSD but which are hallucinogenic, such as the cannabinoids (e.g. delta-9-tetrahydrocannabinol from cannabis), bufotenin and phencyclidine.

LSD was discovered accidentally by the Swiss chemist Hofmann in 1943 while he was trying to prepare oxytocin derivatives related to the ergot alkaloids. The profound visual hallucinations which LSD produced suggested that an understanding of the mechanism of action of such drugs may give some insight into the basis of psychotic disorders. Although drugs like LSD have had no lasting clinical application, they have been used illicitly for over two decades. However, while the illicit use of LSD has declined, particularly in the US, a resurgence of its use has occurred in the UK recently with the arrival of the ''acid house'' culture.

Mechanism of action

Research into the action of the hallucinogens has largely concentrated on the serotonergic system, following the seminal hypothesis of Woolley and Shaw (1954) that LSD blocked 5-HT receptors in the brain. It was subsequently found that the firing rate of dorsal raphe neurons was specifically attenuated by low doses of LSD applied systemically or micro-iontophoretically. It is now known that such drugs stimulate the presynaptic 5-HT receptors, thereby inhibiting the firing of the raphe neurons; similar effects can be produced by applying 5-HT. The net result is a decreased activity of 5-HT terminals in the forebrain. It would appear that the hallucinogens produce their effects by activating 5-HT2-

type receptors, effects which can be selectively blocked by the specific antagonist ritanserin. Most hallucinogens can also affect the activity of the locus coeruleus, again via the 5-HT2 receptors located on the noradrenergic cell bodies. These receptors are linked to the phosphatidyl inositol second messenger system, and it has been observed that drugs like LSD have an effect on this system more like a partial than a full agonist. The rapid development of tolerance to the hallucinogenic effects of LSD-like drugs has been related to the rapid desensitization of these receptors.

Pharmacological effects

Doses of 20-50 p.g LSD in the normal adult can produce pronounced effects on the brain, with negligible changes in peripheral organs. Higher doses produce such peripheral sympathomimetic effects as pupillary dilatation, tachycardia, hypertension, hyper-reflexia, tremor, nausea, piloerection and hyperthermia. With slightly higher doses, the euphoriant effects tend to predominate initially, closely followed by visual hallucinations and peripheral changes after two or three hours; auditory hallucinations are rare.

The term "synaesthesia" refers to the phenomenon whereby sensory modalities overlap, so that music is ''seen'' and colours ''heard''. This loss of sensory boundaries can be highly disturbing, and can lead to severe anxiety and even panic. At this stage, mood is often labile. After 4 or 5 hours, should the effects of a ''bad trip'' not occur, the individual may become detached in thinking and behaviour. Doses of LSD in the range 1-16 p.g/kg are associated with an accentuation of all these effects, which may last for 12 hours; the half-life of the drug is 3 hours. There is no evidence of long-term personality changes.

The pattern of effects of other hallucinogens is somewhat similar to that of LSD, but most of these drugs are less potent and often must be inhaled or injected because of their poor oral absorption. With the hallucinogenic amphetamines, such as DOM, low doses produce mild euphoria with hallucinations and enhanced self-awareness, while higher doses have LSDlike effects. These changes can be effectively blocked by selective 5-HT antagonists, suggesting that all hallucinogens act via a common serotonergic pathway.

Tolerance and dependence

Tolerance to the effects of LSD can occur after only three or four daily doses, presumably because of desensitization of the 5-HT2 receptors; the cardiovascular system shows a much slower development of tolerance.

Cross-tolerance occurs between LSD, mescaline and psilocybin, but not between this group and the amphetamine type of hallucinogens. This

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