The pharmacology of hallucinogens.

From the foregoing there emerge a small number of reasonably well confirmed observations: (a) on the basis of similarity (though not identicality) of subjective and behavioural effects, cross-tolerance, and some structure-activity considerations, psychotomimetics form a pharmacological class of hallucinogenic materials whose common properties deserve further investigation; (b) there exist important differences in both chemical structure and in behavioral effects amongst these compounds, and there is little likelihood of finding a simple, unitary explanation of their mechanism of action; (c) a second and reasonably distinct class of hallucinogenic chemicals is formed by those anticholinergic substances which induce delirious states; (d) psychotomimetics appear to exert effects principally upon aminergic systems of the brain, whereas deliriants appear to act principally upon cholinergic systems; (e) the degree to which a molecule can assume the configuration of all or part of the structure of LSD partially predicts hallucinogenic eotency in the case of psychotomimetics, but not in the case of deliriants; (f) investigation of some submolecular properties of psychotomimetics yields the conclusion that electron donation plays an important part in drug-receptor interaction for these substances; (g) no known psychotomimetic fails to diminish 5-HT turnover in brain; (h) psychotomimetics activate the ECoG and cause behavioural alerting if and only if connections between medulla and midbrain are intact; in this respect they differ from all known non-hallucinogenic activators; (i) several psychotomimetics depress the firing rates of some raphe neurons; in the case of LSD, the mechanism appears to be 5-HT antagonism; (i) LSD antagonizes 5-HT excitations in some raphe, reticular, and cortical neurons; no antagonism of 5-HT depressions has been observed; data on other psychotomimetics in this respect is lacking; (k) LSD has non-specific depressant effects on neurons at many locations in the brain; (l) LSD increases the spontaneous firing rates of retinal ganglion cells; (m) LSD has an inhibitory effect upon transmission through the lateral geniculate nucleus, but so do several non-hallucinogenic substances. In the context of the yawning abyss of ignorance and speculation which separates biochemical and behavioural data, the contribution of these few observations on psychotomimetics may be regarded as vanishingly small. Clearly, neither the serotonin nor the sensory system hypothesis gives a full account of the effects of these drugs. A few reasonably sure facts can, however, provide empirical bases for further investigation. For example, the odd and until recently unsuspected fact that neurons in the raphe nuclei both contain 5-HT and can be excited by 5-HT applied to their membranes allows an explanation of the slowed 5-HT turnover induced by psychotomimetics in terms of the postsynaptic, anti-5-HT effects of these drugs. Since there is very good evidence that the raphe nuclei form part of an inhibitory lower brainstem system, and since separation of the lower brainstem from the midbrain abolishes the ECoG-activating effects of psychotomimetics, it is very likely that both the ECoG-activating and the 5-HT turnover effects of psychotomimetics result from lower brainstem, anti-5-HT actions. The relation of these lower brainstem actions, however, to perceptual and cognitive functions—that is, the relation between the serotonin and sensory system theories—remains hypothetical until it is shown that the lower brainstem effects have an impact upon more rostral sensory systems. There appear to be no very strong reasons for assuming that these raphe and reticular effects are sufficient in themselves for the induction of psychotic functioning, and therefore it is to be hoped that the demonstrated effects of psychotomimetics on diencephalic and telencephalic structures—for example the retina, the lateral geniculate nucleus, the cortex, the hippocampus and amygdala—will attract further investigation. An explanation of psychotomimetic action must in the end relate drug effects to events at specified neural sites. In this regard, the application of recent improvements in histochemical technique for the study of more discrete brain areas ought to be rewarding. Microelectrophoresis, which allows under some circumstances reasonably quantitative dose-response studies of the impact of a drug on the physiological functioning of single neurons, can profitably be combined in experimental design with techniques of sensory physiology; in this regard the experiments of Satinsky (188) and Tebecis (224) are models, although dose-response studies were not attempted. Also, it would be useful to have dose-response data on more global effects of psychotomimetics, for example on temperature, activity, autonomic activity, and ECoG rhythms. Finally, it must be remembered that many of the general statements on psychotomimetic drug actions rest upon data regarding a single drug, lysergic acid diethylamide, and that the hypothesis implicit in these generalizations require confirmation from experiments with the methoxylated amphetamines, indolealkylamines, and other lysergic acid derivatives before they can be admitted to the pharmacological archives.