There are, in the main, two principal methods of biological research into the problem of causation of schizophrenia. In the first, or direct method, studies are made of the body fluids and of the metabolism of schizophrenics in the hope of turning up some toxic factor or error of metabolism. Such studies are currently under way in a number of centres and, although many claims as to positive findings have been made, none of these has as yet been substantiated and the majority have actually been refuted by subsequent analysis. These studies have been directed by two main hypotheses of the causation of the illness described in a previous communication (14). Now it is clear that one great difficulty entailed in using this approach is that our basic knowledge of neuro-chemistry and neuropharmacology is still extremely limited. The very complexity of the neurochemical processes of the brain would seem to offer a large number of possible loci of metabolic disturbance, any of which might be responsible for the onset of schizophrenia. Thus, we can say that the probable results of all such investigations at present will be purely negative, i.e. we will discover that the given metabolism of injected adrenaline, serotonin, etc., is normal in the illness. Thus, the second, or indirect, method becomes increasingly important. This consists of two parts. The first is implied merely by the general statement that the advance of neurochemistry and neuropharmacology may disclose other areas of function in which specific hypotheses of the causation of the illness may be constructed. The second consists of a detailed study of the precise mode of action of known psychotomimetic agents. Knowledge of the mode of action of mescaline and LSD-25 in detail would pinpoint areas for research in the metabolism of schizophrenics. Unfortunately, however, very little seems to be known at present of the mode of action of these drugs. Most of the work that has been done has been carried out on LSD-25 (see e.g. the annotated bibliography put out by Sandoz Inc., Hanover, New Jersey, 1958). However, the important field of the structure-activity relationships (SAR) of mescaline seems to have been strangely neglected. The research programme here would include the synthesis of a number of analogues of mescaline according to systematic principles to determine the role the details of its molecular structure play in the mode of action. These analogues would be subjected to a number of tests—psychopharmacological, neurophysiological and neurochemical—comparison between the results of which would give important information not only of the SAR of mescaline but also of the details of its mode of action and the interrelationships between behavioural, neurophysiological and neurochemical factors involved that would help us explain the former effects in terms of the latter, which reduction is the main aim of biological science. The present paper reviews the little that is known at present about the SAR of mescaline and then reports some new studies in the psychopharmacology of this field.
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