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Shulgin AT, Sargent T, Naranjo C. 
“Structure--activity relationships of one-ring psychotomimetics”. 
Nature. 1969 Feb 07;221(5180):537-41.
INVESTIGATIONS of the aetiology of psychoses have followed the functional or the biochemical approach. The latter stems from a hypothesis advanced by Osmond and Smythies in 1952 ref. 1 that an aberration in the metabolism of catecholamines could produce an endogenous psychotogen resembling the well known psychotomimetic mescaline. Our work has stemmed directly from this. The purpose of this article is to examine the structure- activity relationships of related compounds which may reflect the metabolic processes involved in psychosis.

The idea of an endogenous psychotogen finds support in that some aspects of schizophrenia can be produced in healthy subjects by chemical means. This mimicry was initially viewed as the 'model psychosis', but subsequent studies have revealed shortcomings' and as investigational tools psychotomimetic compounds have recently fallen into disuse and even disrepute'. Many of the features characteristic of the induced intoxication are nevertheless frequently observed as symptoms of schizophrenia: distortion of time and space, synaesthesia, occasional hallucinatory experiences, delusional states, d epersonalization, changes in effect, and an easy and often uncontrolled access to subconscious materiaL There is now evidence for a genetic basis of schizophrenia'', and this supports the h ypothesis of a biochemical lesion. Possibly the complexity of the syndrome is the result of multiple alleles, and permutations of these may account in some part for this complexity'. The diversity in the syndrome, and also in the nature of the chemically induced intoxication produced by phenethylarnines, indoles and carbolines6', may imply a multiplicity of metabolic sites of action. R ecently there has been a eontroversy over the presence of 3,4-dimethoxyphenethylamine DMPEA, XXXVIII in the urine of schizophrenic patients. Although DMPEA itself has been reported not to be psychotomimetic, it may nevertheless reflect the metabolism of an endogenous psychotogen.

Rather than systematizing the complex features of the chemically induced psychosis, we have considered this state constant and have investigated the dose-response relationships instead_ Some recent studies have shown accord between human effective levels, and both biological ref. 11 and private communication from H. E. Himwich and physical properties. Although animal studies have shown a general correlation with human results, there are some exceptions possibly attributable to metabolic differences between species. Furthermore, the dosage required to obtain behavioma l effects in test animals is usually many times the effective human dosage. Because of these difficulties with animal results, we have limited this report to data obtained from human experiments.

Mescaline was selected as t he initial compound for this study. Although it is less active than most psychotomimetics, it has the dual virtue of chemical simplicity, allowing many structmal permutations, and a close relationship to compounds known to be naturally present in humans.
Notes # : See also the version of article republished in Handbook of Psychopharmacology
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