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A review of recent studies of the biosynthesis and excretion of hallucinogens formed by methylation of neurotransmitters or related substances


Pages: 90 - 105

Abstract

The original interest in the possibility that hallucinogens might be formed from neurotransmitters or other endogenous compounds stemmed from the proposal that these hallucinogens might play a role in the etiology and pathogenesis of psychosis. Much of the early work not reviewed here was concerned with the measurement of hallucinogens in body fluids and attempts to compare various psychiatric patient groups with relevant control populations. Probably because of the failure of those studies to resolve the issues under investigation, a great deal of the more recent work has been directed toward the improvement of technology and the development of basic information. As a corollary of this shift in emphasis, there has been a major change from the measurement of metabolites toward the investigation of enzymes involved in biosynthesis. The main source of concern in this field, adequate compound identification, continues to be a problem. In some instances, traditional methods of radioisotopelabeled product identification have not been used. Authentic radio-labeled reference material for the various hallucinogens and derivatives, however, cannot always be obtained. Some identification problems have been resolved by the use of mass spectrometry, but the limited availability of adequate instruments has restricted the use of this approach. In other instances, the inherent limitations of the technique itself have not been fully recognized. Despite these problems, a substantial advance has been made in our understanding of the mechanisms involved in the formation of endogenous hallucinogens, although we do not understand their role, if any, in the CNS. In the opinion of the reviewers, the following conclusions are warranted by the studies carried out to date by a large number of investigators. • Tryptamine, or NMT, can be enzymatically converted to DMT by a SAM-dependent enzyme or enzymes shown to be highly active in lung or adrenal, particularly of the rabbit. This enzyme system can be demonstrated in brain, but its activity is very low. Similar findings have been made with regard to the formation of bufotenine from serotonin. • In brain, red blood cells, and platelets, indolethylamines are transformed primarily to j3-carbolines (pyridoindoles, tryptolines) rather than methylated derivatives when SAM is used as a methyl donor. • The formation of DMT from tryptamine or NMT has not been shown to occur in any tissue when 5MTHF is used as potential methyl donor instead of SAM. • Dopamine can be transformed to N-methyldopamine (epinine) by a SAM-dependent enzyme found in adrenal tissue, but not by a 5MTHF-dependent enzyme in any tissue. • In the presence of 5MTHF, indolethylamines are transformed to |3-carbolines (pyridoindoles, tryptolines) and dopamine is transformed to TIQ rather than to methylated derivatives. • Enzymes have been found in mammalian tissues that can catalyze, in vitro, each step in the transformation of dopamine to DMPEA and mescaline. The in-vivo biosynthesis of these compounds has not been demonstrated. • A definitive assessment of the relationship of endogenous hallucinogens to the various psychotic states awaits the conduct of studies in which better product identification is carried out with drug-free subjects. Hallucinogenic substances, if they have a role, may be formed intermittently, or may be related to symptom pathogenesis rather than central etiology. Long-term longitudinal studies of carefully selected patients, in whom both symptoms and chemical parameters are studied, might result in important insights if they are adequately designed and use suitable methodology.