There is a striking structural similarity between several classes of compounds found in plants that produce hallucinatory or psychedelic effects in man and several neurotransmitters found in the mammalian brain. These psychotomimetic substances are generally N- or O-methylated analogs of biogenic amine transmitters or of closely related endogenous compounds. Dimethyltryptamine DMT, bufotenine, and 5-methoxydimethyltryptamine 5MeODMT are present in piptadenia peregrina, used by South American Indians in their snuffs, and are psychotomimetic in man Briggs 1972, Fabing and Hawkins 1956, Fuxe, Holmstedt, and Jonsson 1972, Gessner 1970, Gessner and Page 1962, Holmstedt 1965, Holmstedt and Lindgren 1967, Koslow 1974, and Szara 1956 and 1961. All of these substances are methylated analogs of tryptamine or serotonin, substances that can be derived from the brain Green, Koslow, and Costa 1973, Martin et al. 1972, and Saavedra and Axelrod 1972a. Mescaline, a hallucinogenic derivative of the peyote cactus lophophora wllliamsii Kapadia and Fayez 1970, is structurally related to the methylated derivatives of the catecholamine neurotransmitters dopamine and norepinephrine Ernst 1965.
The transmethylation hypothesis of schizophrenia Osmond and Smythies 1952 was proposed after it was observed that the transfer of a methyl group to each of the hydroxyl groups of norepinephrine would transform this compound to one closely similar in structure to mescaline. This observation was made in the early 1950's before it was recognized that an important pathway for the inactivation of the catecholamines in mammals involves their O-methylation to structures more closely resembling mescaline-type hallucinogens than the parent catecholamines. The usual monomethylated metabolites of catecholamines are not hallucinogens and in fact are pharmacologically inert. However, these metabolites could serve as precursors for di- or tri-O-methylated derivatives, which do have the pharmacological effects of mescaline Smythies and Sykes 1966, Smythies, Sykes, and Lord 1966, and Vacca et al. 1968. It was hypothesized, therefore, that a metabolic aberration in a methylating system could lead to the formation of hallucinogenic substances resembling mescaline in structure. Later the hypothesis evolved further to include the possibility that hallucinogens might also be formed from serotonin or tryptamine, compounds that could be transformed to bufotenine or DMT.