The transmethylation hypothesis was the idea that schizophrenia might come from an error of metabolism that made hallucinogens in the brain. A 2018 review traces it to Humphry Osmond and John Smythies in 1952, and notes that the only known hallucinogens found in the body at the time were tryptamines such as DMT (Barker, 2018). Osmond moved to the Weyburn Mental Hospital in Saskatchewan in 1951, according to his BMJ obituary, which gives the idea a Canadian chapter.
The name comes from methylation, the chemical step that adds methyl groups to a molecule. The search led to real discoveries. In 1961 Julius Axelrod reported an enzyme that converts serotonin and tryptamine into bufotenine and DMT, which he called psychotomimetic metabolites (Axelrod, 1961). That enzyme is now known as INMT.
The core hypothesis did not hold. More than 60 studies tried to link DMT in blood or urine to a psychiatric diagnosis, and none found a clear, repeatable link (Barker, 2018). Stephen Szára, who first tested DMT in people, later wrote that it had not proved to be a “schizotoxin” (Szára, 2007). The question of what DMT does in the body did not go away; it moved to new methods, such as rat-brain measurements (Dean et al., 2019).
Sources
- Barker, 2018, Frontiers in Neuroscience: DMT, an endogenous hallucinogen
- Axelrod, 1961, Science: enzymatic formation of psychotomimetic metabolites
- Barker, 2022, Psychopharmacology: DMT in research and the study of endogenous DMT
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