We licked the frogs so you don’t have to: A comprehensive history and analysis of the chemical syntheses of the classical psychedelics Bufotenin(e) and 5-methoxy-N,N-dimethyltryptamine

Bufotenin (also spelt as bufotenine) and its methylated derivative, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) are potent psychedelics (although the activity of the former is attenuated due to its low propensity to cross the blood-brain-barrier) that are found in many plants but also excreted by specific species of toads. The compounds are regulated differently around the world, and although they have been used in traditional medicine, 20th century prohibition culture has slowed research into their utility for ameliorating psychological disorders and inflammatory & neurodegenerative diseases. However, the global trend towards legalization and a renewed interest in the therapeutic potential of psychedelics has increased the number of clinical and preclinical studies of these and related materials. This necessitates access to large amounts of these compounds, but they are not commercially available on scale. This leaves researchers with a need to either contract for, or make their own, bufotenin. The first synthesis was reported in 1935 by Hoshino and coworkers, and novel syntheses are still being disclosed in the 2020s. This is the first effort to collate and compare all extant academic and patent syntheses (as of fall 2024) into a single review so that researchers can identify the most appropriate route for their own purposes. We conclude by highlighting outstanding challenges that are ripe for solutions to reduce the cost of any future commercial-scale production.