We Licked the Toads so You Don’t Have to: A Comprehensive Analysis of the Chemical Syntheses of the Classical Psychedelics Bufotenin(e) and 5‐Methoxy‐ N , N ‐Dimethyltryptamine

Bufotenin and 5-MeO-DMT are potent psychedelics found in plants and toad secretions. Although used in traditional medicine, 20th-century prohibition slowed research into their therapeutic potential for psychological disorders and inflammatory and neurodegenerative diseases. Recent global trends toward legalization have increased clinical and preclinical studies, creating demand for large amounts of these compounds that are not commercially available on scale. The first bufotenin synthesis was reported in 1935, and new syntheses continue to appear in the 2020s. This review collates and compares all extant academic and patent syntheses as of fall 2024, enabling researchers to identify the most appropriate route. Outstanding challenges for reducing commercial-scale production costs are highlighted.

Study at a glance

Abstract

Bufotenin (also spelt as bufotenine) and its methylated derivative, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), are potent psychedelics that are found in many plants but also excreted by some species of toads. The compounds are regulated differently around the world, and although used in traditional medicine, 20th-century prohibition culture has slowed research into their utility for ameliorating psychological disorders and inflammatory and neurodegenerative diseases. However, the global trend toward 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, leaving researchers with a need to either contract out, or make their own. The first bufotenin 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.