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.
A streamlined, chromatography-free synthesis of 5-MeO-DMT from melatonin achieves 76% overall yield, producing 64 g of analytically pure product in under 5 days. Demethylation of 5-MeO-DMT yields bufotenin hydrobromide in 51% yield (22 g) within an additional 2 days. Candidate prodrugs of bufotenin are prepared to potentially improve nanoformulation and blood-brain-barrier passive uptake. The method uses inexpensive, widely available melatonin, avoiding expensive starting materials, extensive chromatography, and late-stage chemistries that raise toxicity concerns.
Bufotenin and 5-MeO-DMT are potent psychedelics found in plants and toad secretions, but their therapeutic potential for psychological disorders and inflammatory or neurodegenerative diseases has been hindered by prohibition and limited commercial availability. This review collates all known academic and patent syntheses of bufotenin from 1935 to 2024, comparing routes to help researchers choose the most suitable method. The authors highlight challenges that need solving to reduce costs for future commercial-scale production, aiming to support the growing clinical and preclinical research into these compounds.