A streamlined synthesis of 5-methoxy-N,N-dimethyltryptamine, bufotenin, and bufotenin prodrugs from melatonin
Anton A. Homon, P. V. Vara Prasad, Elham Pourian, Jaxon Laramie, John J. Hayward, John F. Trant
ChemRxiv November 26, 2025 DOI: 10.26434/chemrxiv-2025-8c92n via OpenAlex
Summary
AI-generated from the abstractA 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.
Study at a glance
| Characteristics | Methodology report Peer reviewed |
|---|---|
| Keywords | Prodrug Yield engineering Hydrobromide Demethylation Derivative finance |
| Key finding | A chromatography-free synthesis of 5-MeO-DMT from melatonin yields 76% analytically pure product, and demethylation yields bufotenin hydrobromide at 51% yield. |
Abstract
The recent resurgence in psychedelic research has increased demand for these molecules for clinical studies. Due to the differences between national regulations and considering the dominance of the American market and its continued prohibition of many such molecules, the commercial availability of many of these compounds remains poor. This has also inhibited research into developing scalable and economic routes to these compounds. Many of the approaches to date use expensive starting materials, require extensive chromatography, or incorporate late-stage chemistries that raise toxicity concerns. Herein we report a streamlined, chromatography-free synthesis of analytically pure 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT, 76% overall yield from melatonin) and its demethylated derivative bufotenin (51% from 5-MeO-DMT) from the inexpensive and widely available compound melatonin. The sequence to 5-MeO-DMT can be conducted on lab scale (64 g of product) in under 5 days (3 days if you discount the initial hydrolysis) by a single operator. Demethylation to obtain bufotenin hydrobromide takes up to an additional 2 days and was done on 22 g of product. We then report the preparation of candidate prodrugs of bufotenin with the potential to increase its suitability for both nanoformulation and/or passive uptake across the blood-brain-barrier.