A streamlined synthesis of 5-methoxy-N,N-dimethyltryptamine, bufotenin, and bufotenin prodrugs from melatonin
OpenAlex – November 26, 2025
Source: OpenAlex
Summary
A streamlined synthesis method for 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) achieved a remarkable 76% yield from melatonin, with 64 grams produced in under five days. Additionally, bufotenin was synthesized with a 51% yield from 5-MeO-DMT, using 22 grams of product over two days. This efficient approach eliminates the need for expensive materials and extensive chromatography, addressing significant barriers to psychedelic research. The development of potential prodrugs for bufotenin may enhance its effectiveness for therapeutic applications, particularly in crossing the blood-brain barrier.
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.