Synthesis and characterization of high‐purity N,N‐dimethyltryptamine hemifumarate for human clinical trials

A slightly modified Speeter–Anthony synthesis produced DMT hemifumarate with over 99.9% purity, meeting regulatory standards for human intravenous administration. Aluminum hydride generated in situ from lithium aluminum hydride was used for the first time to reduce an intermediate to DMT, and a quench protocol yielded exceptionally pure free base DMT. The final salt was analyzed by multiple techniques including X-ray powder diffraction, NMR, GC–MS, and HPLC. No significant impurities or residual solvents were detected. The work supports planned clinical trials of DMT for major depressive disorder.

Study at a glance

Abstract

Abstract Since 2006, there has been a resurgent interest in the pharmacology and therapeutics of psychedelic drugs. Psilocybin, the 4‐phosphoryl ester of N,N ‐dimethyltryptamine (DMT), has been studied most often, but DMT itself is also appealing because of its brief but profound psychological effects and its presence as an endogenous substance in mammalian brain. Although there have been a few studies of ayahuasca , a DMT‐containing water infusion, only one human study with pure DMT has been reported since the early 2000s. Newly planned clinical trials to assess the safety and efficacy of DMT in humans with major depressive disorders require high‐purity water‐soluble DMT for intravenous administration. Accordingly, we synthesized and characterized DMT hemifumarate for these upcoming studies. The synthetic approach of Speeter and Anthony was slightly modified to gain some efficiency in time. In particular, this is the first known report to use aluminum hydride, generated in situ from lithium aluminum hydride, to reduce the intermediate 2‐(1 H ‐indol‐3‐yl)‐ N , N ‐dimethyl‐2‐oxoacetamide to DMT. A quench protocol was developed to produce a good yield of exceptionally pure free base DMT upon workup, which was then converted to the hemifumarate salt. Analysis of the final product included differential scanning calorimetry, thermogravimetric analysis, gas chromatography–mass spectrometry (GC–MS), 1 H and 13 C nuclear magnetic resonance spectroscopy, high‐performance liquid chromatography, residual solvent analysis by GC headspace sampling, X‐ray powder diffraction analysis, and residual lithium analysis by inductively coupled plasma‐mass spectrometry. The DMT hemifumarate was minimally 99.9% pure, with no significant impurities or residual solvents, thus meeting regulatory standards for administration to humans.