Synthesis and characterization of high‐purity N,N‐dimethyltryptamine hemifumarate for human clinical trials
Drug Testing and Analysis – July 01, 2020
Source: OpenAlex
Summary
A highly pure form of the psychedelic DMT is now ready for clinical trials, crucial for advancing drug studies. Through novel chemical synthesis, using aluminum hydride from lithium aluminum hydride, a DMT hemifumarate salt was produced. Extensive chemistry analysis—mass spectrometry, differential scanning calorimetry, thermogravimetric analysis, nuclear magnetic resonance, and chromatography—confirmed minimal 99.9% purity. This rigorous standard, essential across all drug studies from cannabis to other alkaloids, ensures safety. No significant impurities or residual lithium were detected, meeting regulatory requirements.
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.