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

Abstract

Since 2006, there has been a resurgent interest in the pharmacology and therapeutics of psychedelic drugs. Psilocybin, the 4-phosphoryl ester of N,Ndimethyltryptamine (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-(1Hindol-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 chromatographymass 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.

Discovery and In Vitro Characterization of SPL028: Deuterated N,N-Dimethyltryptamine

“…The first described synthesis of 1 converted tryptamine 2 via alkylation with methyl iodide . The synthetic approaches to deliver 1 have been reviewed, while the synthesis and characterization of 1 hemifumarate for human clinical trials have been reported . Three potential routes were considered, as illustrated in the retrosynthesis shown in Scheme .…”

“…An initial comparison of routes (5 g) starting with indole 3 or 4 indicated little difference between the routes in terms of output yield and purity compared to previously reported yields. 45 However, the route starting with 4 was favored as it starts from the inexpensive and readily available starting material auxin, has a shorter overall route (isolation of intermediate not required), uses low toxicity reagents (1-ethyl-3-carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) versus oxalyl chloride), and required less LiAlH 4 in the second step (0.9 equiv versus 2.0 equiv) when compared to the double reduction of β-keto-amide 5.…”

1H Nuclear Magnetic Resonance: A Future Approach to the Metabolic Profiling of Psychedelics in Human Biofluids?

“…There were two papers in this review that aimed to create salt forms of psychedelic substances. Cozzi and Daley ( 86 ) made DMT hemifumurate salt and Sherwood et al ( 84 ) made 5-MeO-DMT succinate salt; these are both molecules that have been used significantly less in clinical trials compared to psilocybin. Previous research investigating consumption of DMT and 5-MeO-DMT in a naturalistic setting noted that the administration for these substances have primarily been through oral administration of ayahuasca for DMT ( 144 ) and the inhalation of vapour for 5-MeO-DMT ( 136 , 137 ).…”

“…Two research groups used 1 H NMR spectroscopy during the process of synthesising psychedelic molecules into their water-soluble salt forms. Sherwood et al ( 84 ), synthesised 5-MeO-DMT succinate salt and Cozzi and Daley ( 86 ) synthesised DMT hemifumarate salt. The reactions used to synthesis these molecules were different; 5-MeO-DMT succinate salt was produced using a Fischer indole reaction, whereas the DMT hemifumarate salt was produced with a Speeter and Anthony approach.…”

Overcoming epistemic injustices in the biomedical study of ayahuasca: Towards ethical and sustainable regulation

“…His nigerine was later identified as being the same as Manske's DMT (Bigwood & Ott, 1977;Ott, 2002), which Szára would only start studying after reading about its presence in the South American psychoactive snuff cohoba (Winter, 2019). If there are current attempts to develop DMT through large-scale synthesis for therapeutic purposes (Cozzi & Daley, 2020), and if it includes patenting, indigenous knowledge and rights should not once again be disrespected. Importantly, this kind of process can also be considered extractive, colonial, and traumatizing to indigenous people (Fotiou, 2020;George et al, 2020).…”