There is considerable interest in the therapeutic potential of psychedelic drugs. Dimethyltryptamine (DMT) is a potent, rapid-onset, and short-acting psychedelic drug that has not yet been independently tested for the treatment of depression. The safety, tolerability, and efficacy of intravenous DMT were investigated in treatment-resistant individuals with major depressive disorder (MDD) and healthy controls (HC) in an open-label, fixed-order, dose-escalation (0.1 mg/kg followed by 0.3 mg/kg) exploratory phase 1 study that was conducted in a typical hospital setting with strategic psychoeducation/support, but minimal psychotherapy. Tolerability, safety, cardiovascular function, abuse liability, psychedelic, and psychotomimetic effects, mood, and anxiety were assessed at each dosing session. In addition, depression was measured using the HAMD-17 in MDD participants 1 day after each dosing session. DMT was tolerated by both HC (n = 3) and MDD participants (n = 7) studied; there were no dropouts. HAMD-17 scores decreased significantly (p = 0.017) compared to baseline in MDD participants the day after receiving 0.3 mg/kg DMT (mean difference −4.5 points, 95% CI: −7.80 to −1.20, Hedge’s g = 0.75). Adverse events were mostly mild with one self-limited serious event. DMT increased blood pressure, heart rate, anxiety, psychedelic effects, and psychotomimetic effects, which resolved within 20–30 min of injection. There were no dose-related differences in measures of drug reinforcement and abuse liability. In this small exploratory pilot study, intravenous DMT at doses of 0.1 and 0.3 mg/kg was mostly safe and tolerated and may have next-day (rapid) antidepressant effects in patients with treatment-resistant MDD. Further rigorous trials are warranted to replicate these findings and to determine the durability of antidepressant effects.
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The expertise of Rick Strassman who served as a paid consultant. The expertise of Dr Paul Daley of the Alexander Shulgin Research Institute in performing GC/MS analysis of some of the intermediates in the DMT synthesis procedure. Dr Raja at Hybrid Pharma for the sterile compounding of DMT. The research nursing staff of the Neurobiological Studies Unit and the research pharmacists of VA Connecticut Healthcare System.
This work was supported by Henry Wallace Foundation. DCD receives research funding administered through Yale University from the US National Institute of Health, US Department of Veteran Affairs, Takeda, Biogen, Boehringer Ingelheim, Ceruvia, Heffter Institute, and Wallace Foundation. DCD has served as a paid consultant to Jazz Pharmaceuticals, Biohaven, and Abide. None of these represent a conflict of interest.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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D’Souza, D.C., Syed, S.A., Flynn, L.T. et al. Exploratory study of the dose-related safety, tolerability, and efficacy of dimethyltryptamine (DMT) in healthy volunteers and major depressive disorder. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01344-y