Exploratory study of the dose-related safety, tolerability, and efficacy of dimethyltryptamine (DMT) in healthy volunteers and major depressive disorder
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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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In DMT studies, 1 participant of 6 (16.7%) with depression and a clinical history suggestive of orthostasis experienced a substantial blood pressure drop, reported as an SAE.
“In DMT studies,21 1 participant of 6 (16.7%) with depression and a clinical history suggestive of orthostasis experienced a substantial blood pressure drop, which was reported as an SAE.”
From Adverse Events in Studies of Classic Psychedelics: A Systematic Review and Meta-Analysis (2024) · cites this paper as [21]
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- Authors
- D’Souza, D. C., Syed, S. A., Flynn, L. T., Safi-Aghdam, H., Cozzi, N. V., & Ranganathan, M.
- Affiliations
- Yale University (US)
- University of Wisconsin–Madison (US)
- Corresponding author
- D’Souza, Deepak Cyril
- Venue
- Neuropsychopharmacology
- Published
- 2022-06-03
- Volume
- 47
- Issue
- 10
- Pages
- 1854-1862
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC9372173
- OpenAlex
- W4281703399
- Cited by
- 162
- References
- 12
- Citations by year
- 2026: 28 · 2025: 35 · 2024: 61 · 2023: 33 · 2022: 4
- FWCI
- 28.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wallace Foundation
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- dimethyltryptamine, major depressive disorder, treatment-resistant depression, psychedelic therapy, antidepressant effects, dose escalation, drug safety and tolerability, psychotomimetic effects, anxiety, cardiovascular effects, abuse liability, intravenous administration
- MeSH terms
- Antidepressive Agents, Major Depressive Disorder, N,N-Dimethyltryptamine, Humans, Pilot Projects, Healthy Volunteers
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