Exploratory study of the dose-related safety, tolerability, and efficacy of dimethyltryptamine (DMT) in healthy volunteers and major depressive disorder.
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 mgkg followed by 0.3 mgkg) exploratory phase 1 study that was conducted in a typical hospital setting with strategic psychoeducationsupport, 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 mgkg DMT (mean difference -4.5 points, 95% CI -7.80 to -1.20, Hedges 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 mgkg 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.