Exploratory study of the dose-related safety, tolerability, and efficacy of dimethyltryptamine (DMT) in healthy volunteers and major depressive disorder

Abstract

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.

Fig. 1. Blood pressure and heart rate.

Figure shows changes in means (error bars indicate standard error of mean) of systolic and diastolic blood pressure (mm Hg), and heart rate (beats/min) over time on the 0.1 and 0.3 mg/kg DMT. Arrow indicates the time at which DMT was administered. n = 10 for 0.1 mg/kg (n = 3 healthy, n = 7 depressed) and n = 9 for 0.3 mg/kg (n = 3 healthy, n = 6 depressed).

Fig. 2. Change in depression.

Figure shows changes in HamD-17 total scores of individual participants the day after 0.1 and 0.3 mg/kg DMT relative to baseline. Each subject is represented by a line in a different color. The group mean is shown in black. *Note that subject 7 completed the 0.1 mg/kg dosing session before being withdrawn for administrative reasons.