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

Psychedelic compounds are receiving renewed attention for therapeutic use in neuropsychiatric disorders, but important questions remain about which agents work, which components of the psychedelic experience are necessary for benefit, and how resource-intensive the treatment model must be. Earlier clinical work with psilocybin and with ayahuasca has suggested antidepressant effects, yet psilocybin is orally administered with a slow onset and long duration, and ayahuasca contains multiple active constituents in addition to DMT, complicating attribution of effects to DMT alone. Cyril and colleagues set out to explore whether intravenous DMT, a rapid-onset and short-acting serotonergic hallucinogen, is safe, tolerable, and has signal of antidepressant efficacy in people with treatment-resistant major depressive disorder (MDD) as well as in healthy controls (HC). The study aimed to characterise dose-related physiological and subjective effects using a fixed-order dose-escalation design (0.1 mg/kg then 0.3 mg/kg), delivered in a typical hospital setting with preparatory psychoeducation but minimal psychotherapy, as a first step toward larger, controlled trials.

This exploratory Phase I study used an open-label, fixed-order, dose-escalation design with two intravenous DMT dosing sessions separated by at least 48 hours. All participants received 0.1 mg/kg first and, if tolerated and approved by study clinicians, 0.3 mg/kg on a second occasion. DMT hemifumarate (water‑soluble, ≥99.9% pure) was administered by intravenous push over 30–60 seconds in a plain hospital room; two psychiatrists and other clinical staff were present for each session. Preparatory contact included a single ~45 minute session describing likely psychological effects and coping approaches; formal psychotherapy was minimised. Participants comprised treatment‑resistant MDD patients and healthy controls. Inclusion for MDD required DSM‑5 MDD with HAMD‑17 ≥17, engagement in treatment and at least two prior adequate treatment failures including at least one failure in the current episode. Key exclusions were psychotic disorder, history of mania, recent high suicide risk, pregnancy, current drug dependence, lifetime hallucinogen use disorder, regular psychedelic use, and use of serotonergic over‑the‑counter products. Screening involved psychiatric and medical assessment and laboratory testing; MDD participants required collateral information from their treating clinician. Primary tolerability and safety assessments followed FDA definitions and included a post‑session visual analogue scale (VAS) for overall tolerability, willingness to use the drug again, and willingness to pay for the experience. Physiological safety included repeated blood pressure, continuous heart rate and pulse oximetry, and adverse event (AE) monitoring with rescue medications available. Acute subjective effects were measured with a 23‑item Psychedelic Effects VAS and the Psychotomimetic States Inventory (PSI); depression was assessed using the clinician‑administered HAMD‑17 at screening (baseline) and by telephone the day after each dosing session. Statistical analyses used paired t‑tests or Wilcoxon signed‑rank tests for subjective measures, repeated‑measures ANOVA for cardiovascular parameters, and Hedge's g to report effect sizes; multiplicity corrections were applied to PSI subscales and psychedelic VAS items.

Of 52 individuals phone‑screened, 14 underwent in‑person screening and 12 were enrolled (3 HC, 9 MDD); two MDD participants dropped out before receiving the intervention. Seven MDD participants and three healthy controls completed both dosing sessions. Among MDD participants, three had severe depression (HAMD‑17 ≥24) and four had moderate severity (HAMD‑17 17–<24). Most MDD participants were not taking antidepressant medication that could interfere with DMT effects, with all but one having discontinued such medications more than three months prior to dosing. Tolerability ratings on a 0–100 VAS were high for the low dose (mean 89.80, SD 12.95) and lower but still generally positive for the higher dose (mean 71.11, SD 24.52); the mean difference between doses was −17.78 (95% CI −32.81 to −2.75), t = −2.72, p = 0.026. All participants who completed the first session were judged appropriate to proceed and indicated willingness to return for the second session. Physiologically, DMT produced transient increases in systolic and diastolic blood pressure and heart rate with significant effects over time for both doses; there were no significant dose or dose–time interactions. Posthoc testing showed significant systolic increases at +5, +10, and +15 minutes, diastolic increases through +30 minutes, and a heart‑rate increase at +5 minutes. The most common adverse events were transient pre‑dose or onset anxiety (n = 6), transient headache (n = 2), and transient hypertension (n = 2). One serious adverse event occurred after 0.3 mg/kg in a female participant who developed asymptomatic bradycardia and hypotension that resolved after Trendelenburg positioning and intravenous fluids; there were no sequelae. No clinically relevant psychotic symptoms or need for psychotropic rescue medications were reported during dosing sessions. Subjective psychedelic effects appeared rapidly (2–5 minutes), peaked at 5–10 minutes, and subsided by about 30 minutes. Dose‑related differences were significant on 16 of 23 VAS items after correction; the largest dose effects were on intensity, complex visual imagery, experiencing a different reality/dimension, things looking strange, and vivid imagination. PSI total peak change increased from mean 7.33 (SD 7.62) at 0.1 mg/kg to 31.67 at 0.3 mg/kg (difference 24.33; 95% CI 12.74 to 35.94; t = 4.84; p = 0.001; Hedge's g = 1.89), with the perceptual disturbance subscale driving the dose effect. Measures related to drug desirability showed low reinforcement potential: willingness to use DMT again averaged 24.00 (SD 17.91) at 0.1 mg/kg and 22.44 (SD 22.72) at 0.3 mg/kg, and participants' monetised valuation of the experience was about $25 (scale $0–100) for both doses; differences were not statistically significant. On the primary efficacy measure, clinician‑rated HAMD‑17 scores in MDD participants were significantly reduced from baseline to the day after the 0.3 mg/kg session, with a mean difference of −4.5 points (95% CI −7.80 to −1.20), t = −3.50, p = 0.017, Hedge's g = 0.75. The change between the 0.1 and 0.3 mg/kg sessions was also significant (difference −3.5; 95% CI −6.87 to −0.013; t = −2.67; p = 0.044). The extracted text does not clearly report the exact mean baseline and post‑dose HAMD‑17 values in a consistent manner, but the reported mean differences and effect sizes indicate a moderate effect size for next‑day reduction in depressive symptoms. Individual responses varied, with one participant experiencing a large and sustained improvement and requesting further dosing.

Cyril and colleagues interpret these results as the first evidence that intravenous DMT can be administered safely and is generally tolerable in individuals with treatment‑resistant MDD, and that it may produce rapid, next‑day reductions in depressive symptoms. The most notable finding was a statistically significant mean reduction of about 4.5 HAMD‑17 points the day after 0.3 mg/kg DMT, corresponding to a medium–large effect size (Hedge's g = 0.75), although responses varied across participants. The investigators place their findings in context by noting differences from prior psilocybin and ayahuasca studies: route of administration, duration of psychedelic experience, setting, and psychotherapy augmentation may all influence effect magnitude. Importantly, this study used a plain hospital environment with minimal psychotherapy and still observed reductions in depression scores, prompting questions about how critical set, setting and integrative psychotherapy are for therapeutic benefit. The authors report that acute psychedelic or psychotomimetic measures did not significantly correlate with antidepressant change, but emphasise that larger samples are needed to explore predictors of response. Safety and tolerability findings were broadly concordant with prior nonclinical work: transient dose‑related perceptual disturbances, increases in blood pressure and heart rate, and transient anxiety were observed. One SAE of transient hypotension and bradycardia occurred and was attributed to an interaction with an undisclosed predisposition to autonomic instability; the event resolved without sequelae. The authors therefore recommend careful cardiovascular screening and readiness to manage acute autonomic events in future studies. Limitations acknowledged include the small sample size, open‑label and fixed‑order design, brief follow‑up that does not address durability of effect, and challenges in blinding given the rapid, intense effects of IV DMT. The lack of a pre‑dose depression assessment immediately before the 0.3 mg/kg session means carryover from the 0.1 mg/kg session cannot be excluded. The authors suggest future directions: randomised, double‑blind, placebo‑controlled trials (potentially using active controls or sub‑psychedelic doses), exploration of infusion rates that might prolong effects and permit psychotherapy, systematic assessment of expectancy and blinding success, and mechanistic studies examining targets such as TAAR‑1 and sigma‑1 receptors. Overall, the study team concludes that the data support further, more rigorous investigation of IV DMT as a rapid antidepressant, while emphasising the need for replication and larger safety assessments.