The antidepressant effects of vaporized N,N-Dimethyltryptamine: a preliminary report in treatment-resistant depression

N,N-Dimethyltryptamine (DMT) is a naturally occurring psychedelic tryptamine that produces brief but intense alterations in consciousness when administered parenterally. The compound is a component of the traditional brew ayahuasca, in which monoamine oxidase inhibitors permit oral activity; clinical research on ayahuasca has suggested rapid antidepressant effects. Despite emerging evidence for psychedelic treatments in mood disorders, the effects of isolated, vaporized DMT in patients with treatment‑resistant depression (TRD) had not been tested in a Phase II clinical trial prior to this study. Falchi‑Carvalho and colleagues set out to evaluate the efficacy and tolerability of inhaled, isolated DMT in patients with TRD. The study aimed to examine whether a single-day, fixed-order, dose‑escalation administration of vaporized DMT produces rapid and sustained reductions in depressive symptoms, and to characterise acute subjective effects and safety in a therapeutic setting. This Phase 2a trial therefore probes an alternative, short‑acting route of administration that could have practical advantages over longer‑acting oral psychedelics.

The study was an open‑label, fixed‑order, dose‑escalation Phase 2a clinical trial conducted at a university hospital and approved by a local ethics committee (registration NCT06094907). Six patients who completed assessments to one month are reported in this preliminary extract. Recruitment was by physician referral with psychiatrist screening. Inclusion criteria required a current moderate to severe depressive episode (MADRS ≥ 20 for at least four weeks) and prior failure of at least two antidepressant medications, consistent with a definition of TRD. Participants provided informed consent, continued their regular pharmacological treatments, and abstained from other psychedelics for 14 days before dosing. The paper refers to exclusion criteria provided in Supplemental Methods; these are not detailed in the extracted text. On dosing day participants received two successive inhaled administrations of DMT free base delivered with a medical vapouriser device. The first, lower dose was 15 mg and the second, higher dose 60 mg; the higher dose is reported as occurring 90 minutes after the first dose in the extracted text, which is partially garbled but implies a 90‑minute interval. Psychological preparation was provided prior to dosing. During the approximately 15‑minute acute effects of each administration, patients lay on a recliner with eyeshades and listened to music; immediate psychological integration and questionnaires about intensity, valence and altered states of consciousness (ASC) followed each dosing. Two hours after the second dose patients were evaluated by a psychiatrist and discharged with a companion. Clinical assessments used clinician‑rated MADRS and self‑reported PHQ‑9 at baseline (D0), D1, D7, D14 and one month (M1). The primary outcome was mean change in MADRS from baseline to D7. Secondary outcomes comprised MADRS change at other time points, response (≥50% reduction in baseline MADRS), remission (MADRS ≤ 10), PHQ‑9 changes, and ASC measures. Depression scores were analysed using repeated measures General Linear Models (GLM) with time as a within‑subjects factor and a two‑tailed significance threshold of 0.05; the extracted text indicates post‑hoc pairwise comparisons were performed but does not provide their full procedural details.

Six patients completed all assessments through one month and are the basis for this preliminary report. For clinician‑rated depressive symptoms (MADRS) there was a strong main effect of time (F(4,20) = 10.41, p = 0.0001, partial η² = 0.67). Pairwise comparisons showed significant reductions from baseline at D1 (p < 0.0001; Hedges' g = 4.70), D7 (p = 0.0002; g = 2.89), D14 (p = 0.0002; g = 3.34) and M1 (p = 0.003; g = 1.80). The mean MADRS change reported was −22 points at D7 versus baseline and −17 points at M1 versus baseline. Individual percentage changes in MADRS at each time point are referenced in the figures of the source text but full individual data are not reproduced in the extract. Response and remission rates were substantial in this small sample. Response (≥50% MADRS reduction) was observed in 5/6 patients (83.33%) at D1, D7 and D14, and in 4/6 patients (66.67%) at M1. Remission (MADRS ≤ 10) was achieved by 4/6 patients (66.67%) at D1, D7 and D14, and by 3/6 patients (50%) at M1. Self‑reported depressive symptoms on the PHQ‑9 are reported to have decreased in a pattern mirroring MADRS, though specific PHQ‑9 numerical results are not clearly reported in the extracted text. Safety findings indicated no serious adverse events. Transient physiological effects included rapid but temporary increases in blood pressure and heart rate during dosing, and an acute rise in peripheral oxygen saturation. The authors note these safety observations are consistent with their Phase I experience. The Results section also contrasts the present findings with small, recent studies: an exploratory intravenous DMT study in seven patients reported a more modest effect size (g = 0.75) and a mean Hamilton scale reduction of 4.5 points at D1, while a 5‑MeO‑DMT vapour study in 16 TRD patients found a mean MADRS reduction of −24.4 points at D7. The source text attributes possible reasons for differences in effect size to therapeutic setting, psychological support, administration route, dose regimen and patient characteristics.

Falchi‑Carvalho and colleagues interpret the results as evidence that a single‑day inhalation protocol with ascending doses of vaporized DMT produced rapid and, in most patients, sustained antidepressant effects up to one month in this very small TRD sample. They emphasise the large effect sizes observed at early time points and the substantial proportions of responders and remitters, and propose that pairing psychedelic dosing with psychological support in a specialised therapeutic environment may enhance outcomes relative to studies lacking these elements. The authors position their findings alongside other preliminary reports of short‑acting psychedelic tryptamines, noting a similar magnitude of antidepressant effect to a vapourised 5‑MeO‑DMT study and a larger effect than an exploratory intravenous DMT study; they highlight differences in compound, dosing strategy and therapeutic support as plausible explanations for divergent results. Practical advantages of vaporized DMT are discussed: its short duration of action and non‑invasive inhalation route could reduce healthcare complexity, lower operational costs and increase accessibility, potentially facilitating integration into public health systems. Key limitations are acknowledged: the open‑label design and very small sample prevent disentangling placebo and expectancy effects and limit generalisability. The extracted text also notes that exclusion criteria and some procedural details are provided only in supplemental materials and are not available in the extract. For future work the authors recommend larger samples, randomised placebo‑controlled designs, exploration of repeated dosing schedules, and continued safety evaluation to better define the therapeutic potential and operational models for DMT in interventional psychiatry.