This Phase 2a open‑label, dose‑escalation study in six patients with treatment‑resistant depression found that a single‑day session of vapourised N,N‑dimethyltryptamine produced rapid and sustained reductions in depressive symptoms (mean MADRS change −22 at Day 7 and −17 at one month), with 83.3% response and 66.7% remission at Day 7 and 66.7% response and 50% remission at one month. The authors highlight the non‑invasive, short‑acting delivery as a practical advantage that could improve accessibility of psychedelic-assisted interventional psychiatry.
Papers cited by this study that are also in Blossom
Strassman, R. J., Qualls, C .R. · JAMA Psychiatry (1994)
Introduction
N,N-Dimethyltryptamine (DMT), a naturally occurring psychedelic tryptamine contained in the indigenous ayahuasca brew has shown antidepressant effects. This Phase 2a clinical trial investigates for the first time the efficacy of isolated DMT in treatment-resistant depression (TRD).
Methods
Six TRD patients participated in an open-label, fixed-order, dose-escalation study, receiving a lower (15 mg) and then a higher (60 mg) dose of vaporized DMT in a single-day session. Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Patient Health Questionnaire-9 (PHQ-9) up to one-month post-dosing.
Results
Significant reductions in MADRS and PHQ-9 scores were noted from Day 1 to M1. The mean MADRS score variation from baseline to D7 was −22 points and −17 points at M1. PHQ-9 scores also showed significant decreases, mirroring the MADRS results. By D7, 83.33% of patients responded to treatment, with 66.67% achieving remission. At M1, 66.67% maintained response, and 50% maintained remission.
Discussion
The rapid onset and sustained antidepressant effects of vaporized DMT align with the paradigm of rapid-acting antidepressants to be used in the scope of interventional psychiatry. The non-invasive route and short-acting nature of DMT offer practical advantages, potentially enhancing accessibility to psychedelic treatments. Clinical
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.
N,N-Dimethyltryptamine (DMT) is a naturally occurring psychedelic tryptamine, endogenous in small amounts in humans. When administered parenterally it induces profound changes in consciousness, including altered visual and auditory perceptions, frequently accompanied by deep emotional meaning, insights, significant shifts in thought processes, and mystical experiences, all condensed into an intensely powerful yet brief psychedelic experience. Despite its potent psychedelic properties, the function and regulation of endogenous DMT within the human body is still a mystery. Although DMT is orally inactive due to the presence of monoamine oxidase (MAO) in the gut, South American Indigenous populations have long harnessed the psychoactive properties of DMT through Ayahuasca. This brew ingeniously incorporates monoamine oxidase inhibitors (MAOIs) to prevent DMT's rapid deamination by MAO, thus enabling its psychotropic effects. In this case, the effects last a few hours, commonly including nausea and vomiting, besides the psychedelic effects 3 . Recent clinical evidence has suggested the therapeutic effects of ayahuasca, particularly in the context of mood disorders. The results from our Phase 2a and Phase 2b clinical trials with Ayahuasca in treatment-resistant depression (TRD) have been remarkable, suggesting rapid and sustained antidepressant effects in individuals with TRD, a condition notoriously challenging to manage. Following a comprehensive Phase 1 dose-escalation study, vaporized DMT proved safe and well-tolerated among healthy participants within the dosage range explored 8 . Encouraged by these findings, we have embarked on the first Phase 2a clinical trial to investigate the efficacy of pure DMT in treatment-resistant depression. By exploring this alternative route of administration, we aim to untangle the intricate relationship between DMT's rapid psychedelic effects and its impact on depressive symptoms, contributing to the expanding horizon of psychedelic-assisted therapies.
This is an open-label, fixed-order, dose-escalation phase 2a clinical trial in patients with TRD. The study was approved by the Ethics Committee of the University Hospital Onofre Lopes (HUOL) (#45532421.0.0000.5292), registered at clinicaltrials.gov (NCT06094907).
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Timmermann, C., Roseman, L., Haridas, S. et al. · PNAS (2023)
Osório, F. L., Sanches, R. F., Macedo, L. et al. · brazilian Journal of Psychiatry (2015)
Sanches, R. F., Osório, F. L., Dos Santos, R. G. et al. · Journal of Clinical Psychopharmacology (2016)
Palhano-Fontes, F., Barreto, D., Onias, H. et al. · Psychological Medicine (2018)
Falchi, M., Wießner, I., Silva, S. R. B. et al. · European Neuropsychopharmacology (2024)
Reckweg, J., Mason, N. L., van Leeuwen, C. et al. · Frontiers in Pharmacology (2021)
D’Souza, D. C., Syed, S. A., Safi-Aghdam, H. et al. · Neuropsychopharmacology (2022)
Papers in Blossom that reference this study
Lima, G., Soares, C., Teixeira, M. et al. · Scientific Reports (2025)
Candidates were recruited by physician referrals and were screened by a trained psychiatrist. Inclusion criteria: patients in a moderate/severe depressive episode according to MADRS (MADRS ≥ 20) during at least four weeks, and who have previously used at least two antidepressant medications, but without successful results (treatment-resistant, TRD). For exclusion criteria, see Supplemental Methods. Patients signed an informed consent before participation, maintained their pharmacological treatment, and abstained from psychedelics 14 days before dosing. Substance DMT free base was vaporized using a device used for medical purposes in similar studies(for details, see Supplemental Methods).
The study was conducted in the university hospital. After the screening, patients underwent psychological preparation. On dosing day (D0), they first received a lower DMT dose (15 mg), followed by a higher DMT dose (60 mg), 90 min after 1 . During the 15-minutes acute effects, patients remained lying down on a recliner with eyeshades and listened to music 2 . After the end of each dosing, patients underwent an immediate psychological integration, followed by questionnaires about the intensity, valence, and altered consciousness(ASC; see Supplemental Measurements). Two hours after the second dosing, patients were evaluated by a psychiatrist and discharged with a family member or friend. One (D1) and seven (D7) days after the session, patients participated in follow-up integration sessions. At D0, D1, D7, D14, and one month (M1), depressive symptoms were evaluated by psychiatrists using the MADRS 11 (Montgomery-Asberg Depression Rating Scale) and self-reports on the PHQ-9(Patient Health Questionnaire-9).
The primary outcome measure was the mean change in depression severity assessed by the MADRS scale, comparing baseline with seven days after the dosing session. Secondary outcomes included the mean change in MADRS scores from baseline to D1, D14, and M1 after the dosing session; the response rate, defined as the proportion of patients meeting a reduction of 50% or more in baseline MADRS scores, and remission rates (MADRS⩽10); the mean change in PHQ-9 scores from baseline to D1, D7, D14, and M1 after the dosing session; changes in the ASC during the acute effects of DMT.
Depression scores (D0 to M1) were analyzed in repeated measures General Linear Models (GLM; within-subjects factor = time; significance level = 0.05 (two-tailed)). Post hocThe definition of these doses was based on our Phase I trial, which investigated 10 different doses across 5 schemes, ranging from 5 to 60mg 8 .
In this preliminary report, we included data from six patients who completed all assessments until M1. Patients' sociodemographic, medication, and drug use are depicted in For MADRS scores, there was a main effect of time (F(4,20) = 10.41, p = 0.0001, ηp² = 0.67). Pairwise comparisons revealed a significant reduction of depressive symptoms at D1 (p < 0.0001; Hedge's g = 4.70), D7 (p=0.0002; Hedge's g = 2.89), D14 (p=0.0002; Hedge's g = 3.34) and M1 (p=0.003; Hedge's g = 1.80); Figure). Figureshows the proportion of patients who responded at D1: 5/6 (83.33%), at D7: 5/6 (83.33%), at D14: 5/6 (83.33%), and at M1: 4/6 (66,67%); and the remission rate at D1: 4/6 (66.67%), at D7: 4/6 (66.67%), at D14: 4/6 (66.67%) and at M1: 3/6 (50%). Individual % of change from baseline of MADRS scores at each time point are depicted in Figure. No serious adverse events were observed during or after dosing. This is in line with what we observed in the phase I study 8 . During both sessions involving DMT, there was a rapid yet temporary increase in blood pressure and heart rate. DMT caused an acute rise in peripheral oxygen saturation. Overall, the findings suggest that our intervention with DMT is safe and tolerable for patients with depression. A recent exploratory study on the antidepressant effects of intravenous DMT in seven patients with Major Depressive Disorder reported a moderate effect size (Hedge's g = 0.75) with a mean reduction of 4.5 points in the Hamilton depression scale at D1. This study lacks a specialized therapeutic environment and psychological support, factors that could have contributed to the modest outcomes regarding response and remission rates. In contrast, our study achieved a higher effect size (Hedge's g = 4.70) at D1, which was sustained for one month. This disparity highlights the potential for enhanced therapeutic effects when psychedelic interventions are paired with psychological support in a thoughtfully designed setting. The superior response observed in our study may be attributed to this integrative approach, though variations in administration routes, dosages, and patient profiles are important considerations as well. Another recent study investigated the safety and efficacy of vaporized 5-methoxy-N,Ndimethyltryptamine (5-MeO-DMT) in sixteen patients with TRD. They found a mean MADRS reduction at D7 vs. baseline of -24.4 points, whereas we found a mean reduction of -22 points (D7 vs. baseline). Both studies highlight the rapid antidepressant effects of shortacting psychedelic tryptamines using the same vaporizer device. However, our study differs in its use of DMT (vs. 5-MeO-DMT) and a single ascending fixed-dose approach, as opposed to an individualized dosing regimen. The positive outcomes in both studies reinforce the viability of using vaporized psychedelics as a promising therapeutic approach. Furthermore, our data suggests the use of a short-acting psychedelic like DMT, as opposed to longer-lasting oral psychedelics (e.g., psilocybin, ayahuasca), maintains the therapeutic effects and offers practical advantages in terms of cost and operationalization, especially in settings requiring psychiatric and psychotherapeutic involvement. Along with the non-invasive inhalation route, contrasting to the intravenous methods, we believe lower level of healthcare complexity required (secondary vs. tertiary or in-hospital care). Those aspects could be crucial in enhancing accessibility to psychedelic treatments and becoming suitable for public health systems, such as the Brazilian SUS (Unified Health System). The open-label design and reduced number of patients in this study is a limitation, as it does not allow for the disentanglement of placebo effects from the results observed. Future directions include increasing the number of patients, assessing the need for repeated doses over time, and employing a more controlled experimental design (randomized and placebocontrolled). As we continue to understand the therapeutic potential of DMT, this preliminary study is poised to offer novel insights into the antidepressant capabilities of DMT, potentially transforming our understanding of its role in treating mood disorders.