Inhaled DMT for Major Depressive Disorder (DMT-MDD)

Randomized, Double-Blind, Placebo-Controlled Phase IIb Trial of Inhaled N,N-Dimethyltryptamine (DMT) for Major Depressive Disorder

This Phase 2b, randomized, double-blind, active-controlled clinical trial will evaluate the efficacy and safety of inhaled N,N-dimethyltryptamine (DMT) in adults with Major Depressive Disorder (MDD).

The study will test whether inhaled DMT can rapidly reduce depressive symptoms and suicide risk compared with a low-dose active comparator. A total of 140 participants will be randomized 1:1 to receive either 15 mg followed 1 hour later by 60 mg of inhaled DMT, or 1 mg followed 1 hour later by 4 mg of inhaled DMT.

Participants who do not achieve remission at Day 7 will enter an open-label extension and receive a high-dose DMT session on Day 14 (±3 days). All participants will be followed for up to 12 months to evaluate the durability of response, safety, functioning, and quality of life.

Study Overview

• Status: Recruiting
• Conditions: Suicidal Ideation; Suicide; Major Depression; Major Depressive Disorder (MDD); MDD
• Intervention / Treatment: Drug: N,N-Dimethyltryptamine (15 mg + 60 mg); Drug: N,N-Dimethyltryptamine (1 mg + 4 mg)

Detailed Description

Major depressive disorder (MDD) is a common and disabling condition associated with high functional burden, incomplete response to standard antidepressant treatments, and persistent suicide risk. Current pharmacological treatments often require weeks to months to achieve meaningful benefit and are limited by delayed onset, side effects, and non-response in a substantial proportion of patients. Other interventions, including esketamine and electroconvulsive therapy, may provide benefit in selected cases but present limitations related to durability, logistics, invasiveness, or tolerability.

N,N-dimethyltryptamine (DMT) is a classic serotonergic psychedelic with rapid onset and short duration of action when administered by inhalation, with acute effects typically lasting about 10 to 20 minutes. Prior studies conducted by the study group suggested that inhaled DMT has a favorable safety and tolerability profile and may produce rapid antidepressant and antisuicidal effects.

This study is a multicenter Phase 2b clinical trial designed in 2 stages. In Stage 1, participants are randomized 1:1 in a double-blind parallel-group design to receive either a higher-dose inhaled DMT regimen (15 mg followed 1 hour later by 60 mg) or a lower-dose inhaled DMT regimen used as an active comparator (1 mg followed 1 hour later by 4 mg). The total planned sample size is 140 randomized participants.

Participants who do not achieve remission at Day 7, defined in the protocol as MADRS >10, enter Stage 2, an open-label extension in which all non-remitters receive the higher-dose DMT regimen on Day 14 (±3 days). The study will also explore the clinical effects of re-dosing among non-remitters from both initial treatment groups.

The trial recruits adults with DSM-5 MDD and a current moderate-to-severe depressive episode, with baseline MADRS score ≥20, stable treatment regimen for at least 4 weeks, and ability to provide informed consent. Participants are followed for up to 12 months after treatment. Recruitment is multicenter and includes psychiatric clinical sites at Brazilian universities.

The primary efficacy objectives are to compare the two treatment groups with respect to change in total MADRS score from baseline to Day 7 and change in the suicidal ideation item of the MADRS (MADRS-SI, item 10) from baseline to Day 1. Secondary outcomes include additional depression, suicidality, safety, functioning, quality-of-life, subjective experience, and psychological measures assessed across follow-up visits through Month 12.

The primary analysis follows the intention-to-treat principle. The primary endpoint is analyzed using a generalized linear mixed model / mixed model for repeated measures framework with fixed effects for treatment group, time, and treatment-by-time interaction, with participant-level random intercepts. Missing data are handled by restricted maximum likelihood estimation. Additional analyses include response and remission comparisons, effect size estimation, and exploratory associations between acute subjective effects, biomarkers, and clinical outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Ceará
    • Fortaleza, Ceará, Brazil
      • Not yet recruiting
      • Hospital de Saúde Mental Professor Frota Pinto
      • Contact: Jarbas de Sá Roriz-Filho, MD; Phone Number: +55 85 98206-0526; Email: jarbasroriz@gmail.com
      • Principal Investigator: Jarbas de Sá Roriz-Filho, PhD
  • Estado de Bahia
    • Salvador, Estado de Bahia, Brazil
      • Not yet recruiting
      • Complexo Hospitalar Universitário Professor Edgard Santos, Federal University of Bahia (HUPES-UFBA)
      • Contact: Lucas Quarantini, PhD; Phone Number: +5571992767743; Email: quarantini@gmail.com
      • Principal Investigator: Lucas Quarantini, PhD
  • Rio Grande do Norte
    • Natal, Rio Grande do Norte, Brazil
      • Recruiting
      • Hospital Universitário Onofre Lopes - HUOL - UFRN
      • Contact: Fernanda Palhano-Fontes, PhD; Phone Number: +5584999435830; Email: fernandapalhano@neuro.ufrn.br
      • Contact: Dráulio Barros de Araújo, PhD; Phone Number: +5584991225987; Email: draulio@neuro.ufrn.br
      • Principal Investigator: Marcelo Falchi-Carvalho, MD
      • Sub-Investigator: Daniel Montanini, MD
  • Rio de Janeiro
    • Rio de Janeiro, Rio de Janeiro, Brazil
      • Not yet recruiting
      • Instituto de Psiquiatria da Universidade Federal do Rio de Janeiro (IPUB-UFRJ)
      • Contact: Tiago Arruda Sanches, PhD; Phone Number: +55 21 98173-7000; Email: tiago@medicina.ufrj.br
      • Principal Investigator: Thiago Arruda Sanches, PhD
  • São Paulo
    • São Paulo, São Paulo, Brazil
      • Not yet recruiting
      • Instituto de Psiquiatria - Hospital das Clínicas - IPq - HC - USP
      • Contact: Henrique Ribeiro, MD; Phone Number: +55 11 99712-3513; Email: clinicahenriqueribeiro@gmail.com
      • Principal Investigator: Rodrigo Furlan Damiano, PhD
      • Sub-Investigator: Henrique Ribeiro, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18 years or older, capable of making decisions, and able to provide informed consent.
• Major Depressive Disorder (MDD) according to DSM-5 criteria
• Current depressive episode of moderate to severe intensity
• Episode duration of at least two weeks
• Baseline MADRS score ≥ 20
• No treatment changes (including antidepressants) in the 4 weeks prior to the study
• Abstain from psychedelics ≥14 days before dosing (D0) and during the 12-month follow-up

Exclusion criteria:

• Major cardiac, hepatic, or renal disease; unstable cardiovascular conditions
• Uncontrolled hypertension, QTc prolongation, arrhythmias, or valvular disease COPD or asthma
• Severe obesity, uncontrolled diabetes, coagulopathy, thyroid disease, or glaucoma
• Neurological risk (e.g., aneurysm, ↑ICP, epilepsy/seizures, severe disorders)
• MAO deficiency or history of serotonin syndrome
• Pregnant, breastfeeding, positive test, or no effective contraception
• Secondary depression
• Cluster B personality disorders (incl. borderline with ≥2 suicidal behaviors in past 12 months) or poor therapeutic rapport
• Psychotic disorders, MDD with psychotic features, or first-degree family history of psychosis/bipolar disorder
• Mania/hypomania (YMRS ≥8)
• OCD, dissociative disorders, active PTSD, or decompensated eating disorders
• Moderate-severe use disorder (past 6 months; except nicotine/caffeine)
• Lifetime ketamine, PCP, psychedelics, or MDMA use disorder
• Current use of MAO inhibitors, unless discontinued at least 14 days prior to dosing
• Psychedelic trial participation in past 12 months
• Cognitive impairment affecting valid assessment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High-Dose DMT → Remitters (No Re-dosing); Participants randomized to the high-dose DMT group (15 mg followed by 60 mg on Day 0) who achieve remission at Day 7 (MADRS ≤10) receive no further dosing and enter long-term follow-up.	Drug: N,N-Dimethyltryptamine (15 mg + 60 mg); Inhaled N,N-dimethyltryptamine (DMT) administered via a Volcano Medic 2 vaporizer in two inhalations 1 hour apart, using a high-dose regimen (15 mg + 60 mg).; Other Names: N,N-dimethyltryptamine; DMT
Experimental: High-Dose DMT → Non-Remitters (Open-Label Re-dosing); Participants randomized to the high-dose DMT group (15 mg followed by 60 mg on Day 0) who do not achieve remission at Day 7 (MADRS >10) receive an additional open-label high-dose session (15 mg followed by 60 mg) on Day 14 (±3 days), followed by long-term follow-up.	Drug: N,N-Dimethyltryptamine (15 mg + 60 mg); Inhaled N,N-dimethyltryptamine (DMT) administered via a Volcano Medic 2 vaporizer in two inhalations 1 hour apart, using a high-dose regimen (15 mg + 60 mg).; Other Names: N,N-dimethyltryptamine; DMT
Active Comparator: Low-Dose DMT → Remitters (No Re-dosing); Participants randomized to the low-dose DMT group (1 mg followed by 4 mg on Day 0) who achieve remission at Day 7 (MADRS ≤10) receive no further dosing and enter long-term follow-up.	Drug: N,N-Dimethyltryptamine (1 mg + 4 mg); Inhaled N,N-dimethyltryptamine (DMT) administered via a Volcano Medic 2 vaporizer in two inhalations 1 hour apart, using a low-dose regimen (1 mg + 4 mg).; Other Names: DMT; N,N-Dimethyltryptamine
Active Comparator: Low-Dose DMT → Non-Remitters (Open-Label Re-dosing); Participants randomized to the low-dose DMT group (1 mg followed by 4 mg on Day 0) who do not achieve remission at Day 7 (MADRS >10) receive an open-label high-dose session (15 mg followed by 60 mg) on Day 14 (±3 days), followed by long-term follow-up.	Drug: N,N-Dimethyltryptamine (15 mg + 60 mg); Inhaled N,N-dimethyltryptamine (DMT) administered via a Volcano Medic 2 vaporizer in two inhalations 1 hour apart, using a high-dose regimen (15 mg + 60 mg).; Other Names: N,N-dimethyltryptamine; DMT; Drug: N,N-Dimethyltryptamine (1 mg + 4 mg); Inhaled N,N-dimethyltryptamine (DMT) administered via a Volcano Medic 2 vaporizer in two inhalations 1 hour apart, using a low-dose regimen (1 mg + 4 mg).; Other Names: DMT; N,N-Dimethyltryptamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score (Antidepressant efficacy)	The MADRS is a clinician-rated scale used to evaluate the severity of depressive symptoms. It consists of 10 items, each rated from 0 to 6. The total score ranges from 0 to 60. Higher scores indicate greater severity of depression (worse outcome).	Baseline and Day 7 (D7) after the dosing session
Incidence of Suicidal Ideation and Behavior as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)	The C-SSRS is a standardized tool used to evaluate the occurrence, severity, and intensity of suicidal ideation and behavior. It assesses 5 levels of ideation (from "wish to be dead" to "active ideation with specific plan and intent") and 5 types of suicidal behavior. Results are reported as the number of participants who endorse any suicidal ideation or behavior (Yes/No) during the assessment period.	Day 1 post-intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score	The MADRS is a clinician-rated scale to monitor depression severity. Total score ranges from 0 to 60. Higher scores indicate greater severity of depression (worse outcome). This measure will assess the durability of the antidepressant effect in participants who achieved remission.	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Number and proportion of adverse events (AEs)	AEs defined by CTCAE v5.0, occurring after DMT administration and compared between study arms across assessment time points.	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Incidence of Suicidal Ideation and Behavior as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)	The C-SSRS is a standardized tool used to evaluate the occurrence, severity, and intensity of suicidal ideation and behavior. It assesses 5 levels of ideation (from "wish to be dead" to "active ideation with specific plan and intent") and 5 types of suicidal behavior. Results are reported as the number of participants who endorse any suicidal ideation or behavior (Yes/No) during the assessment period.	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Montgomery-Åsberg Depression Rating Scale - Suicidal Ideation (MADRS-SI, Item 10) Score (Antisuicidal efficacy)	This is a single item (Item 10) from the MADRS scale that specifically evaluates suicidal ideation. The score ranges from 0 to 6. Higher scores indicate greater severity of suicidal thoughts (worse outcome).	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Beck Scale for Suicide Ideation (BSI) Total Score	The Beck Scale for Suicide Ideation (BSI) is a 21-item instrument used to assess the severity of suicidal ideation. Each item is rated on a 3-point scale (0 to 2), yielding a total score ranging from 0 to 42. Higher scores indicate greater severity of suicidal ideation. Higher scores indicate a higher risk of suicide (worse outcome).	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Clinical Global Impression - Severity of Suicidality (CGI-SS) Score	The CGI-SS is a clinician-rated scale used to assess the patient's overall severity of suicidality. The scoring is strictly informed by the findings of the Columbia-Suicide Severity Rating Scale (C-SSRS) to ensure objective evaluation. The score ranges from 1 (normal, not at all suicidal) to 7 (among the most extremely suicidal patients). Higher scores indicate greater severity of suicidality (worse outcome).	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the State-Trait Anxiety Inventory (STAI)	The State-Trait Anxiety Inventory (STAI) is a 40-item self-report questionnaire that differentiates between temporary, situational anxiety (State) and long-term personality anxiety (Trait). It features two 20-item subscales rated on 4-point Likert scales, with higher scores indicating greater anxiety.	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Patient Health Questionnaire-9 (PHQ-9)	The PHQ-9 is a self-report tool for screening and monitoring depression. Scores range from 0 to 27. Higher scores indicate more severe depressive symptoms (worse outcome).	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Brief Psychiatric Rating Scale (BPRS)	A clinician-rated scale used to assess a range of psychiatric symptoms. In the 18-item version with 1-7 item scoring, total scores range from 18 to 126, with higher scores indicating greater severity of psychopathology.	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Young Mania Rating Scale (YMRS)	The YMRS is a clinician-rated scale to assess manic symptoms. Total scores range from 0 to 60. Higher scores indicate greater severity of mania (worse outcome).	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the World Health Organization Quality of Life - Abbreviated Version (WHOQOL-BREF).	The WHOQOL-BREF is a 26-item instrument that assesses quality of life across four domains: Physical health, Psychological, Social relationships, and Environment. Domain scores can be transformed to a 0-100 scale, with higher scores indicating better quality of life.	Baseline to 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the EuroQol 5-Dimension 3-Level (EQ-5D-3L) Questionnaire	The EuroQol 5-Dimension 3-Level (EQ-5D-3L) is a standardized instrument used to measure health outcomes. It comprises a descriptive system covering five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a Visual Analogue Scale (VAS). The VAS records the respondent's self-rated health on a vertical scale ranging from 0 ('Worst imaginable health state') to 100 ('Best imaginable health state'). Higher scores indicate a better health state.	Baseline to 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Psychedelic Experience Integration Scale (PEIS).	The Psychedelic Experience Integration Scale (PEIS) is an instrument designed to assess the extent to which individuals integrate insights from a psychedelic experience into their daily life. It evaluates domains such as behavioral change, psychological processing, and meaning-making following the experience. Total scores range from 0 to 60, with higher scores indicating greater integration of the psychedelic experience (better outcome).	Baseline to 1 month, 3 months, and 12 months post-intervention
Hallucinogen Rating Scale (HRS) Scores During DMT Administration	The HRS is a 100-item instrument designed to assess the subjective effects of hallucinogens across six domains: Somaesthesia, Affect, Perception, Cognition, Volition, and Intensity. Items are typically rated on a 0-4 scale. Higher scores indicate a more intense psychedelic experience.	Day of dosing (Day 0), assessed approximately 120 minutes post-administration.
Awe Experience Scale - Self Report (AWE-S) Scores During DMT Administration.	The Awe Experience Scale (AWE-S) is a self-report instrument used to assess dimensions of awe, including vastness, need for accommodation, and self-diminishment. It consists of 30 items, with higher scores indicating a more intense experience of awe.	Day of dosing (Day 0), assessed approximately 120 minutes post-administration.
Five-Dimensional Altered States of Consciousness Rating Scale (5D-ASC) Scores	The Five-Dimensional Altered States of Consciousness Rating Scale (5D-ASC) is a 94-item visual analogue scale (VAS) used to retrospectively assess subjective effects of psychoactive substances. It captures five core dimensions: Oceanic Boundlessness, Dread of Ego Dissolution, Visionary Restructuralization, Auditory Alterations, and Vigilance Reduction. Each item is rated from 0 to 100, with higher scores indicating greater alterations from normal waking consciousness. Scores are typically aggregated into dimension-specific and total scores.	Day of dosing (Day 0), assessed approximately 120 minutes post-administration
Change from Baseline in Blood Glucose Levels	Measurement of blood sugar concentration (mg/dL) to assess metabolic effect.	Baseline (pre-dose) and 120 minutes after the DMT session
Number of participants with clinically significant abnormal Lipid Profile values	Evaluation of lipid safety parameters, including Total Cholesterol, High-Density Lipoprotein (HDL), Low-Density Lipoprotein (LDL), and Triglycerides. Results will be reported as the number of participants who experienced treatment-emergent changes meeting pre-defined criteria for clinical significance (out-of-range values).	Baseline (pre-dose) and 120 minutes after the DMT session
Number of participants with clinically significant abnormal Liver Function laboratory values.	Evaluation of hepatic safety using Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT). Results will be reported as the number of participants whose values exceeded the upper limit of normal (ULN) meeting criteria for clinical significance. Measure: units per liter (U/L).	Baseline (pre-dose) and 120 minutes after the DMT session
Number of participants with clinically significant abnormal Renal Function laboratory values	Evaluation of kidney function through Serum Creatinine and Blood Urea levels. Results will be reported as the number of participants meeting pre-defined criteria for clinically significant out-of-range values. Marker of renal function (mg/dL).	Baseline (pre-dose) and 120 minutes after the DMT session
Change from Baseline in Serum Sodium levels	Measurement of electrolyte balance (mEq/L)	Baseline (pre-dose) and 120 minutes after the DMT session
Change from Baseline in Serum Potassium levels	Measurement of electrolyte balance (mEq/L)	Baseline (pre-dose) and 120 minutes after the DMT session
Change from Baseline in Prolactin Levels	Serum concentration of prolactin (ng/mL)	Baseline (pre-dose) and 120 minutes after the DMT session
Change from Baseline in Oxytocin Levels	Measurement of plasma oxytocin (pg/mL)	Baseline (pre-dose) and 120 minutes after the DMT session
Change from Baseline in Brain-Derived Neurotrophic Factor (BDNF) Levels	Serum concentration of BDNF (pg/mL)	Baseline (pre-dose) and 120 minutes after the DMT session
Change from Baseline in C-Reactive Protein (CRP) Levels	Measurement of high-sensitivity CRP (mg/L)	Baseline (pre-dose) and 120 minutes after the DMT session
Change from Baseline in Interleukin-6 (IL-6) Levels	Measurement of the pro-inflammatory cytokine IL-6 (pg/mL)	Baseline (pre-dose) and 120 minutes after the DMT session
Change from Baseline in Interleukin-10 (IL-10) Levels.	Measurement of the anti-inflammatory cytokine IL-10 (pg/mL).	Baseline (pre-dose) and 120 minutes after the DMT session
Number of participants with clinically significant abnormal Complete Blood Count (CBC) laboratory values	Evaluation of CBC safety parameters (including Red Blood Cells, Hemoglobin, Hematocrit, White Blood Cells, and Platelets). Results will be reported as the number of participants who experienced treatment-emergent changes meeting pre-defined criteria for clinical significance (out-of-range values).	Baseline (pre-dose) and 120 minutes after the DMT session
Change from Baseline in Tumor Necrosis Factor-alpha (TNF-a) Levels	Measurement of the pro-inflammatory cytokine TNF-alpha (pg/mL)	Baseline (pre-dose) and 120 minutes after the DMT session
Change from Baseline in Growth Hormone (GH) levels.	Serum concentration of GH (ng/mL)	Baseline (pre-dose) and at 2, 5, 10, 15, and 120 minutes after dosing on Day 0.
Change from Baseline in Beta-endorphin Levels.	Measurement of plasma beta-endorphin (pg/mL)	Baseline (pre-dose) and at 2, 5, 10, 15, and 120 minutes after dosing on Day 0.
Plasma Concentration of DMT	The concentration of N,N-Dimethyltryptamine achieved in the blood plasma after vaporized administration. Unit of Measure: Nanograms per milliliter (ng/mL).	Baseline (pre-dose) and at 2, 5, 10, 15, and 120 minutes after dosing on Day 0.
Change from Baseline in Cortisol Levels.	Measurement of serum cortisol (mcg/dL)	Baseline (pre-dose) and at 2, 5, 10, 15, and 120 minutes after dosing on Day 0.
Urinary Concentration of N,N-Dimethyltryptamine (DMT)	Quantitative measurement of unchanged DMT excreted in urine to assess the elimination profile of the substance after vaporized administration. Unit of Measure: Nanograms per milliliter (ng/mL).	150 minutes after the DMT session (D0)
Urinary Concentration of DMT-N-oxide (DMT-NO)	Quantitative measurement of DMT-N-oxide, a primary metabolite of DMT, to evaluate the metabolic pathway and clearance. Unit of Measure: Nanograms per milliliter (ng/mL).	150 minutes after the DMT session (D0)
Urinary Concentration of Indole-3-acetic acid (IAA).	Quantitative measurement of Indole-3-acetic acid, the major breakdown product of DMT metabolism via monoamine oxidase (MAO). Unit of Measure: Nanograms per milliliter (ng/mL).	150 minutes after the DMT session (D0)
Quantitative measurement of cortisol concentration in saliva samples	Measurement of salivary cortisol (mcg/dL)	Baseline (immediately before DMT administration), 40 minutes, and 60 minutes post-administration on dosing day (Day 0)
Subjective Intensity of the Psychedelic Experience via Visual Analogue Scale (VAS)	A participant-rated Visual Analogue Scale (VAS) used to measure the overall peak intensity of the subjective effects during the DMT session. The scale consists of a 100mm line where 0 represents "No effects at all" and 100 represents "Extremely intense effects." Higher scores indicate a more intense psychedelic experience. Unit of Measure: units on a scale (0-100).	Day of dosing (Day 0), assessed approximately 120 minutes post-administration
Affective Valence of the Psychedelic Experience via Visual Analogue Scale (VAS).	A participant-rated Visual Analogue Scale (VAS) used to measure the emotional quality (valence) of the experience. The scale is bipolar, ranging from -50 to +50, where -50 represents an "Extremely unpleasant/negative experience," 0 represents a "Neutral experience," and +50 represents an "Extremely pleasant/positive experience." Positive scores indicate a better outcome (pleasant experience), while negative scores indicate a worse outcome (unpleasant experience). Unit of Measure: units on a scale (-50 to +50).	Day of dosing (Day 0), assessed approximately 120 minutes post-administration
Change from Baseline in Heart Rate during acute DMT effects	Continuous monitoring of heart rate to assess the sympathomimetic effects of DMT. Data will be reported as the change from pre-dose levels. Unit of Measure: Beats per minute (bpm).	Baseline (pre-dose) up to 90 minutes post-administration
Change from Baseline in Systolic Blood Pressure during acute DMT effects.	Measurement of systolic blood pressure to monitor cardiovascular safety and potential transient hypertension during the experience. Unit of Measure: Millimeters of mercury (mmHg).	Time Frame: Baseline (pre-dose) up to 90 minutes post-administration.
Change from Baseline in Diastolic Blood Pressure during acute DMT effects.	Measurement of diastolic blood pressure to assess acute cardiovascular response. Unit of Measure: Millimeters of mercury (mmHg).	Baseline (pre-dose) up to 90 minutes post-administration.
Change from Baseline in Oxygen Saturation (SpO₂) during acute DMT effects.	Monitoring of blood oxygen levels via pulse oximetry to ensure respiratory safety during DMT administration. Unit of Measure: Percentage of oxygen saturation (%).	Baseline (pre-dose) up to 90 minutes post-administration.
Change from Baseline in Respiratory Rate during acute DMT effects.	Assessment of breaths per minute to evaluate the impact of DMT on the respiratory system. Unit of Measure: Breaths per minute.	Baseline (pre-dose) up to 90 minutes post-administration.
Change from Baseline in the Clinical Global Impression - Severity (CGI-S) Score	The Clinical Global Impression - Severity (CGI-S) is a clinician-rated scale used to assess the patient's overall severity of illness at the time of evaluation. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Death Attitude Profile-Revised (DAP-R) score	The Death Attitude Profile-Revised (DAP-R) is a 32-item multidimensional scale that assesses attitudes toward death across five domains: Fear of Death, Death Avoidance, Neutral Acceptance, Approach Acceptance, and Escape Acceptance. Items are rated on a 7-point Likert scale (1 = strongly disagree to 7 = strongly agree). Higher scores indicate greater endorsement of each respective attitude dimension.	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Credibility/Expectancy Questionnaire (CEQ) scores	The Credibility/Expectancy Questionnaire (CEQ) is a 6-item self-report measure developed to assess patients' beliefs in the credibility of a therapy and their expectations of improvement. It splits into two subscales: credibility (items 1-3) and expectancy (items 4-6). Subscale scores are computed by averaging the three items each (range 0-9 for credibility, and 0-9 for expectancy). Higher scores indicate greater perceived credibility and positive expectations	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Treatment Satisfaction Questionnaire for Medication (TSQM-9) scores	The Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a 9-item self-report instrument that assesses patients' satisfaction with a medication across three domains: Effectiveness, Convenience, and Global Satisfaction. Domain scores are transformed to a 0-100 scale, with higher scores indicating greater satisfaction with treatment (better outcome).	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Watts Connectedness Scale (WCS) score	The Watts Connectedness Scale (WCS) is a self-report questionnaire developed to measure feelings of connectedness to self, others, and the world, particularly in psychedelic therapy contexts. It has 19 items rated on a 0-100 visual analogue scale ("Not at all" to "Entirely"), reflecting experiences over the past 2 weeks.	Baseline to 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Duke University Religion Index (DUREL)	The Duke University Religion Index (DUREL) is a 5-item self-report instrument that assesses religious involvement across three dimensions: organizational religious activity (ORA), non-organizational religious activity (NORA), and intrinsic religiosity (IR). Higher scores indicate greater religious or spiritual involvement.	Baseline to 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Meaning in Life Questionnaire (MLQ)	The Meaning in Life Questionnaire (MLQ) is a 10-item self-report instrument that assesses two distinct dimensions of meaning in life: Presence of Meaning (MLQ-P) and Search for Meaning (MLQ-S). Each item is rated on a 7-point Likert scale ranging from 1 (Absolutely Untrue) to 7 (Absolutely True). Subscale scores range from 5 to 35.	Baseline to 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Big Five Inventory (BFI) domain scores	The Big Five Inventory (BFI) is a 44-item self-report inventory that assesses the Five Factor Model of personality: Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience. Each item is rated on a 5-point Likert scale. Domain scores are calculated for each trait and analyzed separately. This measure is used to evaluate potential changes in personality traits following the DMT experience. Changes such as reductions in Neuroticism or increases in Openness are commonly reported in psychedelic research and may be associated with positive psychological outcomes.	Baseline to 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Cognitive Triad Inventory (CTI) score	The Cognitive Triad Inventory (CTI) is a self-report instrument designed to assess the cognitive triad, encompassing views of the self, world, and future. It evaluates patterns of depressive and non-depressive thinking. Items are rated on a Likert scale, and total scores are calculated, with higher scores indicating more positive and adaptive cognitive patterns (better outcome).	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, and Day 7 post-intervention
Change from Post-Session in the Psychological Flexibility Scale (Psy-Flex) total score	The Psychological Flexibility Scale (Psy-Flex) is a 6-item self-report instrument designed to assess psychological flexibility based on the Acceptance and Commitment Therapy (ACT) hexaflex model. Each item is rated on a 5-point Likert scale ranging from 1 ("very rarely") to 5 ("very often"). Total scores range from 6 to 30, with higher scores indicating greater psychological flexibility (better outcome).	Baseline to 1 day post-intervention
World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) (12-item version) total score	The WHODAS 2.0 (12-item) is a self-report instrument assessing functioning across six domains: cognition, mobility, self-care, getting along, life activities, and participation. Each item is rated on a 5-point scale (1 = none to 5 = extreme/cannot do). Total scores are calculated by summing item responses (range 12-60), with higher scores indicating greater disability (worse outcome).	1 month, 3 months, and 12 months post-intervention.
Change from Baseline in the Positive and Negative Affect Schedule (PANAS) - Negative Affect (NA) score	The PANAS-NA is a 10-item subscale that assesses subjective distress and unpleasurable engagement, including states such as anger, contempt, and fear. Participants rate each item (e.g., "distressed," "guilty," "scared") on a 5-point Likert scale (1 = "very slightly or not at all" to 5 = "extremely"). The total subscale score ranges from 10 to 50. Higher scores indicate greater negative affect (worse outcome).	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Positive and Negative Affect Schedule (PANAS) - Positive Affect (PA) score	The PANAS-PA is a 10-item subscale that assesses the extent to which a person feels enthusiastic, active, and alert. Participants rate each item (e.g., "interested," "excited," "proud") on a 5-point Likert scale (1 = "very slightly or not at all" to 5 = "extremely"). The total subscale score ranges from 10 to 50. Higher scores indicate a greater level of positive affect (better outcome).	Baseline (pre-DMT session), 150 minutes post-DMT session (Day 0), Day 1, Day 7, Day 14, 1 month, 3 months, and 12 months post-intervention
Therapeutic alliance as measured by the Helping Alliance Questionnaire II (HAq-II) total score (patient-rated)	The HAq-II is a 19-item questionnaire assessing the quality of the therapeutic alliance. Both patients and therapists complete parallel versions of the instrument independently. Each item is rated on a 6-point Likert scale. Total scores range from 19 to 114, with higher scores indicating a stronger therapeutic alliance (better outcome).	Baseline (pre-DMT session), Day 1, and Day 7 post-intervention
Therapeutic alliance as measured by the Helping Alliance Questionnaire II (HAq-II) total score (therapist-rated)	The HAq-II is a 19-item questionnaire assessing the quality of the therapeutic alliance. Both patients and therapists complete parallel versions of the instrument independently. Each item is rated on a 6-point Likert scale. Total scores range from 19 to 114, with higher scores indicating a stronger therapeutic alliance (better outcome).	Baseline (pre-DMT session), Day 1, and Day 7 post-intervention
Change from Baseline in QTc Interval (ECG)	QTc interval measured by electrocardiogram. Values are expressed in milliseconds (ms). Higher values indicate greater risk of cardiac repolarization abnormalities (worse outcome).	Baseline (pre-DMT session), and 20 minutes post-DMT session (Day 0)

Collaborators and Investigators

• Sponsor: Universidade Federal do Rio Grande do Norte
• Collaborators: Financiadora de Estudos e Projetos

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: March 27, 2026
• First Submitted That Met QC Criteria: April 24, 2026
• First Posted (Actual): May 1, 2026

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 22, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: major depressive disorder; suicidality; N,N-dimethyltryptamine; DMT; non invasive; psychedelic therapy; inhaled DMT; vaporized DMT
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Self-Injurious Behavior; Mood Disorders; Depressive Disorder; Behavior; Suicide; Suicidal Ideation; Depressive Disorder, Major; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amines; Indoles; Biogenic Monoamines; Biogenic Amines; Tryptamines; N,N-Dimethyltryptamine
• Other Study ID Numbers: UFRN-DMT-MDD-IIb-2026; FINEP-0366/24 (Other Grant/Funding Number: Financiadora de Estudos e Projetos (FINEP) / National Fund for Scientific and Technological Development, Brazil)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Deidentified individual participant data underlying the results reported in this study will be shared. This includes demographic characteristics, baseline clinical data, treatment allocation, dosing information, outcome measures (e.g., MADRS total score and suicidal ideation item, C-SSRS, BSI), safety data (e.g., adverse events and vital signs), and follow-up assessments across study time points.

Data will be coded to protect participant identity and will not include any direct identifiers.

• IPD Sharing Time Frame: Data and supporting documents will be available beginning 12 months after publication of the primary results. There is no predefined end date for data availability.

IPD Sharing Access Criteria

Access to deidentified individual participant data and supporting documents will be granted to researchers who provide a methodologically sound research proposal. Requests will be reviewed by the study investigators and sponsoring institution.

Data will be shared for purposes consistent with the approved proposal, subject to institutional review, ethical approvals when applicable, and execution of a data use agreement. Access will be provided through secure transfer mechanisms to ensure data confidentiality and compliance with applicable regulations.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No