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.
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 objective is to compare the two treatment groups with respect to change in total MADRS score from baseline to Day 7. 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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
140
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).
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).
Hospital de Saúde Mental Professor Frota Pinto
Fortaleza, Ceará, Brazil
NOT_YET_RECRUITINGComplexo Hospitalar Universitário Professor Edgard Santos, Federal University of Bahia (HUPES-UFBA)
Salvador, Estado de Bahia, Brazil
NOT_YET_RECRUITINGInstituto de Psiquiatria da Universidade Federal do Rio de Janeiro (IPUB-UFRJ)
Rio de Janeiro, Rio de Janeiro, Brazil
NOT_YET_RECRUITINGHospital Universitário Onofre Lopes - HUOL - UFRN
Natal, Rio Grande do Norte, Brazil
RECRUITINGInstituto de Psiquiatria - Hospital das Clínicas - IPq - HC - USP
São Paulo, São Paulo, Brazil
NOT_YET_RECRUITINGChange 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).
Time frame: Baseline and Day 7 (D7) after the dosing session
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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: Baseline to 1 month, 3 months, and 12 months post-intervention
Change from Baseline in the Psychedelic Integration Scales (PIS)
The Psychedelic Integration Scales (PIS) is a 24-item self-report instrument designed to assess internal and experiential aspects of how an individual integrates insights from a psychedelic experience into their daily life. Each item is scored on a 5-point Likert scale ranging from 1 (Strongly Disagree) to 5 (Strongly Agree). Total scores are calculated by summing the items and range from 24 to 120, where higher scores indicate a greater internal sense of psychedelic integration (better outcome).
Time frame: Baseline to 1 month, 3 months, and 12 months post-intervention
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.
Time frame: Day of dosing (Day 0), assessed approximately 120 minutes post-administration
Change from Baseline in Brain-Derived Neurotrophic Factor (BDNF) Serum Levels
Change from baseline in serum brain-derived neurotrophic factor (BDNF) levels, measured in nanograms per milliliter (ng/mL). Positive values indicate an increase in serum BDNF levels from baseline, with greater increases representing a more favorable outcome.
Time frame: Baseline (pre-dose) and 1 day after the DMT session
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).
Time frame: 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).
Time frame: 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).
Time frame: 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: 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).
Time frame: 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 (%).
Time frame: 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).
Time frame: 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-Improvement (CGI-I) Score
The Clinical Global Impression-Improvement (CGI-I) is a clinician-rated scale that assesses the patient's overall clinical improvement relative to baseline. Scores range from 1 (very much improved) to 7 (very much worse), with lower scores indicating greater clinical improvement. Time Frame: 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.
Time frame: 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.
Time frame: 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 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: Baseline to 1 day, 7 days, and 12 months 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).
Time frame: Baseline to 7 days, and 12 months 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).
Time frame: 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).
Time frame: 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).
Time frame: 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
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