Randomized, Double-Blind, Placebo-Controlled Phase IIb Trial of Inhaled N,N-Dimethyltryptamine (DMT) for Major Depressive Disorder
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 140
- 试验地点
- 5
- 主要终点
- Change from Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score (Antidepressant efficacy)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
- •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
研究组 & 干预措施
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.
干预措施: N,N-Dimethyltryptamine (15 mg + 60 mg) (Drug)
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.
干预措施: N,N-Dimethyltryptamine (15 mg + 60 mg) (Drug)
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.
干预措施: N,N-Dimethyltryptamine (1 mg + 4 mg) (Drug)
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.
干预措施: N,N-Dimethyltryptamine (15 mg + 60 mg) (Drug)
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.
干预措施: N,N-Dimethyltryptamine (1 mg + 4 mg) (Drug)
结局指标
主要结局
Change from Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score (Antidepressant efficacy)
时间窗: Baseline and Day 7 (D7) after the dosing session
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).
Incidence of Suicidal Ideation and Behavior as Assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
时间窗: Day 1 post-intervention
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.
次要结局
- Change from Baseline in Blood Glucose Levels(Baseline (pre-dose) and 120 minutes after the DMT session)
- Change from Baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score(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)(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)(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)(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(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(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)(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)(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)(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)(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).(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(Baseline to 1 month, 3 months, and 12 months post-intervention)
- Change from Baseline in Prolactin Levels(Baseline (pre-dose) and 120 minutes after the DMT session)
- Change from Baseline in the Psychedelic Experience Integration Scale (PEIS).(Baseline to 1 month, 3 months, and 12 months post-intervention)
- Hallucinogen Rating Scale (HRS) Scores During DMT Administration(Day of dosing (Day 0), assessed approximately 120 minutes post-administration.)
- Awe Experience Scale - Self Report (AWE-S) Scores During DMT Administration.(Day of dosing (Day 0), assessed approximately 120 minutes post-administration.)
- Five-Dimensional Altered States of Consciousness Rating Scale (5D-ASC) Scores(Day of dosing (Day 0), assessed approximately 120 minutes post-administration)
- Number of participants with clinically significant abnormal Lipid Profile values(Baseline (pre-dose) and 120 minutes after the DMT session)
- Number of participants with clinically significant abnormal Liver Function laboratory values.(Baseline (pre-dose) and 120 minutes after the DMT session)
- Number of participants with clinically significant abnormal Renal Function laboratory values(Baseline (pre-dose) and 120 minutes after the DMT session)
- Change from Baseline in Serum Sodium levels(Baseline (pre-dose) and 120 minutes after the DMT session)
- Change from Baseline in Serum Potassium levels(Baseline (pre-dose) and 120 minutes after the DMT session)
- Change from Baseline in Oxytocin Levels(Baseline (pre-dose) and 120 minutes after the DMT session)
- Change from Baseline in Brain-Derived Neurotrophic Factor (BDNF) Levels(Baseline (pre-dose) and 120 minutes after the DMT session)
- Change from Baseline in C-Reactive Protein (CRP) Levels(Baseline (pre-dose) and 120 minutes after the DMT session)
- Change from Baseline in Interleukin-6 (IL-6) Levels(Baseline (pre-dose) and 120 minutes after the DMT session)
- Change from Baseline in Interleukin-10 (IL-10) Levels.(Baseline (pre-dose) and 120 minutes after the DMT session)
- Number of participants with clinically significant abnormal Complete Blood Count (CBC) laboratory values(Baseline (pre-dose) and 120 minutes after the DMT session)
- Change from Baseline in Tumor Necrosis Factor-alpha (TNF-a) Levels(Baseline (pre-dose) and 120 minutes after the DMT session)
- Change from Baseline in Growth Hormone (GH) levels.(Baseline (pre-dose) and at 2, 5, 10, 15, and 120 minutes after dosing on Day 0.)
- Change from Baseline in Beta-endorphin Levels.(Baseline (pre-dose) and at 2, 5, 10, 15, and 120 minutes after dosing on Day 0.)
- Plasma Concentration of DMT(Baseline (pre-dose) and at 2, 5, 10, 15, and 120 minutes after dosing on Day 0.)
- Change from Baseline in Cortisol Levels.(Baseline (pre-dose) and at 2, 5, 10, 15, and 120 minutes after dosing on Day 0.)
- Urinary Concentration of N,N-Dimethyltryptamine (DMT)(150 minutes after the DMT session (D0))
- Urinary Concentration of DMT-N-oxide (DMT-NO)(150 minutes after the DMT session (D0))
- Urinary Concentration of Indole-3-acetic acid (IAA).(150 minutes after the DMT session (D0))
- Quantitative measurement of cortisol concentration in saliva samples(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)(Day of dosing (Day 0), assessed approximately 120 minutes post-administration)
- Affective Valence of the Psychedelic Experience via Visual Analogue Scale (VAS).(Day of dosing (Day 0), assessed approximately 120 minutes post-administration)
- Change from Baseline in Heart Rate during acute DMT effects(Baseline (pre-dose) up to 90 minutes post-administration)
- Change from Baseline in Systolic Blood Pressure during acute DMT effects.(Time Frame: Baseline (pre-dose) up to 90 minutes post-administration.)
- Change from Baseline in Diastolic Blood Pressure during acute DMT effects.(Baseline (pre-dose) up to 90 minutes post-administration.)
- Change from Baseline in Oxygen Saturation (SpO₂) during acute DMT effects.(Baseline (pre-dose) up to 90 minutes post-administration.)
- Change from Baseline in Respiratory Rate during acute DMT effects.(Baseline (pre-dose) up to 90 minutes post-administration.)
- Change from Baseline in the Clinical Global Impression - Severity (CGI-S) Score(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(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(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(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(Baseline to 1 month, 3 months, and 12 months post-intervention)
- Change from Baseline in the Duke University Religion Index (DUREL)(Baseline to 1 month, 3 months, and 12 months post-intervention)
- Change from Baseline in the Meaning in Life Questionnaire (MLQ)(Baseline to 1 month, 3 months, and 12 months post-intervention)
- Change from Baseline in the Big Five Inventory (BFI) domain scores(Baseline to 1 month, 3 months, and 12 months post-intervention)
- Change from Baseline in the Cognitive Triad Inventory (CTI) score(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(Baseline to 1 day post-intervention)
- World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) (12-item version) total score(1 month, 3 months, and 12 months post-intervention.)
- Change from Baseline in the Positive and Negative Affect Schedule (PANAS) - Negative Affect (NA) score(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(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)(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)(Baseline (pre-DMT session), Day 1, and Day 7 post-intervention)
- Change from Baseline in QTc Interval (ECG)(Baseline (pre-DMT session), and 20 minutes post-DMT session (Day 0))
- Change from Baseline in the Psychedelic Integration Scales (PIS)(Baseline to 1 month, 3 months, and 12 months post-intervention)
- Change from Baseline in Brain-Derived Neurotrophic Factor (BDNF) Serum Levels(Baseline (pre-dose) and 1 day after the DMT session)
- Change from Baseline in The Clinical Global Impression-Improvement (CGI-I) Score(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 Cognitive Triad Inventory (CTI) score(Baseline to 1 day, 7 days, and 12 months post-intervention)
- Change from Post-Session in the Psychological Flexibility Scale (Psy-Flex) total score(Baseline to 7 days, and 12 months post-intervention)
研究者
Draulio Barros de Araujo
PhD, Full Professor at Brain Institute (Instituto do Cérebro - ICe), Federal University of Rio Grande do Norte (UFRN)
Universidade Federal do Rio Grande do Norte