A Phase 2 interventional study of Psilocybin and modafinil in Major Depression, sponsored by VA Office of Research and Development. Not yet recruiting at 4 sites in United States. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2026-10-26.
Sponsored by VA Office of Research and Development · Phase 2, Interventional, and Treatment
More efficacious treatments for Major Depressive Disorder (MDD) in Veterans are urgently needed. Psilocybin is a promising novel treatment that is likely to be the first FDA-approved psychedelic, but its safety and efficacy remain unclear. To address this gap, the investigators propose a randomized controlled trial of a single dose of psilocybin paired with a brief course of a VA-endorsed evidence-based psychotherapy (Acceptance and Commitment Therapy) in Veterans with MDD. Our trial addresses key limitations of previous studies including the challenge of management of expectancy effects, a focus on Veterans with input from Veterans, and a study population that reflects the demographics and medical and psychiatric complexity of the VHA patient population. Our study also explores psilocybin's antidepressant mechanisms focusing on changes in psychological flexibility and synaptic plasticity. In sum, this study will provide critical and timely data to determine if psilocybin treatment is a safe and efficacious treatment for MDD in Veterans.
Major depressive disorder (MDD) affects 1 in 8 Veterans, leading to functional impairment, increased mortality, and high suicide risk. Veterans face complex psychiatric and medical comorbidities that often render conventional treatments inadequate, creating critical gaps in their mental health care. Psilocybin has emerged as a promising candidate treatment for MDD, but its safety and efficacy remain unclear. To address this gap, the investigators propose a four-site randomized clinical trial (RCT; N=120) to evaluate psilocybin-assisted Acceptance and Commitment Therapy (PACT) specifically for Veterans with MDD. The trial will determine if and how PACT decreases depressive and related symptoms, providing essential data that may lead to the development of a novel, efficacious treatment and guide potential VHA implementation. Our study incorporates Veteran input to ensure real-world relevance and addresses key limitations of previous psilocybin trials. The investigators will systematically evaluate safety, tolerability, and acceptability using gold-standard measures. PACT combines a single dose of psilocybin with a brief course of standardized, VA-endorsed ACT, overcoming issues of non-standardized psychotherapy that have hindered reproducibility and scalability. To tackle ineffective masking-which has plagued prior trials-the investigators employ a rigorous control condition pairing identical psychotherapy with a psychoactive multidrug placebo that mimics psilocybin's subjective effects, along with incomplete disclosure to minimize expectancy biases. A representative sample ensures generalizability to the VHA population, while mechanistic evaluations will inform a precision medicine approach that may extend to other disorders with similar neurobiological dysfunctions.
2,805 studies on the registry are indexed under Depressive Disorder, Major; 565 are open to participants now.
This study's planned enrollment of 150 is above the median of 80 across 2,338 interventional studies indexed under Depressive Disorder, Major.
Browse Depressive Disorder, Major studies →VA Office of Research and Development is the lead sponsor of 1,768 studies on the registry; 393 are open to participants now.
Of its 210 completed or terminated interventional studies of FDA-regulated products, 183 (87%) have results posted.
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Exclusion Criteria:
Participants will receive a single dose of 1-30mg of psilocybin, in addition to 3 other drugs: modafinil, zolpidem, pimavanserin. All participants will be masked to the probability of being assigned to a specific arm
Drug: Psilocybin · Drug: modafinil · Drug: zolpidem · Drug: pimavanserin
Participants will receive a single dose of 1-30mg of psilocybin, in addition to 2 other drugs: modafinil and zolpidem and placebo. All participants will be masked to the probability of being assigned to a specific arm
Drug: Psilocybin · Drug: modafinil · Drug: zolpidem
Participants will receive a single dose of 1-30mg of psilocybin, in addition to 2 other drugs: modafinil, pimavanserin, and placebo. All participants will be masked to the probability of being assigned to a specific arm
Drug: Psilocybin · Drug: modafinil · Drug: pimavanserin
Participants will receive a single dose of 1-30mg of psilocybin, in addition to 1 other drug: modafinil, and placebo. All participants will be masked to the probability of being assigned to a specific arm
Drug: Psilocybin · Drug: modafinil
Participants will receive a single dose of 1-30mg of psilocybin, in addition to 1 other drug: zolpidem, and placebo. All participants will be masked to the probability of being assigned to a specific arm
Drug: Psilocybin · Drug: zolpidem
Participants will receive a single dose of 1-30mg of psilocybin, in addition to 1 other drug: pimavanserin, and placebo. All participants will be masked to the probability of being assigned to a specific arm
Drug: Psilocybin · Drug: pimavanserin
Participants will receive a single dose of 1-30mg of psilocybin, and placebo. All participants will be masked to the probability of being assigned to a specific arm
Drug: Psilocybin
Participants will receive a single dose of 1-30mg of psilocybin, in addition to 2 other drugs: zolpidem, pimavanserin, and placebo. All participants will be masked to the probability of being assigned to a specific arm
Drug: Psilocybin · Drug: zolpidem · Drug: pimavanserin
1-30mg
FDA-approved dosage
FDA approved dosage
FDA-approved dosage
Hamilton Depression Rating Scale-6 (HAMD-6)
A clinician-administered, 6-item version of the Hamilton Depression Rating Scale that assesses core depressive symptoms including depressed mood, guilt, work and activities, psychomotor retardation, psychic anxiety, and somatic symptoms. Scores range from 0-22, with higher scores indicating greater depression severity. Administered at Baseline, Day 1, Day 7, Day 30, and Day 90.
Time frame: Baseline to 30 and 90 days post-drug administration
Change in EEG-measured LTP-like visual plasticity from baseline to Day 7, assessed by P1-N1b visual evoked potential amplitude (micro volts)
LTP-like cortical plasticity will be assessed using an EEG-based visual stimulation paradigm. Visual evoked potential (VEPs) will be recorded before and after 10 minutes of repetitive checkerboard stimulation at 2 Hz. Within-session potentiation will be quantified as the change in P1-N1b peak-to-peak VEP amplitude (micro-volts) from pre- to post-stimulation. The outcome measure is the change in within-session potentiation from baseline to Day 7 following study drug administration, calculated as the D7 potentiation minus baseline potentiation..
Time frame: Baseline to 7 days post-drug administration
Change in Multidimensional Psychological Flexibility Inventory (MPFI)
The Multidimensional Psychological Flexibility Inventory (MPFI) is a self-report questionnaire assessing psychological flexibility, the core therapeutic process in Acceptance and Commitment Therapy (ACT). The psychological flexibility score is calculated as the mean of six subscales: acceptance, present moment awareness, self as context, defusion, values, and committed action. Scores range from 1 to 6, with higher scores indicating greater psychological flexibility (better outcome).
Time frame: Baseline to 30 and 90 days post-drug administration
Change in Symptoms of Depression Questionnaire (SDQ)
The Symptoms of Depression Questionnaire (SDQ) is a 44-item self-report questionnaire assessing depressive symptoms across five domains: lassitude, mood, and cognitive functioning; anxiety, agitation, irritability, and anger; suicidal ideation; sleep disturbances; and appetite and weight changes. Each item is scored from 1 to 6, yielding a total score ranging from 44 to 264. Higher scores indicate greater depressive symptom severity (worse outcome). Administered at Baseline, Day 30, and Day 90. Endpoints include change from Baseline to Days 30 and 90 post-treatment.
Time frame: Baseline to 30 and 90 days post-drug administration
Change in Columbia-Suicide Severity Rating Scale - Suicidal Ideation Subscale (C-SSRS-SI)
The Columbia-Suicide Severity Rating Scale - Suicidal Ideation Subscale (C-SSRS-SI) is a structured assessment of suicidal ideation across five levels of increasing severity: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods, active suicidal ideation with intent, and active suicidal ideation with plan and intent. Scores range from 0 (no suicidal ideation) to 5 (active suicidal ideation with specific plan and intent), based on the highest severity level endorsed. Higher scores indicate more severe suicidal ideation (worse outcome). The score will be analyzed as a numerical measure of suicidal ideation severity. Trained study staff will administer the assessment at Baseline, Day 30, and Day 90. Endpoints include change from Baseline to Days 30 and 90 post-treatment.
Time frame: Baseline to 30 and 90 days post-drug administration
Change in WHO Disability Assessment 2.0 (WHODAS 2.0)
The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) is a self-report questionnaire assessing functional disability across six domains: cognition, mobility, self-care, getting along, life activities, and participation. Standardized total scores range from 0 (no disability) to 100 (complete disability), with higher scores indicating greater functional disability (worse outcome). Administered at Baseline, Day 30, and Day 90. Endpoints include change from Baseline to Days 30 and 90 post-treatment.
Time frame: Baseline to 30 and 90 days post-drug administration
Change in EEG Theta Band Phase Synchrony
Change in EEG theta-band (4-8 Hz) phase synchrony induced by repetitive visual stimulation, measured using intertrial coherence (ITC). ITC is a unitless measure ranging from 0 to 1, with higher values indicating greater consistency of neural oscillatory phase across trials. EEG assessments are performed at Baseline and Day 7, with changes in stimulation-induced ITC compared between visits.
Time frame: Baseline to 7 days post-drug administration.
Change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a centrally administered structured clinical interview assessing the 20 DSM-5 PTSD symptoms. The CAPS-5 provides both categorical PTSD diagnoses and continuous symptom severity scores. Each symptom is rated from 0 to 4, yielding a total severity score ranging from 0 to 80, with higher scores indicating greater PTSD symptom severity (worse outcome). Administered by trained, licensed clinical staff at Baseline and Day 30. The endpoint is change from Baseline to Day 30 post-drug administration.
Time frame: Baseline to 30 days post-drug administration
Change in EEG Theta Band Power
Change in EEG theta-band (4-8 Hz) power induced by repetitive visual stimulation, measured using a visual long-term potentiation (LTP)-like plasticity paradigm. EEG assessments are performed at Baseline and Day 7, with changes in stimulation-induced theta power compared between visits.
Time frame: Baseline to 7 days post-drug administration
Plan to share: No
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From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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