Psilocybin Intervention for Veterans Overcoming Treatment-Resistant Depression

NCT ID: NCT07226232

Last Updated: 2025-11-10

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

NOT_YET_RECRUITING

Clinical Phase

PHASE3

Total Enrollment

240 participants

Study Classification

INTERVENTIONAL

Study Start Date

2026-06-01

Study Completion Date

2031-04-30

Brief Summary

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The purpose of this multi-site randomized controlled trial is to evaluate the efficacy and risks of psilocybin for the treatment of depression in U.S. military Veterans with and without (±) concurrent posttraumatic stress disorder.

Detailed Description

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Treatment-resistant depression (TRD) is a serious mental health problem in Veterans, frequently comorbid with post-traumatic stress disorder (PTSD), and in need of novel and effective treatments. Clinical studies have revealed antidepressant effects of psilocybin for depression in civilians, but less is known about its efficacy and safety in Veterans. Very limited data is available on the effects of psilocybin in the treatment of PTSD. Thus, it is important to evaluate the safety and efficacy of psilocybin in the treatment of TRD with and without PTSD among Veterans.

The purpose of this multi-site, double-blind, randomized controlled trial is to evaluate the efficacy and risks of psilocybin for the treatment of TRD in U.S. military Veterans with and without (±) concurrent PTSD. Eligible and consenting Veterans will two psilocybin dosing sessions along with preparation, administration, and integration psychological support provided by a facilitator. For the 1st psilocybin administration, participants will be randomized to one of two doses under blinded conditions. One month later, all participants will receive a 25mg dose at their 2nd psilocybin visit. Outcomes will be measured by an independent evaluator masked from all treatments at 2 and 4 weeks after each dosing session. Longer-term follow-up will be conducted over 6 months. Both expected and unanticipated adverse events will be collected by type, severity and relatedness to the study drug.

Conditions

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Major Depression

Keywords

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depression psilocybin veterans post-traumatic stress disorder

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Enrolled participants who meet eligibility criteria and attend 3 preparatory visits with a psychological support facilitator will be randomized to either the control group or the intervention group in parallel until the primary endpoint at week 4 post randomization.
Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors
Only pharmacist will know the treatment assignment. All others are masked to treatment assignment.

For the 1st of 2 dosing sessions, Veterans are randomized to receive one of two doses of psilocybin. One month later, participants return for a 2nd psilocybin dosing session in which all participants get the same dose of psilocybin.

Study Groups

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Control

Psilocybin comparator dose

Group Type ACTIVE_COMPARATOR

Psilocybin

Intervention Type DRUG

Psilocybin comparator dose

Intervention

Psilocybin intervention dose

Group Type EXPERIMENTAL

Psilocybin

Intervention Type DRUG

Psilocybin Intervention Dose

Interventions

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Psilocybin

Psilocybin comparator dose

Intervention Type DRUG

Psilocybin

Psilocybin Intervention Dose

Intervention Type DRUG

Other Intervention Names

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COMP360 COMP360

Eligibility Criteria

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Inclusion Criteria

* Veteran of the U.S. military who is English-speaking
* Signed informed consent and HIPAA
* Adults \</= 75 years of age
* Meets DSM-5 criteria for current major depressive episode (MDE)
* MADRS \>/= 20 at baseline
* Failure to respond satisfactorily to \>/= 2 antidepressant treatments for \>/= 8 weeks, including \>/= 2 weeks at an adequate dose (\>/= 50% of the FDA-approved uppermost dose) for major depression. Augmentation with a medication for depression (e.g., neuroleptics, lithium, levothyroxine) is considered a separate course of treatment.
* If applicable, concurrent \& permitted antidepressants must be at stable doses for \>/= 4 weeks prior to baseline (see allowed \& prohibited medication list)
* Participants of child-bearing potential must have negative pregnancy test \& agree to adhere to a medically acceptable method of birth control during the study
* Has a responsible adult who will provide transportation to the participant's home or place of lodging on the days of psilocybin administration

Exclusion Criteria

* Lifetime bipolar, schizophrenia spectrum, or other psychotic disorders
* First-degree relative with history of bipolar I, schizophrenia spectrum or other psychotic disorder
* Presence of psychotic symptoms (e.g., MDE with psychotic symptoms)
* Sedative-hypnotic, stimulant, inhalant and/or opioid use disorder within past 6 months (lifetime substance use disorder is allowed at the discretion of the LSI)
* Severe alcohol and/or cannabis use disorder within the past 6 months (mild or moderate alcohol and/or cannabis use is allowed at the discretion of the LSI)
* Lifetime hallucinogen persisting perception or hallucinogen use disorders
* Use of psilocybin, ayahuasca, mescaline, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), peyote, or 3,4-methylenedioxymethamphetamine (MDMA) within past 6 months
* Participant agrees to not use psychedelics (listed above) during the study, except as prescribed by the study protocol
* Taking prohibited medication within 2 weeks of baseline (see allowed and prohibited concomitant medication list)
* History of severe traumatic brain injury (TBI)
* Diagnosis of dementia or related progressive neurocognitive disorder
* Suicidal ideation/behavior Type 4 or Type 5 intensity on C-SSRS within past 6 months of baseline
* Psychiatric inpatient treatment within past 3 months of baseline
* Treatment with electroconvulsive therapy, deep brain stimulation, vagus nerve stimulation, or transcranial magnetic stimulation within 3 months of baseline
* Implanted central nervous system device
* Treatment with evidence-based psychotherapy (EBP) for MDD or PTSD within 2 weeks prior to baseline. If receiving EBP therapy, he/she must complete treatment at least 2 weeks prior to baseline. Other forms of non-EBP psychotherapy for MDD or PTSD are allowed to continue during the study period.
* Pregnancy or lactation, or anticipated pregnancy or breastfeeding during the active treatment phase
* History of myocardial infarction, congestive heart failure, diabetic ketoacidosis, brain cancer, stroke and/or severe cardiac disease
* Clinically significant cardiac, pulmonary, renal, liver and/or other medical disease that, in the opinion of the investigator, may contraindicate the use of psilocybin, interfere with the interpretation of study results and/or constitute a health risk for the participant if they take part in the study
* Seizure disorder, except for seizures due to fever or withdrawal from a substance
* Clinically significant hypertension (\>160/95 mmHg), hypotension (\<90/60 mmHg) tachycardia (\>100 bpm at rest), QTc prolongation (\>450 msec men; \>470 msec women) or clinically significant arrhythmia on ECG
* Clinically significant abnormal laboratory results on chemistry panel, liver function tests, complete blood count, and/or thyroid stimulating hormone
* Positive urine drug screen for illicit drugs of abuse (except for THC) at screening or baseline
* Prior allergic, adverse reaction or adverse experience to a psilocybin formulation
* Litigating for disability income for a mental disorder outside the VA compensation and pension process
Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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VA Office of Research and Development

FED

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Lori Lynne Davis, MD AB

Role: PRINCIPAL_INVESTIGATOR

Birmingham VA Medical Center, Birmingham, AL

Locations

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Birmingham VA Medical Center, Birmingham, AL

Birmingham, Alabama, United States

Site Status

Tuscaloosa VA Medical Center, Tuscaloosa, AL

Tuscaloosa, Alabama, United States

Site Status

VA Portland Health Care System, Portland, OR

Portland, Oregon, United States

Site Status

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Philadelphia, Pennsylvania, United States

Site Status

VA Puget Sound Health Care System Seattle Division, Seattle, WA

Seattle, Washington, United States

Site Status

Countries

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United States

Central Contacts

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Lori L Davis, MD AB

Role: CONTACT

Phone: (205) 554-3819

Email: [email protected]

Anchal Ghera, MS

Role: CONTACT

Phone: (205) 899-1273

Email: [email protected]

Facility Contacts

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Lori L Davis, MD AB

Role: primary

Anchal Ghera, MS

Role: backup

Patricia Pilkinton, MD

Role: primary

Kaleb Murry, MS

Role: backup

Christopher Stauffer, MD

Role: primary

Michael Thase, MD

Role: primary

Rebecca Hendrickson, MD

Role: primary

Other Identifiers

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MHBC-002-25S

Identifier Type: -

Identifier Source: org_study_id