Psilocybin Intervention for Veterans Overcoming Treatment-Resistant Depression (PIVOT)

June 3, 2026 updated by: VA Office of Research and Development

A Multi-site Randomized Controlled Trial of Psilocybin for Treatment-Resistant Depression (TRD) in Veterans

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
240

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233-1927
        • Birmingham VA Medical Center, Birmingham, AL
        • Contact:
        • Principal Investigator:
          • Lori Lynne Davis, MD AB
        • Contact:
      • Tuscaloosa, Alabama, United States, 35404-5015
    • Oregon
      • Portland, Oregon, United States, 97207-2964
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104-4551
        • Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
        • Contact:
    • Washington
      • Seattle, Washington, United States, 98108-1532
        • VA Puget Sound Health Care System Seattle Division, Seattle, WA
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: Control
Psilocybin comparator dose
Drug: Psilocybin
Psilocybin comparator dose
Other Names:
  • COMP360
Drug: Psilocybin
Psilocybin Intervention Dose
Other Names:
  • COMP360
Experimental: Intervention
Psilocybin intervention dose
Drug: Psilocybin
Psilocybin comparator dose
Other Names:
  • COMP360
Drug: Psilocybin
Psilocybin Intervention Dose
Other Names:
  • COMP360

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Montgomery-Asberg Rating Scale (MADRS)
Time Frame: 2 weeks
10-item clinician-administered rating scale for depression. Scored 0 to 60; higher score indicates more severe symptomatology.
2 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Swiss Psychedelic Side Effects Inventory Overall Score
Time Frame: one day
A clinician guided self-report form that has a list of effects pertaining to psychedelics; has the option to add other side effects (or expected effects) as desired and includes an open text field to provide additional details that are not captured in the inventory list. In addition to rating severity of the side effects, the SPSI captures impact, causality, timing and duration, and has a global rating on tolerability. Scoring: Calculate total scores for the number of side effects, severity, and impact by adding the relevant columns. Calculate total scores for the number of side effects, severity, and impact by adding the relevant columns. The overall score is calculated by subtracting total severity from total impact. The overall score represents the burden of side effects for that person within the specified timeframe.
one day

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Clinician-Administered PTSD Scale for DSM-5 - Revised
Time Frame: one month
A 30-item interview used to rate the past-month PTSD severity in those participants diagnosed with PTSD by CAPS-5-R at baseline. Higher score (0 to 200) indicates higher PTSD severity.
one month
Hamilton Depression Rating Scale
Time Frame: two weeks
A validated rater-administered measure of depression severity. The 17-item version yields a score of 0 to 50; higher score indicates more severe depression.
two weeks
Patient Health Questionnaire 9
Time Frame: two weeks
A 9-item self-report measure designed to characterize severity of depression; has excellent psychometrics, total score range 0 to 27, higher = more severe.
two weeks
PTSD Checklist for DSM-5
Time Frame: one month
A 20-item self-report of PTSD symptoms; score 0-80; higher=more severe. Only collected in those with PTSD diagnosis at baseline.
one month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
VA Office of Research and Development

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Lori Lynne Davis, MD AB, Birmingham VA Medical Center, Birmingham, AL

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 30, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 2, 2030

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 30, 2031

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 5, 2025

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 6, 2025

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
November 10, 2025

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 5, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 3, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • MHBC-002-25S

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified data and a data dictionary will be shared pending required IRB approval, and if needed, a Data Use Agreement.

IPD Sharing Time Frame

At the conclusion of the study after a data repository has been made operational.

IPD Sharing Access Criteria

De-identified data of those participants who signed informed consent, to include baseline demographics and clinical characteristics, primary outcome measure over time, treatment assignment, secondary safety outcomes, and exploratory outcomes. Data will be available for 6 years after the closure of the main study.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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