Major DepressionPhase 3PIVOTNCT07226232
Psilocybin Intervention for Veterans Overcoming Treatment-Resistant Depression
A Phase 3 study testing Psilocybin in people with Major Depression, run by VA Office of Research and Development at 5 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Major Depression
- What is being tested?
- Psilocybin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 240 participants
- Where
- 5 sitesUnited States
- Study dates
- 3 Aug 2026to 30 Jun 2031
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Veteran of the U.S. military who is English-speaking
- Signed informed consent and Health Insurance Portability and Accountability Act (HIPAA)
- Adults </= 75 years of age
- Meets DSM-5 criteria for current major depressive episode (MDE)
- Montgomery-Asberg Rating Scale (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.
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- 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
Who cannot join
- 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
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- 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 XX 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
Trial locations and contacts
5 sites in 1 country. Contact the study team or a site near you to ask about taking part.
5 sites in 1 country
United States5 sites, 5 recruiting
- Recruiting
Birmingham VA Medical Center, Birmingham, AL
Birmingham, Alabama, 35233-1927
Lori L Davis, MD AB, (205) 554-3819, lori.davis@va.gov
Anchal Ghera, MS, (205) 899-1273, anchal.ghera@va.gov
- Recruiting
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
Philadelphia, Pennsylvania, 19104-4551
Michael Thase, MD, 215-823-5903, michael.thase@va.gov
Mora Grehl, PhD, 2158235800 ext. 20-7888
- Recruiting
VA Portland Health Care System, Portland, OR
Portland, Oregon, 97207-2964
Christopher Stauffer, MD, 971-710-6204
Audrey Shoultz, MS, 9717106204, audrey.shoultz@va.gov
- Recruiting
VA Puget Sound Health Care System Seattle Division, Seattle, WA
Seattle, Washington, 98108-1532
Rebecca Hendrickson, MD, 206-277-1337, rebecca.hendrickson@va.gov
Renata Daniels, MS, 2062771337
- Recruiting
Tuscaloosa VA Medical Center, Tuscaloosa, AL
Tuscaloosa, Alabama, 35404-5015
Patricia Pilkinton, MD, 205-554-2000 ext. 4392
Kaleb Murry, MS, 2055542000 ext. 4392, kaleb.murry@va.gov
About this study
Official title: 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.
Read the 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 the same 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
- Major Depression
- Being tested
- Psilocybin
- Keywords
- depression, psilocybin, veterans, post-traumatic stress disorder
- Medical subject headings
- Depressive Disorder, Major, Depression, Stress Disorders, Post-Traumatic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PsilocybinDrug
Also called COMP360
Psilocybin comparator dose
PsilocybinDrug
Also called COMP360
Psilocybin Intervention Dose
| Study group | Role | What they receive |
|---|---|---|
| Control | Active comparator | Psilocybin comparator dose Receives: Drug: Psilocybin |
| Intervention | Experimental | Psilocybin intervention dose Receives: Drug: Psilocybin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Montgomery-Asberg Rating Scale (MADRS)
10-item clinician-administered rating scale for depression. Scored 0 to 60; higher score indicates more severe symptomatology.
Measured: 2 weeks
Secondary outcomes (1)
Swiss Psychedelic Side Effects Inventory Overall Score
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.
Measured: one day
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Nov 2025
- Study start3 Aug 2026
- Primary completion2 Dec 2030 (estimated)
- Study completion30 Jun 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Major DepressionStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 240 participants (estimated)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Lori Lynne Davis, MD AB, Principal investigator, Birmingham VA Medical Center, Birmingham, AL
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07226232
- Sponsor's protocol ID
- MHBC-002-25S
- Other IDs
- 1I01RD001520-01A1
- Acronym
- PIVOT
- Status last verified
- Oct 2026
- First submitted
- 5 Nov 2025
- Last updated
- 23 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-identified data and a data dictionary will be shared pending required IRB approval, and if needed, a Data Use Agreement.