Clinical TrialTreatment-Resistant Depression (TRD)PsilocybinPsilocybinNot yet recruiting

Psilocybin Intervention for Veterans Overcoming Treatment-Resistant Depression

This Phase III, randomised, quadruple‑masked, parallel trial (n=240) will evaluate the efficacy and risks of psilocybin for treatment‑resistant depression in U.S. military veterans with and without concurrent post‑traumatic stress disorder, with the primary outcome being change in the Montgomery‑Åsberg Depression Rating Scale (MADRS) at 2 weeks. This multi‑site study randomises participants to either a psilocybin intervention dose or a psilocybin comparator dose under blinded conditions. Consenting veterans will receive two psilocybin dosing sessions with psychological preparation, administration and integration support from a facilitator; participants are randomised at the first administration to one of the two doses and one month later all participants receive a 25 mg dose at the second session. Outcomes are measured by an independent evaluator masked to treatment at 2 and 4 weeks after each dosing session, with longer‑term follow‑up over 6 months, and both expected and unanticipated adverse events collected. Key eligibility includes English‑speaking U.S. veterans aged 18–75 years with a current major depressive episode (MADRS ≥20) who have not responded to ≥2 adequate antidepressant treatments.

Target Enrollment
240 participants
Study Type
Phase III interventional
Design
Randomized, quadruple Blind

Detailed Description

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 Arms & Interventions

Control

active comparator

Psilocybin comparator dose

Interventions

  • Psilocybin

Intervention

experimental

Psilocybin intervention dose

Interventions

  • Psilocybin

Participants

Ages
18 – 75
Sexes
Male & Female

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

  • 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 Details

Study Team

Sponsors & Collaborators

Locations

Birmingham VA Medical Center, Birmingham, AL — Birmingham, Alabama, United States
Tuscaloosa VA Medical Center, Tuscaloosa, AL — Tuscaloosa, Alabama, United States
VA Portland Health Care System, Portland, OR — Portland, Oregon, United States
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA — Philadelphia, Pennsylvania, United States
VA Puget Sound Health Care System Seattle Division, Seattle, WA — Seattle, Washington, United States

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