Clinical TrialPsilocybinPlaceboPsilocybinPlaceboRecruiting

RCT of Psilocybin-assisted CBT for Depression

This Phase I/II, randomised trial (n=50) will evaluate the acceptability and feasibility of psilocybin-assisted cognitive behavioural therapy (PA-CBT) for patients with major depressive disorder (MDD). Participants will receive either 12 sessions of CBT combined with two doses of psilocybin (10 mg and 25 mg, taken orally) or 6 sessions of minimal supportive therapy alongside the same psilocybin doses. The primary objectives include assessing the integration of psilocybin with psychotherapy and examining its clinical benefits as an adjunct to CBT. In this two-arm trial, participants in the experimental group will undergo a structured CBT programme, which includes psychoeducation and skills training, while those in the active comparator group will receive supportive therapy focused on preparation and integration of the psilocybin experience. Both groups will have a one-month interval between the two psilocybin sessions. Key outcome measures will include client satisfaction, retention rates, and changes in depression severity as assessed by the Hamilton Depression Rating Scale over a follow-up period of seven months. The study is set to begin in January 2026 and aims for completion by November 2027.

Target Enrollment
50 participants
Study Type
Phase I/II interventional
Design
Randomized, double Blind

Detailed Description

The primary objectives of this clinical investigation are to (1) determine the acceptability and feasibility of joining psilocybin-assisted therapy with cognitive-behavioral therapy (PA-CBT) for patients with depression, (2) optimize CBT to most effectively integrate the psilocybin experience with psychotherapy and (3) examine the clinical benefit of psilocybin as an adjunct to cognitive-behavioral therapy (CBT) for major depressive disorder.

This study is a randomized, two-arm, fixed dose trial that will test the feasibility, acceptability, and participant and therapist adherence to PA-CBT. Both treatment arms will receive two doses of psilocybin (10mg and then 25mg, separated by one month). In Phase II, participants will be randomized (1:1) to either a 12-session PA-CBT or a 6-session standard psilocybin-assisted therapy (PAT) condition (3 hours of preparation plus 3 hours of supportive therapy integration following the psilocybin experiences).

Study Arms & Interventions

Experimental: Psilocybin + CBT

experimental

Participants will receive 12 sessions of cognitive-behavioral therapy (CBT) along with two psilocybin-drug sessions -- the first following the third CBT session (10mg of psilocybin, taken orally) and the second following the sixth CBT session (25mg of psilocybin, taken orally).

Interventions

  • Psilocybin
  • Placebo
    • 12 sessions

    Unmatched intervention: cognitive behavioral therapy

Psilocybin + Minimal supportive therapy

active comparator

Participants will receive 6 sessions of supportive, non-directive therapy along with two psilocybin-drug sessions -- the first following the third therapy session (10mg of psilocybin, taken orally) and the second following the fourth therapy session (25mg of psilocybin, taken orally).

Interventions

  • Psilocybin
  • Placebo
    • 6 sessions

    Unmatched intervention: Minimal supportive therapy

Participants

Ages
21 – 60
Sexes
All

Inclusion Criteria

  • Ages 21-60,
  • * Able to swallow capsules,
  • * Patients with a current major depressive episode or a history of major depressive episodes based on the DSM-5 criteria (American Psychiatric Association, 2013),
  • * Active current depressive symptoms (i.e., scores \>16 on the Hamilton-Depression Rating Scale (HAM-D) covering the prior 2 weeks; Hamilton, 1986),
  • * Have an identified support person who can pick up the individual from UCLA Semel Institute and drive individual home following psilocybin sessions,
  • * For women of child-bearing potential - using one form of highly effective contraception (e.g., oral contraceptive pill) and willingness to continue contraceptive use for duration of study
  • * Patient has been medically cleared for the study by a physician.

Exclusion Criteria

  • A personal or family history (first or second-degree) of psychosis or bipolar disorder
  • * Resting blood pressure above 140 systolic, 90 diastolic (averaged across four separate measurements)
  • * Meeting criteria for a DSM-5 cluster B personality disorder (narcissistic, histrionic, borderline, antisocial personality disorder),
  • * Active suicidality (as indicated by a 3 or greater on item 3 of the HAM-D) or other psychiatric disturbance requiring acute treatment
  • * Current use of antidepressants or other serotonergic-affecting substances (e.g., St. John's Wort and 5-hydroxytryptophan),
  • * Currently receiving cognitive behavioral therapy,
  • * Any of the following cardiovascular conditions: uncontrolled hypertension, coronary artery disease, congenital long QT syndrome, cardiac hypertrophy, cardiac ischemia, congestive heart failure, myocardial infarction, tachycardia, artificial heart valve, a clinically significant screening ECG abnormality, or any other significant cardiovascular condition
  • * A history of stroke or Transient Ischemic Attack (TIA)
  • * Epilepsy or history of seizures
  • * Insulin-dependent diabetes
  • * Meeting criteria for a DSM-5 substance abuse or dependence within prior 6 months
  • * Positive urine drug screen for illicit substances
  • * Use of other psychedelics or ketamine within prior 12 months
  • * Adverse prior reaction to a psychedelic agent
  • * Pregnant, trying to get pregnant, or nursing

Study Details

  • Status
    Recruiting
  • Phase
    Phase IPhase II
  • Type
    interventional
  • Design
    Randomizeddouble Blind
  • Target Enrollment50 participants
  • Timeline
    Start: 2026-01-05
    End: 2027-11-30
  • Compounds
    PsilocybinPlaceboPsilocybinPlacebo

Study Team

Locations

UCLA Semel Institute — Los Angeles, California, United States

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