RCT of Psilocybin-assisted CBT for Depression

NCT07281352 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 21-2134R34AT013077
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Major Depressive Diorder

Keywords

psilocybin; cognitive behavioral therapy

Outcome Measures

Primary Outcomes (4)

• Client Satisfaction Questionnaire - 8

  Treatment acceptability as measured by the participant. Total scores range from 8 to 32, with the higher number indicating greater satisfaction.

  4-month treatment period

• Retention/Attrition

  Feasibility as measured by the number of participants retained in each treatment condition over the course of the study treatment

  4-month treatment period

• Hamilton Depression Rating Scale

  symptom severity scored from 0-53, with larger values indicating greater depressive severity

  7-month study period

• Global Assessment of Functioning

  psychosocial functioning scored from 0-100, with larger values indicating better functioning

  7-month study period

Study Arms (2)

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).

Drug: Psilocybin (drug); Behavioral: 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).

Drug: Psilocybin (drug); Behavioral: Minimal supportive therapy

Interventions

Psilocybin (drug) DRUG

Participants will receive two doses of psilocybin (10mg, 25mg).

Experimental: Psilocybin + CBT; Psilocybin + Minimal supportive therapy

cognitive behavioral therapy BEHAVIORAL

Twelve total sessions of therapy, including manualized cognitive behavioral therapy for major depressive disorder, including psychoeducation about depression, cognitive skills, and behavioral skills as well as preparation for psilocybin.

Experimental: Psilocybin + CBT

Minimal supportive therapy BEHAVIORAL

Six total therapy sessions. Preparation for psilocybin in the first three sessions plus supportive, nondirective psychotherapy in the final three sessions.

Psilocybin + Minimal supportive therapy

Eligibility Criteria

• Age: 21 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, Los Angeles: lead
• National Center for Complementary and Integrative Health (NCCIH): collaborator

Study Sites (1)

UCLA Semel Institute

Los Angeles, California, 90095, United States

RECRUITING

MeSH Terms

Interventions

Psilocybin; Pharmaceutical Preparations; Cognitive Behavioral Therapy

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Behavior Therapy; Psychotherapy; Behavioral Disciplines and Activities

Central Study Contacts

Shelby Grody

CONTACT

310-825-4354; UCLAPAT@mednet.ucla.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: The study involves randomization of 50 participants (1:1) to either PA-CBT or psilocybin-assisted therapy with minimal therapeutic support.

Study Record Dates

• First Submitted: December 8, 2025
• First Posted: December 15, 2025
• Study Start: January 5, 2026
• Primary Completion (Estimated): November 30, 2027
• Study Completion (Estimated): November 30, 2027
• Last Updated: February 12, 2026

Record last verified: 2025-12

Locations

US (1)