RCT of Psilocybin-assisted CBT for Depression

Psilocybin-Assisted Cognitive Behavioral Therapy for Depression

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 Overview

• Status: Recruiting
• Conditions: Major Depressive Diorder
• Intervention / Treatment: Drug: Psilocybin (drug); Behavioral: cognitive behavioral therapy; Behavioral: Minimal supportive therapy

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Shelby Grody; Phone Number: 310-825-4354; Email: UCLAPAT@mednet.ucla.edu

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • Recruiting
      • UCLA Semel Institute
      • Contact: Shelby Grody; Phone Number: 3108254354; Email: UCLAPAT@mednet.ucla.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Psilocybin + Minimal supportive therapy; 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); Participants will receive two doses of psilocybin (10mg, 25mg).; Behavioral: Minimal supportive therapy; Six total therapy sessions. Preparation for psilocybin in the first three sessions plus supportive, nondirective psychotherapy in the final three sessions.
Experimental: Experimental: Psilocybin + CBT; 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); Participants will receive two doses of psilocybin (10mg, 25mg).; Behavioral: cognitive behavioral therapy; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2026
• Primary Completion (Estimated): November 30, 2027
• Study Completion (Estimated): November 30, 2027

Study Registration Dates

• First Submitted: December 8, 2025
• First Submitted That Met QC Criteria: December 11, 2025
• First Posted (Actual): December 15, 2025

Study Record Updates

• Last Update Posted (Actual): February 12, 2026
• Last Update Submitted That Met QC Criteria: February 11, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: cognitive behavioral therapy; psilocybin
• Additional Relevant MeSH Terms: Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Indoles; Behavior Therapy; Psychotherapy; Behavioral Disciplines and Activities; Indole Alkaloids; Indolizidines; Indolizines; Tryptamines; Psilocybin; Cognitive Behavioral Therapy; Pharmaceutical Preparations
• Other Study ID Numbers: 21-2134; R34AT013077 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No