Psilocybin for Major Depressive Disorder (MDD)

NCT06308653 | Active Not Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: PSIL301
• Study Type: interventional
• Target: 238
• Locations: 1 country
• Sites: 29

Brief Summary

Approximately 240 eligible adult participants (≥18 years old) who meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) criteria for Major Depressive Disorder (MDD) will be enrolled. Participants will be randomly assigned to receive a single oral dose of Psilocybin 25 mg, Psilocybin 5 mg, or inactive placebo. The purpose of this study is to evaluate the efficacy, safety, and tolerability of Psilocybin 25 mg versus placebo in adults with MDD, as assessed by the difference between groups in change in depressive symptoms from Baseline to Day 43 post-dose, and to characterize the durability of initial treatment effect and subsequent response to optional Psilocybin 25 mg re-administration(s) during the 1-year Follow-up Period.

Conditions

Depressive Disorder, Major

Keywords

Psilocybin; Psychedelic; Depression; Major Depressive Disorder; MDD; Psychosocial; Psychoeducation; Set and Setting

Outcome Measures

Primary Outcomes (1)

• Change in central rater Montgomery-Asberg Depression Rating Scale (MADRS) total score from Baseline to Trial Day 43

  The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. The total (composite) MADRS score is used as the endpoint.

  From Trial Baseline to Trial Day 43

Secondary Outcomes (2)

• Change in central rater Clinical Global Impression-Severity (CGI-S) total score from Baseline to Trial Day 43

  From Trial Baseline to Trial Day 43

• Change in on-site rater administered Sheehan Disability Scale (SDS) score from Baseline to post-dose Day 43

  From Trial Baseline to Trial Day 43

Study Arms (4)

Psilocybin 25 mg

EXPERIMENTAL

During the Double-blind Period, participants randomized to receive Psilocybin 25 mg will receive a single dose administered orally as a capsule and taken with water, along with the "Set and Setting" (SaS) Protocol. The "Set and Setting" (SaS) Protocol includes preparatory meetings with two Facilitators prior to dosing, a 7-10 hour dosing session in a comfortable room under the supervision of the same two Facilitators, and 4 hours of post-dose integration sessions with Facilitators. During the dosing session, participants are encouraged to wear eyeshades and listen to a curated playlist on headphones.

Drug: Psilocybin 25 mg

Psilocybin 5 mg

ACTIVE COMPARATOR

During the Double-blind Period, participants randomized to receive Psilocybin 5 mg will receive a single dose administered orally as a capsule and taken with water, along with the "Set and Setting" (SaS) Protocol. The "Set and Setting" (SaS) Protocol includes preparatory meetings with two Facilitators prior to dosing, a 7-10 hour dosing session in a comfortable room under the supervision of the same two Facilitators, and 4 hours of post-dose integration sessions with Facilitators. During the dosing session, participants are encouraged to wear eyeshades and listen to a curated playlist on headphones.

Drug: Psilocybin 5 mg

Inactive Placebo

PLACEBO COMPARATOR

During the Double-blind Period, participants randomized to receive inactive placebo will receive a single dose of Microcrystalline Cellulose (MCC) 25 mg administered orally as a capsule and taken with water, along with the "Set and Setting" (SaS) Protocol. The "Set and Setting" (SaS) Protocol includes preparatory meetings with two Facilitators prior to dosing, a 7-10 hour dosing session in a comfortable room under the supervision of the same two Facilitators, and 4 hours of post-dose integration sessions with Facilitators. During the dosing session, participants are encouraged to wear eyeshades and listen to a curated playlist on headphones.

Drug: Inactive Placebo

Long-Term Follow-Up

OTHER

After the initial 6-week Double-blind Period, all participants will proceed to a 1-year Follow-up Period. Participants will be followed via in-clinic visits and telephone visits during which clinic staff will assess changes in MDD symptom severity and safety measures including concomitant medications, adverse events (AEs), and suicidal ideation and behavior. Participants will also engage in group psychosocial support sessions, including psychoeducation, throughout this period. Participants may also be eligible to receive open-label re-administration(s) of Psilocybin 25 mg under the "Set and Setting" (SaS) Protocol if re-administration eligibility criteria are met.

Drug: Psilocybin 25 mg; Behavioral: Psychosocial Support

Interventions

Psilocybin 25 mg DRUG

The Psilocybin used in this study is synthetically manufactured in a laboratory and meets quality specifications suitable for human research use. The active drug is encapsulated within a hydroxypropyl methylcellulose (HPMC) capsule and contains 25 mg of Psilocybin.

Also known as: Psilocybine, Psilocibin, Indocybin

Long-Term Follow-Up; Psilocybin 25 mg

Inactive Placebo DRUG

The inactive placebo is encapsulated within a hydroxypropyl methylcellulose (HPMC) capsule and contains 25 mg of Microcrystalline Cellulose (MCC). The MCC is synthetically manufactured in a laboratory and meets quality specifications suitable for human research use.

Also known as: Microcrystalline Cellulose (MCC), Placebo

Inactive Placebo

Psilocybin 5 mg DRUG

The Psilocybin used in this study is synthetically manufactured in a laboratory and meets quality specifications suitable for human research use. The active comparator is encapsulated within a hydroxypropyl methylcellulose (HPMC) capsule and contains 5 mg of Psilocybin.

Also known as: Psilocybine, Psilocibin, Indocybin, Active Comparator

Psilocybin 5 mg

Psychosocial Support BEHAVIORAL

Psychosocial Support, including psychoeducation, begins after the Double-blind Period and continues throughout the 1-year Follow-up Period in order to enhance participant safety and maximize retention for the entire trial duration.

Long-Term Follow-Up

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults ≥18 years old.
• Able to swallow capsules.
• If of childbearing potential, agree to practice an effective means of birth control throughout the duration of the study.
• Meet the DSM-5-TR criteria for a diagnosis of major depressive disorder and are currently experiencing a major depressive episode of at least a 60-day duration at the time of Screening.
• Have at least moderate severity of depression symptoms at Screening and Trial Baseline.

You may not qualify if:

• Participants who are pregnant, who intend to become pregnant during the trial, or who are currently nursing.
• Have any of the following cardiovascular conditions: coronary artery disease, congenital long QT syndrome, cardiac hypertrophy, cardiac ischemia, congestive heart failure, clinically-relevant valvular heart disease, pulmonary hypertension, myocardial infarction, a clinically significant ECG abnormality, or tachycardia.
• Have elevated blood pressure.
• Have neurological conditions such as stroke, including transient ischemic attack, epilepsy, neurodegenerative disease (e.g., dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, etc.), or brain tumor.
• Have severe hepatic or renal impairment.
• Have uncontrolled diabetes mellitus or unstable existing thyroid disorder.
• Are hepatitis or HIV positive.
• Have a positive urine drug test for illicit, non-prescribed, or prohibited substances.
• Meet DSM-5-TR criteria for schizophrenia spectrum or other psychotic disorders, including major depressive disorder with psychotic features ,bipolar disorder (types 1 or 2), antisocial personality disorder, borderline personality disorder or moderate or severe alcohol or drug use disorder
• Meet DSM-5-TR criteria for active post-traumatic stress disorder within 6 months prior to Screening.
• Have a first-degree relative with schizophrenia spectrum or other psychotic disorders, or bipolar I disorder.

Sponsors & Collaborators

• Usona Institute: lead

Study Sites (29)

University of Alabama Clinical Research Unit

Birmingham, Alabama, 35209, United States

Location

Preferred Research Partners-NWA, LLC

Fayetteville, Arkansas, 72703, United States

Location

Preferred Research Partners, Inc.

Little Rock, Arkansas, 72211, United States

Location

Kadima Neuropsychiatry Institute

La Jolla, California, 92037, United States

Location

West LA VA Medical Center - Mental Health Department

Los Angeles, California, 90073, United States

Location

Pacific Neuroscience Institute (PNI) at Saint John's Physician Partners

Santa Monica, California, 90404, United States

Location

Psychedelic Science Institute

Santa Monica, California, 90404, United States

Location

Mountain View Clinical Research

Denver, Colorado, 80209, United States

Location

Connecticut Mental Health Center, Yale University

New Haven, Connecticut, 06519, United States

Location

Clinical Neuroscience Solutions Inc.

Jacksonville, Florida, 32256, United States

Location

Innovative Clinical Research, Inc.

Lauderhill, Florida, 33319, United States

Location

Clinical Neuroscience Solutions, Inc.

Orlando, Florida, 32801, United States

Location

Emory University

Atlanta, Georgia, 30329, United States

Location

CenExel iResearch, LLC

Decatur, Georgia, 30030, United States

Location

Great Lakes Clinical Trials

Chicago, Illinois, 60640, United States

Location

Johns Hopkins School of Medicine, Center for Psychedelic and Consciousness Research

Baltimore, Maryland, 21224, United States

Location

Sunstone Medical PC

Rockville, Maryland, 20850, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

VA Nebraska Western Iowa Health Care System

Omaha, Nebraska, 68105, United States

Location

Global Medical Institutes, LLC; Princeton Medical Institute

Princeton, New Jersey, 08540, United States

Location

University of New Mexico (UNM) Interdisciplinary Substance Use and Brain Injury (ISUBI) Center

Albuquerque, New Mexico, 87106, United States

Location

NYU Clinical & Translational Science Institute

New York, New York, 10016, United States

Location

Bronx Veterans Research Foundation at the James J. Peters VAMC

The Bronx, New York, 10468, United States

Location

AIM Trials, LLC

Plano, Texas, 75093, United States

Location

Clinical Trials of Texas, LLC

San Antonio, Texas, 78229, United States

Location

Cedar Clinical Research

Draper, Utah, 84020, United States

Location

Cedar Clinical Research, Inc.

Murray, Utah, 84107, United States

Location

Seattle Neuropsychiatric Treatment Center

Bellevue, Washington, 98004, United States

Location

VA Portland Health Care System

Vancouver, Washington, 98661, United States

Location

Related Publications (2)

• Raison CL, Sanacora G, Woolley J, Heinzerling K, Dunlop BW, Brown RT, Kakar R, Hassman M, Trivedi RP, Robison R, Gukasyan N, Nayak SM, Hu X, O'Donnell KC, Kelmendi B, Sloshower J, Penn AD, Bradley E, Kelly DF, Mletzko T, Nicholas CR, Hutson PR, Tarpley G, Utzinger M, Lenoch K, Warchol K, Gapasin T, Davis MC, Nelson-Douthit C, Wilson S, Brown C, Linton W, Ross S, Griffiths RR. Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA. 2023 Sep 5;330(9):843-853. doi: 10.1001/jama.2023.14530.

  PMID: 37651119 RESULT

• Palitsky R, Maples-Keller JL, Peacock C, Dunlop BW, Mletzko T, Grant GH, Raison CL, Chao S, Shub I, Mendelbaum-Kweller M, Smolyar L, Kaplan DM, Rothbaum BO, Zarrabi AJ. A critical evaluation of psilocybin-assisted therapy protocol components from clinical trial patients, facilitators, and caregivers. Psychotherapy (Chic). 2025 Sep;62(3):348-362. doi: 10.1037/pst0000551. Epub 2025 Jan 13.

  PMID: 39804360 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Interventions

Psilocybin; microcrystalline cellulose; Psychiatric Rehabilitation

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Rehabilitation; Therapeutics; Health Services; Health Care Facilities Workforce and Services

Study Officials

• Tanya Ramey, MD, PhD

  Usona Institute

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The following roles will be blinded to the treatment group assignment in the Double-blind Period during the trial: Participant, Investigator, Site Personnel, Facilitators, Efficacy Raters (including Site Raters, Participant Raters, and Central Raters), Contract Research Organization (CRO) Staff, and Sponsor. All roles other than the Sponsor, CRO, and Ethics Committees will also be blinded to the randomization ratio and Patient Health Questionnaire-9 (PHQ-9) score for re-administration eligibility. The Central MADRS Rater will also be blinded to all aspects of the protocol and trial visit for each participant. Blinded trial site personnel will complete administration of the IP. Full blinding of trial personnel, Sponsor, and participants will be maintained until database lock at the conclusion of the trial.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants will be randomized to receive Psilocybin 25 mg, Psilocybin 5 mg, or inactive placebo under double-blind conditions. After the initial 6-week Double-blind Period, all participants will proceed into a 1-year Follow-up Period. During this 1-year Follow-up Period, eligible participants who meet pre-determined criteria may be offered open-label Psilocybin 25 mg in the context of a "Set and Setting" (SaS) Protocol.

Study Record Dates

• First Submitted: March 6, 2024
• First Posted: March 13, 2024
• Study Start: March 13, 2024
• Primary Completion: January 5, 2026
• Study Completion (Estimated): January 30, 2027
• Last Updated: April 24, 2026

Record last verified: 2026-04

Locations

US (29)