Psilocybin for Major Depressive Disorder (MDD) (uAspire)

A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Psilocybin in Adults With Major Depressive Disorder (MDD)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Depressive Disorder, Major
• Intervention / Treatment: Drug: Psilocybin 25 mg; Drug: Psilocybin 5 mg; Drug: Inactive Placebo; Behavioral: Psychosocial Support

Detailed Description

Double-blind Period:

Participants who show stable depression symptoms between Screening and Trial Baseline will be randomly assigned to receive a single oral dose of Psilocybin 25 mg, Psilocybin 5 mg, or inactive placebo.

Investigational Product (IP) will be administered in the context of a "Set and Setting" (SaS) Protocol for psychosocial support, comprised of 1) a period of preparation with Facilitators prior to dosing; 2) administration of IP in an aesthetically pleasing room under the supervision of two Facilitators; and 3) post-dose integration sessions during which participants will discuss their dosing experience with the Facilitators.

Trial outcome measures will assess depressive symptoms, functional disability, health-related quality of life, and clinical global impression of disease severity.

Long-term Follow-up Period:

After the initial 6-week Double-blind Period and completion of the post-dosing Trial Day 43 assessments, all participants will proceed into a 1-year Follow-up Period.

During the 1-year Follow-up Period, participants will be followed regularly by clinic staff to assess MDD symptom severity, functional disability, and health-related quality of life; long-term safety data will also be collected. In addition to scheduled clinic visits, clinic staff will contact participants by telephone every two weeks to assess for changes in MDD symptom severity, concomitant medications, adverse events (AEs), and suicidal ideation and behavior.

Participants who meet the pre-defined MDD severity criteria and meet all re-administration eligibility criteria may be offered re-administration(s) of open-label Psilocybin 25 mg administered under a "Set and Setting" (SaS) Protocol. Psychosocial support, including psychoeducation, is also incorporated in the long-term Follow-up Period.

• Study Type: Interventional
• Enrollment (Actual): 238
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • University of Alabama Clinical Research Unit
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Preferred Research Partners-NWA, LLC
    • Little Rock, Arkansas, United States, 72211
      • Preferred Research Partners, Inc.
  • California
    • La Jolla, California, United States, 92037
      • Kadima Neuropsychiatry Institute
    • Los Angeles, California, United States, 90073
      • West LA VA Medical Center - Mental Health Department
    • Santa Monica, California, United States, 90404
      • Psychedelic Science Institute
    • Santa Monica, California, United States, 90404
      • Pacific Neuroscience Institute (PNI) at Saint John's Physician Partners
  • Colorado
    • Denver, Colorado, United States, 80209
      • Mountain View Clinical Research
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Connecticut Mental Health Center, Yale University
  • Florida
    • Jacksonville, Florida, United States, 32256
      • Clinical Neuroscience Solutions Inc.
    • Lauderhill, Florida, United States, 33319
      • Innovative Clinical Research, Inc.
    • Orlando, Florida, United States, 32801
      • Clinical Neuroscience Solutions, Inc.
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University
    • Decatur, Georgia, United States, 30030
      • CenExel iResearch, LLC
  • Illinois
    • Chicago, Illinois, United States, 60640
      • Great Lakes Clinical Trials
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins School of Medicine, Center for Psychedelic and Consciousness Research
    • Rockville, Maryland, United States, 20850
      • Sunstone Medical PC
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nebraska
    • Omaha, Nebraska, United States, 68105
      • VA Nebraska Western Iowa Health Care System
  • New Jersey
    • Princeton, New Jersey, United States, 08540
      • Global Medical Institutes, LLC; Princeton Medical Institute
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico (UNM) Interdisciplinary Substance Use and Brain Injury (ISUBI) Center
  • New York
    • New York, New York, United States, 10016
      • NYU Clinical & Translational Science Institute
    • The Bronx, New York, United States, 10468
      • Bronx Veterans Research Foundation at the James J. Peters VAMC
  • Texas
    • Plano, Texas, United States, 75093
      • AIM Trials, LLC
    • San Antonio, Texas, United States, 78229
      • Clinical Trials of Texas, LLC
  • Utah
    • Draper, Utah, United States, 84020
      • Cedar Clinical Research
    • Murray, Utah, United States, 84107
      • Cedar Clinical Research, Inc.
  • Washington
    • Bellevue, Washington, United States, 98004
      • Seattle Neuropsychiatric Treatment Center
    • Vancouver, Washington, United States, 98661
      • VA Portland Health Care System

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Psilocybin 25 mg; 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; 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.; Other Names: Psilocybine, Psilocibin, Indocybin
Active Comparator: Psilocybin 5 mg; 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; 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.; Other Names: Psilocybine, Psilocibin, Indocybin, Active Comparator
Placebo Comparator: Inactive Placebo; 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; 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.; Other Names: Microcrystalline Cellulose (MCC), Placebo
Other: Long-Term Follow-Up; 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; 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.; Other Names: Psilocybine, Psilocibin, Indocybin; Behavioral: Psychosocial Support; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in central rater Clinical Global Impression-Severity (CGI-S) total score from Baseline to Trial Day 43	The CGI-S is a 7-point scale, with a minimum score of 1 and a maximum score of 7, with higher scores representing more severe illness, that assesses the global severity of the participant's illness at the time of assessment relative to the clinician's past experience with patients who have the same diagnosis.	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	The SDS is a composite of three self-rated items designed to measure the extent to which three major sectors in the patient's life are impaired by psychiatric symptoms, including depression. The SDS total score ranges from 0 to 30 with higher representing greater functional disability.	From Trial Baseline to Trial Day 43

Collaborators and Investigators

• Sponsor: Usona Institute
• Collaborators: Worldwide Clinical Trials
• Investigators: Study Chair: Tanya Ramey, MD, PhD, Usona Institute

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2024
• Primary Completion (Actual): January 5, 2026
• Study Completion (Estimated): January 30, 2027

Study Registration Dates

• First Submitted: March 6, 2024
• First Submitted That Met QC Criteria: March 6, 2024
• First Posted (Actual): March 13, 2024

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Depression; MDD; Major Depressive Disorder; Psychoeducation; Psilocybin; Psychosocial; Psychedelic; Set and Setting
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Depressive Disorder; Behavior; Depression; Depressive Disorder, Major; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Therapeutics; Alkaloids; Indoles; Health Services; Health Care Facilities Workforce and Services; Rehabilitation; Indole Alkaloids; Indolizidines; Indolizines; Tryptamines; Psilocybin; microcrystalline cellulose; Psychiatric Rehabilitation
• Other Study ID Numbers: PSIL301

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No