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

Official 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.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: TRIPLE
• Enrollment: 238 participants

Study Arms

• 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 d
• 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 do
• 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 integratio
• 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

Interventions

• 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.
• 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.
• 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.
• 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.

Primary Outcomes

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

Secondary Outcomes

• 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)

Eligibility Criteria

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.

Trial Locations

• University of Alabama Clinical Research Unit, Birmingham, Alabama, United States
• Preferred Research Partners-NWA, LLC, Fayetteville, Arkansas, United States
• Preferred Research Partners, Inc., Little Rock, Arkansas, United States
• Kadima Neuropsychiatry Institute, La Jolla, California, United States
• West LA VA Medical Center - Mental Health Department, Los Angeles, California, United States
• Pacific Neuroscience Institute (PNI) at Saint John's Physician Partners, Santa Monica, California, United States
• Psychedelic Science Institute, Santa Monica, California, United States
• Mountain View Clinical Research, Denver, Colorado, United States
• Connecticut Mental Health Center, Yale University, New Haven, Connecticut, United States
• Clinical Neuroscience Solutions Inc., Jacksonville, Florida, United States
• ...and 10 more locations

Study Officials

• Tanya Ramey, MD, PhD — STUDY_CHAIR
  Usona Institute

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