A Phase 3 interventional study of Psilocybin 25 mg and Inactive Placebo in Depressive Disorder, Major, sponsored by Usona Institute. Active, not recruiting at 29 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-07-23.
Sponsored by Usona Institute · Phase 3, Interventional, and Treatment
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.
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.
2,741 studies on the registry are indexed under Depressive Disorder, Major; 559 are open to participants now.
This study's enrollment of 238 is above the median of 80 across 2,283 interventional studies indexed under Depressive Disorder, Major.
Browse Depressive Disorder, Major studies →Usona Institute is the lead sponsor of 5 studies on the registry; none are open to participants now.
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Exclusion Criteria:
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
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
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
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
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
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
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
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.
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.
Time frame: From Trial Baseline to Trial Day 43
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.
Time frame: 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.
Time frame: From Trial Baseline to Trial Day 43
This study is active, not recruiting, as verified in Jul 2026. You cannot join it, but the record below documents what was studied.
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