A Study of Psilocybin for Major Depressive Disorder (MDD)

Study Overview
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Brief Summary
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One hundred participants, ages 21 to 65, who meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for major depressive disorder (MDD) will be stratified by study site and randomized with a 1-to-1 allocation under double-blind conditions to receive a single 25 mg oral dose of psilocybin or a single 100 mg oral dose of niacin. Niacin will serve as an active placebo. The purpose of this study is to evaluate the potential efficacy of a single 25 mg oral dose of psilocybin for MDD compared to the active placebo in otherwise medically-healthy participants, assessed as the difference between groups in changes in depressive symptoms from Baseline to Day 43 post-dose.

Detailed Description
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Major depressive disorder (MDD) has become a health crisis of epidemic proportions in the modern world. One in six individuals in the United States will experience an episode of major depression in his or her lifetime, and it is estimated that major depression will rank second after cardiac disease as a cause of international medical morbidity by the year 2020. Depression is associated with greater disability than are most other chronic illnesses and is a risk factor for mortality. Additionally, depression predicts the later development of a number of medical conditions, including cardiac and cerebrovascular disease, hypertension, diabetes, obesity, metabolic syndrome, dementia, and cancer. Unfortunately, most patients with depression do not experience a complete resolution of symptoms with antidepressant treatment. Partial-but incomplete-response to antidepressants is associated with an increased risk of full symptomatic relapse (even when on therapy) and a worse long-term disease course. Combined with the high prevalence and significant disability associated with MDD, the fact that currently available treatments are not fully adequate highlights the tremendous need to identify novel treatment strategies. Data suggest that psilocybin may have behavioral effects relevant to the treatment of depression and recent studies also suggest that psilocybin may possess antidepressant properties. To further assess the effects of psilocybin on MDD signs and symptoms, this trial will enroll 100 participants, ages 21 to 65, who meet criteria for MDD. Participants will be stratified by study site and randomized with a 1-to-1 allocation under double-blind conditions to receive a single 25 mg oral dose of psilocybin or a single 100 mg oral dose of niacin. Niacin will serve as an active placebo. To enhance participant safety, a Set and Setting (SaS) protocol will be utilized similar to the protocol that has been used in all modern studies of psilocybin. The SaS protocol for this study includes: 1) a period of preparation with session Facilitators prior to dosing; 2) administration of study medications in an aesthetically pleasing room under the supervision of two Facilitators who are present throughout the session; and 3) three post-dose integration sessions during which participants are encouraged to discuss their intervention experience with the Facilitators. The SaS protocol will be identical for those randomized to psilocybin or active placebo. The primary objective of this study is to evaluate the potential efficacy of a single 25 mg oral dose of psilocybin for MDD compared to the active placebo (niacin), assessed as the difference between groups in changes in depressive symptoms from Baseline to Day 43 post-dose.

Official Title
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A Randomized, Double-Blind, Support-of-Concept Phase 2 Study of Single-Dose Psilocybin for Major Depressive Disorder (MDD)

Conditions
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Depressive Disorder, Major

Intervention / Treatment
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* Drug: Psilocybin
* Drug: Niacin
* Other: Set and Setting (SaS) Protocol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 21 to 65 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 Have an identified support person and agree to be accompanied home by that person following dosing Have sustained moderate-severe depression symptoms at Screening and Baseline Meet DSM-5 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 Exclusion Criteria: Women who are pregnant or who intend to become pregnant during the study or who are currently nursing Have 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 Have a history of stroke or Transient Ischemic Attack (TIA) Have moderate to severe hepatic impairment Have epilepsy Have insulin-dependent diabetes Have a positive urine drug test Nicotine dependence that would disallow an individual to be nicotine free for the 7-10 hours during the dosing period Meet DSM-5 criteria for schizophrenia spectrum or other psychotic disorders, including major depressive disorder with psychotic features, or Bipolar I or Bipolar II Disorder Meet DSM-5 criteria for antisocial personality disorder Meet DSM-5 criteria for a moderate or severe alcohol or drug use disorder

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Psilocybin<br>Participants will receive a single 25 mg dose of psilocybin along with the Set and Setting (SaS) protocol. Psilocybin is administered orally as a capsule and taken with water. | Drug: Psilocybin<br>* 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 using a hydroxypropyl methylcellulose (HPMC) capsule and contains 25 mg of psilocybin.<br>* Other names: Psilocybine, Psilocibin, Indocybin;Other: Set and Setting (SaS) Protocol<br>* The SaS Protocol prescribes 6-8 hours of 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.<br>|
| Active Comparator: Niacin<br>Participants will receive a single 100 mg dose of niacin along with the Set and Setting (SaS) protocol. Niacin is administered orally as a capsule and taken with water. | Drug: Niacin<br>* The active placebo is encapsulated using a HPMC capsule and contains 100 mg of pharmaceutical grade niacin.<br>* Other names: Vitamin B3;Other: Set and Setting (SaS) Protocol<br>* The SaS Protocol prescribes 6-8 hours of 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in central rater Montgomery-Asberg Depression Rating Scale (MADRS) total score from Baseline to post-dose 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. | Baseline; Day 43 post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in central rater MADRS score from Baseline to post-dose Day 8 | 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. | Baseline, Day 8 post-dose | 
| 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. | Day 8, 15, 29, and 43 post-dose | 
| Sustained depressive symptom response defined as a ≥ 50% reduction from Baseline central rater MADRS score at all post-dose assessments | 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. | Day 8, 15, 29, and 43 post-dose | 
| Sustained depressive symptom remission defined as a central rater MADRS total score ≤ 10 at all post-dose assessments | 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. | Day 8, 15, 29, and 43 post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Psilocybin, Psychedelics, Depression, MDD