A Randomized, Double-Blind Study of Single-Dose Psilocybin for Major Depressive Disorder (MDD)
Phase: PHASE2
Conditions: Depressive Disorder, Major
Sponsor: Usona Institute

Study Protocol 
 
 
 
Official Title 
A Randomized, Double-Blind Study of Single-Dose 
Psilocybin for Major Depressive Disorder (MDD) 
 
Unique Protocol ID 
PSIL201  
 
NCT Number 
NCT03866174 
 
Document Date 
05-Mar-2021 
 
 
 
 
Usona Institute 
2881 Woods Hollow Rd, Madison, WI 53711 
 

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PROTOCOL AMENDMENTS  
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol (V1.0) 
09-Feb-2018 
Protocol (V2.0) 
18-Dec-2018 
Protocol (V3.0) 
03-Jan-2019 
Protocol (V4.0) 
26-Feb-2019 
Protocol (V5.0) 
21-Mar-2019 
Protocol (V6.0) 
27-Sep-2019 
Protocol (V7.0) 
18-Dec-2019 
Protocol (V8.0) 
27-Jan-2020 
Protocol (V9.0) 
17-Jul-2020 
Protocol (V10.0) 
05-Mar-2021 
 
 
 
 

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TABLE OF CONTENTS 
 
LIST OF TABLES ............................................................................................................................... 8 
LIST OF FIGURES ............................................................................................................................. 8 
LIST OF ABBREVIATIONS ............................................................................................................. 9 
PROTOCOL SYNOPSIS .................................................................................................................. 12 
1 
INTRODUCTION ....................................................................................................................... 22 
1.1 
Usona Institute .................................................................................................................. 22 
1.2 
Purpose .............................................................................................................................. 22 
1.3 
Study Rationale ................................................................................................................. 22 
1.4 
Background ....................................................................................................................... 22 
1.4.1 
Major Depressive Disorder (MDD)....................................................................... 22 
1.4.2 
Psilocybin ............................................................................................................... 23 
1.4.3 
Previous Clinical Experience with Psilocybin Relevant to MDD ......................... 24 
1.5 
The Set and Setting (SaS) Protocol ................................................................................... 25 
2 
OBJECTIVES AND ENDPOINTS ............................................................................................ 26 
2.1 
Primary Objective ............................................................................................................. 26 
2.2 
Secondary Objectives........................................................................................................ 26 
2.3 
Exploratory Objectives ..................................................................................................... 26 
2.4 
Exploratory Mechanism-Based Objectives....................................................................... 27 
2.5 
Safety Objectives .............................................................................................................. 27 
2.6 
Specific Safety Monitoring Objectives ............................................................................. 27 
2.7 
Primary Study Endpoint .................................................................................................... 29 
2.7.1 
Justification for Primary Study Endpoint .............................................................. 29 
2.8 
Secondary Study Endpoints .............................................................................................. 30 
2.9 
Exploratory Study Endpoints ............................................................................................ 30 
2.10 
Exploratory Mechanism-Based Endpoints ....................................................................... 30 
2.11 
Safety Endpoints ............................................................................................................... 30 
2.12 
Outcome Measures............................................................................................................ 31 
2.12.1 
Montgomery-Asberg Depression Rating Scale (MADRS) ..................................... 31 
2.12.2 
Sheehan Disability Scale (SDS) ............................................................................. 32 
2.12.3 
Hamilton Anxiety Rating Scale (HAM-A) .............................................................. 33 
2.12.4 
Clinical Global Impression – Severity (CGI-S) ..................................................... 33 
2.12.5 
Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) ................. 34 
2.12.6 
30-item Mystical Experience Questionnaire (MEQ-30) ........................................ 34 
2.12.7 
Emotional Breakthrough Inventory (EBI) ............................................................. 34 
2.12.8 
Symptoms of Major Depressive Disorder Scale (SMDDS).................................... 35 
2.12.9 
Oxford Depression Questionnaire (ODQ) ............................................................. 35 
2.13 
Eligibility and Safety Measures ........................................................................................ 36 
2.13.1 
Structured Interview for DSM-5 Disorders-Clinical Trials Version (SCID-CT) .. 36 
2.13.2 
SCID-5-Personality Disorders (SCID-PD) ........................................................... 36 
2.13.3 
Drug History Questionnaire (DHQ) ...................................................................... 37 
2.13.4 
Alcohol Use Disorders Identification Test (AUDIT) ............................................. 37 
2.13.5 
Drug Use Disorders Identification Test (DUDIT) ................................................. 37 

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2.13.6 
Timeline Followback (TLFB) ................................................................................. 38 
2.13.7 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................ 38 
2.13.8 
Lifetime Illness Characteristic Questionnaire (LICQ) .......................................... 39 
2.13.9 
Massachusetts General Hospital Antidepressant Treatment History Questionnaire 
(ATRQ) ................................................................................................................... 39 
2.13.10 
Family History Screen (FHS) ................................................................................ 40 
2.13.11 
Questionnaire Order of Assessments ..................................................................... 40 
2.13.12 
Laboratory Assessments......................................................................................... 40 
2.13.13 
Physical Examinations ........................................................................................... 41 
3 
PROTOCOL DESIGN ................................................................................................................ 42 
3.1 
Overall Study Design ........................................................................................................ 42 
3.2 
Justification for Selected Aspects of the Study Design .................................................... 43 
3.2.1 
Use of a single psilocybin dose .............................................................................. 43 
3.2.2 
Psilocybin and Niacin Dosing ............................................................................... 43 
3.3 
Planned Duration of Study ................................................................................................ 44 
4 
PARTICIPANT POPULATION ................................................................................................ 50 
4.1 
Inclusion and Exclusion Criteria ....................................................................................... 50 
4.1.1 
Inclusion Criteria ................................................................................................... 50 
4.1.2 
Exclusion Criteria .................................................................................................. 50 
4.2 
Justification for Inclusion/Exclusion Criteria ................................................................... 53 
4.2.1 
Medication Taper ................................................................................................... 53 
4.2.2 
Outside Psychotherapy .......................................................................................... 54 
4.2.3 
Benzodiazepines ..................................................................................................... 54 
4.2.4 
Age range ............................................................................................................... 54 
4.2.5 
Medically Healthy Participants ............................................................................. 55 
4.2.6 
Psychiatric Symptoms ............................................................................................ 56 
4.2.7 
Medication Exclusions ........................................................................................... 56 
4.2.8 
Blood Pressure ....................................................................................................... 57 
5 
SCREENING PROCESS AND PROCEDURES ...................................................................... 58 
5.1 
Recruitment ....................................................................................................................... 58 
5.1.1 
Study Recruitment Website and Pre-Screener Questionnaire ............................... 58 
5.2 
Telephone Screen .............................................................................................................. 58 
5.2.1 
Telephone Screen Waiver of Documentation of Informed Consent ....................... 59 
5.3 
Written Informed Consent ................................................................................................ 59 
5.3.1 
Informed Consent Comprehension ........................................................................ 60 
5.4 
Screening Visit (7-35 days) .............................................................................................. 60 
5.4.1 
Medication Taper ................................................................................................... 61 
5.4.2 
Suspending Outside Psychotherapy ....................................................................... 61 
5.5 
Baseline Visit (maximum 7 days prior to dose)................................................................ 61 
5.5.1 
Inclusion/ Exclusion Criteria Confirmation .......................................................... 61 
5.6 
Re-Screening ..................................................................................................................... 61 
6 
PREPARATION, RANDOMIZATION, DOSING AND FOLLOW UP PROCEDURES ... 62 
6.1 
Preparatory Sessions with Clinical Facilitators (1-6 days prior to dose) .......................... 62 
6.1.1 
Post Preparatory Session Assessment (1-4 days prior to dose) ............................ 62 
6.2 
Randomization .................................................................................................................. 63 

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6.3 
Day 1: Dosing Session ...................................................................................................... 63 
6.3.1 
Pre-Dose ................................................................................................................ 63 
6.3.2 
Dosing .................................................................................................................... 65 
6.3.3 
Post-Dosing Release Procedures ........................................................................... 69 
6.4 
Day 2: Post Dose ............................................................................................................... 69 
6.5 
Day 5: Post Dose Phone Call (±1 day) ............................................................................. 69 
6.6 
Day 8, 15 and 29: Post Dose (-1/+2 days) ........................................................................ 70 
6.7 
Day 9 and 16: Integration Sessions #2 and #3 (-1/+4 days) ............................................. 70 
6.8 
Day 43: Post Dose/End of Study (±3 days) ...................................................................... 70 
6.8.1 
End of Study Plan................................................................................................... 70 
6.9 
Blinding Related to Delivery of Study Interventions and Collection of Outcome Data .. 70 
6.9.1 
Unblinding Procedure ........................................................................................... 71 
6.10 
Early Termination Visit .................................................................................................... 71 
6.11 
Unscheduled Visits ........................................................................................................... 71 
7 
STUDY DISCONTINUATION AND COMPLETION CRITERIA ....................................... 72 
7.1 
Screen Failures .................................................................................................................. 72 
7.2 
Evaluable Participants ....................................................................................................... 72 
7.3 
Early Termination from the Study .................................................................................... 72 
7.3.1 
Early Termination Post-Baseline and Pre-Randomization (Preparation Phase 
Termination) .......................................................................................................... 72 
7.3.2 
Early Terminations Post-Randomization and Pre-Dosing .................................... 73 
7.3.3 
Early Termination Post Dosing ............................................................................. 73 
7.3.4 
Dropouts ................................................................................................................ 73 
7.3.5 
Lost to Follow-up Post Dosing .............................................................................. 73 
7.3.6 
End of Study Definition .......................................................................................... 74 
7.3.7 
Premature Study Discontinuation .......................................................................... 74 
8 
INVESTIGATIONAL PRODUCT ............................................................................................ 75 
8.1 
Description of Investigational Product ............................................................................. 75 
8.2 
Description of Active Placebo .......................................................................................... 75 
8.3 
Source ............................................................................................................................... 75 
8.4 
Study Drugs Administered ................................................................................................ 75 
8.5 
Dosing ............................................................................................................................... 76 
8.6 
Drug Delivery, Storage, Handling, and Accountability .................................................... 76 
9 
STATISTICAL CONSIDERATIONS ....................................................................................... 77 
9.1 
Hypotheses ........................................................................................................................ 77 
9.2 
Power and Sample Size Determination............................................................................. 79 
9.2.1 
Rationale for Sample Size Assumptions ................................................................. 79 
9.2.2 
Sample Size Calculations ....................................................................................... 82 
9.3 
Populations for Analyses .................................................................................................. 82 
9.4 
Statistical Analyses ........................................................................................................... 83 
9.4.1 
Efficacy Analyses ................................................................................................... 83 
9.4.2 
Mechanism-Based Exploratory Analyses .............................................................. 84 
9.4.3 
Safety Analyses....................................................................................................... 84 
9.4.4 
Interim Analyses..................................................................................................... 85 
10 SAFETY MANAGEMENT ........................................................................................................ 86 

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10.1 
Risks Associated with Psilocybin ..................................................................................... 86 
10.1.1 
Physiological and Psychological Adverse Effects ................................................. 86 
10.1.2 
Visual Perceptual Effects ....................................................................................... 87 
10.1.3 
Drug Interactions ................................................................................................... 87 
10.1.4 
Pregnancy .............................................................................................................. 87 
10.2 
Risk of Worsening MDD .................................................................................................. 87 
10.3 
Risks Associated with Collection of Potentially Sensitive Information ........................... 88 
10.3.1 
Genetic Testing ...................................................................................................... 88 
10.4 
Risks Associated with Psychiatric Questionnaires ........................................................... 88 
10.5 
Risks Associated with Venipuncture ................................................................................ 89 
10.6 
Contacting Emergency Services ....................................................................................... 89 
10.7 
Data and Safety Monitoring Board (DSMB) .................................................................... 90 
10.8 
Abuse Liability.................................................................................................................. 90 
10.8.1 
Abuse Monitoring................................................................................................... 90 
11 ADVERSE EVENTS ................................................................................................................... 92 
11.1 
Definitions......................................................................................................................... 92 
11.1.1 
Adverse Event......................................................................................................... 92 
11.1.2 
Treatment Emergent Adverse Events ..................................................................... 92 
11.1.3 
Solicited Safety Events ........................................................................................... 92 
11.1.4 
Unsolicited Adverse Events .................................................................................... 93 
11.1.5 
Suspected Adverse Reaction .................................................................................. 93 
11.1.6 
Adverse Reaction ................................................................................................... 94 
11.1.7 
Serious Events (Serious Adverse Events, Serious Suspected Adverse Reactions or 
Serious Adverse Reactions) .................................................................................... 94 
11.1.8 
Unexpected Adverse Event ..................................................................................... 94 
11.1.9 
Suspected Unexpected Serious Adverse Reaction .................................................. 94 
11.1.10 
Definition of Terms ................................................................................................ 94 
11.2 
Guidelines for Assessing Intensity of an Adverse Event .................................................. 95 
11.3 
Guidelines for Determining Causality of an Adverse Event ............................................ 95 
11.4 
Actions to be Undertaken.................................................................................................. 95 
11.5 
AE Collection Period and Follow up ................................................................................ 95 
11.6 
Medical Dictionary for Regulatory Activities (MedDRA) ............................................... 95 
11.7 
Site AE Reporting Procedures .......................................................................................... 96 
11.8 
Regulatory Reporting ........................................................................................................ 96 
11.9 
Reporting of Pregnancy .................................................................................................... 97 
12 STUDY MONITORING, AUDITING AND DOCUMENTATION ....................................... 98 
13 HUMAN SUBJECTS PROTECTIONS .................................................................................... 99 
13.1 
Study Conduct ................................................................................................................... 99 
13.2 
Principal Investigator Responsibilities ............................................................................. 99 
13.3 
Human Subjects Training ................................................................................................. 99 
13.4 
Financial Disclosure.......................................................................................................... 99 
13.5 
Voluntary Participation ................................................................................................... 100 
13.6 
Benefits of Participation ................................................................................................. 100 
13.7 
Alternatives to Participation ........................................................................................... 100 
13.8 
Study and Site Closure .................................................................................................... 100 

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13.9 
Vulnerable Populations ................................................................................................... 101 
13.10 ClinicalTrials.gov Registration ....................................................................................... 101 
13.11 Certificate of Confidentiality .......................................................................................... 101 
13.12 Cost to Participants ......................................................................................................... 101 
13.13 Participant Compensation ............................................................................................... 102 
13.14 Treatment/ Compensation for Study Related Injury ....................................................... 102 
13.15 Protocol Deviations and Violations ................................................................................ 102 
13.16 Record Retention ............................................................................................................ 102 
13.17 Publication Policy ........................................................................................................... 103 
14 CONFIDENTIALITY AND DATA SECURITY.................................................................... 104 
14.1 
Confidentiality and Data Security at Research Sites ...................................................... 104 
14.2 
Advantage eClinical ........................................................................................................ 104 
14.3 
Rebar ............................................................................................................................... 105 
14.4 
Signant Health (formerly Bracket Global) ...................................................................... 105 
15 CORONAVIRUS DISEASE 2019 (COVID-19) MITIGATION ........................................... 106 
16 PREGNANCY ............................................................................................................................ 107 
16.1 
Definitions: Women of Childbearing Potential (WOCBP) ............................................ 107 
16.2 
Contraception Guidance.................................................................................................. 107 
16.2.1 
Male participants ................................................................................................. 107 
16.2.2 
Female participants ............................................................................................. 107 
16.3 
Pregnancy Testing ........................................................................................................... 108 
16.4 
Reporting Pregnancy Information................................................................................... 108 
Appendix A: Prohibited Medications ............................................................................................. 115 
Appendix B: Questionnaire Assessments ....................................................................................... 118 
 
LIST OF TABLES 
Table 1. Schedule of Assessments ..................................................................................................... 47 
Table 2: Pre-Dose Blood Pressure Monitoring ................................................................................ 64 
Table 3: Pre-Dose Heart Rate Monitoring ...................................................................................... 65 
Table 4: Blood Pressure Monitoring during Dosing ....................................................................... 67 
Table 5: Heart Rate Monitoring during Dosing .............................................................................. 67 
Table 6: 7-hour Blood Pressure and Heart Rate Monitoring ........................................................ 68 
Table 7: IP and Active Placebo Information ................................................................................... 75 
Table 8. Summary of Relevant Results from Prior Psilocybin Studies in Depression ................ 81 
Table 9: Participant Compensation................................................................................................ 102 
Table 10: Highly Effective Contraceptive Methods ...................................................................... 108 
 
LIST OF FIGURES 
Figure 1: Summary of Events Flowchart ......................................................................................... 45 
Figure 2: Study Diagram ................................................................................................................... 46 

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LIST OF ABBREVIATIONS 
 
21 CFR 
Title 21 of the Code of Federal Regulations 
AD 
Antidepressant 
AE 
Adverse Event 
ATRQ 
Massachusetts General Hospital Antidepressant Treatment History Questionnaire  
AUDIT 
Alcohol Use Disorders Identification Test 
BDI 
Beck Depression Inventory   
BP 
Blood Pressure 
CBC 
Complete Blood Count  
CGI-S 
Clinical Global Impression—Severity 
CIOMS 
Council for International Organizations of Medical Sciences 
CMP 
Complete Metabolic Panel  
CoC 
Certificate of Confidentiality 
CRF 
Case Report Form 
C-SSRS 
Columbia Suicide Severity Rating Scale 
d 
Cohen’s d 
DBS 
Deep Brain Stimulation 
DEA 
Drug Enforcement Agency 
DESS 
Discontinuation Emergent Signs and Symptoms 
DHQ 
Drug History Questionnaire 
DNA 
Deoxyribonucleic Acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
DUDIT 
Drug Use Disorders Identification Test 
EBI 
Emotional Breakthrough Inventory 
ECG 
Electrocardiogram 
eCOA 
Electronic Clinical Outcome Assessments 
ECT 
Electroconvulsive Therapy 
ED 
Emergency Department 
EDC 
Electronic Data Capture 
Emmes 
The Emmes Company 
FDA 
Food and Drug Administration 
FISMA 
Federal Information Security Management Act of 2002 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HAM-A 
Hamilton Anxiety Rating Scale 
HAM-D 
Hamilton Depression Scale 
g 
Hedges g 

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HDPE 
High-Density Polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
 
Human Immunodeficiency Virus 
Hopkins 
Johns Hopkins University 
HPMC 
Hydroxypropl Methylcellulose 
HPPD 
Hallucinogen-Persisting Perception Disorder 
HR 
Heart Rate 
Hrs 
Hours  
HRT 
Hormonal Replacement Therapy  
hs-CRP 
High-Sensitivity C-Reactive Protein 
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug  
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device  
IUS 
Intrauterine Hormone-releasing System  
LICQ 
Lifetime Illness Characteristic Questionnaire 
LSD 
Lysergic Acid Diethylamide  
MADRS 
Montgomery-Asberg Depression Rating Scale  
MAOIs 
Monoamine Oxidase Inhibitors  
MedDRA 
Medical Dictionary for Regulatory Activities  
MEQ-30 
Mystical Experience Questionnaire  
MD 
Medical Doctor  
MDD 
Major Depressive Disorder 
MDMA 
3,4-Methylenedioxy-methamphetamine  
mm Hg 
Millimeters of Mercury 
MMRM 
Mixed-effect Model with Repeated Measures  
MoP 
Manual of Procedures  
NIST 
National Institute of Standards and Technology  
NP 
Nurse Practitioner  
NYU 
New York University 
ODQ 
Oxford Depression Questionnaire 
OMB 
Office of Management and Budget 
p 
Probability 
PCP 
Phencyclidine 
PI 
Principal Investigator 
QIDS 
Quick Inventory of Depressive Symptomatology  

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Q-LES-Q 
Quality of Life Enjoyment and Satisfaction Questionnaire 
Rebar 
Rebar Interactive 
rTMS 
Repetitive Transcranial Magnetic Stimulation  
RX 
Prescription/ treatment/ dose 
SAEs 
Serious Adverse Events  
SAMe 
S-adenosyl-methionine 
SAP 
Statistical Analysis Plan 
SaS 
Set and Setting Protocol 
SCC 
Study Coordinating Center 
SCID 
Structured Clinical Interview for DSM-5 
SCID-II 
Structured Clinical Interview for DSM-IV Axis II Personality Disorders 
SCID-5-PD 
Structured Clinical Interview for DSM-5 – Personality Disorder  
SCID-5-SPQ SCID - Screening Personality Questionnaire 
SCID-CT 
Structured Clinical Interview for DSM-5 – Clinical Trials Version 
SCID-RV 
SCID – Research Version 
SDS 
Sheehan Disability Scale  
SMDDS 
Symptoms of Major Depressive Disorder Scale 
SNRIs 
Serotonin-norepinephrine reuptake inhibitors 
SSRIs 
Selective Serotonin Reuptake Inhibitors  
TBI 
 
Traumatic Brain Injury  
TCAs 
Tricyclic Agents  
TEAE 
Treatment Emergent Adverse Event  
TLFB 
Timeline Followback 
THC 
Tetrahydrocannabinol 
TIA 
Transient Ischemic Attack 
TMS 
Transcranial Magnetic Stimulation 
TRD 
Treatment-Resistant Depression 
TSH 
Thyroid Stimulating Hormone  
VNS 
Vagus Nerve Stimulation  
WOCBP 
Woman of Childbearing Potential 
 
 

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PROTOCOL SYNOPSIS 
 
Title 
 
A Randomized, Double-Blind Study of Single-Dose Psilocybin for Major Depressive Disorder 
(MDD) 
 
Study Code 
 
PSIL201 
 
Name of Sponsor 
 
Usona Institute  
2800 Woods Hollow Rd 
Madison, WI 53711 
 
Medical Monitor 
 
 
The Emmes Company 
401 N. Washington St., #700 
Rockville, MD 20850 
 
Phase of Study 
 
Phase 2 
 
Sample Size 
 
~100 randomized 
 
Name of Investigational Product (IP) 
 
Psilocybin 3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate 
 
Name of Active Placebo 
 
Niacin 
 
ClinicalTrials.gov Identifier 
 
NCT03866174 
 

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Description of IP and Active Placebo  
 
Study Description and Overview 
One hundred participants (males and females) ages 21 to 65 who, at Screening, meet DSM-5 
criteria for major depressive disorder (MDD), have a current depressive episode of at least 
60-day duration, have a Screening Montgomery-Asberg Depression Rating Scale (MADRS) total 
VFRUHDQGPHHWDOORWKHULQFOXVLRQH[FOXVLRQFUiteria 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 
control that provides an acute physiological response (flushing) that is intended to aid in blinding 
of intervention allocation. All randomized participants will be included in the intent-to-treat 
(ITT) population for testing primary, secondary and exploratory study endpoints.  
 
Only participants who meet depressive symptom severity criteria at Screening (Screening 
0$'56VFRUHRQERWKWKHFHQWUDOUDWHUDQGFRPSXWHUDVVHVVPHQWV) and who do not show an 
unacceptably large degree of symptom improvement between the Screening visit and the 
Baseline assessment (indexed by LPSURYHPHQW on both the central rater and computer 
MADRS assessments) will be eligible for randomization. In addition, at Screening and Baseline, 
only participants with a score difference EHWZHHQWKHFHQWUDOUDWHUDQGFRPSXWHU0$'56 
assessments will be eligible for randomization. A larger discrepancy has been associated with an 
exceptionally high placebo response in prior studies conducted by the study’s central rater 
vendor (data on file). In addition, inability to be consistent in response to the same questions 
likely identifies individuals not sufficiently capable of providing reliable responses. 
 
Study Intervention 
Name: 
Psilocybin 
(active drug product) 
Niacin 
(active placebo product) 
Dosage formulation: 
 
One active capsule contains 25 
mg of psilocybin 
One active placebo capsule 
contains 100 mg of niacin  
Capsule: 
Size 2 hydroxypropyl 
methylcellulose (HPMC), 
opaque 
Size 2 HPMC, opaque 
Unit dose strength: 
25 mg 
100 mg 
Route of 
Administration: 
Oral (solid dose) 
Oral (solid dose) 
Dosing instructions: 
 
 
 
One capsule administered with 
water 
One capsule administered with 
water 
Packaging and 
Labeling: 
Study Intervention will be provided in a high-density polyethylene 
(HDPE) bottle. Each bottle will contain one capsule (psilocybin or 
niacin) and will be labeled as required per country requirement for 
blinded study. 

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Potential participants who meet all other entry criteria at Screening but who are taking an 
antidepressant or an antidepressant plus an augmenting agent (e.g., a second antidepressant, an 
atypical antipsychotic, lithium) will be eligible for continuation in the study but will enter a 
medication taper during which current psychotropic medications will be withdrawn under the 
supervision of a study psychiatric medical provider. Participants will be eligible to undergo the 
Baseline assessment at least 2 weeks after the last dose of the applicable medication taper. 
 
Participants deemed eligible following successful completion of all screening assessments will 
complete central rater, site rater and self-report measures at Baseline for a final eligibility 
determination.  Eligible participants at Baseline will undergo preparation sessions and be eligible 
for randomization on Dosing Day to receive either psilocybin or niacin active-placebo and will 
complete follow-up visits and assessments on study Day 2, 8, 15, 29 and 43 (within 
corresponding visit windows). Study outcome measures will assess depressive symptoms, 
clinical global functioning, functional disability, anxiety symptoms and health-related quality of 
life. Safety outcome measures will be collected at all assessment time points from the time of 
consent through the end of study. 
 
To enhance participant safety, the current study does not propose to test psilocybin as a “context-
less” pharmacological agent, but rather within a “set and setting” (SaS) protocol similar to the 
protocol that has been used in all modern studies of psilocybin in both diseased and normal healthy 
populations. 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 (with the 
exception of short, temporary allowances for facilitator breaks; e.g. bathroom breaks); and 3) 
three post-dose integration sessions during which participants are encouraged to discuss their 
intervention experience with the Facilitators. The SaS will be identical for those randomized to 
psilocybin or niacin active placebo. 
 
Study Duration 
 
The planned maximum study duration for each participant will be approximately 12 weeks (87 
days), with variation primarily dependent on the length of the screening period, the number of 
days between baseline and dosing, and the visit windows provided for each post-dose 
assessment.  
 
Primary Objective 
 
The primary objective of this study is to evaluate the potential efficacy of a single 25 mg oral dose 
of psilocybin for major depressive disorder (MDD) compared to an active placebo (niacin) in 
otherwise medically healthy participants between the ages of 21 and 65, assessed as the difference 
between groups in changes in depressive symptoms from Baseline to Day 43 post-dose. 
 
Primary Outcome Measure 
 
Central rater administered MADRS  
 

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Secondary, Exploratory and Exploratory-Mechanism Based Objectives 
 
The key secondary objective is to evaluate the potential efficacy of a single 25 mg dose of 
psilocybin for MDD compared to an active placebo in medically healthy participants ages 21 to 
65, measured as between-group difference in change in MADRS-assessed depressive symptoms 
from Baseline to Day 8. Additional secondary, exploratory, and exploratory-mechanism based 
objectives are to evaluate depressive symptoms at other time points and to assess between-group 
differences in rates of sustained response and remission, clinical global functioning, anxiety 
symptoms, functional disability, health-related quality of life, mystical-type experiences, and 
emotional breakthrough experiences.  
 
Secondary, Exploratory, and Exploratory-Mechanism Based Outcome Measures  
 
Secondary: MADRS (Day 8 key secondary), Sheehan Disability Scale (SDS); Exploratory: 
Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression – Severity (CGI-S), 
Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q); Symptoms of Major 
Depressive Disorder Scale (SMDDS), Oxford Depression Questionnaire (ODQ); Exploratory-
Mechanism Based: 30-item Mystical Experience Questionnaire (MEQ-30), and Emotional 
Breakthrough Inventory (EBI) 
 
Safety Objectives  
 
The overall safety objective of this study is to evaluate a single 25 mg oral dose of psilocybin 
compared to an active placebo in incidence, severity and frequency of Adverse Events (AEs), 
Treatment Emergent AEs (TEAEs), Solicited AEs, and Serious Adverse Events (SAEs) before, 
during and after the dosing session and at all follow-up visits.  
 
1)  Period 1 (Screening Period): Screening through end of Baseline;  
2) Period 2 (Preparation Period): Preparation until Randomization;  
3)  Period 3 (Dosing Period): Randomization through Day 9; and  
4)  Period 4 (Follow-up Period): Day 10 through Day 43  
 
Solicited Adverse Events  
 
The following solicited AEs will be collected: 
 
 
Visual perceptual effects (Periods 3-4) will be solicited by asking the following questions: 1) 
Since your dosing session have you experienced any uncontrolled or disturbing return of study 
drug effects?, and 2) Since your dosing session have you experienced any visual distortions (e.g. 
geometric hallucinations, false perceptions of movement in the peripheral visual fields, flashes of 
color, intensified color, trails for images of moving objects, positive after-images, halos around 
objects)?  If a participant reports “Yes” to any of the above questions a study psychologist or 
psychiatrist will follow up for further assessment/diagnosis.  
 

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Additional solicited AEs include: 
 
x Active suicidal ideation identified through the C-SSRS and/or MADRS and verified 
by clinical assessment (recorded for Periods 1-4; would result in screen failure or 
early termination in Periods 1-2) 
x Headache (Period 3); and  
x Nausea (Period 3); and 
x Elevated blood pressure (BP) as defined by systolic blood pressure (SBP) >140 
mmHg or diastolic blood pressure (DBP) >90 mmHg on three separate readings and 
requiring medication (recorded for Periods 1-4; may result in screen failure or early 
termination in Periods 1-2); and  
x Elevated heart rate (HR) as defined as >100 beats per minute (BPM) and requiring 
medication (recorded for Periods 1-4; may result in screen failure or early termination 
in Periods 1-2); and 
x Drug overdose with suicidal intent (recorded for Periods 1-4; would result in screen 
failure or early termination in Periods 1-2) 
 
Unsolicited Adverse Events 
 
Any other observed and participant reported AEs and SAEs will be recorded for all study periods 
(Periods 1-4), following written informed consent. SAEs will be reported per FDA guidelines.  
 
Specific Safety Monitoring Objectives 
 
Safety will be continually evaluated by study staff through monitoring and assessment of AEs, 
vital signs, concomitant medication use, physical exams, safety labs, site rater administered 
measures, and integration with session Facilitators. The study will also assess abuse liability, 
including non-clinical, illicit use of psilocybin and other psychedelics and other illicit and non-
prescribed drug use via the AUDIT and DUDIT, Timeline Followback, and Substance Use 
Disorders module of the SCID-CT, participant self-report, and urine drug testing per the 
Schedule of Assessments (Table 1). Additionally, a Data and Safety Monitoring Board (DSMB) 
will review and oversee safety data.  
 
Eligibility and Safety Measures 
 
Structured Interview for DSM-5 Disorders-Clinical Trials Version (SCID-5-CT), SCID-5-
Personality Disorders (PD), Alcohol Use Disorders Identification Test (AUDIT), Drug Use 
Disorders Identification Test (DUDIT), Timeline Followback (TLFB), Drug History 
Questionnaire (DHQ), Columbia Suicide Severity Rating Scale (C-SSRS), Lifetime Illness 
Characteristic Questionnaire (LICQ), Massachusetts General Hospital Antidepressant Treatment 
History Questionnaire (ATRQ), and the Family History Screen (FHS). 
 

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Inclusion/ Exclusion Criteria 
 
Inclusion Criteria 
Individuals eligible to be randomized in this protocol are those who meet all of the following 
criteria:  
 
1. Are 21 to 65 years old at the time of written informed consent at the Screening visit 
2. Are able to read, speak, and understand English 
3. Are able and willing to adhere to study requirements, including attending all study visits, 
preparatory and follow-up sessions, and completing all study evaluations 
4. Are able to swallow capsules  
5. Women of childbearing potential (WOCBP) must agree to practice an effective means of 
birth control throughout the duration of the study, from Screening through the Day 43 
assessment (see Section 15 Pregnancy for a definition of WOCBP)  
6. 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 the 
Screening  
7. Have sustained moderate-severe depression symptoms at Screening and Baseline, as 
defined by a Screening MADRS total VFRUHDQG LPSURYHPHQWLHGHFUHDVH
in MADRS total score from Screening to Baseline on both the central rater and computer 
assessments 
8. &HQWUDOUDWHU0$'56DQGFRPSXWHUDGPLQLVWHUHG0$'56WRWDOVFRUHVVKRZSRLQW
difference between scores at both Screening and Baseline 
9. Have an identified support person 
a. Agree to be accompanied home (or to an otherwise safe destination) by the 
support person, or another responsible party, following dosing 
 
Exclusion Criteria 
Individuals not eligible to be randomized in this protocol are those who meet any of the 
following criteria: 
 
1. Women who are pregnant, as indicated by a positive urine pregnancy test at Screening or 
Baseline. Women who intend to become pregnant during the study or who are currently 
nursing.  
2. Unwilling or unable to discontinue formal psychotherapy (Section 4.2.2) 
3. Unwilling to discontinue any current prescription or supplemental psychotropic agents 
(including trazodone for sleep) or are unable according to Section 4.2.1 Medication Taper 
o Note: Benzodiazepine medications and non-benzodiazepine sleeping medications 
will be allowed to continue through the study period for participants who have 
been on a stable dose of such a medicine for at least 6 weeks prior to Screening. 
4. Have previously received the following non-medication treatments: 
a. deep brain stimulation (DBS) 
b. vagus nerve stimulation (VNS) 

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5. Currently receiving electroconvulsive therapy (ECT) or transcranial magnetic stimulation 
(TMS) 
o Note: Previous treatment with ECT or TMS is allowed as long as last treatment 
ZDVGD\VIURPWKHWLPHRI6FUHHQLQJ 
6. Unable or unwilling to discontinue any current medications having a primary centrally-
acting serotonergic effect, including monoamine oxidase inhibitors (MAOIs) or 
dopaminergic antagonists 
o Note: Any prohibited agents must have been stopped at least 5x the elimination 
half-life of the specific drug at the time of Baseline. See Appendix A for a full list 
of prohibited medications. 
7. Unable or unwilling to discontinue any current medications that are known uridine 
diphosphate (UDP) or glucuronosyltransferase (UGT) enzyme modulators, such as 
valproate 
o Note: Any prohibited agents must have been stopped at least 5x the elimination 
half-life of the specific drug at the time of Baseline. See Appendix A for a full list 
of prohibited medications. 
8. Report the following psychedelic substances use: 
a. Have used a psychedelic substance in the previous 5 years; or 
b. Have used psychedelic substances > 10 times in their lifetime 
o Note: Psychedelic substances include psilocybin, Lysergic acid diethylamide 
(LSD), mescaline (and natural products containing mescaline including peyote 
and San Pedro cactus), N,N-Dimethyltryptamine (DMT), natural products 
containing DMT including ayahuasca and 5-Methoxy-N,N-dimethyltryptamine 
(5-MeO-DMT), ibogaine, 2C compounds, 3,4-methylenedioxy-
methamphetamine  (MDMA), methylone or other psychedelics. 
9. Have the following cardiovascular conditions:  
a. coronary artery disease, congenital long QT syndrome (prior diagnosis), cardiac 
hypertrophy, cardiac ischemia, congestive heart failure, myocardial infarction 
(prior diagnosis); 
b. tachycardia (defined as heart rate > 100 beats per minute); 
c. a clinically significant Screening ECG abnormality (e.g., atrial fibrillation); 
o Note: A QTcF interval > 450 milliseconds is considered a clinically 
significant ECG abnormality 
d. artificial heart valve; or 
e. any other significant current or history of cardiovascular condition, based on the 
clinical judgment of study physician, that would make a participant unsuitable for 
the study  
10. At Screening or Baseline have elevated blood pressure as defined as: 
a. Screening blood pressure SBP >135 mmHg or DBP > 85 mmHg on three separate 
readings; or  
b. Baseline blood pressure SBP >140 mmHg or DBP > 90 mmHg on three separate 
readings 
o Note: Please see justification for blood pressure parameters in Section 4.2.8  
11. Have a history of stroke or Transient Ischemic Attack (TIA) 
12. Have moderate to severe hepatic impairment, as indexed by a Child-3XJKVFRUH 
13. Have epilepsy 

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14. Have insulin-dependent diabetes  
o Note: Participants who are taking oral hypoglycemic agent and have a history of 
hypoglycemia requiring medical intervention will be excluded 
15. Are unable or unwilling to adhere to the following medication requirements:  
a. Agree to suspend sildenafil (Viagra®), tadalafil, or similar medications at least 72 
hours prior to dosing 
b. If taking any supplement containing >20 mg of niacin, agrees to suspend use for 
at least five days prior to dosing and for the duration of the study 
16. Have a positive urine drug test including Amphetamines, Barbiturates, Buprenorphine, 
Benzodiazepines, Cocaine, Cannabis, Methamphetamine, MDMA, Methadone, Opiates 
(Morphine, Oxycodone), Phencyclidine (PCP), and Tetrahydrocannabinol (THC). 
Exceptions are made for prescribed Benzodiazepines (stable dose for sleep or anxiety).  
o Note: Prescribed benzodiazepine medications and non-benzodiazepine sleeping 
medications will be allowed to continue through the study period for participants 
who have been on a stable dose of such a medicine for at least 6 weeks prior to 
Screening, as determined during review of concomitant medications. 
o Note: Participants using cannabis, including legal cannabis, for any purposes must 
agree to refrain from use beginning at Screening, as confirmed with a negative 
Baseline drug test, and through to the end of the study.   
o Note: Participants who are taking prescription maintenance methadone or 
buprenorphine naloxone will be excluded. 
o Note: Prescription opiates must have been stopped at least 5x the elimination half-
life of the specific drug at the time of dosing, as confirmed with a negative urine 
drug screen on Day 1 (prior to dosing). They can resume use following the 
Integration Session # 1 the day after dosing. 
o Note: Participants using prescribed psychostimulants (amphetamines and Ritalin), 
must agree to refrain from use two weeks prior to baseline visit, as confirmed 
with a negative Baseline drug test, and through to the end of the study. 
o Note: Participants using prescribed trazodone for sleep (at any dose) must agree to 
refrain from use two weeks prior to baseline visit and through to the end of the study. 
17. Nicotine dependence that would disallow an individual to be nicotine free for the 7-10 
hours during the dosing period 
18. Meet DSM-5 criteria for schizophrenia spectrum or other psychotic disorders, including 
MDD with psychotic features (except substance/medication-induced or due to another 
medical condition), or Bipolar I or Bipolar II Disorder 
o Note: Participants with any lifetime diagnosis of schizophrenia spectrum or other 
psychotic disorders will be excluded 
19. Meet DSM-5 criteria for antisocial personality disorder 
20. Meet DSM-5 criteria for a moderate or severe alcohol or drug use disorder (excluding 
caffeine)  
o Note: Participants with a diagnosis of alcohol or drug use disorder within the past 
12 months will be excluded 
21. Have presence of any psychiatric condition or symptom judged by the PI (or designee) to 
be a more significant clinical problem than MDD for the participant, including a DSM-5 
personality disorder 

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22. Have a first-degree relative with schizophrenia spectrum or other psychotic disorders 
(except substance/medication-induced or due to another medical condition), or Bipolar I 
Disorder 
23. Have a psychiatric condition judged to be incompatible with establishment of rapport 
with the Facilitators or safe exposure to psilocybin  
24. Report the following suicidal ideation or suicidal thoughts defined as: 
a. Answer ‘Yes’ to C-SSRS Suicidal Ideation items 4 or 5 within the last 2 months 
at Screening or “since last visit” at Baseline;  
b. Report having had any C-SSRS Suicidal Behavior item within the past 12 months 
at Screening or “since last visit” at Baseline, as defined by ‘Yes’ to any of the 
following on the C-SSRS: actual attempt, interrupted attempt, aborted attempt, or 
preparatory acts; or 
c. Have a score of 5 on Item 10 (suicidal thoughts) of the central-rater or computer 
administered MADRS at Screening or Baseline; or 
d. Have any suicidal ideation or thoughts, in the opinion of the study physician or PI, 
that presents a serious risk of suicidal or self-injurious behavior at any time prior 
to randomization 
25. Have any suicidal ideation or thoughts, in the opinion of the study physician or PI, that 
presents a serious risk of suicidal or self-injurious behavior 
26. Have any physical or psychological symptom, medication or other relevant finding prior 
to randomization, based on the clinical judgment of clinical/medical study personnel, that 
would make a participant unsuitable for the study.  
27. Have an allergy or intolerance to any of the materials contained in either drug product 
 
Statistical Analysis 
 
This Phase 2 study has been powered to evaluate the clinical efficacy of psilocybin for the primary 
and key secondary objectives, i.e. to test the difference between psilocybin and niacin in the 
change in central rater MADRS score from Baseline to Day 43 and Day 8, respectively, in the 
randomized analysis set.  Two open-label studies of psilocybin in MDD (Davis et al., 2019) and 
TRD (Carhart-Harris et al., 2016) indicated 62WR69PHDQUHGXFWLRQLQGHSUHVVLRQV\PSWRPV 
1-week following the final dosing session in the psilocybin arms, and this reduction was sustained 
at 4-5 weeks post dosing with reduction in depression symptoms of 57WR66 (Table 8). Two 
prior studies of psilocybin in cancer-related depression and anxiety showed a similar trend with a 
mean reduction LQGHSUHVVLYHV\PSWRPVDWZHHNVSRVWGRVHRILQWKHKLJK-dose group in 
Griffiths et al., 2016DQGUHGXFWLRQDWZHHNVSRVWGRVe in Ross et al., 2016. Based on prior 
controlled studies of psilocybin in cancer-related depression and anxiety (Ross et al., 2016), a 
decrease in depression symptoms from baseline to 43 days post-dose of approximately  in the 
niacin active-control arm is expected. 
 
Approximately 100 patients are planned to be randomized into this study.  Assuming a placebo 
group MADRS mean change from baseline = 10 at all time points, MADRS change from 
baseline SD = 10, psilocybin group MADRS mean change from baseline at Day 8 = 18 (d = 0.8) 
and Day 43 = 17 (d = DQGRYHUDOOGURSRXWE\'D\DVDPSOHVL]HRI100 
participants would result in 92SRZHUIRUSULPDU\'D\HQGSRLQWDQG8SRZHUIRUWKHNH\

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secondary Day 8 endpoint. Key assumptions are in alignment with what has been observed in 
previous psilocybin studies.    
 
In the final intent to treat (ITT) analysis, a mixed effect model for repeated measures (MMRM) 
with an unstructured or other appropriate covariance matrix, with Baseline questionnaire score as 
a covariate and site, sex, and TRD status as fixed effects will be employed to test primary and 
key secondary study endpoints. 

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1 
INTRODUCTION 
1.1 
Usona Institute 
Usona Institute (Usona) is a non-profit medical research organization founded in 2014. As part 
of its mission to explore the therapeutic effects of consciousness-expanding medicines, Usona is 
conducting research to further understand the therapeutic effects of psilocybin (3-[2-
(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate). The purpose of this study is to 
evaluate the safety and efficacy of psilocybin for major depressive disorder (MDD) in the 
general population (under Investigational New Drug [IND] #129532). 
1.2 
Purpose 
The overarching purpose of this study is to conduct an initial examination of the safety, efficacy and 
tolerability of single-dose psilocybin in otherwise medically healthy patients with MDD. The 
overall objectives of this study are to examine the potential efficacy of a single, fixed, 25 mg oral 
dose of psilocybin in reducing depressive and anxious symptoms and improving functional 
disability and quality of life in medically healthy patients with MDD when compared to active 
placebo; and to collect safety and tolerability data on single-dose psilocybin intervention in 
medically healthy patients with MDD. Of note, this study represents the first randomized, double-
blind, placebo-controlled study of single-dose psilocybin in a general-population (i.e. medically 
healthy) MDD sample (prior studies of depression have either used an open design or occurred in 
patients with a concomitant medical illness). 
1.3 
Study Rationale 
MDD is currently the leading cause of disability in the world 
(http://www.who.int/mediacentre/factsheets/fs369/en/). This highlights the urgent need to identify 
and test novel pharmacological agents that might benefit depressed patients who have not achieved 
symptom remission with currently approved antidepressant modalities. Recent studies suggest that 
psilocybin produces a substantial and sustained improvement in depressive symptoms following a 
single administration. 
1.4 
Background 
1.4.1 Major Depressive Disorder (MDD) 
Major depression has become a health crisis of epidemic proportions in the modern world 
(http://www.who.int/mediacentre/factsheets/fs369/en/). The prevalence of major depression has 
risen over the last several generations in every country examined (Weissman et al., 1992) and 
age of symptom onset has decreased (Chengappa et al., 2003). It is estimated that major 
depression will rank second after cardiac disease as a cause of international medical morbidity by 
the year 2020 (Global Burden of Disease Study, 2015). One in six individuals in the United 
States will experience an episode of major depression in his or her lifetime (Kessler et al., 2003), 
and the risk of subsequent episodes rises dramatically once a person has been depressed (Frank, 
Kupfer, Wagner, McEachran, & Cornes, 1991). Indeed, depression is now recognized to be a 
highly chronic and recurrent illness (Frank et al., 1990; Greden, 2001b). On average, patients 
ZLWKPDMRUGHSUHVVLRQDUHV\PSWRPDWLFRIWKHWLPHHYHQZKHQUHFHLYLQJFRPPXQLW\-

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standard antidepressant treatment (Judd et al., 1998). Recent estimates place the economic 
burden of depression in the United States at 200 billion dollars a year (Greenberg, Fournier, 
Sisitsky, Pike, & Kessler, 2015). Depression is associated with greater disability than are most 
other chronic illnesses and is a risk factor for mortality (Wulsin, Vaillant, & Wells, 1999). 
Suicide ranks among the top ten causes of death in the United States (Akiskal, 2005), and best 
estimates suggest that 60-RISHRSOHZKRNLOOWKHPVHOYHVDUHFOLQLFDOO\GHSUHVVHG (Sudak, 
2005). Between 10-RIVHYHUHO\GHSUHVVHGSHRSOHHYHQWXDOO\FRPPLWVXLFLGH (Sudak, 2005). 
In addition, many studies indicate that depression significantly increases all-cause mortality 
independently of suicide (Wulsin et al., 1999). Depression predicts the later development of a 
number of medical conditions, including cardiac and cerebrovascular disease (Joynt, Whellan, & 
O'Connor, 2003; Thomas, Kalaria, & O'Brien, 2004), hypertension (Davidson, Jonas, Dixon, & 
Markovitz, 2000; Jonas & Lando, 2000), diabetes (Eaton, Armenian, Gallo, Pratt, & Ford, 1996; 
Kawakami, Takatsuka, Shimizu, & Ishibashi, 1999), obesity and metabolic syndrome (Barefoot 
et al., 1998; Pine, Goldstein, Wolk, & Weissman, 2001; Raikkonen, Matthews, & Kuller, 2002), 
dementia (Jorm, 2001), and cancer (Spiegel & Giese-Davis, 2003). Depression also markedly 
increases mortality in medically ill patients and has been associated with decreased responses to 
pharmacological treatments for cancer and hepatitis C (Raison et al., 2005; Spiegel & Giese-
Davis, 2003). 
 
Unfortunately, most patients with depression do not experience a complete resolution of 
symptoms with antidepressant treatment (Greden, 2001a). The risks of not responding 
completely to (or tolerating) treatment have been highlighted by recent studies documenting that 
partial—but incomplete—response is associated with an increased risk of full symptomatic 
relapse (even when on therapy) and a worse long term disease course, as well as with 
significantly impaired quality of life (Judd et al., 2000; Miller et al., 1998; Simon, 2000). 
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. 
1.4.2 Psilocybin 
Psilocybin is a natural product produced by numerous species of Psilocybe mushrooms. The 
phosphate group is enzymatically cleaved in the body to produce psilocin, an agonist at a variety 
of serotonin receptors, the most important of which for its behavioral effects is the 5-HT2A 
receptor (Carhart-Harris et al., 2014; Nichols, 2004). Psilocybin was first isolated from Psilocybe 
mushrooms in 1957, followed by de novo synthesis in 1958 (Passie, Seifert, Schneider, & 
Emrich, 2002). Psilocybin was marketed worldwide by Sandoz in the 1960s as Indocybin™ for 
experimental and psychotherapeutic purposes. Although it was well tolerated and demonstrated 
potentially useful effects, it was classified as a controlled substance, placed in Schedule I in 
1970, and effectively removed from clinical use or scientific study. Psilocybin, and similar  
drugs such as lysergic acid diethylamide (LSD) and mescaline, fall into a pharmacological class 
referred to in this application as “classic psychedelics” to differentiate them from other 
psychoactive substances (i.e. MDMA [3,4-methylenedioxy-methamphetamine] that have different 
psychological/ behavioral effects and different adverse effect profiles and risk/benefit ratios than 
psilocybin (Carhart-Harris & Nutt, 2013; Nutt, King, Phillips, & Independent Scientific 
Committee on, 2010). 
 

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Psilocybin is currently a Schedule I controlled substance, which means it is considered to have 
high potential for abuse and no currently accepted medical use, according to the Drug 
Enforcement Agency (DEA). The psilocybin used in this study is synthetically manufactured in a 
laboratory and meets quality specifications suitable for human research use. No mushrooms 
naturally containing psilocybin are used in the manufacturing process. The active drug is 
encapsulated using a hydroxypropyl methylcellulose (HPMC) capsule and contains 25 mg of 
psilocybin. The active placebo is encapsulated using a HPMC capsule and contains 100 mg of 
niacin USP. Psilocybin and niacin are administered orally and taken with water.  
 
Information regarding the pharmacology and toxicology of psilocybin can be found in the 
Investigator’s Brochure (IB). 
1.4.3 Previous Clinical Experience with Psilocybin Relevant to MDD 
Data reaching back to the 1960s suggest that classic psychedelics, including psilocybin, have 
behavioral effects relevant to the treatment of depression. Recent studies (Carhart-Harris et al., 
2016; R. R. Griffiths et al., 2016; Ross et al., 2016) suggest that psilocybin may possess 
antidepressant properties. Specifically, two randomized, double-blind, placebo-controlled studies 
in patients with life-threatening cancer and clinically-significant depression/anxiety and an open 
trial in patients with Treatment-Resistant Depression (TRD) suggest that a single intervention 
with psilocybin conducted within a set and setting (SaS) protocol, described below, produces 
antidepressant effects that are sustained for up to six months post- intervention, while having a 
minimal, time-limited side effect profile (Carhart-Harris et al., 2016; R. R. Griffiths et al., 2016; 
Ross et al., 2016). More recently a small randomized, wait-list controlled trial of two doses of 
psilocybin in the range proposed for the current protocol produced a large improvement in 
depressive symptoms, whether assessed as change from baseline or in comparison to the wait-list 
condition (Davis et al., 2020).   
 
 
The current proposal advances our knowledge of the value of single-dose psilocybin for the 
treatment of MDD in several ways. To date, placebo-controlled studies of psilocybin to treat 
depression have only been conducted in patients with cancer, not in medically healthy patients. 
And the single 12 participant study conducted to date of psilocybin intervention in medically 
healthy patients with TRD was not blinded and did not include a placebo condition. The recent 
wait-list controlled trial in MDD also did not have a placebo condition and no allocation blinding 
was done. The scientific rationale for the current study is that it will address both these gaps in 
understanding the potential value of single dose psilocybin for MDD in medically healthy 
patients. Specifically, this study will address this research gap by: 1) randomizing a population of 
medically healthy participants with MDD; 2) utilizing a randomized, double-blind, placebo-
controlled, parallel-group design to control for baseline covariates, placebo and other therapeutic 
effects not specifically linked to medication exposure; and 3) utilizing an offsite independent 
centralized rating service to reduce the risk of functional unblinding of raters assessing the 
study’s primary endpoint. 
 
In addition, data derived from this study will allow for a refinement of effect size estimates for 
larger studies of single dose psilocybin in MDD. Moreover, because previous psilocybin studies 

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utilized weight-based dosing, the current study will allow us to examine whether fixed-dose 
psilocybin will produce effect size benefits consistent with those seen with weight-based dosing. 
1.5 
The Set and Setting (SaS) Protocol  
Early studies with psilocybin, administered for research purposes but without a supportive setting, 
observed a wide range of responses, including panic reactions and episodes of paranoia that were 
highly distressing (R. R. Griffiths et al., 2011; R. R. Griffiths, Richards, McCann, & Jesse, 2006). 
From these early experiments came an increasing appreciation of the importance of designing the 
optimal conditions under which psilocybin could be safely administered within the research setting. 
Such attention was aimed at reducing the risk of these negative responses while simultaneously 
increasing the likelihood of participants having the types of positive mystical-type experiences that 
appear to play an important causal role in long-term positive behavioral/emotional changes. By 
addressing what are now known as “set” (i.e. participant emotional/cognitive/behavioral 
state/mindset and expectations just prior to psilocybin exposure) and “setting” (the physical 
environment in which the exposure occurs), the rate of adverse responses to classic psychedelic 
exposure dropped significantly (Metzner, Litwin, & Weil, 1965; Pahnke, 1969). Confirmation of the 
importance of context for optimizing the therapeutic benefit of psilocybin (and other psychedelics) 
comes from a meta-analysis of 23 controlled studies and provides a strong rationale for the use of 
the SaS in this protocol (Studerus, Gamma, Kometer, & Vollenweider, 2012). 
 
By the mid-1960s, a set and setting approach had been widely accepted as including three 
components: 1) preparation prior to drug session; 2) drug session; and 3) post session meetings to 
integrate the psychedelic experience. In component 1, participants underwent pre-exposure 
preparation sessions designed to build rapport with the Facilitators who would be present during the 
drug exposure session and to identify personal themes and struggles that might be especially likely 
to impact the session experience. In component 2, the drug session itself was conducted by two 
Facilitators (typically a male and female dyad) who were present throughout the session. Sessions 
were typically conducted in a room designed to be quiet, comfortable, and aesthetically pleasing, 
and participants were encouraged to wear eyeshades and listen to a program of music on 
headphones during the drug exposure to aid them in focusing their attention inward. In component 
3, participants engaged in a series of drug-free interview meetings of variable frequency, sometimes 
over a period of several weeks, to discuss their session experience thoroughly.  
 
The SaS protocol proposed in the current study is in line with this 3-component model. A full and 
detailed description of information and instructions given during the study preparation, dosing, and 
integration sessions is provided in the Usona Facilitator Training Manual and in the study manual 
of procedures (MoP). The intervention protocol, for purposes of this research study, includes the 
period of participant preparation prior to drug administration, the 7-10 hour drug session, and the 
post-dose integration sessions to maximize participant safety and support. It is for this reason that 
eligibility verification is conducted prior to the preparatory sessions rather than immediately 
preceding the delivery of study medication (psilocybin vs. active placebo).  
 

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2 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the potential efficacy of a single 25 mg oral dose 
of psilocybin for major depressive disorder (MDD) compared to an active placebo (niacin) in 
otherwise medically healthy participants ages 21 to 65, assessed as the difference between groups in 
changes in MADRS-assessed depressive symptoms from Baseline to Day 43 post-dose. 
2.2 
Secondary Objectives 
The key secondary objective of this study is to evaluate the potential efficacy of a single 25 mg 
dose of psilocybin for MDD compared to an active placebo in medically healthy participants 
ages 21 to 65, measured as between-group difference in change in MADRS-assessed depressive 
symptoms from Baseline to Day 8 post-dose.  
 
Additional secondary objectives are to evaluate between-group differences in: 
x Change in Sheehan Disability Scale (SDS)-assessed functional disability status from 
Baseline to Day 43 post-dose 
x Sustained depressive symptom response following dosing 
x Sustained depressive symptom remission following dosing 
2.3 
Exploratory Objectives 
Exploratory objectives of this study are to evaluate the potential efficacy of a single 25 mg oral 
dose of psilocybin for MDD compared to an active placebo in medically healthy participants 
between the ages of 21 and 65, measured as between-group differences in: 
 
x Change in MADRS-assessed depressive symptoms from Baseline to post-dose Day 2, 15 
and 29  
x Change in Clinical Global Impression—Severity (CGI-S) score from Baseline to post-
dose Day 8, 15, 29 and 43 
x Change in Hamilton Anxiety Rating Scale (HAM-A)-assessed anxiety symptoms from 
Baseline to post-dose Day 8, 15, 29 and 43 
x Change in Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)-
assessed health-related quality of life from Baseline to post-dose Day 8, 15, 29 and 43 
x Change in SDS-assessed functional disability to post-dose Day 8, 15 and 29 
x Degree of concordance between central-rated and computer-administered MADRS 
measures of depressive symptoms at Baseline and post-dose time points 
x Change in Symptoms of Major Depressive Disorder Scale (SMDDS)-assessed depressive 
symptoms from Baseline to post-dose Day 8 and 43  
x Change in SMDDS-assessed depressive symptoms from pre-dose Day 1 to post-dose Day 
8 and 43 
x Change in Oxford Depression Questionnaire (ODQ)-assessed depressive symptoms from 
Baseline to post-dose Day 43 

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2.4 
Exploratory Mechanism-Based Objectives 
Exploratory mechanism-based objectives of this study are to evaluate the potential impact of 
acute psychological effects of a single 25 mg dose of psilocybin on longer-term antidepressant 
effects in MDD compared to an active placebo in medically healthy participants ages 21 to 65, 
measured as between group differences in: 
 
x 30-item Mystical Experience Questionnaire (MEQ-30) score reported post-dose 
x Emotional Breakthrough Inventory (EBI) score reported post-dose 
x Association between mystical-type experiences reported post-dose and longer-term 
changes in MADRS-assessed depressive symptoms 
x Association between EBI-assessed emotional break through experiences reported post-
dose and longer-term changes in MADRS-assessed depressive symptoms 
2.5 
Safety Objectives 
The overall safety objective of this study is to evaluate a single 25 mg oral dose of psilocybin 
compared to an active placebo in incidence, severity and frequency of Adverse Events (AEs), 
Treatment Emergent AEs (TEAEs), Solicited AEs, and Serious Adverse Events (SAEs) before, 
during and after the dosing session and at all follow-up visits.  
 
1)  Period 1 (Screening Period): Screening through end of Baseline;  
2) Period 2 (Preparation Period): Preparation until Randomization;  
3)  Period 3 (Dosing Period): Randomization through Day 9; and  
4)  Period 4 (Follow-up Period): Day 10 through Day 43  
2.6 
Specific Safety Monitoring Objectives 
Safety will be continually evaluated by study staff through monitoring and assessment of AEs, 
vital signs, concomitant medication use, physical exams, safety labs, site rater administered 
measures, and integration with session Facilitators. The study will also assess abuse liability, 
including non-clinical, illicit use of psilocybin and other psychedelics and other illicit and non-
prescribed drug use via the AUDIT and DUDIT, Timeline Followback, Substance Use Disorders 
module of the SCID-CT, participant self-report, and urine drug testing per the Schedule of 
Assessments (Table 1). Additionally, a Data and Safety Monitoring Board (DSMB) will review 
and oversee safety data.  
 
Specific safety monitoring objectives in each of the study periods are as follows: 
 
Period 1: 
  
x Incidence of AEs by severity  
x Incidence of AEs requiring medical attention 
x Incidence of AEs requiring psychiatric attention 
x Incidence of AEs leading to withdrawal from study 
x Incidence of SAEs 

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x Incidence of new concomitant medications 
x Incidence of self-report or urine toxicology identified illicit and non-prescribed drug use 
 
Period 2: 
 
x Incidence of AEs by severity  
x Incidence of AEs requiring medical attention 
x Incidence of AEs requiring psychiatric attention 
x Incidence of AEs leading to termination from study 
x Incidence of SAEs 
x Incidence of new concomitant medications 
x Incidence of self-report or urine toxicology identified illicit and non-prescribed drug use 
 
Period 3: 
 
Differences between the psilocybin and active placebo groups in: 
 
x Incidence of AEs by severity  
x Incidence of AEs requiring medical attention  
x Incidence of AEs requiring psychiatric attention  
x Incidence of AEs leading to termination from the study 
x Incidence of TEAEs  
x Incidence of TEAEs by severity  
x Incidence of solicited AEs  
x Incidence of solicited AEs by severity  
x Incidence of SAEs  
x Incidence of new concomitant medications 
x Incidence of psychiatric concomitant medications  
x Incidence of self-report or urine toxicology identified illicit and non-prescribed drug use 
x Incidence of clinically significant abnormalities on safety laboratory assessments or 
physical examination 
 
Period 4: 
 
Differences between the psilocybin and active placebo groups in: 
 
x Incidence of AEs by severity  
x Incidence of AEs requiring medical attention  
x Incidence of AEs requiring psychiatric attention  
x Incidence of AEs leading to withdrawal from the study  
x Incidence of TEAEs, to assess the relationship between study intervention and each 
occurrence of the relevant AE/SAE based on relative incidence in the psilocybin group  
x Incidence of TEAEs by severity  
x Incidence of solicited AEs  
x Incidence of solicited AEs by severity  

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x Incidence of SAEs  
x Incidence of new concomitant medications 
x Incidence of psychiatric concomitant medications reported 
x Incidence of self-report or urine toxicology identified illicit and non-prescribed drug use 
x Incidence of clinically significant abnormalities on safety laboratory assessments or 
physical examination 
2.7 
Primary Study Endpoint 
x Between-group difference in mean change of central rater Montgomery-Asberg 
Depression Rating Scale (MADRS) score from Baseline to post-dose Day 43 
 
2.7.1 Justification for Primary Study Endpoint 
The selection of Day 43 (week 6) as the primary study endpoint is consistent with standard 
practice in antidepressant trials. As the final time point in the current protocol it is also the most 
relevant for evaluating the persistence of benefit for the study drug vs niacin. In regards to the 
key secondary endpoint, as with other rapidly acting investigational antidepressant agents 
(e.g. ketamine), a single dose of psilocybin has shown to induce a large effect-size reduction in 
depressive symptoms within a day of administration in comparison to active placebo, with no 
further improvement in symptom scores seen at subsequent assessment points (i.e. at 2 weeks 
and 6 weeks post-intervention) (Ross et al., 2016). These findings demonstrate that an 
assessment at one week post-intervention will likely capture the entire antidepressant effect of 
psilocybin, both in comparison to active placebo and in comparison to baseline symptom score. 
Further support for the appropriateness of one week post-intervention as the key secondary study 
endpoint comes from the association of immediate (e.g. one day post-intervention) and longer-
term (e.g. six weeks post-intervention) antidepressant responses to both psilocybin and niacin in 
the New York University (NYU) study of depressed/anxious patients with cancer. In that study 
reductions in Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale 
(HADS) depression subscale scores between baseline and one day post-intervention showed very 
large effect size correlations with reductions in BDI and HADS depressive subscale scores 
between baseline and six weeks post-intervention (unpublished data), as shown in this table: 
 
 
The selection of the MADRS to assess the study’s primary endpoint is consistent with it being 
the most commonly used assessment tool for assessment of primary endpoints in recent phase 3 
antidepressant registration trials. This is consistent with data indicating that in comparison to the 
other historically-used instrument, the Hamilton Depression Rating Scale (HAM-D), the 
MADRS shows improved ability to capture meaningful clinical improvement in response to 
active antidepressants versus placebo (Carmody et al., 2006).  
Instrument 
Niacin 
Psilocybin 
HADS-Depression 
.750 (p = .002) 
.925 (p = .000016) 
BDI 
.863 (p =.001) 
.877 (p = .000082) 

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2.8 
Secondary Study Endpoints 
x Between-group difference in change in central rater MADRS score from Baseline to post-
dose Day 8 (Key Secondary) 
x Between-group difference in change in site rater administered SDS score from Baseline 
to post-dose Day 43 
x Between-group difference in sXVWDLQHGGHSUHVVLYHV\PSWRPUHVSRQVHGHILQHGDVD
reduction from Baseline central rater MADRS score at the following post-dose 
assessments: Day 8, 15, 29 and 43 
x Between-group difference in sustained depressive symptom remission defined as a 
FHQWUDOUDWHU0$'56WRWDOVFRUHDWthe following post-dose assessments: Day 8, 15, 
29 and 43 
2.9 
Exploratory Study Endpoints 
x Between-group difference in change in central rater MADRS score from Baseline to Day 
2, 15 and 29 post-dose 
x Between-group difference in change in central rater CGI-S score from Baseline to Day 8, 
15, 29 and 43 post-dose 
x Between-group difference in change in HAM-A score from Baseline to Day 8, 15, 29 and 
43 post-dose 
x Between-group difference in change in Q-LES-Q score from Baseline to Day 8, 15, 29 
and 43 post-dose 
x Between-group difference in change in site rater administered SDS score from Baseline 
to Day 8, 15, and 29 post-dose 
x Degree of concordance between change in central rater MADRS score from Baseline to 
all post-dose assessments and computer-administered MADRS score over the same 
assessment period. 
x Between-group difference in change in SMDDS score from Baseline to Day 8 and Day 
43 
x Between-group difference in change in SMDDS score from pre-dose Day 1 to post-dose 
Day 8 and 43 
x Between-group difference in change in ODQ score from Baseline to Day 43 
2.10 Exploratory Mechanism-Based Endpoints 
x Between-group difference in post-dose 30-item MEQ-30 score 
x Between-group difference in post-dose EBI score 
2.11 Safety Endpoints 
x Relative incidence of AEs by severity  
x Relative incidence of TEAEs by severity 
x Relative incidence of SAEs by severity 
x Relative incidence of treatment-emergent concomitant medication use  
x Relative incidence of solicited AEs by severity 

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x Relative incidence of clinically significant abnormalities and changes from Baseline in 
clinical laboratory values 
x Relative incidence of clinically significant abnormalities and changes from Baseline in 
vital signs  
x Relative incidence of clinically significant physical examination findings 
x Relative incidence of self-report or urine toxicology identified illicit and non-prescribed 
drug use 
2.12 Outcome Measures 
See Appendix B for a table of clinical outcome assessments.  
2.12.1 Montgomery-Asberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item depression rating scale developed in 1979 to be more sensitive to 
symptom changes induced by antidepressants than were currently available instruments 
(Montgomery & Asberg, 1979). The MADRS has been used for assessing primary outcomes in 
registration trials for new pharmacological agents for treating MDD, whether these agents are 
traditional monoamine modulators (e.g., vilazodone, vortioxetine) or agents with novel 
mechanisms of action (e.g., esketamine) (Daly et al., 2018). The MADRS includes questions on 
the following symptoms 1. Reported sadness 2. Apparent sadness 3. Inner tension 4. Reduced 
sleep 5. Reduced appetite 6. Concentration difficulties 7. Lassitude 8. Inability to feel 9. 
Pessimistic thoughts 10. Suicidal thoughts. Items are scored via a clinical interview that 
progresses from more broadly phrased questions about symptoms to more detailed queries that 
allow a precise rating of severity. Items are rated to capture the patient’s clinical state over the 
prior week. Each item yields a score of 0 to 6, and higher scores indicate more severe depression. 
The overall score ranges from 0 to 60. Various studies have suggested cut scores from < 9 to 
< DVDGHILQLWLRQRIUHPLVVLRQ)RUWKHFXUUHQWVWXG\UHPLVVLRQZLOOEHGHILQHGDVDVFRUH 
 
To reduce the risk of functional unblinding during collection of the primary study outcome 
measure, MADRS assessments will be conducted by a blinded, remote and independent central 
rater. Central raters will be blinded to participant allocation, visit number (i.e. where in the study 
any given participant is for any given assessment), and the specifics of the protocol and study 
design. 
 
At the site, the central-rated MADRS assessments will be conducted by telephone in a private 
room. Use of telephone/audio is the standard administration method recommended by Signant 
Health and has been selected instead of video for the following reasons: (1) it should be noted 
that rating certain items, such as Apparent Sadness, can reliably be administered by telephone 
(Hermens et al., 2006), and because it is based on the prior 7 days and not just the 20-30 minutes 
of the interview, visual inspection of the participant is not required; and (2) the rating without 
visual cues asks questions using a structured algorithm-driven process which assures high intra-
rater reliability as well as high inter-rater reliability. Additionally, ratings made without visual 
cues are less prone to functional unblinding and are highly concordant with live ratings (K. A. 
Kobak, Williams, Jeglic, Salvucci, & Sharp, 2008). It is expected that the random assignment of 
blinded visits to central raters, and interference effects between visits from one respondent, will 
mitigate the possibility of voice recognition. Video recordings would greatly increase any 

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possible effect of unblinding the central raters. Most importantly, the study design compares 
drug placebo differences and there is no reason to believe any discrepancy would differentially 
impact the treatment groups.   
 
In addition to the independent central-rater administered MADRS administration via telephone, 
to enhance quality control of the primary outcome instrument, each participant will complete a 
brief interactive, computer-administered MADRS on the dedicated study device. The computer-
administered MADRS will involve a series of standardized queries and follow up questions with 
multiple-choice response options. This type of tandem assessment strategy is now frequently 
used in registration trials to enhance reliability of the data by screening out participants who are 
unable to provide consistent reports of their current depressive symptomatology. The tandem 
MADRS ratings also provide a quality metric that facilitates assessment of rater and site quality.   
 
At Screening, the computer administered MADRS will be collected first, followed by the central 
rater administered MADRS. At Baseline and through the Day 43/ End of Study assessment, the 
central rater administered MADRS will come before the computer administered MADRS. The 
purpose of conducting the computer administered MADRS first at Screening is to assess 
eligibility early and eliminate further screening activities. The central rater assessment will be 
conducted first at later visits as it is the primary endpoint assessment.  
 
MADRS item LQTXLUHVDERXWVXLFLGDOLGHDWLRQ$VFRUHRIVXJJHVWVWKDWDSDUWLFLSDQWPD\
be experiencing a level of active suicidal ideation that will require a clinical assessment, 
management and disposition. 
 
The computer administered MADRS will be collected electronically [electronic Clinical 
Outcome Assessments (eCOA)] on a study specific tablet or computer.  The central rater 
telephone MADRS will be collected using a Signant Health specific tablet or computer, with 
data entered in real time by the central rater. 
2.12.2 Sheehan Disability Scale (SDS) 
The SDS will be utilized to determine the impact of psilocybin vs. placebo on functional 
disability (psychosocial functioning). This will be an important secondary endpoint for the 
current study. 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 (D. Sheehan, 1983; K. H. Sheehan & Sheehan, 2008). This scale has been used 
widely in psychopharmacology randomized controlled trials and has been accepted by the Food 
and Drug Administration (FDA) for functional disability labeling. The SDS uses visual-spatial, 
numeric, and verbal descriptive anchors simultaneously to assess disability across three domains: 
work, social life, and family life. The SDS was developed as an intervention outcome measure 
that would be sensitive to change and to drug placebo differences over time. The SDS asks 
patients to rate the extent to which his or her 1) work/school, 2) social life or leisure activities, 
and 3) home life or family responsibilities are impaired by his or her symptoms on a 10-point 
visual analog scale. There are verbal descriptors for the points on the scale as well as numerical 
scores that provide more precise levels of the verbal descriptors. Typically, four scores are 
derived from the scale in research studies – one for each of the work, social life and family life 
disability measures and an aggregate total score of these three scores combined. 

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To limit missing data and ensure standardized administration, the SDS will be administered 
electronically in a clinician-rated format by trained site raters. The site rater administration will 
be important in limiting misinterpretation of the Work/school impairment item that could 
contribute to elevated rates of skipping out, which can also be completed in reference to school, 
unpaid or volunteer work, and may not immediately come to mind in a participant-reported 
format. As the scale cannot be modified, if a participant indicates that Item 1 (work/school) is not 
applicable, the reason that it is not applicable will be documented in the site rater notes, with data 
entered into the Signant Health system and integrated into the full study dataset. 
2.12.3 Hamilton Anxiety Rating Scale (HAM-A) 
The computer-administered form of the HAM-A (Kenneth A. Kobak, Reynolds, & Greist, 1993) 
is an anxiety rating scale designed to have high correspondence with the standard version of the 
HAM-A (HAMILTON, 1959). The computer-administered version consists of 153 questions that 
are scored to match the 14 items of the standard HAM-A: anxious mood, tension, fear, insomnia, 
intellectual (cognitive) symptoms, depressed mood, behavior at interview, somatic (sensory), 
cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic and somatic (muscular) 
symptoms. Each scored symptom is rated from 0 (absent) to 4 (maximum severity). Total scores 
range from 0 to 56.  
 
The HAM-A is a self-report instrument that will be collected electronically (eCOA) on a study 
specific tablet or computer and will involve a series of probe and follow up questions with 
multiple-choice response options. 
2.12.4 Clinical Global Impression – Severity (CGI-S) 
The CGI rating scales are measures of symptom severity, intervention response and the efficacy 
of interventions in intervention studies of patients with mental disorders (Guy, 1976). The CGI-S 
is a 7-point scale that requires the central rater to rate the severity of the patient’s illness at the 
time of assessment, relative to the clinician’s past experience with patients who have the same 
diagnosis. Possible ratings are:  
 
1. Normal, not at all ill 
2. Borderline mentally ill 
3. Mildly ill 
4. Moderately ill 
5. Markedly ill 
6. Severely ill 
7. Among the most extremely ill patients 
 
The same central rater (Signant Health) who conducted the MADRS will conduct the CGI-S 
using a Signant Health specific tablet or computer with data entered in real time by the central 
rater. Likewise, they will be blinded to the protocol, study design and time-point (i.e. where in 
the study protocol a participant is at any given assessment). 

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2.12.5 Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) 
The Q-LES-Q is a 16-item self-report measure, will be used to evaluate intervention-related 
changes in quality of life (Endicott, Nee, Harrison, & Blumenthal, 1993). A total score is derived 
from summing the first 14 items on the scale, with the last two items serving as stand-alone 
queries. Total score ranges from 14 to 70. In addition to a total score, the total raw score can be 
transformed into a percentage maximum possible score using a standard formula. The Q-LES-Q-
SF was designed specifically to assess quality of life in the context of psychiatric disease, and 
has been repeatedly shown to be sensitive to clinical improvements in intervention trials and to 
capture unique variance in outcomes when compared to depressive symptom scales alone 
(Stevanovic, 2011). 
 
The Q-LES-Q is a self-report instrument that will be collected electronically (eCOA) on a study 
specific tablet or computer. 
2.12.6 30-item Mystical Experience Questionnaire (MEQ-30) 
The MEQ is a self-report measure developed to assess the effects of classic psychedelics in 
laboratory studies. It is based on Stace’s conceptual framework of mystical experiences (Stace, 
1960), and covers the major dimensions of classic mystical experience: unity, transcendence, 
noetic quality, sacredness, positive mood, and ineffability/paradoxicality. The MEQ has been 
administered in various forms in a number of studies over the past 50 or more years 
(Bogenschutz et al., 2015; Garcia-Romeu, Griffiths, & Johnson, 2015; R. Griffiths, Richards, 
Johnson, McCann, & Jesse, 2008; R. R. Griffiths et al., 2011; R. R. Griffiths et al., 2006; 
Johnson, Garcia-Romeu, Cosimano, & Griffiths, 2014; Maclean, Leoutsakos, Johnson, & 
Griffiths, 2012; Richards, 1975). Items on the questionnaire are rated on a 6-point scale, where 
0= “None; not at all”, 1= “So slight cannot decide”, 2= “Slight”, 3= “Moderate”, 4= “Strong”, 
and 5= “Extreme”. A factor analysis conducted by MacLean et, al. found that the most recent 
version of the MEQ, a revised 30 item (MEQ30), is a psychometrically sound instrument for 
assessing psychedelic-occasioned mystical experiences (Barrett & Griffiths, 2017; Maclean et 
al., 2012).  
 
The MEQ-30 will be administered upon completion of the dosing session when all behavioral 
effects of the intervention have resolved. The MEQ-30 is a self-report instrument that will be 
collected electronically (eCOA) on a study specific tablet or computer at the site.  
2.12.7 Emotional Breakthrough Inventory (EBI) 
The EBI is a new 6-item scale developed by researchers at Imperial College London that 
assesses the presence and severity of emotionally challenging/distressing experiences that occur 
during a psychedelic experience. The scale utilizes visual analog responses captured on a line 
anchored by “not at all” on one end and “very much so” on the other. Experiences queried 
include 1) facing emotionally difficult feelings that are usually pushed aside; 2) experiencing a 
resolution of a personal conflict/trauma; 3) being able to explore challenging emotions and 
memories; 4) having an emotional breakthrough; 5) getting a sense of closure on an emotional 
problem, and 6) achieving an emotional release followed by a sense of relief.  
 

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The EBI will be administered upon completion of the dosing session when all behavioral effects 
of the intervention have resolved. The EBI is a self-report instrument that will be collected 
electronically (eCOA) on a study specific tablet or computer at the site.  
2.12.8 Symptoms of Major Depressive Disorder Scale (SMDDS)  
The SMDDS assesses participant-reported symptoms associated with MDD to be used as an 
exploratory outcome. This 16-item instrument has a 7-day recall period, and participants respond 
to each question using a rating scale between 0 (“Not at all” or “Never”) to 4 (“Extremely” or 
“Always”). The total score ranges from 0 to 60 with a higher score indicating more severe 
depressive symptomatology. 
 
The SMDDS is a self-report instrument that will be collected at Baseline and on Days 1 
(pre-dose), 8, and 43. 
2.12.9 Oxford Depression Questionnaire (ODQ) 
The Oxford Depression Questionnaire (ODQ) is a patient-centered, self-report measure of 
emotional symptoms present in patients treated with antidepressants. In particular, it is a clinical 
tool that can facilitate the identification of patients with the syndrome of emotional blunting that 
they attribute to the effect of their antidepressant medication. It can also be used in studies 
to advance understanding of the nature, causes and particularly the treatment of this 
phenomenon (Price, Cole, Doll, & Goodwin, 2012). 
  
The ODQ is a 26-item patient self-report measure, spread over 3 sections and covering 
4 dimensions of 1) not caring (NC), 2) emotional detachment (ED), 3) positive reduction (PR), 
and 4) general reduction (GR). Section 1 includes 12 items, three items from each of the 
4 dimensions (NC, ED, PR and GR). Recall period is the last week. In Section 2 there are 8 items 
(2 from each of the four dimensions) comparing respondents’ experiences during the previous 
week with in comparison to their experiences before they developed their illness / problem. 
Section 3 addresses the extent to which participants attribute their emotional difficulties to their 
antidepressant, and the extent to which they would therefore be considered by participants to be 
“emotional side-effects”. It also addresses the possible impact of emotional side-effects on 
antidepressant adherence. For the purposes of this study the questionnaire will substitute “study 
medication” for antidepressant, as approved by the questionnaire’s author. Response options are 
based on 5-point Likert scale with a score applied to each response. Results can be presented on 
a dimension basis or summed to give an overall ODQ score. If required as an additional 
dimension “Antidepressant as cause (AC)” can also be scored.  
  
The ODQ will be administered at Baseline and Day 43 (at Baseline Section 3 will not be 
completed per questionnaire instructions as it is a study requirement all participants be off 
antidepressants at this point: “If you are not currently prescribed antidepressants for your illness 
/ problem, please tick this box  and do not answer any more questions.”). The ODQ is a self-
report instrument that will be collected electronically (eCOA) on a study specific tablet or 
computer. 

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2.13 Eligibility and Safety Measures 
2.13.1 Structured Interview for DSM-5 Disorders-Clinical Trials Version (SCID-CT) 
The Structured Interview for DSM Disorders (SCID) is a semi structured, clinician-administered 
diagnostic interview that will be administered at the screening visit. The SCID is a semi-
structured interview for making the major DSM-5 Axis I diagnoses. The SCID is considered to 
be the gold standard semi-structured assessment instruments for clinical and personality 
disorders (Williams et al., 1992). This study will use the SCID-Clinical Trials Version  (First, 
Williams, Spitzer, L., & Gibbon, 2007), which has been developed specifically for clinical trials. 
This version provides customizable indication-specific configurations of the modules, so it can 
be easily tailored for use in specific studies, including MDD. 
 
A new version of the SCID, the SCID-CT, has been developed in conjunction with i3 Research 
specifically for clinical trials. It aims to retain the diagnostic accuracy of the SCID, while 
streamlining for efficiency and simpler navigation. It also provides customizable indication-
specific configurations of the modules, so it can be easily tailored for use in specific studies. 
While the format of the SCID-CT has been simplified to make it easier to use, the study 
participant questions remain the same as those found in the SCID – Research Version (SCID-
RV). 
 
Modified features of the SCID-CT include: 
 
1)  Only essential elements for drug indications that incorporate typical inclusion and 
exclusion criteria are included.  
2) Subtypes and specifiers have been eliminated. 
3) Criteria ratings have been streamlined into a “-” and “+” format rather than “?” “1” “2” 
“3” used in the Schedule of Assessments.ġ
4)ġ The Overview has been abridged to entail clinical trial relevant questions only.  
 
The SCID-CT will be collected on paper and administered by a site rater with experience in the 
diagnosis of mental health disorders. Training to enhance interrater reliability within and 
between sites will be provided by Signant Health.  
 
The SCID-CT will be used at Screening to assess study eligibility. At Day 43/End of Study, if 
there is a concern that the participant has developed a potential substance or alcohol use disorder 
(based on results from Timeline Followback and investigator discretion), the Substance Use 
Disorders module of the SCID will be used to identify potential substance and alcohol use 
disorders that develop since dosing. 
2.13.2 SCID-5-Personality Disorders (SCID-PD) 
The SCID-PD (Association) is the updated version of the former Structured Clinical Interview 
for DSM-IV Axis II Personality Disorders (SCID-II). The SCID-PD assesses the 10 DSM-5 
Personality Disorders across Clusters A, B, and C as well as Other Specified Personality 
Disorder. Designed to build rapport, the SCID-PD can be used to make personality disorder 
diagnoses, either categorically (present or absent) or dimensionally. The SCID-PD name reflects 

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the elimination of the multiaxial system in DSM-5. Although the DSM-IV Personality Disorder 
criteria are unchanged in DSM-5, the SCID-5-PD interview questions have been thoroughly 
reviewed and revised to optimally capture the construct embodied in the diagnostic criteria. The 
instrument assesses the DSM-5 criteria for each of the 10 personality disorders: Avoidant 
Personality Disorder, Dependent Personality Disorder, Obsessive-Compulsive Personality 
Disorder, Paranoid Personality Disorder, Schizotypal Personality Disorder, Schizoid Personality 
Disorder, Histrionic Personality Disorder, Narcissistic Personality Disorder, and Antisocial 
Personality Disorder. Administration of the SCID-PD will allow identification of exclusionary 
personality disorder (antisocial personality disorder) and an assessment of whether a personality 
disorder is a more primary problem than MDD. 
 
Modules of the SCID-PD relevant for study inclusion/exclusion criteria will also be collected on 
paper and administered by qualified study personnel with experience in the diagnosis of mental 
health disorders. Training will be provided by Signant Health.  
2.13.3 Drug History Questionnaire (DHQ) 
The Drug History Questionnaire (Sobell, Kwan, & Sobell, 1995) is a one-page form that collects 
data for nine different drug classes: alcohol, cannabis, hallucinogens, depressants, inhalants, 
narcotics, stimulants, tranquilizers, and other drugs. For each drug class, the following 
information is collected: was the drug ever used and, if so:  number of years used; total years 
used; injection drug use (Yes/No), year last used; and frequency of use in the past 6 months. 
 
The DHQ will be collected at screening to assess prior lifetime illicit and non-prescribed drug 
use. The DHQ will be collected electronically (eCOA) on a study specific tablet or computer. 
2.13.4 Alcohol Use Disorders Identification Test (AUDIT) 
The AUDIT is a ten-item assessment and respondents answer on a 5-point scale (0=Never or 
none, 4=Daily or greatest number) (Saunders, Aasland, Babor, de la Fuente, & Grant, 1993). The 
ninth item addresses occurrence of injury of self or other as a result of drinking and the tenth 
addresses others’ concerns about the respondent’s drinking, with only three responses provided 
(0=No, 2=Yes, but not during the last year, 3=Yes, during the last year). The measure can readily 
detect alcohol abuse disorders in a wide array of individuals (Allen, Litten, Fertig, & Babor, 
1997).  
 
At the Baseline visit the time frame covered by the AUDIT will be last year, consistent with 
scale instructions. At Day 43 the time frame will be specified as “since the last assessment.” The 
AUDIT will be collected electronically (eCOA) on a study specific tablet or computer. 
2.13.5 Drug Use Disorders Identification Test (DUDIT) 
The DUDIT is an 11-item measure designed to assess presence of substance use disorders 
(Berman, Bergman, Palmstierna, & Schlyter, 2005). Responses to items are made on a 5-point 
scale with exact responses varying across questions. When present, use can be described in 
monthly or less than monthly versus four times a week or daily. A list of substances is provided 
at the end of the measure. The DUDIT is reliable, with a Cronbach’s alpha of 0.80. When 

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compared with an interview based on ICD 10, the DUDIT had a sensitivity to detecting 
VXEVWDQFHXVHGLVRUGHUVRIDQGDVSHFLILFLW\RI (Berman et al., 2005). The English 
translation was developed from a Swedish-language original. Estimated time to complete is 2 to 
4 minutes.  
 
At the Baseline visit the time frame covered by the DUDIT will be last year, consistent with 
scale instructions. At Day 43 the time frame will be specified as “since the last assessment.” The 
DUDIT will be collected electronically (eCOA) on a study specific tablet or computer. 
2.13.6 Timeline Followback (TLFB) 
The Timeline Followback (Sobell & Sobell, 1992) is a widely used, calendar-based self-report 
measure used to assess frequency and quantity of alcohol (Carney, Tennen, Affleck, K Del Boca, 
& R Kranzler, 1998) and cannabis and other illicit substance use (Hjorthoj, Hjorthoj, & 
Nordentoft, 2012). It involves asking participants to retrospectively estimate their use for a 
period of time prior to the interview date. The instrument uses a visual calendar in which the 
respondent charts life events in order to enhance recall of alcohol and substance use. The TLFB 
can be administered by an interviewer, self-administered, or administered by computer. For this 
study, it will be administered by a site rater at the time of self-reported use and at the Day 43/ 
End of Study to assess use since dosing.   
2.13.7 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS was created to provide a more exhaustive examination of suicidal ideation and 
history than is provided by other depression-related outcome measures. The C-SSRS rates an 
individual’s degree of suicidal ideation on a scale, ranging from “wish to be dead” to “active 
suicidal ideation with specific plan and intent.” Questions are phrased for use in an interview 
format. Each item queries how frequently participants have these thoughts, how long the 
thoughts last and whether the thoughts can be controlled. They are asked about deterrent factors, 
and for the reasons for thinking of suicide. They are asked about “Actual Attempt[s]”, which is a 
“potentially self-injurious act committed with at least some wish to die, as a result of act.”  
 
Each of the following questions addresses a different component of the respondent’s suicide 
ideation severity: 
 
Question 1: Wish to be dead 
Question 2: Non-specific active suicidal thoughts 
x 
If the respondent answers “Yes” to Question 2, he/she is instructed to answer 
Questions 3-5. If the respondent answers “No” to Question 2, he/she may proceed 
with the Suicidal Behavior section.   
Question 3: Active suicidal ideation with any methods (not plan) without intent to act 
Question 4: Active suicidal ideation with some intent to act, without specific plan 
Question 5: Active suicidal ideation with specific plan and intent 
 
The “Baseline-Screen” version of the scale will assess active suicidal ideation in the past 2 
months and any suicidal behavior in the past 12 months as well as lifetime suicidal 
ideation/behavior.  

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The “Since Last Visit” version of the scale assesses suicidality since the patient’s last visit. The 
“Since Last Visit” version will be used for all assessments from Baseline through Day 43. The 
C-SSRS has been found to be reliable and valid in the identification of suicide risk in several 
research studies (James C. Mundt et al., 2010; J. C. Mundt et al., 2013; Posner et al., 2011).  
 
A score of 4 or endorsement of any suicidal behavior item on the C-SSRS suggests that a 
participant may be experiencing a level of active suicidal behavior that will require a clinical 
assessment, management and disposition. 
 
The C-SSRS will be collected electronically by a site rater using a study specific tablet or 
computer. It will be administered by study personnel qualified and trained to conduct the 
assessment. 
2.13.8 Lifetime Illness Characteristic Questionnaire (LICQ) 
The LICQ will collect data about the participant’s MDD history and the current episode and is a 
diagnostic tool relevant in the screening process. Administration of the LICQ is a two-part 
process to include a computer-assessment followed by review of the information by a central 
rater. First, participants will complete a computer-administered LICQ assessment at the 
screening visit prior to the site rater administered SCID, on a designated device provided to the 
site. Second, the participants’ diagnostic information, based on the responses to the computerized 
interview, will be reviewed by clinicians, and any uncertainty raised by the participant’s 
responses on the diagnostic interview or between the SCID-CT and the LICQ will be discussed 
with the PI or site rater in order to establish confidence in the diagnosis. The LICQ does not 
provide data that will be directly used to determine eligibility. Rather, it provides an overview of 
the participant’s history and current symptoms that can be used by clinicians to gain an overall 
impression of the likely suitability of an individual for study participation.  
 
As the LICQ is a diagnostic tool, the central raters at Signant Health who are reviewing the 
assessment are not blinded (they are separate from the raters performing the blinded MADRS 
assessments). The LICQ is a self-report instrument that will be collected electronically (eCOA) 
on a study specific tablet or computer followed by review by clinicians at Signant Health.  
2.13.9 Massachusetts General Hospital Antidepressant Treatment History 
Questionnaire (ATRQ) 
The ATRQ is a standard validated measure for assessing antidepressant treatment history and 
will be administered at screening. Although originally designed for self-report, in the current 
study it will be administered by a trained site rater to aid the potential participant in identifying 
all relevant details of past medication use. The ATRQ GH¿QHV8 weeks on an adequate dose of 
DQWLGHSUHVVDQWPHGLFDWLRQDVDQDGHTXDWHGXUDWLRQRIWUHDWPHQW,WDOVRSURYLGHVVSHFL¿F
operational criteria for adequate dosage for each of the most commonly used antidepressants and 
allows for assessment of a range of other psychotropic agents used to augment antidepressants in 
individuals with depression. The ATRQ has shown excellent validity when compared to 
interview by medical facilitators (Chandler, Iosifescu, Pollack, Targum, & Fava, 2010) and has 

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been shown to perform as well as more complex and time-consuming treatment-history scoring 
methods (Hazari, Christmas, & Matthews, 2013). 
 
The ATRQ will be collected on paper and administered by study personnel qualified and trained 
to conduct the assessment. 
2.13.10 Family History Screen (FHS) 
The FHS collects information on symptoms of 15 psychiatric disorders for participant’s first- 
degree relatives, including biological parents, siblings and children (Milne et al., 2009). The 
form itself is not diagnostic but rather it asks about symptoms of a disorder; final determination 
will come from further discussion with the rater once an endorsement is made on the FHS. For 
this study it will be administered by a site rater at screening to assess for first-degree relatives 
with schizophrenia spectrum or other psychotic disorders (except substance/medication-induced 
or due to another medical condition), or Bipolar I Disorder.  
 
The FHS will be collected on paper and administered by a site rater qualified and trained to 
conduct the assessment. 
 
2.13.11   Questionnaire Order of Assessments 
At all visits, starting at Baseline, the central rater MADRS interview will be conducted prior to 
all other outcome assessments, followed by additional central rater assessments, patient-reported 
outcome measures and site rater administered assessments. Specific order of outcome 
assessments is provided in the MoP. 
2.13.12 Laboratory Assessments 
The following laboratory assessments will be performed in this study: Complete Metabolic Panel 
(CMP), Complete Blood Count with Differential (CBC w/ Diff), Thyroid Stimulating Hormone 
(TSH), high-sensitivity C-reactive Protein (hs-CRP), Urinalysis, INR (screening only), Urine 
Drug Test (including Buprenorphine) and Pregnancy Testing. A review of the literature finds no 
prior studies that examined the impact of psilocybin on safety lab values. To address this gap in 
the literature, these labs will be collected at Screening, Baseline, Day 2, Day 8, and Day 43. 
These blood samples will be collected for safety purposes and for pharmacodynamic analyses 
such as the determination of the impact of pre-treatment levels of hs-CRP on placebo-adjusted 
antidepressant response to psilocybin, as have been noted for other serotonergic antidepressant 
agents (Jha et al., 2017; Uher et al., 2014). Blood samples will also be collected in PAXgene 
tubes (or functional equivalent) at each sampling timepoint (i.e., Screening, Baseline, Day 2, Day 
8, and Day 43) and stored for potential future transcriptome analysis. 
 
In addition, subject to a participant’s provision of consent, a pharmacogenomic blood sample 
will be collected at one of the sampling timepoints (i.e., at Screening, Baseline, Day 2, Day 8, or 
Day 43) for storage and potential future analysis. Participants will be given the option to consent 
to pharmacogenomic sample collection, which will not be required for entry into the study, and 
only those participants providing informed consent will have such samples collected. Future 

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analysis of these pharmacogenomic samples may include (but is not limited to) whole genome 
sequencing (deoxyribonucleic acid (DNA)) analysis.   
2.13.13  Physical Examinations 
Physical examinations will be conducted at Screening and Baseline to confirm eligibility for the 
study and at Day 8 and Day 43 visits to examine health related physical changes. Additional 
physical exams may be administered depending on participant’s signs and symptoms at the 
discretion of the investigator. 
 

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3 
PROTOCOL DESIGN 
3.1 
Overall Study Design 
Approximately 100 patients (males and females) ages 21 to 65 who, at Screening, meet DSM-5 
criteria for MDD with a current depressive episode of at least a 60-day duration, a Screening 
0$'56VFRUHDQGZKRPHHWDOORWKHULQFOXVLRQH[FOXVLRQFULWHULDat Baseline will be 
enrolled into the study 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 that provides an acute physiological response (flushing) that may aid 
in blinding of intervention allocation. All randomized participants will be included in the intent-
to-treat (ITT) sample that will provide data for testing primary, secondary and exploratory study 
endpoints. 
 
Only participants who meet depressive symptom severity criteria and who do not show an 
unacceptably large degree of symptom improvement between the Screening visit and the 
BDVHOLQHDVVHVVPHQWLQGH[HGE\LPSURYHPHQWRQERWKWKHFHQWUDOUDWHUDQGFRPSXWHU
MADRS assessments) will be eligible for randomization. In addition, at Screening and Baseline, 
RQO\SDUWLFLSDQWVZLWKDVFRUHGLIIHUHQFHEHWZHHQWKHFHQWUDOUDWHUDQGFRPSXWHU0$'56
assessments will be eligible for randomization. A larger discrepancy has been associated with an 
exceptionally high placebo response in prior studies conducted by the study central rater vendor 
(data on file). In addition, inability to be consistent in response to the same questions likely 
identifies individuals not sufficiently capable of providing reliable responses. 
 
Potential participants who meet all other entry criteria at Screening but who are taking an 
antidepressant or an antidepressant plus an augmenting agent (e.g., a second antidepressant, an 
atypical antipsychotic, lithium) will be eligible for continuation in the study but will enter a 
medication taper during which current psychotropic medications will be withdrawn under the 
supervision of a study psychiatric medical provider. Participants will be eligible to undergo the 
Baseline assessment at least 2 weeks after the last dose of the applicable medication. 
 
Participants deemed eligible following successful completion of all screening assessments will 
complete central rater, site rater and self-report measures at Baseline for a final eligibility 
determination.  Eligible participants at Baseline will undergo preparation sessions and be eligible 
for randomization on Dosing Day to receive either psilocybin or niacin active-placebo and will 
complete follow-up visits and assessments on study Day 2, 8, 15, 29 and 43 (within 
corresponding visit windows). Study outcome measures will assess depressive symptoms, 
clinical global functioning, functional disability, anxiety symptoms and health-related quality of 
life. Safety outcome measures will be collected at all assessment time points from the time of 
consent through the end of study. 
 
To enhance participant safety, the current study does not propose to test psilocybin as a “context-
less” pharmacological agent, but rather within a “set and setting” (SaS) protocol similar to the 
protocol that has been used in all modern studies of psilocybin in both diseased and normal healthy 
populations. 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 (with the 

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exception of short, temporary allowances for facilitator breaks; e.g. bathroom breaks); and 3) 
three post-dose integration sessions during which participants are encouraged to discuss their 
intervention experience with the Facilitators. The SaS will be identical for those randomized to 
psilocybin or niacin active placebo. 
3.2 
Justification for Selected Aspects of the Study Design 
3.2.1 Use of a single psilocybin dose 
Traditional psychotropic agents used to treat MDD (e.g. antidepressants) require continued 
administration for maintenance of clinical efficacy (Andrews, Kornstein, Halberstadt, Gardner, 
& Neale, 2011), and single doses of novel agents such as ketamine that produce an 
antidepressant effect that outlasts the medication’s direct biological activity rarely induce a 
therapeutic response that lasts more than a week (McGirr et al., 2015). On the other hand, 
available evidence suggests that a single dose of psilocybin when administered under the SaS 
protocol produces an antidepressant effect durable enough to justify this treatment modality as a 
significant addition to the antidepressant armamentarium. For example, in a study conducted at 
Johns Hopkins University (Hopkins) (R. R. Griffiths et al., 2016), 24 participants with cancer 
and clinically significant depression (mean HAM-D score = 22.84 [0.97]) randomized to receive 
DVLQJOHGRVHRISVLORF\ELQGHPRQVWUDWHGUHPDUNDEO\KLJKUDWHVRIV\PSWRPDWLFUHVSRQVH
DQGUHPLVVLRQVL[PRQWKVSRVW-intervention without requiring additional pharmacologic 
intervention. A similarly high rate of response at 26 weeks post-intervention was seen in 
11 participants randomized to psilocybin in the study of depression/anxiety in patients with 
cancer conducted at NYU %',UHVSRQVH +$'6'HSUHVVLRQUHVSRQVH  (Ross et 
al., 2016). Finally, a 12 participant open trial of two doses of psilocybin separated by a week in 
otherwise medically healthy patients with TRD reported BDI response rates at 3 months post-
intervention DVDQGPRQWKSRVW-intervention UHPLVVLRQUDWHVDV (Carhart-Harris et al., 
2016). Taken together, these data suggest that clinically-meaningful antidepressant efficacy for 
single dose (or two doses with one being less than half the dose proposed for the current study) 
can be observed out to 6 months post-intervention in the context of cancer, and at least 3 months 
post-intervention in medically healthy individuals with MDD.  
3.2.2 Psilocybin and Niacin Dosing 
This study will compare the depression-relevant behavioral effects of a single 25 mg oral dose of 
psilocybin with a single 100 mg oral dose of a niacin active placebo. A 25 mg oral dose of 
psilocybin was selected based on data from an open trial of psilocybin in otherwise medically 
healthy patients with TRD showing that this dose produced a robust and sustained antidepressant 
response. Moreover, this dose is within range of the absolute dosages received in previous trials 
of single-dose psilocybin for depression and anxiety in patients with cancer (actual mean dose 
based on weight of patients at each site was 23.4 mg for the study conducted at Hopkins (Roland 
Griffiths, PhD, personal communication) and 21.4 mg for the study conducted at NYU (Steve 
Ross, MD, personal communication). Justification for a fixed dose, as opposed to a weight-based 
strategy, comes from data pooled from four studies (N =141) in which participants of varying 
weight were administered 30 mg/70 kg psilocybin, and from data from six studies of individuals 
of varying weight who received a dose of 23 mg (N = 21) [Garcia-Romeu A, Johnson MW, 

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Barrett FS, Carbonaro TM, Griffiths RR. Psilocybin effects in humans: absolute vs. body weight 
adjusted dose, in preparation]. 
In both cases, no significant effect of weight was seen on any acute psychological effects of 
psilocybin, suggesting that a fixed-dose strategy should be as effective as weight-based dosing 
while significantly simplifying future medication delivery. Moreover, a fixed dose of 25 mg of 
psilocybin produced large effect size reductions in depressive symptoms in medically healthy 
patients with TRD, as described in Section 3.2.1. 
 
The selection of 100 mg as the dose for niacin is based on several factors. First, it is above the 
75 mg dosage that reliably induces skin flushing that may provide a physiological effect to help 
blind the study (https://articles.mercola.com/sites/articles/archive/2017/03/06/is-niacin-flush-
dangerous.aspx). Second, it is less likely to induce the severity of flushing that was frequently 
seen when a dose of 250 mg was used to blind the NYU phase 2 study of psilocybin in patients 
with cancer and depression/anxiety (Ross et al., 2016). This level of flushing produced 
uncomfortable physical sensations that might induce a dysphoric state that would artificially 
inflate psilocybin-placebo differences. In addition, the degree of flushing induced by a 250 mg 
dose was occasionally patently apparent to observers (i.e. Facilitators), which may have worked 
against its use as a blinded active placebo. 
3.3 
Planned Duration of Study 
The planned maximum study duration for each participant will be approximately 12 weeks 
(87 days), with variation primarily dependent on the length of the screening period, the number 
of days between Baseline and dosing, and the visit windows provided for each post-dose 
assessment.  
 
The screening period will last between 7 and 35 days to allow for scheduling and completion of 
all screening activities and to allow for medication taper, if indicated. As noted above, this time 
period will also allow for identification of participants who respond to study screening with a 
significant reduction in depression severity (i.e. likely placebo responders). Participants who 
enter the screening medication taper and require more than 35 days to discontinue their 
medication and meet the time period to be medication, will be re-screened when the medication-
free period has been met. Participants who are re-screened will have a longer overall study 
duration. 
 
The period between eligibility verification at the Baseline assessment and the dosing session will 
be a maximum of 7 days, with variation being dependent upon participant and research team 
scheduling needs. Approximately 6-8 hours of preparation will occur over a 1-6 day period 
following the Baseline assessment. The intervention session will occur following completion of 
these preparation sessions but no later than 7 days following Baseline.  
 
The period between the dosing session and completion of the final post-dose assessment will be 
on average 6 weeks (43 days), with some variation allowed as a result of each post-dose session 
having a window for completion.  
 

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Figure 1: Summary of Events Flowchart 
 
 
 
 
 

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1  Inclusion/ Exclusion Verification will occur at Screening and Baseline; eligibility confirmation will be ongoing until dosing and will occur at post prep and 
prior to randomization; 
2  Complete physical exam conducted at Screening, Baseline, Day 8, and Day 43;  
3  INR is collected to calculate Child-Pugh score;  
4  All WOCBP who were assigned biological sex of female at birth, and have had no change in biological sex regardless of gender identification, will be 
required to undergo urine pregnancy testing; documentation of birth control method for all WOCBP will occur at screening and confirmed at each follow up 
visit; 
5  The DHQ will assess lifetime psychedelic and other illicit and non-prescribed drug use at Screening (reassessed by self-report from Baseline to 
Randomization); all subsequent use starting with dosing will be assessed via the Timeline Followback at the time of self-reported use and at the Day 43/ End 
of Study visit;   
6  Enrollment occurs at the time the informed consent form is signed;  
7  Blood sample for biobanking and future analysis , CMP, CBC/ w Diff, TSH, hs-CRP, Urinalysis, physical exam and pregnancy testing will be done at Day    
   8 visit only and not the Day 15 or 29 visits.  
8 Day 1 vital sign assessments will occur pre-dose; during the dosing session only BP and HR will be collected; BP, HR and temp will be collected at the end 
of dosing (7-hours); 
9   Height collected at screening only;  
10  Urine drug screen and pregnancy testing (if applicable) will occur prior to randomization, and completion of the SMDDS will occur prior to investigational   
   drug administration;  
11  The SMDDS is collected at Day 8 only visit and not the Day 15 or 29 visits;  
12 The Facilitator Dosing Monitoring Form will be collected during dosing; 
13  MEQ-30 and EBI are completed at the end of the dosing session;  
14  Medication taper applies only to those who qualify;  
15  Preparatory sessions can occur over multiple days consisting of at least one in-person preparatory session. Additional preparatory sessions may be conducted 
remotely, if necessary ;  
16 Integration Session #1 on Day 2 should occur after all Day 2 assessments have been completed; Day 9 (Integration Session #2) should occur after all Day 8 
activities have been completed; Day 16 (Integration Session #3) should occur after all Day 15 activities have been completed. Integration sessions may be 
completed remotely, if necessary; 
17 Eligibility will be verified prior to Randomization, including confirmation of negative urine drug and pregnancy testing (for WOCBP only); 
18  To assess readiness for release from the research facility following the dosing session, study staff will evaluate medical and psychiatric functioning;  
19  Collection of AEs includes solicited AEs at every visit; 
20  At Day 43/ End of Study, only the Substance Use Disorders module of the SCID-CT will be completed, if warranted and based on results of the TLFB and 
investigator discretion 
21  Blood samples will be collected in PAXgene tubes (or functional equivalent) at each sampling timepoint (i.e., Screening, Baseline, Day 2,  
Day 8, and Day 43) and stored for potential future transcriptome analysis. A pharmacogenomic blood sample will be collected only once and can be 
collected at any timepoint that involves a blood draw (i.e., Screening, Baseline, Day 2, Day 8, or Day 43). Participant must provide optional informed 
consent to enable collection of a pharmacogenomic blood sample and may opt out of providing such a sample during the informed consent process. Future  
analysis of these pharmacogenomic samples may include (but is not limited to) whole genome sequencing DNA analysis. 
22  Procedure or measurement may be conducted remotely, if necessary.    
 

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4 
PARTICIPANT POPULATION  
4.1 
Inclusion and Exclusion Criteria 
 
4.1.1 
Inclusion Criteria 
Individuals eligible to be randomized in this protocol are those who meet all of the following 
criteria:  
 
1. Are 21 to 65 years old at the time of written informed consent at the Screening visit 
2. Are able to read, speak, and understand English 
3. Are able and willing to adhere to study requirements, including attending all study visits, 
preparatory and follow-up sessions, and completing all study evaluations 
4. Are able to swallow capsules  
5. Women of childbearing potential (WOCBP) must agree to practice an effective means of 
birth control throughout the duration of the study, from Screening through the Day 43 
assessment (see Section 15 Pregnancy for a definition of WOCBP)  
6. 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 the 
Screening  
7. Have sustained moderate-severe depression symptoms at Screening and Baseline, as 
defined by a Screening MADRS total VFRUHDQG LPSURYHPHQWLHGHFUHDVH
in MADRS total score from Screening to Baseline on both the central rater and computer 
assessments 
8. &HQWUDOUDWHU0$'56DQGFRPSXWHUDGPLQLVWHUHG0$'56WRWDOVFRUHVVKRZSRLQW
difference between scores at both Screening and Baseline 
9. Have an identified support person 
a. Agree to be accompanied home (or to an otherwise safe destination) by the 
support person, or another responsible party, following dosing 
4.1.2 
 Exclusion Criteria 
Individuals not eligible to be randomized in this protocol are those who meet any of the 
following criteria: 
 
1. Women who are pregnant, as indicated by a positive urine pregnancy test at Screening or 
Baseline. Women who intend to become pregnant during the study or who are currently 
nursing.  
2. Unwilling or unable to discontinue formal psychotherapy (Section 4.2.2) 
3. Unwilling to discontinue any current prescription or supplemental psychotropic agents 
(including trazodone for sleep) or are unable according to Section 4.2.1 Medication Taper 
o Note: Benzodiazepine medications and non-benzodiazepine sleeping medications 
will be allowed to continue through the study period for participants who have 
been on a stable dose of such a medicine for at least 6 weeks prior to Screening. 
4. Have previously received the following non-medication treatments: 
a. deep brain stimulation (DBS) 
b. vagus nerve stimulation (VNS) 

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5. Currently receiving electroconvulsive therapy (ECT) or transcranial magnetic stimulation 
(TMS) 
o Note: Previous treatment with ECT or TMS is allowed as long as last treatment 
ZDVGD\VIURPWKHWLPHRI6FUHHQLQJ 
6. Unable or unwilling to discontinue any current medications having a primary centrally-
acting serotonergic effect, including monoamine oxidase inhibitors (MAOIs) or 
dopaminergic antagonists 
o Note: Any prohibited agents must have been stopped at least 5x the elimination 
half-life of the specific drug at the time of Baseline. See Appendix A for a full list 
of prohibited medications. 
7. Unable or unwilling to discontinue any current medications that are known uridine 
diphosphate (UDP) or glucuronosyltransferase (UGT) enzyme modulators, such as 
valproate 
o Note: Any prohibited agents must have been stopped at least 5x the elimination 
half-life of the specific drug at the time of Baseline. See Appendix A for a full list 
of prohibited medications. 
8. Report the following psychedelic substances use: 
a. Have used a psychedelic substance in the previous 5 years; or 
b. Have used psychedelic substances > 10 times in their lifetime 
o Note: Psychedelic substances include psilocybin, Lysergic acid diethylamide 
(LSD), mescaline (and natural products containing mescaline including peyote 
and San Pedro cactus), N,N-Dimethyltryptamine (DMT), natural products 
containing DMT including ayahuasca and 5-Methoxy-N,N-dimethyltryptamine 
(5-MeO-DMT), ibogaine, 2C compounds, 3,4-methylenedioxy-
methamphetamine  (MDMA), methylone or other psychedelics. 
9. Have the following cardiovascular conditions:  
a. coronary artery disease, congenital long QT syndrome (prior diagnosis), cardiac 
hypertrophy, cardiac ischemia, congestive heart failure, myocardial infarction 
(prior diagnosis); 
b. tachycardia (defined as heart rate > 100 beats per minute); 
c. a clinically significant Screening ECG abnormality (e.g., atrial fibrillation); 
o Note: A QTcF interval > 450 milliseconds is considered a clinically 
significant ECG abnormality 
d. artificial heart valve; or 
e. any other significant current or history of cardiovascular condition, based on the 
clinical judgment of study physician, that would make a participant unsuitable for 
the study  
10. At Screening or Baseline have elevated blood pressure as defined as: 
a. Screening blood pressure SBP >135 mmHg or DBP > 85 mmHg on three separate 
readings; or  
b. Baseline blood pressure SBP >140 mmHg or DBP > 90 mmHg on three separate 
readings 
o Note: Please see justification for blood pressure parameters in Section 4.2.8  
11. Have a history of stroke or Transient Ischemic Attack (TIA) 
12. Have moderate to severe hepatic impairment, as indexed by a Child-3XJKVFRUH 
13. Have epilepsy 

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14. Have insulin-dependent diabetes  
o Note: Participants who are taking oral hypoglycemic agent and have a history of 
hypoglycemia requiring medical intervention will be excluded 
15. Are unable or unwilling to adhere to the following medication requirements:  
a. Agree to suspend sildenafil (Viagra®), tadalafil, or similar medications at least 72 
hours prior to dosing 
b. If taking any supplement containing >20 mg of niacin, agrees to suspend use for 
at least five days prior to dosing and for the duration of the study 
16. Have a positive urine drug test including Amphetamines, Barbiturates, Buprenorphine, 
Benzodiazepines, Cocaine, Cannabis, Methamphetamine, MDMA, Methadone, Opiates 
(Morphine, Oxycodone), Phencyclidine (PCP), and Tetrahydrocannabinol (THC). 
Exceptions are made for prescribed Benzodiazepines (stable dose for sleep or anxiety).  
o Note: Prescribed benzodiazepine medications and non-benzodiazepine sleeping 
medications will be allowed to continue through the study period for participants 
who have been on a stable dose of such a medicine for at least 6 weeks prior to 
Screening, as determined during review of concomitant medications. 
o Note: Participants using cannabis, including legal cannabis, for any purposes must 
agree to refrain from use beginning at Screening, as confirmed with a negative 
Baseline drug test, and through to the end of the study.   
o Note: Participants who are taking prescription maintenance methadone or 
buprenorphine naloxone will be excluded. 
o Note: Prescription opiates must have been stopped at least 5x the elimination half-
life of the specific drug at the time of dosing, as confirmed with a negative urine 
drug screen on Day 1 (prior to dosing). They can resume use following the 
Integration Session # 1 the day after dosing. 
o Note: Participants using prescribed psychostimulants (amphetamines and Ritalin), 
must agree to refrain from use two weeks prior to baseline visit, as confirmed 
with a negative Baseline drug test, and through to the end of the study. 
o Note: Participants using prescribed trazodone for sleep (at any dose) must agree to 
refrain from use two weeks prior to baseline visit and through to the end of the 
study. 
17. Nicotine dependence that would disallow an individual to be nicotine free for the 7-10 
hours during the dosing period 
18. Meet DSM-5 criteria for schizophrenia spectrum or other psychotic disorders, including 
MDD with psychotic features (except substance/medication-induced or due to another 
medical condition), or Bipolar I or Bipolar II Disorder 
o Note: Participants with any lifetime diagnosis of schizophrenia spectrum or other 
psychotic disorders will be excluded 
19. Meet DSM-5 criteria for antisocial personality disorder 
20. Meet DSM-5 criteria for a moderate or severe alcohol or drug use disorder (excluding 
caffeine)  
o Note: Participants with a diagnosis of alcohol or drug use disorder within the past 
12 months will be excluded 
21. Have presence of any psychiatric condition or symptom judged by the PI (or designee) to 
be a more significant clinical problem than MDD for the participant, including a DSM-5 
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22. Have a first-degree relative with schizophrenia spectrum or other psychotic disorders 
(except substance/medication-induced or due to another medical condition), or Bipolar I 
Disorder 
23. Have a psychiatric condition judged to be incompatible with establishment of rapport 
with the Facilitators or safe exposure to psilocybin  
24. Report the following suicidal ideation or suicidal thoughts defined as: 
a. Answer ‘Yes’ to C-SSRS Suicidal Ideation items 4 or 5 within the last 2 months 
at Screening or “since last visit” at Baseline;  
b. Report having had any C-SSRS Suicidal Behavior item within the past 12 months 
at Screening or “since last visit” at Baseline, as defined by ‘Yes’ to any of the 
following on the C-SSRS: actual attempt, interrupted attempt, aborted attempt, or 
preparatory acts; or 
c. Have a score of 5 on Item 10 (suicidal thoughts) of the central-rater or computer 
administered MADRS at Screening or Baseline; or 
d. Have any suicidal ideation or thoughts, in the opinion of the study physician or PI, 
that presents a serious risk of suicidal or self-injurious behavior at any time prior 
to randomization 
25. Have any suicidal ideation or thoughts, in the opinion of the study physician or PI, that 
presents a serious risk of suicidal or self-injurious behavior 
26. Have any physical or psychological symptom, medication or other relevant finding prior 
to randomization, based on the clinical judgment of clinical/medical study personnel, that 
would make a participant unsuitable for the study.  
27. Have an allergy or intolerance to any of the materials contained in either drug product 
4.2 
Justification for Inclusion/Exclusion Criteria 
Provided below is a justification for criteria that are either not self-evident or differ in some way 
from standard practice in clinical trials in patients with MDD. 
4.2.1 Medication Taper 
The current study is designed to evaluate psilocybin as monotherapy for MDD, it is therefore 
important that individuals who otherwise qualify for study entry but who are currently receiving 
psychotropics, from which they do not appear to be benefitting based on the continued presence of 
significant depressive symptoms at Screening, be discontinued from these agents to participate in 
the study. Only individuals taking antidepressants who meet symptom severity criteria at Screening 
and endorse that the antidepressant they are taking is not providing benefit will be eligible. Any 
participant who believes he/she is being helped by the antidepressant, even if he/she endorses 
significant depressive symptoms, will not be eligible. In addition to the requirement to discontinue 
antidepressants to allow for an accurate assessment of the potential of psilocybin as monotherapy 
for depression, it should be noted that a strong rationale for not continuing these agents in a trial of 
psilocybin comes from evidence that antidepressants attenuate the types of behavioral responses to 
psychedelics that are linked to their antidepressant effect (Bonson, Buckholtz, & Murphy, 1996). 
Potential participants who have been on a stable dose of a benzodiazepine or a non-benzodiazepine 
sleeping agent for at least 6 weeks will be allowed to continue these medications on this fixed dose 
throughout the study period. Participants will be required to have taken their last antidepressant dose 

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at least 14 days prior to baseline. Details of the medication taper requirements are specified in the 
MoP.  
4.2.2 Outside Psychotherapy 
Participants will only be eligible for study enrollment if they agree and are judged able, from a 
safety perspective, based on the opinion of a study psychiatrist, to suspend any ongoing outside 
psychotherapy for the duration of study involvement. The rationale for suspending outside 
therapy is to allow for adequate evaluation of the study intervention. Suspending outside 
psychotherapy for the duration of the study is similar to the need for participants not to be taking 
outside psychotropic medications (e.g. antidepressants) during the study period. As with 
continuing pre-existing antidepressant medications, allowing participants to continue pre-
existing outside psychotherapy would potentially confound the ability to unambiguously 
interpret study findings regarding whether monotherapy with psilocybin delivered in a 
therapeutic context shows an antidepressant effect when compared to placebo. This is true for 
several reasons. First and foremost, continuance of outside psychotherapy would not be “per 
protocol” and hence would not be standardized, nor would it be randomized, leading to the 
possibility of it being unequally distributed across groups. Moreover, it is completely unknown 
whether outside psychotherapy would potentiate or diminish antidepressant responses to 
psilocybin. 
4.2.3 Benzodiazepines 
Benzodiazepine medications and non-benzodiazepine sleeping medications will be allowed for 
participants who have been on a stable dose of such a medicine for at least 6 weeks prior to 
Screening. These medications are allowed because they have no psychotropic effects that might 
confound any potential differential antidepressant signal from the psilocybin vs. niacin placebo. 
On the other hand, requiring discontinuation of these sleeping agents prior to study drug dosing 
would likely disrupt stable sleep patterns that were part of the pre-treatment depressive symptom 
profile, and by doing this might interfere with potential antidepressant signals from the study 
drugs. Because these agents are used at bedtime, they will be out of participants’ systems prior to 
study drug dosing and thus should not interfere with either psychodynamic or pharmacokinetic 
properties of psilocybin. 
4.2.4 Age range 
The age range for the current study is typical for most antidepressant studies, with enrollment 
limited to individuals 21 years of age and older, but not older than 65 years. The rationale for 
excluding individuals with MDD younger than 21 is that they are at an increased risk of 
demonstrating a bipolar disease course with the passage of time and bipolar disease is believed to 
be contraindicated for the use of psilocybin (Moreno et al., 2012). There are no data to support 
the use of psilocybin in patients with bipolar disorder, nor data on how likely psilocybin would 
be to induce a manic episode in patients with a bipolar diathesis. In addition to this particular 
concern regarding incipient or misdiagnosed bipolar disorder in those younger than 21, 
individuals in this age group are in general at increased risk for adverse psychological reactions 
to antidepressants, as demonstrated by the black box warning for increased risk of suicidal 
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health/antidepressant-medications-for-children-and-adolescents-information-for-parents-and-
caregivers.shtml).  
 
This study will also exclude individuals older than 65 years of age. In addition, as with 
individuals younger than 21, older adults often differ from younger adults in factors associated 
with their depression and in their intervention response. For example, depression in older adults, 
especially when it is new onset, is significantly associated with the subsequent development of 
dementia (Alexopoulos, Young, & Meyers, 1993). And studies suggest that older adults are less 
likely than younger adults to respond to pharmacological treatments for MDD when depression 
is associated with brain changes also associated with dementia (Hsieh et al., 2002; Kalayam & 
Alexopoulos, 1999).  
 
Additionally, over the course of its long-term clinical development phase, over a thousand 
participants have received psilocybin under controlled conditions in clinical settings for various 
indications (including healthy control subjects), with subsequent results published in peer-
reviewed journals (Rucker, Iliff, & Nutt, 2017). The modern-day trials, enrolling approximately 
165 adult participants, include open-label, dose-escalating studies, as well as randomized, 
double-blind placebo-controlled trials, and enrolled both healthy volunteers and various 
subpopulations with differing indications (Carhart-Harris et al., 2016; R. R. Griffiths et al., 2016; 
Ross et al., 2016). Multiple ongoing studies are continuing this exploration. All these studies had 
or currently have approval to enroll participants > 55 years (age ranges from 18-80 years). 
Furthermore, of the approximate 165 participants receiving study drugs in completed trials, 
73 adult participants were > 55 years (Roland Griffiths, PhD; Matthew Johnson, PhD; Robin 
Carhart-Harris, PhD; Francisco Moreno, MD, Paul Hutson, PharmD; Stephen Ross, MD; Charles 
Grob, MD, personal communication). To date, no Serious Adverse Events attributed to the study 
drug were reported for any participant in these trials, regardless of age. 
 
For these reasons, selecting the 21-65 year age range maximizes the generalizability of any 
potential positive findings while reducing risk and constraining biological/phenomenological 
variance that might decrease the power to detect clinically-relevant effects. Should results from 
the proposed study be promising, separate trials of psilocybin intervention in younger adult and 
geriatric populations would be warranted. 
4.2.5 Medically Healthy Participants 
The current study will enroll participants in good general overall medical health. While this 
somewhat limits the potential generalizability of any positive findings given the high 
comorbidity between mood disorders and medical disease, there are two primary reasons for 
choosing this strategy. First, medically-ill participants often have complex patterns of depressive 
pathogenesis born of the psychological stress of serious disease, but also likely from the direct 
physiological effects of the disease state itself, most notably the chronic immune activation that 
accompanies a wide range of medical illnesses (Raison, Capuron, & Miller, 2006). Given this, 

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separate studies are indicated to examine the potential antidepressant effects of psilocybin in 
patients with MDD and significant medical comorbidity.  
4.2.6 Psychiatric Symptoms 
Study inclusion/exclusion criteria include several exclusions related to psychiatric symptoms and 
conditions. Participants with active suicidal ideation with intent to act are excluded because these 
individuals require immediate psychiatric intervention with currently approved therapeutic 
modalities. The safe study of such individuals would require an inpatient setting and the current 
study will be conducted on an out-patient basis. Similarly, individuals with a history of 
medically-significant suicide attempt will be excluded given evidence that a recent history of 
suicide attempts increases the short-term risk for subsequent suicide attempts.  
 
Individuals who are experiencing depression in the context of conditions characterized by a 
heightened risk for psychotic features, including schizophrenia and bipolar I and II disorder, are 
also excluded, including individuals with first-degree relatives with these conditions. These 
exclusions are based on the fact that not enough is known regarding the risks of a psychedelic 
experience in individuals with a vulnerability to psychosis to justify their inclusion in the current 
study. At the least, such individuals might have experiences occasioned by psilocybin that would 
differ markedly in their character and effects from experiences that would be more typical for 
individuals without psychosis risk.  
 
As is common practice in phase 2 studies of new antidepressant modalities, individuals with 
active drug/alcohol abuse are excluded, as are those who have only recently achieved sobriety. 
Justification for these exclusions comes from evidence that antidepressant treatments are less 
effective in those who are actively abusing drugs/alcohol and from the fact that relapse rates are 
high during early sobriety, increasing the risk of a return to substance use during the study.  
 
Because psilocybin administered under the SaS requires the development of rapport between 
participant and his/her intervention Facilitators, participants will be excluded prior to 
intervention if it is judged by the Facilitators (with agreement from a study clinician) that a given 
participant is not demonstrating a minimal degree of involvement/engagement with the 
intervention team.  
 
Also, because this study focuses on MDD, participants with comorbid psychiatric conditions 
(e.g., obsessive-compulsive disorder, panic disorder) that are judged at Screening to be a more 
significant source of distress/impairment than the MDD will be excluded from study 
participation. Comorbid psychiatric disorders other than those specifically disallowed 
(i.e. psychotic disorders, bipolar I and II disorder, antisocial personality disorder) will be allowed 
if it is determined based on assessment at Screening that the participant’s primary condition is 
MDD. 
4.2.7 Medication Exclusions 
In addition to these medical and psychiatric inclusion/exclusion criteria, participants will be 
required to abstain from medications/supplements that might interact with, or impact the 
experience of, psilocybin administration as listed in Appendix A. This strategy is proposed both 

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to enhance safety (i.e. by limiting co-exposure to medications that might increase potential 
serotonin-related side effects of psilocybin) and to reduce biological heterogeneity of participants 
entering the intervention session. 
4.2.8 Blood Pressure 
The Screening and Baseline blood pressure criteria are in place for both safety and feasibility 
reasons. First, the American College of Cardiology and American Heart Association recently 
lowered their criteria for Stage 1 hypertension from SBP140 mmHg/ DBP 90 mmHg to SBP 
130mmHg/DBP 80 mmHg, citing strong observational data to support this change (Whelton et 
al., 2018). By lowering the Screening BP criteria to SBP > 135 mmHg or DBP > 85 mmHg, the 
study will in effect recruit a healthier population that is at less risk for cardiovascular events. 
Second, due to the nature of the study, it is likely that some percentage of participants will 
present on the dosing day with vital signs elevated above Baseline values due to anxiety over the 
upcoming procedure (i.e. “white coat syndrome”). By reducing the Screening criteria to 
135/85 mmHg, it is expected that the number of participants who fail to meet the dosing day 
(pre-dose) BP criteria of <140/90 mmHg due to elevated BP resulting from anxiety will be 
reduced. This change will significantly reduce the time burden and psychological stress on 
participants who would otherwise qualify but fail to meet BP criteria on the dosing day. 
Importantly, by setting more stringent BP parameters at screening we will also reduce the 
number of participants who will unnecessarily taper off from psychotropic agents and 
psychotherapy prior to dosing day should they be discontinued due to “white coat syndrome” 
elevation of BP on dosing day. 
 

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5 
SCREENING PROCESS AND PROCEDURES 
Study screening procedures and their timing are summarized in the Schedule of Assessments 
(Table 1) and full details are provided in the MoP. Participants will be provided with visit 
reminders. Adherence to the study design requirements, including those specified in the Schedule 
of Assessments, is essential and required for study conduct.  
5.1 
Recruitment 
Participants for the study will be recruited from the following sources: 1) a study specific 
website (see Section 5.1.1), 2) relevant clinical programs at each participating institution 
(e.g., departments of psychiatry, family medicine, etc.); 3) via advertisements on the web, in 
local print and radio and via flyers posted in relevant locations in the metropolitan areas in which 
the study will occur; and 4) via relevant national clinician-focused listservs and patient-advocate 
listservs. All advertisements, flyers and notices on listservs will be approved by all relevant IRBs 
prior to posting. As this study will require intensive study recruitment measures and new and 
various recruitment opportunities are found often, there may be instances of recruitment which 
do not fall under the above categories. However, prior to initiation of any recruitment activities, 
approval will be obtained from all relevant IRBs with IRB approved recruitment language/text.  
5.1.1 Study Recruitment Website and Pre-Screener Questionnaire 
A clinical research recruitment website will serve as the anchor for Usona’s digital patient 
recruitment efforts and as the hub for study digital recruitment activities. The website contains 
basic educational content about clinical trials, depression and psilocybin. The study profile page 
provides key study details for prospective participants. Study profile page visitors who are 
interested in participating in the study may complete an eligibility pre-screener questionnaire. 
 
Pre-Screener Questionnaire 
The pre-screener includes questions regarding demographics and availability, medical and mental 
health questions, and prior psychedelic and other illicit drug use. It also includes a waiver of 
documentation of consent as it does not present more than minimal risk of harm to participants and 
involves no procedures for which written consent is normally required outside of the research 
context. During the pre-screener, participants will be informed, via the website, that answering 
questions is voluntary and that any information shared will be kept confidential. Identifiable 
contact information in the Rebar system will be encrypted.  
 
Approval of the Sponsor’s study recruitment website will fall under the purview of a central IRB, 
whereas each site will obtain institutional IRB approval for site specific recruitment activities. 
5.2 
Telephone Screen 
Prospective participants will be prescreened by telephone at each participating institution, 
according to a local IRB-approved script, to learn if they meet basic eligibility criteria. The 
Telephone Screen will include questions similar to the pre-screener regarding demographics and 
availability, medical and mental health questions, and prior psychedelic and other illicit drug use. If 
a potential participant prefers, the telephone screen questions can be asked in person.   

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If at any time during the telephone screen process a potential participant discloses suicidal 
ideation, he or she will be immediately referred to a suicide crisis line or encouraged to call 911. 
 
If the initial telephone screen suggests that the participant is eligible, a Screening visit will be 
scheduled. If the participant does not qualify or decides not to participate the reason will be 
documented in the Electronic Data Capture (EDC) system with all identifiable information 
encrypted.   
 
Telephone Screen information will be verified at the Screening visit prior to written informed 
consent.  
5.2.1 Telephone Screen Waiver of Documentation of Informed Consent 
The Telephone Screen will include a waiver of documentation of consent as the Telephone Screen 
does not present more than minimal risk of harm to participants and involves no procedures for 
which written consent is normally required outside of the research context. During the telephone 
screen, staff will indicate that answering questions is voluntary, identifiable contact information in 
the EDC system will be encrypted. If a potential participant is deemed ineligible based on the 
telephone screen, their information will remain encrypted.  
5.3 
Written Informed Consent 
For this trial, written informed consent will occur at the initial Screening visit. Study participants 
will be considered enrolled in the study when they provide written informed consent. All 
individuals who sign an ICF will be assigned a participant ID number in the EDC, which will be 
assigned sequentially. Written informed consent will be obtained from all participants before 
undergoing any study procedures. Prisoners, pregnant women and mentally impaired persons 
will not be included. Competent persons meeting other eligibility criteria will be welcomed, 
regardless of race, gender, ethnicity, religion or socioeconomic status. Additionally, students, 
employees, patients or family members affiliated with the PI(s) will not be enrolled, and family 
members of any study team member will be prohibited from participating in this study. 
 
The following consent process will be adhered to for each participant: 
 
x The PI or a qualified representative will explain the screening process and nature of 
the study to the participant and answer all questions.  
x Participants must be informed that their participation is voluntary and that he/she may 
withdraw from the study at any time, for any reason. 
x Participants will be provided adequate time for review and discussion prior to his/her 
making a decision about participation in the study, including the option to take the 
information home to discuss with family prior to making a decision. 
x Participants will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR part 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
Institutional Review Board (IRB)/Institutional Ethics Committee (IEC) or study site.  

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x Participants will be encouraged to ask any questions at any time for any reason, and 
to seek outside counsel when appropriate.  
x To verify informed consent was obtained before the participant was enrolled in the 
study, the ICFs will contain the date and time written consent was obtained. The 
authorized person obtaining informed consent must also sign the ICFs. 
x Participants must be re-consented to the most current version of the ICFs during their 
participation in the study, per institutional IRB requirements, and they will be 
informed of any changes to the consent form.  
x A copy of the ICFs must be provided to the participant. 
 
The ICF and any other written participant information to be provided to participants will be 
revised whenever important new information becomes available that may be relevant to the 
participant’s consent. Any revised ICF and written participant information will receive IRB 
approval before being implemented. The participant will be informed of any changes and re-
consented with the current version of the consent form and provided a copy at their next visit.  
Communication of this information to the participant will be documented.  
 
The informed consent process may be handled remotely, see the MoP for full details. 
5.3.1 
 Informed Consent Comprehension 
The informed consent comprehension process will serve as a way to engage with potential 
research participants about their study participation. Prior to signing the ICF, the person 
facilitating the consent process will assess the participant’s comprehension of the study, via an 
Informed Consent Form Process Checklist, and their understanding of what the study involves by 
asking specific study-related questions. The questions will serve as a way to identify areas where 
the participant may lack understanding. In that case, those sections of the consent will be 
reviewed again until comprehension is achieved.  
5.4 
Screening Visit (7-35 days) 
After preliminary eligibility is determined via the Telephone Screen, the Screening visit will 
confirm eligibility for the study. Screening will occur in an appropriate venue at each study site, 
and certain assessments may be conducted remotely (see Table 1 and the MoP for full details). 
Upon signing the Informed Consent Form (ICF), the potential participant may commence study-
related screening activities. No study related procedures, other than the study pre-screening 
questionnaire and telephone screen, will occur prior to obtaining written informed consent.  
 
Screening will take 7 to 35 days to allow for full medical and psychiatric evaluation and to allow 
for psychiatric medication taper (Section 4.2.1), if needed, prior to Baseline. It is expected that 
Screening may require multiple days/visits to reduce participant burden and allow for appropriate 
assessment. The purpose of the Screening visit is to evaluate medical and psychiatric 
appropriateness for the study. If at any point the participant is found to be ineligible, the 
screening process may be discontinued and any remaining procedures will not take place.   

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5.4.1 
Medication Taper  
As was reviewed in Section 4.2.1, only participants who agree and have been successfully 
tapered off their psychiatric medications are eligible. Psychiatric medications will be tapered 
based on standard of care tapering for each medication per the direction of the study psychiatric 
medical provider. Guidelines will also be provided in the MoP, which study medical providers 
can utilize to guide the taper.  
5.4.2 
Suspending Outside Psychotherapy 
As was covered in Section 4.2.2, participants will only be eligible for study enrollment if they 
agree and are judged able to suspend any ongoing outside psychotherapy for the duration of 
study involvement. If deemed appropriate, communication between the outside psychotherapist 
and/or psychiatrist (if one had been previously established), the Lead Facilitator, and study 
clinicians at each site will be coordinated following informed consent. However, because clinical 
care for study participants will be assumed by study clinicians following enrollment, active 
discussions among an outside psychiatrist or psychotherapist and study clinicians will occur only 
in case of an emergency or psychiatric need until the study’s final end-point (Day 43).  
5.5 
Baseline Visit (maximum 7 days prior to dose) 
The Baseline visit will occur at the end of the screening process, following completion of all 
screening procedures, including medication tapering (Section 5.4.1). For the timing and 
frequency of assessments see Table 1. This visit will occur in-clinic, though certain assessments 
may be conducted remotely (see Table 1 and the MoP for full details).  
5.5.1 
Inclusion/ Exclusion Criteria Confirmation  
Following the completion of all Screening and Baseline medical and psychiatric assessments, the 
PI will confirm participant eligibility on an ongoing basis until dosing.  
5.6 
Re-Screening 
Participants may be eligible for re-screening at the discretion of the site PI or MD, including 
participants who screen fail or who are unable to complete the screening assessments within 
35 days (including requirement for slow medication tapering due to withdrawal symptoms). The 
purpose of the re-screen is to assure continued safety and eligibility for participating in the study. 
Re-screening includes repeating all screening assessments. However, if a subject is found to be 
ineligible at any point during the re-screen process, the re-screen will be discontinued at that 
point. A participant who is rescreened is not required to sign another ICF unless a new version of 
the ICF has been approved since the date the original ICF was signed. 
 

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6 
PREPARATION, RANDOMIZATION, DOSING AND FOLLOW UP 
PROCEDURES 
This section outlines the purpose and content of all preparation, randomization, dosing and 
follow up study procedures. Participants will be provided with visit reminders. For the timing 
and frequency of assessments at each visit see Table 1. Full details are provided in the MoP.  
6.1 
 Preparatory Sessions with Clinical Facilitators (1-6 days prior to dose) 
Following successful completion of Screening and Baseline, participants will be assigned a Lead 
Clinical Facilitator and a Co-Facilitator. Both Facilitators will remain with the participant 
throughout the preparatory and integration sessions to the greatest extent feasible. For the 
entirety of the dosing session both Facilitators will be present in the session room and will attend 
to the participant to continuously observe and evaluate the participant’s physical and mental 
status, with the exception of infrequent, short and unavoidable breaks (e.g. facilitator bathroom 
breaks). Such breaks are expected to be minimal and kept to the shortest possible duration. At 
least one Facilitator will always be present in the session room with the participant. For criteria 
required to be a Session Facilitator see Section 6.3.2.  
 
The main objective during preparatory sessions is to build rapport and therapeutic alliance 
between the participant and Session Facilitators, which can support the participant as they 
navigate the dosing session. Participants will meet with one or both of the Facilitators who will 
attend the participant’s study dosing session. Whenever possible, these meetings will occur in the 
room in which dosing will take place so participants can develop a level of comfort and 
familiarity with the intervention location. If necessary, the meetings may be held remotely; 
however, one in-person preparatory session should be conducted. Consistent with previous 
psilocybin protocols, the participant’s life history and current situation in life will be reviewed, 
and intentions and expectations for the intervention session will be discussed. It is also expected 
that the participant’s support person will meet the session Facilitators before dosing. For the 
specific contents and structure of the preparatory sessions see the Usona Facilitator Training 
Manual.   
 
The pre-intervention preparatory sessions will occur as follows:  
 
x 
approximately 6-8 hours of preparation, which can occur over multiple days in the 1-
6 days prior to intervention 
 
The reason for allowing for multiple days is to reduce participant burden due to the number of 
hours of preparation required to cover all content.  
6.1.1 
Post Preparatory Session Assessment (1-4 days prior to dose) 
This assessment can occur on the same day as the last preparatory assessment but must be 
performed after all preparatory session activities are complete. These assessments may be 
conducted remotely (see Table 1 and the MoP for full details). The assessment will include the 
‘Since Last Visit’ C-SSRS as an additional safety check prior to administration of the study drug. 
Before dosing, Facilitators will communicate with the PI and Study Physician to discuss overall 

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appropriateness for dosing. If the Facilitators, PI or Study Physician believes the dosing session 
is contraindicated, the session will be cancelled or postponed.  
6.2 
Randomization 
Randomization will occur following Screening, Baseline, and specific Day 1 (dosing day) 
assessments (i.e., vital signs, urine pregnancy test, urine drug test, and eligibility verification) for 
participants who have been determined to be eligible for the study. Randomization will occur on 
Day 1 (dosing day) prior to the participant being dosed. Prior to randomization, participants will 
be stratified by study site. Following this, participants will be randomized to one of two 
intervention groups in the EDC system. A centralized, computer-generated randomization 
schedule will be created in which participants are randomized in a 1:1 ratio in a blinded fashion 
to the psilocybin group or the active control group. Once data collection from the assessments 
required for participant randomization is complete and study eligibility is verified, the database 
will assign an intervention group code.  
 
The master randomization code will be maintained in a secured location until the time of 
unblinding. 
 
In the event of unforeseen circumstances that prohibit use of the database to generate the 
randomization assignment, procedures for determining the assignment manually are available 
and are described in the MoP. 
6.3 
Day 1: Dosing Session 
Participants will be asked to report to the research site in the morning. Sessions are expected to 
last 7-10 hours, on average.  
6.3.1 Pre-Dose  
Upon arrival, and prior to the dosing, the following assessments will occur:  
 
1. Study personnel will inquire about any possible changes in health  
2. Study personnel will inquire about any change in concomitant medication use and 
adherence.  
3. A urine drug test for drugs of abuse with be performed  
4. Urine pregnancy testing (women of childbearing potential only) will be performed 
5. The study coordinator will remind the participant of their agreement to the following 
during the dosing session, as previously agreed to during the preparation sessions 
(also see Manual for Clinical Facilitators for agreements):  
o The participant agrees to remain on-site for a minimum of 7 hours on their 
dosing day after ingesting the psilocybin or placebo capsule and all identified 
study personnel agree that the participant may safely leave the facility with their 
identified support person.  
o The participant agrees to not harm himself or herself or anyone else during the 
dosing day.  

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mental status, with the exception of infrequent, short and unavoidable breaks (e.g. facilitator 
bathroom breaks). Such breaks are expected to be minimal and kept to the shortest possible 
duration. At least one Facilitator will always be present in the session room with the participant. 
Continuous supervision provides a safety structure and ensures that the participant will receive 
reassurance and emotional support from the Facilitators should he/she experience strong 
emotions or become anxious or agitated during the session. Specific dosing session safety 
monitoring, via the Facilitator Monitoring Form, will be conducted at regular, pre-specified 
times through assessment of the following: nausea, acute physical or psychological distress, 
including self-harm, and self-reported anxiety. This is intended to provide Facilitators with an 
enhanced ability to monitor participant safety and communicate any observed symptoms to the 
Study Physician, who will determine if immediate clinical assessment is warranted.   
 
Role of the Study Physician During Dosing 
The on-call Study Physician is responsible for the overall safety of participants, and he/she will 
oversee the medical management of study participants during the dosing session, as needed.  
x Availability during Dosing: The Study Physician will be on-call throughout the duration 
of the dosing session and will need to be available to be onsite within approximately 
5 minutes in the event of an emergency for medical/psychiatric assessment. The Study 
Physician is responsible for administering rescue medications, should these be warranted.  
x End of Dosing Day: The Study Physician will assess the participant in-person at the end 
of the dosing day to determine if he/she is ready to be released from the research site.  
x Overnight: The Study Physician will be on-call following participant release and until the 
following morning when the participant returns for his/her integration session.  
 
Rescue Medications Available During Dosing 
In the unlikely event that a participant requires medication management for blood pressure, 
anxiety or psychosis, the study physician may use the following medications (or similar 
medications available on site) per his/her medical discretion: 
1. Nitroglycerin  
2. Clonidine 
3. Diazepam  
4. Risperidone  
The use of rescue medications to control symptoms will be at the judgment of the treating 
physician, therefore use of specific medications is not protocolized. The study site will supply 
the rescue medications, which will be obtained locally at each institution. The date and time of 
medication administration, reason for administration, as well as the name and dosage regimen of 
the rescue medication must be recorded on the Concomitant Medications log. Use of 
psychotropic agents (e.g. diazepam, risperidone) will be on a single dose/time limited basis and 
hence will not fall under the study exclusionary criteria regarding chronic use of these agents 
prior to enrollment.  
 
In the unlikely event of a medical or psychiatric emergency that cannot be safely managed by 
staff with reassurance or pharmacological intervention, the study physician will determine if the 
participant can be safely escorted by medical staff to the nearest emergency department, or if 911 
needs to be called for transport.  

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6.3.3 Post-Dosing Release Procedures 
Following the 7-hour vital sign assessment, if the participant appears to have returned to his/her 
baseline psychological and physiological state and expresses a readiness to begin the discharge 
process, the Lead Facilitator and Study Physician will assess the participant using the Participant 
Release Form (for a copy of the form see the Manual of Procedures). This assessment will 
confirm whether the participant is ready to safely leave the research facility accompanied by 
his/her support person (family or a trusted friend). This support person will have already been 
identified and briefed by Facilitators on basic guidelines for accompanying the participant home 
during preparation session #2. Self-care activities and additional safety precautions will be 
reviewed with the participant before the participant and support person leave the premises. 
 
If the participant is experiencing residual study drug effects, such as mild persistent sensorial 
distortions, he or she will be asked to remain on-site for continued observation by Facilitators 
and/or the attending physician until cleared to leave with the support person.  
 
While it is unlikely, if it is found that the participant is experiencing severe persisting physical or 
perceptual drug effects or is exhibiting signs of significant/severe emotional distress including 
suicidal ideation, or any other circumstance deemed an emergency per the Study Physician, the 
Study Physician will evaluate the participant for transport to the emergency department by study 
personnel for further assessment. 
 
The participant will be given a post-dosing session summary form which they can use to record 
recollection of the dosing session before returning for Integration Session #1 on Day 2. This 
summary may be reviewed with the participant throughout the integration sessions. Additional 
details about this summary can be found in the Manual for Clinical Facilitators.  
 
The Lead Clinical Facilitator, Co-Facilitator, and Study Physician will be on-call throughout the 
night to speak with the participant or support person should any issues or safety concerns arise.  
6.4 
Day 2: Post Dose 
The Day 2 visit will occur in person, though certain assessments may be conducted remotely (see 
Table 1 and the MoP for full details). The purpose of the Day 2 visit is to assess the participant 
for safety and to allow for integration of the dosing session with the session Facilitators.  
6.5 
Day 5: Post Dose Phone Call (±1 day) 
Five days post-dose, study personnel will contact participants by phone. The primary goal of this 
telephone contact will be to ensure participant safety. Each call will last on average 5-15 minutes 
but could be longer to address participant concerns and to adequately assess wellbeing. In 
consultation with the site PI, additional telephone contact can be initiated at the request of study 
personnel, Facilitators or the participant. 

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6.6 
Day 8, 15 and 29: Post Dose (-1/+2 days) 
Day 8 consists of collection of the primary study outcome as well as other safety and efficacy 
outcomes, and Days 15 and 29 allow for continued safety and efficacy follow-up. These visits 
will occur in person, though certain assessments may be conducted remotely (see Table 1 and the 
MoP for full details). 
6.7 
Day 9 and 16: Integration Sessions #2 and #3 (-1/+4 days) 
The purpose of these visits is to allow for further integration of the dosing session. These visits 
take place in person unless specific circumstances do not allow the participant to attend in 
person. In that case, video conferencing or phone calls will be arranged.  
 
Day 9 and Day 16 visits can occur on Days 8 and 15, respectively, and must take place after all 
Day 8 and Day 15 procedures and assessments have taken place.  
6.8 
Day 43: Post Dose/End of Study (±3 days) 
This visit will occur in person, though certain assessments may be conducted remotely (see 
Table 1 and the MoP for full details). These assessments will constitute study termination 
measures. After all study measures and assessments are completed, the participant is considered 
to have completed the study. The study team will also discuss the End of Study plan, described 
below. 
 
Whenever possible, participants who have withdrawn from the study but agree to follow-up will 
also complete this assessment. 
6.8.1 End of Study Plan 
During Integration Session #3, Facilitators will discuss the participant’s plans after the study has 
ended. The study clinician and/or PI will confirm the End of Study plan at the Day 43/ End of 
Study visit. Additionally, study participants will be referred back to their primary care provider, 
psychiatrist or therapist for additional follow up as needed. Any verbal or written handoff will be 
documented. 
6.9 
Blinding Related to Delivery of Study Interventions and Collection of Outcome Data 
As with any interventions that produce noticeable psychological effects following 
administration, blinding psilocybin poses unique challenges. Several strategies will be employed 
to minimize the impact of the blinding challenges posed by psilocybin. Most importantly, the 
study’s primary outcome assessment (MADRS) will be conducted by remote blinded central 
raters who will have no interactions with either participants or study personnel other than 
conducting the MADRS assessments, which will be conducted by telephone, as is standard 
practice when central raters are used in pharmaceutical trials. These raters will have no 
information regarding specifics of the study design and will not know where in the study 
protocol any given participant is when assessed.  
 

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Prior to site activation, all study site staff will receive extensive training in basic research 
principles of maintaining the study blind and ensuring only appropriate personnel have access to 
this information. Blinding will be consistent at each site through the use of study specific 
procedures defined in the MoP.  
 
Session Facilitators, who will be in the room with participants throughout their dosing sessions, 
may become functionally unblinded as a result of participants demonstrating changes in behavior 
and/or speech suggestive of a psychedelic experience, or as a result of participants not 
demonstrating these types of changes. To reduce the risk that these potentially unblinded 
Facilitators might unintentionally unblind personnel who will assess symptom status via central 
rater interviews with the participants after the dosing sessions, Facilitators will have no contact 
with the remote central raters who will assess the primary study outcome. 
6.9.1 Unblinding Procedure 
Full blinding of study personnel, the Sponsor and participants will be maintained until data lock 
at the conclusion of the study. Exceptions on an individual subject basis will be made in cases in 
which it is determined by site PI, the Medical Monitor or the Sponsor that unblinding of a 
participant’s intervention assignment is required for participant safety. Anyone requesting 
individual unblinding prior to study-wide unblinding will first be referred to the site PI. The site 
PI must notify the medical monitor of the request and discuss the circumstances surrounding the 
request. The medical monitor will notify the Study Coordinating (SCC) Project Director, the 
study director and the Sponsor’s medical expert of the request and if unblinding occurred. 
Attempts should be made to maintain the blind of the investigators prior to the study-wide 
unblinding. Unblinding during the study will be recorded on the Protocol Deviation Form. All 
instances of unblinding must be reported to the site IRB, the Sponsor’s medical expert, and the 
study director. The details of the process for maintaining the blind and for unblinding are 
described in the MoP. 
6.10 Early Termination Visit 
Should a participant terminate early, including Prep Phase Terminations and participants who are 
randomized and later terminate or are terminated for safety reasons (see Section 7.3.3), the End 
of Study visit assessments will be completed to the extent possible within 14 days. The End of 
Study Plan will be discussed at the termination/End of Study visit. An End of Study visit will not 
be conducted for Screen Failures (for more information on Screen Failures see Section 7.1).  
6.11 Unscheduled Visits 
Unscheduled visits are any visits conducted to perform additional procedures other than regularly 
scheduled visit procedures, including additional integration sessions, if needed. Procedures 
performed will be based on the clinical judgment of the PI, Study Physician, or session 
Facilitators. Procedures and results will be recorded as an Unscheduled Visit. 

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7 
STUDY DISCONTINUATION AND COMPLETION CRITERIA 
7.1 
Screen Failures 
Screen Failures are defined as participants who are deemed ineligible either at the Screening or 
Baseline assessment. Screen failures may fail to meet one or more Inclusion Criteria and/or may 
meet one or more Exclusion Criteria or withdraw consent. Screen Failures may be identified by 
various ways, including review of medical history, assessments, measures, laboratory results, or 
conversations with the participant. Medical assessments may be repeated for confirmation. At 
any time during Screening, if a potential participant is deemed to be ineligible and therefore 
qualify as a Screen Failure, study personnel will notify the potential participant that he/she is not 
eligible and no additional Screening assessments will be scheduled or conducted. All potential 
participants who begin Screening will be tracked in the EDC study database and reasons for 
Screen Failure will be recorded.  
 
At the discretion of the site PI or Study Physician, participants who screen fail may be eligible to 
be re-screened. See Section 5.6 for Re-Screening requirements. 
 
Screen Failures may request or be referred to an outside mental health clinician/ medical 
provider or to their health care provider, if needed. 
 
Screen Failures are not considered evaluable.  
7.2 
Evaluable Participants  
A participant is considered evaluable and eligible for the ITT analysis if he or she meets study 
eligibility criteria and is randomized to psilocybin or active placebo.  
7.3 
Early Termination from the Study 
Participants can withdraw consent or terminate from the study at any time at his/her request 
without prejudice. Study personnel can withdraw a participant if, in their clinical judgment, it is 
in the best interest of the participant or if the participant cannot comply with elements of the 
protocol that are critical for safety or for the scientific integrity of the study. If study personnel 
withdraw a participant from the study, study personnel will explain the reason for withdrawing 
the participant. The reason for early termination will be recorded.  
 
Randomized participants who prematurely terminate from the study will not be replaced. 
7.3.1 Early Termination Post-Baseline and Pre-Randomization (Preparation Phase 
Termination) 
It is possible that participants will discontinue study participation between the end of the 
Baseline assessments and up to randomization on the morning of dosing. This might occur for 
any of following reasons, including, but not limited to, a decision to withdraw, a decision on the 
part of site personnel to withdraw the participant prior to dosing, a change in mental or physical 
health status, or become ineligible to be randomized during the preparatory sessions. These 
participants will be considered Preparation Phase Terminations and will complete an End of 

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Study visit (see Section 6.9 ) within 14 days.  Similar to Screen Failures, these participants will 
not be included in the ITT analysis population but will be included in the safety analysis 
population.  
7.3.2 Early Terminations Post-Randomization and Pre-Dosing 
If a participant is terminated or withdraws post-randomization but prior to dosing, he/she will be 
encouraged to continue with all scheduled follow-up assessments if it is safe to do so. Data from 
these participants will be included in the ITT analysis population as well as the safety analysis 
population.  
7.3.3 Early Termination Post Dosing 
If a participant develops any condition post-dosing that, in the opinion of the PI (and upon 
consultation with the study Sponsor as needed), would negatively impact safety should he/she 
remain in the study, the participant will be asked to complete the End of Study visit within 14 
days. Efforts will be made to obtain information about AE outcomes, if deemed necessary by the 
PI, Medical Monitor and/or Sponsor.  
 
For other post-dosing exclusion criteria not judged to impact participant safety, participants will 
be encouraged to remain in the study and continue with all follow up assessments, given that no 
additional exposure to the study medication is required following the dosing day. If a participant 
does not agree to remain in the study, or if a participant chooses to withdraw from the study for 
any other reason post-dosing, he/she will be asked to complete the End of Study visit 
assessments within 43 days of their dosing day, so that the maximal time between dosing and 
assessment is no longer than the time period for participants who complete the study. 
7.3.4 Dropouts 
If a participant withdraws consent they will be terminated from the study without further follow 
up. These participants are defined as dropouts. If they withdraw consent prior to or during 
Baseline they are considered Screen Failures. If they withdraw consent post dosing then study 
records/data generated until the date consent is withdrawn will remain available for use by the 
Sponsor and PI. 
7.3.5 Lost to Follow-up Post Dosing 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits post dosing and is unable to be contacted by the study site. The following 
actions must be taken if a participant fails to return to the clinic for a required study visit: 
 
x The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
x Before a participant is deemed lost to follow up, the PI or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if 

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necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
study file. 
x Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
7.3.6 End of Study Definition  
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the Schedule of Assessments.  
7.3.7 Premature Study Discontinuation 
The Sponsor, FDA, IRBs, and Data Monitoring Committee have the right to discontinue this 
study at any time. If the trial is prematurely terminated, the PI is to promptly inform the study 
participants and will assure appropriate referral and follow-up. If the study is prematurely 
discontinued, all procedures and requirements pertaining to retention and storage of documents 
will be observed. All other study materials will be returned to the Sponsor and will be treated in 
accordance with federal and state regulations. 

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8 
INVESTIGATIONAL PRODUCT 
8.1 
Description of Investigational Product 
The investigational product (IP) to be used in this protocol is psilocybin, a tryptamine that 
produces its behavioral effects primarily by acting as post-synaptic agonists at serotonin 5-HT2A 
and 5-HT2C receptors (Sanders-Bush & Mayer, 2006). Refer to the IB for a comprehensive 
review of the pharmacology, effects and proposed mechanisms of action of psilocybin. 
8.2 
Description of Active Placebo 
Niacin, also known as nicotinic acid or vitamin B3, will be used as the active placebo in this 
protocol. Upon ingesting niacin, one commonly experiences a physiological reaction including 
warmth or flushing of the skin and mild dizziness.  
8.3 
Source 
Usona Institute has contracted the manufacture of cGMP psilocybin (active pharmaceutical 
ingredient), cGMP psilocybin capsules (25 mg) and cGMP niacin capsules (100 mg). 
Compendial grade (USP) niacin will be used in the preparation of the niacin active-control drug 
product.  
8.4 
 Study Drugs Administered 
Identical capsules will contain either 25 mg of psilocybin or 100 mg of niacin. Each capsule is 
provided in an HDPE bottle; bottles of study medication will be stored in the research pharmacy 
or other DEA-approved storage location of each study site. A capsule will be provided to a 
participant at the appropriate time during the dosing session. The participant will swallow the 
capsule with water. 
 
Table 7: IP and Active Placebo Information 
Study Intervention 
Name: 
Psilocybin Capsule 
(active drug product) 
Niacin Capsule 
(active placebo product) 
Dosage formulation: 
One active capsule contains 
25 mg of psilocybin 
One active placebo capsule 
contains 100 mg of niacin  
Capsule: 
Size 2 HPMC, white opaque 
Size 2 HPMC, white opaque 
Unit dose strength: 
25 mg25 mg25 mg25 mg 
100 mg100 mg100 mg100 mg 
Route of 
Administration: 
Oral (solid dose) 
Oral (solid dose) 
Dosing instructions: 
One capsule administered with 
water 
One capsule administered with 
water 
Packaging and 
Labeling: 
Study Intervention will be provided in an HDPE bottle. Each bottle 
will contain one capsule (psilocybin or niacin) and will be labeled as 
required per country requirement for blinded study. 

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8.5 
Dosing 
Participants in this study will receive one dose of either psilocybin or niacin during their dosing 
session. Participants randomized to psilocybin will receive a 25 mg of psilocybin taken with 
approximately 8 ounces of water. Participants randomized to niacin will receive 100 mg of 
niacin taken with approximately 8 ounces of water.  
8.6 
Drug Delivery, Storage, Handling, and Accountability 
1. The PI or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study medication. 
2. Only participants randomized in the study may receive study medication and only 
authorized site staff may supply or administer study medication. All study medication 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited 
to the PI and authorized site staff. 
3. The PI (or designee) is responsible for study medication accountability, 
reconciliation, and record maintenance (receipt, reconciliation, and final disposition 
records). 
4. Further guidance and information for the final disposition of unused study 
medications are provided in the Pharmacy Manual. 
 

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9 
STATISTICAL CONSIDERATIONS 
Full details of statistical analysis will be provided in the statistical analysis plan (SAP). 
9.1 
Hypotheses 
Primary Study Objective: To evaluate the impact of a single administration of psilocybin on 
depressive symptoms in patients with MDD when compared to an active niacin placebo 
 
Hypothesis 1.1 (PRIMARY STUDY HYPOTHESIS): When compared to a single administration 
of niacin placebo, a single administration of psilocybin will result in a significant reduction in 
central rater MADRS scores from Baseline to Day 43 post intervention (primary study outcome). 
 
Hypothesis 1.2: (KEY SECONDARY STUDY HYPOTHESIS) When compared to a single 
administration of niacin placebo, a single administration of psilocybin will result in a significant 
reduction in central rater MADRS scores from Baseline to Day 8 post-dose (key secondary study 
outcome). 
 
Hypothesis 1.3: When compared to a single administration of niacin placebo, a single 
administration of psilocybin will result in significantly higher rates of sustained response, defined as 
DUHGXFWLRQfrom Baseline central rater MADRS scores to Day 8, 15, 29 and 43 post-dose 
(secondary study outcome). 
 
Hypothesis 1.4: When compared to a single administration of niacin placebo, a single 
administration of psilocybin will result in significantly higher rates of sustained remission, defined 
as a central rater MADRS scores from Baseline to Day 8, 15, 29 and 43 post-dose (secondary 
study outcome). 
 
Hypothesis 1.5: When compared to a single administration of niacin placebo, a single 
administration of psilocybin will result in a significant reduction in central rater MADRS scores 
from Baseline to Day 2, Day 15 and 29 post-dose (exploratory study outcome). 
 
Hypothesis 1.6: When compared to a single administration of niacin placebo, a single 
administration of psilocybin will result in a significant reduction in SMDDS scores from Baseline to 
Day 8 and 43 post-dose (exploratory study outcome). 
 
Hypothesis 1.7: When compared to a single administration of niacin placebo, a single 
administration of psilocybin will result in a significant reduction in SMDDS scores from Day 1 
(pre-dose) to Day 8 and 43 post-dose (exploratory study outcome). 
 
Hypothesis 1.8: When compared to a single administration of niacin placebo, a single 
administration of psilocybin will result in a significant reduction in ODQ scores from Baseline to 
Day 43 post-dose (exploratory study outcome). 
 
 

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Specific Aim 2: To evaluate the impact of a single administration of psilocybin on functional 
disability in patients with MDD when compared to an active niacin placebo 
 
Hypothesis 2.1: When compared to a single administration of niacin placebo, a single 
administration of psilocybin will result in a significant reduction in SDS scores from Baseline to 
Day 43 post-intervention (secondary study outcome). 
 
Hypothesis 2.2: When compared to a single administration of niacin placebo, a single 
administration of psilocybin will result in a significant reduction in SDS scores from Baseline to 
Day 8, 15, and 29 post-dose (exploratory study outcome). 
 
Specific Aim 3: To evaluate the impact of a single administration of psilocybin on anxiety 
symptoms in patients with MDD when compared to an active niacin placebo 
 
Hypothesis 3.1: When compared to a single administration of niacin placebo, a single 
administration of psilocybin will result in a significant reduction in HAM-A scores from Baseline to 
Day 8, 15, 29 and 43 post-dose (exploratory study outcome). 
 
Specific Aim 4: To evaluate the impact of a single administration of psilocybin on quality of 
life in patients with MDD when compared to an active niacin placebo 
 
Hypothesis 4.1: When compared to a single administration of niacin placebo, a single 
administration of psilocybin will result in a significant increase in the Q-LES-Q scores from 
Baseline to Day 8, 15, 29 and 43 post-dose (exploratory study outcome). 
 
Hypothesis 4.2: When compared to a single administration of niacin placebo, a single 
administration of psilocybin will result in a significant decrease in CGI-S scores from Baseline to 
Day 8, 15, 29 and 43 post-dose (exploratory study outcome). 
 
Specific Aim 5: To examine whether the occurrence of mystical-type or emotional 
breakthrough-type experiences in response to study medications predicts subsequent 
antidepressant responses 
 
Hypothesis 5.1: Scores on MEQ-30 will be significantly higher post-dose in participants receiving a 
single administration of psilocybin than in those receiving niacin placebo (exploratory study 
outcome). 
 
Hypothesis 5.2: Scores on the EBI will be significantly higher post-dose in participants receiving a 
single administration of psilocybin than in those receiving niacin placebo (exploratory study 
outcome). 
 
Hypothesis 5.3: A significant indirect effect through post-dose MEQ-30 scores of the effect of 
treatment assignment, psilocybin compared to niacin, on change in central rater MADRS scores will 
be observed for the post-dose time point at which MADRS score differences between the psilocybin 
and niacin placebo groups are maximal (exploratory study outcome). 
 

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Hypothesis 5.4: A significant indirect effect through post-dose EBI scores of the effect of treatment 
assignment, psilocybin compared to niacin, on change in central rater MADRS scores will be 
observed for the post-dose time point at which MADRS score differences between the psilocybin 
and niacin placebo groups are maximal. (exploratory study outcome). 
 
Specific Aim 6: To examine the relationship between central-rated and computer-
administered MADRS measures of depressive symptoms 
 
Hypothesis 6.1: Good agreement will be observed when comparing central-rated and computer-
administered versions of MADRS scores at all time points (exploratory study outcome). 
9.2 
Power and Sample Size Determination 
This Phase 2 study has been powered to evaluate the clinical efficacy of psilocybin for the 
primary and key secondary objectives, i.e. to test the difference between psilocybin and niacin in 
the change in central rater MADRS score from Baseline to Day 43 and Day 8 respectively, in the 
ITT analysis set.   
 
Approximately 100 patients are planned to be randomized into this study. Section 9.2.1 provides 
rationale for assumptions used in sample size calculations and section 9.2.2 provides 
specifications of sample size calculations. 
 
9.2.1 Rationale for Sample Size Assumptions 
Table 8 presents a review of studies of psilocybin in MDD, TRD and cancer-related anxiety 
and/or depression; additional details of these studies are described in the Investigator’s Brochure. 
In addition, data currently under embargo support a psilocybin-niacin difference on the MADRS 
of 8 points and a standard deviation between 9-10 points. 
 
Because previous studies of psilocybin for depression have been designed as open label, cross-
over, or wait-list control, and some studies have included multiple dosing sessions, effect size 
estimates from these studies should be utilized with caution in informing sample size 
assumptions for this randomized, double-blind, placebo-controlled trial. Two open-label studies 
of psilocybin in MDD (Davis et al., 2020) and TRD (Carhart-Harris et al., 2016) indicated 62
to 69PHDQUHGXFWLRQLQGHSUHVVLRQV\PSWRPV 1-week following the final dosing session in the 
psilocybin arms, and this reduction was sustained at 4-5 weeks post dosing with reduction in 
depression symptoms of 57WR66 (Table 8). The two prior studies of psilocybin in cancer-
related depression and anxiety showed a similar trend with a mean reduction in depressive 
symptoms at 5 weeks post dose of 71LQWKHKLJK-dose group in Griffiths et al., 2016DQG
reduction at 6 weeks post dose in Ross et al., 2016.  
 
Based on changes over time observed in very low dose psilocybin, niacin, and delayed treatment 
groups of the previous studies, a decrease in depression symptoms from baseline to 43 days post-
dose of approximately  in the niacin active-control arm is expected. 
 

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In the Carhart-Harris et al., 2016 study, a standard deviation for 1-week change from baseline in 
MADRS score was 9.9. Other studies of esketamine for MDD have reported MADRS change 
from baseline standard deviations of 12.0 to 14.0 (FDA Ref ID 4392083). 
 
Dropout rates for time points around 6 weeks in prior studies were between 9-ZLWKWKH
H[FHSWLRQRIWKHGURSRXWLQWKHRSHQODEHO trial.    
 

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9.2.2 Sample Size Calculations 
Simulations were generated to estimate power for a primary endpoint of MADRS change from 
baseline to Day 43 and key secondary endpoint of MADRS change from baseline to Day 8 
assuming a MMRM model as specified in Section 9.4.1. 
 
Assuming a placebo group MADRS mean change from baseline = 10 at all time points, MADRS 
change from baseline SD = 10, psilocybin group MADRS mean change from baseline at Day 8 = 
18 (d = 0.8) and Day 43 = 17 (d = 0.7DQGRYHUDOOGURSRXWE\'D\DVDPSOHVL]HRI
100 participants would result in 92SRZHUIRUSULPDU\'D\HQGSRLQWDQG8SRZHUIRUWKH
key secondary Day 8 endpoint. Additional details regarding sample size calculations are 
provided in the PSIL201 Statistical Analysis Plan.  
 
Key assumptions are in alignment with what has been observed in previous psilocybin studies 
noted in Section 9.2.1.  
 
9.3 
Populations for Analyses 
Efficacy analyses of primary, secondary and exploratory outcomes will be conducted on an ITT 
population that will include all randomized participants. Participants who withdraw from the 
study for any reason after receiving a study intervention but prior to the Day 43 assessment will 
be asked to complete an exit assessment of the primary study endpoint (change in MADRS score 
from Baseline to Day 43 post-dose).  
 
Safety sets  
The following populations will be used for analysis of safety data:  
x All Enrolled Population: All participants who have signed written informed consent.  
x Safety Population: Participants who were randomized and received study product.  
x Preparation Phase Termination Population: Participants who discontinue study 
participation between the end of the Baseline assessments and up to randomization.  
 
 
ITT set 
Participants randomized to receive a study intervention (psilocybin vs. active placebo)  
 
 
Per Protocol Set 
Subset of the ITT set who received investigational product, completed post-dose Day 8 and 
Day 43 central-rater MADRS assessment, and have no major protocol deviations that may 
affect the primary or key secondary outcome measures.  
 

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9.4 
Statistical Analyses 
Descriptive statistics (proportions, means, standard deviation, quartiles) will be used to characterize 
Baseline demographic characteristics and continuous measures of behavioral response over time. 
Distributional features of all measurements will be evaluated, and data transformation (e.g., 
logarithm, rank transform) will be performed where indicated. Unless otherwise specified, all tests 
will be two-tailed with an alpha level set at p < 0.05. 
 
9.4.1 Efficacy Analyses  
The primary efficacy analysis will use a de facto estimand defined in alignment with the 
treatment policy strategy specified in ICH E9 (R1):  
x Treatment: Psilocybin vs. niacin 
x Population: All randomized subjects (ITT population) 
x Variable: Change in central rater MADRS scores from Baseline to post-dose Day 43 
x Population-level summary: Between-group difference in least squares means using 
MMRM model. 
 
In the final ITT analysis, mixed effect models for repeated measures (MMRM) with an 
unstructured covariance matrix, with Baseline questionnaire score as a covariate and site, sex, 
and TRD status as fixed effects will be employed to test primary, key secondary, and other 
continuous secondary and exploratory study endpoints. Because Baseline score is included as a 
covariate, the primary outcome of interest will be between-group differences, however a 
treatment by time effect will also be included in MMRM to evaluate between group differences 
in the slopes of mean scores. For the primary, key secondary, and other continuous secondary 
and exploratory endpoints, MMRM will test whether there is a significant group difference at 
post-dose time points (i.e. Day 8, 15, 29 and 43). Hypothesis 1.1 (primary endpoint), Hypothesis 
1.2 (key secondary endpoint), Hypotheses  and 2.1 (secondary endpoint) will be tested by a priori 
contrasts within the MMRM analysis regardless of whether the overall model is statistically 
significant. Exploratory hypotheses 1.5; 1.6; 1.7; 1.8; 2.2; 3.1; 4.1; and 4.2 will be evaluated 
similarly. For MMRM analyses, alternative covariance structures will be examined if an 
unstructured covariance matrix is found not to fit the data distribution.  
 
Chi-square or Fisher’s exact tests will be employed to test for between group differences in 
central rater MADRS-defined sustained response and remission (secondary endpoint, 
Hypotheses 1.3 and 1.4).  
 
Hypothesis 6.1 will be evaluated using a measure of agreement such as intraclass correlation. 
 
Alpha level for testing all endpoints ZLOOEHĮ 5. To mitigate the risk of alpha inflation, a 
sequential significance testing procedure will be employed, such that testing of primary, key 
secondary, and other secondary hypotheses will proceed in the following pre-specified order 
with testing being halted upon the first confirmation of the null hypothesis (Hypothesis 1.1; 1.2; 

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2.1; 1.3; 1.4). Hypotheses associated with exploratory study endpoints will be tested with no 
adjustment made to the alpha level given the pre-specified exploratory nature of these 
hypotheses.  
 
9.4.2 Mechanism-Based Exploratory Analyses 
To conduct an exploratory analysis of the impact of mystical-type and/or emotional 
breakthrough-type experiences during the dosing sessions on subsequent longer-term 
antidepressant responses (Specific Aim 5), MEQ-30 and EBI scores post-dose will be compared 
between intervention groups using a two-sample t-test, or a Wilcoxon rank-sum test if data are 
not normally distributed. As a further exploratory analysis, structural equation modeling (path 
analysis) will be used to provide estimates of the magnitude and significance of hypothesized 
causal connections between MEQ and EBI score post-dose and subsequent antidepressant 
response at the post-dose time point at which MADRS score differences between the psilocybin 
and niacin placebo groups are maximal. By representing two pre-specified causal hypotheses 
(5.3 and 5.4) within a single input path diagram, the relative sizes of path coefficients in the 
output path diagram will indicate which behavioral construct (mystical-type vs. emotional 
breakthrough-type experience) explains more of the variance in psilocybin-induced 
antidepressant effects. Path analysis will also provide insight into potential causal relationships 
between emotional breakthrough and mystical-type experiences, should such relationships exist. 
 
9.4.3 Safety Analyses 
Qualitative safety analyses will examine safety data with summary tables listing concomitant 
medications/therapies, and AEs with frequencies and percentages tabulated overall, by group, and 
by Study Period. AEs will be tabulated by body system and coded for severity. Summaries of AEs, 
TEAEs, solicited AEs by severity will be provided. SAEs will be summarized similarly. AEs 
leading to discontinuation from the study will be listed and tabulated. Safety data collected for the 
period from Screening through the Baseline assessment and during the Preparation Phase will be 
presented separately from post-dose safety data. Laboratory values, physical examination finding 
and vital signs collected at study visits and vital signs collected during study dosing sessions will 
be summarized for all scheduled timepoints. Solicited AEs observed in randomized participants 
ZKRUHFHLYHGSVLORF\ELQZLWKDQLQFLGHQFHRIRUJUHDWHUDQGDWOHDVWWZLFHWKDWRIQLDFLQSODFHER 
will be reported separately. AEs will be categorized according to Council for International 
Organizations of Medical Sciences (CIOMS) parameters, as follows:  
 
x Very common:  
x Common (frequent): 1/100 and <1/10 
x Uncommon (infrequent): 000 and <1/1000 
x Very rare: <1/10000 
 
When possible, statistical analyses will be used to evaluate selected safety outcomes by intervention 
group, as well as by relevant demographic characteristics (e.g., age, gender, ethnicity, severity of 
depressive symptomatology, and need for pre-intervention medication tapering). 
 

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9.4.4 Interim Analyses  
No formal interim analyses are planned for this study. Accumulating data will be reviewed by the 
DSMB as specified in the PSIL201 DSMB Charter.  
 

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10 
SAFETY MANAGEMENT 
Below are the risks associated with participation in this study as well as the risk mitigation 
strategy associated with each risk. Safety measures will be applied, as described below, to 
minimize risks associated with participation in this study. This study proposes a combination of 
careful screening, preparation, supervision, and follow-up designed to minimize any risks. 
 
Presented below are several domains that relate to adverse effects of psilocybin administration, 
which are further detailed in the IB. Following the section on psilocybin, the risks associated 
with the non-drug aspects of the study are described. Participation in this study may include risks 
that are currently unknown.  
10.1 Risks Associated with Psilocybin  
10.1.1 Physiological and Psychological Adverse Effects  
The clinical safety of psilocybin has been extensively studied, both as a single agent and as 
adjunctive treatment in adult populations. Psilocybin is administered orally, and has been studied 
in open-label, and double-blind, controlled trials. Dosing regimens have ranged from 0.014 
mg/kg to 0.6 mg/kg, administered as either a single dose, or multiple doses weeks apart.  
 
Adverse event data from previous clinical trials has been used to evaluate the physiological 
profile of psilocybin. The IB for psilocybin summarizes the adverse event data collected from 
controlled clinical trials utilizing psilocybin in conjunction with cognitive enhancement therapy 
across multiple subpopulations. 
 
The most likely potential acute adverse effects of psilocybin were shown to be anxiety, as well as 
panic, delusion, and cognitive impairments, particularly at higher doses (> 25 mg oral psilocybin) 
during the period of acute drug action. Such transient episodes of fear or anxiety respond well to 
reassurance and have not required pharmacological intervention. In previous clinical experience, 
acute psychological events were resolved by the end of the dosing day.  
 
Overall, the most commonly reported physiological adverse events associated with psilocybin 
are: 
x cardiovascular changes (including increased blood pressure and heart rate) 
x nausea 
x headache  
 
These adverse events were generally classified as mild to moderate and were found to be 
transient in nature. No psilocybin-related serious adverse events were reported. 
 
For this study, vital signs, including blood pressure and heart rate, are monitored frequently 
before, during and following the dosing session, as outlined in the MoP. Medications for 
cardiovascular emergencies are outlined in Section 6.3.2. Section 11.1.3 provides further details 
of AE reporting for blood pressure, heart rate, nausea, and headache.  
 
 

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10.1.2 Visual Perceptual Effects 
Some people who have used serotonergic hallucinogens, such as psilocybin, experience 
persistent, distressing alterations in mostly visual perception that last from weeks to years after 
use (Espiard, Lecardeur, Abadie, Halbecq, & Dollfus, 2005) This condition is now diagnosed as 
hallucinogen persistent perception disorder (HPPD). To date, however, no cases of HPPD have 
occurred in volunteers given psilocybin in contemporary research studies (Studerus et al., 2011). 
The risk of HPPD occurring after psilocybin administration can be reduced by screening 
participants for potential risk factors such as substance dependence and by excluding people 
reporting HPPD or other significant adverse events after prior use of hallucinogens.  
 
Visual perceptual effects will be assessed as a solicited AE during Periods 3 and 4.  
10.1.3 Drug Interactions 
See Appendix A for a list of prohibited medications. Additional information is provided in the 
IB. 
10.1.4 Pregnancy   
There have been no human case reports or studies involving the effects of psilocybin on 
pregnancy. It is recommended that women who are pregnant avoid using psilocybin. See Section 
15 for pregnancy testing and results requirements.  
10.2 Risk of Worsening MDD 
An exacerbation of depressive symptoms including increased suicidal ideation could occur prior 
to or during the study. Participants in the study will be foregoing established treatments for 
depression while they are enrolled in the study. This risk of having a depressive exacerbation 
may be greater for participants in the niacin placebo group, as they will undergo a longer period 
of time without receiving a known active treatment. Although placebo interventions often have 
significant therapeutic benefits in patients with MDD, participants who receive niacin placebo 
may be at increased risk for worsening of depressive symptoms or development of active suicidal 
ideation with plan during the course of the study.  
 
Study clinicians at each site will assume the role of mental health provider when a participant 
enrolls in the study through the final primary outcome time-point at post-dose Day 43. 
Monitoring for suicidality will be ongoing (Section 11.1.3). Study team members will inform a 
study clinician of any substantial worsening of depression or suicidality, or of any other concerns 
regarding a participant’s health. Study clinicians will then assess the health and safety of this 
participant. If a study clinician decides that an antidepressant medication is warranted, or if the 
participant desires conventional treatment during or after the study, the study clinician will 
develop an appropriate treatment plan including referring the participant to an outpatient 
provider or to the clinician treating the participant prior to study entry.  

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10.3 Risks Associated with Collection of Potentially Sensitive Information 
Sensitive information may be revealed during the screening process and/or during the course of 
the study. Identification of disease may occur during the screening process and may impact 
future insurability of the participant. In addition, some diagnoses can create stigmatization or 
self-stigmatization for the participant. Both the PI and participants may be at risk for a violation 
of privacy and/or loss of confidentiality. This risk will increase as the study progresses as 
ongoing health information will be collected.  
 
Best practices will be followed at all stages of the study to ensure maximum protection in the 
collection, storage and usage of potentially sensitive information. All collected data will be 
stored on a secure electronic database coded by a study ID number and stored separately from 
any documents with personally identifiable information and/or a key that would link such 
information to study data. All research staff will complete human subjects training (per 
institutional requirements) to promote the proper conduct of scientific research in humans. 
Additionally, each study site will obtain a Certificate of Confidentiality (CoC) (Section 13.11). 
10.3.1 Genetic Testing 
The risks of collecting DNA samples and conducting genetic tests include: 
x 
Personal stigmatization, discrimination or labeling if it is found that the individual has a 
form of a gene linked to a particular condition or trait 
x 
Potential loss of or difficulty in obtaining employment or insurance either because of 
what the test results show with respect to the genetics of the tested individual or the 
genetics of an identified group with which the individual is associated because of a 
medical condition, ethnicity or social standing 
x 
Group stigmatization, discrimination or labeling resulting from genetic inferences 
associated with certain medical conditions or certain ethnic or social groups 
These risks will be reduced in this study by: 
x Not disclosing results to participants 
x De-identifying samples before genetic tests are conducted 
x Limiting the number of individuals who have access to identifiable results 
x Only retaining samples from participants that are randomized 
10.4 Risks Associated with Psychiatric Questionnaires 
The study psychiatric assessments may uncover strong and potentially disturbing feelings about 
the participant’s past or present emotional state. While it is expected the risk for SAEs resulting 
from psychiatric assessments is very low, the likelihood of these risks occurring will be 
minimized by procedures described below. 
 
Care will be taken to avoid bringing about undue psychological distress during the psychiatric 
interviews. This will be accomplished by using trained central and site raters and by collecting 
the “minimum necessary” information required for study purposes. In the event that a participant 

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becomes unduly distressed, a study clinician will be immediately contacted, and an appropriate 
clinical intervention plan will be developed. 
10.5 Risks Associated with Venipuncture 
The risks of drawing blood include discomfort, bruising, infection, bleeding and fainting. The 
amount of blood drawn during the study (approximately 20 mls) will not have any adverse 
physiological effects, nor will it lead to any long-term distress. Risks for blood borne pathogens 
from accidental needle stick and during sample processing exist. Not uncommonly a bruise may 
form at the puncture site.  
 
To reduce risk of infection and bleeding standard sterile procedures for drawing blood will be 
used by certified personnel with extensive phlebotomy experience. To reduce the risk of fainting 
all participants will be asked about tendency to faint prior to venipuncture and will be placed in a 
recumbent position if they answer in the affirmative. 
 
10.6 Contacting Emergency Services 
Generally, if at any time during the study, including during your dosing session, study staff feel a 
participant is in danger of hurting him/herself or someone else then the study physician, PI 
and/or Lead Facilitator will be contacted immediately for further evaluation and follow up. In 
certain circumstances 911 may be called or the participant may be taken to the emergency room, 
including the following: 
x 
If at any time during the study physician, PI and/or Lead Facilitator feels your situation is 
an emergency that requires immediate attention they will call 911 or the participant will 
be taken to the emergency room.   
x 
If the participant becomes violent or aggressive during the dosing session and he/she does 
not respond to medications or calming by your session Facilitators, then the study 
physician, PI and/or Lead Facilitator may call 911, or the participant may be escorted to 
the emergency room.  
x 
If the participant insists on leaving the research site before the dosing session is complete 
(they must remain on site for a minimum of 7 hours) and the study physician, PI and/or 
Lead Facilitator feels he/she is a threat to him/herself or others then they will call 911. 
x 
If the study participant insists on leaving the research site before the dosing session is 
complete and the study physician, PI and/or Lead Facilitator do not feel he/she a threat to 
him/herself or others then they will call the support person previously identified to take 
the participant home.   
If the study physician, PI and/or Lead Facilitator feels the participant may have a serious, but not 
urgent, psychiatric condition then he/she will be referred to his/her previously identified mental 
health provider, if one was identified, or to mental health services in the community. 

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10.7 Data and Safety Monitoring Board (DSMB) 
A DSMB will oversee the safety monitoring for this study and will be comprised of experienced 
members with expertise required for overseeing the study. The DSMB will review protocol-
specific reports, which will include an overview of the study objectives, actual and projected 
accrual, evaluation of patient demographics, and a summary of the number and seriousness of 
AEs. Cumulative reports of serious AEs requiring expedited reporting and any new serious AEs 
will also be reviewed per the DSMB plan. See the Study PSIL201 DSMB Charter for full details.  
10.8 Abuse Liability 
Like other psychoactive drugs, psilocybin is sometimes used in a manner that jeopardizes the 
safety or well-being of the individual or others (e.g., driving while impaired; a pattern of use that 
interferes with work, school, or relationships). Under such circumstances, psilocybin would be 
said to be abused. However, psychedelic medicines such as psilocybin are not typically 
considered drugs of dependence in that they do not engender compulsive drug seeking behavior 
(Johnson, Griffiths, Hendricks, & Henningfield, 2018; O'Brien, 2011), consistent with the 
observation that they are not reliably self-administered in nonhuman animals (Fantegrossi, 
Woods, & Winger, 2004; R.R. Griffiths, 1980; Poling & Bryceland, 1979). Further, they are not 
associated with a known withdrawal syndrome (O'Brien, 2011). Therefore, there is little risk that 
exposing human volunteers to psilocybin will leave participants physically or psychologically 
dependent on the compounds. In previous (R. R. Griffiths et al., 2011; R. R. Griffiths et al., 
2006) and ongoing studies with psilocybin, exposing individuals with either no history of 
hallucinogen use or a history of minimal use (e.g., less than 10 times total and not within the last 
5 years) in the context of a supervised and controlled research setting has not resulted in reported 
instances of subsequent illicit hallucinogen abuse. In the meta-analysis conducted by Studerus 
and colleagues (Studerus, Kometer, Hasler, & Vollenweider, 2011), the large majority of 
SDUWLFLSDQWVLQSVLORF\ELQVWXGLHVDSSUR[LPDWHO\UHSRUWHG³QRFKDQJH´LQWKHLUSVLORF\ELQ
use following their laboratory sessions, as well as “no change” in their overall drug consumption 
habits (e.g., use of alcohol, nicotine, cannabis, MDMA). Those who did report changes often 
described decreased consumption (see Table 5 in Studerus et al., 2011). Specifically, in terms of 
psilocybin use, more participants reported using it less RIWHQDIWHUWKHLUODERUDWRU\VHVVLRQV
RIDOOSDUWLFLSDQWVWKDQPRUHRIWHQRIDOOSDUWLFLSDQWV 
10.8.1 Abuse Monitoring  
Based on current information, it does not appear that psilocybin demonstrates signals associated 
with known abuse liability patterns when administered in a therapeutic setting under continuous 
observation in a single-dose session, for which further evidence will be collected in this study. 
Any abuse potential is further limited since the drug is not supplied to the participant to take 
home and is administered under careful clinical supervision in a restrictive setting. All clinical 
sites will comply with local and national requirements pertaining to clinical research with 
controlled substances. Each PI responsible for dispensation or administration of the 
investigational product will maintain current registration with authorities with oversight of 
controlled substances. Participants will never have the study drug in their possession or have 
access to it outside the closely supervised clinical setting, which removes the possibility of drug 
diversion (e.g., missing medication, loss of drug) or unrecognized non-compliance with 

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medication ingestion. While there is still a possibility of site drug diversion, this risk is mitigated 
through Drug Accountability process, documentation and monitoring. See Section 8.6 Drug 
Deliver, Storage, Handling, and Accountability. 
  
A CoC will be obtained to encourage study participants to be honest regarding addictive 
behaviors post-dosing. The following measures will be employed to monitor the abuse liability 
of psilocybin: 
x Cases of noncompliance, protocol violations, participants lost to follow-up, and any other 
reasons why participants dropped out of the study will be assessed for signals of abuse 
x Qualitative urine drug test data will be collected at Screening, Baseline and all post-dose 
assessments. Any positive findings that cannot be attributed to pre-approved concomitant 
medications or diet will be reviewed by the site medical clinician for evaluation and 
management.  
x Prior lifetime illicit and non-prescription drug use will be collected at Screening via the 
Drug History Questionnaire and reassessed by self-report from Baseline to 
Randomization. Self-reported behaviors of alcohol and illicit and non-prescribed drug use 
will be collected via the AUDIT, DUDIT and SCID-CT at Baseline and Day 43/ End of 
Study, the Timeline Follow-Back will be used at Day 43/ End of Study to assess drug and 
alcohol use since dosing to characterize any illicit drug or alcohol use, including 
psilocybin, during that period. Additionally, urine drug screens, as described above, will 
be used to identify drug use during the study period. Behaviors will be compared before 
and after intervention in exploratory analyses. These measures will be used to provide 
objective data to assess the impact of single-dose psilocybin on addictive behaviors, not 
just in relation to non-study psilocybin use but also in relation to other addictive 
substances/behaviors. 
x Drug overdose with suicidal intent will be captured as a solicited AE.  
x Terms related to abuse liability appearing the MedDRA Preferred Terms will used to be 
classify abuse liability AEs as specified in Section 11.1.1. 
Additional detail regarding AE reporting related to substance or alcohol use is described in 
Section 11.  

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11 
ADVERSE EVENTS 
11.1 Definitions 
11.1.1 Adverse Event 
An AE is any untoward medical occurrence in a research participant, whether or not considered 
drug related which occurs during the conduct of a clinical trial. Any change in clinical status, 
ECGs, routine labs, x-rays, physical examinations, etc., that is considered clinically significant 
by the PI is considered an AE.  
 
Blood pressure (BP) and heart rate (HR) must meet one of the following criteria to be considered 
an AE for the purposes of this study: 
 
x Systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg 
on three separate readings and requiring medication 
x Clinically significant decrease in BP requiring medication 
x Heart rate (HR) >100 beats per minute (BPM) and requiring medication 
x Clinically significant decrease in HR requiring medication  
 
The AE terms listed below are MedDRA Preferred Terms to be used in classifying abuse liability 
AEs when deemed appropriate by the PI (or designee): 
x Euphoria-related terms: euphoric mood, elevated mood, feeling abnormal, feeling drunk, 
feeling of relaxation, dizziness, thinking abnormal, hallucination, inappropriate affect 
x Terms of impaired attention, cognition, and mood: somnolence, mood disorders, and 
disturbances 
x Dissociative/psychotic terms: pychosis, aggression, confusion, and disorientation 
 
Evidence of substance or alcohol abuse, whether captured via one of the assessments in Section 
10.8.1 or via unsolicited self-report, will be reported as an AE only if it meets SAE criteria. 
Solicited AEs related to drug overdose are described in Section 11.1.3.  
11.1.2 Treatment Emergent Adverse Events 
Treatment emergent adverse events are undesirable events not present prior to medical treatment, 
or an already present event that worsens either in intensity or frequency following the treatment. 
Events with an onset after study drug administration will be considered TEAEs. 
11.1.3 Solicited Safety Events 
The following solicited AEs will be collected: 
 
 
Visual perceptual effects (Periods 3-4) will be solicited by asking the following questions: 1) 
Since your dosing session have you experienced any uncontrolled or disturbing return of study 
drug effects?, and 2) Since your dosing session have you experienced any visual distortions (e.g. 
geometric hallucinations, false perceptions of movement in the peripheral visual fields, flashes of 
color, intensified color, trails for images of moving objects, positive after-images, halos around 

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objects)?  If a participant reports “Yes” to any of the above questions a study psychologist or 
psychiatrist will follow up for further assessment/diagnosis.  
 
Additional solicited AEs include: 
 
x Active suicidal ideation identified through the C-SSRS and/or MADRS and verified 
by clinical assessment. (recorded for Periods 1-4; would result in screen failure or 
early termination in Periods 1-2) 
x Headache (Period 3); and  
x Nausea (Period 3); and 
x Elevated blood pressure (BP) as defined by systolic blood pressure (SBP) >140 
mmHg or diastolic blood pressure (DBP) >90 mmHg on three separate readings and 
requiring medication (recorded for Periods 1-4; may result in screen failure or early 
termination in Periods 1-2); and  
x Elevated heart rate (HR) as defined as >100 beats per minute (BPM) and requiring 
medication (recorded for Periods 1-4; may result in screen failure or early termination 
in Periods 1-2); and 
x Drug overdose with suicidal intent (recorded for Periods 1-4; would result in screen 
failure or early termination in Periods 1-2).  
 
Monitoring for suicidality will be ongoing throughout the duration of the study using the C-
SSRS and MADRS. All participants who meet criteria specified in Section 2.13.7 and Section 
2.12.1 will undergo further clinical evaluation.  If at any time during an evaluation or follow up 
there is concern a participant is suicidal study staff will follow their institutional standard of care 
procedures for managing suicidality. General guidelines will also be provided in the MoP, which 
sites can utilize. 
 
To assess for headache after psilocybin administration, participants will be asked if they have or 
experienced a headache during Period 3, and these will be classified as a migraine, tension 
headache, or other headache. On the dosing day, participants reporting headache will be 
encouraged to take non-steroidal anti-inflammatory agents or acetaminophen at home, if needed. 
 
Visual perceptual effects, suicidal ideation verified by clinical assessment, headache, nausea, and 
overdose with suicidal intent will be reported through normal AE/SAE mechanisms.  
11.1.4 Unsolicited Adverse Events 
Any other observed and participant reported AEs and SAEs will be recorded for all study periods 
(Periods 1-4), following written informed consent. SAEs will be reported per FDA guidelines. 
11.1.5 Suspected Adverse Reaction 
Suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. A reasonable possibility implies that there is evidence that the drug caused the 
event. 

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11.1.6 Adverse Reaction 
Adverse reaction is any AE caused by the drug. A Serious Adverse Event that is deemed to be 
caused by the drug is considered a Serious Adverse Reaction. 
11.1.7 Serious Events (Serious Adverse Events, Serious Suspected Adverse Reactions 
or Serious Adverse Reactions)  
An SAE or serious suspected adverse reaction or serious adverse reaction as determined by the 
PI or the Sponsor is any event that results in any of the following outcomes: 
 
1. Death 
2. Life-threatening AE (Life-threatening means that the study participant was, in the 
opinion of the PI or Sponsor, at immediate risk of death from the reaction as it 
occurred.)  
3. Inpatient hospitalization or prolongation of existing hospitalization  
4. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5. Congenital abnormality or birth defect 
6. Important medical event that may not result in one of the above outcomes but may 
jeopardize the health of the study participant or require medical or surgical intervention 
to prevent one of the outcomes listed in the above definition of serious event.  
11.1.8 Unexpected Adverse Event 
Any AE, the specificity or severity of which has not been previously observed.  
Observed/expected adverse events are those described in the IB.  The determination of 
expectedness will be made by the Medical Monitor. 
11.1.9 Suspected Unexpected Serious Adverse Reaction 
Unexpected adverse reactions are considered suspected unexpected serious adverse reactions if the 
following three conditions are met: 
1. The event must be serious (see Section 11.1.7); 
2. There must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of the 
administered dose; and 
3. The adverse reaction must be unexpected (see Section 11.1.8) 
11.1.10  Definition of Terms 
Life threatening: A life threatening AE is defined as an event in which the participant is at risk of 
death at the time of the event. It does not refer to an event that hypothetically might have caused 
death if it was more severe.  
 
Disability: A disabling AE is defined as a substantial disruption of a person’s ability to conduct 
normal life functions. 

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Important Medical Event: Examples of such events include invasive or malignant cancers, 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
11.2 Guidelines for Assessing Intensity of an Adverse Event 
The PI should use the following definitions when assessing Intensity of an AE: 
 
x MILD:   
Participant is aware of symptoms or has minor findings, but tolerates 
them well and no or minimal intervention required 
x MODERATE:  Participant experiences enough symptoms or findings to require 
intervention  
x SEVERE:   
Participant experiences symptoms or findings that require significant 
intervention 
11.3 Guidelines for Determining Causality of an Adverse Event 
The PI and Medical Monitor will use the following question when assessing causality of an AE 
due to the study drug or as a result of study participation:  Is there a reasonable possibility that 
the study drug or procedure caused the event? 
 
A reasonable possibility implies there is evidence that the specific event was caused by the study 
drug or as a result of participation in the study. An affirmative answer designates the event as a 
suspected adverse reaction, and the AE is therefore considered “related.” If the answer is no, then 
the AE is considered “unrelated.”  
11.4 Actions to be Undertaken 
The PI is responsible for the appropriate medical management of all AEs and for the personal 
safety and well-being of participants. In case of an AE, the PI will initiate appropriate treatment 
according to his/her medical judgment and will decide whether to withdraw the participant from 
the study. 
11.5 AE Collection Period and Follow up 
All AEs and SAEs will be monitored continuously during the study from the time of signing the 
ICF until the Day 43/ End of Study. SAEs will be followed until resolution, including post Day 
43/ End of Study if warranted. 
11.6 Medical Dictionary for Regulatory Activities (MedDRA) 
AEs will be coded according to MedDRA, a clinically validated, standardized international 
medical terminology dictionary developed by the International Council for Harmonisation (ICH) 
of Technical Requirements for Registration of Pharmaceuticals for Human Use.  

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11.7 Site AE Reporting Procedures 
Regardless of severity or relationship to the investigational product, all AEs occurring during the 
study must be recorded on the AE Case Report Form (CRF) set in the EDC. 
 
x Description (medical diagnosis, if possible) 
x Date of onset and resolution (if known when reported) 
x Severity 
x Assessment of relatedness to test article 
x Action taken 
x Outcome 
 
If all information is not known at the time of initial reporting, an initial report should still be 
made. In the event there is a question as to whether the experience is serious, the information 
should be forwarded to the Medical Monitor for review. The PI is responsible for following up 
on completion of the SAE Form. 
 
All serious events will be recorded on the SAE CRF set in the EDC data system within 24 hours 
of identification. If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper SAE data collection forms and electronically transfer (for example email) the 
information into the Study Coordinating Center and Medical Monitor. The site will enter the 
SAE data into EDC as soon as it becomes available. 
 
The PI will conduct supplemental measurements and/or evaluations as medically indicated or as 
requested by the Medical Monitor or the Sponsor to elucidate the nature and/or causality of the 
AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 
If a participant dies during participation in the study or during a recognized follow-up period, the 
PI will provide the Medical Monitor with a copy of a death certificate and any post-mortem 
findings.  
 
New or updated information relevant to an AE or potential SAE will be recorded in the originally 
completed CRF and updated within 24 hours of the PI being aware of the new information. 
 
Any serious event entered into the EDC will generate an automatic email notification to the site 
staff entering the data, Study Coordinating Center, Medical Monitor and the Sponsor.  
 
The Medical Monitor will review all SAEs at the time they are reported and will determine whether 
the SAE must be reported to FDA/regulatory authorities on an expedited basis. 
11.8 Regulatory Reporting  
Any event that requires expedited reporting based on federal regulations will be communicated 
to the IND Sponsor. The IND Sponsor or its representative will submit expedited safety reports 
(e.g. IND safety reports) to the regulatory agencies as necessary. Events that are serious, related 
and unexpected and result in death or a life-threatening event will be reported within 7 days, with 

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a follow-up report within 15 days. All other serious, related and unexpected events will be 
reported in 15 days to the regulatory authorities. The Sponsor will inform the PI of such 
regulatory reports (Investigator Safety Report). The site PI must submit safety reports as required 
by their IRB. Documentation of the submission and receipt by the IRB must be retained for each 
expedited safety report. 
 
All serious events irrespective of their designation as “related” or “not related” to study product(s) 
will be reported to the FDA at least annually in a summary format in the IND Annual Report. 
11.9 Reporting of Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE. A confirmed pregnancy in a participant (by 
urine or blood test) should be reported in the data system within 24 hrs of the PI being aware of 
the pregnancy.  
The pregnancy should be followed until an outcome is known. (i.e., spontaneous miscarriage, 
elective termination, normal birth). All live births must be followed for a minimum of 30 days or 
to the first well-baby visit. All reports of congenital abnormalities/birth defects and spontaneous 
abortions/miscarriages should be reported as an SAE for this study. Elective abortion procedures, 
without complications, will not be considered as AEs, but will be captured on a pregnancy 
outcome form. 

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12 
STUDY MONITORING, AUDITING AND DOCUMENTATION 
The PI and the study team will be trained prior to the start of the study. The study sites will be 
monitored on site and remotely by monitors with the SCC. The site will be monitored as 
appropriate for the rate of enrollment in order to comply with GCP guidelines and to ensure 
validity of the study data. During each monitoring visit, consent forms will be reviewed, and 
source data verification will be performed to ensure compliance, including accurate and 
complete recording of data on CRFs, Source Records, and drug accountability records. A CRF 
collation supplied by the SCC will be completed for each participant randomized.  
 
During or after the study, the regulatory authorities, the IRB, and/or representatives of the 
Sponsor may request access to all source documents, CRFs, and other protocol documentation 
for on-site audit or inspection. 
 
All activities and responsibilities related to monitoring will be outlined in the study Monitoring 
Plan. 

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13 
HUMAN SUBJECTS PROTECTIONS 
13.1 Study Conduct 
This study will be conducted in accordance with the protocol and with the following: 
x Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
x Applicable ICH GCP Guidelines 
x Applicable laws and regulations 
x The protocol, protocol amendments, ICFs, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the PI and reviewed and approved 
by the IRB/IEC before the study is initiated.  
x Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
13.2 Principal Investigator Responsibilities 
The PI will be responsible for the following: 
x Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
x Notifying the IRB/IEC of SAEs, Unanticipated Problems or other significant safety 
findings as required by IRB/IEC procedures 
x Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, and all other applicable local regulations 
13.3 Human Subjects Training 
All study staff, to include any individual interacting with a participant or who has access to 
participant data, will be required to complete mandatory human subjects training per local 
institutional requirements prior to interacting with study participants.  
13.4 Financial Disclosure 
PIs, co-investigators and sub-investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. PIs, co-
investigators and sub-investigators are responsible for providing information on financial 
interests during the course of the study and for 1 year after completion of the study. The purpose 
of obtaining Financial Disclosure information is to minimize potential for bias.  

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13.5 Voluntary Participation 
Participants will be informed, via the ICFs and the consent process, that participation is 
voluntary, that refusal to participate will involve no penalty or loss of benefits to which the 
participant would otherwise be entitled, and that the participant may discontinue participation at 
any time. 
13.6 
Benefits of Participation 
There is no guarantee participants will receive a direct benefit from participating in this study.  
Study participation will include receiving a psychiatric and medical evaluation, including 
standard blood and urine-based safety laboratory tests. In addition, eligible participants will have 
DFKDQFHRIUHFHLYLQJDQLQWHUYHQWLRQSVLORF\ELQWKDWKDV been reported in past studies to 
provide benefit for the treatment of symptoms. In addition, many individuals’ depressive 
symptoms improve with placebo treatment. 
 
Participants will have the chance to contribute to a scientific investigation, which may be of 
benefit to future patients, and may provide a sense of personal satisfaction in this regard. 
Benefits to others may include gaining significant knowledge regarding the potential utility of 
psilocybin for patients with MDD. 
13.7 
Alternatives to Participation 
Potential participants may choose not to participate in this study. Individuals suffering with 
major depressive disorder (MDD), even when treatment resistant, have at their potential disposal 
a wide range of treatments and/or procedures that are viable alternatives to participation in the 
current study. These alternatives include: 
 
x Pharmacologic treatments – a wide range of psychotropic medications have been studied 
for the treatment of MDD  
x Somatic treatments - a variety of somatic treatments for MDD exist with various levels of 
evidence of efficacy and/or side effect profiles including ECT, repetitive transcranial 
magnetic stimulation (rTMS) and vagal nerve stimulation (VNS) 
x Psychotherapeutic interventions - examples of psychotherapeutic interventions for which 
data are available include cognitive behavioral therapy, interpersonal psychotherapy and 
various forms of behavioral activation therapy 
x Miscellaneous interventions - a wide range of behavioral and non-traditional 
interventions are in use for the treatment of depression including aerobic and strength-
building exercise, meditation, acupuncture, yoga and massage 
13.8 Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. See Section 7 for Premature Study 
Discontinuation procedures. 
 

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Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed.  
 
The PI may initiate study-site closure at any time, provided reasonable cause and sufficient 
notice is given in advance of the intended termination. 
 
Reasons for the early closure of a study site by the Sponsor or PI may include but are not limited 
to: 
x Failure of the PI to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, the Sponsor's procedures, or GCP guidelines 
x Inadequate participant recruitment  
x Discontinuation of further study intervention development 
13.9 
Vulnerable Populations 
Prisoners, pregnant women and mentally impaired persons or any other individuals considered a 
Vulnerable Population will not be enrolled in this study.  
13.10 ClinicalTrials.gov Registration 
This study will be registered with ClinicalTrials.gov according to Section 801 of the Food and 
Drug Administration Amendments Act (FDAAA 801) regulations, which requires Applicable 
Clinical Trials to be registered within 21 days of enrollment of the first participant. In addition, 
the International Committee of Medical Journal Editors (ICMJE) and other journals require 
registration of clinical trials prior to enrollment of the first participant.  
13.11 Certificate of Confidentiality 
To further ensure the protection of participant data, upon IRB approval the PI at each study site 
will apply for a CoC through the FDA. With this CoC, the researchers cannot be forced to 
disclose information that may identify research participants, even by a court subpoena, in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings. The CoC 
cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of federally funded projects or for information 
that must be disclosed in order to meet the requirements of the FDA. The CoC does not prevent 
the researchers from disclosing voluntarily, without a participant’s consent, information that 
would identify them as a participant in the research project under the following circumstances: 
intent to hurt themselves or others. If this situation is an emergency, study personnel will call 
911. In this situation, identifying information might be released to the appropriate authorities. 
13.12 Cost to Participants 
Aside from travel to and from the study site, there will be no costs to research participants for 
participating in this research study. As part of their study participation, study participants will 
receive study visits with labs/assessments, including medical and psychiatric screening, 

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preparatory sessions prior to dosing, dosing with psilocybin or active placebo, and integration 
sessions following dosing at no cost.  
13.13 Participant Compensation 
Table 9 provides an itemized list of payment for study participation. Compensation will be 
prorated based on the extent of participation completed.  
 
Table 9: Participant Compensation 
 
Activity 
Compensation 
Screening and Re-Screening: Informed Consent ($15); 
remaining Screening activities ($35) 
$50 
Baseline assessment  
$25 
Preparation Sessions 
$50 
Dosing session 
$100 
Days 8, 15, 29 and 43 assessments ($50 each) 
$200 
TOTAL COMPENSATION 
$425 
13.14 Treatment/ Compensation for Study Related Injury 
The Sponsor will cover reasonable costs of treating a study-related injury if such costs are not 
covered by a participant’s health insurance; Sponsor will not be responsible for such costs when 
injury is due to (a) negligence, recklessness or willful misconduct of Study site or investigators 
or site personnel or their failure to follow Protocol, applicable law or Sponsor instructions; (b) 
subject’s non-compliance with Protocol requirements; or (c) natural disease progression or pre-
existing disease. Some study-related injuries can be treated by the study physician, as described 
in Section 6.3.2.  
13.15 Protocol Deviations and Violations 
All protocol violations and deviations must be addressed in study source and electronic 
documents, reported to the Sponsor, and must be sent to the site IRB per their guidelines. The 
site PI/study staff is responsible for knowing and adhering to their IRB requirements. Further 
details about the handling of protocol deviations will be included in the MoP.  
 
13.16 Record Retention 
The PI must retain all study records required by the Sponsor and applicable ICH-GCP and FDA 
regulations in a secure and safe facility. The PI must consult a representative of the Sponsor 
before disposal of any study records. Essential documents are defined as documents that 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced. These documents will be filed according to ICH-GCP regulations in the Investigator 
Site File (ISF). All records must be retained until at least 2 years after the date a marketing 
application is approved by FDA for the drug for the indication for which is it has been 
investigated or for 2 years after development of the drug is discontinued and the FDA is notified. 

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It is the responsibility of the Sponsor to inform the PI or institution as to when these documents 
no longer need to be retained.  
13.17 Publication Policy 
The Sponsor recognizes the importance of communicating medical study data and therefore 
encourages publications in reputable scientific journals and presentations at seminars or 
conferences. It is understood by the PI that the information generated in this study will be used 
by the Sponsor in connection with the development of the investigational product and therefore 
may be disclosed to government agencies in various countries. To allow for the use of 
information derived from the study, it is understood that the PI is obliged to provide the Sponsor 
with complete test results, all study data, and access to all study records. It is mandatory that all 
data analysis is done on the official monitored Sponsor database and that the analysis plan is 
agreed upon with the Sponsor statistician. 
 
Any results of medical investigations with the Sponsor products and/or publication/lecture/ 
manuscripts based thereon, shall be exchanged and discussed by the PI and the Sponsor clinical 
research representative(s) prior to submission for publication or presentation. Due regard shall be 
given to the Sponsor's legitimate interests, e.g., manuscript authorship, obtaining optimal patient 
protection, coordinating and maintaining submissions to health authorities, and coordinating with 
other ongoing studies in the same field. 
 
x The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the PI agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments.  
 
x The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating PI will be designated by mutual agreement. 
 
x Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements. 
 

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Advantage eClinical is 21 CFR part 11 compliant.  
14.3 
Rebar 
Rebar will develop the website using Rebar Recruit, a proprietary platform which enables 
efficient and secure digital patient engagement and recruitment. Data security is ensured by 
encrypting data in transit and at rest, limiting data access to authenticated users (and only to the 
extent necessary to complete tasks associated with a study), and employing additional software 
and physical safeguards. Rebar’s approach to digital patient recruitment has been honed through 
years of crafting, implementing, and optimizing digital patient recruitment campaigns across a 
variety of indications and geographic regions. Rebar will develop content that complements the 
website design and is tailored to the needs of the study team and patient populations, while 
adhering to regulatory and legal constraints.  
14.4 
Signant Health (formerly Bracket Global)  
The Signant Health platform, which includes the device that the sites and central raters will use, 
along with the servers and other databases, is 21 CFR part 11 compliant. Signant Health also has 
a Privacy Shield certification.  
 
The computer-administered MADRS interview will involve a series of probe and follow up 
questions with multiple-choice response options. Each participant will respond to the computer 
prompts presented. The software places an unalterable time and date stamp on each report which 
cannot be modified, and the user’s access to the study device is restricted to the participant-user 
interface. The study assigned participant ID is the only identifying information that is stored in 
the study device. The computer administered MADRS and other electronic outcome assessments 
(eCOA) completed on the study device will be encrypted and securely transferred to the central 
eCOA vendor, Signant Health. Study sites will have access to electronic records documenting 
the participant’s computer-administered interview and other eCOA completed on the study 
device. 
 

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15 CORONAVIRUS DISEASE 2019 (COVID-19) MITIGATION 
In recognition of the Coronavirus Disease 2019 (COVID-19) pandemic and in response to the 
FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Public 
Health Emergency, several measures have been implemented to mitigate the effect of COVID-19 
on participant safety and trial integrity (see MoP for full details). Additionally, requirements for 
in-person study visits have been relaxed such that certain study assessments are allowed to be 
conducted remotely to minimize the length of the in-clinic visit and minimize physical contact 
between participants and clinic staff (see Table 1). The Sponsor and sites will continue to 
monitor the ongoing public health emergency and will evaluate the need for additional/fewer 
mitigation measures in accordance with local and institutional regulations.  

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16 
PREGNANCY 
16.1 Definitions: Women of Childbearing Potential (WOCBP) 
All individuals who were assigned biological sex of female at birth, and who have had no change 
in biological sex regardless of gender identification, will be considered Women of Childbearing 
Potential and will be required to have documented method of birth control and undergo urine 
pregnancy testing. For the purposes of this protocol, they will herein be referred to as “women” 
for biological purposes only.  
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
x Documented hysterectomy 
x Documented bilateral salpingectomy 
x Documented bilateral oophorectomy 
Note:  Documentation will be via self-report 
3. Postmenopausal female 
x A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  
x Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
16.2 Contraception Guidance 
16.2.1 Male participants 
There are no restrictions on birth control choices/methods for male study participants. 
16.2.2 Female participants 
Women of childbearing potential are eligible to participate if they agree to use a highly effective 
method of contraception consistently and correctly as described in Table 10. Documentation of 
birth control method will be obtained at Screening and confirmed at all follow up visits. Changes 
in birth control method will be documented. If there was a lapse in birth control coverage, 
additional pregnancy testing may be warranted. 
 
 
 

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Table 10: Highly Effective Contraceptive Methods 
 
Highly Effective Contraceptive Methods That Are User Dependent   
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation  
x Oral  
x Intravaginal  
x Transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
x Oral  
x Injectable  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
x Intrauterine device (IUD) 
x Intrauterine hormone-releasing system (IUS) 
x Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.  
 
16.3 Pregnancy Testing 
x 
All WOCBP who were assigned biological sex of female at birth and have had no change in 
biological sex regardless of gender identification, will be required to undergo urine 
pregnancy testing. 
x 
WOCBP should only be included after a negative highly sensitive urine pregnancy test. 
x 
Pregnancy testing will be performed at Screening, Baseline, morning of dosing, Day 8, Day 
43 and at any other time if it is suspected the participant may be pregnant.  
x 
Pregnancy testing at all participating institutions will be conducted using a commercial urine 
dipstick.  
16.4 Reporting Pregnancy Information 
See Section 11.9  
 
 
 

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