The Safety and Efficacy of Psilocybin in Participants With Treatment Resistant Depression
Phase: PHASE2
Conditions: Treatment Resistant Depression
Sponsor: COMPASS Pathways

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THE SAFETY AND EFFICACY OF PSILOCYBIN IN 
PARTICIPANTS WITH TREATMENT-RESISTANT DEPRESSION 
(P-TRD) 
DRUG: 
Psilocybin 
3-[2-(Dimethylamino)ethyl]-1H-indol-4-yl 
dihydrogen phosphate 
STUDY NUMBER: 
COMP 001 
 
CLINICAL PHASE 
2 
 
EudraCT NUMBER: 
2017-003288-36 
 
SPONSOR: 
COMPASS Pathways, Ltd 
16 Old Bailey 
London, England, UK EC4M 7EG 
 
ORIGINAL PROTOCOL 
DATE: 
11 Oct 2017 
 
VERSION NUMBER: 
V4.0 
 
VERSION DATE: 
22 Jul 2019 
 

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CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title: The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant 
Depression (P-TRD) 
Study No: COMP 001 
Original Protocol Date: 11 Oct 2017 
Protocol Version No: v4.0 
Protocol Version Date: 22 Jul 2019 
This study protocol was reviewed and approved by the sponsor. The information 
contained in this protocol is consistent with: 
• The current risk-benefit evaluation of the investigational product. 
• The moral, ethical and scientific principles governing clinical research as set out in 
the Declaration of Helsinki, and principles of Good Clinical Practices (GCP) as 
described in the Code of Federal Regulations (CFR) 21 CFR parts 50, 54, 56 and 312 
and according to applicable local requirements. 
The investigator will be supplied with details of any significant or new findings, 
including adverse events, relating to treatment with the investigational product. 
 
Sponsor Approval: 
 
Signature: 
 
 
Date: 
 
Name (print): 
Ekaterina Malievskaia, MD MScPH 
 
 
 
 
 
 
 
 
Title: 
Co-Founder, Head of Research and 
Development 
COMPASS Pathways 
 
 
 
 
 
 
25 July 2019

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STUDY NUMBER COMP 001 
THE SAFETY AND EFFICACY OF PSILOCYBIN IN 
PARTICIPANTS WITH TREATMENT-RESISTANT DEPRESSION 
(P-TRD) 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to 
psilocybin are the confidential and proprietary information of COMPASS Pathways, Ltd 
(COMPASS), and except as may be required by federal, state or local laws or regulation, 
may not be disclosed to others without prior written permission of COMPASS. 
I have read the protocol, including all appendices, and I agree that it contains all the 
necessary information for me and my staff to conduct this study as described. I will 
conduct this study as outlined herein, in accordance with the regulations stated in the 
Code of Federal Regulations (CFR) for Good Clinical Practices (GCP) and International 
Conference on Harmonisation (ICH) guidelines, and will make a reasonable effort to 
complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by COMPASS or specified 
designees. I will discuss the material with them to ensure that they are fully informed 
about psilocybin and the study. 
 
 
 
Principal Investigator Name (printed)  
Signature 
 
 
Date) 
 
Site Number 
 
 
 

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SUMMARY OF CHANGES 
The changes made to the prior version of the protocol, dated 11 Oct 2017, in Version 4.0, 
dated 22 Jul 2019, are summarised in a standalone document.  
 
 

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STUDY SUMMARY 
Title:  
The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant 
Depression (P-TRD) 
EudraCT 
Number: 
2017-003288-36/ 
Clinical Phase: 
2 
Rationale: 
A recent open-label study of the effects of psilocybin in participants with 
treatment-resistant depression (TRD) showed rapid significant decrease of depressive 
symptoms after treatment with psilocybin coupled with psychological support. Over 
40% of participants sustained response at 3 months. In this study, the aim is to assess 
effectiveness of 3 different doses of psilocybin (1 mg, 10 mg, and 25 mg) in TRD. 
Target 
Population: 
TRD 
Number of 
Participants: 
216 participants 
Objectives:  
The main purpose of this study is to allow COMPASS to determine the optimal dose 
of psilocybin, either 10 mg or 25 mg. The intent of the primary efficacy analysis is to 
demonstrate superiority of at least one therapeutic dose of psilocybin (10 mg or 
25 mg) versus the 1 mg psilocybin via the following objectives. 
The primary objective of this study is to evaluate the efficacy of psilocybin (25 mg or 
10 mg) compared to 1 mg, administered under supportive conditions to adult 
participants with TRD, in improving depressive symptoms, as assessed by the change 
in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from 
Baseline. Baseline is defined as the assessment score obtained on Day -1. The 
primary timepoint is Week 3; this variable will be analysed for the change from 
Baseline to Day 1, and Weeks 1, 3, 6, 9, and 12.  
The secondary objectives are: 
• 
To assess the efficacy of psilocybin compared to 1 mg psilocybin on: 
o 
Proportion of participants with response defined as a ≥ 50% decrease in 
MADRS total score from Baseline to Week 3. This will also be assessed at 
Day 1 and at Weeks 1, 6, 9, and 12.  
o 
The proportion of participants who have a sustained response at Week 12. 
Sustained response is defined as the proportion of patients fulfilling 
response criteria at any visit up to and including Week 3, that also fulfills 
response criteria at all subsequent visits up to and including Week 12. 
Response is defined as ≥ 50% decrease in MADRS total score from 
Baseline.  
• 
To evaluate the safety and tolerability of psilocybin in participants with TRD 
based on adverse events (AEs), changes in vital signs, and suicidal 
ideation/behaviour (measured using the Columbia-Suicide Severity Rating Scale 
[C-SSRS]) score at all visits. 
The exploratory objectives are: 
• 
To evaluate the effects of psilocybin on quality of life and wellbeing, functioning 
and associated disability, cognitive function, and anxiety compared to 1 mg 
psilocybin on: 

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o 
Quality of life in participant EuroQoL (EQ)- 5 dimension-3 level scale 
(EQ-5D-3L) score change from Baseline to Week 3. This will also be 
assessed at Week 12. 
o 
Quality of life in caregiver EQ-5D-3L score change from Baseline to Week 
3. This will also be assessed at Week 12. This assessment is not mandatory. 
o 
Functioning and associated disability in the Sheehan Disability Scale (SDS) 
score change from Baseline to Week 3. This will be also assessed at 
Week 12. 
o 
Cognitive function as measured by the Digit Symbol Substitution Test 
(DSST) score change from Baseline to Week 3. This will also be assessed at 
Day 1 and Week 12. 
o 
Level of anxiety as measured using the change in Generalised Anxiety 
Disorder 7 item Scale (GAD-7) total score change from Baseline to Week 3. 
This will also be assessed at Week 12. 
o 
Participant determined level of depression as measured using the change in 
Quick Inventory of Depressive Symptomatology Self Rated (QIDS-SR-16) 
total score from Baseline to Week 3. This will also be assessed at Day 1, and 
Weeks 1, 2, 6, 9, and 12. 
o 
Psychosocial functioning and predictor of response duratbility as measured 
using the change in Work and Social Adjustment Scale (WSAS) from 
Baseline to Week 3. This will also be assessed at Week 12.  
o 
To evaluate the impact of different psilocybin doses on real life functional 
activity estimated from passive data streams collected on a mobile app on 
participants’ mobile phones. The data collected from the participant’s phone 
will include: 
▪ 
Number of and time of phone calls/e-mails/texts (content will not be 
collected) 
▪ 
Gestures used (taps, swipes, other) 
▪ 
Gyroscope (orientation) of the phone (the way the phone is pointing) 
▪ 
Acceleration of the phone (sudden movements of the phone) 
▪ 
Keystroke patterns with characters redacted 
▪ 
Location information from the GPS 
▪ 
The app also maintains a histogram of daily words that the participant 
types on their phone. These words will be stripped from their context 
and syntax, thus preventing the content of any particular message from 
being deciphered. 
o 
The Positive and Negative Affect Schedule, Five Dimension Altered States 
of Consciousness questionnaire, 2a receptor polymorphism test and the 
Scale to Assess Therapeutic Relationship (Clinician and Patient version, 
STAR-C and STAR-P, respectively) will be assessed for correlation with the 
primary and secondary outcomes as possible predictors of response. 
Study Design: 
This is a Phase 2, international multicentre, randomised, fixed-dose, double-blind 
trial. The study population will include adult men and women, 18 years of age and 
older, with TRD. Participants with TRD are defined as those who meet the 
Diagnostic and Statistical Manual of Mental Disorders (5th Edition; DSM-5) 

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diagnostic criteria for single or recurrent episode of major depressive disorder 
(MDD) without psychotic features which have failed to respond to an adequate dose 
and duration of 2, 3, or 4 pharmacological treatments for the current episode; if 
single-episode MDD, the duration of the current episode must be at least 3 months 
but not more than 2 years. Augmentation counts as a second treatment, provided it is 
approved for the adjunctive treatment of MDD in that country..  
Participants will be outpatients and will be recruited primarily through referrals from 
general practitioners and specialised psychiatric services.  
The majority of participants will have no prior exposure to psilocybin or so-called 
magic mushrooms; however, to reflect the prevalence of experience in general 
population, we will allow up to 10% of participants with prior recreational experience 
with psilocybin or magic mushrooms. Past exposure to psilocybin has to be more 
than 12 months prior to Screening and not during the current depressive episode. This 
will be constrained by the centralised randomisation process, Interactive Web-based 
Response System. 
After signing the informed consent form (ICF), participants will be assessed for their 
eligibility with the Mini International Neuropsychiatric Interview (MINI), the 
Hamilton Depression Rating Scale (HAM-D-17), the Massachusetts General Hospital 
Antidepressant Treatment History Response Questionnaire (MGH-ATRQ), the 
C-SSRS, and McLean Screening Instrument for Borderline Personality Disorder. 
Those who meet the eligibility criteria will enter the screening period, which will last 
between 3 and 6 weeks. At the initial Screening visit (V1), the participant will also be 
evaluated with the QIDS-SR-16, and the Adult Self-Report Scale. Additionally, a 
medical history, an electrocardiogram (ECG), blood tests, and vital signs will be 
obtained.  
During the screening period, participants who are on antidepressant medications will 
be expected to complete the taper at least 2 weeks prior to Baseline (V2). Participants 
will be given a choice of the tapering rate. During the tapering period all participants 
will be supported by the study clinician.  
Once a patient completes all V1 assessments and all screening data is entered into the 
Electronic Data Capture (EDC), the Medical Monitor (MM) and Clinical Assessment 
Technologies Team (CAT) will review data entered and issue approval, if the patient 
is eligible. Once approval is issued, the patient should then be invited for a screening 
V1a visit. The V1a visit is the point at which the patient begins tapering off their 
antidepressant and/or antipsychotic medications, if appropriate. The patient must 
complete the taper within the first 4 weeks of this period, prior to 2 weeks completely 
off antidepressant and/or antipsychotic medications, before Baseline V2. The 
tapering period used in the study is set at the industry standard for depression trials.  
The designated study team member will be in frequent contact with the participants 
to monitor for withdrawal and worsening of depression symptoms. Participants will 
be assessed for suicidality with the C-SSRS at each contact/visit. 
The participant will meet with a therapist for a minimum of 3 visits during screening. 
These are safety sessions and will cover what to expect during the psilocybin session. 
The therapist and the participant will review psychoeducational materials provided at 
the time of enrolment. 
All participants will be evaluated for safety at the clinic weekly for a minimum of 
3 weeks prior to psilocybin administration to ensure safe discontinuation of current 
antidepressant therapy required by the protocol. Participants’ companions (friends or 
family members) will be educated about the signs of worsening of depression and 
suicidality, and instructed on ways to contact the study team in case of significant 

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worsening of depression. Any safety assessment visits during the screening period 
will be called V1a, V1b, etc. During these visits, the C-SSRS and any changes in 
medications since the previous visit will be obtained in addition to other assessments 
at the study clinician’s discretion.  
The day before psilocybin session, the participants will undergo a baseline 
assessment (3 to 6 weeks after initial Screening [V1]) that will consist of the 
HAM-D-17, MADRS, QIDS-SR-16, C-SSRS, SDS, GAD-7, DSST, EQ-5D-3L 
(administered to both participant and caregiver [the latter is not mandatory]), WSAS, 
vital signs, urinalysis, urine drug screen, and urine pregnancy test (only for women of 
childbearing potential). Both the therapist and the participant will be asked to fill out 
a therapeutic alliance evaluation questionnaire, STAR-C and STAR-P, respectively. 
After baseline data is entered into EDC, the CAT team will complete a final review 
to ensure the participant’s continued eligilblilty. Participants cannot be progressed to 
V3 until this approval is received. 
The psilocybin administration session (V3, Day 0) will last approximately 6 hours 
and will be supported by a trained therapist. Psilocybin session may be video 
recorded for training and adherence monitoring. A full description of the activities of 
the psilocybin administration session is found in the Therapist Manual. After the 
acute effects of the psilocybin pass, participants will be evaluated for safety and 
accompanied home. On Day 1 (V4), the day following psilocybin administration, 
participants will be seen in person for a safety check, assessment of suicidality, and 
to discuss their experience during the psilocybin session. All sessions between the 
therapist and the participant may be audio recorded for adherence monitoring and 
quality assurance. Audio and video recording of the sessions are subject to participant 
consent. Participants who do not consent to either or all recordings will not be 
excluded from the study.  
All participants will be asked to remain off their antidepressant medications for at 
least 3 weeks following the psilocybin session until the primary endpoint assessment, 
or longer. Rescue medications are allowed as noted in the protocol. Participants who 
restart their antidepressant medications during the first 3 weeks after the psilocybin 
treatment administration will be assessed for reasons of resuming their medications 
and followed until 12 weeks post psilocybin administration.  
The treatment period will determine the optimal therapeutic dose; 216 participants 
will be randomised in a 1:1:1 ratio to receive 1 mg psilocybin, 10 mg psilocybin, or 
25 mg psilocybin. 
Participants will be seen at the clinic for Screening (V1 plus a minimum of 3 safety 
visits), Baseline (V2, Day -1), Day 0 (V3, Dosing), Day 1 (V4), Week 1 (V5), Week 
2 (V6), Week 3 (V7), and Week 12 (V10). Participants will also be contacted for 
follow-up at Week 6 (V8) and Week 9 (V9). The MADRS will be done by telephone 
and the other assessments will be done electronically. Participants are seen at the 
clinic for safety visits between the initial Screening (V1) and the Baseline (V2) visit, 
and the visits will be labelled V1a, V1b, V1c, etc. 
Eligibility 
Criteria: 
Inclusion Criteria 
Participants meeting all the following inclusion criteria at Screening (V1) should be 
considered for admission into the study 
1. Signed ICF. 
2. 18 years of age or older at Screening (V1). 

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3. At least moderate MDD (single or recurrent episode as informed by DSM-5; if 
single episode, duration of ≥ 3 months and ≤ 2 years) based on medical records, 
clinical assessment and documented completion of the version 7.0.2 MINI. 
4. HAM-D-17 (17-item) score ≥ 18 at Screening (V1) and at Baseline (V2).  
5. Failure to respond to an adequate dose and duration of 2, 3, or 4 pharmacological 
treatment for the current episode as determined through the MGH-ATRQ and 
using the supplementary advice on additional antidepressants not included in 
MGH-ATRQ (Appendix III). Augmentation with an add-on treatment counts as 
a second treatment, provided it is approved for the adjunctive treatment of MDD 
in that country.  
6. McLean Screening Instrument for Borderline Personality Disorder < 7 at 
Screening (V1). 
7. Have successfully discontinued all antidepressant medications at least 2 weeks 
prior to Baseline (V2). 
8. Ability to complete all protocol required assessment tools without any assistance 
or alteration to the copyrighted assessments, and to comply with all study visits.  
Exclusion Criteria 
Participants meeting any of the following exclusion criteria at Screening (V1) will 
not be enrolled in the study. 
Psychiatric Exclusion Criteria: 
1. Current or past history of schizophrenia, psychotic disorder (unless substance 
induced or due to a medical condition), bipolar disorder, delusional disorder, 
paranoid personality disorder, schizoaffective disorder, borderline personality 
disorder, or any serious psychiatric comorbidity as assessed by medical history 
and a structured clinical interview (version 7.0.2 MINI). 
2. Prior electroconvulsive therapy and/or ketamine for current episode. 
3. Current cognitive behavioural therapy (CBT) that will not remain stable for the 
duration of the study. CBT cannot be initiated within 21 days of baseline.  
4. Current (within the last year) alcohol or substance abuse as informed by DSM-5 
at Screening (V1). 
5. Significant suicide risk as defined by (1) suicidal ideation as endorsed on items 4 
or 5 on the C-SSRS within the past year, at Screening or at Baseline, or; 
(2) suicidal behaviors within the past year, or; (3) clinical assessment of 
significant suicidal risk during subject interview. 
6. Depression secondary to other severe medical conditions.  
7. Other personal circumstances and behaviour judged to be incompatible with 
establishment of rapport or safe exposure to psilocybin, including exposure to 
psilocybin within the past year and use of psychedelics, such as ayahuasca, 
during the current depressive episode. 
General Medical Exclusion Criteria:  
8. Women who are pregnant, nursing, or planning a pregnancy. Participants who 
are sexually active must agree to use a highly effective contraceptive method 
throughout their participation in the study. Women of child bearing potential 
must have a negative urine pregnancy test at Screening (V1) and Baseline (V2). 

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9. Cardiovascular conditions: recent stroke (< 1 year from signing of ICF), recent 
myocardial infarction (< 1 year from signing of ICF), hypertension (blood 
pressure > 140/90 mmHg) or clinically significant arrhythmia within 1 year of 
signing the ICF. 
10. Uncontrolled insulin-dependent diabetes. 
11. Seizure disorder.  
12. Positive urine drug screen for illicit drugs or drugs of abuse at V1 and/or V2. 
Any positive urine drug test will be reviewed with participants to determine the 
pattern of use and eligibility will be determined at the investigator’s discretion in 
conjunction with the medical monitor.  
13. Current enrolment in any investigational drug or device study or participation in 
such within 30 days of Screening (V1). 
14. Current enrolment in an interventional study for depression or participation in 
such within 30 days of Screening (V1).  
15. Abnormal and clinically significant results on the physical examination, vital 
signs, ECG, or laboratory tests at Screening (V1).  
16. Any other clinically significant cardiovascular, pulmonary, gastrointestinal, 
hepatic, renal or any other major concurrent illness that, in the opinion of the 
investigator, may interfere with the interpretation of the study results or 
constitute a health risk for the participant if he/she takes part in the study. 
Investigational 
Product(s): 
Single 5-capsule oral psilocybin dose:  
o 
25 mg treatment: 5 × 5 mg capsules  
o 
10 mg treatment: 2 × 5 mg capsules and 3 × placebo capsules 
o 
1 mg treatment: 1 × 1 mg capsule and 4 × placebo capsules 
Primary 
Endpoint:  
The primary endpoint is the change in MADRS total score from Baseline (Day -1) to 
3 weeks post psilocybin.  
Secondary 
Endpoints: 
The secondary endpoints are: 
• 
The proportion of participants with a response (defined as a ≥ 50% improvement 
in MADRS total score from Baseline) at Week 3 post psilocybin. 
• 
The proportion of participants with remission (defined as a MADRS total score 
≤ 10) at Week 3 post psilocybin.  
• 
The proportion of participants who have a sustained response at Week 12. 
Sustained response is defined as the proportion of patients fulfilling response 
criteria at any visit up to and including Week 3, that also fulfills response criteria 
at all subsequent visits up to and including Week 12. Response is defined as 
≥ 50% decrease in MADRS total score from Baseline. 
• 
Time to event measures: restart antidepressant medication for any reason, restart 
medication for continuing depressive symptoms, and relapse from a previously 
recovered state (clinical judgement, supported by the QIDS-SR-16). Participants 
who withdraw from the study will be censored from the time to event analysis. 
Exploratory 
Endpoints: 
The exploratory endpoints are: 

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• 
Change from Baseline in the following: 
o 
Participant EQ-5D-3L at Week 3 
o 
Caregiver EQ-5D-3L at Week 3 (this assessment is not mandatory) 
o 
SDS at Week 3 
o 
DSST at Week 3 
o 
GAD-7 at Week 3 
o 
QIDS-SR-16 at Week 3 
o 
WSAS at Week 3 
o 
Measures derived from smart phone usage via the Mindstrong app. 
Efficacy and 
Outcome 
Measures: 
• 
MADRS 
• 
QIDS-SR-16  
• 
SDS 
• 
GAD-7 
• 
DSST 
• 
EQ-5D-3L (participant and caregiver, the latter is not mandatory) 
• 
WSAS 
Safety 
Assessments 
• 
ECG 
• 
Vital signs  
• 
Blood test including liver function tests  
• 
Suicide risk as assessed by the C-SSRS 
• 
AEs and Serious AEs  
Statistical 
Procedures 
Analysis Sets 
The Safety Population will consist of all randomised participants who receive study 
treatment, regardless of whether or not treated. This population will be used for all 
summaries of participant accountability, demographic and baseline data, and safety 
information, including AE incidence.  
The Full Analysis Set (FAS) will consist of all participants randomised who also 
receive the dose of investigational product (IP). 
The modified intention-to-treat population will consist of all participants in the FAS 
that have at least 1 post dose assessment.  
The Per Protocol (PP) population will consist of all participants in the FAS who do 
not have a major protocol deviation. Major protocol deviations will be reviewed and 
determined prior to unblinding. The PP population will be used for supportive 
sensitivity analyses.  
Sample Size Determination  
The intent of the primary efficacy analysis is to demonstrate superiority of at least 
one therapeutic dose of psilocybin (10 mg or 25 mg) versus the 1 mg psilocybin 
based on the change from Baseline in MADRS score at Week 3.  

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For this primary analysis, a sample size of 216 randomised participants (72:72:72) 
will provide 90% power at the alpha = 0.05 level to detect a 6-point difference in 
average MADRS total score between the optimal therapeutic dose of psilocybin and 
1 mg psilocybin, assuming the common standard deviation is 11.0.  
It is assumed that up to 90% of randomised participants may not have prior 
psychedelic experience. The power for this post hoc subgroup is approximately 86%, 
if the maximum number of participants to have prior psychedelic experience were 
10% of randomised participants. 
Primary and Secondary Efficacy Analyses 
The primary efficacy endpoint (change from Baseline in MADRS total score at 
Week 3) will be evaluated with a mixed-effects model for repeated measures 
analysis. The model will include treatment, visit, study site, prior psychedelic 
experience, treatment-by-visit interaction, participant as a random effect, and 
baseline MADRS total score. Comparison of the psilocybin optimal dose versus 1 mg 
psilocybin will be performed at the 0.05 testing level. A sensitivity analysis will be 
performed on the primary mixed model repeated measures model adding treatment 
by study site or country interaction into the model. If it is significant (at the 10% 
level), then further investigations of sites will be performed. 
The 4 secondary efficacy endpoints that are dichotomous variables (proportion of 
participants who are responders, remitters, and sustained responders) will be analysed 
using the Cochran-Mantel-Haenszel chi-square test, stratified by country, to compare 
the psilocybin optimal therapeutic dose versus 1 mg psilocybin. A stepdown 
procedure to correct for multiplicity will be employed.  
Time-to-event measures will be evaluated using Kaplan-Meier methods. 
Response and remission rates will be summarised at each visit.  
Exploratory Analyses 
Change from Baseline in continuous efficacy measures, including the QIDS-SR-16 
scale and GAD-7 total scores at each point, will be analysed based on last 
observation carried forward data using an analysis of covariance model, with 
treatment and study site as factors, and the respective baseline score as the covariate. 
The exploratory analyses for quality of life and wellbeing, functioning and associated 
disability, cognitive function, and anxiety are not hierarchical; there will be no 
correction for multiplicity in these analyses.  
Scores for all efficacy endpoints, including dimension scores of the EQ-5D-3L and 
the EQ visual analogue scale, will be summarised over time using descriptive 
statistics for all visits during the observation period.  
The covariate selection process will be addressed in the Statistical Analysis Plan to 
be approved before any analyses are undertaken.  
Continuous behavior sampling will be tested with the Mindstrong application 
technology in a subgroup of smart phone users consented to this part of the study. 
Participants who do not consent to the app installation, or don’t have a smart phone, 
will not be excluded from the study. Following the installation of the Mindstrong app 
on the participant’s smart phone, the app will begin to collect data from the smart 
phone and periodically send these data back to the secure database. The participant 
does not need to do anything at this stage, except use their phone as they normally 
do. As explained above personal data from mobile phone usuage will be analysed in a 
sub-group of consenting participants.  

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The correlation between sensor data, keyboard behavior, or voice and speech metrics 
will be assessed for correlation with standard clinical assessments and the ability of 
app features to identify impending relapse before clinical change is apparent with 
traditional ratings. The goal of these exploratory assessments is to identify mobile use 
patterns (app features) predictive of clinically significant mood changes that will 
have an impact on care and treatment outcomes.  
Safety Analysis 
Safety analyses will be performed using data from the Safety Population. Safety will 
be evaluated based on AEs, vital signs, clinical laboratory assessments, and ECG 
findings. A Data and Safety Monitoring Board (DSMB) will periodically review and 
evaluate the accumulated study data for participant safety, study conduct and 
progress and when appropriate, efficacy. 

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TABLE OF CONTENTS 
CLINICAL PROTOCOL APPROVAL FORM .............................................................2 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ...................................3 
SUMMARY OF CHANGES .............................................................................................4 
STUDY SUMMARY ..........................................................................................................5 
TABLE OF CONTENTS ................................................................................................14 
LIST OF TABLES ...........................................................................................................17 
LIST OF ABBREVIATIONS .........................................................................................18 
INTRODUCTION AND RATIONALE .........................................................................21 
1.1 
Background ..........................................................................................................21 
1.2 
Study Rationale ....................................................................................................21 
1.2.1 
Pharmacokinetics ...........................................................................................22 
1.2.2 
Preclinical Pharmacology ..............................................................................22 
1.2.3 
Clinical Adverse Event Profile ......................................................................23 
1.2.4 
Potential Risk to Foetal Development ..........................................................23 
1.2.5 
Dosing Regimen ..............................................................................................23 
2 
STUDY OBJECTIVES ............................................................................................24 
2.1 
Primary .................................................................................................................24 
2.2 
Secondary..............................................................................................................24 
2.3 
Exploratory ...........................................................................................................24 
3 
STUDY ENDPOINTS ..............................................................................................27 
3.1 
Primary .................................................................................................................27 
3.2 
Secondary..............................................................................................................27 
3.3 
Exploratory ...........................................................................................................27 
3.4 
Efficacy and Outcome Measures ........................................................................28 
4 
STUDY PLAN ...........................................................................................................29 
4.1 
Study Design .........................................................................................................29 
4.2 
Study Schematic ...................................................................................................32 
4.3 
Schedule of Assessments ......................................................................................33 
5 
POPULATION ..........................................................................................................37 
5.1 
Number of Participants .......................................................................................37 
5.2 
Inclusion Criteria .................................................................................................37 
5.3 
Exclusion Criteria ................................................................................................37 
5.4 
Participant Screening ..........................................................................................39 
5.5 
Deviation from Inclusion/Exclusion Criteria ....................................................39 
6 
STUDY CONDUCT ..................................................................................................40 
6.1 
General Instructions ............................................................................................40 
6.2 
Study Procedures by Time Point ........................................................................40 
6.2.1 
Screening Period ............................................................................................40 
6.2.2 
Baseline Visit – Visit 2 – Day -1 ....................................................................41 
6.2.3 
Visit 3 – Day 0 – Psilocybin Session ..............................................................43 
6.2.4 
Visit 4 – Day 1 Postdosing .............................................................................43 
6.2.5 
Visit 5 – 1 Week Postdosing ..........................................................................44 

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6.2.6 
Visit 6 – 2 Weeks Postdosing .........................................................................44 
6.2.7 
Visit 7 – 3 Weeks Postdosing .........................................................................45 
6.2.8 
Visit 8 – 6 Weeks Postdosing .........................................................................45 
6.2.9 
Visit 9 – 9 Weeks Postdosing .........................................................................46 
6.2.10 
Visit 10 – 12 Weeks Postdosing – End of Study ..........................................46 
6.3 
Premature Discontinuation .................................................................................47 
7 
DESCRIPTION OF STUDY PROCEDURES .......................................................48 
7.1 
Efficacy Assessments ...........................................................................................48 
7.1.1 
Montgomery-Asberg Depression Rating Scale ...........................................48 
7.1.2 
Quick Inventory of Depressive Symptomatology........................................48 
7.1.3 
Sheehan Disability Scale ................................................................................48 
7.1.4 
Generalised Anxiety Disorder scale .............................................................48 
7.1.5 
Digit Symbol Substitution Test .....................................................................49 
7.1.6 
EuroQoL-5-dimension 3-level Scale .............................................................49 
7.1.7 
Work and Social Adjustment Scale ..............................................................49 
7.2 
Safety Assessments ...............................................................................................50 
7.2.1 
Columbia-Suicide Severity Rating Scale .....................................................50 
7.2.2 
Vital Signs .......................................................................................................50 
7.2.3 
Electrocardiogram .........................................................................................50 
7.2.4 
Clinical Laboratory Tests..............................................................................51 
7.2.5 
Adverse Events ...............................................................................................51 
7.3 
Other Assessment Instruments ...........................................................................52 
7.3.1 
Hamilton Depression Rating Scale – 17-item ..............................................52 
7.3.2 
Mini International Neuropsychiatric Interview ..........................................52 
7.3.3 
Massachusetts General Hospital-Antidepressant Treatment 
History Questionnaire ...................................................................................52 
7.3.4 
McLean Screening Instrument for Borderline Personality 
Disorder ..........................................................................................................52 
7.3.5 
Adult Self-Report Scale .................................................................................53 
7.3.6 
Scale to Assess Therapeutic Relationships – Patient and Clinician 
Version ............................................................................................................53 
7.3.7 
Five Dimension Altered States of Consciousness Questionnaire ...............53 
7.3.8 
The Positive and Negative Affect Schedule .................................................53 
7.3.9 
Emotional Breakthrough Inventory .............................................................54 
7.3.10 
Mindstrong application .................................................................................54 
7.4 
Protocol Deviations ..............................................................................................55 
8 
INVESTIGATIONAL PRODUCT MANAGEMENT ..........................................56 
8.1 
Description ............................................................................................................56 
8.1.1 
Formulation ....................................................................................................56 
8.1.2 
Storage ............................................................................................................56 
8.2 
Packaging and Blinding .......................................................................................56 
8.3 
Dose and Administration .....................................................................................57 
8.4 
Accountability ......................................................................................................58 
8.5 
Concomitant Therapy ..........................................................................................58 
8.5.1 
Permissible Medications ................................................................................58 

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8.5.2 
Definition of Women of Childbearing Potential and/or Acceptable 
Contraceptive Methods .................................................................................59 
8.5.3 
Prohibited Medications .................................................................................60 
8.5.4 
Rescue Medication .........................................................................................60 
8.6 
Compliance ...........................................................................................................61 
9 
ADVERSE EVENTS ................................................................................................62 
9.1 
Documenting Adverse Events .............................................................................62 
9.2 
Assessment of Intensity........................................................................................63 
9.3 
Assessment of Causality ......................................................................................64 
9.4 
Action Taken Regarding Investigational Product ............................................64 
9.5 
Other Action Taken for Event ............................................................................64 
9.6 
Adverse Event Outcome ......................................................................................65 
9.7 
Clinical Laboratory Changes ..............................................................................65 
9.8 
Overdose ...............................................................................................................65 
9.9 
Adverse Events of Special Interest .....................................................................66 
9.10 
Adverse Event Follow-up ....................................................................................67 
10 SERIOUS ADVERSE EVENTS ..............................................................................68 
10.1 
Definition of Serious Adverse Event ..................................................................68 
10.2 
Reporting Serious Adverse Events .....................................................................69 
11 STATISTICS .............................................................................................................72 
11.1 
General Procedures .............................................................................................72 
11.2 
Sample Size ...........................................................................................................72 
11.3 
Statistical Methods ...............................................................................................72 
11.3.1 
Efficacy and Outcome Measures ..................................................................73 
11.3.2 
Analysis of Efficacy ........................................................................................73 
11.3.3 
Multiplicity .....................................................................................................74 
11.3.4 
Analysis of Safety ...........................................................................................75 
11.3.5 
Demographic and Baseline Characteristics .................................................76 
11.4 
Interim Analysis ...................................................................................................76 
12 ETHICS AND RESPONSIBILITIES .....................................................................77 
12.1 
Good Clinical Practice .........................................................................................77 
12.2 
Data and Safety Monitoring Board ....................................................................77 
12.3 
Steering Committee .............................................................................................77 
12.4 
Institutional Review Board/Independent Ethics Committee ...........................77 
12.5 
Informed Consent ................................................................................................77 
12.6 
Exposure in Utero During Clinical Studies .......................................................77 
12.7 
Records Management ..........................................................................................78 
12.8 
Source Documentation.........................................................................................78 
12.9 
Study Files and Record Retention ......................................................................78 
13 AUDITING AND MONITORING ..........................................................................80 
14 AMENDMENTS .......................................................................................................81 
15 STUDY REPORT AND PUBLICATIONS ............................................................82 
16 STUDY DISCONTINUATION ...............................................................................83 
17 CONFIDENTIALITY ..............................................................................................84 
18 REFERENCES .........................................................................................................85 

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19 APPENDICES ...........................................................................................................89 
19.1 
APPENDIX I – Names of Study Personnel........................................................89 
19.2 
APPENDIX II – Declaration of Helsinki ...........................................................90 
19.3 
APPENDIX III – MGH-ATRQ – Additional Detail Regarding the 
Assessment of Previous Antidepressant Treatment..........................................95 
 
LIST OF TABLES 
Table 8.1 
Details of Investigational Product ..........................................................56 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
5D-ASC 
Five Dimension Altered States of Conscniousness questionnaire 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ASRS 
Adult Self-Report Scale 
AST 
aspartate aminotransferase 
bpm 
beats per minute 
CBT 
cognitive behavioural therapy 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
COMPASS 
COMPASS Pathways, Ltd 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
DSMB 
Data and Safety Monitoring Board 
EBI 
Emotional Breakthrough Inventory 
EC50 
half-maximal effective concentration 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EIU 
Exposure In Utero 
EOS 
End of Study 
EQ 
Euro QoL 
EQ-5D-3L 
Euro QoL-5 dimension-3 level 
EQ VAS 
Euro QoL visual analog scale 
ET 
early termination 
FAS 
full analysis set 
GAD-7 
Generalised Anxiety Disorder Scale 
GCP 
Good Clinical Practices 
h 
hours 
HAM-D-17 
Hamilton Depression Rating Scale 
HDPE 
high density polyethylene 
IB 
Investigator’s Brochure 

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Abbreviation 
Definition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous 
IWRS 
Interactive Web-based Response System 
kg 
kilogram 
L 
litres 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MGH-ATRQ 
Massachusetts General Hospital Antidepressant Treatment History Questionnaire 
min 
minute 
MINI 
Mini International Neuropsychiatric Interview 
mL 
millilitre 
mmHg 
millimetres of mercury 
MSI-BPD 
McLean Screening Instrument for Borderline Personality Disorder 
ng 
nanogram 
PANAS 
Positive and Negative Affect Schedule 
PP 
per protocol (analysis population) 
PRN 
pro re nata, as needed 
PS 
Prescreen 
PT 
Preferred Term 
P-TRD 
psilocybin for treatment-resistant depression 
QIDS 
Quick Inventory of Depressive Symptoms 
QIDS-SR-16 
Quick Inventory of Depressive Symptomatology – Self-Rated 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SDS 
Sheehan Disability Scale 
STAR-C 
Scale to Assess Therapeutic Relationship – Clinician version 

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Abbreviation 
Definition 
STAR-P 
Scale to Assess Therapeutic Relationship – Patient version 
TRD 
treatment-resistant depression 
UK 
United Kingdom 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
Worldwide 
Worldwide Clinical Trials, Inc. 
WSAS 
Work and Social Adjustment Scale 

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INTRODUCTION AND RATIONALE 
The following is a summary of the information found in the current Investigator’s 
Brochure (IB).5  
1.1 
Background 
Psilocybin belongs to a class of drugs referred to as psychedelics (‘mind-manifesting’). 
Specifically, psilocybin is considered a 5-hydroxytryptaminergic (serotonergic) 
psychedelic, along with other tryptamines such as dimethyltryptamine (DMT), ergolines 
such as lysergic acid diethylamide (LSD), and phenethylamines such as mescaline. 
Psilocybin was first isolated from psilocybe mushrooms by Hofmann in 1957, and later 
synthesised by him in 1958.24 Psilocybin has been used in psychiatric research and in 
psychodynamic orientated psychotherapy from the early to mid-1960s up until it became 
a Schedule 1 substance in the United States (US) in 1970, and until the 1980s in 
Germany.24,25 Research on the effects of psilocybin resumed in the mid-1990s, and it is 
currently the preferred compound for use in clinical research of 5-hydroxytryptaminergic 
psychedelics,3,10,15 because it has a shorter duration of action and suffers from less 
notoriety and stigma than other similar drugs.  
1.2 
Study Rationale 
Carhart-Harris conducted an open-label feasibility study in 12 patients (6 men and 
6 women) with moderate-to-severe, unipolar, treatment-resistant major depression 
(ISRCTN 14426797).2 Each patient received 2 oral doses of psilocybin (10 mg and 
25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological 
support was provided before, during, and after each session. The primary outcome 
measure was patient-reported intensity of psilocybin’s effects. Patients were monitored 
for adverse events (AEs) during the dosing sessions and at subsequent clinic and remote 
follow-ups. Depressive symptoms were assessed using the 16-item Quick Inventory of 
Depressive Symptoms (QIDS); QIDS scores were obtained from week 1 to the 3 months 
following dosing. Psilocybin's acute psychedelic effects were detectable 30 to 60 minutes 
(min) after dosing, peaked 2 to 3 hours (h) after dosing, and subsided at least 6 h after 
dosing. Mean self-rated intensity (on a scale of 0-1) was 0.51 (standard deviation [SD] 
0.36) for the low-dose session and 0.75 (SD 0.27) for the high-dose session. Compared to 
Baseline, depressive symptoms were markedly reduced 1 week (means QIDS 
difference -11.8, 95% confidence interval (CI) -9.15 to -14.35, p=0.002, Hedges’ g=3.1) 
and 3 months (-9.2, 95% CI -5.69 to -12.71, p=0.003, Hedges’ g=2) after high-dose 
treatment. Marked and sustained improvements in anxiety and anhedonia were also 
noted. Psilocybin was well tolerated and no serious or unexpected AEs were reported. 
The AEs noted were transient anxiety (12/12 patients, 100%) during psilocybin onset, 
transient confusion or thought disorder (9/12 patients, 75%), mild transient nausea 
(4/12 patients, 33%), and transient headache (4/12 patients, 33%).  
This study provides preliminary support for the safety and efficacy of psilocybin for 
treatment-resistant depression and motivates further trials, with more rigorous designs, to 

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better examine the therapeutic potential of this approach. In this study, the aim is to 
assess effectiveness of 2 doses of psilocybin (10 mg and 25 mg) in treatment-resistant 
depression (TRD) as compared to 1 mg psilocybin. 
1.2.1 
Pharmacokinetics 
Psilocybin is detectable in plasma 20 to 40 min after oral administration of 0.224 mg/kg 
(10-20 mg total dose).13 Orally ingested psilocybin is metabolised (dephosphorylated) in 
the liver, and primarily transformed into the active hydroxy metabolite, psilocin. 
Psilocybin is detectable in plasma 30 min after administration,13,16,20,24 and psilocin is 
detectable in plasma 15 to 50 min after oral administration of 0.2 mg/kg psilocybin. 
Therefore, psilocybin is essentially a prodrug and psilocin represents the 
pharmacologically active agent in systemic circulation. The elimination half-life of 
psilocybin is 50 min.20 Psilocin’s half-life ranges between 2 and 3 h, and is detectable 6 h 
after oral administration.13,20 Hasler et al.13 and Lindenblatt et al.20 reported similar but 
not identical findings, with peak levels of psilocin appearing between 80 to 105 min and 
psilocin half-life ranging between 2.25 h for 0.2 mg/kg and 2.7 h for 0.22 mg/kg. The 
majority, 80%, of psilocin in plasma was found to be in a conjugated form. Both psilocin 
(at 90-97%) and psilocybin (3-10%) are detectable in human urine, unmodified (only 
3-10%) and particularly conjugated with glucuronic acid.14 The majority of psilocin 
recovered in urine is excreted within 3 h after oral administration and is completely 
eliminated from the body within 24 h.14 
1.2.2 
Preclinical Pharmacology 
Psilocybin and its active metabolite psilocin directly affect a number of 5-HT receptor 
subtypes without directly affecting other neurotransmitter systems.  
Human psilocybin research has confirmed the importance of 5-HT2A stimulation for the 
psychedelic effects of psilocybin and psilocin as the effects can be blocked by a 5-HT2A 
receptor antagonist.37 Reviews of the pharmacology of psilocybin is provided by Passie, 
and more current knowledge and perspective by Tyls et al.24,36 
When assessed for potential effects on the human-ether-à-go-go related gene channel 
psilocybin was shown to be without significant effects when tested up to concentrations 
of 1 mM. 
Although the literature on the effect of psilocin at the 5-HT2B is somewhat contradictory, 
the most recent publication by Rickli et al. indicates that the half-maximal effective 
concentration (EC50) for activation of the 5-HT2B receptor is greater than 20 μM.27 That 
concentration would generally be considered to be pharmacologically inactive in vivo 
because plasma concentrations would never reach 20 μM or greater after a single 
administration of psilocin. Brown et al. indicate that the maximal plasma concentration 
achieved after a single dose of 0.45 mg/kg in normal humans would not reach 200 nM 
(0.2 μM).1 In any event, all studies suggest that chronic activation of the 5-HT2B is 
necessary in order to invoke cardiac valvulopathy, and with a single administration there 

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should be no concern for that effect. With the EC50 reported by Rickli et al, even multiple 
administrations of psilocin would not be expected to be harmful. The valvulopathy 
induced by Fen-phen, or ergoline type anti-Parkinson agents, involved daily 
administration of the drugs over a significant period of time. Thus, there is no expectation 
that single use of psilocybin will be problematic. 
1.2.3 
Clinical Adverse Event Profile 
The use of psilocybin in psychotherapy have been reported since the 1960’s, but these 
studies suffer from a lack of experimental control and standardised assessments. Owing 
to the absence of adequate control groups, and use of follow-up measurements with 
vague criteria for therapeutic outcomes, the studies do not clearly distinguish between the 
drug or the therapeutic engagement itself that produced the reported beneficial effect.  
The safety of psilocybin should be considered in terms of benefit and risk. Within the 
context of psilocybin administration in a controlled setting, a participant may report 
visual or auditory disturbances, feelings of unreality, altered sense of time, and other 
changes in mood or affect amongst other neuropsychiatric observations which have been 
previously described (see Table 4.1 of the current Psilocybin IB).5 These effects are both 
expected, and may be a necessary component of therapeutic response. Investigators must 
follow regulatory guidance under 21 CFR 312.32(a) for AE reporting which addresses 
untoward medical occurrences associated with the use of a drug in humans, whether or 
not considered drug related. An AE can be any unfavourable and unintended sign (eg, an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a drug, without any judgment about causality.  
1.2.4 
Potential Risk to Foetal Development 
Reproductive toxicology studies have not been performed to establish risk to the fetus; 
however, the results of Ames test, the human lymphocyte micronucleus assay and the in 
vivo rat micronucleus study clearly indicate no potential for genotoxicity with psilocybin. 
It is recommended to prevent or eliminate such risk, if any, women should not be 
pregnant or lactating and should be using an effective method of birth control when using 
psilocybin.  
1.2.5 
Dosing Regimen 
Carhart-Harris successfully evaluated 2 oral doses of psilocybin (10 mg and 25 mg) 
administered 7 days apart to patients with unipolar TRD; minimal AEs were reported in 
this study.2 Work by the Griffiths group showed that under supportive conditions, 
psilocybin at doses of 20 to 30 mg/70 kg can dose-dependently occasion mystical-type 
experiences.11 
Therefore, this study will evaluate 3 single psilocybin doses (1 mg, 10 mg, or 25 mg 
psilocybin) under supportive conditions in this study.  

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2 STUDY OBJECTIVES 
The main purpose of this study is to allow COMPASS to determine the optimal dose of 
psilocybin, either 10 mg or 25 mg. The intent of the primary efficacy analysis is to 
demonstrate superiority of at least one optimal therapeutic dose of psilocybin (10 mg or 
25 mg) versus the 1 mg psilocybin via the following objectives. 
2.1 
Primary 
The primary objective of this study is to evaluate the efficacy of psilocybin (25 mg or 
10 mg) compared to 1 mg, administered under supportive conditions to adult participants 
with TRD, in improving depressive symptoms, as assessed by the change in the 
Montgomery-Asberg Depression Rating Scale (MADRS) total score from Baseline. 
Baseline is defined as the assessment score obtained on Day -1. The primary timepoint is 
Week 3; this variable will be analysed for the change from Baseline to Day 1, and 
Weeks 1, 3, 6, 9, and 12.  
2.2 
Secondary 
The secondary objectives are: 
• To assess the efficacy of psilocybin compared to 1 mg psilocybin on: 
o Proportion of participants with response defined as a ≥ 50% decrease in MADRS 
total score from Baseline to Week 3. This will also be assessed at Day 1 and at 
Weeks 1, 6, 9, and 12.  
o The proportion of participants who have a sustained response at Week 12. 
Sustained response is defined as the proportion of patients fulfilling response 
criteria at any visit up to and including Week 3, that also fulfills response criteria 
at all subsequent visits up to and including Week 12. Response is defined as 
≥ 50% decrease in MADRS total score from Baseline. 
• To evaluate the safety and tolerability of psilocybin in participants with TRD based 
on AEs, changes in vital signs, and suicidal ideation/behaviour (measured using the 
Columbia-Suicide Severity Rating Scale [C-SSRS]) score at all visits. 
2.3 
Exploratory  
The exploratory objectives are: 
o To evaluate the effects of psilocybin on quality of life and wellbeing, functioning 
and associated disability, cognitive function, and anxiety compared to 1 mg 
psilocybin on: 

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▪ Quality of life in participant EuroQoL (EQ) 5 dimension 3 level scale 
(EQ-5D-3L) score change from Baseline to Week 3. This will also be assessed 
at Week 12. This assessment is not mandatory. 
▪ Quality of life in caregiver EQ-5D-3L score change from Baseline to Week 3. 
This will also be assessed at Week 12. 
▪ Functioning and associated disability in the Sheehan Disability Scale (SDS) 
score change from Baseline to Week 3. This will be also assessed at Week 12. 
▪ Cognitive function as measured by the Digit Symbol Substitution Test (DSST) 
score change from Baseline to Week 3. This will also be assessed at Day 1 
and Week 12. 
▪ Level of anxiety as measured using the change in Generalised Anxiety 
Disorder 7 item Scale (GAD-7) total score change from Baseline to Week 3. 
This will also be assessed at Week 12. 
▪ Participant determined level of depression as measured using the change in 
Quick Inventory of Depressive Symptomatology Self-Rated (QIDS-SR-16) 
total score from Baseline to Week 3. This will also be assessed at Screening, 
Day 1, and Weeks 1, 2, 6, 9, and 12. 
▪ Psychosocial functioning and predictor of response durability as measured 
using the change in Work and Social Adjustment Scale (WSAS) from 
Baseline to Week 3. This will also be assessed at Week 12.  
▪ To evaluate the impact of different psilocybin doses on real life functional 
activity estimated from passive data streams collected on a mobile app on 
participants’ mobile phones. The data collected from the participant’s phone 
will include: 
• Number of and time of phone calls/e-mails/texts (content will not be 
collected) 
• Gestures used (taps, swipes, other) 
• Gyroscope (orientation) of the phone (the way the phone is pointing) 
• Acceleration of the phone (sudden movements of the phone) 
• Keystroke patterns with characters redacted 
• Location information from the GPS 

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• The app also maintains a histogram of daily words that the participant 
types on their phone. These words will be stripped from their context and 
syntax, thus preventing the content of any particular message from being 
deciphered. 
▪ Positive and Negative Affect Schedule (PANAS), Five Dimension Altered 
States of Consciousness Questionnaire (5D-ASC), 2a receptor polymorphism 
test and Scale to Assess Therapeutic Relationship (Clinician and Patient 
version, STAR-C and STAR-P, respectively) will be assessed for correlation 
with the primary and secondary outcomes as possible predictors of response. 

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3 STUDY ENDPOINTS  
3.1 
Primary 
The primary endpoint is the change in MADRS total score from Baseline (Day -1) to 
3 weeks post psilocybin.  
3.2 
Secondary 
The secondary endpoints are: 
o The proportion of participants with a response (defined as a ≥ 50% improvement 
in MADRS total score from Baseline) at Week 3 after the psilocybin session. 
o The proportion of participants with remission (defined as a MADRS total score 
≤ 10) at Week 3 post psilocybin.  
o The proportion of participants who have a sustained response at Week 12. 
Sustained response is defined as the proportion of patients fulfilling response 
criteria at any visit up to and including Week 3, that also fulfills response criteria 
at all subsequent visits up to and including Week 12. Response is defined as 
≥ 50% decrease in MADRS total score from Baseline. 
o Time to event measures: restart antidepressant medication for any reason, restart 
medication for continuing depressive symptoms, and relapse from a previously 
recovered state (clinical judgement, supported by the QIDS-SR-16). Participants 
who withdraw from the study will be censored from the time to event analysis. 
3.3 
Exploratory 
The exploratory endpoints are: 
o Change from Baseline in the following: 
▪ Participant EQ-5D-3L at Week 3 
▪ Caregiver EQ-5D-3L at Week 3 (this assessment is not mandatory) 
▪ SDS at Week 3 
▪ DSST at Week 3 
▪ GAD-7 at Week 3 
▪ QIDS-SR-16 at Week 3 
▪ WSAS at Week 3 

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▪ Measures derived from smart phone usage via the Mindstrong app 
3.4 
Efficacy and Outcome Measures 
Measures of interest include: 
o MADRS 
o SDS 
o QIDS-SR-16  
o GAD-7 
o DSST 
o EQ-5D-3L (participant and caregiver [latter is not mandatory]) 
o WSAS 

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4 STUDY PLAN 
4.1 
Study Design 
This is a Phase 2, international multicentre, randomised, fixed dose, double-blind trial. 
The study population will include adult men and women, 18 years of age and older, with 
TRD. Participants with TRD are defined as those who meet the Diagnostic and Statistical 
Manual of Mental Disorders (5th Edition; DSM-5) diagnostic criteria for single or 
recurrent episode of major depressive disorder (MDD) without psychotic features which 
have failed to respond to an adequate dose and duration of 2, 3, or 4 pharmacological 
treatments for the current episode; if single episode MDD, the duration of the current 
episode must be at least 3 months but not more than 2 years. Augmentation counts as a 
second treatment, provided it is approved for the adjunctive treatment of MDD in that 
country.  
Participants will be outpatients and will be recruited primarily from general practitioners 
and specialised psychiatric services.  
The majority of participants will have no prior exposure to psilocybin or so-called magic 
mushrooms; however, to reflect the prevalence of experience in general population, we 
will allow up to 10% of participants with prior recreational experience with psilocybin or 
magic mushrooms. Past exposure to psilocybin has to be more than 12 months prior to 
Screening and not during the current depressive episode. This will be constrained by the 
centralised randomisation process, Interactive Web-based Response System (IWRS). 
After signing the informed consent form (ICF), participants will be assessed for their 
eligibility with the Mini International Neuropsychiatric Interview (MINI), the Hamilton 
Depression Rating Scale (HAM-D-17), the Massachusetts General Hospital 
Antidepressant Treatment History Response Questionnaire (MGH-ATRQ), the C-SSRS, 
and McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD). 
Those who meet the eligibility criteria will enter the screening period which will last 
between 3 and 6 weeks. At the initial Screening visit (V1), the participant will also be 
evaluated with the QIDS-SR-16, and the Adult Self Report Scale (ASRS). Additionally, a 
medical history, an electrocardiogram (ECG), blood tests, and vital signs will be 
obtained.  
During the screening period, participants who are on antidepressant medications will be 
expected to complete the taper at least 2 weeks prior to Baseline (V2). Participants will 
be given a choice of the tapering rate. During the tapering period all participants will be 
supported by the study clinician. The designated study team member will be in frequent 
contact with the participants to monitor for withdrawal and worsening of depression 
symptoms. Participants will be assessed for suicidality with the C-SSRS at each 
contact/visit. 
Once a patient completes all V1 assessments and all screening data is entered into the 
Electronic Data Capture (EDC), the Medical Monitor (MM) and Clinical Assessment 

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Technologies Team (CAT) will review data entered and issue approval, if the patient is 
eligible. Once approval is issued, the patient should then be invited for a screening V1a 
visit. The V1a visit is the point at which the patient begins tapering off their 
antidepressant and/or antipsychotic medications, if appropriate. The patient must 
complete the taper within the first 4 weeks of this period, prior to 2 weeks completely off 
antidepressant and/or antipsychotic medications, before Baseline V2. The tapering period 
used in the study is set at the industry standard for depression trials. 
All participants will be evaluated for safety at the clinic weekly for a minimum of 
3 weeks prior to psilocybin administration to ensure safe discontinuation of current 
antidepressant therapy required by the protocol. Participants’ companions (friend or 
family member) will be educated about the signs of worsening of depression and 
suicidality, and instructed on ways to contact the study team in case of significant 
worsening of depression. Any safety assessment visits during the screening period will be 
called V1a, V1b, etc. During these visits, the C-SSRS and any changes in medications 
since the previous visit will be obtained in addition to other assessments at the study 
clinician’s discretion.  
The participant will meet with a therapist for a minimum of 3 visits during screening. 
These are called safety sessions and will cover what to expect during the psilocybin 
session. The therapist and the participant will review psychoeducational materials 
provided at the time of enrolment. 
The day before the psilocybin session, the participants will undergo a baseline assessment 
(3 to 6 weeks after initial Screening [V1]) that will consist of the HAM-D-17, MADRS, 
QIDS-SR-16, C-SSRS, SDS, GAD-7, DSST, EQ-5D-3L (administered to both participant 
and caregiver; [the latter is not mandatory]), WSAS, vital signs, urinalysis, urine drug 
screen, and urine pregnancy test (only for women of childbearing potential). Both the 
therapist and the participant will be asked to fill out a therapeutic alliance evaluation 
questionnaire, STAR-C and STAR-P, respectively. After baseline data is entered into 
EDC, the CAT team will complete a final review to ensure the participant’s continued 
eligibility. Participants cannot be progressed to V3 until this approval is received. 
The psilocybin administration session (V3, Day 0) will last approximately 6 h and will be 
supported by a trained therapist. Psilocybin sessions may be video recorded for training 
and adherence monitoring. A full description of the activities of the psilocybin 
administration session is found in the Therapist Manual. After the acute effects of the 
psilocybin pass, participants will be evaluated for safety and accompanied home. On 
Day 1 (V4), the day following psilocybin administration, participants will be seen in 
person for a safety check, assessment of suicidality, and to discuss their experience 
during the psilocybin session. All sessions between the therapist and the participant may 
be audio recorded for adherence monitoring and quality assurance. Audio and video 
recording of the sessions are subject to participant consent. Participants who do not 
consent to either or all recordings will not be excluded from the study.  

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All participants will be asked to remain off their antidepressant medications for at least 
3 weeks following the psilocybin session until the primary endpoint assessment, or 
longer. Rescue medications are allowed as noted in Section 8.5.4. Participants who restart 
their antidepressant medications during the first 3 weeks after the psilocybin treatment 
administration will be assessed for reasons of resuming their medications and followed 
until 12 weeks post psilocybin administration.  
The treatment period will determine the optimal therapeutic dose; 216 participants will be 
randomised in a 1:1:1 ratio to receive 1 mg psilocybin, 10 mg psilocybin, or 25 mg 
psilocybin. 
Participants will be seen at the clinic for Screening (V1, plus a minimum of 3 safety 
visits), Baseline (V2, Day -1), Day 0 (V3, Dosing), Day 1 (V4), Week 1 (V5), Week 2 
(V6), Week 3 (V7), and Week 12 (V10). Participants will also be contacted for follow-up 
at Week 6 (V8) and Week 9 (V9). The MADRS will be done by telephone and the other 
assessments will be done electronically. Participants are seen at the clinic for safety visits 
between the initial Screening (V1) and the Baseline (V2) visit, and the visits will be 
labelled V1a, V1b, V1c, etc. 
The study schematic is presented in Section 4.2 and the schedule of assessments is 
presented in Section 4.3.

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4.2 
Study Schematic 
 
 
Abbreviations: D = day; EoS = End of Study; V = Visit 
 
Randomisation 
1:1:1
D-1   D0    D1
Week 3
Week 12
3-6 weeks
Screening (V1)
D-1: Baseline (V2)
D0: Psilocybin Session (V3)
D1 (V4)
Week 1 (V5)
Week 2 (V6)
Week 3 (V7)
Additional 
Weekly 
Visits
(V1b, V1c, 
V1d, V1e, V1f)
Week 6 (V8) 
Week 9 (V9) 
Week 12 (EOS, V10)
25 mg psilocybin
72 subjects
10 mg psilocybin
72 subjects
1 mg psilocybin
72 subjects
Variable
Screening (V1a)

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4.3 
Schedule of Assessments 
 
 
3-6 weeks 
prior to 
Baseline 
 
 
Time Post Psilocybin Session 
 
Screen Visit2 
Screening 
Period 
Baseline 
(Day -1) 
Psilocybin 
Session  
(Day 0) 
Day 1 
Week 1 
Day 7 
Week 2 
Day 14 
Week 3 
Day 21 
Week 6 
Day 42 
Week 9 
Day 63 
Week 12 
Day 84 
(ET) 
Visit 
1 
1a, 1b, 
etc 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Location of Visit1 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Remote 
Remote 
Clinic 
Allowable Window 
 
Weekly 
 
≤ 7 days 
none 
±1 day 
±1 day 
± 1 day 
± 3 days 
± 3 days 
± 7 days 
 
Clinic Assessments and Procedures 
Informed Consent 
✓ 
 
 
 
 
 
 
 
 
 
 
Medical History 
✓ 
 
✓ 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
Criteria 
✓ 
 
✓ 
 
 
 
 
 
 
 
 
MINI 
✓ 
 
 
 
 
 
 
 
 
 
 
HAM-D-17 
✓ 
 
✓ 
 
 
 
 
 
 
 
 
MGH-ATRQ 
✓ 
 
 
 
 
 
 
 
 
 
 
STAR-C 
 
 
✓ 
 
 
 
 
 
 
 
 
C-SSRS3 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Vital signs 
✓ 
 
✓ 
✓ 
✓ 
 
 
 
 
 
 
Weight 
✓ 
 
 
 
 
 
 
 
 
 
 
Height 
✓ 
 
 
 
 
 
 
 
 
 
 
ECG 
✓ 
 
 
 
✓ 
 
 
 
 
 
 
Clinical laboratory 
tests and biomarker4 
✓ 
 
 
 
✓ 
 
 
✓ 
 
 
 
Urinalysis4 
✓ 
 
 
 
✓ 
 
 
 
 
 
 

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3-6 weeks 
prior to 
Baseline 
 
 
Time Post Psilocybin Session 
 
Screen Visit2 
Screening 
Period 
Baseline 
(Day -1) 
Psilocybin 
Session  
(Day 0) 
Day 1 
Week 1 
Day 7 
Week 2 
Day 14 
Week 3 
Day 21 
Week 6 
Day 42 
Week 9 
Day 63 
Week 12 
Day 84 
(ET) 
Visit 
1 
1a, 1b, 
etc 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Location of Visit1 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Remote 
Remote 
Clinic 
Allowable Window 
 
Weekly 
 
≤ 7 days 
none 
±1 day 
±1 day 
± 1 day 
± 3 days 
± 3 days 
± 7 days 
Urine Drug Screen4  
✓ 
 
✓ 
 
 
 
 
 
 
 
 
Urine Pregnancy Test5 
✓ 
 
✓ 
 
 
 
 
 
 
 
 
Documentation of 
Birth Control to be 
used6 
✓ 
 
 
 
 
 
 
 
 
 
 
2a polymorphism 
(optional)  
✓ 
 
 
 
 
 
 
 
 
 
 
Activate/deactivate 
Mindstrong (optional) 
✓ 
 
 
 
 
 
 
 
 
 
✓ 
Provide access to 
psychoeducational 
material (Longboat) 
✓ 
✓9 
 
 
 
 
 
 
 
 
 
Psilocybin dose 
 
 
 
✓10 
 
 
 
 
 
 
 
Prior/Concomitant 
Medications 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
AE/SAE 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Randomisation 
 
 
✓ 
 
 
 
 
 
 
 
 
 
Participant Completed Assessments 
5D-ASC 
 
 
 
✓7 
 
 
 
 
 
 
 
ASRS 
✓ 
 
 
 
 
 
 
 
 
 
 

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3-6 weeks 
prior to 
Baseline 
 
 
Time Post Psilocybin Session 
 
Screen Visit2 
Screening 
Period 
Baseline 
(Day -1) 
Psilocybin 
Session  
(Day 0) 
Day 1 
Week 1 
Day 7 
Week 2 
Day 14 
Week 3 
Day 21 
Week 6 
Day 42 
Week 9 
Day 63 
Week 12 
Day 84 
(ET) 
Visit 
1 
1a, 1b, 
etc 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Location of Visit1 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Remote 
Remote 
Clinic 
Allowable Window 
 
Weekly 
 
≤ 7 days 
none 
±1 day 
±1 day 
± 1 day 
± 3 days 
± 3 days 
± 7 days 
DSST 
 
 
✓ 
 
✓ 
 
 
✓ 
 
 
✓ 
EBI  
 
 
 
 
✓ 
 
 
 
 
 
 
EQ-5D-3L8 
 
 
✓ 
 
 
 
 
✓ 
 
 
✓ 
GAD-7 
 
 
✓ 
 
 
 
 
✓ 
 
 
✓ 
MSI-BPD 
✓ 
 
 
 
 
 
 
 
 
 
 
PANAS 
 
 
✓ 
 
✓ 
 
 
✓ 
 
 
 
QIDS-SR-16 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
SDS 
 
 
✓ 
 
 
 
 
✓ 
 
 
✓ 
STAR-P 
 
 
✓ 
 
 
 
 
 
 
 
 
WSAS 
 
 
✓ 
 
 
 
 
✓ 
 
 
✓ 
 
Remote-rater Assessment 
MADRS 
 
 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
Abbreviations: 5D-ASC, Five Dimension Altered States of Consciousness Questionnaire; AE, adverse event; ASRS, Adult Self-Report Scale; CRP, C-reactive protein; C-SSRS, Columbia-Suicide 
Severity Rating Scale; DSM-5 Diagnostic and Statiscal Maual of Mental Disorders (5th edtion);DSST, Digit Symbol Substitution Test; EBI, Emotional Breakthrough Inventory; 
ECG, electrocardiogram; EQ-5D, EuroQoL 5-dimension; ET, early termination; GAD-7, Generalised Anxiety Disorder 7; h, hour(s); HAM-D-17, Hamilton Depression Rating Scale; 
MADRS, Montgomery-Asberg Depression Scale; MGH-ATRQ, Massachusetts General Hospital Antidepressant Treatment History Questionnaire; MINI, Mini International Neuropsychiatric 
Interview; MSI-BPD, McLean Screening Instrument for Borderline Personality Disorder; PANAS, Positive and Negative Affect Schedule; QIDS-SR-16, Quick Inventory of Depressive 
Symptomatology-Self-rated; SAE, serious adverse event; SDS, Sheehan Disability Scale; STAR-C, Scale to Assess the Therapeutic Relationship-Clinician; STAR-P, Scale to Assess the Therapeutic 
Relationship-Patient; UK, United Kingdom; VAS, visual analogue scale; WSAS, Work and Social Adjustment Scale 
 
1  On site clinic visits; visits allowed remotely will have the MADRS performed by telpehone and other assessments will be done electronically. 

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2  If additional visits are needed to ensure adequate time for discontinuation of prior antidepressant therapy, visits should occur weekly prior to the psilocybin session (V3). At subsequent screening 
period visits (V1a, V1b, etc), medications taken and any changes in medications since the previous visit and C-SSRS will be obtained, in addition, to other assessments at the study clinician’s 
discretion. Assessments may be performed over several days, but all scales should be completed on the same day.  
3 The “Last 12 Months” version will be administered at Screening and the “Since Last Visit” version will be administered at all other visits.  
4 See Section 7.2.4 for complete list of required tests to be performed.  
5 For women of child-bearing potential only. 
6 Site is to document method of contraception agreed to be used by each participant. 
7 To be administered immediately after the psilocybin session. 
8 The EQ-5D-3L will be administered to both the participant and their caregiver (latter is not mandatory).   
9 Longboat access can be granted at V1 or V1a at the study team’s discretion. 
10 After baseline data is entered into EDC the CAT team will complete a final review to ensure the participant’s continued eligilblilty. Participants cannot complete psilocybin dose at V3 until this 
approval is received.   
11 Screening period visits should not be initiated until initial MM and CAT approval is received. Screening visits are to occur weekly 3-6 weeks prior to Baseline, number of visits is determined by the 
length of the participant’s taper off antidepressant medication. 
 
Instruments (all measures below will be captured electronically): 
5D-ASC – The Five Dimension Altered States of Consciousness Questionnaire measures the acute drug effects. 
ASRS – The Adult Self-Report Scale is a tool to screen for attention deficit hyperactivity disorder. The 6-item screener version will be administered.  
C-SSRS – Columbia-Suicide Severity Rating Scale assesses treatment-emergent suicidal thoughts. This scale should be administered prior to dosing, if possible. 
DSST – The Digit Symbol Substitution Test is a measure of cognition. It consists of a number of digit-symbol pairs, and requires individuals to note the corresponding symbol for a given digit under 
time-limited conditions. This test should be administered at approximately the same time of day each time to minimise the impact of diurnal variation on the results  
EBI – The Emotional Breakthrough Inventory is an 8-item brief measure intended to index the degree to which an individual experiences his/her emotion during a psilocybin session. It is a VAS style 
scale, typically with units from 0 to 100. It is typically rated within 24 h of a psychedelic experience and ideally within 5 h of the 'end' of the psychedelic experience or once acute drug effects have 
significantly subsided. 
EQ-5D-3L – The 3-level EQ-5D version (EQ‑5D‑3L) was introduced by the EuroQoL Group in 1990. The EQ-5D-3L essentially consists of 2 pages: the EQ-5D-3L descriptive system and the EQ 
visual analogue scale (EQ VAS). 
HAM-D-17 – The 17-item Hamilton Depression Rating scale measure the degree of symptom severity in depressed patients.  
GAD-7 – The Generalised Anxiety Disorder scale is a 7-item participant completed scale to assess anxiety in a participant.  
MADRS – the Montgomery-Asberg Depression Scale is a clinician rated outcome measure to assess a participant’s level of depression.  
MSI-BPD – The McLean Screening Instrument for Borderline Personality Disorder is a self-reporting screening tool to determine the presence of DSM-5 borderline personality disorder. 
PANAS - Positive and Negative Affect Schedule measures the acute emotional drug effects.  
QIDS-SR-16 – Quick Inventory of Depressive Symptomatology scale is a participant-rated scale to assess their depression.  
SDS – The Sheehan Disability Scale is a patient-reported outcome measure used to assess functional impairment and associated disability. 
STAR-C and STAR-P –Scale to Assess the Therapeutic Relationship completed by the clinician (STAR-C) and the patient (STAR-P) to assess the therapeutic relationship in community psychiatry with 
good psychometric properties sutiable for both research and routine care.  
WSAS – Work and Social Adjustment Scale is a self-report scale used to assess psychosocial functioning and to predict durability of response to antidepressant treatment. 
 
 
 

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5 POPULATION 
5.1 
Number of Participants 
A total of 216 participants are planned to be enrolled in the study. 
5.2 
Inclusion Criteria 
Participants meeting all the following inclusion criteria at Screening (V1) should be 
considered for admission into the study. 
1. Signed ICF. 
2. 18 years of age or older at Screening (V1). 
3. At least moderate MDD (single or recurrent episode as informed by DSM-5; if single 
episode, duration of ≥ 3 months and ≤ 2 years) based on medical records, clinical 
assessment and documented completion of the version 7.0.2 MINI. 
4. HAM-D-17 (17-item) score ≥ 18 at Screening (V1) and at Baseline (V2).  
5. Failure to respond to an adequate dose and duration of 2, 3, or 4 pharmacological 
treatments for the current episode as determined through the MGH-ATRQ and using 
the supplementary advice on additional antidepressants not included in MGH-ATRQ 
(Appendix III). Augmentation with an add on treatment counts as a second treatment, 
provided it is approved for the adjunctive treatment of MDD in that country. 
6. McLean Screening Instrument for Borderline Personality Disorder < 7 at Screening 
(V1). 
7. Have successfully discontinued all antidepressant medications at least 2 weeks prior 
to Baseline (V2) (see Section 8.5.3). 
8. Ability to complete all protocol required assessment tools without any assistance or 
alteration to the copyrighted assessments, and to comply with all study visits.  
5.3 
Exclusion Criteria 
Participants meeting any of the following exclusion criteria at Screening (V1) will not be 
enrolled in the study. 
Psychiatric Exclusion Criteria: 
1. Current or past history of schizophrenia, psychotic disorder (unless substance induced 
or due to a medical condition), bipolar disorder, delusional disorder, paranoid 
personality disorder, schizoaffective disorder, or borderline personality disorder, or 

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any serious psychiatric comorbidity as assessed by medical history and structured 
clinical interview (version 7.0.2 MINI). 
2. Prior electroconvulsive therapy and/or ketamine for current episode. 
3. Current cognitive behavioural therapy (CBT) that will not remain stable for the 
duration of the study. CBT cannot be initiated within 21 days of Baseline.  
4. Current (within the last year) alcohol or substance abuse as informed by DSM-5 at 
Screening (V1). 
5. Significant suicide risk as defined by (1) suicidal ideation as endorsed on items 4 or 5 
on the C-SSRS within the past year, at Screening or at Baseline, or; (2) suicidal 
behaviors within the past year, or; (3) clinical assessment of significant suicidal risk 
during subject interview.  
6. Depression secondary to other medical conditions.  
7. Other personal circumstances and behaviour judged to be incompatible with 
establishment of rapport or safe exposure to psilocybin, including exposure to 
psilocybin within the past year and use of psychedelics, such as ayahuasca, during the 
current depressive episode.  
General Medical Exclusion Criteria:  
8. Women who are pregnant, nursing, or planning a pregnancy. Participants who are 
sexually active must agree to use a highly effective contraceptive method (as listed in 
Section 8.5.2) throughout their participation in the study. Women of child bearing 
potential must have a negative urine pregnancy test at Screening (V1) and Baseline 
(V2). 
9. Cardiovascular conditions: recent stroke (< 1 year from signing of ICF), recent 
myocardial infarction (< 1 year from signing of ICF), hypertension (blood pressure 
> 140/90 mmHg) or clinically significant arrhythmia within 1 year of signing the ICF. 
10. Uncontrolled insulin-dependent diabetes. 
11. Seizure disorder.  
12. Positive urine drug screen for illicit drugs or drugs of abuse at V1 and/or V2 
(cannabis for medicinal purposes or recreational use is permitted). Any positive urine 
drug test will be reviewed with participants to determine the pattern of use and 
eligibility will be determined at the investigator’s discretion in conjunction with the 
medical monitor.  
13. Current enrolment in any investigational drug or device study or participation in such 
within 30 days of Screening (V1). 

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14. Current enrolment in an interventional study for depression or participation in such 
within 30 days of Screening (V1).  
15. Abnormal and clinically significant results on the physical examination, vital signs, 
ECG, or laboratory tests at Screening (V1).  
16. Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, 
renal or any other major concurrent illness that, in the opinion of the investigator, 
may interfere with the interpretation of the study results or constitute a health risk for 
the participant if he/she takes part in the study.  
5.4 
Participant Screening 
Participants will be outpatients and will be recruited from general practitioners and 
specialised psychiatric services. Those participants considered eligible for the study will 
be further assessed to confirm eligibility after the participant has signed an ICF. All 
participants will then be seen weekly for at least 3 weeks prior to the Psilocybin Session 
(V3) to ensure the safe discontinuation of current antidepressant therapy required by the 
protocol. Rescreening of participants considered not eligible for the study will be 
allowed. 
5.5 
Deviation from Inclusion/Exclusion Criteria 
No deviations will be permitted from the Inclusion or Exclusion Criteria. The investigator 
may call the Medical Monitor to discuss the eligibility of any given participant.  
 

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6 STUDY CONDUCT 
The procedures to be performed throughout the study are outlined in the Schedule of 
Assessments (Section 4.3). A detailed description of each assessment may be found in 
Section 6.2.  
6.1 
General Instructions 
Participants will be outpatients and will be recruited from general practitioners and 
specialised psychiatric services. Those participants considered eligible for the study will 
be further assessed to confirm eligibility after the participant has signed an ICF.  
6.2 
Study Procedures by Time Point 
6.2.1 
Screening Period 
The participant will be seen initially to evaluate suitability for the study. All participants 
will be seen at the clinic weekly for a minimum of 3 weeks prior to Baseline (V2) to 
ensure safe discontinuation of current antidepressant therapy required by the protocol, 
and to conduct psychoeducation. 
At the initial Screening visit (V1), the following assessments will be performed and 
recorded. These assessments may be performed over several days, but all scales should 
be completed on the same day. All clinician or participant-rated assessments throughout 
the study will be captured electronically. 
o ICF 
o Medical history 
o Prior and current medications; the participant will be tapered from prohibited 
medications (see Section 8.5.3), if any, under the supervision of the study 
clinician 
o Review of inclusion/exclusion criteria (Section 5) 
o MINI version 7.0.2 
o HAM-D-17 
o MGH-ATRQ 
o C-SSRS (Last 12 Months) 
o MSI-BPD 
o ASRS 

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o QIDS-SR-16 
o Vital signs (ie, sitting blood pressure, pulse, body temperature, and respiratory 
rate) 
o Weight 
o Height 
o 12-lead ECG 
o Blood and urine samples for: 
▪ Clinical laboratory tests  
▪ 2a polymorphism (optional) 
▪ Biomarker (C-reactive protein [CRP]) 
▪ Urinalysis 
▪ Urine drug screen 
▪ Urine pregnancy test for all women of childbearing potential 
o Document contraceptive method to be used by the participant 
o If the participant opts to participate in the Mindstrong app, the app will be loaded 
on the participant’s mobile phone and activated 
o All participants will undergo an in-person preparatory session before receiving 
access to a digital study platform (Longboat) for psychoeducation 
Before the participant progresses further in the screening period (ie, before they attend 
Visit 1a), the PI will receive 2 email notifications, 1 from the medical monitor and 1 from 
the CAT group, to confirm eligibility. Once these notifications are received (and the 
participant is deemed eligible), the participant can proceed to the next visit (V1a). 
Patients cannot begin psychoeducation or tapering off their antidepressant medication 
until they attend the clinic for the screening visit V1a. 
At subsequent screening period visits (V1a, V1b, etc), medications taken and any 
changes in medications since the previous visit, and the C-SSRS will be obtained. 
6.2.2 
Baseline Visit – Visit 2 – Day -1 
The Baseline visit (V2) should occur 3 to 6 weeks after initial Screening (V1). At the 
Baseline visit (V2), the participant’s eligibility will be confirmed by reviewing the 

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Inclusion/Exclusion Criteria (Sections 5.2 and 5.3) and updating the medical history. The 
Baseline visit (V2) should occur the day before the anticipated psilocybin session. The 
following procedures will be performed and recorded at the Baseline visit (V2): 
o Remote-rater MADRS 
o HAM-D-17 
o STAR-C 
o C-SSRS (Since Last Visit) 
o SDS 
o STAR-P 
o GAD-7 
o EQ-5D-3L (administered to both participant and caregiver; the latter is not 
mandatory) 
o PANAS 
o DSST 
o QIDS-SR-16 
o WSAS 
o Vital signs (ie, sitting blood pressure, pulse, body temperature, and respiratory 
rate) 
o Urine samples for: 
▪ Urinalysis 
▪ Urine drug screen 
▪ Urine pregnancy test for all women of childbearing potential 
o Medications taken and any changes in medications since the previous visit 
If the participant continues to meet the eligibility criteria, the trained therapist will review 
the psychoeducational material and the anticipated psilocybin session with the 
participant. If the participant remains eligible, randomise the participant to the 
appropriate investigational product (IP) (ie, 1 mg, 10 mg, or 25 mg psilocybin) using the 
IWRS (Section 8.2) and arrange for the participant to return to the study site for IP 

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administration the next day. After baseline data is entered into EDC, the CAT team will 
complete a final review to ensure the participant’s continued eligibility. Participants 
cannot be progressed to V3 until this approval is received. 
6.2.3 
Visit 3 – Day 0 – Psilocybin Session 
The psilocybin session (V3) should occur the day after Baseline visit (V2). In exceptional 
circumstances the participant may visit the clinic ≤ 7 d following the Baseline visit (V2). 
A preparation session with the therapist is always conducted the day before the 
psilocybin session, even if the psilocybin session is not conducted the day after Baseline 
(V2). If the participant is out of the ≤ 7-day window, all baseline assessments are to be 
repeated, except randomisation. At the psilocybin session (the day of IP administration), 
the following are to be obtained: 
o Vital signs (ie, sitting blood pressure, pulse, body temperature, and respiratory 
rate)  
o Administer IP (Section 8.3). The psilocybin session may be video recorded for 
training and adherence monitoring. A full description of the activities of the 
psilocybin session is found in the Therapist Manual. After the acute effects of the 
psilocybin pass, participants will be accompanied home.  
o 5D-ASC 
o C-SSRS (Since Last Visit) 
o QIDS-SR-16 
o Medications taken and any changes in medications since the previous visit 
o AEs and Serious AEs (SAEs) (Sections 9 and 10)  
6.2.4 
Visit 4 – Day 1 Postdosing 
On the day following IP administration, the participant will return to the study site for a 
safety check and to discuss their experience during IP during the psilocybin 
administration session. The following will be obtained at this visit: 
o Remote-rater MADRS 
o C-SSRS (Since Last Visit) 
o Emotional Breakthrough Inventory (EBI)  
o PANAS 
o DSST 

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o QIDS-SR-16 
o Vital signs (ie, sitting blood pressure, pulse, body temperature, and respiratory 
rate) 
o 12-lead ECG 
o Blood samples for clinical laboratory tests and biomarker 
o Medications taken and any changes in medications since the previous visit 
o AE and SAE (Sections 9 and 10) 
Participants will be reminded to remain off any antidepressant medications until after V7. 
6.2.5 
Visit 5 – 1 Week Postdosing 
The participant will visit the clinic 1 week (7 days ± 1 day) following IP administration; 
the following assessments will be obtained at this visit: 
o Remote-rater MADRS 
o C-SSRS (Since Last Visit) 
o QIDS-SR-16 
o Medications taken and any changes in medications since the previous visit 
o AE and SAE (Sections 9 and 10)  
Participants will be reminded to remain off any antidepressant medications until after V7. 
6.2.6 
Visit 6 – 2 Weeks Postdosing 
The participant will visit the clinic 2 weeks (14 days ± 1 day) following IP 
administration; the following assessments will be obtained at this visit: 
o C-SSRS (Since Last Visit) 
o QIDS-SR-16 
o Medications taken and any changes in medications since the previous visit 
o AE and SAE (Sections 9 and 10) 
Participants will be reminded to remain off any antidepressant medications until after V7. 

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6.2.7 
Visit 7 – 3 Weeks Postdosing 
The participant will visit the clinic 3 weeks (21 days ± 1 day) following IP 
administration; the following assessments will be obtained at this visit: 
o Remote-rater MADRS 
o C-SSRS (Since Last Visit) 
o SDS 
o GAD-7 
o EQ-5D-3L (administered to both participant and caregiver [the latter is not 
mandatory]) 
o PANAS 
o DSST 
o QIDS-SR-16 
o WSAS 
o Blood samples for clinical laboratory tests and biomarker  
o Medications taken and any changes in medications since the previous visit 
o AE and SAE (Sections 9 and 10) 
Participants will be reminded to remain off any antidepressant medications until after V7. 
6.2.8 
Visit 8 – 6 Weeks Postdosing 
The participant will be contacted by telephone by site staff or visit the clinic at the 
investigator’s discretion 6 weeks (42 days ± 3 days) following IP administration. All 
clinician or participant-rated assessments throughout the study will be captured 
electronically: 
o Remote-rater MADRS 
o C-SSRS (Since Last Visit) 
o QIDS-SR-16 
o Medications taken and any changes in medications since the previous visit  
o AE and SAE (Sections 9 and 10)  

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6.2.9 
Visit 9 – 9 Weeks Postdosing 
The participant will be contacted by telephone 9 weeks (63 days ± 3 days) following IP 
administration; the following assessments will be obtained: 
o Remote-rater MADRS 
o C-SSRS (Since Last Visit) 
o QIDS-SR-16 
o Medications taken and any changes in medications since the previous visit  
o AE and SAE (Sections 9 and 10) 
6.2.10 
Visit 10 – 12 Weeks Postdosing – End of Study 
The participant will visit the clinic 12 weeks (84 days ± 7 days) following IP 
administration for the End of Study (EOS) visit; this visit is also to be completed if the 
participant is discontinued from the study early (early termination [ET]). The following 
assessments will be obtained at this visit: 
o Remote-rater MADRS 
o C-SSRS (Since Last Visit) 
o SDS 
o GAD-7 
o EQ-5D-3L (administered to both participant and caregiver [the latter is not 
mandatory]) 
o DSST 
o QIDS-SR-16 
o WSAS 
o Deactivate Mindstrong app, if appropriate 
o Medications taken and any changes in medications since the previous visit  
o AEs and SAEs (Sections 9 and 10) 

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6.3 
Premature Discontinuation 
If the participant’s participation in the study is terminated prematurely for any reason, the 
reason for such ET should be documented and the V10 (EOS) procedures should be 
performed as noted in Section 6.2.10. 
A termination electronic Case Report Form (eCRF) page should be completed for every 
participant who is randomised, whether the participant completes the study or not. The 
reason for any ET should be indicated on this form; as much information should be 
provided as possible. The primary reason for a participant discontinuing early should be 
selected from the following standard categories of ET: 
• Screen Failure: Participant does not qualify to participate in the study. 
• Lack of efficacy 
• Adverse Event: Clinical or laboratory events occurred that, in the medical judgment of 
the investigator for the best interest of the participant, are grounds for discontinuation. 
This includes serious and nonserious AEs regardless of relation to the IP. 
• Death: The participant died. 
• Withdrawal of Consent: The participant desired to withdraw from further 
participation in the study in the absence of an investigator-determined medical need 
to withdraw. If the participant gave a reason for withdrawing, it should be recorded in 
the eCRF. 
• Protocol Violation: The participant’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements (eg, drug 
noncompliance, failure to return for defined number of visits). The violation 
necessitated early discontinued from the study. 
• Lost to Follow-Up: The participant stopped coming for visits and study personnel 
were unable to contact the participant. 
• Non-compliance: The participant was non-compliant with study visits or procedures.  
• Other: The participant was discontinued for a reason other than those listed above, 
such termination of study by COMPASS. 

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7 DESCRIPTION OF STUDY PROCEDURES 
7.1 
Efficacy Assessments 
All measures below will be captured electronically. 
7.1.1 
Montgomery-Asberg Depression Rating Scale 
MADRS evaluations will be performed by an independent remote rater who is blinded to 
the participant’s treatment assignment at Baseline, Day 1, and Weeks 1, 3, 6, 9, and 12 
(V2, V4, V5, V7, V8, V9, and V10, respectively). The MADRS is a clinician-rated scale 
measuring depression severity, consisting of 10 items, each scored from 0 (normal) to 
6 (severe), for a total possible score of 60; higher scores denote greater severity.22 The 
structure of the telephone-based interview will be controlled through the use of The 
Structured Interview Guide for the MADRS (SIGMA),41 which provides structured 
probes to ensure standardisation of administration and comprehensive coverage of 
10 questions. 
7.1.2 
Quick Inventory of Depressive Symptomatology 
The 16-item QIDS-SR-16 a self-rated scale designed to assess the severity of depressive 
symptoms in the nine diagnostic symptom domains of a major depressive episodes, 
exclusive of atypical or melancholic symptoms.27 The QIDS-SR-16 is sensitive to change 
with various treatments, demonstrating its utility in research settings. The total score 
ranges from 0 to 27 with 0 representing no depression and 27 representing severe 
depression. The total score is the sum of the 9 symptom domains. The QIDS-SR-16 will 
be collected at every clinic visit or contact with the participant. 
7.1.3 
Sheehan Disability Scale 
The SDS is a brief, 5-item self-report inventory that assesses functional impairment in 
work/school, social life, and family life. The total score ranges from 0 to 30 with 
0 representing no impairment and 30 representing severe impairment. The last two items 
of the scale (Days Lost and Days Unproductive) do not count toward the total score. Each 
domain is rated on a 10-point visual analogue scale (VAS).30 The SDS will be obtained at 
Baseline, and Weeks 3 and 12 (V2, V7, and V10, respectively).  
7.1.4 
Generalised Anxiety Disorder scale 
The GAD-7 is useful in primary care and mental health settings as a screening tool and 
symptom severity measure for the seven most common anxiety disorders.32 Participants 
choose one of 4 severity scores associated problems related to the common anxiety 
disorders and then indicate the degree to which these problems caused functional and/or 
social difficulties. Scores are determined by calculating the values for each column. A 
total score is obtained by the sum of all total column values. The GAD-7 will be obtained 
using the ePRO device at Baseline, and Weeks 3 and 12 (V2, V7, and V10, respectively).  

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7.1.5 
Digit Symbol Substitution Test 
The DSST is a neuropsychological test sensitive to brain damage, dementia, age and 
depression.36 The DSST consists of digit-symbol pairs followed by a list of digits. The 
participant will select the corresponding symbol as fast as possible. The number of 
correct symbols within 90 seconds will be recorded at Baseline, Day 1, and Weeks 3 and 
12 (V2, V4, V7, and V10, respectively). 
7.1.6 
EuroQoL-5-dimension 3-level Scale 
The 3-level EQ-5D version (EQ‑5D‑3L) was introduced by the EuroQoL Group in 
1990.17,35 The EQ-5D-3L essentially consists of 2 pages: the EQ-5D-3L descriptive 
system and the EQ visual analogue scale (EQ VAS).  
The descriptive system comprises five dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, slight 
problems, moderate problems, severe problems and extreme problems. The participant is 
asked to indicate his/her health state by ticking the box next to the most appropriate 
statement in each of the five dimensions. This decision results in a 1-digit number that 
expresses the level selected for that dimension. The digits for the five dimensions can be 
combined into a 5-digit number that describes the participant’s health state. 
The EQ VAS records the participant’s self-rated health on a vertical VAS, where the 
endpoints are labelled ‘The best imaginable health state’ and ‘The worst imaginable 
health state’. The VAS can be used as a quantitative measure of health outcome that 
reflect the participant’s own judgement.  
The EQ-5D-3L will be obtained at Baseline, and Weeks 3 and 12 (V2, V7, and V10, 
respectively). Administration to a caregiver is not mandatory. 
7.1.7 
Work and Social Adjustment Scale 
The WSAS is a 5-item self-report scale used to assess psychosocial functioning and to 
predict durability of response to antidepressant treatment.18 Each of the 5 questions is 
rated on a scale from 0 to 8, where 0 is no impairment and 8 is very severe impairment. A 
WSAS score above 20 appears to suggest moderately severe or worse psychopathology.23 
Scores between 10 and 20 are associated with significant functional impairment but less 
severe clinical symptomatology. Scores below 10 appear to be associated with subclinical 
populations. 
The WSAS will be performed at Baseline and Weeks 3 and 12 (V2, V7, and V10, 
respectively), and will be captured electronically.  

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7.2 
Safety Assessments 
7.2.1 
Columbia-Suicide Severity Rating Scale 
The C-SSRS will be used to assess suicide potential or tendency as a study entry criteria 
and monitored throughout the study. 
The C-SSRS is a semi-structured interview designed to assess the severity and intensity 
of suicidal ideation, suicidal behavior, and nonsuicidal self-injurious behavior over a 
specified time period. The measurement of suicidal ideation is based on 5 “yes” or “no” 
questions with accompanying descriptions arranged in order of increasing severity. If the 
patient answers “yes” to either questions 1 or 2, the intensity of ideation is assessed in 
5 additional questions related to frequency, duration, controllability, deterrents, and 
reasons for the most severe suicidal ideation. Suicidal behavior is assessed by asking 
questions categorizing behaviors into actual, aborted, and interrupted attempts; 
preparatory behavior; and nonsuicidal self-injurious behavior.  
If any item(s) on the C-SSRS are answered “yes”, the primary investigator or physician 
investigator must review the patient’s responses in order to (a) at screening and Baseline 
determine the patient’s study eligibility and potential need for referral to a mental health 
professional, and (b) during the study evaluate the patient’s need for appropriate medical 
management such as a referral to a mental health professional. 
A significant risk of suicide is defined as a “yes” in answer to (a) questions 4 or 5 on the 
suicidal ideation section; or (b) any questions on any item in the suicidal behavior 
section. This must be reported as an SAE and followed up accordingly. Additionally, if a 
patient responds “yes” to any of the suicidal ideation questions 1 through 3, the 
investigator should apply clinical judgment to determine the need for reporting this as an 
AE or SAE and the need for any appropriate referral.  
7.2.2 
Vital Signs  
Blood pressure will be measured supine, after at least 5 min at rest. The three 
measurements should be recorded 1 to 2 min apart, and the results averaged to inform 
eligibility. Respiratory rate, body temperature, and pulse rate will be obtained at 
Screening, Baseline, Day 0, and Day 1 (V1, V2, V3, and V4, respectively).  
7.2.3 
Electrocardiogram  
Standard 12-lead ECGs will be obtained at Screening (V1) and Day 1 (V4). 

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7.2.4 
Clinical Laboratory Tests 
Blood samples will be obtained at Screening (V1), Day 1 (V4), and Week 3 (V7) for the 
following:  
• Haematology: haemoglobin, haematocrit, red blood cell count, mean corpuscular 
haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin 
concentration, white blood cell count (with differential), and platelet count.  
• Chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), amylase, 
aspartate aminotransferase (AST), bicarbonate, bilirubin (direct, indirect, and total), 
calcium, chloride, creatine kinase, creatinine, gammaGT, glucose, lactate 
dehydrogenase, lipase, magnesium, phosphate, potassium, protein-total, sodium, urea 
(blood urea nitrogen), and uric acid.  
• Biomarker: C-reactive protein. 
• Other: 2a polymorphism at Screening (V1) only (optional). 
Urine samples will be obtained at Screening (V1) and Baseline (V2) for the following:   
• Urinalysis: A dipstick urinalysis will be performed for blood, glucose, ketone, 
protein, pH, specific gravity, nitrite, leukocytes, bilirubin, and urobilinogen. 
• Urine Drug Screen: for illicit drugs or drugs of abuse at Screening (V1) and Baseline 
(V2). Results of a positive drug screen will be reviewed by the study clinican for 
pattern of use. 
• Urine Pregnancy Test: a dipstick test in women of childbearing potential at Screening 
(V1) and Baseline (V2).  
Laboratory samples will be analysed by a central laboratory (Eurofins) to ensure 
consistent interpretation of results. Instructions for shipment of samples and review of 
results is provided in the Laboratory Manual. In the event of an unexplained clinically 
significant abnormal laboratory test value, the test should be repeated and followed up 
until it has returned to the normal range and/or an adequate explanation of the 
abnormality is found. 
7.2.5 
Adverse Events 
All AEs occurring after the participant signs the ICF and up to the last study event will be 
recorded. Any AEs occurring before the start of treatment (ie, before the dose of the IP on 
Day 0 [V3]) will be recorded in the medical history. Any AE ongoing at V10 (EOS/ET) 
will be followed until resolution or no longer considered clinically significant by the 
investigator.  

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See Section 9 and 10 for additional information. 
7.3 
Other Assessment Instruments  
7.3.1 
Hamilton Depression Rating Scale – 17-item 
The HAM-D-17 17-item scale is used to measure the degree of symptom severity in 
depressed patients.12 The HAM-D-17 rating will be performed by the investigator using 
the eCOA device at the Screening (V1) and Baseline (V2) only. The total score from this 
assessment will be used as eligibility criteria prior to treatment (minimal total symptom 
score ≥ 18). The Structured Interview Guide for the HAM-D-17 (SIGH-D) will be 
administered.40 This will be captured electronically. 
7.3.2 
Mini International Neuropsychiatric Interview 
The MINI was designed as a brief structured interview for the major Axis I psychiatric 
disorders in DSM-5 and International Classification of Diseases-10. Validation and 
reliability studies have been done comparing the MINI to the Structured Clinical 
Interview for DMS-5 Patient Edition and the Composite International Diagnostic 
Interview (a structured interview developed by the World Health Organization). 
Version 7.0.2 of the MINI will be used for this study. The results of these studies show 
that the MINI has similar reliability and validity properties, but can be administered in a 
much shorter period (mean 18.7 ± 11.6 min, median 15 min) than the above referenced 
instruments. It can be used by clinicians after a brief training session.31 
At Screening (V1), participants will be assessed for MDD, as documented by DSM-5 
criteria, and the lack of other psychiatric diagnoses will be confirmed by use of the 
MINI.31 
7.3.3 
Massachusetts General Hospital-Antidepressant Treatment 
History Questionnaire 
The MGH-ATRQ is a self-rated scale used to determine treatment resistance in major 
depressive disorder.4 The scale examines the efficacy (improvement from 0%, not 
improved at all to 100% completely improved, and adequacy of a treatment. Participants 
are asked by clinician about treatment adherence to each medication trial and examines 
the participants’ antidepressant history to identify pseudo-resistance and treatment 
resistance. The MGH-ATRQ will be collected at Screening (V1) only. This will be 
captured electronically. 
7.3.4 
McLean Screening Instrument for Borderline Personality Disorder  
The MSI-BPD is a commonly used measure to assess for BPD.42 The scale consists of 
10 items based on the DSM-5 BPD criteria; the first 8 items represent the first eight 
criteria in the DSM-5 for BPD diagnosis, while the last two questions assess the paranoia 
and dissociation criteria for BPD. Scores for the MSI-BPD range from 0 to 10, with each 

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item rated as “1” if present and “0” if absent. A score of 7 or higher indicates a likelihood 
for the participant to meet criteria for BPD. The MSI-BPD will be collected at Screening 
(V1) only. This will be captured electronically. 
7.3.5 
Adult Self-Report Scale 
The ASRS is a self-reported questionnaire used to determine the presence of attention 
deficit hyperactivity disorder in adults.19 The screener (6-item) version of the scale will 
be used in this study. The first question concerns inattention and the other 5 questions 
assess hyperactivity-impulsivity. Each question is answered on a 5-point Likert-type 
scale, ranging from “Never” to “Very Often”. This scale will be obtained at Screening 
(V1) only and will be captured electronically. 
7.3.6 
Scale to Assess Therapeutic Relationships – Patient and Clinician 
Version 
The STAR-P and STAR-C is a 12-item measure assessing the therapeutic relationship 
between patient and clinician on three components: Collaboration, Positive Clinician 
Input, and Emotional Difficulties (clinician version)/Non-Supportive Clinician (patient 
version) input.21 The Collaboration subtest reflects a good rapport and a shared 
understanding of goals, mutual understanding, openness, and trust. Positive Clinician 
Input reflects the perception (by the participant) of the clinician to encourage, support, 
and listen to the participant. Emotional Difficulties/Non-Supportive Clinician Input 
reflect problems in the relationship. The range of total scores for both versions is 0–48, 
with a higher score suggesting better therapeutic relationships. Each version of the scale 
takes approximately 5 min to complete. Total scores and subscale totals can be obtained. 
The STAR-P and STAR-C will be collected at Baseline (V2) only. These will be 
captured electronically. 
7.3.7 
Five Dimension Altered States of Consciousness Questionnaire 
The 5D-ASC measures the acute drug effects using 5 primary dimensions and respective 
subdimensions to assess alterations in mood, perception, and experience of self in relation 
to environment and thought disorder. The 5 dimensions include oceanic boundlessness, 
anxious ego dissolution, visionary restructuralization, auditory alterations, and reduction 
of vigilance.6,7,33 This will be administered immediately after the psilocybin session on 
Day 0 (V3). This will be captured electronically. 
7.3.8 
The Positive and Negative Affect Schedule 
The PANAS measures the acute emotional drug effects, and comprises 2 mood scales 
that measure positive and negative affect.38 Participants respond to 20 items using a 
5-point scale that ranges from “slightly or not at all (1)” to “extremely (5)”. A total higher 
score on the positive affect questions indicates more of a positive affect while a lower 
score on the negative affect questions indicates less of a negative affect. This will be 

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administered at Baseline (V2), the day after the psilocybin session (V4), and at Week 3 
(V7). This will be captured electronically. 
7.3.9 
Emotional Breakthrough Inventory  
The EBI is a VAS that describes the intensity and quality of the emotional experience 
following the psilocybin session, developed by the Imperial College London. This is 
collected on Day 1 (V4) electronically.  
7.3.10 
Mindstrong application 
If the participant opts to participate in the Mindstrong portion of the study, an app will be 
activated on the participant’s mobile phone at V1; it will be deactivated at the EOS. 
Mobile data collection: The Mindstrong app will collect data from the participant’s smart 
phone and periodically send these data back to the Mindstrong secure database. The 
participant will not need to do anything to collect these, except use their phone as they 
normally do. The data collected from the participant’s phone will include: 
o Number of and time of phone calls/e-mails/texts (content will not be collected) 
o Location information from the GPS 
o Orientation of the smart phone (the way the phone is pointing) 
o Acceleration of the smart phone (sudden movements of the phone) 
o Keystroke information with characters redacted 
o Gestures used (taps, swipes, other) 
The app may also maintain a list of target words and the participant’s use-frequency of 
these words. These words will be completely stripped from their context, thus preventing 
the content of any particular message from being deciphered. 
The data collection application does NOT collect information on who or what number the 
participant calls or receive calls from. The data collection application does NOT capture 
the content of messages the participant sends or receives in a readable format. No 
personally identifiable information is captured and all other data are encrypted on the 
smartphone before transmission to the Mindstrong data enclave hosted on Amazon Web 
Service’s cloud computers. 
Specifically, the application does NOT collect: 
o Email addresses of the emails that the participant sends or receives 
o Phone numbers of the phone calls that the participant makes or receives 

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o Phone numbers of the text messages that the participant makes or receives 
o Messages sent or received in a readable format 
7.4 
Protocol Deviations 
All protocol deviations will be assessed and documented on a case-by-case basis before 
the database lock, and deviations considered having a serious impact on the efficacy 
results will lead to the relevant participant being excluded from the analysis. 
Protocol deviations will be summarised by centre and grouped into different categories, 
as follows:  
o those who entered the study even though they did not satisfy the entry criteria; 
o those who developed withdrawal criteria during the study but were not 
withdrawn; 
o those who received the wrong treatment or incorrect dose; 
o those who took any prohibited medications during the study. 
 

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8 INVESTIGATIONAL PRODUCT MANAGEMENT 
8.1 
Description 
Information about the IP is provided in Table 8.1. 
Table 8.1 
Details of Investigational Product 
 
Psilocybin 
Psilocybin 
Placebo 
Ingredient 
Psilocybin 
Psilocybin 
placebo 
Manufacturer 
Juniper Pharma Services Ltd,  
8 Orchard Place,  
Nottingham Business Park,  
Nottingham, NG8 6PX, UK 
Dose(s) 
1 mg 
10 mg and 25 mg 
Not applicable 
Route 
Oral 
Oral 
Oral 
Formulation 
Capsule 
Capsule 
Capsule 
Strength(s) 
1 mg 
5 mg 
Not applicable 
8.1.1 
Formulation  
Matching psilocybin capsules, 1 mg and 5 mg, and the matching placebo capsules were 
manufactured by Juniper Pharma Services, Ltd.  
8.1.2 
Storage 
All IP must be kept in a locked area with limited access. The high-density polyethylene 
(HDPE) bottles of IP are to be stored as indicated in the IP Handling Manual. Deviations 
of storage temperature outside this required range should be documented and COMPASS 
or its designee should be notified promptly. Bottles of IP should not be frozen. If any 
component of the IP is damaged, COMPASS or its designee must be notified as soon as 
possible.  
8.2 
Packaging and Blinding 
Psilocybin and placebo capsules were packaged into HDPE containers with 
child-resistant, tamper-evident screw cap lids with a mounted desiccant by Fisher Clinical 
Services UK Ltd (Langhurstwood Road, Horsham, West Sussex, RH12 4QD, UK). Each 
bottle contains 5 capsules for a single dose administration. Labels are affixed on to the 
bottles consistent with regulations in participating countries. Single individual bottles will 
be provided for use by a given participant. Bottles for each participant will be assigned 
according to unique identifiers by IWRS. Refer to the IP Handling Manual for additional 
details. 

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The IWRS will be programmed with blind-breaking instructions. The study blind should 
NOT be broken for a given participant except in a medical emergency where knowledge 
of the dose of IP received would impact treatment of the emergency. If, in the opinion of 
the investigator, it is in the participant's best interest to know the IP assignment, the blind 
may be broken as instructed in the IWRS. COMPASS must be notified before the blind is 
broken unless identification of the IP is required for a medical emergency in which the 
knowledge of the specific blinded IP will affect the immediate management of the 
participant's condition. In this case, COMPASS must be notified within 24 h after 
breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and eCRF, as applicable. 
8.3 
Dose and Administration 
In preparation for dosing on Day 0 (V3), the site will use the IWRS to randomise the 
participant to the appropriate therapy after it is confirmed at Baseline (V2) the participant 
remains eligible to participate in the study; randomisation will be stratified by country. 
Using IWRS, each participant will be assigned 1 treatment bottle containing 5 capsules 
packaged in a double-blind fashion, depending on the randomised treatment arm, the 
bottle will contain 1 of the following: 
o 10 mg treatment bottle: 2 × 5 mg capsules and 3 × placebo capsules 
o 25 mg treatment bottle: 5 × 5 mg capsules 
o 1 mg treatment bottle: 1 × 1 mg capsule and 4 × placebo capsules 
After a light breakfast taken 2 h prior to dosing and under observation of study staff, the 
5-capsule dose is to be swallowed with a full glass of water; due to the number of 
capsules in a dose, additional water may be necessary to swallow the dose. Study staff 
will ensure the entire 5-capsule dose has been swallowed.  
To prepare for the drug experience, the participant will take the IP and lie down on a 
couch in a room with dim lights and a standard playlist of relaxing music playing quietly. 
The trained therapist will be present with the participant at all times. 
The effects of psilocybin usually start about 20 to 30 min after administration, becoming 
most intense in the first 90 to 120 min, and gradually subside in 5 to 6 h. The participants 
will be asked to remain in the room for the duration of the session regardless of the 
intensity of the effects, prefreably lying down and mostly silent unless they have a 
concern or need to communicate a discomfort or seek reassurance from the therapist, or 
use the restroom. The therapist will ‘check-in’ with the participant (ie, ask how the 
participant is doing) in 30- to 60-min intervals postdosing. A light meal and fruit will be 
available for the participant. 
About 5 to 6 h after dosing, trained therapist will discuss the IP administration experience 
with the participant. The participant is to be discharged 6 to 8 h postdosing when, in the 
opinion of the investigator, the acute effects of psilocybin are resolved. The participant 

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will be accompanied home . The site is to be notified that they have returned home safely, 
and in the absence of receiving a phone call, site staff will directly contact the participant.  
8.4 
Accountability 
The investigator must keep an accurate accounting of the number of IP units delivered to 
the site, administered to participants, and returned to COMPASS or its designee during 
and at the completion of the study. The IP must be administered to participants only by 
an appropriately qualified person. The IP is to be used in accordance with the protocol by 
participants who are under the direct supervision of the investigator. Investigators should 
maintain records that document adequately that the participants were administered the IP 
dose specified by the protocol and reconcile all IPs received at the site before final 
disposition. At the end of the study, or as directed, all IP, including unused, partially 
used, and empty containers, will be returned to the sponsor or its designee. 
8.5 
Concomitant Therapy 
All prescription and non-prescription medications (eg, over-the-counter drugs and herbal 
supplements) that participants report taking during the 30 days prior to Screening (V1) 
will be assessed and recorded at that visit. For each medication, documentation should 
list the trade or generic name, the total daily dose including units (or the dose, units and 
scheduled and actual frequency of administration if the medication is not taken daily), the 
route of administration, and the reason for use.  
Concomitant medication refers to all drugs and therapies used from the time the ICF was 
signed through the end of study participation.  
Changes, additions, or discontinuations to medications will be assessed and recorded in 
the eCRF during each study visit. All as-needed (pro re nata, PRN) prescriptions should 
be converted to reflect actual number of pills or dose taken per day. 
8.5.1 
Permissible Medications 
Medications for the management of concurrent anxiety and insomnia, or nonpsychiatric 
medications that have a potential psychotropic effect are permitted within the following 
limitations. From the initial Screen Visit (V1) through final study visit (V10, EOS), 
participants are permitted to use benzodiazepines (up to 2 mg of lorazepam equivalents 
per day for insomnia and anxiety if it is not taken within 12 h before the psilocybin dose. 
Prescription and nonprescription medications with psychoactive properties that are used 
as needed for nonpsychiatric conditions (eg, pseudoephedrine for allergies or cold 
symptoms; zopiclone for sleep disorders) should be used no more than 2 times a week 
and not in the 12 h before any study assessment. Documentation of the use of adjunctive 
anxiolytics, hypnotics, or medication with potential psychotropic properties (including 
over-the-counter preparations) will be obtained at each clinic visit. 

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Therapy considered necessary for the participant’s welfare may be given at the discretion 
of the study clinician. If the permissibility of a specific medication/treatment is in 
question, please contact COMPASS or its designee. 
8.5.2 
Definition of Women of Childbearing Potential and/or Acceptable 
Contraceptive Methods 
A woman is considered of childbearing potential (ie, fertile) following menarche and 
until becoming postmenopasusal unless permanently sterilised (ie, subject had 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).  
A woman who is not of childbearing potential is considered to be postmenopausal after at 
least 12 months without menstruation. The following methods of contraception, if used 
properly and used for the duration of the study, are generally considered highly effective:  
o Combined estrogen- and progestogen-containing hormonal contraception 
associated with inhibition of ovulation: 
▪ Oral 
▪ Intravaginal 
▪ Transdermal 
o Progestogen-only hormonal contraception associated with inhibition of ovulation: 
▪ Oral  
▪ Injectable 
▪ Implantable 
o Intrauterine devise 
o Intrauterine hormone-releasing system 
o Bilateral tubal occlusion 
o Vasectomised partner 
o Sexual abstinence 
Periodic abstinence (ie, calendar, symptothermal, or postovulation methods, and tubal 
ligation/occlusion) is not an acceptable form of contraception for this study.   
These methods of contraception also apply to partners of male participants. 

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The investigator and each participant will determine the appropriate method of 
contraception for the participant during the participation in the study. This will be 
documented at Screening (V1). 
If a participant or the partner of a male participant becomes pregnant during the study, the 
investigator will notify COMPASS or Worldwide immediately after the pregnancy is 
confirmed according to Section 12.6.  
8.5.3 
Prohibited Medications 
Participants are to be discontinued from antidepressant and/or antipsychotic medications 
at least 2 weeks prior to Baseline (V2). These medications include the following 
2 classes of the Anatomical Therapeutic Chemical (ATC) Classification System: - NO5A 
Antipsychotics & NO6A Antidepressants. Methylphenidate is also excluded. 
The medical monitor should be contacted if there is any question that a used medication 
is thought to be in one of these classes. These medications are not to be reintroduced to 
the participant until after V7 (Week 3). Participants who require concomitant 
medication(s) specifically for the treatment of depression at any time through the duration 
of the study will be assessed for reasons of resuming their medications and followed until 
12 weeks post psilocybin administration. The study clinician should initiate treatment of 
symptoms of depression per local site practice and may change the venue of therapy (ie, 
outpatient to inpatient) if deemed clinically necessary. The intervention may be a 
combination of somatic (eg, approved antidepressant medication) and nonsomatic 
(various forms psychotherapy, eg, CBT) whose therapeutic intention is remediation of the 
depressive episode. Because the anticipated half-life of psilocybin is approximately 3 h, 
and only 1 administration of test product is permitted, no known issues regarding PK or 
pharmacodynamic interactions are envisioned within approximately 7 days of product 
administration. 
8.5.4 
Rescue Medication 
Rescue medications may be used during and after the psilocybin session. 
The decision to medicate a participant will depend on whether the monitors and 
responsible physician judge that they are capable of maintaining the safety of the patient 
and others without medical intervention. 
• Benzodiazepine anxiolytics is the pharmacological intervention of choice in case of 
acute psychological distress (eg, medications such as lorazepam or alprazolam that 
have a rapid onset, a short time until peak plasma concentration, and a short duration 
of therapeutic action; the oral route is preferable because IV injection procedures may 
further exacerbate the participant’s anxiety). 
• Antipsychotic medications (eg, risperidone) should be available in the event that an 
adverse reaction escalates to unmanageable psychosis.  

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In case of development of acute anxiety or psychotic symptoms requiring 
pharmacological intervention, the participant will be managed appropriately. The 
participant may be discharged from the clinic when, in the opinion of investigator, the 
condition has stabilized. The participant will be accompanied home. The site is to be 
notified by the participant that they have returned home safely, and in the absence of 
receiving a phone call site staff will directly contact the participant.  
Information for how to manage subjects during difficult psychological states are detailed 
in the Therapist Manual.  
8.6 
Compliance 
Administration of IP will be supervised by study personnel to ensure compliance. 
 

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9 ADVERSE EVENTS 
Throughout the course of the study, all AEs will be monitored and recorded on an AE 
eCRF, including the AE’s description, start and end date, seriousness, severity, action 
taken, and relationship to the IP. If AEs occur, the first concern will be the safety of the 
study participants.  
Per ICH E2A: An AE is any untoward medical occurrence in a participant or clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be 
any unfavourable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether considered related to the medicinal product. 
Medical interventions such as surgeries, diagnostic procedures, and therapeutic 
procedures are not AEs but the action taken to treat the medical condition. They should 
be recorded as treatment of the AEs. 
The investigator will promptly notify COMPASS or Worldwide of all SAEs and 
nonserious AEs occurring during the clinical trial so that legal obligations and ethical 
responsibilities towards the safety of participants and the safety of the product under 
clinical investigation are met.  
COMPASS or Worldwide has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a product under clinical 
investigation. COMPASS or Worldwide will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC), and investigators. These will be 
detailed in the safety plan. 
9.1 
Documenting Adverse Events 
AEs occurring from when the participant signs the ICF until the last study event will be 
recorded. Any AEs occurring before the start of treatment (ie, before the dose of the IP on 
Day 0 [V3]) will be recorded in the medical history. Also, the sign, symptom, or disease 
present before starting the treatment period are only considered AEs if they worsen after 
starting the treatment period. Investigators should document all significant illnesses that 
the participant has experienced within 3 months of the Screening visit. Additional 
illnesses present at the time informed consent is given are to be regarded as concomitant 
illnesses. Illnesses first occurring or detected during the study and/or worsening of a 
concomitant illness during the study are to be documented as AEs on the eCRF. 
All clinical laboratory results, vital signs, and ECG results or findings should be 
appraised by the investigator to determine their clinical significance. Isolated abnormal 
clinical laboratory test results, vital sign findings, or ECG findings (ie, not part of a 
reported diagnosis) should be reported as AEs if they are symptomatic, lead to IP 

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discontinuation, require corrective treatment, or constitute an AE in the investigator’s 
clinical judgment. 
At each time point, the investigator will determine whether any AEs have occurred by 
evaluating the participant. AEs may be directly observed, reported spontaneously by the 
participant or by questioning the participant at each time point. Participants should be 
questioned in a general way, without asking about the occurrence of any specific 
symptoms. The investigator must assess all AEs to determine intensity, causality and 
seriousness, in accordance with the definitions in Sections 9.2, 9.3, and 10.1, 
respectively. The investigator’s assessment must be clearly documented in the study 
site’s source documentation with the investigator’s signature.  
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, 
report the primary sign or symptom as the AE or SAE term with additional details 
included in the narrative until the diagnosis becomes available. If the signs and symptoms 
are distinct and do not suggest a common diagnosis, report them as individual entries of 
AE or SAE. 
The investigator should report all AEs on the AE page(s) of the eCRF and source 
documents, regardless of seriousness, severity, and causality. Whenever possible, an AE 
will be reported using a diagnostic term, (eg, “common cold” or “upper respiratory 
infection” rather than “runny nose, cough, mild fever”) and should be described with the 
attributes described in Sections 9.2 and 9.3.  
9.2 
Assessment of Intensity 
Each AE will be classified according to the following criteria: 
 
Mild: 
The AE does not interfere in a significant manner with the 
participant’s normal level of functioning. 
Moderate: 
The AE produces some impairment of functioning, but is not 
hazardous to the participant’s health. 
Severe: 
The AE produces significant impairment of functioning or 
incapacitation and is a definite hazard to the participant’s 
health. 
Severity versus Seriousness: Severity is used to describe the intensity of a specific event 
while the event itself, however, may be of relatively minor medical significance (such as 
severe headache). This is not the same as "seriousness," which is based on 
participant/event outcome at the time of the event. 
When changes in the intensity of an AE occur more frequently than once a day, the 
maximum intensity for the experience should be noted. If the intensity category changes 
over several days, those changes should be recorded separately (with distinct onset dates). 

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9.3 
Assessment of Causality 
Each AE will be assessed as to its relationship to the IP, based on the following criteria. 
Although the attribution by the investigator will be collected for reported events, for 
analytic purposes a temporal association with the use of the IP will be assumed sufficient 
for at least plausible association. 
 
Not related: 
No causal relationship exists between the IP and the AE, but an 
obvious alternative cause exists, eg, the participant’s underlying 
medical condition or concomitant therapy. 
Possibly related: 
A connection with the administration of the IP appears unlikely, 
but cannot be ruled out with certainty. An AE may be 
considered possibly related if or when it meets 2 of the 
following criteria: (1) it follows a reasonable temporal sequence 
from administration of the IP; (2) it could not readily have been 
produced by the participant’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the 
participant; or (3) it follows a known pattern of response to the 
IP. 
Related: 
There is a reasonable/plausible possibility that the AE may have 
been caused by the IP. 
When assessing the relationship to the IP, the following criteria will be considered: 
o Known class effect 
o Biological plausibility 
o Lack of alternative explanation—concomitant drug or disease 
9.4 
Action Taken Regarding Investigational Product 
Dose modifications of IP (ie, dose not changed, drug withdrawn, drug interrupted, or 
dose increased) are not applicable as this is a single dose study.  
o Not Applicable: Participant died, study treatment had been completed prior to 
reaction/event, or reaction/event occurred prior to start of treatment. 
9.5 
Other Action Taken for Event 
1 = None (ie, no treatment was required) 
2 = Medication required (ie, prescription and/or OTC medication was required to treat 
the AE) 

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3 = Hospitalisation or prolongation of hospitalisation required (ie, hospitalisation was 
required or prolonged because of the AE, whether medication was required) 
4 = Other 
9.6 
Adverse Event Outcome 
1 = Recovered/Resolved (ie, the participant fully recovered from the AE with no 
residual effect observed) 
2 = Recovering/Resolving (ie, the AE improved but has not fully resolved) 
3 = Not Recovered/Not Resolved (ie, the AE itself is still present and observable) 
4 = Recovered/Resolved with Sequelae (ie, the residual effects of the AE are still 
present and observable, including sequelae/residual effects) 
5 = Fatal (ie, ‘fatal’ should be used when death is a direct outcome of the AE) 
6 = Unknown 
9.7 
Clinical Laboratory Changes 
Any abnormality in a laboratory value that is new in onset or which has worsened in 
severity or frequency from the baseline condition and meets 1 of the following criteria 
will be recorded on the AE pages of the eCRF: 
o Requires therapeutic intervention or diagnostic tests 
o Leads to discontinuation of IP 
o Has accompanying or inducing symptoms or signs 
o Is judged by the investigator as clinically significant 
Combined elevations of aminotransferases and bilirubin, either serious or nonserious, and 
whether causally related, meeting the criteria of a potential Hy’s Law case (total bilirubin 
level ≥ 2 × upper limit of normal [ULN] with simultaneous ALT or AST ≥ 3 × ULN) 
should always be reported to the sponsor as soon as possible following the procedures 
outlined in Section 10.2 for SAE reporting, with the investigator’s assessment of 
seriousness, causality, and a detailed narrative. 
9.8 
Overdose 
Any instance of overdose (suspected or confirmed) must be communicated to Worldwide 
or a specified designee within 24 h and be fully documented as an AE or SAE if it meets 

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the SAE criteria. Details of any signs or symptoms and their management should be 
recorded including details of any antidote(s) administered. 
9.9 
Adverse Events of Special Interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific 
and medical concern specific to the study drug, for which ongoing monitoring and 
immediate notification by the investigator to the sponsor is required. Such AEs may 
require further investigation to characterise and understand them.  
The following events will be reported as AESI: 
o Euphoric mood 
o Dissociative disorder 
o Hallucination 
o Psychotic disorder 
o Cognitive disorder 
o Disturbance in attention 
o Mood altered 
o Psychomotor skills impaired 
o Inappropriate affect 
o Overdose 
o Intentional product misuse 
The investigator must report to the Sponsor all the above event on the eCRF page within 
24 h of learning about the event regardless of relationship to study drug. 
The report should include the following minimum information: 
o Subject number 
o Event 
o Date/time of onset 
o Duration of the event 
o Dose of drug taken 

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o Severity 
o Outcome 
All AESIs will be followed until resolved or stable. 
9.10 Adverse Event Follow-up 
All AEs will be followed until resolved or stable and the outcome documented on the 
eCRF. 
If the investigator detects an AE in a study participant after the last scheduled follow-up 
visit and considers the event possibly related or related to prior study treatment, the 
investigator should report it to Worldwide. 
 

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10 SERIOUS ADVERSE EVENTS 
10.1 Definition of Serious Adverse Event 
An SAE is any event that meets any of the following criteria: 
o Death 
o Life-threatening 
o Inpatient hospitalisation or prolongation of existing hospitalisation 
o Persistent or significant disability/incapacity 
o Congenital anomaly/birth defect in the offspring of a participant who received 
psilocybin. 
o Other: Important medical events that may not result in death, be life-threatening, 
or require hospitalisation, may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardise the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such events are: 
▪ Intensive treatment in an emergency room or at home for allergic 
bronchospasm 
▪ Blood dyscrasias or convulsions that do not result in inpatient hospitalisation 
▪ Development of drug dependency or drug abuse 
Definition of Terms 
Life threatening: An AE is life threatening if the participant was at immediate risk of 
death from the event as it occurred; ie, it does not include a reaction that if it had 
occurred in a more serious form might have caused death. For example, drug-induced 
hepatitis that resolved without evidence of hepatic failure would not be considered life 
threatening even though drug-induced hepatitis can be fatal. 
Hospitalisation: AEs requiring hospitalisation should be considered SAEs. 
Hospitalisation for elective surgery or routine clinical procedures that are not the result of 
AEs (eg, elective surgery for a pre-existing condition that has not worsened) need not be 
considered AEs or SAEs. If anything untoward is reported during the procedure, that 
occurrence must be reported as an AE, either 'serious' or 'nonserious' according to the 
usual criteria. 
In general, hospitalisation signifies that the participant has been detained (usually 
involving at least one an overnight stay) at the hospital or emergency ward for 

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observation and/or treatment that would not have been appropriate in the physician's 
office or outpatient setting. When in doubt as to whether 'hospitalisation' occurred or was 
necessary, the AE should be considered serious. 
For deaths, the underlying or immediate cause of death should always be reported as an 
SAE. 
Any serious, untoward event that may occur subsequent to the reporting period that the 
investigator assesses as related to IP should also be reported and managed as an SAE. 
The investigator should follow participants with AEs until the event has resolved or the 
condition has stabilised. In case of unresolved AEs, including significant abnormal 
clinical laboratory values at the end of study assessment, these events will be followed 
until resolution or until they become clinically not relevant.  
Disability/incapacitating: An AE is incapacitating or disabling if the experience results in 
a substantial and/or permanent disruption of the participant's ability to carry out normal 
life functions. 
10.2 Reporting Serious Adverse Events 
Each AE will be assessed to determine whether it meets seriousness criteria 
(Section 10.1). If the AE is considered serious, the investigator should report this event to 
Worldwide and to the IRB/IEC according to its standard operating procedures. 
If the investigator detects an SAE in a study participant after the last scheduled follow-up 
visit, and considers the SAE related or possibly related to this study’s IP administration, 
the investigator should report it to Worldwide. 
The investigator must report to the sponsor all SAEs on the eCRF page within 24 h of 
learning about the event regardless of relationship to IP.  
All information about SAEs will be collected and reported via the SAE form and sent by 
e-mail message or facsimile (contact information will be contained in the investigator site 
file). The investigator should send the initial report within 24 h of becoming aware of the 
SAE. At minimum, the initial report should include the following information: 
o Event 
o Study code 
o Participant number, initials, and date of birth 
o IP 
o Reporter name and contact information 

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If the site experiences a temporary disruption of the eCRF system, a back-up paper SAE 
Report Form will be available for site staff to complete. 
• Site staff will complete the paper SAE report form and e-mail it within 24 h to the 
following address: drugsafety@worldwide.com 
• In cases where the email system is unavailable, site staff will send the SAE by fax 
to: +1-866-387-5539 (US) and +44 208 043 4813 (ROW). 
If notification is made via email or fax, site staff must enter the SAE information into the 
eCRF system as soon as the system becomes available. Should a back-up SAE form be 
used, the original SAE form should be kept at the study site. 
If the SAE has not resolved at the time the investigator submits an initial SAE report, the 
investigator must provide a follow-up report as soon as the event resolves (or upon 
receipt of significant information if the event is still ongoing). Additional follow-up 
information must be reported in the eCRF within 24 h of awareness following 
investigator (or site) awareness of the information. The investigator should not delay 
reporting an SAE in order to obtain additional information. Additional information, when 
available, should be reported per the reporting procedures described above. 
All SAEs shall be followed until resolution, until the condition stabilises, or until the 
participant is lost to follow-up, or otherwise explained. Once the SAE is resolved, the 
corresponding AE eCRF page shall be updated. Additionally, any relevant laboratory test 
reports, consultation reports from other health care professionals, discharge summaries, 
or other information that has been gathered about the event shall be transmitted to the 
sponsor.  
In the case of a “minimum report” (one that solely comprises the information bulleted 
above), a more detailed follow-up report should be sent as soon as more information 
becomes available but no later than 7 calendar days after the date of the initial report. 
Each SAE should be followed up until resolution or stabilisation and for reported deaths, 
the investigator should supply Worldwide and the IRB/IEC with any additional requested 
information (eg, autopsy reports and terminal medical reports). 
The original SAE form should be kept at the study site. The sponsor or its representative 
will be responsible for determining and in turn, reporting SAEs to regulatory authorities 
according to the applicable regulatory requirements. 
All SAEs will be followed until resolved or stable and the outcome documented on the 
eCRF. 
Investigator safety reports will be prepared for suspected unexpected serious adverse 
reactions (those not listed in the IB) according to local regulatory requirements and 
COMPASS/Worldwide policy and are forwarded to investigators as necessary.  

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An investigator who receives an investigator safety report describing an SAE(s) or other 
specific safety information (eg, summary or listing of SAEs) from COMPASS or 
Worldwide will file it with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 

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11 STATISTICS 
11.1 General Procedures 
The statistical analysis will be undertaken by Worldwide in collaboration with 
COMPASS. A detailed Statistical Analysis Plan (SAP) will be finalised and signed 
before database lock and before study unblinding. Any deviations from the analyses 
described below will be included in the SAP, which will be included in the clinical study 
report. All statistical testing will be performed at the two-sided alpha 0.05 level unless 
otherwise stated. 
11.2 Sample Size 
The intent of the primary efficacy analysis is to demonstrate superiority of at least one 
therapeutic dose of psilocybin (10 mg or 25 mg) versus the 1 mg psilocybin based on the 
change from Baseline in MADRS score at Week 3. The 3 treatment groups will be 
randomised in a 1:1:1 ratio.  
For this primary analysis, a sample size of 216 randomised participants (72:72:72) will 
provide 90% power at the alpha = 0.05 level to detect a 6-point difference in average 
MADRS total score between the optimal therapeutic dose of psilocybin and 1 mg 
psilocybin, assuming the common SD is 11.0.  
The 6-point difference in average MADRS total score on a group level is supported by 
the pilot study with psilocybin,2 and is within the range of potential differences that have 
been used to power other studies in major depression and TRD. The assumed SD of 11.0 
is based on a review of other studies for this condition. A blinded interim analysis may be 
performed to verify this assumption. 
It is assumed that up to 90% of randomised participants may not have prior psychedelic 
experience. The power for this post hoc subgroup is approximately 86%, if the maximum 
number of participants to have prior psychedelic experience were 10% of randomised 
participants.  
11.3 Statistical Methods 
The Safety Population will consist of all randomised participants who receive study 
treatment, regardless of whether or not treated. This population will be used for all 
summaries of participant accountability, demographic and baseline data, and safety 
information, including AE incidence.  
The Full Analysis Set (FAS) will consist of all participants randomised who also receive 
the dose of IP. 
The modified intention-to-treat population will consist of all participants in the FAS that 
have at least 1 post dose assessment.  

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The Per Protocol (PP) population will consist of all participants in the FAS who do not 
have a major protocol deviation. Major protocol deviations will be reviewed and 
determined prior to unblinding. The PP population will be used for supportive sensitivity 
analyses. 
11.3.1 
Efficacy and Outcome Measures  
• MADRS 
• QIDS-SR-16 
• SDS 
• GAD-7 
• DSST 
• EQ-5D-3L (participant and caregiver; the latter is not mandatory) 
• WSAS 
11.3.2 
Analysis of Efficacy 
The primary efficacy endpoint (change from Baseline in MADRS total score at Week 3) 
will be evaluated with a mixed effects model for repeated measures analysis. The model 
will include treatment, visit, study site, prior psychedelic experience, treatment by visit 
interaction, participant as a random effect, and Baseline MADRS total score. Comparison 
of the psilocybin optimal dose versus 1 mg psilocycbin will be performed at the 0.05 
testing level. A sensitivity analysis will be performed on the primary mixed model 
repeated measures model adding treatment by study site or country interaction into the 
model. If it is significant (at the 10% level), then further investigations of sites will be 
performed. 
The 4 secondary efficacy endpoints that are dichotomous variables (proportion of 
participants who are responders, remitters, and sustained responders) will be analysed 
using the Cochran Mantel Haenszel chi square test, stratified by country, to compare the 
psilocybin optimal therapeutic dose versus 1 mg psilocybin. A stepdown procedure to 
correct for multiplicity will be employed.  
Time-to-event measures will be evaluated using Kaplan-Meier methods.  
Response and remission rates will be summarised at each visit.  
Change from Baseline in continuous efficacy measures, including the QIDS-SR-16 scale 
and GAD-7 total scores at each point, will be analysed based on last observation carried 
forward data using an analysis of covariance model, with treatment and study site as 

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factors, and the respective baseline score as the covariate. The exploratory analyses for 
quality of life and wellbeing, functioning and associated disability, cognitive function, 
and anxiety are not hierarchical; there will be no correction for multiplicity in these 
analyses.  
Scores for all efficacy endpoints, including dimension scores of the EQ-5D-3L and the 
EQ VAS, will be summarised over time using descriptive statistics for all visits during 
the observation period.  
The covariate selection process will be addressed in the SAP to be approved before any 
analyses are undertaken.  
Continuous behavior sampling will be tested with the Mindstrong application technology 
in a subgroup of smart phone users consented to this part of the study. Participants who 
do not consent to the app installation, or don’t have a smart phone, will not be excluded 
from the study. Following the installation of the Mindstrong app on the participant’s 
smart phone, the app will begin to collect data from the smart phone and periodically 
send these data back to the secure database. The participant does not need to do anything 
at this stage, except use their phone as they normally do. As explained above, personal 
data from mobile phone usuage will be analysed in a sub-group of consenting 
participants.  
The correlation between sensor data, keyboard behavior, or voice and speech metrics will 
be assessed for correlation with standard clinical assessments and the ability of app 
features to identify impending relapse before clinical change is apparent with traditional 
ratings. The goal of these exploratory assessments is to identify mobile use patterns (app 
features) predictive of clinically significant mood changes that will have an impact on 
care and treatment outcomes. 
11.3.3 
Multiplicity 
To control the overall Type 1 error rate, the following hierarchical testing method will be 
employed. A sequential test procedure will be applied across the primary and key 
secondary efficacy endpoints, with all testing between 1 mg psilocybin and the optimal 
dose done at the 0.05 level. Thus, in the final analysis, statistical testing will be 
performed at the 0.05 level in a prespecified order, such that testing will not continue 
once non-significance is observed. If a non-significant p-value is observed, the remaining 
endpoints will still have nominal p-values presented but will not be considered 
statistically significant. The pre-specified testing order will be: 
• Primary endpoint, change in MADRS total score from Baseline to 3 Weeks, for 
25 mg versus 1 mg 
• Primary endpoint, change in MADRS total score from Baseline to 3 Weeks, for 
10 mg versus 1 mg 

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• Secondary endpoint, proportion of participants with a response (≥ 50% improvement 
in MADRS total score from Baseline) at Week 3, for 25 mg versus 1 mg 
• Secondary endpoint, proportion of participants with a response (≥ 50% improvement 
in MADRS total score from Baseline) at Week 3, for 10 mg versus 1 mg 
• Secondary endpoint, proportion of participants with remission (MADRS total 
score ≤ 10) at Week 3, for 25 mg versus 1 mg 
• Secondary endpoint, proportion of participants with remission (MADRS total 
score ≤ 10) at Week 3, for 10 mg versus 1 mg 
• Secondary endpoint, proportion of participants who have a sustained response at 
Week 12, for 25 mg versus 1 mg 
• Secondary endpoint, proportion of participants who have a sustained response at 
Week 12, for 10 mg versus 1 mg 
11.3.4 
Analysis of Safety 
Safety analyses will be performed using data from the Safety Population. Safety will be 
evaluated based of AEs, vital signs, clinical laboratory assessments, and ECG findings.  
11.3.4.1 
Columbia-Suicide Severity Rating Scale 
Item scores from the C-SSRS, all visits by randomised treatment, the item scores from 
the version assessing suicidality since the last visit, and all postbaseline visits (V3 to V10, 
inclusive) by treatment will be tabulated. Summary statistics of suicidal ideation and 
suicidal behavior following IP administration will be presented by randomised treatment. 
11.3.4.2 
Adverse Events 
AEs will be coded by Preferred Term (PT) using the Medical Dictionary for Regulatory 
Activities (MedDRA) classification. All reported AEs with onset or worsening after the 
administration of study medication will be included in the analysis. The incidence of AEs 
will be summarised by treatment group, and by severity and relationship to IP. Serious 
AEs and AEs leading to withdrawal from the study will be tabulated. 
A TEAE is defined as any AE that has an onset on or after the dose of IP, or any 
pre-existing condition that has worsened on or after the dose of IP.  
The incidence of TEAEs and treatment-related AEs will also be summarised by 
maximum severity and most-related relationship to IP by MedDRA primary system organ 
class and PT. The summary will include the total number and percentage of participants 
reporting an event. In counting the number of events reported, a continuous event, ie, 
reported more than once and which did not cease, will be counted only once; 

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non-continuous AEs reported several times by the same participant will be counted as 
multiple events. 
11.3.4.3 
Electrocardiographic Data 
The ECG data will be summarised descriptively based on measures of change in each 
ECG parameter from V1 to post-treatment (V4). Frequency tabulations of the 
abnormalities will be provided. ECG variables to be analysed will include heart rate, PR 
interval, QRS interval, QT interval, and corrected QT interval using the following 
correction methods: QT corrected according to Bazett’s formula and QT corrected 
according to Fridericia’s formula. 
11.3.4.4 
Laboratory Data 
Laboratory data (haematology and blood chemistry parameters) will be presented for 
each treatment group using descriptive statistics, including mean and mean change from 
baseline values at each scheduled time point. Shift tables will display numbers of 
participants with normal/abnormal values at Baseline versus post-treatment. The 
frequency of laboratory abnormalities will be tabulated. By-participant data listings will 
flag laboratory values that are outside normal reference ranges or markedly abnormal 
findings. 
11.3.4.5 
Vital Signs 
Changes from Baseline in vital signs, blood pressure (systolic and diastolic), body 
temperature, pulse rate, and respiratory rate, will be summarised for each treatment group 
using descriptive statistics. The last measurement obtained prior to IP administration will 
serve as baseline. The percentage of participants with values outside clinically important 
limits will be summarised. A listing of weight and height at V1 will be provided.  
11.3.5 
Demographic and Baseline Characteristics 
Treatment groups will be compared with respect to participant demographics and 
baseline characteristics will be summarised using descriptive statistics, no formal 
statistical analysis tests will be performed. 
11.4 Interim Analysis 
There may be a blinded interim analysis after approximately 50% of the planned 
216 participants have been randomized and had an opportunity to complete 3 weeks of 
the study post treatment. The purpose of this blinded interim would be to perform an 
assessment of the overall combined (across all treated participants) SD of the change 
from Baseline in the MADRS collected at Week 3. If the SD in this assessment is greater 
than the SD assumed for the study sample size calculation (11.0), then a sample size 
re-estimation may be performed. The sample size re-estimation would not result in a 
reduction of the sample size. 

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12 ETHICS AND RESPONSIBILITIES 
12.1 Good Clinical Practice 
The study will be performed in accordance with this protocol, US investigational new 
drug (IND) regulations (21 Code of Federal Regulations [CFR] 312), ICH guidelines for 
Good Clinical Practice (GCP), the regulations on electronic records and electronic 
signature (21 CFR 11), and the most recent guidelines of the Declaration of Helsinki 
(Section 19.2). These guidelines are on file at Worldwide. 
The study will also be performed in accordance with any laws and regulations in force in 
the country in which the research is carried out.  
12.2 Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will periodically review and evaluate the 
accumulated study data for participant safety, study conduct and progress and when 
appropriate, efficacy.  The DSMB will make recommendations concerning the 
continuation, modification or termination of the trial, always ensuring participant safety 
is paramount.  The composition, the frequency of the review, range of decisions 
permitted, and the methods for dissemination of information will be addressed in a 
separate charter. 
12.3 Steering Committee 
A Steering Committee will not be used for this study.  
12.4 Institutional Review Board/Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted IRB/ IEC. 
Approval is required for the study protocol, protocol amendments, ICFs, participant 
information sheets, and advertising materials. No IP will be shipped to a site until written 
IRB/IEC authorisation has been received by the sponsor or its representative. 
12.5 Informed Consent 
Participants should be informed that they may withdraw from the study at any time. They 
will receive all information that is required by local regulations and ICH guidelines. The 
principal investigator or a designated representative will provide the sponsor or its 
representative with a copy of the IRB/IEC-approved ICF before the start of the study. 
12.6 Exposure in Utero During Clinical Studies 
Sponsor must be notified of any participant who becomes pregnant within 30 days of 
receiving the IP. Reporting after the follow-up visit or ET is done voluntarily by the 
investigator. 

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Sponsor must be notified of any male participant whose partner becomes pregnant within 
30 days of the participant receiving the IP. Reporting after any follow-up visit or ET is 
done voluntarily by the investigator. 
Although pregnancy is not technically an AE, all pregnancies must be followed to 
conclusion to determine their outcome. This information is important for both drug safety 
and public health concerns. It is the responsibility of the investigator, or designee, to 
report any pregnancy in a participant or the partner of a male participant using the eCRF 
pregnancy within 24 h of becoming aware of the event. Exposure in Utero (EIU) 
Reporting form. Please contact your study monitor to receive the EIU Reporting form 
upon learning of a pregnancy. The investigator should make every effort to follow the 
participant until completion of the pregnancy and complete the EIU Reporting form 
eCRF with complete pregnancy outcome information, including normal delivery and 
induced abortion. The adverse pregnancy outcome, either serious or nonserious, should 
be reported in accordance with study procedures. If the outcome of the pregnancy meets 
the criteria for immediate classification as an SAE (ie, post-partum complications, 
spontaneous or induced abortion, stillbirth, neonatal death, or congenital anomaly, 
including that in an aborted foetus), the investigator should follow the procedures for 
reporting SAEs outlined in Section 10. In the event the eCRF system is unavailable, a 
back-up paper Pregnancy Reporting Form will be available for site staff to complete 
following the reporting guidelines as outlined in Section 10.2. 
For reports of pregnancy in the partner of a male participant, the pregnancy eCRF page 
EIU form (or SAE form if associated with an adverse outcome) should be completed with 
the participant’s randomisation number, initials, and date of birth, and details regarding 
the partner of the male participant should be entered in the narrative section. 
12.7 Records Management 
By signing this protocol, the investigator grants permission to personnel from the 
sponsor, its representatives, and appropriate regulatory authorities, for on-site monitoring 
of all appropriate study documentation, paper and electronic, as well as on-site review of 
the procedures employed in eCRF generation, where clinically appropriate. 
12.8 Source Documentation 
Note that a variety of original documents, data, and records will be considered as source 
documents in this trial. The eCRF itself is not to be used as a source document under any 
circumstances.  
12.9 Study Files and Record Retention 
The investigator must arrange for retention of study records at the site. The nature of the 
records and the duration of the retention period must meet the requirements of the 
relevant regulatory authority. In addition, because this is an international study, the 
retention period must meet the requirements of the most stringent authority. The 

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investigator should take measures to prevent accidental or premature destruction of these 
documents. 

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13 AUDITING AND MONITORING 
This study will be monitored for quality assurance at all stages of its development by the 
clinical research personnel employed by the sponsor or its representative. Monitoring will 
include personal visits and telephone communication to assure that the investigation is 
conducted according to the protocol, standard operating procedures, GCP guidelines, and 
applicable regulatory requirements. Quality control procedures will be applied to each 
stage of data handling to ensure that all data are reliable and have been processed 
correctly. On-site review of eCRFs will include a review of forms for completeness and 
clarity, and consistency with source documents available for each Participant.  
Medical advisors and clinical research associates or assistants may request to witness 
participant evaluations occurring as part of this protocol. The investigator and appropriate 
personnel will be periodically requested to attend meetings/workshops organised by the 
sponsor to assure acceptable protocol execution. The study may be audited by the sponsor 
or by regulatory authorities. If such an audit occurs, the investigator must agree to allow 
access to required Participant records. By signing this protocol, the investigator grants 
permission to personnel from the sponsor, its representatives, and appropriate regulatory 
authorities, for on-site monitoring of all appropriate study documentation, as well as 
on-site review of the procedures employed in eCRF generation, where clinically 
appropriate. 

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14 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study 
participants, may be made only by COMPASS. A protocol change intended to eliminate 
an apparent immediate hazard to participants may be implemented immediately, provided 
the IRB/IEC is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The 
written amendment must be submitted to the IRB/IEC and the investigator must await 
approval before implementing the changes. COMPASS will submit protocol amendments 
to the appropriate regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, and/or COMPASS, the amendment to 
the protocol substantially changes the study design and/or increases the potential risk to 
the participant and/or has an impact on the participant's involvement as a study 
participant, the currently approved written informed consent form will require similar 
modification. In such cases, informed consent will be renewed for participants enrolled in 
the study before continued participation. 
 

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15 STUDY REPORT AND PUBLICATIONS 
COMPASS is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory 
requirements. 
The publication policy of COMPASS is discussed in the investigator's Clinical Research 
Agreement. 
 

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16 STUDY DISCONTINUATION  
Both COMPASS and the Principal Investigator reserve the right to terminate the study at 
the investigator’s site at any time. Should this be necessary, COMPASS or a specified 
designee will inform the appropriate regulatory authorities of the termination of the study 
and the reasons for its termination, and the Principal Investigator will inform the IRB/IEC 
of the same. In terminating the study, COMPASS and the Principal Investigator will 
assure that adequate consideration is given to the protection of the participants’ interests. 
 

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17 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from COMPASS. However, authorised regulatory officials, IRB/IEC 
personnel, COMPASS and its authorised representatives are allowed full access to the 
records. 
Identification of participants and CRFs shall be by initials, screening and treatment 
numbers only. If required, the participant's full name may be made known to an 
authorised regulatory agency or other authorised official. 
 

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18 REFERENCES 
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Sheehan DV, Alphs LD, Mao L, et al. Comparative validation of the SSTS, the 
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Tylš F, Páleníček T, Horáček J. Psilocybin-summary of knowledge and new 
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37. 
Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell 
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40. 
Williams JB. A structured interview guide for the Hamilton depression rating 
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Williams JB, Kobak KA. Development and reliability of a structured interview 
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19 APPENDICES 
19.1 APPENDIX I – Names of Study Personnel 
Sponsor: 
Ekaterina Malievskaia, MD, MScPH 
Co-Founder, Head of Research and Development 
COMPASS Pathways, Ltd 
16 Old Bailey 
London, England, EC4M 7EG 
UK 
Telephone: +44 (0) 79 2087 6562 (UK) 
+1 (516) 805 3533 (US) 
Medical Monitor: 
Olga Kolotilina, Medical Director, Medical Affairs 
Worldwide Clinical Trials 
Kemerovo, 650065, Russia 
Telephone: +7 906 925 1812 (mobile) 
+7 812 346 8247, #1504 (office) 
+7 812 346 8248 (fax) 
Clinical Research 
Organisations: 
Worldwide Clinical Trials 
3800 Paramount Parkway, Suite 400 
Morrisville, NC 27560 
Telephone: +1 (919) 674 2900 
Central Laboratory: 
Eurofins Central Laboratory B.V. 
Bergschot 71 
4817 PA Breda 
The Netherlands 
Telephone: +31 76 573 75 21 
+31 76 573 77 76 (fax) 
Investigational 
Product Distribution: 
Fisher Clinical Services UK Ltd  
Langhurstwood Road,  
Horsham, West Sussex, RH12 4QD,  
UK 
Telephone: +44 (0) 1403 224308 
 

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19.2 APPENDIX II – Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical Principles 
for 
Medical Research Involving Human Participants 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DS, USA, October 2002 
55th WMA General Assembly, Tokyo, Japan, October 2004 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
and the 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
A. INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a statement 
of ethical principles to provide guidance to physicians and other participants in medical 
research involving human participants. Medical research involving human participants 
includes research on identifiable human material or identifiable data. 

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It is the duty of the physician to promote and safeguard the health of the people. The 
physician’s knowledge and conscience are dedicated to the fulfillment of this duty. 
The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my participant will be my first consideration," and the 
International Code of Medical Ethics declares that, "A physician shall act only in the 
participant's interest when providing medical care which might have the effect of 
weakening the physical and mental condition of the participant." 
Medical progress is based on research, which ultimately must rest in part on 
experimentation involving human participants. 
In medical research on human participants, considerations related to the well being of the 
human participant should take precedence over the interests of science and society. 
The primary purpose of medical research involving human participants is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the etiology 
and pathogenesis of disease. Even the best-proven prophylactic, diagnostic, and 
therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 
In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
Medical research is participant to ethical standards that promote respect for all human 
beings and protect their health and rights. Some research populations are vulnerable and 
need special protection. The particular needs of the economically and medically 
disadvantaged must be recognised. Special attention is also required for those who cannot 
give or refuse consent for themselves, for those who may be participant to giving consent 
under duress, for those who will not benefit personally from the research and for those for 
whom the research is combined with care. 
Research investigators should be aware of the ethical, legal and regulatory requirements 
for research on human participants in their own countries as well as applicable 
international requirements. No national ethical, legal or regulatory requirement should be 
allowed to reduce or eliminate any of the protections for human participants set forth in 
this Declaration. 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human participant. 
Medical research involving human participants must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 

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relevant sources of information, and on adequate laboratory and, where appropriate, 
animal experimentation. 
Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human 
participants should be clearly formulated in an experimental protocol. This protocol 
should be submitted for consideration, comment, guidance, and where appropriate, 
approval to a specially appointed ethical review committee, which must be independent 
of the investigator, the sponsor or any other kind of undue influence. This independent 
committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed. The committee has the right to monitor ongoing 
trials. The researcher has the obligation to provide monitoring information to the 
committee, especially any SAEs. The researcher should also submit to the committee, for 
review, information regarding funding, sponsors, institutional affiliations, other potential 
conflicts of interest and incentives for participants. 
The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration.  
Medical research involving human participants should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. The 
responsibility for the human participant must always rest with a participant of the 
research, even though the participant has given consent. 
Every medical research project involving human participants should be preceded by 
careful assessment of predictable risks and burdens in comparison with foreseeable 
benefits to the participant or to others. This does not preclude the participation of healthy 
volunteers in medical research. The design of all studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human 
participants unless they are confident that the risks involved have been adequately 
assessed and can be satisfactorily managed. Physicians should cease any investigation if 
the risks are found to outweigh the potential benefits or if there is conclusive proof of 
positive and beneficial results. 
Medical research involving human participants should only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the participant. 
This is especially important when the human participants are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research. 
The participants must be volunteers and informed participants in the research project. 

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The right of research participants to safeguard their integrity must always be respected. 
Every precaution should be taken to respect the privacy of the participant, the 
confidentiality of the participant’s information and to minimise the impact of the study on 
the participant's physical and mental integrity and on the personality of the participant. 
In any research on human beings, each potential participant must be adequately informed 
of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail. The participant should be informed of the right to abstain 
from participation in the study or to withdraw consent to participate at any time without 
reprisal. After ensuring that the participant has understood the information, the physician 
should then obtain the participant's freely-given informed consent, preferably in writing. 
If the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
When obtaining informed consent for the research project the physician should be 
particularly cautious if the participant is in a dependent relationship with the physician or 
may consent under duress. In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
For a research participant who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain informed 
consent from the legally authorised representative in accordance with applicable law. 
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons. 
When a participant deemed legally incompetent, such as a minor child, is able to give 
assent to decisions about participation in research, the investigator must obtain that assent 
in addition to the consent of the legally authorised representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population. The 
specific reasons for involving research participants with a condition that renders them 
unable to give informed consent should be stated in the experimental protocol for 
consideration and approval of the review committee. The protocol should state that 
consent to remain in the research should be obtained as soon as possible from the 
individual or a legally authorised surrogate. 
Both authors and publishers have ethical obligations. In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results. Negative as 
well as positive results should be published or otherwise publicly available. Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared 

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in the publication. Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED 
WITH MEDICAL CARE 
The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value. 
When medical research is combined with medical care, additional standards apply to 
protect the participants who are research participants. 
The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods. This does not 
exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 
diagnostic or therapeutic method exists. 
At the conclusion of the study, every participant entered into the study should be assured 
of access to the best-proven prophylactic, diagnostic and therapeutic methods identified 
by the study. 
The physician should fully inform the participant which aspects of the care are related to 
the research. The refusal of a participant to participate in a study must never interfere 
with the participant-physician relationship. 
In the treatment of a participant, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
the participant, must be free to use unproven or new prophylactic, diagnostic and 
therapeutic measures, if in the physician’s judgment it offers hope of saving life, 
re-establishing health or alleviating suffering. Where possible, these measures should be 
made the object of research, designed to evaluate their safety and efficacy. In all cases, 
new information should be recorded and, where appropriate, published. The other 
relevant guidelines of this Declaration should be followed. 
 
 

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19.3 APPENDIX III – MGH-ATRQ – Additional Detail Regarding the 
Assessment of Previous Antidepressant Treatment 
The MGH-ATRQ scale elicits information regarding prior antidepressant use. Additional 
drugs with regulatory approval for use in major depressive disorder in different countries 
are listed at the end of this document. Among these drugs are atypical antipsychotics 
approved for the treatment of major depressive disorder, as adjunctive treatments or as a 
monotherapy. The drug list may not be exhaustive. 
For a drug treatment to be considered appropriate, it must have been administered at a 
dose approved for the treatment of major depressive disorder in the country where the 
study site is located. The minimum duration of treatment must be deemed appropriate by 
the investigator, and as a guidance, 6 to 8 weeks can often be considered as an adequate 
treatment duration. 
Some drugs are occasionally dosed based on therapeutic drug monitoring results. Prior 
use of drugs approved for major depressive disorder using therapeutic drug monitoring 
should be considered an appropriate intervention, if the concentrations are within the 
target range, irrespective of dose, and if the duration is considered adequate. 
Antidepressants, if administered at an adequate dose and duration, can support a 
characterisation of Treatment-Resistant Depression (TRD), in addition to medications 
listed in the Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire (MGH-ATRQ). 
Tri- and tetra-cyclic antidepressants 
Noveril  
 
Dibenzepin  
Prothiaden  
 
Dosulepin  
Gamanil  
 
Lofepramine   
Sintamil  
 
Nitroxazepine 
Insidon  
 
Opipramol 
Asendin  
 
Amoxapine 
Tecipul  
 
Setiptiline 
MAO inhibitors 
Humoryl  
 
Toloxatone  
Celeport  
 
Bifemelane   
Other antidepressants 
Spravato  
 
Esketamine 
Brexanolone  
Zulresso 
Sediel   
 
Tandospirone 

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Atypical antipsychotics 
Abilify  
 
Aripiprazole 
Rexulti  
 
Brexpiprazole 
Zyprexa  
 
Olanzapine 
Seroquel  
 
Quetiapine 
Combination products 
Etafron  
 
Amitriptyline/perphenazine 
Deanxit  
 
Flupentixol/melitracen  
Symbyax  
 
Olanzapine/fluoxetine 
Parmodalin  
 
Tranylcypromine/trifluoperazine