Does Psilocybin Require Psychedelic Effects to Treat Depression? A 4-Week, Double-Blind, Proof-of-Concept Randomized Controlled Trial
Phase: PHASE2
Conditions: Treatment-resistant Depression
Sponsor: Centre for Addiction and Mental Health

 
 
 
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Does Psilocybin Require Psychedelic Effects to 
Treat Depression? A 4-Week, Double-Blind, 
Proof-of-Concept Randomized Controlled Trial  
  
Principal Investigator: Dr. Ishrat Husain 
Version Number:  5.0 
REB Number: 080-2022 
Version Date: January 6th, 2025 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Sponsor: 
 
 
 
 
 
Principal Investigator: 
 
 
 
 
Centre for Addiction and Mental Health 
1025 Queen Street West 
Toronto, Ontario M6J 1H1 
416-535-8501 ext. 39412 
 
Dr. Ishrat Husain MBBS, MD (Res.), MRCPsych 
Centre for Addiction and Mental Health (CAMH) 
1025 Queen Street West, Room 2104 
Toronto, Ontario M6J1H1 
416-535-8501 ext. 37838 
 
 
Funder: 
Canadian Institutes of Health Research 
160 Elgin Street 
Ottawa ON L1A 0W9 
613-941-2672 
 
University of Toronto, Department of Psychiatry 
250 College Street, 8th Floor 
Toronto, Ontario M5T1R8 
416-970-6948 
 
 

 
 
 
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Table of Contents 
 
STATEMENT OF COMPLIANCE ................................................................................................. 5 
LIST OF ABBREVIATIONS ........................................................................................................ 6 
CLINICAL TRIAL SUMMARY ..................................................................................................... 9 
1.0 INTRODUCTION...............................................................................................................11 
1.1 
BACKGROUND .............................................................................................................11 
1.2 
STUDY INTERVENTION ...................................................................................................11 
1.3 
PRECLINICAL DATA TO DATE...........................................................................................11 
1.4 
CLINICAL DATA TO DATE................................................................................................13 
1.5 
RISKS/BENEFITS..........................................................................................................15 
2.0 CLINICAL TRIAL OBJECTIVES .........................................................................................17 
2.1 
PRIMARY OBJECTIVE ....................................................................................................17 
2.2 
SECONDARY OBJECTIVE ................................................................................................17 
3.0 CLINICAL TRIAL DESIGN .................................................................................................17 
3.1 
OVERALL DESIGN ........................................................................................................17 
3.2 
PRIMARY ENDPOINTS....................................................................................................20 
3.3 
SECONDARY ENDPOINTS ...............................................................................................20 
4.0 PARTICIPANT SELECTION AND WITHDRAWAL ................................................................21 
4.1 
TARGET POPULATION ...................................................................................................21 
4.2 
PARTICIPANT RECRUITMENT AND SCREENING .....................................................................21 
4.3 
EQUITY, DIVERSITY AND INCLUSION CONSIDERATIONS ..........................................................23 
4.4 
ELIGIBILITY CRITERIA ....................................................................................................23 
4.4.1 
Inclusion Criteria ....................................................................................................23 
4.4.2 
Exclusion Criteria ...................................................................................................24 
4.5 
LIFESTYLE CONSIDERATIONS ..........................................................................................25 
4.6 
SCREEN FAILURES .......................................................................................................25 
4.7 
PARTICIPANT WITHDRAWAL CRITERIA ...............................................................................26 
4.7.1 
When and How to Withdraw Participants ...................................................................26 
4.7.2 
Follow-up for Withdrawn Participants ........................................................................26 
4.7.3 
Early Termination Visit……………………………………………………………………………..14 
4.7.4 
Participants who are lost to Follow-up……………………………………………………………15 
 
5.0 STUDY INTERVENTION ....................................................................................................27 
5.1 
DESCRIPTION..............................................................................................................27 
5.2 
TREATMENT REGIMEN...................................................................................................29 
5.3 
METHOD FOR ASSIGNING PARTICIPANTS TO TREATMENT GROUPS ...........................................29 
5.4 
ADMINISTRATION OF STUDY INTERVENTION ........................................................................29 
5.5 
PARTICIPANT COMPLIANCE MONITORING ...........................................................................30 
5.6 
CONCOMITANT THERAPY ...............................................................................................30 
5.7 
PACKAGING ................................................................................................................33 
5.8 
BLINDING OF STUDY INTERVENTION..................................................................................34 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN................................................................34 
5.9.1 
Receipt of Study Intervention Supplies ......................................................................34 
5.9.2 
Storage ................................................................................................................34 
5.9.3 
Dispensing of Study Intervention ..............................................................................34 
5.9.4 
Return or Destruction of Study Intervention ................................................................35 

 
 
 
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6.0 RESEARCH PROCEDURES ..............................................................................................35 
6.1 
RESEARCH VISITS ........................................................................................................35 
6.2 
SCHEDULE OF EVENTS ..................................................................................................44 
7.0 STATISTICAL PLAN .........................................................................................................47 
7.1 
SAMPLE SIZE DETERMINATION ........................................................................................47 
7.2 
STATISTICAL METHODS .................................................................................................47 
8.0 SAFETY AND ADVERSE EVENTS .....................................................................................48 
8.1 
DEFINITIONS ...............................................................................................................48 
8.2 
RECORDING OF ADVERSE EVENTS ...................................................................................50 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS .......................................................................50 
8.3.1 
Investigator Reporting: Notifying the Sponsor .............................................................50 
8.3.2 
Investigator Reporting: Notifying the REB ..................................................................51 
8.3.3 
Sponsor Reporting of SUADRs: Notifying Health Canada .............................................51 
8.3.4 
Sponsor Reporting of SUADRs: Notifying Sites ...........................................................51 
8.4 
REPORTING OF DEVICE DEFICIENCIES...............................................................................51 
8.5 
SAFETY MANAGEMENT PLAN ..........................................................................................51 
8.6 
UNBLINDING PROCEDURES.............................................................................................52 
8.7 
DATA AND SAFETY MONITORING BOARD............................................................................53 
9.0 CLINICAL TRIAL DISCONTINUATION AND CLOSURE ........................................................53 
9.1 
CLINICAL TRIAL DISCONTINUATION ...................................................................................53 
10.0 DATA HANDLING AND RECORD KEEPING........................................................................53 
10.1 
SOURCE DOCUMENTS & CASE REPORT FORMS ..................................................................53 
10.2 
PROTOCOL DEVIATIONS ................................................................................................54 
10.3 
RECORD RETENTION ....................................................................................................54 
10.4 
CLINICAL TRIAL REGISTRATION .......................................................................................54 
11.0 STUDY MONITORING, AUDITING, AND INSPECTING..........................................................54 
11.1 
STUDY MONITORING PLAN .............................................................................................54 
11.2 
AUDITING AND INSPECTING.............................................................................................55 
12.0 ETHICAL CONSIDERATIONS ............................................................................................55 
12.1 
RESEARCH ETHICS BOARD (REB) APPROVAL.....................................................................55 
12.2 
INFORMED CONSENT PROCESS & DOCUMENTATION .............................................................55 
13.0 PRIVACY AND CONFIDENTIALITY ....................................................................................56 
14.0 CLINICAL TRIAL FINANCES .............................................................................................57 
14.1 
FUNDING SOURCE........................................................................................................57 
14.2 
CONFLICT OF INTEREST .................................................................................................57 
15.0 PUBLICATION POLICY/DATA SHARING ............................................................................57 
15.1 
FUTURE SECONDARY USE OF DATA .................................................................................57 
16.0 REFERENCES .................................................................................................................57 

 
 
 
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STATEMENT OF COMPLIANCE 
 
This clinical trial will be carried out in accordance with the following:  
• International Conference on Harmonisation Good Clinical Practice (ICH GCP) 
• Tri-Council Policy Statement 2018 (TCPS 2) 
• ISO 14155:2020 for Medical Device Clinical Trials 
• Personal Health Information Protection Act (PHIPA), 2004; Chapter 3 Schedule A 
(PHIPA) and applicable regulations 
• Food and Drugs Act  
o Part C, Division 5 of the Food and Drug Regulations 
• Institutional and REB policies and procedures 
 
 
 
 
 
 
________________________________  
_____________________________ 
Signature of PI 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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LIST OF ABBREVIATIONS 
AE 
 
Adverse Event 
ALT 
 
Alanine aminotransferase 
AST  
Aspartate aminotransferase 
ATC  
Anatomical Therapeutic Chemical 
ATHF  
Antidepressant Treatment History Form 
CAMH 
Center for Addiction and Mental Health 
CGI 
 
Clinical Global Impression Scale 
CIHR  
Canadian Institutes of Health Research 
CRF   
Case report form(s) 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMT  
5-Hydroxytryptamine 
DSMB 
Data Safety & Monitoring Board 
ECG 
Electrocardiography 
ECT 
Electroconvulsive therapy 
EDI 
Equity, diversity, and inclusion 
GAD-7 
Generalized Anxiety Disorder 7-Item Scale 
GCP  
Guidelines for Good Clinical Practice 
HamD-17 
Hamilton Depression Rating Scale 
HDPE  
High-density polyethylene 
HIPPD  
Hallucinogen-induced persistent perceptual disorder 
HPMC 
Hydroxypropyl methyl cellulose 
GCP   
Good Clinical Practice 

 
 
 
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ICF  
 
Informed consent form 
IP 
 
Investigational product 
IPAC  
Infection prevention and control 
LSD   
Lysergic acid diethylamide  
MADRS 
Mongomery-Åsberg Depression Rating Scale 
MDD  
Major depressive disorder 
MDE  
Major depressive episode 
PAP  
Psilocybin-Assisted Psychotherapy 
PHI 
 
Personal Health Information 
PHIPA 
Personal Health Information Protection Act 
PI 
 
Principal Investigator 
PRN  
Pro Re Nata 
QI 
 
Qualified Investigator 
RCT  
Randomized controlled trial 
REB  
Research ethics board 
rTMS  
Repetitive Transcranial Magnetic Stimulation 
SAE  
Serious Adverse Event 
SCID-5 
Structured Clinical Interview for DSM-5 
SETS  
Stanford Expectations of Treatment Scale 
SHAPS 
Snaith-Hamilton Pleasure Scale 
SSRI  
Selective Serotonin Reuptake Inhibitor 
SUSAR  
Suspected unexpected serious adverse reaction 
TASS  
Transcranial Magnetic Stimulation Adult Safety Screen 

 
 
 
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TCPS 2 
Tri-Council Policy Statement  
TRD  
Treatment Resistant Depression 
TSC  
Trial Steering Committee 
 
WEMWS 
Warwick-Edinburgh Mental Wellbeing Scale 
WHO-QoL-BREF 
World Health Organization Quality of Life Questionnaire – Brief 
Version 
5D-ASC 
Five Dimensions of Altered States of Consciousness 
 
 
 
 
 
 
 
 

 
 
 
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CLINICAL TRIAL SUMMARY 
 
Title 
Does Psilocybin Require Psychedelic Effects to Treat 
Depression? An 4-Week, Double-Blind, Proof-of-concept 
Randomized Controlled Trial 
 
Short Title 
PSI-RIS 
Phase 
Phase II 
Methodology 
Double-blind randomized clinical trial 
Clinical trial 
Duration 
36-months to complete all recruitment, study procedures, and 
data analysis.  
Participating site(s) 
CAMH 
Objectives 
To assess the tolerability, feasibility, and clinical effects of 
risperidone and psilocybin administered in combination with 
supportive therapy to adult participants with treatment-
resistant depression. The main objective is to evaluate the 
feasibility and tolerability of administering psilocybin with 
risperidone by evaluating recruitment, retention, tolerability 
and safety. The secondary and exploratory aims are to 
measure the psychedelic effects by the 5-dimensional altered 
states of consciousness rating scale (5D-ASC) and 
antidepressant effects as assessed by the frequency of 
serious adverse events and the change in the total score of 
the MADRS from Baseline (V2) to Week 1 (V5). 
Number of 
Participants 
Sixty participants diagnosed with treatment-resistant 
depression 
Study Intervention 
Reference 
Therapy/Comparator 
1 mg of risperidone in combination with 25 mg of psilocybin 
taken in conjunction with psilocybin-assisted psychotherapy 
(PAP) compared to placebo + 25mg of psilocybin or 1 mg of 
risperidone + placebo. 
Duration of 
Intervention 
One day: 5-6hours  

 
 
 
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Statistical 
Methodology 
Characteristics of the trial cohort will be summarized by mean 
(SD), median (minimum, maximum). Summary raw scores 
will be presented at each assessment time both numerically 
and graphically. All analyses will be conducted under the ITT 
approach and run with a blinded grouping variable. Missing 
data will be handled by using full information maximum 
likelihood method. Feasibility, safety and tolerability 
endpoints (primary aim) will be examined by standard 
frequency analysis. The primary analytic strategy will be 
mixed-effects generalized linear model to inspect group 
differences on clinical outcomes at endpoint of the secondary 
and exploratory aims. Exploratory analysis will be performed 
on a modified ITT principle, including all participants receiving 
a study intervention. Dichotomous outcomes (e.g. response, 
remission, adverse events), serious adverse events and 
dropouts attributed to adverse events will be compared 
between groups using a Chi-squared test for assessments at 
a single time-point, and using generalized estimating 
equations for repeated assessments. 
Exact paired permutation t-tests will be used to determine 
whether psilocybin-assisted psychotherapy with risperidone 
achieves a 50% reduction in MADRS. 
 

 
 
 
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1.0 INTRODUCTION 
1.1 
Background 
Treatment-Resistant Depression (TRD) affects up to a third of all depressed individuals 
(Wiles et al., 2013). Major depressive disorder (MDD) is a leading cause of disability 
worldwide. Although depressive symptoms are amenable to pharmacotherapy, a high 
proportion of patients experience TRD, typically defined as not responding to two or more 
adequate antidepressant trials, or relapse during treatment (Gaynes et al., 2020; Rush et 
al., 2006). TRD is associated with a significant decline in social and occupational 
functioning and higher rates of death by suicide and all-cause mortality (Reutfors et al., 
2018). Persistent symptoms in TRD often translate into substantial increases in work loss, 
healthcare resource utilization, and costs, compared to more responsive forms of illness 
(Li et al., 2020). Current pharmacotherapy for TRD, including augmentation of 
antidepressants with atypical antipsychotics, lithium, or ketamine have high rates of non-
response (Carter et al., 2020) and can be associated with problematic adverse effects 
(e.g., sedation, weight gain, diabetes, tardive dyskinesia) leading to non-adherence (Ho 
et al., 2017). Electroconvulsive therapy (ECT) is the most efficacious intervention for TRD. 
However, many patients with TRD refuse ECT because of stigma, lack of access, and 
fears of cognitive adverse effects (Wilkinson et al., 2021). Transcranial magnetic 
stimulation (rTMS) is an alternative to ECT but its response and remission rates are 
similar to pharmacotherapy (Carter et al., 2020), leaving a large proportion of patients 
with TRD in need of novel interventions. 
1.2 
Study Intervention 
Psilocybin is a chemical compound that naturally occurs in certain species of mushrooms, 
(for example, in the psilocybe genus, among others). It belongs to a class of drugs 
referred to as ‘psychedelics’. Psilocybin is a tryptamine that is chemically similar to the 
neurotransmitter, serotonin, and the essential amino acid, tryptophan (Johnson et al., 
2019). It is considered a 5-hydroxytrptamineric (serotonergic) psychedelic along with 
other similar drugs such as dimethyltryptamine (DMT) and lysergic acid dieythamide 
(LSD). Psilocybin is a prodrug for the pharmacologically active ingredient psilocin, which 
readily crosses the blood-brain barrier and acts as a potential partial agonist at serotonin 
5HT2A and 5HT2c receptors in the brain (Halberstadt et al., 2011; Madsen et al., 2019). 
Typical effects of psilocybin include significantly altered states of consciousness, 
experienced through visual and sometimes auditory effects, changes in perception, 
distortions of time, and a range of effects including a sense of awe, novel perspectives, 
existential and personal insight, dramatically heightened empathy and feelings of 
compassion, strong emotions, and unitive experience. These mystical experiences are 
correlated with improvements in mood in healthy volunteers and palliative patients with 
end-of-life distress (Johnson et al., 2019). However, there is no convincing evidence that 
these psychedelic effects are required for an antidepressant effect in patients with MDD 
(Johnson et al., 2019). In fact, in a recent study, 24 participants who received PAP for 
MDD, showed no associations between psychedelic effects and sustained improvement 
in depressive symptoms, suggesting that psychedelic effects may not be necessary to 
harness psilocybin’s antidepressant effects (Gukasyan et al., 2022).  

 
 
 
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Recently, ‘microdosing’ – a way of administering psilocybin that involves taking ~10% of 
a recreational dose two or three times per week – has gained public popularity as a way 
to achieve the mental health benefits of the drug without inducing psychedelic effects.  
However clinical trials in healthy subjects indicate that ‘microdosing’ psilocybin and other 
psychedelics confers no mental health benefits over placebo (de Wit et al., 2022; Szigeti 
et al., 2021). Given the increasing public use of ‘microdosing’, determining whether 
psilocybin’s psychedelic effects are necessary for its antidepressant effects will inform its 
acceptability (i.e., in patients apprehensive about the psychedelic “trip” and its associated 
effects) and its scalability (by reducing the resources required for its safe administration). 
 
Psilocybin-assisted psychotherapy (PAP) has been gaining traction as a promising 
potential treatment for many mental illnesses, including end-of-life anxiety and treatment-
resistant depression (Perkins et al., 2021). PAP procedures typically involve 
psychological preparation prior to therapist-supported psilocybin dosing sessions. These 
sessions are used to establish a therapeutic relationship, inform participants about what 
to expect, and set expectations for the dosing session. During the psilocybin dosing 
session, trained therapists support the individual through their experience and 
psychological integration therapy occurs after the dosing experience. Evidence from 
recent clinical trials suggest that PAP can help in the reduction of anxiety, depression, 
and substance use (Carhart-Harris et al., 2021; Griffiths et al., 2016; Grob et al., 2011; 
Ross et al., 2016). With proper screening and preparation, psilocybin has a safe 
physiological and psychological profile.  
 
In its current form, psilocybin is not suitable for wide scale clinical adoption. Despite 
published safety data, psilocybin-induced alterations in perception and consciousness 
remain a major barrier to widespread clinical implementation, necessitating an 5-6 hour 
session of intensive psychological support in a clinical setting during administration, in 
addition to several lengthy preparation and integration sessions pre- and post-dosing. 
This complex process could be greatly simplified if the psychedelic effects could be 
diminished without impairing the antidepressant effects. In humans, the intensity of 
psilocybin-induced perceptual changes correlates with 5-HT2A activation (Madsen et al., 
1995). However, psilocybin’s antidepressant effects may be mediated through rapid 
activation of other critical 5-HT receptors. Two 5-HT2A-receptor antagonists – risperidone 
(an atypical antipsychotic) and ketanserin (an antihypertensive) – eliminate self-reported 
psilocybin psychedelic effects in humans (Vollenweider et al., 1998). Thus, this 
intervention will involve the administration of risperidone followed by PAP to determine if 
the psychedelic experience of psilocybin is necessary to produce antidepressant effects. 
1.3 
Preclinical Data to Date 
Animal studies looking into the effects of psychedelics in rodents have found evidence for 
improvements in behavioral outcomes, assessed by measures of coping strategy and 
cognitive function. The long-term effects using LSD (Buchborn et al., 2014; Hibicke et al., 
2020), psilocin (Horsley et al., 2018), psilocybin (Hibicke et al., 2020), and DMT (Cameron 
et al., 2019; Cameron et al., 2018) were comparable to traditional treatment 

 
 
 
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antidepressants. Moreover, there is evidence suggesting improvements in dimensions of 
cognitive function, such as enhanced associative learning (Buchborn et al., 2014; Harvey, 
2003) which are commonly impaired in major depressive disorder (Castaneda et al., 
2008). In vitro studies with rat brain preparations have demonstrated that risperidone has 
a 10-20 fold greater affinity for the 5-HT2A receptor than for the D2 receptor (Meltzer et al., 
1989). Similarly, psilocybin also has a high affinity for the 5-HT2A receptor. The intensity 
of psilocybin-induced perceptual changes is correlated with serotonin 2A receptor (5-
HT2AR) activation (Madsen et al., 2019). In a study involving 8-week old mice exposed 
to a chronic multimodal stress paradigm, hedonic state was assayed with an appetize 
choice task: a two-bottle sucrose preference test comparing consumption of a 1% sucrose 
solution and water (Hesselgrave et al., 2021). Psilocybin injections restored preference 
for sucrose solution whereas mice given a saline injection retained low sucrose 
(Hesselgrave et al., 2021). In the second part of the study, researchers pre-treated the 
mice with a 5-HT2A/2C antagonist prior to the psilocybin or saline injection. The results 
indicated that the behavioural responses to the sucrose test were not prevented when the 
antagonist was administered (Hesselgrave et al., 2021). These results indicate that 
psilocybin’s antidepressant mechanism of action may not be dependent on the 
psychedelic effects (Hesselgrave et al., 2021).  
1.4 
Clinical Data to Date 
During the past decade, there has been a resurgence of interest in psychedelic 
compounds as novel treatments for mental disorders including TRD. In particular, 
psilocybin, the chemical component of “magic mushrooms” at doses of 20-30 mg, in 
conjunction 
with supportive 
psychotherapy, 
has shown large 
and sustained 
antidepressant effects in patients with MDD and TRD in contemporary open-label and 
randomized clinical trials (RCTs) (Carhart Harris et el., 2016; Carhart Harris et al., 2021; 
Davis et al., 2021). For instance, in an open-label trial of psilocybin-assisted 
psychotherapy (PAP), 63% of 19 participants with TRD responded 1 week after treatment, 
and 32% were not on any antidepressant or therapy for a further year (Carhart Harri et 
al., 2016). Similarly, an RCT of 24 participants with MDD showed large effect sizes for 
PAP at week 1 (Cohen d = 2.5) and week 4 (Cohen d = 2.6) post-treatment compared 
with waitlist control (Davis et al., 2021). A long-term follow-up study of the same 
participants showed response and remission rates of 75% and 58%, respectively, at 12 
months (Gukasyan et al., 2022). More recently, a trial comparing PAP with escitalopram 
in 59 participants with non-refractory MDD showed that PAP was as effective as 
escitalopram in reducing depressive symptoms with no differences in adverse effects 
between groups (Carhart Harris et a;., 2021). Recently, an international phase II RCT of 
PAP for 233 patients with TRD was completed. Preliminary findings indicate that 
psilocybin 25 mg led to a significant reduction in scores on the Montgomery-Abserg 
Depression Rating Scale (MADRS) for at least 6 weeks post-treatment, compared to 
psilocybin 1 mg (an active placebo), without significant differences in serious adverse 
events between groups (COMPASS, 2021). 
 
However, all published trials to date are limited by small sample sizes, inadequate control 
groups, lack of blinding, or highly selected participants. Despite these methodological 

 
 
 
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limitations, the results of these trials have led to growing enthusiasm for the clinical 
translation of psilocybin for the treatment of MDD and related disorders. Currently, it is 
assumed that psilocybin’s therapeutic effects in MDD require altered consciousness (i.e. 
the psychedelic “trip”), which is dependent on serotonin 2A (5-HT2A) receptor activation 
(Vollenweider et al., 1997). All contemporary clinical trials have investigated psilocybin in 
the context of several hours of intensive psychotherapy given its highly potent psychedelic 
effects and the need for continuous monitoring. The psychotherapy involves at least 2 
hours of preparatory sessions,5-6hours of supportive therapy during the dosing session 
in the presence of two trained therapists, and 2 hours of post-dosing integration sessions. 
This amount of specialized psychotherapy impedes scalability of psilocybin as a 
pragmatic intervention for MDD and TRD given the limited resources and access to 
trained therapists in most jurisdictions. However, pre-clinical studies in animal models 
show that psilocybin’s antidepressant effects may not be dependent on 5-HT2A activation 
(and hence the psychedelic effects) (Hesselgrave et al., 2021). This hypothesis has never 
been tested in humans. Before psilocybin can be administered in the clinic, we need to 
understand whether its psychedelic effects are needed for its antidepressant effects.  
 
We propose a proof-of-concept randomized clinical trial to determine whether the 
psychedelic effects of psilocybin are required to yield antidepressant effects. Using a 
“double-dummy” design, 60 participants with TRD will receive 10 hours of manualized 
psychotherapy (which includes 5 to 6 hours of psilocybin dosing session) that has 
previously been used with psilocybin (Guss et al., 2020) and be randomized to three 
groups: (1) psilocybin 25 mg plus risperidone 1 mg; (2) psilocybin 25 mg plus placebo; 
(3) placebo plus risperidone 1 mg. We are only recruiting patients with TRD, as psilocybin 
has not demonstrated superiority over first-line antidepressants for non-refractory MDD 
(Carhart-Harris et al., 2021). We are using the atypical antipsychotic risperidone, a potent 
blocker of the 5-HT2A receptor, due to two reasons: (1) a previous study in healthy 
volunteers has demonstrated that risperidone 1 mg effectively blocks psilocybin’s 
psychedelic effects (Vollenweider et al., 1998), and (2) risperidone is a readily available, 
safe, and inexpensive generic drug that is used for the treatment of TRD and other mental 
disorders. Hence, it would be easily adopted in clinical practice if effective when combined 
with psilocybin. Although risperidone also has actions on dopaminergic receptors, 
psilocybin has no direct dopaminergic activity (Creese et al., 1975), and psilocybin’s 
psychedelic effects are not blocked by traditional D2-receptor antagonists like haloperidol 
(Vollenweider et al., 1998).  
 
In summary, if the proposed proof-of-concept study indicates that psilocybin’s psychedelic 
effects may not be required for its antidepressant effects, and this is confirmed in a future 
RCT, the use of psilocybin could be standardized and safely expanded without the need 
for intensive psychotherapy, providing a scalable, novel rapid-acting intervention for TRD. 
It will also inform the development of further trials studying this combination without 
psychotherapy and continuous monitoring. This may accelerate clinical translation, social 
acceptance, and therapeutic development for treatment of TRD, and possibly MDD. 
 

 
 
 
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1.5 
Risks/Benefits 
 
Possible Benefits 
As with any research study, no direct benefit can be promised to research participants. 
Clinical trials investigating psilocybin-assisted psychotherapy in depression cohorts have 
indicated rapid and dramatic reductions in participants’ symptoms. Therefore, participants 
may receive some benefit from the study if PAP alone or in combination with risperidone 
is effective in improving depressive symptoms. Participants may also benefit from close 
monitoring of their clinical conditions.  
 
Psilocybin & Risperidone Risks 
 
We do not expect any major risks to the safety of participants. Psilocybin-containing 
mushrooms have been used safely by indigenous cultures in Central and South America 
for hundreds of years (Carod-Artal, 2015; Johnson et al., 2018). Expert consensus 
indicates that psilocybin is safe in human pre-clinical and clinical trial research (Johnson 
et al., 2008). A meta-analysis of clinical trials of psilocybin and other serotonergic 
psychedelics found no significant differences in adverse events between those receiving 
psilocybin and placebo. (Galvão-Coelho et al., 2021). In recently conducted RCTs, these 
adverse events were transient, tolerable, and resolved within the timeframe of the 5-6 
hour dosing session, including: transient anxiety; minor elevation in heart rate or blood 
pressure; and mild nausea upon initiating the dose. (Carhart-Harris et al., 2016; Davis et 
al., 2021; Griffiths et al., 2016; Grob et al., 2013; Ross et al., 2016). However, psilocybin, 
especially at higher doses, can be associated with more concerning psychological effects. 
Psilocybin given at a dose of 25mg is expected to alter mood, cognition, and perception. 
Common psychological and adverse effects of psilocybin include transient anxiety, 
changes in thought form or thought speed (slowing down or speeding up of thought 
processes), depersonalization, derealization, inattention, impaired concentration, labile 
mood, altered perception of time. In addition, these effects are both expected component 
of the therapeutic response and it is anticipated that these effects will be diminished when 
given with risperidone. Psilocybin can produce sympathetic system activation resulting in 
physiological effects such as pupillary dilation and detectable, but moderate increases in 
blood pressure or heart rate, transient nausea, diarrhea, paresthesia, dizziness, fatigue 
and headache. In rare cases, hallucinogen-induced persistent perceptual disorder 
(HIPPD) where individuals experience the effects of psilocybin for longer than expected. 
These have not been any reported cases of this in modern clinical settings, but it has 
been rarely reported following recreational use. With proper screening and preparation, 
psilocybin has a safe physiological and psychological profile. As with any investigational 
product trial, there is a possibility that some participants may experience a worsening of 
their mental state after the drug experience. Reports of this are very rare and have not 
been seen in other similar studies. Published findings on harm profiles associated with 
drugs most commonly used in the UK and Australia consistently rate ‘magic mushrooms’ 
as being one of the least harmful substances to one’s self and to society (Nutt et al., 
2010). In order to mitigate risks, a preparatory therapy session will be scheduled with 
each participant to prepare them for what to expect during the experience. It is important 

 
 
 
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to assess psilocybin tolerability (Primary Aim) given the high rate of noncompliance with 
antidepressant treatment related to perceived adverse effects. (Nomi et al., 2017). 
 
 
On the other hand, in larger RCTs in patients with TRD, risperidone 0.5 – 3.0 mg daily 
has been safe for use (Cantù et al., 2021). Thus, we expect that a single low dose (1 mg) 
of risperidone to have minimal adverse effects. Risperidone administered alone has 
common side effects (>10%) of drowsiness, headache, tremors, twitching or 
uncontrollable muscle movements, dizziness, nausea, and/or dry mouth. It is possible 
that participants may experience these side effects but this is unlikely with a single 1 mg 
dose. Previous studies in healthy volunteers indicate that risperidone, a potent blocker of 
the 5-HT2A receptor, can effectively blocks psilocybin’s psychedelic effects (Vollenweider 
et al., 1998). This study also demonstrated that the combination of risperidone 1 mg and 
psilocybin 25 mg is safe to use in healthy volunteers (Vollenweider et al., 1998). Thus, 
we expect a single low dose (1 mg) of risperidone to have minimal adverse effects.  
 
Medication Tapering Risks 
There will be a washout period of a minimum of 2 weeks (4 weeks for fluoxetine) for 
participants taking any concomitant medications prior to Baseline (V2). Withdrawing from 
medications may result in difficulty sleeping, nausea, diarrhea, flu-like symptoms, and 
jitters. These symptoms are not dangerous and usually pass in a few days. In addition, 
tapering off antidepressant medications can result in the worsening of a participant’s 
symptoms. During the tapering period, the participant will be seen clinically by the study 
physician. If the participant is not on any prohibited medication, a monitoring period of 2 
weeks will apply, prior to the baseline visit.   
 
Blood Draw 
There may be mild temporary discomfort, minor bruising or irritation, and in rare cases 
there may be local infection at the vein site. The blood draws are required to establish 
safety and eligibility for the trial.   
 
ECG 
Skin irritation from the ECG electrode pads or pain when removing the sticky pads are 
possible side effects. 
 
Assessment Measures 
Assessment measures are designed to address various aspects of psychopathology and 
as such, may be distressing. Participants may experience emotional reactions to the 
questions and when providing responses about the material on the questionnaires and in 
the interviews. Any distress or discomfort encountered by participants will be addressed 
by a member of the study team. In addition, the assessments may cause fatigue. These 
risks will be mitigated by offering breaks throughout the study visits.  
 

 
 
 
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2.0 CLINICAL TRIAL OBJECTIVES  
The overall objective is to conduct a proof-of-concept RCT that will: (1) establish the 
feasibility and tolerability of combining psilocybin and risperidone in patients with TRD; 
(2) show that this combination blocks the psychedelic effects of psilocybin; and (3) provide 
pilot data on the antidepressant effect size of this combination (compared to the 
antidepressant effect size of psilocybin alone), in preparation of a future larger RCT.  
2.1 
Primary Objective 
To evaluate the feasibility and tolerability of administering psilocybin (25mg) with 
risperidone (1 mg) in adults with TRD by evaluating recruitment, retention, tolerability and 
safety.  
 
Hypothesis 1a (feasibility): We will be able to recruit 60 participants within 24 months with 
a retention of >90%. 
Hypothesis 1b (safety): There will be no significant difference between the three groups 
in the frequency of dropouts attributed to adverse effects (tolerability) or serious adverse 
events (safety). 
 
2.2 
Secondary Objective 
The secondary objectives is to evaluate subjective psychedelic effects as measured by 
the 5-Dimensional Altered States of Consciousness Rating Scale in the three groups, 
which will be completed at V3 when the acute effects of psilocybin have worn-off.  
• Hypothesis 2: The psychedelic effect size in the psilocybin plus placebo group will 
be larger than in the psilocybin plus risperidone group and the placebo plus 
risperidone group (in which it will be close to zero). 
2.3 
Exploratory Objective 
To evaluate antidepressant effects in the three groups as measured by the change in the 
MADRS from Baseline (V2) to 1-week post-treatment (V5). The antidepressant effect 
sizes are expected to be comparable in the psilocybin plus placebo group and psilocybin 
plus risperidone group and larger than in the placebo plus risperidone group. 
3.0 CLINICAL TRIAL DESIGN 
3.1 
Overall Design 
 
This study is a three-arm, 4-week, double blind, proof-of concept RCT for investigating 
psilocybin-assisted psychotherapy (PAP) administered with risperidone in treating TRD. 
This three-arm “double dummy” design allows for an assessment of risperidone’s anti-
psychedelic effects, while allowing for an assessment of psilocybin’s antidepressant 
effects alone and combined with risperidone, compared to an “active placebo” (i.e. 
placebo plus risperidone 1 mg). 

 
 
 
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Overview of Study Design: 
A study team member will obtain informed consent from interested participants prior to 
study activities being initiated. Following this, participants will undergo a screening 
assessment where they will complete lab tests, and clinical and psychiatric assessments 
to determine eligibility. Following the screening visit, eligible participants will undergo a 
washout period where they will be tapered off concomitant medication over a period of 4 
to 6 weeks. The length of the tapering period will depend on the type of medication the 
participant is being tapered off (based on the half-life of the medication) and the 
participant’s preference for the length of the tapering period. Most medications will require 
a minimum of a 2-week tapering period before the baseline, with the exception of 
fluoxetine, which will require a minimum of 4-weeks. Additional time may be added at the 
discretion of the study investigator. Participants who are not on prohibited medications 
will undergo a 2-week monitoring period prior to Baseline (Visit 2). During the tapering 
period, the study psychiatrist will see participants weekly (V1a, V1b, etc.) for at least 2 
weeks to monitor for withdrawal and worsening of depressive symptoms and suicidality. 
Suicidality will be closely monitored using the Columbia Suicide Severity Rating Scale (C-
SSRS). Participants and their family members/carers will be educated on the signs and 
symptoms of worsening depression and suicidality and will be given contact details of the 
study team in case of major decline in mental state. 
 
At the Baseline visit (V2), which occurs the day before the dosing session, participants 
will complete clinical measures, pre-intervention clinical bloodwork and undergo a 
preparatory session (up to 4 hours) with the study therapists. These sessions will build a 
therapeutic alliance, provide psychoeducation about, and set intentions for, the psilocybin 
session. To reduce participant burden, baseline can be broken up into multiple days, 
however all assessments must be completed within 7-days of the intervention. Ideally, 
baseline occurs the day before the intervention is administered.  
 
The psilocybin session (Day 0 [V3]) will last 5 to 6 hours and will be conducted in the 
existing psychedelic treatment suite developed at the Centre for Addiction and Mental 
Health (CAMH) Mood Disorder Service by Dr. Husain (PI). Two trained study therapists 
will be supporting each participant during the dosing session. Participants will receive 
psilocybin 25 mg plus risperidone 1 mg, or psilocybin 25 mg plus placebo, or placebo plus 
risperidone 1 mg. All participants will receive 10 hours of manualized supportive 
psychotherapy (which includes the 5-6 hour dosing session). After 5 hours of dose 
administration, participants will be evaluated for safety by the study psychiatrist and 
discharged home in the company of a caregiver or a family member.  
 
After the dosing session, participants will be seen for two 1-hour integration sessions (Day 
1 [V4], Week 1 [V5]). At Visit 4, participants will also undergo post-intervention clinical 
bloodwork. Thereafter, participants will be followed-up after 2 [V6], 3 [V7] and 4 weeks 
[V8] post-dosing (see Figure 1). A study psychiatrist will be available throughout the 
duration of the RCT to respond to any concerns or changes in mental/physical state. 
Participants will not start other interventions for MDD during the study.

 
 
 
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Figure 1. Study Schematic: 
 
Timeline 
In total, there are a minimum of 12 
study visits (8 study visits and a 
minimum of 2 check-in visits during the 
washout period). There may be more 
study visits scheduled at the discretion 
of the study team or the participant. 
These study visits will take place over 
the span of approximately 2.5 months. 
The total expected duration of the 
clinical trial from the time the study 
team 
starts recruiting 
until 
data 
analysis has been complete is 36 
months. Following a 6-month startup 
period 
including 
hiring, 
obtaining 
psilocybin and receiving a Section 56 exemption, the study team will recruit approximately 2-3 participants per month 
over the period of 24 months. Study interventions and follow-up assessments will be completed by month 28. This leaves 
approximately 6 months for data analysis, which will be completed at month 36.  
 
 

 
 
 
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3.2 
Primary Endpoints 
Feasibility endpoints will be evaluated by monitoring recruitment and retention rates.  
 
Dropouts during three periods will be evaluated: 1) during medication tapering and 
washout period, 2) during the acute course of the study intervention, and 3) the one-
month follow-up period. Throughout all three periods, we will also evaluate adverse 
events including psychological distress and serious adverse events (e.g., hospitalization, 
suicide attempt, death). 
 
Safety endpoint is the number and severity of adverse events reported, it will be evaluated 
using standardized adverse events monitoring at all-time points. Adverse event 
monitoring will be prioritized to closely and thoroughly evaluate safety profile of the 
psilocybin plus risperidone combination. Constant observation by therapists will monitor 
for adverse events during the dosing sessions. An on-call psychiatrist will be available at 
all times to further assess as needed for acute concerns, as needed.  
 
3.3 
Secondary Endpoints 
The secondary endpoints for psychedelic effect are the scores on the 5D-ASC visual 
analogue scale (Dittrich et al., 2010) administered at Visit 3.  
3.4 
Exploratory Endpoints 
The antidepressant effects will be assessed by measuring changes from Baseline to 
Week 1 (V5) on MADRS. Baseline is defined as the assessment score obtained on Day 
-1 (V2). The primary time-point is Week 1 (V5). The changes in MADRS from Baseline to 
Day 1 (V4), and Weeks 2 (V6), 3 (V7), and 4 (V8) post-dosing will also be analyzed. Other 
clinical outcomes include response defined as a reduction of 50% or more of the MADRS 
score and remission defined as a score of <7 on the MADRS from Baseline (V2) to Week 
1 (V5). 
 
Other outcome measures will be changes from Baseline (V2) to Week 1 (V5) in the 
Clinical Global Impression (CGI) scale (Busner & Targum, 2007), World Health 
Organization Quality of Life Short Version (WHOQOLBREF) (Skevington et al., 2004), 
and the Generalized Anxiety Disorder scale (GAD-7) (Spitzer et al., 2006). Additional 
behavioural assessments will include measures of anhedonia (Snaith Hamilton 
Anhedonia Pleasure Scale, SHAPS) (Snaith et al., 1995), wellbeing (Warwick-Edinburgh 
Mental Wellbeing Scale, WEMWS) (Tennant et al., 2007) and the experience after 
psilocybin administration (Mystical Experiences Questionnaire, MEQ) (Barrett et al., 
2015). 
 
 

 
 
 
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4.0 PARTICIPANT SELECTION AND WITHDRAWAL 
4.1 
Target Population 
The target population for this study are adults aged 18-65 who are diagnosed with major 
depressive disorder and experiencing a clinically significant depressive episode that has 
failed to respond to at least two adequate trials of antidepressants. Participants must meet 
all inclusionary/exclusionary study criteria as confirmed by the study investigator. In order 
to be eligible, these criteria must be met at the Baseline visit (V2). For participants on 
concomitant medications, confirmation of eligibility occurs after a successful washout 
period in which the participant has been tapered off concomitant medications for a period 
of at least 2-weeks prior to baseline (4-weeks for fluoxetine), as confirmed by the study 
investigator.  
4.2 
Participant Recruitment and Screening 
The target sample size is 60 participants (N=60) diagnosed with treatment-resistant 
depression. The study will take place at a single site: the Centre for Addiction and Mental 
Health (CAMH) in Toronto, Ontario.  
 
The source of participants in this study will come from CAMH outpatient clinics and 
external referrals. Participants in this trial must be CAMH patients. External referrals will 
need to go through the usual referral and admissions processes at CAMH. Clinicians at 
CAMH may identify potential research participants and obtain verbal permission from 
these potential participants for a member of the research team to approach them. 
Potential participants that are interested in participating in the study will be prescreened 
by a member of the study team, as outlined below. After referral and consented to 
screening, I-Care will be used to confirm their eligibility. 
 
The CAMH Research Registry will also be used to recruit participants for this clinical trial. 
Upon REB approval to use the Research Registry as a recruitment strategy, authorized 
research personnel will search and contact potential research participants included within 
the member database of the Research Registry for study participation. This clinical trial 
will also be posted on the Research Registry website, as well as the public CAMH 
website. The recruitment material posted on these websites will be reviewed and 
approved by Research Communications as well as the REB prior to posting. Once posted, 
interested participants can use the “Find a CAMH study” feature to explore clinical trials 
that they are interested in. 
 
Advertisements (Flyers and pamphlets) for the current study will also be posted in patient 
areas around the CAMH campus (e.g., clinic waiting rooms, main lobbies, etc.).  
 
Prescreening Procedures 
Once a potential participant contacts the research team or is referred to the research 
team as an interested potential participant, a research team member will schedule a 
phone call. This phone call will be referred to hereafter as the Pre-Screening 
conversation. During the pre-screening conversation, a brief description of the study is 

 
 
 
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provided to the potential participant and then, if the person agrees, the following eligibility 
criteria is obtained: 
• Contact information (phone number and/or email) 
• Partial date of birth  
• Ability to read and speak English 
• Whether they have a clinical diagnosis of major depressive disorder 
• Whether they are currently experiencing a major depressive episode 
• Treatments taken for major depressive episode (frequency and type of treatment) 
• Whether the potential participant has been diagnosed with psychotic disorder, 
bipolar disorder, paranoid personality disorder, schizoaffective disorder, or 
borderline personality disorder; 
• Diagnosis of a substance use disorder (recreational use of tobacco, alcohol, 
cannabis, and prescribed opioids are permitted) within the previous 6-months; 
• If they are currently undergoing therapy and if they are, the date that they started 
• Whether the potential participant would be willing to discontinue current 
antidepressant medications  
• Whether they are seeing a doctor on a regular basis for a medical problem 
• If they are currently taking medications for the treatment of a physical health 
problem 
• Difficulty with giving blood or needles 
• Currently nursing or pregnant 
• Willingness to take contraceptives for the duration of the study 
• History of allergy or adverse reaction to risperidone 
• Currently enrolled in another study involving an investigational product or device 
• If they are able to take medication orally 
• If they have ever used psychedelic drugs  
 
The information collected during this conversation will be recorded on the pre-screen form 
which will be reviewed by the study PI. If the potential participant does not meet any 
exclusionary criteria as listed on the Pre-Screen form, then the potential participant is 
called back to invite them to schedule a consent and screening visit.  
 
If the person meets any exclusionary criteria during the pre-screening conversation or as 
determined by the study investigator, then the person is asked whether they would be 
interested in participating in any other studies (current or future) within our program. If 
they are interested in other studies within our department, their name and contact 
information will be transferred to a password protected log that is only accessible by the 
Mood Disorder Services and the Centre for Complex Interventions staff. If they fail the 
pre-screen and do not wish to be contacted, their pre-screen form will be discarded in the 
confidential shredding bin which will then be securely disposed of. However, their name 
will be kept in a password protected log along with the date and result (pass/fail) of their 
pre-screen so if they contact us again (e.g. to inquire about their eligibility) we can refer 
back to it.  
 

 
 
 
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Compensation 
Participants will not be charged for research-only services for their participation in this 
study. All research-only services, such as clinical assessments, blood work, and the IP 
will be provided at no cost to the participant.  
 
Participants will be reimbursed for the cost of parking incurred at each study visit. To 
receive reimbursement for parking expenses incurred at each study visit, participants 
must provide the research team with a parking receipt. In addition, reimbursement will be 
provided if the participant used public transit for transportation to and/or from study 
appointments.  
 
Participants will also be reimbursed for the time spent at study visits occurring after the 
screening and washout period where treatment (therapy or the intervention) is not 
administered. Participants will be reimbursed $10 per hour for each study visit that they 
attend (V6, V7, and V8). In total, if participants complete all study visits, they may be 
reimbursed up to $25 for their time. Compensation will be provided for all applicable visits 
and travel reimbursement at the participant’s final study visit (Visit 8) via gift card. No 
payment will be provided in advance.  
 
Study Visit: 
Duration: 
Compensation: 
Follow-Up: Visit 6 
~1 hour 
$10 
Follow-Up: Visit 7 
~ 30 min. 
$5 
Follow-Up: Visit 8 
~1 hour 
$10 
 
 
4.3 
Equity, Diversity and Inclusion Considerations 
Equity, diversity, and inclusion (EDI) are important to ensuring the study design is ethically 
sound. No exclusions will be made based on race, ethnicity, religion, sex, or gender.  
4.4 
Eligibility Criteria 
4.4.1 
Inclusion Criteria 
The participant must meet all of the inclusion criteria to eligible for this clinical trial: 
 
1. Adults 18 to 65 years old; 
2. Are outpatients; 
3. Must be deemed to have capacity to provide informed consent; 
4. Must sign and date the informed consent form; 
5. Stated willingness to comply with all study procedures; 
6. Ability to read and communicate in English, such that their literacy and comprehension 
is sufficient for understanding the consent form and study questionnaires, as 
evaluated by study staff obtaining consent; 

 
 
 
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7. Primary DSM-5 diagnosis of non-psychotic MDD, single or recurrent, based on the 
Structured Clinical Interview for DSM-5 (SCID-5) administered at the first screening 
visit; 
8. Participants diagnosed with treatment-resistant depression defined as individuals with 
a baseline HamD-17 score > 14 and that have not responded to two or more separate 
trials of antidepressants at an adequate dosage and duration (an antidepressant 
resistance rating score of three or more is considered an adequate trial) based on the 
Antidepressant Treatment History Form (ATHF) (Sackeim & Sackeim, 2001); there is 
no upper limit on the number of treatment failures; 
9. Ability to take oral medication; 
10. Individuals with an eGFR above 40mL/min/1.73m2 and all blood work on clinical 
laboratory tests assessed as not clinically significant by study delegate physician at 
Screening (V1) 
11. Individuals who are capable of becoming pregnant: use of highly effective 
contraception for at least 1 month prior to screening and agreement to use such a 
method during study participation; 
12. Individuals who are willing to and tapered off current antidepressant and antipsychotic 
medications for a minimum of 2-weeks (or more depending on the medication) prior 
to Baseline (V2) and for the duration of the study and whose physician confirms that 
it is safe for them to do so;  
13. Individuals who are willing to and have tapered off current inhibitors of 5'-diphospho-
glucuronosyltransferase (UGT)1A9 and 1A10, aldehyde dehydrogenase inhibitors 
(ALDHs) and alcohol dehydrogenase inhibitors (ADHs)  for a minimum of 2-weeks 
(or more depending on the medication) prior to Baseline (V2) and for the duration of 
the study and whose physician confirms that it is safe for them to do so; AND 
14. Agreement to adhere to Lifestyle Considerations (section 4.5) throughout study 
duration. 
4.4.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in 
this clinical trial: 
1. Pregnant as assessed by a urine pregnancy test at Screening (V1) and Baseline (V2) 
or individual’s that intend to become pregnant during the study or are breastfeeding; 
2. Treatment with another investigational drug or other intervention within 30 days of 
Screening (V1); 
3. Have initiated psychotherapy in the preceding 12 weeks prior to Screening (V1); 
4. Have a DSM-5 diagnosis of substance use disorder (recreational use of tobacco, 
alcohol, cannabis and prescribed opioids are permitted) within the preceding 6 
months; 
5. Have active suicidal ideation with intent and plan as determined by item 3 of the 
HamD-17; 

 
 
 
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6. Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder; obsessive-
compulsive disorder, psychotic disorder (unless substance induced or due to a 
medical condition), bipolar I or II disorder, paranoid personality disorder, borderline 
personality disorder, or neurocognitive disorder as determined by medical history and 
the SCID-5 clinical interview; 
7. Any first-degree relative with a diagnosis of schizophrenia-spectrum disorder; 
psychotic disorder (unless substance-induced or due to a medical condition); or 
bipolar I or II disorder as determined by the family medical history form and 
discussions with the participant; 
8. Presence of a relative or absolute contraindication to psilocybin, including a drug 
allergy, recent stroke history, uncontrolled hypertension, low or labile blood pressure, 
recent myocardial infarction, cardiac arrhythmic, severe coronary artery disease, or 
moderate to severe renal or hepatic impairment. 
9. Presence of baseline prolonged QTc or Torsade de Pointes as measured by the ECG 
or a history of long QTc syndrome or related risk factors; 
10. History of allergy or contraindication to risperidone including insulin-dependent 
diabetes, history of hypoglycemia on oral hypoglycemic agent(s); 
11. Lifetime use of serotonergic psychedelic drugs; OR 
12. Any other clinically significant physical illness including chronic infectious diseases 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 they take part in the study.  
4.5 
Lifestyle Considerations 
During this clinical trial, participants are asked to: 
• Abstain from alcohol for 24 hours before the intervention and for up to 6hrs after 
administration (V3). 
• Abstain from the use of any prescribed opioids, benzodiazepines, or sleep aids (Z-
drugs) within 12hrs prior to the intervention (V3) and for up to 6hrs after administration.  
• Abstain from any illicit drugs (e.g. cocaine, ecstasy/MDMA, hallucinogens) and/or 
cannabis for the duration of the study. Presence of these substances will be assessed 
at a urine drug screening at Visit 1 and Baseline (V2) 
• Abstain from driving or operating heavy machinery for up to 24hrs after the intervention. 
4.6 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical trial 
but do not meet one or more eligibility criteria required for participation. The screening 
period for participants in this study occurs before Baseline (V2) and eligibility for the study 
cannot be confirmed until the participant had tapered off any concomitant medication. In 
order to be eligible, the participant must meet all eligibility criteria as outlined in Section 
4.4. The information collected about the participant during the screening process 
including demography, screen failure details, eligibility criteria not met, and any AEs/SAEs 
will be used for the purposes of transparent reporting. Participants who are deemed 
ineligible will continue with their usual standard of care or may be referred to other 
research protocols for TRD.  

 
 
 
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4.7 
Participant Withdrawal Criteria 
4.7.1 
When and How to Withdraw Participants 
Participants are free to withdraw from participation in the clinical trial at any time.  
An investigator may discontinue or withdraw a participant from the clinical trial for the 
following reasons: 
• Pregnancy or if participants cease effective contraception; 
• Significant study intervention non-compliance; 
• If any adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the clinical trial would not be in the 
best interest of the participant; 
• Disease progression which requires discontinuation of the study intervention; 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation; or 
 
The reason for participant discontinuation or withdrawal from the study will be recorded      
within the participant’s research record, and/or health record at CAMH. 
 
Participants that are withdrawn from the study will be replaced using the same recruitment 
methods as outlined in Section 4.2: Participant Recruitment and Screening.  
4.7.2 
Follow-up for Withdrawn Participants 
If a participant withdraws consent, the information that was provided by the participant 
and recorded by the study team before they withdrew consent will not be destroyed. 
However, once withdrawn from the clinical trial, no further research procedures or 
evaluations will be performed, or additional research-specific data collected on the 
participant. Reasonable effort will be made to obtain permission to document the reason 
for withdrawal.  
 
Withdrawn participants will be seen clinically by the study investigator to ensure a plan 
for continued care outside of the study is established. If the participant is interested in 
hearing about other treatment options, they may be offered a referral to the CBT group at 
CAMH and/or a consultation with a psychiatrist to discuss pharmacotherapy options.   
4.7.3 
Early Termination Visit 
If a participant withdraws from the clinical trial, every effort should be made to perform an 
Early Termination Visit. 
 
Participants that withdraw after the first dosing session:  
If the participant is willing to attend an early termination visit, the following information will 
be documented: 
• Assessment of new and ongoing AEs; 
• Assessment of any complications following the study intervention; 
• Documentation of all concomitant medications; 

 
 
 
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The PI will also ensure the participant is appropriately transitioned/followed for any 
additional care as required. 
4.7.4 
Participants who are Lost to Follow-up 
A participant will be considered lost to follow-up if they fail to return for 2 or more 
scheduled visits and is unable to be contacted by the research team.  
 
The following actions will be taken if a participant fails to attend a required study visit: 
• The research team will attempt to contact the participant and reschedule the missed 
visit 7 days, counsel the participant on the importance of maintaining the assigned visit 
schedule, and reconfirm whether the participant wishes to and/or should continue in 
the clinical trial.  
• Before a participant is deemed lost to follow-up, the research team will make every 
effort to regain contact with the participant via 2 different methods of contact (e.g. 
telephone and email). These contact attempts should be documented in the 
participant’s research record and/or legal health record.   
• Should the participant continue to be unreachable, they will be considered to have 
withdrawn from the clinical trial with a primary reason of lost to follow-up. 
5.0 STUDY INTERVENTION  
5.1 
Description 
Pharmacokinetics and Psilocybin Effects 
Psilocybin is detectable in plasma 20 to 40 minutes after oral administration of 0.224 
mg/kg (10-20mg total dose) (Hasler et al., 1997). Orally ingested psilocybin is 
metabolized in the liver, and primarily transformed into the active hydroxyl metabolite, 
psilocin. Psilocybin is essentially a prodrug and psilocin represents the pharmacologically 
active agent in systemic circulation. The elimination half-life of psilocybin is 50 minutes 
(Lindenblatt et al., 1998). Psilocin’s half-life ranges between 2 and 3 hours and it 
detectable 6 hours after oral administration (Hasler et al., 1997; Hasler et al., 2004; 
Lindenblatt et al., 1998). Both psilocin and psilocybin are detectable in human urine, 
unmodified and particularly conjugated with glucuronic acid(Hasler et al., 2002). The 
majority of psilocybin recovered in urine is excreted within 3 hours after oral administration 
and is completely eliminated from the body within 24 hours (Hasler et al., 2002).  
 
As a 5HT2A/2C agonist, psilocin is regarded as a “classical” psychedelic; in humans, it 
commonly elicits significantly altered states of consciousness, experienced through visual 
and sometimes auditory effects, changes in perception, distortions of time, and a range 
of effects including a sense of awe, novel perspectives, existential and personal insight, 
dramatically heightened empathy and feelings of compassion, strong emotions, and non-
dual or unitive experience. A number of these ‘peak’ experiences have been associated 
with improved quality of life and improvement in mood (Griffiths et al., 2016; McClain et 
al., 2003; Visser et al., 2010). For a more detailed explanation on the effects of psilocybin 
and its mechanism of action, please refer to the investigators brochure.  

 
 
 
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Pharmacokinetics and Risperidone Effects 
Risperidone is an atypical antipsychotic with antagonist binding affinity at serotoninergic, 
dopaminergic, adrenergic, and histaminergic receptors (Schatzberg & Nemeroff, 2009). 
It has a very high affinity for the 5-HT2A receptor (Meltzer et al., 1989) and moderately 
high affinity for the D2 dopamine receptor (Schatzberg & Nemeroff, 2009).  Risperidone 
is taken orally and almost entirely absorbed in the GI tract and metabolized in the liver 
(Schatzberg & Nemeroff, 2009). The plasma half-life is approximately 3 hours in extensive 
metabolizers and 20 hours in poor metabolizers (Broder et al., 2012). Clearance values 
for risperidone and the active metabolite are estimated to be 4.6 and 6L/hr, respectively 
(Vandenberghe et al., 2015). In general, risperidone is well-tolerated. It does have a broad 
range of common side effects (>10%) which include somnolence, nausea, dizziness, dry 
mouth, and tremor (Chopko & Lindsley, 2018). Risperidone has been shown to improve 
depression in SSRI-resistant patients (Correia & Vicente, 2007). In healthy subjects, 
risperidone (1 mg) blocked (98-99%) the psychedelic effects of psilocybin including the 
perceptual disturbances and hallucinatory phenomena (Vollenweider et al., 1998). 
 
Psilocybin-Assisted Psychotherapy 
All participants will receive manualized psychotherapy in conjunction to their assigned 
pharmacological treatment. The participant will attend 1 preparatory session (V2) that 
occurs within 7-days of the psilocybin dosing session (V3) to develop a therapeutic 
alliance, set intentions for the experience, and learn what to expect during the dosing 
session. Ideally, the preparatory therapy session will occur the day before dosing. In 
addition, the participant will undergo 2 integrative therapy sessions after the intervention 
(V4 & V5).  
There will be an experienced clinical psychologist trained in PAP serving as a master 
trainer for the study. We will also use the Yale psilocybin-assisted therapy for depression 
manual to deliver psychotherapy and train each therapist (see manual attached). The 
therapy is closely related to Acceptance and Commitment Therapy, with a focus on 
“psychological flexibility” i.e. a person’s ability to: 1) adapt to fluctuating situational 
demands; 2) reconfigure mental resources; 3) shift perspective; and 4) balance 
competing desires, needs, and life domains. The therapists’ role is to witness the 
participant’s therapeutic process and provide unconditional positive regard during the 
experience.  
Therapy sessions will not be video recorded. At least one of the therapists will be a 
clinician and will be available at all times during the dosage session to assess and 
manage any medical or psychiatric adverse events.  
 
How the study intervention will appear: 
The psilocybin will be provided by Filament Health CORP. (Burnaby, British Columbia, 
Canada). The dose of psilocybin used in this study will be 25mg. The psilocybin will be 
administered in size 2 hydroxypropyl methyl cellulose (HPMC). The risperidone will be 
provided by CAMH pharmacy and will appear as a 1mg oral compounded capsule. 

 
 
 
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5.2 
Treatment Regimen 
There will be 1 intervention day (V3 – Day 0) following Baseline (V2) and after the 
participant has been deemed eligible to participate. The procedures are outlined below: 
 
Each participant will be assigned 2 treatment bottles with 1 capsule in each containing: 1 
capsule of 25mg psilocybin or 1 capsule of 1mg of risperidone, or 1 capsule of placebo. 
Under the supervision of a clinician and based on the group they have been randomized 
to, the participant will take the intervention in the following order: 
1. 1mg capsule of risperidone followed 60 minutes later by a 25 mg capsule of 
psilocybin 
2. Placebo followed 60 minutes later by a 25 mg capsule of psilocybin 
3. 1mg capsule of risperidone following 60 minutes later by placebo  
 
Each treatment will be taken orally with a glass of water. There will be no modifications 
to the dosage, each participant will receive the same dosage for both medications. In 
addition to the psilocybin, two study therapists trained in psilocybin-assisted 
psychotherapy will be supporting the participant during the dosing session. There will be 
1 therapist present at all times throughout the dosing session. The total treatment time 
will be 5-6 hours when the acute effects of the psilocybin have passed. 
5.3 
Method for Assigning Participants to Treatment Groups 
Participants will be randomized to three groups in a 1:1:1 allocation: 1) psilocybin 25 mg 
plus risperidone 1 mg; 2) psilocybin 25 mg plus placebo; 3) placebo plus risperidone 1 
mg. Randomization will be computer-generated, using a random permuted block method 
with variable block sizes. The sample will be stratified for severity of depressive symptoms 
[17-item Hamilton Depression Rating Scale (HamD-17) (Hamilton, 1960) score < 25 vs. 
> 26]. We have not included additional stratification variables as per best practice in RCTs 
(Therneau, 1993).  We will assess other potential prognostic characteristics (age, self-
reported biological sex, gender) in our a priori subgroup analyses. After randomization, 
the research pharmacist will dispense medication on the day of dosing.  
5.4 
Administration of Study Intervention 
The IP will be prepared by the CAMH pharmacy and picked up by a trained research staff 
member. The IP will be given to the participant by the study psychiatrist who will supervise 
the participant. The participant will receive: 
1. 1mg capsule of risperidone followed 60 minutes later by a 25 mg capsule of 
psilocybin 
2. Placebo followed 60 minutes later by a 25 mg capsule of psilocybin 
3. 1mg capsule of risperidone following 60 minutes later by placebo  
 
The capsules should not be opened or chewed. 
  
After taking the IP, the participant will lie down on a bed in a non-clinical environment. 
Therapists will encourage participants to focus their attention inward and stay with any 
experience that arises. To enhance inward reflect, a pre-selected music playlist will be 

 
 
 
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played quietly. Two study therapists trained in PAP will be supporting each participant 
during the dosing session with at least one therapist being present at all times to respond 
to the emotional and physical needs of the participant. Constant observation by therapists 
will monitor for adverse events during the dosing sessions. At least one member of the 
dyad will be a clinician. An on-call psychiatrist will be available at all times to further 
assess as needed for acute concerns. 
 
The effects of risperidone will take approximately 60 minutes after administration. The 
effects of psilocybin usually start about 20 to 30 minutes after administration, becoming 
the most intense in the first 90 to 120 minutes and gradually subsiding in 5 to 6 hours. 
The participants will be asked to remain in the room for the duration of the session 
regardless of the intensity of the effects, preferably 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 therapists will ‘check-in’ with the participant (i.e., ask 
how the participant is doing) in 30 to 60 minute intervals post-dosing.  
 
About 5 hours after dosing, the trained therapists will discuss the IP administration 
experience with the participant. The participant will be discharged 5-6 hours post-dosing 
when, in the opinion of the investigator, the acute effects of psilocybin are resolved. The 
participant must be accompanied home by a caregiver who will remain with the participant 
for up to 24hrs after the intervention was given. The study team is to be notified that the 
participant has arrived home safely via phone call. In the absence of receiving a phone 
call, the study staff will directly contact the participant.  
5.5 
Participant Compliance Monitoring 
The IP will be administered to the participant in front of study personnel. Thus, 
administration of the IP will be supervised by study personnel to ensure compliance.  
5.6 
Concomitant Therapy 
All prescription and non-prescription medications (e.g. 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 V1. 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. Where applicable, medication reports 
should be corroborated with participant medical records. All as-needed (pro re nata, PRN) 
prescriptions should be converted to reflect the actual number of pills or dose taken per 
day. 
 
Concomitant medication refers to all drugs and therapies used from the time the ICF is 
signed through until the end of study participation. 
Changes, additions, 
or 
discontinuations to medications and/or therapy will be assessed, recorded, and verified 
with participants in the source document during each study visit.  
 
Permissible Medications 

 
 
 
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Medications for the management of concurrent anxiety and insomnia, or non-psychiatric 
medications that have a potential psychotropic effect are permitted within the following 
limitations. 
 
From the initial Screening Visit (V1) through to the final study visit (V8), participants are 
permitted to use benzodiazepines (up to 2mg of lorazepam equivalent per day for 
insomnia and anxiety if it is not taken within 12 hours of the psilocybin dose) (V3). 
Prescription and nonprescription medications with psychoactive properties that are used 
as needed for non-psychiatric conditions (e.g. pseudoephedrine for allergies or cold, 
zoplicone for sleep disorders) should be used no more than 2 times a week and not within 
12 hours 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 visit.  
 
Permissible Contraceptive Methods 
A woman/female or person who is not of childbearing potential is considered to be 
postmenopausal after at least 12 months without menstruation. The participant must be 
on a permissible contraceptive for a minimum of 1 month prior to screening and for the 
duration of the study. The following methods of contraception, if used properly and used 
for the duration of the study, are permissible: 
 
• Combine 
estrogen-and 
progestogen-containing 
hormonal 
contraception 
associated with inhibition of ovulation: 
o Oral 
o Intravaginal 
o Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubual occlusion 
• Vasectomized partner 
• Sexual abstinence 
• Tubal ligation/ occlusion 
 
Periodic abstinence (e.g. calendar, symptothermal, or postovulation methods) is not an 
acceptable form of contraception for this study. 
 
These methods of contraception also apply to partners of male participants.  
 
The investigator (or delegate) 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). 

 
 
 
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Prohibited Medications 
Participants are to be discontinued from antidepressants and/or antipsychotic 
medications at least 2 weeks prior to Baseline (V2). Participants on fluoxetine will be 
taped off the medication at least 4-weeks prior to Baseline (V2). Additional time may be 
required as determined by the study investigator. Medications that must be discontinued 
include the following 2 classes of the Anatomical Therapeutic Chemical (ATC) 
Classification System: NO5A Antipsychotics & NO6A Antidepressants. Methylphenidate 
is also included in this list. In addition, participants must also taper off inhibitors of 5'-
diphospho-glucuronosyltransferase (UGT)1A9 and 1A10, aldehyde dehydrogenase 
inhibitors (ALDHs), and alcohol dehydrogenase inhibitors (ADHs)  for a minimum of 2-
weeks (or more depending on the medication) prior to Baseline (V2). 
 
These medications should not be re-introduced until after Week 4 (V8) when the study is 
complete. If the medications are re-introduced, the study investigator must be notified and 
the medications will be documented in the participant’s data collection form. 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. 
 
 
Rescue Medication 
The decision to medicate a participant will depend on if the therapists and study 
investigator determine the safety of the patient and others can be maintained without 
medical intervention. The final decision will be made by the study investigator. 
• Benzodiazepine anxiolytics 
o The preferred pharmacological intervention of choice in case of acute 
psychological distress (e.g. 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).  
o The oral route is preferable because IV injection procedures may further 
exacerbate the participant’s anxiety. 
• Antipsychotic medications (e.g. additional risperidone) should be available in the 
event that an adverse reaction escalates to unmanageable psychosis.  
• Management of blood pressure: 
o Asymptomatic with blood pressure (BP) < 180/100 
 Reassure, ensure lights are dim or off, tilt head of bed 15 degrees up 
and continue to monitor 
 Increase blood pressure measurement frequency to q15min until BP 
has partly normalized (sBP = 100-159; dBP = 60-99)  
o Asymptomatic with BP >180/100 for >30 minutes 
 Administer captopril* 12.5mg PO/SL x 1 with MD order 
 Increase blood pressure measurement frequency to q15min until BP has 
partly normalized (sBP = 100-159; dBP = 60-99)  

 
 
 
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o Asymptomatic with BP persisting at >180/100 for >60 minutes post-dose, 
despite administering first captopril dose: 
 Consider potential transfer to ER – decision to be made by study 
investigator 
 Administer 2nd dose of captopril 12.5mg x 1 with MD order 
o Management of severe treatment emergent hypertension: 
 Consider potential transfer to ER – decision to be made by study 
investigator 
 Administer captopril 25mg PO/SL x 1  
 Call 911 immediately for patients experiencing symptoms of a 
hypertensive crisis (e.g., chest paint, shortness of breath) or 
hypertensive encephalopathy (e.g., sudden severe headache, visual 
disturbances, 
seizures, diminished 
consciousness, or focal 
neurological deficit) 
o Note: if there are contraindications to captopril, substitute for hydralazine 
10mg PO 
 
In case of development 
of acute anxiety or psychotic symptoms requiring 
pharmacological intervention, the participant will be managed under the care of the onsite 
psychiatrist. The participant may be discharged from the clinic when, in the opinion of the 
investigator, the condition has stabilized. The participant will be accompanied home. The 
participant is to notify the site when they have returned home safely. 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 Yale Manual for Psilocybin-Assisted Therapy of Depression. All therapists will 
undergoing training with the study investigator using this manual. 
5.7 
Packaging 
The risperidone 1 mg will be provided and packaged by CAMH pharmacy. The psilocybin 
and placebo will be provided by Filament Health Corp (Burnaby, British Columbia, 
Canada). The dose of psilocybin used in this study will be 25mg. Filament will provide 
extra 20% of the capsules needed. The entire shipment for this trial will be sent in bulk 
(i.e. 48 capsules of psilocybin x 25mg each and 48 capsules of placebo). Psilocybin 
capsules will be packaged individually in high-density polyethylene bottles with silica 
desiccant and cotton. The dose for each participant will be stored in individual boxes 
labelled with the protocol number, trial name, lot number, unique box number, and a 
statement that the drug is for clinical use only. The IP will only be removed from the safe 
for one participant at a time on the day of their session. Filament Health Corp will be sent 
safety reports on adverse events, and suspected unexpected serious adverse reactions. 
For a description of safety reporting, please see Section 8.3.1 of the protocol.  

 
 
 
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5.8 
Blinding of Study Intervention 
The randomized allocation will be concealed from all except the research pharmacist, 
who will have no contact with the study team. Risperidone 1 mg has mild psychoactive 
effects such as drowsiness and dysphoria. Those receiving risperidone plus psilocybin 
or risperidone plus placebo may experience these mild psychoactive effects which can 
help to preserve the blinding.  
5.9 
Receiving, Storage, Dispensing and Return 
5.9.1 
Receipt of Study Intervention Supplies 
Upon receipt of the study intervention supplies, an inventory will be performed and a 
receipt log filled out and signed by the person accepting the shipment. Designated 
research staff/pharmacy must count and verify that the shipment contains all the items 
noted in the shipment inventory.  Any damaged or unusable study intervention in a given 
shipment (active drug or comparator) will be documented in the clinical trial files.   
5.9.2 
Storage 
The risperidone will be stored with CAMH pharmacy. All IP will 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 investigators brochure. Bottles must be maintained at room 
temperature in a locked, secure location within research pharmacy. Deviations of storage 
temperature outside this required range should be documented and the study investigator 
should be notified immediately. Bottles of IP should not be frozen. If any component of 
the IP is damaged, the PI must be notified immediately. Any storage deviations that meet 
criteria for reporting will be reported to the REB as a protocol deviation.  
5.9.3 
Dispensing of Study Intervention 
 
Each participant will be assigned 2 treatment bottles with 1 capsule in each containing: 1 
capsule of 25mg psilocybin or 1 capsule of 1mg of risperidone, or 1 capsule of placebo. 
Under the supervision of a clinician and based on the group they have been randomized 
to, the participant will take the intervention in the following order: 
1. 1mg capsule of risperidone followed 60 minutes later by a 25 mg capsule of 
psilocybin 
2. Placebo followed 60 minutes later by a 25 mg capsule of psilocybin 
3. 1mg capsule of risperidone following 60 minutes later by placebo  
 
 
Capsules should not be opened or chewed. 
 
The investigator must keep an accurate accounting of the number of IP delivered to the 
site, administered to participants, and destroyed during and at the completion of the study. 
The IP is to be used in accordance with the protocol by participants. The study team, 
overseen by the PI, should maintain records that adequately document that the 
participants were administered the IP dose specified by the protocol.  

 
 
 
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Regular study intervention reconciliation will be performed to document study intervention 
assigned, consumed, and remaining. This reconciliation will be logged on an 
accountability log (i.e. drug accountability log), and signed and dated by delegated 
research and/or pharmacy staff. 
5.9.4 
Return or Destruction of Study Intervention 
At the completion of the clinical trial, there will be a final reconciliation of the study 
intervention shipped, consumed and remaining. This reconciliation will be logged on an 
accountability form, and signed and dated by delegated research and/or pharmacy staff.  
Any discrepancies noted will be investigated, resolved, and documented prior to 
destruction of unused study intervention. Intervention destroyed on site will be 
documented in the clinical trial’s files. 
6.0 RESEARCH PROCEDURES 
6.1 
Research Visits 
Description of Measures 
 
Screening Measures 
 
Structured Clinical Interview for DSM-5 (SCID-5). The SCID-5 is a semi-structured 
diagnostic interview for ascertaining DSM-5 diagnoses (First, 2015). It will be 
administered by a trained study staff member.  
 
Hamilton Depression Rating Scale (HamD-17). HamD-17 is a clinician-rated measure of 
depressive symptoms that consists of 17 items rated using a semi-structured interview. 
Eight of the 17 items are rated on a 5-point scale (0=absent; 1=doubtful or mild; 2=mild 
to moderate; 3=moderate to severe; 4=very severe), while the remaining 9 items are rated 
on a 3-point scale (0=absent; 1=doubtful or mild; 2=clearly present), yielding a minimum 
total score of 0 (least severe) and a maximum score of 52 (most severe) (Hamilton, 1960).  
 
Safety Measures 
Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS will be used to assess 
suicide potential or tendency as a study entry criteria and monitored throughout the study 
to help rapidly identify this potential serious adverse event and intervene appropriately 
(e.g. further specialized assessment and hospitalization if needed). The C-SSRS is a 
semi-structured, clinician-rated interview designed to assess the severity and intensity of 
suicidal ideation, suicidal behavior, and non-suicidal 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 

 
 
 
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categorizing behaviors into actual, aborted, and interrupted attempts; preparatory 
behavior; and non-suicidal 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 (washout period only) and Baseline to 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.  
 
Outcome Measures: 
 
Clinical Global Impression scale (CGI). The CGI is a brief observer-rated instrument that 
measures the clinician’s view of the patient’s global functioning prior to and after initiating 
a study medication. It consists of two one-items measures that evaluate 1) severity of 
psychopathology from 1 (‘normal – not at all ill, symptoms of disorder not present in the 
past seven days’) to 7 (‘among the most extremely ill patients – pathology drastically 
interferes in many life functions;) and 2) change from the initiation of treatment on a similar 
seven-point scale (1 = ‘very much improved’ and 7 = ‘very much worse’). It has been used 
in both research and clinical practice (Busner & Targum, 2007).  
 
Generalised Anxiety Disorder 7-item (GAD-7) scale. The GAD-7 is a brief self-report 
measure of generalised anxiety, it consists of 7 items rated from 0 (‘not at all sure’) to 3 
(‘nearly every day’). It has good psychometric properties and is a widely used research 
instrument in assessing adult anxiety (Spitzer et al., 2006).  
 
Montgomery-Åsberg Depression Rating Scale (MADRS;(Montgomery & Asberg, 1979)). 
The MADRS is a clinician-rated measure of severity of depressive symptoms. It consists 
of 10-items rated from 0 to 6. It is one of the most widely used clinician-rated 
assessments of depressive severity with well-established psychometric properties.   
 
Snaith-Hamilton Pleasure Scales (SHAPS). The SHAPS is a 14-item self-report scale 
that measures hedonic capacity. Participants are asked to rate themselves on a Likert 
scale from 0 (‘strongly disagree’) to 3 (‘strongly agree’). It is both a reliable and valid 
measure that is frequently used in research and clinical settings (Snaith et al., 1995). 
 
Stanford Expectancy of Treatment (SETS). The SETS is an instrument to measure 
positive and negative treatment expectancies in clinical trials. It contains two subscales 
for both negative and positive expectancies. There are 6-items which are participant 
rated from ‘strongly disagree’ to ‘strongly agree’. Items 7 to 10 are direct questions 
asked to the participant (Younger et al., 2012). 
 
 

 
 
 
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World Health Organization Quality of Life Questionnaire – Brief Version (WHO-QoL – 
Bref). This 26-item, self-report measure was developed by the WHO in order to assess 
quality of life in the following areas: physical, psychological, level of independence, social 
relationships, environment, and spirituality/religion/personal beliefs. Responses are rated 
on a 5-point Likert scale rating from 1 = (not at all, over poor, very dissatisfied, never) 
through to 5 = (very good, very satisfied, an extreme amount, completely, always).  
 
Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS). The WEMWBS consists of a 
12-item scale used to assess the mental wellbeing of people. The self-report scale 
consists of positively worded statements covering feelings and functioning aspects of 
mental wellbeing. Responses are rated on a 5-point Likert scale ranging from 1 (‘none of 
the time’) to 5 (‘all of the time’).  
 
Five Dimensions of Altered States of Consciousness (5D-ASC). The 5D-ASC is a visual 
analogue scale of 94-items that consists of five subscales: 1) oceanic boundlessness; 2) 
anxious ego dissolution; 3) visionary re-structuralization; 4) auditory alterations; 5) 
reduction of vigilance (Dittrich, 1998; Studerus et al., 2010). It is well validated and widely 
used to characterize the subjective effects of psychedelic drugs. This self-rated scale 
appears as at 10-item Likert scale ranging from 1 to 10.  
 
Mystical Experiences Questionnaire (MEQ). The MEQ is a 30-item self-report measure 
that has been used to assess the experience after psilocybin administration. The scale 
consists of four factors: 1) mystical; 2) positive Mood; 3) transcendence of time and space 
and 4) ineffability. Responses are rated on a 6-point Likert scale rating from 0 = (none; 
not at all) through to 5 = (extreme). 
 
 
Outline of Study Procedures 
 
Visit 1 (V1) – Screening Visit   
o Administered by trained study staff: 
 Informed consent 
 Review of medical history, family medical history, and demographics 
 ATHFSCID-5 
 HamD-17 
 Vital Signs (blood pressure, pulse) 
 Height and weight 
o Clinician administered: 
 Review of prior and current medications; the participant will be tapered 
from prohibited medications (see Section 5.6), if any, under the 
supervision of the study clinician 
 The study clinician will discuss options of tapering off 
medications with the participant and their healthcare provider.  

 
 
 
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 Participants will be given a choice of how quickly they would like 
to come off the medications, but participants must be off 
concomitant medications (see Section 5.6) at least 2 weeks 
prior to the Baseline Visit (V2). Some medications may require a 
longer tapering period.  
 Review of eligibility criteria, medical history, and family medical history 
 Review of assessments 
 Documentation of contraceptive method to be used by the participant 
o Biological specimen collection and laboratory evaluations collected at the Queen 
Street CAMH laboratory:  
 Clinical laboratory tests: 
 Approximately 20 mL blood will be drawn to conduct the 
following evaluations: 
 Haematology: hemoglobin, hematocrit, red blood cell count, 
mean corpuscular hemoglobin, mean corpuscular volume, mean 
corpuscular hemoglobin 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. 
 Urine Samples: 
 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. Results of 
a positive drug screen will be reviewed by the study clinician for 
pattern of use.  
 Urine pregnancy test for all women/people of childbearing 
potential 
 ECG: Standard 12-lead ECG to check heart function 
 
 
Washout Period: Minimum of 2-Weeks  
Participants who are on concomitant medications (Section 5.6) must be tapered off at 
least 2 weeks prior to Baseline (V2). The plan for tapering off medications will be 
determined at the first screening visit (V1) with the participant and the study physician. 
During the washout period, the study physician will have weekly appointments with the 
participant to check how they are doing and ensure they are safe. The weekly 
appointments can be scheduled in-person or remote (via telephone/WebEx) based on 
the participant’s preference and at the discretion of the study physician. Participants will 
be assessed for suicidality with the C-SSRS at each contact/visit. Participants who are 
not on any prohibited medications will still undergo a two week period between Screen 
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Any safety assessment visits during the washout 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.  
 
 
Visit 2 (V2) - Baseline Visit  - Day -7 to Day -1 
The Baseline visit (V2) will occur approximately 3-6 weeks after the initial Screening 
(V1) when the participant has successfully been tapered off any concomitant 
medication. At the Baseline Visit (V2), the participant’s eligibility will be confirmed by the 
study investigator by reviewing the Inclusion/Exclusion Criteria (Section 4.4) and 
updating the medical history. The Baseline visit (V2) can occur within 7 days before the 
anticipated psilocybin session and may be split over multiple days to reduce the burden 
on the participant (additional study visits will be labelled V2a, V2b etc). The following 
procedures will be performed and recorded at the Baseline visit (V2): 
o Administered by trained study staff: 
 Vital Signs (blood pressure, pulse) 
 C-SSRS 
 CGI 
 GAD-7 
 MADRS 
 SETS 
 SHAPS 
 WHOQOL-BREF 
 WEMWBS 
o Clinician administered: 
 Confirmation of eligibility criteria  
 Review of assessments administered 
o Optional laboratory evaluations collected at the Queen Street CAMH laboratory:  
 
Blood: 20mL of blood will be withdrawn under fasting conditions (minimum 6-hour fast) 
from participants at Visit 4. The plasma will be separated by centrifuging the blood at 
1500 rpm for 10 min at 4°C, and subsequently stored at -80°C for future analysis. This 
is optional for all participants.  
 
 Mitochondrial biomarkers: (1) circulating cell-free mitochondrial DNA 
(ccf-mtDNA): We will use the QIAmp 96 DNA Blood kit (Qiagen, 
Valence, USA) to extract DNA from 200μL of the plasma, according to 
manufacturer protocols for blood and body fluids. The total DNA will be 
quantified using spectrophotometric analysis at 260/280 nm in 
NanoPhotometer ® P-Class (Implen, Westlake Village, CA, US). 
Quantitative analysis of the ccf-mtDNA will be performed using a real-
time polymerase chain reaction (RT-PCR). The PCR reaction will be 
performed using SYBR Green Technology (Thermo Fisher Scientific, 
Waltham, MA, USA). Each 20 μL reaction contained 5 μL of template, 1 
μL of each primer (10 μM), 10 μL SYBR MIX (2× Sensifast, Bioline, 

 
 
 
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London, UK), and 3 μL of nuclease-free water. Each reaction will be run 
in triplicate on CFX96 Touch Real-Time PCR Detection System (Bio-
rad, Hercules, California, USA). PCR program: initial denaturation at 95 
◦C for 10 min, followed by 45 cycles consisting of 95 ◦C in 10 s 
(melting), 65 ◦C for 10 s (annealing), and 72C for 10sec (extension). 
The program ended with a melting curve analysis measuring 
fluorescence continuously from 60 to 97 ◦C. We will use primers to 
amplify the mtDNA genes MT-ND1 and MT-ND4, as well as nuclear β-2 
microglobulin.  
 (2) mtDNA next-generation sequencing: Genomic DNA will be purified 
from blood samples (10 ml) (ChemagicTM MSM I DNA extractor; 
Perkin-Elmer, Waltham, MA) following manufacturer protocol. Briefly, 
whole mtDNA will be amplified in one large fragment of 16.6kb in length 
using long-range polymerase chain reaction approach. The mtDNA next 
generation sequencing (NGS) will be performed on Illumina MiSeq v3 
device using 2x300 read length. Libraries will be prepared using 
standard Illumina DNA Preparation for NGS. The CAMH Biobank team 
will prepare the samples (pre-sequencing preparation), and send them 
to the Ontario Institute for Cancer Research facility for DNA 
sequencing.We will use in-house pipeline for raw data cleaning and 
variant call. (3) mtDNA-copy number: The mtDNA copy number will be 
assayed using the relative quantification method using a mtDNA 
amplicon and a nuclear single copy gene (β-2 microglobulin). The ratio 
of mtDNA to nuclear DNA will be quantified by 2−ΔCt method using 
primers for mtDNA and nuclear β-2 microglobulin as well as thermal 
cycler condition as standard. All qPCR will be performed on the BioRad 
CFX96 RT-PCR detection system (Bio-Rad Laboratories, Inc.). Each 
sample will be run in triplicate using 0.6ng of DNA in a 20μl reaction. 
The PCR reactions will be performed on separate runs with the same 
samples in the same well positions. Primers will be the same as 
describe for ccf-mtDNA. 
 Neuroinflammation markers: Brain Derived Neurotrophic Factor (BDNF) 
and Inflammatory Cytokines,  
 Plasma levels of Tryptophan, 5-HT and Kynurenine 
 
 Urine drug screen: for illicit drugs or drugs of abuse. Results of a 
positive drug screen will be reviewed by the study clinician for pattern 
of use.  
 Urine pregnancy test for all women of childbearing potential 
o Preparatory session (up to 4-hours) with the study therapists which will involve 
building a therapeutic alliance, psychoeducation about the psychedelic experience, 
and setting intentions for the intervention.  
 Note: Therapists will have the option to schedule an additional 
preparatory session at their discretion or combine two preparatory visits 
into a single session, lasting up to four hours.  

 
 
 
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 Prep therapy can occur in-person or via secure videoconferencing 
software (i.e. WebEx). 
 For a more detailed explanation of the preparatory therapy session, 
please refer to the Yale Manual for Psilocybin-Assisted Therapy of 
Depression. 
 
 
Visit 3 (V3) – Intervention – Day 0  
The intervention will occur the day after Baseline (V2). The participant may have this 
session ≤7 days following the Baseline visit (V2). If the participant is out of the ≤7 day 
window, all baseline assessments are to be repeated. On the day of the intervention the 
following procedures will take place: 
o Study intervention administration (Section 5.0) – one of the following:  
 1 oral dose of 1mg of risperidone, followed 60-minutes later by 1 oral 
dose of 25mg of psilocybin administered in conjunction with supportive 
therapy (PAP).  
 1 oral dose of 1mg of risperidone, followed 60-minutes later by 1 oral 
dose of placebo administered in conjunction with supportive therapy 
(PAP).  
 1 oral dose of placebo, followed 60-minutes later by 1 oral dose of 25 
mg of psilocybin administered in conjunction with supportive therapy 
(PAP).  
  
o Vital signs (body temperature, blood pressure and pulse) will be taken three times 
during this session (Once pre-dosing, once 3 hours after dosing and once at the 
end of dosing session) and documented in the data collection form.  
o At least one therapist will be present in the room at all times during PAP and be 
available to respond to participants’ physical and emotional needs 
o Participants will be instructed to lie on a bed in a non-clinical environment, and 
therapists will encourage participants to focus their attention inward and stay with 
any experience that arises. To enhance inward reflection, a pre-selected music 
playlist will be played. Administration of questionnaires or other instruments to be 
completed at the end of the dosing session when the acute effects of psilocybin 
have resolved:  
 Study team administered: 
 5D-ASC and MEQ to assess the acute drug effects using 5 
primary dimensions and respective sub dimensions after 5 hours 
of dose administration.  
 C-SSRS 
 Treatment Allocation Questionnaire (TAQ): To assess the 
integrity of blinding procedures, participants, a member of the 
study team and both  therapists will be asked to fill a conventional 
guess form asking them whether they believe the participant 
received psilocybin alone, psilocybin with risperidone or 
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assessments. This will be completed at the end of the dosing 
session (V3). 
 
o The participant will be discharged 5-6 hours post-dosing when, in the opinion of the 
study PI (or delegate), the acute effects of psilocybin are resolved. The participant 
must be accompanied home by a caregiver who will remain with them for up to 
24hrs after the dose was administered. 
o Rescue medications are permitted during this visit as outlined in Section 5.6.  
 
Visit 4 & Visit 5 (V4 & V5) – Post-Intervention – Day 1 & Day 7 
o Administered by trained study staff: 
 CSSRS 
 CGI 
 MADRS 
 SHAPS 
 
o Integrative psychotherapy session will occur with the study therapists. The 
participant will discuss their experience during the dose session including their 
thoughts, feelings, and experiences. Integration therapy can occur in-person or via 
secure videoconferencing software (i.e. WebEx). For more detailed information on 
the integrative therapy sessions, please refer to the therapists manual (Yale Manual 
for Psilocybin-Assisted Therapy of Depression). 
 
On Visit 4 (V4) only 
o Biological specimen collection and laboratory evaluations collected at the Queen 
Street CAMH laboratory:   
Optional blood collection: 20mL of blood will be withdrawn under fasting conditions 
(minimum 6-hour fast) from participants at Visit 4. The plasma will be separated by 
centrifuging the blood at 1500 rpm for 10 min at 4°C, and subsequently stored at -80°C 
for future analysis. This is optional for all participants.  
 Mitochondrial biomarkers: (1) circulating cell-free mitochondrial DNA (ccf-
mtDNA): We will use the QIAmp 96 DNA Blood kit (Qiagen, Valence, 
USA) to extract DNA from 200μL of the plasma, according to 
manufacturer protocols for blood and body fluids. The total DNA will be 
quantified using spectrophotometric analysis at 260/280 nm in 
NanoPhotometer ® P-Class (Implen, Westlake Village, CA, US). 
Quantitative analysis of the ccf-mtDNA will be performed using a real-
time polymerase chain reaction (RT-PCR). The PCR reaction will be 
performed using SYBR Green Technology (Thermo Fisher Scientific, 
Waltham, MA, USA). Each 20 μL reaction contained 5 μL of template, 1 
μL of each primer (10 μM), 10 μL SYBR MIX (2× Sensifast, Bioline, 
London, UK), and 3 μL of nuclease-free water. Each reaction will be run 
in triplicate on CFX96 Touch Real-Time PCR Detection System (Bio-rad, 
Hercules, California, USA). PCR program: initial denaturation at 95 ◦C for 
10 min, followed by 45 cycles consisting of 95 ◦C in 10 s (melting), 65 ◦C 
for 10 s (annealing), and 72C for 10sec (extension). The program ended 

 
 
 
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with a melting curve analysis measuring fluorescence continuously from 
60 to 97 ◦C. We will use primers to amplify the mtDNA genes MT-ND1 
and MT-ND4, as well as nuclear β-2 microglobulin.  
 (2) mtDNA next-generation sequencing: Genomic DNA will be purified 
from blood samples (10 ml) (ChemagicTM MSM I DNA extractor; 
Perkin-Elmer, Waltham, MA) following manufacturer protocol. Briefly, 
whole mtDNA will be amplified in one large fragment of 16.6kb in length 
using long-range polymerase chain reaction approach. The mtDNA next 
generation sequencing (NGS) will be performed on Illumina MiSeq v3 
device using 2x300 read length. Libraries will be prepared using 
standard Illumina DNA Preparation for NGS. The CAMH Biobank team 
will prepare the samples (pre-sequencing preparation), and send them 
to the Ontario Institute for Cancer Research facility for DNA 
sequencing.We will use in-house pipeline for raw data cleaning and 
variant call. (3) mtDNA-copy number: The mtDNA copy number will be 
assayed using the relative quantification method using a mtDNA 
amplicon and a nuclear single copy gene (β-2 microglobulin). The ratio 
of mtDNA to nuclear DNA will be quantified by 2−ΔCt method using 
primers for mtDNA and nuclear β-2 microglobulin as well as thermal 
cycler condition as standard. All qPCR will be performed on the BioRad 
CFX96 RT-PCR detection system (Bio-Rad Laboratories, Inc.). Each 
sample will be run in triplicate using 0.6ng of DNA in a 20μl reaction. 
The PCR reactions will be performed on separate runs with the same 
samples in the same well positions. Primers will be the same as 
describe for ccf-mtDNA. 
 Neuroinflammation markers: Brain Derived Neurotrophic Factor (BDNF) 
and Inflammatory Cytokines,  
 Plasma levels of Tryptophan, 5-HT and Kynurenine 
 
Visit 6 (V6), Visit 7 (V7) & Visit 8 (V8) – Follow-Up: Week 2, Week 3 & Week 4 
Follow-up visits occur at Weeks 2 (V6), 3 (V7), and 4 (V8) after the intervention. The 
following assessments will occur at each visit: 
o Administered by trained study staff: 
 CSSRS 
 CGI 
 GAD-7 (except Visit 7) 
 MADRS 
 SHAPS  
 WHOQOL-BREF (except Visit 7) 
 WEMWBS (except Visit 7) 
o Clinician administered: 
 Review of safety assessments 
o These scales will be administered in-person and/or via secure videoconference 
software (alternatives to in-person for COVID-19 or other travel restrictions). Study 
visits will be coordinated along with follow-up with the study psychiatrists to provide 
added security and screening for suicidality.  

 
 
 
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6.2 
Schedule of Events 
 
Procedures 
Screening (Visit 1) 
Washout period1 
(3-6 weeks) 
Baseline2 (Visit 2, 
Day -7 to Day -1) 
Intervention (Visit 
3, Day 0) 
1-Day Post-
Intervention (Visit 4, 
Day 1) 
1-Week Post-
Intervention (Visit 5, 
Day 7) 
2-Weeks Post-
Intervention (Visit 6, 
Day 14) 
3-Weeks Post-
Intervention (Visit 7, 
Day 21) 
4-Weeks Post-
intervention (Visit 8, 
Day 28) 
Location of Visit 
Clinic 
Remote 
Clinic 
Clinic 
Clinic 
Clinic 
Remote 
Remote 
Remote 
Allowable Window 
 
Weekly 
 
= or < 7 days 
from Baseline 
None
 
±3 day 
±3 day 
±3 day 
±3 day 
Informed Consent 
✔ 
 
 
 
 
 
 
 
 
Demographics 
✔ 
 
 
 
 
 
 
 
 
Medical history 
✔ 
 
✔ 
 
 
 
 
 
 
Prior/concomitant medication 
review 
✔ 
 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
Inclusion/Exclusion Criteria Review 
✔ 
✔ 
✔ 
 
 
 
 
 
 
ATHF 
✔ 
 
 
 
 
 
 
 
 
CGI8 
 
 
✔ 
 
✔ 
✔ 
✔ 
✔ 
✔ 
CSSRS3 
 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
HamD-17 
✔ 
 
 
 
 
 
 
 
 
MADRS 
 
 
✔ 
 
✔ 
✔ 
✔ 
✔ 
✔ 
SCID-5 
✔ 
 
 
 
 
 
 
 
 
Vital signs (blood pressure, pulse) 
✔ 
 
✔ 
✔ 
 
 
 
 
 
Vital signs (body temperature) 
 
 
 
✔ 
 
 
 
 
 
Weight 
✔ 
 
 
 
 
 
 
 
 
Height 
✔ 
 
 
 
 
 
 
 
 
ECG 
✔ 
 
 
 
 
 
 
 
 
Clinical laboratory tests4 
✔ 
 
 
 
 
 
 
 
 

 
 
 
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Blood collection for future analysis 
 
 
✔ 
 
✔ 
 
 
 
 
Urinalysis 
✔ 
 
 
 
 
 
 
 
 
Urine drug screening 
✔ 
 
✔ 
 
 
 
 
 
 
Urine pregnancy test5 
✔ 
 
✔ 
 
 
 
 
 
 
Documentation of birth control 
✔ 
 
 
 
 
 
 
 
 
Preparatory/Integrative therapy & 
psychoeducation6 
 
 
✔ 
✔ 
✔ 
✔ 
 
 
 
Intervention (1mg of risperidone + 
25mg of psilocybin) 
 
 
 
✔ 
 
 
 
 
 
Adverse event and serious adverse 
event review and evaluation 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
Source documentation & CRF 
completion 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
5D-ASC7 
 
 
 
✔ 
 
 
 
 
 
MEQ 
 
 
 
✔ 
 
 
 
 
 
GAD-7 
 
 
✔ 
 
 
 
✔ 
 
✔ 
SETS 
 
 
✔ 
 
 
 
 
 
 
SHAPS 
 
 
✔ 
 
✔ 
✔ 
✔ 
✔ 
✔ 
WEMWBS 
 
 
✔ 
 
 
 
✔ 
 
✔ 
WHO-QOL-BREF 
 
 
✔ 
 
 
 
✔ 
 
✔ 
Treatment Allocation Questionnaire  
 
 
✔ 
 
 
 
 
 
1. 
Additional visits may be needed during the w ashout period to ensure adequate time for discontinuation of medication. Visits w ill occur on a w eekly basis 
during this period (V1a, V1b, etc.). Review  of medications and assessments for suicidality w ill occur in addition to other assessments at the discretion of 
the study investigator. 
2. 
Baseline assessments can occur on separate days (= or <7 days from dosing day) to reduce the burden on participants. These visits w ill be V2a, V2b etc. 
3. 
The “Last 12 Months” version w ill be administered at Screening and the “Since Last Visit” version w ill be administered at all other visits.  
4. 
See Section 6.0: Research Procedures for complete list of required laboratory tests to be performed. 
5. 
For w omen/females and people of child-bearing age only 
6. 
Additional therapy visits may be scheduled at the discretion of the study therapists and/or the study investigator and therapy can occur in-person or via 
WebEx. 
7. 
To be administered immediately after the acute effects of psilocybin have subsided. 
8. 
The CGI severity index w ill be used at Baseline and the CGI follow -up (included question #2) w ill be used at the follow -up visits 
 
Instruments: 
ATHF: Antidepressant Treatment History Form; CGI: Clinical Global Impression; CSSRS: Columbia Suicide Severity Rating Scale; ECG: Electrocardiogram; GAD-
7: Generalized Anxiety Disorder assessment form; HamD-17: Hamilton Depression Rating Scale; MADRS: Montgomery-Asberg Depression Rating Scale; SCID-5: 
Structured Clinical Interview  for DSM-5; SETS: Stanford Expectations of Treatment Scale; SHAPS: Snaith Hamilton Anhedonia Scale; WEMWBS: Warw ick-

 
 
 
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Edinburgh Mental Wellbeing Scale; WHO-QoL-BREF: World Health Organization Quality of Life abbreviated scale; 5D-ASC: 5-Dimensional Altered States of 
Consciousness Rating Scale. 

 
 
 
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7.0 STATISTICAL PLAN 
7.1 
Sample Size Determination 
The proposed sample size will provide informative confidence interval estimates for 
continuous and binary outcomes. E.g., the margins of error are 8.9% for recruitment rate 
and 7.6% for retention rate. For continuous outcomes, the margin of error is 
approximately 0.66SD for between group differences. For the secondary aim, with the 
planned total sample size of 60 (20 per group) we will have sufficient power (0.80) to 
detect an effect size (ES) of 0.96 (Cohen’s d) for the psychedelic effects measured by 
5D-ASC when comparing the psilocybin plus placebo group with the psilocybin plus 
risperidone and placebo plus risperidone group. Previous RCTs in healthy volunteers, 
have reported larger effects on the 5D-ASC when comparing psilocybin alone with 
psilocybin plus a 5HTA receptor antagonist (Vollenweider et al., 1998).  
 
For the exploratory aim, meta-analyses of published trials report very large psilocybin 
antidepressant ES’ (Cohen’s d > 0.8, CIs − 1.285 to − 0.367) (Galvão Coelho et al., 2021) 
but these are likely inflated due to the small sample sizes in each study and hence it 
would be unwise to base our sample size calculation on this data. Instead, we based the 
sample size determination on published recommendations for pilot trials (Julious, 2005). 
Nonetheless we have sufficient power to detect ES’ of 0.96 and 0.91 for the primary 
clinical endpoint (Week 1) and longitudinal analyses (Day 1, Weeks 1 to 4) respectively, 
when comparing changes on MADRS between the two psilocybin groups and the placebo 
plus risperidone group. The power reduces to 0.67 for an ES of 0.8 and 0.33 for an ES of 
0.5. The power/sample size calculations assume a 10% dropout rate, two-tailed tests, 
and significance of 0.05. 
7.2 
Statistical Methods 
Characteristics of the trial cohort will be summarized by mean (SD), median (minimum, 
maximum). Summary raw scores will be presented at each assessment time both 
numerically and graphically.  
 
All analyses will be run with a blinded grouping variable. Analyses will be conducted under 
the ITT approach and full information maximum likelihood method will be employed to 
tackle missing data. Diagnostic analysis and sensitivity analysis will be implemented to 
examine outliers, high influential cases, normality and missing at random assumptions. 
Standard frequency analysis will be completed for feasibility (recruitment, retention), 
safety and tolerability outcomes (e.g., frequency and duration of adverse events). 
Exploratory analysis of clinical outcomes will be performed on the modified ITT principle, 
including all participants receiving a study intervention.  
 
The primary analytic strategy will be generalized linear model to inspect group differences 
on clinical outcomes at endpoint. Individual level random effects will be added to the 
model for longitudinal analysis (thus mixed-effects models). For the secondary aim, we 
will examine group differences in psychedelic effects measured by 5D-ASC by treating 

 
 
 
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treatment assignment as the primary predictor in the linear models. For the exploratory 
aim, treatment difference on antidepressant effects will be examined by comparing 
changes in MADRS across groups from baseline to one-week post-treatment (i.e. Week 
1/V5). Age, self-reported biological sex, and baseline MADRS total scores (to account for 
potentially larger changes in those with higher baseline symptoms) will be included as 
covariates. Mixed-effects model will be used to inspect change over time (Day 1, Weeks 
1 to 4). Also for the exploratory aim, while not fully powered, non-inferiority test will be 
conducted to examine if the psilocybin plus risperidone group demonstrate comparable 
effects on MADRS to the psilocybin plus placebo group. Exact paired permutation t-tests 
will be used to determine whether psilocybin-assisted psychotherapy with risperidone 
achieves a 50% reduction in MADRS. 
 
Dichotomous outcomes (e.g., response, remission, adverse effects) will be compared 
between groups using a Chi-squared test for assessments at a single time, and using 
generalized estimating equations for repeated assessments. Serious adverse events and 
dropouts attributed to adverse effects will be compared between groups using a Chi-
squared test for assessments at a single time, and using generalized estimating 
equations for repeated assessments. We will also examine changes in secondary clinical 
measures using the same general linear model framework. Point and confidence 
estimates will be the preferred measure to report group differences. These exploratory 
results will be reported uncorrected as they are provided mainly for descriptive purposes 
and do not represent primary outcomes. The trial will be conducted and reported as per 
the CONSORT statement for RCTs. 
 
Subgroup analyses 
Subgroup analysis will be completed to compare treatment effects between groups 
formed by: (1) biological sex (self-reported); and (2) gender, by adding interactions with 
treatment to the regression models. Results for each sex will be reported separately 
irrespective of whether self-reported sex is a significant mediator. Exploratory analysis 
will be conducted to compare responders versus non-responders to identify potential 
clinical and demographic factors that are associated with clinical benefits. 
 
Final statistical analysis will be completed only at the end of the trial. There will be no 
interim analysis.   
 
8.0 SAFETY AND ADVERSE EVENTS 
8.1 
Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a research participant 
administered an investigational product and which does not necessarily have a causal 
relationship with this treatment. An adverse event (AE) can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 

 
 
 
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temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the investigational product.   
 
AE severity can be defined as: 
• 
Mild: discomfort noticed but no disruption of normal activity 
• 
Moderate: discomfort sufficient to reduce or affect normal daily activity 
• 
Severe: interferes significantly with the participant’s normal activity or course of illness 
 
Serious Adverse Event 
A serious adverse event (SAE) is any AE that is:  
• Fatal; 
• Life-threatening; 
• Requires or prolongs hospital stay; 
• Results in persistent or significant disability or incapacity; 
• A congenital anomaly or birth defect; or 
• An important medical event (events that may not be life threatening but are of major 
clinical significance, such as a drug overdose or seizure that did not result in in-patient 
hospitalization).  
 
Adverse Drug Reactions 
An adverse drug reaction is any noxious, unintended or undesirable response to a 
medicinal product related to any dose.  
 
Unexpected Adverse Reactions 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g. Investigator’s Brochure).  
 
Adverse Event Collection Period 
AEs occurring as of the first screening visit and until the last follow-up visit. AEs recorded 
during this period will be followed through to resolution, or until the event is assessed as 
chronic or stable.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the clinical trial.  A preexisting 
condition will be recorded as an adverse event if the frequency, intensity, or the character 
of the condition worsens during the study period. At the Screening Visit (V1), any clinically 
significant abnormality will be recorded as a preexisting condition in the participant’s data 
collection form. Where applicable and at the consent of the participant, additional 
information from the participant’s healthcare provider including medical records, may be 
requested. 
Throughout 
the 
clinical 
trial, 
any 
new 
clinically 
significant 
findings/abnormalities that meet the definition of an adverse event will also be recorded 
and documented as an adverse event.  
 
Post-study Adverse Event 

 
 
 
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At the last scheduled visit, the PI and/or QI should instruct each participant to report any 
subsequent event(s) that the participant believes might reasonably be related to 
participation in this clinical trial.  The PI and/or QI should notify Health Canada of any 
death or adverse event (meeting reporting criteria) occurring at any time after a participant 
has discontinued or terminated participation that may reasonably be related to this clinical 
trial.  Health Canada and Filament Health Corp. should also be notified if the PI and/or QI 
should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a participant that was involved in this clinical trial.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one 
of the following conditions are met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality; 
• The abnormality suggests a disease and/or organ toxicity; 
• The abnormality is of a degree that requires active management (e.g. change of dose, 
discontinuation of the study intervention, more frequent follow-up assessments, further 
diagnostic investigation, etc.); or 
• Any laboratory abnormalities assessed as being clinically significant by a study 
physician or qualified individual. 
8.2 
Recording of Adverse Events 
All adverse events occurring during the study period must be recorded. At each contact 
with the research participant, the research team must seek information on adverse events 
by specific questioning.  Information on all adverse events should be recorded 
immediately in the participant’s data collection form and/or legal health record, and 
recorded in the adverse event log. All adverse events will be assessed the PI for 
relatedness, expectedness, seriousness, and severity in relation to the study intervention. 
All clearly related signs, symptoms, and abnormal diagnostic procedure results should be 
recorded in the data collection form and/or legal health record and assessed by the PI in 
a timely manner allowing sufficient time to meet required reporting timelines for SAEs and 
SUADRs (severe unexpected adverse drug reactions) if needed. Adverse events related 
to the study drug will be reported to Filament Health Corp within 24hrs of the study team 
becoming aware of the event. These reports should not contain PHI. 
8.3 
Reporting of Serious Adverse Events 
8.3.1 
Investigator Reporting: Notifying the Sponsor 
CAMH is the sponsor for this study and will be notified in accordance reporting guidelines.  
Filament Health Corp. is the supplier of the psilocybin used in this trial. Filament Health 
Corp will be sent safety reports on adverse events and serious adverse events within 
24hrs of the study team becoming aware of the event.  None of these safety reports will 
contain PHI and all data will be coded.  

 
 
 
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8.3.2 
Investigator Reporting: Notifying the REB 
The process for notification to the REB for applicable serious adverse events (SAEs) must 
be completed as per REB reporting requirements. SAEs and unanticipated events must 
be recorded and reported to the REB in accordance with the REB’s reporting 
requirements and timelines. Copies of each report and documentation of REB notification 
and REB receipt/acknowledgement must be kept in the Investigator Study Binder. 
8.3.3 
Sponsor Reporting of SUADRs: Notifying Health Canada 
The PI/QI is responsible for reporting the safety information to Health Canada as 
required. The SUADR report must be reported to Health Canada in the following cases: 
• Where the ADR is neither fatal nor life-threatening, within 15 days after becoming 
aware of the information 
• Where it is fatal or life-threatening, immediately where possible and, in any event, 
within 7 days after becoming aware of the information 
• And within 8 days after having informed Health Canada of the ADR, submit as 
complete as possible, a report which includes an assessment of the importance 
and implication of any findings.  
8.3.4 
Sponsor Reporting of SUADRs: Notifying Sites 
Not applicable. 
8.4 
Reporting of Device Deficiencies 
Not applicable. 
8.5 
Safety Management Plan 
Safety of the participants (including data confidentiality) and the scientific integrity of the 
project will be ensured by the research team led by the PI. Participant safety will be 
monitored at each study visit by asking the participant about their experience and about 
any adverse events from the last study visit. All adverse events will be reviewed by the 
study PI and reported to the REB and/or Health Canada in accordance with the regulatory 
guidelines as outlined by each entity. Adverse events will be recorded and/or reported as 
outlined in Section 8.2 and 8.3. Safety reports on AEs and SAEs will be provided to 
Filament Health within 24hrs of the study team becoming aware of the event. In addition, 
all safety data related to the psilocybin will be provided to Filament Health.. None of these 
safety reports will contain PHI and all data will be coded. The study team will also use a 
published Suicide Risk Management Protocol to assess and reduce suicide risk (Herbeck 
et al., 2015). Participants experiencing a serious adverse event will be immediately 
withdrawn from the study. In the case of increased suicidality, the study physician will 
conduct an urgent psychiatric assessment with the participant 
 
The study investigator and study team will meet regularly to review the accrued data, data 
confidentiality, recruitment, and participants complaints. Participant confidentiality will be 
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records will be kept in a locked file and no participants will be identified in any published 
report.  
 
Participants may be removed from the study at the discretion of the PI. Reasons for 
possible withdrawal from the clinical trial are outlined in Section 4.7.1. 
 
Therapeutic Risk Management Measures for Psychological Harm 
Psychological well-being will be closely monitored by the study team and study therapists 
throughout the trial. Study therapists will provide the participant with information about 
what might be experienced during the dosing session, including physiological, sensory 
and psychological effects, and the possibility of challenging experiences. The role of the 
therapists at each of the therapy sessions is to provide support for the participant and 
create a psychologically safe environment.  Therapists will work with the participant to 
develop grounding exercises according to the participant’s preference (e.g., deep 
breathing, breath-focused awareness, progressive muscle relaxation etc.). These 
grounding techniques will be re-reviewed on the day of the intervention. Following dosing, 
integration therapy sessions will be conducted where participants can reflect on their 
dosing experience with the study therapists. For a full description of therapeutic safety 
monitoring procedures, refer to the Yale Manual for Psilocybin-Assisted Therapy of 
Depression. Participants will continue to be followed by the study team for up to 4-weeks 
after the intervention. Psychological well-being (including suicidality) and adverse event 
monitoring will be assessed at all time-points.  
 
Remote Assessment Safety Procedures 
All remote assessments will be conducted in a private room. The research team will not 
require identification from the participant as the research team will already be familiar with 
the participant and will be able to identify them visually through WebEx. The sessions 
occuring over WebEx or over the phone will not be recorded. If the assessment requires 
screen sharing, the individual administering the assessment will ensure that any 
documents or windows on the desktop containing PHI or personal information will be 
closed. The individual administering the assessment will also have access to necessary 
communication technology in order to communicate with relevant research supports or 
emergency services in case of an emergent situation. When sending invitations for 
remote assessments or communicating via email, the research team will limit personal 
information in all emails by avoiding full names ot direct identifiers in the subject line of 
the email or meeting invitation.  
8.6 
Unblinding Procedures 
Emergency unblinding will be limited to situations when the PI has determined that 
appropriate emergency medical care of a study participant requires access to the 
treatment assignment. The study team will report any intentional or unintentional 
unblinding to the REB through the protocol deviation reporting process and this will be 
documented and explained in the final clinical report.  
 

 
 
 
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8.7 
Data and Safety Monitoring Board 
The international guidelines for the Data and Safety Monitoring Board will be followed. A 
DSMB will monitor the conduct of the protocol to ensure the safety of participants and 
validity and integrity of the data. The DSMB will advise investigators on matters pertaining 
to participant safety, conduct of the study, and its continuation. Members of the DSMB 
will create and follow the DSMB charter, which will be agreed upon by all members and 
submitted to the REB as an amendment for approval. The DSMB will include a chair with 
expertise in clinical trials, a biostatistician, and one clinician with expertise in safety 
monitoring. The DSMB will meet prior to initiation of recruitment to review their 
responsibilities and at least once a year after recruitment begins. The DSMB will have 
exclusive access to the unblinded data.  The study team will be accountable to this 
independent DSMB, which will make recommendations to the PI and Trial Steering 
Committee (TSC). The TSC will comprise a patient representative and three external 
experts in clinical trials, of which at least one who will have expertise in psilocybin. The 
TSC will meet once prior to initiation of recruitment, and then bi-annually thereafter to 
ensure that the standards set out in Guidelines for Good Clinical Practice (GCP) are met, 
monitor and supervise the progress of the study and adherence to the study protocol, and 
advise on ethical issues. As this is a pilot trial, there are no criteria for early study 
termination.  
 
9.0 CLINICAL TRIAL DISCONTINUATION AND 
CLOSURE 
9.1 
Clinical Trial Discontinuation 
This clinical trial may be temporarily suspended or prematurely terminated if there is 
sufficient reasonable cause (i.e. closure based on PI decision, sponsor/funder decision, 
REB or other oversight bodies’ decision; review of serious, unexpected and related AEs; 
noncompliance; futility). Notification, which includes the reason for study suspension or 
termination, will be provided by the suspending or terminating party to research 
participants, the PI, funding agency, CAMH, and regulatory authorities.  If the clinical trial 
is prematurely terminated or suspended, the PI will promptly inform research participants, 
the REB, and the sponsor, and will provide the reason(s) for the termination or 
suspension. All communication with participants for this purpose will go through REB 
review and approval.  Research participants will then be contacted, as applicable, and be 
informed of changes to the study visit schedule. 
10.0 DATA HANDLING AND RECORD KEEPING 
10.1 Source Documents & Case Report Forms 
Source data will be collected on paper data collection forms (i.e. source documentation). 
We will also collect health card information from all participants that will be securely 
transferred to ICES, which is a prescribed entity under section 45 of Ontario’s Personal 
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information for the purposes health system management and evaluation without individual 
consent or research ethics approval. The purpose of this transfer will be to link the 
individual’s clinical data with health administrative databases to study long-term safety 
and efficacy outcomes. 
 
REDCap  
Data for this clinical trial will be managed using REDCap electronic case report forms. 
This system is maintained on central CAMH servers, with data backed up daily, and is 
supported by the Research Informatics department.  
10.2 Protocol Deviations 
No deviations from or changes to the protocol will be implemented without approval from 
the REB or Health Canada, unless to eliminate an immediate hazard to a participant. All 
study staff will monitor the study procedures to detect any potential protocol deviations. 
All potential protocol deviations will be reviewed by the study PI. The protocol deviation 
will be reported to the REB if any of the following criteria are met: 
• Deviations that, in the opinion of the PI, jeopardize the safety of research 
participants, or that jeopardize the research efficacy or data integrity 
• Any intentional or unintentional breaking of the blind 
• Any change in the approved process for obtaining consent 
• Any deviations that lead to a serious adverse event or unanticipated problem 
• Any unauthorized collection, use, or disclosure of personal health information (PHI) 
 
Note: any intentional or unintentional breaking of the blind will be reported and explained 
in the final clinical report. 
10.3 Record Retention 
Research records pertaining to this clinical trial will be retained for 15 years.  
10.4 Clinical Trial Registration 
In accordance with TCPS 2, a description of this trial will be registered on 
www.clinicaltrials.gov before the start of recruitment activities, and the content will be 
updated throughout the duration of the clinical trial. All results, including negative results 
should be entered at the completion of the clinical trial. 
11.0 STUDY MONITORING, AUDITING, AND 
INSPECTING 
11.1 Study Monitoring Plan 
Site monitoring is conducted to ensure that the rights and well-being of research 
participants are protected, the reported trial data are accurate, complete, and verifiable, 
and the conduct of the clinical trial is in compliance with the currently approved 
protocol/amendment(s), ICH GCP, and applicable regulatory requirement(s). Reference 
the study monitoring plan for specific monitoring information.  

 
 
 
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11.2 Auditing and Inspecting  
The PI and site will permit study-related audits, and inspections by the REB, CAMH, 
sponsor, and applicable granting agencies or regulatory bodies, including access to all 
study-related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data, etc.). The PI will ensure the capability for audits/inspections of 
applicable study-related facilities (e.g. research pharmacy, clinical laboratory, imaging 
facility, etc.).  
12.0 ETHICAL CONSIDERATIONS 
12.1 Research Ethics Board (REB) Approval 
Research Ethics Board (REB) approval will be obtained prior to beginning any research-
specific procedures. Following initial ethics approval, ongoing ethical approval will be 
maintained and the clinical trial will undergo REB review at least annually, in accordance 
with regulatory and REB requirements. The clinical trial will be conducted in accordance 
with the REB-approved study documents and the determinations (including any 
limitations) of the REB, and in compliance with REB requirements. Any amendments to 
the protocol will require review and approval by the REB before the changes are 
implemented in the clinical trial, unless to eliminate an immediate hazard to the 
participant. 
 
Whenever new information becomes available that may be relevant to participant 
consent, a consent form and/or consent for addendum will be presented to the REB for 
review and approval prior to its use. Any revised written information will receive REB 
approval prior to use. 
12.2 Informed Consent Process & Documentation 
Informed consent is a process that is initiated prior to the individual agreeing to take part 
in the clinical trial and continues throughout their participation. 
 
Informed consent will be obtained from each participant prior to their participation in the 
clinical trial. Informed consent will be obtained by appropriately trained and qualified 
CAMH research personnel who do not have an existing clinical relationship with the 
participant or caregiver The PI will not obtain participant consent. Informed consent will 
be obtained in-person.  
 
Each participant will be provided with a current copy of the REB approved ICF prior to the 
consent discussion. Research personnel will explain the clinical trial to the participant and 
answer any questions that may arise. This discussion will include an explanation of the 
clinical trial purpose, procedures, potential 
risks and benefits, confidentiality 
considerations and participant rights (e.g. participants will not be penalized or lose any 
benefits regardless of what they decide and they have the right to withdraw from the 
clinical trial at any time). Participants may take as much time as they need to make their 
decision, and may consult with others (e.g. family members, other health care providers, 
etc.) if they like. Following the consent discussion, and once the participant has decided 

 
 
 
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to take part, the participant, and the person conducting the consent discussion will 
personally sign and date the ICF. Each participant will be provided with a complete (fully 
signed) copy of the ICF. The original ICF(s) and the informed consent process will be 
documented in the source documents. 
 
Each study visit occurring onsite, including the consent visit, will follow the most current  
institutional IPAC guidelines put forth by CAMH to ensure staff and participants are 
protected against COVID-19 and other infectious diseases (e.g. participant screening 
upon entry, frequent hand-washing, masks for participants and staff).  
13.0 PRIVACY AND CONFIDENTIALITY 
All clinical trial-related documents and data will be held in strict confidence and stored at 
CAMH or on CAMH servers, and will follow CAMH policies and procedures to ensure 
participant privacy and confidentiality.  
 
All research activities will be conducted in as private a setting as possible. The study team 
(including the PI), the study monitor, representatives of the REB, and Health Canada may 
inspect all documents and records required to be maintained by the PI, including but not 
limited to, medical records and pharmacy records for the participants in this clinical trial. 
The participant’s contact information will be securely stored at CAMH for internal use 
during the clinical trial. At the end of the clinical trial, all records will continue to be kept in 
a secure location in accordance to applicable institutional and regulatory requirements. 
Safety reports on AEs and SAEs will be reported to Filament Health within 24hrs of the 
event occurring. In addition, safety data generated from the trial regarding the use of 
psilocybin and a report on the safety and efficacy of the clinical trial data will be provided 
to Filament Health Corp. . None of these reports will contain PHI and all data will be 
coded.  
 
There is a potential risk of breach of confidentiality that is inherent in all research 
protocols. Breach of confidentiality will be minimized by the research staff who will 
maintain research data (identified only by participant code number not related to name, 
or date of birth). A list of participant names, their ID numbers, and information about how 
they can be reached will be kept in a separate locked cabinet with access only to study 
personnel authorized by the PI. To minimize the risk of breach of confidentiality formal 
training sessions for all research staff emphasizing the importance of confidentiality will 
be conducted and formal mechanisms limiting access to information that can link data to 
individual participants will be monitored and established by study personnel. All 
information obtained from participants will be kept as confidential as possible. Computer-
based files/data will be entered into password-secured databases (details below) and 
paper-based files will be stored in a secure location. These data will only be accessible 
to personnel involved in the study and they will abide by confidentiality regulations of the 
REB.  
 
In unusual cases, a participant’s research record may be released in response to a court 
order. If the research team learns that a participant or someone with whom the participant 

 
 
 
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is involved with is in serious danger or harm, an investigator will inform the appropriate 
agencies. 
 
Data from this study will be entered into a secure REDCap database.  At point-of-entry, 
data values will undergo consistency edits (e.g., ID validation, range verification, duplicate 
detection) and personnel will be required to correct errors. Reports will be created via the 
REDCap program. Data management staff will run logic error programs to check for 
accuracy and irregularities within and across data structures and within and across sites. 
Quality assurance checks will be conducted regularly by study personnel. Although 
unlikely, instances may occur where REDCap is not available.  In the case that this 
happens, we will follow the CAMH REDCap Downtime Procedures. 
 
14.0 CLINICAL TRIAL FINANCES 
14.1 Funding Source 
This study is funded by the Canadian Institutes of Health Research (CIHR).  
14.2 Conflict of Interest 
The research team does not have any conflicts of interest to disclose.  
 
15.0 PUBLICATION POLICY/DATA SHARING 
In the publication of the results of research, the investigators are obliged to preserve the 
confidentiality of all research participants. Participants will not be identified in any 
publication of research results. The results of this study will be published as group data 
without the use of characteristics that would identify individual participants. The study 
investigator will hold the primary responsibility for the publication of the results of the 
clinical trial. All publications will follow CAMH policies associated with publications.  
 
15.1 Future Secondary Use of Data 
 
De-identified data from this project may be used for future research by internal and/or 
external project collaborators in the future. The research team may share de-identified 
data with other researchers at CAMH or with collaborators around the world. Coded data 
that has been collected may also be combined with data collected from other people on 
other studies or it may be saved in a database. This is an optional part of the study for 
participants. On the ICF, participants can indicate whether they consent to allowing their 
data to be shared and/or pooled in the future.  
 

 
 
 
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