Evaluating the Feasibility, Clinical Effects, and Safety of Psilocybin-assisted Psychotherapy for Treatment-resistant Obsessive-compulsive Disorder: An Open-label Clinical Trial
Phase: PHASE1
Conditions: Obsessive-Compulsive Disorder
Sponsor: Centre for Addiction and Mental Health

Protocol Version Number: 1.0
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Evaluating the feasibility, clinical effects, and 
safety of psilocybin-assisted psychotherapy for 
treatment-resistant obsessive-compulsive 
disorder: An open-label clinical trial. 
Protocol Identifying Number: 149/2021 
Principal Investigator: Dr. Gwyneth Zai 
Version Number:  1.0 
Version Date: October 20, 2023 

2 
Sponsor: 
Principal Investigator: 
Centre for Addiction and Mental Health 
1025 Queen St. West 
Toronto, ON 
M6J1H4 
Dr. Gwyneth Zai MSc, PhD, MD FRCPC 
Centre for Addiction and Mental Health (CAMH) 
250 College Street, R120 
Toronto, Ontario, M5T 1R8 
416-535-8501 ext. 30145
Funders: 
Centre for Complex Interventions and Temerty 
Centre for Therapeutic Brain Intervention 
Centre for Addiction and Mental Health (CAMH) 
60 White Squirrel Way, Room 317 
Toronto, Ontario M6J1H4 
416-535-8501 ext. 39412
CAMH Alternative Funding Plan (AFP) Innovation 
Fund 
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Table of Contents
STATEMENT OF COMPLIANCE ................................................................................................................. 5 
LIST OF ABBREVIATIONS.......................................................................................................................... 6 
CLINICAL TRIAL SUMMARY ...................................................................................................................... 8 
1.0 INTRODUCTION .................................................................................................................................. 9 
1.1 
BACKGROUND ................................................................................................................................ 9 
1.2 
STUDY INTERVENTION .................................................................................................................... 9 
1.3 
PRECLINICAL DATA TO DATE ......................................................................................................... 10 
1.4 
CLINICAL DATA TO DATE............................................................................................................... 10 
1.5 
RISKS/BENEFITS .......................................................................................................................... 11 
2.0 CLINICAL TRIAL OBJECTIVES ....................................................................................................... 14 
2.1 
PRIMARY OBJECTIVE .................................................................................................................... 14 
2.2 
SECONDARY OBJECTIVE ............................................................................................................... 14 
2.3 
EXPLORATORY OBJECTIVES ......................................................................................................... 15 
3.0 CLINICAL TRIAL DESIGN ................................................................................................................ 15 
3.1 
OVERALL DESIGN ......................................................................................................................... 15 
3.2 
PRIMARY ENDPOINTS ................................................................................................................... 18 
3.3 
SECONDARY ENDPOINTS .............................................................................................................. 18 
4.0 PARTICIPANT SELECTION AND WITHDRAWAL .......................................................................... 18 
4.1 
TARGET POPULATION ................................................................................................................... 18 
4.2 
PARTICIPANT RECRUITMENT AND SCREENING................................................................................ 18 
4.3 
EQUITY, DIVERSITY AND INCLUSION CONSIDERATIONS ................................................................... 21 
4.4 
ELIGIBILITY CRITERIA ................................................................................................................... 21 
4.4.1 
Inclusion Criteria .................................................................................................................... 21 
4.4.2 
Exclusion Criteria................................................................................................................... 22 
4.5 
LIFESTYLE CONSIDERATIONS ........................................................................................................ 23 
4.6 
SCREEN FAILURES ....................................................................................................................... 23 
4.7 
PARTICIPANT WITHDRAWAL CRITERIA ........................................................................................... 23 
4.7.1 
When and How to Withdraw Participants .............................................................................. 23 
4.7.2 
Follow-up for Withdrawn Participants .................................................................................... 24 
5.0 STUDY INTERVENTION ................................................................................................................... 25 
5.1 
DESCRIPTION ............................................................................................................................... 25 
5.2 
TREATMENT REGIMEN .................................................................................................................. 27 
5.3 
METHOD FOR ASSIGNING PARTICIPANTS TO TREATMENT GROUPS ................................................. 27 
5.4 
ADMINISTRATION OF STUDY INTERVENTION ................................................................................... 27 
5.5 
PARTICIPANT COMPLIANCE MONITORING ....................................................................................... 28 
5.6 
CONCOMITANT THERAPY .............................................................................................................. 28 
5.7 
PACKAGING ................................................................................................................................. 32 
5.8 
BLINDING OF STUDY INTERVENTION .............................................................................................. 32 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 32 
5.9.1 
Receipt of Study Intervention Supplies ................................................................................. 32 
5.9.2 
Storage .................................................................................................................................. 32 
5.9.3 
Dispensing of Study Intervention........................................................................................... 32 
5.9.4 
Return or Destruction of Study Intervention .......................................................................... 33 
6.0 RESEARCH PROCEDURES ............................................................................................................. 33 

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6.1 
RESEARCH VISITS ........................................................................................................................ 33 
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 ................................................................................................... 47 
8.1 
DEFINITIONS ................................................................................................................................ 47 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 49 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS .................................................................................. 49 
8.3.1 
Investigator Reporting: Notifying the Sponsor ....................................................................... 49 
8.3.2 
Investigator Reporting: Notifying the REB ............................................................................. 49 
8.3.3 
Sponsor Reporting of SUADRs: Notifying Health Canada .................................................... 50 
8.3.4 
Sponsor Reporting of SUADRs: Notifying Sites .................................................................... 50 
8.4 
REPORTING OF DEVICE DEFICIENCIES ........................................................................................... 50 
8.5 
SAFETY MANAGEMENT PLAN ........................................................................................................ 50 
8.6 
UNBLINDING PROCEDURES ........................................................................................................... 51 
8.7 
DATA AND SAFETY MONITORING BOARD ....................................................................................... 51 
9.0 CLINICAL TRIAL DISCONTINUATION AND CLOSURE ................................................................. 52 
9.1 
CLINICAL TRIAL DISCONTINUATION ................................................................................................ 52 
10.0 DATA HANDLING AND RECORD KEEPING ................................................................................... 52 
10.1 
SOURCE DOCUMENTS & CASE REPORT FORMS ............................................................................. 52 
10.2 
PROTOCOL DEVIATIONS ............................................................................................................... 52 
10.3 
RECORD RETENTION .................................................................................................................... 53 
10.4 
CLINICAL TRIAL REGISTRATION ..................................................................................................... 53 
11.0 STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 53 
11.1 
STUDY MONITORING PLAN ............................................................................................................ 53 
11.2 
AUDITING AND INSPECTING ........................................................................................................... 53 
12.0 ETHICAL CONSIDERATIONS .......................................................................................................... 53 
12.1 
RESEARCH ETHICS BOARD (REB) APPROVAL ............................................................................... 53 
12.2 
INFORMED CONSENT PROCESS & DOCUMENTATION ...................................................................... 54 
13.0 PRIVACY AND CONFIDENTIALITY ................................................................................................. 54 
14.0 CLINICAL TRIAL FINANCES ............................................................................................................ 56 
14.1 
FUNDING SOURCE ........................................................................................................................ 56 
14.2 
CONFLICT OF INTEREST ................................................................................................................ 56 
15.0 PUBLICATION POLICY/DATA SHARING ........................................................................................ 56 
15.1 
FUTURE SECONDARY USE OF DATA .............................................................................................. 56 
16.0 REFERENCES ................................................................................................................................... 56 

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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 
CAMH 
Center for Addiction and Mental Health 
CGI 
 
Clinical Global Impression Scale 
CRF   
Case report form(s) 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DLPFC 
Dorsolateral Prefrontal Cortex 
DMPFC 
Dorsomedial Prefrontal Cortex 
DSMB  
Data Safety & Monitoring Board 
ECG 
Electrocardiography 
EEG 
 Electroencephalography 
EMG 
Electromyography 
GAD-7 
Generalized Anxiety Disorder 7-Item Scale 
GCP   
Good Clinical Practice 
ICF  
 
Informed consent form 
MEP  
Motor Evoked Potential 
MEQ  
Mystical Experiences Questionnaire 
MSI-BPD 
Mclean Screening Instrument for Borderline Personality Disorder 
OCD  
Obsessive Compulsive Disorder 
PAP  
Psilocybin-Assisted Psychotherapy 
PHI 
 
Personal Health Information 
PHIPA 
Personal Health Information Protection Act 
PHQ-9 
Patient Health Questionnaire 

 
 
 
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PI 
 
Principal Investigator 
QI 
 
Qualified Investigator 
RMT  
Resting Motor Threshold 
SAE  
Serious Adverse Event 
SCID-5 
Structured Clinical Interview for DSM-5 
SI 1mV 
Stimulus Intensity that evokes MEPs with an average amplitude of 1 mV 
SUSAR  
Suspected unexpected serious adverse reaction 
TASS  
Transcranial Magnetic Stimulation Adult Safety Screen 
TCPS 2 
Tri-Council Policy Statement  
TMS 
 Transcranial Magnetic Stimulation 
TR-OCD 
Treatment Resistant Obsessive-Compulsive Disorder 
VAS  
Visual Analog Scale 
WMSWBS 
Warwick-Edinburgh Mental Wellbeing Scale 
WHODAS 
World Health Organization Disability Assessment Schedule 
WHO-QoL-BREF 
World Health Organization Quality of Life Questionnaire – Brief 
Version 
YBOCS 
Yale-Brown Obsessive Compulsive Scale 
5D-ASC 
Five Dimensions of Altered States of Consciousness 
 
 
 
 
 
 
 
 

 
 
 
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CLINICAL TRIAL SUMMARY 
 
Title 
Evaluating the feasibility, clinical effects, and safety of 
psilocybin-assisted psychotherapy for treatment-resistant 
obsessive-compulsive disorder: An open-label clinical trial. 
 
Short Title 
Psilocybin-assisted therapy for OCD 
Phase 
Phase I 
Methodology 
Open-label clinical trial 
Clinical trial 
Duration 
18-months to complete all recruitment, study procedures, and 
data analysis.  
Participating site(s) 
Single-Center   
Objectives 
To assess the safety, feasibility, and clinical effects of 
psilocybin, administered under supportive conditions to adult 
participants with treatment-resistant OCD, in improving OCD 
symptoms as assessed by the frequency of serious adverse 
events and the change in the Yale-Brown Obsessive 
Compulsive Scale (YBOCS) total score from Baseline (V2) to 
Week 3 (Visit 8). 
Number of 
Participants 
Ten participants diagnosed with treatment-resistant 
obsessive compulsive disorder 
Study Intervention 
Reference 
Therapy/Comparator 
Two sessions of orally administered 25mg of psilocybin taken 
in conjunction with psilocybin-assisted psychotherapy (PAP).  
Duration of 
Intervention 
Two days: 5-6 hours each day.  
Statistical 
Methodology 
Characteristics of the trial cohort will be summarized by mean 
(SD), median (minimum, maximum). Conservative 
nonparametric testing will be used to address the primary and 
secondary objectives. Exact paired permutation t-tests will be 
used to determine whether psilocybin-assisted psychotherapy 
achieves a 50% reduction in YBOCS symptoms. 
 
 

 
 
 
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1.0 INTRODUCTION 
1.1 
Background 
Obsessive-compulsive disorder (OCD) is a highly debilitating illness that has a lifetime 
prevalence of 2-3% (Ruscio et al., 2010; Weissman et al., 1994). Although the 
presentation can vary, OCD is characterized by intrusive thoughts, images, or urges 
which are typically accompanied by repetitive behaviors or mental acts (compulsions). It 
is a chronic disorder that has significant negative effects on an individual’s quality of life 
particularly impacting social relationships (Stein et al., 2019; Subramaniam et al., 
2013).Treatment options for OCD include pharmacological treatment, cognitive 
behavioural therapy (CBT), and as a last resort, surgery. However, up to 40% of patients 
diagnosed with OCD do not respond to the available treatment modalities (Bloch et al., 
2006; Pallanti & Quercioli, 2006). Although there is some debate in the literature, 
treatment-resistant OCD is defined as individuals’ who have failed to respond to at least 
2 therapeutic trials of selective serotonin reuptake inhibitors (SSRIs) or serotonin 
norepinephrine reuptake inhibitors (SNRIs) (Husted & Shapira, 2004; Pittenger et al., 
2005). Given the increased risk of morbidity and mortality associated with treatment-
resistant OCD, there is an urgent need for novel interventions (Meier et al., 2016). 
 
1.2 
Study Intervention 
Recently, 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). It has been suggested that 
psilocybin has the potential to disrupt an individual’s maladaptive habits of cognition, 
affect, and behavior, alongside well-aligned psychotherapy, can lead to sustained clinical 
improvements.   
 
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 which is chemically similar to the 
neurotransmitter, serotonin, and the essential amino acid, tryptophan. It is considered a 
5-hydroxytrptamineric (serotonergic) psychedelic along with other similar drugs such as 
dimethyltryptamine (DMT) and lysergic acid diethylamide (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. With proper screening and preparation, psilocybin has a safe 
physiological and psychological profile. Psilocybin is currently the preferred compound 
for use in clinical research involving 5-hydroxytrptaminergic psychedelics because it has 

 
 
 
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a shorter duration of action and suffers from less notoriety and stigma than other similar 
drugs (Carter et al., 2005; Gouzoulis-Mayfrank et al., 1999; Hasler et al., 2004).  
 
Psilocybin administered in conjunction with psychotherapy has been used in psychiatry 
since the 1950s. However, there was a paucity of research until the mid-1990s due to its 
classification as a Schedule 1 substance in the United Stated (US) (Passie et al., 2002). 
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 occur 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).   
 
1.3 
Preclinical Data to Date 
Preclinical data on the use of psilocybin for the treatment of OCD is limited as it is 
difficult to for a true animal model to be determined for a condition that is primarily 
characterized by obsessive thoughts. There is one study published on a rodent model of 
OCD. Matsushima et al. (2009) studied the effects of psilocybin on marble-burying 
behavior in mice. Marble-burying behavior has been widely used as a cost-effective 
model of OCD on the grounds that it is a non-functional and repetitive behavior that may 
be an outward expression of OCD (Matsushima et al., 2009). Both synthetic psilocybin 
and the mushroom solution used in the study reduced marble burying behavior without 
reducing general locomotor activity (Matsushima et al., 2009). Although this study 
shows interesting results, the generalizability and applicability of these findings in other 
animal models is yet to be determined (Jacobs, 2020).  
 
1.4 
Clinical Data to Date 
To date, there are numerous studies supporting the clinical efficacy of PAP for the 
treatment of depression and end-of-life anxiety (Carhart-Harris et al., 2021; Griffiths et al., 
2016; Ross et al., 2016). Currently, there are over 60 studies registered on 
ClinicalTrials.gov exploring the use of psilocybin to treat various mental health disorders. 
A recent randomized control trial (RCT) demonstrated large effect sizes sustained for 4.5 
years after a single dose of psilocybin administered with psychotherapy in patients with 
cancer-related existential distress (Agin-Liebes et al., 2020). In addition, several trials 
have observed rapid and sustained improvements in patients with treatment-resistant 
depression with one RCT demonstrating similar efficacy between psilocybin compared 
with an SSRI. Interestingly, secondary outcomes favoured psilocybin (Carhart-Harris et 
al., 2021).  
 
Although there are several studies demonstrating the efficacy of PAP for the treatment of 
depression and anxiety, there is limited clinical data available reporting on the use of 

 
 
 
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psilocybin-assisted psychotherapy to treat OCD. To date, there are several case reports 
in the literature that indicate psilocybin-mediated relief of OCD symptoms (Leonard & 
Rapoport, 1987; Lugo-Radillo A Md & Cortes-Lopez, 2021; Moreno & Delgado, 1997; 
Wilcox, 2014). The most recent report, of a 30-year old male with debilitating OCD 
symptoms for more than 10 years, described significant reductions in symptoms for up to 
6-months after the initial use (Wilcox, 2014). Regrettably, the published case studies do 
not include precise doses, psychotherapy, or controlled assessment measures.  
 
An open-label study of psilocybin for OCD, Moreno et al. (2006) enrolled nine participants 
who had an average of 3.4 previous treatment failures. Patients received escalating 
doses of psilocybin (7mg/70kg – 21mg/70kg), each separated by at least a week. In the 
24-hr post-administration monitoring period, all patients experienced a 23-100% 
reduction from baseline on the Yale-Brown Obsessive-Compulsive Scale (YBOCS), 
indicating a marked relief from symptoms (Moreno et al., 2006). Two-thirds of patients 
maintained a greater than 50% decrease in YBOCS score at 24 hours for at least one 
session. Two patients reported symptomatic relief lasting nearly a week with one patient 
still in remission at the 6-month follow-up (Jacobs, 2020; Moreno et al., 2006). It is 
believed that PAP may function as a ‘reset button’ in individuals with OCD whereby there 
is an acute disruption in the maladaptive functioning of the default mode network (DMN) 
(Carhart-Harris et al., 2017; Jacobs, 2020). 
 
There are promising results, but limited studies demonstrating the use of PAP to treat 
OCD. This study will serve as an important milestone in helping to investigate the 
feasibility of using PAP as a novel treatment in OCD populations. The goal is to provide 
preliminary support for the feasibility, clinical effects and safety of psilocybin in treatment-
resistant OCD with the hope of motivating further trials, with more rigorous designs, to 
better examine the therapeutic potential of this approach.  
 
1.5 
Risks/Benefits 
 
Possible Benefits 
As with any research study, no direct benefit can be promised to research participants. 
Case reports and one previous study investigating psilocybin-assisted psychotherapy in 
OCD cohorts have indicated rapid and dramatic reductions in participants’ symptoms. 
Therefore, participants may receive some benefit from the study if PAP is effective in 
improving OCD symptoms. Participants may also benefit from close monitoring of their 
clinical conditions.  
 
Psilocybin Risks 
Expert consensus indicates that psilocybin is safe in human pre-clinical and clinical trial 
research (Johnson et al., 2008). 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, 

 
 
 
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impaired concentration, labile mood, altered perception of time, altered visual perception, 
mild paranoid ideas and unusual thoughts. Previous studies indicate that these events 
are transient, tolerable, and largely resolved within the timeframe of the 8-hour PAP 
session (Griffiths et al., 2016; Grob et al., 2011; Ross et al., 2016). In addition, these 
effects are both expected and may be a necessary component of the therapeutic 
response. 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.. 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.  
 
Medication Tapering Risks 
There will be a washout period of 3-6 weeks for participants taking any concomitant 
medications. 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 medications used to treat OCD can result in 
the worsening of a participant’s symptoms. During the tapering period, the participant will 
be seen clinically by the study physician. 
 
fMRI 
Minimal risk except for people with metal or magnetic implants (such as metallic clips in 
the brain or cardiac pacemakers) due to strong magnetic field in scanner. Participants will 
be screened by the study personnel and by the MR technician at the MR Centre prior to 
scanning. Some people may feel uncomfortable lying still in the confined space of the 
MRI scanner. The study physician may prescribe a mild sedative to help relax the 
participant during the MRI session. In addition, participants may feel tingling sensations 
during the scan or feel dizzy for a few minutes at the end of the MRI. These are infrequent, 
but expected sensations. Participants will be able to contact the technologist at any time 
during the scan.  
 
There are no long term risks caused by the magnetic field strength used in this study. 
There is a possibility of unexpected or incidental findings. The scan used in this clinical 
trial is not for diagnostic purposes. If an atypical finding is seen on the scan, a radiologist 
or other qualified health professional will look at the scan. The participant’s identity will 
not be revealed and if it is recommended that further testing is required, the research 
team will schedule an appointment to arrange follow-ups with the participant.  

 
 
 
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Some of the images collected will use new methods or “investigational” protocols that 
were developed by GE as a Work in Progress (WIP). These do not pose any additional 
risk to the participants as they images can only be acquired if the images are within the 
established safety limits.  
 
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. 
 
EMG 
Skin irritation from the EMG electrode pads or pain when removing the sticky pads are 
possible side effects. 
 
EEG 
Scalp irritation from the EEG sensors and preparation gel are possible side effects. OCD 
symptom provocation during the rest EEG is designed to cause obsessional distress 
which is expected to cause temporary discomfort that is familiar to the study participant.  
 
TMS 
TMS is a non-invasive method to stimulate brain tissue through electromagnetic fields 
that poses no significant health risk to properly screened study participants. Single pulse 
TMS is a routine clinical diagnostic tool used in hundreds of neurophysiological 
laboratories worldwide. Prospective studies designed to systematically evaluate health 
effects have not found changes in EEG, blood pressure, heart rate, serum cortisol, serum 
prolactin, cerebral blood flow, memory or cognition. Single pulse TMS of the motor cortex 
has been used in children and infants as young as 2 weeks of age with no adverse effects 
reported. The induced electrical current is well below that which is expected to cause 
harm to nervous tissue. The US FDA has concluded that stimulation at <1 Hz carries 
virtually no risk seizure and is therefore classified as a non-significant risk device. 
 
TMS of left prefrontal cortex is approved for therapeutic use in OCD. However, the use of 
TMS in this study is diagnostic. The number of pulses and the minimum pause between 
pulses is selected such that no significant neuromodulatory effects are induced. 
 
The TMS pulse cause a clicking noise. Study participants will wear earphones and 
earmuffs to protect their hearing. 
 
Neuronavigation 
Neuronavigation uses infrared light reflected by small spheres attached to the head and 
the TMS stimulation coil to determine the relative positioning and has no known side-
effects or health risks. 

 
 
 
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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.  
 
2.0 CLINICAL TRIAL OBJECTIVES  
2.1 
Primary Objective 
To assess the feasibility and clinical effects of psilocybin, administered with psychological 
support to adult participants with treatment-resistant OCD, in improving OCD symptoms 
as assessed by the change in the YBOCS total score from baseline. Baseline is defined 
as the assessment score obtained on Day -1 (V2). The primary time point is Week 3 
(V10). We will also analyze changes in YBOCS score from Baseline to Day 1 (V8), and 
Weeks 3 (V10), 6 (V11), 9 (V12), and 12 (V13) post-dosing.   
• To assess feasibility, we will evaluate recruitment and retention rates. Dropout 
rates during three periods will be evaluated, namely: 1) screening period in which 
the participant undergoes medication tapering and washout; 2) during the acute 
course of the study intervention; and 3) during the follow-up after the second 
dosing session. Throughout all three periods, we will also evaluate adverse events 
including psychological distress and serious adverse events (e.g., hospitalization, 
suicide attempt, death). 
 
Hypothesis 1: Two sessions of psilocybin 25mg administered under supportive conditions 
to participants with treatment-resistant OCD will lead to significant reductions in OCD 
symptoms from Baseline (V2) compared to Week 3 (V10) as measured by the YBOCS 
total score, and will be safe and feasible. 
 
2.2 
Secondary Objective 
The secondary objectives are: 
• To assess the clinical effects of psilocybin on: 
o Proportion of participants with response defined as a 35% or more of the 
YBOCS total score and remission defined as a score of ≤7on the YBOCS 
from Baseline (V2) to Week 3 (V10).  
o Changes in the Patient Health Questionnaire (PHQ-9), Clinical Global 
Impression (CGI) scale, World Health Organization Quality of Life Short 
Version 
(WHOQOL-BREF), 
World 
Health 
Organization 
Disability 
Assessment Schedule (WHODAS 2.0), and Generalized Anxiety Disorder 
scale (GAD-7) from Baseline (V2) compared to Week 3 (V10).  

 
 
 
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o Changes in behavioural assessments for well-being (Warick-Edinburgh 
Mental Wellbeing Scale, WMWS) from Baseline (V2) compared to Week 3 
(V10). 
To evaluate the safety of psilocybin in participants with TR-OCD by using standardized 
adverse events monitoring at all-time points. Adverse event monitoring will be prioritized 
to closely and thoroughly evaluate the acute and sub-acute psychological safety profile. 
Constant observation by therapists will monitor for adverse events during the dosing 
sessions. A study psychiatrist or a licensed physician delegated by the qualified 
investigator will be readily available on site for the entire duration of the psilocybin effect. 
2.3 
Exploratory Objectives 
The exploratory objectives are: 
• Five Dimension Altered States of Consciousness Questionnaire (5D-ASC) and the 
Mystical Experiences Questionnaire (MEQ) will be assessed for correlation with 
the primary and secondary outcomes as possible predictors of response.  
• To assess the effect of psilocybin on neurophysiological measures: 
o Changes in Resting EEG, Task EEG, and TMS-EEG between Visit 3 (V3), 
taking place before the first Psilocybin administration session, and Visit 9 
(V9), taking place after the last Psilocybin administration session. 
• To investigate changes in the ongoing EEG recording during the administration of 
psilocybin, i.e. during Visit 4 (V4) and Visit 7 (V7) 
• To investigate correlations between neurophysiological markers and symptom 
severity 
• To investigate changes in the functional connectivity profiles associated with the 
neurobiological effects of PAP. This will be conducted by examining the changes 
in functional connections using an EEG and fMRI at Baseline (V2) compared to 
study Visit 10 (V10).  
 
3.0 CLINICAL TRIAL DESIGN 
3.1 
Overall Design 
 
This study is an open-label, proof of concept study investigating the use of psilocybin-
assisted psychotherapy (PAP) in treating TR-OCD. The findings of this study will provide 
preliminary data on the safety and clinical effects of PAP as a treatment option for patients 
with TR-OCD. 
 
 
Overview of Study Design: 
All 10 participants will follow the same study design. Each participant will undergo a 
screening assessment where they will complete lab tests, and clinical and psychiatric 
assessments to determine eligibility. Following the screening visit, participants will 
undergo a washout period where they will be tapered off concomitant medications over a 

 
 
 
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period of 3 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. All medications will 
require a minimum of a 2-week tapering period 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. During this period, there will be weekly check-ins with the study physician. 
At study Visit 2 (Baseline, V2), participants will complete a series of questionnaires and 
assessments, preparatory therapy with trained study therapists, and undergo a brain 
fMRI. To reduce participant burden, baseline can be broken up into multiple days, 
however all assessments must be completed within 7-days of the first dose. At study Visit 
3 (V3), neurophysiological measurements will be performed.  Upon completion of V2 and 
V3, participants will undergo the first psilocybin dosing session at Visit 4 (V4) where they 
will receive an active dose (25mg) of psilocybin in conjunction with supportive therapy. 
On the day after the dosing session (Visit 5, V5) and one-week after the dosing session 
(Visit 6, V6), participants will be asked to complete the same questionnaires that were 
done at Baseline (V2) and will undergo an integrative therapy session with the trained 
study therapist. At Visit 7 (V7), 2-weeks after the first psilocybin dose, participants will 
undergo the second psilocybin dosing session where they will receive an active dose 
(25mg) of psilocybin in conjunction with supportive therapy. On the day after the second 
dosing session (Visit 8, V8) and one-week after the second dosing session [3-weeks after 
dose 1] (Visit 9, V9), participants will be asked to complete the same questionnaires that 
were done at Baseline (V2) and will undergo an integrative therapy session with the 
trained study therapist. Between Visit 8 (V8) and Visit 10 (V10), during study Visit 9 (V9), 
the same neurophysiological measurements will be performed as during Visit 3 (V3). 
Follow-up assessments will also occur at 6, 9, and 12 weeks (Visit 11, 12, and 13) after 
the second psilocybin dosing session. The same questionnaires administered at Baseline 
(V2) will be repeated at each of these study visits.

 
 
 
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Figure 1. Study Schematic: 
Assessments are defined as questionnaires and clinician administered interviews (Section 6.0) administered at Baseline and 
repeated throughout the trial. 
 
 
 
 
 
 
 
 
 
 
 
Timeline 
In total, there are a minimum of 16 study visits (13 study visits and a minimum of 3 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 4.0 months. The total expected duration of the clinical trial from the 
time the study team starts recruiting until data analysis has been complete is 18-months. The study team will recruit 
approximately 1 participant per month over the period of 10 months. All study interventions and follow-up assessments 
will be completed by month 14. This leaves approximately 4 months for data analysis which will be completed at month 
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3.2 
Primary Endpoints 
The primary endpoint for clinical effects is the change in the YBOCS total score from 
Baseline (Day -1, V2) to Week 3 (V10). We hypothesize there will be a significant 
reduction of ≥35% in OCD symptom severity on the YBOCS from Baseline (V2) compared 
to Week 3 (10).   
 
The co-primary safety endpoint is the number and severity of adverse events reported 
throughout the duration of the trial. The endpoint for tolerability will be the number of 
participants that dropped out of the study due to an adverse event.  
 
3.3 
Secondary Endpoints 
The secondary endpoints are changes from Baseline (V2) to Week 3 (V10) on the 
YBOCS, PHQ-9, CGI, WHODAS 2.0, WEMWBS, WHOQoL-BREF, and GAD-7.  
 
 
4.0 PARTICIPANT SELECTION AND WITHDRAWAL 
4.1 
Target Population 
The target population for this study are adults aged 18-65 who are experiencing clinically 
significant obsessive-compulsive disorder that has been resistant to at least two courses 
of pharmacological treatment and at least one course of psychotherapy. 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 4-weeks prior to baseline for fluoxetine and 2-weeks prior to baseline for all 
other medications, as confirmed by the study investigator.  
4.2 
Participant Recruitment and Screening 
The target sample size is 10 participants (N=10) diagnosed with treatment-resistant OCD. 
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 units and external 
healthcare providers. 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. 
 
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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.  
 
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 
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 obsessive-compulsive disorder 
• Treatments taken for OCD (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; 
• 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 
medications used to treat OCD 
• 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  
• Currently enrolled in another study involving an investigational product or device 
• If they are able to take medication orally 
• If they have used psychedelic drugs in the last 12 months 
• Whether they have contraindications to TMS 
 
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 
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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 
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.  
 
 
Compensation 
Participants will not be charged for research-only services for their participation in this 
study. All research-only services, such as clinical assessments, fMRI, 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 undergoing the fMRI,the pre- and 
post-neurophysiology assessments, as well as study visits occurring after the washout 
period where treatment (therapy or psilocybin) is not administered. The fMRI is an 
optional part of the study and participants will be in the scanner for roughly 1 hour, 
however additional time will be needed for preparation (e.g. changing clothes). 
Participants will be reimbursed $50 per fMRI (maximum of 2), paid in cash on the day the 
fMRI is completed. The pre- and post-neurophysiology assessments are not an optional 
portion of the study. Participants will be reimbursed for their time spent completing the 
neurophysiology sessions. These assessments will take approximately 4hrs each, 
participants will be reimbursed about $40 per session. Finally, participants will be 
reimbursed $10 per hour for each study visit that they attend after the washout period 
where treatment is not administered (Visit 11, Visit 12, Visit 13). In total, if participants 
complete all study visits, they may be reimbursed up to $240 for their time. Compensation 
will be provided for all applicable visits and travel reimbursement at the participant’s final 
study visit (V13) in cash if they are attended in-person or e-gift card, if the session is 
conducted virtually. No payment will be provided in advance.  
 
Study Visit: 
Duration: 
Compensation: 
Neurophysiology before first PAP session 
[Visit 3] 
~4 hours 
$40 
Neurophysiology after second PAP session 
[Visit 9] 
~4 hours 
$40 
6-week follow-up [Visit 11, Day 42] 
~2 hours 
$20 
9-week follow-up [Visit 12, Day 63] 
~2 hours 
$20 
12-week follow-up [Visit 13, Day 84] 
~2 hours 
$20 

 
 
 
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fMRI (maximum of 2) 
~2 hours each 
$50 each 
 
 
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; 
7. Primary DSM-5 diagnosis of obsessive compulsive disorder (OCD) based on medical 
records and assessment using the Structured Clinical Interview for DSM-5 (SCID-5) 
administered at the first screening visit; 
8. Participants diagnosed with treatment-resistant OCD defined as individuals with a 
score of ≥ 16 on the YBOCS (i.e. moderate symptom severity) and that have not 
responded to two or more separate pharmacological interventions and one or more 
trials of cognitive behavioural therapy (CBT); there is no upper limit on the number of 
treatment failures; 
9. Individuals with an eGFR above 40mL/min/1.73m2 and all blood work within normal 
limits as assessed by clinical laboratory tests at Screening (V1) 
10. Ability to take oral medication; 
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 have tapered off current OCD medications for a 
minimum of 2-weeks prior to Baseline (V2) 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-
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(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 (use of tobacco and prescribed 
opioids are permitted) within the preceding 6 months; 
5. Have active suicidal ideation as determined by the C-SSRS and/or clinical interview. 
Significant suicide risk is defined by suicidal ideation as endorsed by items 4 or 5 of 
the C-SSRS; 
6. Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum 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.  Have contraindications to TMS as determined by the TASS questionnaire; 
9. Have a history of seizures; 
10. Are taking anticonvulsants or benzodiazepines (Lorazepam up to 2mg/day is 
acceptable); 
11. Presence of a relative or absolute contraindication to psilocybin, including a drug 
allergy, history of a stroke in the last year, uncontrolled hypertension, low blood 
pressure defined as ≤90/60mmHg or labile blood pressure defined as recurrent, 
sudden, unexplainable BP surges to levels of 140/90mmHg or higher, history of 
myocardial infarction in the last year, cardiac arrhythmic, severe coronary artery 
disease, or moderate to severe renal or hepatic impairment, defined by an eGFR 
≤40mL/min/1..73m2 for moderate renal impairment, and a total bilirubin of ≤50µmol/L 
and serum albumin ≤3.5 for moderate hepatic impairment (please note that 
participants must have an eGFR above 40mL/min/1.73m2 and within normal limits on 
the results in all clinical laboratory tests including liver function tests at Screening [V1] 
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12. Use of classic psychedelic drugs such as the serotonergic psychedelics drugs, 
psilpocybin, ayahausca, and 5-MeO DMT, etc., within the previous 12 months; OR 
13. 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 start of each psilocybin treatment session 
for up to 6 hrs after administration (V4 & V7). 
• Abstain from the use of any prescribed opioids, benzodiazepines, or sleep aids (Z-
drugs) within 12hrs prior to each psilocybin treatment sessions (V4 & V7) and for up to 
6hrs after administration.  
• Abstain from any illicit drugs (e.g. cocaine, ecstasy/MDMA, hallucinogens) and 
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 each psilocybin 
administration. 
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.  
 
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; 
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• 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; 
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.  
 
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• 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.  
 
Psilocybin-Assisted Psychotherapy 
The participant will attend 1 preparatory session that occurs within 7-days of the first 
psilocybin dosing session (V4) to develop a therapeutic alliance, set intentions for the 
experience, and learn what to expect during the dosing session. An additional 

 
 
 
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preparatory therapy session can be added at the discretion of the study therapists and 
study investigator. In addition, the participant will undergo 2 integrative therapy sessions 
after each psilocybin dose (V8 & V10). During dosing, there will be two therapists 
present. A physician will be available at all times during each dosing session to assess 
and manage any medical or psychiatric adverse events (either on-call or as a therapist 
in the room with the patient). Efforts will be made to ensure that the therapists remain 
the same at every therapy session, however the only days that require two therapists 
are dosing. Therapy sessions will not be video recorded.  
Each therapist will undergo training by the study investigator or delegated investigator 
using the adapted Yale Manual for Psilocybin-Assisted Therapy of OCD, an evidence 
informed protocol for PAP . Therapy sessions will not be video recorded. For a full 
description of each therapy session and PAP, please refer to the Yale Manual for 
Psilocybin-Assisted Therapy of OCD. This manual will be adapted to meet the needs of 
the study protocol.  
In addition, therapists will undergo protocol-specific training for the study. Therapists 
involved in the trial must be licensed to provide therapy by a regulatory body. 
Unlicensed therapists will be directly supervised by a licensed therapist.  
Requirements for lead study therapists: 
1. Licensed to provide psychotherapy in the province of Ontario:  
a. Social worker 
b. Psychologist 
c. Psychiatrist or physician (M.D or equivalent) with psychotherapy training 
d. Nurse with psychotherapy training (e.g. nurse psychotherapist certificate) 
2. Registered with the appropriate regulatory body in Ontario: 
a. College of Registered Psychotherapists of Ontario 
b. College of Psychologists of Ontario 
c. Ontario College of Social Workers and Social Service Workers 
d. The College of Physicians and Surgeons of Ontario 
e. College of Nurses of Ontario 
3. Previous experience administering PAP 
Unlicensed therapists who are in the process of becoming licensed or therapists who 
have not had any PAP experience must be supervised under the direct supervision of a 
lead therapist.   
  
 
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), white capsules.  

 
 
 
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5.2 
Treatment Regimen 
There will be 2 dosing sessions. The first dosing session will occur at Visit 4 (V4, Day 0), 
after the participant has been deemed eligible to participate. The second dosing session 
will occur 2-weeks after the first dosing session at Visit 7 (V7, Day 14). The participant 
will follow the same procedures for both dosing sessions. These procedures are outlined 
below: 
 
Each participant will be assigned 1 treatment bottle containing 1 capsule of 25mg 
psilocybin. The IP will be given to the participant by the study psychiatrist or a licensed 
physician delegated by the qualified investigator who will supervise the participant orally 
take the medication.  It will be taken orally with a glass of water provided by the study 
team. There will be no modifications to the dosage, each participant will receive 1 capsule 
of 25mg of psilocybin at study Visit 4 and study Visit 7. The effects of psilocybin start 
about 20 to 30 minutes after administration with peak effects usually occurring in the first 
90 to 120 minutes and gradually subsiding in 5 to 6 hours. 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 to 6 hours when the 
acute effects of the psilocybin have passed. 
 
We chose psilocybin 25 mg dosage for standardization across the study participants, 
which is the most frequently chosen dose in other psilocybin research studies with almost 
guaranteed and observed psychedelic effects. A recent study reported no significant 
differences in weight-adjusted dosing versus fixed dosing (Garcia-Romeu et al., 2021). 
Furthermore, advantages of fixed dosing outweigh potential minimal advantage of weight-
adjusted dosing given that fixed dosing has a lower cost of administering psilocybin and 
is more convenient to the study team. 
 
We have consulted with our colleagues at Yale University, who are currently conducting 
a clinical trial comparing one dosing to two dosing schedule (ClinicalTrials.gov ID 
NCT05370911) and we opted for a two-dosing regimen since OCD symptoms are 
generally more difficult and rigid to target when compared to anxiety and depressive 
symptoms; therefore, a second dosing may improve OCD symptoms further due to the 
ritualistic and ruminating nature of the illness. 
5.3 
Method for Assigning Participants to Treatment Groups 
Not applicable. 
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 or a licensed 
physician delegated by the qualified investigator who will supervise the participant while 
the medication is taken orally, with water. The capsules should not be opened or chewed. 
  

 
 
 
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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 
played quietly. Participants do not have the option to choose the type of music since the 
playlist is pre-set specifically for the standardization of psilocybin-assisted psychotherapy 
sessions across all other psilocybin studies in our institution. 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. An on-call psychiatrist will be available at all times to further assess as 
needed for acute concerns. Therapy sessions will not be video recorded. 
 
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. A light 
meal and fruit will be available for the participant for lunch.  
 
About 5 to 6 hours after dosing, the trained therapists will discuss the IP administration 
experience with the participant. The participant will be discharged 5 to 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 and have a 
responsible adult present with them for 24hrs after the intervention. 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. 
 

 
 
 
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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 data collection forms during each study visit.  
 
Permissible Medications 
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. 
 
For the initial Screening Visit (V1) through to the final study visit (V13), 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 before both of psilocybin doses (V4 
& V7). 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 1month prior to screening and for the 
duration of the study, including up to 12-weeks after the first psilocybin dose (V13). 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 
 
Periodic abstinence (e.g. calendar, symptothermal, or postovulation methods, and tubual 
ligation/occlusion) is not an acceptable form of contraception for this study. 

 
 
 
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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). 
 
 
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 3 (V10) until the primary 
endpoint assessment, or longer if possible. If the medications are re-introduced, the study 
investigator must be notified and the medications will be documented in the data 
collection form . Participants who require concomitant medication(s) specifically for the 
treatment of OCD at any time through the duration of the study will be assessed for 
reasons of resuming their medications and followed until 12-weeks after the first dose of 
psilocybin (V13).  
 
 
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. 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 

 
 
 
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 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)  
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 OCD. This manual will be adapted 
for administration to participants diagnosed with OCD by a clinical psychologist. In 
addition, the manual will be adapted to this study’s REB approved protocol. In addition, 
each therapist will undergo training by the study investigator or delegated investigator 
using the adapted Yale Manual for Psilocybin-Assisted Therapy of OCD. 
 

 
 
 
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5.7 
Packaging 
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 entire shipment for 
this trial will be sent in bulk (i.e. 20 capsules x 25mg each). Psilocybin capsules will be 
packaged individually in high-density polyethylene bottles. Each of the two 25mg 
psilocybin doses 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.  
 
5.8 
Blinding of Study Intervention 
Not applicable. 
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 
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 (15 to 30 degrees Celsius) 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 
All participants will receive the same intervention. Each participant will be assigned 1  
treatment bottle containing 1 capsule of 25mg of psilocybin for each dosing session. The 
IP will be dispensed and administered to the participants by the study psychiatrist or a 
licensed physician delegated by the qualified investigator. The study intervention will be 
administered orally, with water. The capsules should be administered in an unaltered 
state, by mouth, with water. The capsules should not be opened, chewed, or held in the 
mouth for an extended period without swallowing.  
 

 
 
 
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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.  
 
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 
McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD) 42. The 
MSI-BPD is a commonly used measure to assess for borderline personality disorder 
(BPD). The scale consists of 10 items based on the DSM-5 BPD criteria; the first 8 items 
represent the first eight criteria in the DSM-5 for BPD diagnosis; while the last two 
questions assess paranoia and dissociation criteria for BPD (Zanarini et al., 2003). Score 
for the MSI-BPD range from 0 to 10 with each item rated as 1 ‘if present’ and 0 ‘if absent’. 
A score of 7 or higher indicates a likelihood for the participant to meet criteria for BPD.  
 
Structured Clinical Interview for DSM-5 (SCID-5). The SCID-5 is a semi-structured 
diagnostic interview for ascertaining DSM-5 diagnoses. It will be administered by a trained 
study staff member.  
 
TMS Safety Questionnaire. The Transcranial Magnetic Stimulation Adult Safety Screen 
(TASS) Questionnaire will be used to determine eligibility.  
 
 
Safety Measures 

 
 
 
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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. 
The C-SSRS is a semi-structured 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 
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, during the washout period, and Baseline determine the patient’s 
study eligibility and potential need for referral to a mental health professional, and  
(b) During the study evaluate the patient’s need for appropriate medical management 
such as a referral to a mental health professional.  
 
 
Primary Outcome Measures: 
Yale-Brown Obsessive-Compulsive Scale (YBOCS). The YBOCS is a 10-item scale 
designed to measure the severity and type of symptoms for OCD. The scale is clinician-
rated where the interviewer provides a rating from 0 (‘no symptoms’) to 4 (‘extreme 
symptoms’). The total score ranges from 0 to 40 with higher scores indicating greater 
severity of symptoms. It has good psychometric properties and is frequently used to 
monitor improvement during treatment (Goodman et al., 1989).  
 
Secondary 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).  
 
Patient Health Questionnaire (PHQ-9): The PHQ-9 is a brief measure to screen for the 
presence and severity of depression. It consists of 9 items rated from 0 (‘not at all’) to 3 

 
 
 
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(‘nearly every day’). It is a reliable and valid measure for depression that is widely used 
in clinical and research settings.   
 
World Health Organization Disability Assessment Schedule (WHODAS 2.0). The 
WHODAS 2.0 is a brief measure to assess health status and disability across different 
cultures and settings. It is a 12-item self-report questionnaire where the participant is 
asked to rate themselves on a Likert scale from 1 (‘none) to 4 (‘extreme’) across six 
different domains from functioning: cognition, mobility, self-care, getting along, life 
activities, 
and 
participation.  
 
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’).  
 
Exploratory Measures: 
Five Dimensions of Altered States of Consciousness (5D-ASC). The 5D-ASC is a 94-item 
scale 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) (Griffiths et al., 2006; Maclean et al., 
2012).The MEQ consists of 30 items of the larger 100-item ‘States of Consciousness 
Questionnaire’ (Griffiths et al., 2006; Maclean et al., 2012), and assesses 4 empirically 
derived factors: mystical experiences (including ‘internal unity’, ‘external unity’, ‘noetic 
quality’ and ‘sacredness’), positive mood (awe, joy, peace and tranquillity); transcendence 
of time and space (sense of being outside of time, in a realm of no space boundaries, 
sense of timelessness) and ineffability (e.g. inability to adequately describe experience in 
words). Responses are rated on a 6-point Likert scale ranging from 0 (none, not at all), 
through to 5 (extreme, more than ever before in my life).  
 

 
 
 
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fMRI:  The MRI will be take place at the CAMH College Street location. The participant 
will be given ear protection provided by the MRI Unit to wear in the scanner. During the 
scan, the participant will rest and let their mind wander with their eyes open. There will be 
a mixture of very short scans and some longer scans up to 10 minutes.  
The CAMH MRI Unit is a research site, and one of the mandates is to develop and test 
new MRI pulse sequences that will advance our understanding of brain function and 
structure. CAMH has established a research agreement with General Electric (GE) to 
help achieve these goals. This research agreement allows us to modify the stock pulse 
sequences to generate higher quality data, and to operate the scanner in “research 
mode”, which gives us the ability to alter certain parameters of the stock pulse sequences. 
MRI machines are designed to operate with patient safety in mind. Our GE MR750 has 
three operating levels: Normal Level, First Level and Second Level. All GE scanners in 
Canada can operate in Normal and First Level mode, and ours is operated at First Level 
mode for all studies. Second Level mode is available only if a research agreement is in 
place with GE and REB approval is in place for any changes to safety thresholds beyond 
First Level. No studies at CAMH are operated at Second Level. When a pulse sequence 
is prescribed and loaded into memory, the scanner determines whether the parameters 
selected will exceed the safety limits for First Level. If they do, the scanner will not allow 
the scan to proceed as prescribed, and the technologist must change the parameters so 
that the First Level limits are not exceeded.  
 
Some of the images we collect use new methods or “investigational” protocols that we 
have developed by GE as a Work in Progress (WIP). These do not pose any additional 
risk to the subjects – we can only acquire the images if we are within the established 
safety limits.  
Storage and maintenance of software: Any software associated with GE WIPs will be 
installed and maintained by the MRI Unit in collaboration with GE engineers.  
 
120 min EEG: A 120 min EEG recording during the Psilocybin session will be recorded. 
Preparation will take about 20 minutes. The measurement should be started at least 5 
minutes before oral administration of Psilocybin and should last until 115 min after oral 
administration of Psilocybin. A thin EEG cap will be prepared using procedures 
established in EEG sleep studies that will allow the study participant to lie in a bed. The 
music played during the session will be recorded as a synchronized track by the EEG 
amplifier to enable post-hoc synchronization of brain activity to sound. 
 
The following neurophysiological measures will be acquired at the Temerty Centre for 
Therapeutic Brain Intervention (Queen Street West site), as part of the Pre- and Post-
Psilocybin Neurophysiology Sessions. EEG and EMG preparation will require 40 minutes. 
 
Neuronavigation: Anatomical MRI data acquired in the Baseline session will be co-
registered with a stereoscopic tracker on the head of the participant. The TMS coil will be 
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Target coil positions for left DMPFC and left DLPFC will be determined. The duration of 
this measurement will be 30 minutes. In the event that the fMRI is unavailable, the BEAM 
F3 method will be used to localize targets. 
 
Rest EEG: In the first phase of the Rest EEG the participant will rest and let their mind 
wander with their eyes open for 5 minutes. Symptoms of OCD will then be provoked using 
an individualized external provocation method (Blair Simpson et al., 2000; Tendler et al., 
2019), they will for example be asked to touch a surface. Following symptom provocation, 
another 5 minutes of EEG will be recorded as part of the second phase of the Rest EEG 
measurement. The provocation will then be removed and (if feasible) the study participant 
will be able to ritualize (e.g. hand washing). The above two phases will then be repeated. 
The severity of OCD symptoms will be assessed between phases using a VAS. The 
duration of this measurement will be 30 minutes. 
 
Task EEG: During the Task EEG, the participant will perform an auditory oddball task 
consisting of 600 auditory stimuli (sinus tones, intensity of 80 dB, duration 40 ms) 
delivered binaurally through headphones, with an interstimulus interval (ISI) of 1500 ms 
(Andreou et al., 2013). The duration of this measurement will be about 20 minutes. 
 
RMT and 1mv SI: The stimulation intensity (measured in units of percentage of maximum 
stimulator output) will be determined that is required for TMS of the hand area of left 
primary motor cortex (motor hotspot) to result in a motor evoked potential (MEP) recorded 
from the right hand muscles with an amplitude above 50 µV 50% of the time (resting motor 
threshold), and similarly the stimulation intensity required to elicit MEPs with an average 
peak-to-peak amplitude of 1mV. The motor hotspot will be found manually and an 
automatic thresholding procedure will be used to determine RMT and SI 1mV. This part 
of the measurement will take about 20 minutes. 
 
TMS-EEG: TMS-EEG will be applied in blocks consisting of 150 biphasic single pulses of 
TMS with an inter-pulse interval ≥ 2.5 seconds using masking noise to reduce the auditory 
evoked EEG potential. There will be six blocks of stimulation with brief pauses between 
blocks. Target stimulation sites will be left DMPFC and left DLPFC (the order will be 
counterbalanced between different study participants but remain consistent in any given 
study participant). The severity of OCD symptoms will be assessed between blocks using 
a VAS. Before stimulation, participants will be encouraged to relax into a neutral state of 
mind. Block 1 and 2 stimulates left DMPFC and left DLPFC. OCD symptoms will then be 
provoked using a similar approach as for the Rest EEG. Block 3 and 4 stimulates left 
DMPFC and left DLPFC again while OCD symptoms are being experienced. The 
provocation will then be removed and the study participant will be asked to relax again 
into a neutral state of mind. Block 5 and 6 stimulates left DMPFC and left DLPFC again. 
In total, the TMS-EEG procedure will take about 80 minutes. 
 
 
Outline of Study Procedures 
 
Visit 1 (V1) – Screening Visit   

 
 
 
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o Administered by trained study staff: 
 Informed consent 
 Review of medical history, family medical history, and demographics 
 SCID-5 
 MRI screening checklist to ensure that it is safe for the participant to 
partake in the MRI.  
• This will be reviewed by the MRI technologist.  
 TASS 
 Vital Signs (blood pressure, pulse) 
 Height and weight 
 YBOCS  
 MSI-BPD 
 CSSRS  
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.  
• 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 
 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: 
• Hematology: 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, 
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• 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: 3-6 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. 
 
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 3 to 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, heart rate) 
• YBOCS  
• C-SSRS 
• CGI 
 Administration of participant completed questionnaires: 
• PHQ-9 
• WHODAS 2.0 
• WHOQOL-BREF 
• GAD-7 to assess symptom severity for common anxiety disorders 
• WEMWBS 
o Clinician administered: 
 Confirmation of eligibility criteria  

 
 
 
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o Laboratory evaluations collected at the Queen Street CAMH laboratory:  
 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 Imaging session to be completed at CAMH College Street (Brain Health Imaging 
Center) 
 fMRI scan 
o 2-hour preparatory session with the study therapists which will involve building a 
therapeutic alliance, psychoeducation about the psychedelic experience, and 
setting intentions for the psilocybin sessions.  
 Documentation of participant preference and consent for therapeutic 
touch 
 Note: Therapists will have the option to schedule an additional 
preparatory session at their discretion.  
 For a more detailed explanation of the preparatory therapy session, 
please refer to the Yale Manual for Psilocybin-Assisted Therapy of OCD 
which will be adapted to the protocol and participant population for this 
study. 
 Prep therapy can occur in-person or via secure videoconferencing 
software (i.e. WebEx). 
 
 
Visit 3 (V3) – Pre-Psilocybin Neurophysiology – Day -7 to Day -1 
The Pre-Psilocybin Neurophysiology visit (V3) should occur within 7-days of Psilocybin 
Session Dose 1 (V4). The following procedures will be performed and recorded at the 
Pre-Psilocybin Neurophysiology visit (V3): 
o  Administered by trained study staff with a responsible Clinician available on site: 
 Assessment of TMS contraindications 
 EEG, EMG Preparation 
 Neuronavigation 
 Rest EEG (with intermittent symptom provocation) 
 Task EEG 
 RMT and 1mv SI determination 
 Auditory masking noise stimulation 
 TMS-EEG stimulating DMPFC and DLPFC (with intermittent symptom 
provocation) 
 
 
Visit 4 (V4) – Psilocybin Session Dose 1 – Day 0  
The psilocybin dose 1 visit (V4) should 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. At the Psilocybin 
Session Dose 1 (V4), the following procedures will take place: 
o Review and confirmation of participant preference and consent for therapeutic 
touch 

 
 
 
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o Urine dip pregnancy test before dosing begins. 
o EEG will be prepared for a 120 min recording. The recording will be started at least 
5 minutes before study intervention administration 
o Study intervention administration (Section 5.0): 1 oral dose of 25mg of psilocybin 
administered in conjunction with supportive therapy (PAP).  
o Vital signs (body temperature, blood pressure and pulse) will be taken once before 
dosing, 3 hours post dosing, and at the end of dosing, and documented in the data 
collection form. Vital signs will also be taken as needed in addition to scheduled 
times.  
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:  
 Physician administered 
• C-SSRS 
 Study team or therapist administered: 
• MEQ: measures  
• 5D-ASC to assess the acute drug effects using 5 primary 
dimensions and respective sub dimensions.  
o The participant will be discharged 5 to 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 and have a responsible adult 
present with them for 24hrs after the intervention.  
o Rescue medications are permitted during this visit as outlined in Section 5.6.  
 
Visit 5 & Visit 6 (V5 & V6) – Post-Psilocybin Dose 1 – Day 1 & Day 7 
o Administered by trained study staff: 
 Administration of assessments: : 
• PHQ-9 
• WHODAS 2.0 
• WHOQOL-BREF 
• GAD-7 
• YBOCS  
• C-SSRS 
• CGI 
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 

 
 
 
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for Psilocybin-Assisted Therapy of OCD) which will be adapted to fit this study 
protocol and participant population. 
 
 
Visit 7 (V7) – Psilocybin Session Dose 2 – Day 14 
The psilocybin dose 2 visit (V7) should occur 14 days after the first dosing session. The 
following procedures will take place: 
o Urine dip pregnancy test before dosing begins. 
o EEG will be prepared for a 120 min recording. The recording will be started at least 
5 minutes before study intervention administration 
o Study intervention administration (Section 5.0) 1 oral dose of 25mg of psilocybin 
administered in conjunction with supportive therapy (PAP).  
o Vital signs (body temperature, blood pressure and pulse) will be taken once before 
dosing, 3 hours post dosing, and at the end of dosing, and documented in the data 
collection form. Vital signs will also be taken as needed in addition to scheduled 
times.  
o Review and confirmation of participant preference and consent for therapeutic 
touch 
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. 
o Administration of questionnaires or other instruments to be completed at the end of 
the dosing session when the acute effects of psilocybin have resolved:  
 Physician administered 
• C-SSRS 
 Study team or therapist administered: 
• MEQ  
• 5D-ASC 
o The participant will be discharged 5 to 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 and have a responsible adult 
present with them for 24hrs after the intervention.   
o Rescue medications are permitted during this visit as outlined in Section 5.6.  
 
Visit 8 & Visit 10 (V8 & V10) – Post-Psilocybin Dose 2 – Day 15 & Day 21 
o Administered by trained study staff: 
 Administration of assessments: 
• GAD-7 
• PHQ-9 
• WHODAS 2.0 
• WHOQOL-BREF 
• WEMWBS 

 
 
 
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• YBOCS  
• C-SSRS 
• CGI 
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. For more detailed information on the 
integrative therapy sessions, please refer to the therapists manual (Yale Manual for 
Psilocybin-Assisted Therapy of OCD which will be adapted to fit this study protocol 
and participant population.  
o fMRI imaging to be completed at Visit 10 (V10 – Day 21) at CAMH College Street 
(Brain Health Imaging Center). Note: This is only for Visit 10 (V10 – Day 21). 
 
Visit 9 (V9) – Post-Psilocybin Neurophysiology 
The Post-Psilocybin Neurophysiology visit (V9) should occur between Visit 8 (Day 15) 
and Visit 10 (Day 21). The following procedures will be performed and recorded at the 
Post-Psilocybin Neurophysiology visit (V9): 
o  Administered by trained study staff with a responsible Clinician available on site: 
 Assessment of TMS contraindications 
 EEG, EMG Preparation 
 Neuronavigation 
 Rest EEG (with symptom provocation) 
 Task EEG 
 RMT and 1mv SI determination 
 Auditory masking noise stimulation 
 TMS-EEG stimulating DMPFC and DLPFC (with intermittent symptom 
provocation) 
 
Visit 11 - 13 (V1 – V11) – Follow-Up Assessments – Days 42, 63, 84 
Follow-up visits occur at Weeks 6 (V11), 9 (V12), and 13 (V13) after the second psilocybin 
dose. The following assessments will occur at each visit: 
o Administered by trained study staff: 
 GAD-7 
 PHQ-9 
 WHODAS 2.0 
 WHO-QoL-BREF 
 Review of prior/concomitant medications 
• Any changes will be reviewed by the study physician 
 YBOCS 
 CSSRS 
 CGI 
o The WEMWBS is the only assessment that will not be administered at each study 
visit. The WEMWBS will only be administered at the Follow-Up at Week 12 (V13).  
 
 

 
 
 
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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) 
Pre-Psilocybin 
Neurophysiology 
(Visit 3, Day -7 to 
Day -1) 
Psilocybin Session 
– Dose 1 (Visit 4, 
Day 0) 
1-Day post dose 1 
(Visit 5, Day 1) 
1-week post dose 1 
(Visit 6, Day 7) 
Psilocybin Session 
– Dose 2 (Visit 7, 
Day 14)
1-day post dose 2 
(Visit 8, Day 15) 
Post-Psilocybin 
Neurophysiology 
(Visit 9) 
3-weeks post-dose 
1 (Visit 10, Day 21) 
6 weeks post-dose 
1 (Visit 11, Day 42) 
9 weeks post dose 1 
(Visit 12, Day 63) 
12 weeks post dose 
1(Visit 13, Day 84) 
Location of Visit 
Clinic 
Clinic or 
remote 
Clinic 
Temerty 
Centre 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Temerty 
Centre 
Clinic 
Clinic or 
remote 
Clinic or 
remote 
Clinic or 
remote 
Allowable Window 
 
Weekly 
 
≤7 days 
from V4 
≤7 days 
from 
Baseline 
None 
±1 day 
None 
None 
≤7 days 
±1 day  
±3 days  
±3 days  
±7 days 
Informed Consent 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
✔ 
 
✔ 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medication review 
✔ 
X------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Inclusion/Exclusion 
Criteria Review 
✔ 
✔ 
✔ 
 
 
 
 
 
 
 
 
 
 
 
MRI Screening Form 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
TASS 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-5 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (blood 
pressure, pulse) 
✔ 
 
✔1 
 
✔1 
 
 
✔1 
 
 
 
 
 
 
Vital signs (body 
temperature) 
 
 
 
 
✔1 
 
 
✔1 
 
 
 
 
 
 
Weight 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
tests3 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Urine drug screening 
✔ 
 
✔ 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test4 
✔ 
 
✔ 
 
✔ 
 
 
✔ 
 
 
 
 
 
 
Documentation of birth 
control 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
fMRI 
 
 
✔ 
 
 
 
 
 
 
 
✔ 
 
 
 
YBOCS 
✔ 
 
✔ 
 
 
✔ 
✔ 
 
✔ 
 
✔ 
✔ 
✔ 
✔ 
C-SSRS5 
✔ 
✔ 
✔ 
 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
✔ 
✔ 
✔ 
CGI8 
 
 
✔ 
 
 
✔ 
✔ 
 
✔ 
 
✔ 
✔ 
✔ 
✔ 
Neuronavigation 
 
 
 
✔ 
 
 
 
 
 
✔ 
 
 
 
 
Resting EEG 
 
 
 
✔ 
 
 
 
 
 
✔ 
 
 
 
 
Task EEG 
 
 
 
✔ 
 
 
 
 
 
✔ 
 
 
 
 
TMS-EEG 
 
 
 
✔ 
 
 
 
 
 
✔ 
 
 
 
 
Preparatory/Integrative 
therapy & 
psychoeducation6 
 
 
✔ 
 
✔ 
✔ 
✔ 
✔ 
✔ 
 
✔ 
 
 
 
120 min EEG 
 
 
 
 
✔ 
 
 
✔ 
 
 
 
 
 
 
Psilocybin Dose 
(25mg) 
 
 
 
 
✔ 
 
 
✔ 
 
 
 
 
 
 
Adverse event and 
serious adverse event 
review and evaluation 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
Source documentation 
& CRF completion 
✔ 
X---------------------------------------------------------------------------------------------------------------------------------------------------------------
X 
MSI-BDP 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
5D-ASC7 
 
 
 
 
✔ 
 
 
✔ 
 
 
 
 
 
 
MEQ7 
 
 
 
 
✔ 
 
 
✔ 
 
 
 
 
 
 
GAD-7 
 
 
✔ 
 
 
✔ 
✔ 
 
✔ 
 
✔ 
✔ 
✔ 
✔ 
PHQ-9 
 
 
✔ 
 
 
✔ 
✔ 
 
✔ 
 
✔ 
✔ 
✔ 
✔ 
WEMWBS 
 
 
✔ 
 
 
 
 
 
✔ 
 
✔ 
 
 
✔ 
WHODAS 2.0 
 
 
✔ 
 
 
✔ 
✔ 
 
✔ 
 
✔ 
✔ 
✔ 
✔ 
WHO-QOL-BREF 
 
 
✔ 
 
 
✔ 
✔ 
 
✔ 
 
✔ 
✔ 
✔ 
✔ 
1. 
Additional visits may be needed during the washout period to ensure adequate time for discontinuation of medication. Visits will occur on a weekly basis 
during this period (V1a, V1b, etc.). Review of medications and assessments for suicidality will occur in addition to other assessments at the discretion of 
the study investigator. 
2. 
Baseline assessments can occur on separate days ( ±7 days from the day of the first intervention) to reduce the burden on participants. These visits will 
be V2a, V2b etc. 

 
 
 
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3. 
See Section 6.0: Research Procedures for complete list of required laboratory tests to be performed. 
4. 
For women/people of child-bearing age only 
5. 
The “Last 12 Months” version will be administered at Screening and the “Since Last Visit” version will be administered at all other visits.  
6. 
Additional therapy visits may be scheduled at the discretion of the study therapists and/or the study investigator and pre as well as integration therapy can 
occur in-person or via WebEx 
7. 
To be administered immediately after PAP when the acute effects of psilocybin have subsided. 
8. 
CGI severity will be used at Baseline and the follow-up version with efficacy index will be administered at all other visits.  
Instruments: 
CGI: Clinical Global Impression; ECG: Electrocardiogram; fMRI: Functional Magnetic Resonance Imaging; GAD-7: Generalized Anxiety Disorder assessment form; 
MEQ: Mystical Experience Questionnaire; MSI-BPD: McLean Screening Instrument for Borderline Personality Disorder; PHQ-9: Patient Health Questionnaire; 
SCID-5: Structured Clinical Interview for DSM-5; TASS: Transcranial Magnetic Stimulation Adult Safety Screen; WEMWBS: Warwick-Edinburgh Mental Wellbeing 
Scale; WHODAS 2.0: World Health Organization Disability Assessment Schedule; WHO-QoL-BREF: World Health Organization Quality of Life abbreviated scale; 
YBOCS: Yale-Brown Obsessive-Compulsive Scale; 5D-ASC: 5-Dimensional Altered States of Consciousness Rating Scale. 

 
 
 
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7.0 STATISTICAL PLAN 
7.1 
Sample Size Determination 
Sample size was based on the primary outcome measure of YBOCS. We based this on 
the primary outcomes from the study of Moreno et al. (2006), which established marked 
reductions in YBOCS at 24 hours for different dose groups and presented effect sizes ≥ 
1.2  (within group Cohen's d).  
 
Using an effect size of d = 1.2 and 5% significance will require N=10 completers to 
achieve 90% power. This calculation is for a single-arm design (2-sided) using a paired-
sample t-test. This sample size is also sufficient to detect large correlations (r=0.71) 
between change scores with 5% significance and 80% power.  
 
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. The small sample size means that conservative 
nonparametric testing is required in order to address the primary and secondary 
objectives. Exact paired permutation t-tests will be used to determine whether 
psilocybin-assisted psychotherapy achieves a 50% reduction in YBOCS symptoms. 
 
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 
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; 

 
 
 
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• 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 
source documentation. 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 
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:  

 
 
 
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• 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 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 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. the study. 
These reports should not contain PHI.  
8.3 
Reporting of Serious Adverse Events 
8.3.1 
Investigator Reporting: Notifying the Sponsor 
There is no sponsor for this study, however 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.  
 
 
 
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. 
 

 
 
 
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8.3.3 
Sponsor Reporting of SUADRs: Notifying Health Canada 
There is no sponsor for this study, thus 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 
maintained through the use of code numbers to identify all participants. All research 
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 8.7.1. 

 
 
 
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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 OCD. 
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 
Not applicable. 
8.7 
Data and Safety Monitoring Board 
The trial is a preliminary, open-label, Health Canada regulated clinical trial and therefore, 
a DSMB is not required.  
 

 
 
 
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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 documentation will be recorded in data collection forms.  
 
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.  
 
XNAT Research Data 
fMRI imaging for this clinical trial will be managed using XNAT.  XNAT is a secure, 
professionally administered, web-based application for managing research data. This 
system is maintained on central CAMH servers, with data backed up daily, and is 
supported by the Research Informatics department.  
 
Rest EEG, Task EEG and TMS-EEG Data 
Raw EEG and task data will be maintained on a shared folder on the CAMH IT 
infrastructure. 
 
10.2 
Protocol Deviations 
No deviations from or changes to the protocol will be implemented without approval from 
the REB and/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 if any of the following criteria are met: 

 
 
 
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• Deviations that, in the opinion of the PI, jeopardize the safety of research 
participants, or that jeopardize the research efficacy or data integrity 
• 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) 
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.  
 
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 

 
 
 
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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 
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.  

 
 
 
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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 dosing information, AEs, and concomitant medications will be provided 
annually. Safety reports on demography, AEs, and concomitant medications will be 
provided at the end of the study. Safety reports on serious adverse events that have a 
causal relationship to the IP and on pregnancy will occur within 24hrs of the study team 
being notified. None of these safety reports will contain PHI and all data will be coded. A 
description of the reporting procedures can be found in the agreement with Filament 
Health Corp.    
 
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 
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. 
 

 
 
 
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14.0 CLINICAL TRIAL FINANCES 
14.1 
Funding Source 
This study is funded by the Centre for Complex Interventions at the Centre for Addiction 
and Mental Health (CAMH).  
14.2 
Conflict of Interest 
The research team does not have any conflicts of interest to disclose. However, Dr. 
Ishrat Husain, provides advisory services to MindSet Pharma Inc, Wake Network Inc, 
and PsychEd Therapeutics Inc. In addition, Dr. Feusner provides advisory services for 
NODC Inc. These organizations are not involved in the study and do not impact the 
design, conduct, or interpretation of results.  
 
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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