A Phase 2a, Open-label, Pilot Study to Assess the Safety and Efficacy of Psilocybin Administration in Concert With Psychotherapy Among Adult Patients With Fibromyalgia
Phase: PHASE2
Conditions: Fibromyalgia
Sponsor: Kevin Boehnke

A Phase 2a, Open-label, Pilot Study to Assess the Safety and Efficacy of Psilocybin 
Administration in Concert with Psychotherapy Among Adult Patients with Fibromyalgia 
 
Date of IRB Approval: March 28, 2024 
 
NCT05128162 
 

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Protocol Title: A Phase 2a, Open-label, Pilot Study to Assess the Safety and Efficacy of 
Psilocybin Administration in Concert with Psychotherapy Among Adult Patients with 
Fibromyalgia 
Compound: TRP-8802 
Study Phase: 2a 
Sponsor Name: Anesthesiology Department, Michigan Medicine, University of Michigan 
 
Legal Registered Address:  
 
 
 
 
 
Kevin Boehnke, PhD 
  
Department of Anesthesiology 
 
 
 
           Michigan Medicine, University of Michigan 
                                               Domino’s Farms, Lobby M, Suite 3100 
                                               24 Frank Lloyd Wright Drive 
                                               Ann Arbor, MI 48106 
                                               Telephone: 734-998-6939 
Regulatory Agency Identifier Number(s) 
IND: 155845 
 
FDA Approval Date: 19 November, 2021 
 
 
 

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Tool Revision History 
 
 
Version Number: 1.1 
Version Date: 12/14/2022 
Summary of Revisions Made:  
1. Pg 1 Removed Tryp 002 from the title. Added the University of Michigan, Department of 
Anesthesiology to the sponsor’s name and address. Removed header, “Tryp Therapeutics, 
Inc.” Protocol TRYP 002 and signature line. Updated date in the footer.Pg 2, Removed 
the Investigator’s Agreement and signature line. 
2. Pg 4-6 Rewrote the Table of Contents – removed EEG 
3. Pg 10 Removed TRYP 002 from the protocol tilte and added generic name in the 
rationale. 
4. Pp 12-13, Schedule of assessments: Removed CMSI, Sleep-related Impairment (4a), 
painDETECT, and PANAS short form (state). Removed PGIC from visits 5-12.  
5. Pg 14: Updated typo in subscript e, which read “Error! Reference Source not found”.  
6. Pg 23: Removed CMSI description. 
7. Pg 32: there was a typo of HPPD, which was removed. 
8. Pg 41: Removed description of painDETECT, the PANAS, and Sleep-related Impairment 
scale short form 4a 
9. Pg 43: Removed language with the proposed overview of EEG tasks. Also removed 
language about having electrodes affixed to scalp via electrolyte gel. 
10. Pg 44: Removed language in Table 5 to say it is proposed overview of EEG tasks. Also 
changed time of cap placement given different cap will be used. Removed language on 
Diffusion tensor imaging as this will no longer be done. Also removed visual stimulus 
task and post-pain resting EEG (eyes closed) task from Table 6. 
11. Pg 45: Modified language in Table 6 to say it is a proposed overview of fMRI task. Also 
changed resting state fMRI assessment to 20-30 minutes and removed mention to 
diffusion tensor imaging as this will no longer be done.  
 
Version Number: 1.2 
Version Date: 6/2/2023 
Summary of Revisions Made:  
1. Pg 1 Removed Tryp Therapeutics University of Michigan under sponsor’s name and 
address from the title page and add Kevin Boehnke’s name and address. Updated date in 
footer 
2. Section 1.3 – Table 2:  Checked off next day monitor forms (V6,7 and V9) 
 
(F.) Added Breathalyzer performed only on dosing days 
 
              (N.) Wrist Actigraph Day 1 to 14 and Day 50 to 64.  
3. Section 4.1.1. Screening: Removed breath alcohol test 
4. Section 4.1.5. Removed FM survey and PGI-C at V10, 11, and 12 
5. Section 5.2 – Removed “Currently undergoing acceptance and commitment therapy” 
from the exclusion criteria. 

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6. Section 8.2.3.3: Noted that participants will wear either the Fitbit Charge 5 or Actiwatch 
Spectrum.  
7. Pg 51: The protocol stated that there would be 20 participants, a holdover from the 
previous protocol version. Corrected to 10 participants.   
8. Pg 66: Corrected typo in the last line of the table, which currently misspells study drug.  
 
Version Number: 1.3 
Version Date: 8/23/2023 
Summary of Revisions Made:  
 
1. Section 4.1 – Added, “One of the physicians associated with the study will have a 
brief visit with the study participant during screening or prior to the first dosing 
session.” 
2. Section 6.8.1 – Removed “a research pharmacist at the research site will dispense the 
medication and” from the sentence. 
3. Section 10.1.8 - Removed “Definition of what constitutes source data can be found in 
the Monitoring Plan.” 
4. Updated date in footer. 
 
Version Number: 1.4 
Version Date: 12/05/2023 
Summary of Revisions Made:  
 
1. Updated Schedule of assessments to reflect addition of self-pain enmeshment task, self-
complexity task, Life events checklist and expectation assessments. Also updated 
superscripts to reflect these changes on pages 12-14.  
2. Page 22: Noted that Life events checklist is now during screening 
3. Page 23: Noted that preparation sessions (Visits 3 and 4) can be in-person or virtual.  
4. Page 24: Noted that Visit 7 can be in-person or virtual.  
5. Page 28: Removed #11. Participants must agree that for 7 days before each TRP-8802 
session, he/she will refrain from taking any nonprescription medication, cannabis, 
nutritional supplement, or herbal supplement except when approved by the Principal 
Investigator. Exceptions will be evaluated by the Principal Investigator and will include 
acetaminophen, non-steroidal anti-inflammatory drugs, and common doses of vitamins 
and minerals. 
6. Added Section 8.2.2.5 (self-pain enmeshment), Section 8.2.2.6 (Self-complexity task), 
Section 8.2.2.7 (expectations assessment) on pages 41-43 
7. Page 45: Changed Table 6 to include five, 5-minute resting state fMRI scans (25 minutes 
total), and edited the tonic cuff fMRI scan into two 5-minutes scans. Also removed 
evoked pain task. This is now reflected in the text saying, “The fMRI assessment should 
take a total of approximately 55 minutes to complete and may include any of the 
assessments included in Table 6.”  
8. Page 46: Updated text to read “Participants will rest comfortably in the scanner with eyes 
open for 25 minutes at the beginning of the scan session to obtain baseline measures of 

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functional brain connectivity. Participants will be asked about current levels of pain 
intensity, fatigue and anxiety before and after resting state runs. Participants will also 
undergo two fMRI scans with tonic cuff pressure pain to evaluate functional brain 
connectivity response to deep pain. Pressure intensity will be set to each participant’s 
Pain 30 to 50 level, as determined during the behavioral visit, and applied for 5 minutes 
for each scan.” 
 
Removed Evoked Pressure Pain task from the imaging tasks from page 47.   
 
Version Number: 1.5 
Version Date: 1/10/2024 
Summary of Revisions Made:  
 
1. Section 1.3, Page 11: Increased visit window for preparation from +/-3 days to +/-7 days. 
Also updated screening window from 28 to 42 days. These changes were also made 
throughout the rest of the document where relevant per tracked changes (e.g., section 
4.1.1, Screen period now is -42 days prior to trial initiation). 
2. Page 13: Removed the self-complexity task from dosing day, as it should not be 
performed that day.  
3. Page 13: Per protocol, added monitor rating form for Integration visits 10-12.  
4. Page 13: Noted that COVID-19 test is performed on dosing days only, as with breath 
alcohol test.  
5. Page 14: Corrected typo in subscript m to read and instead of an.  
6. Section 4.1.3, page 23: We note that “one preparatory therapy sessions may occur via a 
HIPAA-compliant video conferencing platform if necessary.” 
7. Section 4.1.5: removed language “same two therapists” from this section.  
8. Section 5.1, Page 27: Updated inclusion criteria to note that participants must meet 
“criteria for FM per the 2016 FM survey criteria.” 
9. Section 5.2, Page 29: Updated language about antidepressant medications  
10. Section 6.1.2, page 33: Removed language: “Participants will be expected to be on the 
research site for at least 8 hours.” 
11. Page 38: clarified that this is research record rather than medical record.  
12. Page 57: Updated SRC language to read: “The SRC will be responsible for the 
assessment of safety and to make recommendations regarding study progression. The 
SRC will be composed of the principal investigator, a study therapist, and a study 
physician. Participant safety, which includes safety signal detection at any time during 
the study, will be continuously monitored by the SRC. All safety data collected will be 
summarized and reviewed by the SRC for agreement of next steps.” 
 
Version Number: 1.6 
Version Date: 2/27/2024 
Summary of Revisions Made:  
 
1. Schedule of Assessment: added the +/-7 day window to the preparation sessions. 
2. Section 6.1.2, page 32: Added back language: “Participants will be expected to be on the 
research site for at least 8 hours.” 

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3. Section 1.1, page 10: Updated Safety Review Committee language to “The SRC will be 
responsible for the assessment of safety and to make recommendations regarding study 
progression. The SRC will be composed of the principal investigator, a study therapist, 
and a study physician. Participant safety, which includes safety signal detection at any 
time during the study, will be continuously monitored by the SRC. All safety data 
collected will be summarized and reviewed by the SRC for agreement of next steps, 
which may include:” 
4. Section 5, page 30. Removed breathalyzer information from the eligibility criteria 16. 
This is covered in Lifestyle considerations.  
5. Updated dates to 2/27/2024 in footer.  

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Table of Contents 
1. 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis ..........................................................................................................................10 
1.2. 
Schema ............................................................................................................................12 
1.3. 
Schedule of Activities .....................................................................................................14 
2. 
Introduction ...................................................................................................................17 
2.1. 
Study Rationale ...............................................................................................................18 
2.2. 
Background .....................................................................................................................19 
2.3. 
Benefit/Risk Assessment ................................................................................................19 
3. 
Objectives and Endpoints ............................................................................................22 
4. 
Study Design ..................................................................................................................24 
4.1. 
Overall Design ................................................................................................................24 
4.1.1. 
Screening Period (Visit 1, Day -42 to Trial Initiation) ...................................................24 
4.1.2. 
Baseline (Visit 2, Day 1) .................................................................................................25 
4.1.3. 
Preparation Period (Visits 3 and 4, Day 11 and Day 18) ................................................25 
4.1.4. 
TRP-8802 Administration Period (Visit 5 to Visit 9, Day 22 to 
Day 37)............................................................................................................................26 
4.1.5. 
Integration Period (Visits 10 to 12, Day 43 to Day 57) ..................................................27 
4.1.6. 
End of Therapy (Visit 13, Day 64) .................................................................................27 
4.1.7. 
Follow-up Period (Visits 14 and 15, Day 120 and Day 204)..........................................27 
4.2. 
Scientific Rationale for Study Design ............................................................................27 
4.3. 
Justification for Doses ....................................................................................................27 
4.4. 
End of Study Definition ..................................................................................................28 
5. 
Study Population ...........................................................................................................29 
5.1. 
Inclusion Criteria ............................................................................................................29 
5.2. 
Exclusion Criteria ...........................................................................................................30 
5.3. 
Lifestyle Considerations .................................................................................................32 
5.4. 
Screen Failures ................................................................................................................33 
5.5. 
Criteria for Temporarily Delaying Enrollment or Administration 
of Study Intervention ......................................................................................................33 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................35 
6.1. 
Study Intervention TRP-8802 .........................................................................................35 
6.1.1. 
TRP-8802 Administration ...............................................................................................35 
6.1.2. 
Leaving the Research Unit ..............................................................................................35 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................36 
6.3. 
Measures to Minimize Bias ............................................................................................36 
6.4. 
Study Intervention Compliance ......................................................................................36 
6.5. 
Dose Modification ..........................................................................................................36 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................37 
6.7. 
Treatment of Overdose ...................................................................................................37 
6.8. 
Concomitant Therapy .....................................................................................................37 
6.8.1. 
Rescue Medicine .............................................................................................................38 

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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................39 
7.1. 
Discontinuation of Study Intervention ............................................................................39 
7.1.1. 
Temporary Discontinuation ............................................................................................39 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................39 
7.3. 
Lost to Follow up ............................................................................................................39 
8. 
Study Assessments and Procedures.............................................................................41 
8.1. 
Safety Assessments (Primary Endpoints) .......................................................................41 
8.1.1. 
Vital Signs .......................................................................................................................41 
8.1.2. 
Adverse events ................................................................................................................41 
8.2. 
Efficacy Assessments (Secondary and Exploratory Endpoints) .....................................41 
8.2.1. 
Patient Reported Outcomes (Secondary Efficacy Endpoints) ........................................42 
8.2.2. 
Patient Reported Outcomes (Exploratory Endpoints).....................................................42 
8.2.3. 
Study Personnel Reported Outcomes (Exploratory Endpoints) ......................................46 
8.3. 
Other Safety Assessments ...............................................................................................50 
8.3.1. 
Electrocardiograms .........................................................................................................50 
8.3.2. 
Pregnancy Testing ...........................................................................................................50 
8.3.3. 
Urine Drug and Breath Alcohol Testing .........................................................................50 
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting ........................................................................................................................51 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................51 
8.4.2. 
Method of Detecting AEs and SAEs ..............................................................................51 
8.4.3. 
Follow-up of AEs and SAEs ...........................................................................................51 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...............................................................52 
8.4.5. 
Pregnancy ........................................................................................................................52 
8.5. 
Clinical Safety and Monitoring.......................................................................................53 
8.6. 
Pharmacokinetics ............................................................................................................53 
8.7. 
Genetics and/or Pharmacogenomics ...............................................................................54 
8.8. 
Biomarkers ......................................................................................................................54 
8.9. 
Immunogenicity Assessments.........................................................................................54 
8.10. 
Medical Resource Utilization and Health Economics ....................................................54 
9. 
Statistical Considerations .............................................................................................55 
9.1. 
Statistical Hypotheses .....................................................................................................55 
9.2. 
Sample Size Justification ................................................................................................55 
9.3. 
Analysis Sets ...................................................................................................................55 
9.4. 
Statistical Analyses .........................................................................................................56 
9.4.1. 
General Considerations ...................................................................................................56 
9.4.2. 
Primary Endpoints (Safety).............................................................................................56 
9.4.3. 
Secondary Endpoints (Efficacy) .....................................................................................57 
9.4.4. 
Exploratory Endpoints (Efficacy) ...................................................................................57 
9.4.5. 
Handling of Missing Data ...............................................................................................57 
9.4.6. 
Subgroup Analysis ..........................................................................................................57 
9.5. 
Interim Analysis ..............................................................................................................57 
10. 
Supporting Documentation and Operational Considerations ..................................58 

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10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................58 
10.1.1. Regulatory and Ethical Considerations ...........................................................................58 
10.1.2. Financial Disclosure........................................................................................................58 
10.1.3. Informed Consent Process ..............................................................................................58 
10.1.4. Data Protection................................................................................................................59 
10.1.5. Safety Review Committees Structure .............................................................................59 
10.1.6. Dissemination of Clinical Study Data.............................................................................59 
10.1.7. Data Quality Assurance ..................................................................................................60 
10.1.8. Source Documents ..........................................................................................................60 
10.1.9. Study and Site Start and Closure ....................................................................................61 
10.1.10. Publication Policy ...........................................................................................................61 
10.2. 
Appendix 2: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................62 
10.2.1. Definition of AE .............................................................................................................62 
10.2.2. Definition of SAE ...........................................................................................................63 
10.2.3. Recording and Follow-Up of AE and/or SAE ................................................................63 
10.2.4. Reporting of SAEs ..........................................................................................................65 
10.3. 
Appendix 3: Abbreviations and Definitions ...................................................................67 
11. 
References ......................................................................................................................69 
 
List of Tables 
Table 1:  Overview of Objectives and Endpoints ......................................................................... 10 
Table 2:  Schedule of Activities .................................................................................................... 14 
Table 3:  Study Objectives and Endpoints .................................................................................... 22 
Table 4:  Study Treatments Administered .................................................................................... 35 
Table 5. The Self-Complexity Trait List....................................................................................... 45 
Table 6. Proposed Overview of Neuroimaging Visit fMRI Procedures ....................................... 47 
Table 7. Populations for Analysis ................................................................................................. 56 
 
List of Figures 
Figure 1:  Study Schema ............................................................................................................... 13 
Figure 2. Examples of the Pictorial Representation of Illness and Self Measure (PRISM), with 
the red “pain” circle (fibromyalgia) and the yellow "self” circle. Adapted from Paschali et al., 
2021............................................................................................................................................... 44 
 

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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A Phase 2a, Open-label, Pilot Study to Assess the Safety and Efficacy of 
Psilocybin Administration in Concert with Psychotherapy Among Adult 
Patients with Fibromyalgia 
Rationale:  
The pressing need for effective fibromyalgia (FM) treatments, the known safety of psilocybin 
therapy, and the mechanistic plausibility for potential benefit provide a rationale for investigating 
TRP-8802 (i.e., synthetic psilocybin) therapy as a treatment for FM. An overview of the 
objectives and endpoints is presented in Table 1. The complete list of study objectives and 
endpoints is presented in Table 3. 
Table 1:  Overview of Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To assess the safety of TRP-8802 under the conditions 
of this trial  
Safety during dosing sessions: vital signs (HR, BP), 
AEs 
Safety during trial: AEs   
Secondary 
To evaluate the clinical benefit of oral TRP-8802 in 
concert with psychotherapy to treat chronic pain 
symptoms in patients with FM 
Aggregate weekly worst pain score change from 
Baseline (Days 1 to 7) to End of Therapy visit (Day 64) 
on a pain intensity numeric rating scale (PI-NRS) 
11-item pain scale  
To assess other potential therapeutic effects of 
TRP-8802 in conjunction with psychotherapy on FM 
symptoms 
Participant self-reported outcomes: 
• 
pain interference 
• 
sleep 
• 
chronic pain acceptance 
• 
Patient Global Impression of Change (PGI-C) 
Exploratory 
To characterize other TRP-8802 clinical and PD 
effects  
 
AEs=adverse events; BP=blood pressure; FM=fibromyalgia; HR=heart rate; PD=pharmacodynamic; PROs=patient reported 
outcomes.  
Note: The aggregate weekly pain score is over a 7-day period. 
 

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Overall Design: 
Participants with FM and with no exclusionary co-morbid psychiatric disorders are planned for 
enrollment in the study. This study comprises approximately a 42-day screening period 
(Days -42 to -1), 3 weeks for baseline and preparation (Days 1 to 18), a 2-dose administration 
period (Days 22 to 37), integration (Days 43 to 57), the End of Therapy (EOT) visit (Day 64 
[with last aggregate worst pain score for the 7 days immediately prior to EOT visit assessed for 
change from baseline]) and 3- and 6-month follow-up visits (Days 120 and 204).   
Brief Summary: 
Fibromyalgia is a chronic syndrome of widespread musculoskeletal pain that often manifests 
with a cluster of co-occurring symptoms, including sleep disturbances, fatigue, cognitive 
dysfunction, and mood problems including anxiety and depression. Recent studies have provided 
evidence of altered central pain pathways. Current management of FM typically takes a 
multidimensional approach including behavioral therapy, exercise, and medication. However, 
current medications provide only modest benefit and carry significant side effect burden, leading 
many people with FM to seek other alternatives.  
Psilocybin therapy (psilocybin delivered in concert with psychotherapy) may be a safe and 
effective treatment for symptoms associated with FM. Indeed, psilocybin therapy has shown 
positive effects in treating cancer-related psychiatric distress, depression, and anxiety; treatment-
resistant depression; and nicotine or alcohol addiction. The United States Food and Drug 
Administration (FDA) has granted Breakthrough Therapy designation for psilocybin in 
treatment-resistant depression and major depressive disorder. Psilocybin therapy is generally safe 
and well-tolerated when conducted under controlled conditions. While no clinical studies have 
explored psychedelic effects among people with FM, a recent review outlined potential 
mechanisms through which psychedelics could alleviate chronic pain symptoms (Castellanos 
2020). 
Number of Participants: 
Participants will be screened with the goal of 10 participants who will complete both doses of 
TRP-8802 and the primary and secondary outcome measures and complete the study and follow-
up periods.  
Intervention Groups and Duration: 
This is an open-label study, and participants who meet the inclusion and exclusion criteria will 
be eligible and invited to enroll. Enrolled participants are planned to receive 2 doses of 
TRP-8802: a 15 mg dose followed 2 weeks later by a 25 mg dose. The total planned duration of 
the study for an individual participant from screening to last follow-up is approximately 
8 months. 
Safety Review Committee:  
The SRC will be responsible for the assessment of safety and to make recommendations 
regarding study progression. The SRC will be composed of the principal investigator, a study 
therapist, and a study physician. Participant safety, which includes safety signal detection at any 

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time during the study, will be continuously monitored by the SRC. All safety data collected will 
be summarized and reviewed by the SRC for agreement of next steps, which may include: 
• continue the study as planned 
• continue the study with modifications of procedures, such as dose, safety monitoring, or 
other 
• suspend enrollment to further evaluate safety events (mandatory for any event that meets 
a Stopping Rule [Section 5.5]) 
• terminate the study 
1.2. 
Schema 
A study schema is presented in Figure 1.  
 

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Figure 1:  Study Schema 
 
fMRI=functional connectivity magnetic resonance imaging; PRO=patient reported outcome; QST=Quantitative Sensory Testing. 
 
 
 

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1.3. 
Schedule of Activities 
Table 2:  Schedule of Activities 
Procedures 
Screening
a 
Baseline 
Preparation 
Administration 
Integrationb 
(2 h) 
End of 
Therapyc 
Follow-up 
3 and 
6 months 
Deep 
Pheno-
typing 
Therapy 
Dose 1  
(8 h) 
Between 
Dose 1 & 2 
(2 h) 
Dose 2  
(8 h) 
After 
Dose 2  
(2 h) 
Deep 
Pheno-
typing 
Visit Number 
1 
2 
3, 4 
5 
6, 7 
8 
9 
10, 11, and 12 
13 
14 and 15 
Day Number 
Up to -42 
1 to 7 
11 and  
18 ±7 
22 ±3 
23 and  
29 ±3 
36 ±3 
37 ±3 
43, 50, and 57 
±3 
64 ±3 
120 and  
204 ±7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
• 
Demographics 
• 
Medical history 
• 
SCID-5 and SCID-5-PD 
X 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete blood count and 
metabolic panel 
X 
 
 
 
 
 
 
 
 
 
12-lead electrocardiogramd 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test for WOCBPe 
X 
X 
 
X 
 
X 
 
 
X 
 
Urine drug                       
Breath alcohol test and 
COVID-19 testf 
X 
X 
 
X 
 
X 
 
 
X 
 
PHQ-8g 
Life events Checklist 
X 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
X 
 
X 
 
X 
 
 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2016 FM Survey Criteria 
X 
X 
 
 
 
 
 
 
X 
X 
Expectations assessment 
 
X 
 
 
 
 
 
 
 
 

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Procedures 
Screening
a 
Baseline 
Preparation 
Administration 
Integrationb 
(2 h) 
End of 
Therapyc 
Follow-up 
3 and 
6 months 
Deep 
Pheno-
typing 
Therapy 
Dose 1  
(8 h) 
Between 
Dose 1 & 2 
(2 h) 
Dose 2  
(8 h) 
After 
Dose 2  
(2 h) 
Deep 
Pheno-
typing 
Visit Number 
1 
2 
3, 4 
5 
6, 7 
8 
9 
10, 11, and 12 
13 
14 and 15 
Day Number 
Up to -42 
1 to 7 
11 and  
18 ±7 
22 ±3 
23 and  
29 ±3 
36 ±3 
37 ±3 
43, 50, and 57 
±3 
64 ±3 
120 and  
204 ±7 
• 
STOP-Bang 
 
X 
 
 
 
 
 
 
 
 
• 
Sleep Disturbance (8b) 
• 
CPAQ-8 
• 
Catastrophizing 
 
X 
 
 
 
 
 
 
X 
X 
PI-NRS daily diaryi 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event reportingj 
 
Xk 
X 
X 
X 
X 
X 
X 
X 
 
• 
Quantitative sensory test 
• 
fMRI 
 
X 
 
 
 
 
 
 
X 
 
Wrist actigraphyl 
 
X 
X 
 
 
 
 
X 
X 
 
PROMIS-29+2 
 
X 
 
X 
 
X 
 
 
X 
X 
Self-enmeshment task 
 
X 
 
Xm 
 
Xm 
 
 
X 
 
Self-Complexity task 
 
X 
 
 
 
 
 
 
X 
 
TRP-8802 administration 
 
 
 
X 
 
X 
 
 
 
 
Audio/video record of dose 
 
 
 
X 
 
X 
 
 
 
 
Monitor rating formb 
 
 
 
X 
X 
X 
X 
X 
 
 
• 
Mystical Experiences Q30 
• 
Challenging Experiences 
Q27 
 
 
 
Xn 
 
Xn 
 
 
 
 
Psychological Insight Q 
 
 
 
Xn 
 
Xn 
 
 
X 
X 
PGI-C 
 
 
 
 
 
 
 
 
X 
X 
Qualitative (written) 
assessment 
 
 
 
X 
 
X 
 
 
 
Xo 

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Procedures 
Screening
a 
Baseline 
Preparation 
Administration 
Integrationb 
(2 h) 
End of 
Therapyc 
Follow-up 
3 and 
6 months 
Deep 
Pheno-
typing 
Therapy 
Dose 1  
(8 h) 
Between 
Dose 1 & 2 
(2 h) 
Dose 2  
(8 h) 
After 
Dose 2  
(2 h) 
Deep 
Pheno-
typing 
Visit Number 
1 
2 
3, 4 
5 
6, 7 
8 
9 
10, 11, and 12 
13 
14 and 15 
Day Number 
Up to -42 
1 to 7 
11 and  
18 ±7 
22 ±3 
23 and  
29 ±3 
36 ±3 
37 ±3 
43, 50, and 57 
±3 
64 ±3 
120 and  
204 ±7 
AE=adverse event; CPAQ-8=Chronic Pain Acceptance Questionnaire 8; C-SSRS=Columbia Suicide Severity Rating Scale; FM=fibromyalgia; fMRI=functional connectivity 
magnetic resonance imaging; PGI-C= Patient Global Impression of Change; PI-NRS=pain intensity numeric rating scale; Q=questionnaire; PHQ-8=Patient Health 
Questionnaire depression scale; PROMIS-29+2=Patient Reported Outcomes Measurement Information System 29-item profile measure plus 2 cognitive functioning items; 
SAE=serious adverse event; SCID-5=Structured Clinical Interview for Diagnostic and Statistical Manual for Mental Disorders 5th Edition; SCID-5-PD= Structured Clinical 
Interview for Diagnostic and Statistical Manual for Mental Disorders-5 for Personality Disorders; WOCBP=women of childbearing potential. 
Note: Assessments scheduled on a day of study drug administration should be performed prior to study drug dosing unless otherwise specified. 
a 
Informed consent must be obtained before any study-specific screening assessments are performed. Screening assessments are to be performed within 42 days preceding 
Dose 1. 
b 
The Monitor Rating Form will be used by the same 2 therapists to provide ratings from Dose 1 up to 3 weeks postdose that focus on integration. 
c 
Participants who do not complete both doses of TRP-8802 will return to the clinic within 28 days after their last dose of study intervention for an End of Therapy Visit. 
d 
Participants should be supine and rested for at least 5 minutes before the ECG is recorded. 
e 
A urine pregnancy test will be performed and results determined locally (Section 8.3.2). 
f 
Urine drug and breath alcohol testing will be performed and results determined locally. Breathalyzer and COVID-19 test will be performed only on dosing days. 
(Section 8.3.3) 
g 
A result of “severe depression” on PHQ-8 will exclude the participant from the study.  
h 
Includes heart rate, systolic and diastolic blood pressure preferably with an automated device. Participants should be supine and rested for at least 5 minutes in a quiet 
setting before testing. 
i 
PI-NRS pain diary is to be completed daily, by the participant and checked for completeness by study site staff at each on-site visit indicated (Section 8.2.1.1). 
j 
All AEs and SAEs are to be recorded at the times indicated regardless off attribution. 
k 
Medical occurrences that begin before Baseline but after obtaining informed consent will be recorded as medical history, not as AEs. 
l 
Wear wrist actigraph Day 1 to 14 and Day 50 to 64 
m 
To be performed prior to and approximately 7 hours after dosing 
n 
To be performed approximately 7 hours after dosing.  
o 
Qualitative written assessment is to be completed at Visit 14 only. 
 

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2. 
Introduction 
Psilocybin 3-[2-(dimethylamino) ethyl]-1H-indol-4-yl] dihydrogen phosphate is a natural 
product produced by numerous species of Psilocybe mushrooms. The phosphate group is 
enzymatically cleaved in the body to produce psilocin, an agonist at a variety of serotonin 
receptors, the most important of which, for its behavioral effects, is the 5-hydroxytryptamine 
(5-HT)2A receptor (Carhart-Harris 2014; Nichols 2004). Psilocybin was first isolated from 
Psilocybe mushrooms in 1957, followed by de novo synthesis in 1958 (Passie 2002). It was 
marketed worldwide in the 1960s as Indocybin™ for experimental and psychotherapeutic 
purposes. Although it was well tolerated and demonstrated potentially useful effects, it was 
classified as a controlled substances in the United States and designated as a Schedule I 
Controlled Substance in 1970; thus, it was effectively removed from clinical use or scientific 
study.  
Psilocybin and similar drugs, such as lysergic acid diethylamide and mescaline, fall into a 
pharmacological class that are referred to in this application as “classic psychedelics” to 
differentiate them from other psychoactive substances (3,4 methylenedioxy—methamphetamine 
[MDMA]) that have different psychological/behavioral effects and different adverse effect 
profiles and risk/benefit ratios than psilocybin (Carhart-Harris 2013; Nutt 2010). Several lines of 
evidence suggest that serotonergic hallucinogens, such as psilocybin, have clinical potential for 
inducing therapeutically beneficial behavior change in patients with a variety of psychiatric 
conditions (Carhart-Harris 2013). TRP-8802 is being developed for the treatment of FM, other 
forms of nociplastic pain and overeating disorders. 
The pharmacokinetics (PK), pharmacology, and human metabolism of psilocybin are well 
known and well characterized. Psilocybin has been used as a single agent and as an adjunctive 
treatment in adult populations. Psilocybin is administered orally and has been studied in open-
label and double-blind, controlled trials. Dosing regimens have ranged from 0.014 mg/kg to 
0.6 mg/kg, administered as either a single dose or multiple doses weeks apart (Tryp-8802  
Investigator’s Brochure [IB]). 
Thousands of participants have received psilocybin under controlled conditions in a clinical 
setting for various indications, with subsequent results published in peer-reviewed journals 
(Rucker 2017; Metzner 2005). These clinical trials have demonstrated an improvement in 
symptoms of anxiety, depression, substance use disorder, and other complex neuropsychological 
conditions. Previous studies in healthy participants have shown oral psilocybin to be well 
tolerated. No drug- related serious adverse events (SAEs) were reported. Common AEs that were 
observed after psilocybin administration included cardiovascular (increased blood pressure [BP] 
and heart rate [HR]), gastrointestinal (nausea, vomiting, and diarrhea), and headache. As these 
studies were predominantly performed in an academic setting, safety reporting criteria and the 
level of data verification varied greatly between studies, but these data can be used to elucidate 
the expected adverse event profile of TRP-8802. 
Fibromyalgia is a chronic syndrome of widespread musculoskeletal pain that often manifests 
with a cluster of co-occurring symptoms, including sleep disturbances, fatigue, cognitive 

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dysfunction, and mood problems including anxiety and depression. TRP-8802 therapy delivered 
in concert with psychotherapy may be a safe and effective treatment for symptoms associated 
with FM. The pressing need for effective FM treatments, the known safety of psilocybin therapy, 
and the mechanistic plausibility for potential benefit provide a rationale for investigating 
TRP-8802 therapy as a treatment for FM.  
This is an open-label pilot study to assess the clinical benefit of oral TRP-8802 in concert with 
psychotherapy to treat chronic pain symptoms in patients with FM. Participants will undergo an 
initial pain phenotyping assessment and will complete a daily electronic pain diary until the end 
of active intervention. TRP-8802-psychotherapy intervention, the structure of which has been 
used in previous psilocybin clinical trials, will begin. During the two study drug administration 
sessions, participants will receive TRP-8802 in a comfortable setting under the guidance of two 
therapists. Participants will have an in-person study visit the day after each TRP-8802 
administration visit to ensure their safety and comfort. Psychotherapy with the same two 
therapists will occur between and after TRP-8802 sessions with a focus on integration, helping 
participants gain insight and understanding from the experience. After the final dosing session, 
participants will undergo 3 weekly integration sessions, and then complete a post-treatment deep 
phenotyping session. Participants will complete patient reported outcome questionnaires at 84 
and 168 days after the final TRP-8802 dose to examine persistence of changes.  
2.1. 
Study Rationale 
Fibromyalgia is a chronic pain condition that affects 2% to 4% of the population and is 
characterized by widespread pain as well as a cluster of co-occurring symptoms that include 
sleep disturbances and cognitive fog. Current treatments for FM are inadequate and there is an 
unmet need for treatment. Fibromyalgia treatment is challenging: many nonpharmacological 
therapies are inaccessible due to cost and lack of treatment providers, and most pharmacological 
therapies are only modestly effective and cause a significant side-effect burden. Some 
researchers have proposed that psychedelic drugs, such as psilocybin may have potential 
therapeutic value for treating FM and chronic pain.  
Much of this interest has been generated by the results from small clinical trials among 
individuals with psychiatric disorders such as anxiety, depression, and addiction (Carhart-Harris 
2021; Davis 2021a; Carhart-Harris 2018; Johnson 2017; Carhart-Harris 2016; Griffiths 2016; 
Ross 2016; Johnson 2014; Grob 2011), which show remarkable improvements in otherwise 
seemingly intractable conditions. Studies with modern neuroimaging techniques (e.g., functional 
connectivity magnetic resonance imaging [fMRI]) have shown that psilocybin dramatically alters 
maladaptive patterns of connectivity between different brain regions, which in combination with 
psychotherapy may promote improved clinical symptoms. Basic science research has identified 
the serotonin 5-HT2A receptor as the primary target for psychedelics – a finding of interest given 
that polymorphisms in the encoding 5-HT2A gene are associated with FM and chronic 
widespread pain (Nicholl 2011; Bondy 1999). While case series and retrospective surveys do 
suggest that psychedelic use may improve chronic pain due to cluster headache/migraine 
(Schindler 2015), phantom limb pain (Ramachandran 2018), and nociplastic and neuropathic 
pain (Castellanos 2020), no studies have examined the potential role of psychedelics in FM.  

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To better understand the potential benefits of psychedelics in chronic pain management, we are 
conducting this pilot clinical study with TRP-8802 among individuals with FM. Key procedures 
have been adapted from other clinical trials using psilocybin (Davis 2020), including 
psychotherapy sessions for participants to both prepare for and to integrate the TRP-8802 
experience after administration.  
2.2. 
Background 
Nonclinical in vivo and in vitro studies of psilocybin found via literature searches demonstrate 
that when administered orally to rats psilocybin is rapidly dephosphorylated to psilocin in the 
intestinal mucosa by alkaline phosphatase and a nonspeciﬁc esterase, with approximately 50% of 
the total volume of psilocin absorbed from the digestive tract (Kalberer 1962). Maximum plasma 
levels are achieved after approximately 90 minutes (Chen 2011). When administered 
systemically (i.e., bypassing the gut), initial psilocybin metabolism is performed by tissue 
phosphatases, with in vitro studies indicating the kidneys as being among the most active 
metabolic organs (Horita 1961). Across species tested, the highest levels of psilocin were found 
in the neocortex, hippocampus, and thalamus (Hopf 1974). 
Recent clinical studies using pharmaceutical-grade oral psilocybin under controlled conditions 
have been performed in healthy volunteers and various subpopulations to characterize the safety 
profile and evaluate the biological response (Tryp-8802 IB). The clinical studies presented 
similar safety profiles, with both psychological and physical AEs reported. During dose sessions, 
the most common adverse psychological events included anxiety, negative emotional states and 
paranoid/delusional thinking, and the most common physical effects were increased BP and HR, 
mild nausea, and mild headache. 
Preliminary efficacy of psilocybin in clinical studies showed an improvement in symptomatic 
response in indications including substance use disorder, treatment resistant depression, and 
anxiety. Overall, psilocybin has been well tolerated at the doses examined in the clinical studies.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of TRP-8802 is 
provided in the current Tryp-8802 IB. 
2.3. 
Benefit/Risk Assessment 
Information about the known and expected benefits and risks and reasonably expected adverse 
events of TRP-8802 may be found in the Tryp-8802 IB.  
Due to the psychoactive nature of TRP-8802, it should only be administered in a controlled 
setting per this clinical protocol. The safety of participants in this study will be enhanced by 
testing within a “set and setting” protocol as described by Lyons (2018) and by Johnson (2008). 
By addressing the set (the emotional/cognitive/behavioral state/mindset and expectations of 
study participants before TRP-8802 exposure) and setting (the physical environment in which the 
exposure occurs) of the experience, the risk of participants reporting an event which is 
distressing or injuring themselves can be reduced. Participants will be asked to discuss their 
session experience thoroughly with the goal of maximizing its therapeutic benefit. 

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Hallucinogen-persisting perception disorder (HPPD) is a very rare but potentially serious 
disorder that may occur as a significant adverse effect with the use of psychedelic compounds 
(mainly lysergic acid diethylamide [LSD]). It is characterized by symptoms such as visual 
disturbances, derealization, and depersonalization that last from weeks to years after use (Espiard 
2005). No cases of HPPD have been reported in volunteers given psilocybin in recent research 
studies (Griffiths 2016, Studerus 2012, Griffiths 2011). In studies involving cancer patients 
examining cancer-related anxiety and depression, no cases of HPPD were identified and no 
patients developed any symptoms of paranoia or anxiety that required pharmacological 
intervention or anything more than reassurance from session therapists (Studerus 2011).  
The risk of experiencing HPPD with 2 doses of TRP-8802 is expected to be very low, and the 
risk of its occurrence will be reduced by screening participants for potential risk factors such as 
severe substance use disorder and by excluding people reporting HPPD or other significant 
adverse events after prior use of hallucinogens. As these symptoms can present even after the 
duration of the study, participants will be educated about HPPD. If the symptoms were to occur, 
participants will be instructed to inform the study team immediately (during the study period), 
and to seek medical care (after the study period), to rule out HPPD. 
Higher doses of psilocybin (greater than 0.3 mg/kg) also may transiently lead to elevated mean 
BP, peaking 30 to 60 minutes following psilocybin administration and returning to baseline 
levels after 90 to 180 minutes without necessitating further interventions (Griffiths 2006; Hasler 
2004). The severity of elevations in BP was usually asymptomatic and was graded as mild or 
moderate. Although several subjects in a University of Wisconsin dose-escalation study reached 
BP elevations that were graded as moderate, they remained asymptomatic (Brown 2017). It is not 
clear whether the changes in BP and HR are due to the elevated psilocin concentration directly or 
to the psychedelic effect caused by this active metabolite. Psilocybin appears to produce only 
slight sympathetic system activation (Hasler 2004; Gouzoulis-Mayfrank 1999).  
Transient elevations of HR were common in subjects receiving psilocybin at doses of 0.3 mg/kg 
or more. The time course of these elevations in HR is similar to those seen for the elevation in 
BP, peaking between 60 to 120 minutes after the dose. This is similar to time of peak psilocin 
concentrations and peak psychedelic effect. Again, it is not clear whether or not the changes in 
BP and HR are directly due to the elevated psilocin concentration or caused indirectly by the 
psychedelic effect. In a phase 1 dose-escalation study in healthy volunteers, there were several 
instances in which mild bradycardia and tachycardia were noted. Psilocybin resulted in an 
increased HR, with slightly higher mean change from baseline in HR (ΔHR) at higher psilocybin 
doses and corresponding higher psilocin exposures (Dahmane 2021). The maximum mean ΔHR 
was observed at the time of psilocin maximum observed concentration (Cmax) (i.e., at 2 hours 
post dose) in nearly all psilocybin dose groups, and mean ΔHR decreased with decreasing 
psilocin concentration at subsequent time points. Instances of bradycardia or tachycardia were 
unimodal, with no swing between bradycardia and tachycardia after a given dose. The episodes 
of bradycardia and tachycardia reported in recent studies were asymptomatic (“mild” or Grade 1) 
and did not require treatment (Tryp-8802 IB). Further information can be found in the current 
Tryp-8802 IB. 
Mild headaches are common within the 24 hours after a dose of psilocybin. No auras or 
photo/phonophobia are associated with these headaches, which respond well to a single dose of 

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acetaminophen. The headaches did not appear to be dose-related in one study, with no higher 
incidence after doses of 0.6 mg/kg versus 0.3 mg/kg (Brown 2017). 
Taking into account the measures taken to minimize risk to participants in this study, the known 
and potential risks identified in association with TRP-8802 are justified by the anticipated 
benefits that may be afforded to participants with FM. 

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3. 
Objectives and Endpoints  
Table 3:  Study Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To assess the safety of TRP-8802 under 
the conditions of this trial  
Safety during dosing sessions: vital signs (HR, BP) (Section 8.1.1); 
AEs (Section 8.1.2), 
Safety during trial:  AEs  
Secondary 
To evaluate the clinical benefit of oral 
TRP-8802 in concert with 
psychotherapy to treat chronic pain 
symptoms in patients with FM 
 
To assess other potential therapeutic 
effects of TRP-8802 assisted therapy on 
FM symptoms 
Participant self-reported outcomes: 
• 
pain interference (Section 8.2.1.2) 
• 
sleep (Section 8.2.1.3) 
• 
chronic pain acceptance (Section 8.2.1.4) 
• 
Patient Global Impression of Change (PGI-C) (Section 8.2.1.5) 

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Objectives 
Endpoints 
Exploratory 
To characterize other TRP-8802 clinical 
and PD effects  
Patient reported outcomes relevant to chronic pain (Sections 8.2.2.1, 
8.2.2.2) 
• 
FM survey score, affect, catastrophizing, fatigue, anxiety, 
depression, cognitive impairment 
Dosing-specific patient reported outcomes (Section 8.2.2.3) 
• 
Mystical experiences 
• 
Challenging experiences 
• 
Psychological insight 
Dosing-specific therapist reported outcomes 
• 
Monitor rating scale (Section 8.2.2.3) 
Qualitative written assessment (Section 8.2.2.4) to determine 
subjective participant experiences  
Self-pain enmeshment (Section 8.2.2.5) 
Self-complexity task (Section 8.2.2.6) 
QST (Section 8.2.3.1) 
• 
Change in cuff P40 pre- and post-intervention 
• 
Visual hypersensitivity 
fMRI (Section 8.2.3.2) 
• 
Change in insula-default mode network connectivity 
• 
Change in Glx and/or GABA in anterior insula 
• 
Change in evoked pressure pain (tonic cuff) 
• 
Change in grey matter volume 
Wrist actigraphy (Section 8.2.3.3) 
• 
Sleep onset latency 
• 
Wake after sleep onset 
• 
Total sleep time 
• 
Sleep efficiency (%) 
AEs=adverse events; BP=blood pressure; FM=fibromyalgia; GABA=gamma aminobutyric acid; Glx=glutamine+glutamate; 
HR=heart rate; P40=pain rating of 40 out of 100; PD=pharmacodynamic; QST=Quantitative Sensory Testing. 
Note: The aggregate weekly pain score is over a 7-day period.  
 

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4. 
Study Design 
This is a single-arm, single center, open-label (uncontrolled) pilot study in participants with FM.  
4.1. 
Overall Design 
• All participants must have FM or have had FM symptoms for at least a year, and meet the 
2016 FM Survey Criteria for FM. Exclusion criteria include certain co-morbid psychiatric 
disorders (e.g., psychotic disorders, bipolar I or II disorder, substance use disorder), 
history of a medically significant suicide attempt, and use of certain medications (e.g., 
anti-depressants). 
• All participants enrolled in the study are expected to receive 2 doses of TRP-8802 
separated by 2 weeks during in-center study intervention sessions.  
• “Active intervention” includes baseline deep phenotyping, preparation, study drug 
administration, integration, and EOT deep phenotyping.  
• Study visits may have visit “windows” as shown in the Schedule of Activities (SoA, 
Section 1.3) 
• Further details regarding dosing and therapy sessions are provided in the Psychotherapy 
Manual. 
• One of the physicians associated with the study will have a brief visit with the study 
participant during screening or prior to the first dosing session.  
• The Lead Facilitator will be a doctoral level PhD/MD-level psychotherapist (or 
equivalent).  Acceptable degrees for Lead Facilitators are: Clinical and Counseling 
Psychologists (PhD/PsyD), Physicians and Psychiatrists (MD or DO) or Masters of 
Social Work (MSW).  The Co-Facilitator will have at least a bachelor’s degree in mental 
health and at least one year of clinical experience in a licensed mental health care setting.  
• The total duration of study participation for an individual participant is approximately 
8 months, including screening, preparation, administration, integration, EOT, and 
follow-up.  
• The total planned duration of the entire study is expected to be 18 months.  
• There are no provisions for extending the study for any participants or for entry to roll-
over studies. 
• An SRC will be responsible for the assessment of safety and to make recommendations 
with regard to study progression (Appendix 1, Section 10.1.5).  
The timing and a description of these assessments are also provided in the SoA, Section 1.3 and 
in Section 8. 
4.1.1. 
Screening Period (Visit 1, Day -42 to Trial Initiation) 
Once candidates are pre-screened for interest and eligibility, they will complete a screening visit 
in which the informed consent process (Appendix 1, Section 10.1.3) is completed before any 
other procedures are assessed. When inclusion and exclusion criteria are confirmed, other 
assessments are completed as follows:  
• demographic and baseline characteristics  
• medical history 
• prior/concomitant medications 

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• Structured Clinical Interview for Diagnostic and Statistical Manual for Mental Disorders 
5th Edition (SCID-5) and SCID-5 for Personality Disorders (SCID-5-PD) 
• The Life Events Checklist for DSM-5 (LEC-5) (Weathers 2013) will be used to assess 
past history of or exposure to trauma. Participants indicate how many of 16 potentially 
traumatic events (e.g., natural disaster, physical assault) they experienced personally or 
witnessed, as well as an additional item assessing any other very stressful event or 
experience. The number of events that participants indicate happened to them personally 
is summed, with scores potentially ranging from 0 to 17. Participants will be asked these 
questions verbally (recorded by study staff) or to fill out the questionnaire themselves.  
• 12-lead electrocardiogram (ECG)  
• pregnancy test for women of childbearing potential (WOCBP) 
• urine drug tests 
• vital signs 
• patient reported outcomes (Patient Health Questionnaire depression scale-8 [PHQ-8], 
Columbia Suicide Severity Rating Scale [C-SSRS], 2016 FM Survey Criteria) 
• Comprehensive Metabolic Panel (CMP): Na+, K+, Cl-, HCO3-, Ca++, Mg++, P, BUN, 
creatinine, glucose, total bilirubin, albumin, ALT, AST, GGT, CK, LDH, alkaline 
phosphatase 
• Hematology: CBC with white cell differential and platelet count 
 
Any clinically significant abnormal laboratory findings for blood chemistry or hematology 
would be exclusionary from study participation.  
4.1.2. 
Baseline (Visit 2, Day 1) 
Assessments on Day 1 will be considered baseline assessments. On Day 1, participants will 
undergo a rigorous pain phenotyping assessment (i.e., deep phenotyping) as shown in the SoA 
(Section 1.3). A validated battery of patient reported outcomes includes the following: 
• STOP-Bang (Chung 2016; Nagappa 2015) will be used to screen for sleep apnea which 
can interfere with sleep. The STOP-Bang questionnaire consists of 8 questions that assess 
risk of sleep apnea, including snoring, tiredness, whether anyone has observed the person 
stop breathing in their sleep, high BP, body mass index, age, neck circumference 
> 16 inches, and sex.  
From this deep phenotyping session until the end of active intervention (28 days after final 
TRP-8802 dosing session), participants will complete a daily electronic pain diary to evaluate 
pain level on a scale of 0 to10, on the Pain Intensity-Numeric Rating Scale (PI-NRS).  
4.1.3. 
Preparation Period (Visits 3 and 4, Day 11 and Day 18) 
Participants will begin psychotherapy intervention, the structure of which has been used in 
previous psilocybin clinical trials. As with other psilocybin studies, discussions will include 
information on the participant’s life history, current situation in life, as well as the participant’s 
understanding, expectations, and intentions for the TRP-8802 administration sessions. In brief, 
during the approximately 8 hours of preparatory therapy at Visits 3 and 4, participants will 
develop rapport with two assigned therapists, learn about FM, as well as build comfort and 

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understanding around the physical space and what will occur in the dosing sessions. Details of 
these sessions are provided in the Psychotherapy Manual. One of these preparatory therapy 
sessions may occur via a HIPAA-compliant video conferencing platform if necessary. 
4.1.4. 
TRP-8802 Administration Period (Visit 5 to Visit 9, Day 22 to Day 37) 
The procedures used during the administration period will be consistent with those from other 
published studies using psilocybin assisted therapy (Davis 2021a). Participants will be asked to 
eat a low-fat breakfast before reporting to the Rachel Upjohn Building for their dosing sessions. 
Before administration of study drug, participants will provide urine samples that will be tested 
for drugs (Section 8.3.3) as well as for pregnancy for WOCBP (Section 8.3.2); tested for 
COVID-19; and a breath alcohol test will also be administered (Section 8.3.3). All tests must be 
negative for participants to proceed. Participants will also complete pre-session questionnaires 
and a brief interview with study personnel. The purpose of this brief interview is to assess if the 
session is contraindicated. If so, then that session will be postponed if possible. 
Participants will receive an initial 15 mg dose of TRP-8802 (lower dose) on Day 22 followed by 
the second dose of 25 mg (higher dose) on Day 36. TRP-8802 will be administered in a 
comfortable setting under the guidance of the same two therapists from the preparation period. 
The 15 mg dose can be repeated at Dose 2 if the participant or Investigator determines that the 
higher dose is not advantageous and/or may not provide further benefit, based on observations 
for Dose 1. Participants will have an in-person study visit the day after each dose administration 
(Day 23 and Day 37) to ensure participant safety and comfort. There will also be a visit (virtual 
using a HIPAA-compliant video conferencing platform or in-person) 7 days after administration 
of the first dose (Day 29) to integrate the first experience and prepare the second dosing day.  
During the dosing sessions, which will take at least 8 hours, two therapists will be present in the 
room and available to support participants’ physical and emotional needs. A study physician will 
be on call and within 5 minutes of the session room during the first 3 hours or until the peak 
effects of psilocybin have abated, and will remain available for the remainder of the course of the 
TRP-8802 dosing session if needed for consultation. During these sessions, participants will be 
instructed to lie on a comfortable couch or bed, wear eyeshades, and listen to music through 
headphones, all of which are meant to enhance and encourage internal attention and reflection. 
Participants will be encouraged by the therapist to direct their attention inward. Recumbent BP 
and HR will be monitored (Section 8.1.1) until the drug effects have lessened. There will be an 
automated external defibrillator located on site and a crash cart containing medicine (Section 
6.8.1) and equipment for emergency resuscitation. 
During the same period as the vital signs measurements, therapists will also complete the 
monitor rating form, which includes questions about the presence/intensity of behaviors, signs, 
and reported symptoms, such as peacefulness, yawning, nausea/vomiting, quantity of speech, 
anxiety, sleepiness, crying, restlessness, visual changes, euphoria, and feelings of unreality. 
These sessions will be video and audio recorded. After the study drug effects have subsided, 
participants will complete questionnaires that assess the subjective experiences of the TRP-8802 
dosing session, and the therapists will complete questionnaires that assess participant mood and 
safety. Participants will be asked to process the experience at home by writing a reflection about 

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their experiences during the dosing session (Section 8.2.2.4). This reflection will be discussed at 
follow-up meetings. 
4.1.5. 
Integration Period (Visits 10 to 12, Day 43 to Day 57) 
After the final dosing session, participants will have 3 weeks of therapy integration sessions (up 
to 2 hours/week). Psychotherapy will occur during this period with a focus on integration, 
helping participants gain insight and understanding from the experience. These visits can occur 
in person or via a Health Insurance Portability and Accountability Act (HIPAA)-compliant video 
conference platform. Sleep (wrist actigraphy) will also be assessed. 
4.1.6. 
End of Therapy (Visit 13, Day 64) 
The EOT assessment will occur approximately 28 days after the last dosing session, when 
participants will complete their final deep phenotyping session. Regardless of whether or not a 
participant completes both dosing sessions or chooses to discontinue the study early, participants 
will be asked to complete all EOT and follow-up assessments if they have received at least 
1 dose of TRP-8802.  
4.1.7. 
Follow-up Period (Visits 14 and 15, Day 120 and Day 204) 
Patient reported outcome measures will be administered to each participant at 84 and 168 days 
after the final dose to examine persistence of changes of TRP-8802 and the therapy sessions. 
4.2. 
Scientific Rationale for Study Design 
This is a pilot study designed to understand the safety and potential benefits of TRP-8802 in 
concert with psychotherapy in the chronic pain management of FM. Participants must be 25 to 
64 years of age, inclusive, at the time of signing the informed consent form. This age range is 
included as the prevalence of FM increases with age and treatment outcomes remain poor (Sarzi-
Puttini 2020). 
4.3. 
Justification for Doses 
A single-site, open-label, dose-escalating clinical trial was conducted to evaluate the PK, safety, 
and cardiovascular effects of an oral formulation of psilocybin in 12 normal, healthy adults 
(Brown 2017). Psilocybin was administered in sequential, escalating oral doses of 0.3, 0.45, and 
0.6 mg/kg. with a mean dose level, as defined by the average participant weight, of 23.4 mg 
(0.3 mg/kg), 35.1 mg (0.45 mg/kg), and 46.9 mg oral psilocybin (0.6 mg/kg). The dose range 
used in the study by Brown (2017) covers the dose range proposed herein, which uses fixed 
doses of 15 mg and 25 mg. Several other studies of psilocybin administered in this dose range 
are presented in the Tryp-8802 IB.  
No parent psilocybin was found in plasma or urine after a single dose of psilocybin, confirming 
the rapid metabolism of psilocybin to psilocin (Dinis-Oliveira 2017). The PK profile of psilocin 
was linear within the 2-fold range of doses, and the elimination half-life of psilocin was 3 hours 
(SD 1.1). In general, all 3 dose strengths were physically and psychologically well tolerated, and 
no serious physical or psychological AEs up to 30 days after dose administration were reported.  

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This 2-dose level design has been used in several studies, including the recent investigation of 
psilocybin in major depressive disorder (Davis 2021a). The first TRP-8802 dosing session 
(15 mg) is not expected to produce full psychedelic effect, but is instead meant to help 
familiarize participants with study intervention effects and study procedures. The second, higher-
dose TRP-8802 dosing session (25 mg) is expected to produce a greater likelihood of therapeutic 
effect. The 2-dose level design also allows the investigators to assess the suitability of the 
participant to the study procedures and to gauge whether the participant is suitable for receiving 
the higher dose at Dose 2. Additionally, the 2-dose level design is being used to reduce the 
likelihood of an unexpected AE in participants who may have higher bioavailability and/or 
higher rates of conversion to psilocin.  
4.4. 
End of Study Definition 
A participant is considered a study completer if they complete all phases of the study through 
Visit 13 (EOT). Participants will be encouraged to complete follow up assessments (Visits 14 
and 15) which occur 3 and 6 months after the final dose. Study participation ends after Visit 15 
(final study visit). A participant who discontinues the study early/withdraws from the study will 
be asked to complete the EOT and both follow-up visits.  
The end of the study is defined as the date of the last visit of the last participant in the study.  

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5. 
Study Population 
Candidates who express an interest in participating in this study will undergo pre-screening. 
Prior to coming in for the screening visit, potential participants will be asked questions to see if 
they meet the inclusion/exclusion criteria. If they meet these criteria and are interested in 
participating, potential participants will provide informed consent electronically or will be 
invited to come in for the official screening visit, at which time obtaining informed consent will 
be completed.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, will not be permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 25 to 64 years of age, inclusive, at the time of signing the informed 
consent form.  
Type of Participant and Disease Characteristics 
2. Participant has had a diagnosis of FM for ≥ 3 months or has had FM symptoms for at 
least 1 year per self-report. 
3. Participant must meet criteria for FM per the 2016 FM survey criteria. 
4. Concurrent psychotherapy is allowed if the type and frequency of the therapy has been 
stable for at least 2 months prior to screening and is expected to remain stable during 
participation in the study.  
5. Participant must be a non-smoker (tobacco) per self-report. 
6. Participant must be medically stable as determined by screening for medical problems 
via a personal interview and/or, a medical questionnaire, and an ECG, within 1 month 
of starting active intervention (performed during screening). 
7. Participant must agree to consume approximately the same amount of caffeine-
containing beverage (e.g., coffee, tea, cola) that he/she consumes on a usual morning, 
before arriving at the research unit on the mornings of TRP-8802 session days. If the 
participant does not routinely consume caffeinated beverages, he/she must agree to not 
do so on TRP-8802 session days. 
8. Participant must agree to refrain from using any psychoactive drugs, including 
alcoholic beverages and nicotine, within 24 hours before and after each TRP-8802 
administration. The exception is caffeine.  
9. Participant must agree to not take sildenafil (Viagra®), tadalafil, or similar medications 
within 72 hours before and after each TRP-8802 administration. 

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10. Participant must agree to not take any pro re nata (PRN) medications on the mornings 
of TRP-8802 sessions. 
11. Participant must have at least a high school level of education or equivalent (e.g., 
General Educational Development [GED] Test).  
12. Up-to-date vaccination for COVID-19 (at least two doses).  
Sex and Contraceptive/Barrier Requirements 
13.  Contraceptive use by women and men should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
Adequate birth control methods include intrauterine device, 
injected/implanted/intravaginal/transdermal hormonal method, oral hormones plus a 
barrier contraception, abstinence, vasectomized sole partner, or double barrier 
contraception. 
a. Females of reproductive potential must agree to use effective birth control for the 
duration of active intervention (defined as the time from the Baseline [deep 
phenotyping] visit until the EOT [deep phenotyping] visit). 
b. Sexually active male participants and/or their female partners must agree to use 
effective birth control for the duration of active intervention (defined as the time 
from the Baseline [deep phenotyping] visit until the EOT [deep phenotyping] visit) 
of the male participant. Male participants must also agree not to donate sperm for 
the duration of active intervention. 
Informed Consent 
14. Participant has provided informed consent as described in Appendix 1, Section 10.1.3 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Participant has had (within the past 1 year) a cardiovascular condition such as coronary 
artery disease, stroke, angina, uncontrolled hypertension, a clinically significant ECG 
abnormality (e.g., atrial fibrillation), prolonged QTc interval (i.e., QTc > 450 msec), 
artificial heart valve, or transient ischemic attack.  
2. Participant has epilepsy with a history of seizures. 
3. Participant has insulin-dependent diabetes. 

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4. Participant is taking an oral hypoglycemic agent and has a history of hypoglycemia.  
5. Participant has active auto-immune disease (e.g., lupus, rheumatoid arthritis). 
6. Participants has any clinically significant lab abnormalities per a complete blood count 
and metabolic panel (e.g., elevated liver enzymes). Please see screening in section 
4.1.1.   
7. Participant has a current or past history of meeting Diagnostic and Statistical Manual of 
Mental Disorders, 5th edition (DSM-5) criteria for schizophrenia spectrum or other 
psychotic disorders (except substance/medication-induced or due to another medical 
condition), or bipolar I or II disorder measured via SCID-5 and SCID-5-PD. 
8. Participant has a current or past history (within 1 year) of meeting DSM-5 criteria for a 
moderate or severe alcohol, tobacco, or other drug use disorder (excluding caffeine) 
measured via relevant questions from the SCID-5. 
9. Participant has a history of a medically significant suicide attempt. 
Prior/Concomitant Therapy 
10. Participant is taking psychoactive prescription medication (e.g., opioids, tramadol, 
benzodiazepines) on a regular basis (i.e., more than 2 times a week). 
11. Participant is currently taking 300mg/day of bupropion or antidepressants other than 
selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake 
inhibitors (SNRIs).  
12. Participant is currently taking monoamine oxidase inhibitors (MAOIs) on a regular 
basis (daily or most days). For individuals who have intermittent or PRN use of such 
medications, TRP-8802 sessions will not be conducted until at least 5 half-lives of the 
agent have elapsed after the last dose. 
13. Subjects taking prohibited medications. The list of prohibited medications should 
include antihypertensive medications, UGT1A9 or 1A10 inhibitors (e.g., regorafenib, 
rifampicin, phenytoin, eltrombopag, mefenamic acid, diflunisal, niflumic acid, 
sorafenib, isavuconazole, deferasiroxor, ginseng) and aldehyde or alcohol 
dehydrogenase inhibitor (e.g,, disulfiram).  
14. Participant is currently taking prohibited drugs of abuse, including methamphetamine, 
illicit opioids (e.g., heroin), cocaine, 3,4-Methylenedioxymethamphetamine 
(Ecstasy/Molly), or hallucinogens (e.g., mescaline or peyote).  
15. Participant has any use of hallucinogens in the past 6 months or has had a total lifetime 
hallucinogen use of 10 or more times. 
16. Participant tests positive for cocaine, methamphetamine, or opioids on urine drug 
testing.  

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17. Participant has a psychiatric condition judged to be incompatible with establishment of 
rapport or safe exposure to TRP-8802. 
 
Prior/Concurrent Clinical Study Experience 
18. Participant is currently in another clinical trial.  
Diagnostic assessments 
19. Participant has a significant suicide risk as defined by: 
a. suicidal ideation as endorsed on items 4 or 5 on the C-SSRS within the past year at 
Screening or at Baseline; or  
b. suicidal behaviors within the past year; or  
c. clinical assessment of significant suicidal risk during participant interviews 
20. Participant has severe depression as measured through PHQ-8 at Screening. 
Other Exclusions 
21. Participant is pregnant (as indicated by a positive urine pregnancy test assessed at 
Screening and before each TRP-8802 session) or nursing. 
22. Participant is a WOCBP and sexually active, or a man and sexually active, and not 
practicing an effective means of birth control. 
23. Participant has a confirmed first- or second-degree relative with schizophrenia 
spectrum or other psychotic disorders (except substance/medication-induced or due to 
another medical condition), or bipolar I or II disorder. 
 
 
5.3. 
Lifestyle Considerations 
Some lifestyle considerations (e.g., diet, smoking habits, alcohol, or recreational drug 
consumption) could be of relevance for this study. Therefore, the following restrictions apply:  
• Caffeine-containing beverages are allowed during the study, including on TRP-8802 
session days. However, participants are expected to consume approximately the same 
amount of caffeine-containing beverages that they usually consume before arriving at the 
research unit on the mornings of TRP-8802 drug sessions.  
• Participants must be non-smokers (tobacco) before and during the entire study. 
• Psychoactive drugs, including prescription and recreational drugs, are only allowed 
during the study period as described in the study protocol. 
• Alcoholic beverages and psychoactive drugs are not allowed within 24 hours before and 
after each TRP-8802 administration. 
• For 7 days before each TRP-8802 session, participants must refrain from taking any 
nonprescription medication, nutritional supplement, or herbal supplement except when 
approved by the Principal Investigator. Exceptions must be evaluated by the Principal 

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Investigator and may include acetaminophen, non-steroidal anti-inflammatory drugs, and 
common doses of vitamins and minerals. No PRN medications are allowed on the 
mornings of TRP-8802 administration.  
• Drugs such as sildenafil (Viagra®), tadalafil, or similar medications are not allowed 
within 72 hours before and after each TRP-8802 administration. 
There are no restrictions on physical activity during the study. TRP-8802 session days will be 
held under the supervision of two therapists who are present throughout the session. Sessions 
will be conducted in a room designed to be quiet, comfortable, and aesthetically pleasing, and 
participants are encouraged to wear eyeshades and listen to a program of music through 
headphones during the drug exposure to aid them in focusing their attention inward. 
Participants should agree to not drive or operate machinery on the day of TRP-8802 
administration. Participants must agree to be driven home after TRP-8802 drug sessions. Once 
they are considered to be medically stable post-dose by the Investigator, participants will be 
discharged and should accompanied for the evening by a family member or caregiver. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. If a participant is taking an exclusionary medication at screening, and the participant 
and their health care provider(s) agree that it is appropriate to change medication(s), then 
rescreening may occur after the appropriate washout period.  
Rescreened participants should be assigned a new participant number for every screening/ 
rescreening event. 
5.5. 
Criteria for Temporarily Delaying Enrollment or Administration of 
Study Intervention 
If any of the stopping rules below is met, dosing will pause until the SRC convenes (either 
routine or ad hoc) to review details of the event and/or additional data. If, after further review of 
the data, the SRC determines that no stopping rule has been met (e.g., AE determined to be 
unrelated to the study drug) or that if a stopping rule has been met there is a way to safely 
continue the trial (e.g., appropriate safety monitoring can be implemented), then dosing may 
resume. The occurrence of any of the following events will result in a temporary halt of dosing: 
• one SAE considered at least possibly related to the study drug  
• one Grade 3 or Grade 4 AE considered at least possibly related to the study drug 
• clinically similar Grade 2 AEs considered at least possibly related to the study drug in 
2 participants 

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The study may be discontinued at any time by the Institutional Review Board (IRB), the FDA, or 
other government agencies as part of their duties to ensure that research participants are 
protected. 

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6. 
Study Intervention(s) and Concomitant Therapy 
In this protocol, study intervention is the combination of the investigational TRP-8802 and 
psychotherapy. This Section covers the administration of TRP-8802; psychotherapy treatment is 
covered in more detail in the Psychotherapy Manual.  
6.1. 
Study Intervention TRP-8802 
TRP-8802 intervention, doses, and route of administration are presented in Table 4. 
Table 4:  Study Treatments Administered 
Intervention Name 
TRP-8802 
Type  
Drug 
Dose Formulation 
Capsule 
Unit Dose Strengths 
5 mg and 25 mg 
Dosage Levels 
15 mg (3 x 5 mg) and 25 mg (1 x 25 mg) 
Route of Administration 
Oral 
Use 
Experimental 
Sourcing 
Provided centrally by the Sponsor  
Packaging and Labeling 
TRP-8802 will be provided in high-density polyethylene bottles. Each bottle 
will be labeled in accordance with appropriate regulatory requirements. 
Current/Former Name 
Psilocybin 
Manufacturer 
Usona Institute 
6.1.1. 
TRP-8802 Administration 
Participants will be instructed to consume a light, low-fat breakfast before TRP-8802 
administration. Capsules of TRP-8802 will be administered orally with 8 ounces of water at the 
research unit under the supervision of study staff. Capsules should not be opened or chewed. The 
drug session will be rescheduled if a friend or family member of the participant is not available 
to accompany them home after being discharged from the research unit.  
6.1.2. 
Leaving the Research Unit 
Participants will not be allowed to leave the research until the study staff makes the judgment 
that the effects of the study intervention have completely subsided. Participants will expected to 
be on the research site for at least 8 hours. The discharge criteria are as follows (all of the 
following must be met): 
• A responsible friend/family member is available to accompany the participant home. 

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• The participant’s clinical status is not deemed to be of concern by the clinical judgment 
of a study physician. 
• The participant is deemed by study staff to be free of any acute drug effects. 
• The participant believes they have approximately returned to their psychological 
baseline. 
• The study staff judges that it is safe to discharge the participant. 
• The participant expresses a readiness to go home. 
 
6.2. 
Preparation/Handling/Storage/Accountability 
• The investigator or designee must confirm appropriate temperature conditions of 15°C to 
25°C have been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
• The investigator or designee must confirm appropriate temperature conditions of 15°C to 
25°C have been maintained at the study site for all study intervention and any 
discrepancies are reported and resolved before use of the study intervention. 
• Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff. 
• The investigator is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
• Further guidance including information for the final disposition of unused study 
interventions are provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias 
Efforts will be made to ensure a representative sample of the local FM community participates in 
the study. The chance of observer bias is minimized by the use of widely used, validated 
objective measures during the study. However, as this is an open-label pilot study, sources of 
bias will remain.  
6.4. 
Study Intervention Compliance 
Participants will receive study intervention directly from the Investigator or designee, under 
medical supervision. The date and time of each dose administered in the clinic will be recorded 
in the source documents. The dose of study intervention and study participant identification will 
be confirmed at the time of dosing by a member of the study site staff other than the person 
administering the study intervention. Study site staff will examine each participant’s mouth to 
ensure that the study intervention was ingested. 
6.5. 
Dose Modification 
The only dose modification allowed would be with the second dose (of 2 planned doses) to be 
15 mg (instead of 25 mg) if the participant or Investigator determines that the higher dose is not 
advantageous and may not provide further benefit.  

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The reason for dose modification must be noted in the source documents and case report form 
(CRF).  
Note: If participants exhibit an increased risk of harm to self or others, or any other sign that 
continuing in the study would present undue risks the second dose should not be administered. 
Similarly, participants will not be allowed to continue with a second dose if they have adverse 
events such as psychosis or hypertension.  
6.6. 
Continued Access to Study Intervention after the End of the Study 
There are no provisions for any participant for extending the study or for entry to roll-over 
studies. There is no intervention planned after the end of the study.  
6.7. 
Treatment of Overdose 
For this study, any dose of TRP-8802 greater than the intended dose (15 mg [Day 22] or 25 mg 
[Day 36]) in a 24-hour time period will be considered an overdose. 
No confirmed incidences of an overdose of pharmaceutical psilocybin have been reported. 
Previous clinical trials involved single or multiple doses of oral psilocybin in predefined 
quantities administered in a controlled environment. Should an accidental overdose occur, 
appropriate symptomatic measures should be initiated, followed by monitoring any AEs to 
resolution. 
In the event of an overdose, the site staff should immediately contact the site physician, who will 
determine whether the participant should be treated with rescue medication and if further 
treatment is needed (e.g., emergency department visit). The participant should be closely 
monitored for any AE/SAE for at least 1 day. The quantity of the excess dose(s) should be 
documented in the source documents and the Study Drug Administration CRF. 
6.8. 
Concomitant Therapy 
Any medication or vaccine (including over the counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant receives beginning at the time of 
screening or receives during the study must be recorded along with: 
• reason for use 
• dates of administration including start and end dates 
• dosage information including dose and frequency 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
Participants must abstain from taking nonprescription drugs (including vitamins, recreational 
drugs, and dietary or herbal supplements) within 7 days before each study drug session day, 
unless, in the opinion of the investigator and sponsor, the medication will not interfere with the 
study. 

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6.8.1. 
Rescue Medicine 
The session therapists are trained to reassure the participants if they experience acute anxiety, 
agitation, paranoia, or panic. However, in the unlikely event that those symptoms do not respond 
to reassurance, or if a participant experiences a severe AE outside of the expected challenging 
experiences associated with psilocybin therapy, one of the session therapists will contact the on-
call study physician. The study physician will use their clinical judgment to determine the most 
appropriate medical intervention. 
The study site will supply rescue medication that will be obtained locally. The following rescue 
medications may be used: 
• In the event of a psychiatric emergency, an oral benzodiazepine (e.g., lorazepam) will be 
available for on-site treatment of panic or anxiety. An oral antipsychotic (e.g., 
risperidone) will be available for on-site treatment of psychosis or severe agitation.  
• In the event of symptomatic hypertension, labetalol or similar will be available for on-site 
treatment of symptomatic hypertension. 
• In the event of new-onset chest pain, the participant will be evaluated in-person by the 
study physician to determine whether the pain is cardiovascular, musculoskeletal, or 
reflects acute panic/anxiety. Vital signs and ECG will be monitored (and compared to 
baseline measurements) for evidence of acute ischemia. Based on physician judgment, 
sublingual nitroglycerin (available on-site) may be administered as the standard of care 
for cardiac chest pain while Emergency Medical Services is called to transport the 
participant to an emergency department. The goal will be to transport an acutely 
decompensating patient to an emergency department prior to the point where advanced 
cardiac life support care is required. 
• In the event of headache, ibuprofen (400 mg orally) or similar will be available for on-
site treatment. If the study physician decides that the use of a rescue medication is 
warranted, then the study physician or a member of the nursing staff will administer the 
medication to the participant. 
The date and time of rescue medication administration as well as the name and dosage regimen 
of the rescue medication must be recorded in the CRF. In the unlikely event that a medical or 
psychiatric emergency occurs during a drug session and cannot be safely managed by study 
personnel using reassurance or medication, study staff will contact 911 so that the participant can 
be transported to an emergency medical department. 
In the event that rescue medication is needed, the Investigator and study physicians may use their 
clinical judgment to implement a future dose modification (Section 6.5) or to discontinue future 
study intervention (Section 7.1) for that participant.  

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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention before both doses of TRP-8802 are administered. If study intervention is 
permanently discontinued, the participant will not remain in the study, although they will be 
asked to complete study assessments. See the SoA (Section 1.3) for data to be collected at the 
EOT and follow-up visits.  
If participants exhibit an increased risk of harm to self or others, or any other sign that continuing 
in the study would present undue risks the second dose should not be administered. Similarly, 
participants will not be allowed to continue with a second dose if they have serious adverse 
events such as psychosis or hypertension. Any female participant who becomes pregnant while 
participating in the study will discontinue study intervention and be withdrawn from the study 
(Section 8.4.5).  
 
7.1.1. 
Temporary Discontinuation 
Temporary discontinuation of study intervention will not be allowed. A participant who 
discontinues study intervention will be considered to be discontinued from the study.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, the EOT and follow-up visits 
should be conducted, as shown in the SoA (Section 1.3). See SoA for data to be collected 
at the time of study discontinuation and follow-up. 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
7.3. 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
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• Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
research record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
• Site personnel will attempt to collect the vital status of the participant within legal and 
ethical boundaries for all participants enrolled, including those who did not get study 
intervention. Public sources may be searched for vital status information.  If vital status is 
determined as deceased, this will be documented and the participant will not be 
considered lost to follow-up. Sponsor personnel will not be involved in any attempts to 
collect vital status information. 
Discontinuation of a specific site or of the study as a whole is presented in Appendix 1 
(Section 10.1.9). 

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8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Audio and video recordings will be made for the length of the dosing session days. The 
recordings will be used for quality assurance and staff training purposes; they will not be 
used for any other purpose for this study. 
8.1. 
Safety Assessments (Primary Endpoints) 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). Safety 
assessments will always be performed before efficacy assessments at each visit.  
8.1.1. 
Vital Signs  
Heart rate and BP will be assessed before TRP-8802 capsule administration and at 30, 60, 90, 
120, 180, 240, 300, and 360 minutes after capsule administration. Blood pressure and pulse 
measurements should be preceded by at least 5 minutes of rest for the participant in a quiet 
setting without distractions (e.g., television, cell phones). Blood pressure and pulse 
measurements will be assessed with a completely automated device. Manual techniques will be 
used only if an automated device is not available. If a patient's blood pressure is >200 systolic or 
>110 diastolic for more than 15 minutes (i.e. 4 consecutive readings) they will be transferred to 
ED whether or not they are symptomatic. 
8.1.2. 
Adverse events  
Adverse events will be assessed throughout the study as detailed in Section 8.4.  
New onset of suicidal ideation will be considered an AE. Suicidal ideation will be assessed 
during every in-person visit using the C-SSRS and clinical assessment during participant 
interviews. The C-SSRS was developed by researchers at Columbia University and is widely 
used in clinical and research settings (https://cssrs.columbia.edu/). Significant suicidal ideation is 
endorsed on items 4 or 5 on the C-SSRS.  
8.2. 
Efficacy Assessments (Secondary and Exploratory Endpoints) 
Planned time points for the efficacy assessments are provided in the SoA (Section 1.3).  

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All efficacy assessments measured by questionnaires or surveys will be collected electronically 
for inclusion in the electronic data capture (EDC) database. 
8.2.1. 
Patient Reported Outcomes (Secondary Efficacy Endpoints) 
8.2.1.1. 
Aggregate Worst Pain Score Change  
To evaluate the efficacy of oral TRP-8802 to treat chronic pain symptoms in patients with FM, 
the aggregate worst pain intensity (0 to 10) on the PI-NRS at baseline (Days 1 to 7) will be 
compared to the 7 day (Days 57 to 63) aggregate immediately prior to the EOT visit (Day 64).  
Pain will be measured daily using an electronic pain diary. Participants will receive a message 
via text or email at 6pm each evening with the PI-NRS questions. If the participant does not 
respond within 2 hours, a reminder text or email will be sent at 8pm. Response options will be 
closed at midnight. Participants who miss a day will be contacted the following day to remind 
them to complete their daily diary.  
8.2.1.2. 
Pain Interference  
Pain interference is the degree to which pain affects important aspects of an individual’s life, 
such as social, cognitive, and physical activities. Pain interference will be assessed using the 
4-item PROMIS pain interference scale from the PROMIS‐29+2 Profile v2.1 (PROPr) which is 
published at HealthMeasures.net (2021). 
8.2.1.3. 
Sleep  
Sleep disturbance includes assessment of sleep quality, perceived ability to fall and stay asleep, 
satisfaction of sleep, and depth of sleep. Sleep disturbance will be measured using the PROMIS 
Sleep Disturbance Short Form 8b which is published at HealthMeasures.net (2021).  
8.2.1.4. 
Chronic Pain Acceptance  
The CPAQ-8 (Fish 2010) is a validated measure that assesses activity engagement and pain 
willingness (e.g., recognizing that trying to avoid or control pain may be maladaptive for chronic 
pain). Participants rate items on a 0 to 6 scale, with 0 being “never true” and 6 being “always 
true”. 
8.2.1.5. 
Patient Global Impression of Change  
The PGI-C is a questionnaire that gauges the participant’s response to medical interventions 
using a 7-point Likert scale ranging from 1 to 7 with 1 being “very much improved” and 7 being 
“very much worse” and has been used in many pain clinical trials (Dworkin 2008; Dworkin 
2005).  
8.2.2. 
Patient Reported Outcomes (Exploratory Endpoints)  
8.2.2.1. 
Pain Mechanism Characteristics 
The 2016 FM survey, a combined measure of widespread pain (using the Michigan Body Map 
[Brummett 2016] with number of painful sites 0 to19) and symptom severity (e.g., fatigue, 

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subjective cognitive problems, headache, poor mood, scores range 0 to 12 [Neville 2018; 
Brummett 2015; Janda 2015; Brummett 2013]), will be used to form a continuous proxy index of 
nociplastic pain characteristics (range 0 to 31) (Wolfe 2016; Wolfe 2011; Wolfe 2009).  
8.2.2.2. 
Domains Relevant to Chronic Pain 
Questionnaires that measure physical and mental traits associated with pain centralization will 
include:  
• The catastrophizing scale from the Coping Strategies Questionnaires Pain (Rosenstiel 
1983) assesses pain catastrophizing, a thinking style that has been associated with the 
progression of acute pain to chronic states and with generally poorer outcomes (Kratz 
2015).  
• The PROMIS-29+2 Profile v2.1 (PROPr) (Healthmeasures.net [2021]) will be used to 
assess multiple domains: physical function, anxiety, depression, fatigue, sleep 
disturbance, ability to participate in social roles, pain interference, cognitive function, and 
pain intensity. The addition of the 2 cognitive functioning items differentiates this 
instrument from its parent the PROMIS Profile 29 (Hays 2018). The PROMIS-29+2 can 
also be used to calculate a preference score (PROMIS Preference, PROPr) (DeWitt 2020; 
DeWitt 2018; Hanmer 2018) Preference‐based scores provide an overall summary of 
health‐related quality of life on a common metric. Preference‐based scores summarize 
multiple domains on a metric ranging from 0 (as bad as dead) to 1 (perfect or ideal 
health). Scores can be used in comparisons across groups and for cost‐utility analyses. T‐
scores from the measure can be used to calculate a preference‐based score. The 
PROMIS-29+PROPr is published along with all other PROMIS measures at 
HealthMeasures.net (2021). An optional addition to the PROPr is the use of items from 
the Patient Acceptable Symptom State Questionnaire. These items added to each domain 
allow for assessment of whether the patient believes each domain is adequately managed 
(Salaffi 2015)  
8.2.2.3. 
Questionnaires and Forms Utilized During Dosing Sessions 
• The Mystical Experience Questionnaire (MEQ30) has been widely used to assess the 
mystical experiences occasioned by psychedelics (Barrett 2015; MacLean 2011). This 
30-item scale includes questions that assess mystical experiences, positive mood, 
transcendence of time and space, and ineffability.  
• The Challenging Experience Questionnaire (CEQ27) assesses challenging experiences 
and has been frequently used in studies with psychedelics, including psilocybin. 
Questions assess the difficulty, meaningfulness, spiritual significance, and change in 
well-being attributed to the psychedelic experience (Barrett 2016).  
• The Psychological Insight Questionnaire is a 23-item questionnaire that assesses insights 
into avoidance and maladaptive patterns; and goals and adaptive patterns (Davis 2021b). 
• The Monitor Rating Form is used by the therapists present during the dosing session to 
provide ratings at different time points, including during/within the dosing session, the 
day after the dosing session, and at follow-up (i.e., monitor rating of enduring effects). 

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8.2.2.4. 
Qualitative (Written) Assessment 
Participants will be asked to write a narrative describing their experience of the TRP-8802 
sessions (i.e., Visits 5 and 8) before their next in-person meeting. This narrative description will 
be discussed at the integration sessions, and will also be used in qualitative analyses to 
investigate common themes associated with this therapy in the context of FM. In addition, 
participants will be asked open-ended questions at Visit 14 to gauge persistent changes in 
behavior, thought patterns, and emotions related to the TRP-8802-assisted therapy. 
 
8.2.2.5. 
Self-Pain Enmeshment 
The enmeshment of the “self” and “pain” will be assessed by the Pictorial Representation of 
Illness and Self Measure (PRISM) (Paschali et al., 2021). PRISM can be conducted via paper or 
digitally on a computer using commercial software (https://prismium.ch/en/get-to-know-
prism.html).This task involves participants defining how they perceive themselves in relation to 
their experience of pain. To illustrate this relationship, the self and one’s pain condition are 
represented by circles on a flat surface like a piece of paper or a computer screen. Participants 
are asked to imagine that the background surface represents their life and that one of the circles 
symbolizes their concept of self. They will then be given another circle and asked to imagine that 
it represents their pain, positioning this pain circle in a location relative to the "self" circle that 
best reflects the importance or intrusiveness of pain on their life.  
[Note: When conducted via paper, the circles are operationalized by pieces of paper cut into 
circular disks that can be moved around on flat sheet of paper.] The outcome metric, called self-
illness separation (SIS), is the numerical distance between the circles and represents how much 
pain is intertwined with their concept of self. 
Figure 2. Examples of the Pictorial Representation of Illness and Self Measure (PRISM), with 
the red “pain” circle (fibromyalgia) and the yellow "self” circle. Adapted from 
Paschali et al., 2021. 

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8.2.2.6. 
Self-Complexity Task.  
Participants are given a stack of randomly ordered index cards, each containing the name of a 
descriptor (trait) from the list below (Table 5), along with a blank sheet of paper divided into 
vertical columns. The task is to group the traits that they believe go together, with each group 
representing an aspect of the patient or their life. They are free to create as many stacks of cards 
as they wish, and each stack can have as many or as few traits as desired. Participants do not 
have to use all the cards, and they can also use each card multiple times if needed. Once they 
form the stacks, they are asked to write down the index number of each trait card in the 
respective column on the blank paper, with each column dedicated to each of the stacks of cards 
the patient has formed. The outcome is the number of columns used/groups formed, and the 
number of traits in each.  
 
Table 5. The Self-Complexity Trait List. 
Accepting 
Resentful 
1.  
Outgoing 
Shy 
2.  
Courageous  
Fearful 
3.  
Independent 
Dependent 
4.  
Organized 
Unorganized 
5.  
Empathetic  
Selfish 
6.  
Creative 
Unimaginative 
7.  
Sensible  
Impulsive 
8.  
Adaptable 
Rigid 
9.  
Honest  
Manipulative 
10.  
Smart 
Stupid 
11.  
Energetic 
Fatigued 
12.  
Confident  
Insecure 
13.  
Resilient  
Helpless 
14.  
Self-Reflective  
Confused  
15.  
Focused  
Unfocused 
16.  
Assertive 
Passive 
17.  
Easygoing 
Tense 
18.  
Hardworking   
Irresponsible 
19.  
Optimistic  
Pessimistic 
20.  
Compromising 
Aggressive 
21.  
Happy 
Grieving  
22.  
Patient 
Impatient 
23.  
Open-minded 
Closed-minded 
24.  
Humorous 
Guilty 
25.  

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8.2.2.7. 
Expectations assessment 
Participants will complete the 10-item Stanford Expectations of Treatment Scale (SETS) 
(Younger 2012) to assess participant expectations of outcomes associated with this treatment. 
This scale asks participants to rate whether they think the treatment will be effective, their 
worries about their condition, whether their condition will be resolved after treatment, and fears, 
confidence, and nervousness about the treatment. 
8.2.3. 
Study Personnel Reported Outcomes (Exploratory Endpoints) 
8.2.3.1. 
Quantitative Sensory Testing 
The Quantitative Sensory Testing (QST) behavioral session will have the effect of rendering 
participants non-naïve to the experimental conditions in the imaging session, an aspect that might 
be argued to have some impact on the imaging results (particularly with regard to brain activity 
underlying cognitive and emotional functions). Advantages of this session include: identification 
of individuals with unstable ratings; a thorough training in the use of the rating scales; and the 
reduced potential for developing experiment-related anxiety and head motion in the imaging 
session. All QST procedures have been evaluated for safety and are well tolerated by chronic 
pain patients (Petersen 2015, Goodin 2009, Weissman-Fogel 2009, Price 2002). 
Cuff Pressure Pain 
Large volume, deep muscle pressure sensitivity (Graven-Nielsen 2015, Izumi 2014) will be 
assessed using an MRI-compatible rapid cuff inflator (Hokanson, Bellevue, WA) (Loggia 2012, 
Polianskis 2002, Polianskis 2001). This system includes an air compressor, computerized 
pressure controller, and a 13.5 cm by 82.5 cm Velcro-adjusted pressure cuff. Participants will 
first receive an ascending series of cuff pressures, starting at 20 mm Hg to 40 mm Hg and 
increasing in 20 mm Hg steps (10 second pressures, 20 second intervals) to tolerance or a 
maximum of 400 mm Hg. Each pressure will be rated after deflation on a 0 to 100 NRS. These 
pain ratings will be used to interpolate a series of eight tolerable cuff pressures that will be 
delivered in pseudo-randomized order and rated individually on pain intensity and 
unpleasantness. Stimulus response curves will be constructed for each participant and used for 
analysis, along with several derived variables: cuff-PPT, cuff-Pain50, and cuff-tolerance. In 
addition, tonic pain induced by continuous cuff pressure will be assessed (tonic-cuff). Each 
participant’s individually calibrated Pain40-60 pressure (i.e., pressure that evokes a 40 to 60/100 
pain rating) will be applied for 6 to 8 minutes to one gastrocnemius muscle. Pain intensity and 
unpleasantness ratings will be obtained every 60 seconds. This tonic cuff procedure will also be 
performed during fMRI. 
Visual Hypersensitivity Assessment  
In addition to hypersensitivity to painful stimuli applied to the body, many people with chronic 
pain report hypersensitivity to nonpainful sensory stimuli, including to auditory, olfactory, and 
visual stimulation (Lopez-Sola 2014, Wilbarger 2011, Geisser 2008), suggesting a global state of 
multisensory amplification in centralized pain. To measure non-somatic sensitivity, we will 
present to each participant a series of nonpainful yet aversive visual stimuli (Harte 2016). This 
10 minute task consists of different visual stimuli presented in an alternating block design. The 
control stimulus is a fixed crosshair centered in the middle of a solid color background or a black 

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screen, whereas experimental stimulus is a flashing annulus checkerboard. Participants will view 
the stimuli on a calibrated HD radiological LCD monitor. The visual stimulus will be delivered 
in ascending and random order, adjusted to varying degrees of frequency (checkerboard flashing 
only), color, shape, motion, and/or brightness level, and rated on an NRS of sensory intensity and 
unpleasantness. To avoid possible AEs in vulnerable patients, this visual stimulation task will not 
be performed if the participant has a history of photo-induced migraines or seizures. These 
participants will still be allowed to complete all other procedures.  
8.2.3.2. 
Functional Magnetic Resonance Imaging 
Note: Participants who undergo MRI will meet all institutional guidelines and safety measures 
for MRI (e.g., no metal in the body, no claustrophobia, etc…).  
The MRI sessions may include the following: 
• structural MRI  
• resting fMRI 
• proton magnetic resonance spectroscopy (1H-MRS) in the right anterior insula  
• fMRI with tonic cuff pressure evoked experimental pain 
Functional neuroimaging will include blood oxygenation level dependent (BOLD) fMRI at 3T 
using a T2*-weighted gradient echo sequence on a General Electric MR750 Discovery MR 
system with a 32-channel head coil (University of Michigan Functional MRI Laboratory). The 
entire imaging session will take no more than 1 hour in total. Familiarization procedures will be 
completed prior to fMRI to reduce anxiety. Participants will be instructed that the neuroimaging 
can be stopped at any time if a procedure becomes unbearable. The fMRI assessment should take 
a total of approximately 55 minutes to complete and may include any of the assessments 
included in Table 6. 
Table 6. Proposed Overview of Neuroimaging Visit fMRI Procedures 
Event 
Duration (mins) 
Structural 
6 
Resting state fMRI (eyes open) – five 5-minute scans 
25 
1H-MRS anterior insula (right) 
5 
Tonic cuff fMRI (eyes open) – left side – two 5-minute scans 
10 
1H-MRS anterior insula (right) 
5 
1H-MRS=proton magnetic resonance spectroscopy; fMRI=functional magnetic resonance imaging 
Functional Connectivity Magnetic Resonance Imaging  
Functional connectivity MRI (fMRI) focuses on the default mode network (DMN) and salience 
network (SLN). The DMN is a constellation of brain regions engaged in self-referential 
cognition, which are “deactivated” during externally focused tasks (Buckner 2007, Fox 2007). 
Patients with more centralized pain display increased connectivity between the DMN and the 
insula (an SLN region [Menon 2015]) which is diminished with successful treatment (Napadow 
2012). Whole-brain BOLD functional images will be acquired on the same 3 Tesla GE scanner 
described above, using a T2* weighted echo-planar sequence. Parameters will be: TR/TE 

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2040/30msec, flip angle=77°, FoV=240 mm, 33 AC-PC aligned slices, thickness 2.9 mm. 
Participants will rest comfortably in the scanner with eyes open for 25 minutes at the beginning 
of the scan session to obtain baseline measures of functional brain connectivity. Participants will 
be asked about current levels of pain intensity, fatigue and anxiety before and after resting state 
runs. Participants will also undergo two fMRI scans with tonic cuff pressure pain to evaluate 
functional brain connectivity response to deep pain. Pressure intensity will be set to each 
participant’s Pain 30 to 50 level, as determined during the behavioral visit, and applied for 
5 minutes for each scan. The pressure level from the behavioral visit will be verified prior to the 
scan initiation and re-calibrated in the event that it evokes more or less pain than anticipated. 
Pain intensity and unpleasantness ratings will be obtained at certain intervals during the test, up 
to three times and following stimulus presentation.   
Pre-processing and Analyses of fMRI 
Data will be quality checked, pre-processed using fMRIPrep (version 1.1.8) running on the high-
performance computing resources at the University of Michigan. Briefly, preprocessing steps 
include physiological noise removal (RETROICOR), motion correction, realignment, co-
registration, normalization to standard Montreal Neurological Institute (MNI) template, 
regression of nuisance variables (CompCor, motion parameters), and spatial smoothing (FWHM 
Gaussian kernel of 8 mm), and analyzed using Statistical Parametric Mapping (SPM)12 running 
under Matlab R2017a (Mathworks, Sherborn, MA, USA). The first 5 images will be discarded 
from the data set and not used for further analysis in order to correct for equilibration effects. 
Dual Regression Independent Component Analysis Approach  
The within-participant resting and cuff pain fMRI data analysis will be performed using the 
Group Independent Component Analysis (ICA) of fMRI Toolbox (GIFT) (Calhoun 2004). 
Intrinsic brain networks will be identified and quantified as component estimates. These 
components will then be validated using ICASSO software (Himberg 2004) for 10 iterations to 
ensure the reliability of ICA algorithm and to increase the robustness of the results. The number 
of independent components (networks) will be limited to 20 to 25 to minimize splitting into 
subcomponents. Participant-specific spatial maps and time courses will then be back 
reconstructed using spatio-temporal regression or dual regression options available in the toolbar, 
which ultimately creates a best approximation for each individual participant-specific Z-score 
component map. These Z-values reflect the degree of connectivity between each voxel and the 
group averaged time course of the component. To assure accuracy or know resting state 
networks, component maps will be identified with a spatial correlation using templates provided 
by previously published work (Smith 2009, Beckmann 2005). Individual resting state network 
maps will then be passed onto group second level analyses in SPM. Group analyses will be 
performed to evaluate intrinsic brain connectivity differences pre- and post-TRP-8802 treatment, 
how this intrinsic connectivity covaries with spontaneous pain intensity, and how networks 
differentially change following TRP-8802 treatment. The results will be thresholded at p < 0.001 
voxelwise and p < 0.05, cluster-corrected for multiple comparisons.   
Seed-voxel Functional Connectivity Approach 
A complementary approach to evaluate intrinsic connectivity involving seed-voxels from distinct 
brain regions will be performed using the functional connectivity “CONN” toolbox (Cognitive 
and Affective Neuroscience Laboratory, Massachusetts Institute of Technology, Cambridge, 

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USA), version 15, running on Matlab R2017a (Whitfield-Gabrieli 2012). Pre-processed fMRI 
data from each participant are entered into the toolbox along with seed-voxel regions of interest, 
where time-series from each seed is extracted. White matter, cerebrospinal fluid (CSF) signal, 
and motion parameters are entered into the analysis as covariates of no interest. A band pass field 
(frequency window: 0.01 Hz to 0.1 Hz) will be applied in order to remove linear drift artifacts 
and high frequency noise. First level analyses will be performed by correlated seed-voxel signal 
with voxel signal throughout the whole brain, thereby creating seed region to voxel Fisher 
transformed r to z connectivity maps for each time point. These connectivity maps will be passed 
on to group level analysis and analyzed similar to those described in the Dual Regression ICA 
Approach section. While this approach can yield more focused inferences, there is some bias in 
choice of exact seed location and contour (Cole 2010). Thus, seeds will be carefully chosen 
based on the results of the evoked pain fMRI scan, with particular focus on insular clusters. 
1H-MRS Acquisition and Processing 
1H-MRS provides metrics amenable to longitudinal studies. High-resolution anatomical scans 
isolate identical brain structures within individuals over time thus minimizing error that 
otherwise would occur because of slight differences in voxel location from one evaluation to the 
next. Previous 1H-MRS studies have utilized this approach to examine changes in the levels of 
central nervous system metabolites in test-retest studies (Evans 2010). 1H-MRS will be focused 
on the right posterior insula cortex both prior to and following evoked cuff pressure pain. The 
right and left sides of the brain are chosen, as this these areas have been shown to be involved in 
chronic FM pain (Harris 2009, Harris 2008). 1H-MRS studies will be performed on the same 3 
Tesla GE system as for fMRI. Details of the 1H-MRS methods are presented in previously 
published work (Harris 2009, Harris 2008). Single voxel MRS will be performed on the right 
anterior insula with a voxel size of 2 x 3 x 3 cm. The 1H-MRS scanning protocol will be PRESS 
TR/TE=2000/35 ms with and without water suppression with 64 averages and a total scan time 
of approximately 5 minutes. The water signal will be recorded using 8 averages (scan time 
16 seconds). Participants will be at rest during the 1H-MRS session.  
The raw data will undergo manual post-processing using 1H-MRS software (LCModel; Stephen 
Provencher, Oakville, Ontario, Canada). LCModel uses a linear combination of individual 
spectra obtained from pure molecular species to fit the experimental spectra (Provencher 2001). 
Values for Glx (glutamine+glutamate) will be calculated as ratios to total creatine as well as 
absolute concentrations using the water signal for normalization. Resulting metabolite absolute 
concentrations will be reported in arbitrary institutional units. Since the voxels used incorporate 
CSF, and the volume of CSF dilutes 1H-MRS-derived metabolite values, metabolite levels for 
CSF volume for each participant will be corrected as reported previously (Harris 2009). Voxel 
Based Morphometry, a toolbox that operates within the image analysis program SPM, Functional 
Imaging Laboratories, London, UK) will be used.  
Feasibility of 1H-MRS Approach 
All of the 1H-MRS procedures outlined above have been successfully implemented (Mawla 
2021, Harris 2009, Harris 2008). These studies suggest that changes in Glx and gamma 
aminobutyric acid (GABA) within the posterior and anterior insula are strongly correlated with 
improvements in pain, with reductions in clinical pain being associated with lower Glx and 
higher GABA levels.  

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8.2.3.3. 
Wrist Actigraphy 
Wrist actigraphy is a method of longitudinal sleep tracking in the ambulatory environment. Wrist 
actigraphy via the Fitbit Charge 5 or Actiwatch Spectrum (Philips Respironics) will be used. 
Actigraphy will be conducted among all participants to identify changes in sleep associated with 
TRP-8802 and psychotherapy treatment.  
Objective measures of total sleep time (sleep duration), wake after sleep onset (sleep continuity), 
and sleep timing (sleep onset and wake time) will be assessed with wrist actigraphy. Participants 
will be trained to use actigraphic devices and will also complete a sleep log (0 to 10 NRS daily 
sleep quality, time in bed, number of wake times, final wake time, estimated sleep onset) via the 
actigraphic device as well as a paper diary every morning during actigraphy for additional 
validation (Burgess 2010a, Burgess 2010b). Data extraction, cleaning, and analysis will be 
performed using the proprietary algorithm provided by the manufacturer.  
8.3. 
Other Safety Assessments  
8.3.1. 
Electrocardiograms 
For screening purposes only, a single 12-lead ECG will be obtained at the Screening visit using 
an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and QTc 
intervals. Participants will be supine and rested for approximately 5 minutes before the ECG is 
recorded.  
Screening ECGs will be read locally by the Principal Investigator for determination of meeting 
study entry criteria.  
8.3.2. 
Pregnancy Testing 
A urine pregnancy test will be performed, and results will be determined locally. Pregnancy test 
results must be negative at Screening, before TRP-8802 is administered on drug session days, 
and before fMRI is performed. 
8.3.3. 
Urine Drug and Breath Alcohol Testing 
The urine drug screen will be performed locally to detect tricyclic antidepressants, 
amphetamines, methamphetamine, MDMA (ecstasy), phencyclidine, barbiturates, 
benzodiazepines, cocaine, cannabis, and opioids, including opiates, oxycodone, and methadone. 
A breathalyzer will be used to estimate the blood alcohol content.  
At Screening, participants who test positive for cocaine, methamphetamine, or opioids will be 
excluded from the study.  
On drug session days, drug (excepting cannabis) and alcohol test results must be negative (blood 
alcohol content of less than 0.02% [verified with a second test]) before TRP-8802 is 
administered. If a participant does not have a negative result, they will be given a chance to 
reschedule (within the allowed window). A second failure will result in the participant’s study 
termination.  

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8.4. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions of AEs and SAEs can be found in Appendix 2, Section 10.2.1 and Section 10.2.2, 
respectively. Adverse event grading will be performed using the Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 
(US FDA Guidance for Industry 2007).  
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (Section 7). During dosing sessions, 
manifestations of the psychedelic experience will not be recorded as AEs unless judged by the 
therapists to exceed the intensity and/or duration of expected reactions. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the Baseline visit until the EOT visit, at the time points 
specified in the SoA (Section 1.3). Medical occurrences that begin before Baseline deep 
phenotyping but after obtaining informed consent will be recorded as Medical History, not as 
AEs. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 2, Section 10.2.3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek information on AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Recording and 
Follow-up of AE and/or SAE (Appendix 2, Section 10.2.3 and Section 10.2.4). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 

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is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Appendix 2, Section 10.2.3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB, and investigator(s). 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the TRP-8802 IB or state other documents and will 
notify the IRB, if appropriate according to local requirements. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB, if appropriate according 
to local requirements. 
8.4.5. 
Pregnancy 
• Details of all pregnancies in female participants and in female partners of male 
participants will be collected for the duration of active intervention.  
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the female 
participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner). 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• The participant/pregnant female partner of a male participant will be followed until the 
end of pregnancy, either live birth or termination, to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the 
participant/pregnant female partner and the neonate and the information will be 
forwarded to the sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information in 
former study participants/pregnant female partner, he or she may learn of an SAE through 
spontaneous reporting. 

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• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study. 
8.5. 
Clinical Safety and Monitoring 
At enrollment, potential participants will be appropriately screened for exclusionary psychiatric 
conditions, medical co-morbidities, and concomitant medications. In addition medical screening 
will include blood tests including complete blood count (CBC), comprehensive metabolic panel 
(CMP), urine drug screen (UDS). Subjects with any clinically significant lab abnormalities will 
be excluded from participation. 
Throughout the entire study, suicidal ideation will be assessed during every in-person visit using 
the C-SSRS and clinical assessment during participant interviews. Significant suicidal ideation is 
endorsed on items 4 or 5 on the C-SSRS. If the patient screens positive on the C-SSRS at any 
time during the study, they will undergo a more detailed suicidal risk assessment by study 
clinician. If they are determined to be at risk of suicide they will be transferred to ED for further 
Psychiatric evaluation. 
During administration, heart rate and BP will be assessed before TRP-8802 capsule 
administration and at 30, 60, 90, 120, 180, 240, 300, and 360 minutes after capsule 
administration. Blood pressure and pulse measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, cell phones). If a 
patient's blood pressure is >200 systolic or >110 diastolic for more than 15 minutes (i.e. 4 
consecutive readings) they will be transferred to ED whether or not they are symptomatic. 
AEs will be monitored at every study visit. Study staff will also be available throughout the 
course of the study for emergent AEs. Throughout the administration period, therapists will 
assess the presence and intensity of participant behaviors, symptoms, and non-verbal cues, which 
includes questions about the presence/intensity of behaviors, signs, and reported symptoms, such 
as peacefulness, yawning, nausea/vomiting, quantity of speech, anxiety, sleepiness, crying, 
restlessness, visual changes, euphoria, and feelings of unreality. They will also complete 
assessments of mood and safety at the end of the administration sessions.  
The session therapists are trained to reassure the participants if they experience acute anxiety, 
agitation, paranoia, or panic. However, in the unlikely event that those symptoms do not respond 
to reassurance, or if a participant experiences a severe AE outside of the expected challenging 
experiences associated with psilocybin therapy, one of the session therapists will contact the on-
call study physician. The study physician will use their clinical judgment to determine the most 
appropriate medical intervention. There will be an automated external defibrillator located on 
site and a crash cart containing medicine and equipment for emergency resuscitation, including 
rescue medication as described in section 6.8.1. After dosing sessions, participants will be 
discharged only if they meet all criteria in section 6.1.2., including being accompanied home by 
a responsible friend or family member.  
During the post-dosing period (visits 6, 7, 9, 10), monitors will also complete assessments of 
participant mood and safety after therapy visits.  
8.6. 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 

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8.7. 
Genetics and/or Pharmacogenomics 
Genetics and/or pharmacogenomics are not evaluated in this study. 
8.8. 
Biomarkers 
Neurophysiologic biomarkers being evaluated in this study include fMRI (Section 8.2.3.2). 
8.9. 
Immunogenicity Assessments 
Immunogenicity assessments are not evaluated in this study. 
8.10. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 

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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
The objective of this study is to evaluate the safety of oral TRP-8802 in concert with 
psychotherapy among adult participants with FM. Based on previous studies with psilocybin in 
other conditions (Davis 2021a, Carhart-Harris 2016), it is hypothesized that oral TRP-8802 in 
concert with psychotherapy will be safe and well-tolerated among participants with FM.  
9.2. 
Sample Size Justification 
The study is intended to gather preliminary evidence of safety of TRYP-8802 in conjunction 
with psychotherapy in participants with FM, and to help inform future clinical studies. As this is 
a pilot study, the sample size was selected based on previous pilot studies of psilocybin-assisted 
therapy in other conditions (e.g., major depression disorder) (Davis 2021a, Carhart-Harris 2016). 
Accordingly, for this pilot, proof-of-concept study, participants will be screened with the goal of 
enrolling approximately 10 participants who will complete both doses of TRP-8802 and the 
primary and secondary outcome measures, and complete the study and follow-up periods. 
Note: “Enrolled” means a participant's agreement to participate in the clinical study following 
completion of the informed consent process and all screening assessments successfully. Potential 
participants who are screened for the purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled.  
9.3. 
Analysis Sets 
The following analysis populations have been defined for this study: Safety Population, Full 
Analysis Set Population (FAS), and Per Protocol (PP) Population. For this analysis, the 
definitions are presented in Table 7. 

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Table 7. Populations for Analysis 
 
Analysis Set 
Description 
Safety Population 
All participants who are enrolled, and for whom study intervention is 
initialized under the study protocol. Participants who do not receive 
any amount of the study drug will still contribute to the safety 
analysis if study intervention was initialized but not completed, since 
all AEs of intervention must be assessed. All safety analyses will 
utilize the Safety Population. 
Full Analysis Set Population 
All participants who receive 2 doses of study drug, and who have any 
post-baseline clinical assessments. The secondary efficacy analyses 
will be performed using data from the FAS Population.  
Per Protocol Population 
The subset of the FAS Population who complete 4 weeks of follow 
up post second dose with no major protocol deviations (including but 
not limited to: failure to satisfy all inclusion and exclusion criteria, 
failure to adhere to all protocol-required restrictions and prohibitions, 
receipt of prohibited concomitant procedures or therapies, and non-
compliance to protocol-specific procedures) as determined by a 
review of participant data. The analysis of efficacy performed using 
data from the PP Population will be considered supportive of the 
FAS analysis. 
AEs=adverse events; FAS=Full Analysis Set; PP=Per Protocol 
9.4. 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized and approved prior to the database lock and 
will include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints. 
9.4.1. 
General Considerations 
All descriptive statistical analyses will be performed using SAS (Version 9.4 or higher) or 
R (Version 3.6.2 or higher), unless otherwise noted. For categorical variables, the number and 
percentage within each category of the parameter will be calculated. For continuous variables, 
the number of participants with no missing data (n), mean, median, standard deviation (SD), 
minimum, and maximum values will be presented. 
For the purpose of statistical analyses, a month is considered equivalent to 30 days, and a year is 
considered equivalent to 365 days.  
9.4.2. 
Primary Endpoints (Safety) 
The safety of treatment with TRP-8802, which is evaluated by vital signs (HR and BP) and AEs, 
is the primary endpoint. Vital signs and AEs will be collected from the Baseline (deep 

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phenotyping) visit until the EOT visit (Day 64) at the time points specified in the SoA 
(Section 1.3).  
Descriptive statistics will be used to present the count and the percentage of participants in the 
Safety Population who experience an AE. 
9.4.3. 
Secondary Endpoints (Efficacy) 
The results of secondary endpoints will be shown at the baseline and each follow up visits based 
on Full Analysis Set Population and the PP Population. Pain score, pain interference, sleep 
disturbance, chronic pain acceptance, and the patient global impression of change were chosen as 
secondary measures given their relevance to FM symptom management (Clauw 2014; Williams 
2011; Kratz 2007; Farrar 2001).  
Aggregate worst pain score change from baseline to EOT (Day 64) will be measured on the 
11-item PI-NRS. Average daily pain score will be measured from Day 1 to 7 (baseline) versus 
the 7 days immediately before EOT (Days 57 to 63). Changes in the worst pain intensity from 
the baseline through EOT will be presented in Full Analysis Set Population and the PP 
Population. A 30% or 2-point decrease in aggregated worst pain scores at either movement or 
rest will be considered a clinically significant response (Farrar 2001). 
Pain interference is the degree to which pain affects important aspects of an individual’s life, 
such as social, cognitive, and physical activities. The pain interference and its change from the 
baseline will be shown at the baseline and each follow up visit. Sleep disturbance includes 
assessment of sleep quality, perceived ability to fall and stay asleep, satisfaction of sleep, and 
depth of sleep. Sleep disturbance and its change from the baseline will be reported as well. In 
addition, chronic pain acceptance will be presented at baseline and follow up. Finally, patient 
impression in clinical status change will be shown.  
9.4.4. 
Exploratory Endpoints (Efficacy) 
Exploratory endpoints may be used for possible future investigation(s) and are further described 
in the SAP.  
9.4.5. 
Handling of Missing Data 
Every effort will be undertaken to limit premature discontinuations and ascertain completeness 
of data collection. All other analyses will utilize only actual participant data which is collected; 
no imputation of missing data will be performed unless there is > 10% of data missing. 
9.4.6. 
Subgroup Analysis 
Due to small sample sizes, there no subgroup analyses are planned in this study. 
9.5. 
Interim Analysis 
No interim analysis is planned. 

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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, TRP-8802 IB, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB by the investigator and reviewed and 
approved by the IRB before the study is initiated. 
• Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB 
o Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
o Providing oversight of the conduct of the study at the site and adherence to the IRB 
and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of local 
regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB or 
study center. 

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• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. These data may be shared in this form with other research collaborators after 
completion of appropriate data sharing agreements via the University of Michigan.  
• The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the informed consent. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB members, and by inspectors from regulatory authorities. 
10.1.5. 
Safety Review Committees Structure 
 
The SRC will be responsible for the assessment of safety and to make recommendations 
regarding study progression. The SRC will be composed of the principal investigator, a study 
therapist, and a study physician. Participant safety, which includes safety signal detection at any 
time during the study, will be continuously monitored by the SRC. All safety data collected will 
be summarized and reviewed by the SRC for agreement of next steps. 
In particular, data will be reviewed by the SRC if one of the following Stopping Rules is met 
(Section 5.5):  
• one SAE considered at least possibly related to the study drug 
• one Grade 3 or Grade 4 AE considered at least possibly related to the study drug 
• clinically similar Grade 2 AEs considered at least possibly related to the study drug in 
2 participants 
• HPPD 
10.1.6. 
Dissemination of Clinical Study Data 
This study will be registered at ClinicalTrials.gov, and results from this study will be submitted 
to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed 
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10.1.7. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on CRFs unless transmitted to 
the sponsor or designee electronically (e.g., questionnaire data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in the reference section of the EDC 
system. 
• The investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can 
impact participant safety and/or reliability of study results. These pre-defined parameters 
will be monitored during the study and important deviations from the QTLs and remedial 
actions taken will be summarized in the clinical study report. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 7 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. 
10.1.8. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• Case report form data that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 

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10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. The study site will be closed upon study 
completion. The study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of the study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants 
by the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IRB, the regulatory authorities, and any contract research organization(s) used 
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up 
10.1.10. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings.  
• Study participants shall not be identified in any publication or presentation; only study 
identification numbers shall be used. If photographs are to be used as illustrations, 
separate informed consent shall be obtained for this purpose, and photographs shall be 
rendered anonymous. 
 
 

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10.2. 
Appendix 2: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.2.1. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 

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10.2.2. 
Definition of SAE 
An SAE is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. Examples of such events include invasive 
or malignant cancers, intensive treatment for allergic bronchospasm, blood dyscrasias, 
convulsions or development of intervention dependency or intervention abuse. 
• HPPD – see Section 2.3 for definition.  
 
10.2.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 

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• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s medical 
records in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested. 
In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Tryp-8802 IB in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report. However, it is very important that 
the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data. 

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• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide a copy of any post-mortem findings including 
histopathology.  
• New or updated information will be recorded in the originally submitted documents. 
• The investigator will submit any updated SAE data within 24 hours of receipt of the 
information. 
10.2.4. 
Reporting of SAEs 
SAE Reporting via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE will be the electronic data collection 
tool.  
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• If the electronic system is unavailable, then the site will email a scanned copy of a 
completed paper AE CRF within 24 hours.  
• If a paper copy of the AE CRF is unavailable, the site will email the Sponsor’s 
designee to report the subject number, SAE term, and relationship of the event to the 
investigational product. Email contact information for reporting SAE data when the 
electronic data collection tool is unavailable will be provided to the site during the Site 
Initiation Visit. 
• Initial notification of an SAE via telephone does not replace the need for the 
investigator to complete the AE CRF within the designated reporting time frames.  
• After the study is completed at the site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
information on a previously reported ongoing SAE deemed related to the study 
intervention after the electronic data collection tool has been taken off-line, then the 
site can report this information on a paper SAE form (see next section) directly to the 
Sponsor. 
• Contacts for SAE reporting will be provided during the Site Initiation Visit. 
 
SAE Reporting to via Paper Data Collection Tool 

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• Facsimile transmission of the SAE paper data collection tool is the preferred method 
to transmit this information to the Safety Associate. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
• Contacts for SAE reporting will be provided during the Site Initiation Visit. 
 
 

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10.3. 
Appendix 3: Abbreviations and Definitions  
Term 
Definition 
1H-MRS 
proton magnetic resonance spectroscopy 
5-HT 
5-hydroxytryptamine  
ΔHR 
change in heart rate 
AE 
adverse event 
BOLD 
blood oxygen level dependent 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
CPAQ-8 
Chronic Pain Acceptance Questionnaire 8 
CRF 
case report form 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMN 
default mode network 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOT 
end of therapy 
FAS 
Full analysis set 
FDA 
(United States) Food and Drug Administration 
FM 
fibromyalgia 
fMRI 
functional connectivity magnetic resonance imaging 
GABA 
gamma aminobutyric acid 
GLM 
general linear model 
Glx 
glutamine+glutamate 
HIPAA 
Health Insurance Portability and Accountability Act 
HPPD 
hallucinogen persistent perception disorder 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICA 
Independent Component Analysis 
IRB 
Institutional Review Board 
MDMA 
3,4-methylenedioxy-methamphetamine 
MNI 
Montreal Neurological Institute 
MRI 
magnetic resonance imaging 
PANAS 
Positive and Negative Affect Schedule 
PGIC 
Perceived Global Impression of Change 
PHQ-8 
Patient Health Questionnaire depression scale 
PI-NRS 
Pain Intensity-Numeric Rating Scale 

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Term 
Definition 
PK 
pharmacokinetics 
PP 
per protocol 
PRN 
pro re nata translated as needed 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PROMIS29+2 
Patient Reported Outcomes Measurement Information System 29-item profile measure 
plus 2 cognitive functioning items 
QST 
Quantitative Sensory Testing 
QTLs 
quality tolerance limits 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCID-5 
Structured Clinical Interview for DSM-5 
SCID-5-PD 
Structured Clinical Interview for DSM-5 for Personality Disorders 
SLN 
salience network 
SoA 
Schedule of Activities 
SPM 
Statistical Parametric Mapping 
SRC 
Safety Review Committee 
TRP-8802 
psilocybin drug substance prepared according to current manufacturing processes at 
Usona Institute, which is supplying study drug 
 
 
 
 
 
 
 

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11. 
References 
Barrett FS, Bradstreet MP, Leoutsakos JS, Johnson MW, Griffiths RR. (2016). The Challenging 
Experience Questionnaire: Characterization of challenging experiences with psilocybin 
mushrooms. J Psychopharmacol. 30(12):1279-1295. 
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