A Pilot Study to Assess the Use of Methylone in the Treatment of PTSD IMPACT-1 (Investigation of Methylone for Post-Traumatic Stress Disorder [PTSD])
Phase: PHASE1
Conditions: Post Traumatic Stress Disorder
Sponsor: Transcend Therapeutics

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 1 of 80 
Clinical Study Protocol 
A Pilot Study to Assess the Use of Methylone in the Treatment 
of PTSD 
IMPACT-1 (Investigation of Methylone for Post-Traumatic 
Stress Disorder [PTSD]) 
Investigational Medicinal Product: Methylone 
Sponsor Reference: TT-TSND-201 
 
IND Number: 167109 
 
Amendment #7 Protocol Version and Date: V 6.0, USA, 11 Oct 2024 
Amendment #6 Protocol Version and Date: V 5.2, USA, 15 Jul 2024 
Amendment #5 Protocol Version and Date: V 5.1, USA, 17 May 2024 
Amendment #4 Protocol Version and Date: V 5.0, 08 Feb 2024 
Amendment #3 Protocol Version and Date: V 4.0, 21 Apr 2023  
Amendment #2 Protocol Version and Date: V 3.1, 11 Oct 2022 
Amendment #1 Protocol Version and Date: V 2.0, 08 Jun 2022 
Original Protocol Version and Date: V 1.0, 11 March 2022 
Clinical Development Phase: 1b/2a 
 
 
 
 
 
 
Sponsor: Transcend Therapeutics 
 
80 5th Avenue, 18th Floor 
 
New York, New York  
 
10011 
 
United States of America 
 
 
 
 
CONFIDENTIALITY STATEMENT
The information provided in this document is strictly confidential and is available for review to Investigators, 
potential Investigators, appropriate ethics committees and other national authorities. No disclosure should take 
place without the written authorisation from the Sponsor, except to the extent necessary to obtain informed 
consent from potential participants. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 2 of 80 
SPONSOR SIGNATURE PAGE 
 
For and on behalf of the Study Sponsor: 
Signatures:  
 
 
 
 
 
 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 3 of 80 
Site Investigator Signature Page 
PROTOCOL NUMBER: 
TT-TSND-201 
PROTOCOL TITLE:  
A Pilot Study to Assess the Use of Methylone in the Treatment 
of PTSD 
IMPACT-1 (Investigation of Methylone for Post-Traumatic 
Stress Disorder [PTSD]) 
Protocol Date and Version:  US V6.0, 11Oct2024 
 
The undersigned confirms that the following Protocol has been agreed and accepted and that 
the Site Investigator agrees to conduct the study in compliance with the approved Protocol and 
in accordance with the revised Declaration of Helsinki 1996. I will adhere to all ICH, GCP, 
FDA and local applicable regulations and guidelines regarding clinical studies during and after 
study completion. I will ensure that all sub-investigators and other study staff members have 
read and understand all aspects of this protocol. I agree to cooperate fully with Transcend and 
its designated vendors during the study. I agree to ensure that the confidential information 
contained in this document will not be used for any other purpose other than the evaluation or 
conduct of the clinical study without the prior written consent of the Sponsor. 
I also confirm that I will, when required by the Sponsor, make the findings of the study publicly 
available through publication or other dissemination tools without any unnecessary delay and 
that an honest accurate and transparent account of the study will be provided; and that any 
discrepancies and serious breaches of GCP from the study as planned in this Protocol will be 
explained.  
 
Site Investigator Name: 
Signature:  
 
...................................................................................................... 
  
 
Date:....../....../...... 
 
 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 5 of 80 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................ 2 
KEY STUDY CONTACTS ..................................................................................................... 4 
TABLE OF CONTENTS ........................................................................................................ 5 
LIST OF TABLES ................................................................................................................... 9 
1 
PROTOCOL SUMMARY ......................................................................................... 10 
1.1 
Synopsis .................................................................................................................... 10 
1.2 
Study Design Schema ................................................................................................ 14 
1.3 
Schedule of Assessments (SoA) ................................................................................ 15 
1.4 
List of Abbreviations ................................................................................................. 17 
2 
INTRODUCTION ...................................................................................................... 19 
2.1 
Background ............................................................................................................... 19 
2.1.1 
Post-Traumatic Stress Disorder ........................................................................ 19 
2.2 
Study Rationale ......................................................................................................... 20 
2.3 
Nonclinical Development .......................................................................................... 20 
2.4 
Clinical Development ................................................................................................ 21 
2.4.1 
Completed Open-Label Study in PTSD Patients (IMPACT-1 Part A) .............. 21 
2.4.2 
Completed Healthy Volunteer Studies ............................................................... 22 
2.4.3 
Retrospective Case Series .................................................................................. 23 
3 
OBJECTIVES AND ENDPOINTS ........................................................................... 25 
4 
STUDY DESIGN ......................................................................................................... 28 
4.1 
Study Design Overview ............................................................................................ 28 
4.2 
Study Visit Breakdown ............................................................................................. 29 
4.3 
Planned Duration of Study ........................................................................................ 34 
4.4 
Rationale for Study Design ....................................................................................... 35 
4.5 
Dose Rationale .......................................................................................................... 35 
4.6 
End of Study .............................................................................................................. 37 
4.6.1 
End-of-Study Definition ..................................................................................... 37 
4.6.2 
Exit Plan ............................................................................................................. 37 
4.7 
Data and Safety Monitoring Board ........................................................................... 37 
4.8 
Criteria For Termination of Dosing for An Individual Participant ........................... 38 
4.9 
Criteria for Interruption of Randomization/Dosing of New Participants .................. 39 
5 
STUDY TREATMENTS ............................................................................................ 41 
5.1 
Name and Description of Investigational Product(s) ................................................ 41 
5.2 
Study Drug Administration ....................................................................................... 41 
5.3 
Psychological and Medical Support on Dosing Days ............................................... 41 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 6 of 80 
5.3.1 
Psychological Support ....................................................................................... 41 
5.3.2 
Medical Support ................................................................................................. 42 
5.4 
Discharge Criteria ..................................................................................................... 42 
5.5 
Concomitant Medication ........................................................................................... 43 
5.5.1 
Prohibited Medications ...................................................................................... 43 
5.6 
Special Warnings and Guidance ............................................................................... 44 
5.6.1 
General Considerations ..................................................................................... 44 
5.6.2 
Recorded Content ............................................................................................... 44 
5.6.3 
Management of Suicidality ................................................................................ 44 
5.6.4 
Management of Psychological Events ............................................................... 44 
5.6.5 
Management of Cardiovascular Events ............................................................. 45 
5.6.6 
Management of Thermoregulation .................................................................... 45 
5.6.7 
Management of Osmoregulation ........................................................................ 46 
5.7 
Assessment of Compliance with Treatment .............................................................. 46 
5.8 
Blinding ..................................................................................................................... 46 
5.9 
Emergency Unblinding ............................................................................................. 46 
6 
SELECTION OF PARTICIPANTS .......................................................................... 47 
6.1 
Inclusion Criteria ....................................................................................................... 47 
6.2 
Exclusion Criteria ...................................................................................................... 48 
6.3 
Study Restrictions ..................................................................................................... 50 
6.3.1 
Lifestyle Restrictions .......................................................................................... 50 
6.3.2 
Meals and Dietary Restrictions ......................................................................... 51 
6.4 
Participant Withdrawal Criteria ................................................................................ 51 
6.5 
Follow-Up Procedures ............................................................................................... 52 
7 
SAFETY ASSESSMENTS ......................................................................................... 53 
7.1 
Clinical Laboratory Evaluations ................................................................................ 53 
7.2 
12-Lead Electrocardiogram ....................................................................................... 53 
7.3 
Vital Signs and Temperature ..................................................................................... 54 
7.4 
Physical Examinations .............................................................................................. 54 
7.5 
Pregnancy Testing ..................................................................................................... 54 
7.6 
Columbia-Suicide Severity Rating Scale .................................................................. 54 
7.7 
Adverse Event Reporting .......................................................................................... 55 
7.7.1 
Definition and Criteria ...................................................................................... 55 
7.8 
Evaluating Adverse Events and Serious Adverse Events ......................................... 57 
7.8.1 
Reporting Procedures and Requirements .......................................................... 58 
7.8.2 
Prompt Reporting of Serious Adverse Events .................................................... 60 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 7 of 80 
7.8.3 
Special Considerations ...................................................................................... 60 
7.9 
Other Assessments .................................................................................................... 61 
8 
PSYCHOMETRIC ASSESSMENTS ........................................................................ 62 
8.1 
Clinician-Administered Psychometric Assessments ................................................. 62 
8.1.1 
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) ............................... 62 
8.1.2 
Mini International Neuropsychiatric Interview ................................................. 62 
8.1.3 
Structured Clinical Interview for DSM-5 Personality Disorders (SCID-5-PD) 62 
8.1.4 
Structured Interview Guide for the Montgomery-Åsberg Depression Rating 
Scale (MADRS) (SIGMA) ................................................................................................. 63 
8.1.5 
Clinician Global Impressions Scale – Severity .................................................. 63 
8.1.6 
Clinician Global Impressions Scale – Improvement ......................................... 63 
8.2 
Participant-Completed Psychometric Assessments .................................................. 63 
8.2.1 
PTSD Checklist for DSM-5 (PCL-5) .................................................................. 63 
8.2.2 
Life Events Checklist for DSM-5 (Extended Version) ........................................ 63 
8.2.3 
Structured Clinical Interview for DSM-5 Screening Personality Questionnaire 
(SCID-5-SPQ) ................................................................................................................... 64 
8.2.4 
Sheehan Disability Scale .................................................................................... 64 
8.2.5 
Patient Global Impression of Change ................................................................ 64 
8.2.6 
Patient Global Impression of Severity ............................................................... 64 
8.2.7 
Warwick-Edinburgh Mental Wellbeing Scale .................................................... 64 
8.2.8 
Post-Traumatic Growth Inventory ..................................................................... 64 
8.2.9 
Beck Depression Inventory-II ............................................................................ 64 
8.3 
Sleep Quality Assessments ........................................................................................ 65 
8.3.1 
Pittsburgh Sleep Quality Index .......................................................................... 65 
 
 
 
 
 
 
8.4.3 
Blinding Integrity Questionnaire (Part B only) ................................................. 65 
9 
STATISTICS AND DATA ANALYSIS .................................................................... 66 
9.1 
Randomization and Participant Allocation ............................................................... 66 
9.2 
Sample Size Determination ....................................................................................... 66 
9.3 
Statistical Analysis Plan ............................................................................................ 66 
9.4 
Analysis Sets ............................................................................................................. 66 
9.4.1 
Modified Intent-to-Treat (mITT) Population ..................................................... 66 
9.4.2 
Per-Protocol Population .................................................................................... 67 
9.4.3 
Safety Population ............................................................................................... 67 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 8 of 80 
9.5 
Statistical Analysis .................................................................................................... 67 
9.5.1 
Safety Statistical Analysis .................................................................................. 67 
9.5.2 
Efficacy Statistical Analysis ............................................................................... 68 
9.6 
Handling of Missing or Incomplete Data .................................................................. 68 
10 
DATA HANDLING AND RECORD KEEPING ..................................................... 69 
10.1 Collection of Data ..................................................................................................... 69 
10.2 Inspection of Records ................................................................................................ 69 
10.3 Retention of Records ................................................................................................. 69 
10.4 Confidentiality and Data Protection .......................................................................... 70 
11 
MONITORING, AUDIT, AND INSPECTION ....................................................... 71 
11.1 Study Monitoring ...................................................................................................... 71 
11.2 Audits and Inspections .............................................................................................. 71 
11.3 Quality Control and Quality Assurance .................................................................... 71 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ....................................... 72 
12.1 Ethical Conduct of the Study .................................................................................... 72 
12.2 Approval by Institutional Review Board / Ethics Committee ................................... 72 
12.3 Written Informed Consent ......................................................................................... 72 
13 
REFERENCES ............................................................................................................ 73 
14 
APPENDICES ............................................................................................................. 76 
14.1 Appendix 1– Sampling Summary ............................................................................. 76 
14.2 Appendix 2 – Prohibited Medications – Psychoactive Substances ........................... 77 
14.3 Appendix 3 – Prohibited Medications/Elimination Half-Life - Drug Interactions ... 78 
14.4 Appendix 4 – Childbearing Potential ........................................................................ 80 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 9 of 80 
LIST OF TABLES  
Table 1: 
Objectives and Endpoints for Part A ..................................................................... 25 
Table 2: 
Objectives and Endpoints for Part B ..................................................................... 26 
Table 3:  
Study Interventions Administered ......................................................................... 41 
Table 4:  
Clinical Laboratory Evaluations ............................................................................ 53 
 
 
 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 10 of 80 
1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Study Title: A Pilot Study to Assess the Use of Methylone in the Treatment of PTSD 
IMPACT-1 (Investigation of Methylone for Post-Traumatic Stress Disorder [PTSD]) 
Investigational Medicinal Product: Methylone 
Clinical Phase: 1b / 2a 
 
Rationale: 
Methylone is a new and potentially effective treatment option for participants with PTSD. The purpose of this 
pilot study is to evaluate the safety, tolerability, and efficacy of methylone in adult participants with PTSD. 
The study will be conducted in two parts. Part A will be open-label and will enroll approximately 15 evaluable 
participants with PTSD in the United States (US), United Kingdom (UK) and Europe. After completion of Part 
A, enrollment will begin for Part B, which will be double-blind, placebo-controlled multi-site global study and 
will enroll approximately 64 evaluable participants with PTSD.   
Objectives and Endpoints: 
This is a two-part study with Part A focusing on safety as the primary objective and Part B focusing on efficacy 
as the primary objective. Therefore, each Part of the study has separate objectives and endpoints as presented 
in the tables below. 
 
Part A 
Objective 
Endpoints 
Primary 
 
To assess the safety and tolerability 
of oral methylone administered 
weekly over 4 weeks in 
participants with PTSD.  
• 
Incidence and severity of TEAEs. 
• 
Incidence and severity of AESIs. 
• 
Change in HR, SBP, DBP and temperature. 
• 
Clinically significant changes in ECG. 
• 
Changes from baseline in clinical laboratory parameters 
(clinical chemistry, hematology and urinalysis). 
Secondary 
 
To assess the efficacy of methylone 
in treating PTSD symptoms. 
Mean change from baseline to Week 10 in CAPS-5 (total severity 
score assessed over 1 week)  
 
Percentage of participants having: 
• 
Treatment response, defined as a  
o 
≥ 10 point reduction on the CAPS-5 from baseline 
o 
30% improvement from baseline on CAPS-5 
o 
50% improvement from baseline on CAPS-5 
• 
Remission, defined as a score of ≤ 11 on the CAPS-5 
To assess the effect of methylone 
on sleep quality, functional 
disability, treatment satisfaction, 
quality of life, and physical 
function in participants with PTSD.  
Mean change from baseline in the following scales: 
• 
CGI-S 
• 
MADRS 
• 
SDS 
• 
PCL-5 
• 
PGI-S 
• 
BDI-II 
• 
WEMWBS 
• 
PSQI 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 12 of 80 
Abbreviations: 
 AE = adverse event; AESI = adverse event of special interest; 
BDI-II = Beck Depression Inventory-II; DBP = diastolic blood pressure; CAPS-5 = Clinician-Administered PTSD Scale for DSM-5; CGI-
I = Clinician Global Impression of Improvement; CGI-S = Clinical Global Impression of Severity; C-SSRS = Columbia Suicide Severity 
Rating Scale; DBP = diastolic blood pressure; ECG = electrocardiogram; HR = heart rate; LEC-5 = Life Events Checklist for DSM-5; 
MADRS =  Montgomery-Åsberg Depression Rating Scale; 
 MINI = Mini 
International Neuropsychiatric Interview; PCL-5 = PTSD Checklist for DSM-5; PGI-C = Patient Global Impression of Change; PGI-S = 
Patient Global Impression of Severity; PSQI = Pittsburgh Sleep Quality Index; PTGI = Post-traumatic Growth Inventory; PTSD = Post-
traumatic stress disorder; SDS = Sheehan Disability Scale; SBP = systolic blood pressure; TEAEs = treatment-emergent adverse events; 
WEMWBS = Warwick-Edinburgh Mental Wellbeing Scale.  
Overall Design 
Brief Summary: 
This is a two-part study to assess methylone for the management of the symptoms of PTSD. Part A is an open-
label, non-controlled assessment in approximately 15 evaluable participants with PTSD to assess early safety 
and efficacy and to confirm procedures included in the blinded portion (Part B) of the study. After completion 
of Part A, enrollment for Part B will begin in approximately 64 participants. Unless otherwise stated, Part B is 
identical to Part A with the exception of the inclusion of a placebo arm in Part B. 
 
The open-label treatment in Part A is: 
• 
Methylone 150 mg, with a booster administration of 100 mg administered 90 (±10) minutes after the 
initial administration, during each dose session. 
 
Part B is a randomized, double-blind, parallel-group, placebo-controlled assessment of methylone for the 
management of the symptoms of PTSD. This multi-center study will be conducted in up to 25 sites globally. 
Planned enrollment includes approximately 79 evaluable participants (approximately 15 in Part A and 
approximately 64 in Part B). There are 4 planned dose sessions for each participant. Participants in Part B will 
be randomized 1:1 to the two study treatment arms and will receive the randomized treatment at each of the 
weekly dose sessions for the duration of the study. 
 
The two blinded study treatment arms in Part B are: 
• 
Methylone 150 mg, with a booster administration of 100 mg administered 90 (±10) minutes after the 
initial administration, during each dose session. 
• 
Matched placebo at each timepoint (initial + booster) during each dose session.  
 
For each participant in Parts A and B, the study will consist of: 
• 
Screening Period (Day -28 to Baseline): Informed consent, eligibility assessment, and enrollment of 
eligible participants. 
• 
Baseline/Preparatory Session (Day -4 to Day -1): Baseline assessments, confirmation of eligibility, 
and a preparatory psychoeducation session leading to enrollment confirmation.  
• 
Treatment Period (Day 1 to Day 24): Four weekly dose sessions, with associated remote sessions. 
The dose sessions will last at least 8 hours, and until all effects (physical and psychological) have 
resolved (whichever is longer). Each dose session will be followed by a safety phone call 1 day after 
dosing and efficacy assessments 2 days after dosing.  Each dosing period will be recorded for quality 
and training purposes. The recordings may be reviewed to ensure the dosing session monitor is adhering 
to the dosing session monitor training. 
• 
Follow-Up Period (Day 29 to Day 64): Follow-Up visits for safety and efficacy will occur at 1, 2, 3 
and 6 weeks post-final study drug administration. In addition, there will be Reflection Sessions 1, 2 and 
3 weeks post-final study drug administration. Participants will be contacted via telephone on Day 57 
(±2 days) for Follow-Up. 
 
The expected duration of participation for each participant who completes all study visits, from Screening to 
the EOS visit, is up to 16 weeks. 
Study Participants:  
Medically healthy adult participants aged between 18 to 65 years, inclusive. Participants must meet the 
diagnostic and statistical manual of mental disorders, fifth edition (DSM-5) criteria for current moderate to 
severe PTSD diagnosis with a symptom duration of at least 6 months at Screening, as assessed by the CAPS-

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 13 of 80 
5 and the Life Events Checklist for DSM-5 (LEC-5) and must have failed at least one treatment for PTSD 
(either psychotherapy or pharmacological treatment).  
In addition, participants must not have a primary diagnosis of any other DSM-5 disorder, as assessed by the 
MINI Version 7.0.2, or have any history, physical or psychological symptoms, medication or other relevant 
findings that would make a participant unsuitable for the study based on the clinical judgement of study 
personnel. 
Treatment Duration: 
The treatment duration for both Parts A and B will be the same: four weeks as weekly dosing (Day 1, Day 8 
[±1 day], Day 15 [±1 day], and Day 22 [±1 day]). 
Data Monitoring  
The objective of the Data and Safety Monitoring Board (DSMB) is to provide an independent review of safety 
data (Parts A and B) during the clinical trial.  
DSMB meetings will be scheduled to occur after 8 participants in Part A have completed the Day 29 Follow-
Up visit, or EOS if the participant withdraws early (Safety Run-in Phase), and once at the conclusion of 
enrollment in Part A and after all participants in Part A have the opportunity to complete the Day 29 Follow-
Up visit.  
For Part B, DSMB meetings will occur at intervals of approximately 20 participants completing the Day 29 
Follow Up Visit or EOS if the participant withdraws early. Ad hoc DSMB meetings can occur if needed. 
 
Dose and Route of Administration:  
Participants will be fasted for 2 hours predose and until 2 hours after the initial administration during each dose 
session. Methylone (or matched placebo in Part B) will be orally administered on Day 1, Day 8 (±1 day), 
Day 15 (±1 day) and Day 22 (±1 day). An initial administration of 150 mg methylone (or matched placebo in 
Part B) will be given, followed by a booster administration of 100 mg methylone (or matched placebo in Part B) 
90 (±10) minutes later. 
Criteria for Evaluation: 
Safety will be assessed through adverse event (AE) reporting, monitoring of AESIs, 12-lead ECG, vital signs, 
physical examinations and clinical laboratory evaluations; suicidal ideation and behavior will be evaluated 
using the Columbia-Suicide Severity Rating Scale (C-SSRS).  
 
Efficacy will be assessed through several psychometric assessments and scales that assess PTSD symptoms 
and quality of life. 
 
In addition, assessments will be made of sleep quality, treatment satisfaction, and psychedelic effects. 
Statistical Analysis:  
Safety parameters will be listed and summarized using descriptive statistics for Parts A and B. 
All efficacy endpoint data will be listed for individual participants. All continuous efficacy endpoints will also 
be summarized by descriptive statistics (n, arithmetic mean, standard deviation [SD], median, minimum, and 
maximum) by study part, overall, and by treatment (for Part B) and study period. All categorical efficacy 
endpoints will be summarized by descriptive statistics (n, percentage). 
For Part A the change from baseline to each timepoint will be presented along with a Paired t-test p-value. 
A Mixed Model for Repeated Measures (MMRM) will be fitted for select efficacy endpoints to analyze the 
difference between treatments for Part B. The model will include treatment, visit, and treatment by visit 
interaction as fixed effects, where visit is the repeated effect. The baseline value will be included (if applicable) 
as a covariate. All tests will be based on two-sided significant level of 0.05. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 14 of 80 
1.2 
Study Design Schema 
 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 15 of 80 
1.3 
Schedule of Assessments (SoA)  
 
Screening 
Treatment Period  
Follow-Up Period 
ET 
Visit Number 
1 
2  
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
- 
Visit Session 
Scrn 
BL/ 
Prep 
Treatment 1 
Treatment 2 
Treatment 3 
Treatment 4 
FU1 
FU2 
FU3 
TC 
FU4 
/EOS 
ET visit 
Study Day(s) 
-28 to 
BL 
-4 to -
1 
1 
2 
3 
(+1) 
8 
(±1) 
9 
10 
(+1) 
15 
(±1) 
16 
17 
(+1) 
22 
(±1) 
23 
24 
(+1) 
29 
(±1) 
36 
(±2) 
43 
(±2) 
57 
(±2) 
64 
(±3) 
- 
ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med Hx  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance Use Hx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Use Assessment1 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Pregnancy Test2 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X3 
Physical Exam 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X4 
X3 
Vital Signs5 
X 
X 
X6 
 
 
X6  
 
 
X6 
 
 
X6 
 
 
X 
 
 
 
 
X3 
12-Lead ECG 
X 
 
X7 
 
 
X7 
 
 
X7 
 
 
X7 
 
 
X 
 
 
 
 
X3 
Clinical Labs8 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X3 
MINI (central rater) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LEC-5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPQ  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-PD (Central rater)12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CAPS-5 (past month; central 
rater) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Preparatory Session10 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization11 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Admin13 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
1 Urine drug screen must be confirmed as negative prior to enrollment and each dose. Site must confirm patient is not otherwise impaired prior to dosing. 
2 Urine test for WOCBP only. Pregnancy test must be confirmed as negative prior to enrollment and each dose. Serum FSH may be conducted at Screening to confirm non-childbearing potential. 
3 Only required if the ET visit occurs prior to the Day 29 visit. 
4 Height and weight will be collected at Screening; weight will be conducted at the end of study. 
5 Includes heart rate, blood pressure, and temperature.  
6 Vital signs during the dose session: BP and HR - predose, every 30-minutes post-initial dose, and prior to the booster dose; temperature- predose (within 10 min), and every 60 minutes.  
7 ECGs will be captured predose and at the end of the dosing session.  
8 Clinical labs will be assessed by a central lab. 
9 C-SSRS should be conducted at any unscheduled visits. 
10 To be performed after all baseline assessments. 
11 Subjects enrolled in Part B only. 
12 Completed only if participant endorses a positive response to paranoid personality disorder, antisocial personality disorder, and borderline personality disorder on the SPQ. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 16 of 80 
 
Screening 
Treatment Period  
Follow-Up Period 
ET 
Visit Number 
1 
2  
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
- 
Visit Session 
Scrn 
BL/ 
Prep 
Treatment 1 
Treatment 2 
Treatment 3 
Treatment 4 
FU1 
FU2 
FU3 
TC 
FU4 
/EOS 
ET visit 
Study Day(s) 
-28 to 
BL 
-4 to -
1 
1 
2 
3 
(+1) 
8 
(±1) 
9 
10 
(+1) 
15 
(±1) 
16 
17 
(+1) 
22 
(±1) 
23 
24 
(+1) 
29 
(±1) 
36 
(±2) 
43 
(±2) 
57 
(±2) 
64 
(±3) 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CAPS-5 (past-week; central 
rater) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
MADRS (central rater) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
CGI-S (central rater) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
CGI-I (central rater) 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
PCL-5 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
BDI-II 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
SDS 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
WEMWBS 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
PGI-S 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
PGI-C 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
PSQI 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
PTGI 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
BIQ11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
Reflection session  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
Abbreviations: 
AE = adverse event; BDI-II = Beck Depression Inventory-II; BIQ = blinding integrity questionnaire; BL = 
baseline; BP = blood pressure; CAPS-5 = Clinician-Administered PTSD Scale for DSM-5; CGI-I = Clinician Global Impression of Improvement; CGI-S = Clinical Global Impression of 
Severity; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EOS = end of study; ET = early termination; FSH = follicle stimulating hormone; FU = follow up; 
HR = heart rate; LEC-5 = Life Events Checklist for DSM-5; MADRS =  Montgomery-Åsberg Depression Rating Scale; MINI = Mini International Neuropsychiatric Interview; 
 
 PCL-5 = PTSD Checklist for DSM-5; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; PSQI 
= Pittsburgh Sleep Quality Index; PTGI = Post-traumatic Growth Inventory; Scrn = screening; SCID-5-PD = Structured Clinical Interview for DSM-5 Personality Disorders; SDS = Sheehan 
Disability Scale; SPQ = Screening Personality Questionnaire; TC = telephone call; WEMWBS = Warwick-Edinburgh Mental Wellbeing Scale; WOCBP = women of childbearing potential. 
 
 
13 Study drug is administered in clinic and patients are monitored for at least 8 hours following each dose. The dose is given in two divided doses: an initial dose, followed by a booster dose 90 minutes later.  

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 17 of 80 
1.4 
List of Abbreviations 
Abbreviation 
Definition 
 
 
5-HT 
serotonin 
AE 
adverse event 
ADHD 
attention deficit hyperactivity disorder 
ADL 
activities of daily living 
AESI 
Adverse Events of Special Interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ARCI 
Addiction Research Center Inventory 
BDI-II 
Beck Depression Inventory – II 
BIQ 
Blinding Integrity Questionnaire 
BMI 
body mass index 
BP 
blood pressure 
CAPS-5 
Clinician-Administered PTSD Scale for DSM-5 
CGI-I 
Clinician Global Impressions Scale – Improvement 
CGI-S 
Clinician Global Impressions Scale – Severity 
CNS 
central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DA 
dopamine 
DAT 
dopamine transporters 
DBP 
diastolic blood pressure 
DED 
dread of ego dissolution 
DMT 
dimethyltryptamine 
DSMB 
Data and Safety Monitoring Board 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
EC 
ethics committee 
ECG 
electrocardiogram  
eCRF 
electronic case report form 
eGFR 
glomerular filtration rate 
EOS 
End-of-Study 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
HR 
heart rate 
HRT 
hormonal replacement therapy 
HV 
healthy volunteers 
IB 
Investigator Brochure 
ICH 
International Council for Harmonisation 
ICF 
informed consent form 
IM 
intramuscularly 
IMP 
investigational medicinal product 
IRB 
institutional review board 
ITT 
Intention-to-Treat 
LEC-5 
Life Events Checklist for DSM-5 
LFTs 
Liver Function Tests 
LSD 
lysergic acid diethylamide 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MAOI 
monoamine oxidase inhibitors 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 18 of 80 
Abbreviation 
Definition 
 
 
MDMA 
3,4-methylenedioxymethamphetamine 
MDPV 
methylenedioxypyrovalerone 
MINI 
Mini International Neuropsychiatric Interview 
MMRM 
Mixed Model for Repeated Measures 
NCS 
non-clinically significant 
NE 
norepinephrine 
NET 
Norepinephrine transporters 
OB 
oceanic boundlessness 
OTC 
over-the-counter 
PCL-5 
PTSD Checklist for DSM-5 
PGI-C 
Patient Global Impression of Change Scale 
PGI-S 
Patient Global Impression of Severity Scale 
PK 
pharmacokinetic 
PSQI 
Pittsburgh Sleep Quality Index 
PT 
preferred term 
PTSD 
post-traumatic stress disorder 
PTGI 
post-traumatic growth inventory 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
REC 
research ethics committee 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SCID-5-PD 
Structured Clinical Interview for DSM-5 Personality Disorders 
SD 
standard deviation 
SDS 
Sheehan Disability Scale 
SERT 
serotonin transporter 
SIGMA 
Structured Interview Guide for the MADRS 
SNRI 
serotonin and norepinephrine reuptake inhibitors 
SOC 
system-organ class 
SOP 
Standard Operating Procedure 
SPQ 
Screening Personality Questionnaire 
SSRI 
selective serotonin reuptake inhibitor 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VESSPA-SS 
Evaluation of Subjective Effects of Substances with Abuse Potential 
questionnaire  
VMAT-2 
vesicular monoamine transporter 2 
VRS 
visionary re-structuralization 
WEMWBS 
Warwick-Edinburgh Mental Wellbeing Scale 
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential 
WONCBP 
woman of non-childbearing potential 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 19 of 80 
2 
INTRODUCTION 
2.1 
Background 
Methylone 
(3,4-methylenedioxy-N-methylcathinone) 
is 
a 
synthetic 
empathogen, 
psychostimulant and member of the drug class known as synthetic cathinones (Poyatos 2021, 
Poyatos 2022, Poyatos 2023, WHO 2014). Methylone acts by altering the function of plasma 
membrane transporters for serotonin (5-HT), dopamine (DA), and norepinephrine (NE) 
(Baumann 2018, Cameron 2013). Methylone and 3,4-methylenedioxymethamphetamine 
(MDMA) are structurally and pharmacologically similar but have distinct differences in 
potency and activity. Both methylone and MDMA act as mixed reuptake inhibitor/releasing 
agents. However, methylone has lower effects on serotonin (4x) and dopamine (3x) but a 
greater (2x) effect on norepinephrine release compared to MDMA. In addition, methylone’s 
affinity for the vesicular monoamine transporter 2 (VMAT2) is about 13 times lower than that 
of MDMA (Eshleman 2013). Unlike MDMA, methylone does not directly interact with 5-HT2A 
receptors which likely contributes to the lack of hallucinogenic effect. These results suggest 
that the subjective experience and physiological effects of methylone may be less pronounced 
than MDMA.  
Methylone was first synthesized and proposed as a potential antidepressant in the 1990s 
(Shulgin 1996). Based on healthy volunteer and nonclinical studies, methylone has 
physiological effects that may translate into a fast acting treatment for psychiatric disorders 
such as PTSD. Nonclinical studies show that methylone has fast-acting, robust, long-lasting 
anxiolytic and antidepressant-like activity (Warner-Schmidt 2023). Methylone also facilitates 
fear extinction in a preclinical model of PTSD (Yu 2022), like MDMA (Baumann 2018) and 
is consistent with the potential therapeutic benefit.  Data from studies in healthy volunteers 
(Poyatos 2021, Poyatos 2022, Poyatos 2023) suggest a shorter acting pharmacokinetic profile 
compared with MDMA, which is further is supported by uncontrolled clinical use in a case 
series of methylone in patients with PTSD (Kelmendi 2022).  
Methylone likely involves MDMA-like entactogenic effects with a strong sense of emotional 
openness, enhanced empathy and reduced fear. These physiological effects could be 
particularly well-suited as treatment for persistent neuropsychiatric disorders characterized by 
excessive anxiety, fear, or that arise following exposure to traumatic events, potentially with 
milder side effects than is seen with MDMA. 
2.1.1 Post-Traumatic Stress Disorder 
Post-traumatic stress disorder (PTSD) is a serious debilitating disorder that occurs in people 
who have experienced or witnessed a traumatic event such as a natural disaster, a serious 
accident, or who have been threatened with death, sexual violence, or serious injury. Current 
estimates suggest that 1 in 3 people that experience a traumatic event will be affected by PTSD, 
however there is no clear biomarker that explains why some people develop the condition and 
others do not (NHS 2023). Post-traumatic stress disorder has a point prevalence estimated at 
nearly 3% in the UK (McManus 2009). International studies of lifetime prevalence show 
considerable variations in rates between nations, however it is estimated that 6.8% of US adults 
and one in 11 people in the UK will be diagnosed with PTSD in their lifetime (McManus 2009, 
NIMH 2023, Greenberg 2015). Symptoms of PTSD include intrusive thoughts and memories, 
negative effects on cognition and mood, hyperarousal and reactivity, and avoidance that do not 
remit for at least 1 month subsequent to exposure to a traumatic event (Koenen 2017). 
Individuals with PTSD may experience a substantial reduction in quality of life and 
relationships, and the disability resulting from PTSD can have further negative consequences 
such as obesity, hypertension, comorbid mental health conditions, and suicidality (Scott 2008, 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 20 of 80 
Kibler 2009, Dorrington 2014, Tarrier 2004). Approximately half of people diagnosed with 
PTSD also have a diagnosis of major depressive disorder (MDD) across a range of populations 
with varying health and social histories (Flory 2015, Kessler 1995, Peconga 2020, Stein 2001).  
First-line pharmacological treatments for PTSD include selective serotonin reuptake inhibitor 
(SSRI) medications, and psychotherapy (Arroll 2005, Cipriani 2018, Forbes 2010, Hoskins 
2015, Kato 2018, Stein 2006). Unfortunately, many people suffering from PTSD either do not 
receive treatment or are not responsive to existing treatments (Stein 2006). Thus, there is a 
substantial treatment gap for patients with PTSD, which creates considerable burdens on 
patients and healthcare systems.  
2.2 
Study Rationale 
Methylone is a new and potentially effective treatment option for participants with PTSD. This 
consideration is based on: 
1. Nonclinical data supporting the efficacy of methylone in animal models of depression, 
anxiety, and PTSD (Schmidt-Warner 2023, Yu 2022) 
2. The efficacy and safety demonstrated in the clinical use of methylone in patients with 
PTSD (Kelmendi 2022) and MDD (see Section 2.4.3). 
3. The similarity of the physiological responses to methylone and MDMA (see 
Sections 2.4.2 and 2.4.2) with the knowledge that MDMA has demonstrated 
effectiveness for PTSD (Mitchell 2021). 
4. The belief that the reduced intensity of those physiological responses to methylone will 
improve tolerability compared with MDMA. 
The purpose of this two-part study is to evaluate the safety, tolerability, and efficacy of four 
boosted administrations of methylone (two administrations per dose session) at weekly 
intervals in participants with PTSD. This study will be open-label, non-controlled in Part A 
and double-blind, placebo-controlled in Part B. Part A of the study will enroll approximately 
15 evaluable participants with PTSD and will provide early safety and efficacy information as 
well as confirm study procedures for the study. Part B is identical to Part A with the exception 
of the addition of a placebo arm. Findings from this study will be used to design and power 
future clinical trials to further evaluate the efficacy and safety of methylone for the treatment 
of PTSD. 
2.3 
Nonclinical Development 
Methylone has been assessed in multiple GLP and non-GLP primary pharmacology, safety 
pharmacology, pharmacokinetic (PK) and toxicology nonclinical studies. These are described 
in detail in the Investigator Brochure (IB); key safety findings are summarized below: 
• Methylone demonstrates fast-acting, robust, long-lasting anxiolytic and antidepressant-
like activity (Warner-Schmidt 2023). 
• Methylone readily crosses the blood-brain barrier and exhibits rapid kinetics, with peak 
blood concentrations (Cmax) occurring 1.5 hours after oral administration. Methylone 
plasma concentrations increased in a dose-related manner; the half-life of methylone in 
rats is relatively short (approximately 3 hours). 
• Mild hyperthermia has been observed in pharmacological safety studies (maximum 
+1.2°C at 15 mg/kg/day in beagle dogs and +1.2°C at 50 mg/kg/day in Sprague-Dawley 
rats). 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 21 of 80 
• Methylone does not inhibit any cardiac ion channels (Cardiac Profiler Panel, Eurofins), 
or bind to serotonin receptor 5HT2B, a known cardiotoxic signal. 
• Methylone hydrochloride-related respiratory effects included dose-dependent increases 
in respiratory rate and minute volume, and concomitant decreases in tidal volume. 
Respiratory effects were noted for all dose groups and did not resolve by the end of 
monitoring (≥6 hours post-dose). These results are consistent with the known 
pharmacology of methylone and other psychomotor stimulants. 
• Notable effects were observed on all measured neurobehavioral domains (activity, 
autonomic, excitability, neuromuscular, physiological, and sensorimotor) in some 
animals following 25, 50, and 75 mg/kg doses in Sprague-Dawley rats. These effects 
generally peaked by 1.5 to 6 hours post-dose and resolved by 24 hours post-dose. In the 
highest dose group, effects arousal and decreased pupil response persisted past 24 
hours. 
• Repeat dose toxicology study in dogs noted no abnormal coagulation, clinical 
chemistry, or urinalysis. There was no indication of damage to the renal or hepatic 
systems following repeated dosing with methylone  
2.4 
Clinical Development 
Methylone is currently in development for post-traumatic stress disorder (PTSD) and other 
neuropsychiatric conditions. To date methylone has been formally evaluated in 51 participants, 
including 14 PTSD patients from Part A of this study (Jones 2023) and 37 healthy volunteers 
from two completed pharmacokinetic studies (Poyatos 2021, Poyatos 2022, Poyatos 2023). 
Additionally, two case series in 21 patients with PTSD (Kelmendi 2022) and 7 patients with 
MDD (Averill 2023) have been published. These case series supported the initial therapeutic 
rationale of methylone for neuropsychiatric conditions. 
2.4.1 Completed Open-Label Study in PTSD Patients (IMPACT-1 Part A) 
Part A of this study, completed in the UK, was an open-label evaluation of the safety, 
tolerability, and efficacy of methylone in adults with severe PTSD (CAPS-5 ≥ 35; Jones 2023). 
Fourteen (14) participants were treated with open-label methylone once a week for 4 weeks (4 
treatment sessions). During each treatment session, participants received an initial dose of 150 
mg methylone followed by 100 mg of methylone 90 minutes later. Following the Treatment 
Period, participants entered a 6-week Follow-up Period and a final study visit at Week 10. The 
primary efficacy endpoint was the change from baseline on the CAPS-5 total severity score. 
At baseline, the mean CAPS-5 score was 47.8 points. 
Treatment with methylone resulted in rapid, robust, and durable effects. Two days after the 
first dose, the mean change from baseline in CAPS-5 total severity score was -8.4 points. 
Methylone provided robust improvements in CAPS-5, with the mean change from baseline of 
-23.3 points two days after the 2nd dose. Six weeks after the last dose, the results were durable 
with a mean change from baseline in CAPS-5 of -36.2 points. Remission, defined as a CAPS-
5 total score of ≤11, was achieved by the majority of participants (61.5%) at the end of study.  
Methylone was well tolerated with no drug-related or treatment-emergent serious adverse 
events to date. The most commonly occurring treatment-emergent adverse event (TEAE) was 
headache (43%), followed by decreased appetite (29%), non-cardiac chest pain (21%), and 
fatigue (21%). One unrelated serious adverse event of ‘victim of assault’ occurred after a 
participant was off study drug for 20 days. 
 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 22 of 80 
2.4.2 Completed Healthy Volunteer Studies  
Two healthy volunteer studies have been conducted evaluating the safety, pharmacokinetics 
(PK), and physiological effects of methylone.  
Open Label Comparison of Methylone and MDMA Study 
An open-label study was conducted to evaluate the acute subjective and physiological effects 
of methylone compared to MDMA after oral administration (Poyatos 2021). The study enrolled 
14 participants who received single oral doses of methylone (n=8) ranging from 100 mg to 300 
mg (mean: 187.5 mg) or MDMA (n=6) ranging from 75 mg to 100 mg (mean: 87.5 mg). 
Subjects were assessed for vital signs, subjective effects using visual analogue scales (VAS), 
the Addiction Research Centre Inventory (ARCI) short form, and the Evaluation of the 
Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) questionnaire, and oral 
fluid concentrations.  
Acute pharmacological effects produced by methylone followed the prototypical 
psychostimulant and empathogenic profile associated with MDMA, although they were less 
intense. Oral fluid concentrations of MDMA and methylone peaked at 2 hours and rapidly 
decreased by 4 hrs.  
Methylone, at doses up to 300 mg, was well tolerated without safety concerns. Both methylone 
and MDMA were well-tolerated, and no SAEs were reported. Subjects mentioned slight 
feelings of dizziness and headache after methylone and MDMA administration. MDMA 
produced a higher mean increase in both systolic (SBP) and diastolic (DBP), whereas 
methylone produced a slightly higher mean increase in heart rate, with similar time to maximal 
effect for both compounds.  
Randomized Double-Blind Phase 1 Clinical Trial 
A randomized, double-blind, placebo-controlled, cross-over study was conducted to evaluate 
the pharmacokinetic and subjective experiences in 29 healthy volunteers. The study was 
divided into two parts, a methylone dose-range finding study in 12 healthy volunteers 
(Poyatos 2022), followed by a study evaluating 200 mg methylone, 100 mg MDMA, and 
placebo in 17 healthy volunteers (Poyatos 2023). 
Each subject participated in a total of 3 sessions during which they received single oral doses 
of study drug, each separated by 1 week. In Part 1 three methylone dose escalation cohorts and 
one MDMA comparison was evaluated:  
• 50 mg, 100 mg, placebo (n=3) 
• 100 mg, 150 mg, placebo (n=2) 
• 150 mg, 200 mg, placebo (n=4) 
• 200 mg methylone, 100 mg MDMA, placebo (n=3) 
In Part 2, all subjects (n=17) received 200 mg methylone, 100 mg MDMA, and placebo. A 
200 mg methylone dose was selected because it evoked similar subjective effects to the 100 mg 
dose of MDMA (e.g., high or liking feelings), which is considered a common dose used in 
previous pharmacological studies. 
Study outcome measures included pharmacokinetic parameters of methylone, MDMA, and 
their respective metabolites, subjective effects (eg, VAS, ACRI, and VESSPA), physiological 
effects (SBP, DPB, HR), and drug tolerability. All subjects completed the methylone doses 
without any serious adverse effects, including psychiatric symptoms, psychotic episodes, or 
hallucinations. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 23 of 80 
Subjective Effects  
Subjective effects of methylone on VAS subscales related to euphoria (stimulated, high, good 
effects, liking, feeling close to others), ARCI MBG subscale (euphoria), and the VESSPA SOC 
(pleasure and sociability) subscale, displayed dose-dependent increases in effects with higher 
doses. All methylone doses ≥100 mg were significantly different from placebo. 
Changes in subjective effects measured using VAS and questionnaires were comparable 
between methylone and MDMA. The magnitude of the peak effects was similar between active 
drug treatments, however, methylone typically reached maximal response earlier (0.5 h vs 0.75 
h) and resolved more quickly compared to MDMA (2.5-3 h vs 4 h). Changes in VAS were 
mainly related to stimulation and well-being, altered perception, and empathy.   
Methylone was well tolerated, with no serious adverse events at doses ranging from 50 mg to 
200 mg. A total of 3 subjects (21.4%) treated with methylone experienced a total of 5 treatment-
emergent adverse events (TEAE). No TEAE term occurred in more than 1 subject. None of the 
TEAEs were considered to be related to methylone administration. 
Dose-dependent increases in blood pressure and heart rate occurred after treatment with 
methylone. The maximum mean increase in systolic blood pressure was 25.2 mmHg at 0.75 h 
following administration of 200 mg methylone. Blood pressure increases were transient and 
returned to baseline values within approximately 3 hours at all doses. Temperature was 
relatively unchanged following methylone administration. 
Overall, both methylone and MDMA administration resulted in significant physiological, 
subjective, and psychomotor effects compared to placebo. However, these effects occurred 
earlier and dissipated more quickly following methylone administration compared to MDMA 
administration. These results indicate that the pharmacological effects of methylone and 
MDMA occur before maximal plasma concentrations. 
2.4.3 Retrospective Case Series 
PTSD Patients 
In a clinical case series of 21 patients with severe PTSD, treatment with methylone produced 
acute and enduring improvements in PTSD symptoms, without any notable lasting adverse 
effects.  
Starting doses of methylone were between 100 mg and 270 mg. In 19 of 21 cases, an additional 
“booster” dose of methylone was administered 1 h after the initial dose to extend the therapeutic 
window and optimize clinical response. 
All patients achieved at least minimal improvement on the clinical global impression of 
improvement (CGI-I score of 1, 2 or 3) following treatment, with 17 achieving “much” or “very 
much improved” ratings. This trend was observed even for patients who received only a single 
dose of methylone (n=9), where 8 patients (89%) achieved CGI-I scores of 1 or 2. For patients 
with multiple methylone dosing sessions (n=12), initial improvement was noted after the first 
session in 83% (n=10) of patients. Methylone was well tolerated, and no patients discontinued 
treatment due to adverse events. 
These results suggest that methylone has the potential to be a safe, rapid, and effective 
treatment for PTSD. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 24 of 80 
Major Depressive Disorder (MDD) Patients 
In a clinical case series of 7 patients with MDD, treatment with methylone produced acute and 
enduring improvements in MDD symptoms, without any notable lasting adverse effects.  
Following methylone dosing session(s), which included single methylone dosing sessions in 2 
of the 7 MDD patients, a CGI-I score of 1 or 2, corresponding to “much improved” or “very 
much improved” was achieved by all participants. 
Four of the 7 case narratives included information on durable response, of greater than 5 years 
in 1 patient, greater than 2 years in 2 patients, and of unknown duration in 1 patient. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 27 of 80 
Checklist for DSM-5; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; PSQI = 
Pittsburgh Sleep Quality Index; PTGI = Post-traumatic Growth Inventory; PTSD = Post-traumatic stress disorder; SDS = 
Sheehan Disability Scale; SBP = systolic blood pressure; TEAEs = treatment-emergent adverse events; WEMWBS = 
Warwick-Edinburgh Mental Wellbeing Scale.  
 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 28 of 80 
4 
STUDY DESIGN 
4.1 
Study Design Overview 
This is a two-part study to assess methylone for the management of the symptoms of PTSD. 
Part A is an open-label, non-controlled assessment in approximately 15 evaluable participants 
with PTSD to provide early safety and efficacy information and to confirm procedures for the 
study. After completion of Part A, Part B will begin and enroll approximately 64 participants. 
Part B is identical to Part A with the exception of the inclusion of a placebo arm in Part B. 
The open-label treatment in Part A is: 
• Methylone 150 mg, with a booster administration of 100 mg administered 
90 (±10) minutes after the initial administration, during each dose session. 
 
Part B is a randomized, double-blind, parallel-group, placebo-controlled portion of the study 
designed to assess the utility of methylone for the management of the symptoms of PTSD. This 
is a multi-center global study that will be conducted in up to approximately 25 sites. 
Planned enrollment includes approximately 79 evaluable participants (approximately 15 in Part 
A and approximately 64 in Part B). There are 4 planned dose sessions for each participant at 
weekly intervals. During each dose session, participants will receive two administrations of 
study drug (initial dose plus a booster dose). Participants in Part B will be randomized 1:1 to 
receive either methylone or placebo at each of the weekly dose sessions for the duration of the 
study. 
The first 8 participants from Part A who have the opportunity to complete the Day 29 Follow-
Up visit are considered the Safety Run-in participants. The DSMB will be convened to review 
the safety data of these participants. The DSMB will subsequently be convened to review the 
safety data after all participants in Part A have the opportunity to complete the Day 29 Follow-
Up visit. 
The two blinded study treatment arms for Part B are: 
• Methylone, an initial administration of 150 mg, followed by a booster administration 
of 100 mg 90 (±10) minutes after the initial administration, during each dose session.  
• Matched placebo at each timepoint (initial + booster) during each dose session.  
For Part B, DSMB meetings will occur at intervals of approximately 20 participants completing 
the Day 29 Follow Up Visit or EOS if the participant withdraws early.  
For each participant in Parts A and B, the study will consist of: 
• Screening Period: Informed consent, eligibility assessment, and enrollment of eligible 
participants. 
• Baseline/Preparatory Session: Baseline assessments, confirmation of eligibility, and 
a preparatory psychoeducation session leading to enrollment confirmation. 
• Treatment Period: Four weekly dose sessions, with associated remote sessions. The 
dose sessions will last at least 8 hours, and until all effects (physical and psychological) 
have resolved (whichever is longer). Each dose session will be followed by a safety 
phone call 1 day after dosing and efficacy assessments 2 days after dosing. Each dosing 
period may be recorded for quality and training purposes. The recordings will be 
reviewed to ensure the dosing session monitor is adhering to the dosing session monitor 
training and for training purposes. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 37 of 80 
• Based on the completed Phase 1 studies and PK modelling, an initial administration of 
150 mg would be anticipated to induce meaningful psychological effects that would be 
extended by the booster administration of 100 mg given 90 minutes later (±10 minutes). 
• Based on the retrospective case series, the use of multiple dose sessions would optimize 
the likelihood of a clinical benefit. 
• This dose regimen would provide a total dose during a dose session of 250 mg, but 
because the dose is split, the Cmax is anticipated to be lower than if 250 mg was given 
as a single dose. 
o This initial administration is lower than the maximum single dose given to the 
healthy volunteers (up to 300 mg) in the open-label Phase 1 study. 
o The proposed dose is significantly lower than the dose given to most patients 
reported in the Case Series. 
Taken together, these data suggest that a dose of 150 mg plus a booster dose of 100 mg 
administered on four occasions over 4 weeks would provide a physiological response that is 
believed to predict clinical benefit, and that this regimen would be well tolerated and provide 
confidence that this proposed study can be conducted safely. 
To further ensure the safety of participants, all study drug administration will be under the 
direct supervision of the Research Site Staff and a dosing session monitor, and a DSMB will 
regularly review emerging safety data. 
4.6 
End of Study 
4.6.1 End-of-Study Definition 
The EOS is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study including the last visit (Day 64).  
4.6.2 Exit Plan 
At the conclusion of each participant’s participation, they will be provided with an Exit Plan. 
The Exit Plan summarizes the study treatment, their current medications, and provides them a 
contact for more information about the study if needed. Participants may request a referral for 
further therapeutic or medical care if appropriate. Enrolled participants who terminate the study 
early will be provided an Exit Plan at their last contact.  Participants who continue into an 
extension study are not required to have an Exit Plan. 
4.7 
Data and Safety Monitoring Board  
The objective of the DSMB is to review safety data (Part A and Part B) during the clinical trial.  
The DSMB will comprise: 
• A psychiatrist, preferably with PTSD experience. 
• Cardiologist/Internal medicine specialist. 
• A statistician. 
Data and Safety Monitoring Board meetings will be scheduled to occur after 8 participants in 
Part A have completed the Day 29 Follow-Up visit, or EOS if the participant withdraws early 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 38 of 80 
(Safety Run-in Phase) and once after all participants in Part A have the opportunity to complete 
the Day 29 Follow-Up visit.  
For Part B, DSMB meetings will occur at intervals of approximately 20 participants completing 
the Day 29 Follow Up Visit or EOS if the participant withdraws early. Ad hoc DSMB meetings 
will occur as needed.  
The safety and tolerability data to be reviewed will include, at a minimum, AEs, physical 
examinations, 12-lead ECGs, vital signs, clinical laboratory evaluation results, and C-SSRS 
results, summarized by a non-voting Statistician. There are no stopping rules for either efficacy 
or futility. 
Further details on the operation of the DSMB will be defined in a standalone supporting 
document.  
4.8 
Criteria For Termination of Dosing for An Individual Participant 
Dosing will be terminated for an individual participant if any of the following occur: 
1) If a participant experiences an intolerable AE. 
2) If a participant demonstrates significant non-compliance. 
3) If a participant is administered a prohibited medication which, in the opinion of the 
Investigator and Medical Monitor, has the potential to significantly impact participant 
safety or data integrity. 
4) If a female participant becomes pregnant. 
5) If any participant reports Active Suicidal Ideation since last study drug administration, as 
evidenced by a ‘Yes’ response to the C-SSRS Suicidal Ideation questions 4 or 5. 
6) If a participant reports any suicidal behavior since last study drug administration, as 
evidenced by a ‘Yes’ response to the following suicidal behavior questions on the C-SSRS: 
a) Actual attempt, or 
b) Interrupted attempt, or 
c) Aborted attempt. 
7) If a participant experiences Grade 3 Hypertension (as defined in the National Cancer 
Institute CTCAE [Version 5.0]) during a dosing session: 
a) Grade 3: SBP ≥160 mmHg or DBP ≥100 mmHg, requiring the need for medical 
intervention with more than one drug or more intensive therapy than previously used. 
8) If a participant develops an abnormality of liver function tests (LFTs) that meets the 
following criteria during the treatment period: 
a) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT): 
i) >5-fold upper limit of normal (ULN), or  
ii) >3-fold ULN with concomitant serum total bilirubin ≥2-fold the ULN with ≥35% 
direct. 
9) If a participant experiences a clinically significant elevation of their temperature by >2.0oC 
(and ≥38oC) during the dosing session. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 39 of 80 
10) If a participant experiences a severe psychological event related to dosing that requires an 
intervention. 
11) If a participant experiences a cardiovascular event associated with dosing that requires an 
intervention. 
12) If a participant develops a neurological deficit. 
13) If a participant experiences a treatment-related SAE. 
a) Note that an SAE that is considered not treatment-related by the Investigator should not 
automatically lead to discontinuation of dosing. Instead, that participant and the SAE 
should be discussed with the Medical Monitor and Sponsor (or delegate) to make a 
determination as to whether dosing should continue or be terminated. 
Any participant who discontinues the study early will complete an Early Termination visit and 
an Exit Plan will be provided to the participant. 
 
4.9 
Criteria for Interruption of Randomization/Dosing of New Participants 
If the following occur, enrollment/randomization and dosing of new participants will be 
interrupted until a DSMB review has indicated that it is safe to continue: 
1) If there appears to be an unacceptable tolerability profile based on the nature, frequency 
and severity of observed AEs and/or clinical safety monitoring.  
2) If two participants report Active Suicidal Ideation since last study drug administration, as 
evidenced by a ‘Yes’ response to the C-SSRS Suicidal Ideation questions 4 or 5. 
3) If two participants report any suicidal behavior since last study drug administration, as 
evidence by a ‘Yes’ response to the following suicidal behavior questions on the C-SSRS: 
a) Actual attempt, or 
b) Interrupted attempt, or 
c) Aborted attempt. 
4) If two participants experience Grade 3 Hypertension (SBP ≥160 mmHg or DBP ≥100 
mmHg), or Grade 2 (SBP ≥140 mmHg or DBP ≥90 mmHg), (as defined in the National 
Cancer Institute CTCAE [Version 5.0]), persisting over 48 hours post dosing, and require 
the need for medical intervention with more than one drug or more intensive therapy than 
previously used. 
5) If two participants develop an abnormality of LFTs that meets the following criteria during 
the treatment period: 
a) AST or ALT: 
i) >5-fold ULN, or  
ii) >3-fold ULN with concomitant serum total bilirubin ≥2-fold the ULN with ≥35% 
direct. 
6) If two participants experience a clinically significant elevation of their temperature by >2oC 
(and ≥38oC) during the dosing session. 
7) If two participants experience a severe psychological event related to dosing that requires 
an intervention. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 40 of 80 
8) If two participants experience a cardiovascular event associated with dosing that requires 
an intervention. 
9) If two participants develop a neurological deficit. 
10) If three participants experience a treatment-related SAE of any nature. 
11) If two participants experience the same SAE. 
The Investigators and Sponsor have the right to terminate the study or suspend enrollment at 
any time. The Investigator(s) will be notified by telephone and in writing if the Sponsor decides 
to suspend or terminate the study for any reason. The written notice will provide the 
Investigator with the reason that the site and/or study was suspended or terminated, along with 
instructions on how the site should proceed. Should the Sponsor terminate the study early, all 
participants will complete an Early Termination visit and an Exit Plan will be provided to the 
participant. 
Reasons for terminating the study may include, but are not limited to, the following: 
• Discovery (from this or other studies) of an unexpected, serious or unacceptable health 
hazard to participants. 
• A decision on the part of the Sponsor to suspend or discontinue testing, evaluation or 
development of the product. 
• Evidence from the data that there are sufficient technical problems with the study to believe 
with a high degree of certainty that participants are being exposed without a realistic 
expectation of evaluable data. 
• Participant enrollment is unsatisfactory. 
• Insufficient adherence to Protocol requirements or an unacceptably high rate of missing, 
erroneous or improperly collected data that threaten the scientific integrity of the study. 
Reasons for suspending enrollment at a site may include, but are not limited to, the following: 
• Failure of the Investigator to comply with pertinent regulatory regulations. 
• Submission of knowingly false information from the research facility to the Sponsor. 
• Participant enrollment is unsatisfactory. 
• Insufficient adherence to Protocol requirements or an unacceptable high rate of missing, 
erroneous or improperly collected data that threaten the scientific integrity of the study. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 41 of 80 
5 
STUDY TREATMENTS 
5.1 
Name and Description of Investigational Product(s) 
The study interventions to be administered are detailed in Table 3. Further supportive 
information will be provided in the Pharmacy Manual.  
Table 3:  
Study Interventions Administered 
Intervention Name 
Methylone 
Placebo (Part B) 
Dose Formulation 
Capsule 
Capsule 
Unit Dose Strength 
50 mg methylone capsule 
50 mg placebo capsule 
Dosage Level 
Initial Administration: 150 mg 
(3 × 50 mg methylone capsules) 
Booster Administration: 100 mg 
(2 × 50 mg methylone capsules) 
Initial Administration: 150 mg 
(3 × 50 mg placebo capsules) 
Booster Administration: 100 mg 
(2 × 50 mg placebo capsules) 
Route of Administration 
Oral 
Oral 
Use 
Investigational 
Placebo 
The Investigational Medicinal Product (IMP) supplied by the Sponsor or delegate is to be used 
exclusively in the clinical study according to the instructions in this Protocol and the Pharmacy 
Manual.  
The Site Investigator will be responsible for storage and accountability of the IMP taking into 
account that methylone is a controlled substance (detailed storage/security guidance is provided 
in the Pharmacy Manual).  
5.2 
Study Drug Administration 
Participants should have fasted (water only) for at least 2 hours prior to initial dosing and for 
at least 2 hours after the booster dose. Water and clear fluids will be encouraged up to a 
maximum of 3 liters over the dose session (see Section 5.6).  
Study drug (methylone) (or matched placebo for Part B) will be orally administered on Day 1, 
Day 8 (±1 day), Day 15 (±1 day) and Day 22 (±1 day). An initial administration of 150 mg 
methylone (or matched placebo for Part B) will be given, followed by a booster administration 
of 100 mg methylone (or matched placebo for Part B) 90 (±10) minutes later.  
5.3 
Psychological and Medical Support on Dosing Days 
5.3.1 Psychological Support 
On the dosing days, participants will be provided unstructured psychological support for at 
least 8 hours after the dose and until the subjective effects have subsided. The psychological 
support will be provided by a lead dosing session monitor (in the room) with an assistant 
monitor reviewing via live remote video monitoring. The lead dosing session monitor must be 
a licensed healthcare provider with graduate-level professional training and clinical experience 
in psychotherapy. The lead dosing session monitor must be licensed to practice independently. 
Examples of acceptable credentials for the lead dosing session monitor are as follows: 
• Clinical or counseling psychologist (PhD or PsyD) 
• Psychiatrist or other physician (MD or DO) 
• Master of Social Work (MSW) 
• Masters Licensed Clinical Professional Counselor (LCPC) 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 42 of 80 
• Licensed Marriage and Family Therapist (LMFT) 
• Psychiatric Nurse Practitioner (Psychiatric NP) 
Each lead dosing session monitor will undergo formal training prior to working with 
participants in this study. The assistant monitor must have a bachelor’s degree and at least 1 
year of clinical experience in a licensed mental healthcare setting. 
The clinical sites will make every effort to ensure the same lead dosing session monitor will be 
present for all sessions with each participant. Their role will be to provide unstructured 
psychological support as the participant explores their response to the medication. The dosing 
session monitor will not be involved in any medical, nursing, or other research activities. 
During the Preparatory session, the dosing session monitor will provide unstructured 
psychological guidance. This session will focus on psychoeducation about PTSD, possible 
physiological and psychological effects of methylone (including possible adverse and 
challenging effects), building safety for the therapeutic relationship, obtaining the background 
for the trauma and preparing the participant for dose sessions. Goals and expectations for the 
dose sessions will also be discussed. 
During each dose session, the dosing session monitor will provide non-directive support of 
psychological well-being continuously during each dose session. 
• During the early stages of the dose session, while the acute effects of methylone are 
active, the dosing session monitor will provide reactive support and engaged listening. 
The dosing session monitor will provide guidance if the participant falls into a negative 
pattern.  
• At the end of each dose session, the dosing session monitor will encourage the 
participant to reflect on their experience and on any strong emotions or thoughts they 
might have encountered.  
On Days 29, 36 and 43, post-dosing Reflection Sessions will be performed; the dosing session 
monitor will help the participant integrate their experiences over the four weeks of treatment, 
and to draw-out (if necessary) particular aspects of the experience. The dosing session monitor 
will assess and discuss the participant’s symptoms, medical condition and psychological 
status/well-being following the treatment period. 
Each dosing session should be recorded. The recordings will be reviewed to ensure the dosing 
session monitor is adhering to training and to facilitate training of future dosing session 
monitors. 
5.3.2 Medical Support 
During dosing days, a licensed and Basic Life Support (BLS)-certified physician must be on 
site (or on call and able to reach the clinical site within 15 minutes) in the event of a medical 
emergency. 
 
5.4 
Discharge Criteria 
The following criteria must be met prior to discharging a participant: 
• No clinically significant suicidal ideation or behaviors are present. 
• Vital signs are stable and have returned to near pre-dose values or are otherwise not 
clinically significant. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 43 of 80 
• Participant is alert and oriented to person, place, and things. Mental status is 
appropriate for normal daily activities. 
The participant should be discharged to a trusted person. 
 
5.5 
Concomitant Medication 
Participants should remain on a stable regimen of all allowable medications for the duration of 
the study.  
Participants must agree to abstain from receiving outside psychotherapy or pharmacotherapy 
to treat their PTSD (or other mental conditions) for the duration of participation in this study 
(from Screening through to the EOS visit). Prohibited medication may be used at the 
Investigator’s discretion during an acute AE or for the treatment of AEs. Such use may lead to 
the discontinuation of dosing for that participant. 
Section 14.2 and Section 14.3 provides a list of prohibited concomitant medications/therapies.  
The Site Investigator and study team will review medication use on a case-by-case basis to 
determine if its use would compromise participant safety or interfere with study procedures or 
data interpretation (exclusion criteria relating to concomitant medication are presented in 
Section 6.2). All concomitant medications used (including over-the-counter [OTC] 
medications and herbal supplements) will be recorded in the source documents and in the 
electronic case report form (eCRF). 
5.5.1 Prohibited Medications 
No formal drug interaction studies with methylone have been conducted in man. Based on the 
mechanism of action and metabolism of methylone, drug interactions between methylone and 
other psychoactive substances are possible. 
The following medications are prohibited within 8 weeks, or 5 half-lives, whichever is longer 
of Day 1 and through the End of Study visit:  
• Selective serotonin reuptake inhibitor (SSRIs) 
• Serotonin and norepinephrine reuptake inhibitors (SNRIs) 
• Tricyclic/tetracyclic antidepressants 
• Other medications to treat PTSD  
The following medications are prohibited within 14 days or 5 half-lives, whichever is longer 
of Day 1 and through the End of Study visit: 
• Lithium and other mood stabilizers 
• Antipsychotics 
• Stimulants  
• Efavirenz 
• Strong CYP2D6 inhibitors or inducers 
• Serotonin-acting dietary supplements (such as 5-hydroxy-tryptophan or St. John’s 
wort) 
• QT-prolonging medications (such as antiarrhythmics and some antibiotics) 
The following are restricted within 24 hours of a dosing session: 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 44 of 80 
• Benzodiazepines 
• Opioids 
• Alcohol 
5.6 
Special Warnings and Guidance 
5.6.1 General Considerations 
Each research site should have resuscitation equipment and appropriate staff training, 
especially the staff member who will remain with the participant during the dose session. 
In addition, each research site should be aware of the location of local emergency 
services/support, how to communicate with such services and how to transport a participant to 
such services, if needed. 
During each dose session, each participant will be in a private space so they cannot see or 
interact with other individuals for the duration of their dose session. The space will have a 
quiet, calm atmosphere where they are comfortable talking about personal matters. The space 
will have ambient temperature controls and access to water.  
The participants will be asked to remain in the clinic for the duration of the dose session, for at 
least 8 hours post-administration. 
5.6.2 Recorded Content 
All dosing sessions and central rater assessments may be recorded for research and training 
purposes. Participants may feel uncomfortable with having their sessions recorded. The dosing 
session recordings are necessary for assessing adherence to the dosing session monitor training 
and continued development of training material. The recording of central rater assessments is 
necessary to establish inter-rater reliability. 
The sponsor uses encrypted, secure technology to transfer and store recordings, but there is 
always a risk of a security breach. The sponsor is committed to taking preventative measures 
to avoid such an event. In the case of a security breach, the participant will be notified, and all 
efforts will be made to minimize the dissemination of recorded content. 
5.6.3 Management of Suicidality 
Suicidal ideation or attempts are not anticipated as a result of treatment, but both are recognized 
complications of PTSD. Furthermore, such thoughts may be provoked by the intense emotional 
experiences during the Preparatory Session (before any drug administration). 
The risk of the development of suicidal ideation is minimized by the inclusion/exclusion 
criteria and the awareness of the potential issue.  
To proactively assess any risk of suicidality, the C-SSRS questionnaire will be administered at 
every interaction with all participants throughout the duration of the study and used to identify 
‘at risk’ participants who should not receive further doses. 
Participants experiencing new suicidal ideation or attempt will not receive further dosing. Such 
participants need immediate medical/psychiatric Follow-Up. 
5.6.4 Management of Psychological Events 
Drug-related adverse psychological events (e.g., psychotic symptoms) are not anticipated, but 
may occur during, or following, the dose sessions. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 45 of 80 
The risk of such events occurring is minimized by the inclusion/exclusion criteria and the 
Preparatory Session. A physician will be available, defined as the ability to reach the clinical 
site within 15 minutes, throughout the dosing day to help support any psychological events. 
If medical intervention is required, diazepam (5 to 10 mg, orally), lorazepam (1 mg, orally or 
intramuscularly [IM]) or olanzapine (5 to 10 mg, orally or IM) may be administered, according 
to the clinical judgement of the responsible physician. Lorazepam and olanzapine should not 
be given at the same time due to the possibility of excessive sedation and cardiorespiratory 
depression.  
The participant should not be discharged from the clinic until, in the opinion of the Site 
Investigator, the condition has stabilized.  
Participants experiencing a psychological event related to dosing that requires an intervention 
will not receive further dosing. 
If psychological events arise after the participant has left the clinic, they will be instructed to 
contact the site immediately. Based on the situation, the Investigator and dosing session 
monitor will determine the most appropriate course of action. 
5.6.5 Management of Cardiovascular Events 
Elevations in blood pressure and heart rate are to be anticipated. 
The risk of such elevations will be minimized by the inclusion/exclusion criteria and frequent 
monitoring of blood pressure and heart rate during each dose session. 
Blood pressure and heart rate will be closely monitored with readings recorded at least every 
30 minutes during the dose session. The study team will attend to clinical signs and symptoms 
of potential rare complications of the cardiovascular effects of methylone, such as stroke or 
acute myocardial infarction, during dose sessions. Any symptoms such as chest pain, shortness 
of breath, neurological deficit or confusion, or other potential indicators of end organ effects, 
will prompt additional vital sign measurements, and intervention if appropriate, and the 
participant will not receive any further doses of IMP and will be followed until resolution.  
If a participant experiences ischemic type chest pain, whether or not it is associated with 
hypertensive crisis, they will be given 0.4 mg of sublingual nitroglycerin every 5 minutes as 
needed for chest pain pending transport to a hospital, and the Site Investigator will be promptly 
notified.  
Further evaluation and management will be determined by the appropriate trained healthcare 
providers.  
Participants experiencing a cardiovascular event associated with dosing that requires an 
intervention will not receive further dosing. 
5.6.6 Management of Thermoregulation 
Changes in body temperature are not anticipated. 
The risk of such changes can be minimized by managing the ambient temperature and 
minimizing participant activity. 
The participant’s temperature will be systematically monitored during the dose session. 
If a participant’s temperature rises more than 1oC, or the participant states that they feel hot, 
attempts will be made to decrease body temperature and increase comfort by removing blankets 
and layers of clothing, decreasing the ambient temperature and, if necessary, directing a fan 
toward the participant.  

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 46 of 80 
If at any time the temperature rises more than 1.5oC above pre-dose despite these efforts, the 
Site Investigator will be consulted for further evaluation and treatment. 
Participants experiencing a temperature rise during a dosing session of more than 2oC above 
pre-dose (and ≥38oC) will not receive further dosing. 
5.6.7 Management of Osmoregulation 
Methylone is not expected to have any risks of osmoregulatory changes. 
In order to minimize risk, participants should be encouraged to drink, but intake should be 
limited to no more than 3 liters over the course of the dose session. Fluid intake should be 
spread out over the dose session. 
If a participant exhibits any signs of toxicity or clinically significant dilutional hyponatremia 
despite these precautions, they should not receive further dosing. 
5.7 
Assessment of Compliance with Treatment 
All doses will be administered by study staff under direct observation. The administration of 
the study drug will be recorded within the appropriate pages of the eCRF. Any deviations from 
the planned dosing procedure will be recorded within the eCRF. 
Incorrect dosing will be recorded in the eCRF and reported to the Sponsor or delegate within 
48 hours. During this study, any initial administration of methylone greater than 150 mg 
(>3 capsules), and any booster administration of methylone greater than 100 mg (>2 capsules) 
will be considered an overdose. In the event of an overdose, the Investigator should: 
• Evaluate the participant to determine, in consultation with the Medical Monitor, 
whether study drug administration should be interrupted (ie, hold the booster dose) or 
if the booster dose should be reduced. 
• Document the quantity of the excess dose. 
5.8 
Blinding  
Part B will be double-blinded (Investigator- and participant-blinded) with observer-blinded 
assessments of efficacy. The randomization list will be kept in a secure location until the end 
of the study.  
5.9 
Emergency Unblinding  
The study blind for Part B should not be broken except in a medical emergency where 
knowledge of the IMP would inform treatment of an emergency.  
The Site Investigator has the sole responsibility for determining if unblinding of treatment is 
necessary for medical management. The Investigators will inform the Medical Monitor and 
Sponsor of this decision within 48 hours. The applicable procedures will be followed to break 
the blind. 
Emergency unblinding will be performed by the trial supply management system. 
After database lock, the overall randomization code will be broken only for reporting purposes.  

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 47 of 80 
6 
SELECTION OF PARTICIPANTS 
The study population includes approximately 15 (Part A) and approximately 64 (Part B) 
healthy adult participants with PTSD. Each participant must meet all the inclusion criteria and 
none of the exclusion criteria for this study. Under no circumstances can there be exceptions 
to this rule. 
6.1 
Inclusion Criteria 
1. Male or female participants aged between 18 to 65 years, inclusive. 
2. Participant meets the DSM-5 criteria for current severe PTSD diagnosis, with a 
symptom duration of at least 6 months at Screening, as assessed by the following 
psychometric assessments: 
a. CAPS-5 (past month version). 
b. Life Events Checklist for DSM-5 (LEC-5). 
• The PTSD diagnosis will be confirmed at Baseline by the central rater. 
3. Participant must have a CAPS-5 score of ≥35 at Screening and ≥28 at Baseline. 
4. Participant has failed at least one treatment for PTSD (either psychotherapy or 
pharmacological treatment). 
5. Proficient in reading and writing in local language sufficient to complete 
questionnaires. 
6. Free from any other clinically significant illness or disease that may adversely affect: 
a. the safety of the participant, or, 
b. the integrity of the study (see Section 6.2). 
7. Willing to refrain from taking any psychiatric medications or interventions during the 
study, unless provided by the Site Investigator. 
• No participant will be asked to discontinue potentially beneficial treatment in 
order to participate in this study. 
8. Willing to provide a contact for emergencies. 
9. Willing to be contacted via telephone for all necessary telephone contacts. 
10. <Removed in Amendment 3>  
11. Males who engage in sexual activity that has the risk of pregnancy must agree to use 
one of the following acceptable contraceptive methods and agree to not donate sperm 
throughout the study and for at least 90 days after the last dose of the study medication:  
a. Use of a double barrier method (male condom with a diaphragm or a cervical 
cap) 
b. Female use of hormonal contraceptives (as described below) 
c. Either partner is surgically sterilized (as described below) 
d. Abstinence, if consistent with the participants preferred and usual lifestyle 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 48 of 80 
12. Females of childbearing potential* who are sexually active with a male partner must be 
willing to use one of the following acceptable contraceptive methods throughout the 
study and for at least 1 month after the last study drug administration.   
a. Hormonal contraceptives or intrauterine devices: at least 4 weeks before first 
dosing and must follow that product’s package insert instructions including 
additional protection at times when hormonal contraceptive doses might be 
missed 
b. Male condom with a diaphragm or cervical cap: consistent use for at least 21 
days prior to the first dosing 
c. Sterile male partner: vasectomized for at least 6 months prior to the first dose  
d. Abstinence, if consistent with the participant’s preferred and usual lifestyle 
* A non-childbearing female is defined as:  
• 
Post-menopausal female (absence of menses for 12 months prior to drug 
administration, bilateral oophorectomy or hysterectomy with bilateral 
oophorectomy at least 6 months prior to drug administration); OR  
• 
Surgically sterile female (hysterectomy or tubal ligation at least 6 months prior 
to drug administration)  
Women of childbearing potential (WOCBP; see Section 14.4) must have a negative 
highly sensitive urine pregnancy test at Screening, Baseline, and Day 1, and prior to 
dosing. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required to be confirmed as negative prior to dosing.  
13. Agree to not participate in any other interventional clinical trials for the duration of this 
study. 
14. Willing to provide written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form. 
6.2 
Exclusion Criteria  
1. Participant has a primary diagnosis of any other DSM-5 disorder, as assessed by the 
MINI Version 7.0.2. 
2. Participant has a body mass index (BMI) <18 kg/m2 or ≥40 kg/m2. 
3. Participant is known (or meets DSM-5 criteria for moderate or severe substance use 
disorder [mild substance use disorder may be allowed, after consultation with the 
sponsor, if use of the substance is unlikely to confound the study results]) to abuse 
illegal drugs or has a positive urine test for illegal drugs at Screening, Baseline, or prior 
to dosing on Day 1. The Investigator must confirm the participant is not otherwise 
impaired prior to dosing on Day 1.  
4. Known history of:  
a. Hepatitis B, 
b. Hepatitis C, or 
c. Infection with human immunodeficiency virus. 
5. Participant smokes an average of >10 cigarettes and/or e-cigarettes per day. 
6. Abnormal LFTs at Screening: 
a. AST, ALT or gamma-glutamyl transferase (GGT) >2 × the ULN. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 49 of 80 
b. Total bilirubin levels >1.5 × the ULN (participants with a diagnosis of Gilbert’s 
syndrome with high unconjugated bilirubin are eligible provided they meet 
other LFT criteria). 
7. Moderate to severe renal impairment at Screening, with an estimated glomerular 
filtration rate (eGFR) of ≤80 mL/min according to the Cockcroft-Gault equation. 
8. Active suicidal ideation and/or intent within 2 months of Screening, indicated by a 
‘Yes’ response to suicidal ideation question 4 or 5 on the C-SSRS. 
9. Any history of suicidal behavior within the last 5 years (excluding suicidal ideation): 
a. Medical history of suicide attempt, or 
b. ‘Yes’ response to the following suicidal behavior questions on the C-SSRS: 
i. actual attempt, or 
ii. interrupted attempt, or 
iii. aborted attempt. 
10. Uncontrolled hypertension at Screening (after 5 minutes rest): 
a. SBP >140 mmHg, or 
b. DBP >90 mmHg. 
11. Resting heart rate at Screening of ≥90 bpm (after 5 minutes rest). 
12. Have any history, physical or psychological symptoms, medication or other relevant 
findings that would make a participant unsuitable for the study based on the clinical 
judgement of study personnel. This would include (but is not limited to): 
a. A need to continue active psychotherapy or pharmacotherapy during the study 
period. 
b. Moderate or severe alcohol use disorder (as assessed by the MINI 
Version 7.0.2) Note: Moderate alcohol use disorder in early remission is not 
exclusionary: 
i. the inability to refrain from alcohol use for 24 hours before Screening 
and each scheduled dose session. 
c. Medical or psychiatric condition that is incompatible with: 
i. establishment of rapport with the dosing session monitor, or 
ii. safe exposure to methylone. 
13. Prior treatment within the 90 days prior to Baseline, with: 
a. deep brain stimulation, 
b. vagus nerve stimulation, 
c. treatment with electroconvulsive therapy, or 
d. transcranial magnetic stimulation. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 50 of 80 
14. Use of a psychedelic (e.g., lysergic acid diethylamide [LSD], psilocybin, 
dimethyltryptamine [DMT], mescaline), or entactogens such as MDMA, within 12 
months of Screening. 
15. Use of prohibited concomitant medications or therapies (see Section 5.5.1). 
16. Current or previous history of clinically significant cardiovascular/cerebrovascular 
conditions. 
a. Presence of underlying cardiovascular or cerebrovascular conditions where an 
acute rise in blood pressure would pose a clinical concern, including but not 
limited to, aneurysms or arteriovenous malformations, a history of cardiac or 
cerebral ischemia. 
17. Any clinically significant abnormal 12-lead ECG findings at Screening. 
a. Resting QT interval corrected for heart rate using Fridericia's formula (QTcF) 
≥450 msec for males, ≥470 msec for females at Screening, or inability to 
determine QTcF interval. 
b. Presence of risk factors for Torsades de Pointes. 
18. Any history of head injury with loss of consciousness for more than 30 minutes within 
12 months of Screening. 
19. Clinically relevant history of schizophrenia, psychotic disorder, bipolar disorder, 
delusional disorder, paranoid personality disorder, antisocial personality disorder, 
schizoaffective disorder, borderline personality disorder or panic disorder, as assessed 
by the MINI and SPQ (and SCID-5-PD, if needed). 
20. Have a first-degree relative with: 
a. schizophrenia spectrum, or 
b. other psychotic disorders (except substance/medication-induced or due to 
another medical condition), or 
c. Bipolar I disorder. 
21. Participant has participated in a clinical study with an IMP within 3 months, or 
5 half-lives (whichever is longer), prior to Screening. 
22. Has an allergy or intolerance to any of the materials contained in the investigational 
formulations (methylone or placebo [Part B]). 
23. Donation of blood or plasma of >400 mL within 3 months prior to Screening. 
24. Family member of a member of the investigating team, Sponsor or Contract Research 
Organization. 
6.3 
Study Restrictions 
6.3.1 Lifestyle Restrictions 
Participants should agree to abstain from strenuous exercise for 24 hours prior to each dose 
session. Participants are also not allowed to operate any motor vehicle for at least 24 hours 
after each administration of study drug. Site staff should ensure participants have organized 
transport after discharge from the study site during the treatment period. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 51 of 80 
Participants cannot donate blood for the duration of the study until 3 months after the EOS 
visit. 
6.3.2 Meals and Dietary Restrictions 
The participants are required to adhere to the following restrictions: 
• Participants should abstain from alcohol for 24 hours prior to Screening and each dose 
session until after discharge from the study site.  
• Participants should abstain from tobacco and nicotine-containing products for 2 hours 
prior to dosing until at least 8 hours after the initial administration on each dosing day.  
• Participants should abstain from (methyl) xanthine- and caffeine-containing products 
for 2 hours prior to dosing until at least 8 hours after the initial administration on each 
dosing day.  
• Participants should have fasted (water only) for at least 2 hours prior to dosing and for 
at least 2 hours after the booster dose. 
• Participants should refrain from consuming poppy seeds 48 hours prior to Screening 
and Days 1, 8, 15 and 22 to avoid a positive result on the drugs of abuse screen. 
6.4 
Participant Withdrawal Criteria 
Participants may withdraw from the study at any time for any reason. If a participant elects to 
withdraw before the completion of the study, the participant should be encouraged to attend an 
Early Termination visit to capture safety and efficacy data. 
For all participants withdrawn from the study, discontinuation procedures as described in 
Schedule of Assessments (Section 1.3) should be conducted prior to discharge in the study. 
Reasons for study withdrawal or study drug discontinuation at any time during the study may 
include any of the following reasons: 
• Pregnancy of participant or partner. 
• Adverse event: Clinical or para-clinical events occurred that, in the medical judgement 
of the Site Investigator for the best interest of the participants, are grounds for 
discontinuation. This includes serious and non-serious AEs regardless of relation to the 
study drug (see Section 4.8).  
• Withdrawal of consent: The participant desired to withdraw from further participation 
in the study in the absence of an Investigator determined medical need to withdraw. If 
the participant gave a reason for withdrawing it should be recorded in the eCRF.  
• Investigator decision. 
• Lost to Follow-Up: The participant stopped coming for visits and study personnel were 
unable to contact the participant. 
• Other: The participant was discontinued for a reason other than those listed above, such 
as termination of the study by the Sponsor. The reason(s) should be recorded in the 
eCRF.  
• Participant has a positive urine test for an illegal medication (eg, MDMA or cocaine). 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 52 of 80 
o A positive urine drug test for stimulants or if the subject is otherwise impaired 
will result in missing that dose session. 
6.5 
Follow-Up Procedures 
The Investigator will make diligent attempts to contact participants who fail to return for a 
scheduled visit or were otherwise unable to attend the EOS visit. All discontinuations and the 
reason for early discontinuation will be documented by the Investigator, and if appropriate on 
the AE form.  

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 53 of 80 
7 
SAFETY ASSESSMENTS 
The participants will attend a safety visit on Day 29 (±1 day), Day 36 (±2 days), Day 43 
(±2 days) and Day 64 (±3 days) for Follow-Up procedures as shown in the Schedule of 
Assessments (Section 1.3). 
7.1 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations and urine drug screens will include the analytes listed in Table 
4. Approximate blood sampling volumes are provided in Section 14.1. 
All blood and urine analyses will be conducted on-site or at a central laboratory at the sampling 
times indicated in the Schedule of Assessments (Section 1.3). The clinical laboratory 
evaluation results will be collected at Screening in time for results to be reviewed prior to the 
first study drug administration. For abnormal values, additional testing may be performed, or 
clinical laboratory evaluations may be added to evaluate the abnormal values. Clinically 
significant values should be followed until resolution or until they reach a stable state.  
Table 4:  
Clinical Laboratory Evaluations 
Blood Chemistry 
Amylase 
BUN 
Creatinine 
Glucose 
Sodium 
Potassium 
Phosphate 
Chloride 
Calcium 
AST 
ALT 
GGT 
Alkaline phosphatase 
Total, direct, indirect bilirubin 
Uric acid 
Albumin 
Total protein 
Lactate dehydrogenase 
Urinalysis 
Glucose 
Bilirubin 
Ketone 
Specific Gravity 
Blood 
pH 
Protein 
Urobilinogen 
Nitrite 
Leukocyte Esterase 
 
Hematology 
Hemoglobin  
Hematocrit 
RBC count 
RBC indices (MCV, MCH, MCHC) 
Platelet count 
White blood cell count with differential 
Urine drug screen 
Amphetamines  
Benzodiazepines 
Cocaine 
MDMA  
Opiates 
Other Testing 
Urine pregnancy test (WOCBP only) 
Follicle stimulating hormonea 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; GGT = gamma-glutamyl 
transferase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular 
volume; RBC = red blood cell; WOCBP = women of childbearing potential. 
a Suspected perimenopausal female participants only, based on surgical history or <12 months amenorrhea. 
 
7.2 
12-Lead Electrocardiogram 
The 12-lead ECG will be collected within approximately 30 minutes predose and at the end of 
the dose session. The 12-Lead ECG should be obtained after the participant has rested in the 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 54 of 80 
supine position for at least 5 minutes. The ECG machine used should automatically calculate 
the HR and PR, QRS, QT and QTcF intervals.  
 
7.3 
Vital Signs and Temperature 
Vital signs, including HR, BP, and temperature will be collected after the participant has rested 
in the seated position for at least 5 minutes. Predose vital signs should be collected within 
10 minutes predose. Blood pressure and HR will be collected 10 minutes predose and at 30-
minute intervals (±15 min) post-initial dose-administration until the end of the dose session. In 
addition, BP and HR will be recorded 15 minutes (+5 minutes) before administration of the 
booster dose. This pre-booster vital signs collection is the equivalent of the 90-minute vital 
signs collection timepoint. Temperature will be recorded predose (within 10 minutes) and at 
60-minute intervals (±15 min) post-initial dose-administration, until end of the dose session. 
7.4 
Physical Examinations 
A physical examination, including body weight (Screening and EOS) and height (Screening 
only), and assessments of the head, eyes, ears, nose, throat, skin, neurological, lungs, 
cardiovascular system, abdomen, and lymph nodes will be conducted. 
7.5 
Pregnancy Testing 
Dosing should not proceed until a negative pregnancy test is confirmed. 
• Refer to Section 6.1 for pregnancy testing entry criteria. 
• A urine pregnancy test will be performed at Screening, and Day 1, to confirm eligibility.  
• Pregnancy testing (urine) will be conducted prior to dosing on dosing days and on 
Day 29. 
• A positive or inconclusive urine pregnancy test should be confirmed by a serum 
pregnancy test (see Section 7.8.3.1). 
• Additional serum or urine pregnancy tests may be performed, as determined necessary 
by the Investigator or required by local regulation, to establish the absence of pregnancy 
at any time during the participant’s participation in the study. 
• The Investigator is responsible for review of medical history, menstrual history 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
7.6 
Columbia-Suicide Severity Rating Scale 
The C-SSRS will be used to assess suicide potential or tendency as a study entry criterion and 
monitored throughout the study. 
The C-SSRS is a semi-structured interview designed to assess the severity and intensity of 
suicidal ideation, suicidal behavior and non-suicidal self-injurious behavior over a specified 
time period. The measurement of suicidal ideation is based on five ‘yes’ or ‘no’ questions with 
accompanying descriptions arranged in order of increasing severity. If the participant answers 
‘yes’ to either questions 1 or 2, the intensity of ideation is assessed in five additional questions 
related to frequency, duration, controllability, deterrents and reasons for the most severe 
suicidal ideation. Suicidal behavior is assessed by asking questions categorizing behaviors into 
actual, aborted and interrupted attempts; preparatory behavior, and non-suicidal self-injurious 
behavior. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 55 of 80 
If any item(s) on the C-SSRS are answered ‘yes’, the Investigator must review the participant’s 
responses in order to (a) at the Screening visit and Baseline/Preparatory session to determine 
the participant’s study eligibility and potential need for referral to a mental health professional, 
and (b) during the study evaluate the participant’s need for appropriate medical management 
such as a referral to a mental health professional, or appropriateness of further study drug 
administration in consultation with the Medical Monitor and Sponsor. 
A significant risk of suicide is defined as a ‘yes’ in answer to:  
(a) questions 4 or 5 on the suicidal ideation section; or,  
(b) any questions on any item in the suicidal behavior section.  
This must be reported as an AE or SAE as appropriate and followed up accordingly. 
Additionally, if a participant responds ‘yes’ to any of the suicidal ideation questions 1 
through 3, the Investigator should apply clinical judgement to determine the need for reporting 
this as an AE or SAE and the need for any appropriate referral. 
For any participant who responds ‘yes’ to relevant questions post-study drug administration, 
they will be handled appropriately.  
7.7 
Adverse Event Reporting 
Adverse events will be elicited through non-leading questions and spontaneous reporting by 
participants.  
At all times, the Investigator should be alert to comments that imply an AE. 
The Investigator is responsible for evaluating AEs and for the appropriate medical care of 
participants during the study. 
7.7.1 Definition and Criteria 
7.7.1.1 Adverse Event  
An AE is any untoward medical occurrence in a study participant which either emerges, or 
worsens from enrollment/randomization, during the clinical study, regardless of its potential 
relationship to the medicinal product. An AE, therefore, can be any unfavorable or unintended 
sign, including a clinically significant abnormal laboratory finding, symptom, or disease 
temporally, whether or not it is considered to be study drug-related.  
Examples of an AE include: 
• Exacerbation of a pre-existing condition including either an increase in frequency 
and/or severity of the condition. 
• New conditions detected or diagnosed. 
• Signs or symptoms of a drug interaction. 
• Signs or symptoms of a suspected overdose of either IMP or a concurrent medication 
(overdose per se should not be reported as an AE/SAE). 
• A new laboratory abnormality occurring after the start of the study (i.e., following 
enrollment/randomization) or are present at baseline and significantly worsen following 
the start of the study that results in discontinuation of the study drug, medical treatment 
or further follow-up. The Site Investigator will exercise their medical and scientific 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 56 of 80 
judgement in deciding whether an abnormal laboratory finding, or other abnormal 
assessment is clinically significant. 
Note: abnormal laboratory or other values obtained during Screening that preclude a participant 
from entering the study are not considered AEs but will be recorded as the reason for screen 
failure.  
Adverse events may include pre- or post-treatment events that occur as a result of 
Protocol-mandated procedures (i.e., invasive procedures, modification of participant’s 
previous therapeutic regimen).  
A medical intervention to address an AE is an “action taken” and not an AE itself. 
7.7.1.2 Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death, 
• Is life-threatening, 
Note: 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. 
• Requires hospitalization or prolongation of existing hospitalization,  
Note: In general, hospitalization signifies that the participant has been detained (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 complication prolongs 
hospitalization or fulfils any other serious criteria, the event is serious. When in doubt whether 
‘hospitalization’ occurred or was necessary, the AE should be considered serious.  
• Results in persistent or significant disability or incapacity, 
Note: 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 or prevent everyday life 
functions but do not constitute a substantial disruption.  
• Is a congenital abnormality or birth defect, 
• Is an important medical event.  
Note: Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening, or result in death or hospitalization, but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These should also be considered serious. Examples of such events are invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
Note: The terms “serious” and “severe” ARE NOT synonymous. The term “severe” is often 
used to describe the intensity (severity) of a specific event (as in mild, moderate or severe 
myocardial infarction); the event itself, however, may be of relatively minor medical 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 57 of 80 
significance (such as severe headache). This is NOT the same as “serious”, which is based on 
participant/event outcome or action criteria described above and are usually associated with 
events that pose a threat to a participant’s life or functioning. A severe AE does not necessarily 
need to be considered serious. For example, persistent nausea of several hours duration may be 
considered severe nausea but not an SAE. On the other hand, a stroke resulting in only a minor 
degree of disability may be considered mild but would be defined as an SAE based on the 
above criteria. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations.  
Only SAEs will be recorded from the time of informed consent until the time of 
enrollment/randomization. 
7.7.1.3 Adverse Events of Special Interest 
The Sponsor will pay special attention to a subset of AEs; these AEs will be marked in the 
eCRF with the denotation AESIs whether serious or non-serious. These should be reported to 
the Sponsor or delegate; they include:   
• Grade 3 hypertension, SBP ≥160 mmHg or DBP ≥100 mmHg, requiring the need for 
medical intervention with more than one drug or more intensive therapy than previously 
used.  
• Significant cardiovascular events 
• AEs related to suicide risk, such as; suicides, suicide attempts, self-injurious behavior 
associated with suicidal ideation and suicidal ideation judged to be serious or severe in 
the opinion of the Investigator. 
• Signals of abuse potential AE involving terms of behavioral addiction, drug abuser, 
substance abuser. 
If an AESI is an SAE or if it involves suicide risk, it should be reported to the Sponsor or 
delegate within 24 hours of the site’s awareness of the event. 
7.8 
Evaluating Adverse Events and Serious Adverse Events 
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. 
All AEs will be assessed on two descriptive parameters: severity and relationship to the study 
drug: 
• Severity refers to the severity of an event and references impact on a participant’s 
functioning. 
• Relationship refers to the likelihood that the event being assessed was caused by the 
study drug.  
The Investigator will make an assessment of severity for each AE and SAE reported during the 
study.  Adverse events will be assessed according to the general guidelines for grading: 
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily living 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 58 of 80 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject 
• Severe: Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention 
For AEs and SAEs, the relationship to the study treatment is to be assessed according to the 
following definitions: 
• Not related: There is no reasonable association between the study treatment and the 
suspected event. 
• Unlikely related: It is doubtful that there is an association between the study treatment 
and the suspected event. The event could have been produced by the participant’s 
clinical state or other modes of therapy administered to the participant. 
• Possibly related: The suspected AE may or may not follow a reasonable temporal 
sequence from study drug administration. The event could have been produced or 
mimicked by the participant’s clinical state or by other modes of therapy concomitantly 
administered to the participant. 
• Probably related: The suspected AE follows a reasonable temporal sequence from 
study treatment administration, abates upon discontinuation of the treatment; and 
cannot be reasonably explained by the known characteristics of the participant’s clinical 
state.  
When assessing the relationship to the study drug, the following criteria will be considered: 
• Known class effect 
• Positive rechallenge 
• Positive dechallenge (resolution after a dose session, in absence of other interventional 
treatment) 
• Biological plausibility  
• Lack of alternative explanation – concomitant drug or disease 
7.8.1 Reporting Procedures and Requirements 
7.8.1.1 Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the signing of the informed consent form (ICF) until the EOS 
visit at the timepoints specified in the Schedule of Assessments (see Section 1.3). 
All AEs will be collected from enrollment/randomization until the EOS visit at all interactions 
with the participants (see Section 1.3). A baseline safety assessment will occur after Screening. 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded as medical history/current medical conditions, not as AEs. 
The Investigator is not obligated to actively seek information on AEs or SAEs after 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 the Investigator 
considers the event to be reasonably related to the study intervention or study participation, the 
Investigator must promptly notify the Sponsor. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 59 of 80 
7.8.1.2 Adverse Events 
All AEs between enrollment/randomization to the EOS visit will be recorded in source data 
and eCRF, whether or not considered study drug-related. All AEs that are possibly or probably 
related to study drug will be followed until resolution or database lock, whichever occurs first. 
Also, the sign, symptom, or disease present before the baseline safety assessment are only 
considered AEs if they worsen after this point. Any AEs already documented at a previous 
assessment and designated as ongoing should be reviewed at subsequent visits as necessary. If 
these have resolved, this should be documented. The Investigator should report all AEs on the 
AE page(s) of the eCRF and source documents, regardless of seriousness, severity, and 
causality. Whenever possible, an AE will be reported using a diagnostic term, (e.g., “common 
cold” or “upper respiratory infection” rather than “runny nose, cough, mild fever”) and should 
be described with the attributes described in Section 7.7.1.1.  
7.8.1.3 Serious Adverse Events 
Each AE will be assessed to determine whether it meets seriousness criteria (Section 7.7.1.2). 
If the AE is considered serious the Investigator must report this event to the Sponsor or 
delegate. The Sponsor or delegate will report the event to the IRB/EC according to relevant 
standard operating procedures (SOPs). Serious adverse events occurring from the time of 
signed informed consent to the EOS visit or 7 days after the last administration of study drug 
(whichever occurs later) will be recorded in source and electronic data capture. All serious, 
treatment-related adverse events, regardless of the time of onset after treatment, should be 
reported. All information about SAEs will be collected and reported via the SAE form and sent 
by email message (contact information will be contained in the Investigator site file). At a 
minimum, the initial report should include the following information: 
• Event 
• Seriousness criteria 
• Protocol number 
• Participant number and year of birth 
• Study drug (blinded for Part B unless unblinding is required for medical management) 
• Reporter name and contact information 
In the case of a “minimum report” (one that solely comprises the information bulleted above), 
a more detailed Follow-Up report should be sent as soon as more information becomes 
available but no later than 7 calendar days after the date of the initial report. Each SAE should 
be followed up until resolution or stabilization and for reported deaths, the Investigator should 
supply Sponsor, or designee, and the IRB/EC with any additional requested information (e.g., 
autopsy reports and terminal medical reports), if available. The original SAE form should be 
kept at the study site. The Investigators will be responsible for determining and in turn, 
reporting SAEs to the Sponsor. The Sponsor, or designee, will be responsible for reporting 
SAEs to regulatory authorities according to the applicable regulatory requirements. The 
Sponsor, or designee, will be responsible for completing the safety reports and for notifying 
the relevant authorities of any SAE as outlined in the International Council for Harmonisation 
(ICH) Guidelines and per local regulatory requirements.  

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 60 of 80 
7.8.2 Prompt Reporting of Serious Adverse Events 
Any SAE, occurring in a participant receiving treatment or if the Investigators become aware 
of any SAE post-treatment during the EOS visit, must be reported by the Investigators to the 
Medical Monitor within 24 hours even if the SAE does not appear to be medication-related. 
An emailed copy of the SAE form, in addition to other related information should be sent to 
the appropriate contact as outlined in the Investigator site file. Additionally, it may be necessary 
for the Medical Monitor or Sponsor, or delegate, to directly communicate with the Investigators 
if additional information is required. 
7.8.2.1 Follow-Up of Adverse Events 
All AEs will be followed to a satisfactory resolution, until it becomes stable, or until it can be 
explained by another known cause(s) (i.e., concurrent condition or medication) and clinical 
judgment indicates that further evaluation is not warranted. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The Sponsor, or designee, is responsible for the reporting of SUSARs in accordance with 
regulatory guidelines. An AE will be considered unexpected if the nature, severity, frequency 
of the event is not consistent with the risk information previously described for the IMP. The 
'expectedness’ for any SAE will be determined against the reference safety information (RSI) 
included in the IB. 
A list of expected potential adverse reactions are provided in the IB. 
7.8.3 Special Considerations 
7.8.3.1 Pregnancy of Female Participant and/or of Female Partner of Male Participant 
Details of all pregnancies in female participants and female partners of male participants will 
be collected after the start of the study until the end of the study. The Investigators should 
report pregnancy to the Sponsor or designee within 24 hours after learning of the pregnancy. 
If a pregnancy is reported, the Investigator should contact the designated individual(s) 
following the pregnancy notification process and record information related to the pregnancy 
on the designated pregnancy form provided. 
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. 
The event meets the SAE criterion only if it results in a spontaneous abortion, congenital 
anomaly, or reports of suspected adverse reactions in the neonate that are classified as serious. 
The female participant or pregnant female partner will be followed to determine the outcome 
of the pregnancy. The Investigator will collect Follow-Up information on the female participant 
or 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 7.8.2. While the 
Investigator is not obligated to actively seek this information in former study participants or 
pregnant female partners, they may learn of an SAE through spontaneous reporting. 
For pregnant female participants, no further dosing will be permitted. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 61 of 80 
7.9 
Other Assessments 
Assessments to be performed at Screening only are detailed in the Schedule of Assessments 
(Section 1.3). 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 62 of 80 
8 
PSYCHOMETRIC ASSESSMENTS 
Psychometric assessments will be administered in a neutral, non-leading manner to minimize 
the chance for bias. Avoiding a biased administration can be achieved by adhering to 
questionnaire administration guidelines verbatim and only deviating from the script to clarify, 
re-direct or query further if behavioral examples are needed to determine the appropriate 
symptom intensity rating.  
All clinician-rated psychometric assessments will be administered by a central rater via 
telephone or video call. Remote assessments assure that the assessor who is collecting the 
primary outcome measures will not witness dose sessions and the acute effects of methylone, 
which strengthens the study blind. The central ratings will be recorded in order to ensure quality 
ratings and rater fidelity across the central rater pool. 
Copies of each scale can be found in the Investigator Site File. 
8.1 
Clinician-Administered Psychometric Assessments 
8.1.1 Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) 
The CAPS-5 is a 30-item structured interview that can be used to: 
• 
Make current diagnosis of PTSD. 
• 
Assess change in PTSD symptoms over time.  
In addition to assessing the 20 DSM-5 PTSD symptoms, questions target the onset and duration 
of symptoms, subjective distress, impact of symptoms on social and occupational functioning, 
improvement in symptoms since a previous CAPS administration, overall response validity, 
overall PTSD severity and specifications for the dissociative subtype (depersonalization and 
derealization). The CAPS-5 also rates intrusion symptoms (intrusive thoughts or memories), 
avoidance, cognitive and mood symptoms, arousal and reactivity symptoms, duration and 
degree of distress. For each symptom, standardized questions and probes will be provided.  
The ‘past month’ version of the CAPS-5 will be performed at Screening. The ‘past week’ 
version of the CAPS-5 will be performed at each subsequent study visit. The participant will 
report on the same Criterion A event specified at Screening for all CAPS-5 assessment 
timepoints. 
Each CAPS-5 will be administered by a central rater via telephone or video call.  
8.1.2 Mini International Neuropsychiatric Interview 
The MINI 7.0.2 is a short, structured diagnostic interview that is compatible with DSM-5 and 
International Classification of Disease criteria for psychiatric disorders. Each module of the 
MINI consists of two or three questions where the answer is either ‘Yes’ or ‘No’, and a 
decision-tree logic is used to determine whether to ask additional questions. The PTSD, 
suicidality, and antisocial personality disorder modules of the MINI are not required to be 
administered as these are addressed via other scales. 
The MINI will be administered at Screening by a central rater. 
8.1.3 Structured Clinical Interview for DSM-5 Personality Disorders (SCID-5-PD) 
The SCID-5-PD is a structured diagnostic interview to assess for DSM-5 personality disorders.  

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 63 of 80 
In this study, participants who endorse a positive response for paranoid personality disorder, 
antisocial personality disorder, or borderline personality on the SPQ will be administered the 
SCID-5-PD for those personality disorders. 
The SCID-5-PD, if needed, will be administered at Screening by a central rater. 
8.1.4 Structured Interview Guide for the Montgomery-Åsberg Depression Rating 
Scale (MADRS) (SIGMA) 
The SIGMA is a standardized version of the MADRS. The SIGMA maintains the original 
format of the MADRS, which is a 10-item clinician-rated, diagnostic questionnaire used to 
measure depression severity, with the exception that the first two items are reversed. Each item 
is measured on a 7-point scale, from 0 to 6. Higher total MADRS scores indicate more severe 
depression. Follow-up questions are also provided to clarify symptoms, if required.  
The MADRS will be administered at by a central rater. 
8.1.5 Clinician Global Impressions Scale – Severity 
The CGI-S is designed to acquaint the participant’s severity of symptoms with those of other 
people experiencing the same mental ailment. The CGI-S rates this severity on a 7-point scale, 
with (1) representing normal symptoms, meaning the participant is not ill, and (7) representing 
participants among the most severely ill. The rating (4) represents a participant that is defined 
a participant that is defined as moderately ill.  
The CGI-S will be administered at by a central rater. 
8.1.6 Clinician Global Impressions Scale – Improvement  
The CGI-I is a 7-point scale that requires the assessor to assess how much the participant’s 
illness has improved or worsened relative to a baseline state prior to dosing. The CGI-I scale 
rates improvement with (1) representing a ‘very much improved’ participant to (7) representing 
a participant who has become ‘very much worse’ due to treatment. The rating (4) represents a 
participant displaying no change from the treatment.  
The CGI-I will be administered at by a central rater. 
8.2 
Participant-Completed Psychometric Assessments 
8.2.1 PTSD Checklist for DSM-5 (PCL-5) 
The PCL-5 is a 20 item self-report measure that assesses the presence and severity of the 
20 DSM-5 symptoms of PTSD. The PCL-5 has a variety of purposes, including: 
• 
Monitoring symptom changes during and after treatment. 
• 
Screening individuals for PTSD. 
• 
Making a provisional PTSD diagnosis. 
Participants will be asked to rate each item from 0 (‘not at all’) to 4 (‘extremely’) to indicate 
the degree to which they have been affected by that particular symptom over the past week; the 
results will be interpreted by a clinician.  
8.2.2 Life Events Checklist for DSM-5 (Extended Version) 
The LEC-5 is a brief, 17-item self-report measure designed to screen for potentially traumatic 
events in a participant’s lifetime, to facilitate the diagnosis of PTSD. It is a companion to the 
PCL-5 and will be used to assess PTSD. The extended version of the LEC-5 should be used to 
establish the worst event if more than one event occurred.  

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 64 of 80 
8.2.3 Structured Clinical Interview for DSM-5 Screening Personality Questionnaire 
(SCID-5-SPQ) 
The SCID-5-SPQ is a self-report screening tool to assess for DSM-5 personality disorders.   
Participants will be required to only complete questions specific for assessing personality 
disorders (paranoid personality disorder, antisocial personality disorder, or borderline 
personality). In this study, participants who endorse a positive response for paranoid 
personality disorder, antisocial personality disorder, or borderline personality on the SPQ will 
be administered the SCID-5-PD for those personality disorders. 
8.2.4 Sheehan Disability Scale 
The SDS is a brief, 5-item self-report tool that assesses functional impairment in work, social 
life/leisure activities and family life/home responsibilities. The SDS is designed to measure the 
extent to which the three major domains in the participant’s life are functionally impaired by 
psychiatric or medical symptoms. Each domain is rated from 0 to 10, with a total score from 
0 to 30, where 0 – Unimpaired and 30 – Highly impaired.  
8.2.5 Patient Global Impression of Change 
The PGI-C is a self-report tool to reflect a participant’s belief about the efficacy of treatment. 
The PGI-C is a 7-point scale depicting a participant’s rating of overall improvement. 
Participants rate their change from ‘1 – Very much improved’ through to ‘7 – Very much 
worse’.  
8.2.6 Patient Global Impression of Severity 
The PGI-S is a self-report tool to measure disease severity. The PGI-S is a 5-point scale, 
ranging from ‘1 – None’, through to ‘5 – Very severe’.  
8.2.7 Warwick-Edinburgh Mental Wellbeing Scale 
The WEMWBS is a scale of 14 positively worded items for assessing a population’s mental 
wellbeing. The items cover both physiological functioning aspects of mental wellbeing 
(including: optimism, autonomy, agency, curiosity, clarity of thought and positive 
relationships) and positive effect (feelings, including: confidence, feeling relaxed, cheerful, 
having the energy to spare). The scale has 5 response categories, summed to provide a single 
score. 
8.2.8 Post-Traumatic Growth Inventory 
The Post-Traumatic Growth Inventory measures the extent to which survivors of traumatic 
events perceive personal benefits, including changes in perceptions of self, relationships with 
others and philosophy of life, accruing from their attempts to cope with trauma and its 
aftermath. This 21-item scale includes factors of: new possibilities, relating to others, personal 
strength, spiritual change and appreciation of life. 
8.2.9 Beck Depression Inventory-II 
The BDI-II is a 21-item self-report measure assessing depressive symptoms and their severity. 
Items include hopelessness and irritability, cognitions such as guilt or feelings of being 
punished, as well as physical symptoms such as fatigue and weight loss. Each item is rated on 
a 4-point scale, from 0 to 3. Items are summed to create a total score, with higher scores 
indicating higher levels of depression.  

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 66 of 80 
9 
STATISTICS AND DATA ANALYSIS 
9.1 
Randomization and Participant Allocation 
After informed consent is obtained, participants will be allocated a unique study number. 
Only participants who comply with all the inclusion criteria, and none of the exclusion criteria 
will be randomized/enrolled onto the study. For Part A eligible participants will be enrolled 
into the open-label study. 
For Part B, a randomization scheme will be produced by an unblinded Statistician in SAS 9.4 
or higher. The participants will be randomized 1:1 in block sizes of 4 (2 treatments, 2 placebo) 
to the appropriate treatment (methylone or placebo) using an electronic Randomization and 
Trial Supply Management.  
The participants in Part B will be assigned a randomization number in the order of 
randomization.  
9.2 
Sample Size Determination 
No formal sample size calculation was performed for Part A of the study. The sample size of 
approximately 15 participants in the open-label study is based on medical and clinical 
considerations. 
Sample size calculations for Part B were performed using PASS 2022 to determine the sample 
size required to detect a significant difference between CAPS-5 scores in the methylone and 
placebo groups (the efficacy endpoint). A previous phase 3 trial investigating the effects of 
MDMA versus placebo on CAPS-5 scores found a placebo-corrected treatment effect at the 
end of treatment of 11 points and a pooled standard deviation (SD) of 12 (Mitchell 2021). 
Assuming a treatment effect of 11 points and a pooled SD of 12 in this trial, with a sample size 
of 20 or 27 evaluable participants in each treatment group, the trial should provide 80% or 90% 
power, respectively, to detect a treatment difference at two-sided significance level of 0.05. 
Assuming a dropout rate of 15%, a target sample size of 46 (23 per treatment group) or 64 (32 
per treatment group) will provide 80% or 90% power, respectively.  
A DSMB will monitor the clinical data.   
An N of 20 or more in each treatment group should also provide useful safety and tolerability 
data, without exposing too many individuals.  
9.3 
Statistical Analysis Plan  
A Statistical Analysis Plan (SAP) will be prepared after finalizing the Protocol and before 
database lock. The methods describe in these sections may be modified, for example, due to 
regulatory feedback.  The final analysis methods will be described in the Final SAP that must 
be approved before database lock. The SAP will provide full details of the analyses, data 
displays, and algorithms to be used for data derivation. 
9.4 
Analysis Sets 
Unless otherwise stated in the SAP, the analysis set definitions apply to both Parts A and B of 
the study. 
9.4.1 Intent-to-Treat (ITT) Population 
The ITT population for Part A includes all participants who receive at least one administration 
of study treatment. Participants are analyzed on the treatment to which they received for Part 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 67 of 80 
A.  The ITT population for Part B includes all participants who are randomized. Participants 
are analyzed on the treatment to which they are randomized to receive for Part B. 
9.4.2 Per-Protocol Population 
The Per-Protocol population includes all participants in the ITT population who received at 
least one administration of study treatment and have no important major protocol deviations. 
9.4.3 Safety Population 
The Safety population includes all participants who receive at least one administration of study 
treatment. Participants will be summarized according to treatment received. The Safety 
population will be used to analyze the safety endpoints. 
9.5 
Statistical Analysis 
Statistical analyses will be performed using SAS 9.4 or higher.  
9.5.1 Safety Statistical Analysis 
Safety assessments will include clinical laboratory evaluations (clinical chemistry, hematology 
and urinalysis), vital signs (HR, BP and body temperature), 12-lead ECG, physical 
examinations, C-SSRS and AE monitoring. 
9.5.1.1 Adverse Events 
All AEs will be listed according to system-organ class (SOC) and preferred term (PT) assigned 
to the event using Medical Dictionary for Regulatory Activities (MedDRA). The number and 
percentage of participants experiencing any AEs will be summarized overall and by treatment 
for Part B, causality and maximum severity. Any SAEs, TEAEs and/or AEs that led to 
withdrawal will also be listed in the same manner.  
The number and percentage of participants experiencing TEAEs, SAEs, and AEs leading to 
withdrawal from the trial drug will be tabulated by MedDRA SOC, PT, causality, and 
maximum severity. The AE tables will also include frequency counts for each SOC and PT. 
All AESIs will be summarized similarly to the AEs. 
9.5.1.2 Clinical Laboratory Evaluations 
Clinical Laboratory evaluation results will be listed and compared to laboratory reference 
ranges, with those values outside of the applicable range flagged as high (H) or low (L). Clinical 
chemistry and hematology data will be summarized using descriptive statistics (n, arithmetic 
mean, SD, median, minimum and maximum) for each parameter overall and by treatment for 
Part B and trial period. Urinalysis data will be listed only. 
9.5.1.3 Vital Signs 
Vital signs (SBP, DBP, HR, respiratory rate and body temperature) will be listed for individual 
participants. Descriptive statistics (n, arithmetic mean, SD, median, minimum and maximum) 
will be calculated and plotted for each parameter overall and by treatment for Part B, trial 
period, and timepoint. 
9.5.1.4 12-Lead Electrocardiogram 
Standard 12-lead ECG parameters (PR, QRS, QT, and QTcF intervals, and HR) will be listed 
for individual participants. Descriptive statistics (n, arithmetic mean, SD, median, minimum 
and maximum) will be calculated for each parameter overall and by treatment for Part B and 
trial period. Where multiple values are recorded at a time for a participant, the mean of the 
values will be used in the descriptive statistics. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 68 of 80 
9.5.1.5 Physical Examination 
Physical examination data will be listed by participant for abnormal findings only. 
9.5.1.6 C-SSRS 
C-SSRS data, including item scores, suicidal ideation and suicidal behavior will be listed for 
individual participants. Scores will be summarized using descriptive statistics (n, arithmetic 
mean, SD, median, minimum and maximum) overall and by treatment for Part B and trial 
period. 
9.5.2 Efficacy Statistical Analysis 
The primary efficacy endpoint is the CAPS-5 total score change from baseline to Week 10 as 
compared to placebo. 
All efficacy endpoint data will be listed for individual participants. All continuous efficacy 
endpoints will also be summarized by descriptive statistics (n, arithmetic mean, SD, median, 
minimum and maximum) by study part, overall, by treatment (for Part B) and study period. All 
categorical efficacy endpoints will be summarized by descriptive statistics (n, percentage). 
For Part A the change from baseline to each timepoint will be presented along with a paired 
t-test p-value. 
A Mixed Model for Repeated Measures (MMRM) will be fitted for select efficacy endpoints 
to analyze the difference between treatments for Part B. The model will include treatment, visit, 
and treatment by visit interaction as fixed effects, where visit is the repeated effect. The 
baseline value will be included (if applicable) as a covariate. All tests will be based on two-
sided significant level of 0.05. Full details of the statistical analysis for each endpoint will be 
described in the SAP. 
9.6 
Handling of Missing or Incomplete Data 
Unrecorded values will be treated as missing. The appropriateness of the method(s) described 
for handling missing data will be reassessed and documented as the data review prior to 
database lock. Depending on the extent of the missing values, further investigation may be 
made into sensitivity of the analysis results to the method(s) specified. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 69 of 80 
10 DATA HANDLING AND RECORD KEEPING 
10.1 Collection of Data 
Data collected from each completed participant will be recorded on source documents, which 
will be entered into an eCRF. The Investigator is responsible for ensuring that all sections of 
the eCRF are completed correctly and that entries can be verified against the source documents. 
If certain data are not available or not applicable this will be indicated as such within the 
appropriate area of the eCRF. 
Screening failures are defined as participants who signed consent to take part in the study but 
were not subsequently assigned to study intervention. Screening failures may fail to meet any 
inclusion criteria and may meet one or more exclusion criteria or withdraw consent prior to 
enrollment. All potential participants who begin Screening will be tracked on a Screening Log. 
Screening failures are not considered evaluable. Minimal data on screening failures will be 
recorded in the clinical study database. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants to meet the CONSORT publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAEs. 
Data produced by automatic devices with original printouts (i.e., clinical laboratory evaluation 
results, ECG traces) will be attached to the source documents. Clinical laboratory parameters 
will be provided in laboratory printouts which are to be signed by the Investigators. Comments 
on all clinically significant abnormal values will be provided and documented by the 
Investigators or appropriately recorded within the eCRF. 
Adverse Events and Medical History will be reported by the MedDRA SOC and PT; the most 
current version at the time of study start will be applied to all terms. All Medical History and 
AEs will be included in the data listings. Furthermore, all Prior Medications and Concomitant 
Medications will be reported using the WHODRUG categorization; the most current version 
at the time of study start will be applied to all terms. 
All Prior Medications and Concomitant Medications will be summarized within the data 
listings. 
Any missing, implausible, or inconsistent recordings within the eCRFs will be referred to the 
Investigator using data query validation procedures; will be documented and resolved for each 
individual participant before database lock is declared. 
All processes pertaining to the Data Management activities will be detailed within the Data 
Management Plan. 
10.2 Inspection of Records 
Authorized representatives of the Sponsor or delegate will be allowed to conduct site visits for 
the purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability and participant records, 
study source documents and any other pertinent records relative to study conduct.  
10.3 Retention of Records 
The Investigator should maintain all documentation relating to the study for a period of 25 
years or per local regulations, whichever is longer. If it becomes necessary for the Sponsor or 
delegate or a regulatory authority to review any documentation relating to the study, the 
Investigator must permit access to such records.  

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 70 of 80 
10.4 Confidentiality and Data Protection 
All data collected in this study will be recorded, processed, stored, and handled in such a way 
that it can be accurately reported, interpreted, and verified, while preserving the confidentiality 
of the records. Every effort will be made to strictly safeguard the confidentiality of participants. 
Participants will be assigned a participant number/identifier and study data will be associated 
only with this number/identifier. Source documents will be stored securely at clinical sites and 
access will be limited to regulatory agencies, researchers, and individuals analyzing data. Study 
data will be recorded in a secure EDC system compliant with 21 CFR Part 11 and applicable 
regional (i.e. EU) directives. All data entered is de-identified and participants are referred by 
their assigned participant number/identifier. 
The Sponsor serves as Data Controller according to the General Data Protection Regulation 
(GDPR) and maintains robust contractual agreements with any vendor processing participant 
data. These contractual agreements outline the technical and organizational measures that 
comply with Data Protection Laws and ensure a level of security appropriate to the risk of 
processing participants data. 
 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 71 of 80 
11 MONITORING, AUDIT, AND INSPECTION 
11.1 Study Monitoring 
Before an Investigator can enter a participant into the study, a representative of the Sponsor or 
delegate will visit the site to: 
• Determine the adequacy of the facilities and staff, 
• Discuss with the Investigator and other personnel their responsibilities with regard to 
Protocol adherence, and the responsibilities of the Sponsor or delegate. This will be 
documented in a Clinical Trial Agreement between the Sponsor or delegate and the 
Investigator. 
During the study, a Clinical Research Associate from the Sponsor or delegate will have regular 
contacts with the site, for the following: 
• Provide information and support to the Investigator. 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the Protocol, that data are being 
accurately recorded in the eCRFs, and that study drug accountability checks are being 
performed.  
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the participant’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
participant (e.g., clinic charts). 
• Record and report any protocol deviations not previously sent to the Sponsor or 
delegate. 
• Confirm AEs and SAEs have been appropriately documented within eCRFs and 
confirm any SAEs have been communicated to the Sponsor or delegate and those SAEs 
that met criteria for reporting have been provided to the IRB/EC. 
The Clinical Research Associate will be available between visits if the Investigator or other 
staff needs information or advice. 
11.2 Audits and Inspections 
Authorized representatives of the Sponsor or delegate, a regulatory authority, or the IRB/EC 
may visit the site to perform audits or inspections, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents. The inspection determines whether these activities were 
conducted, in addition to data being recorded, analyzed, and accurately reported according to 
the Protocol; ICH-GCP and any applicable regulatory requirements. The Investigator is 
responsible for making contact with the Sponsor or delegate immediately, if approached by a 
regulatory agency regarding an inspection. 
11.3 Quality Control and Quality Assurance 
To ensure compliance with GCP and all regulatory requirements, the Sponsor or delegate may 
conduct a Quality Assurance Audit. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 72 of 80 
12 ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 Ethical Conduct of the Study 
The study will be conducted in accordance with this protocol, the principles of Good Clinical 
Practice and applicable regulatory requirement(s) (i.e. the EU Clinical Trial Regulation 
536/2014, the ICH guideline for GCP E6(R2) dated December 2016, and the ethical principles 
laid down in the Declaration of Helsinki). Current regulatory requirements will be followed, as 
applicable.  
12.2 Approval by Institutional Review Board / Ethics Committee 
A valid IRB/EC must review and approve this protocol before study initiation. Written 
notification of approval is required before shipment of investigational drug supplies and will 
include the date of the committee’s approval and the chairperson’s signature.  
Until written approval by the IRB/EC has been received by the investigator, no participant may 
undergo any procedure solely for determining eligibility for this study. 
Protocol amendments must also be reviewed and approved in writing by the IRB/EC prior to 
implementation. 
12.3 Written Informed Consent 
Potential participants will have a detailed verbal presentation of the nature, purpose, risks and 
requirements, in addition to receiving detailed written information provided in the Participant 
Information Sheet. They will have adequate opportunity to ask the healthcare professional 
presenting the study about any aspect of the study. Participants must also be notified that they 
are free to discontinue from the study at any time. The participant should be given the 
opportunity to ask questions and allowed time to consider the information provided. Once the 
participant is satisfied that they are willing to participate in the study, they will be asked to sign 
a copy of the study ICF. The participant’s signed and dated informed consent must be obtained 
before conducting any study procedures. The Investigator must maintain the original, signed 
ICF. A copy of the signed ICF will be provided to the participant. 
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
Records up to the time of early termination should be completed. In the event that a participant 
does not receive a study treatment, the primary reason will be recorded. A list of the procedures 
conducted at Screening are presented in the Schedule of Assessments (see Section 1.3). 
Informed consent will be obtained prior to the participant undergoing procedures that are 
specifically for the purposes of the study. 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 73 of 80 
13 REFERENCES 
Arroll B, Macgillivray S, Ogston S, et al. Efficacy and tolerability of tricyclic antidepressants 
and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. 
Annals of Family Medicine. 2005;3(5):449-456.  
Averill LA, Perelman M, Ching THW, Farré M, Mandell B, Stogniew M, et al. A Case Series 
Providing Clinical Evidence that Methylone Produces Rapid and Robust Improvements in 
Major Depressive Disorder. Ann Clin Case Rep. 2023; 8: 2519 
Baumann MH, Walters HM, Niello M, Sitte HH. Neuropharmacology of Synthetic Cathinones. 
Handb Exp Pharmacol. 2018;252:113-142.  
Cameron KN, Kolanos R, Solis E Jr, Glennon RA, De Felice LJ. Bath salts components 
mephedrone and methylenedioxypyrovalerone (MDPV) act synergistically at the human 
dopamine transporter. Br J Pharmacol. 2013;168(7):1750-1757.  
Dorrington S, Zavos H, Ball H, et al. Trauma, post-traumatic stress disorder and psychiatric 
disorders in a middle-income setting: prevalence and comorbidity. Br J Psychiatry. 
2014;205(5):383-9.  
Cipriani A, Williams T, Nikolakopoulou A, et al. Comparative efficacy and acceptability of 
pharmacological treatments for post-traumatic stress disorder in adults: a network meta-
analysis. Psychological Medicine. 2018;48(12):1975-1984.  
Eshleman AJ, Wolfrum KM, Hatfield MG, et al. Substituted methcathinones differ in 
transporter and receptor interactions. Biochem Pharmacol. 2013;85(12):1803-15.  
Flory JD, Yehuda R. Comorbidity between post-traumatic stress disorder and major depressive 
disorder: alternative explanations and treatment considerations. Dialogues in Clinical 
Neuroscience. 2015;17(2):141-150. 
Forbes D, Creamer M, Bisson JI, et al. A guide to guidelines for the treatment of PTSD and 
related conditions. Journal of Traumatic Stress. 2010;23(5):537-552.  
Greenberg N, Brooks S, Dunn R. Latest developments in post-traumatic stress disorder: 
diagnosis and treatment. Br Med Bull.  2015;114(1):147-55.  
Hassan Z, Bosch OG, Singh D, et al. Novel Psychoactive Substances-Recent Progress on 
Neuropharmacological Mechanisms of Action for Selected Drugs. Front Psychiatry. 
2017;8:152.  
Hoskins M, Pearce J, Bethell A, et al. Pharmacotherapy for post-traumatic stress disorder: 
systematic review and meta-analysis. Br J Psychiatry. 2015;206(2):93-100.  
Jones, A., Warner-Schmidt, J., Stogniew, M., et al. Methylone for the treatment of PTSD: 
initial results from an open-label study (IMPACT-1), 2023 ACNP, Tampa, FL. 
Kato T, Furukawa TA, Mantani A, et al. Optimising first- and second-line treatment strategies 
for untreated major depressive disorder — the SUN☺D study: a pragmatic, multi-centre, 
assessor-blinded randomised controlled trial. BMC Medicine. 2018;16:103.  
Kelmendi B, Pittenger C, Farre M, et al. Clinical Evidence for the Use of Methylone in the 
Treatment of PTSD: A Case Series with Long-Term Follow-up. Annals of Clinical Case 
Reports. 2022; 7: 2209  
 
Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the 
National Comorbidity Survey. Archives of General Psychiatry. 1995;52(12):1048-1060.  

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 74 of 80 
Kibler JL. Posttraumatic stress and cardiovascular disease risk. J Trauma Dissociation. 
2009;10(2):135-50.  
Koenen KC, Ratanatharathorn A, Ng L, et al. Posttraumatic stress disorder in the World Mental 
Health Surveys. Psychol Med. 2017;47(13):2260-2274.  
McManus S, Bebbington PE, Jenkins R, Brugha T. Mental health and wellbeing in England: 
Adult Psychiatric Morbidity Survey 2014. Leeds: NHS Digital, 2016. 
Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: 
a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025-
1033.  
National Health Service (NHS). Causes - Post-traumatic stress disorder. Accessed March 27, 
2023. 
https://www.nhs.uk/mental-health/conditions/post-traumatic-stress-disorder-
ptsd/causes/ 
National Institute of Mental Health (NIMH). Post-Traumatic Stress Disorder (PTSD). 
Accessed March 27, 2023. https://www.nimh.nih.gov/health/statistics/post-traumatic-stress-
disorder-ptsd 
Peconga EK, Høgh Thøgersen M. Post-traumatic stress disorder, depression, and anxiety in 
adult Syrian refugees: What do we know? Scandinavian Journal of Public Health. 
2020;48(7):677-687.  
Poyatos L, Papaseit E, Olesti E, et al. A Comparison of Acute Pharmacological Effects of 
Methylone and MDMA Administration in Humans and Oral Fluid Concentrations as 
Biomarkers of Exposure. Biology (Basel). 2021;10(8):788.  
Poyatos L, Lo Faro AF, Berardinelli D, et al. Methylone and MDMA Pharmacokinetics 
Following Controlled Administration in Humans. Int J Mol Sci. 2022;23(23):14636.  
Poyatos L, Pérez-Mañá C, Hladun O, et al. Pharmacological effects of methylone and MDMA 
in humans. Front Pharmacol. 2023;14:1122861.  
Scott KM, McGee MA, Wells JE, Oakley Browne MA. Obesity and mental disorders in the 
adult general population. J Psychosom Res. 2008;64(1):97-105.  
Shulgin A, inventor; Methylone Patent, International Application Published under the Patent 
Cooperation Treaty.  December 12, 1996. 
Stein DJ, Ipser JC, Seedat S. Pharmacotherapy for post traumatic stress disorder (PTSD). 
Cochrane Database Syst Rev.. 2006;(1):CD002795.  
Stein MB, Kennedy C. Major depressive and post-traumatic stress disorder comorbidity in 
female victims of intimate partner violence. Journal of Affective Disorders. 2001;66(2-3):133-
138.  
Tarrier N, Gregg L. Suicide risk in civilian PTSD patients--predictors of suicidal ideation, 
planning and attempts. Soc Psychiatry Psychiatr Epidemiol. 2004;39(8):655-61.  
Warner-Schmidt J, Pittenger C, Stogniew M, Mandell B, Olmstead SJ, Kelmendi B. 
Methylone, a rapid acting entactogen with robust anxiolytic and antidepressant-like activity. 
Front Psychiatry. 2023;13:1041277.  
Watterson LR, Hood L, Sewalia K, et al. The Reinforcing and Rewarding Effects of Methylone, 
a Synthetic Cathinone Commonly Found in "Bath Salts". J Addict Res Ther. 2012;Suppl 9:002 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 75 of 80 
World Health Organization. (2014). Methylone (bk‐MDMA) critical review report. Expert 
Committee on Drug Dependence 36th Meeting, Geneva, Switzerland. https://legal-high-
inhaltsstoffe.de/sites/default/files/uploads/methylone.pdf Accessed: March 27, 2023. 
Yu A, Basu A, Dibbs M, et al. Circuit- and behavioral-level investigation of plasticity after 
administration of psychedelics and entactogens in mice. Society for Neuroscience 2022 Annual 
Meeting, San Diego, CA, USA 

Protocol Number: TT-TSND-201 
October 11, 2024 
Version: Final, V 6.0 
CONFIDENTIAL 
Page 80 of 80 
14.4 Appendix 4 – Childbearing Potential 
Woman of Childbearing Potential 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming postmenopausal unless permanently sterile 
(see below) 
• A postmenopausal state is defined as no menses for ≥12 months without an 
alternative medical cause. 
o A high FSH level in the postmenopausal range will be used to confirm 
a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT) with ≤12 months of amenorrhea. 
o Females on HRT and whose menopausal status is in doubt will be 
required to use one of the non-estrogen hormonal highly effective 
contraception methods if they wish to continue their HRT during the 
study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status (i.e., ≥12 months of amenorrhea) before study 
enrollment. 
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
Investigator discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination or medical history review. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first administration of study drug, the participant will be considered as 
a WOCBP and will be required to follow the contraception guidelines.