A Randomized, Double-Blind, Placebo-Controlled, Multi-Site Phase 3 Study of the Efficacy and Safety of Manualized MDMA-Assisted Psychotherapy for the Treatment of Severe Posttraumatic Stress Disorder
Phase: PHASE3
Conditions: Posttraumatic Stress Disorder
Sponsor: Lykos Therapeutics

CONFIDENTIAL 
 
 
 Protocol MAPP1 
IND #063384 
 
Original Protocol Version 1: 16 January 2017 
Original Protocol Version 2: 07 June 2017 
Amendment 1 Version 1: 26 February 2018 
Amendment 2 Version 1: 12 September 2019 
Amendment 3 Version 1: 13 November 2019 
Amendment 4 Version 1: 22 May 2020 
 
A Randomized, Double-Blind, Placebo-Controlled, Multi-Site Phase 3 Study of the 
Efficacy and Safety of Manualized MDMA-Assisted Psychotherapy for the 
Treatment of Severe Posttraumatic Stress Disorder 
 
 
SPONSOR 
Multidisciplinary Association for Psychedelic Studies (MAPS) 
1115 Mission Street 
Santa Cruz, CA 95060 
 
SPONSOR REPRESENTATIVE 
Rick Doblin, Ph.D. 
Executive Director 
MAPS 
SPONSOR DELEGATE  
&TRIAL ORGANIZER  
MAPS Public Benefit Corporation 
1115 Mission Street 
Santa Cruz, CA 95060 
 
SPONSOR DESIGNEE 
Amy Emerson 
Executive Director 
MAPS Public Benefit Corporation 
Phone number: 510-393-7224 
Email: amy@mapsbcorp.com 
 
CLINICAL INVESTIGATOR 
Multi-site Study 
 
MEDICAL MONITOR 
Michael C. Mithoefer, M.D. 
Email: michael@mapsbcorp.com 
Alia Lilienstein, M.D., M.P.H. 
Email: alia@mapsbcorp.com  
 
USE 
In conjunction with relevant Food and Drug Administration (FDA), 
Health Canada (HC), and Israeli Ministry of Health (MOH) guidance 
 

MAPS Public Benefit Corporation 
 
MAPP1 Protocol Synopsis 
IND #063384 
 
Amendment 4 Version 1: 22 May 2020 
 
Page 2 of 104 
 
MAPP1 Protocol Synopsis 
Full protocol begins on Page 11. 
 
 
Rationale 
 
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit research and 
educational organization working as a clinical trial sponsor to obtain approval for the prescription 
use of 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct to psychotherapy in patients 
with posttraumatic stress disorder (PTSD). PTSD is a serious debilitating disorder that negatively 
impacts a person’s daily life, and can result in diminished cognitive and psychosocial functioning, 
fractured relationships, inability to maintain employment, substance abuse, high-cost healthcare 
utilization, increased depression, and suicide risk. People who suffer from PTSD relive their 
traumatic experience(s) through nightmares and flashbacks, have difficulty sleeping, and feel 
detached or estranged. Symptoms can be severe and long lasting. 
 
MDMA is a monoamine releaser and re-uptake inhibitor with indirect effects on neurohormone 
release. The combined neurobiological effects reduce defenses and fear of emotional injury, 
enhance communication and introspection, and increase empathy and compassion. MDMA may 
enhance fear extinction learning in humans. The subjective effects of MDMA create a productive 
psychological state that enhances the therapeutic process. Data from an international series of 
Phase 2 pilot studies of MDMA-assisted psychotherapy conducted by the sponsor provide 
preliminary evidence that chronic PTSD, independent of cause, is treatable with two to three 
sessions of MDMA-assisted psychotherapy and associated non-drug preparatory and integrative 
psychotherapy. This Phase 3 study is intended to confirm the efficacy and safety of manualized 
MDMA-assisted psychotherapy as a treatment for PTSD. 
 
Study Design 
 
This multi-site, randomized, double-blind study assesses the efficacy and safety of MDMA-
assisted psychotherapy versus psychotherapy with placebo control in participants diagnosed with 
at least severe PTSD. A flexible dose of MDMA hydrochloride salt (referred to as MDMA 
throughout) or placebo, followed by a supplemental half-dose unless contraindicated, is 
administered during the Treatment Period with manualized psychotherapy in three blinded 
monthly Experimental Sessions. This ~12-week Treatment Period is preceded by three 
Preparatory Sessions. During the Treatment Period, each Experimental Session is followed by 
three Integrative Sessions of non-drug psychotherapy. Experimental Sessions are followed by an 
overnight stay; a sub-study (Appendix A) will assess feasibility of Experimental Sessions without 
an overnight stay. The Primary Outcome measure, the change in Clinician Administered PTSD 
Scale (CAPS-5) from Baseline (Visit 3), is assessed by a blinded centralized Independent Rater 
(IR) pool at 18 weeks post Baseline (Visit 19). The CAPS-5 is also administered as an 
exploratory measure after Treatments 1 and 2 (Visits 8 and 13). The IR pool will be blinded to 
visit number and number of treatments received and will not have access to data collected by the 
sites during the active treatment period.  
 
The study will be conducted in N≈100 participants, randomized with a 1:1 allocation to Group 1: 
MDMA-assisted psychotherapy or Group 2: placebo with psychotherapy, with a planned interim 
analysis for sample size re-estimation by an independent Data Monitoring Committee (DMC) 
after 100 participants are enrolled and at least 60% of participants have completed their final 
CAPS-5 assessment and terminated treatment. Prior to this study, there will be separate open-

MAPS Public Benefit Corporation 
 
MAPP1 Protocol Synopsis 
IND #063384 
 
Amendment 4 Version 1: 22 May 2020 
 
Page 3 of 104 
label lead-in protocols following identical study procedures for new therapy teams to receive 
clinical supervision from the sponsor. 
 
Any sub-studies other than what is outlined in Appendix A will be detailed in separate 
documents. 
 
For each participant, the study will consist of:  
 
• 
Screening Period: phone screen, informed consent, eligibility assessment, and 
enrollment of eligible participants  
• 
Preparatory Period with Enrollment Confirmation: medication tapering, Preparatory 
Sessions and Baseline assessments leading to Enrollment Confirmation 
• 
Treatment Period: three monthly Experimental Sessions and associated Integrative 
Sessions over ~12 weeks plus two CAPS-5 assessments 
• 
Follow-up Period and Study Termination: 4 weeks with no study visits, followed by 
Primary Outcome CAPS-5 and Study Termination visit 
• 
Invitation to participate in Long-term Follow-up (LTFU) extension study: 12 months 
after last Experimental Session. 
 
After study unblinding which occurs following database lock, participants in the placebo group, 
regardless of their CAPS-5 scores, will be offered the opportunity to enroll at no cost in an open-
label safety extension study to receive treatment with the same method of MDMA-assisted 
psychotherapy as in the initial study. Data will be included in the sponsor’s overall safety 
database. 
 
Study Design Overview 
Screening Period 
From Consent to Enrollment (Visit 0): ~4 weeks (±2 weeks) 
Study Visit 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Screening 
Screening  
Multiple visits 
over 7 to 28 days/ 
After phone 
screen/ 
 
At initial visit, obtain Informed Consent and assess all 
screening measures (including PCL-5, Lifetime C-SSRS), 
medical history, and pre-study medications. Contact outside 
providers and order medical records, physical exam, labs 
(including pregnancy and drug tests), ECG, and 1-minute 
rhythm strip. Once all results and records are obtained, 
review along with notes from all screening visits and 
measures. If eligible, send results of LEC-5 & SCID-5-SPQ 
to IR. Screening may take place over 7 to 28 days at 
multiple visits. 
Independent 
Rater 
Screening 
1 hour/ 
2 to 9 days after 
initial eligibility 
established during 
Screening 
After PCL-5 and initial eligibility are reviewed, an IR will 
conduct the Since Last Visit C-SSRS, SCID-5-PD, DDIS, 
and MINI via telemedicine. Results will be confirmed by 
clinical observation during the Preparatory Period, but the 
SCID-5-PD, DDIS, and MINI will not be repeated.  
Enrollment 
Enrollment 
(Visit 0) 
1.5 hours/ 
2 to 14 days after 
Independent Rater 
Screening 
Prior to enrolling: review all screening measures, medical 
history, discussion with outside providers and sponsor, and 
any clarification phone calls with participant. Visit is 1.5 
hours to review eligibility and medical tapering plan. If 
enrolled, begin taper, (5 half-lives plus 7 days for 
stabilization prior to V3). Adverse Event (AE) collection 
begins. 
 

MAPS Public Benefit Corporation 
 
MAPP1 Protocol Synopsis 
IND #063384 
 
Amendment 4 Version 1: 22 May 2020 
 
Page 4 of 104 
Preparatory Period with Enrollment Confirmation  
From Preparatory Session 1 (Visit 1) to Preparatory Session 3 (Visit 4): ~6 weeks (+5/-5 weeks) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Preparatory Period 
Preparatory 
Session 1 
(Visit 1) 
1.5 hours/ 
0 to 12 days after 
Enrollment (V0) 
90-minute Preparatory Session. Target visit timing 
on tapering needs. If needed, schedule calls between 
Visits 1 and 2 if indicated for tapering, safety, or 
further questions about medical history. 
Preparatory 
Session 2 
(Visit 2) 
 
1.5 hours/ 
2 to 21 days after V1 
90-minute Preparatory Session/ongoing assessment. 
If tapering is complete or not needed, check 
eligibility and schedule Visits 3 and 4. If tapering is 
ongoing, schedule post taper call for ongoing 
assessment. 
Phone Call 
End Taper 
 
1 hour/ 
0 to 7 days after taper 
and stabilization end; up 
to 56 days after V0; 
prior to V3 
If needed, confirm medication taper and 
stabilization is complete and participant is eligible 
for Baseline CAPS-5. Schedule Visits 3 and 4. 
Baseline & Enrollment Confirmation 
Baseline 
CAPS-5 T1 
(Visit 3) 
1.5 hours/ 
Post V2 & Medication 
Taper; before V4 
CAPS-5, SDS, and DSP-I completed by an IR via 
telemedicine after taper is complete. CAPS scores 
sent ASAP to the therapy team/PI. 
 
Due to possibilities of negative side effects of 
withdrawal from psychiatric medications, the 
Baseline CAPS-5 should be scheduled as close to 
the end of tapering as clinically appropriate so that 
participants who do not meet eligibility criteria can 
resume their previously prescribed medications as 
quickly as required for symptom management and 
participants who do meet criteria can be enrolled 
and treated as quickly as possible. 
Preparatory 
Session 3 
& Enrollment  
Confirmation 
(Visit 4) 
3 hours (90-minute 
measures, 90-minute 
therapy)/ 
3 to 6 days after V3; 
1 to 4 days prior to V5 
 
 
Prior to visit, ensure CAPS-5 confirms PTSD 
diagnosis and Total Severity Score of ≥35 and 
confirm enrollment by reassessing eligibility 
criteria. Complete Baseline self-report measures. 
Complete 3-hour Preparatory Session (~90-minute 
measures, 90-minute therapy) and schedule Visit 5. 
If enrollment is not confirmed, do not randomize; 
complete Study Termination. 
 

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Amendment 4 Version 1: 22 May 2020 
 
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Treatment Period 
From Randomization to Integrative Session 3.3 (Visit 18): 12 weeks (-3/+4) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Treatment 1 
Randomization 
.5 hours/ 
24 to 48 hours before 
V5 
Complete after enrollment and scheduling Visit 5. 
Enter demographics in Medrio for use in 
randomization. The participant does not need to be 
present for this. 
Experimental 
Session 1 
(Visit 5) 
8 hours + overnight/ 
4 to 7 days after V3; 
1 to 4 days after V4 
First Experimental Session is within 2 weeks of the 
Baseline CAPS-5 (Visit 3), it lasts 8 hours with 
overnight stay. Dose is 80 mg with supplemental 
half-dose of 40 mg unless contraindicated. 
Integrative 
Session 1.1 
(Visit 6) 
1.5 hours/ 
Morning after V5 
Visit 6 is a 90-minute Integrative Session the 
morning after Visit 5. Followed by phone check-ins 
that includes Since Last Visit C-SSRS assessment 
on Days 2, 4, 6, 7, 8, 10, 12, 14 post Visit 5.  
Integrative 
Session 1.2 
(Visit 7) 
1.5 hours/ 
3 to 14 days after V5; 
at least 2 days after V6 
Between 3 and 14 days after Visit 5, a 90-minute 
Integrative Session (Visit 7) is completed. 
CAPS-5 T2 
(Visit 8) 
1 hour 
18 to 30 days after V5; 
between V7 and V9 
(may be on same day as 
either) 
Between Visits 7 and 9 (may be same day as either), 
CAPS-5, SDS, and DSP-I assessment completed by 
an IR via telemedicine.  
Integrative 
Session 1.3 
(Visit 9) 
1.5 hours/ 
20 to 34 days after V5; 
at least 2 days after V7; 
1 to 7 days before V10  
90-minute Integrative Session post Visit 8 and in 
preparation for Visit 10. Can occur 1 to 7 days 
before Visit 10. Measures include LEC-5 and C-
SSRS. 
Treatment 2 
Experimental 
Session 2 
(Visit 10) 
8 hours + overnight/ 
21 to 35 days after V5 
21 to 35 days after Visit 5. The second 
Experimental Session lasts 8 hours with an 
overnight stay. Dose is 80 or 120 mg plus 
supplemental half-dose unless contraindicated. 
Integrative 
Session 2.1 
(Visit 11) 
1.5 hours/ 
Morning after V10 
 
Visit 11 is a 90-minute Integrative Session the 
morning after Visit 10. Followed by phone check-
ins that includes Since Last Visit C-SSRS 
assessment on Days 2, 4, 6, 7, 8, 10, 12, 14 post 
Visit 10.  
Integrative 
Session 2.2 
(Visit 12) 
1.5 hours/ 
3 to 14 days after V10; 
at least 2 days after V11 
Between 3 and 14 days after Visit 10, a 90-minute 
Integrative Session (Visit 12) is completed. 
CAPS-5 T3 
(Visit 13) 
1 hour/ 
18 to 30 days after V10; 
between V12 and V14 
(may be on same day as 
either) 
Between Visits 12 and 14 (may be on same day as 
either), CAPS-5, SDS, and DSP-I assessment 
completed by an IR via telemedicine. 
Integrative 
Session 2.3 
(Visit 14) 
1.5 hours/ 
20 to 34 days after V10; 
at least 2 days after 
Integrative Session 2.2 
(V12) 
1 to 7 days before V15 
90-minute Integrative Session post Visit 13 and in 
preparation for Visit 15. Can occur 1 to 7 days 
before Visit 15. Measures include LEC-5 and C-
SSRS. 
 
 

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IND #063384 
 
Amendment 4 Version 1: 22 May 2020 
 
Page 6 of 104 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Treatment 3 
Experimental 
Session 3 
(Visit 15) 
8 hours + overnight/ 
21 to 35 days after V10 
21 to 35 days after Visit 10. The third Experimental 
Session lasts 8 hours with an overnight stay. Dose 
is 80 or 120 mg plus supplemental half-dose unless 
contraindicated. 
Integrative 
Session 3.1 
(Visit 16) 
1.5 hours/ 
Morning after V15 
Visit 16 is a 90-minute Integrative Session the 
morning after Visit 15. Followed by phone check-
ins that includes Since Last Visit C-SSRS 
assessment on Days 2, 4, 6, 7, 8, 10, 12, 14 post 
Visit 15. 
Integrative 
Session 3.2 
(Visit 17) 
1.5 hours/ 
3 to 14 days after V15; 
at least 2 days after V16 
Between 3 and 14 days after Visit 15, a 90-minute 
Integrative Session (Visit 12) is completed. 
Integrative 
Session 3.3 
(Visit 18) 
1.5 hours/ 
21 to 35 days after V15 
90-minute Integrative Session post Visit 17, 21 to 
35 days after Visit 15. Measures include LEC-5 and 
C-SSRS. 
 
Follow-up Period and Study Termination 
From Integrative Session 3.3 (Visit 18) until Study Termination (Visit 20): 4 weeks (±2). After 
Integrative Session 3.3 (Visit 18), ~4 weeks with no scheduled study visits until the Primary Outcome is 
completed. 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Primary Outcome 
Primary 
Outcome 
CAPS-5 T4 
(Visit 19) 
1 hour/ 
18 (±3) weeks (105 to 
147 days) after V3; 
8 (±2) weeks (42 to 70 
days) after V15 
Occurs 105 to 147 days of Baseline and 42 to 70 
days) after Experimental Session 3 (Visit 15), 
Primary Outcome CAPS-5, SDS, and DSP-I 
assessment completed by an IR via telemedicine. 
Although there are allowable windows for all visits 
throughout the protocol, this visit is targeted to be 
completed within the overall window. Other visits 
should be scheduled to ensure the timing of the 
Primary Outcome CAPS-5 T4 assessment is 
appropriate. In the case of study interruption, Visit 
19 should be scheduled 42 to 70 days after Visit 15. 
Study Termination 
Study 
Termination 
Visit 20 
2 hours  
~18 (±3) weeks (105 to 
147 days) after V3; 
1 to 9 days after V19 
Occurs 105 to 147 days post Baseline and within 1 
to 9 days of Visit 19. Complete self-reported and 
safety measures; create an exit plan for participant. 
Invite participant to the extension study for LTFU. 
Let participant who completed the protocol know 
how they will be informed of unblinding and at that 
time, if in the placebo group, regardless of CAPS-5 
scores, they will be offered the opportunity to enroll 
at no cost in an open-label safety extension study. 
 
 
Qualified, blinded IRs selected based on availability from the IR Pool will perform the CAPS-5 
assessments as described in the following. 
 

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MAPP1 Protocol Synopsis 
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Amendment 4 Version 1: 22 May 2020 
 
Page 7 of 104 
Primary Outcome (CAPS-5) Data Collection by Visit 
CAPS Number 
Visit 
Description/Timing 
Target Timing 
Post Baseline (V3) 
Baseline CAPS-5 T1 
V3 
Baseline 
Between Visits 2 and 4 Preparatory Sessions 
0 days 
CAPS-5 T2 
V8 
Post Experimental Session 1 (~3 weeks) 
Between Visits 7 and 9 Integrative Sessions 
~6 weeks 
CAPS-5 T3 
V13 
Post Experimental Session 2 (~3 weeks) 
Between Visits 12 and 14 Integrative Sessions 
~10 weeks 
Primary Outcome  
CAPS-5 T4 
V19 
Post Experimental Session 3 (~8 weeks) 
~18 weeks 
 
Dose Selection 
 
This study will compare the effects of three blinded manualized Experimental Sessions of 
psychotherapy assisted by flexible doses of MDMA or placebo as described in the table below, 
along with associated non-drug preparatory and integrative psychotherapy. Similar MDMA doses 
to those proposed in this study have been safely used in previous Phase 2 studies sponsored by 
MAPS. 
 
Dose Regimen of MDMA or Placebo 
Experimental 
Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative Dose 
1 
80 mg 
40 mg 
80 mg to 120 mg 
2 
80 or 120 mg 
40 or 60 mg 
80 mg to 180 mg 
3 
80 or 120 mg 
40 or 60 mg 
80 mg to 180 mg 
Total Cumulative Dose 
240 mg to 480 mg 
* Unless contraindicated 
 
Protocol Objective 
 
The overall objective of this study is to use standard clinical measures to confirm the efficacy and 
safety of manualized MDMA-assisted psychotherapy with a flexible dose of MDMA in reducing 
PTSD and associated symptoms in comparison to the same psychotherapy combined with an 
inactive placebo control. 
 
Primary Objective 
 
The primary objective of this study is to evaluate the efficacy of MDMA-assisted psychotherapy 
for PTSD compared to the identical psychotherapy with inactive placebo, based on comparison of 
CAPS-5 Total Severity Score at Visit 3 (Baseline) to Visit 19 (18 weeks post Baseline). 
 
Secondary Objective 
 
The secondary objective of this study is to evaluate the efficacy of MDMA-assisted 
psychotherapy for PTSD compared with identical psychotherapy with inactive placebo in 
clinician-rated functional impairment, as measured by the mean change in Sheehan Disability 
Scale (SDS) item scores from Visit 3 (Baseline) to Visit 19 (18 weeks post Baseline).  
 

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Amendment 4 Version 1: 22 May 2020 
 
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Safety Objectives 
 
The overall safety objective is to assess differences between groups in severity, incidence and 
frequency of AEs, Treatment Emergent AEs (TEAEs), AEs of Special Interest (AESIs), and 
Serious Adverse Events (SAEs), concomitant medication use, suicidal ideation and behavior, and 
vital signs to support the package insert for MDMA-assisted psychotherapy.  
The following safety objectives will evaluate the safety of MDMA-assisted psychotherapy 
compared to identical psychotherapy with inactive placebo: 
 
1. Compare relative incidence of AEs during Experimental Sessions that may be indicative 
of a medical complication of the Investigational Medicinal Product (IMP), such as 
clinical signs and symptoms of chest pain, shortness of breath, or neurological symptoms 
or any other signs or symptoms that prompt additional vital sign measurements. 
2. Compare relative incidence of AEs by severity. 
3. Compare relative incidence of TEAEs, to determine relationship to the IMP based on 
relative incidence in the MDMA group. 
4. Compare relative incidence of TEAEs by severity reported during an Experimental 
Session, 1 day, and 2 days after IMP administration. 
5. Compare relative incidence of AESIs, defined as AEs specified in the protocol related to 
cardiac function and abuse liability. 
6. Compare relative incidence of AEs by severity categorized as leading to discontinuation 
of IMP, resulting in death or hospitalization, and continuing at Study Termination. 
7. Compare relative incidence of SAEs. 
8. Compare relative incidence of psychiatric concomitant medications taken during an 
Experimental Session, 1 day, and 2 days after IMP administration. 
9. Compare relative incidence of any psychiatric concomitant medications taken during the 
Treatment Period. 
10. Compare relative incidence of positive or serious suicidal ideation and positive suicidal 
behavior assessed with the Columbia Suicide Severity Rating Scale (C-SSRS) by 
treatment group. 
11. Compare mean changes in blood pressure, heart rate, and body temperature from pre-IMP 
administration to end of each Experimental Session by treatment group. 
 
Recruitment and Participant Population 
 
Approximately N≈100 participants with a confirmed diagnosis of at least severe PTSD will be 
enrolled. Participants will be recruited through print and internet advertisements, referrals from 
other treatment providers, and by word of mouth. The sponsor will monitor demographics on an 
ongoing basis and encourage diversity (representative of PTSD population) in enrollment of study 
participants by communicating with sites. Randomization will be stratified by clinical site.  
 
Participants will be persons aged 18 or older, with a confirmed diagnosis of at least severe PTSD 
per the PCL-5 (PTSD Checklist for DSM-5) at Screening with symptoms present for at least 6 
months. At Baseline, participants must qualify for a PTSD diagnosis per the CAPS-5 and have a 
Total Severity Score equal to or greater than 35 (severe). Participants would not be excluded for 
having more than one traumatic event or for having tried, not tolerated, or refused a selective 
serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) 
prescribed for PTSD. Participants with confirmed diagnosis of specific psychological and 
personality disorders will be excluded. Participants must be in good physical health and without 
major medical disorders that could affect the safety or tolerability of MDMA. 
 

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MAPP1 Protocol Synopsis 
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Amendment 4 Version 1: 22 May 2020 
 
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Statistical Analysis of Efficacy 
 
The statistical power calculations were made by fitting a Mixed-Effect Model Repeated Measure 
(MMRM) model to CAPS-4 (Clinician-Administered PTSD Scale for DSM-4) data from the 
Phase 2 study MP1 to obtain covariance parameter estimates. The Phase 2 MP1 study followed a 
similar design with outcomes measured by CAPS-4 outcome scores, which allowed for 
estimation of within-subject covariance parameters. With a sample size of 50 participants per 
treatment group in the modified Intent-to-Treat (mITT) population, this study has 90% power to 
detect a treatment effect, using a two-sided test with an alpha of 0.0499. Additional participants 
may be enrolled, depending on sample size re-estimation by an independent DMC, with 
conditional power analysis conducted at a group-unblinded interim analysis for efficacy when 
100 participants are enrolled and at least 60% of the blinded participants (N=60) have completed 
their final CAPS-5 assessment and terminated treatment. Under no circumstances will the number 
of participants enrolled (at V0) be reduced below the initial planned 100, in order to obtain 
additional safety data. 
 
Primary Efficacy Analysis 
 
All efficacy analyses will be based on the mITT analysis set. The primary treatment comparison 
will be made at a 2-sided, 0.0499 level of significance. The reduction from Visit 3 (Baseline) in 
CAPS-5 Total Severity Scores between groups will be compared at Visit 19 (Primary Outcome) 
with least squares means from an MMRM model. The mITT analysis set will include all 
randomized participants who receive IMP in at least one blinded Experimental Session and have 
at least one follow-up CAPS-5 assessment. 
 
 
 
 

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Page 10 of 104 
Study Structure Overview
Prestudy
Treatment Period 
-
 
Treatment 1:
Approximately 4 weeks
Treatment 2:
Approximately 4 weeks
Treatment 3:
Approximately 4 weeks
 Medication Tapering
Preparatory Period and Enrollment 
Confirmation: Approximately 6 weeks 
Follow-Up Period:
Approximately 18 weeks post Baseline
Summary of Events
Primary 
Outcome
 
Medication Tapering
Preparatory Sessions
14 Day Phone 
Follow-up 
Experimental 
Session 1
Integrative Sessions
1.1, 1.2, 1.3
-
14 Day Phone 
Follow-up 
Experimental 
Session 2
Integrative Sessions 
2.1, 2.2, 2.3
14 Day Phone 
Follow-up 
Integrative Sessions 
3.1,3.2,3.3
 Screening     V0                    V1          V2        V3         V4                                      V5          V6                           V7         V8        V9                    V10        V11                         V12      V13      V14                   V15        V16                         V17        V18                               
                                    
Outcome  CAPS T4 (IR)
 
 
 
SCID-PD (IR)
 
SCID-PD (IR)
 
V19
Study 
Termination
V20
 
Baseline  CAPS T1 (IR)
 
Baseline  CAPS T1 (IR)
Medication Tapering
Enroll
Randomization
 
 CAPS T2 (IR)
 
 CAPS T2 (IR)
 
 CAPS T3 (IR)
 
 CAPS T3 (IR)
Experimental 
Session 3

 
CONFIDENTIAL 
 
 
 Protocol MAPP1 
IND #063384 
 
Original Protocol Version 1: 16 January 2017 
Original Protocol Version 2: 07 June 2017 
Amendment 1 Version 1: 26 February 2018 
Amendment 2 Version 1: 12 September 2019 
Amendment 3 Version 1: 13 November 2019 
Amendment 4 Version 1: 22 May 2020 
 
A Randomized, Double-Blind, Placebo-Controlled, Multi-Site Phase 3 Study of the 
Efficacy and Safety of Manualized MDMA-Assisted Psychotherapy for the 
Treatment of Severe Posttraumatic Stress Disorder 
 
 
SPONSOR 
Multidisciplinary Association for Psychedelic Studies (MAPS) 
1115 Mission Street 
Santa Cruz, CA 95060 
 
SPONSOR REPRESENTATIVE 
Rick Doblin, Ph.D. 
Executive Director 
MAPS 
SPONSOR DELEGATE  
&TRIAL ORGANIZER  
MAPS Public Benefit Corporation 
1115 Mission Street 
Santa Cruz, CA 95060 
 
SPONSOR DESIGNEE 
Amy Emerson 
Executive Director 
MAPS Public Benefit Corporation 
Phone number: 510-393-7224 
Email: amy@mapsbcorp.com 
 
CLINICAL INVESTIGATOR 
Multi-site Study 
 
MEDICAL MONITOR 
Michael C. Mithoefer, M.D. 
Email: michael@mapsbcorp.com 
Alia Lilienstein, M.D., M.P.H. 
Email: alia@mapsbcorp.com  
 
USE 
In conjunction with relevant Food and Drug Administration (FDA), 
Health Canada (HC), and Israeli Ministry of Health (MOH) guidance 
 

MAPS Public Benefit Corporation 
 
MAPP1 Protocol 
IND #063384 
 
Amendment 4 Version 1: 22 May 2020 
 
Page 12 of 104 
Table of Contents 
List of Tables ................................................................................................................................. 16 
List of Figures ............................................................................................................................... 17 
1.0 List of Abbreviations .............................................................................................................. 18 
2.0 Introduction ............................................................................................................................ 21 
2.1 Rationale ............................................................................................................................... 21 
2.2 Background ........................................................................................................................... 21 
2.2.1 PTSD ............................................................................................................................. 21 
2.2.2 MDMA .......................................................................................................................... 23 
2.2.3 MDMA-Assisted Psychotherapy for PTSD .................................................................. 23 
2.2.4 Previous Clinical Experience with MDMA ................................................................... 24 
3.0 Protocol Objectives ................................................................................................................. 25 
3.1 Primary Objective ................................................................................................................. 25 
3.2 Key Secondary Objective ..................................................................................................... 26 
3.3 Safety Objectives .................................................................................................................. 26 
3.4 Exploratory Objectives ......................................................................................................... 26 
4.0 Eligibility Criteria ................................................................................................................... 27 
4.1 Inclusion Criteria .................................................................................................................. 27 
4.2 Exclusion Criteria ................................................................................................................. 28 
4.3 Lifestyle Modifications ......................................................................................................... 30 
5.0 Protocol Design ....................................................................................................................... 31 
5.1 Study Design Overview ........................................................................................................ 31 
5.2 Planned Duration of Study ................................................................................................... 38 
5.2.1 Interruptions and Accommodations Due to COVID-19 Pandemic or Any Other 
Unforeseen Emergency at Clinic Locations ........................................................................... 38 
5.3 Discontinuation and Completion Criteria ............................................................................. 39 
5.3.1 Complete or Evaluable Participants............................................................................... 39 
5.3.2 Screen Failures............................................................................................................... 39 
5.3.3 Pre-Randomization Early Terminations ........................................................................ 40 
5.3.4 Early Termination from the Study ................................................................................. 40 
5.3.5 Lost to Follow-up .......................................................................................................... 41 
5.4 End of Study Definition and Premature Discontinuation ..................................................... 41 
5.5 Rationale of Dose Selection.................................................................................................. 42 
6.0 Psychotherapy ......................................................................................................................... 43 
6.1 Description of Therapeutic Method ...................................................................................... 43 
6.2 Therapy Team Qualifications ............................................................................................... 43 
6.3 Training ................................................................................................................................ 43 
6.4 Adherence to Therapeutic Method ....................................................................................... 43 
7.0 Measures and Reliability ........................................................................................................ 44 
7.1 Primary Outcome Measure and Reliability .......................................................................... 45 
7.1.1 CAPS-5 (Clinician-Administered PTSD Scale for DSM-5) ......................................... 45 
7.2 Secondary Measure ............................................................................................................... 46 
7.2.1 SDS (Sheehan Disability Scale) .................................................................................... 46 
7.3 Safety Measures .................................................................................................................... 46 
7.3.1 C-SSRS (Columbia Suicide Severity Rating Scale) ...................................................... 46 
7.4 Screening Measures and Reliability ..................................................................................... 46 
7.4.1 MINI (Mini-International Neuropsychiatric Interview) ................................................ 46 
7.4.2 SCID-5-PD (Structured Clinical Interview for DSM-5 for Personality Disorders) ...... 47 
7.4.3 LEC-5 (Life Events Checklist for DSM-5) ................................................................... 47 
7.4.4 PCL-5 (PTSD Checklist) ............................................................................................... 47 
7.4.5 DDIS (Dissociative Disorders Interview Schedule for DSM-5) ................................... 47 

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7.5 Exploratory Measures ........................................................................................................... 47 
7.5.1 DSP-I (The Dissociative Subtype of PTSD Interview) ................................................. 47 
7.5.2 ACE (Adverse Childhood Experience Questionnaire) .................................................. 48 
7.5.3 BDI-II (Beck Depression Inventory II) ......................................................................... 48 
7.5.4 CPGS (Chronic Pain Grade Scale) ................................................................................ 48 
7.5.5 EQ-5D-5L (EuroQol Five Dimensions-Five Levels Questionnaire) ............................. 48 
7.5.6 IASC (Inventory of Altered Self Capacities)................................................................. 49 
7.5.7 IPF (Inventory of Psychosocial Functioning) ................................................................ 49 
7.5.8 SCS (Self-Compassion Scale) ....................................................................................... 49 
7.5.9 TAS-20 (Toronto Alexithymia Scale) ........................................................................... 50 
7.5.10 AUDIT (Alcohol Use Disorders Identification Test) .................................................. 50 
7.5.11 DUDIT (Drug Use Disorders Identification Test) ....................................................... 50 
7.5.12 SRNU (Self-reported Nicotine Use) ............................................................................ 50 
7.5.13 EAT-26 (Eating Attitudes Test)................................................................................... 50 
7.5.14 HPQSF (Health and Work Performance Absenteeism and Presenteeism Short Form)
 ................................................................................................................................................ 51 
7.5.15 UFEC (Utilization of Facility-based and Emergent Care) .......................................... 51 
8.0 Study Procedures .................................................................................................................... 51 
8.1 Screening Period ................................................................................................................... 56 
8.1.1 Screening ....................................................................................................................... 56 
8.1.2 Independent Rater Screening ......................................................................................... 58 
8.1.3 Enrollment ..................................................................................................................... 59 
8.2 Preparatory Period with Enrollment Confirmation............................................................... 59 
8.2.1 Preparatory Sessions 1 and 2 ......................................................................................... 59 
8.2.2 Baseline: CAPS-5 by Independent Rater ....................................................................... 60 
8.2.3 Baseline: Preparatory Session 3 & Enrollment Confirmation ....................................... 61 
8.3 Treatment Period .................................................................................................................. 61 
8.3.1 Experimental Sessions ................................................................................................... 62 
8.3.2 Telephone Contact After Experimental Sessions .......................................................... 64 
8.3.3 Integrative Sessions ....................................................................................................... 65 
8.3.4 Independent Rater Assessments .................................................................................... 66 
8.4 Follow-up Period and Study Termination ............................................................................ 66 
8.4.1 Follow-up Period ........................................................................................................... 66 
8.4.2 Final Independent Rater Assessment ............................................................................. 66 
8.4.3 Study Termination ......................................................................................................... 66 
8.4.3.1 Extension Studies ................................................................................................... 67 
8.4.3.2 Exit Plan ................................................................................................................. 68 
9.0 Investigational Product .......................................................................................................... 68 
9.1 Description of Active Compounds ....................................................................................... 68 
9.1.1 Doses ............................................................................................................................. 68 
9.1.2 Dose Modifications ........................................................................................................ 68 
9.1.3 Stability .......................................................................................................................... 69 
9.2 Handling ............................................................................................................................... 69 
9.2.1 Encapsulation, Packaging, and Labeling ....................................................................... 69 
9.2.2 Accountability................................................................................................................ 69 
9.2.3 Storage ........................................................................................................................... 70 
9.2.4 Administration ............................................................................................................... 70 
9.2.5 Treatment Compliance................................................................................................... 70 
9.3 Randomization and Participant Numbering.......................................................................... 70 
9.4 Blinding and Bias Minimization ........................................................................................... 71 
10.0 Risks ....................................................................................................................................... 72 
10.1 Non-drug Related Risks ...................................................................................................... 72 

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10.1.1 Medical Assessments ................................................................................................... 72 
10.1.2 PTSD, Suicide Risk, and Psychotherapy ..................................................................... 72 
10.1.3 Recorded Content ........................................................................................................ 74 
10.2 Risks of Receiving MDMA ................................................................................................ 74 
10.2.1 High Level Risks ......................................................................................................... 74 
10.2.2 Medium Level Risks .................................................................................................... 75 
10.2.2.1 Cardiovascular and Cerebrovascular Risks and Mitigation ................................. 75 
10.2.2.2 Psychological Risks and Mitigation ..................................................................... 76 
10.2.3 Low Level Risks .......................................................................................................... 77 
10.2.3.1 Thermoregulatory Risks and Mitigation ............................................................... 77 
10.2.3.2 Osmoregulatory Risk and Mitigation ................................................................... 78 
10.2.3.3 Genotoxicity Risk and Mitigation ........................................................................ 78 
10.2.3.4 Reproductive and Developmental Risks and Mitigation ...................................... 78 
10.2.4 Minimal Risks .............................................................................................................. 78 
10.2.4.1 Common AEs ....................................................................................................... 78 
10.2.4.2 Potential Neurotoxicity Associated with Ecstasy Use .......................................... 79 
10.2.4.3 Abuse Liability ..................................................................................................... 79 
11.0 Safety ...................................................................................................................................... 80 
11.1 Adverse Events ................................................................................................................... 80 
11.1.1 Adverse Events of Special Interest .............................................................................. 80 
11.1.2 Serious Adverse Events ............................................................................................... 81 
11.2 Other Significant Events ..................................................................................................... 82 
11.3 Pregnancy ........................................................................................................................... 82 
11.3.1 Definition of Childbearing Potential ........................................................................... 82 
11.3.2 Contraception Guidelines ............................................................................................ 82 
11.3.3 Follow-up Requirements ............................................................................................. 83 
11.4 Medical Monitor ................................................................................................................. 83 
12.0 Concomitant Medications .................................................................................................... 83 
12.1 Tapering Instructions .......................................................................................................... 83 
12.2 Allowed Concomitant Medications .................................................................................... 84 
12.3 Prohibited Medications ....................................................................................................... 85 
13.0 Clinical Laboratory Assessments ........................................................................................ 85 
14.0 Statistical Considerations ..................................................................................................... 87 
14.1 Power and Sample Size Determination .............................................................................. 87 
14.2 Statistical Analyses ............................................................................................................. 87 
14.2.1 Efficacy Analyses ........................................................................................................ 88 
14.2.1.1 Primary Outcome .................................................................................................. 88 
14.2.1.2 Secondary Outcome .............................................................................................. 88 
14.2.1.3 Exploratory Secondary Outcomes ........................................................................ 88 
14.2.2 Safety Analyses ........................................................................................................... 89 
14.2.3 Administrative Interim Analysis.................................................................................. 89 
14.3 Data Monitoring Committee ............................................................................................... 90 
15.0 Study Governance ................................................................................................................. 90 
15.1 Ethics .................................................................................................................................. 90 
15.1.1 Financial Disclosure .................................................................................................... 91 
15.1.2 Informed Consent ........................................................................................................ 91 
15.2 Study Monitoring, Auditing, and Documentation .............................................................. 92 
15.2.1 Source Records ............................................................................................................ 92 
15.3 Confidentiality .................................................................................................................... 92 
15.4 Costs to Participants ........................................................................................................... 93 
15.5 Treatment and Compensation for Study Related Injury ..................................................... 93 
15.6 Record Retention ................................................................................................................ 94 

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15.7 Publication Policy ............................................................................................................... 94 
16.0 References .............................................................................................................................. 95 
Appendix A: Sub-study without Overnight Stays ................................................................... 101 
 
 
 

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List of Tables 
 
Table 1: Study Design Overview .................................................................................................... 34 
Table 2: Primary Outcome (CAPS-5) Data Collection by Visit .................................................... 38 
Table 3: Dose Regimen of MDMA or Placebo .............................................................................. 42 
Table 4: Protocol Objectives and Assessment Tools ...................................................................... 44 
Table 5: Time and Events-Study Procedures.................................................................................. 52 
Table 6: Time and Events-Study Measures .................................................................................... 55 
Table 7: Schedule of Procedures for Experimental Sessions ......................................................... 62 
 
 

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List of Figures 
 
Figure 1: Study Structure Overview ............................................................................................... 33 
Figure 2: Example Label ................................................................................................................ 69 
 
 

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1.0 List of Abbreviations 
 
°C 
 
Degrees Celsius 
A:G 
 
Albumin:Globulin 
ACE 
 
Adverse Childhood Experiences Questionnaire 
ADHD  
Attention Deficit/Hyperactivity Disorder 
AE 
 
Adverse Event 
AESI  
Adverse Event of Special Interest 
ALT 
 
Alanine Aminotransferase 
AMI 
 
Acute Myocardial Infarction 
API 
 
Active Pharmaceutical Ingredient 
AST 
 
Aspartate Aminotransferase 
AUDIT  
Alcohol Use Disorders Identification Test 
BDI-II  
Beck Depression Inventory-II 
BMI 
 
Body Mass Index 
BP 
 
Blood Pressure 
BUN 
 
Blood Urea Nitrogen 
CAPS-4 
Clinician-Administered PTSD Scale for DSM-4 
CAPS-5 
Clinician-Administered PTSD Scale for DSM-5 
CBC 
 
Complete Blood Count 
%CDT  
%Carbohydrate-deficient Transferrin 
CMC  
Chemistry Manufacturing and Control 
COVID-19        Coronavirus Disease 2019 
CPGS  
Chronic Pain Grade Scale 
CRA 
 
Clinical Research Associate 
CRP 
 
C-Reactive Protein 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DDIS  
Dissociative Disorders Interview Schedule 
DID 
 
Dissociative Identity Disorder 
dIGPP  
Cohen’s d Independent Groups Pre-test Post-test 
DMC  
Data Monitoring Committee 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
DSP-I  
Dissociative Subtype of PTSD Interview 
DUDIT  
Drug Abuse Disorders Identification Test 
EAT-26 
Eating Attitudes Test 
 
ECG 
 
Electrocardiogram 
eCRF  
Electronic Case Report Form 
ECT 
 
Electroconvulsive Therapy 
ED 
 
Emergency Department 
EDC 
 
Electronic Data Capture 
EMDR  
Eye Movement Desensitization and Reprocessing 
EMS 
 
Emergency Medical Services 
ePRO  
Electronic Participant Reported Outcome 
EQ-5D-5L 
EuroQol Five Dimensions-Five Levels Questionnaire 
FDA 
 
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
GMP 
 
Good Manufacturing Practice 
HCV 
 
Hepatitis C Virus 
HIV 
 
Human Immunodeficiency Virus 
HIPAA  
Health Insurance Portability and Accountability 
HPA 
 
Hypothalamic-pituitary-adrenal 

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HPQSF  
Health and Work Performance Absenteeism and Presenteeism Short Form 
IASC  
Inventory of Altered Self-Capacities 
IB 
 
Investigator’s Brochure 
ICD 
 
International Classification of Disease 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonisation 
IND 
 
Investigational New Drug 
IMP 
 
Investigational Medicinal Product 
IPF 
 
Inventory of Psychosocial Functioning 
IR 
 
Independent Rater 
IRDB  
Independent Rater Database 
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
ITT 
 
Intent-to-Treat 
IUD 
 
Intrauterine Device 
IUS 
 
Intrauterine Hormone-releasing System 
IWRS  
Interactive Web Randomization System 
kg 
 
Kilogram 
LEC-5  
Life Events Checklist 
LTFU  
Long-term Follow-up 
MAPS  
Multidisciplinary Association for Psychedelic Studies 
MAOI  
Monoamine Oxidase Inhibitor 
MCH  
Mean Corpuscular Hemoglobin 
MCHC  
Mean Corpuscular Hemoglobin Concentration 
MCV  
Mean Corpuscular Volume 
MDMA 
3,4-methylenedioxymethamphetamine 
mg 
 
Milligram 
mITT   
Modified Intent-to-Treat  
 
 
mmHg  
Milligrams of Mercury 
MMRM 
Mixed Model Repeated Measure 
MPBC  
MAPS Public Benefit Corporation 
ms 
 
Millisecond 
PCL-5  
PTSD Checklist for DSM-5  
PTCA  
Percutaneous Transluminal Coronary Angioplasty 
PTSD  
Posttraumatic Stress Disorder 
RACT  
Risk Assessment and Categorization Tool  
RBC 
 
Red Blood Cell 
RDW  
Red Cell Distribution Width 
SAE 
 
Serious Adverse Event 
SCID-5-PD 
Structured Clinical Interview for DSM-5 Personality Disorders 
SCID-5-SPQ 
SCID-5 Self-report Personality Questionnaire 
SCS 
 
Self-compassion Scale 
SDS 
 
Sheehan Disability Scale 
SGOT  
Serum Glutamic Oxaloacetic Transaminase 
SNRI  
Serotonin-norepinephrine Reuptake Inhibitor 
SRNU  
Self-reported Nicotine Use 
SSRI 
 
Selective serotonin reuptake inhibitor 
TAS-20 
Toronto Alexithymia Scale 
TEAE  
Treatment Emergent Adverse Event 
TSH 
 
Thyroid-stimulating Hormone 
UFEC  
Utilization of Facility-based and Emergent Care 
U.S. 
 
United States 

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VA 
 
U.S. Department of Veterans Affairs 
VAS 
 
Visual Analog Scale 
WBC  
White Blood Cell 
WHO  
World Health Organization 
 

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2.0 Introduction 
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit research and 
educational organization working as a clinical trial sponsor to obtain marketing approval for the 
prescription use of 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct to 
psychotherapy in patients with posttraumatic stress disorder (PTSD). Controlled Phase 1 studies, 
nonclinical studies, and investigator-initiated studies formed the basis for the Clinical 
Development Program of MDMA under Investigational New Drug (IND) #063384. MAPS-
sponsored studies are implemented through MAPS’ wholly owned subsidiary and delegate, the 
MAPS Public Benefit Corporation (MPBC). 
 
2.1 Rationale 
PTSD is a serious debilitating disorder that negatively impacts a person’s daily life. MDMA has 
been shown to reduce defenses and fear of emotional injury, enhance communication, and 
increase empathy. MDMA may enhance fear extinction learning in humans. These subjective 
effects of MDMA create a productive psychological state that enhances the therapeutic process 
for the treatment of PTSD and other anxiety disorders. This is supported by data from an 
international series of Phase 2 pilot studies of MDMA-assisted psychotherapy conducted by the 
sponsor that provide preliminary evidence that chronic PTSD, independent of cause, is treatable 
with two to three sessions of MDMA-assisted psychotherapy and associated non-drug preparatory 
and integrative psychotherapy. This pivotal Phase 3 study is intended to confirm the efficacy and 
safety of manualized MDMA-assisted psychotherapy as a treatment for PTSD. 
 
The results from multiple independent studies in Phase 2 efficacy analyses demonstrate 
superiority of MDMA-assisted psychotherapy over psychotherapy with placebo and low dose 
MDMA. The acceptable risk-benefit ratio in early trials justifies confirmation in a Phase 3 
program. To further assess the efficacy and safety of this treatment for participants with at least 
severe PTSD, the sponsor is conducting this pivotal Phase 3 randomized, placebo-controlled, 
two-arm, double-blind, multi-site study which will include an interim analysis of CAPS-5 data for 
sample size re-estimation. This novel treatment package consists of three once-monthly 
Experimental Sessions of psychotherapy combined with either a flexible dose of MDMA or 
inactive placebo, along with non-drug preparatory and integrative psychotherapy. The Primary 
Outcome measure, the Clinician Administered PTSD Scale (CAPS-5), evaluates changes in 
PTSD symptom severity and is assessed by a blinded centralized Independent Rater (IR) pool. 
 
2.2 Background 
2.2.1 PTSD 
PTSD is a serious debilitating disorder associated with increased mortality and cardiometabolic 
morbidity. PTSD is a stress-related psychiatric condition that may occur following a traumatic 
event such as war, disaster, sexual abuse, violence, terrorism, and accidents. The four main 
symptom categories described in the Diagnostic and Statistical Manual of Mental Disorders, 5th 
edition (DSM-5), include arousal and reactivity, avoidance of triggers, negative thoughts and 
feelings, and intrusive thoughts and nightmares. PTSD negatively impacts a person’s daily life, 
resulting in fractured relationships, inability to maintain employment, diminished cognitive and 
psychosocial functioning, substance abuse, high-cost healthcare utilization, and increased 
depression and suicide risk. People who suffer from PTSD often relive the experience through 
nightmares and flashbacks, have poor sleep quality, and feel detached or estranged. Confronting 
overwhelming internal distress and frightening external environments can also lead to high levels 
of depersonalization and derealization, which led clinicians to identify a dissociative subtype of 

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PTSD in the DSM-5. Adaptations in normal brain function have been observed in imaging studies 
of patients with PTSD that underlie alterations in emotional processing and regulation, cognition, 
and many aspects of behavior, though clinical symptoms and changes in brain activity are not 
homogenous across patients [1]. The dissociative subtype occurs in 12 to 30% of people with 
PTSD and is characterized by detachment and emotional numbing and visualized in the brain as 
overmodulation of affect mediated by midline prefrontal inhibition of limbic regions, while the 
non-dissociative subtype presents symptoms of hyperarousal and re-experiencing, an emotional 
undermodulation mediated by failure of prefrontal inhibition of the same limbic regions [2, 3]. 
Patients suffering from the dissociative subtype of PTSD typically have early childhood trauma 
and appear to be particularly difficult to treat, with mixed response to existing evidence-based 
treatments. 
 
Approximately 7% of the population in the United States (U.S.) will have PTSD sometime in 
their life, but this figure jumps to 10.8% to 13% of veterans with combat experience [4]. For 
soldiers returning from Iraq and Afghanistan, the incidence of PTSD is 17.1% with 400,000 to 
500,000 U.S. Iraq/Afghanistan veterans reportedly having PTSD. In 2004, the Defense 
Department and U.S. Department of Veterans Affairs (VA) spent $4.3 billion on PTSD disability 
payments to approximately 215,000 veterans [5]. In 2012 alone the VA spent $294 million and $3 
billion, respectively, on care for veterans with the disorder and disability payments, even with this 
funding the demand for services far outreached the availability of VA doctors and services. As of 
June 30, 2016, more than 868,000 veterans with a diagnosis of PTSD were receiving disability 
compensation for service-connected mental disorders, with an estimated cost of about $17 billion 
per year [6]. There are an estimated 20 to 22 suicides a day by veterans [7]. 
 
Available PTSD treatments, including medications and therapy, effectively treat only a fraction of 
people who try them for adequate dose and duration. This indicates a need to develop treatments 
targeting durable remission of PTSD. The Food and Drug Administration (FDA) has approved 
only two pharmacotherapies for PTSD, both of which are selective serotonin reuptake inhibitors 
(SSRIs). Paroxetine and sertraline (Paxil and Zoloft) both demonstrated statistically significant 
superiority over placebo on the CAPS in 12-week confirmatory clinical trials with daily dosing, 
but some studies were less effective in treating combat-related PTSD and sertraline demonstrated 
gender differences with minimal efficacy in men [8-10]. PTSD rarely remits after 12 weeks of 
SSRIs, and many patients who are placed on maintenance treatment experience partial relief of 
symptoms, which fully return upon discontinuation of treatment. Adverse effects of maintenance 
SSRI treatment that contribute to discontinuation include sexual dysfunction, weight gain, and 
sleep disturbance. Variable SSRI treatment outcomes have led to recommendations of trauma-
focused psychotherapy as routine first-line treatment by the VA’s National Center for PTSD in 
the U.S., as well as by the World Health Organization (WHO). An extensive list of medications, 
namely antipsychotics, anxiolytics, antidepressants, and sleep aids, are frequently prescribed off-
label but have only small effect sizes in reducing PTSD symptoms. PTSD brings a high public 
burden, both economically and socially, by increased use of health and social services, lost 
wages, and disability payments [11, 12]. Given the chronicity of PTSD, low compliance 
evidenced by high dropouts, and limited recovery with current medications contributing to 
serious outcomes, PTSD patients suffer from unmet medical need.  
 
One treatment approach is to develop medications and/or psychotherapeutic treatments that may 
indirectly decrease or eliminate the neurochemical pathologies underlying the chronic 
hyperarousal and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis associated with 
PTSD. Cognitive behavioral therapies, particularly prolonged exposure and cognitive processing 
therapy, are considered among the most effective psychotherapies. Other methods such as 
psychodynamic therapy and eye movement desensitization and reprocessing (EMDR) have also 
proven to be effective in treating some symptoms of PTSD [13, 14], although some patients may 

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need more than one type of treatment to reduce or resolve those symptoms. A meta-analysis 
concluded that all “bona fide” psychotherapies, including those listed above, are similarly 
effective with PTSD [15]. In the past decade, there has been a growing amount of research into 
medications and other methods that may augment the effectiveness of psychotherapy for PTSD 
(see [16] for a review). Examples of this are virtual reality-assisted exposure therapy [17, 18] and 
D-cycloserine-assisted psychotherapy [19]. MDMA-assisted psychotherapy is another such 
approach. 
 
2.2.2 MDMA 
MDMA is a ring-substituted phenylisopropylamine derivative invented by the Merck 
pharmaceutical company in 1912 [20, 21]. Similar to SSRIs, MDMA binds to the serotonin 
transporter, but has additional effects on carrier-mediated release and reuptake inhibition of 
norepinephrine, and to a lesser extent in humans, dopamine [22-28]. MDMA also increases levels 
of affiliative neurohormones oxytocin and vasopressin, which increases trust and attenuates 
reactivity to threatening cues, and some researchers have suggested a role for oxytocin in treating 
PTSD. The indirect effects of MDMA on central and peripheral neurohormone release contribute 
to a novel mechanism that may help regulate the HPA axis, which would treat the core 
psychopathology of PTSD for a durable remission. 
 
Onset of MDMA effects occurs ~0.5 to 1 hour after oral administration, and peak effects occur 
1.25 to 2 hours after the initial dose. Effects of the initial dose last 3 to 6 hours, which is extended 
to 5 to 8 hours with a supplemental half-dose administered 1.5 to 2 hours post initial dose. Orally 
administered doses of MDMA have a half-life of 7 to 9 hours in humans. Unlike approved PTSD 
medications, therapeutic effects of MDMA have a rapid-onset and do not require daily dosing or 
a steady state in the blood to be effective. Thus, the effects of MDMA are distinct from and go 
well beyond anxiolytics and SSRIs. Furthermore, there is no evidence that MDMA creates a 
physical dependency, as benzodiazepines do. Previous studies of polydrug users have found a 
small percentage of people exhibit problematic use of Ecstasy (material represented as containing 
MDMA) [29, 30]. Studies of regular or problematic Ecstasy users indicate that on average, 
regular use occurs no more often than once a week [31]. Hence, MDMA may have moderate 
abuse potential. See the Investigator’s Brochure (IB) for a more detailed explanation. 
  
2.2.3 MDMA-Assisted Psychotherapy for PTSD 
Many psychotherapies for PTSD involve the induction and extinction of abnormal autonomic 
responses through revisiting traumatic experiences in psychotherapy with an appropriate level of 
emotional engagement [14]. To be effective, exposure must be accompanied by a degree of 
emotional engagement or “fear activation” while avoiding dissociation or overwhelming emotion 
[32]. This has been referred to as working within the “optimal arousal zone” or “window of 
tolerance” [33-35]. 
 
The combined neurobiological effects of MDMA increase compassion, reduce defenses and fear 
of emotional injury, and enhance communication and introspection. MDMA produces anxiolytic 
and prosocial effects, which counteract avoidance and hyperarousal in the context of therapy. 
PTSD increases amygdala activity, causing heightened encoding of fearful memories and 
decreasing blood flow in the prefrontal cortex. In contrast, MDMA acutely decreases activity in 
the amygdala [36], and there is some indication that MDMA may increase activity in the 
prefrontal cortex [37]. Brain imaging after MDMA indicates less reactivity to angry facial 
expressions and greater reward in happy faces [36]. This action is compatible with its reported 
reduction in fear or defensiveness, and is in contrast to the stimulation of the amygdala observed 
in animal models of conditioned fear, a state similar to PTSD [38-40]. The reduction in stress-

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induced activation of the amygdala may be supported and enhanced by interacting with the 
therapy team during and after the MDMA experience. The subjective effects of MDMA create a 
productive psychological state that enhances the therapeutic process. MDMA is capable of 
inducing unique psychopharmacological effects, including decreased fear and increased 
wellbeing, sociability, interpersonal trust, acceptance of self and others, and ability to address 
these issues without extreme disorientation or ego loss due to alert state of consciousness. These 
factors taken together can provide the opportunity for a corrective emotional experience. 
 
A combined treatment of MDMA and psychotherapy may be especially useful for treating PTSD 
because MDMA can attenuate the fear response of a perceived threat to one’s emotional integrity 
and decrease defensiveness without blocking access to memories or preventing a deep and 
genuine experience of emotion [41-44]. Elimination of these conditioned fear responses can lead 
to more open and comfortable communication about past traumatic events and greater access to 
information about them [45]. Participants are able to experience and express fear, anger, and grief 
with less likelihood of feeling overwhelmed by these emotions. MDMA seems to engender 
internal awareness that even painful feelings that arise are an important part of the therapeutic 
process. In addition, feelings of empathy, love, and deep appreciation often emerge, along with a 
clearer perspective of the trauma as a past event, a more accurate perspective about its 
significance, and a heightened awareness of the support and safety that exists in the present. As a 
result, MDMA-assisted psychotherapy may enable the participants to restructure their intra-
psychic realities and develop a wider behavioral and emotional repertoire with which to respond 
to anxiogenic stimuli.  
 
The therapeutic method is described in further detail in the Treatment Manual of MDMA-
Assisted Psychotherapy, which the sites and therapy teams will be trained on prior to the study. 
 
2.2.4 Previous Clinical Experience with MDMA 
MDMA-assisted psychotherapy is a novel treatment package that combines psychotherapeutic 
techniques with the administration of MDMA as a pharmacological adjunct intended to enhance 
certain aspects of psychotherapy. Chemists Shulgin and Nichols were the first to report on the 
effects of MDMA in humans [46], with 80 to 160 milligrams (mg) MDMA required to produce 
desired subjective effects in humans [46, 47]. MDMA was found to robustly influence human 
emotional status in a unique way [46] without adversely affecting physiological functions or 
perception, such as visual perception or cognition [48-51]. In the 1970s, psychotherapists used 
MDMA-assisted psychotherapy to treat psychological disorders, including anxiety [52]. Legal 
therapeutic use continued until its placement on the U.S. list of Schedule 1 substances in 1985 
[42, 45, 53]. An estimated 500,000 doses of MDMA were administered during psychotherapy and 
personal growth sessions in North America prior to its scheduling [42, 54]. A few uncontrolled 
human studies of MDMA assessing safety in a therapeutic setting occurred in the 1980s [55, 56]. 
 
Controlled human studies for clinical development of MDMA commenced in the mid-1990s with 
a MAPS-funded investigator-initiated Phase 1 dose-response safety study [57, 58]. Starting in 
2000 in Spain, MAPS funded a Phase 2 investigator-initiated dose-response effect and safety pilot 
study in participants with PTSD that was terminated early due to political pressure. This study 
enrolled six participants, with four receiving a single session of MDMA-assisted psychotherapy 
without any safety concerns and with some PTSD symptom reduction [44]. These studies formed 
the basis of clinical experience with MDMA prior to studies subsequently conducted under a 
MAPS IND. 
 
Under IND #063384, MAPS initiated an international series of Phase 2 clinical trials to develop 
the medical use of MDMA-assisted psychotherapy for patients with chronic, at least moderate 

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PTSD (CAPS-4 score: 50+), with at least 6 months of symptoms. Participants were not excluded 
for having more than one traumatic event, or for having tried, not tolerated, or refused an SSRI or 
serotonin-norepinephrine reuptake inhibitor (SNRI) prescribed for PTSD. Outcomes from six 
Phase 2 studies with evaluable data have been promising and have generated a range of 
methodological information for the design of future studies.  
 
Results from two Phase 2 studies have been published: one study in the U.S. with a long-term 
follow-up (LTFU) conducted an average of 3.8 years after the final MDMA-assisted 
psychotherapy session (MP1) [43, 59] and one in Switzerland (MP2) [60, 61]. MP1 was followed 
by a small open-label extension study examining the treatment of relapse in three participants 
with a single MDMA-assisted psychotherapy treatment and a 12-month follow-up (MP1E2). 
Three additional studies have completed treatments (MP8, MP9, MP12) and two international 
studies were terminated early for logistical reasons with partial datasets (MP3, MP4). These 
studies tested a range of designs, such as a placebo control (MP1, MP4), low dose MDMA 
comparator control (MP2, MP9), and three-arm dose response studies (MP8, MP12). MP4 was 
terminated early due to delays in regulatory approval and enrollment timelines, with available 
efficacy data presented without a formal analysis. MP3 was terminated early by the sponsor due 
to inadequate data collection procedures at the site and insufficient therapy team training; efficacy 
data are not available for these reasons (MP3 is excluded from Phase 2 data). 
 
Intent-to-treat (ITT) analysis of primary efficacy and safety data from six MAPS-sponsored 
MDMA PTSD Phase 2 clinical trials worldwide (MP1, MP2, MP4, MP8, MP9, MP12) consisting 
of 107 blinded participants with chronic PTSD was completed in 2016. In these studies, PTSD, 
independent of cause, appears treatable with a two to three-session treatment package of MDMA-
assisted psychotherapy. As of October 1, 2018, with 248 individuals exposed to MDMA in the 
sponsor’s development program across various indications and at least 1,286 participants in 
MDMA research studies conducted without sponsor support, the sponsor has observed an 
acceptable risk-benefit ratio for MDMA-assisted psychotherapy. Across Phase 2 studies, 75 mg to 
125 mg MDMA was statistically superior to 0 mg to 40 mg MDMA based on a t-test of 
difference in CAPS-4 severity scores from Baseline, 2 months after two blinded Experimental 
Sessions (p<0.001). The dropout rate across studies was 7.5% (8 of 107). Large between-groups 
effect size estimates (0.9), initial indications of efficacy, and favorable safety outcomes support 
expanding the research initiative to encompass a larger sample of participants with PTSD in a 
Phase 3 program. 
 
A comprehensive review of MDMA research can be found in the IB supplied by the sponsor. 
This document should be reviewed prior to initiating the protocol. 
 
3.0 Protocol Objectives 
The overall objective of this study is to use standard clinical measures to confirm the efficacy and 
safety of manualized MDMA-assisted psychotherapy with a flexible dose MDMA in reducing 
PTSD and associated symptoms in comparison to the same psychotherapy combined with an 
inactive placebo control. 
 
3.1 Primary Objective 
The primary objective of this study is to evaluate the efficacy of MDMA-assisted psychotherapy 
for PTSD compared to identical psychotherapy with inactive placebo, as measured by the 
reduction in CAPS-5 Total Severity Score from Visit 3 (Baseline) to Visit 19 (18 weeks post 
Baseline). 
 

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3.2 Key Secondary Objective 
The key secondary objective of this study is to evaluate the efficacy of MDMA-assisted 
psychotherapy for PTSD compared to identical psychotherapy with inactive placebo in clinician-
rated functional impairment, as measured by the mean change in Sheehan Disability Scale (SDS) 
item scores from Visit 3 (Baseline) to Visit 19 (18 weeks post Baseline).  
 
3.3 Safety Objectives 
The overall safety objective is to assess differences between groups in severity, incidence and 
frequency of Adverse Events (AEs), Treatment Emergent AEs (TEAEs), AEs of Special Interest 
(AESIs), and Serious Adverse Events (SAEs), concomitant medication use, suicidal ideation and 
behavior, and vital signs to support the package insert for MDMA-assisted psychotherapy. The 
following safety objectives will evaluate the safety of MDMA-assisted psychotherapy compared 
to identical psychotherapy with inactive placebo:  
 
1. 
Compare relative incidence of AEs during Experimental Sessions that may be 
indicative of a medical complication of the Investigational Medicinal Product (IMP) 
such as clinical signs and symptoms of chest pain, shortness of breath, or 
neurological symptoms or any other signs or symptoms that prompt additional vital 
sign measurements. 
2. 
Compare relative incidence of AEs by severity. 
3. 
Compare relative incidence of TEAEs, to determine relationship to the IMP based on 
relative incidence in the MDMA group. 
4. 
Compare relative incidence of TEAEs by severity reported during an Experimental 
Session, 1 day, and 2 days after IMP administration. 
5. 
Compare relative incidence of AESIs, defined as AEs specified in the protocol 
related to cardiac function and abuse liability. 
6. 
Compare relative incidence of AEs by severity categorized as leading to 
discontinuation of IMP, resulting in death or hospitalization, and continuing at Study 
Termination. 
7. 
Compare relative incidence of SAEs. 
8. 
Compare relative incidence of concomitant medications taken during an 
Experimental Session, 1 day, and 2 days after IMP administration. 
9. 
Compare relative incidence of psychiatric concomitant medications taken during the 
Treatment Period. 
10. 
Compare relative incidence of positive or serious suicidal ideation and positive 
suicidal behavior assessed with the Columbia Suicide Severity Rating Scale (C-
SSRS) by treatment group. 
11. 
Compare mean changes in blood pressure, heart rate, and body temperature from pre-
IMP administration to end of each Experimental Session by treatment group. 
 
3.4 Exploratory Objectives 
These objectives may be explored to characterize participants receiving MDMA-assisted 
psychotherapy in comparison to those receiving psychotherapy with inactive placebo to support 
the primary objective: 
 
1. Explore the effect of presence of secondary traumatic stressors (LEC-5) on the CAPS-5 
Total Severity analyses. 

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2. Explore changes in PTSD symptom clusters of re-experiencing, avoidance, negative 
alterations in cognition and mood, and hyperarousal, as measured by changes in CAPS-5 
subscale scores from Visit 3 (Baseline) to Visit 19 (18 weeks post Baseline). 
3. Characterization of CAPS-5 Total Severity score at weeks 6, 10, and 18 to explore onset 
of treatment efficacy with a descriptive time course plot.  
4. Explore the effect of adverse childhood experiences (ACE) on the CAPS-5 Total Severity 
analyses. 
5. Explore differences between treatment groups in:  
a. Dissociative symptoms associated with PTSD (DSP-I) 
b. Depression (BDI-II)  
c. Chronic pain (CPGS) 
d. Quality of life (EQ-5D-5L) 
e. Functioning in relation to self and others (IASC) 
f. Psychosocial functioning (IPF) 
g. Self-compassion (SCS) 
h. Alexithymia (TAS-20) 
i. 
Addictive behaviors including: alcohol use (AUDIT), drug use (DUDIT), and 
nicotine use (SRNU)  
j. 
Eating habits (EAT-26) 
k. Workplace productivity (HPQSF) 
l. 
Healthcare utilization (UFEC)  
 
4.0 Eligibility Criteria 
4.1 Inclusion Criteria 
At the completion of Screening, participants must meet all eligibility criteria (except Inclusion 
Criterion #13) and agree to all lifestyle modifications to be enrolled. Each participant will then 
enter the Preparatory Period which includes medication tapering, if needed, and non-drug 
Preparatory Sessions. The Preparatory Period ends with Enrollment Confirmation. A participant’s 
enrollment will be confirmed if they have completed medication tapering, have a confirmed 
PTSD diagnosis per the CAPS-5 assessment and a Total Severity Score of 35 or greater, continue 
to agree to all lifestyle modifications, and continue to meet all eligibility criteria.  
 
Potential participants are eligible to enroll in the protocol if they: 
 
1. 
Are at least 18 years old. 
2. 
Are fluent in speaking and reading the predominantly used or recognized language of 
the study site. 
3. 
Are able to swallow pills. 
4. 
Agree to have study visits recorded, including Experimental Sessions, Independent 
Rater assessments, and non-drug psychotherapy sessions. 
5. 
Must provide a contact (relative, spouse, close friend or other support person) who is 
willing and able to be reached by the investigators in the event of a participant 
becoming suicidal or unreachable. 
6. 
Must agree to inform the investigators within 48 hours of any medical conditions and 
procedures. 
7. 
If of childbearing potential, must have a negative pregnancy test at study entry and 
prior to each Experimental Session, and must agree to use adequate birth control 
through 10 days after the last Experimental Session. Adequate birth control methods 
include intrauterine device (IUD), injected, implanted, intravaginal, or transdermal 
hormonal methods, abstinence, oral hormones plus a barrier contraception, 

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vasectomized sole partner, or double barrier contraception. Two forms of 
contraception are required with any barrier method or oral hormones (i.e. condom 
plus diaphragm, condom or diaphragm plus spermicide, oral hormonal contraceptives 
plus spermicide or condom). Not of childbearing potential is defined as permanent 
sterilization, postmenopausal, or assigned male at birth. 
8. 
Agree to the following lifestyle modifications (described in more detail in Section 4.3 
Lifestyle Modifications): comply with requirements for fasting and refraining from 
certain medications prior to Experimental Sessions, not participate in any other 
interventional clinical trials during the duration of the study, remain overnight at the 
study site after each Experimental Session and be driven home after, and commit to 
medication dosing, therapy, and study procedures. 
 
Medical History 
 
9. 
At Screening, meet DSM-5 criteria for current PTSD with a symptom duration of 6 
months or longer. 
10. 
At Screening, have at least severe PTSD symptoms in the last month based on PCL-5 
total score of 46 or greater. 
11. 
May have well-controlled hypertension that has been successfully treated with anti-
hypertensive medicines, if they pass additional screening to rule out underlying 
cardiovascular disease. 
12. 
May have asymptomatic Hepatitis C virus (HCV) that has previously undergone 
evaluation and treatment as needed. 
13. 
At Baseline, have at least severe PTSD per CAPS-5 and symptoms in the last month 
constituting a CAPS-5 Total Severity Score of 35 or greater. 
14. 
May have current mild alcohol or cannabis use disorder (meets 3 of 11 diagnostic 
criteria per DSM-5) or moderate alcohol or cannabis use disorder in early remission 
for the 3 months prior to enrollment (meets 5 of 11 diagnostic criteria per DSM-5).  
15. 
May have a history of or current Diabetes Mellitus (Type 2) if additional screening 
measures rule out underlying cardiovascular disease, if the condition is judged to be 
stable on effective management, and with approval by the Medical Monitor. 
16. 
May have hypothyroidism if taking adequate and stable thyroid replacement 
medication. 
17. 
May have a history of, or current, glaucoma if approval for study participation is 
received from an ophthalmologist. 
 
4.2 Exclusion Criteria 
Potential participants are ineligible to enroll in the protocol if they: 
 
1. 
Are not able to give adequate informed consent. 
2. 
Are currently engaged in compensation litigation whereby financial gain would be 
achieved from prolonged symptoms of PTSD or any other psychiatric disorders. 
3. 
Are likely, in the investigator’s opinion and via observation during the Preparatory 
Period, to be re-exposed to their index trauma or other significant trauma, lack social 
support, or lack a stable living situation. 
4. 
Have used Ecstasy (material represented as containing MDMA) more than 10 times 
within the last 10 years or at least once within 6 months of the first Experimental 
Session; or have previously participated in a MAPS-sponsored MDMA clinical trial. 
5. 
Have any current problem which, in the opinion of the investigator or Medical 
Monitor, might interfere with participation. 
 

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Psychiatric History 
 
6. 
Have received Electroconvulsive Therapy (ECT) within 12 weeks of enrollment. 
7. 
Have a history of or a current primary psychotic disorder, bipolar disorder 1 assessed 
via MINI and clinical interview or dissociative identity disorder assessed via 
Dissociative Disorders Interview Schedule (DDIS) and clinical interview. 
8. 
Have a current eating disorder with active purging assessed via MINI and clinical 
interview. 
9. 
Have current major depressive disorder with psychotic features assessed via MINI. 
10. 
Have a current moderate (not in early remission in the 3 months prior to enrollment; 
meets 5 of 11 diagnostic criteria per DSM-5) or severe alcohol or cannabis use 
disorder within the 12 months prior to enrollment (meets at least 6 of 11 diagnostic 
criteria per DSM-5). 
11. 
Have an active illicit (other than cannabis) or prescription drug substance use 
disorder at any severity within 12 months prior to enrollment. 
12. 
Have current Personality Disorders Cluster A (paranoid, schizoid, schizotypal), 
Cluster B (antisocial, borderline, histrionic, narcissistic), or Cluster C (avoidant, 
dependent, obsessive-compulsive) assessed via SCID-5-PD (Structured Clinical 
Interview for DSM-5 Personality Disorders). 
13. 
Any participant presenting current serious suicide risk, as determined through 
psychiatric interview, responses to C-SSRS, and clinical judgment of the investigator 
will be excluded; however, history of suicide attempts is not an exclusion. Any 
participant who is likely to require hospitalization related to suicidal ideation and 
behavior, in the judgment of the investigator, will not be enrolled. Any participant 
presenting with the following on the Baseline C-SSRS will be excluded: 
a. 
Suicidal ideation score of 4 or greater within the last month of the assessment 
at a frequency of once a week or more 
b. 
Suicidal ideation score of 5 within the last 6 months of the assessment 
c. 
Any suicidal behavior, including suicide attempts or preparatory acts, within 
the last 6 months of the assessment. Participants with non-suicidal self-
injurious behavior may be included if approved by the Medical Monitor. 
14. 
Would present a serious risk to others as established through clinical interview and 
contact with treating psychiatrist. 
15. 
Require ongoing concomitant therapy with a psychiatric medication with exceptions 
described in Section 12.0: Concomitant Medications. 
 
Medical History 
 
16. 
Have a history of any medical condition that could make receiving a 
sympathomimetic drug harmful because of increases in blood pressure and heart rate. 
This includes, but is not limited to, a history of myocardial infarction, 
cerebrovascular accident, or aneurysm. Participants with other mild, stable chronic 
medical problems may be enrolled if the site physician, CI, and Medical Monitor 
agree the condition would not significantly increase the risk of MDMA 
administration or be likely to produce significant symptoms during the study that 
could interfere with study participation or be confused with side effects of the IMP. 
Examples of stable medical conditions that could be allowed include, but are not 
limited to Diabetes Mellitus (Type 2), Human Immunodeficiency Virus (HIV) 
infection, Gastroesophageal Reflux Disease (GERD), etc. Any medical disorder 
judged by the investigator to significantly increase the risk of MDMA administration 
by any mechanism would require exclusion.  

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17. 
Have uncontrolled essential hypertension using the standard criteria of the American 
Heart Association (values of 140/90 milligrams of Mercury [mmHg] or higher 
assessed on three separate occasions). 
18. 
Have a history of ventricular arrhythmia at any time, other than occasional premature 
ventricular contractions (PVCs) in the absence of ischemic heart disease. 
19. 
Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not 
been successfully eliminated by ablation. 
20. 
Have a history of arrhythmia, other than occasional PVCs in the absence of ischemic 
heart disease, within 12 months of screening. Participants with a history of atrial 
fibrillation, atrial tachycardia, atrial flutter or paroxysmal supraventricular 
tachycardia or any other arrhythmia associated with a bypass tract may be enrolled 
only if they have been successfully treated with ablation and have not had recurrent 
arrhythmia for at least 1 year off all antiarrhythmic drugs, and confirmed by a 
cardiologist.  
21. 
Have a marked Baseline prolongation of QT/QTc interval (e.g., repeated 
demonstration of a QTc interval>450 milliseconds [ms] in males and>460 ms in 
females corrected by Bazett’s formula). For transgender or non-binary participants, 
QTc interval will be evaluated based on sex assigned at birth, unless the participant 
has been on hormonal treatment for 5 or more years. 
22. 
Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, 
hypokalemia, family history of Long QT Syndrome). 
23. 
Require use of concomitant medications that prolong the QT/QTc interval during 
Experimental Sessions. Refer to Section 12.0 Concomitant Medications. 
24. 
Have symptomatic liver disease or have significant liver enzyme elevations. 
25. 
Have history of hyponatremia or hyperthermia. 
26. 
Weigh less than 48 kilograms (kg). 
27. 
Are pregnant or nursing, or are of childbearing potential and are not practicing an 
effective means of birth control. 
28. 
Have engaged in ketamine-assisted therapy or used ketamine within 12 weeks of 
enrollment. 
 
4.3 Lifestyle Modifications 
All participants must agree to the following lifestyle modifications at enrollment and throughout 
the duration of the study. Participants are eligible to enroll in the study if they: 
 
• 
Are willing to commit to medication dosing, psychotherapy sessions, follow-up sessions, 
completing evaluation instruments, and all necessary telephone contact. 
• 
Agree to not participate in any other interventional clinical trials during the duration of 
this study. 
 
Leading up to Experimental Sessions 
 
• 
Agree to take nothing by mouth except alcohol-free liquids after 12:00 A.M. (midnight) 
the evening before each Experimental Session. 
• 
Refrain from the use of any psychoactive medication not approved by the research team 
from Baseline through Study Termination. 
• 
Agree not to use caffeine or nicotine for 2 hours before and at least 6 hours after the 
initial dose during each Experimental Session. 
• 
Are willing to comply with medication requirements per protocol (refer to Section 12.0 
Concomitant Medications). Medications will only be discontinued after enrollment per 
clinical judgment of the site physician in consultation with the prescribing physician. 

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• 
Are able to decrease dose of allowable opiates (per Section 12.0 Concomitant 
Medications), if used for pain management, leading up to the Experimental Session in 
order to avoid taking the medication for at least 12 hours prior to the initial IMP 
administration and 24 hours after. During this period, the participant will be allowed to 
take the medication if needed for intolerable pain flare-ups. 
• 
Agree that, for 1 week preceding each Experimental Session to refrain from: 
o Taking any herbal supplement (except with prior approval of the research team). 
o Taking any nonprescription medications (with the exception of non-steroidal 
anti-inflammatory medications or acetaminophen unless with prior approval of 
the research team). 
o Taking any prescription medications (with the exception of birth control, thyroid 
hormones, or other medications approved by the research team). 
 
Post Experimental Session (for exceptions, see Appendix A sub-study) 
 
• 
Are willing to remain overnight at the study site after each Experimental Session until 
after the Integrative Session the next morning. 
• 
Are willing to be driven home on the morning after the Experimental Sessions after the 
Integrative Session, either by a driver arranged by the participant, site personnel or taxi. 
 
5.0 Protocol Design 
5.1 Study Design Overview 
This multi-site, randomized, double-blind study assesses the efficacy and safety of MDMA-
assisted psychotherapy versus psychotherapy with placebo control in participants diagnosed with 
at least severe PTSD.  
 
The study will be conducted in N≈100 participants, randomized with a 1:1 allocation to Group 1: 
MDMA-assisted psychotherapy or Group 2: placebo with psychotherapy. The design includes a 
planned interim analysis for sample size re-estimation by an independent Data Monitoring 
Committee (DMC) after 100 participants are enrolled and at least 60% of participants have 
completed their final CAPS-5 assessment and terminated treatment. There will be separate open-
label lead-in protocols following identical study procedures for new therapy teams to receive 
clinical supervision from the sponsor.  
 
For each participant, the study will consist of:  
 
• 
Screening Period: phone screen, informed consent, eligibility assessment, and 
enrollment of eligible participants  
• 
Preparatory Period with Enrollment Confirmation: medication tapering, Preparatory 
Sessions and Baseline assessments leading to Enrollment Confirmation 
• 
Treatment Period: three monthly Experimental Sessions and associated Integrative 
Sessions over ~12 weeks plus two CAPS-5 assessments 
• 
Follow-up Period and Study Termination: 4 weeks with no study visits, followed by 
Primary Outcome CAPS-5 and Study Termination visit 
• 
Invitation to participate in Long-term Follow-up (LTFU) extension study: 12 months 
after last Experimental Session 
 
The treatment consists of a flexible dose of MDMA or placebo, followed by a supplemental half-
dose unless contraindicated, administered with manualized psychotherapy in three blinded 
monthly Experimental Sessions. This ~12-week Treatment Period is preceded by three 

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Preparatory Sessions. During the Treatment Period, each Experimental Session is followed by 
three Integrative Sessions of non-drug psychotherapy. Experimental Sessions are followed by an 
overnight stay; a sub-study (Appendix A) will assess feasibility of Experimental Sessions without 
an overnight stay. The Primary Outcome measure, the change in CAPS-5 from Baseline (Visit 3), 
is assessed by a centralized IR pool at 18 weeks post Baseline (Visit 19). The CAPS-5 is also 
administered as an exploratory measure after Treatments 1 and 2 (Visits 8 and 13). The IR pool 
will be blinded to treatment assignment, visit number, and number of treatments received, and 
will not have access to data collected by the sites during the active Treatment Period. 
 
Upon unblinding after database lock, all participants who were assigned to placebo (regardless of 
CAPS-5 scores), completed the study, meet criteria, and are in good standing with the clinical site 
will be offered the opportunity to enroll in an open-label safety extension study of manualized 
MDMA-assisted psychotherapy.

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Figure 1: Study Structure Overview 
 
 
 
 
Prestudy
Treatment Period 
-
 
Treatment 1:
Approximately 4 weeks
Treatment 2:
Approximately 4 weeks
Treatment 3:
Approximately 4 weeks
 Medication Tapering
Preparatory Period and Enrollment 
Confirmation: Approximately 6 weeks 
Follow-Up Period:
Approximately 18 weeks post Baseline
Summary of Events
Primary 
Outcome
 
Medication Tapering
Preparatory Sessions
14 Day Phone 
Follow-up 
Experimental 
Session 1
Integrative Sessions
1.1, 1.2, 1.3
-
14 Day Phone 
Follow-up 
Experimental 
Session 2
Integrative Sessions 
2.1, 2.2, 2.3
14 Day Phone 
Follow-up 
Integrative Sessions 
3.1,3.2,3.3
 Screening     V0                    V1          V2        V3         V4                                      V5          V6                           V7         V8        V9                    V10        V11                         V12      V13      V14                   V15        V16                         V17        V18                               
                                    
Outcome  CAPS T4 (IR)
 
 
 
SCID-PD (IR)
 
SCID-PD (IR)
 
V19
Study 
Termination
V20
 
Baseline  CAPS T1 (IR)
 
Baseline  CAPS T1 (IR)
Medication Tapering
Enroll
Randomization
 
 CAPS T2 (IR)
 
 CAPS T2 (IR)
 
 CAPS T3 (IR)
 
 CAPS T3 (IR)
Experimental 
Session 3

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Table 1: Study Design Overview 
Screening Period 
From Consent to Enrollment (Visit 0): ~4 weeks (±2 weeks) 
Study Visit 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Screening 
Screening  
Multiple visits over 7 to 
28 days/ 
After phone screen/ 
 
At initial visit, obtain Informed Consent and assess 
all screening measures (including PCL-5, Lifetime 
C-SSRS), medical history, and pre-study 
medications. Contact outside providers and order 
medical records, physical exam, labs (including 
pregnancy and drug tests), ECG, and 1-minute 
rhythm strip. Once all results and records are 
obtained, review along with notes from all screening 
visits and measures. If eligible, send results of LEC-
5 & SCID-5-SPQ to IR. Screening may take place 
over 7 to 28 days at multiple visits. 
Independent 
Rater Screening 
1 hour/ 
2 to 9 days after initial 
eligibility established 
during Screening 
After PCL-5 and initial eligibility are reviewed, an 
IR will conduct the Since Last Visit C-SSRS, SCID-
5-PD, DDIS, and MINI via telemedicine. Results 
will be confirmed by clinical observation during the 
Preparatory Period, but the SCID-5-PD, DDIS, and 
MINI will not be repeated.  
Enrollment 
Enrollment 
(Visit 0) 
1.5 hours/ 
2 to 14 days after 
Independent Rater 
Screening 
Prior to enrolling: review all screening measures, 
medical history, discussion with outside providers 
and sponsor, and any clarification phone calls with 
participant. Visit is 1.5 hours to review eligibility 
and medical tapering plan. If enrolled, begin taper, 
(5 half-lives plus 7 days for stabilization prior to 
V3). Adverse Event (AE) collection begins. 
 

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Preparatory Period with Enrollment Confirmation  
From Preparatory Session 1 (Visit 1) to Preparatory Session 3 (Visit 4): ~6 weeks (+5/-5 weeks) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Preparatory Period 
Preparatory 
Session 1 
(Visit 1) 
1.5 hours/ 
0 to 12 days after 
Enrollment (V0) 
90-minute Preparatory Session. Target visit timing 
on tapering needs. If needed, schedule calls between 
Visits 1 and 2 if indicated for tapering, safety, or 
further questions about medical history. 
Preparatory 
Session 2 
(Visit 2) 
 
1.5 hours/ 
2 to 21 days after V1 
90-minute Preparatory Session/ongoing assessment. 
If tapering is complete or not needed, check 
eligibility and schedule Visits 3 and 4. If tapering is 
ongoing, schedule post taper call for ongoing 
assessment. 
Phone Call 
End Taper 
 
1 hour/ 
0 to 7 days after taper 
and stabilization end; up 
to 56 days after V0; 
prior to V3 
If needed, confirm medication taper and 
stabilization is complete and participant is eligible 
for Baseline CAPS-5. Schedule Visits 3 and 4. 
Baseline & Enrollment Confirmation 
Baseline 
CAPS-5 T1 
(Visit 3) 
1.5 hours/ 
Post V2 & Medication 
Taper; before V4 
CAPS-5, SDS, and DSP-I completed by an IR via 
telemedicine after taper is complete. CAPS scores 
sent ASAP to the therapy team/PI. 
 
Due to possibilities of negative side effects of 
withdrawal from psychiatric medications, the 
Baseline CAPS-5 should be scheduled as close to 
the end of tapering as clinically appropriate so that 
participants who do not meet eligibility criteria can 
resume their previously prescribed medications as 
quickly as required for symptom management and 
participants who do meet criteria can be enrolled 
and treated as quickly as possible. 
Preparatory 
Session 3 
& Enrollment  
Confirmation 
(Visit 4) 
3 hours (90-minute 
measures, 90-minute 
therapy)/ 
3 to 6 days after V3; 
1 to 4 days prior to V5 
 
 
Prior to visit, ensure CAPS-5 confirms PTSD 
diagnosis and Total Severity Score of ≥35 and 
confirm enrollment by reassessing eligibility 
criteria. Complete Baseline self-report measures. 
Complete 3-hour Preparatory Session (~90-minute 
measures, 90-minute therapy) and schedule Visit 5. 
If enrollment is not confirmed, do not randomize; 
complete Study Termination. 
 

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Treatment Period 
From Randomization to Integrative Session 3.3 (Visit 18): 12 weeks (-3/+4) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Treatment 1 
Randomization 
.5 hours/ 
24 to 48 hours before 
V5 
Complete after enrollment and scheduling Visit 5. 
Enter demographics in Medrio for use in 
randomization. The participant does not need to be 
present for this. 
Experimental 
Session 1 
(Visit 5) 
8 hours + overnight/ 
4 to 7 days after V3; 
1 to 4 days after V4 
First Experimental Session is within 2 weeks of the 
Baseline CAPS-5 (Visit 3), it lasts 8 hours with 
overnight stay. Dose is 80 mg with supplemental 
half-dose of 40 mg unless contraindicated. 
Integrative 
Session 1.1 
(Visit 6) 
1.5 hours/ 
Morning after V5 
Visit 6 is a 90-minute Integrative Session the 
morning after Visit 5. Followed by phone check-ins 
on Days 2, 4, 6, 7, 8, 10, 12, 14 post Visit 5.  
Integrative 
Session 1.2 
(Visit 7) 
1.5 hours/ 
3 to 14 days after V5; 
at least 2 days after V6 
Between 3 and 14 days after Visit 5, a 90-minute 
Integrative Session (Visit 7) is completed. 
CAPS-5 T2 
(Visit 8) 
1 hour 
18 to 30 days after V5; 
between V7 and V9 
(may be on same day as 
either) 
Between Visits 7 and 9 (may be same day as either), 
CAPS-5, SDS, and DSP-I assessment completed by 
an IR via telemedicine.  
Integrative 
Session 1.3 
(Visit 9) 
1.5 hours/ 
20 to 34 days after V5; 
at least 2 days after V7; 
1 to 7 days before V10  
90-minute Integrative Session post Visit 8 and in 
preparation for Visit 10. Can occur 1 to 7 days 
before Visit 10. Measures include LEC-5 and C-
SSRS. 
Treatment 2 
Experimental 
Session 2 
(Visit 10) 
8 hours + overnight/ 
21 to 35 days after V5 
21 to 35 days after Visit 5. The second 
Experimental Session lasts 8 hours with an 
overnight stay. Dose is 80 or 120 mg plus 
supplemental half-dose unless contraindicated. 
Integrative 
Session 2.1 
(Visit 11) 
1.5 hours/ 
Morning after V10 
 
Visit 11 is a 90-minute Integrative Session the 
morning after Visit 10. Followed by phone check-
ins on Days 2, 4, 6, 7, 8, 10, 12, 14 post Visit 10.  
Integrative 
Session 2.2 
(Visit 12) 
1.5 hours/ 
3 to 14 days after V10; 
at least 2 days after V11 
Between 3 and 14 days after Visit 10, a 90-minute 
Integrative Session (Visit 12) is completed. 
CAPS-5 T3 
(Visit 13) 
1 hour/ 
18 to 30 days after V10; 
between V12 and V14 
(may be on same day as 
either) 
Between Visits 12 and 14 (may be on same day as 
either), CAPS-5, SDS, and DSP-I assessment 
completed by an IR via telemedicine. 
Integrative 
Session 2.3 
(Visit 14) 
1.5 hours/ 
20 to 34 days after V10; 
at least 2 days after 
Integrative Session 2.2 
(V12) 
1 to 7 days before V15 
90-minute Integrative Session post Visit 13 and in 
preparation for Visit 15. Can occur 1 to 7 days 
before Visit 15. Measures include LEC-5 and C-
SSRS. 
 

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Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Treatment 3 
Experimental 
Session 3 
(Visit 15) 
8 hours + overnight/ 
21 to 35 days after V10 
21 to 35 days after Visit 10. The third Experimental 
Session lasts 8 hours with an overnight stay. Dose 
is 80 or 120 mg plus supplemental half-dose unless 
contraindicated. 
Integrative 
Session 3.1 
(Visit 16) 
1.5 hours/ 
Morning after V15 
Visit 16 is a 90-minute Integrative Session the 
morning after Visit 15. Followed by phone check-
ins that includes Since Last Visit C-SSRS 
assessment on Days 2, 4, 6, 7, 8, 10, 12, 14 post 
Visit 15. 
Integrative 
Session 3.2 
(Visit 17) 
1.5 hours/ 
3 to 14 days after V15; 
at least 2 days after V16 
Between 3 and 14 days after V15, a 90-minute 
Integrative Session (Visit 17) is completed. 
Integrative 
Session 3.3 
(Visit 18) 
1.5 hours/ 
21 to 35 days after V15 
90-minute Integrative Session post Visit 17, 21 to 
35 days after Visit 15. Measures include LEC-5 and 
C-SSRS. 
 
Follow-up Period and Study Termination 
From Integrative Session 3.3 (Visit 18) until Study Termination (Visit 20): 4 weeks (±2). After 
Integrative Session 3.3 (Visit 18), ~4 weeks with no scheduled study visits until the Primary Outcome is 
completed. 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Primary Outcome 
Primary 
Outcome 
CAPS-5 T4 
(Visit 19) 
1 hour/ 
18 (±3) weeks (105 to 
147 days) after V3;  
8 (±2) weeks (42 to 70 
days) after V15 
Occurs 105 to 147 days of Baseline and 42 to 70 
days) after Experimental Session 3 (Visit 15), 
Primary Outcome CAPS-5, SDS, and DSP-I 
assessment completed by an IR via telemedicine. 
Although there are allowable windows for all visits 
throughout the protocol, this visit is targeted to be 
completed within the overall window. Other visits 
should be scheduled to ensure the timing of the 
Primary Outcome CAPS-5 T4 assessment is 
appropriate. In the case of study interruption, Visit 
19 should be scheduled 42 to 70 days after Visit 15. 
Study Termination 
Study 
Termination 
(Visit 20) 
2 hours  
~18 (±3) weeks (105 to 
147 days) after V3; 
1 to 9 days after V19 
Occurs 105 to 147 days post Baseline and within 1 
to 9 days of Visit 19. Complete self-reported and 
safety measures; create an exit plan for participant. 
Invite participant to the extension study for LTFU. 
Let participant who completed the protocol know 
how they will be informed of unblinding and at that 
time, if in the placebo group, regardless of CAPS-5 
scores, they will be offered the opportunity to enroll 
at no cost in an open-label safety extension study. 
 
Qualified, blinded IRs selected based on availability from the IR Pool will perform the CAPS-5 
assessments as described in table below.  
 

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Table 2: Primary Outcome (CAPS-5) Data Collection by Visit 
CAPS Number 
Visit 
Description/Timing 
Target Timing 
Post Baseline (V3) 
Baseline CAPS-5 T1 
V3 
Baseline 
Between Visits 2 and 4 Preparatory Sessions 
0 days 
CAPS-5 T2 
V8 
Post Experimental Session 1 (~3 weeks) 
Between Visits 7 and 9 Integrative Sessions 
~6 weeks 
CAPS-5 T3 
V13 
Post Experimental Session 2 (~3 weeks) 
Between Visits 12 and 14 Integrative Sessions 
~10 weeks 
Primary Outcome  
CAPS-5 T4 
V19 
Post Experimental Session 3 (~8 weeks) 
~18 weeks 
 
5.2 Planned Duration of Study 
Full screening may take 28 days after completion of phone screening. The Preparatory Period 
begins at enrollment and can be as brief as 7 days, but depending on medication tapering could be 
as long as 56 days to ensure an appropriate medication washout of at least five half-lives of pre-
study psychiatric medications and active metabolites, and at least 7 days for stabilization prior to 
the Baseline CAPS-5 T1 (Visit 3). 
 
Enrollment Confirmation takes place at the completion of the Preparatory Period, at which time 
the Treatment period will commence. The approximately 12-week Treatment Period will consist 
of three Experimental Sessions 3 to 5 weeks apart with associated non-drug Integrative Sessions 
and CAPS-5 assessments.  
 
After the final Integrative Session 3.3 (Visit 18), participants will enter follow-up with no planned 
study visits for approximately 4 weeks, after which the Primary Outcome CAPS-5 T4 assessment 
will take place. Although there are allowable windows for all visits throughout the protocol, the 
overall timelines should comply with the target timing of the Primary Outcome CAPS-5 T4 
assessment, which must be completed 18 weeks (±3 weeks) (105 to 147 days) post Baseline, even 
if the maximum possible visit windows were used between visits. Other visits should be 
scheduled to ensure the timing of the Primary Outcome CAPS-5 T4 assessment is appropriate. 
The Study Termination visit follows 1 to 9 days after the final CAPS-5 assessment. 
 
The minimum time that a participant who completes all study visits from Screening to Study 
Termination will be in the clinical trial is 19 weeks, and the maximum is 38 weeks. The average 
participant is expected to complete the study in 27 weeks. Any delays between visits outside of 
the protocol-defined windows may result in a corresponding extension of study duration and 
should be documented as a deviation as appropriate.  
 
All participants who complete the study will be asked to participate in a LTFU extension study 
with one visit 12 months after the last Experimental Session. Upon unblinding after database 
lock, all participants who were assigned to placebo (regardless of CAPS-5 scores), completed the 
study, meet criteria, and are in good standing with the clinical site will be offered the opportunity 
to enroll in an open-label safety study of manualized MDMA-assisted psychotherapy. This open-
label safety study will take place at least 18 months after the first participant is enrolled in 
MAPP1 and will last 19 to 38 weeks, and will follow a design similar to this protocol. 
 
5.2.1 Interruptions and Accommodations Due to COVID-19 Pandemic or Any 
Other Unforeseen Emergency at Clinic Locations 
This clinical trial has been interrupted by the Coronavirus Disease 2019 (COVID-19) global 
pandemic. Accommodations may be required for study continuation and participant and study site 

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staff safety due to this emergency or any other unforeseen emergency in the future. The following 
accommodations in the protocol will be allowed, captured and noted in the Clinical Study Report 
as COVID-19 deviations: 
 
• 
Integrative Sessions may be conducted by telemedicine  
• 
Delaying the start of medication tapering after enrollment and the subsequent Treatment 
Period per Section 12.1 Tapering Instructions 
• 
Delaying Experimental Sessions and associated Integrative Sessions  
• 
Delaying Independent Rater assessments for participants who cannot complete them 
remotely off-site 
• 
Use of prohibited medications and/or cannabis or initiation of new psychotherapy for 
participants with significant study delays, which will be reviewed by the study team 
before each Experimental Session and re-tapered prior to resuming treatment per Section 
12.0 Concomitant Medications. 
 
For any participant with COVID-19 related illness, continued trial participation after full recovery 
of the disease may be appropriate after discussion between the site physicians and Medical 
Monitors on a case-by-case basis. 
 
5.3 Discontinuation and Completion Criteria 
5.3.1 Complete or Evaluable Participants 
Participants who are considered complete or evaluable will be defined as follows:  
 
• 
A participant is considered ‘Evaluable’ and eligible for the mITT analysis if they have 
completed at least one Experimental Session and one CAPS-5 assessment beyond 
Baseline.  
• 
A participant is considered ‘Evaluable and Completed Per Protocol’ if they have 
completed all Experimental Sessions and CAPS-5 assessments as planned. These 
participants will be included in the mITT analysis set and the Per Protocol analysis set. 
• 
A participant is considered ‘Evaluable and Early Termination’ if they have completed at 
least one Experimental Session and one CAPS-5 assessment beyond Baseline but 
terminated early. These participants will be included in the mITT analysis.  
• 
A participant is considered to be in good standing with the clinical site if, in the opinion 
of the investigator and/or therapy team, the participant was compliant with protocol 
requirements, even if they were unable to complete all study visits. 
 
5.3.2 Screen Failures 
‘Screen Failures’ are defined as participants who pass phone screening but are deemed ineligible 
before successfully enrolling in the study at Visit 0. Screen failures may fail to meet all 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, and reasons 
for Screen Failure will be recorded. Screen Failures are not considered evaluable.  
 
Screen Failures may be identified through review of medical history, assessments, measures, 
laboratory results, or conversations with the participant. Medical assessments may be repeated for 
confirmation. At any time during Screening, if a potential participant is deemed to be ineligible, 
classify as a Screen Failure, notify the potential participant that they are unfortunately not eligible 
for the study, and do not schedule additional Screening assessments. Participants who fail 

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Screening may be rescreened at a later date if deemed appropriate by the investigator but should 
sign a new copy of the Informed Consent Form (ICF). Screen Failures may request a referral to 
an outside therapist if needed. Screen Failures that were scheduled for an IR assessment will be 
entered into the Electronic Data Capture (EDC) system. 
 
5.3.3 Pre-Randomization Early Terminations 
‘Pre-randomization Early Terminations’ are defined as participants who were deemed eligible 
and enrolled in the study at Visit 0, but are deemed ineligible prior to the first Experimental 
Session and do not have enrollment confirmed at Visit 4. These participants may fail to meet all 
Inclusion Criteria and may meet one or more Exclusion Criteria or withdraw consent prior to 
Enrollment Confirmation or the site may withdraw the participant for reasons described in 
Section 5.3.4 Early Termination from the Study). Participants who fail Enrollment Confirmation 
may not be re-enrolled into this study at a later date. All enrolled participants, even those failing 
Enrollment Confirmation, will be maintained in the EDC system. Pre-randomization Early 
Terminations are not considered evaluable. 
 
Pre-randomization Early Terminations may be identified through review of medical history, 
assessments, measures, laboratory results, or conversations with the participant. At any time 
during the Preparatory Period, if a potential participant is deemed to be ineligible, classify as a 
Pre-randomization Early Termination, notify the potential participant that they are unfortunately 
not eligible for the study, and do not schedule additional assessments. Do not randomize the 
participant. Pre-randomization Early Terminations will be provided an Exit Plan as described in 
Section 8.4.3.2 Exit Plan.  
 
5.3.4 Early Termination from the Study 
Participants who are removed from the study after they are randomized and receive IMP but do 
not complete the study may fall into one of these categories: Post-randomization Early 
Termination or Dropout. If the participant has received IMP in at least one Experimental Session 
and completed one CAPS-5 assessment beyond Baseline, they will be considered evaluable. All 
participants who receive IMP in at least one Experimental Session will be included in all safety 
analyses.  
 
Participants can withdraw from treatment or withdraw consent at any time for any reason without 
judgment. The site team can withdraw a participant if, in their clinical judgment, it is in the best 
interest of the participant or if the participant cannot comply with elements of the protocol that 
are critical for safety or for the scientific integrity of the study. If the site team makes the decision 
to terminate the participant from treatment or the study, they will explain the reason for 
withdrawal and document in the participant’s source records and Electronic Case Report Form 
(eCRF). If a participant develops any Exclusion Criteria that, in the opinion of the Medical 
Monitor or Site, affects the safety of the participant, including psychiatric diagnosis, medical 
diagnosis, pregnancy, or requiring use of prohibited medications, the participant will discontinue 
treatment in Experimental Sessions but remain in the study for the associated Integrative 
Sessions. Participants whose Experimental Sessions are delayed by the COVID-19 pandemic may 
start any of these medications during the delay, as clinically indicated. When study visits resume, 
they will be given the option to resume Experimental Sessions after tapering off of these 
medications per Section 12.1 Tapering Instructions. Any time a participant terminates from the 
study early, the site team will attempt to obtain information about AE outcomes if appropriate, as 
determined by the site physician and Medical Monitor. The site team will provide the participant 
with an Exit Plan as described in Section 8.4.3.2 Exit Plan. 
 

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Data will be collected from participants who terminate early as follows:  
 
• 
Post-randomization Early Termination: Participants who discontinue study treatment 
but continue to participate in Independent Rater primary and secondary outcome 
assessments. Data collection by IRs will continue on the same schedule as planned 
through Study Termination visit procedures. 
• 
Dropout: If a participant decides to withdraw consent completely, they will terminate 
without further follow-up. If the participant agrees, they will complete a final CAPS-5 
assessment. These participants are defined as dropouts who withdraw consent due to any 
reason after receiving at least one dose of IMP and no longer participate in the study (i.e., 
no further contact with investigators or site staff). Data collected on study participants up 
to the time of withdrawal of consent will remain in the trial database in order to maintain 
scientific validity. Removal of data from the database would undermine the scientific and 
ethical integrity of the research. 
 
5.3.5 Lost to Follow-up 
A participant will be considered lost to follow-up if they fail to attend scheduled visits and are 
unable to be contacted by the site staff. If the participant has completed at least one Experimental 
Session and one CAPS-5 assessment beyond Baseline, they will be considered evaluable. All 
participants with at least one Experimental Session will be included in the safety analysis. 
 
If a participant does not attend a scheduled visit, the site must attempt to contact the participant to 
reschedule the visit as soon as possible and emphasize the importance of complying with the 
protocol specified visit schedule. The staff should determine if the participant is willing to 
comply with future visits. 
 
If a participant does not respond to this initial contact, the site staff must make multiple efforts to 
contact the study participant and document each attempt in the source record. At least three 
attempts should be made via telephone, over the course of approximately 7 days, with calls at 
different times of day. If telephone contact fails, an email should be sent if such contact 
information was provided. The emergency contact the participant provided should be contacted 
and asked to attempt contact with the participant. Lastly, a certified letter (or equivalent) should 
be sent to their last known mailing address. If the participant fails to respond to all of these 
contacts, they will be considered to have withdrawn from the study and are lost to follow-up. 
 
5.4 End of Study Definition and Premature Discontinuation 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in Table 5: Time and Events for the last participant in the trial 
globally. 
 
The sponsor has the right to discontinue this study at any time. If the trial is prematurely 
terminated, the investigator is to promptly inform participants and will ensure they receive 
appropriate therapy, follow-up, and Exit Plan. If the study is prematurely discontinued, all 
procedures and requirements pertaining to retention and storage of documents will be observed. 
All other study materials will be returned to the sponsor and will be treated in accordance with 
federal and state regulations. 
 

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5.5 Rationale of Dose Selection 
Similar MDMA doses to those proposed in this study have been safely used in previous Phase 2 
studies sponsored by MAPS. Phase 2 studies indicate that 75, 100 and 125 mg MDMA initial 
doses with the supplemental dose are active and effective in two to three Experimental Sessions. 
MDMA doses with an optimal risk-benefit ratio range from 75 mg (Cohen’s d Independent 
Groups Pre-test Post-test [dIGPP]=2.73, N=7) to 125 mg (Cohen’s dIGPP=0.77, N=58) initial 
dose of MDMA with a 2-session treatment package. In Phase 2 studies, the sponsor observed a    
-36.4 point mean change in CAPS-4 scores among active dose participants receiving two 
Experimental Sessions (N=72) compared to a -44.2 point mean change after three Experimental 
Sessions (N=51). Although uncontrolled, the additional 7.8 point mean reduction observed after 
three Experimental Sessions compared to two, along with the observed favorable safety profile 
formed the basis for selection of a 3-session treatment package. A flexible dosing regimen has 
been explored previously in Phase 2 studies, where participants who received doses of 0 mg to 75 
mg MDMA in the blinded portion of the study crossed over to receive open-label 100 mg MDMA 
in the first Experimental Session with an option to increase to 125 mg MDMA in the second and 
third Experimental Sessions. In the opinion of the participants and therapy teams administering 
this treatment in Phase 2 studies, this flexible dosing regimen and three Experimental Sessions 
produced an optimal treatment response. Larger doses have been administered safely in MP2 (150 
mg and 75 mg supplemental) and in Phase 1 studies (150 mg and 160 mg). The results of these 
Phase 2 studies led to the selection of 80 mg and 120 mg MDMA as the initial active doses to be 
compared to inactive placebo in Phase 3 trials. 
 
This blinded study will compare the effects of a flexible dose of MDMA or placebo administered 
in three Experimental Sessions. Initial doses per Experimental Session range from 80 mg to 120 
mg of MDMA compounded with inactive excipients or indistinguishable weight placebos 
comprised entirely of inactive excipients, followed 1.5 to 2 hours later by a supplemental half-
dose (40 mg or 60 mg, or placebo). A flexible dosing regimen was chosen to mimic proposed 
clinical practice and better adapt to risk-benefit considerations. The initial active doses of 80 mg 
and 120 mg are expected to produce all commonly reported effects of MDMA. The supplemental 
half-dose will prolong subjective effects of MDMA without producing physiological effects 
much greater than peak effects occurring after the initial dose, and will be administered unless 
contraindicated. Total amounts of MDMA to be administered per Experimental Session range 
from 80 mg to 180 mg.  
 
An inactive placebo has been selected as the control to allow differentiation of any additional 
MDMA effect from psychotherapy alone. This pivotal study will generate unequivocal 
assessment of safety data and demonstration of efficacy of MDMA-assisted psychotherapy 
compared to psychotherapy plus placebo. 
 
Table 3: Dose Regimen of MDMA or Placebo 
Experimental 
Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative Dose 
1 
80 mg 
40 mg 
80 mg to 120 mg 
2 
80 or 120* mg 
40 or 60 mg 
80 mg to 180 mg 
3 
80 or 120* mg 
40 or 60 mg 
80 mg to 180 mg 
Total Cumulative Dose 
240 mg to 480 mg 
* Unless contraindicated 
 
In the first Experimental Session, the initial dose will be 80 mg MDMA or placebo. In the second 
and third Experimental Sessions, the initial dose may be increased to 120 mg MDMA or placebo 
unless contraindicated in the opinion of the site team. The choice of whether to keep the dose the 

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same or change it from the first Experimental Session will be made by the site team based on 
observed response, tolerability to the previously administered dose, and discussion with the 
participant. In each Experimental Session, 1.5 to 2 hours after the initial dose is given, the 
participant will be administered a supplemental half-dose unless contraindicated. Participants will 
not know if they have been assigned MDMA or placebo but can indicate if they want the dose to 
change or remain the same. 
 
6.0 Psychotherapy 
6.1 Description of Therapeutic Method 
The largely non-directive therapeutic method of MDMA-assisted psychotherapy is described in 
detail in the Treatment Manual. All therapy teams will be extensively trained in a multi-week 
training program prior to the study to ensure all participants are treated in a similar manner. The 
non-directive approach pertains to inviting inquiry and providing suggestion rather than directing 
the participant in the therapeutic approach. This requires active or engaged listening and 
responding, as well as facilitation of therapeutic action by providing support for approaching 
difficult material in a manner that does not interfere with the participant’s spontaneous 
experience. 
 
6.2 Therapy Team Qualifications 
Therapy teams will be trained by the sponsor. Sites must ensure that the minimum requirements 
below are met: 
 
• 
One person licensed to manage and administer controlled substances for each site  
• 
A physician to assess participant safety at Screening 
• 
One or more two-person therapy teams, male/female preferred 
• 
One person per therapy team is required to be licensed to provide psychotherapy 
according to state and local requirements 
• 
If one person on the therapy team is unlicensed, they will work under the direct 
supervision of the licensed team member 
 
6.3 Training 
The sponsor’s Therapy Training Program is designed to teach competency in applying the 
essential elements of this method of MDMA-assisted psychotherapy. Therapy team members will 
receive specific training in the MDMA-assisted psychotherapy method, protocol, and latest 
version of the IB. Training in the psychotherapy method consists of reading the Treatment 
Manual, completing an online training module, and participating in an in-person training program 
that includes watching and discussing videos of Experimental Sessions. The final part of training 
includes supervision from the training team during a Phase 2 open-label lead-in protocol. The 
required elements of the therapy are defined in the Treatment Manual, and teams will be trained 
on visit-specific sets of adherence criteria. In addition to this specific training, it is required that 
participating therapy team members have the proper background, education, and experience.  
 
6.4 Adherence to Therapeutic Method 
Psychotherapy sessions, including Experimental Sessions, may be recorded, with recordings 
preserved for research and training purposes. Adherence criteria and competence ratings will be 
conducted by qualified, trained, and blinded Adherence Raters who will analyze video data from 
specific and randomly selected Preparatory Sessions, Experimental Sessions, and Integrative 

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Sessions. The elements included in adherence criteria are specific to each type of session and are 
defined in the Treatment Manual. These ratings will be collected, at minimum, for each therapy 
team in the study. Ratings will be used to provide feedback to new therapy teams, to further 
characterize the manualized therapy, and for future exploratory research. 
 
7.0 Measures and Reliability 
The following eligibility, outcome, exploratory, and safety measures will be used in the study, in 
accordance with Table 6: Time and Events-Study Measures.  
 
Table 4: Protocol Objectives and Assessment Tools 
Objectives 
Measure 
Measure Type 
Administration 
Eligibility 
Assess psychiatric disorders 
 
 
MINI 
Eligibility 
Telemedicine 
(IR) 
Assess personality disorders 
SCID-5-PD 
with SCID-
5-SPQ 
Eligibility 
Telemedicine 
(IR)/ self-report 
measure at Site 
Confirm PTSD diagnosis and severity 
PCL-5 with 
LEC-5 
Eligibility 
Site 
Identify dissociative disorders  
 
DDIS 
Eligibility 
Site 
Primary 
Assess changes in PTSD symptom severity 
from Visit 3 to Visit 19 compared between 
groups 
 
CAPS-5 
Outcome 
Telemedicine 
(IR) 
Secondary 
Assess changes in clinician-rated functional 
impairment from Visit 3 to Visit 19 compared 
between groups 
 
SDS 
Outcome 
Telemedicine 
(IR) 
Safety 
Compare relative incidence of positive or 
serious ideation and suicidal behavior 
between groups 
C-SSRS 
Safety 
Site 
Exploratory 
Characterization of CAPS-5 Total Severity 
score at weeks 6, 10, and 18 to explore onset 
of treatment efficacy with a descriptive time 
course plot 
CAPS-5 
Outcome 
Telemedicine 
Explore changes in PTSD symptom clusters 
of re-experiencing, avoidance, negative 
alterations in cognition and mood, and 
hyperarousal as measured by changes in 
CAPS-5 subscale scores 
CAPS-5 
Outcome 
Telemedicine 
Assess changes in severity of dissociative 
symptoms associated with PTSD from Visit 3 
to Visit 19 compared between groups  
DSP-I 
Outcome 
Telemedicine 
(IR) 
Explore correlation of dissociative symptoms 
associated with PTSD with the CAPS-5 Total 
Severity analyses 
DSP-I 
CAPS-5 
Outcome 
Telemedicine 
(IR) 

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Objectives 
Measure 
Measure Type 
Administration 
Explore the effect of presence of secondary 
traumatic stressors during the assessment 
period as a covariate on the CAPS-5 Total 
Severity analyses  
LEC-5 
CAPS-5 
Outcome 
Site or 
Telemedicine 
Explore the effect of adverse childhood 
experiences on PTSD treatment outcomes as a 
covariate on the CAPS-5 Total Severity 
analyses 
ACE 
CAPS-5 
Outcome 
Site or 
Telemedicine 
Assess changes in depression symptoms from 
Visit 4 to Visit 20 compared between groups 
BDI-II 
Outcome 
Site or 
Telemedicine 
Assess changes in chronic pain from Visit 4 
to Visit 20 compared between groups 
CPGS 
Outcome 
Site or 
Telemedicine 
Assess changes in quality of life from Visit 4 
to Visit 20 compared between groups 
EQ-5D-5L 
Outcome  
Site or 
Telemedicine 
Assess changes in functioning in relation to 
self and others from Baseline to Visit 20 
compared between groups 
IASC 
Outcome 
Site or 
Telemedicine 
Assess changes in self-reported psychosocial 
functioning from Visit 4 to Visit 20 compared 
between groups 
IPF 
Outcome 
Site or 
Telemedicine 
Assess changes in self-compassion from Visit 
4 to Visit 20 compared between groups 
SCS 
Outcome 
Site or 
Telemedicine 
Assess changes in alexithymia from Visit 4 to 
Visit 20 compared between groups 
TAS-20 
Outcome 
Site or 
Telemedicine 
Assess changes in alcohol use from Screening 
to Visit 20 compared between groups  
AUDIT 
Healthcare cost 
Site or 
Telemedicine 
Assess changes in drug use from Screening to 
Visit 20 compared between groups  
DUDIT 
Healthcare cost 
Site or 
Telemedicine 
Assess changes in nicotine use from Visit 4 to 
Visit 20 compared between groups 
SRNU 
Healthcare cost 
Site or 
Telemedicine 
Assess changes in disordered eating from 
Visit 4 to Visit 20 compared between groups  
EAT-26 
Healthcare cost 
Site or 
Telemedicine 
Assess changes in workplace productivity 
from Visit 4 to Visit 20 compared between 
groups 
HPQSF 
Healthcare cost 
Site or 
Telemedicine 
Assess facility-based healthcare utilization at 
Screening 
UFEC 
Healthcare cost 
Site or 
Telemedicine 
 
7.1 Primary Outcome Measure and Reliability 
7.1.1 CAPS-5 (Clinician-Administered PTSD Scale for DSM-5) 
The last month CAPS-5 is a semi-structured interview that assesses index history of DSM-5-
defined traumatic event exposure [62], including the most distressing event, time since exposure, 
to produce a diagnostic score (presence vs. absence) and a PTSD Total Severity score [62]. The 
CAPS-5 rates intrusion symptoms (intrusive thoughts or memories), avoidance, cognitive and 
mood symptoms, arousal and reactivity symptoms, duration and degree of distress and 
dissociation. The CAPS-5 will be administered by a blinded IR via telemedicine. Interviews will 
be conducted by the centralized remote IR pool to enhance quality control by reducing site-level 
variation in interview fidelity and quality. The IRs will be trained and supervised by a research 
reliable trainer and will be supervised by qualified personnel. Per the CAPS-5 Training Manual 
for the IR Pool, IRs will ensure that every single item-level score is collected in every CAPS-5 
interview. The CAPS-5 is administered by the IR in a neutral, non-leading manner to minimize 
the chance for bias. Additionally, the IRs are trained to carefully assess trauma-relatedness of 

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each symptom according to standard CAPS-5 procedures. Doing so ensures that all symptoms 
contributing to the CAPS-5 PTSD diagnostic status and total severity score are either temporally 
or functionally related to the index trauma rather than attributable to non-trauma current life 
stressors or current world events such as the COVID-19 pandemic. Avoiding a biased 
administration can be achieved by adhering to 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. Avoiding building therapeutic/clinical 
rapport beyond the basic level of rapport needed to conduct the interview in the research setting 
also minimizes the chance for bias. Remote assessment assures that the rater who is collecting the 
Primary Outcome will not witness Experimental Sessions and the acute effects of IMP, which 
strengthens the study blind. Interviews may be recorded in as many instances as necessary to 
establish reliability of a random selection of interviews for accuracy. After the initial screening 
visit, the IRs will be blinded to visit number, number of treatments received, treatment 
assignment, and any study data for the participant. IR visits will be assigned based on availability. 
 
7.2 Secondary Measure 
7.2.1 SDS (Sheehan Disability Scale) 
The SDS is a clinician-rated assessment of functional impairment [63]. The items indicate degree 
of impairment in the domains of work/school, social life, and home life, with response options 
based on an eleven-point scale (0=not at all to 10=extremely), and five verbal tags (not at all, 
mildly, moderately, markedly, extremely). The SDS takes 1 to 2 minutes to complete. The 
measure can be scored for each of the three domains. The SDS has high internal consistency and 
accurately identified 80% of a sample of primary care patients with mental disorders [64].  
 
7.3 Safety Measures 
7.3.1 C-SSRS (Columbia Suicide Severity Rating Scale) 
The C-SSRS is a clinician-administered measure of suicidal behavior devised to detect potential 
suicidal thoughts or behaviors during a clinical trial [65]. It consists of a Lifetime version and a 
Since Last Visit version that assess suicidal ideation, ideation intensity, and behavior. The C-
SSRS consists of a series of questions and can be administered during a face-to-face interview or 
over the telephone. The Lifetime version will only be administered at the initial Screening visit. 
All subsequent administrations will utilize the Since Last Visit version. Participants who are 
discontinuing medications to participate in the study will complete the C-SSRS before and after 
medication washout. The C-SSRS Intensity scale for Lifetime obtained a Cronbach’s alpha of 
0.93 and 0.94 for the Since Last Visit form, and Last Visit C-SSRS severity scores were 
positively correlated with the BDI “suicide thoughts” item [66]. 
 
7.4  Screening Measures and Reliability 
7.4.1 MINI (Mini-International Neuropsychiatric Interview) 
This version of the MINI (7.0.2), a structured interview that was first developed in 1998 to be 
compatible with DSM and International Classification of Disease (ICD) criteria for psychiatric 
illnesses [67], is now compatible with DSM-5 and will be administered by a member of the 
Independent Rater Pool to screen for psychiatric conditions per DSM-5. Each module of the 
MINI consists of two or three questions where the answer is either “Yes” or “No,” and decision-
tree logic is used to determine whether to ask additional questions [68]. The MINI takes between 
15 and 20 minutes to perform and addresses major psychiatric disorders. MINI items were highly 

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reliable (interrater reliability between kappa of 0.8 and 0.99; test-retest reliability between 0.6 and 
0.9 for all scales save “current mania), and diagnosis via MINI was comparable to that made with 
the Composite Diagnostic Interview and the SCID [68, 69] Testing on nonpsychiatric samples did 
not create false positives [67]. 
 
7.4.2 SCID-5-PD (Structured Clinical Interview for DSM-5 for Personality 
Disorders) 
The SCID-5-PD will be administered by a blinded IR via telemedicine [70]. Prior to the SCID-5-
PD clinical interview, participants will complete a brief self-report questionnaire called the SCID-
5 Self-report Personality Questionnaire (SCID-5-SPQ) as a self-report screening tool used to 
assess for personality disorders. Potential personality disorders that satisfy diagnostic thresholds 
will be further assessed via clinical interview during the SCID-5-PD. IRs will receive training on 
administering these measures from a research reliable trainer. Interviews may be recorded in as 
many instances as necessary to establish reliability of a random selection of interviews for 
accuracy. 
 
7.4.3 LEC-5 (Life Events Checklist for DSM-5) 
The LEC-5 is a 17-item self-report instrument designed to determine the presence of traumatic 
life events in the assessment and diagnosis of PTSD. It is a companion measure to the PCL-5 and 
will be used to assess PTSD. The participant indicates whether each event listed has occurred 
during their lifetime, permitting the possibility of marking multiple events [71]. 
 
7.4.4 PCL-5 (PTSD Checklist) 
The PCL-5 is a 20-item self-report questionnaire in which respondents indicate the presence and 
severity of PTSD symptoms, derived from the symptoms of PTSD per DSM-5 [72]. Participants 
indicate how much distress they have experienced due to symptoms such as "Repeated, disturbing 
memories, thoughts, or images of a stressful experience from the past," "Trouble remembering 
important parts of a stressful experience from the past," and "Feeling irritable or having angry 
outbursts" on a five-point Likert-type scale (1=Not at all to 5=Extremely). A total PCL-5 score of 
46 at Screening will be required for initial enrollment. 
 
7.4.5 DDIS (Dissociative Disorders Interview Schedule for DSM-5) 
Questions on the DDIS specifically addressing dissociative disorder symptoms (items 117 to 130) 
will be asked by an IR during Screening. These questions are part of an intensive interview that 
includes questions concerning somatic and psychiatric symptoms. The interview is intended to 
assess and potentially distinguish between dissociative disorders and other disorders and between 
Dissociative Identity Disorder (DID) and a dissociative disorder not otherwise specified [73]. 
Owing to overlap with items found between the DDIS and other screening measures, only 
questions specifically addressing DID will be assessed. 
 
7.5 Exploratory Measures 
7.5.1 DSP-I (The Dissociative Subtype of PTSD Interview) 
The DSP-I is a clinician-administered interview designed by an international team of PTSD 
researchers to detect and assess severity of the dissociative type of PTSD and recommended for 
use as an additional or complementary measure (“add-on”) to the CAPS-5 [74]. Assessments of 
military veterans and civilians support the existence of a dissociative subtype of PTSD that is 

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associated with PTSD severity and derealization and depersonalization [75-77]. The DSP-I takes 
approximately 5 to 15 minutes to complete. It consists of two parts, only Part 1 will be 
administered. Part 1 contains five items addressing depersonalization, four items addressing 
derealization, and a section that is administered if dissociative episodes are endorsed that assesses 
duration and perceived cause of episodes (seven items) and observer items (three items) 
addressing interviewee demeanor, including evidence of dissociation, such as forgetfulness or 
giving a statement that is bizarre within the context of the interview. If two or more items within 
this section are endorsed, this indicates the presence of other dissociative symptoms beyond 
depersonalization and derealization. The DSP-I was first developed in 2016 and revised in 2017.  
 
7.5.2 ACE (Adverse Childhood Experience Questionnaire) 
The ACE is a 10-item checklist measure assessing number and types of adverse childhood 
experiences, including neglect and emotional, physical, and sexual abuse. Respondents are asked 
if an experience happened “often” and if so, to write “1”. The total score reflects the number of 
adverse childhood experiences. The measure was first used in the context of a study investigating 
the relationship between childhood adverse experiences and health outcomes in adulthood [78]. 
Number of frequent adverse childhood experiences is associated with adverse health outcomes in 
adulthood, including greater likelihood of heart disease, chronic pain, and poor work performance 
[79-82]. The scoring method has been used in archival research, finding an association between 
increased scores and health problems in several generations [81].  
 
7.5.3 BDI-II (Beck Depression Inventory II) 
The BDI-II is a revision of the BDI, a 21-item self-report measure [83, 84] that will serve as a 
measure of depression symptom severity [85]. The BDI-II has been validated, has high internal 
consistency and good test/re-test reliability, and is not overly sensitive to daily variations in 
mood. It takes 5 to 10 minutes to complete [85]. Score cutoffs indicate: 0 to 13 minimal 
depression, 14 to 19 mild depression, 20 to 28 moderate depression, and 29 to 63 severe 
depression. Initial and subsequent studies report that the BDI-II total score has a reliability 
coefficient of 0.90 to 0.91 which is related to other measures of depression symptoms [85, 86]. 
Higher scores indicate more severe depressive symptoms.  
 
7.5.4 CPGS (Chronic Pain Grade Scale) 
The CPGS is a seven-item measure of pain. Responses to six of the seven items are made on a 10-
point Likert scale, and a response on the other item is the number of days in the past 3 to 6 
months when pain prevented the respondent from carrying out everyday activities [87]. 
Responses to questions are used to attain a rating (grade) for pain from zero (no pain) to five 
(high disability, severely limiting). The instrument has three scale scores: pain severity, pain 
intensity, and pain-related disability. Estimated time to complete is 3 to 5 minutes. The CPGS is a 
validated scale with high internal consistency (Cronbach’s alpha=0.90) and correlated with other 
instruments assessing pain [88]. 
 
7.5.5 EQ-5D-5L (EuroQol Five Dimensions-Five Levels Questionnaire) 
The EQ-5D-5L is a two-part self-report questionnaire assessing health status. It consists of five 
dimensions; mobility, self-care, usual activities, pain-discomfort and anxiety-depression, and one 
visual analog scale (VAS). Responses are made on each dimension by checking one of five 
statements that best reflects their health on the day of measure completion, from the healthiest or 
fewest problems (e.g., “I have no trouble walking about”) to the most trouble (e.g., “I am unable 
to walk about”) [89, 90]. In the second part of the EQ-5D-5L, current degree of health (“your 

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health today”) is indicated by marking a 20 cm line marked form one to 100, with 100 considered 
“the best health you can imagine” and one “the worst health you can imagine.” The EQ-5D-5L 
does not sum responses, but treats each response on a dimension as a scale score, and the VAS is 
the location of the mark in centimeters. The scale can permit comparison across groups on health 
profiles, and an index can be derived from matching the five dimension scores and the VAS 
response with nation-specific datasets and calculator software or statistical software syntax 
designed for the measure. The EQ-5D-5L began as part of the EuroQoL measure, published in 
1990 [91]. The instrument has been validated in populations from eight countries. EQ-5D-5L 
index scores and VAS scores assessed in people with stroke varied with degree of recovery 
assessed via long-term observation. EQ-5D-5L index scores and VAS scores assessed in people 
with stroke varied with degree of recovery assessed via long-term observation [92]. The EQ-5D-
5L takes about 3 minutes to complete. 
 
7.5.6 IASC (Inventory of Altered Self Capacities) 
The IASC is a 63-item self-report measure of difficulties with relationships, identity, and affect 
regulation [93]. The measure is completed by rating the frequency that an event or experience has 
occurred in the last 6 months or last month (1=Never to 5=Very often) on a 5-point Likert scale. 
The IASC consists of seven 9-item scales: interpersonal conflicts, idealization-disillusionment, 
abandonment concerns, identity impairment, susceptibility to influence, affect dysregulation, and 
tension reduction activities. Subscale scores are summed into raw scale scores. Level of 
symptomatology is assessed through use of t-scores based upon scale norms. IASC subscales 
range in reliability from Cronbach’s alpha of 0.78 to 0.93. IASC scale scores were correlated with 
a measure of personality disorders and psychiatric symptoms, and affect dysregulation scale 
scores were associated with a measure of depression [93]. 
 
7.5.7 IPF (Inventory of Psychosocial Functioning) 
The IPF will be administered as an exploratory measure at Baseline and 2-Month Follow-up. The 
IPF is a self-report instrument designed to assess functional impairment across a spectrum of 
domains [94]. The IPF is an 80-item measure that was developed for use among individuals with 
PTSD. It assesses current psychosocial functioning across seven domains: romantic relationships, 
family, work, friendships, parenting, education, and self-care. Responses are made on a six point 
Likert scale, (1=Never to 6=Always). Domain scores can be computed for each subscale, which 
possess positive correlations with similar scales or subscales on other measures. The IPF has 
excellent psychometric properties, with Cronbach’s alpha for the total scale computed at 0.93 and 
good internal consistency for subscales (ranging from 0.80 to 0.90) [95].  
 
7.5.8 SCS (Self-Compassion Scale) 
The SCS is a 26-item self-report measure of self-compassion, or responding to one's own failure, 
suffering or inadequacies with kindness and compassion and recognizing one's own flaws and 
suffering as part of common human experience [96]. Respondents complete the SCS by 
indicating how typical they feel on each item on a 5-point Likert scale (1=Almost never and 
5=Almost always). It is estimated to take between 4 to 8 minutes to complete. The scale has six 
sub-scales: Self-Kindness, Self-Judgment, Common Humanity, Isolation, Mindfulness, and Over-
Identified. The mean of subscale scores serves as a total score. Analysis of SCS response 
indicated that subscales are all related to a higher order factor of self-compassion, and the 
measure has high test-test reliability at a level of 0.93. Neff et al. reported an inverse relationship 
between SCS total scores and scores on measures of depression and anxiety. Self-compassion and 
global self-esteem are both related to positive mood and optimism, but self-compassion may be 

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more strongly associated with stable mood and less associated with self-rumination and anger 
[97]. 
 
7.5.9 TAS-20 (Toronto Alexithymia Scale) 
The TAS-20 is a 20-item measure of self-reported difficulties with recognizing and verbalizing 
emotions [98, 99]. Responses are made on a 5-point Likert scale (1=Strongly disagree to 
5=Strongly agree). Estimated time of measurement is 5 to 8 minutes. The scale is comprised of 
three subscales: Difficulty Describing Feelings, Difficulty Identifying Feelings, and Externally-
Oriented Thinking, with all scales summed to create a total score reflecting presence and degree 
of alexithymia. The TAS-20 is an established measure and can be used diagnostically with a score 
of 61 or higher indicative of alexithymia. The TAS-20 is reliable and has good test-retest 
reliability (Cronbach's alpha of 0.81, test-retest of 0.77). 
 
7.5.10 AUDIT (Alcohol Use Disorders Identification Test) 
The AUDIT is a ten-item self-report test. Respondents answer on a 5-point scale (0=Never or 
none, 4=Daily or greatest number) [100]. The ninth item addresses occurrence of injury of self or 
other as a result of drinking and the tenth addresses others’ concerns about the respondent’s 
drinking, with only three responses provided (0=No, 2=Yes, but not during the last year, 3=Yes, 
during the last year). The measure can readily detect alcohol abuse disorders in a wide array of 
individuals [101]. 
 
7.5.11 DUDIT (Drug Use Disorders Identification Test) 
The DUDIT is an 11-item measure designed to assess presence of substance use disorders [102]. 
Responses to items are made on a 5-point scale with exact responses varying across questions. 
When present, use can be described in monthly or less than monthly versus four times a week or 
daily. A list of substances is provided at the end of the measure. The DUDIT is reliable, with a 
Cronbach’s alpha of 0.80. When compared with an interview based on ICD 10, the DUDIT had a 
sensitivity to detecting substance use disorders of 90% and a specificity of 80% [102]. The 
English translation was developed from a Swedish-language original. Estimated time to complete 
is 2 to 4 minutes. 
 
7.5.12 SRNU (Self-reported Nicotine Use) 
The SRNU is a sponsor-developed measure that will assess participant’s use of nicotine, 
including approximate frequency of use in the last month and attitudes towards quitting. The 
measure will take less than 3 minutes to complete. 
 
7.5.13 EAT-26 (Eating Attitudes Test) 
The EAT-26 is a 26-item self-report measure that assesses attitudes about eating and food and is 
used to assess presence of eating disorders. Responses are made on a six-point scale (1=Always 
to 6=Never), and gathers information on gender, age, height, and weight. The EAT-26 produces a 
total score and can be used to generate a “referral score.” The 27th item addresses the occurrence 
and frequency of specific eating behaviors, such as binge eating. Estimated time to complete is 4 
to 8 minutes. Items on the EAT-26 have high reliability coefficients (Cronbach alpha of 0.83 to 
0.90) and has concurrent validity [103].  
 

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7.5.14 HPQSF (Health and Work Performance Absenteeism and Presenteeism Short 
Form) 
The HPQSF is a short form of a larger measure of health and work performance that has selected 
items referring to absenteeism and work performance [104]. The larger measure was created by 
the WHO as part of the Global Burden of Disease initiative. It consists of eight questions selected 
from the larger Health and Work Performance Questionnaire, with one question containing five 
additional items. Items include questions concerning hours worked during an average week, 
number of whole and partial days missed during a 4-week period, and items that rate average 
coworker and self-work performance on a ten-point Likert scale (1=Worst performance to 
10=Top performance). Hours spent in work over a 4-week period and over the last 7 days can be 
used to estimate absenteeism, and the HPQSF can also score presenteeism, a measure of actual 
performance in relation to possible performance. Self-reports on measure appear to match 
employer records of presence or absence [105], and the HPQSF appears to be reliable between 
one time point and another (reliability of 0.52) and is sensitive to change [104]. 
 
7.5.15 UFEC (Utilization of Facility-based and Emergent Care) 
The UFEC is a sponsor-developed measure assessing participant health events, including 
hospitalization and use of healthcare facilities, including in-patient hospitalization, rehabilitation 
facilities and other health care facilities for a set period prior to study entry. 
 
8.0 Study Procedures 
All assessments must be performed by qualified study staff delegated these duties on the Site 
Responsibilities Log. The Clinical Research Associate (CRA) should be notified of any delays or 
deviations to study procedures and Medical Monitor consulted if necessary. If there are delays of 
more than 7 days between visits or contact, the site should assess the need for additional 
telephone contact with the participant to ensure safety. 
 

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Table 5: Time and Events-Study Procedures 
 
Screening Period 
(up to 28 days) 
Preparatory Period w/ Enrollment Confirmation 
(1 to 11 weeks) 
Screening 
Enrollment 
Preparatory 
Baseline 
CAPS-5 T1 
Baseline & Enrollment 
Confirmation 
Visit 
Phone 
Screening 
Screening 
IR Screening 
V0 
V1 
V2 
V3 
V4 
Visit Description 
Phone 
Calls 
In-person 
Visits & Labs 
Telemedicine 
Enrollment 
Prep. 1 
Prep. 2 
Telemedicine 
Prep. 3 & Enrollment 
Confirmation 
Visit Timing 
Prior to Initial 
Screening 
Over 1 to 4 
weeks 
1 to 9 days 
after initial 
eligibility met 
2 to 14 days post IR 
Screening 
0 to 12 days 
after V0 
2 to 21 days 
after V1 
Post V2 & 
Taper 
3 to 6 days after V3; 1 to 4 
days before V5 
Initial Phone Screen 
 
 
 
 
 
 
 
 
Informed Consent 
Send Copy 
 
 
 
 
 
 
 
Follow-up Phone Screen 
 
 
 
 
 
 
 
 
Assess Eligibility 
 
 
 
 
 
 
 
 
Medical/Psychiatric History 
 A 
 
 
 
 
 
 
 
Past/Current Medication & Adherence 
 
 
 
 
 
 
 
 
Weight, Resting Vitals 
 
 
 
 
 
 
 
 
Physical Exam  
 
 
 
 
 
 
 
 
ECG & Rhythm Strip 
 
 
 
 
 
 
 
 
Clinical Lab Tests 
 
 
 
 
 
 
 
 
Drug Screen 
 
 
 
 
 
 
 
 
Pregnancy Screen  
 
 
 
 
 
 
 
 
Enter Participant in eCRF B 
 
 
 
 
 
 
 
 
Record 
 
 
 
 
 
 
 
 
Medication Taper 
 
 
 
 
 
 
 
 
Study Enrollment  
 
 
 
 
 
 
 
 Confirmed 
All AEs C 
 
 
 
 
 
 
 
 
90-minute Preparatory Session 
 
 
 
 
 
 
 
 
Phone Call Follow-up D 
 
 
 
 
 
 
 
 
A  At Screening, collect data on previous hospitalizations and healthcare utilization. Request participants to obtain medical/psychiatric records to bring to the in-person screening. 
B  Participants will be entered into the eCRF after the IR visit is scheduled 
C  All Adverse Events (AEs) includes collecting Serious Adverse Events, AEs of Special Interest, AEs of Psychiatric Status, AEs requiring medical advice or attention, AEs that 
indicate withdrawal of a participant, and all other AEs 
D  If needed, call participant to confirm medication tapering and stabilization is complete prior to Visit 3 
  

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Treatment Period 
~12 weeks (±3 weeks) 
Follow-up Period & 
Study Termination 
(~4 weeks) 
 
Treatment 1 
Treatment 2 
Treatment 3 
Primary 
Outcome 
Study 
Termi-
nation 
Visit 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
Visit Description 
Exp. 1 
Int. 1.1 
Int. 
1.2 G 
CAPS-5 
T2: 
Tele- 
medicin
e 
Int.  
1.3 G 
Exp. 2 
Int. 2.1 
Int. 
2.2 G 
CAPS-5 
T3: 
Tele- 
medicin
e 
Int.  
2.3 G 
Exp. 3 
Int. 3.1 
Int.  
3.2 G 
Int.  
3.3 G 
CAPS-5 T4 
Outcome: 
Tele-
medicine F 
Study 
Termi-
nation 
Visit Timing 
4 to 7 
days 
after 
V3; 1 
to 4 
days 
after 
V4 
Morn-
ing 
after 
V5 
3 to 
14 
days 
after 
V5  
18 to 30 
days 
after V5  
20 to 
34 days 
after 
V5; 1 
to7 
days 
before 
V10 
21 to 
25 
days 
after 
V5 
Morn-
ing 
after 
V10 
3 to 
14 
days 
after 
V10 
18 to 30 
days 
after 
V10 
20 to 
34 days 
after 
V10; 1 
to 7 
days 
before 
V15 
21 to 
35 
days 
after 
V10 
Morn-
ing 
after 
V15 
3 to 14 
days 
after 
V15 
21 to 
35 
days 
after 
V15  
105 to 147 
days after 
V3; 42 to 
70 days 
after V15 
105 to 
147 
days 
after 
V3; 1 to 
9 days 
after 
V19 
Past/Current 
Medication & 
Adherence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Screen  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All AEs A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Container 
Assignment B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer IMP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8-hour Exp. 
Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BP, Pulse, 
Temperature C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 D 
Overnight Stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
90-minute 
Integrative 
Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Call 
Follow-up E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A All Adverse Events (AEs) includes collecting Serious Adverse Events, AEs of Special Interest, AEs of Psychiatric Status, AEs requiring medical advice or attention, AEs that indicate 
withdrawal of a participant, and all other AEs 
B Randomize 24 to 48 hours prior to first Experimental Session; obtain container assignment 24 to 48 hours prior to each Experimental Session 

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C During Experimental Sessions, vitals are measured before Investigational Product administration, immediately before the supplemental dose is administered (or would be, if 
supplemental dose not given), and approximately 8 hours after initial dose, and as needed 
D At Study Termination, only blood pressure needs to be measured 
E 14 days of phone call follow-up: Days 2, 4, 6, 7, 8, 10, 12, 14 after each Experimental Session 
F All visits must be scheduled to ensure that the Primary Outcome CAPS-5 T4 assessment is within the overall window provided: 105 to 147 days post Visit 3 
G All Integrative Sessions must be at least 2 days apart. An Integrative Session and CAPS-5 assessment may take place on the same day (in the appropriate order, per protocol). 
 

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Table 6: Time and Events-Study Measures 
 
 
 
Screening 
Baseline & 
Enrollment 
Confirmation 
Treatment 1 
Treatment 2 
Treatment 3 
Follow-up & Study 
Termination 
Visit # 
Site A 
IR 
Screening 
IR 
V3 
V4 
V5 
V6&7 
IR 
V8 
V9 
V10 
V11&12 
IR 
V13 
V14 
V15 
V16&17 
V18 
IR 
V19 
V20 
Visit Description 
~Time to 
Complete 
Measure 
(minutes) 
Site Visit 
Tele-
medicine 
Tele-
medicine 
Site 
Visit 
Exp. 
Session 
1 
Int. 
Sessions 
1.1 & 
1.2 
CAPS-5 
T2: Tele-
medicine 
Int. 
Session 
1.3 
Exp. 
Session 2 
Int. 
Sessions 
2.1 & 
2.2 
CAPS-5 
T3: Tele- 
medicine 
Int. 
Session 
2.3 
Exp. 
Session 3 
Int. 
Sessions 
3.1 & 3.2 
Int. 
Session 
3.3 
CAPS-5 
T4: 
Outcome: 
Tele-
medicine 
Study 
Termi-
nation 
CAPS-5 
90 (Baseline) 
60 (all others)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SDS 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSP-I 
 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS B 
10 
 
 
 
 
C 
C 
 
 
C 
C 
 
 
C 
C 
 
 
 
MINI 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-SPQ 
20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-PD 
60 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LEC-5 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PCL-5 
8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DDIS D 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACE 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI-II 
10 (Baseline) 
5 (all others) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPGS 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IASC 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IPF 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCS 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TAS-20 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUDIT 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DUDIT 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SRNU 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EAT-26 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HPQSF 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UFEC 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
~Total Time of Completing 
Measures (minutes) 
49 
90 
107 
85 
 
10 
10 
77 
15 
10 
10 
77 
15 
10 
10 
15 
77 
87 
 
A Ensure that LEC-5 and SCID-5-SPQ results are sent to the Independent Rater who will be conducting the SCID-5-PD 
B First C-SSRS is a Lifetime assessment, other assessments are Since Last Visit 
C Conducted pre- and post-Investigational Product administration, and at phone calls on Days 2, 4, 6, 7, 8, 10, 12, and 14 after Experimental Sessions 
D The relevant questions (117 to 130) from the DDIS will be asked by the Independent Rater during the SCID-5-PD assessment. The entire measure will never be administered. 

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8.1 Screening Period 
8.1.1 Screening 
Prospective participants will be pre-screened by telephone according to an Institutional Review 
Board (IRB)-approved script to ascertain if they meet basic eligibility criteria. All individuals 
who are pre-screened should be assigned a Screening Number and recorded on the Screening 
Log. Data from potential participants who do not pass telephone screening will not be entered in 
the eCRF but reason of ineligibility will be documented on the Screening Log. At any time during 
Screening, if a potential participant is deemed ineligible, they will be classified as a Screen 
Failure, notified that they are not eligible for the study, and not be scheduled for any additional 
Screening assessments. 
 
If deemed potentially eligible, the potential participant will receive a copy of the ICF for review 
and invited to the site for in-person screening. Relevant medical and psychiatric records are 
required for the site physician to obtain a well-characterized medical history and assess eligibility. 
The physician may need to contact the prescribing physician to discuss the tapering of 
medications (see Section 12.0 Concomitant Medications). 
 
Site staff (preferably the therapy team who would be treating this potential participant) will 
explain and obtain written informed consent using the IRB-approved ICF. Written consent must 
be obtained prior to performing any tests or evaluations for the study. Discussion about the ICF 
may take place over a telemedicine visit or at the first in-person visit. If a participant fails 
Screening and is rescreened at a later date, a new copy of the ICF should be signed. 
 
Screening will take place over multiple visits and will be completed in-person, via telemedicine, 
or over the telephone. All procedures must be completed but there can be some flexibility in 
timing and order of individual assessments within the Initial Eligibility and Medical Assessments 
categories below: 
 
• 
Initial Eligibility, including measures, in-person discussions, and review of medical 
records 
• 
Medical Assessments, including labs, electrocardiogram (ECG), and physical exam 
• 
The site staff will schedule the IR assessment and send IR the results of initial measures 
 
The sponsor recommends the following order of assessments: 
 
Initial Eligibility 
Qualified site staff will: 
 
• 
Review medical and psychiatric history with the participant via interview and review of 
provided records. If no records were provided or those provided are not sufficient, 
request additional records. Collect data on previous hospitalizations and healthcare 
utilization. 
• 
Support the participant during completion of the LEC-5 with PCL-5 to confirm PTSD 
diagnosis and severity. Support is needed to ensure proper identification of the index 
trauma on the PCL-5. Symptom severity is assessed in relation to the index trauma. 
• 
Administer the Lifetime C-SSRS to assess history of suicidal behavior and ideation. 
• 
Review past and current medications and adherence to prescriptions. 
• 
Assess childbearing potential and discuss requirement for commitment to adequate birth 
control for the duration of the study. Perform urine pregnancy test for participants who 
are of childbearing potential. 

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• 
Perform a urine drug test. 
• 
Direct participant to complete self-reported Screening measures: 
o SCID-5-SPQ 
o AUDIT  
o DUDIT  
• 
Review results of all measures and discussions against eligibility criteria to assess initial 
eligibility. If deemed initially eligible, potential participant will be provided with 
instructions (and appointments, if applicable) for a physical exam, laboratory 
assessments, an electrocardiogram (ECG), and 1-minute rhythm strip. Some or all of 
these assessments may be at outside facilities. 
 
Medical Assessments 
The physical exam must be performed by a qualified physician and lab assessments must be 
completed at a designated lab. Medical assessments will include: 
 
• 
Blood pressure, pulse, and body temperature measurement. 
• 
Height and weight, which will be used to calculate Body Mass Index (BMI). 
• 
Examination of head, eyes, ears, nose, throat, skin, heart, lungs, abdomen, and 
extremities. 
• 
Brief neurological exam (cranial nerves 2 to 12, sensory, motor, reflexes, and cerebellar 
function). 
• 
ECG and 1-minute rhythm strip. 
• 
Clinical laboratory assessments, per Section 13.0 Clinical Laboratory Assessments. The 
clinical laboratory values will not be captured in the eCRF but will be used to establish 
eligibility and will be kept with the participant’s source record. Clinically significant 
abnormal values will be captured as medical history. 
• 
If there is evidence of liver disease by history, physical examination or laboratory testing, 
HCV serology will be performed. 
• 
If there is evidence of significant hepatic disease other than HCV, the potential 
participant will not be eligible for enrollment and will be advised to see their personal 
physician for further evaluation. If HCV serology is positive and the potential participant 
has not already been evaluated for possible treatment of HCV, they will be referred to a 
physician with expertise in evaluating and treating liver disease. After this evaluation and 
after completion of any recommended treatment, if the HCV is judged by this physician 
to be relatively stable and of mild severity, the participant may be enrolled, if there are no 
other contraindications. 
• 
If the potential participant has a condition such as controlled hypertension or Diabetes 
Mellitus (Type 2) that warrants additional testing to ensure they do not have evidence of 
significant vascular or other cardiac disease, they have no other evidence of 
cardiovascular or cerebrovascular disease by history, physical exam or ECG, and if the 
investigator judges their overall health and other cardiovascular risk factors to be 
acceptable (family history, smoking, lipid levels, body weight, level of physical activity), 
they will be referred for nuclear exercise testing by a cardiologist and for carotid 
ultrasound. If these tests fail to reveal evidence of significant vascular disease or other 
cardiac disease, the person may be enrolled if there are no other contraindications. 
Participants taking one or more antihypertensives may be enrolled in the study. The 
investigators will record and review medications used to control hypertension prior to 
enrollment. 
 

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Additional visits (in person, by telephone, or via telemedicine) may be scheduled at the discretion 
of the study staff to collect more information for determining eligibility or to discuss study 
expectations with the potential participant.  
 
Once all results are obtained, the site team will review all medical assessments, notes from 
interviews and discussions, medical records, and measures against eligibility criteria. If, upon 
examination, there are questions raised about possible medical problems, the site physician will 
request additional tests, assessments, or measures as indicated. The site physician may also 
contact outside providers with participant permission as needed. If deemed initially eligible, the 
site staff will schedule the IR screening and send results of LEC-5 and SCID-5-SPQ to the IR. 
Although the IR visit is by telemedicine, the participant will be provided a location to complete 
the telemedicine visits at the study site if needed. For the first IR assessment, the site can provide 
technical support before the assessment and therapeutic support after, if needed. The site staff will 
instruct the participant on how to access the telemedicine visits going forward. For all IR visits 
discuss with the participants that they should have adequate internet access and be in a private 
and quiet space where they are comfortable talking about personal matters. 
 
8.1.2 Independent Rater Screening 
If participants meet initial eligibility during Screening, a blinded IR will continue the eligibility 
assessment via telemedicine after reviewing the results of the LEC-5 and SCID-5-SPQ. The 
blinded IR interview may be recorded to assess reliability of ratings. If possible, the potential 
participant should be present at the study site during this assessment, in case the therapy team is 
needed for support. If a participant reports suicidal ideation during this assessment, the IR will 
contact the therapy team after the call and present any concerns. The therapy team will follow-up 
with the participant to ensure safety, provide support, recommend treatment, or schedule a visit to 
the study site.  
 
The IR will perform the following assessments: 
 
• 
Using the results of the SCID-5-SPQ to guide the interview, the IR will perform the 
SCID-5-PD to assess personality disorders. Only appropriate modules will be completed.  
• 
The IR will also ask relevant questions from the DDIS to identify dissociative disorders 
and administer the Since Last Visit C-SSRS to determine suicidal risk. 
• 
The IR will complete MINI interview to assess psychiatric disorders.  
 
The results from the MINI, SCID-5-PD, DDIS, and C-SSRS will be provided to the therapy team 
at the site to review along with all other Screening information to determine eligibility. Items 
assessed by the IR at this visit will be confirmed in the Preparatory Period by clinical observation, 
but the measures will not be repeated. If site staff deem the participant eligible, schedule 
Enrollment (Visit 0). 
 
If the results of the any interview indicate an exclusionary psychological disorder diagnosis is 
present, the Senior IR reviewer will review the recording of the MINI and/or SCID-5-PD 
assessment. The Senior IR will invite the study team (including therapists, site physician, and 
Clinical Investigator) to provide any additional information that may inform the Senior IR 
reviewer’s opinion. The Senior IR reviewer will make the final judgment on whether or not the 
participant has an exclusionary diagnosis. Participants with exclusionary diagnoses will not be 
enrolled. However, if any diagnosis is not present or uncertain according to any measure or 
interview, but the investigator believes the participant presents with a particular disorder, they 
may diagnose and deem the participant ineligible if appropriate. 
 

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After the initial screening visit the IRs will be blinded to visit number, treatment assignment, 
number of treatments received, and any study data for the participant. IR visits will be assigned 
based on availability.  
 
8.1.3 Enrollment 
In advance of Visit 0, the site team will review all notes from Screening visits, medical 
assessments, IR assessments, notes, discussions, medical records, and measures against eligibility 
criteria. If the participant is eligible, medication tapering and concomitant medications dose 
adjustments will be discussed, if applicable. The site physician will consult the prescribing 
physician to initiate medication tapering for participants. For all details on concomitant 
medications, tapering, allowed, and prohibited medications refer to Section 12.0 Concomitant 
Medications.  
 
At study onset at each site, if a potential participant is eligible, the study team will contact the 
Medical Monitor and send a summary of the medical history for approval to enroll the potential 
participant. After the Medical Monitor establishes confidence in the enrollment procedures at 
each site, the Medical Monitor will inform the site that for future participants they need only 
contact the Medical Monitor if they have questions about further participants’ eligibility. If a 
participant is approved by the sponsor, the participant will be notified of enrollment at Visit 0 in-
person, via telemedicine, or by telephone. Medical history and medication information will be 
reviewed for completeness. A medication tapering plan will be discussed with the participant, if 
applicable. If agreeable, the participant will be enrolled in the study. Once enrolled, AE collection 
requirements begin (refer to Section 11.0 Safety). Visit 0 should take place 2 to 14 days after 
Independent Rater Screening is completed. Visit 0 and Visit 1 may take place on the same day. 
 
8.2 Preparatory Period with Enrollment Confirmation 
Participants will undergo three Preparatory Sessions (Visits 1, 2, and 4) lasting approximately 90 
minutes with the therapy team prior to the first Experimental Session. The Preparatory Period will 
be initiated within 12 days of Visit 0 and last 1 to 11 weeks, depending on duration of medication 
tapering. There must be at least 48 hours between Preparatory Sessions. The minimum time to 
complete the Preparatory Period is 5 days. The Preparatory Period will also include the Baseline 
CAPS-5 assessment (Visit 3), which will be assessed by a blinded IR. Adherence criteria for 
Preparatory Sessions should be followed per the Treatment Manual. In these visits the therapy 
team will work with the participant to prepare for MDMA-assisted psychotherapy, begin building 
therapeutic alliance, and promote a safe set and setting for confronting trauma-related memories, 
emotions, and thoughts.  
 
8.2.1 Preparatory Sessions 1 and 2 
Preparatory Sessions during the Preparatory Period will focus on psychoeducation about PTSD, 
building safety for the therapeutic relationship, developing the therapeutic alliance, obtaining the 
background for the trauma, and preparing the participant for the first Experimental Session. 
Telephone calls may be scheduled between visits if indicated for tapering, safety, or any further 
questions about medical history.  
 
The Preparatory Sessions will be scheduled as follows: 
 
• 
Preparatory Session 1 (Visit 1) will occur 0 to 12 days after Visit 0. The visit timing 
should take in to account appropriate times for monitoring medication tapering.  

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• 
Preparatory Session 2 (Visit 2) will occur 2 to 21 days after Visit 1. The visit timing 
should take into account appropriate times for monitoring medication tapering. 
• 
If tapering is ongoing at Preparatory Session 2 (Visit 2), the site team will schedule a 
telephone phone call within 7 days of completion of tapering and stabilization to confirm 
that the participant is eligible for the Baseline CAPS-5 assessment. If tapering is 
complete or not needed, the site team will confirm eligibility and schedule Baseline 
CAPS-5 T1 (Visit 3) and Preparatory Session 3 (Visit 4) as soon as possible.  
 
At each 90-minute psychoeducation and psychotherapy Preparatory Session, the therapy team 
will: 
 
• 
Record the therapy session. 
• 
Inquire about any possible changes in health to ensure the participant continues to meet 
all eligibility requirements. Record AEs as described in Section 11.0 Safety. 
• 
Inquire about concomitant medication use and adherence. 
• 
Confirm that medication tapering is ongoing or complete, as appropriate. 
• 
Discuss goals and expectations for the Experimental Session, following standard 
procedures and techniques described in the Treatment Manual [106]. 
 
If a participant would like a companion present during or after the Experimental Session, a 
meeting between the therapy team and that individual will be scheduled prior to the first 
Experimental Session. There must be mutual agreement between the participant and therapy team 
concerning the presence of the companion. 
 
During one of the Preparatory Sessions, if possible, the therapy team will introduce the 
participant to the attendant who will remain with the participant during each overnight stay after 
each MDMA-assisted psychotherapy session. The attendant will be an individual with previous 
training in managing psychological distress. The site will make all attempts to have the same 
attendant for each Experimental Session for a given participant, but it is not guaranteed. 
 
At any time during the Preparatory Period, if a potential participant is deemed to be ineligible, the 
site team will classify them as a Pre-randomization Early Termination, notify the potential 
participant that they are unfortunately not eligible for the study, and not schedule additional 
assessments. The site team will not randomize participants classified as Pre-randomization Early 
Terminations. 
 
8.2.2 Baseline: CAPS-5 by Independent Rater  
At Visit 3, an IR will measure the Baseline CAPS-5 (referred to as Baseline CAPS-5 T1) via 
telemedicine as soon as possible after medication tapering, stabilization, and two Preparatory 
Sessions are complete. This visit may be recorded to video to establish inter-rater reliability. The 
scores will be sent as soon as possible to the site staff. A CAPS-5 Total Severity Score of at least 
35 is required to meet Enrollment Confirmation criteria. The IR will also administer the DSP-I 
and SDS. 
 
Due to possibilities of negative side effects of withdrawal from psychiatric medications, the 
Baseline CAPS-5 should be scheduled as close to the end of tapering as clinically appropriate so 
that participants who do not meet eligibility criteria can resume their previously prescribed 
medications as quickly as required for symptom management and participants who do meet 
criteria can be enrolled and treated as quickly as possible. 
 

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8.2.3 Baseline: Preparatory Session 3 & Enrollment Confirmation 
Prior to Visit 4, the site team will review the results of the IR visit to ensure that the CAPS-5 
Total Severity Score is at least 35. Visit 4 should be scheduled 3 to 6 days after the Baseline 
CAPS-5 assessment and 1 to 4 days before Experimental Session 1 (Visit 5).  
 
At Visit 4, the site team will confirm eligibility by reassessing specified eligibility criteria and 
ensuring that the participant continues to agree to all lifestyle modifications. If the participant 
continues to be eligible for the study, enrollment will be confirmed (after approval from the 
Medical Monitor for the initial participants until confidence is established). If any requirements 
are not met before or during Visit 4, the participant will be considered a Pre-randomization Early 
Termination. 
 
For eligible participants at Visit 4, qualified site staff will: 
 
• 
Perform urine pregnancy test for participants who are of childbearing potential. 
• 
Perform urine drug test. 
• 
Administer Since Last Visit C-SSRS to determine suicidal risk. 
• 
Actively support participant in the completion of Baseline self-reported measures. 
Completion of measures does not need to be recorded. 
o ACE 
o BDI-II 
o CPGS 
o EQ-5D-5L 
o IASC 
o IPF 
o SCS 
o TAS-20 
o SRNU 
o EAT-26  
o HPQSF 
o UFEC  
• 
Complete the third 90-minute Preparatory Session (as described in Section 8.2.1 
Preparatory Sessions 1 and 2) with the purpose of confirming all enrollment is met and 
completing final preparation for the first Experimental Session. 
• 
Remind the participants of lifestyle modifications, including fasting and refraining from 
using psychoactive or non-approved medications, pertinent prior to the Experimental 
Session per Section 4.3 Lifestyle Modifications.  
• 
Schedule Visit 5. 
 
8.3 Treatment Period 
During the Treatment Period, which occurs over a duration of 9 to 15 weeks (Visits 5 to 18), 
participants will complete three treatments. Each treatment consists of an Experimental Session, 
followed the morning after by an Integrative Session, phone follow-ups over the next week, a 
second Integrative Session within 2 weeks, and a third Integrative Session within 3 to 5 weeks. 
The Experimental Sessions will be scheduled 3 to 5 weeks apart. The CAPS-5 will be assessed at 
two time points during the Treatment Period: CAPS-5 T2 after Integrative Session 1.2 (Visit 7) 
and CAPS-5 T3 after Integrative Session 2.2 (Visit 12). The Primary Outcome CAPS-5 (T4) will 
be assessed after the last Experimental Session during the Follow-up Period. 
 

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8.3.1 Experimental Sessions 
There will be three blinded Experimental Sessions (Visits 5, 10, 15). Procedures for MDMA-
assisted psychotherapy will remain the same across all sessions and all procedures regardless of 
dose received. Experimental Sessions must be at least 8 hours long, measured from 30 minutes 
prior to IMP administration.  
 
Experimental Sessions will be scheduled as follows: 
 
• 
Experimental Session 1 (Visit 5) will occur within 4 to 7 days after the Baseline CAPS-5 
(Visit 3) assessment; 1 to 4 days after Preparatory Session 3 and Enrollment 
Confirmation (Visit 4). Experimental Session 1 (Visit 5) must occur within 7 days of the 
Baseline CAPS-T1 (Visit 3) and after Preparatory Session 3 and Enrollment 
Confirmation (Visit 4). If the Baseline CAPS-5 assessment is completed outside of the 
allowed window, the investigator should consult the CRA and Medical Monitor to 
determine if the assessment should be repeated. The first Experimental Session will 
include 80 mg of IMP followed by a supplemental half-dose 1.5 to 2 hours after the 
initial dose unless contraindicated. 
• 
Experimental Session 2 (Visit 10) will occur 21 to 35 days after Experimental Session 1 
(Visit 5) and at least 1 day after Integrative Session 1.3. A dose of 80 or 120 mg MDMA 
or placebo will be administered. A supplemental half-dose will be administered 1.5 to 2 
hours after the initial dose unless contraindicated. 
• 
Experimental Session 3 (Visit 15) will occur 21 to 35 days after the second Experimental 
Session (Visit 10) and after Integrative Session 2.3. A dose of 80 or 120 mg MDMA or 
placebo will be administered. A supplemental half-dose will be administered 1.5 to 2 
hours after the initial dose unless contraindicated. 
 
Table 7: Schedule of Procedures for Experimental Sessions 
Approximate Time 
Procedure or Action 
9:30  
Urine drug screen and pregnancy test, concomitant medication 
information collected, participant acclimated to environment, C-SSRS 
9:55 
Baseline BP (Blood Pressure), body temperature, pulse 
10:00  
IMP Administration, Begin video recording  
11:30  
BP, body temperature pulse 
Supplemental Dose Administration, unless contraindicated  
17:30 
C-SSRS, BP, body temperature, pulse 
 
Pre-IMP administration 
 
• 
24 to 48 hours prior to the first Experimental Session, the participant will be randomized 
using a web-based randomization program.  
• 
24 to 48 hours prior to each Experimental Session, the site team will obtain the container 
assignment. 
• 
On the day of the Experimental Session, the participant will arrive approximately 30 to 
60 minutes prior to IMP administration. 
• 
The site team will ensure the participant has not used caffeine or nicotine 2 hours prior 
and has fasted for 10 hours prior to IMP administration and complied with all other 
requirements per Section 4.3 Lifestyle Modifications. 
• 
The site team will inquire about any possible changes in health to ensure the participant 
continues to meet all eligibility requirements and record AEs as described in Section 11.0 
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• 
The site team will instruct the participant that they will not be able to use caffeine or 
nicotine at least 6 hours after the IMP administration. 
• 
The site team will complete urine drug screen, pregnancy test, and concomitant 
medication review. 
o A positive drug screen will be reviewed by the site physician and may be cause for 
delaying IMP administration to a later time, rescheduling the session to a later date, 
or withdrawing the participant from the study, based on Medical Monitor review.  
o A positive pregnancy screen is cause for withdrawal from the protocol.  
• 
The therapy team will administer Since Last Visit C-SSRS. 
• 
The therapy team will review procedures for the Experimental Session with the 
participant and discuss the participant’s goals, intentions, and concerns and some of the 
commonly experienced effects of MDMA. The choice of whether to keep the dose the 
same or change it from the first Experimental Session will be made by the therapy team 
in consultation with the site physician based on observed response, tolerability to the 
previously administered dose, and discussion with the participant.  
• 
If the participant continues to be eligible, the session will proceed. 
• 
Baseline blood pressure, body temperature, and pulse will be measured just prior to 
administration of the initial dose. 
 
During the Experimental Session 
 
• 
After video recording has begun, at approximately 10:00 in the morning, a qualified staff 
member will administer the initial dose of IMP with an electrolyte-containing fluid. The 
participant will sit or recline on comfortable furnishings. Eyeshades and a program of 
music will be provided for the participant if they wish to use them. Whenever they wish, 
participants may speak to the therapy team, who will provide guidance and support, as 
needed.  
• 
After the first hour, if the participant has not spoken spontaneously, the therapy team will 
check in with them about the nature of the experience. For the rest of the experience, as 
appropriate, the therapy team will support and encourage the participant in emotional 
processing and resolution of whatever psychological material is emerging, as described in 
the Treatment Manual. 
• 
Electrolyte-containing fluids will be provided throughout the session but not to exceed 
three liters overall. 
• 
Blood pressure, body temperature, and pulse will be measured approximately 1.5 to 2 
hours after the initial dose, before the supplemental dose is administered. 
• 
If the participant prefers not to have the supplemental dose, the therapy team will 
document the reason. 
• 
The site physician will be contacted with a brief description of how the session is 
progressing and the recent vital signs. The site physician will approve or deny the 
administration of the supplemental dose. If an AE requiring medical attention has 
occurred between the initial and supplemental dose, the site physician will determine 
whether the supplemental dose is contraindicated. If medical attention is needed, the site 
physician will provide further instruction or consult the Medical Monitor. 
• 
A supplemental half-dose will be administered with a glass of electrolyte-containing fluid 
approximately 1.5 to 2 hours after the initial dose, unless contraindicated. 
• 
Food will be provided during the latter part of the session.  
• 
If there is an approved companion, that person may arrive as agreed upon but will wait in 
the waiting room until a member of the therapy team brings them to the session room. 
Alternatively, the companion may arrive after the session has ended. 
 

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End of Experimental Session 
 
• 
The therapy team will administer Since Last Visit C-SSRS. 
• 
The therapy team will record AEs and concomitant medications. 
• 
The session may be ended if all medical and psychiatric parameters are acceptable, 
elevations in vital signs have resolved to pre-IMP levels, the participant is alert, 
ambulatory, and emotionally stable, and the night attendant has arrived. 
• 
The therapy team or site physician shall remain available to participants via 24-hour 
cellular phone for integration, as needed. 
 
Overnight Stay (See Appendix A for sub-study with exceptions) 
 
• 
Participants will remain overnight in an appropriately furnished room at or near the study 
site until after the Integrative Session the morning after each Experimental Session. The 
stay will be in an appropriately furnished room at the study site. With prior approval of 
the therapy team, a companion may accompany the participant during the overnight stay.  
• 
An attendant will check in periodically on the participant during the overnight stay, even 
if a companion is present. The attendant will monitor participant condition and will help 
participants relax during the overnight stay. The attendant will be an individual with 
some previous training in managing psychological distress and will be supportive but not 
intrusive. If there is an emergency or the participant needs additional support, the 
attendant can contact the therapy team.  
• 
The participant and a companion (if applicable) will receive information that will allow 
them to contact the therapy team during the overnight stay in the case of an emergency or 
to request for additional support.  
• 
Participants will be encouraged to use much of the time during their overnight stay for 
rest and as a period of reflection and integration in a quiet atmosphere. 
• 
The participant will be driven home after the integration session by either a driver 
arranged by the participant, by site personnel, or taxi. 
 
8.3.2 Telephone Contact After Experimental Sessions 
The goal of the telephone contact is to assess health changes, ensure participant safety, and offer 
support. The therapy team will follow-up with the participant by telephone on Days 2, 4, 6, 7, 8, 
10, 12, and 14 after each Experimental Session. Each call will last on average 5 to 20 minutes but 
could be longer to address participant concerns and to adequately assess wellbeing. Additional 
telephone contact can be initiated at the request of the therapy team or participant. If any planned 
phone contact would occur on the date of an Integrative Session, the phone contact does not need 
to be completed. 
 
At each telephone contact, the therapy team will: 
 
• 
Inquire about any possible changes in health, assess the participant’s mental health and 
the status of any previously recorded AEs, and record AEs as described in Section 11.0 
Safety. 
• 
Inquire about concomitant medication use and adherence. 
• 
Offer support in accordance with the Treatment Manual. 
• 
Administer the Since Last Visit C-SSRS. 
 

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8.3.3 Integrative Sessions 
After each Experimental Session, three Integrative Sessions will take place. Each session will 
consist of 90 minutes of psychotherapy. Integrative Sessions should not be less than 48 hours 
apart. 
 
Treatment 1 
 
• 
Integrative Session 1.1 (Visit 6): morning after Experimental Session 1 (Visit 5) 
• 
Integrative Session 1.2 (Visit 7): 3 to 14 days after Experimental Session 1 (Visit 5) 
• 
Integrative Session 1.3 (Visit 9): 20 to 34 days after Experimental Session 1 (Visit 5) and 
1 to 7 days in advance of Experimental Session 2 (Visit 10). This visit serves two 
purposes: to continue integration and to prepare for the next Experimental Session. The 
participant will complete the LEC-5 self-report measure. 
 
Treatment 2 
 
• 
Integrative Session 2.1 (Visit 11): morning after Experimental Session 2 (Visit 10) 
• 
Integrative Session 2.2 (Visit 12): 3 to 14 days after Experimental Session 2 (Visit 10)  
• 
Integrative Session 2.3 (Visit 14): 20 to 35 days after Experimental Session 2 (Visit 10) 
and 1 to 7 days in advance of Experimental Session 3 (Visit 15). This visit serves two 
purposes: to continue integration and to prepare for the next Experimental Session. The 
participant will complete the LEC-5 self-report measure. 
 
Treatment 3 
 
• 
Integrative Session 3.1 (Visit 16): morning after Experimental Session 3 (Visit 15)  
• 
Integrative Session 3.2 (Visit 17): 3 to 14 days after Experimental Session 3 (Visit 15) 
• 
Integrative Session 3.3 (Visit 18): 21 to 35 days after Experimental Session 3 (Visit 15). 
This visit will be the final Integrative Session prior to entering the follow-up period. The 
participant will complete the LEC-5 self-report measure.  
 
During Integrative Sessions, the therapy team will: 
 
• 
Record the session.  
• 
Inquire about any possible changes in health. Assess the participant’s mental health and 
the status of any previously recorded AEs. Record AEs as described in Section 11.0 
Safety. 
• 
Inquire about concomitant medication use and adherence. 
• 
Administer Since Last Visit C-SSRS to determine suicidal risk. 
• 
Discuss and review events that occurred with the participant during the Experimental 
Session, including thoughts, feelings, and memories. If necessary, the therapy team will 
help the participant to reduce any residual psychological distress they are experiencing. 
The therapy teams will also encourage the transfer of states of acceptance, feelings of 
intimacy, closeness, and reduced fear experienced in Experimental Sessions to 
emotionally threatening everyday situations. The therapy teams will be supportive, 
validate the experience, and facilitate understanding and emotional clearing. 
• 
Be accessible for additional support via phone or telemedicine if needed. 
• 
At each third Integrative Session, direct the participants to complete the LEC-5. 
 

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8.3.4 Independent Rater Assessments 
Participants will have two CAPS-5 assessments during the treatment period of the study (Visits 8 
and 13). A blinded IR from the IR Pool will conduct the assessments via telemedicine. These 
assessments may be recorded to establish inter-rater reliability. The results will not be sent to site 
staff but instead will be sent to a blinded IR Coordinator to enter the data which will be blinded to 
sponsor and site personnel. Participants will be instructed to withhold their opinion on treatment 
group assignment or the number of study visits they have completed from IRs. The IR will also 
administer the DSP-I and SDS at these time points. 
 
An Integrative Session and CAPS-5 assessment may take place on the same day (in the 
appropriate order, per protocol). The assessments will be scheduled as follows: 
 
• 
CAPS-5 T2 (Visit 8):18 to 30 days after Experimental Session 1 (Visit 5), between 
Integrative Session 1.2 (Visit 7) and Integrative Session 1.3 (Visit 9) 
• 
CAPS-5 T3 (Visit 13):18 to 30 days after Experimental Session 2 (Visit 10), between 
Integrative Session 2.2 (Visit 12) and Integrative Session 2.3 (Visit 14). 
 
8.4 Follow-up Period and Study Termination 
8.4.1 Follow-up Period 
After the last Integrative Session 3.3 (Visit 18), participants will enter follow-up for 
approximately 4 weeks (±2 weeks) with no protocol required visits until the final CAPS-5 
assessment (Visit 19) followed by Study Termination (Visit 20). Participants will have access to 
therapy teams for support if needed, and additional visits via phone, telemedicine, or in person 
can be scheduled if requested. Participants will continue to comply with protocol requirements for 
concomitant medications until after Study Termination. 
 
8.4.2 Final Independent Rater Assessment 
Participants will have a final CAPS-5 assessment at the completion of the follow-up period (Visit 
19). A blinded IR from the IR Pool will conduct the assessments via telemedicine. These 
assessments may be recorded to establish inter-rater reliability. The results will not be sent to or 
seen by site staff but instead will be sent to a blinded IR Coordinator to enter the data which will 
also be blinded to the sponsor. Participants will be instructed to withhold their opinion on 
treatment group assignment from IRs. Although there are allowable windows for all visits 
throughout the protocol, the Primary Outcome CAPS-5 T4 assessment is targeted to be completed 
18 weeks (±3 weeks) (105 to 147 days) after the Baseline CAPS-5 assessment (Visit 3) and 8 
weeks (±2 weeks) (42 to 70 days) after Experimental Session 3 (Visit 15). If there are significant 
delays in the timing of Experimental Session 2 (Visit 10) and/or Experimental Session 3 (Visit 
15), the visit should be scheduled 8 weeks (±2 weeks) (42 to 70 days) after Experimental Session 
3 (Visit 15). Participants who have withdrawn from treatment will also complete a final CAPS-5 
assessment immediately upon withdrawal. The IR will also administer the DSP-I and SDS. 
 
8.4.3 Study Termination 
Study Termination (Visit 20) will take place 1 to 9 days after the final CAPS-5 assessment (Visit 
19). Participants who have withdrawn from treatment but have continued for follow-up will also 
complete this assessment immediately upon withdrawal. 
 

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The site team will: 
 
• 
Inquire about any possible changes in health. Assess the participant’s mental health and 
the status of any previously recorded AEs. Record AEs as described in Section 11.0 
Safety. 
• 
Inquire about concomitant medication use and adherence. 
• 
Administer Since Last Visit C-SSRS. 
• 
Measure weight (used to calculate BMI). 
• 
Measure blood pressure. 
• 
Provide and discuss a study exit plan. 
• 
Ask them to enroll into the LTFU extension study with a visit at 12 months after the last 
Experimental Session. Review contact information and Informed Consent procedures for 
LTFU. 
• 
Review potential timeline until study unblinding and how they will be informed of their 
treatment group at that time. 
• 
Actively support participant in completion of Study Termination self-reported measures. 
Completion of the measures does not need to be recorded. 
o LEC-5  
o BDI-II 
o CPGS 
o EQ-5D-5L 
o IASC 
o IPF 
o SCS 
o TAS-20 
o AUDIT  
o DUDIT  
o SRNU 
o EAT-26 
o HPQSF 
 
After all Study Termination measures and assessments are completed, the participant is 
considered terminated from the study. The participant can resume normal everyday life. The 
study team will provide an Exit Plan, which may include a referral for additional medical or 
therapeutic care, as described in Section 8.4.3.2 Exit Plan. Eligible participants will be asked to 
participate in the LTFU extension study, described in Section 8.4.3.1 Extension Studies. 
 
8.4.3.1 Extension Studies 
Upon completion of the study, defined as completing at least one Experimental Session and one 
CAPS assessment beyond Baseline, participants will be asked to join the LTFU extension study. 
The ICF for this study will be provided to eligible participants at the Study Termination visit. 
This study will measure outcomes 12 months after the last Experimental Session. 
 
Upon unblinding after database lock, all participants who were assigned to placebo (regardless of 
final CAPS-5 scores), completed the study, meet criteria, and are in good standing with the 
clinical site, will be offered the opportunity to enroll in an open-label safety study using the same 
manualized MDMA-assisted psychotherapy as administered during the study. This open-label 
safety study will take place at least 18 months after the first participant is enrolled in MAPP1 and 
will last 19 to 38 weeks, similar to this protocol. Data from this study will be included in the 
sponsor’s overall safety database. 
 

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Any sub-studies other than what is outlined in Appendix A will be detailed in separate 
documents. 
 
8.4.3.2 Exit Plan 
At Study Termination, participants will be provided with an Exit Plan. This Exit Plan will 
summarize treatments completed, current medications, and contact information 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. Screen Failures will be provided a referral if requested. 
 
9.0 Investigational Product 
9.1 Description of Active Compounds 
The Active Pharmaceutical Ingredient (API) to be used in this protocol is MDMA (as 
hydrochloride salt). This ring-substituted phenethylamine has a complex pharmacology, but it 
acts most prominently as a monoamine releaser and re-uptake inhibitor. Its direct actions on 
serotonergic, adrenergic, and other receptors are considerably lower. Refer to the IB for a 
comprehensive review of the pharmacology, effects and proposed mechanisms of action of the 
IMP. Mannitol and a lubricant, such as magnesium stearate, will serve as inactive excipients. 
 
9.1.1 Doses 
This study will compare the effects of three blinded manualized Experimental Sessions of 
psychotherapy assisted by flexible doses of MDMA HCl or placebo. Initial doses per 
Experimental Session include 80 mg or 120 mg MDMA compounded with mannitol and 
magnesium stearate or indistinguishable weight placebos comprised entirely of mannitol and 
magnesium stearate, followed 1.5 to 2 hours later by a supplemental half-dose (40 mg or 60 mg 
MDMA HCl or placebo). Total amounts of MDMA HCl to be administered per Experimental 
Session range from 80 mg to 180 mg. All drug is encapsulated with HPMC capsules. 
 
Refer to Table 3: Dose Regimen of MDMA or Placebo.  
 
9.1.2 Dose Modifications 
In the first Experimental Session, the initial dose will be 80 mg MDMA HCl or placebo. In the 
second and third Experimental Sessions, the initial dose may be increased to 120 mg MDMA HCl 
or placebo unless contraindicated. The choice of whether to keep the dose the same or change it 
from the first Experimental Session will be made by the therapy team the in consultation with the 
site physician based on observed response, tolerability to the previously administered dose, and 
discussion with the participant. In each Experimental Session, 1.5 to 2 hours after the initial dose 
is given, the participant will be administered a supplemental half-dose unless contraindicated. If 
an AE requiring medical attention occurs between the initial and supplemental dose this will be 
evaluated as a potential contraindication by the site physician. If a participant prefers not to take 
the supplemental dose, the reason will be documented. Participants will not know if they have 
been assigned MDMA or placebo but can indicate if they want the dose to change or remain the 
same. 
 

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9.1.3 Stability 
IMP will be manufactured and packaged according to Good Manufacturing Practices (GMP). 6-
month accelerated stability studies will be completed for the IMP along with an ambient stability 
study that will remain ongoing throughout the duration of the study. All required Chemistry 
Manufacturing and Control (CMC) submissions will be made to the IND. 
 
9.2 Handling 
9.2.1 Encapsulation, Packaging, and Labeling 
The IMP for each Experimental Session will be packaged in one primary container, labeled with a 
unique container number, protocol number, blinded IMP name and lot number, sponsor name, 
Experimental Session number, and a statement that the IMP is restricted to clinical trial use only. 
All labels will comply with local, state, and federal regulations. The initial and supplemental dose 
will be packaged separately within the primary container. There will be one primary container per 
participant per Experimental Session.  
 
Figure 2: Example Label 
 
 
9.2.2 Accountability 
Forms will be provided to track IMP accountability and administration throughout the study. 
Blinded IMP accountability and administration logs will be reviewed during routine monitoring 
visits or through central monitoring. MDMA will be handled in accordance with all local, state, 
and federal regulations and forms pertaining to the use of controlled substances, and forms will be 
maintained by the appropriate controlled substance license holder or delegate.  
 
Each primary container label will contain a unique container number for the IMP assigned to a 
single Experimental Session. The container numbers will be used to track IMP administration in 

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the Source Record and the IMP administration log. The web-based randomization system will 
enable tracking of blinded primary containers for accountability purposes. 
 
9.2.3 Storage 
MDMA is a controlled substance and will be stored and handled in compliance with all relevant 
federal and state regulations. In accordance with these requirements, the appropriate license 
holder or designee will be responsible for storing, dispensing, and administering the MDMA. It 
will be stored securely in accordance with federal, state, and local regulations.  
 
9.2.4 Administration 
IMP will only be removed for a single Experimental Session at a time and will be administered 
orally at the study site. All doses administered will be recorded on the appropriate accountability 
and administration logs. Only the initial dose is required to be given at each Experimental 
Session. Supplemental doses should be administered unless contraindicated. Each dose (initial 
and supplemental) will be administered with a glass of electrolyte-containing fluid. 
 
A person at the site authorized to manage and administer controlled substances will dispense the 
appropriate container for each Experimental Session. If a supplemental dose is not administered, 
the unused IMP will be kept for accountability.  
 
Records pertaining to the use of scheduled, regulated compounds will be maintained in 
accordance with relevant federal and state regulations.  
 
9.2.5 Treatment Compliance 
Compliance to protocol required doses will be guaranteed by the person licensed to manage and 
administer controlled substances for Experimental Sessions at each site. All administered doses 
will be recorded for IMP accountability. The IMP will be stored securely per regulations. 
 
9.3 Randomization and Participant Numbering 
Every potential participant who is prescreened by telephone according to the IRB-approved script 
will be assigned a seven-character alphanumeric Screening Number and recorded on the 
Screening Log. This number will begin with ‘S5’ to identify that it is a Screening Number. The 
next two digits represent the site number (e.g., ‘11’), followed by a three-digit screening identifier 
starting with ‘501’. The screening identifier will be assigned to each prescreened participant at a 
site sequentially. For example, the first Screening Number at Site 11 will be S511501 and first 
Screening Number at Site 12 will be S512501. 
 
Each participant who passes Screening and is enrolled in the trial at Visit 0 will be assigned a 
seven-digit Participant Number. The first two digits will be ‘11’. The next two digits represent the 
site number (e.g., ‘11’), followed by a three-digit participant identifier starting with ‘001’. The 
Participant Number will be assigned to each enrolled participant at a site sequentially. For 
example, the first Participant Number at Site 12 will be 1112001. Eligible participants will be 
enrolled in the study and sequentially assigned an identification number. All participants will also 
be assigned a unique participant identifier within the database for use in analysis.  
 
Participants will be randomized in 1:1 allocation in a blinded fashion to the MDMA-assisted 
psychotherapy group and the placebo plus psychotherapy group, stratified by clinical site. 
Randomization will be managed via an Interactive Web Randomization System (IWRS) based on 

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a centralized randomization schedule developed by an independent third-party vendor to maintain 
blinding.  
 
9.4 Blinding and Bias Minimization 
Eligibility will be determined by review of screening by the PI, site team and as needed the 
sponsor Medical Monitor prior to randomization. Participants, site staff, and the sponsor will 
remain blinded to subject group assignment until after the database is locked.  
 
To further minimize bias in measuring efficacy, the sponsor will use an observer-blind, 
centralized, reliable IR pool to administer the Primary Outcome measure via live video 
interviews. The IR Pool will have no knowledge of AEs and will only evaluate participants at 
Baseline and at the assessments scheduled after each Experimental Session. The IR Pool is 
blinded to full study design, visit number, treatment assignment, number of treatments, and any 
data from the treating therapy team after Baseline. IRs will be assigned to participants based on 
availability. Participants will be instructed to withhold their opinion on treatment group 
assignment from IRs. The participants, sponsor, and site staff will not see the CAPS-5 results 
until the end of the study. Timing of CAPS-5 assessments are pre-specified in the study protocol 
within visit windows. Changes in study management and analysis, if any, will be made by 
sponsor personnel who are blinded to group assignment and CAPS-5 data.  
 
As a site-independent review method that evaluates and confirms diagnoses, symptom severity, 
and subject validity prior to randomization, the Senior IR will review video recordings of actual 
clinical interviews conducted by the IR Pool. The recordings of these interviews accompanied by 
digital notes will be electronically submitted for independent review and 'dual' scoring of key 
rating instruments. This site-independent Senior IR reviewer either affirms subject eligibility or 
identifies administrative and/or clinical issues that may preclude study eligibility (screen failure). 
The Senior IR reviewer will invite the study team (including therapists, site physician, and 
Clinical Investigator) to provide any additional information that may inform the Senior IR 
reviewer’s opinion. The Senior IR reviewer will make the final judgment on whether or not the 
participant has an exclusionary diagnosis. 
 
To minimize bias, protect the study's double-blind and to ensure data quality, the sponsor will use 
a second Electronic Data Capture (EDC) database that is dedicated to the collection of critical 
primary and key secondary outcome measures, including the Total Severity Score on the CAPS-5 
and item scores on the Sheehan Disability Scale (SDS), administered by the centralized blinded 
IR Pool through live video. This second database is termed the Independent Rater Database 
(IRDB) and it will be separate from the blinded, clinical EDC database in order to ensure that site 
and sponsor staff engaged in study conduct are masked from study outcomes. The IRDB will only 
be accessible by: (1) qualified, observer-blind individuals who are in the established IR Pool, (2) 
the Senior IR responsible for oversight and data quality of the IR Pool, and (3) the IR Coordinator 
responsible for data entry based on paper Source Records completed by the IR Pool. All CAPS-5 
and SDS scores and supporting documentation will be reviewed by the IR Coordinator prior to 
data entry. Frequent assessments of the CAPS-5 and timely entry into the EDC system will help 
ensure that data reviewed by the DMC is as accurate and free of bias as possible. 
 
Once data is entered into the IRDB, the Senior IR will oversee the data quality by centrally 
monitoring the critical data using a risk-based approach. The risk-based monitoring methodology 
will utilize the following strategies: 1) To perform remote, source data review of the IRDB to 
check logic and to confirm reliability between the IR's, 2) To perform remote, source data 
verification to check the IRDB for administrative, data entry, or transcription errors made by the 
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and/or to trigger implementation of pre-defined, risk-mitigation strategies when specific data 
thresholds are exceeded. 
 
To ensure that all participants regardless of group assignment are treated in a similar manner, the 
sites will be required to follow the protocol and Treatment Manual delineating minimum length 
of time per visit type and describing delivery of treatment. All Experimental Sessions are required 
to be at least 8 hours long. Adherence to the Treatment Manual will be randomly checked by 
review of video by blinded Adherence Raters. The sponsor will monitor data in real-time to 
ensure complete data collection for all participants, including those who discontinue treatment. 
Sites will be required to make and document a specific number of attempts to obtain follow-up 
data per protocol. All randomized participants who receive at least one dose of IMP and complete 
at least one follow-up assessment will be included in the final mITT primary efficacy analysis.  
 
The DMC will act in an advisory capacity to the sponsor to monitor participant safety, data 
quality, and review Phase 3 outcomes to ensure the trial is conducted safely, ethically, and meets 
endpoint objectives. The DMC will be the only group reviewing group-unblinded interim data. 
The DMC will not be able to recommend early Study Termination for efficacy at the interim 
analysis, which will be conducted after N=100 have been enrolled. A single representative within 
MAPS will be designated to receive written communication of recommendations following the 
interim DMC review of the trial. This communication will be limited to the results needed for the 
decision of sample size re-estimation. The sponsor representative within MAPS and DMC 
members will sign a written confidentiality agreement in order that the precise rules governing 
sample size re-estimation may not be disclosed to the outside community. No other adaptions to 
the study design will be made based on this interim analysis. The sponsor representative from 
MAPS will not be part of any trial decisions or administration after the sample size re-estimation 
has been communicated to MPBC who will continue to be the trial organizer. 
 
If there is an emergency requiring knowledge of a participant’s condition assignment, the blind 
may be broken for an individual participant through the IWRS. Upon database lock, the study 
will be unblinded and participants will be notified of treatment assignment. 
 
10.0 Risks 
10.1 Non-drug Related Risks 
10.1.1 Medical Assessments 
In preparation for MDMA-assisted psychotherapy sessions, blood draws and a full medical 
examination, including a physical examination, ECG, 1-minute rhythm strip, and laboratory tests, 
are required to establish eligibility for the study. Temporary discomfort, inflammation, or 
infection could arise as a result of sampling blood at the punctured vein. Submitting to a full 
medical examination may also cause discomfort or psychological distress. Since medical 
examinations and blood draws are required to establish eligibility for the study, they cannot be 
omitted from the protocol. 
 
10.1.2 PTSD, Suicide Risk, and Psychotherapy 
During Screening, throughout MDMA-assisted psychotherapy, and during assessment of study 
measures, participants will be asked to think about and discuss their thoughts and emotions 
relating to the traumatic event or events. They may experience intense emotional responses or 
suicidal ideation as a result of recalling and speaking about this material. Even in a therapeutic 
context, thinking about and discussing the trauma, symptoms related to the trauma or the effects 

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of PTSD on life function can produce distress and exacerbate suicidal ideation during and 
immediately after psychotherapy sessions. Psychotherapy is conducted as part of this study, and 
people undergoing psychotherapy are expected to confront unpleasant thoughts, feelings and 
memories in the process. Because psychotherapy is an integral part of the research study design, 
the potential distress arising from psychotherapy is unavoidable. Therapy teams will provide 
emotional support to participants during any psychological distress. 
 
The therapy team will minimize risks by carefully evaluating all participants to determine if there 
is a current risk of suicidal behavior. Participants with a history of suicide attempts will not be 
excluded unless significant risk of suicidal ideation and/or behavior is detected, per Exclusion 
Criteria described in Section 4.2. Participants will be enrolled according to the Eligibility Criteria 
based on the clinical judgment of the site physician, therapy team, and Medical Monitor. 
 
A qualified individual will administer the C-SSRS according to Table 6: Time and Events-Study 
Measures, and as needed depending on clinical presentation of the participants, to monitor for 
development and intensity of suicidal ideation and/or behavior. The therapy team will implement 
the following plan to assess elevated or imminent suicide risk. 
 
If the Since Last Visit C-SSRS reveals current serious Suicidal Ideation (scores of four or 
greater), indicating risk at the time of the assessment, or positive Suicidal Behavior (scores of one 
or greater), the participant will be referred for further management as described below. 
 
1. If the participant has current suicidal ideation, but no specific plan to commit suicide 
(Suicidal Ideation Score=4), the individual administering the C-SSRS will ensure: 
a. The participant is evaluated by the investigator and/or site physician to determine 
an appropriate course of action. Findings will be discussed with the participant 
and their personal therapist, if applicable. 
b. Regular check-ins via phone or in-person will be continued until the participant 
has stabilized or a new course of action is taken based on changes in C-SSRS 
score and/or ongoing clinical assessment. 
c. Notification of the sponsor within 24 hours of this event and provide a narrative 
for the AE for expedited reporting to FDA. Increases in suicidality will be 
captured as an AESI per Section 11.1.1 and evaluated for seriousness. SAEs will 
be reported per regulatory guidance. 
d. Treatment would be continued when deemed appropriate by the investigator and 
Medical Monitor, unless it is determined that treatment should be discontinued, 
in which case the participant will enter follow-up. 
2. 
If the participant has suicidal ideation, and a plan to commit suicide (Suicidal 
Ideation Score=5) or positive Suicidal Behavior (Score greater than or equal to 1), the 
individual administering the C-SSRS will assess whether the risk is imminent. A 
Suicidal Ideation score of five does not necessarily indicate an immediate risk if the 
thoughts are fleeting, fairly easily controlled, and deterrents are strong. If there is no 
imminent risk, the individual will follow the procedure described above. If there is 
imminent risk of suicidal behavior, the individual will ensure: 
a. Participants are evaluated by the investigator or site physician to determine an 
appropriate course of action, and the therapy team will contact their personal 
therapist, who will be invited to come to the study site to assist, depending on 
their location. 
b. If it is determined that the participant is at imminent risk of suicide, the therapy 
team will do one of the following: 
i. Escort the participant to the ED (Emergency Department); 

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ii. Escort the participant to an appropriate mental health services facility 
(e.g., hospital psychiatric unit); or  
iii. Call EMS (Emergency Medical Services) and ensure that the participant 
is transferred to the responding medical personnel. 
c. If the participant will not comply and wishes to leave without consultation, call 
EMS. Explain that the participant is in immediate danger of committing suicide. 
Provide a complete description of the participant and give any other needed 
details to ensure the participant’s safety. 
d. Notification of appropriate members of the study team and sponsor 
representatives within 24 hours, provide a narrative for the AE for expedited 
reporting to FDA. 
e. The event will be collected as an AESI per Section 11.1.1 and seriousness will be 
evaluated. SAEs will be reported per regulatory guidance. 
f. Treatment would be continued when deemed appropriate by the investigator and 
Medical Monitor, unless it is determined that treatment should be discontinued, 
in which case the participant will enter follow-up. 
 
10.1.3 Recorded Content 
All psychotherapy sessions and IR assessments may be recorded for research and training 
purposes. Participants may feel uncomfortable with having their sessions recorded. The 
recordings are necessary for developing the experimental treatment and assessing adherence to 
the Treatment Manual. Any requests for use of video outside of research and training requests 
will result in participants receiving information on the request. They will have control over any 
presentation of this material beyond viewing by researchers or regulatory agencies. 
 
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. 
 
10.2 Risks of Receiving MDMA  
Study procedures and eligibility criteria have been developed based on Phase 2 clinical trials to 
exclude potential participants with pre-existing exclusionary medical conditions that would 
exacerbate risk. The therapy teams and site physicians will be available via mobile phone 
throughout the study if any problem occurs when a participant is not at the site. In the event of a 
medical emergency or any other medical problem during an Experimental Session, the site 
physician will be immediately available by telephone, and based on assessment of the situation, 
they will make the decision to either evaluate the participant themselves at the site, have the 
therapy team call EMS to transport the participant to the ED, or instruct the therapy team to take 
the participant to the ED. 
 
Further information on the risks associated with MDMA can be found in the IB and risk 
mitigation procedures are described by risk category below. Risk Categories were determined by 
review of possible risks within the Risk Assessment and Categorization Tool (RACT).  
 
10.2.1 High Level Risks 
High Risk does not indicate an event is more likely to happen but indicates per the RACT 
assessment that new and or more complex procedures are required in the study to ensure 

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screening is adequate to eliminate or manage the risk in the patient population. No high level 
risks have been identified in this study. 
 
10.2.2 Medium Level Risks 
Medium Risk does not indicate the likelihood the event will occur but indicates per the RACT 
assessment that new or many procedures, which are not complex, are needed to ensure screening 
is adequate to eliminate or manage the risk in the patient population. 
 
10.2.2.1 Cardiovascular and Cerebrovascular Risks and Mitigation 
MDMA is known to transiently increase heart rate and blood pressure in a dose-dependent 
manner that is generally not problematic for physically healthy individuals. These changes should 
last no more than 8 hours. Participants with PTSD in MAPS-sponsored Phase 2 studies do not 
appear to differ from healthy individuals in this sympathomimetic, physiological response. Most 
people do not experience elevations in cardiovascular parameters that exceed those seen after 
moderate exercise. An examination of safety data drawn from Phase 2 studies of MDMA-assisted 
psychotherapy detected a dose-dependent increase in systolic blood pressure but not diastolic 
blood pressure. Characterization of sympathomimetic effects among participants with controlled 
hypertension is ongoing.  
 
Risks posed by elevated blood pressure will be addressed by excluding people with pre-existing 
uncontrolled hypertension and monitoring blood pressure and pulse, as described in Section 4.2 
Exclusion Criteria. Before and after IMP administration in Experimental Sessions, the therapy 
team will monitor vital signs. The therapy team will attend to clinical signs and symptoms of 
potential rare complications of the cardiovascular effects of MDMA, such as stroke or acute 
myocardial infarction (AMI) during Experimental 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. The 
therapy team will notify the site physician for evaluation if this occurs.  
 
If any participant has neurological deficits, as assessed by the site physician, whether or not they 
are associated with hypertensive crisis, they will be monitored, as described above and 
transported to the hospital if medically indicated. If evaluation at the hospital reveals a 
nonhemorrhagic stroke, there will be sufficient time to administer recombinant tissue 
plasminogen within the 3-hour time frame recommended in the American Academy of 
Neurology/American Heart Association guidelines [107, 108]. 
 
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 the hospital, and the site physician will be promptly 
notified. Nitroglycerin should be stocked on site per applicable national and local regulations in 
order to respond promptly in case of need. If further evaluation at the hospital reveals that the 
participant has had an AMI, they will be well within the time frame required for definitive 
therapy. The American College of Cardiology/American Heart Association guidelines for the 
treatment of AMI recommend percutaneous transluminal coronary angioplasty (PTCA) as the 
treatment of choice when it can be performed within 90 minutes of arrival at the hospital in 
participants who present within 12 hours of an episode of chest pain lasting more than 30 minutes 
and who have ECG evidence of AMI [109]. Any participant who experiences such medical 
complications during an Experimental Session will not be given another Experimental Session, 
unless it is approved by the investigator, site physician, and the Medical Monitor.  
 

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As the characterization of QT effects for the API is ongoing, QT interval will be evaluated in the 
event of hospitalization for management of cardiovascular or cerebrovascular event. If at any time 
a participant develops a QT/QTc interval>500 ms or of>60 ms over Baseline during ECG 
evaluation, the participant will be discontinued from treatment.  
 
10.2.2.2 Psychological Risks and Mitigation 
Mild anxiety and depressed mood are occasionally reported 1 to 3 days after MDMA 
administration [49, 110]. Psychological distress from MDMA could arise from the first 
indications of MDMA effects until the last effects have dissipated or even later. Anxiety or 
distress during the session may last for as little as 5 minutes or for as long as 5 hours or more. In 
addition, psychological distress could arise following an Experimental Session as a result of 
participants having difficulty integrating their experience after the MDMA effect has subsided. In 
previous Phase 1 and Phase 2 studies, these symptoms have been self-limiting and have 
responded well to reassurance from the therapy team, with occasional use of benzodiazepines for 
anxiety. In this study, participants will have the intention of confronting and working through 
traumatic experiences. Accordingly, signs of psychological distress, panic, or other unpleasant 
psychological reactions are to be expected and may be considered an element of the 
psychotherapeutic process.  
 
Proper preparation and follow-up support will reduce the difficulties participants might have with 
acute or sub-acute reactions. The potential for destabilizing psychological distress will be 
minimized by: 
 
• 
Excluding people who might be more vulnerable to it (such as people diagnosed with 
bipolar affective disorder type 1 or with psychotic disorders). 
• 
Preparatory Sessions of non-drug psychotherapy before the Experimental Session. 
• 
Creating an atmosphere of trust during the Experimental Session. 
• 
Close monitoring. 
• 
Phone contact with participants during the week after the Experimental Session. 
• 
Integrative Sessions. 
• 
Overnight stays at the study site for the night of each Experimental Session. Qualified 
personnel will be available during the overnight stay to respond to the needs of the 
participant. Attendants will be instructed to contact the therapy team upon request or at 
the appearance of signs of a potential Serious Adverse Event.  
 
During the Preparatory Sessions, participants will be made aware of the fact that difficult 
emotions, including grief, rage, fear, or panic, may arise during Experimental Sessions. Every 
effort will be made to help participants resolve difficult symptoms and to arrive at a more 
comfortable and relaxed state by the conclusion of the Experimental Session, including empathic 
listening on the part of the therapy team and performance of diaphragmatic breathing by 
participants.  
 
If the participant is severely agitated, anxious, in danger of self-harm or suicide, or is 
experiencing any other severe psychological distress, at the end of a psychotherapy session, at 
least one member of the therapy team will remain with the participant for at least 2 more hours. 
During this time, the therapy team will employ affect management techniques, will talk with the 
participant to help them gain cognitive perspective of their experiences, and will help the 
participant implement the self-soothing and stress inoculation techniques presented during the 
Preparatory Sessions. If the participant remains severely anxious, agitated, in danger of self-harm 

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or suicide, or is otherwise psychologically unstable at the end of the 2-hour stabilization period, 
the site physician and therapy team will decide between the following options: 
 
1. If severe distress occurs at the end of an Experimental Session, a psychiatric nurse, 
therapeutic assistant, physician, or therapy team member will stay with the participant 
until the severe distress resolves or until the time of their Integrative Session appointment 
the following morning. The therapy team will then meet with the participant daily until 
the period of destabilization has passed.  
2. If the participant experiences severe, persisting emotional distress, such as panic attacks, 
severe generalized anxiety, or insomnia following an Experimental Session, a licensed 
therapy team member or the site physician may prescribe a benzodiazepine (specifically, 
lorazepam) and/or sleep aid (e.g., zolpidem). The route, frequency, and dose should be 
determined by the site physician. If these medications are stocked on site, they should be 
stored according to applicable national and local regulations. This medication will be 
captured on the Concomitant Medications eCRF. The site physician should not prescribe 
an SSRI, SNRI, or monoamine oxidase inhibitor (MAOI) in this context, unless it has 
been determined that the participant will be withdrawn from the study. Residual 
symptoms will be addressed during the frequent follow-up psychotherapy visits with the 
therapy team. 
3. If a participant should become psychotic, arrangements will be made to stabilize them or 
transfer them to the ED if hospitalization is necessary. Any participant who is 
hospitalized after a severe psychological reaction will be suspended from the protocol 
until after recovery or stabilization, at which time the investigator and/or site physician 
will carefully evaluate the participant’s emotional status.  
 
For those participants engaged in an ongoing therapeutic relationship with a psychotherapist or 
psychiatrist, the participant’s outside therapist(s) will be involved in the management of any 
psychiatric complications. For those participants engaged in an ongoing psychotherapeutic 
relationship with the investigator or member of the therapy team, the management of any 
psychiatric complications will be undertaken by them in their capacity as the participant’s 
therapist. 
 
10.2.3 Low Level Risks 
Low Level Risk does not indicate the likelihood the event will occur but indicates per the RACT 
assessment that no new or complex procedures are needed to ensure screening is adequate to 
eliminate or manage the risk in the patient population. 
 
10.2.3.1 Thermoregulatory Risks and Mitigation 
MDMA administered in a controlled setting produces only a slight increase in body temperature 
[110]. Ambient temperature does not enhance or attenuate this slight elevation in humans. In data 
gathered from sponsor-supported Phase 2 studies, it was found that compared to placebo, a higher 
percentage of participants receiving MDMA had peak body temperatures greater than 1 degree 
Celsius (°C) above Baseline. However, there was no strong relationship between dose of MDMA 
and peak body temperature or between MDMA dose and elevation above threshold of 1°C above 
Baseline.  
 
Ambient temperature will be kept at a comfortable level during Experimental Sessions. If a 
participant’s temperature rises more than 1°C 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 

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participant. If at any time the temperature rises more than 1.5°C above Baseline despite these 
efforts, the site physician will be consulted for further evaluation and treatment.  
 
10.2.3.2 Osmoregulatory Risk and Mitigation 
MDMA administered in a controlled setting is not expected to have any risks of osmoregulatory 
changes. Participants will not be allowed to drink more than three liters of electrolyte-containing 
fluids over the course of the Experimental Session and fluid intake will be spread out 
appropriately during the session. If a participant exhibits any signs of toxicity or clinically 
significant dilutional hyponatremia despite these precautions after an Experimental Session, they 
will not receive another Experimental Session unless it is approved by the investigator, site 
physician, and the Medical Monitor. 
 
10.2.3.3 Genotoxicity Risk and Mitigation 
To reduce the risk of metabolic activation and formation of nitroso-derivatives of MDMA due to 
interactions with nitrates or nitrites in food, participants are required to have fasted (no intake 
other than alcohol-free liquids) for 10 hours prior to IMP administration at Experimental 
Sessions. 
 
10.2.3.4 Reproductive and Developmental Risks and Mitigation 
Risks posed by MDMA to pregnant people are not known. One of two studies of Ecstasy users 
suggests that use of Ecstasy and other drugs during pregnancy may be associated with some 
abnormalities at birth while the other failed to find this association [111, 112]. 
 
Pregnant and lactating people will be excluded from participation in the study. Participants who 
are able to become pregnant must have a negative pregnancy screen before undergoing each 
Experimental Session and must agree to use adequate birth control for the duration of the study 
during the Treatment Period. Paternal drug exposure studies show that exposure to MDMA was 
not a factor in adverse pregnancy outcomes, so partners of participants who were assigned male at 
birth will not be required to practice birth control. Due to the limited number of single-dose 
exposures being studied in this trial, the chance of birth defects are low. Procedures described in 
Section 11.3 Pregnancy have been put in place to mitigate risk of reproductive or developmental 
exposure to the IMP. 
 
10.2.4 Minimal Risks 
Minimum Level Risk does not indicate the likelihood the event will occur but indicates per the 
RACT assessment that no procedures are needed beyond basic monitoring to ensure screening is 
adequate to eliminate or manage the risk in the patient population. 
 
10.2.4.1 Common AEs 
Common AEs are typically observed during IMP administration, but are transient and diminish as 
the IMP is metabolized and excreted over the next 72 hours after dosing. Common AEs most 
frequently reported during Experimental Sessions include muscle tightness in the jaw, lack of 
appetite, dizziness, and nausea. During the week following treatment, lack of appetite, muscle 
tightness in the jaw, restlessness, weakness, dry mouth, thirst, impaired gait/balance, and 
sensitivity to cold may be reported. Severe anxiety, insomnia, fatigue, and depressed mood are 
commonly reported in PTSD studies in both placebo and MDMA groups. Common AEs are 
typically self-limiting. Elevations in anxiety and poor sleep respond to management with short-

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acting low dose benzodiazepines (specifically, lorazepam) or sleep aids as needed, per clinical 
judgment of the site physician. 
 
10.2.4.2 Potential Neurotoxicity Associated with Ecstasy Use 
Some researchers believe that MDMA is neurotoxic in humans even at doses used in clinical 
trials [113]. However, these claims are based on studies that employed inappropriately high doses 
of MDMA utilized in animal studies and on human studies comparing the effects of repeated use 
of Ecstasy, often along with other drugs. Meanwhile, another recently published meta-analysis 
has taken careful steps to overcome methodological limitations in previous work and found only 
modest evidence of neurotoxicity [114]. The sponsor has carefully considered the risks of such 
neurotoxicity and conclude that they are minimal in the proposed study. This conclusion is 
supported by empirical and toxicokinetic evidence and is consistent with the lack of toxicity 
reported in previous clinical MDMA studies. It does not appear that MDMA-assisted 
psychotherapy negatively impacts cognitive function. Neurotoxicity and neurocognitive effects of 
MDMA were studied in the sponsor’s Phase 2 studies and provided sufficient data to conclude 
that limited exposures to MDMA allowed for adequate time for reversibility of any effects at the 
synaptic level. Furthermore, limited dosing of MDMA has shown to have no effect on 
neurocognitive functioning. 
 
10.2.4.3 Abuse Liability 
Findings in humans and animals suggests that MDMA possesses moderate abuse potential that is 
higher than that reported for “classic hallucinogens,” like psilocybin, but lower than that reported 
for psychostimulants, such as cocaine or methamphetamine. In sponsor-supported Phase 2 PTSD 
studies in 107 participants treated with MDMA-assisted psychotherapy in a controlled clinical 
setting, 29.9% (32 of 107) of participants had tried Ecstasy at least 6 months prior to enrollment, 
with U.S. samples demonstrating a higher prevalence of use than international studies. 
Participants reported using Ecstasy an average of 2.3 (SD:1.43) times. Due to the known 
association of substance use disorders and PTSD, this sample was likely not representative of the 
general healthy volunteer population but is congruent with the PTSD population. At long-term 
follow-up across Phase 2 studies, 8.7% of participants (eight of 92) reported “Ecstasy” use across 
studies, with five participants indicating single and not repeated use and three participants 
indicating two uses. Six of these eight subjects had used Ecstasy prior to study participation. Of 
these participants, most were attempting to recreate a therapeutic experience, and most did not 
indicate a desire to repeat this. In addition to self-report data, urine drug screens specific for 
MDMA were performed at random and 2, 6, and 12 months after the final Experimental Session 
during one study (MP2, N=12). All were negative, supporting the observation that study 
participants did not seek out MDMA or Ecstasy after taking part in the study [60]. In addition to 
data on Ecstasy use at follow-up, AEs were reviewed across Phase 2 studies, the sponsor found an 
absence of clinically significant AEs supporting drug dependence, intentional drug misuse, and 
substance abuse, and a low rate (<2%) of secondary terms that reflect acute intoxication.  
 
Based on current information, it does not appear that MDMA-assisted psychotherapy 
demonstrates signals associated with known abuse liability patterns in a PTSD population when 
administered in a therapeutic setting under continuous observation in three single-dose sessions. 
Any abuse potential and diversion is further limited since the IMP is not supplied to the 
participant to take home and is administered in a restrictive setting. Each investigator responsible 
for dispensing or administration of the IMP will maintain current registration with authorities 
with oversight of controlled substances. IMP will be handled following all regulations pertaining 
to the handling and dispensing of controlled substances within research studies. See Section 
11.1.1 for AESI terms. 

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Within-participant elevation in self-reported Ecstasy use post-treatment will be clinically assessed 
for signals of abuse and will be monitored during the Long-term Follow-up extension study 
associated with this protocol.  
 
11.0 Safety 
11.1 Adverse Events 
In accordance with guidance for the specific study site, Health Canada Clinical Safety Data 
Management Definitions and Standards for Expedited Reporting International Conference on 
Harmonisation (ICH) Topic E2A: Guidance for Industry or FDA Safety Reporting Requirements 
for INDs and BA/BE Studies, an Adverse Event (AE) is defined as any medical occurrence in a 
participant, including any abnormal sign (e.g., abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the participant’s involvement in the research, 
whether or not considered related to participation in the research. This definition includes 
concurrent illnesses or injuries and exacerbation of pre-existing conditions.  
 
Events related to planned treatments or physician visits for Baseline conditions collected in the 
medical history will not be collected, unless there is an exacerbation of the condition, in which 
case they will be actively followed until resolution. 
 
An unexpected AE is one that is not listed in the current IB or an event that is by nature more 
specific or more severe than a listed event. 
 
The site physician will be responsible for reviewing and confirming all AEs and SAEs collected 
during the study. The therapy teams will collect AEs during study visits from Enrollment (Visit 0) 
through Study Termination (Visit 20). Participants will be asked directly how they are feeling 
during each contact, and AEs may be captured spontaneously during psychotherapy sessions, 
telephone calls, or other correspondence. Completed measures may create suspicion that an AE 
occurred; in this case, the site staff should follow-up with the participant. 
 
All AEs will be monitored by the therapy team until resolution or, if the AE becomes chronic, a 
cause can be identified. If an AE is unresolved when a participant terminates from the study, a 
clinical assessment will be made by the site physician, investigator, and/or Medical Monitor as to 
whether continued follow-up of the AE is warranted. 
 
The severity of events reported on the “Adverse Events” eCRF will be determined by the site 
physician as: 
 
• 
Mild: No limitation in normal daily activity 
• 
Moderate: Some limitation in normal daily activity 
• 
Severe: Unable to perform normal daily activity 
 
The relationship of each AE to the IMP will be determined via analysis and the opinion of the 
investigator will not be collected, with the exception of SAEs. 
 
11.1.1 Adverse Events of Special Interest  
In accordance with guidance for the specific study site, Health Canada Clinical Safety Data 
Management Definitions and Standards for Expedited Reporting ICH Topic E2A: Guidance for 
Industry or FDA Safety Reporting Requirements for INDs and BA/BE Studies, the sponsor will 

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pay special attention to a subset of AEs involving cardiac function that could be indicative of QT 
interval prolongation or cardiac arrhythmias, including Torsade de pointes, sudden death, 
ventricular extrasystoles, ventricular tachycardia, ventricular fibrillation and flutter, non-postural 
syncope, and seizures. The subset of AEs involving suicide risk under the following terms are 
also of special interest: 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. 
These AEs will be marked in the eCRF with the denotation “Adverse Event of Special Interest” 
(AESIs) whether serious or non-serious. 
 
In order to assess signals of abuse potential for the IMP in the intended patient population: 
 
• 
AESIs involving the terms of Behavioral addiction, Drug abuser, Substance abuser, 
Dependence, Intentional product misuse, Overdose (accidental, intentional, or 
prescribed), or Drug diversion in cases that are related to MDMA or “Ecstasy” (material 
represented as MDMA) will be collected and coded as AESIs in the eCRF. 
• 
Cases of noncompliance, protocol violations, participants lost to follow-up, and any other 
reasons why participants dropped out of the study will be assessed for presence of AESIs. 
• 
Qualitative urine drug test data will be collected prior to each Experimental Session. Any 
positive findings that cannot be attributed to pre-approved concomitant medications or 
diet will be reviewed by the Medical Monitor to assess compliance with ongoing 
eligibility criteria and for presence of AESIs. 
 
If an AESI is a SAE (Serious Adverse Event ) or if it involves suicide risk, it should be reported 
to the sponsor with a narrative via the eCRF within 24 hours of the site’s awareness of the event. 
 
11.1.2 Serious Adverse Events 
In accordance with guidance for the specific study site, Health Canada Clinical Safety Data 
Management Definitions and Standards for Expedited Reporting ICH Topic E2A: Guidance for 
Industry or FDA Safety Reporting Requirements for INDs and BA/BE Studies, an SAE is defined 
as any untoward medical occurrence that at any dose: 
 
• 
Results in death. 
• 
Is life-threatening (i.e., the participant was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires or prolongs inpatient hospitalization. 
• 
Results in persistent or significant disability/incapacity (i.e. the event causes substantial 
disruption of a person’s ability to conduct normal life functions). 
• 
Results in a congenital anomaly/birth defect. 
• 
Requires intervention to prevent permanent impairment or damage. 
• 
Is an important and significant medical event that may not be immediately life-
threatening or resulting in death or hospitalization, but based upon appropriate medical 
judgment, may jeopardize the participant or may require intervention to prevent one of 
the other outcomes listed above. 
 
AEs which do not fall into these categories are defined as non-serious. It should be noted that a 
severe Adverse Event need not be serious in nature and that a SAE need not, by definition, be 
severe. 
 

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In addition, a pre-existing event or condition that results in hospitalization should be recorded on 
the medical history. The hospitalization would not result in the event or condition being reported 
as a study-related SAE, unless, in the view of the site physician, hospitalization was prolonged as 
a result of participation in the clinical trial or was necessary due to a worsening of the pre-
existing condition. This is because the onset of the event (the reason for the procedure) occurred 
before the participant was entered in the trial. Hospitalization for cosmetics, non-emergency 
prophylaxis, or elective abortion does not result in an SAE report, unless, in the view of the site 
physician, hospitalization for these procedures was prolonged as a result of participation in the 
clinical trial. 
 
All SAEs will be collected from enrollment through Study Termination. All SAEs which occur 
during the course of the trial, whether considered to be associated with IMP or not, must be 
reported to the sponsor within 24 hours of the site staff’s awareness of occurrence. Reporting 
procedures will be provided to the site. All SAEs will be assessed for relationship, expectedness 
and any required actions to address safety at the time of reporting of the event. SAEs will be 
evaluated by the site physician and Medical Monitor to determine if it is appropriate for the 
participant to continue treatment or enter follow-up.  
 
11.2 Other Significant Events 
Significant life events that may occur during the course of the study, including death of a loved 
one, loss of employment, or other hardship, may have an impact on treatment outcome. The 
sponsor will capture these life events using the LEC-5 measure. Such events will be entered as 
Comments in the eCRF and if appropriate, described in the Case Study Report for data outliers, if 
any. 
 
11.3 Pregnancy 
11.3.1 Definition of Childbearing Potential 
A participant is considered of childbearing potential if they were assigned female at birth and are 
post-menarche. A participant is considered not of childbearing potential if they are premenarchal, 
surgically sterile (documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy, 
and/or tubal ligation), postmenopausal, or assigned male at birth.  
 
11.3.2 Contraception Guidelines 
Study participants who were assigned male at birth with partners of childbearing potential will 
not be required to practice birth control. Adequate birth control methods are required for 
participants of childbearing potential and include: 
 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Non-oral hormonal methods, including injected, intravaginal, implanted, transdermal 
• 
Oral hormones plus a barrier contraception (condom, diaphragm, or spermicide)  
• 
Double barrier method (at least two of the following: condom, diaphragm, and 
spermicide) 
• 
Vasectomized sole partner 
• 
Abstinence from penile-vaginal intercourse 
o The reliability of abstinence should be evaluated carefully with the participant in 
relation to their general lifestyle. An additional acceptable birth control method 

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should be discussed with the participant in case they decide to engage in penile-
vaginal intercourse during the course of the study. 
 
For questions about acceptable birth control methods, contact the Medical Monitor. 
 
11.3.3 Follow-up Requirements 
Details of all pregnancies in study participants will be collected after Enrollment (Visit 0) and 
collected through 10 days after the last Experimental Session. Pregnancies should be reported to 
the sponsor via telephone or email within 24 hours of site staff awareness. 
 
 
In the event of a pregnancy, the participant will discontinue Experimental Sessions but may 
continue with non-drug Integrative Sessions, the next CAPS-5 assessment, and Study 
Termination procedures. At a minimum, prior to withdrawal from the study, efforts should be 
made to assess the final CAPS-5 immediately and complete Study Termination procedures. The 
participant will be emergency unblinded if the participant wishes as described in Section 9.4 
Blinding, after the final CAPS-5 assessment. 
 
The investigator will collect follow-up information on the participant and neonate and forward to 
the sponsor until the outcome of the pregnancy, which will be reported on an optional Pregnancy 
eCRF. Any termination, elective or spontaneous, will be reported. Abnormal pregnancy 
outcomes, such as spontaneous abortion, fetal death, stillbirth, congenital abnormalities, or 
ectopic pregnancy, will be reported as SAEs. 
 
11.4 Medical Monitor 
The name and contact information for the Medical Monitor is:  
 
Michael C. Mithoefer, M.D.  
Email: michael@mapsbcorp.com  
Telephone: 843-566-4252 
 
Alia Lilienstein, M.D., MPH 
Email: alia@mapsbcorp.com 
Telephone: 510-708-4622 
 
Medical Monitor contact information will also be provided in a separate contact list.  
 
12.0 Concomitant Medications 
12.1 Tapering Instructions 
The site physician will record concomitant medications during Screening. If the prospective 
participant is being treated with psychiatric medications at enrollment, the prospective participant 
will be encouraged to discuss medication tapering with their outside treating physician, if any, 
and will be required to give the site physician permission to do so as well. The medications will 
then be tapered in an appropriate fashion to avoid withdrawal effects and will be discontinued at 
least five half-lives plus one additional week for stabilization before the first Experimental 
Session to avoid the possibility of any interaction. Additionally, participants who are taking 
prohibited opiates will be cross-tapered to an allowable opiate (hydrocodone, morphine, and 
codeine) under the care of their prescribing physician. 
 

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The site physician will consult the prescribing physician to initiate medication tapering for 
participants, as they must refrain from taking psychiatric medications throughout the study, with 
some exceptions (see Section 12.2 Allowed Concomitant Medications). The prescribing 
physician’s opinion about medication discontinuation will be documented either in writing from 
the prescribing physician, or in writing by the site physician documenting phone contact with the 
prescribing physician. Tapering will follow a time course appropriate for the medication based on 
its half-life, with the Baseline CAPS-5 T1 (Visit 3) scheduled to occur after complete washout 
(five half-lives plus at least 1 week for stabilization). 
 
The therapy team will request information about any changes in medication at each contact. The 
site physician will be responsible for reviewing and confirming all medications collected during 
the study.  
 
All medications, non-prescription and prescription, will be collected from Screening through 7 
days after the last Experimental Session. From 7 days after the last Experimental Session through 
Study Termination, only prescription or non-prescription medications taken to treat AEs will be 
collected. Throughout the protocol, all medications used to treat AEs will be collected, and all 
changes including discontinuations or additions to medications will be collected. The study team 
will also inquire about concomitant medication adherence and document all information on the 
Concomitant Medications eCRF. 
 
Participants may return to taking psychiatric medications and discontinue birth control after the 
final Study Termination visit if necessary. 
 
12.2 Allowed Concomitant Medications 
The site physician may prescribe necessary and appropriate medications in accordance with local 
and state regulations during the study to treat AEs that do not respond to other management 
outlined in the Treatment Manual. Examples include concomitant benzodiazepines for 
uncontrolled anxiety (for example, lorazepam at modest doses and occasional use only to avoid 
withdrawal effects of discontinuation between Experimental Sessions) or sleep aids (excluding 
trazodone) in compliance with Section 12.3 Prohibited Medications. Sublingual nitroglycerin will 
be available on site in the case of emergency. 
 
Gabapentin or certain opiates will be allowed when prescribed for pain management. The 
following opiates will be allowed during the study: hydrocodone, morphine, and codeine. Prior to 
randomization, participants who are taking opiates not included on this list will be cross-tapered 
to an allowable opiate under the care of their prescribing physician. Opiate medications may 
reduce the efficacy of MDMA and may prolong QT/QTc interval, but the opiates that are allowed 
during this trial have been selected because they have the lowest potential for QT/QTc interval 
prolongation and minimal serotonergic effects. Individuals using opiates for pain management 
will be asked to decrease the dose leading up to the Experimental Session in order to avoid 
withdrawal effects when they are required to refrain from taking the medication from 12 hours 
before IMP administration at the Experimental Session to 24 hours after. If a participant reports 
lack of analgesic effect during the sub-acute period following each Experimental Session, the site 
physician may approve taking an allowed opiate medication sooner than 24 hours after IMP 
administration. 
 
If the participant is on stimulants for Attention Deficit/Hyperactivity Disorder (ADHD) at 
Baseline, they can continue to use them at the same dose and frequency, as long as they 
discontinue five half-lives before each Experimental Session and do not restart for 10 days after 
each Experimental Session. 

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All psychoactive medications, herbal supplements, nonprescription medications, and prescription 
medications must be reviewed by the research team at least 2 weeks prior to each Experimental 
Session. Failure to comply with protocol requirements for concomitant medications may result in 
withdrawal from treatment, depending on the investigator and Medical Monitor judgment. 
 
12.3 Prohibited Medications 
To be enrolled in the study, participants must: 
 
• 
Refrain from the use of any psychoactive medication not approved by the research team 
from Baseline through Study Termination (with the exception of gabapentin or certain 
opiates for pain control). 
• 
Be willing to comply with all medication requirements per protocol. Medications will 
only be discontinued after enrollment per clinical judgment of the site physician in 
consultation with the prescribing physician. 
• 
Agree that, for 1 week preceding each Experimental Session they will refrain from: 
o Taking any specified herbal supplement (except with prior approval of the 
research team). 
• 
Agree that, for 5 half-lives of the medication preceding each Experimental Session they 
will refrain from: 
o Taking any nonprescription medications (with the exception of non-steroidal 
anti-inflammatory medications or acetaminophen) unless with prior approval of 
the research team. 
o Taking any prescription medications (with the exception of birth control pills, 
thyroid hormones, or other medications approved by the research team). 
 
Use of Marijuana, St. John’s Wort, and other herbs and medicines with notable serotonergic 
effects are prohibited from Baseline to Study Termination. Any investigational treatments under 
study for PTSD treatment are prohibited from use concurrent with this study. 
 
Diphenhydramine is excluded from this study unless prior approval is granted by the site 
physician. 
 
If an SSRI, SNRI, MAOI, or other antidepressant is used between Experimental Session 1 (Visit 
5) and Study Termination (Visit 20), the participant will discontinue study treatment and continue 
in follow-up. Participants whose Experimental Sessions are delayed by the COVID-19 pandemic 
may start any of these medications during the delay, as clinically indicated. When study visits 
resume, they will be given the option to resume Experimental Sessions after tapering off of these 
medications, per the tapering plan described above. 
 
Opiates other than hydrocodone, morphine, and codeine are prohibited from Enrollment 
Confirmation to Study Termination. Participants taking prohibited opiates will be cross-tapered to 
an allowable opiate prior to Experimental Sessions.  
 
13.0 Clinical Laboratory Assessments 
The site physician will confirm laboratory assessments gathered in screening for assessing 
eligibility. The site physician will use a list of normal ranges to conclude whether participants are 
eligible for the protocol and will indicate justification for admitting participants with abnormal 
values after consultation with the Medical Monitor. 
 

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The following laboratory assessments will be performed as a part of Screening:  
 
• 
Serum electrolytes and metabolic profile 
o Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) 
o Albumin:Globulin (A:G) ratio 
o Albumin, serum 
o Alkaline phosphatase, serum 
o Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) 
o Bilirubin, total 
o Blood urea nitrogen (BUN):creatinine ratio 
o Calcium, serum 
o Carbon dioxide 
o Chloride, serum 
o Creatinine, serum 
o C-reactive protein (CRP) 
o Globulin, total 
o Glucose, serum 
o Potassium, serum 
o Protein, total, serum 
o Sodium, serum 
• 
CBC 
o Hematocrit 
o Hemoglobin 
o Mean corpuscular volume (MCV) 
o Mean corpuscular hemoglobin (MCH) 
o Mean corpuscular hemoglobin concentration (MCHC) 
o Red cell distribution width (RDW) 
o Percentage and absolute differential counts 
o Red blood cell (RBC) count  
o White blood cell (WBC) count  
• 
Urinalysis 
o Color 
o Appearance 
o Specific gravity 
o pH 
o Protein 
o Glucose 
o Ketones 
o Occult blood 
o Leukocyte esterase 
o Nitrite 
o Bilirubin 
o Urobilinogen 
• 
Thyroid function 
o Thyroid-stimulating hormone (TSH) high sensitivity (if abnormal, free T3 and T4 
will also be tested) 
• 
HCV if indicated 
• 
HIV serology 
• 
%Carbohydrate deficient transferrin (%CDT) to detect heavy alcohol use 
• 
Urine-dip pregnancy test for participants of childbearing potential will be performed at 
the site 
• 
Urinary drug test will be performed at the site 

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Laboratory assessments, with the exception of urine pregnancy and drug tests, will be performed 
at the nearest clinical laboratory to the site. Clinical laboratories for each site will be specified in 
a separate document. Certificates and normal ranges will be stored in the site’s Investigator Site 
File (ISF). 
 
14.0 Statistical Considerations  
Key personnel, MAPS, and the biostatistician will agree on a Statistical Analysis Plan at the 
beginning of the study, which will provide more detail about analyses than provided in this 
protocol. An overview of the statistical analyses that will be performed is provided in the 
following sections. 
 
14.1 Power and Sample Size Determination 
The statistical power calculations were made by fitting an MMRM model to CAPS-4 data from 
the Phase 2 study MP1 to obtain covariance parameter estimates. The Phase 2 MP1 study had a 
similar design with primary outcomes measured by change in CAPS-4 outcome scores, which 
allowed for estimation of within-subject covariance parameters. The following inputs created the 
90% statistical power estimate using the PASS 14 Mixed Models Repeated Measures module: 
 
a. N=47 per group (allowing for 3 dropouts per treatment group) 
b. Alpha=0.0499 
c. 1000 simulations 
d. Change from Baseline means of 5.5, 12.8, and 20.5 for placebo. Change from Baseline 
means of 17.2, 31.1, and 37.4, for MDMA at visits 1, 2, and 3, respectively 
e. Two levels of treatment factor (MDMA, Placebo) 
f. Three within subject levels (3 treatment visits) 
g. Subject level variance=335 
h. Variance of R (diagonal elements)=280 
i. 
Rho=0.5 
j. 
Unstructured covariance 
 
Additional participants may be added to the sample size at the recommendation of the Data 
Monitoring Committee (DMC) from the results of an administrative interim analysis (Section 
14.2.3) occurring after 60% of the mITT participants have completed a final assessment of the 
Primary Outcome (Visit 19) and terminated treatment. 
 
14.2 Statistical Analyses 
Descriptive statistics will be computed overall for MDMA and placebo, as well as by initial 
MDMA dose received, for all available data from outcome measures, time course of onset of 
treatment effect and including minimum, maximum, average, median, and standard deviation.  
 
The following analysis sets are defined for this study: 
 
• 
All Enrolled: all participants who sign informed consent and are initially enrolled 
• 
mITT: all randomized participants who receive Investigational Product in at least one 
blinded Experimental Session and have at least one follow-up CAPS-5 assessment 
• 
Per Protocol (PP): all randomized participants who receive Investigational Product in 
three blinded Experimental Sessions and have three follow-up CAPS-5 assessments 

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• 
Not Per Protocol (NPP): all participants who are included in the mITT Set but not the 
PP Set 
• 
Safety: all participants who receive any IMP  
 
14.2.1 Efficacy Analyses 
14.2.1.1 Primary Outcome 
The primary analysis will be conducted after all participants complete Study Termination (V20) 
and the study database has been locked. The de jure estimand of treatment efficacy will be used 
to estimate the causal effect of MDMA-assisted psychotherapy on PTSD symptom severity in the 
intended population of patients with PTSD from any cause. All efficacy analyses will be based on 
the mITT analysis set. The primary treatment comparison will be made at a 2-sided, 0.0499 level 
of alpha. The primary estimator of effects of initially randomized treatments will be the 
difference between groups in mean change in CAPS-5 Total Severity Scores from Baseline to 18 
weeks after randomization (Visit 19). Least squares means from a restricted maximum likelihood 
(REML)-based MMRM will be used to compare treatment groups at Visit 19. Baseline CAPS-5 
Total Severity Score and dissociative subtype based on CAPS-5 will be included as covariates in 
the MMRM model. CAPS-5 data collected after treatment discontinuation will not be included in 
the de jure estimand. Missing data will not be imputed. Details of analysis of are described in the 
Statistical Analysis Plan. 
 
14.2.1.2 Secondary Outcome 
If the primary null hypothesis is rejected, overall change in SDS item scores from Visit 3 
(Baseline) to Visit 19 will be analyzed by a Wilcoxon Rank Sum Test. Details of analysis are 
described in the Statistical Analysis Plan. 
 
14.2.1.3 Exploratory Secondary Outcomes 
Longitudinal CAPS-5 Total Severity Score and SDS item scores will be plotted across visits to 
characterize the onset of treatment effect. Cohen’s d IGPP effect size of MDMA will be estimated 
using Cohen’s techniques.  
 
An exploratory responder analysis will further characterize clinical significance of PTSD 
treatment effect in the mITT set after each Experimental Session based on the following 
categories: 
 
• 
Treatment Response: 10-point or greater reduction in CAPS-5 Total Severity Score 
• 
Loss of Diagnosis: 10-point or greater reduction in CAPS-5 Total Severity Score and no 
longer meeting PTSD diagnostic criteria on CAPS-5 
• 
Remission: CAPS-5 Total Severity Score of 11 or less and no longer meeting PTSD 
diagnostic criteria on CAPS-5 
 
Exploratory sub-group analyses may be conducted when possible to evaluate efficacy by 
treatment group and individual demographic characteristics (e.g., age, gender, ethnicity, index 
trauma, dissociative subtype of PTSD, presence of secondary traumatic stressors during the 
assessment period with LEC-5, medication tapering, diagnosis of comorbid depression, diagnosis 
of comorbid psychiatric diagnosis, and number of Experimental Sessions completed). Exploratory 
analyses of secondary outcome measures will be described in the Statistical Analysis Plan. 
 

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14.2.2 Safety Analyses 
Safety analyses will confirm safety data with summary tables listing exposure to IMP, unsolicited 
AEs, concomitant medications, suicidal ideation and behavior, and vital signs overall and by 
group. If a participant has more than one AE mapped to the same PT, that AE will be reported 
once using the highest severity. AEs that occur on Day 0 (Experimental Session), Day 1, Day 2 
after IMP administration will be presented separately. Compare relative incidence of AEs during 
Experimental Sessions such as clinical signs and symptoms, such as chest pain, shortness of 
breath, or neurological symptoms or any other signs or symptoms that may be indicative of a 
medical complication of the IMP.  
 
Frequency and incidence of concomitant medications will be displayed by generic name, sorted 
by class, and summarized by treatment group, analysis set, and category. Concomitant 
medications taken on Day 0 (Experimental Session), Day 1, Day 2 after IMP administration will 
be presented separately. Any psychiatric concomitant medications will be tabulated by period 
(Preparatory, Treatment Period, Follow-up Period). Frequency and incidence of positive or 
serious ideation and suicidal behavior will be presented using descriptive statistics of C-SSRS 
scores in tabular format. Vital signs (heart rate, blood pressure, and body temperature) for 
Experimental Sessions will be summarized using descriptive statistics in tabular format listing 
values at pre-IMP administration, prior to the supplemental dose, and at the end of each 
Experimental Session by treatment group. Additional details are available in the Statistical 
Analysis Plan. 
 
14.2.3 Administrative Interim Analysis 
An unblinded administrative interim analysis is planned to be performed at a single time point 
after the first 60% of participants in the mITT set have completed the final CAPS-5 follow-up 
assessment and terminated treatment, including early Study Termination participants who have 
completed their final CAPS-5, and 100 participants have been enrolled. The objective of the 
administrative interim analysis is to conduct a sample size re-estimation. The detailed results of 
the interim analysis will not be revealed to the site staff, participants, IRs, or sponsor 
staff/designees except for a single designated sponsor representative from MAPS. The 
independent DMC statistician will perform the unblinded administrative interim analysis as 
described in the DMC Charter. In addition, procedures will be developed to ensure the blinding of 
the participant level data for parties outside of the Independent Statistical Group (ISG).  
 
Based on the result of calculating conditional power using the estimated effect size from the first 
60% of participants in the mITT set, the sample size may be increased. The DMC will review the 
group-unblinded interim analysis results provided by the independent statistician and will give 
recommendations to the designated sponsor representative from MAPS. The designated sponsor 
representative from MAPS will provide written information to the trial organizer delegate of 
MPBC indicating how many participants, if any, to add but will not provide any information on 
the corresponding conditional power the additional participants are being added to achieve. Only 
the re-estimation of sample size will be completed at the interim analysis, this will not be used to 
drop or add treatment arms or doses, change entry criteria, change randomization ratio or change 
Primary Endpoint. The sponsor representative from MAPS will not be part of any trial decisions 
or administration after the sample size re-estimation has been communicated to MPBC who will 
continue to be the trial organizer. The full details of the interim analysis plan are described in the 
Statistical Analysis Plan. 
 

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14.3 Data Monitoring Committee 
The sponsor will appoint a DMC with appropriate expertise in the conduct of clinical trials to 
independently monitor subject safety information during this study, conduct the sample size re-
estimation analysis, and make associated recommendations for all reviews. The DMC is an 
independent expert advisory group commissioned and charged with the responsibility of 
periodically evaluating cumulative safety and other clinical trial data for evidence of safety 
concern and recommending Study continuation, discontinuation, or modification. The 
composition of the DMC will include clinician experts and at least one biostatistician.  
 
The objective of the DMC Charter is to outline the specific purposes and functions of the DMC. 
In addition, it describes the procedures for data abstraction and data delivery conventions to and 
from the DMC members for review purposes. Access to the DMC charter will be restricted to the 
DMC and only limited specified sponsor staff who were involved in the trial design. 
 
The DMC will periodically receive blinded safety reports and may receive aggregate data on the 
key secondary outcome measure, the SDS, to assess suitability of continuation of the study based 
on the risk/benefit profile. The objective of the DMC safety review is to monitor the safety of the 
subjects enrolled and to be enrolled in the study.  
 
A single representative within MAPS will be designated to receive written communication of 
recommendations following the interim DMC review of the trial. This communication will be 
limited to the DMC recommendation needed for the decision of sample size re-estimation. The 
sponsor representative within MAPS and DMC members will sign a written confidentiality 
agreement in order that the precise rules governing sample size re-estimation may not be 
disclosed to the outside community, including the trial organizer MPBC.  
 
15.0 Study Governance 
The sponsor, MAPS, holds the IND for MDMA and is responsible for funding the Clinical 
Development Program. The sponsor has delegated the primary responsibility of trial organization 
to MPBC, including designing, initiating, managing, coordinating, continuing, and concluding the 
clinical trials within the Clinical Development Program. MPBC is tasked with maintaining the 
quality of study conduct through ongoing monitoring of data and participating in writing study 
publications. MPBC contracts with independent entities who represent clinical sites to accomplish 
these goals. Collectively, MAPS and MPBC are referred to as sponsor throughout this document. 
 
15.1 Ethics 
This clinical study was designed and shall be implemented and reported in accordance with the 
International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP), 
with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal 
Regulations Title 21) and with the ethical principles laid down in the Declaration of Helsinki.  
 
The protocol and the ICF must be reviewed and approved by a properly constituted institutional 
review board (IRB) or ethics committee and national regulatory agency (FDA, Health Canada, or 
Israeli Ministry of Health) before study start. Signed and dated documentation of approvals must 
be provided to the sponsor. Prior to study start, the investigator is required to sign a signature 
page confirming their agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to the sponsor. 
 

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15.1.1 Financial Disclosure 
Investigators will adequately and accurately disclose financial interests to the sponsor prior to 
study start, during the study if financial interests change, and 1 year after study completion. The 
sponsor will submit necessary disclosures to the appropriate regulatory bodies. 
 
15.1.2 Informed Consent 
The investigator and therapy team are responsible for obtaining informed consent in adherence to 
GCP and according to applicable regulations prior to entering the participant into the trial. 
Potential participants maybe sent the ICF to review after the initial phone screen. Preferably, 
informed consent will be obtained by the therapy team that will treat the participant. Information 
about the study must be given orally and in an understandable written ICF. The informed consent 
discussion must be conducted by a person who is qualified according to federal, state, or local 
regulations. The participant should have the opportunity to inquire about details of the study and 
to consider participation. 
 
The therapy team may meet with the potential participant via telemedicine for ICF review and 
signing prior to in person screening if necessary for scheduling of screening activities. If this is 
completed by telemedicine visit, the team will ensure the ICF is thoroughly explained and 
reviewed just as it would be at an in-person visit. If the potential participant is still interested after 
review, they will sign the consent during that telemedicine visit. The participant will then bring 
their signed copy of the ICF to their next in person visit where study staff will then counter sign 
the ICF, copy the ICF for the participant and file the original at the site. 
 
In addition to the explanation of study visits, the information should include that access to 
original medical records and processing of coded personal information must be authorized. A 
written release is needed to give permission to site staff to request and view the participant’s 
medical records to assess protocol eligibility, if needed. Information necessary for protocol 
participation includes past medical history, psychiatric interview, physical examination, and 
clinical laboratory tests. 
 
Eligible participants may only be included in the study after signing the IRB approved ICF. 
Informed consent must be obtained before conducting any study-specific procedures (i.e., all of 
the procedures described in the protocol beyond phone screening). The process of obtaining 
informed consent should be documented in the participant’s source records. The study staff will 
provide a copy of the signed ICF to the participant and will maintain the original in the ISF. 
 
The written ICF and any other written information to be provided to participants should be 
revised whenever important new information becomes available that may be relevant to the 
participant’s consent. Any revised ICF and written information should receive approval from an 
IRB before use. The participant should be informed in a timely manner if new information 
becomes available that may affect the decision to take part or continue in the study. The 
communication of this information should be documented. Participants can withdraw consent at 
any time without prejudice. If a participant withdraws consent but does not revoke the Health 
Insurance Portability and Accountability Act (HIPAA) authorization, the study team will have 
full access to their medical records, including Study Termination visit information. If a 
participant revokes only the HIPAA authorization, the study team will have full access to all 
medical records prior to the date and time of revocation. 
 
If a participant fails Screening and is rescreened at a later date, a new copy of the ICF should be 
signed. 

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15.2 Study Monitoring, Auditing, and Documentation 
Investigators, therapy teams, and all study staff will be trained prior study start for each site. 
Study sites will be monitored by site visits and telephone calls by representatives of the sponsor. 
In addition, critical data and systemic issues will be subject to centralized monitoring via the EDC 
system to develop and evaluate strategies for correction across sites. Sites will be monitored as 
appropriate for the rate of enrollment to comply with GCP guidelines and to ensure validity of 
study data. During each monitoring visit, source data verification will be performed to ensure 
compliance, including accurate and complete recording of data on eCRFs, source records, and 
IMP accountability records. An eCRF collation will be completed for each participant enrolled 
within the EDC system.  
 
CAPS-5 results will not be sent to site staff but instead will be sent to the IR Coordinator. The IR 
Coordinator will be responsible for review and data entry of the CAPS-5 source records into 
CAPS-5 eCRFs which will be blinded to sponsor and site personnel during the study.  
 
Videos from selected sessions will be reviewed for adherence to the Treatment Manual as 
described in Section 6.4. Findings from video reviews may be discussed with therapy teams as 
needed to ensure continued adherence to the protocol. 
 
During or after the study, the regulatory authorities, the IRB, and/or representatives of the 
sponsor may request access to all source documents, eCRFs, and other protocol documentation 
for on-site audit or inspection. Monitoring and auditing procedures will be supplied in a separate 
document.  
 
15.2.1 Source Records 
Source records contain all primary evidence of existence of the participant and document all 
study procedures. Source records include but are not limited to medical records, measures, 
checklists, notes, emails, and laboratory reports. All data reported in the eCRF are transcribed 
from primary source documents and must be consistent. These documents are maintained at the 
study site securely. Source records of CAPS-5 assessments will be stored in dedicated limited 
access files during the study. 
 
15.3 Confidentiality 
Every effort will be made to strictly safeguard the confidentiality of participants. Despite this, 
privacy cannot be guaranteed. Removing identifying information from data and restricting access 
to researchers directly involved in assessing the participants should prevent the dissemination of 
confidential data. Except for the Screening Log, the Informed Consent, previous medical records, 
emails with the participant, and a Contact Information Sheet that will be stored separately from 
other documents, all source data will be identified only by the participant’s initials and SUBJID. 
If past medical records are needed, participants will sign forms for the release of information 
upon consent to permit screening for protocol enrollment. In accordance with the guidance for a 
specific study site location, Health Canada Guidance for Records Related to Clinical Trials 
(GUIDE-0068) or FDA E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1), all 
assessment records will be kept in a locked file drawer or cabinet in a locked office, and access to 
measures will be limited to regulatory agencies, researchers, and individuals analyzing data. 
Researchers, other than the investigators who are directly involved in the protocol, with access to 
data will not be provided with any information that would identify participants by name or by 
other means, such as social security number.  

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Maintaining data in a secure environment will prevent the accidental or deliberate examination or 
removal of data. The sponsor will utilize confidentiality procedures to assure participant privacy. 
Audiovisual recordings are necessary for sponsor oversight of therapy processes. Any requests 
for use of audiovisual recordings outside of research and training requests will result in 
participants receiving information on the request. Participants will have control over any 
presentation of audiovisual recordings beyond viewing by authorized researchers, sponsor staff, 
or regulatory agencies. 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.  
 
Clinical trial data other than video data will be hosted on an EDC system that is FDA-compliant. 
All data entered into this system will be de-identified. Participants will only be referred to by 
numbers and a secondary identifier code. Source Records and identifying information will be 
retained at clinical sites per GCP. The sponsor will train the study staff on EDC procedures. Each 
study staff member with access to the data will be given an individual password. 
 
The sponsor has developed a feature that will allow participants to create a password and enter 
their self-report questionnaire data directly into Medrio using the electronic Participant Reported 
Outcome (ePRO) feature. Participants will be reminded by email to enter the data. Participant 
emails will be treated as Protected Health Information (PHI) in the database. Participants will 
receive a welcome email and reminder emails to ensure that they provide all necessary data. 
 
15.4 Costs to Participants 
There will be no costs to the study participants for participation. The sponsor will cover all direct 
costs of study procedures required for participation, including any assessments or tests performed 
solely for the purpose of establishing eligibility for participation. Charges for treatment of a 
participant’s condition that are unrelated to the research study or any unrelated procedures will 
not be covered by the sponsor. Patients who previously received therapy from a therapy team 
member prior to the study, and who will continue to receive ongoing treatment outside of the 
study from that therapist, are responsible for those non-study related costs. Participants may be 
reimbursed for reasonable expenses incurred for study participation, such as local travel to the 
treatment site; this will be specified in each site’s consent.  
 
15.5 Treatment and Compensation for Study Related Injury 
Some study-related emergencies can be treated by the site physicians. If the site physicians 
cannot treat a study-related emergency, then there are contingency plans for the transport of 
participants to the nearest hospital. Treatment of a study-related emergency would first be billed 
to a participant’s health insurance provider. If the participant's private or employer health 
insurance plan does not cover clinical trial-related claims, then the sponsor will cover any 
treatment costs directly related to the study. The sponsor will not cover costs of ongoing 
treatment unrelated to the study due to pre-existing conditions, or the cost of the participant's time 
spent obtaining treatment for pre-existing conditions before receiving treatment in the study. In 
the event of a suit against the sponsor, the sponsor carries third-party insurance that will cover 
bodily injury claims and will pay for applicable legal defense if needed/warranted.  
 
 

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15.6 Record Retention 
Investigators must retain all study records required by the sponsor and applicable ICH-GCP and 
FDA regulations, and Health Canada Guidance for Records Related to Clinical Trials (GUIDE-
0068) in a secure and safe facility. The investigator must consult a representative of the sponsor 
before disposal of any study records. “Essential documents” are defined as documents that 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced. These documents will be filed according to ICH-GCP regulations in the ISF. It is the 
responsibility of the sponsor to inform the investigator or institution when these documents no 
longer need to be retained.  
 
15.7 Publication Policy 
The sponsor recognizes the importance of communicating medical research and scientific data 
and their obligations to participants enrolled in a study and therefore, encourage publication of 
such material in reputable scientific journals and at professional and/or academic seminars or 
conferences. For multi-center studies, it is intended that the first publication of the study’s 
primary clinical data be co-authored by designated participating centers and the sponsor or 
designated representatives. Inclusion of Clinical Investigators in the authorship of any multi-
center publication will be based upon substantial contribution to the design, analysis, 
interpretation of data, drafting and/or critically revising any manuscript(s) derived from the 
Study. All publications will follow ICMJE Recommendations for the Conduct, Reporting, 
Editing, and Publication of Scholarly Work in Medical Journals, unless other guidelines are 
required by the journal. It is understood by the Clinical Investigators that the information 
generated in this study will be used by the sponsor in connection with the development of the 
IMP and therefore may be disclosed to government agencies in various countries. To allow for 
the use of information derived from the study, it is understood that the investigators are obliged to 
provide the sponsor with complete test results, all study data, and access to all study records. It is 
mandatory that all data analysis is done on the official monitored sponsor database and that the 
analysis plan is agreed upon with the sponsor statistician. 
 
Any results of medical investigations with the sponsor and/or publication/lecture/manuscripts 
based thereon shall be exchanged and discussed by the investigator and sponsor prior to 
submission for publication or presentation. Due regard shall be given to the sponsor's legitimate 
interests, e.g., manuscript authorship, obtaining optimal patient protection, coordinating and 
maintaining submissions to health authorities, and coordinating with other ongoing studies in the 
same field. The full details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this trial will be described in the Clinical Trial Agreement.  
  
 
 
 
 
 

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39. 
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Appendix A: Sub-study without Overnight Stays 
 
Rationale 
 
This sub-study to the MAPP1 protocol “A Randomized, Double-Blind, Placebo-Controlled, 
Multi-Site Phase 3 Study of the Efficacy and Safety of Manualized MDMA-Assisted 
Psychotherapy for the Treatment of Severe Posttraumatic Stress Disorder" allows participants to 
be discharged in the evening after the Experimental Session is over at two investigational study 
sites. In MAPS’ Phase 2 study MAA1, which tested the safety and efficacy of MDMA-assisted 
psychotherapy for social anxiety among autistic adults, an overnight stay was not required. There 
were no safety concerns due to travel to home or hotel, and this approach was found to be 
feasible. 
 
Study site and participants will follow all protocol procedures described in the main protocol, 
except those related to overnight stays as described below. The overnight stay is included in the 
main study protocol primarily as an opportunity for rest and integration in a relaxed and 
comfortable environment away from the distractions of home, and to facilitate the logistics of 
participation in the integrative visit at the site on the day following the Experimental Session. The 
overnight stay is not required for medical reasons, but in case of emergencies, the therapists and 
study physician are on-call for all sites. 
 
In the main study protocol, a Night Attendant accompanies the participant during the overnight 
stay. The Night Attendant’s primary function is to ensure the participant is comfortable and has a 
meal, to provide minimal support, and to alert qualified site staff in case of need expressed by the 
participant or determined by observation. All Night Attendants are interviewed, trained, and 
approved by therapy teams to ensure they are comfortable providing the necessary support and 
know whom to call if medical support is needed from the therapy team or study physician.  
 
Medically-trained Night Attendants have not been required for any of the five Phase 2 studies of 
MDMA-assisted psychotherapy for PTSD since MP-1 was completed. In MP-1, the first Phase 2 
study, the FDA required that the Night Attendant be a registered nurse. Since MP-1, Night 
Attendants were not required to have medical training in subsequent studies. Among 189 
participants treated under this IND, no medical complications have arisen during overnight stays 
under the watch of Night Attendants. 
 
The sponsor and investigators agree that allowing participants who are screened for stable 
domestic circumstances to return home will not increase the risks of participation in the study. 
The study protocol discusses the risk of psychological distress in a PTSD population and 
mitigation in Section 10.2.2.2. Therapists and site physicians are aware of these risks, including 
anxiety and depressed mood occasionally reported 1 to 3 days after MDMA administration. In 
previous Phase 1 and 2 studies, these reactions have been transient and have responded well to 
reassurance from the therapy team, with occasional use of benzodiazepines for anxiety. If needed, 
the study physician may prescribe a short-acting, low-dose benzodiazepine (specifically, 
lorazepam) or sleep aids (excluding trazodone) as needed. 
 
Consistent with the main study protocol and the sub-study, proper preparation and follow-up 
support will reduce the difficulties participants might have with acute or sub-acute reactions. The 
potential for destabilizing psychological distress will be minimized by: 
 
• 
Excluding people who might be more vulnerable to it (such as people diagnosed with 
bipolar affective disorder type 1 or with psychotic disorders) 
• 
Excluding people who do not have a stable living situation or supportive family/network 

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• 
Preparatory Sessions of non-drug psychotherapy before the Experimental Session 
• 
Creating an atmosphere of trust during the Experimental Session 
• 
Close monitoring 
• 
Phone contact with participants during the week after the Experimental Session 
• 
Conduct of Integrative Session on the morning after the Experimental Session 
 
Specific to sub-study: 
 
• 
Therapist phone contact with participants on the night of the Experimental Session. 
• 
A support person identified by the participant and agreed upon by the therapist must stay 
with the participant overnight on the evening following the Experimental Session. 
• 
The therapists will meet with the support person prior to the first Experimental Session to 
assess their ability to act as an appropriate support person and to give them instructions 
about what to expect following Experimental Sessions and how to contact study 
personnel if needed. 
• 
A support person must assist the participant during transfer from study site after the 
Experimental Session and to the study site on the following morning for the Integrative 
Session. This Integrative Session will start later in the day to allow for logistics of 
transportation. Participants can arrange their own transportation after the Integrative 
Session. 
  
Implementation of Sub-study 
 
All eligibility criteria from the main study protocol will apply, except for the following inclusion 
criteria listed as a Lifestyle Modification: 
 
Post Experimental Session 
 
• 
Are willing to remain overnight at the study site after each Experimental Session until 
after the Integrative Session the next morning 
• 
Are willing to be driven home on the morning after the Experimental Sessions after the 
Integrative Session, either by a driver arranged by the participant, site personnel or taxi. 
 
Sub-study participants will be required to be willing to: 
 
Post Experimental Session 
 
• 
Identify a support person willing to accompany them overnight at a safe location of their 
choice after each Experimental Session. 
• 
Have the support person escort them away from the study site in the evening after the 
Experimental Sessions and to the site on the following morning for the Integrative 
Session. 
 
Screening & Preparatory Periods 
 
During the Screening and Preparatory Period, the participant will identify an appropriate support 
person to stay with the participant on the evening of the Experimental Session. Participants will 
be escorted to and from the study site after Experimental Sessions. The support person is not 
required to be the same as the escort for the participant. There may be more than one support 
person(s), and they will be responsible for providing companionship as needed overnight and 
contacting the study team with any questions or concerns. Any support person spending the night 

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with the participant will meet the therapist team, during the Preparatory Period or in advance of 
the appropriate Experimental Session in-person to be oriented to the role. An escort who is 
responsible only for transportation need not meet with the therapist team to perform that role. The 
participant will provide contact information for the appropriate support person(s) in advance of 
each Experimental Session. 
 
Orienting the Support Person 
 
In advance of the appropriate Experimental Session, the support person staying with the 
participant overnight will be required to meet with the therapist team in person. The support 
person will receive printed instructions, including contact information of the study physician, 
therapists, Principal Investigator, and Study Coordinator and what to do in the case of an 
emergency.  
 
The support person will not provide psychotherapy to the participant. Minimal discussion is 
acceptable, but only if initiated by the participant. The support person should not interpret the 
participant’s experience or act as therapist. The therapy team will discuss this explicitly with the 
support person and include this information in the written instructions. 
 
The main roles of the support person include: 
 
• 
Ensuring the participant has a comfortable place to sleep and discuss the plan for wakeup, 
breakfast, and travel time for the next day’s Integrative Session 
• 
Seeing to the participant’s needs for food and liquids, including providing dinner and 
breakfast in accordance with the participant’s dietary preferences 
• 
Eating with the participant unless they ask to be left alone 
• 
Cleaning up after the participant, including doing the dishes and handling bedding 
• 
Keeping all participant information confidential 
• 
Ensuring the participant is safely transported to and from the study site as appropriate 
(may be completed by a separate support person) 
• 
Ensuring that the participant does not leave the overnight site without accompaniment 
and does not leave the participant alone at the overnight site. The participant may have 
privacy at the overnight site. 
• 
Supervising the participant to ensure they do not consume drugs or alcohol on the night 
of the Experimental Session and that phone/computer time is limited 
• 
Remaining sober throughout the entire overnight stay 
• 
Remaining available to participant’s needs throughout the night, but may sleep if the 
participant is sleeping 
 
End of Experimental Sessions 
 
Consistent with the main protocol, at the end of each Experimental Session, the therapy team and 
site physician will assess the participant to decide if they are physically and emotionally stable. If 
the participant is not stable, the therapy team and/or site physician will stay with the participant 
until stable or escalate for further care as appropriate. If it is in the best interest of the participant 
for them to spend the night at the study site, the therapists will ensure an appropriate stay is 
provided. 
 
In the sub-study, if a participant is deemed medically and psychologically stable by the therapy 
team at the end of the Experimental Session, the participant will be escorted home via car, 
rideshare, or public transportation and will not remain overnight at the study site. The support 

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person will be provided with an instruction sheet including how to contact the Clinical 
Investigator, Site Physician, and/or therapy team to report any issues. The support person will 
stay overnight with the participant and be instructed to call 911 in the case of a psychiatric or 
medical emergency. 
 
Each participant will be instructed to call the therapy team when they arrive where they will stay 
for the night. If the therapy team has not received a call within 2 hours after the participant has 
left the site, the therapists will call the participant and support person to confirm arrival. The 
therapy team will ask about the participant’s emotional well-being and invite them to begin the 
process of integration through self-reflection, journaling, meditation, or other quiet activities. The 
therapy team will remind the participants that this evening should be an opportunity to rest and 
integrate and that they should avoid unnecessary stresses, chores, etc. The therapy team will also 
discuss this with the participant during the Preparatory and Experimental Sessions. The therapy 
team and site physician will remain on-call overnight to attend to any medical or psychological 
issues that may come up for the participant. 
 
On the morning after the Experimental Session, the participant will be escorted to the study site 
via car, rideshare, or public transportation, as participants are not allowed to drive within 24 hours 
of administration of MDMA.  
 
In the sub-study, if a participant is deemed to be not psychologically stable at the end of the 
Experimental Session, they will remain under the care of their therapy team. The therapy team 
will continue to evaluate the participant to make further disposition recommendations depending 
on the participant’s psychological condition. This could include: continued observation, 
psychological support and/or psychopharmacologic interventions; or further evaluation for 
potential transfer as appropriate per site Standard Operating Procedures (SOPs). If the therapy 
team determines that the participant needs ongoing observation and psychological care at the 
same location as the Experimental Session, there will be the option for them to remain overnight 
with the therapy team in accordance with site SOPs. If the participant will not be leaving the site 
for the night, the therapy team will call the support person(s) to inform them and arrange 
appropriate transportation following the Integrative Session on the following day if appropriate. 
 
Sub-Study Objective & Evaluation 
 
The primary objective of this sub-study will be to evaluate the feasibility of conducting MDMA-
assisted psychotherapy for PTSD among participants who do not remain at the study site 
overnight after Experimental Sessions.  
 
This sub-study will include all participants enrolled and treated at two study sites. No formal 
analysis is planned to support this objective due to small sample size. However, case reports and 
AEs collected on the night of the Experimental Session will be evaluated to support feasibility. 
These reports will be used to explore feasibility of expanding the sub-study to include additional 
Phase 3 clinical sites and to support generalizability of potentially delivering this treatment to 
varied treatment settings post-approval.