Clinical trial NCT03282123
Conditions: PTSD
Keywords: MDMA methylenedioxymethamphetamine therapy midomafetamine
Sponsor: Lykos Therapeutics
Start date: 2017-11-16; Completion date: 2019-08-10
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical trial is to learn if MDMA-assisted therapy is safe and effective in people diagnosed with at least severe PTSD.

The main question it aims to answer is: Do three open-label sessions of MDMA-assisted therapy reduce PTSD symptoms?

Participants will receive three non-drug preparatory sessions followed by three sessions of MDMA-assisted therapy. Each MDMA-assisted therapy session is followed by three non-drug integrative therapy sessions.

Detailed description:
This multi-site, open-label, Phase 2, lead-in study assesses the safety and efficacy of MDMA-assisted therapy in participants diagnosed with at least severe posttraumatic stress disorder (PTSD). Therapy teams that have been identified and trained to work on the sponsor's planned Phase 3 studies will treat at least one open-label participant in this study.

This study will compare the effects of three open-label manualized Experimental Sessions of psychotherapy assisted by flexible doses of MDMA. Initial doses per Experimental Session include 80 mg or 120 mg of MDMA compounded with lactose, followed 1.5 to 2 hours later by a supplemental half-dose (40 mg or 60 mg). Total amounts of MDMA to be administered per Experimental Session range from 80 mg to 180 mg. 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. The Primary Outcome measure is the change in Clinician Administered PTSD Scale for DSM 5 (CAPS-5) from Baseline to Primary Endpoint (Visit 19).

Arms: arm 1: Three sessions of MDMA-assisted therapy with flexible dose of midomafetamine HCl from 80 to 120 mg and optional supplemental dose half that of initial dose 1.5 to 2 hours later
Interventions: intervention 1: Midomafetamine intervention 2: Manualized therapy
Intervention descriptions: intervention 1: 80 to 120 mg MDMA intervention 2: Non-directive therapy conducted during MDMA-assisted therapy session

Protocol documents:
Prot_003.pdf: 
 
 
 
 
 
Protocol and Synopsis MP16 
IND #063384 
 
Original Protocol Version 1: 18 May 2017 
Amendment 1 Version 1: 03 January 2018 
 
An Open-Label, Multi-Site Phase 2 Study of the Safety and Effect 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 
 
MAPS Public Benefit Corporation 
1115 Mission Street 
Santa Cruz, CA 95060 
 
SPONSOR DESIGNEE 
Amy Emerson 
Executive Director and Director of Clinical Research 
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. 
208 Scott Street 
Mount Pleasant, SC 29464 
Phone number: 843-849-6899 
Email: michael@mapsbcorp.com 
 
USE 
In conjunction with relevant Food and Drug Administration 
(FDA) guidance 
 
Sponsor emergency contact phone number: 650-248-4647
 
CONFIDENTIAL 
 
 


MAPS Public Benefit Corporation 
 
MP16 Protocol Synopsis  
IND #063384 
 
Amendment 1 Version 1: 03 January 2018 
Page 2 of 93 
MP16 Protocol Synopsis  
Full protocol begins on Page 9. 
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). Data from a series of Phase 2 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 open-
label Phase 2 study will serve as the lead-in to the sponsor’s two planned Phase 3 studies, only 
sites planned for Phase 3 will participate in this study. This open-label lead-in Phase 2 study will 
serve to validate assumptions made for statistical power calculations supporting planned Phase 3 
clinical trials and will provide data on the updated version of the instrument for the Primary 
Outcome measure, the Clinician Administered PTSD Scale for DSM-5 (CAPS-5), which will be 
used in Phase 3. In addition, the study will gather supportive data on the safety and effect of 
manualized MDMA-assisted psychotherapy while providing an opportunity for clinical 
supervision to planned Phase 3 therapy teams. This study will be the sponsor’s first multi-site 
study of MDMA-assisted psychotherapy for PTSD and will explore reproducibility of findings in 
a multi-site format to confirm the Phase 3 study design. 
 
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 can 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.  
 
Study Design 
This multi-site, open-label lead-in study assesses the safety and effect of MDMA-assisted 
psychotherapy in participants diagnosed with at least severe PTSD. All data will be included in 
the sponsor’s safety database. Therapy teams that have been identified to work on the sponsor’s 
planned Phase 3 studies will treat at least one open-label participant in this study. The study will 
be conducted in up to N=60 participants. 
 
A flexible dose of MDMA, followed by a supplemental half-dose unless contraindicated, is 
administered during the Treatment Period with manualized psychotherapy in three open-label 
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 CAPS-5 from Baseline (V3), is 
assessed by a centralized Independent Rater (IR) pool at 18 weeks post Baseline (V19). The 
CAPS-5 is also administered as an exploratory measure after Treatments 1 and 2 (V8 and V13). 
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.  


MAPS Public Benefit Corporation 
 
MP16 Protocol Synopsis  
IND #063384 
 
Amendment 1 Version 1: 03 January 2018 
Page 3 of 93 
 
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. 
 
Study Design Overview 
 
Screening Period 
From Consent to Enrollment (Visit 0): ~4 weeks (+/-2 weeks) 
Study Visit 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Screening 
Screening  
Multiple visits over 3 
weeks/ 
After phone screen/ 
(-2 weeks/+1 week) 
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 3 weeks at multiple visits. 
Independent 
Rater Screening 
1 hour/ 
2 days after initial 
eligibility established 
during Screening/  
(+7 days) 
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 days after 
Independent Rater 
Screening 
(+12 days) 
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 1 week for stabilization). Adverse 
Event (AE) collection begins. 
 
 
 


MAPS Public Benefit Corporation 
 
MP16 Protocol Synopsis  
IND #063384 
 
Amendment 1 Version 1: 03 January 2018 
Page 4 of 93 
Preparatory Period with Enrollment Confirmation  
From Preparatory Session 1 (Visit 1) to Preparatory Session 3 (Visit 4): ~6 weeks (+5/-4 weeks) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Preparatory Period 
Preparatory 
Session 1 
(Visit 1) 
1.5 hours/ 
Within 1 week (0 to 12 
days) of Enrollment 
(V0) 
 
90-minute Preparatory Session. Target visit timing 
on tapering needs. If needed, schedule calls between 
V1 and V2 if indicated for tapering, safety, or further 
questions about medical history. 
Preparatory 
Session 2 
(Visit 2) 
 
1.5 hours/ 
Within 3 weeks of V1 
 
90-minute Preparatory Session/ongoing assessment. 
If tapering is complete or not needed, check 
eligibility and schedule V3 and V4. If tapering is 
ongoing, schedule post taper call for ongoing 
assessment. 
Phone Call 
End Taper 
 
1 hour/ 
Within 1 week of taper 
end & 8 weeks of V0 
If needed, confirm medication taper and stabilization 
is complete and participant is eligible for Baseline 
CAPS-5. Schedule V3 and V4. 
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. 
Preparatory 
Session 3 
& Enrollment  
Confirmation 
(Visit 4) 
3 hours: (95 minutes of 
measures, 90 minute 
therapy) 
Within 6 days of V3 
Prior to visit, ensure CAPS-5 confirms PTSD 
diagnosis and Total Severity Score of ≥35 and 
confirm enrollment by reassessing specified 
eligibility criteria. Complete Baseline self-report 
measures. Complete 3 hour Preparatory Session 
(~95-min measures, 90-min therapy) and schedule 
V5. If enrollment is not confirmed, do not perform 
visit; complete termination and put on waiting list 
for Expanded Access study if appropriate. 
 
Treatment Period 
From Experimental Session 1 (Visit 5) to Integrative Session 3.3 (Visit 18): 12 weeks (-3/+4) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Treatment 1 
Experimental 
Session 1 
(Visit 5) 
8 hours + overnight/ 
Within 1 week of V3, 
at least 2 weeks after 
V2 
First Experimental Session is within 1 week of the 
Baseline CAPS-5 (V3) and 2 weeks after 
Preparatory Session 2 (V2); 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 
V6 is a 90-minute Integrative Session the morning 
after V5. Followed by 4 phone check-ins over the 7 
days post V5.  
Integrative 
Session 1.2 
(Visit 7) 
1.5 hours/ 
within 2 weeks of V5 
Approximately 2 weeks after V5, a 90-minute 
Integrative Session (V7) is completed. 
CAPS-5 T2 
(Visit 8) 
1 hour 
Within 3 weeks after 
V5 
Complete before V9 
Between V7 and V9, CAPS-5, SDS, and DSP-I 
assessment completed by an IR via telemedicine.  
Integrative 
Session 1.3 
(Visit 9) 
1.5 hours/ 
Within 4 weeks of V5 
1-7 days before V10 
90-minute Integrative Session post V8 and in 
preparation for V10. Can occur 1 to 7 days before 
V10. Measures include LEC-5, PCL-5, and C-SSRS. 
 
 
 


MAPS Public Benefit Corporation 
 
MP16 Protocol Synopsis  
IND #063384 
 
Amendment 1 Version 1: 03 January 2018 
Page 5 of 93 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Treatment 2 
Experimental 
Session 2 
(Visit 10) 
8 hours + overnight/ 
Within 4 weeks of V5/ 
(+/-1 weeks), at least 2 
weeks after Visit 7 
3 to 5 weeks after V5, and 2 weeks after Integrative 
Session 1.1 (V6). 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 
V11 is a 90-minute Integrative Session the morning 
after V10. Followed by 4 phone check-ins over 7 
days post V10.  
Integrative 
Session 2.2 
(Visit 12) 
1.5 hours/ 
Within 2 weeks of V10 
Approximately 2 weeks after V10, a 90-minute 
Integrative Session (V12) is completed. 
CAPS-5 T3 
(Visit 13) 
1 hour/ 
Within 3 weeks after 
V10 
Complete before V14 
Between V12 and V14, CAPS-5, SDS, and DSP-I 
assessment completed by an IR via telemedicine. 
Integrative 
Session 2.3 
(Visit 14) 
1.5 hours/ 
Within 4 weeks of V10 
1-7 days before V15 
90-minute Integrative Session post V13 and in 
preparation for V15. Can occur up to 1 to 7 days 
before V15. Measures include LEC-5, PCL-5 and C-
SSRS. 
Treatment 3 
Experimental 
Session 3 
(Visit 15) 
8 hours + overnight/ 
Within 4 weeks of V10 
(+/-1 weeks), at least 2 
weeks after Visit 12 
3 to 5 weeks after V5, and 2 weeks after Integrative 
Session 2.1 (V11). 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 
V16 is a 90-minute Integrative Session the morning 
after V15. Followed by 4 phone check-ins over 7 
days post V15. 
Integrative 
Session 3.2 
(Visit 17) 
1.5 hours/ 
Within 2 weeks of V15 
Within 2 weeks after V15, a 90-minute Integrative 
Session (V12) is completed. 
Integrative 
Session 3.3 
(Visit 18) 
1.5 hours/ 
Within 4 weeks of V15 
90-minute Integrative Session post V17, within 4 
weeks of V15. Measures include LEC-5 and C-
SSRS. 
 
 
 


MAPS Public Benefit Corporation 
 
MP16 Protocol Synopsis  
IND #063384 
 
Amendment 1 Version 1: 03 January 2018 
Page 6 of 93 
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/ 
(Scheduling Window) 
Brief Description of Events  
Primary Outcome 
Primary 
Outcome 
CAPS-5 T4 
(Visit 19) 
1 hour/ 
~18 (+/-3) weeks post 
Baseline & 
8 (+/-2) weeks post 
V15 
Within 18 weeks (+/-3 weeks) of Baseline and 8 
weeks (+/-2 weeks) 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 must 
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. 
Study 
Termination 
Study 
Termination 
(Visit 20) 
2 hours  
~18 (+/-3) weeks post 
Baseline & 
2 days post V19/ 
(-1/+7 days) 
Occurs ~18 weeks post Baseline and within 1 to 9 
days of V19. Complete self-reported and safety 
measures; create an exit plan for participant. Invite 
participant to the extension study for LTFU.  
 
Qualified IRs selected based on availability from the IR Pool will perform the CAPS-5 
assessments as described in the following table.  
 
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 V2 and V4 Preparatory Sessions 
0 days 
CAPS-5 T2 
V8 
Post Experimental Session 1 (~3 weeks) 
Between V7 and V9 Integrative Sessions 
~6 weeks 
CAPS-5 T3 
V13 
Post Experimental Session 2 (~3 weeks) 
Between V12 and V14 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 open-label manualized Experimental Sessions of 
psychotherapy assisted by flexible doses of MDMA 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 
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 


MAPS Public Benefit Corporation 
 
MP16 Protocol Synopsis  
IND #063384 
 
Amendment 1 Version 1: 03 January 2018 
Page 7 of 93 
The overall objective of this study is to use standard clinical measures to explore the safety and 
effects of open-label manualized MDMA-assisted psychotherapy with a flexible dose of MDMA 
in participants with severe PTSD and to serve as an opportunity for supervision of therapy teams 
selected to conduct Phase 3 MDMA-assisted psychotherapy research. 
 
Primary Objective 
The primary objective of this study is to evaluate the effect of MDMA-assisted psychotherapy on 
PTSD, as measured by the estimand of change in CAPS-5 Total Severity Score from Baseline 
(Visit 3) to 18 weeks post Baseline (Visit 19). 
 
Secondary Objective 
 
The secondary objective is to evaluate the effect of MDMA-assisted psychotherapy for PTSD 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).  
Safety Objectives 
The overall safety objective is to assess severity, incidence and frequency of AEs, 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. 
 
1. Assess incidence of AEs during Experimental Sessions that may be indicative of a 
medical complication of the Investigational Product (IP), 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. Assess incidence of AEs by severity. 
3. Assess incidence of Treatment Emergent AEs (TEAEs) by severity. 
4. Assess incidence of TEAEs by severity taken during an Experimental Session and 2 days 
after IP administration. 
5. Assess incidence of AESIs, defined as AEs specified in the protocol related to cardiac 
function and abuse liability. 
6. Assess incidence of AEs by severity categorized as leading to discontinuation of IP, 
resulting in death or hospitalization, and continuing at Study Termination. 
7. Assess incidence of SAEs. 
8. Assess incidence of psychiatric concomitant medications taken during an Experimental 
Session and 2 days after IP administration. 
9. Assess incidence of any psychiatric concomitant medications taken during the Treatment 
Period. 
10. Assess incidence of serious suicidal ideation and positive suicidal behavior assessed with 
the Columbia Suicide Severity Rating Scale (C-SSRS). 
11. Assess mean changes in blood pressure, heart rate, and body temperature from pre-IP 
administration to end of each Experimental Session. 
 
Recruitment and Participant Population 
Therapy teams that have been identified to work on the sponsor’s planned Phase 3 studies will 
treat at least one open-label participant in this study. Up to N=60 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 psychiatrists, psychotherapists, or physicians, and by 


MAPS Public Benefit Corporation 
 
MP16 Protocol Synopsis  
IND #063384 
 
Amendment 1 Version 1: 03 January 2018 
Page 8 of 93 
word of mouth. The sponsor will monitor demographics on an ongoing basis and encourage 
diversity in enrollment by communicating with sites.  
 
Participants will be persons aged 18 or older, with a confirmed diagnosis of at least severe PTSD 
per the PCL-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. 
 
Statistical Analysis  
All outcome analyses will be based on the mITT analysis set. Change from Visit 3 (Baseline) in 
CAPS-5 Total Severity Scores to Visit 19 (Primary Outcome) will be analyzed with least squares 
means from a Mixed-Effect Repeated Measures model (MMRM). The mITT analysis set will 
include all participants who receive IP in at least one Experimental Session and have at least one 
follow-up CAPS-5 assessment. 
 


MAPS Public Benefit Corporation 
 
MP16 Protocol Synopsis  
IND #063384 
Amendment 1 Version 1: 03 January 2018 
 
Page 9 of 93 
Study Structure Overview 
 
 
 
 
 
 
 


 
 
 
 
 
MP16 Protocol 
IND #063384 
 
Original Protocol Version 1: 18 May 2017 
Amendment 1 Version 1: 03 January 2018 
 
An Open-Label, Multi-Site Phase 2 Study of the Safety and Effect 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 and Director of Clinical Research 
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. 
208 Scott Street 
Mount Pleasant, SC 29464 
Phone number: 843-849-6899 
Email: michael@mapsbcorp.com 
 
USE 
In conjunction with relevant Food and Drug Administration 
(FDA) 
 
Sponsor emergency contact phone number: 650-248-4647 
 
 
 


MAPS Public Benefit Corporation 
 
MP16 Protocol  
IND #063384 
 
Amendment 1 Version 1: 03 January 2018 
Page 11 of 93 
Table of Contents 
List of Tables ................................................................................................................................ 14 
List of Figures ............................................................................................................................... 14 
1.0 List of Abbreviations ............................................................................................................. 15 
2.0 Introduction ............................................................................................................................ 18 
2.1 Rationale .............................................................................................................................. 18 
2.2 Background .......................................................................................................................... 19 
2.2.1 PTSD ............................................................................................................................. 19 
2.2.2 MDMA .......................................................................................................................... 20 
2.2.3 MDMA-Assisted Psychotherapy for PTSD .................................................................. 21 
2.2.4 Previous Clinical Experience with MDMA .................................................................. 21 
3.0 Protocol Objectives ................................................................................................................ 23 
3.1 Primary Objective ................................................................................................................ 23 
3.2 Secondary Objective ............................................................................................................ 23 
3.3 Safety Objectives ................................................................................................................. 23 
3.4 Exploratory Objectives ........................................................................................................ 24 
4.0 Eligibility Criteria .................................................................................................................. 24 
4.1 Inclusion Criteria ................................................................................................................. 24 
4.2 Exclusion Criteria ................................................................................................................ 25 
4.3 Lifestyle Modifications ........................................................................................................ 27 
5.0 Protocol Design....................................................................................................................... 27 
5.1 Study Design Overview ....................................................................................................... 27 
5.2 Planned Duration of Study ................................................................................................... 33 
5.3 Discontinuation and Completion Criteria ............................................................................ 34 
5.3.1 Complete or Evaluable Participants .............................................................................. 34 
5.3.2 Screen Failures .............................................................................................................. 34 
5.3.3 Pre-Dosing Early Terminations .................................................................................... 35 
5.3.4 Early Termination from the Study ................................................................................ 35 
5.3.5 Lost to Follow-up .......................................................................................................... 36 
5.4 End of Study Definition and Premature Discontinuation .................................................... 36 
5.5 Rationale of Dose Selection ................................................................................................. 36 
6.0 Psychotherapy ........................................................................................................................ 37 
6.1 Description of Therapeutic Method ..................................................................................... 37 
6.2 Therapy Team Qualifications .............................................................................................. 38 
6.3 Training ................................................................................................................................ 38 
6.3.1 Therapy Training Program ............................................................................................ 38 
6.4 Adherence to Therapeutic Method ....................................................................................... 38 
7.0 Measures and Reliability ....................................................................................................... 38 
7.1 Primary Outcome Measure and Reliability .......................................................................... 40 
CAPS-5 (Clinician-Administered PTSD Scale for DSM-5) .................................................. 40 
7.2 Secondary Outcome Measure .............................................................................................. 41 
SDS (Sheehan Disability Scale) ............................................................................................. 41 
7.3 Safety Measures ................................................................................................................... 41 
C-SSRS (Columbia Suicide Severity Rating Scale) .............................................................. 41 
7.4 Screening Measures and Reliability ..................................................................................... 41 
MINI (Mini-International Neuropsychiatric Interview) ......................................................... 41 
SCID-5-PD (Structured Clinical Interview for DSM-5 for Personality Disorders) ............... 41 
LEC-5 (Life Events Checklist for DSM-5) ............................................................................ 42 
PCL-5 (PTSD Checklist) ....................................................................................................... 42 
DDIS (Dissociative Disorders Interview Schedule for DSM-5) ............................................ 42 
7.5 Exploratory Measures .......................................................................................................... 42 


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Amendment 1 Version 1: 03 January 2018 
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DSP-I (The Dissociative Subtype of PTSD Interview).......................................................... 42 
ACE (Adverse Childhood Experience Questionnaire) .......................................................... 42 
BDI-II (Beck Depression Inventory II) .................................................................................. 43 
CPGS (Chronic Pain Grade Scale)......................................................................................... 43 
EQ-5D-5L (EuroQol Five Dimensions – Five Levels Questionnaire) ................................... 43 
IASC (Inventory of Altered Self Capacities) ......................................................................... 44 
Inventory of Psychosocial Functioning .................................................................................. 44 
SCS (Self-Compassion Scale) ................................................................................................ 44 
TAS-20 (Toronto Alexithymia Scale) .................................................................................... 44 
AUDIT (Alcohol Use Disorders Identification Test)............................................................. 45 
DUDIT (Drug Use Disorders Identification Test) ................................................................. 45 
SRNU (Self-reported Nicotine Use) ...................................................................................... 45 
EAT-26 (Eating Attitudes Test) ............................................................................................. 45 
HPQSF (Health and Work Performance Absenteeism and Presenteeism Short Form) ......... 45 
UFEC (Utilization of Facility-based and Emergent Care) ..................................................... 46 
8.0 Study Procedures ................................................................................................................... 46 
8.1 Screening Period .................................................................................................................. 50 
8.1.1 Screening....................................................................................................................... 50 
8.1.2 Independent Rater Screening ........................................................................................ 52 
8.1.3 Enrollment..................................................................................................................... 53 
8.2 Preparatory Period with Enrollment Confirmation .............................................................. 53 
8.2.1 Preparatory Sessions 1 and 2 ........................................................................................ 53 
8.2.2 Baseline: CAPS-5 by Independent Rater ...................................................................... 54 
8.2.3 Baseline: Preparatory Session 3 & Enrollment Confirmation ...................................... 54 
8.3 Treatment Period .................................................................................................................. 55 
8.3.1 Experimental Sessions .................................................................................................. 55 
8.3.2 Telephone Contact After Experimental Sessions .......................................................... 58 
8.3.3 Integrative Sessions ...................................................................................................... 58 
8.3.4 Independent Rater Assessments .................................................................................... 59 
8.4 Follow-up Period and Study Termination ............................................................................ 59 
8.4.1 Follow-up Period .......................................................................................................... 59 
8.4.2 Final Independent Rater Assessment ............................................................................ 60 
8.4.3 Study Termination ........................................................................................................ 60 
8.4.3.1 Extension Studies ................................................................................................... 61 
8.4.3.2 Exit Plan ................................................................................................................. 61 
9.0 Investigational Product ......................................................................................................... 61 
9.1 Description of Active Compounds ....................................................................................... 61 
9.1.1 Doses ............................................................................................................................. 61 
9.1.2 Dose Modifications ....................................................................................................... 61 
9.1.3 Stability ......................................................................................................................... 62 
9.2 Handling ............................................................................................................................... 62 
9.2.1 Encapsulation, Packaging, and Labeling ...................................................................... 62 
9.2.2 Accountability ............................................................................................................... 62 
9.2.3 Storage .......................................................................................................................... 62 
9.2.4 Administration .............................................................................................................. 63 
9.2.5 Treatment Compliance .................................................................................................. 63 
9.3 Participant Numbering ......................................................................................................... 63 
9.4 Blinding and Bias Minimization .......................................................................................... 63 
10.0 Risks ...................................................................................................................................... 64 
10.1 Non-drug Related Risks ..................................................................................................... 64 
10.1.1 Medical Assessments .................................................................................................. 64 
10.1.2 PTSD, Suicide Risk, and Psychotherapy .................................................................... 64 


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10.1.3 Recorded Content ........................................................................................................ 66 
10.2 Risks of Receiving MDMA ............................................................................................... 66 
10.2.1 High Level Risks ......................................................................................................... 66 
10.2.2 Medium Level Risks ................................................................................................... 66 
10.2.2.1 Cardiovascular and Cerebrovascular Risks and Mitigation ................................. 66 
10.2.2.2 Psychological Risks and Mitigation ..................................................................... 67 
10.2.3 Low Level Risks ......................................................................................................... 69 
10.2.3.1 Thermoregulatory Risks and Mitigation .............................................................. 69 
10.2.3.2 Osmoregulatory Risk and Mitigation ................................................................... 69 
10.2.3.3 Genotoxicity Risk and Mitigation ........................................................................ 69 
10.2.3.4 Reproductive and Developmental Risks and Mitigation ..................................... 69 
10.2.4 Minimal Risks ............................................................................................................. 70 
10.2.4.1 Common AEs ....................................................................................................... 70 
10.2.4.2 Potential Neurotoxicity Associated with Ecstasy Use ......................................... 70 
10.2.4.3 Abuse Liability ..................................................................................................... 71 
11.0 Safety ..................................................................................................................................... 71 
11.1 Adverse Events .................................................................................................................. 71 
11.1.1 Adverse Events of Special Interest ............................................................................. 72 
11.1.2 Serious Adverse Events .............................................................................................. 73 
11.2 Other Significant Events .................................................................................................... 73 
11.3 Pregnancy ........................................................................................................................... 74 
11.3.1 Definition of Childbearing Potential ........................................................................... 74 
11.3.2 Contraception Guidelines ............................................................................................ 74 
11.3.3 Follow-up Requirements ............................................................................................. 74 
11.4 Medical Monitor ................................................................................................................ 75 
12.0 Concomitant Medications ................................................................................................... 75 
12.1 Tapering Instructions ......................................................................................................... 75 
12.2 Allowed Concomitant Medications ................................................................................... 76 
12.3 Prohibited Medications ...................................................................................................... 76 
13.0 Clinical Laboratory Assessments ....................................................................................... 77 
14.0 Statistical Considerations .................................................................................................... 78 
14.1 Statistical Analyses ............................................................................................................ 78 
14.1.1 Effect Analyses ........................................................................................................... 79 
14.1.1.1 Primary Outcome Analyses ................................................................................. 79 
14.1.1.2 Secondary Outcome Analyses ............................................................................. 79 
14.1.1.3 Exploratory Analyses ........................................................................................... 79 
14.1.2 Safety Analyses ........................................................................................................... 79 
15.0 Study Governance ................................................................................................................ 80 
15.1 Ethics ................................................................................................................................. 80 
15.1.1 Financial Disclosure .................................................................................................... 80 
15.1.2 Informed Consent ........................................................................................................ 80 
15.2 Study Monitoring, Auditing, and Documentation ............................................................. 81 
15.2.1 Source Records ........................................................................................................... 82 
15.3 Confidentiality ................................................................................................................... 82 
15.4 Costs to Participants ........................................................................................................... 82 
15.5 Treatment and Compensation for Study Related Injury .................................................... 83 
15.6 Record Retention ............................................................................................................... 83 
15.7 Publication Policy .............................................................................................................. 83 
Appendix A: Sub-study without Overnight Stays .................................................................. 90 
 


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List of Tables 
 
Table 1: Study Design Overview ................................................................................................... 30 
Table 2: Primary Outcome (CAPS-5) Data Collection by Visit .................................................... 33 
Table 3: Dose Regimen of MDMA................................................................................................ 37 
Table 4: Protocol Objectives and Assessment Tools ..................................................................... 38 
Table 5: Time and Events – Study Procedures .............................................................................. 47 
Table 6: Time and Events – Study Measures ................................................................................. 49 
Table 7: Schedule of Procedures for Experimental Sessions ......................................................... 56 
 
List of Figures 
 
Study Structure Overview .............................................................................................................. 29 
 
 


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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 
AED 
 
Automatic External Defibrillator 
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 
BLS 
 
Basic Life Support 
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 
CPGS  
Chronic Pain Grade Scale 
CRA 
 
Clinical Research Associate 
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 
DMF 
 
Drug Master File 
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 
HPMC  
Hydroxypropyl Methylcellulose 


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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 
IP 
 
Investigational Product 
IPF 
 
Inventory of Psychosocial Functioning 
IR 
 
Independent Rater 
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
ITT 
 
Intent-to-Treat 
IUD 
 
Intrauterine Device 
IUS 
 
Intrauterine Hormone-releasing 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 
MedDRA 
Medical Dictionary for Regulatory Activities  
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 
SPGT  
Serum Glutamic Pyruvic Transaminase 
SRNU  
Self-reported Nicotine Use 
SSR 
 
Sample size re-estimation 
SSRI 
 
Selective serotonin reuptake inhibitor 
SUBJID 
Subject Identifier 
TAS-20 
Toronto Alexithymia Scale 
TEAE  
Treatment Emergent Adverse Event 
TSH 
 
Thyroid-stimulating Hormone 


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UFEC  
Utilization of Facility-based and Emergent Care 
U.S. 
 
United States 
VA 
 
U.S. Department of Veterans Affairs 
VAS 
 
Visual Analog Scale 
WBC  
White Blood Cell 
WHO  
World Health Organization 
WHO DDE 
WHO Drug Dictionary EnhancedTM 
 


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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 novel treatment package consists of 
three once-monthly Experimental Sessions of psychotherapy combined with a flexible dose of 
MDMA, along with non-drug preparatory and integrative psychotherapy. 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. The results from multiple independent 
studies in Phase 2 efficacy analyses demonstrate superiority of MDMA-assisted psychotherapy 
over psychotherapy with placebo or low dose MDMA. The acceptable risk-benefit ratio in early 
trials justifies further study.  
 
This open-label lead-in Phase 2 study is intended to gather supportive data on the safety and 
effect of manualized MDMA-assisted psychotherapy as a treatment for PTSD. The Primary 
Outcome measure, the change in Clinician Administered PTSD Scale for DSM-5 (CAPS-5) from 
Baseline, evaluates changes in PTSD symptom severity and is assessed by a centralized 
Independent Rater (IR) pool in this study and in planned Phase 3 clinical trials [1]. This will be 
the first larger study of MDMA-assisted psychotherapy using the CAPS-5 as a primary outcome 
measure to confirm assumptions made for statistical power calculations using the Clinician-
Administered PTSD Scale for DSM-4 (CAPS-4) which support planned Phase 3 clinical trials. 
This study will gather supportive data on the safety and effect of manualized MDMA-assisted 
psychotherapy as a treatment for PTSD and provide clinical supervision to planned Phase 3 
therapy teams. This study will also be the first multi-site study of MDMA-assisted psychotherapy 
for PTSD, and will explore reproducibility of findings in a multi-site format to further confirm the 
Phase 3 study design. 
 
In this Phase 2 study, therapy teams without previous experience on a MAPS-sponsored MDMA-
assisted psychotherapy study will have the opportunity for clinical supervision from the sponsor 
prior to their roles in Phase 3 studies. Only sites planned for Phase 3 will participate in this study. 
The sponsor conducts group and individual training programs to teach therapy team members 
about techniques and procedures for conducting MDMA-assisted psychotherapy for PTSD. These 
programs are designed to support and expand the knowledge and skills of therapy team members 
who will be working on MDMA research studies. 
 
 


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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 
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 [2]. 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 the 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 [6]. Beyond disability payments, in 2012 alone the 
VA spent $294 million and $3 billion, respectively, on care for veterans with the disorder and 
disability payments, and 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 [7]. There are an estimated 20 to 22 
suicides a day by veterans [8, 9]. 
 
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 [9-11]. 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 


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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 [13, 14]. 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 [14, 15], although some patients may 
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 [17]. 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 [18] for a review). Examples of this are virtual reality-assisted exposure therapy [18, 19] and 
D-cycloserine-assisted psychotherapy [20]. 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 [21, 22]. 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 [23-29]. 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) [30, 31]. Studies of regular or problematic Ecstasy users indicate that on average, 
regular use occurs no more often than once a week [32]. Hence, MDMA may have moderate 
abuse potential. See the Investigator’s Brochure (IB) for a more detailed explanation. 
 


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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 [16]. To be effective, exposure must be accompanied by a degree of 
emotional engagement or “fear activation” while avoiding dissociation or overwhelming emotion 
[34]. This has been referred to as working within the “optimal arousal zone” or “window of 
tolerance” [35-37]. 
 
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 [37], and there is some indication that MDMA may increase activity in the 
prefrontal cortex [39]. Brain imaging after MDMA indicates less reactivity to angry facial 
expressions and greater reward in happy faces [37]. 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 [39-41]. The reduction in stress-
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 [42-45]. 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 [47]. 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 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 [48], with 80 to 160 milligrams (mg) MDMA required to produce 
desired subjective effects in humans [48, 49]. MDMA was found to robustly influence human 


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emotional status in a unique way [48] without adversely affecting physiological functions or 
perception, such as visual perception or cognition [49-52]. In the 1970s, psychotherapists used 
MDMA-assisted psychotherapy to treat psychological disorders, including anxiety [54]. Legal 
therapeutic use continued until its placement on the U.S. list of Schedule 1 substances in 1985 
[43, 46, 54]. An estimated 500,000 doses of MDMA were administered during psychotherapy and 
personal growth sessions in North America prior to its scheduling [44, 56]. A few uncontrolled 
human studies of MDMA assessing safety in a therapeutic setting occurred in the 1980s [56, 57]. 
 
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 [58, 59]. 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 [46]. 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 
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) [44, 60] and one in Switzerland (MP2) [61, 62]. 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, 2016, with 154 individuals exposed to MDMA 
in the sponsor’s development program across various indications and at least 1130 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-
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 


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expanding the research initiative to encompass a larger sample of participants with PTSD in 
MP16 and a future 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 explore the safety and 
effects of open-label manualized MDMA-assisted psychotherapy with a flexible dose of MDMA 
in participants with severe PTSD, and to serve as an opportunity for supervision of therapy teams 
selected to conduct Phase 3 MDMA-assisted psychotherapy research.  
 
3.1 Primary Objective 
1. The primary objective of this study is to evaluate the effect of MDMA-assisted 
psychotherapy on PTSD, as measured by the estimand of change in CAPS-5 Total 
Severity Score from Baseline (Visit 3) to 18 weeks post Baseline (Visit 19). 
 
3.2 Secondary Objective 
1. The secondary objective is to evaluate the effect of MDMA-assisted psychotherapy for 
PTSD 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 severity, incidence and frequency of AEs, 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. 
 
1. Assess incidence of AEs during Experimental Sessions that may be indicative of a 
medical complication of the Investigational Product (IP), 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. Assess incidence of AEs by severity 
3. Assess incidence of Treatment Emergent AEs (TEAEs) by severity 
4. Assess incidence of TEAEs by severity taken during an Experimental Session and 2 days 
after IP administration 
5. Assess incidence of AESIs, defined as AEs specified in the protocol related to cardiac 
function and abuse liability 
6. Assess incidence of AEs by severity categorized as leading to discontinuation of IP, 
resulting in death or hospitalization, and continuing at Study Termination 
7. Assess incidence of SAEs 
8. Assess incidence of psychiatric concomitant medications taken during an Experimental 
Session and 2 days after IP administration 
9. Assess incidence of any psychiatric concomitant medications taken during the Treatment 
Period 


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10. Assess incidence of serious suicidal ideation and positive suicidal behavior assessed with 
the Columbia Suicide Severity Rating Scale (C-SSRS) 
11. Assess mean changes in blood pressure, heart rate, and body temperature from pre-IP 
administration to end of each Experimental Session 
 
3.4 Exploratory Objectives 
These objectives may be explored to characterize participants receiving MDMA-assisted 
psychotherapy to support the primary objective: 
 
1. Explore the effect of presence of secondary traumatic stressors (LEC-5) on the CAPS-5 
Total Severity analyses 
2. Explore changes within-participants 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. Explore the effect of adverse childhood experiences (ACE) on the CAPS-5 Total Severity 
analyses 
4. Explore changes in:  
• 
Dissociative symptoms associated with PTSD (DSP-I) 
• 
Depression (BDI-II)  
• 
Chronic pain (CPGS) 
• 
Quality of life (EQ-5D-5L) 
• 
Functioning in relation to self and others (IASC) 
• 
Psychosocial functioning (IPF) 
• 
Self-compassion (SCS) 
• 
Alexithymia (TAS-20) 
• 
Addictive behaviors including: alcohol use (AUDIT), drug use (DUDIT), and 
nicotine use (SRNU)  
• 
Eating habits (EAT-26) 
• 
Workplace productivity (HPQSF) 
• 
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 (those criteria 
marked with an * below will only be assessed at Screening, since they will not change).  
 


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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 or implanted hormonal methods, abstinence, oral 
hormones plus a barrier contraception, 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 50 or greater 
11. *At Screening, 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. *At Screening, 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. 
 
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 


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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 
 
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 affective disorder 
type 1 assessed via MINI or dissociative identity disorder assessed via DDIS 
8. *Have a current eating disorder with active purging assessed via MINI 
9. *Have current major depressive disorder with psychotic features assessed via MINI 
10. *Meet DSM-5 criteria for active substance use disorder for any substance other than 
caffeine or nicotine in the past 60 days assessed via MINI, AUDIT, DUDIT, drug test, 
and blood %carbohydrate-deficient transferrin (%CDT) 
11. 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. Diagnoses will be confirmed via clinical 
interview 
12. 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 
13. Would present a serious risk to others as established through clinical interview and 
contact with treating psychiatrist 
14. Require ongoing concomitant therapy with a psychiatric medication with exceptions 
described in Section 12.0: Concomitant Medications. 
 
Medical History 
15. *Have evidence or history of significant (controlled or uncontrolled) hematological, 
endocrine, cerebrovascular, cardiovascular, coronary, pulmonary, renal, gastrointestinal, 
immunocompromising, or neurological disease, including seizure disorder, or any other 
medical disorder judged by the investigator to significantly increase the risk of MDMA 
administration (participants with hypothyroidism who are on adequate and stable thyroid 
replacement will not be excluded). Note: if participants present with a history of 
glaucoma, enrollment would be allowed only with the approval of their ophthalmologist 
16. *Have uncontrolled 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) 
17. *Have a marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration 
of a QTc interval >450 milliseconds [ms] corrected by Bazett’s formula) 
18. *Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, 
hypokalemia, family history of Long QT Syndrome) 
19. *Require use of concomitant medications that prolong the QT/QTc interval during 
Experimental Sessions. Refer to Section 12.0 Concomitant Medications. 
20. *Have symptomatic liver disease 
21. *Have history of hyponatremia or hyperthermia 
22. *Weigh less than 48 kilograms (kg) 
23. Are pregnant or nursing, or are of childbearing potential and are not practicing an 
effective means of birth control. 
 


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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. 
• 
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 IP 
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 pills, 
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, open-label study assesses the safety and effect of MDMA-assisted psychotherapy 
in participants diagnosed with at least severe PTSD. This study will also serve as an experiential 
training opportunity for therapy teams who will be investigators in future MAPS studies. The 
sponsor will provide clinical supervision, as the sponsor adherence raters and trainers can monitor 
videos of study visits for adherence to the therapeutic method. Written feedback will be provided 
by trainers from the Therapy Training Program or experienced MDMA-assisted therapy team 
members from Phase 2 studies. 
 


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The study will be conducted in up to N=60 participants. Each therapy team that has not 
previously participated in a MAPS-sponsored protocol will treat one open-label participant in this 
study. All data will be included in the sponsor’s safety database. 
 
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, followed by a supplemental half-dose unless 
contraindicated, administered with manualized psychotherapy in three open-label 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 CAPS-5 from Baseline (V3), is 
assessed by a centralized Independent Rater (IR) pool at 18 weeks post Baseline (V19). The 
CAPS-5 is also administered as an exploratory measure after Treatments 1 and 2 (V8 and V13). 
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.  


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Study Structure Overview 
 
 
 
 
 
 
 
 


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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/ 
(Scheduling Window) 
Brief Description of Events  
Screening 
Screening  
Multiple visits over 3 
weeks/ 
After phone screen/ 
(-2 weeks/+1 week) 
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 3 weeks at multiple visits. 
Independent 
Rater Screening 
1 hour/ 
2 days after initial 
eligibility established 
during Screening/  
(+7 days) 
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 days after 
Independent Rater 
Screening 
(+12 days) 
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 1 week for stabilization). 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/-4 weeks) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Preparatory Period 
Preparatory 
Session 1 
(Visit 1) 
1.5 hours/ 
Within 1 week (0 to 12 
days) of Enrollment 
(V0) 
 
90-minute Preparatory Session. Target visit timing 
on tapering needs. If needed, schedule calls between 
V1 and V2 if indicated for tapering, safety, or further 
questions about medical history. 
Preparatory 
Session 2 
(Visit 2) 
 
1.5 hours/ 
Within 3 weeks of V1 
 
90-minute Preparatory Session/ongoing assessment. 
If tapering is complete or not needed, check 
eligibility and schedule V3 and V4. If tapering is 
ongoing, schedule post taper call for ongoing 
assessment. 
Phone Call 
End Taper 
 
1 hour/ 
Within 1 week of taper 
end & 8 weeks of V0 
If needed, confirm medication taper and stabilization 
is complete and participant is eligible for Baseline 
CAPS-5. Schedule V3 and V4. 
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. 
Preparatory 
Session 3 
& Enrollment  
Confirmation 
(Visit 4) 
3 hours: (95 minutes of 
measures, 90 minute 
therapy) 
Within 6 days of V3 
Prior to visit, ensure CAPS-5 confirms PTSD 
diagnosis and Total Severity Score of ≥35 and 
confirm enrollment by reassessing specified 
eligibility criteria. Complete Baseline self-report 
measures. Complete 3 hour Preparatory Session 
(~95-min measures, 90-min therapy) and schedule 
V5. If enrollment is not confirmed, do not perform 
visit; complete termination and put on waiting list 
for Expanded Access study if appropriate. 
 
Treatment Period 
From Experimental Session 1 (Visit 5) to Integrative Session 3.3 (Visit 18): 12 weeks (-3/+4) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Treatment 1 
Experimental 
Session 1 
(Visit 5) 
8 hours + overnight/ 
Within 1 week of V3, 
at least 2 weeks after 
V2 
First Experimental Session is within 1 week of the 
Baseline CAPS-5 (V3) and 2 weeks after 
Preparatory Session 2 (V2); 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 
V6 is a 90-minute Integrative Session the morning 
after V5. Followed by 4 phone check-ins over the 7 
days post V5.  
Integrative 
Session 1.2 
(Visit 7) 
1.5 hours/ 
within 2 weeks of V5 
Approximately 2 weeks after V5, a 90-minute 
Integrative Session (V7) is completed. 
CAPS-5 T2 
(Visit 8) 
1 hour 
Within 3 weeks after 
V5 
Complete before V9 
Between V7 and V9, CAPS-5, SDS, and DSP-I 
assessment completed by an IR via telemedicine.  
Integrative 
Session 1.3 
(Visit 9) 
1.5 hours/ 
Within 4 weeks of V5 
1-7 days before V10 
90-minute Integrative Session post V8 and in 
preparation for V10. Can occur 1 to 7 days before 
V10. Measures include LEC-5, PCL-5, and C-SSRS. 
 
 
 


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Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Treatment 2 
Experimental 
Session 2 
(Visit 10) 
8 hours + overnight/ 
Within 4 weeks of V5/ 
(+/-1 weeks), at least 2 
weeks after Visit 7 
3 to 5 weeks after V5, and 2 weeks after Integrative 
Session 1.1 (V6). 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 
V11 is a 90-minute Integrative Session the morning 
after V10. Followed by 4 phone check-ins over 7 
days post V10.  
Integrative 
Session 2.2 
(Visit 12) 
1.5 hours/ 
Within 2 weeks of V10 
Approximately 2 weeks after V10, a 90-minute 
Integrative Session (V12) is completed. 
CAPS-5 T3 
(Visit 13) 
1 hour/ 
Within 3 weeks after 
V10 
Complete before V14 
Between V12 and V14, CAPS-5, SDS, and DSP-I 
assessment completed by an IR via telemedicine. 
Integrative 
Session 2.3 
(Visit 14) 
1.5 hours/ 
Within 4 weeks of V10 
1-7 days before V15 
90-minute Integrative Session post V13 and in 
preparation for V15. Can occur up to 1 to 7 days 
before V15. Measures include LEC-5, PCL-5 and C-
SSRS. 
Treatment 3 
Experimental 
Session 3 
(Visit 15) 
8 hours + overnight/ 
Within 4 weeks of V10 
(+/-1 weeks), at least 2 
weeks after Visit 12 
3 to 5 weeks after V5, and 2 weeks after Integrative 
Session 2.1 (V11). 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 
V16 is a 90-minute Integrative Session the morning 
after V15. Followed by 4 phone check-ins over 7 
days post V15. 
Integrative 
Session 3.2 
(Visit 17) 
1.5 hours/ 
Within 2 weeks of V15 
Within 2 weeks after V15, a 90-minute Integrative 
Session (V12) is completed. 
Integrative 
Session 3.3 
(Visit 18) 
1.5 hours/ 
Within 4 weeks of V15 
90-minute Integrative Session post V17, within 4 
weeks of V15. Measures include LEC-5 and C-
SSRS. 
 
 
 


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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/ 
(Scheduling Window) 
Brief Description of Events  
Primary Outcome 
Primary 
Outcome 
CAPS-5 T4 
(Visit 19) 
1 hour/ 
~18 (+/-3) weeks post 
Baseline & 
8 (+/-2) weeks post 
V15 
Within 18 weeks (+/-3 weeks) of Baseline and 8 
weeks (+/-2 weeks) 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 must 
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. 
Study 
Termination 
Study 
Termination 
(Visit 20) 
2 hours  
~18 (+/-3) weeks post 
Baseline & 
2 days post V19/ 
(-1/+7 days) 
Occurs ~18 weeks post Baseline and within 1 to 9 
days of V19. Complete self-reported and safety 
measures; create an exit plan for participant. Invite 
participant to the extension study for LTFU.  
 
Qualified IRs selected based on availability from the IR Pool will perform the CAPS-5 
assessments as described in table below.  
 
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 V2 and V4 Preparatory Sessions 
0 days 
CAPS-5 T2 
V8 
Post Experimental Session 1 (~3 weeks) 
Between V7 and V9 Integrative Sessions 
~6 weeks 
CAPS-5 T3 
V13 
Post Experimental Session 2 (~3 weeks) 
Between V12 and V14 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 2 to 6 weeks after completion of phone screening. The Preparatory 
Period begins at enrollment and can be as brief as 2 weeks, but depending on medication tapering 
could be as long as 11 weeks to ensure an appropriate medication washout of at least five half-
lives of pre-study psychiatric medications and active metabolites, and at least one additional week 
for stabilization. 
 
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 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 


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overall timelines should comply with the target timing of the Primary Outcome CAPS-5 T4 
assessment, which must be completed 18 weeks (+/- 3 weeks) 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. 
 
5.3 Discontinuation and Completion Criteria 
5.3.1 Complete or Evaluable Participants 
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 not eligible for the study, 
and do not schedule additional Screening assessments. Participants who fail 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. 
 


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5.3.3 Pre-Dosing Early Terminations 
‘Pre-Dosing 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-Dosing Early Terminations are not 
considered evaluable. 
 
Pre-Dosing 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-Dosing 
Early Termination, notify the potential participant that they are not eligible for the study, and do 
not schedule additional assessments. Do not perform the next visit. Pre-Dosing 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 enrolled and receive IP but do not 
complete the study may fall into one of these categories: Post-Dosing Early Termination or 
Dropout. If the participant has received IP in at least one Experimental Session and completed 
one CAPS-5 assessment beyond Baseline, they will be considered evaluable. All participants who 
receive IP 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 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, 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. 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. 
 
• 
Post-Dosing Early Termination: Participants who discontinue study treatment but 
continue to participate in study evaluations and outcome assessments. Data collection by 
IRs will continue on the same schedule as planned through Study Termination visit 
procedures. 
 


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• 
Dropout: If a participant decides to withdraw consent, they will terminate without further 
follow-up. If the participant agrees, they will complete a final CAPS-5 assessment and 
Study Termination visit procedures. These participants are defined as dropouts who 
withdraw consent due to any reason after receiving at least one dose of IP 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 1 week, 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 attempt contact with their support person. 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. 
 
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 


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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 
previously explored 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 safely administered 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. 
 
This open-label study will examine the effects of a flexible dose of 80 mg to 120 mg MDMA 
administered in three Experimental Sessions. Initial doses per Experimental Session range from 
80 mg to 120 mg MDMA compounded with lactose, followed 1.5 to 2 hours later by a 
supplemental half-dose (40 mg or 60 mg). 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.  
 
Table 3: Dose Regimen of MDMA 
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. In the second and third 
Experimental Sessions, the initial dose may be increased to 120 mg MDMA unless 
contraindicated in the opinion of the site team. The choice of whether to keep the dose the 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. 
 
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 
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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 male/female therapy teams 
• 
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 
6.3.1 Therapy Training Program 
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 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 adherence raters who will analyze video data from specific 
and randomly selected Preparatory Sessions, Experimental Sessions, and Integrative 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 Axis 1 psychiatric disorders 
MINI 
Eligibility 
Site 
Assess Axis 2 personality disorders 
SCID-5-PD 
with SCID-
5-SPQ 
Eligibility 
Telemedicine 
(IR)/ self-report 
measure at Site 


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Objectives 
Measure 
Measure Type 
Administration 
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 overall changes in clinician-rated 
functional impairment from Visit 3 to Visit 
19 compared between groups 
SDS 
item scores 
Outcome 
Site 
Assess changes in severity of dissociative 
symptoms associated with PTSD from Visit 3 
to Visit 19 compared between groups  
DSP-I 
Outcome 
Site 
Explore correlation of dissociative symptoms 
associated with PTSD with the CAPS-5 Total 
Severity analyses 
DSP-I 
CAPS-5 
Outcome 
Site 
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 
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 
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 depression symptoms from 
Visit 4 to Visit 20 compared between groups 
BDI-II 
Outcome 
Site 
Assess changes in chronic pain from Visit 4 
to Visit 20 compared between groups 
CPGS 
Outcome 
Site 
Assess changes in quality of life from Visit 4 
to Visit 20 compared between groups 
EQ-5D-5L 
Outcome  
Site 


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Objectives 
Measure 
Measure Type 
Administration 
Assess changes in functioning in relation to 
self and others from Baseline to Visit 20 
compared between groups 
IASC 
Outcome 
Site 
Assess changes in self-reported psychosocial 
functioning from Visit 4 to Visit 20 
compared between groups 
IPF 
Outcome 
Site 
Assess changes in self-compassion from 
Visit 4 to Visit 20 compared between groups 
SCS 
Outcome 
Site 
Assess changes in alexithymia from Visit 4 
to Visit 20 compared between groups 
TAS-20 
Outcome 
Site 
Assess changes in alcohol use from 
Screening to Visit 20 compared between 
groups  
AUDIT 
Healthcare cost 
Site 
Assess changes in drug use from Screening 
to Visit 20 compared between groups  
DUDIT 
Healthcare cost 
Site 
Assess changes in nicotine use from Visit 4 
to Visit 20 compared between groups 
SRNU 
Healthcare cost 
Site 
Assess changes in disordered eating from 
Visit 4 to Visit 20 compared between groups  
EAT-26 
Healthcare cost 
Site 
Assess changes in workplace productivity 
from Visit 4 to Visit 20 compared between 
groups 
HPQSF 
Healthcare cost 
Site 
Assess facility-based healthcare utilization at 
Screening 
UFEC 
Healthcare cost 
Site 
 
7.1 Primary Outcome Measure and Reliability 
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 [64], including the most distressing event, time since exposure, 
to produce a diagnostic score (presence vs. absence) and a PTSD Total Severity score [64]. 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. 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 IP. 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, and any study data for the participant. IR visits will be assigned based on availability. 


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7.2 Secondary Outcome Measure 
SDS (Sheehan Disability Scale) 
The SDS is a clinician-rated assessment of functional impairment [65]]￼. 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). Per FDA request, for participants who are not able 
to work for reasons related to PTSD, the functional impairment item will be scored as a 10. The 
SDS takes 1 to 2 minutes to complete. [66]64].  
 
7.3 Safety Measures 
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 
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 Axis I 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 [70]. The MINI takes 
between 15 and 20 minutes to perform, and addresses major psychiatric disorders. MINI items 
were highly 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 [70, 71] Testing on 
nonpsychiatric samples did not create false positives [67].  
 
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 [72]. 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 Axis 2 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. 


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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 [73]]. 
 
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 [74]. 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 
50 at Screening will be required for initial enrollment. 
 
DDIS (Dissociative Disorders Interview Schedule for DSM-5) 
Questions on the DDIS specifically addressing dissociative disorder symptoms (items 117-130) 
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 [75]. 
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 
 
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 [76-79]. Assessments 
of military veterans and civilians support the existence of a dissociative subtype of PTSD that is 
associated with PTSD severity and derealization and depersonalization. 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. 
 
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 


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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 [74]. 
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 
[75-78]. The scoring method has been used in archival research, finding an association between 
increased scores and health problems in several generations [83].  
 
BDI-II (Beck Depression Inventory II) 
The BDI-II is a revision of the BDI, a 21-item self-report measure [79, 80] that will serve as a 
measure of depression symptom severity [81]. 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 [81]. 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 [81, 82]. 
Higher scores indicate more severe depressive symptoms.  
 
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 [89]. 
Responses to questions are used to attain a rating (grade) for pain from 0 (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 [90]. 
 
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 
statement 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 
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 [93]. 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. 
 


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IASC (Inventory of Altered Self Capacities) 
The IASC is a 63-item self-report measure of difficulties with relationships, identity, and affect 
regulation [95]. 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 five-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 [95]. 
 
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 [96]. 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) [97].  
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 [98]. Respondents complete the SCS by 
indicating how typical they feel on each item on a five-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 
more strongly associated with stable mood and less associated with self-rumination and anger 
[99]. 
 
TAS-20 (Toronto Alexithymia Scale) 
The TAS-20 is a 20-item measure of self-reported difficulties with recognizing and verbalizing 
emotions [101, 102]. 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). 
 


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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) [102]. 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 [103]. 
 
DUDIT (Drug Use Disorders Identification Test) 
The DUDIT is an 11-item measure designed to assess presence of substance use disorders [105]. 
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% [105]. The 
English translation was developed from a Swedish-language original. Estimated time to complete 
is 2 to 4 minutes. 
 
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. 
 
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 [105].  
 
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 [106]. 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 [107], and the HPQSF appears to be reliable between 
one time point and another (reliability of 0.52) and is sensitive to change [106]. 
 


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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 a week 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 
(2-6 weeks) 
Preparatory Period w/ Enrollment Confirmation 
(2-11 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 3 wks 
(-2 weeks/+1 
wks) 
2 days after 
initial 
eligibility met 
(+7 days) 
2 days post IR 
Screening 
(+12 days) 
Within 1 wk 
of V0 (0 to 
12 days) 
Within 3 wks 
of V1 
Post V2 & 
Taper 
Within 6 days of V3 
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-min 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 wks) 
18 weeks (+/-3 wks) 
post Baseline 
 
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 
CAPS-5 
T2: Tele- 
medicine 
Int. 1.3 
Exp. 2 
Int. 2.1 
Int. 
2.2 
CAPS-5 
T3: Tele- 
medicine 
Int. 2.3 
Exp. 3 
Int. 3.1 
Int. 3.2 
Int. 3.3 
CAPS-5 
T4 
Outcome: 
Tele-
medicineH 
Study 
Termi-
nation 
Visit Timing 
Within 
1 wk of 
V3 
Morn-
ing 
after 
V5 
With-
in 2 
wks 
of V5 
Within 3 
weeks 
after V5 
1-7 
days 
before 
V10 
Within 
4 wks 
of V5 
(+/-1 
wk) 
Morn-
ing 
after 
V10 
With-
in 2 
wks 
of 
V10 
Within 3 
weeks 
after 
V10 
1-7 days 
before 
V15 
Within 
4 wks 
of V10 
(+/-1 
wk) 
Morn-
ing 
after 
V15 
Within 
2 wks 
of V15 
Within 
4 wks 
of V15 
8 wks 
post V15 
(+/-2 wk) 
2 days 
post 
V19 (-
1/+7 
days) 
Past/Current 
Medication & 
Adherence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Screen  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All AEs C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Container 
Assignment D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer IP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8-hour Exp. 
Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BP, Pulse, 
Temperature E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 F 
Overnight Stay I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
90-min Integrative 
Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Call 
Follow-up G 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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  Obtain container assignment 24 to 48 hours prior to each Experimental Session 
E  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 
F  At Study Termination, only blood pressure needs to be measured 
G  4 days of phone call follow-up: Day 2 and 7 after the Experimental Session, with two additional calls in between 
H  All visits must be scheduled to ensure that the Primary Outcome CAPS-5 T4 assessment is within the overall window provided: 18 weeks (+/-3 weeks) post V3 
I  See Appendix A for exceptions to overnight stay directive 
 


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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 
 
 
 
 
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 
93 
 
40 
10 
77 
23 
40 
10 
77 
23 
40 
10 
15 
77 
95 
 
 
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 and 7 after Experimental Session 
D The relevant questions (117-130) 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 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. 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. 
• 
Perform a urine drug test 


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• 
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 2-12, 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 well-controlled hypertension and 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 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. 
 
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.  
 


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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, an IR will continue the eligibility 
assessment via telemedicine after reviewing the results of the LEC-5 and SCID-5-SPQ. The 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. 
 
• 
Using the results of the SCID-5-SPQ to guide the interview, the IR will perform the 
SCID-5-PD to assess Axis 2 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 Axis I 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 measure or interview indicate a diagnosis is present, the investigator is not 
permitted to use their clinical judgment to deny the diagnosis. However, if a 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.  
 
After the initial screening visit the IRs will be blinded to visit number, number of treatments 
received and any study data for the participant. IR visits will be assigned based on availability.  


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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). V0 should take place 2 days (+12 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 one 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 2 weeks. The Preparatory Period will also 
include the Baseline CAPS-5 assessment (Visit 3), which will be assessed by an 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.  
 
• 
Preparatory Session 1 (Visit 1) will occur within 1 week (0 to 12 days) of Visit 0. The 
visit timing should take in to account appropriate times for monitoring medication 
tapering.  
• 
Preparatory Session 2 (Visit 2) will occur within 3 weeks of Visit 0 and at least 2 days 
after Visit 1. The visit timing should take into account appropriate times for monitoring 
medication tapering. Visit 2 must take place at least 2 weeks prior to Experimental 
Session 1 (Visit 5). 


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• 
If tapering is ongoing at Preparatory Session 2 (Visit 2), the site team will schedule a 
telephone phone call after tapering and stabilization are complete 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 [108]. 
 
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 an Enrollment Confirmation Failure, notify the potential 
participant that they are unfortunately not eligible for the study, and not schedule additional 
assessments. If appropriate, the site team will place the participant on a waiting list for an 
Expanded Access study. 
 
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. 
 
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 within 6 days of the Baseline 
CAPS-5 assessment but ideally will take place as close to Experimental Session 1 (Visit 5) as 
possible, but not on the same day.  
 
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 


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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-Dosing Early 
Termination. 
 
For eligible participants at Visit 4, qualified site staff will ensure at least 3 hours are scheduled for 
the visit and: 
 
• 
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: 
o PCL-5- ensure assessment is in relation to index trauma 
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  
 
Completion of the measures does not need to be recorded. 
 
• 
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. 
 
8.3.1 Experimental Sessions 
There will be three open-label Experimental Sessions (Visits 5, 10, 15). Procedures for MDMA-
assisted psychotherapy will remain the same across all sessions and all procedures regardless of 


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dose received. Experimental Sessions must be at least 8 hours long, measured from 30 minutes 
prior to IP administration. 
 
• 
Experimental Session 1 (Visit 5) will occur within 1 week of the Baseline CAPS-5 (Visit 
3) assessment. 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 
IP followed by a supplemental half-dose 1.5 to 2 hours after the initial dose unless 
contraindicated. 
• 
Experimental Session 2 (Visit 10) will occur within 3 to 5 weeks of Experimental Session 
1 (Visit 5) and after Integrative Session 1.3. A dose of 80 or 120 mg MDMA 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 within 3 to 5 weeks of the second 
Experimental Session (Visit 10) and after Integrative Session 2.3. A dose of 80 or 120 mg 
MDMA 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, body temperature, pulse 
10:00  
IP Administration, Begin video recording  
11:30  
BP, body temperature pulse 
Supplemental Dose Administration, unless contraindicated  
17:30 
C-SSRS, BP, body temperature, pulse 
 
Pre-IP administration 
• 
On the day of the Experimental Session, the participant will arrive approximately 30 to 
60 minutes prior to IP administration. 
• 
The site team will ensure the participant has not used caffeine or nicotine 2 hours prior, 
and fasted for 10 hours prior to IP 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 
Safety. 
• 
The site team will instruct the participant that they will not be able to use caffeine or 
nicotine at least 6 hours after the IP administration. 
• 
The site team will complete urine drug screen, pregnancy test, and concomitant 
medication review. 
a. A positive drug screen will be reviewed by the site physician and may be cause 
for delaying IP administration to a later time, rescheduling the session to a later 
date, or withdrawing the participant from the study, based on Medical Monitor 
review.  
b. 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 


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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 IP 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. 
• 
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 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. 
 
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-IP 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. 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 


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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 the second and 
seventh day after each Experimental Session, with two additional telephone contacts in between. 
Each call will last on average five to 15 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. 
 
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 
• 
On the second and seventh contact day after an Experimental Session the therapy team 
will administer the Since Last Visit C-SSRS. 
 
8.3.3 Integrative Sessions 
After each Experimental Session, three Integrative Sessions will take place. Each session will 
consist of 90 minutes of psychotherapy. 
 
Treatment 1 
• 
Integrative Session 1.1 (Visit 6): morning after Experimental Session 1 (Visit 5) 
• 
Integrative Session 1.2 (Visit 7): approximately 2 weeks after Experimental Session 1 
(Visit 5) 
• 
Integrative Session 1.3 (Visit 9): within 3 to 5 weeks of 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 and PCL-5 self-report measures. 
 
Treatment 2 
• 
Integrative Session 2.1 (Visit 11): morning after Experimental Session 2 (Visit 10) 
• 
Integrative Session 2.2 (Visit 12): approximately 2 weeks after Experimental Session 2 
(Visit 10) 
• 
Integrative Session 2.3 (Visit 14): within 3 to 5 weeks of 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 and PCL-5 self-report measures. 


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Treatment 3 
• 
Integrative Session 3.1 (Visit 16): morning after Experimental Session 3 (Visit 15) 
• 
Integrative Session 3.2 (Visit 17): approximately 2 weeks after Experimental Session 3 
(Visit 15) 
• 
Integrative Session 3.3 (Visit 18): within 3 to 5 weeks 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. 
• 
At each third Integrative Session, direct the participants to complete the PCL-5 with the 
exception of Visit 18. 
 
 
8.3.4 Independent Rater Assessments 
Participants will have two CAPS-5 assessments during the treatment period of the study (Visits 8 
and 13). An IR from the IR Pool will conduct the assessments via telemedicine. These 
assessments may be recorded to establish inter-rater reliability. The results may be shared with 
site staff, but the IR Coordinator will enter the data. The IR will also administer the DSP-I and 
SDS at these time-points: 
 
• 
CAPS-5 T2 (Visit 8): 3 weeks 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): 3 weeks 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 a Study Termination (Visit 20). Participants will have access to 
therapy teams for support if needed, and additional visits via phone, telemedicine, or in person 


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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). An IR from the IR Pool will conduct the assessments via telemedicine. These assessments 
may be recorded to establish inter-rater reliability. The IR Coordinator will enter the data in 
stand-alone database. The results may be shared with site staff during supervision by the therapy 
training team. Although there are allowable windows for all visits throughout the protocol, the 
Primary Outcome CAPS-5 T4 assessment must be completed 18 weeks (+/- 3 weeks) after the 
Baseline CAPS-5 assessment and within 8 weeks (+/-2 weeks) of 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 2 (-1/+7) 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. 
 
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. 
• 
Actively support participant in completion of Study Termination self-reported measures: 
o LEC-5  
o PCL-5- ensure assessment is in relation to index trauma 
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 
 
Completion of the measures do not need to be recorded. 
 


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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. 
 
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. 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 IP. Lactose will serve as an 
inactive excipient. 
 
9.1.1 Doses 
This study will compare the effects of three open-label manualized Experimental Sessions of 
psychotherapy assisted by flexible doses of MDMA. Initial doses per Experimental Session 
include 80 mg or 120 mg MDMA compounded with lactose, followed 1.5 to 2 hours later by a 
supplemental half-dose (40 mg or 60 mg). Total amounts of MDMA to be administered per 
Experimental Session range from 80 mg to 180 mg. Refer to Table 5: Dose Regimen of MDMA. 
 
9.1.2 Dose Modifications 
In the first Experimental Session, the initial dose will be 80 mg MDMA. In the second and third 
Experimental Sessions, the initial dose may be increased to 120 mg MDMA 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 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.  
 


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9.1.3 Stability 
Complete details on the chemistry, manufacturing and control of the MDMA hydrochloride (HCl) 
to be used are described in Drug Master file (DMF) # 6293. As described in that file, MDMA was 
prepared for human consumption by David Nichols, Ph.D., Department of Medicinal Chemistry 
and Pharmacology, Purdue University in 1985. The identity and purity of this MDMA was 
confirmed using High Performance Liquid Chromatography (HPLC) in 1997 as described in 
DMF # 6293 and was found to be 99.87% pure. On August 12, 2002, Chemic Laboratories 
reanalyzed the MDMA at the request of the sponsor in relation to the study of MDMA-assisted 
psychotherapy in people with PTSD, the analysis found it to be more than 99.7% pure. A more 
recent analysis performed by Nichols at the request of researcher Dr. Carl Hart in February 2006 
continued to find a high degree of purity, with the analysis finding the MDMA in question to be 
99.9% pure. The latest analyses conducted in May 2017 support that the MDMA is 100.0% pure 
by HPLC. All required Chemistry Manufacturing and Control (CMC) submissions will be made 
to the IND. 
 
9.2 Handling 
9.2.1 Encapsulation, Packaging, and Labeling 
IP will be compounded, encapsulated, packaged, labeled, and shipped to sites by Zeeh 
Pharmaceutical Experiment Station, a Schedule 1-licensed Analytical Laboratory at the 
University of Wisconsin at Madison. IP in bulk will be sent from a Schedule 1-licensed 
Distributor to the Zeeh Station. Zeeh Station will provide bulk lactose for compounding. IP will 
be compounded with lactose (calculated as the weight of the hydrochloride salt) and placed in 
hydroxypropyl methylcellulose (HPMC) capsules. 
 
Initial and supplemental dose IP for each Experimental Session will be stored in individual inner 
envelopes. Inner envelopes for initial and supplemental doses will be placed within each primary 
container. There will be one primary container per participant per Experimental Session. The IP 
for each Experimental Session will be packaged in one primary container, labeled with a unique 
container number, protocol number, IP name, lot number, sponsor name, IND number, 
Experimental Session number and a statement that the IP is restricted to clinical trial use only. All 
labels will comply with local, state, and federal regulations.  
 
9.2.2 Accountability 
Forms will be provided to track IP accountability and administration throughout the study. Open-
label IP accountability and administration logs will be reviewed during routine monitoring visits. 
IP 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 IP assigned to a 
single Experimental Session. The container numbers will be used to track IP administration in the 
Source Record and the IP administration log. 
 
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 


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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 
IP 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 IP 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 IP accountability. The IP will be stored securely per regulations. 
 
9.3 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 ‘S6’ 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 ‘601’. 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 S611601 and first 
Screening Number at Site 12 will be S612601. 
 
Each participant who passes Screening and is enrolled in the trial at Visit 0 will be assigned a 
seven-digit Subject Number. The first digits will be ‘16’. The next two digits represent the site 
number (e.g., ‘12’), followed by a three-digit participant identifier starting with ‘001’. The 
participant identifier will be assigned to each enrolled participant at a site sequentially. For 
example, the first Subject Number at Site 12 will be 1612001. 
 
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.  
 
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 enrollment confirmation. Participants, site staff, and the 
sponsor will be aware that each participant in MP16 will be receiving open-label MDMA.  
 
To further minimize bias in measuring effect, the sponsor will use an observer-blind, centralized, 
reliable IR pool to administer the Primary Outcome measure via live video interviews. The IR 


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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 study design, 
visit number, number of treatments, and any data from the treating therapy team after Baseline. 
IRs will be assigned to participants based on availability. Data will be entered by the IR 
Coordinator who is not part of the study assessments or procedures. Timing of CAPS-5 
assessments are pre-specified in the study protocol within visit windows. 
 
To ensure that all participants 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 checked by review of video by 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 participants 
who receive at least one dose of IP and complete at least one follow-up assessment will be 
included in the final mITT primary effect analysis. 
 
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 
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 behavior is present at the time of Screening. 
Participants will be enrolled according to the Eligibility Criteria based on the clinical judgment of 
the site physician, therapy team, and Medical Monitor. 
 


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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. Increases in suicidality will be captured as an AE. 
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; 
ii. 
Escort the participant to an appropriate mental health services facility 
(e.g., hospital psychiatric unit); or  
iii. 
Call EMS 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. Notify appropriate members of the study team and sponsor representatives. 
e. The event will be collected as an AE and the seriousness will be evaluated. SAEs 
will be reported per FDA 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. 
 


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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 
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 


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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 IP administration in Experimental Sessions, the therapy team 
will monitor vital signs. The therapy team will attend to clinical signs and symptoms during 
Experimental Sessions, such as chest pain, shortness of breath, neurological deficit or confusion 
other potential indicators of end organ effects of hypertension that prompt additional vital sign 
measurements, and intervene 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, for rare complications of cardiovascular effects, such as stroke or acute 
myocardial infarction (AMI). 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. 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 [111, 112]. 
 
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 
[113]. 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.  
 
As the characterization of QT effects for the API is ongoing, QT interval may 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 [50, 114]. 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 
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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 
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). 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.  
 


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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 
[114]. 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 
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 IP 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 [115, 116]. 
 


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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. Procedures described in Section 11.3 Pregnancy have been put in 
place to mitigate risk of reproductive or developmental exposure to the IP. 
 
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 IP administration, but are transient and diminish as 
the IP 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-
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 [117]. 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 [118]. 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.  
 


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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 abuse 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 studies, 7.6% of participants (seven of 92) reported “Ecstasy” use, with five participants 
indicating single and not repeated use and two participants indicating two uses. Six of these seven 
participants had used Ecstasy prior to study participation. Of these participants, most were 
attempting to recreate a therapeutic experience, and none indicated 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 [62]. 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 IP 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 IP will maintain current registration with authorities with 
oversight of controlled substances. IP 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. 
 
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 
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. 
 


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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 IP 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  
The sponsor will 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, 
syncope, and seizures. 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 IP 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 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, it should be reported via the eCRF within 24 hours of the site’s awareness of 
the event. 
 


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11.1.2 Serious Adverse Events 
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. 
 
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 IP 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. 
 


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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 
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 
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 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. 
 


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11.4 Medical Monitor 
The name and contact information for the Medical Monitor is:  
 
Michael C. Mithoefer  
Email: michael@mapsbcorp.com  
Telephone: 843-849-6899 
Fax: 843-278-9188 
 
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 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. 
 
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 Allowable Concomitant Medications). The prescribing 
physician’s opinion about medication discontinuation will 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 first Experimental Session 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. 
 


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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 (specifically, 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 
receiving study drug, 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. 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 IP 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 cross-taper to a 
different allowed opiate medication. 
 
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. 
 
All psychoactive medications, herbal supplements, nonprescription medications, and prescription 
medications must be reviewed by the research team. 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 to refrain from: 
o Taking any specified 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 pills, 
thyroid hormones, or other medications approved by the research team). 
 


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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 be withdrawn from treatment and 
continue in follow-up. 
 
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 during the Preparatory Period. 
 
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. 
 
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 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  


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• 
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 females of childbearing potential will be performed at the 
site 
• 
Urinary drug test will be performed at the site 
 
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 Statistical Analyses 
Descriptive statistics will be computed overall, as well as by initial MDMA dose received, for all 
available data from outcome measures, 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 participants who receive investigational product in at least one Experimental 
Session and have at least one follow-up CAPS-5 assessment 
• 
Per Protocol (PP): all participants who receive investigational product in three 
Experimental Sessions and have three follow-up CAPS-5 assessments 
• 
Not Per Protocol (NPP): all participants who are included in the mITT Set but not the PP 
Set 
• 
Safety: all participants who receive any IP  


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14.1.1 Effect Analyses 
14.1.1.1 Primary Outcome Analyses 
The primary analysis will be conducted after all participants complete Study Termination (Visit 
20) and the study database has been locked. All outcome analyses will be based on the mITT 
analysis set. The de jure estimand of treatment efficacy is of the most relevance to estimate the 
causal effect of three experimental sessions of MDMA-assisted psychotherapy in a controlled 
clinic setting on PTSD symptom severity in the intended population of patients with PTSD from 
any cause. The primary outcome measure, change from baseline in CAPS-5 score, will be 
analyzed with Mixed Model Repeated Measures (MMRM). The model will include terms for 
visit, baseline CAPS-5 score, and dissociative subtype (if possible). Ninety-five percent 
confidence intervals will be calculated for the estimated mean change from baseline CAPS-5 
scores at each visit. 
 
14.1.1.2 Secondary Outcome Analyses 
Sheehan Disability Scale (SDS), the secondary outcome, will be analyzed in the same manner as 
the Primary Outcome.  
 
14.1.1.3 Exploratory Analyses 
One-group pretest-posttest Cohen’s d effect size will be estimated. Exploratory sub-group 
analyses may be conducted when possible to evaluate effects and by 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 Axis 2 diagnosis, and number of 
experimental sessions completed). Post-hoc exploratory analyses not described in the protocol or 
Statistical Analysis Plan may be performed to further examine the study data. These analyses will 
be clearly identified as such in the final clinical study report. 
 
14.1.2 Safety Analyses 
Safety data will be summarized by exposure to IP, unsolicited AEs, concomitant medications, 
suicidal ideation and behavior, and vital signs overall. 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 IP administration will be presented 
separately. Report 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 IP.  
 
Frequency and incidence of concomitant medications will be displayed by generic name, sorted 
by class, and summarized by analysis set and category. Concomitant medications taken on Day 0 
(Experimental Session), Day 1, Day 2 after IP 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-IP administration, prior to the 
supplemental dose, and at the end of each Experimental Session. Additional details are available 
in the Statistical Analysis Plan. 


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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 her or his 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. 
 
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. 
 


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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 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. 
 
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 IP 
accountability records. An eCRF collation will be completed for each participant enrolled within 
the EDC system.  
 
CAPS-5 results may be shared with site staff. The IR Coordinator will be responsible for review 
and data entry of the CAPS-5 source records into CAPS-5 eCRFs.  
 
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.  
 


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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. 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.  
 
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. 
Data to be securely transferred to remote servers. 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. 
 


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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.  
 
 
15.6 Record Retention 
Investigators must retain all study records required by the sponsor and applicable ICH-GCP and 
FDA regulations 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 IP 
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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 Appendix A: Sub-study without Overnight Stays 
Rationale 
 
This sub-study to the MP16 protocol “An Open-Label, Multi-Site Phase 2 Study of the Safety and 
Effect 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 
• 
Preparatory Sessions of non-drug psychotherapy before the Experimental Session 
• 
Creating an atmosphere of trust during the Experimental Session 


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• 
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 (for exceptions see Appendix A sub-study) 
• 
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 
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. 


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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 
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 two hours after the participant has 


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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. 

ICF_004.pdf: 
 
 
 
 
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PARTICIPANT INFORMATION AND CONSENT FORM  
AND HIPAA AUTHORIZATION 
 
Study Title:  
An Open-Label, Multi-Site Phase 2 Study of the 
Safety and Effect of Manualized MDMA-Assisted 
Psychotherapy for the Treatment of Severe 
Posttraumatic Stress Disorder 
 
Protocol #:  
MP16 
 
Study Sponsor:  
Multidisciplinary Association for Psychedelic Studies 
(MAPS) 
1115 Mission Street  
Santa Cruz, CA 95060 
 
Clinical Investigator Name: 
 
 
Research Site Address: 
 
 
Daytime Telephone Number: 
 
 
24-hour Contact Number: 
 
 
You should keep a copy of this form. If you have any questions or problems during the 
study, call the phone number(s) above.


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PURPOSE OF THE PARTICIPANT INFORMATION AND CONSENT FORM 
This consent form describes a research study and your role as a participant.  This 
consent form may have words in it you do not clearly understand. Please read this form 
carefully before you decide to be in this study. You may ask the therapy team anything 
about the information provided.  
 
The purpose of this form is to give you information about the study and, if signed, the 
form gives us your permission to participate. The form describes the purpose, 
procedures, benefits, risks, discomforts and precautions of the study. You should 
participate only if you want to. You may refuse to take part or withdraw from this study 
at any time without penalty or loss of benefits to which you are otherwise entitled. 
Signing this form will not result in you losing any of your rights. The main purpose of this 
form is to make sure that we are doing our job explaining to you what the study is about. 
 
You may take home an unsigned copy of this consent form to think about or discuss 
with family or friends before deciding to participate.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
If you would like to review the information for this study, or a summary of the results, 
ask the therapy team for the ClinicalTrials.gov study registration number. 
 
Your therapy team will be paid for their time to conduct this research study. 
 
This document uses words such as treatment, drug, medication, and participant. Please 
remember this is a research study and the use of these terms does not mean the use of 
the drug has been found to be safe or effective for your condition. 
 
Before you decide whether to participate, you should think about how the tests and 
study visits will affect your time away from work and your schedule.   
 
BACKGROUND 
You are being asked to participate because you have been diagnosed with 
posttraumatic stress disorder (PTSD) with symptoms lasting for at least six months.  
 
This multi-center study is designed to provide information on whether the drug MDMA 
combined with psychotherapy is safe and helpful for people who have PTSD.  
 
MDMA is an experimental drug, which means that it has not been approved by the Food 
and Drug Administration (FDA) for sale for medical use in the United States (U.S.). 
MDMA is also a controlled drug (illegal to use outside of research) and is sometimes 
known as “Ecstasy” or “Molly” (which is supposed to contain MDMA, but often contains 
other drugs instead of or in addition to MDMA). MDMA is a chemical that is structurally 


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similar to some stimulant chemicals, like methamphetamine, which is both a major drug 
of abuse and an FDA-approved treatment for Attention Deficit Disorder, and to some 
psychedelic (hallucinogenic) chemicals, like mescaline, which is found in peyote cactus. 
MDMA has already been used legally in research and illegally in uncontrolled 
environments, such as nightclubs. While much is known about MDMA and its risks, 
much remains unknown about this drug. 
 
The study is sponsored by a U.S.-based non-profit organization, the Multidisciplinary 
Association for Psychedelic Studies (MAPS, www.maps.org). MAPS has completed six 
studies of MDMA-assisted psychotherapy in the U.S., Canada and Israel. 
 
Before MDMA became illegal in 1985, some psychologists and psychiatrists combined it 
with psychotherapy to help people with psychological problems or challenges, including 
PTSD and couples therapy. Though we do not know exactly why it may help people 
with PTSD, we know that MDMA may increase positive mood and changes the way we 
see and think about the world around us, making it easier to think about and recall 
things that happened to us that are upsetting. People say they feel caring and forgiving 
toward themselves and others during the MDMA experience. It is possible that these 
drug effects, when combined with psychotherapy, help people work through thoughts, 
memories and emotions related to PTSD and other past experiences. 
 
This study will test the safety of MDMA-assisted psychotherapy, as whether it works. 
During MDMA-assisted psychotherapy sessions, you will receive a dose of MDMA and 
possibly a second dose equal to half the size of the first dose about two hours later. You 
will have either the same dose or a slightly higher dose for the second and third 
sessions, which will happen roughly one month apart.  
 
TYPE OF STUDY 
This study is open-label, meaning that you will definitely receive MDMA, and both you 
and the study researchers will know. There is no chance that you will receive placebo in 
this study. There will be a total of at least 30 people in the study across multiple 
locations. 
 
LENGTH OF STUDY 
The length of active participation in the study will be about 19 to 38 weeks, depending 
on the length of screening and the time in between your study visits. Participation in the 
study requires a large time commitment from you over the active study period. To 
confirm that you are eligible for the study, there will be multiple in-person visits to the 
study location, lab, and doctor’s office, at least one online meeting with an evaluator, 
and phone calls from the study team. Then, there will be three preparatory visits, three 
day-long visits with overnight stays, and nine integrative (talk-therapy) visits for you in a 
13 to 26-week period (depending on visit scheduling). There will be two evaluation days 
where you complete many questionnaires. There will also be three online meetings with 
an evaluator who will ask you questions about your PTSD symptoms, and meetings with 
the staff and therapy team about two months after your last Overnight Test Session. 
 


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The timeline for starting treatment after enrollment is variable depending on availability 
of open appointments. You may start therapy as soon as two weeks, or as long as six 
weeks after your first visit. Overnight Test Sessions last all day and require an overnight 
stay at the clinic afterwards. After these overnight stays, you will have four brief phone 
calls with the therapy team during the seven days after the visit.  
 
You will be invited to enroll in a 12-month follow-up study at the end of your 
participation. This will be explained in another informed consent form. 
 
TYPES OF VISITS AND DURATION: 
 
Screening Visits: Multiple visits at the study location, lab, and/or doctor’s office, and 
phone calls from the study team. 
 
Preparatory Visits: (~90 minutes each): three introductory sessions at the start of 
participation in the study, spaced about one week apart. 
 
Integration Sessions: (~90 minutes each): three sessions after each Overnight Test 
Session. These are approximately one to three weeks apart and will involve you talking 
to your therapists about your thoughts and feelings. 
 
Overnight Test Sessions: (~8 hours long plus an overnight stay): three visits about a 
month apart. You will be given MDMA during these visits along with psychotherapy. 
 
Online Meetings: (60-90 minutes each): four online video meetings 
 
Evaluation and Testing Visits: (90 to 120 minutes): Testing and completing 
questionnaires two times, starting with the beginning of the study. 
 
You will need to be flexible about taking the appointments offered most of the time 
because there is a limited time frame for each type of visit.  
 
PROCEDURES/WHAT WILL HAPPEN  
 
Screening/Evaluation and Beginning of Study 
If you agree to be in this study, you will first sign this form before any study-related 
procedures are done. If you are taking certain medications, you may need to stop taking 
them before you are enrolled in the study. Only stop medications if the study doctor 
gives you specific instructions for how to stop. Some PTSD medications can cause 
thoughts about wanting to kill yourself if you stop taking them too quickly and without 
the care of a doctor. This is very important. Medications will only be stopped after 
consultation with your prescribing doctor. 
 
Before you can be in the study, the study doctor must first make sure that you qualify for 
the study and that you are generally physically healthy.  This screening process can 
take up to six weeks, and there will be one or more office visits and online meetings 


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during this time. The study doctor may ask you for written permission to contact your 
doctors or psychotherapists to get information about your medical history. They may 
need to do this so that they will know whether you can be in the study or not.  
 
You may need additional testing by a cardiologist if you have hypertension. If this 
occurs, you will sign an additional consent form at the cardiologist’s office. If there are 
other medical concerns during screening, you may be asked to do additional testing. 
The study doctors will explain any tests they are asking you to do. 
 
During online meetings with researchers, you must be in a quiet place with stable 
internet connection. Your device can be a phone, computer, or tablet. Your device must 
have a camera and you must be in a location in which you feel comfortable to discuss 
personal information. If needed, we can arrange for these online visits to occur in our 
offices. 
 
Psychological and medical screening will be done by staff, doctors, or your therapy 
team. The tests will include the following: 
 
 Questions about your medical history, including questions about your emotional 
and psychiatric history. This may include any previous medical or psychiatric 
problems or treatment and may include questions about difficult experiences you 
may have had during childhood or at other times of your life. 
 An interview about any psychological or psychiatric issues you may be 
experiencing, or that you have experienced in the past. 
 A brief interview about thoughts you might have about hurting or killing yourself.  
 Psychological questionnaires you fill out yourself. 
 A physical examination that will include measures of your blood pressure, pulse, 
temperature, and body weight. This information will also be used to calculate 
your Body Mass Index (BMI). 
 An ECG (electrocardiogram) and rhythm strip will also be taken, which are 
recordings of the electrical activity of your heart. 
 A sample of your blood (about 2 tablespoons) and a urine sample for routine 
laboratory testing, including tests of metabolism, liver function, and alcohol use. 
We will also test for the human immunodeficiency virus (HIV) and Hepatitis C 
virus (HCV). 
 
o If you have positive test results for HIV or Hepatitis C, we will notify you.  We 
are required to notify state health authorities of positive results.  If the HIV test 
is positive you cannot take part in this research study.  If you test positive for 
Hepatitis C you will only be able to participate if you currently don’t have 
symptoms of Hepatitis C (asymptomatic) and have been previously treated for 
it.  If you do not want to be tested you should not take part in this research 
study. 
 
 A urine test for drugs of abuse. Urine drug screen will be reviewed in order for 
you to take part in the study. We will not report findings of drugs to any 
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 A urine pregnancy test if you are able to get pregnant. Your urine pregnancy test 
must be negative for you to take part in the study. 
 
If you pass the initial screening and choose to participate, you will be enrolled in the 
study. However, the screening process continues until Visit 3, when you will have 
additional psychological testing by an online video meeting. You will not know for sure 
whether you will get treatment until that time. 
 
Beginning of Study 
Once you are in the study, we will schedule your first preparatory psychotherapy 
session with the therapy team. You will need to be enrolled in the study before receiving 
psychotherapy. If you were taking psychiatric medicines before enrolling in the study, 
you will have to stop taking them after you are enrolled in the study. The study doctors 
and your physician will help you do this. You must let the therapy team know about any 
change in medicines or medical conditions or procedures, like surgery, within 48 hours 
of it happening.  
 
You will need to give the therapy team the name and contact information (telephone 
number, cell phone number or email) of a relative, spouse or close friend to contact in 
case of medical emergency, should you become at risk of hurting yourself or someone 
else, or if the study team cannot get in touch with you, so they can reach that person to 
let them know what is going on or find out if you are okay.  
 
 


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Schedule of Events  
Time is counted from the first study visit after you are selected to be in the study. The tables below show the type of in-
person visits and online sessions you will have. All visits and sessions will be recorded to video so that the therapy team 
will have accurate records of the sessions, and so that they can gather more information about these sessions. 
 
Table 1: Schedule of Events 
 
 
Screening 
(2-6 weeks) 
Screening, 
Intro, 
Preparation  
(1-11 weeks) 
Treatment 1  
(about 4 weeks) 
Treatment 2  
(about 4 weeks) 
Treatment 3  
(about 4 weeks) 
Evaluation 
Study 
Termination  
(about 6 weeks) 
Visit # 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Informed 
Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
Screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bloodwork, 
ECG, rhythm 
strip 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug and 
Pregnancy Test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Measure PTSD 
Symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
Psychological 
Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychotherapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overnight Test 
Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Calls 
over 1 week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overnight Stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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Preparatory Sessions 
The first two preparatory sessions will last approximately 90 minutes and the last 
preparatory session will last about 2 and a half hours. During each preparatory session, 
you will talk about the traumatic incidents that led to your PTSD, the ways PTSD 
symptoms are affecting your life, and what you would like to achieve during the study. 
You will be asked questions about thoughts or feelings you might have about hurting or 
killing yourself and complete psychological questionnaires in the 3rd preparatory 
session. There will be four visits total during this period: three therapy visits and an 
online meeting with a researcher who will ask you questions about your PTSD 
symptoms. This information will be used to learn how you are doing after the study 
treatment. After the online video meeting, the staff will let you know whether you will 
continue on to the treatment part of the study. 
 
Overnight Test Sessions 
There will be three day-long Overnight Test Sessions. These visits will happen three to 
five weeks apart. The first Overnight Test Session will occur after you have had three 
preparatory sessions. During the Overnight Test Session, you will receive a dose of 
MDMA followed 1.5 to 2 hours later by a dose of half the first dose of MDMA. During the 
second and third Overnight Test Sessions, you and your therapy team can decide if you 
would like to take the same dose you took in your first Overnight Test Session, or if you 
would like to try a higher dose. Your therapy team will discuss the optimal dose of 
MDMA with you for the second Overnight Test Session. The goal will be to decide on 
the optimal dose for you. 
 
You must not eat any food or drink any alcohol after midnight on the night before each 
visit, though you can drink non-alcoholic liquids during this time, such as water or juice. 
You cannot use any psychoactive drug, with the exception of caffeine or nicotine, within 
24 hours of each Overnight Test Session (or longer depending on the specific drug – 
this should be discussed with the therapy team).  You cannot use caffeine or nicotine for 
two hours before and six hours after you take the first dose during the Overnight Test 
Session. For one week before each Overnight Test Session, you cannot take any herbal 
supplements, nonprescription medications, or prescription medications that have not 
been discussed and approved with the therapy team and study doctor. 
 
If you are taking certain opioid medications for pain management, you can stay on these 
medications during treatment, although we will ask you to reduce the dose before each 
Overnight Test Session and stop taking them for 12 hours before and at least 24 hours 
after the first dose in each Overnight Test Session. If your pain becomes too severe to 
handle during this period, you will be allowed to take your medication. 
 
First, you and the therapy team will discuss your goals for the Overnight Test Sessions 
and the therapy team will answer any other questions you may have. 
 


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Before an Overnight Test Session: 
 
 Your urine will be tested for drugs of abuse, including stimulants, sedatives, 
opioids and cannabis. 
 If you can become pregnant, you will take a urine pregnancy test. 
 Answer questions about thoughts you might have about hurting or killing yourself.  
 
After urine testing, you will receive a capsule containing MDMA. After taking the 
capsule, you will then sit or lie down in a comfortable position. You can ask for an 
eyeshade if you wish. You will listen to music during much of each Overnight Test 
Session, either through headphones or room speakers. During the session there will be 
times when you will be asked to talk to the therapy team. If you are wearing 
headphones, you may remove them yourself if you want to talk to the therapy team or 
have times of silence. Lying or sitting in a comfortable position and listening to music 
are meant to bring out thoughts and feelings, including thoughts and feelings about past 
traumatic experiences. The therapy team will remain with you, and they will help you if 
you need them to. They will speak with you and ask you to talk to them at least once an 
hour, but you can talk to them whenever you wish. There may be times when the 
therapy team will suggest that you stop talking for a while in order to pay attention to 
your thoughts and feelings. There will be beverages available; including juices or 
Gatorade® or similar sports drinks, and you will be encouraged to drink an adequate 
amount of fluid. You can drink it whenever you wish to do so, within the limits of the 
amount that is safe for your body. Later on, food will also be provided. 
 
Approximately two hours after you take the first capsule, you may take a second 
capsule, after discussion with the study doctor. The second dose will contain half the 
amount of the first capsule. The thought behind taking the second capsule is that it is 
supposed to make the session last longer. If you or the therapy team notice you have 
problems after the first capsule, then you will not get the second capsule. 
 
The therapy team will watch for any side effects (unwanted effects or health problems), 
which will be treated if necessary. If this happens, the therapy team will keep you fully 
informed about any concerns or treatment. Your blood pressure, temperature, and pulse 
will be measured before taking the first and second capsules and at the end of the 
session. If you have any symptoms including confusion, light-headedness, dizziness, 
chest pain, shortness of breath, tell your therapy team. More frequent measurements 
may be needed if this happens. 
 
If you are confused or upset eight or more hours after the start of an Overnight Test 
Session, the therapy team will stay with you until you have fully recovered. If the therapy 
team thinks you are at risk of hurting yourself or others, they will either remain with you 
all night or have you admitted to a hospital until you are no longer at risk. The therapy 
team will ask you how you feel at the beginning and end of the Overnight Test Session 
and on several occasions during the phone follow-up period.  
 


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You will be spending the night in a room at the office of the therapy team with an 
attendant who will be staying in another room nearby. You can use the kitchen or walk 
around outside if you want. If you find you need to talk with the therapy team or you are 
having other problems and need to contact the therapy team, the attendant will contact 
them immediately. 
 
The next day, you will have a non-drug therapy session with the therapy team. You will 
need to have someone drive you to wherever you are staying (home, hotel or another 
location) from the non-drug therapy session on the day after the Overnight Test 
Session, because we do not know how MDMA will affect your ability to drive and 
because some people report feeling tired, less alert, or having trouble concentrating a 
day after having taken MDMA. If you do not have anyone to take you home, the therapy 
team will find someone to drive you. 
 
After you return home from the therapy session, the therapy team will talk to you by 
phone four days out of the following week to ask how you are feeling and see whether 
you should see the therapy team before your next scheduled non-drug psychotherapy 
session. You and your therapy team can decide which days would be best to speak on 
the phone. The phone calls will take approximately 5 to 15 minutes, though they can be 
as long as you need them to be. The therapy team will ask you about thoughts about 
killing or harming yourself during the second and seventh day of phone contact. You 
can call the therapy team at any time; except for a few times when they may be out of 
town. At those times the study doctor will be on call and can be called at the 24-hour 
number provided on this consent form. 
 
The therapy team will give you a card with phone numbers for calling your therapy team 
and the IRB, which is an independent committee that protects the rights and welfare of 
study participants.  You can keep this card in your wallet to make it easier for you to 
contact the therapy team if you need to. 
 
If there are delays in following the usual study schedule, the therapy team will call you 
at least once a week to talk about how you’re doing. These calls will take about 15 
minutes.  You need to agree to call the study doctors if any of the following things 
happen:  
 
 you have an increase in symptoms that you have taken medication for in the past  
 you need to contact your outside therapist other than for the usual appointments  
 you start or stop taking a prescription medicine or an over-the-counter medicine 
that you have not previously cleared with the therapy team 
 you go to the hospital for any reason 
 
If you have very high blood pressure, get sick, or have an uncomfortable and strong 
lasting negative reaction (unwanted effect or health problem) during or after an 
Overnight Test Session, you or the therapy team may decide that you should not have 
the next Overnight Test Session. You may make this decision to stop treatment in the 
study for any reason.  


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If the therapy team decides to take you out of the study, they will let you know that they 
are doing this and their reason for doing it. They will help you find a therapist who can 
continue to help you with your PTSD, if needed. If you are taken out of the study or 
decide you do not want to receive treatment in the study, the study researchers will ask 
you to complete some final questionnaires about your PTSD symptoms. If you decide 
you do not want to continue in the study during an Overnight Test Session, you will still 
have to stay in the office until the therapy team thinks that you are stable enough to 
leave and that all the acute effects of the drug have worn off.  If this happens, you will 
also be asked to take part in some of the same interviews and questionnaires you 
completed at the beginning of the study.  
 
Integration Visits  
The day after each Overnight Test Session, and 2-4 weeks afterward, you will have 
therapy visits to help you express, understand, bring together and connect any thoughts 
or feelings you may be having about your symptoms and their causes, and to think and 
talk about your experience during the Overnight Test Session. There will be three of 
these visits after every Overnight Test Session visit. These visits will last about 90 
minutes. The therapy team will ask you questions about thoughts about killing or 
harming yourself at these sessions. At the last integration therapy visit you will also 
complete a psychological questionnaire. 
 
Measuring PTSD After Sessions 
Within one month after the first two Overnight Test Sessions, you will meet with the 
study researcher online again, which may be recorded. The researcher will ask about 
your PTSD symptoms. You will also meet with your therapy team and the study 
researcher about two months after your last Overnight Test Session to fill out the same 
questionnaires from the start of the study, and to complete the same online interview 
about your PTSD symptoms. You will also be asked if you have had any thoughts about 
hurting or killing yourself. The researchers will measure your blood pressure, weight, 
and BMI. The tests will help the therapy team tell if your symptoms have changed or 
stayed the same over time. 
 
At this visit you will also be invited to participate in a long-term follow-up study for an 
additional visit 12 months from the last time you had an Overnight Test session to see if 
the changes in people’s PTSD symptoms continue to improve, stay the same, or 
worsen over time after the study. There will be a separate consent form for this study. 
 
POSSIBLE RISKS OR DISCOMFORTS 
MDMA has not been widely tested in humans, but as of October 2016 more than 1,260 
people have been given MDMA in clinical research settings, without any serious 
unexpected problems happening. Some of the effects that have been observed are 
listed below.  
 
Side effects that are typically not severe but are frequently reported include: 
 
 Teeth grinding or tight jaw muscles (64%) 
 Lack of appetite (50%) 


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 Dizziness (45%) 
 Sensitivity to cold (40%) 
 Muscle tension (35%) 
 Difficulty balancing or walking (26%) 
 Dry mouth (24%) 
 
Between 40% and 70% of subjects in previous studies reported these side effects. 
Between 15% and 40% of participants reported (from most to least common) feeling 
either hot or cold, feeling that their heart was racing, sweating, dizziness, drowsiness, 
upset stomach, diarrhea, anxiety, tenseness, thirst, weakness, fatigue, shaking, 
headache, irritability, or feeling faint. When these side effects occur, they usually last 
less than four hours. However, some effects have been reported to last for more than 
24 hours and (rarely) for as long as four days. 
 
There may be unknown side effects or risks from the use of MDMA. 
 
Other possible risks of MDMA may include the following: 
 
Serious problems: There have been some serious problems, and even deaths, 
associated with the use of Ecstasy outside of controlled clinical or research settings. 
These problems have included high fever, brain swelling associated with drinking too 
much liquid, convulsions, and liver damage. Some recreational users of ecstasy have 
become severely anxious, depressed or paranoid (thinking that other people are out to 
get them). Since you will be receiving moderate amounts of research grade MDMA in a 
controlled setting with a trained therapy team who will be closely monitoring your 
physical and psychological reactions, these problems are not expected to occur either 
during or after the Overnight Test Session. While this does not guarantee that they will 
not occur, it does mean that if they do occur, the study doctors are prepared to respond 
in a safe and professional manner. 
 
Changes in vision, hearing or other senses: In previous studies in which MDMA was 
given to volunteers, most participants reported experiencing temporary and minor 
changes in vision and hearing, such as sounds seeming closer or farther away than 
usual or objects seeming brighter than usual. These changes typically lasted two to 
three hours. People also reported unusual feelings in their bodies, such as tingling or 
numbness (between 12% and 33%). 
 
Blood pressure and heart rate: The effects of MDMA usually last six to eight hours 
with the first and second dose. At the dose in this experiment, the increases in blood 
pressure and heart rate are likely to be moderate. Average increase in systolic blood 
pressure is 11.3 mmHg (measurement unit for blood pressure) and average diastolic 
blood pressure increase is 13.1 mmHg. Heart rate may increase by approximately 30 
beats per minute (bpm) on average. 
 
In past studies supported by MAPS and published studies, blood pressure rose well 
above normal levels in a few participants (a little less than 5%) after taking MDMA, but 
these participants did not report any discomfort and did not require any treatment. 


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Although these increases in blood pressure are similar to what happens after heavy 
exercise, they could cause serious problems in individuals with pre-existing heart or 
blood vessel conditions. These serious problems could include an irregular heartbeat, 
heart attack or stroke. We will screen all potential participants for preexisting heart 
problems before they are allowed to be in this study. While this doesn't guarantee that 
no heart problems will occur, it does reduce the risk of this happening. 
 
Anxious or jittery feeling: Some participants in past studies with an anxiety disorder 
who received MDMA (70.1%) reported feeling over-stimulated or anxious at a similar 
rate. These feelings usually lasted less than 30 minutes. Letting yourself accept and feel 
these emotions deeply can be part of the psychotherapy. If you are not able to deal with 
these experiences in a way that helps you, the therapy team will work with you to deal 
with these feelings. It is possible that if such periods of heightened emotion do not clear 
up or grow weaker during the session, you could be at increased risk for suicide or other 
self-harm afterwards. You will be encouraged to ask the attendant to call the therapy 
team immediately if you have any thoughts about hurting or killing yourself so they can 
safely help you. If needed, they may prescribe anti-anxiety medication or medication for 
sleep. 
 
The way MDMA affects the brain has the potential to cause mania in some people, 
although mania has not been reported in individuals receiving MDMA or ecstasy. 
 
If you are in immediate danger of hurting or killing yourself or hurting someone else, 
then the researchers may require you to be admitted to a hospital. 
 
Insomnia & drowsiness: In previous studies, between 1.4% and 62% of participants 
have reported insomnia (difficulty sleeping) or feeling tired, irritable, or drowsy for as 
long as 3 days after taking MDMA. If needed, the study doctor may prescribe 
medication for sleep. You should not drive or use machinery immediately after 
Overnight Test Sessions (up to 24 hours afterwards). This is because the study 
drug may cause drowsiness, lack of coordination or slower reaction time. 
 
Mood: Some after-effects of MDMA may be noticed up to two or three days later. While 
some participants feel that their mood is better, 20% to 33% feel that it is worse. 
 
Immune System: You may have a less active immune system for two or three days 
after taking MDMA. This may make you more likely to become sick with a cold or other 
infection during this time. The study describing this finding did not report how many 
people in the study showed these changes. 
 
Addiction: There is a small chance that you will become dependent on (addicted to) 
MDMA. One study found that up to 6% of people using Ecstasy for recreational 
purposes were dependent on it. However, a study of people who had received MDMA 
for the first time in a legal laboratory setting found that they did not want to try MDMA 
again outside of the laboratory. 
 


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People who have recently had problems with drug abuse should not be in this study. 
 
Possible Brain Damage: Experiments in rats and monkeys show that high and 
repeated doses of MDMA can change certain brain cells that release a chemical called 
serotonin; in mice (though not in humans), the affected cells release dopamine. The 
changes include loss of the parts of the cell (called “axons”) that connect different brain 
areas. Rodents given repeated, high doses of MDMA are less sensitive to a later dose 
of MDMA, are more likely to become overheated when placed in a warm room, and 
some studies find they perform worse in difficult memory tests. Recent studies in 
monkeys and rodents suggest that the doses used in these studies are far higher than 
those typically taken by humans in either recreational or laboratory settings. 
 
Many studies found that people who had used Ecstasy many times in recreational 
contexts were not able to recall words, pictures or patterns as well as people who did 
not use Ecstasy, and performed less well on tests of planning and impulse control. 
These differences are not great, but they have lasted for at least a year after people had 
stopped taking Ecstasy.  Not all studies have found Ecstasy users to have difficulty 
recalling words or pictures or to have impulse control problems. When compared with 
people who do not use Ecstasy, studies found Ecstasy users were more likely to report 
feeling generally anxious or depressed. Many of these studies found that using alcohol 
or other drugs was also associated with feeling anxious or depressed.  At least two 
studies found that people who are anxious, depressed or have psychological problems 
before taking any drugs are more likely to take Ecstasy than people without these 
problems, but there is no proof that MDMA might not cause these problems in some 
people. 
 
Only one study has looked at brain scans of people before they got MDMA and then 
again after they have received one or two moderate doses of MDMA. This study did not 
show any changes in the brain following MDMA, though it is possible that there were 
changes that were too small to notice. Other studies looked at people before and after 
they decided to take a few tablets of Ecstasy in a recreational setting and found one 
small change in the amount of blood flow in a specific part of the brain, but did not show 
signs of brain injury. The decrease in blood volume might be from temporary lowering of 
a type of brain receptor, or it might be a sign of reduced function in this area. Findings 
from these studies suggest that the amount of MDMA you will receive in this study will 
not produce any lasting changes in your brain, though this is not guaranteed. 
 
Studies of people receiving one or two doses of MDMA in a laboratory setting have not 
found any lasting changes in memory or planning. Studies comparing people before and 
after they decided to take a few tablets of Ecstasy in a recreational setting with people 
who did not take them found less improvement in memory in the people who took 
ecstasy, and no other changes in thinking or planning. It is believed that the amount of 
MDMA you will receive will not produce any lasting changes in memory or planning, 
though this cannot be guaranteed. 
 


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RISKS OF BEING IN THE STUDY 
If you are tested for drugs of abuse within three days of each Overnight Test Session, 
you may test positive. The therapy team will provide you with an information card in 
case you are tested for drugs of abuse, and if you are tested for drugs of abuse while 
you are in this study, you can have the person(s) testing you call your therapy team to 
verify that you are in this study. This card may not protect you from discipline at work or 
loss of employment. The study doctors will discuss when and how to present the 
information card. The card will not prevent you from being stopped or cited if you are 
driving erratically or poorly so you should not operate machinery or drive a car until you 
feel normal again.   
 
The interviews you have during the study involve no specific risks or discomforts 
beyond those of a standard clinical interview situation. You may feel upset at the review 
of your emotional experiences, or you may feel boredom or fatigue. Answering 
questions about thoughts you might have of hurting or killing yourself may be upsetting. 
 
The medical evaluation involves some blood tests. The risks of blood drawing include 
temporary discomfort from the needle stick, bruising and, rarely, infection at the site of 
the needle stick. Fainting could also happen. 
 
It is possible that after you stop taking psychiatric medicine (as for depression or 
anxiety) as part of the study, you may start to have symptoms again. There is also a risk 
that you may have thoughts of hurting or killing yourself when you stop taking medicine, 
especially if you have had these thoughts before.  If this happens, you should talk with 
your outside therapist and your therapy team. If you have to start taking medicine again, 
then the study doctors will have to take you out of the study. 
 
REPRODUCTIVE RISKS 
Effects of MDMA on the growth and development of an unborn baby are not known; 
therefore, you will not be allowed to be in the study if you are pregnant.  If you get 
pregnant after you have had at least one Overnight Test Session, the study doctors and 
the sponsor, MAPS, will ask you about and keep track of your pregnancy and will need 
to know about the outcome of your pregnancy. 
 
Those who are able to become pregnant and are engaging in penile-vaginal intercourse 
must use one of the allowed birth control methods: intrauterine device (IUD), injected or 
implanted hormonal methods, abstinence, oral hormones plus a barrier contraception or 
double barrier contraception. Two forms of contraception are required with any barrier 
method or oral hormones (i.e. condom + diaphragm, condom or diaphragm + 
spermicide, oral hormonal contraceptives + spermicide or condom). Not being of 
childbearing potential is defined as permanent sterilization or postmenopausal or 
assigned male at birth. The therapy team will explain these methods to you and will help 
you decide which might be best for you, and they can suggest to you where you can get 
more information and advice. 
 


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If you are of childbearing potential, you will be tested at the start of the study and again 
before each Overnight Test Session to see if you are pregnant.  If, at any time during 
the study, you think that you may be pregnant or are worried that you may become 
pregnant, you must tell your therapy team immediately. If you should become pregnant 
during the study, the study doctors will help you get proper advice and help you and 
your unborn baby get proper care while you are pregnant. If you become pregnant, you 
will discontinue treatment but remain in the study for follow-up purposes. 
 
NEW FINDINGS 
If any new information becomes available about MDMA while you are in this study, the 
therapy team will tell you about it as soon as possible. You may be asked to sign a new 
consent form if this occurs. You may contact the therapy team at any time after your 
participation ends to find out if any new information about this study has become 
available. 
 
POSSIBLE BENEFITS 
Your symptoms of PTSD may improve while taking part in this study. There is no 
guarantee that you will benefit from taking part in this research study. Information 
obtained from this study may help doctors and researchers to improve treatment for 
PTSD and relationships in the future. 
 
PAYMENT FOR PARTICIPATION 
There will be no payment for taking part in this study. There are no plans to offer you 
payment for such things as lost wages. 
 
  ***INTERNAL NOTE - PI Specific Comp – delete template wording above the 
bookmark*** 
 
COSTS 
The Sponsor of this study, MAPS, will cover the costs that are directly related to the 
research. This includes the costs for all psychotherapy sessions that are a part of this 
study, for the psychological and laboratory testing, for medical examinations, including 
any extra tests you might have, solely to see if you can be in the study (if you are 
eligible), and for the study drug.  You, your private medical insurance (if any), or public 
health insurance plan will not be charged for any procedures done solely for the 
purpose of the study. You or your insurance company will remain responsible for on-
going treatment not included in the study.  
 
ALTERNATIVES 
One alternative to being in this study is to decide not to take part. You may decide to try 
other treatments for PTSD. There are approved medicines that may help treat your 
symptoms of PTSD and other forms of psychotherapy that you could try. If you are 
currently having psychotherapy and/or taking medicine, you could continue with those 
for a longer period of time. The therapy team can discuss the alternatives and their 
potential risks and benefits with you. 
 


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CONFIDENTIALITY 
To ensure confidentiality, your information will be stored in secure electronic systems or 
in a locked office. Absolute confidentiality and security cannot be guaranteed, but every 
effort will be made to maintain your confidentiality. 
 
People outside of your therapy team will need access to your information to monitor the 
study and conduct further research and training. Any paperwork copied will have any 
information that could be used to identify you removed first, except for videos, which will 
still show your face. If records are copied, only your participant number and initials will 
identify you to the study Sponsor unless you give specific permission, for example at a 
time when you sign a media release.  
 
Medical records, including video, which identify you, and the consent form signed by 
you will be looked at and/or copied for research or regulatory purposes.  These records 
may be looked at by: 
 
 The Sponsor, MAPS and the people they hire. 
 Researchers who cooperate with MAPS to conduct further research, and people 
who conduct therapy trainings on behalf of MAPS. 
 The FDA and similar agencies in other countries. 
 Governmental agencies in other countries. 
 Copernicus Group Independent Review Board (CGIRB).  The IRB is a group of 
scientists and non-scientists who review the ethics of research. The goal of the 
IRB is to protect the rights and welfare of study subjects.  
 
Your records may also be inspected by the Research Advisory Panel of California 
(RAPC) or by State and Federal regulatory agencies.**FOR CA SITES ONLY** 
 
All records are subject to subpoena by a court of law. 
 
The results of this research study may be presented in meetings, presentations, or in 
publications, where your identity will not be disclosed. Video of your sessions may be 
used in training sessions for research therapy teams or other researchers only in 
controlled settings as described below. 
 
Video recordings: The therapy team will video record each visit. The purposes for this 
recording that you are agreeing to by signing this informed consent are: 
 
 So the therapy team will have accurate records of the session. 
 So that trained raters working for the Sponsor can verify that the therapy is being 
carried out properly  
 For further research on the therapy and how it is performed.  
 For training other therapy teams and scientists to develop and work on additional 
research.  
 


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For the above purposes the adherence raters, researchers and therapy team who may 
be viewing these recordings will be selected by the Sponsor, and will sign confidentiality 
agreements to ensure they do not share the identifying information they may receive.  
 
Information contained in recordings that could be used to identify you may include: 
 
 Your physical appearance 
 Your voice 
 Your name (if it is spoken on the recording) 
 Situations from your life that might be discussed 
 
With your permission only, the investigators and/or sponsor may use portions of your 
videos to educate a broader audience at medical conferences or other settings. In these 
settings the audience will not be specifically screened and selected, and confidentiality 
agreements will not be obtained from the audiences. You are not required to agree to 
use of your video in these settings in order to participate in the study. Signing this 
consent form does not mean you have given permission for your videos to be used in 
this way. You will have the opportunity to sign an additional release for these situations 
if they arise and if you choose to allow this use. At the end of the study (Visit 20) when 
you have completed all of the questionnaires and measures, you can make a decision 
about whether or not you wish to grant this additional consent.  
 
These recordings will be stored on hard drives stored in a locked and secure location 
when not in use. No personally identifying information will be used to label the video 
recordings. A copy will be transferred to the Sponsor for secure electronic storage on 
the web to allow for viewing purposes described above. Electronic systems used will 
include measures to protect confidentiality of your identity and protection of this video 
data. Total security cannot be guaranteed, but the Sponsor is consistently working to 
maintain and improve the security of its data systems. 
 
During your study sessions you may ask to stop the recording at any time, but your 
therapy team will ask your permission to turn it back on when you are ready. 
 
By signing this consent form, you consent to the collection, access, use and sharing of 
your information as described above. You have the right to check your study records. 
 
TREATMENT AND COMPENSATION FOR INJURY 
In the event of a study-related injury, the doctor who treats you will bill your insurance 
company. If your insurance company denies coverage or insurance is not available, 
then the Sponsor will pay for any costs that arise from treating a study-related injury, 
including hospitalization. Neither the Sponsor nor the therapy team has a program in 
place to provide additional compensation in the event of an injury. 
 
Your health insurance may not be willing to pay for the costs of treating a study-related 
emergency. The study Sponsor will pay for any study-related procedure that your 
insurance will not cover. 


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LEGAL RIGHTS 
The above section does not restrict your right to seek legal assistance. You do not 
waive any legal rights by signing this form. 
 
VOLUNTARY PARTICIPATION 
Your decision to take part in this research study is completely voluntary. There will not 
be any penalty or loss of benefits to you if you decide not to take part. 
 
In addition, you may withdraw from (leave, stop being in) the study at any time. There 
will be no penalty or loss of benefits if you decide to withdraw from the research study. 
Before withdrawing from this study, notify your study doctor that you wish to withdraw. 
This notice will allow your study doctor to inform you if there are any potential medical 
risks of withdrawal. You may be asked to return to the office for tests. 
 
WITHDRAWAL 
Your therapy team, the Sponsor, or the medicine agency in your country has the right to 
stop your participation in the study at any time, with or without your consent, for any of 
the following reasons:  
 
 if you have an adverse effect from the study drugs,  
 if you need a treatment not allowed in this study, such as restarting medication 
for depression or anxiety,  
 if you do not keep appointments or follow study procedures,  
 if you do not take the study drug as instructed,  
 if you become pregnant, or  
 if the study is canceled by the FDA, IRB, or the Sponsor. 
 
The Sponsor, the FDA, or the IRB may decide to stop the study at any time. 
 
CONTACT FOR QUESTIONS 
If you have any questions, concerns, or complaints about your participation in this study 
or if you feel that you have experienced a study-related injury or reaction to the study 
drug, or have a complaint about the research study, contact the study doctor using the 
information found on page 1 of this form. 
 
You should contact the study doctor first if you have questions, complaints, or concerns 
about the study. 
 
This research is being overseen by an Institutional Review Board (“IRB”). You may talk 
to them at (888)-303-2224, irb@cgirb.com if: 
 
 You have questions, concerns, or complaints that are not being answered by the 
research team. 
 You are not getting answers from the research team. 
 You cannot reach the research team. 
 You want to talk to someone else about the research. 


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 You have questions about your rights as a research subject. 
 
Do not sign this consent form unless you have had a chance to ask questions 
and have received satisfactory answers to all of your questions.  
 


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PARTICIPANT’S STATEMENT OF CONSENT 
 
An Open-Label, Multi-Site Phase 2 Study of the Safety and Effect of Manualized 
MDMA-Assisted Psychotherapy for the Treatment of Severe Posttraumatic Stress 
Disorder  
 
My participation in this study is voluntary. I may refuse to take part in or I may stop 
taking part in this study at any time. I will call the researchers if I decide to do this. My 
decision will not affect my current or future regular medical care or any benefits to which 
I am entitled at this site. The staff and/or the Sponsor may stop my participation in this 
study at any time without my consent if they decide it is in my best interest or if I do not 
follow their instructions. 
 
I agree to have my sessions video-recorded during this study. 
 
I have read the information in this consent form and it has been discussed with me. I 
have been given sufficient opportunity to consider whether to participate. All of my 
questions so far about the study and my participation in it have been answered. I freely 
consent to take part in this research study. 
 
By signing this consent form, I have not waived any of the legal rights which I otherwise 
would have as a participant in a research study. I have been told that I will be given a 
copy of this consent form, as well as a signed and dated copy of the Experimental 
Subject’s Bill of Rights.***For CA Sites Only***. 
 
 
 
Signature of Participant 
 
 
 
 
Date 
 
 
 
Printed Name of Participant 
 
 
 
 
I certify that the information provided was given in language that was understandable 
to the participant. I attest to adhering to informed consent procedures. 
 
 
 
 
 
Signature of Person Obtaining Consent 
 
 
 
 
Date 
Printed Name of Person Obtaining Consent 
 
 
 
 
 


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HIPAA AUTHORIZATION 
 
The United States government has issued a privacy rule to protect the 
privacy rights of patients.  This rule was issued under a law called the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). The 
Privacy Rule is designed to protect the confidentiality of your personal 
health information. The document you are reading called an 
“Authorization,” describes your rights and explains how your health 
information will be used and disclosed (shared). 
 
In working with the Sponsor, the study doctor will use and share personal 
health information about you. This is information about your health that also 
includes your name, address, telephone number or other facts that could 
identify the health information as yours. This includes information in your 
medical record and information created or collected during the study. This 
information may include your medical history, physical exam and laboratory 
test results. Some of these tests may have been done as part of your 
regular care. The study doctor will use this information about you to 
complete this research. 
 
In most cases, the study doctor will use your initials and assign a code 
number to your information that is shared with the sponsor. The sponsor 
and its representatives may review or copy your personal health 
information at the study site. Regulatory authorities such as the U.S. FDA 
and the Copernicus Group Independent Review Board (CGIRB) may also 
review or copy your information to make sure that the study is done 
properly or for other purposes required by law.   
 
By signing this Authorization, you allow the study doctor to use your 
personal health information to carry out and evaluate this study. You also 
allow the study doctor to share your personal health information with: 
 
 The Sponsor and its representatives   
 Copernicus Group Independent Review Board (CGIRB)  
 The U.S. Food and Drug Administration (FDA) 
 Other regulatory agencies  
 
Your records may also be inspected by the Research Advisory Panel of 
California (RAPC) or by State and Federal regulatory agencies.**FOR CA 
SITES ONLY** 


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Your personal health information may be further shared by the groups 
above. If shared by them, the information will no longer be covered by the 
Privacy Rule. However, these groups are committed to keeping your 
personal health information confidential.  
 
You have the right to see and get a copy of your records related to the 
study for as long as the study doctor has this information. However, by 
signing this Authorization, you agree that you might not be able to review or 
receive some of your records related to the study until after the study has 
been completed. 
 
You may choose to withdraw this Authorization at any time, but you must 
notify the study doctor in writing. Send your written withdrawal notice to the 
study doctor using the contact information found on page 1 of this form. 
 
If you withdraw from the study and withdraw your Authorization, no new 
information will be collected for study purposes unless the information 
concerns an adverse event (a bad effect) related to the study. If an adverse 
event occurs, your entire medical record may be reviewed.  
 
All information that has already been collected for study purposes, and any 
new information about an adverse event related to the study, will be sent to 
the study Sponsor.  
 
If you withdraw from the study but do not withdraw your Authorization, new 
personal health information may be collected until this study ends.   
 
If you do not withdraw this Authorization, it will remain in effect. 
 
If the research site is located in California, Delaware, Illinois, Indiana, 
Washington, or Wisconsin this authorization will expire on 31Dec2060. 
 
There is no expiration of this authorization except for research conducted in 
the states listed above. 
 
***For IL Sites Only***You have the right to review any mental health 
information collected about you and shared with others.   
 
You have the right to review and copy your health information. However, 
your access to this information may be delayed until the study is complete. 


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If you do not sign this Authorization, you cannot participate in this research 
study. If you withdraw this Authorization in the future, you will no longer be 
able to participate in this study. Your decision to withdraw your 
Authorization or not to participate will not involve any penalty or loss of 
access to treatment or other benefits to which you are entitled. 
 
AUTHORIZATION 
I authorize the release of my medical records and personal health 
information related to this study to the Sponsor and its representatives, the 
IRB, Research Advisory Panel of California (RAPC) .**FOR CA SITES 
ONLY** the FDA, and other regulatory agencies as described above.  I 
have been told that I will receive a signed and dated copy of this 
Authorization for my records. 
 
 
 
Signature of Participant 
 
 
 
 Date 
 
 
 
Printed Name of Participant 
 
  
 
 
 
  
Signature of Person Obtaining Authorization 
 
 
 
 Date 
Printed Name of Person Obtaining Authorization 
 
  
 
 

SAP_001.pdf: 
 
 
 
 
 
MP16 Statistical Analysis Plan 
 
Version 1: 14 February 2018 
Version 2: 03 September 2019 
 
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 (MPBC) 
1115 Mission Street 
Santa Cruz, CA 95060 
SPONSOR DESIGNEE 
Amy Emerson 
Executive Director and Director of Clinical Research, MPBC 
Phone number: 510-393-7224 
Email: amy@mapsbcorp.com 
MEDICAL MONITOR(S) 
Michael Mithoefer, M.D. 
STATISTICIAN(S) 
Scott Hamilton, Ph.D. 
PREPARED BY 
Scott Hamilton, Ph.D. 
Allison Feduccia, Ph.D. 
Berra Yazar-Klosinski, Ph.D. 
Ilsa Jerome, Ph.D. 
USE 
In conjunction with relevant FDA guidance 


MAPS Public Benefit Corporation 
IND #063384 
MP16 SAP 
Version 2: 03 September 2019 
Page 2 of 24 
 
 
Table of Contents 
List of Tables ................................................................................................................................... 3 
List of Abbreviations ...................................................................................................................... 4 
1.0 Definitions of Terms ................................................................................................................. 7 
2.0 Introduction .............................................................................................................................. 8 
3.0 Study Objectives ....................................................................................................................... 8 
3.1 Primary Objective ................................................................................................................... 8 
3.2 Secondary Objective ............................................................................................................... 8 
3.3 Safety Objectives .................................................................................................................... 8 
3.4 Exploratory Objectives ........................................................................................................... 9 
4.0 Measures .................................................................................................................................. 10 
4.1 Primary Measure ................................................................................................................... 10 
4.2 Secondary Outcome Measure ............................................................................................... 10 
4.3 Safety Measures .................................................................................................................... 10 
4.4 Exploratory Measures ........................................................................................................... 10 
5.0 Study Design ............................................................................................................................ 10 
6.0 Randomization and Blinding ................................................................................................. 15 
7.0 Sample Size and Power Considerations ................................................................................ 15 
8.0 Analyses ................................................................................................................................... 15 
8.1 Analysis Sets ......................................................................................................................... 15 
8.2 Missing Data Handling ......................................................................................................... 15 
8.2.1 Partial or Missing Dates ................................................................................................. 16 
8.3 Protocol Deviations .............................................................................................................. 16 
8.4 Baseline Values .................................................................................................................... 17 
8.5 Participant Disposition and Dosing Summary ...................................................................... 17 
8.6 Demographics and Baseline Characteristics ......................................................................... 17 
8.7 Effectiveness Analyses ......................................................................................................... 17 
8.7.1 Primary Effectiveness Analyses .................................................................................... 17 
8.7.2 Key Secondary Effectiveness Analyses ......................................................................... 19 
8.7.3 Exploratory Analyses ..................................................................................................... 20 
8.7.4 Responder Analyses ...................................................................................................... 21 
8.8 Safety Analyses .................................................................................................................... 22 
8.8.1 Analysis of Exposure ..................................................................................................... 22 
8.8.2 Analysis of Adverse Events ........................................................................................... 22 
8.8.3 Concomitant Medications .............................................................................................. 22 
8.8.4 Analysis of Suicidal Ideation and Behavior .................................................................. 23 
8.8.5 Summary of Vital Signs................................................................................................. 23 
9.0 Timing of Analyses ................................................................................................................. 23 


MAPS Public Benefit Corporation 
IND #063384 
MP16 SAP 
Version 2: 03 September 2019 
Page 3 of 24 
 
 
List of Tables 
 
Table 1: Dose Regimen of MDMA ................................................................................................ 10 
Table 2: Time and Events – Study Procedures ............................................................................... 12 
Table 3: Time and Events – Study Measures ................................................................................. 14 


MAPS Public Benefit Corporation 
IND #063384 
MP16 SAP 
Version 2: 03 September 2019 
Page 4 of 24 
 
 
List of Abbreviations 
° C 
Degrees Celsius 
A:G 
Albumin:Globulin 
ACE 
Adverse Childhood Experiences Questionnaire 
ADHD 
Attention Deficit/Hyperactivity Disorder 
AE 
Adverse Event 
AED 
Automatic External Defibrillator 
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 
BLS 
Basic Life Support 
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 
CPGS 
Chronic Pain Grade Scale 
CRA 
Clinical Research Associate 
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 
DMF 
Drug Master File 
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 
HPMC 
Hydroxypropyl Methylcellulose 
HPQSF 
Health and Work Performance Absenteeism and Presenteeism Short Form 
IASC 
Inventory of Altered Self-Capacities 


MAPS Public Benefit Corporation 
IND #063384 
MP16 SAP 
Version 2: 03 September 2019 
Page 5 of 24 
 
 
IB 
Investigator’s Brochure 
ICD 
International Classification of Disease 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IP 
Investigational Product 
IPF 
Inventory of Psychosocial Functioning 
IR 
Independent Rater 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-releasing 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 
MedDRA 
Medical Dictionary for Regulatory Activities 
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 
SPGT 
Serum Glutamic Pyruvic Transaminase 
SRNU 
Self-reported Nicotine Use 
SSR 
Sample size re-estimation 
SSRI 
Selective serotonin reuptake inhibitor 
SUBJID 
Subject Identifier 
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 
VA 
U.S. Department of Veterans Affairs 


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VAS 
Visual Analog Scale 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WHO DDE 
WHO Drug Dictionary EnhancedTM 


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1.0 Definitions of Terms 
 
Categorical data: refers to discrete (indivisible) variables, such as gender or ethnicity; data will 
be presented as total numbers of each category as needed to describe the sample 
 
Completers: are defined as participants who complete all three planned experimental sessions and 
the CAPS-5 outcome assessment 18 weeks after randomization (Visit 19). 
 
Descriptive data: includes mean, median, standard deviation, minimum, and maximum of 
numerical data used as needed to describe the sample 
 
Difference scores: consist of scores computed by subtracting one value from another, as 
subtracting Baseline from follow-up score, used to test for differences between and within groups 
to determine change as a function of experimental treatment over time 
 
Dropouts: are defined as participants who withdraw consent due to any reason after dosing and 
no longer participate in the study, i.e. no further contact with investigators or site staff. 
 
Effectiveness: type of analysis used to assess therapeutic effects or benefits 
 
Exploratory analyses: inferential or descriptive analysis of the data to determine trends that might 
lead to hypotheses for further study 
 
Frequency listing: tabular listing of numbers and/or percentages of events used as needed to 
describe the sample or data characteristics 
 
Outcome measures: primary and secondary study measures that are used to test the study 
hypotheses 
 
Post-dosing Early Terminators: are defined as participants who discontinue study treatment but 
continue to participate in study evaluations and outcome assessments. 
 
Pre-dosing Early Terminators: are defined as participants who discontinue participation after 
enrollment but before randomization during the Preparatory Period and never receive study drug. 
 
Process measures: study measures or qualitative observations collected during the study that may 
increase depth of understanding of the condition and treatment, although not necessarily related to 
safety or effectiveness 
 
Protocol deviation: event that represents significant divergence from the intended study design as 
described in the protocol 
 
Safety: assessment of indicators of potential risks and adverse events 
 
Safety measures: study measures that assess safety of the Investigational Product (IP), such as 
heart rate monitoring, blood pressure, body temperature 
 
Study design: all elements of a research project that define the study question, experimental 
methods, study procedures including randomization and blinding, measurement techniques, data 
workflow, and statistical analysis 


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Tabular listing: list of each variable or item for each individual participant either in total or by 
treatment group in a table format 
 
2.0 Introduction 
 
This document contains a Statistical Analysis Plan (SAP) for MP16, “An Open-Label, Multi-
Site Phase 2 Study of the Safety and Effect of Manualized MDMA-Assisted Psychotherapy for 
the Treatment of Severe Posttraumatic Stress Disorder.” 
 
MP16 tests a flexible dosing regimen of 80mg MDMA in Session 1, and 80mg or 120mg 
MDMA in Sessions 2 and 3, each followed by a supplemental half-dose.  
 
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit research and 
educational organization working to obtain approval for the prescription use of 3,4- 
methylenedioxymethamphetamine (MDMA) in conjunction with psychotherapy in persons with 
posttraumatic stress disorder (PTSD). MAPS has delegated trial organization activities to its 
wholly owned subsidiary, MAPS Public Benefit Corporation (MPBC). 
 
This open-label Phase 2 study will serve as a lead-in to the sponsor’s two planned Phase 3 
studies, only sites planned for Phase 3 will participate in these studies. This open-label lead-in 
Phase 2 study will serve to validate assumptions made for statistical power calculations 
supporting planned Phase 3 clinical trials and will provide data on the updated version of the 
instrument for the Primary Outcome measure, the Clinician Administered PTSD Scale for DSM-5 
(CAPS-5), which will be used in Phase 3. In addition, this study will gather supportive data on 
the safety and effectiveness of manualized MDMA-assisted psychotherapy while providing an 
opportunity for clinical supervision to planned Phase 3 therapy teams. This study will be the 
sponsor’s first multi-site studies of MDMA-assisted psychotherapy for PTSD and will explore 
reproducibility of findings in a multi-site format to confirm the Phase 3 study design.  
 
This version 2 of the Statistical Analysis Plan was modified from version 1. The changes made 
include the following, 1) separate plans were made for each individual study, MP16 and MP17; 
2) analyses were modified to be within-subject and not comparison between studies; and 3) doses 
used in each study were updated.   
 
3.0 Study Objectives 
 
3.1 Primary Objective 
 
The primary objective of this study is to evaluate the effect of MDMA-assisted psychotherapy on 
PTSD, as measured by the change in CAPS-5 Total Severity Score from Baseline (Visit 3) to 18 
weeks post Baseline (Visit 19). 
 
3.2 Secondary Objective 
 
The secondary objective is to evaluate the effect of MDMA-assisted psychotherapy for PTSD 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 severity, incidence and frequency of AEs, 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 


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psychotherapy. The following safety objectives will evaluate the safety of MDMA-assisted 
psychotherapy. 
 
Assess incidence of AEs during Experimental Sessions that may be indicative of a 
medical complication of the Investigational Product (IP), 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. 
 
Assess incidence of AEs by severity. 
 
Assess incidence of Treatment Emergent AEs (TEAEs) by severity. 
 
Assess incidence of TEAEs by severity taken during an Experimental Session and 2 days 
after IP administration. 
 
Assess incidence of AESIs, defined as AEs specified in the protocol related to cardiac 
function and abuse liability. 
 
Assess incidence of AEs by severity categorized as leading to discontinuation of IP, 
resulting in death or hospitalization, and continuing at Termination. 
 
Assess incidence of SAEs. 
 
Assess incidence of psychiatric concomitant medications taken during an Experimental 
Session and 2 days after IP administration. 
 
Assess incidence of any psychiatric concomitant medications taken during the Treatment 
Period. 
 
Assess incidence of serious suicidal ideation and positive suicidal behavior assessed with 
the Columbia Suicide Severity Rating Scale (C-SSRS). 
Assess mean changes in blood pressure, heart rate, and body temperature from pre-IP 
administration to end of each Experimental Session. 
 
3.4 Exploratory Objectives 
 
These objectives may be used to characterize participants receiving MDMA-assisted 
psychotherapy to support the primary objective and to further explore the effects of treatment: 
1. Explore the effect of presence of secondary traumatic stressors (LEC-5) on the CAPS-5 
Total Severity analyses 
2. Explore changes within-participants 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. Explore the effect of adverse childhood experiences (ACE) on the CAPS-5 Total Severity 
analyses 
4. Explore changes in: 
 
Dissociative symptoms associated with PTSD (DSP-I) 
 
Depression (BDI-II) 
 
Chronic pain (CPGS) 
 
Quality of life (EQ-5D-5L) 
 
Functioning in relation to self and others (IASC) 
 
Psychosocial functioning (IPF) 
 
Self-compassion (SCS) 
 
Alexithymia (TAS-20) 
 
Addictive behaviors including: alcohol use (AUDIT), drug use (DUDIT), and 
nicotine use (SRNU) 
 
Eating habits (EAT-26) 
 
Workplace productivity (HPQSF) 
 
Healthcare utilization (UFEC) 


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5. Characterize the sample and effects of treatment on different outcomes 
 
4.0 Measures 
 
4.1 Primary Measure 
 Clinician Administered PTSD Scale for DSM-5 (CAPS-5)
 
4.2 Secondary Outcome Measure 
• Sheehan Disability Scale (SDS) 
4.3 Safety Measures 
 Treatment-emergent Adverse events
 Concomitant medication use
 Vitals signs during MDMA sessions
 Columbia Suicide Severity Rating Scale (C-SSRS)
 
4.4 Exploratory Measures 
 Life Events Checklist (LEC-5)
 Adverse Childhood Experience Questionnaire (ACE)
 Inventory of Psychosocial Functioning (IPF)
 The Dissociative Subtype of PTSD Interview (DSP-I)
 Beck Depression Inventory II (BDI-II)
 Chronic Pain Grade Scale (CPGS)
 Inventory of Altered Self Capacities (IASC)
 Toronto Alexithymia Scale (TAS-20)
 Self-Compassion Scale (SCS)
 EuroQol Five Dimensions – Five Levels Questionnaire (EQ-5D-5L)
 Eating Attitudes Test (EAT-26)
 Alcohol Use Disorders Identification Test (AUDIT)
 Drug Use Disorders Identification Test (DUDIT)
 Self-reported Nicotine Use (SRNU)
 Utilization of Facility-based and Emergent Care (UFEC)
 Health and Work Performance Absenteeism and Presenteeism Short Form (HPQSF)
 
5.0 Study Design 
 
Table 1: Dose Regimen of MDMA 
Experimental 
Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative Dose 
1 
80 milligrams (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 


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Table 2: Time and Events – Study Procedures 
 
Screening Period 
(2-6 weeks) 
Preparatory Period w/ Enrollment Confirmation 
(2-11 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 3 wks 
(-2 weeks/+1 
wks) 
2 days after 
initial 
eligibility met 
(+7 days) 
2 days post IR 
Screening 
(+12 days) 
Within 1 wk 
of V0 (0 to 
12 days) 
Within 3 wks 
of V1 
Post V2 & 
Taper 
Within 6 days of V3 
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-min 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 wks) 
18 weeks (+/-3 wks) 
post Baseline 
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 
CAPS-5 
T2: Tele- 
medicine 
Int. 1.3 
Exp. 2 
Int. 2.1 
Int. 
2.2 
CAPS-5 
T3: Tele- 
medicine 
Int. 2.3 
Exp. 3 
Int. 3.1 
Int. 3.2 
Int. 3.3 
CAPS-5 
T4 
Outcome: 
Tele- 
medicineH 
Study 
Termi- 
nation 
Visit Timing 
Within 
1 wk of 
V3 
Morn- 
ing 
after 
V5 
With- 
in 2 
wks 
of V5 
Within 3 
weeks 
after V5 
1-7 
days 
before 
V10 
Within 
4 wks 
of V5 
(+/-1 
wk) 
Morn- 
ing 
after 
V10 
With- 
in 2 
wks 
of 
V10 
Within 3 
weeks 
after 
V10 
1-7 days 
before 
V15 
Within 
4 wks 
of V10 
(+/-1 
wk) 
Morn- 
ing 
after 
V15 
Within 
2 wks 
of V15 
Within 
4 wks 
of V15 
8 wks 
post V15 
(+/-2 wk) 
2 days 
post 
V19 (- 
1/+7 
days) 
Past/Current 
Medication & 
Adherence 













Drug Screen 



Pregnancy Screen 



Record 















All AEs C 













Container 
Assignment D 



Administer IP 



8-hour Exp. 
Session 



BP, Pulse, 
Temperature E 



 F 
Overnight Stay I 



90-min Integrative 
Session 









Phone Call 
Follow-up G 



Weight 

 
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 Obtain container assignment 24 to 48 hours prior to each Experimental Session 
E 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 
F At Study Termination, only blood pressure needs to be measured 
G 4 days of phone call follow-up: Day 2 and 7 after the Experimental Session, with two additional calls in between 
H All visits must be scheduled to ensure that the Primary Outcome CAPS-5 T4 assessment is within the overall window provided: 18 weeks (+/-3 weeks) post V3 


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I See Appendix A for exceptions to overnight stay directive 
 
Table 3: 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 



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 
93 
40 
10 
77 
23 
40 
10 
77 
23 
40 
10 
15 
77 
95 
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 and 7 after Experimental Session 
D The relevant questions (117-130) 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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6.0 Randomization and Blinding 
 
MP16 is an open-label study with no randomization or blinding of treatment. 
 
7.0 Sample Size and Power Considerations 
 
MP16 is a one-arm interventional study. Thus, no power nor sample size calculations were 
required. 
 
8.0 Analyses 
 
Every effort will be made to ensure complete, accurate and timely data collection and to avoid 
missing data, to ensure the completeness of the data which can impact the integrity and accuracy 
of the final study analysis. The statistical analyses will be reported using summary tables, figures, 
and data listings. All analyses and tabulations will be performed using SAS® Version 9.4 or 
higher, and S-PLUS. In general, nominal variables will be described in terms of frequencies and 
percentages. Ordinal and non-normal continuous variables will be described using sample median 
and range. 
 
Approximately normal variables will be described using sample mean and standard deviations 
and analyzed by parametric statistical tests. Except for the primary effectiveness analysis, all 
statistical tests will be two-sided and a difference resulting in a p-value of less than or equal to 
0.05 will be considered statistically significant. All p-values will be rounded to and displayed in 
four decimals. If a p-value less than 0.0001 occurs it will be shown in tables as <0.0001. Data not 
subject to analysis according to this plan will not appear in any tables or graphs, but will be 
included in the data listings. Selected results may be presented graphically using standard 
graphical software. 
 
8.1 Analysis Sets 
 
 
Safety: all participants who receive any IP 
 
 
All Enrolled: all participants who signed informed consent 
 
 
Modified Intent-To-Treat (mITT): all randomized participants who receive IP in at least 
one blinded Experimental Session (Visit 5) and have at least one follow-up CAPS-5 
assessment post-treatment  
 
 
Per Protocol (PP): all randomized participants who meet eligibility criteria, who receive 
IP in three Experimental Sessions, and have three follow-up CAPS-5 assessments post- 
treatment  
 
 
Not Per Protocol (NPP): all participants who are included in the mITT set but not the PP 
set  
 
8.2 Missing Data Handling 
 
All possible procedures within Good Clinical Practice (GCP) will be used to minimize Post- 
dosing Early Termination. Based on Phase 2 data it is expected that up to 5% of enrolled and 


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randomized participants will terminate early. Post-dosing Early Terminators will be compared to 
the Completers using baseline demographics and CAPS-5 Total Severity Score at baseline. 
Participants who are removed from the study after they are enrolled and receive IP but do not 
complete the study may fall into one of these categories: Post-Dosing Early Termination or 
Dropout. If the participant has received IP in at least one Experimental Session and completed 
one CAPS-5 assessment beyond Baseline, they will be considered evaluable. All participants who 
receive IP in at least one Experimental Session will be included in all safety analyses. Post- 
Dosing Early Termination are participants who discontinue study treatment but continue to 
participate in study evaluations and outcome assessments. Data collection by IRs will continue on 
the same schedule as planned through Study Termination visit procedures. Dropouts are defined 
as a participant who decides to withdraw consent. They will terminate without further follow-up. 
If the participant agrees, they will complete a final CAPS-5 assessment and Study Termination 
visit procedures. These participants are defined as dropouts who withdraw consent due to any 
reason after receiving at least one dose of IP 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. All observed CAPS-5 data up to the point of discontinuation of treatment will be 
included in the MMRM model of the de jure estimand from Post-dosing Early Terminators. 
Participants will not be replaced. All observed CAPS-5 data from Post-dosing Early Terminators 
and Dropouts collected prior to and after early termination will be included in the supportive 
effectiveness analysis of the de facto estimand. 
 
8.2.1 Partial or Missing Dates 
 
The following conventions will be used to impute missing portions of dates for AEs and 
concomitant medications. Note that the imputed values outlined here may not always provide the 
most conservative date. In those circumstances, the imputed value may be replaced by a date that 
will lead to a more conservative analysis. 
 
Start Dates: 
1. If the year is unknown, then the date will not be imputed and will be assigned a missing 
value. 
2. If the month is unknown, then: 
a. The month and day of the first dose date will be imputed if the year matches the 
first dose date year. 
b. Otherwise, ‘January’ will be assigned. 
3. If the day is unknown, then: 
a. The day of the first dose date will be imputed if the month and year match the 
first dose date month and year. 
b. Otherwise, the first day of the month will be assigned. 
 
Stop Dates: 
1. If the year is unknown, then the date will not be imputed and will be assigned a missing 
value. 
2. If the month is unknown, then ‘December’ will be assigned. 
3. If the day is unknown, then the last day of the month will be assigned. 
 
8.3 Protocol Deviations 
 
A major deviation will be defined as participants enrolled and randomized but did not meet 
eligibility criteria during the course of the study, or any deviations that affect safety or overall 


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data integrity, particularly if it relates to study endpoints. The number of participants in 
each protocol deviation category listed below will be summarized by analysis set and 
treatment group. Individual participants will appear in a listing. 
 
Possible protocol deviations include the following categories: 
 
 
Participant entered study but did not meet criteria 
 
Participant developed withdrawal criteria but was not withdrawn 
 
Participant received excluded concomitant treatment 
 
Protocol procedure not performed per protocol 
 
Participant received incorrect treatment or incorrect dose 
 
Protocol procedure performed out of range 
 
Miscellaneous 
 
8.4 Baseline Values 
 
Baseline values are from Baseline Visits for all measures, except C-SSRS, AUDIT, DUDIT, 
resting blood pressure (BP), Body Mass Index (BMI). For C-SSRS, the initial screening visit 
will be conducted with the ‘Lifetime’ version of the measure. The Independent Rater 
Screening assessment of ‘Since Last Visit’ suicidal ideation and behavior will be used as 
‘Baseline.’ For the AUDIT and DUDIT measures and resting BP, BMI, results collected at 
Screening will be used as the Baseline value. 
 
8.5 Participant Disposition and Dosing Summary 
 
The Safety Set will be included in the summary of participant disposition and accountability. 
The number and percent of participants who completed or discontinued the study will be 
displayed with reasons for early termination, where the percent is with respect to the total 
number of participants. The timepoint of doses and total MDMA (mg) administered will be 
summarized for the Safety Set. 
 
8.6 Demographics and Baseline Characteristics 
 
Participant demographic data and Baseline characteristics will be summarized 
descriptively. The demographic data and baseline characteristics will be summarized for 
the Safety Set and overall. 
 
8.7 Effectiveness Analyses 
 
For all primary, secondary, and exploratory endpoints descriptive statistics (n, mean, 
standard deviation, median, range, or counts and percentages where appropriate) will be 
provided. Longitudinal CAPS-5 Total Severity Score and SDS item scores will be plotted 
across visits to characterize the onset of treatment effect. 
 
8.7.1 Primary Effectiveness Analyses 
 
The de jure estimand of treatment effectiveness will be used to estimate the change in CAPS-
5 score from baseline due to MDMA-assisted psychotherapy on PTSD symptom severity in 
the intended population of patients with PTSD from any cause. The primary estimator of 
effectiveness will be the mean change in CAPS-5 Total Severity Scores from Baseline to 18 
weeks after start of dosing (Visit 19). Least squares means from a restricted maximum 
likelihood (REML)-based mixed model for repeated measures (MMRM) will be used to 
estimate the change in CAPS-5 from baseline to each visit. CAPS-5 data collected after 


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treatment discontinuation will not be included in the de jure estimand. Missing data will not 
be imputed.  
 
8.7.2 Key Secondary Effectiveness Analyses 
 
For the key secondary analysis of effectiveness, the de jure estimand will be used to 
estimate the change from baseline due to  MDMA-assisted psychotherapy on PTSD on the 
SDS in the intended population of patients with PTSD from any cause. The SDS is a 3-item 
scale measuring the severity of disability in the domains of work, family life/home 
responsibilities and social/leisure activities. Each of these three domains is scored on a ten-
point Likert scale, where a score of 0 is ‘not at all impaired’, 5 is ‘moderately impaired’ and 
10 is ‘very severely impaired’. For each study participant at each visit, the responses on the 
3 items of the SDS will be summarized with a mean. In cases where the response on item 1 
is not applicable, it will not be considered missing data. Thus, missing data assumptions and 
methodologies are not required when item 1 is not answered. Whereas when all 3 items have 
a response, the summary measure is the mean of the 3 item responses, in the cases where 
item 1 is not answered the summary measure will consist of the mean of items 2 and 3. It is 
expected that no more than 20% participants will have not have an applicable score for item 
1, based on prior studies of paroxetine with PTSD. To limit missing data and ensure 
standardized administration, the SDS will be administered in a clinician-rated format during 
the same visits as the CAPS-5 by the centralized Independent Rater Pool. 
 
A secondary estimator of effectiveness will be the mean change in SDS Mean Scores from 
Baseline to 18 weeks after start of dosing (Visit 19). Least squares means from a restricted 
maximum likelihood (REML)-based mixed model for repeated measures (MMRM) will be 
used to estimate the change from baseline to each visit. SDS data collected after treatment 
discontinuation will not be included in the de jure estimand. Missing data will not be 
imputed and will be considered missing at random.  
 
8.7.3 Exploratory Analyses 
 
Post-hoc exploratory analyses not identified in this SAP may be performed to further examine 
the study data. These analyses will be clearly identified as such in the final clinical study 
report. 
 
In exploratory analyses, additional baseline covariates (age, gender, ethnicity, index 
trauma, complexity and severity of trauma, medication tapering, diagnosis of comorbid 
depression, diagnosis of comorbid Axis 2 diagnosis, adverse childhood experiences) 
may be assessed for inclusion in the model at a p<0.05. One-group pretest-posttest 
Cohen’s d effect size will be estimated. 


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8.7.4 Responder Analyses 
 
The CAPS-5 produces a Total Severity Score based on severity of PTSD symptom domains 
described in the DSM-5, as well as a categorical rating indicating whether a participant meets 
PTSD diagnostic criteria. A psychometric validation study found the following severity score 
ranges for the CAPS-5: Asymptomatic (0-10), Mild (11-22), Moderate (23-34), Severe (35-46), 
Extreme (47+). Based on these data, a 10-point reduction in CAPS-5 Total Severity Score is 
clinically meaningful. As an alternate definition of treatment response to assess clinical 
significance of study outcomes, the sponsor will conduct a responder analysis to support findings 
from the primary effectiveness analysis, and to explore how many single-dose treatments are 
needed to achieve response (See Figure 1). 
 
Figure 1: CONSORT for PTSD Responder Analysis After Treatment 
 
 
[1] Response at T2, T3, and T4 will be in comparison to Baseline at T1. 
Compare frequency of response between groups 
based on CAPS-5  
Response: ≥10-point reduction  
Loss of diagnosis:  Does not meet Diagnostic 
Criteria + ≥10-point reduction 
Remission: Does not meet Diagnostic Criteria + 
CAPS-5 Total Score   11 
Compare frequency of response between groups 
based on CAPS-5  
Non-responders: < 10-point reduction  
Response 
After 
Session 1 
CAPS-5 T2 
Evaluable mITT  
 
Compare frequency of response between groups 
based on CAPS-5  
Response: ≥10-point reduction  
Loss of diagnosis:  Does not meet Diagnostic 
Criteria + ≥10-point reduction 
Remission: Does not meet Diagnostic Criteria + 
CAPS-5 Total Score   11 
Compare frequency of response between groups 
based on CAPS-5  
Non-responders: < 10-point reduction 
Response 
After 
Session 2 
CAPS-5 T3 
Compare frequency of response between groups 
based on CAPS-5  
Response: ≥10-point reduction  
Loss of diagnosis:  Does not meet Diagnostic 
Criteria + ≥10-point reduction 
Remission: Does not meet Diagnostic Criteria + 
CAPS-5 Total Score   11 
Response 
After 
Session 3 
CAPS-5 T4 
Compare frequency of response between groups 
based on CAPS-5  
Non-responders: < 10-point reduction  


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8.8 Safety Analyses 
 
Safety assessment analyses for this study will include summaries of unsolicited adverse events, 
concomitant medications, suicidal ideation and behavior, and vital signs. Qualitative safety 
analyses will examine safety data with summary tables listing drug exposure, concomitant 
medications/therapies, unsolicited AEs, and percentages tabulated. 
 
8.8.1 Analysis of Exposure 
 
The frequencies and percentages of participants with exposure will be summarized. Data will be 
tabulated for the Safety Set. 
 
8.8.2 Analysis of Adverse Events 
 
The primary measure of safety will be the reporting of unsolicited AEs. All AEs collected from 
Enrollment to Termination will be categorized as follows: 
 
Pretreatment AEs are defined as AEs that occur during the Preparatory Period prior to the 
first dose in the first Experimental Session 
 
Treatment Emergent AEs are defined as AEs that occur during the Treatment Period from 
the first Experimental Session to the last Integrative Session 
 
AEs that occur on and two days after MDMA or placebo administration 
 
AESIs are defined as AEs specified in the protocol related to cardiac function and abuse 
liability 
 
Follow-up Period AEs are defined as AEs that occur during the Follow-up Period after 
the last Integrative Session through Termination 
 
AEs leading to discontinuation of IP 
 
AEs resulting in death or hospitalization. 
 
SAEs 
 
AEs continuing at Termination. 
 
Verbatim terms on case report forms will be mapped to preferred terms (PT) and system organ 
class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) Version 17.0. 
Frequency and incidence of AEs will be displayed by PT, sorted by SOC, and summarized by 
treatment group, analysis set, category (as defined above), severity, and seriousness. AEs will be 
analyzed and presented as follows: 
 
If a participant has more than one AE mapped to the same PT, that AE will be reported 
once using the highest severity 
 
Relationship will be determined based on relative incidence of TEAEs with at least two- 
fold difference between MDMA vs. placebo 
 
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 
investigational product 
 
AEs that occur on day of Experimental Sessions and two days after IP administration will 
be presented separately. 
 
8.8.3 Concomitant Medications 
 
A secondary measure of safety will be the reporting of concomitant medications. All concomitant 
medications collected from Screening to Study Termination will be categorized as follows: 


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 
Pretreatment medications are defined as medications taken prior to and after signing 
informed consent and those taken during the Preparatory Period prior to the first 
Experimental Session. A stop date is expected prior to the first Experimental Session for 
any medications requiring a change in dose, a skipped dose, or tapering. 
 
Treatment Period concomitant medications are defined as those taken or continued during 
the Treatment Period from the first Experimental Session to the last Integrative Session. 
A stop date is expected prior to the each Experimental Session for any medications 
requiring a change in dose, a skipped dose, or tapering. 
 
Concomitant medications with a start date of the day of and two days after IP 
administration 
 
Follow-up Period concomitant medications are defined as those taken or continued 
during the Follow-up Period after the last Integrative Session through Termination 
 
Any concomitant medications that are tapered 
 
Any concomitant medications that are taken to treat an AE 
 
Any concomitant medications that are taken to treat an SAE 
 
Any excluded concomitant medications taken as a deviation from the protocol. 
 
Concomitant medications on case report forms will be classified using the WHO Drug Dictionary 
EnhancedTM (WHO DDE). Frequency and incidence of concomitant medications will be 
displayed by generic name, sorted by class, and summarized by treatment group, analysis set, and 
category as defined above. Concomitant medications will be analyzed and presented as follows: 
 
Concomitant medications taken on the day of and two days after IP administration will be 
presented separately 
 
Any psychiatric concomitant medications by period. 
 
8.8.4 Analysis of Suicidal Ideation and Behavior 
 
Suicidal ideation and behavior will be summarized according to suggestions made in the C-SSRS 
Scoring and Data Analysis Guide [1]. A positive response for suicidal ideation is counted when a 
participant answers “yes” to any one of the five suicidal ideation questions (Categories 1-5) on 
the C-SSRS (i.e., a score >0 for suicidal ideation). Serious suicidal ideation is a suicidal ideation 
score of 4 or 5. A positive response for suicidal behavior occurs when a participant answers “yes” 
to any one of the five suicidal behavior questions (Categories 6-10) on the C-SSRS (i.e., a score 
>0 for suicidal behavior). The number and percent of positive responses of Positive Ideation, 
Serious Ideation, and Positive Behavior will be tabulated by treatment group and time period 
(lifetime, screening, baseline, each Experimental Session (pre- and post-IP), Integrative Sessions, 
and endpoints). Frequency and incidence of positive or serious ideation and suicidal behavior will 
be presented using descriptive statistics in tabular format. 
 
8.8.5 Summary of Vital Signs 
 
Vital signs (heart rate, BP, and body temperature) for Experimental Sessions will be summarized 
using descriptive statistics in tabular format listing values at pre-IP, prior to the supplemental 
dose, and at the end of each Experimental Session. Change from Baseline in vital signs will be 
presented. 
 
9.0 Timing of Analyses 
 
Preliminary analyses and listing reviews will be ongoing throughout the studies to inform 
therapist supervision and assumptions made for upcoming Phase 3 trials. For clinical study 


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reports and publications, only locked database files will be used. The primary effectiveness 
analysis will be conducted after all participants complete Visit 20 and the database is locked. 
 
 
References 
 
1. 
Nilsson, M.E., et al., Columbia Suicide Severity Rating Scale Scoring and Data Analysis 
Guide, in CSSRS Scoring Version 2.0. 2013: 
http://www.cssrs.columbia.edu/documents/ScoringandDataAnalysisGuide_Feb2013.pdf. 
p. 1-13.