Clinical trial NCT04784143
Conditions: PTSD
Sponsor: Lykos Therapeutics
Start date: 2021-11-08; Completion date: 2024-06-27
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical trial is to learn if MDMA-assisted therapy is effective in U.S. military veterans with at least moderate chronic PTSD. The main question it aims to answer is: Are two versus three MDMA-assisted therapy sessions in an outpatient treatment clinic more effective?

Researchers will compare two MDMA-assisted therapy sessions to three MDMA-assisted therapy sessions.

Participants will undergo three non-drug preparatory sessions prior to their first MDMA-assisted therapy session. Each MDMA-assisted therapy session will be followed by three non-drug integrative therapy sessions.

Detailed description:
This open-label, randomized study will assess the comparative effectiveness of two versus three active MDMA-assisted therapy sessions in U.S. military veterans with at least moderate chronic PTSD treated in an outpatient VA treatment clinic. The study will be conducted in up to 60 participants. Prior to the randomized portion of the study, each therapist pair team will treat one participant under the 3-session model, and one participant under the 2-session model. In total, 8 participants will be treated under this proof of principle therapist training lead-in. A 120 mg dose of MDMA, followed by a supplemental dose (60 mg) unless contraindicated, is administered during the treatment period with manualized psychotherapy in 2 or 3 open-label monthly Experimental Sessions. This \~ 8-12-week Treatment Period includes three Preparatory Sessions prior to the first MDMA-assisted session. During the treatment period, each Experimental Session is followed by three Integrative Sessions of non-drug therapy. The Primary Outcome measure, the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), is assessed by a centralized, blinded Independent Rater (IR) pool at post-treatment for each group.

Arms: arm 1: Two experimental sessions of MDMA-assisted therapy arm 2: Three experimental sessions of MDMA-assisted therapy
Interventions: intervention 1: Midomafetamine intervention 2: Psychotherapy
Intervention descriptions: intervention 1: 120 mg midomafetamine HCl followed by a supplemental dose of 60 mg intervention 2: Manualized psychotherapy performed by therapist team

Protocol documents:
Prot_000.pdf: 
MAPS Public Benefit Corporation 
 
MPVA6 Protocol Synopsis 
IND #063384 
 
Amendment 7 Version 1: 04 August 2022  
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Protocol and Synopsis MPVA6  
IND #063384 
 
 
Amendment 1, Version 1: 27 February 2020 
Amendment 2, Version 1: 24 July 2020 
Amendment 3, Version 1: 08 April 2021 
Amendment 4, Version 1: 04 June 2021 
Amendment 5, Version 1: 10 September 2021 
Amendment 6, Version 1: 04 February 2022 
Amendment 7, Version 1: 04 August 2022 
 
A Phase 2, Open-Label, Randomized Comparative Effectiveness Study  
for MDMA-Assisted Therapy in U.S. Veterans with Chronic PTSD 
 
SPONSOR 
Multidisciplinary Association for Psychedelic Studies (MAPS) 
3141 Stevens Creek Blvd #40563 
San Jose, CA 95117 
 
SPONSOR REPRESENTATIVE 
Rick Doblin, Ph.D. Executive Director, MAPS 
 
SPONSOR DELEGATE &TRIAL 
ORGANIZER 
MAPS Public Benefit Corporation  
3141 Stevens Creek Blvd #40547  
San Jose, CA 95117 
 
SPONSOR DESIGNEE 
Amy Emerson 
Chief Executive Officer (CEO) 
MAPS Public Benefit Corporation 
 
CLINICAL INVESTIGATOR 
Rachel Yehuda, Ph.D. 
Director, Mental Health Patient Care Center James J Peters VA 
Medical Center Professor of Psychiatry and Neuroscience Icahn 
School of Medicine at Mount Sinai  
Email: Rachel.Yehuda@va.gov 
Phone number: 718-584-9000x6964 
 
Mustafa Haznedar, M.D. Psychiatrist 
James J Peters VA Medical Center  
Email: Mustafa.Haznedar@va.gov  
Phone number: 718-584-9000x5232 
 
MEDICAL MONITOR 
Kelly Green, PA-C, MPH 
Associate Medical Director, MAPS Public Benefit Corporation  
Email: kelly.green@mapsbcorp.com 
Phone number: 877-748-3767 
 
USE 
In conjunction with relevant Food and Drug Administration 
(FDA) guidance 
 


MAPS Public Benefit Corporation 
 
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Amendment 7 Version 1: 04 August 2022  
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CONFIDENTIAL 
MPVA6 Protocol Synopsis 
Full protocol begins on Page 10. 
 
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 therapy in patients with 
posttraumatic stress disorder (PTSD). PTSD is a serious debilitating disorder that negatively 
impacts a person’s daily life, and can result in diminished cognitive and psychosocial functioning, 
fractured relationships, inability to maintain employment, substance abuse, high-cost healthcare 
utilization, increased depression, and suicide risk. People who suffer from PTSD relive their 
traumatic experience(s) through nightmares and flashbacks, have difficulty sleeping, and feel 
detached or estranged. Symptoms can be severe and long lasting. 
 
MDMA is a monoamine releaser and re-uptake inhibitor with indirect effects on neurohormone 
release. The combined neurobiological effects reduce defenses and fear of emotional injury, 
enhance communication and introspection, and increase empathy and compassion. MDMA may 
enhance fear extinction learning in humans. The subjective effects of MDMA create a productive 
psychological state that enhances the therapeutic process. Data from an international series of 
Phase 2 pilot studies of MDMA-assisted therapy conducted by the sponsor provide preliminary 
evidence that chronic PTSD, independent of cause, is treatable with two to three sessions of 
MDMA-assisted therapy and associated non-drug preparatory and integrative therapy. This open- 
label comparative effectiveness study will serve to explore the relative effectiveness of two vs. 
three randomly assigned active drug sessions in a sample of U.S. military veterans with chronic 
PTSD. 
 
The rationale for the proposal to study two versus three active drug sessions builds in part on 
results of a previous randomized Phase 2 pilot study supported by MAPS [1]. This study found 
mixed results regarding the optimal number of MDMA-assisted sessions. Two active dose (100 
mg and 125 mg) groups showed further clinically significant reductions in PTSD symptoms after 
a third Experimental Session, whereas a low dose (40 mg) group demonstrated significant 
reductions after open-label crossover to two active doses but did not continue to improve after a 
third. The authors concluded that more research is needed to determine the optimal number of 
treatment sessions in order to achieve symptom remission. 
 
This trial will also help establish the effectiveness of MDMA-assisted therapy for PTSD in an 
ethnically diverse military veteran population in the context of a large Veteran’s Affairs 
outpatient mental health clinic. A randomized, Phase 2 pilot trial provided preliminary evidence 
for the efficacy of MDMA-assisted therapy for chronic PTSD in military personnel and first 
responders [2]. The sample in that study (n=26) was primarily White (85%) and treated at a 
private outpatient clinic in the southern U.S. This study represents the first trial of MDMA- 
assisted therapy for PTSD in a treatment seeking veteran population in an outpatient VA mental 
health clinic. The James J Peters VA Medical Center is located in a large urban area (Bronx, NY) 
with a patient population that is approximately 55% Hispanic, and 60% Black or African 
American, 35% White, and 5% Asian. Results from this study will thus extend the findings of 
prior studies with the potential to inform treatment development and policy within the national 
VA system. 
 
In addition to the primary aim of assessing the comparative effectiveness of two vs. three 


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Experimental Sessions, this study will include collection of blood samples for biomarker research 
from participants at two time points (pre- and post-treatment) in order to bank samples for future 
assay. The collection and banking of blood samples in association with treatment will allow for 
future exploratory analyses of potential biological markers that predict, mediate, or change in 
association with changes in PTSD symptom severity following MDMA-assisted therapy for 
PTSD.  
 
In addition, the study will gather supportive data on the safety and effectiveness of manualized 
MDMA-assisted therapy while providing an opportunity for clinical supervision to therapy pairs 
to explore reproducibility of findings in a multi-site format to confirm the Phase 2 study design. 
 
Study Design 
 
This open-label, randomized study will assess the comparative effectiveness of two versus three 
active MDMA-assisted sessions in U.S. military veterans with at least moderate chronic PTSD 
treated in an outpatient VA treatment clinic. The study will be conducted in up to 60 participants, 
randomized with a 1:1 allocation to each treatment group. 
 
There will be one or more two-person therapy pairs. During the lead-in portion of the study, each 
therapy pair will treat one participant who will be randomized in a 1:1 fashion to receive either 2 
Experimental Sessions or 3 Experimental Sessions.  The sponsor will provide clinical supervision 
for therapy pairs treating participants. Each new therapy pair participating in the trial will receive 
clinical supervision at three dedicated time points during treatment of their first subject and 
additional supervision as needed in subsequent cases. The sponsor’s Adherence Raters and 
trainers will monitor videos of study visits for adherence to the therapeutic method and provide 
supervision. 
 
A divided-dose of 160 mg MDMA HCl, with an initial 120 mg dose, followed by a supplemental 
dose of 40 mg approximately an hour and a half after the first dose, unless tolerability issues 
emerge, is administered during the Treatment Period with manualized therapy in two or three 
open-label monthly Experimental Sessions. Participants will be randomized to a 2-session group 
or a 3-session group. Each Experimental Session is followed by three Integrative Sessions of non-
drug therapy. Experimental Sessions are followed by an overnight stay.  
 
The Primary Outcome measure, the change in CAPS-5 from baseline, is assessed by a 
centralized, blinded Independent Rater (IR) pool at post-treatment for each group. The IR pool 
will be blinded to visit number and number of treatments received and will not have access to 
data collected during the active treatment period. The CAPS-5 will be repeated one month 
following the final treatment session (post-treatment). Blood samples will be collected at three 
timepoints: a clinical laboratory blood draw at Screening, and biomarker research blood draw pre- 
and post-treatment. Self-reported PTSD and depression symptoms will be assessed at numerous 
visits by the PCL-5 and BDI-II (see Tables 7 and 8). The blood samples collected at baseline and 
post-treatment will be banked for future analysis for a sub-study described in a separate protocol. 
For each participant, the study will consist of: 
 
 
Screening Period (~4 weeks): Phone or in person screen, informed consent, eligibility, 
and baseline assessment 
 
Preparatory Period with Enrollment Confirmation (at least 7 days, max time 
dependent upon medication tapering): medication tapering, Preparatory Sessions and 
Baseline assessments leading to Enrollment Confirmation. 
 
Study Enrollment and Randomization: Include eligible participants, randomize to 
group, complete baseline self-report measures, collection of pre-treatment biomarker 


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blood samples  
 
Treatment Period (Group 1: 9-15 weeks, Group 2: 6-10 weeks): Each Experimental 
Session followed by 3 non-drug Integrative Sessions. 
 
Post-treatment (~4 weeks): At one-month post final Integrative Session, clinical 
evaluation and self- report measures, collection of post-treatment biomarker blood 
samples.  
o For the 2-session group: additional clinical evaluation one month following post-
treatment as a secondary outcome. 
 
Study Termination: After the Study Termination visit, participants will have the 
opportunity to enroll in a separate LTFU study at least six months from the final 
Experimental Session. 
 
Participants will be recruited through the James J Peters VA Medical Center PTSD Clinic, which 
is housed in an outpatient mental health clinic, from providers who treat veterans, or from 
organizations that serve veterans. The sponsor will monitor demographics on an ongoing basis 
and encourage diversity (representative of PTSD population) in enrollment of study participants 
by communicating with the site. Recruitment efforts may also potentially include print and 
internet advertisements, flyers posted in the mental health clinic, and recruitment of former 
research participants in PTSD studies. 
 
Qualified, blinded IRs selected based on availability from the IR Pool will perform the CAPS-5 
assessments as described in the following table. 
 
CAPS-5 Data Collection by Visit 
 
CAPS Number 
Visit 
Description/Timing 
Target Timing 
Post Baseline 
Baseline CAPS-5 T1 
V3 
Baseline between Visits 2 and 4 
(Preparatory Sessions), after 
medications have been tapered. 
Not Applicable 
CAPS-5 T2 
V13 (2-session group) 
or 
V17 (3-session group) 
Post Treatment Primary 
Outcome  49 to 56 days after last 
Experimental Session 
63 to 98 days or 
85 to 134 days  
CAPS-5 T2.2 
V15 (2-session group 
only) 
Secondary outcome for 2-
session  group only 
28 to 35 days after T2 
85 to 134 days  
 
Dose Selection 
 
This study will compare the effects of two versus three open-label manualized Experimental 
Sessions of therapy assisted by divided doses of MDMA HCl (referred to as MDMA throughout) 
as described in the table below, along with associated non-drug preparatory and integrative 
therapy. Similar MDMA doses to those proposed in this study have been safely used in previous 
Phase 2 and 3 studies sponsored by MAPS. 
 
Dose Regimen of MDMA 
 
Experimental  
Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative Dose 
1 
120 mg 
40 mg 
120 mg to 160 mg 
2 
120 mg 
40 mg 
120 mg to 160 mg 
3 
120 mg 
40 mg 
120 mg to 160 mg 
Total Cumulative Dose: 2 Session Group 
240 mg to 320 mg 
Total Cumulative Dose: 3 Session Group 
360 mg to 480 mg 


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* Unless tolerability issues emerge with the first dose or it is refused by the participant. Supplemental dose 
will be 40 mg for all subjects throughout the study.  
 
Protocol Objective 
 
The overall objective of this study is to use standard clinical measures to explore the relative 
effectiveness in reducing PTSD symptom severity comparing groups randomly assigned to two 
versus three Experimental Sessions of open-label MDMA-assisted therapy, in a diverse sample of 
U.S. military veterans with PTSD in a VA outpatient clinic, and to serve as an opportunity for 
supervision of therapy pairs selected to conduct MDMA-assisted therapy research. 
 
Primary Objective 
 
The primary objective of this study is to compare the effectiveness of two versus three sessions of 
MDMA-assisted therapy in treatment of PTSD, based on mean change in CAPS-5 Total Severity 
Score from T1 (Baseline) to T2 (Primary Outcome). 
 
Secondary Objective 
 
The key secondary objective of this study is to compare the effectiveness of two versus three 
sessions of MDMA-assisted therapy on -rated functional impairment, as measured by the mean 
change in Sheehan Disability Scale (SDS) items score from Baseline to T2 (Primary Outcome). 
 
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, and vital 
signs to support the package insert for MDMA-assisted therapy. The following safety objectives 
will evaluate the safety of MDMA-assisted therapy: 
 
1. Assess incidence of AEs during Experimental Sessions that may be indicative of a 
medical complication of MDMA, 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) from first dose through Study 
Termination by severity. 
4. Assess incidence of TEAEs by severity taken during an Experimental Session and 
through 2 days after MDMA 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 MDMA, 
resulting in death or hospitalization, and continuing at Study Termination. 
7. Assess incidence of SAEs. 
8. Assess incidence of concomitant medications of interest taken during an Experimental 
Session and through 2 days after MDMA 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 C-SSRS. 
11. Assess mean changes in blood pressure, heart rate, and body temperature from pre- 
MDMA administration to end of each Experimental Session. 
 
 


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Recruitment and Participant Population 
 
Previously published trials with similar eligibility criteria have a post-ICF ineligibility rate of 
~62% for individual MDMA-Assisted Therapy. Therefore, therapists or consent delegates trained 
by the sponsor will enroll up to 175 open-label participants in this study. “Enrolled” is defined as 
having signed informed consent. Therefore, the protocol will permit ICF and screening of up to 
175 participants to achieve 60 participants enrolled to study intervention. Up to 60 participants 
will be treated in the study.  Participants will be recruited through the James J Peters VA Medical 
Center PTSD Clinic, which is housed in an outpatient mental health clinic, from providers who 
treat veterans, or from organizations that serve veterans. Recruitment efforts may also potentially 
include print and internet advertisements, flyers posted in the mental health clinic, and 
recruitment of former research participants in PTSD studies. 
 
Participants will be U.S. military veterans aged 18 or older, with a confirmed diagnosis of PTSD 
with at least a 28 on the CAPS-5 with symptoms present for at least 3 months. 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 
 
In this equivalence design the primary hypothesis is a comparison of 3 sessions of MDMA with 
therapy versus 2 sessions of MDMA with therapy. The internal validity of this study is predicated 
upon data already established and approved by the FDA showing that 3 sessions of MDMA with 
therapy has proven superiority over placebo in the treatment of PTSD. Therefore, it is appropriate 
to compare the effectiveness of the experimental arm of 2 sessions of MDMA to the effectiveness 
of the previously established 3 doses in order to test an equivalence hypothesis. If the null 
hypothesis is rejected, the alternative hypothesis will be accepted which states that 2 sessions of 
MDMA shows equivalent efficacy as 3 sessions. The measure of effectiveness is the change from 
baseline in the CAPS-5 Total Severity Score. In this equivalency design the "zone" of 
equivalence is a pre-defined region above or below the difference in mean changes in the CAPS-5 
Total Severity Score in the arm given 3 sessions of MDMA. In a previous study, MP16, it was 
reported that the mean change in baseline among 29 participants with PTSD who were given 3 
sessions of MDMA experienced a mean reduction of 30.7 in the CAPS-5 Total Severity Score, 
with a standard deviation of 12.7. Therefore, the "zone" of equivalence in this study is defined as 
a mean change in the CAPS-5 Total Severity Score in the arm given 2 sessions of MDMA that is 
within 11 points of the mean change in that seen in the arm given 3 sessions. If similar results are 
observed as those seen from the sponsor’s 3 session MP16 study, we would conclude equivalence 
if the difference in mean changes in CAPS-5 Total Severity Score in the arm given 2 sessions of 
MDMA was as low as -19.7 to as high as -41.7. Assuming that in the population of PTSD 
patients there is no difference in the mean change in CAPS-5 Total Severity Score when given 2 
sessions of MDMA or 3 sessions of MDMA, with alpha level set at 5%, power set to 90%, the 
sample size of this study is 30 participants per arm. 
 
The two treatment groups will be compared in post-treatment change in symptom severity, as 
assessed by the mean change in CAPS-5 Total Severity Score from T1 to T2. Exploratory 
responder analyses will also be conducted to determine whether each group obtained a clinically 
significant reduction in symptoms. The two treatment groups will be compared on change from 
baseline in functional impairment, as assessed by the mean change in SDS Score from T1 to T2. 
Details and additional exploratory analyses are described in the Statistical Analysis Plan. 


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      MPVA6 Protocol Synopsis 
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Study Structure Overview 
 
 
 
 
 
 
 
 
 
 
 


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MAPS Public Benefit Corporation 
 
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IND #063384 
 
Amendment 7 Version 1: 04 August 2022 
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Protocol MPVA6  
IND #063384 
 
Amendment 1, Version 1: 27 February 2020 
Amendment 2, Version 1: 24 July 2020 
Amendment 3, Version 1: 08 April 2021 
Amendment 4, Version 1: 04 June 2021 
Amendment 5, Version 1: 09 September 2021 
Amendment 6, Version 1: 04 February 2022 
Amendment 7, Version 1: 04 August 2022 
 
A Phase 2, Open-Label, Randomized Comparative Effectiveness Study  
for MDMA-Assisted Therapy in U.S. Veterans with Chronic PTSD 
 
SPONSOR 
Multidisciplinary Association for Psychedelic Studies (MAPS) 
3141 Stevens Creek Blvd #40563 
San Jose, CA 95117 
 
SPONSOR REPRESENTATIVE 
Rick Doblin, Ph.D. Executive Director, MAPS 
 
SPONSOR DELEGATE &TRIAL 
ORGANIZER 
MAPS Public Benefit Corporation  
3141 Stevens Creek Blvd #40547  
San Jose, CA 95117 
 
SPONSOR DESIGNEE 
Amy Emerson 
Chief Executive Officer (CEO) MAPS Public Benefit 
Corporation 
 
CLINICAL INVESTIGATOR 
Rachel Yehuda, Ph.D. 
Director, Mental Health Patient Care Center James J Peters VA 
Medical Center Professor of Psychiatry and Neuroscience Icahn 
School of Medicine at Mount Sinai  
Email: Rachel.yehuda@va.gov 
Phone number: 718-584-9000x6964 
 
Mustafa Haznedar, M.D. Psychiatrist 
James J Peters VA Medical Center  
Email: Mustafa.haznedar@va.gov  
Phone number: 718-584-9000x5232 
 
MEDICAL MONITOR 
Kelly Green PA-C, MPH 
Associate Medical Director, MAPS Public Benefit Corporation  
Email: kelly.green@mapsbcorp,com 
Phone number: 877-748-3767 
 
USE 
In conjunction with relevant Food and Drug Administration 
(FDA) guidance 
 


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CONFIDENTIAL 
Table of Contents 
List of Tables ................................................................................................................................ 13 
List of Figures .............................................................................................................................. 14 
List of Abbreviations ................................................................................................................... 15 
1.0 Introduction ............................................................................................................................ 18 
1.1 Rationale .............................................................................................................................. 18 
1.2 Background .......................................................................................................................... 19 
1.2.1 PTSD ............................................................................................................................. 19 
1.2.2 MDMA .......................................................................................................................... 21 
1.2.3 MDMA-Assisted Therapy for PTSD ............................................................................ 21 
1.2.4 Previous Clinical Experience with MDMA .................................................................. 22 
2.0 Protocol Objectives ................................................................................................................ 23 
2.1 Primary Objective ................................................................................................................ 24 
2.2 Key Secondary Objective .................................................................................................... 24 
2.3 Exploratory Objectives ........................................................................................................ 24 
2.4 Safety Objectives ................................................................................................................. 25 
3.0 Eligibility Criteria .................................................................................................................. 25 
3.1 Inclusion Criteria ................................................................................................................. 25 
3.2 Exclusion Criteria ................................................................................................................ 26 
3.3 Lifestyle Modifications ........................................................................................................ 28 
4.0 Protocol Design ...................................................................................................................... 29 
4.1 Proof-of-Principle Therapist Training Lead-In .................................................................... 29 
4.2 Study Design Overview ....................................................................................................... 30 
4.3 Planned Duration of Study ................................................................................................... 33 
4.3.1 Interruptions and Accommodations Due to COVID-19 Pandemic or Any Other 
Unforeseen Emergency at Clinic Locations ........................................................................... 34 
4.4 Discontinuation and Completion Criteria ............................................................................ 34 
4.4.1 Complete or Evaluable Participants .............................................................................. 34 
4.4.2 Screen Failures .............................................................................................................. 34 
4.4.3 Early Termination from the Study ................................................................................ 35 
4.4.4 Lost to Follow-up .......................................................................................................... 36 
4.5 End of Study Definition and Premature Discontinuation .................................................... 36 
4.6 Rationale of Dose Selection ................................................................................................. 36 
5.0 Therapy ................................................................................................................................... 37 
5.1 Description of Therapeutic Method ..................................................................................... 37 
5.2 Therapy Pair Qualifications ................................................................................................. 37 
5.3 Training ................................................................................................................................ 38 
5.4 Adherence to Therapeutic Method ....................................................................................... 38 
6.0 Measures and Reliability ....................................................................................................... 38 
6.1 Primary Outcome Measure and Reliability .......................................................................... 40 
6.1.1 CAPS-5 (Clinician-Administered PTSD Scale for DSM-5) ......................................... 40 
6.2 Secondary Measure .............................................................................................................. 41 
6.2.1 SDS (Sheehan Disability Scale) for PTSD for MAPS .................................................. 41 
6.3 Screening Measures and Reliability ..................................................................................... 41 
6.3.1 C-SSRS (Columbia Suicide Severity Rating Scale); MAPS-Adapted.......................... 41 
6.3.2 MINI (Mini-International Neuropsychiatric Interview) ................................................ 42 
6.3.3 SCID-5-PD (Structured Clinical Interview for DSM-5 for Personality Disorders) ...... 42 
6.3.4 LEC-5 (Life Events Checklist for DSM-5) ................................................................... 42 
6.3.5 PCL-5 (PTSD Checklist) .............................................................................................. 42 
6.3.6 DDIS (Dissociative Disorders Interview Schedule for DSM-5) ................................... 42 


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6.4 Exploratory Measures .......................................................................................................... 43 
6.4.1 DSP-I (The Dissociative Subtype of PTSD Interview) ................................................. 43 
6.4.2 ACE (Adverse Childhood Experience Questionnaire) ................................................. 43 
6.4.3 BDI-II (Beck Depression Inventory II) ......................................................................... 43 
6.4.4 CPGS (Chronic Pain Grade Scale) ................................................................................ 43 
6.4.5 SCS (Self-Compassion Scale) ....................................................................................... 44 
6.4.6 AUDIT (Alcohol Use Disorders Identification Test) .................................................... 44 
6.4.7 DUDIT (Drug Use Disorders Identification Test) ........................................................ 44 
6.4.8 MIES (Moral Injury Event Scale) ................................................................................. 44 
6.4.9 PTGI (Posttraumatic Growth Inventory) ...................................................................... 44 
6.4.10 BPAQ-SF (Buss Perry Aggression Questionnaire Short Form) ................................. 45 
6.4.11 AAQ-II (Acceptance and Action Questionnaire) ........................................................ 45 
6.4.12 WHOQOL-BREF (WHO Quality of Life-BREF) ...................................................... 45 
6.4.13 DRRI-II (Deployment Risk and Resilience Inventory-2) ........................................... 45 
6.4.14 UFEC (Utilization of Facility-based and Emergent Care) .......................................... 45 
6.4.15 OSU-TBI-ID (Ohio State University Traumatic Brain Injury Identification Method)45 
7.0 Study Procedures ................................................................................................................... 46 
7.1 Screening and Enrollment Period ........................................................................................ 52 
7.1.1 Screening....................................................................................................................... 52 
7.1.2 Independent Rater Screening Assessments ................................................................... 54 
7.1.3 Enrollment..................................................................................................................... 55 
7.2 Preparatory Period with Enrollment Confirmation .............................................................. 55 
7.2.1 Preparatory Sessions ..................................................................................................... 55 
7.2.2 Baseline CAPS-5 by Independent Rater ....................................................................... 56 
7.2.3 Baseline Self-Reported Measures ................................................................................. 56 
7.2.4 Enrollment Confirmation .............................................................................................. 57 
7.3 Treatment Period .................................................................................................................. 57 
7.3.1 Experimental Sessions .................................................................................................. 57 
7.3.2 Telephone Contact After Experimental Sessions .......................................................... 60 
7.3.3 Integrative Sessions ...................................................................................................... 60 
7.4 Post-treatment Period and Study Termination ..................................................................... 61 
7.4.1 Post-treatment Period .................................................................................................... 61 
7.4.2 Study Termination ........................................................................................................ 62 
7.4.3 Post-Study Plan ............................................................................................................. 62 
8.0 Investigational Medicinal Product ....................................................................................... 62 
8.1 Description of Active Compounds ....................................................................................... 62 
8.1.1 Doses ............................................................................................................................. 63 
8.1.2 Stability ......................................................................................................................... 63 
8.2 Handling ............................................................................................................................... 63 
8.2.1 Encapsulation, Packaging, and Labeling ...................................................................... 63 
8.2.2 Accountability ............................................................................................................... 63 
8.2.3 Storage .......................................................................................................................... 63 
8.2.4 Administration .............................................................................................................. 63 
8.2.5 Treatment Compliance .................................................................................................. 64 
8.3 Randomization and Participant Numbering ......................................................................... 64 
8.4 Blinding and Bias Minimization .......................................................................................... 64 
9.0 Risks ........................................................................................................................................ 65 
9.1 Non-drug Related Risks ....................................................................................................... 65 
9.1.1 Medical Assessments .................................................................................................... 65 
9.1.2 PTSD, Suicide Risk, and Therapy ................................................................................ 65 
9.1.3 Recorded Content .......................................................................................................... 67 
9.2 Risks of Receiving MDMA ................................................................................................. 67 


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9.2.1 High Level Risks ........................................................................................................... 67 
9.2.2 Medium Level Risks ..................................................................................................... 67 
9.2.3 Low Level Risks ........................................................................................................... 70 
9.2.4 Minimal Risks ............................................................................................................... 71 
10.0 Safety ..................................................................................................................................... 72 
10.1 Adverse Events .................................................................................................................. 72 
10.1.1 Adverse Events of Special Interest ............................................................................. 73 
10.1.2 Serious Adverse Events .............................................................................................. 74 
10.2 Other Significant Events .................................................................................................... 75 
10.3 Pregnancy ........................................................................................................................... 75 
10.3.1 Definition of ‘Able to Become Pregnant’ ................................................................... 75 
10.3.2 Contraception Guidelines ............................................................................................ 75 
10.3.3 Follow-up Requirements ............................................................................................. 75 
10.4 Medical Monitor ................................................................................................................ 76 
11.0 Concomitant Medications ................................................................................................... 76 
11.1 Tapering Instructions ......................................................................................................... 76 
11.2 Allowed Concomitant Medications ................................................................................... 77 
11.3 Prohibited Medications ...................................................................................................... 77 
12.0 Clinical Laboratory Assessments ....................................................................................... 78 
13.0 Statistical Considerations .................................................................................................... 79 
13.1 Power and Sample Size Determination .............................................................................. 79 
13.2 Statistical Analyses ............................................................................................................ 80 
13.2.1 Primary Effectiveness Analysis .................................................................................. 80 
13.2.2 Secondary Effectiveness Analysis .............................................................................. 81 
13.2.3 Exploratory Analyses .................................................................................................. 81 
13.2.4 Safety Analyses ........................................................................................................... 81 
13.2.5 Interim Analysis .......................................................................................................... 82 
13.2.6 Safety Review Committee .......................................................................................... 82 
14.0 Study Governance ................................................................................................................ 82 
14.1 Ethics ................................................................................................................................. 82 
14.1.1 Financial Disclosure .................................................................................................... 83 
14.1.2 Informed Consent ........................................................................................................ 83 
14.2 Study Monitoring, Auditing, and Documentation.............................................................. 84 
14.2.1 Source Records ........................................................................................................... 84 
14.3 Confidentiality ................................................................................................................... 84 
14.4 Costs to Participants ........................................................................................................... 85 
14.5 Treatment and Compensation for Study Related Injury .................................................... 85 
14.6 Record Retention ............................................................................................................... 86 
14.7 Publication Policy .............................................................................................................. 86 
 
 
 
 
 
 


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List of Tables 
 
Table 1: CAPS-5 Data Collection by Visit .................................................................................... 33 
Table 2: Dose Regimen of MDMA ................................................................................................ 37 
Table 3: Protocol Objectives and Assessment Tools ..................................................................... 38 
Table 4: Time and Events-Study Procedures-Pre-Treatment (All Groups) ................................... 47 
Table 5: Treatment Period, Follow-Up, and Study Termination-Group 1 (3 Experimental 
Sessions) ................................................................................................................................ 48 
Table 6: Treatment Period, Follow-Up, and Study Termination-Group 2 (2 Experimental 
Sessions) ................................................................................................................................ 49 
Table 7: Time and Events-Study Measures-Group 1 (3 Experimental Sessions) .......................... 50 
Table 8: Time and Events-Study Measures-Group 2 (2 Experimental Sessions) .......................... 51 
Table 9: Schedule of Procedures for Experimental Sessions ......................................................... 58 
 
 


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List of Figures 
 
Figure 1: Study Structure Overview: 2-Session Group .................................................................. 31 
Figure 2: Study Structure Overview: 3-Session Group .................................................................. 32 
 
 
 
 
 
 


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List of Abbreviations 
 
°C 
 
Degrees Celsius 
A:G 
Albumin:Globulin 
AAQ-II  
Acceptance and Action Questionnaire–II 
ACE 
Adverse Childhood Experiences Questionnaire 
ADHD 
Attention Deficit/Hyperactivity Disorder 
AE 
Adverse Event 
AED 
Automatic External Defibrillator 
AESI 
Adverse Event of Special Interest 
AHA 
American Heart Association 
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 
BPAQ-SF 
Buss-Perry Aggression Questionnaire (Short-Form) 
BUN 
Blood Urea Nitrogen 
CAPS-4 
Clinician-Administered PTSD Scale for DSM-4 
CAPS-5 
Clinician-Administered PTSD Scale for DSM-5 
CBC 
Complete Blood Count 
%CDT 
%Carbohydrate-deficient Transferrin  
CMC 
Chemistry Manufacturing and Control 
COVID-19 
Coronavirus Disease 2019 
CPGS 
Chronic Pain Grade Scale 
CRA 
Clinical Research Associate 
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 
DRRI-II 
Deployment Risk & Resilience Inventory-2 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
DSP-I 
Dissociative Subtype of PTSD Interview 
DUDIT 
Drug Abuse Disorders Identification 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 
 FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 


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HIPAA 
Health Insurance Portability and Accountability 
HPA 
Hypothalamic-pituitary-adrenal 
HPMC 
Hypromellose 
IB 
Investigator’s Brochure 
ICD 
International Classification of Disease 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IMP 
Investigational Medicinal Product 
IPF 
Inventory of Psychosocial Functioning 
IR 
Independent Rater 
IRDB 
Independent Rater Database 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-releasing System 
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 
MIES 
Moral Injury Event Scale 
MINI 
Mini-International Neuropsychiatric Interview 
mg 
Milligram 
mITT 
Modified Intent-to-Treat 
mmHg 
Milligrams of Mercury  
MAPS PBC  
MAPS Public Benefit Corporation 
MMRM 
 Mixed Model Repeated Measure 
ms 
Millisecond 
NOAEL 
No-Observed-Adverse-Effect Level 
OSU-TBI 
Ohio State University Traumatic Brain Injury 
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 


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SSR 
Sample size re-estimation 
SSRI 
Selective serotonin reuptake inhibitor 
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 
VAS 
Visual Analog Scale 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WHO DDE 
WHO Drug Dictionary EnhancedTM 
WHOQOL 
World Health Organization Quality of Life Instruments 


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1.0 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 therapy 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 (MAPS PBC). 
 
1.1 Rationale 
PTSD is a serious debilitating disorder that negatively impacts a person’s daily life. MDMA has 
been shown to reduce defenses and fear of emotional injury, enhance communication, and 
increase empathy. MDMA may enhance fear extinction learning in humans. These subjective 
effects of MDMA create a productive psychological state that enhances the therapeutic process 
for the treatment of PTSD and other anxiety disorders. This is supported by data from an 
international series of Phase 2 pilot studies of MDMA-assisted therapy conducted by the sponsor 
that provide preliminary evidence that chronic PTSD, independent of cause, is treatable with two 
to three sessions of MDMA-assisted therapy and associated non-drug preparatory and integrative 
therapy. This open-label comparative effectiveness study will serve to explore the relative 
effectiveness of two vs. three randomly assigned active drug sessions in a sample of U.S. military 
veterans with chronic PTSD. The Primary Outcome measure, the Clinician Administered PTSD 
Scale (CAPS-5), evaluates changes in PTSD symptom severity and is assessed by a blinded 
centralized Independent Rater (IR) pool. 
 
The results from multiple independent studies in Phase 2 efficacy analyses demonstrate 
superiority of MDMA-assisted therapy over therapy with placebo and low dose MDMA. The 
acceptable risk-benefit ratio in early trials justifies further study. The rationale for the proposal to 
study two versus three active drug sessions builds in part on results of a previous randomized 
Phase 2 pilot study supported by MAPS [1]. This study found mixed results regarding the optimal 
number of MDMA-assisted sessions. Two active dose (100 mg and 125 mg) groups showed 
further clinically significant reductions in PTSD symptoms after a third Experimental Session, 
whereas a low dose (40 mg) group demonstrated significant reductions after open-label crossover 
to two active doses but did not continue to improve after a third. The authors concluded that more 
research is needed to determine the optimal number of treatment sessions in order to achieve 
symptom remission. 
 
This trial will also help establish the effectiveness of MDMA-assisted therapy for PTSD in an 
ethnically diverse military veteran population in the context of a large Veteran’s Affairs 
outpatient mental health clinic. A randomized, Phase 2 pilot trial provided preliminary evidence 
for the efficacy of MDMA-assisted therapy for chronic PTSD in military personnel and first 
responders [2]. The sample in that study (n=26) was primarily White (85%) and treated at a 
private outpatient clinic in the southern U.S. This study represents the first trial of MDMA- 
assisted therapy for PTSD in a treatment seeking veteran population within an outpatient VA 
mental health clinic. The James J Peters VA Medical Center is located in a large urban area 
(Bronx, NY) with a patient population that is approximately 55% Hispanic, and 60% Black or 
African American, 35% White, and 5% Asian. Results from this study will thus extend the 
findings of prior studies with the potential to inform treatment development and policy within the 
national VA system. 
 


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In addition to the primary aim of assessing the comparative effectiveness of two vs. three 
Experimental Sessions, this study will include collection of biomarker blood samples from 
participants at two time points (pre- and post-treatment) in order to bank samples for future 
assays. Each blood draw will collect up to 160 mL. Samples will be frozen and stored in locked 
freezers within secure research laboratories at the following address: 
 
James J Peters VA Medical Center  
Research Building, 4th Floor 
130 West Kingsbridge Road  
Bronx, NY 10468 
 
The collection and banking of blood samples in association with treatment will allow for future 
exploratory analyses of potential biological markers that predict, mediate, or change in 
association with changes in PTSD symptom severity following MDMA-assisted therapy for 
PTSD. 
 
In this study, therapy pairs without previous experience on an MDMA-assisted therapy study will 
have the opportunity for clinical supervision. There will be one or more two-person therapy pairs. 
During the lead-in portion of the study Section 4.1 Proof-of-Principle Therapist Training Lead-
In), each therapy pair will treat one participant who will be randomized in a 1:1 fashion to receive 
either 2 Experimental Session or 3 Experimental Sessions. This part of the study is designed to 
support and expand the knowledge and skills of therapy team members who will be working on 
MDMA research studies. 
 
1.2 Background 
1.2.1 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 [3]. 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 [4]. The dissociative subtype occurs in 12 to 30% of people with 
PTSD and is characterized by detachment and emotional numbing and visualized in the brain as 
overmodulation of affect mediated by midline prefrontal inhibition of limbic regions, while the 
non-dissociative subtype presents symptoms of hyperarousal and re-experiencing, an emotional 
undermodulation mediated by failure of prefrontal inhibition of the same limbic regions [5, 6]. 
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. 
 


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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 [7]. 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 [8]. In 2012 alone the VA spent $294 million and $3 
billion, respectively, on care for veterans with the disorder and disability payments, even with this 
funding the demand for services far outreached the availability of VA doctors and services. As of 
June 30, 2016, more than 868,000 veterans with a diagnosis of PTSD were receiving disability 
compensation for service-connected mental disorders, with an estimated cost of about $17 billion 
per year [9]. The most recent VA data from September 2018 reports that more than 1,039,000 
vets receive disability payments for PTSD [10]. There are an estimated 20 to 22 suicides a day by 
veterans [11]. 
 
Available PTSD treatments, including medications and therapy, effectively treat only some 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 [12-14]. PTSD rarely remits after 12 weeks of 
SSRIs, and many patients who are placed on maintenance treatment experience partial relief of 
symptoms, which can fully return upon discontinuation of treatment. Adverse effects of 
maintenance SSRI treatment that contribute to discontinuation include sexual dysfunction, weight 
gain, and sleep disturbance. Variable SSRI treatment outcomes have led to recommendations of 
trauma-focused therapy 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 [15, 16]. 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 therapeutic treatments that may address 
chronic hyperarousal and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis 
associated with PTSD. Trauma-based therapies, particularly prolonged exposure, and cognitive 
processing therapy are considered among the most effective therapies. Other methods such as 
psychodynamic therapy and eye movement desensitization and reprocessing (EMDR) have also 
proven to be effective in treating symptoms of PTSD [17, 18], 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” therapies, including those listed above, are similarly effective with PTSD 
[19]. In the past decade, there has been a growing amount of research into medications and other 
methods that may augment the effectiveness of therapy for PTSD (see [20] for a review). 
Examples of this are virtual reality-assisted exposure therapy [21, 22], and D-cycloserine-assisted 
psychotherapy [23]. MDMA-assisted therapy is another such approach. 
  


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1.2.2 MDMA 
MDMA is a ring-substituted phenylisopropylamine derivative invented by the Merck 
pharmaceutical company in 1912 [24, 25]. Similar to SSRIs, MDMA binds to the serotonin 
transporter, but has additional effects on carrier-mediated release and reuptake inhibition of 
serotonin and to a lesser extent in humans, norepinephrine and dopamine [26-32]. MDMA also 
increases levels of affiliative neurohormones oxytocin and vasopressin, which is hypothesized to 
increase trust and attenuate reactivity to threatening cues. Some researchers have suggested a role 
for oxytocin in treating PTSD. The indirect effects of MDMA on central and peripheral 
neurohormone levels contribute to a novel mechanism that may help regulate the HPA axis 
during therapy. 
 
Onset of MDMA effects occurs ~0.5 to 1 hour after oral administration, and peak effects occur 
1.25 to two 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 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) [33, 34]. Studies of regular or problematic Ecstasy users indicate that on average, 
regular use occurs no more often than once a week [35]. Hence, MDMA may have moderate 
abuse potential. See the Investigator’s Brochure (IB) for a more detailed explanation. 
 
1.2.3 MDMA-Assisted Therapy for PTSD 
Many therapies for PTSD involve the extinction of abnormal autonomic responses through 
revisiting traumatic experiences in therapy with an appropriate level of emotional engagement 
[18]. To be effective, exposure must be accompanied by a degree of emotional engagement or 
“fear activation” while avoiding dissociation or overwhelming emotion [36]. This has been 
referred to as working within the “optimal arousal zone” or “window of tolerance” [37-39]. 
 
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, which is associated with heightened encoding of fearful 
memories, and decreases blood flow in the prefrontal cortex. In contrast, MDMA acutely 
decreases activity in the amygdala [40], and there is some indication that MDMA may increase 
activity in the prefrontal cortex [41]. Brain imaging after MDMA indicates less reactivity to 
angry facial expressions and greater reward in happy faces [40]. This action is compatible with its 
reported reduction in fear or defensiveness and is in contrast to the activation of the amygdala 
observed in animal models of conditioned fear, a state similar to PTSD [42-44]. The reduction in 
stress-induced activation of the amygdala may be supported and enhanced by interacting with the 
therapy pair 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. 
  


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A combined treatment of MDMA and therapy 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 [45-48]. 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 [49]. 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 therapy may enable the participants to restructure their intra-psychic 
realities and develop a wider behavioral and emotional repertoire with which to respond to 
anxiogenic stimuli. 
 
The therapeutic method is described in further detail in the Treatment Manual of MDMA- 
Assisted Psychotherapy, which the new therapy pairs will be trained on prior to the study. 
 
1.2.4 Previous Clinical Experience with MDMA 
MDMA-assisted therapy is a novel treatment package that combines therapeutic techniques with 
the administration of MDMA as a pharmacological adjunct intended to enhance certain aspects of 
therapy. Chemists Shulgin and Nichols were the first to report on the effects of MDMA in 
humans [50], with 80 to 160 milligrams (mg) MDMA required to produce desired subjective 
effects in humans [50, 51]. MDMA was found to robustly influence human emotional status in a 
unique way [50], without adversely affecting physiological functions or perception, such as visual 
perception or cognition [52-55]. In the 1970s, psychotherapists used MDMA-assisted therapy to 
treat psychological disorders, including anxiety [56]. Legal therapeutic use continued until its 
placement on the U.S. list of Schedule I substances in 1985 [46, 49, 57]. An estimated 500,000 
doses of MDMA were administered during therapy and personal growth sessions in North 
America prior to its scheduling [46, 58]. A few uncontrolled human studies of MDMA assessing 
safety in a therapeutic setting occurred in the 1980s [59, 60]. 
 
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 [61, 62]. 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 therapy without 
any safety concerns and with some PTSD symptom reduction [48]. 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 therapy for patients with chronic, at least moderate PTSD 
(CAPS-IV 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. 
  


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Results from four 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 therapy 
session (MP-1) [47, 63], one in Switzerland (MP-2) [64, 65], one in Charleston, South Carolina 
that enrolled veterans and first responders (MP-8) [2], and one in Boulder, Co (MP-12) [1]. MP-1 
was followed by a small open-label extension study examining the treatment of relapse in three 
participants with a single MDMA-assisted therapy treatment and a 12-month follow-up (MP1- 
E2). An additional study conducted in Israel was completed (MP-9) and two international studies 
were terminated early for logistical reasons with partial datasets (MP-3, MP-4). These studies 
tested a range of designs, such as a placebo control (MP-1, MP-4), low dose MDMA comparator 
control (MP-2, MP-9), and three-arm dose response studies (MP-8, MP-12). MP-4 was 
terminated early due to delays in regulatory approval and enrollment timelines, with available 
efficacy data presented without a formal analysis. MP-3 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 (MP-3 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 (MP-1, MP-2, MP-4, MP-8, MP-9, MP-12) 
consisting of 107 blinded participants with chronic PTSD were completed in 2016[66]. In these 
studies, PTSD, independent of cause, appears treatable with a two to three-session treatment 
package of MDMA-assisted therapy, as assessed by difference in CAPS-4 severity scores from 
baseline to 1 to 2 months after the final experimental session. Large placebo-subtracted effect 
sizes (Cohen’s d=0.9), initial indications of efficacy and favorable safety outcomes led to the 
approval of MDMA for the treatment of PTSD as a Breakthrough Therapy Designation (BTD) by 
the FDA in 2017 for expedited drug development [67] Improvements were durable at least 12 
months after the last Experimental Session in 91 participants who received a therapeutically 
active dose of MDMA in these Phase 2 studies with 67% not meeting PTSD diagnostic criteria 
per CAPS-IV assessment [68]. 
 
MAPS completed a pivotal Phase 3 clinical trial (MAPP1) in 2020, further demonstrating the 
efficacy and safety of MDMA-assisted therapy for treatment of PTSD [69]. In a randomized, 
double-blind, placebo-controlled study, 90 participants with severe PTSD (CAPS-5 score: 35+ 
with at least 6 months of symptoms) were treated across 15 sites. Similar to Phase 2 results, 
PTSD symptoms were significantly attenuated by MDMA-assisted therapy. In comparison to an 
inactive placebo, divided-doses of 80+40 mg or 120+60 mg MDMA were statistically superior 
for PTSD treatment in CAPS-5 severity scores from Baseline to 2 months after three blinded 
experimental sessions (p<0.0001). At the primary endpoint, 67% of participants in the MDMA 
group no longer met diagnostic criteria for PTSD, compared to 32% of the placebo group. Based 
on the successful completion of MAPP1, a confirmatory Phase 3 clinical trial (MAPP2) is 
currently underway to encompass a larger sample of participants with moderate to severe PTSD. 
 
As of October 01, 2021, with 358 individuals exposed to MDMA in the sponsor’s development 
program across various indications and at least 1,441 participants in MDMA research studies 
conducted without sponsor support (for a total of at least 1,799 individuals), the sponsor has 
observed an acceptable risk-benefit ratio for MDMA-assisted therapy.  
 
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. 
 
2.0 Protocol Objectives 
The overall objective of this study is to use standard clinical measures to explore the relative 
effectiveness in reducing PTSD symptom severity comparing groups randomly assigned to two 


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versus three Experimental Sessions of open-label MDMA-assisted therapy, in a diverse sample of 
U.S. military veterans with PTSD in a VA outpatient clinic, and to serve as an opportunity for 
supervision of therapy pairs selected to conduct MDMA-assisted therapy research. 
 
2.1 Primary Objective 
The primary objective of this study is to compare the effectiveness of two versus three sessions of 
MDMA-assisted therapy in treatment of PTSD, based on mean change in CAPS-5 Total Severity 
Score from T1 (Baseline) to T2 (Primary Outcome). 
 
2.2 Key Secondary Objective 
The key secondary objective of this study is to compare the effectiveness of two versus three 
sessions of MDMA-assisted therapy in clinician-rated functional impairment, as measured by the 
mean change in Sheehan Disability Scale (SDS) item score from Baseline to T2 (Primary 
Outcome). 
 
2.3 Exploratory Objectives 
Exploratory objectives include analyses of baseline predictors of treatment outcome (e.g., adverse 
childhood experiences, history of mild TBI), and post-treatment changes in self report measures 
of clinical state, including depression, PTSD, and moral injury as assessed by: 
 
1. Explore changes between the two treatment groups 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 Baseline to Post-treatment and 
Follow-up. 
2. Explore trajectories of change and onset of treatment effectiveness within and between 
groups using multiple assessments with PCL 5 self-reports. 
3. Explore the effect of adverse childhood experiences (ACE) on the CAPS-5 Total Severity 
analyses. 
4. Explore differences between treatment groups using measures below regarding changes 
in clinical state associated with MDMA treatment, and regarding baseline predictors of 
outcome using the following measures: 
a. Acceptance and Action Questionnaire (AAQ-II) 
b. Dissociative Subtype of PTSD Interview (DSP-I) 
c. Columbia Suicide Severity Rating Scale (C-SSRS) 
d. Self Compassion Scale (SCS) 
e. Buss-Perry Aggression Questionnaire-Short Form (BPAQ-SF) 
f. Deployment Risk and Resilience Inventory 2 (DRRI-2) 
g. Life Events Checklist (LEC-5) 
h. PTSD Checklist for DSM-5 (PCL-5) 
i. 
Moral Injury (MIES) 
j. 
Depression (BDI-II) 
k. Posttraumatic Growth Inventory (PTGI) 
l. 
Chronic Pain Grade Scale (CPGS) 
m. World Health Organization Quality of Life-Brief Form (WHOQOL-BREF) 
n. Ohio State University Traumatic Brain Injury (OSU-TBI) 
o. The Utilization of Facility and Emergent Care (UFEC) 
p. Addictive behaviors including: Alcohol Use Disorders Identification Test 
(AUDIT), Drug Use Disorders Identification Test (DUDIT) 
 


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2.4 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, and vital 
signs to support the package insert for MDMA-assisted therapy. The following safety objectives 
will evaluate the safety of MDMA-assisted therapy: 
 
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 
through 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 concomitant medications of interest taken during an Experimental 
Session and through 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. 
 
3.0 Eligibility Criteria 
3.1 Inclusion Criteria 
At the completion of Screening, participants must meet all eligibility criteria 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 28 or greater, a total PCL-5 score of 36 or 
greater at Screening, 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). 
 
Potential participants are eligible to enroll in the protocol if they: 
 
1. *Are a U.S. military veteran at least 18 years old 
2. *Are able to provide written, informed consent 
3. *Are able to swallow pills 
4. Agree to have study visits recorded, including Experimental Sessions, Independent Rater 
assessments, and non-drug therapy sessions 


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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 able to become pregnant, must have a negative pregnancy test at study entry and prior 
to each Experimental Session, and must agree to use adequate contraceptive methods 
through 10 days after the last Experimental Session. Adequate contraceptive methods 
include intrauterine device (IUD), injected, implanted, intravaginal, or transdermal 
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 able to become pregnant’ is defined as permanent sterilization, postmenopausal, or 
assigned male at birth 
8. Agree to the following lifestyle modifications (described in more detail in Section 3.3 
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 this study without prior approval of the 
Medical Monitor, remain overnight at the study site after each Experimental Session and 
refrain from driving until cleared by Therapist after Integrative Session the following day 
or be driven home by a support person or by taxi/car service, and commit to medication 
dosing, therapy, and study procedures 
 
Medical History 
9. *At Baseline, meet DSM-5 criteria for current PTSD with a symptom duration of 3 
months or longer and have PTSD symptoms in the last month with a minimum CAPS-5 
Total Severity Score of 28 or greater and a total PCL-5 score of 36 or greater at 
Screening 
10. *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 
11. *At Screening, may have asymptomatic Hepatitis C virus (HCV) that has previously 
undergone evaluation and treatment as needed 
12. * May have current mild alcohol or cannabis use disorder (meets 2 or 3 of 11 diagnostic 
criteria per DSM-5) or moderate alcohol or cannabis use disorder in early remission for 
the 3 months prior to enrollment (meets 4 or 5 of 11 diagnostic criteria per DSM-5). 
13. May have a history of or current Diabetes Mellitus (Type 2) if additional screening 
measures rule out underlying cardiovascular disease, if the condition is judged to be 
stable on effective management, and with approval by the Medical Monitor 
14. May have hypothyroidism if taking adequate and stable thyroid replacement medication 
15. May have a history of, or current, glaucoma if approval for study participation is received 
from an ophthalmologist 
 
3.2 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 


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3. Are likely, in the investigator’s opinion and via observation during the Preparatory 
Period, to be re-exposed to their index trauma or other significant trauma, lack social 
support, or lack a stable living situation 
4. Have used Ecstasy (material represented as containing MDMA) more than 10 times 
within the last 10 years or at least once within 6 months of the first Experimental Session; 
or have previously participated in a MAPS-sponsored MDMA clinical trial 
5. Have any current problem which, in the opinion of the investigator or Medical Monitor, 
might interfere with participation 
6. Have hypersensitivity to any ingredient of the IMP (Investigational Medicinal Product) 
 
Psychiatric History 
7. Have received Electroconvulsive Therapy (ECT) within 12 weeks of enrollment 
8. Have a history of or a current primary psychotic disorder, bipolar disorder 1 assessed via 
MINI and confirmed via clinical interview or dissociative identity disorder assessed via 
DDIS and confirmed via clinical interview 
9. Have a current eating disorder with active purging assessed via MINI and clinical 
interview 
10. Have current major depressive disorder with psychotic features assessed via MINI 
11. Have a current moderate (not in early remission in the 3 months prior to enrollment; 
meets 4 or 5 of 11 diagnostic criteria per DSM-5) or severe alcohol or cannabis use 
disorder within the 12 months prior to enrollment (meets at least 6 of 11 diagnostic 
criteria per DSM-5) 
12. Have an active illicit drug or prescription drug substance use disorder at any severity 
(other than cannabis) within 12 months prior to enrollment 
13. 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 
14. Any participant presenting current serious suicide risk, as determined through psychiatric 
interview, responses to C-SSRS, and clinical judgment of the investigator will be 
excluded; however, history of suicide attempts is not an exclusion. Any participant who 
is likely to require hospitalization related to suicidal ideation and behavior, in the 
judgment of the investigator, will not be enrolled. Any participant presenting with the 
following on the Baseline C-SSRS will be excluded: 
a. Suicidal ideation score of 4 or greater within the last month of the assessment at a 
frequency of once a week or more 
b. Suicidal ideation score of 5 within the last 6 months of the assessment 
c. Any suicidal behavior, including suicide attempts or preparatory acts, within the 
last 6 months of the assessment. Participants with non-suicidal self-injurious 
behavior may be included if approved by the Medical Monitor 
15. Would present a serious risk to others as established through clinical interview and 
contact with treating psychiatrist 
16. Require ongoing concomitant therapy with a psychiatric medication with exceptions 
described in Section 11.0 Concomitant Medications 
 
Medical History 
17. Have a history of any medical condition that could make receiving a sympathomimetic 
drug harmful because of increases in blood pressure and heart rate. This includes, but is 
not limited to, a history of myocardial infarction, cerebrovascular accident, or aneurysm. 
Participants with other mild, stable chronic medical problems may be enrolled if the site 
physician, CI, and Medical Monitor agree the condition would not significantly increase 
the risk of MDMA administration or be likely to produce significant symptoms during 
the study that could interfere with study participation or be confused with side effects of 


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the IMP. Examples of stable medical conditions that could be allowed include, but are not 
limited to Diabetes Mellitus (Type 2), Human Immunodeficiency Virus (HIV) infection, 
Gastroesophageal Reflux Disease (GERD), etc. Any medical disorder judged by the 
investigator to significantly increase the risk of MDMA administration by any 
mechanism would require exclusion 
18. Have a diagnosis of uncontrolled essential hypertension which is assessed using the 
recommended criteria of the American Heart Association for Stage 2 hypertension 
(values of 140/90 milligrams of Mercury [mmHg] or higher assessed on three separate 
occasions) 
19. Have a history of ventricular arrhythmia at any time, other than occasional premature 
atrial contractions (PACs) or premature ventricular contractions (PVCs) in the absence of 
ischemic heart disease 
20. Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been 
successfully eliminated by ablation 
21. Have a history of supraventricular arrythmia within the last 12 months. Participants with 
a history of an allowable supraventricular arrhythmia (see list below) more than 12 
months prior to screening and in the absence of any accessory pathway may be enrolled if 
successfully treated at least 12 months prior and cleared by a cardiologist, the site 
physician, and Medical Monitor. These arrhythmias may include, and must be limited to, 
paroxysmal supraventricular tachycardia, paroxysmal atrial tachycardia, or atrial 
fibrillation that has been successfully treated (e.g., with ablation or cardioversion) at least 
12 months previously. Atrial flutter or other arrhythmias will be excluded 
22. Have a marked baseline QTcF interval >450 ms demonstrated on repeated ECG 
assessments. Participants whose QTcF exceeds this value during screening may be 
initially enrolled if a pre-study concomitant medication is suspected to be prolonging the 
QT-interval. ECGs should be repeated after initial enrollment and tapering off the pre-
study concomitant medication to ensure the participant meets eligibility criteria prior to 
enrolment confirmation and to IMP dosing. 
 
Note: The QTcF is the QT interval corrected for heart rate according to Fridericia’s 
formula. It is either machine-read or manually over-read.  
23. Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, 
hypokalemia, family history of Long QT Syndrome) 
24. Require use of concomitant medications that prolong the QT/QTc interval during 
Experimental Sessions. Refer to Section 11.0 Concomitant Medications 
25. Have symptomatic liver disease or significant liver enzyme elevations 
26. Have history of hyponatremia or hyperthermia 
27. Weigh less than 48 kilograms (kg) 
28. Are pregnant or nursing or are able to become pregnant and are not practicing an 
effective means of contraception 
 
3.3 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, therapy 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 without prior approval of the Medical Monitor 
 
Agree to not begin a new form of mental healthcare during the screening or treatment 
phases of the trial, without first discussing with the PI in consultation with the Medical 
Monitor 


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o It is acceptable for participants to continue ongoing mental healthcare, if it is not 
increased in frequency or specifically excluded by the study protocol 
o All ongoing therapies should be documented by the site and discussed with the 
Medical Monitor prior to enrolment to avoid confounding treatment effects. In 
some instances, the Medical Monitor may request that the participant delay 
enrollment until their planned course of therapy is complete and an integration 
period has elapsed 
 
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 11.0 
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 11.0 Concomitant 
Medications), if used for pain management, leading up to the Experimental Session in 
order to avoid taking the medication prior to the initial IMP administration and 24 hours 
after. During this period, the participant will be allowed to take the medication if needed 
for intolerable pain flare-ups or to prevent withdrawal symptoms 
 
Agree that, for 1 week preceding each Experimental Session, they will refrain from: 
o Taking any herbal supplement (except with prior approval of the research team). 
 
Agree that, for 5 half-lives of the medication preceding each Experimental Session, they 
will refrain from: 
o Taking any non-prescription 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 
 
Are willing to remain overnight at the study site after each Experimental Session until 
after the Integrative Session the next morning 
 
Agree to not drive upon completion of each Experimental Session through completion of 
the Integrative Session the next morning 
 
4.0 Protocol Design 
4.1 Proof-of-Principle Therapist Training Lead-In 
The Proof-of-Principle lead-in will serve as a training and supervision opportunity for therapy 
pairs. The sponsor will provide clinical supervision for therapy pairs treating participants. Each 
new therapy pair participating in the trial will receive clinical supervision at three dedicated time 
points during treatment of their first subject and additional supervision as needed in subsequent 
cases. The sponsor’s Adherence Raters and trainers will monitor videos of study visits for 
adherence to the therapeutic method and provide supervision. Participants in the lead-in will be 
randomized into 2 vs. 3 Experimental Session groups. 
 


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4.2 Study Design Overview 
This open-label, randomized Phase 2 study will assess the relative safety and effectiveness of two 
versus three Experimental Sessions of MDMA-assisted therapy in treatment-seeking veterans 
diagnosed with PTSD. 
 
The study will be conducted in up to 60 participants. Randomization will occur in a 1:1 fashion 
and will be allocated to Group 1: 3 Experimental Sessions of MDMA-assisted therapy or Group 
2: 2 Experimental Sessions of MDMA-assisted therapy. 
 
For each participant, the study will consist of: 
 
 
Screening Period (~4 weeks): Phone or in person screen, informed consent, eligibility, 
and baseline assessment 
 
Preparatory Period with Enrollment Confirmation (at least 7 days, max time 
dependent upon medication tapering): medication tapering, Preparatory Sessions and 
Baseline assessments leading to Enrollment Confirmation. 
 
Study Enrollment and Randomization: Include eligible participants, randomize to 
group, complete baseline self-report measures, collection of pre-treatment biomarker 
blood samples  
 
Treatment Period (Group 1: 9-15 weeks, Group 2: 6-10 weeks): Each Experimental 
Session followed by 3 non-drug Integrative Sessions. 
 
Post-treatment (~4 weeks): At one-month post final Integrative Session, clinical 
evaluation and self- report measures, collection of post-treatment biomarker blood 
samples.  
o For the 2-session group: additional clinical evaluation one month following post-
treatment as a secondary outcome. 
 
Study Termination: After the Study Termination visit, participants will have the 
opportunity to enroll in a separate LTFU study at least six months from the final 
Experimental Session. 
 
A divided dose of up to 160 mg MDMA, with an initial 120 mg dose, followed by a supplemental 
dose of 40 mg unless tolerability issues emerge or it is refused by the participant, is administered 
during the Treatment Period with manualized therapy in two or three open-label monthly 
Experimental Sessions. Each Experimental Session is followed by three Integrative Sessions of 
non-drug therapy. Experimental Sessions are followed by an overnight stay. The Primary 
Outcome measure, the change in CAPS-5 from Baseline, is assessed by a centralized IR pool at 
one month following the final treatment session (post treatment), and again for the 2 
Experimental Session group after a second one-month period (anchored to the date of the baseline 
CAPS-5). The IR pool will be blinded to treatment assignment, visit number, and number of 
treatments received, and will not have access to data collected by the sites during the active 
Treatment Period. Blood samples will be collected at three timepoints: clinical laboratory 
assessment at Screening to determine eligibility, and biomarker laboratory draws at pre- and post-
treatment for future assays. Self-reported PTSD and depression symptoms will be assessed at 
numerous visits by the PCL-5 and BDI-II, as outlined in Tables 7 and 8.


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Figure 1: Study Structure Overview: 2-Session Group 
 
 
 
 
 
 
 
 
 


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Figure 2: Study Structure Overview: 3-Session Group 
 
 
 


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Qualified, blinded IRs selected based on availability from the IR Pool will perform the CAPS-5 
assessments as described in table below. 
 
Table 1: CAPS-5 Data Collection by Visit 
CAPS Number 
Visit 
Description/Timing 
Target Timing 
Post Baseline 
Baseline CAPS-5 
T1 
V3 
Baseline between Visits 2 and 
4 (Preparatory Sessions), after 
medications have been tapered. 
Not Applicable 
CAPS-5 
T2 
V13 (2-session group) 
or 
V17 (3-session group) 
Post Treatment Primary 
Outcome  49 to 56 days after 
last Experimental Session 
63 to 98 days or 
85 to 134 days  
CAPS-5 
T2.2 
V15 (2-session group 
only) 
Secondary outcome for 2-
session  group only 
28 to 35 days after T2 
85 to 134 days  
 
4.3 Planned Duration of Study 
Full screening may take 28 days after completion of initial screening. The Preparatory Period 
begins at enrollment and can be as brief as 7 days but depending on medication tapering could be 
as long as necessary to ensure an appropriate medication washout of at least five half-lives of pre- 
study psychiatric medications and active metabolites, and at least 7 days for stabilization prior to 
Baseline CAPS-5 T1 (Visit 3). Medication taper for psychological medications should occur prior 
to Visit 3. Medication taper for medications with drug-drug interactions without a psychological 
concern should occur prior to Visit 5. 
 
Enrollment confirmation takes place at the completion of the Preparatory Period; at which time 
the Treatment period will commence. Participant eligibility must be confirmed by the Medical 
Monitor prior to participant randomization. Treatment begins within 7 days of Baseline CAPS-5 
T1 (Visit 3). 
 
The approximately 6 to 15-week treatment period consists of two or three Experimental Sessions 
3 to 5 weeks apart with associated non-drug Integrative Sessions. The protocol may remain active 
up to enrollment of 60 participants. All participants who complete the study will be asked to 
participate in a LTFU extension study at least 6 months after the last Experimental Session. 
 
After the final Integrative Session 3.3 (Visit 16) or 2.3 (Visit 12) (for the 3 Experimental Session 
Group and 2 Experimental Session Group, respectively), participants will enter follow-up with no 
planned study visits for approximately 4 weeks, after which the Primary Outcome CAPS- 5 T2 
assessment will take place. Participants in the 2-session group will complete an additional CAPS 
5 T2.2 assessment after 4 more weeks. Although there are allowable windows for all visits 
throughout the protocol, the overall timelines should comply with the target timing of the Primary 
Outcome CAPS-5 T2 assessment, which must be completed 85 to 134 days post Baseline (3-
Session Group) and 63 to 98 days post Baseline (2-Session Group), 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 T2 assessment is appropriate. The Study Termination 
visit occurs 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 13 weeks (2-Session Group) or 16 weeks (3-Session 
Group), and the maximum is dependent on medication tapering. The average participant is 
expected to complete the study in 20 or 24 weeks (Groups 2 and 1, respectively). Any delays 


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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. 
 
4.3.1 Interruptions and Accommodations Due to COVID-19 Pandemic or Any 
Other Unforeseen Emergency at Clinic Locations 
This clinical trial may be interrupted by the Coronavirus Disease 2019 (COVID-19) global 
pandemic. Accommodations may be required for study continuation and participant and study site 
staff safety due to this emergency or any other unforeseen emergency in the future. The following 
accommodations in the protocol will be allowed, captured, and noted in the Clinical Study Report 
as COVID-19 deviations: 
 
 
Participants will stay overnight at the study site after each Experimental Session until 
after the Integrative Session the next morning. The remainder of the Integrative Sessions 
may be conducted by telemedicine. 
 
To reinforce the therapeutic alliance between the participant and the therapist pair, all 
efforts should be reasonably made to conduct Preparatory Sessions (V1, V2, and V4) in 
person and not via telemedicine. 
 
Delaying the start of medication tapering after enrollment and the subsequent Treatment 
Period per Section 11.1 Tapering Instructions 
 
Delaying Experimental Sessions and associated Integrative Sessions 
 
Delaying Independent Rater assessments for participants who cannot complete them 
remotely off-site 
 
Use of prohibited medications and/or cannabis or initiation of new therapy for 
participants with significant study delays, which will be reviewed by the study team 
before each Experimental Session and re-tapered prior to resuming treatment per Section 
11.0 Concomitant Medications. 
 
For any participant with COVID-19 related illness, continued trial participation after full recovery 
of the disease may be appropriate after discussion between the site physicians and Medical 
Monitors on a case-by-case basis. 
 
4.4 Discontinuation and Completion Criteria 
4.4.1 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. 
 
4.4.2 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. 


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Screen Failures may be identified through review of medical history, assessments, measures, 
laboratory results, or conversations with the participant. Medical assessments may be repeated for 
confirmation. At any time during Screening, if a potential participant is deemed to be ineligible, 
classify as a Screen Failure, notify the potential participant that they are unfortunately not eligible 
for the study, and do not schedule additional Screening assessments. Participants who fail 
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 a 
VA therapist if eligible and needed. Screen Failures that were scheduled for an IR assessment will 
be entered into the Electronic Data Capture (EDC) system. 
 
4.4.3 Early Termination from the Study 
Participants who are removed from the study after they are randomized and receive IMP but do 
not complete the study may fall into one of these categories: Post-randomization Early 
Termination or Dropout. If the participant has received IMP in at least one Experimental Session 
and completed one CAPS-5 assessment beyond Baseline, they will be considered evaluable. All 
participants who receive IMP in at least one Experimental Session will be included in all safety 
analyses. 
 
Participants can withdraw from treatment or withdraw consent at any time for any reason without 
judgment. The site team can withdraw a participant if, in their clinical judgment, it is in the best 
interest of the participant or if the participant cannot comply with elements of the protocol that 
are critical for safety or for the scientific integrity of the study. If the site team makes the decision 
to terminate the participant from treatment or the study, they will explain the reason for 
withdrawal and document in the participant’s source records and eCRF. If a participant develops 
any Exclusion Criteria that, in the opinion of the Medical Monitor or Site, affects the safety of the 
participant, including psychiatric diagnosis, medical diagnosis, pregnancy, or requiring use of 
prohibited medications, the participant will discontinue treatment in Experimental Sessions but 
remain in the study for the associated Integrative Sessions. Participants whose Experimental 
Sessions are delayed by the COVID-19 pandemic may start any of these medications during the 
delay, as clinically indicated. When study visits resume, they will be given the option to resume 
Experimental Sessions after tapering off of these medications per Section 11.1 Tapering 
Instructions. Any time a participant terminates from the study early, the site team will attempt to 
obtain information about AE outcomes if appropriate, as determined by the site physician and 
Medical Monitor. The site team will provide the participant with a Post-Study Plan as described 
in Section 7.4.3 Post-Study Plan. 
 
 
Post-randomization Early Termination: Participants who discontinue study treatment 
but continue to participate in Independent Rater primary and secondary outcome 
assessments. Data collection by IRs will continue on the same schedule as planned 
through Study Termination visit procedures. 
 
Dropout: If a participant decides to withdraw consent completely, they will terminate 
without further follow-up. If the participant agrees, they will complete a final CAPS-5 
assessment. These participants are defined as dropouts who withdraw consent due to any 
reason after receiving at least one dose of IMP and no longer participate in the study (i.e., 
no further contact with investigators or site staff). Data collected on study participants up 
to the time of withdrawal of consent will remain in the trial database in order to maintain 
scientific validity. Removal of data from the database would undermine the scientific and 
ethical integrity of the research. 
 
 
 
 


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4.4.4 Lost to Follow-up 
A participant will be considered lost to follow-up if they fail to attend scheduled visits and are 
unable to be contacted by the site staff. If the participant has completed at least one Experimental 
Session and one CAPS-5 assessment beyond Baseline, they will be considered evaluable. All 
participants with at least one Experimental Session will be included in the safety analysis. 
 
If a participant does not attend a scheduled visit, the site must attempt to contact the participant to 
reschedule the visit as soon as possible and emphasize the importance of complying with the 
protocol specified visit schedule. The staff should determine if the participant is willing to 
comply with future visits. 
 
If a participant does not respond to this initial contact, the site staff must make multiple efforts to 
contact the study participant and document each attempt in the source record. At least three 
attempts should be made via telephone, over the course of approximately 7 days, with calls at 
different times of day. If telephone contact fails, an email should be sent if such contact 
information was provided. The emergency contact the participant provided should be contacted 
and asked to attempt contact with the participant. Lastly, a certified letter (or equivalent) should 
be sent to their last known mailing address. If the participant fails to respond to all of these 
contacts, they will be considered to have withdrawn from the study and are lost to follow-up. 
 
4.5 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 4: Time and Events-Study Procedures-Pre-Treatment 
(All Groups) 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 a Post-Study 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. 
 
4.6 Rationale of Dose Selection 
Similar MDMA doses to those proposed in this study have been safely used in previous Phase 2 
studies sponsored by MAPS. Phase 2 studies indicate that 75, 100 and 125 mg MDMA initial 
doses with the supplemental dose are active and effective in two to three Experimental Sessions. 
MDMA doses with an optimal risk-benefit ratio range from 75 mg (Cohen’s d Independent 
Groups Pre-test Post-test [dIGPP]=2.73, N=7) to 125 mg (Cohen’s dIGPP=0.77, N=58) initial 
dose of MDMA with a 2-session treatment package. In Phase 2 studies, the sponsor observed a -
36.4-point mean change in CAPS-4 scores among active dose participants receiving two 
Experimental Sessions (N=72) compared to a -44.2 point mean change after three Experimental 
Sessions (N=51). Although uncontrolled, the additional 7.8 point mean reduction observed after 
three Experimental Sessions compared to two, along with the observed favorable safety profile 
formed the basis for comparing a 2- versus 3-session treatment package. Larger doses have been 
administered safely in MP2 (150 mg and 75 mg supplemental) and in Phase 1 studies (150 mg 
and 160 mg). The results of these Phase 2 studies led to the selection of 80 mg and 120 mg 
MDMA as the initial active doses to be compared to inactive placebo in Phase 3 trials. 
 
This open-label study will compare the effects of initial doses of 120 mg MDMA administered in 
two versus three Experimental Sessions. Initial doses per Experimental Session are 120 mg of 
MDMA compounded with inactive excipients, followed 1.5 to 2 hours later by a supplemental 


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dose of 40 mg unless tolerability issues emerge with the first dose or it is refused by the 
participant. The initial active doses of 120 mg are expected to produce all commonly reported 
effects of MDMA. The supplemental 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 tolerability issues emerge with the first dose or it is refused by the 
participant. Total amounts of MDMA to be administered per Experimental Session range from 
120 mg to 160 mg. 
 
Table 2: Dose Regimen of MDMA 
 
Experimental 
Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative 
Dose 
1 
120 mg 
40 mg 
120 mg to 160 mg 
2 
120 mg 
40 mg 
120 mg to 160 mg 
3 
120 mg 
40 mg 
120 mg to 160 mg 
Total Cumulative Dose: 2 Session Group 
240 mg to 320 mg 
Total Cumulative Dose: 3 Session Group 
360 mg to 480 mg 
* Unless tolerability issues emerge with the first dose or it is refused by the participant. 
Supplemental dose will be 40 mg for all subjects throughout the study.  
 
In each Experimental Session, 1.5 to 2 hours after the initial dose is given, the participant will be 
administered a supplemental dose unless tolerability issues emerge with the first dose or it is 
refused by the participant. 
 
5.0 Therapy 
5.1 Description of Therapeutic Method 
The largely non-directive therapeutic method of MDMA-assisted therapy is described in detail in 
the Treatment Manual. All therapy pairs will be extensively trained in a multi-week training 
program prior to the study to ensure all participants are treated in a similar manner. The non- 
directive approach pertains to inviting inquiry and providing suggestion rather than directing the 
participant in the therapeutic approach. This requires active or engaged listening and responding, 
as well as facilitation of therapeutic action by providing support for approaching difficult material 
in a manner that does not interfere with the participant’s spontaneous experience. 
 
5.2 Therapy Pair Qualifications 
Therapy pairs will be trained by the sponsor. Site must ensure that the minimum requirements 
below are met: 
 
 
One or more two-person therapy pairs will be on the study team, who have been reviewed 
and approved by the MDMA Therapy Training Program. 
 
One person per therapy pair is required to be licensed to provide therapy according to 
state or province and local requirements. 
 
If one person in the therapy pair is unlicensed, they will be required to have, at a 
minimum, a bachelor’s degree and either be trained in mental health (including students 
in a postgraduate internship-type program providing detailed knowledge of mental health 
interventions and treatments) or have completed 1000 hours of behavioral health 
experience prior to co-facilitating sessions as a part of a co-therapy pair. 
 


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A physician will be required to be on the study team, and to be on-site for the duration of 
Experimental Sessions, to assess participant safety. Each site will also be required to have one 
person licensed to manage and administer controlled substances. 
 
5.3 Training 
The sponsor’s Therapy Training Program is designed to teach competency in applying the 
essential elements of this method of MDMA-assisted therapy. Therapy team members will 
receive specific training in the MDMA-assisted therapy method, protocol, and latest version of 
the IB. Training in the therapy method consists of reading the Treatment Manual, completing an 
online training module, and participating in an in-person or online training program that includes 
watching and discussing videos of Experimental Sessions. The final part of training includes 
supervision provided by the sponsor at three dedicated time points during treatment of each 
therapy team member’s first subject, and additionally as needed in subsequent cases. 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. 
 
5.4 Adherence to Therapeutic Method 
Therapy sessions, including Experimental Sessions, may be recorded, with recordings preserved 
for research and training purposes. Adherence criteria and competence ratings will be conducted 
by qualified, trained, and blinded Adherence Raters who will analyze video data from specific 
and randomly selected Preparatory Sessions, Experimental Sessions, and Integrative 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 pair in the 
study. Ratings will be used to provide feedback to new therapy pairs, to further characterize the 
manualized therapy, and for future exploratory research. 
 
6.0 Measures and Reliability 
The following eligibility, outcome, exploratory, and safety measures will be used in the study, in 
accordance with Table 7: Time and Events-Study Measures- Group 1 (3 experimental sessions) 
and Table 8: Time and Events-Study Measures- Group 2 (2 experimental sessions). 
 
Table 3: Protocol Objectives and Assessment Tools 
Objectives 
Measure 
Measure 
Type 
Administration 
Eligibility 
Assess psychiatric disorders 
MINI 
Eligibility 
Telemedicine 
(IR) 
Assess personality disorders 
SCID-5-PD 
with SCID- 
5-SPQ 
Eligibility 
Telemedicine 
(IR)/ self-report 
measures  at Site 
Assess PTSD symptom severity 
PCL-5 with 
LEC-5 
Eligibility 
Site 
Identify dissociative disorders 
DDIS 
Eligibility 
Telemedicine 
(IR) 
Confirm PTSD diagnosis and symptom severity 
CAPS-5 
Eligibility 
Telemedicine 
(IR) 
Primary 


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Assess changes in PTSD symptom severity 
from Baseline to Visit 13 (2-Session 
Group) or Visit 17 (3-Session Group) 
compared between groups  
CAPS-5 
Outcome 
Telemedicine 
(IR) 
Secondary 
Assess changes in clinician-rated functional 
impairment from Baseline to Visit 13 (2-
Session Group) or Visit 17 (3-Session 
Group) compared between groups 
SDS 
Outcome 
Telemedicine 
(IR) 
Assess changes in PTSD symptom severity 
from Baseline to Visit 15 (2- Session Group 
only) 
CAPS-5 
Outcome 
Telemedicine 
(IR) 
Exploratory 
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 
(IR) 
Characterization of PTSD severity and 
cluster scores collected prior to each 
session to explore onset of treatment 
effectiveness with a descriptive time 
course plot 
PCL-5 
Outcome 
Site 
Assess changes in severity of dissociative 
symptoms associated with PTSD from 
Baseline to Visit 13 (2-Session Group) or 
Visit 17 (3-Session Group) compared 
between groups 
DSP-I 
Outcome 
Telemedicine 
(IR) 
Explore correlation of dissociative symptoms 
associated with PTSD with the CAPS-5 Total 
Severity analyses 
DSP-I  
CAPS-5 
Outcome 
Telemedicine 
(IR) 
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 the effect of combat experiences on 
PTSD treatment outcomes as a covariate on 
the CAPS-5 Total Severity analyses 
DRRI-2 
 CAPS-5 
Outcome 
Site 
Assess changes in depression symptoms 
from Visit 4 to Visit 14 (2-Session Group) or  
Visit 18 (3-Session Group) compared 
between groups 
BDI-II 
Outcome 
Site 
Assess changes in chronic pain from 
Visit 4 to Visit 14 (2-Session Group) or 
Visit 18 (3-Session Group) compared  
between groups 
CPGS 
Outcome 
Site 
Assess changes in Moral Injury from 
Visit 4 to Visit 14 (2-Session Group) or 
Visit 18 (3-Session Group) compared 
between groups 
MIES 
Outcome 
Site 
Assess changes in Posttraumatic Growth 
from Visit 4 to Visit 14 (2-Session Group) or 
Visit 18 (3-Session Group) compared  
between groups 
PTGI 
Outcome 
Site 


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Assess changes in self-compassion from 
Visit 4 to Visit 14 (2-Session Group) or 
Visit 18 (3-Session Group) compared 
between groups 
SCS 
Outcome 
Site 
Assess changes in anger from Visit 4 to 
Visit 14 (2-Session Group) or Visit 18 (3-
Session Group) compared between groups 
BPAQ-SF 
Outcome 
Site 
Assess changes in experiential avoidance and 
acceptance from Visit 4 to Visit 14 (2-
Session Group) or Visit 18 (3-Session Group) 
compared between groups 
AAQ-II 
Outcome 
Site 
Assess changes in alcohol use from 
Screening to Visit 14 (2-Session Group) or 
Visit 18 (3-Session Group) compared 
between groups 
AUDIT 
Healthcare 
cost 
Site 
Assess changes in drug use from Screening to 
Visit 14 (2-Session Group) or Visit 18 (3-
Session Group) 
DUDIT 
Healthcare 
cost 
Site 
Assess facility-based healthcare utilization at 
Screening 
UFEC 
Healthcare 
cost 
Site 
Assess changes in clinician-rated functional 
impairment from Visit 4 to Visit 14 (2-
Session Group) or Visit 18 (3-Session Group) 
compared between groups 
WHOQOL- 
BREF 
Outcome 
Site 
Assess the effects of traumatic brain injury on 
PTSD treatment outcomes as a covariate on 
the CAPS-5 Total Severity Analyses 
OSU-TBI 
CAPS-5 
Outcome 
Site 
Assess incidence of positive or serious 
ideation and suicidal behavior  
MAPS-Adapted 
C-SSRS 
Safety and 
Outcome 
Site 
 
6.1 Primary Outcome Measure and Reliability 
6.1.1 CAPS-5 (Clinician-Administered PTSD Scale for DSM-5) 
The last month CAPS-5 is a semi-structured interview that assesses index history of DSM-5- 
defined traumatic event exposure [70], including the most distressing event, time since exposure, 
to produce a diagnostic score (presence vs. absence) and a PTSD Total Severity score [70]. 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 IMP, which strengthens the study blind. 
 
Interviews may be recorded in as many instances as necessary to establish reliability of a random 


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selection of interviews for accuracy. After the initial screening visit, the IRs will be blinded to 
visit number, number of treatments received, treatment assignment, and any study data for the 
participant. IR visits will be assigned based on availability. 
 
6.2 Secondary Measure 
6.2.1 SDS (Sheehan Disability Scale) for PTSD for MAPS 
The SDS is a clinician-rated assessment of functional impairment [71]. The SDS has high internal 
consistency and accurately identified 80% of a sample of primary care patients with mental 
disorders [72]. The Customized version of the SDS for PTSD for the MAPS studies was 
developed utilizing the standard SDS. The first three items indicate degree of impairment in the 
domains of work/school, social life, and home life, with response options based on an eleven-
point scale (0=not at all to 10=extremely), and five verbal tags (not at all, mildly, moderately, 
markedly, extremely). The remaining two items assess Days Lost and Days Unproductive during 
the reporting period. The SDS for PTSD for MAPS maintains the same scale conventions as the 
standard SDS. To limit missing data, the summary measure used to analyze the treatment effect 
on SDS is the mean of the 3 item responses at each visit. Any participant who did not work 
during the reporting period due to reasons related to PTSD is scored as maximal work-related 
impairment on item 1. Any participant who did not work during the reporting period due to 
reasons not related to PTSD reports on the reason for not working and Item 1 is skipped. The 
SDS for PTSD for MAPS has been approved by Dr. David Sheehan for use in MAPS Research 
and is referred to throughout the protocol as SDS. The SDS for PTSD for MAPS takes 5 minutes 
to complete. 
 
Administration and reliability of SDS for PTSD for MAPS: To limit missing data and ensure 
standardized administration, the SDS for PTSD for MAPS will be administered in a clinician-
rated format by the centralized Independent Rater Pool. 
 
 
6.3 Screening Measures and Reliability 
6.3.1 C-SSRS (Columbia Suicide Severity Rating Scale); MAPS-Adapted 
The C-SSRS is a clinician-administered measure of suicidal behavior devised to detect potential 
suicidal thoughts or behaviors during a clinical trial [73]. It consists of a “Baseline/Screening” 
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 Baseline/Screening version assesses the experience of 
the participant with suicidal ideation and behavior over their lifetime and within 6 months prior to 
entry into the trial and will be completed for all potential participants at screening to determine 
eligibility. All subsequent administrations will utilize the Since Last Visit version to assure that 
the participant continues to qualify for the trial. 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 [74]. This study will utilize the MAPS-adapted versions of the 
Baseline/Screening and Since Last Visit C-SSRS measures. The MAPS Adapted C-SSRS was 
developed utilizing Dr. Kelly Posner’s Columbia Suicide Severity Scale. The MAPS Adapted C-
SSRS maintains the content and flow of the standard C-SSRS. The scale was adapted to modify 
formatting and add additional administrative guidance to reduce rater and data entry errors. The 
MAPS Adapted C-SSRS has been approved by Dr. Kelly Posner for use in MAPS Research. 
 


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6.3.2 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 [75], is now compatible with DSM-5 and will be administered by a member of the 
Independent Rater Pool to screen for psychiatric conditions per DSM-5. Each module of the 
MINI consists of two or three questions where the answer is either “Yes” or “No,” and decision- 
tree logic is used to determine whether to ask additional questions [76]. 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 [76, 77]. Testing on nonpsychiatric samples 
did not create false positives [75]. 
 
6.3.3 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 [78]. Prior to the SCID-5- 
PD clinical interview, participants will complete a brief self-report questionnaire called the SCID- 
5 Self-report Personality Questionnaire (SCID-5-SPQ) as a self-report screening tool used to 
assess for personality disorders. Potential personality disorders that satisfy diagnostic thresholds 
will be further assessed via clinical interview during the SCID-5-PD. IRs will receive training on 
administering these measures from a research reliable trainer. Interviews may be recorded in as 
many instances as necessary to establish reliability of a random selection of interviews for 
accuracy. 
 
6.3.4 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 [79]. 
 
6.3.5 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 [80]. 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 
36 or greater at Screening will be required for initial enrollment. 
 
6.3.6 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 [81]. 


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Owing to overlap with items found between the DDIS and other screening measures, only 
questions specifically addressing DID will be assessed. 
 
6.4 Exploratory Measures 
6.4.1 DSP-I (The Dissociative Subtype of PTSD Interview) 
The DSP-I is a clinician-administered interview designed by an international team of PTSD 
researchers to detect and assess severity of the dissociative type of PTSD and recommended for 
use as an additional or complementary measure (“add-on”) to the CAPS-5 [82]. 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 [83-85]. 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. 
 
6.4.2 ACE (Adverse Childhood Experience Questionnaire) 
The ACE is a 10-item checklist measure assessing number and types of adverse childhood 
experiences, including neglect and emotional, physical, and sexual abuse. Respondents are asked 
if an experience happened “often” and if so, to write “1”. The total score reflects the number of 
adverse childhood experiences. The measure was first used in the context of a study investigating 
the relationship between childhood adverse experiences and health outcomes in adulthood [86] 
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[87-90]. The scoring method has been used in archival research, finding an 
association between increased scores and health problems in several generations [89]. 
 
6.4.3 BDI-II (Beck Depression Inventory II) 
The BDI-II is a revision of the BDI, a 21-item self-report measure [91, 92] that will serve as a 
measure of depression symptom severity [93]. 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 [93]. 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 [93, 94]. 
Higher scores indicate more severe depressive symptoms. 
 
6.4.4 CPGS (Chronic Pain Grade Scale) 
The CPGS is a seven-item measure of pain. Responses to six of the seven items are made on a 10- 
point Likert scale, and a response on the other item is the number of days in the past 3 to 6 
months when pain prevented the respondent from carrying out everyday activities [95]. 
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 


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scale with high internal consistency (Cronbach’s alpha = 0.90) and correlated with other 
instruments assessing pain [96]. 
 
6.4.5 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 [97]. 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 
[98]. 
6.4.6 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) [99]. 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 [100]. 
 
6.4.7 DUDIT (Drug Use Disorders Identification Test) 
The DUDIT is an 11-item measure designed to assess presence of substance use disorders [101]. 
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% [101]. The 
English translation was developed from a Swedish-language original. Estimated time to complete 
is 2 to 4 minutes. 
 
6.4.8 MIES (Moral Injury Event Scale) 
The MIES is a 9-item Likert-type scale assessing the experience and impact of potentially 
morally injurious events. The MIES is comprised of two underlying latent factors: Perceived 
Transgressions and Perceived Betrayals. The MIES has good internal validity and temporal 
stability [102]. 
 
6.4.9 PTGI (Posttraumatic Growth Inventory) 
The PTGI is a 21-item scale assessing positive outcomes following trauma. The scale includes 
factors of New Possibilities, Relating to Others, Personal Strength, Spiritual Change, and 
Appreciation of Life [103]. The PTGI is modestly associated with personality traits of optimism 
and extraversion. The scale has been used to assess how individuals have reconstructed or 


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strengthened their perceptions of self, others, and the meaning of events in the aftermath of 
trauma [103, 104]. 
 
6.4.10 BPAQ-SF (Buss Perry Aggression Questionnaire Short Form) 
The BPAQ-SF is a well-validated and widely used 12 item scale with four factors: Physical 
Aggression, Verbal Aggression, Anger, and Hostility [105]. 
 
6.4.11 AAQ-II (Acceptance and Action Questionnaire) 
The AAQ-II is a 7-item, self-rated measure that assesses the construct variously described as 
acceptance, experiential avoidance, and psychological flexibility. The measure has demonstrated 
good reliability and validity, and the AAQ-II has shown concurrent and predictive associations 
with a range of mental health and functional outcomes [106]. 
 
6.4.12 WHOQOL-BREF (WHO Quality of Life-BREF) 
The World Health Organization Quality of Life (WHOQOL) project was initiated in 1991. The 
aim was to develop an international cross-culturally comparable quality of life assessment 
instrument [107, 108]. It assesses the individual’s perceptions in the context of their culture and 
value systems, and their personal goals, standards, and concerns. The WHOQOL instruments 
were developed collaboratively in a number of centers worldwide and have been widely field-
tested. 
 
The WHOQOL-BREF instrument comprises 26 items, which measure the following broad 
domains: physical health, psychological health, social relationships, and environment. The 
WHOQOL-BREF was derived from data collected using the WHOQOL-100. It produces scores 
for four domains related to quality of life: physical health, psychological, social relationships, and 
environment. It also includes one facet on overall quality of life and general health.  
 
6.4.13 DRRI-II (Deployment Risk and Resilience Inventory-2) 
The DRRI, developed by the VA National Center for PTSD, is a suite of scales that assess key 
deployment-related risk and resilience factors with demonstrated implications for Veterans’ long-
term health [109]. Scales D (combat experiences) and E (post-battle experiences) will be 
administered. 
 
6.4.14 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. 
 
6.4.15 OSU-TBI-ID (Ohio State University Traumatic Brain Injury Identification 
Method) 
The OSU TBI-ID is a standardized assessment for eliciting lifetime history of TBI via a 
structured interview [110]. 
 


MAPS Public Benefit Corporation 
 
 MPVA6 Protocol  
IND #063384 
 
Amendment 7 Version 1: 04 August 2022 
 
Page 46 of 94 
7.0 Study Procedures 
All assessments must be performed by qualified study staff delegated these duties on the Site 
Responsibilities Log. The Clinical Research Associate (CRA) should be notified of any delays or 
deviations to study procedures and Medical Monitor consulted if necessary. If there are delays of 
more than 7 days between visits or contact, the site should assess the need for additional 
telephone contact with the participant to ensure safety.


MAPS Public Benefit Corporation 
 
  
 
 
 
       MPVA6 Protocol  
IND #063384 
 
 
            Amendment 7 Version 1: 04 August 2022 
  
Page 47 of 94 
Table 4: Time and Events-Study Procedures-Pre-Treatment (All Groups) 
 
Screening and Enrollment Period 
(~4 weeks, +/- 2 weeks) 
Preparatory Period with Enrollment Confirmation 
At least 7 days, depending on medication tapering plan 
 
Screening 
 
Enrollment 
Preparatory 
Baseline CAPS-5 T1 Baseline & Enrollment 
Confirmation 
Visit 
Phone/in-person 
Screening 
Screening 
IR Evaluation 
V0 
V1 
V2 
V3 
V4 
Visit Description 
Phone/in person 
In-person  
Visits & Labs 
Telemedicine 
Enrollment 
Prep. 1 
Prep. 2 
Telemedicine 
Prep. 3 & 
Enrollment Confirmation 
Visit Timing 
Prior to Initial 
Screening 
Over 7 to  
28  days 
2 to 9 days after 
 initial eligibility 
met 
2 to 14 days  
post IR Screening 
0 to 12 days 
after V0 
At least 2 days after V1 
(depending on 
Medication  tapering) 
Post V2 &  Taper 
(Confirmed by  
Phone call) 
3 to 6 days 
After V3 
Initial Phone Screen 
 
 
 
 
 
 
 
 
Informed Consent 
Send or provide 
copy 
 
 
 
 
 
 
 
Follow-up Phone Screen 
 
 
 
 
 
 
 
 
Assess Eligibility 
 
 
 
 
 
 
 
 
Medical/Psychiatric History 
 A 
 
 
 
 
 
 
 
Past/Current Medication & Adherence 
 
 
 
 
 
 
 
 
Weight, BP, Pulse, Temperature 
 
 
 
 
 
 
 
 
Physical Exam 
 
 
 
 
 
 
 
 
ECG & Rhythm Strip 
 
 
 
 
 
 
 
 
Clinical Lab Tests 
 
 
 
 
 
 
 
 
Drug Screen 
 
 
 

 
 
 
 
Pregnancy Screen G 
 
 
 

 
 
 
 
Biomarker Blood Sample 
 
 
 
 
 
 
 
 D 
Enter Participant in eCRF B 
 
 
 
 
 
 
 
 
Record 
 
 
 

 
 
 
 
Study Enrollment 
 
 
 
  E 
 
 
 
 Confirmed 
Medication Taper 
 
 
 
 
 
 
 
 
All AEs C 
 
 
 
 
 
 
 
 
90-min Preparatory Session 
 
 
 

 
 
 
 
Phone Call Follow-up F 
 
 
 
 
 
 
 
 
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 Blood samples will be drawn from participants at two time points (pre- and post-treatment) in order to bank samples for future assay. Pre-Treatment blood draw will occur after V3 and before V5. 
E Enrollment eligibility must be confirmed by the Medical Monitor prior to participant randomization 
F If needed, call participant to confirm medication tapering and stabilization is complete prior to Visit 3  
G For people able to become pregnant (PABP) only 


MAPS Public Benefit Corporation 
 
  
 
 
 
       MPVA6 Protocol  
IND #063384 
 
 
            Amendment 7 Version 1: 04 August 2022 
  
Page 48 of 94 
Table 5: Treatment Period, Follow-Up, and Study Termination-Group 1 (3 Experimental Sessions) 
 
Treatment Period: Group 1 (3 Experimental Sessions) 
~9-15 weeks 
Post-Treatment Period 
(~5 weeks) 
 
Treatment 1 
Treatment 2 
Treatment 3 
Primary 
Outcome 
Outcome 
Site Visit 
Study 
Termination 
Visit 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
Visit Description 
Exp. 1 
Int. 
1.1 
Int. 1.2 
 
Int. 
1.3  
Exp. 2 
Int. 
2.1 
Int. 
2.2 
 
Int. 
2.3  
Exp. 3 
Int. 3.1 
Int. 
3.2  
Int. 
3.3  
CAPS-5 T2 
Outcome: Tele- 
medicine A 
Outcome 
  Site Visit 
Study 
Termination 
Visit Timing 
Within 7 
days after 
V3 
Morn 
-ing 
after 
V5 
~1 
week 
(3 to 
14 
days) 
after 
V5 
 ~2 
weeks 
(10 to 21 
days) 
after  V5  
~3 
weeks 
(21 to 
35  
days) 
after V5  
Morn 
-ing 
after 
V9 
~1 
week 
(3 to 
14 
days) 
after 
V9 
 ~2 
weeks 
(10 to 
21 
days) 
after V9 
~3 
weeks 
(21 to 
35 days) 
after V9 
Morn-
ing 
after 
V13 
~1 
week 
(3 to 
14 
days) 
after 
V13 
~2 
weeks 
(10 to 
21 
days) 
after 
V13 
85 to 134 
days after 
V3; 
~ 7 weeks 
after V13 
2 days  
(1 to 7 
days) 
after 
V17 
~2 days 
(0 to 7 
days) 
after 
V18 
Past/Current 
Medication & 
Adherence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Screen B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Blood 
Sample 
 
 
 
 
 
 
 
 
 
 
 
 
 C 
 
 
Record 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All AEs D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer IMP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8-hour Exp. Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BP, Pulse, Temp. F 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 G 
Overnight Stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
90-min Integrative 
Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Call 
Follow-up H 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
A All visits must be scheduled to ensure that the Primary Outcome CAPS-5 T2 assessment is within the overall window provided. 
B For people able to become pregnant (PABP) only 
C Blood samples will be drawn from participants at two time points (pre- and post-treatment) in order to bank samples for future assay.  
D 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  
E Randomize 24 to 48 hours prior to first Experimental Session 
F 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 6 to 8 hours after initial dose, and as needed  
G At Study Termination, only blood pressure needs to be measured  
H 14 days of phone follow-up, with one phone call every other day starting 2 days after the Experimental Session   
 


MAPS Public Benefit Corporation 
 
  
 
 
 
       MPVA6 Protocol  
IND #063384 
 
 
            Amendment 7 Version 1: 04 August 2022 
  
Page 49 of 94 
Table 6: Treatment Period, Follow-Up, and Study Termination-Group 2 (2 Experimental Sessions) 
 
Treatment Period: Group 2 (2 Experimental Sessions) 
~6-10 weeks 
Post-Treatment Period 
(~9 weeks) 
 
Treatment 1 
Treatment 2 
Primary 
Outcome 
Outcome  
Site Visit 
Secondary 
Outcome 
Study 
Termination 
Visit 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
Visit Description 
Exp. 1 
Int.  
1.1 
Int. 1.2  
Int. 
1.3 G 
Exp. 2 
Int. 2.1 
Int. 2.2  
Int. 
2.3 
CAPS-5 T2 
Outcome: Tele- 
medicine A 
Outcome  
Site Visit 
CAPS-5 T2.2 
Outcome: Tele- 
medicine 
Study 
Termination 
Visit Timing 
Within 7 
days after 
V3 
  Morning  
 after V5 
~1 week  
(3 to 14 
days)  after 
V5 
~2 weeks  
(10 to 21 
days) after 
V5 
~3 weeks 
(21 to 35 
days) after 
V5 
Morning  
after V9 
~1 week  
(3 to 14 
days)  after 
V9 
~2 weeks  
(10 to 21 
days) after 
V9  
63 to 98 days after 
V3; 
~ 7 weeks after V9 
2 days (1 to 7 
days) after 
V13 
85 to 134 days 
after V3 
~2  
days (1 to 7 
days) post 
V15 
Past/Current 
Medication & 
Adherence 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screen 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
Screen B 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Blood 
Sample 
 
 
 
 
 
 
 
 
 C 
 
 
 
Record 
 
 
 
 
 
 
 
 
 
 
 
 
All Aes D 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization E 
 
 
 
 
 
 
 
 
 
 
 
 
Administer IMP 
 
 
 
 
 
 
 
 
 
 
 
 
8-hour Exp. Session 
 
 
 
 
 
 
 
 
 
 
 
 
BP, Pulse, 
Temperature F 
 
 
 
 
 
 
 
 
 
 
 
 G 
Overnight Stay 
 
 
 
 
 
 
 
 
 
 
 
 
90-min 
Integrative Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Call Follow-
up H 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
A All visits must be scheduled to ensure that the Primary Outcome CAPS-5 T2 assessment is within the overall window provided. 
B For people able to become pregnant (PABP) only 
C Blood samples will be drawn from participants at two time points (pre- and post-treatment) in order to bank samples for future assay. Post-treatment blood draw will occur within 9 days of V13.   
D 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  
E Randomize 24 to 48 hours prior to first Experimental Session  
F 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 6 to 8 hours after initial dose, and as needed  
G At Study Termination, only blood pressure needs to be measured   
H 14 days of phone follow-up, with one phone call every other day starting 2 days after the Experimental Session  


MAPS Public Benefit Corporation 
 
  
 
 
 
       MPVA6 Protocol  
IND #063384 
 
 
            Amendment 7 Version 1: 04 August 2022 
  
Page 50 of 94 
Table 7: Time and Events-Study Measures-Group 1 (3 Experimental Sessions) 
 
Screening 
Baseline & Enrollment 
Confirmation 
Treatment 1 
Treatment 2 
Treatment 3 
Post-Treatment Follow-Up & Study 
Termination 
 
Visit # 
Site A 
IR 
Screening 
V0 
V3 
V4 
V5 
V6 & 7 
V8 
V9 
V10 & 11 
V12 
V13 
V14 & 15 
V16 
V17 
V18 
V19 
Visit 
Description 
~Time to 
Complete 
Measure 
(minutes) 
Site 
Visit 
Tele- 
medicine  
Site 
visit  
Baseline 
CAPS-5 T1 
 Prep. 3 & 
Enrollment 
Confirmation 
Exp. 1 
Int. 1.1 
& 1.2 
Int.  1.3 
Exp. 2 
Int.  2.1 & 
2.2 
Int.  2.3 
Exp. 3 
Int. 3.1 & 
3.2 
Int. 3.3 
CAPS-5 T2 
Outcome: 
Telemedicine 
Outcome 
Site Visit 
Study 
Termination 
CAPS-5 
90 (Baseline) 
60 (all others) 
 
 

 

 
 
 
 
 
 
 
 
 
 
 
 
SDS 
5 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
DSP-I 
15 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 
15 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-PD 
60 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-SPQ 
20 
 



 
 
 
 
 
 
 
 
 
 
 
 
 
WHOQOL- 
BREF 
10 
 
 


 
 
 
 
 
 
 
 
 
 
 

 
AAQ-II 
3 
 
 


 
 
 
 
 
 
 
 
 
 
 

 
C-SSRS B 
10 




  
 C 
 
 
 C 
 
 
 C 
 
 

 
 
SCS 
6 
 
 


 
 
 
 
 
 
 
 
 
 
 

 
DDIS D 
5 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BPAQ-SF 
12 
 
 


 
 
 
 
 
 
 
 
 
 
 

 
DRRI-II E 
11 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
LEC-5 
5 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PCL-5              
8 

 


 
 F 
 
 
 F 
 
 
 F 
 
 



MIES 
4 
 
 


 
 
 
 
 
 
 
 
 
 
 

 
ACE 
4 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
BDI-II 
10 (Baseline) 
5 (all others) 
 
 


 
G 
 
 
G 
 
 
G 
 
 
 

 
CPGS 
5 
 
 


 
 
 
 
 
 
 
 
 
 
 

 
PTGI 
8 
 
 


 
 
 
 
 
 
 
 
 
 
 

 
OSU-TBI 
5 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
UFEC 
3 
 
 


 
 
 
 
 
 
 
 
 
 
 

 
AUDIT 
3 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
DUDIT 
3 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
~Total Time of Completing 
Measures (minutes) 
49 
90 
23 
110 
76 
23 
10 
10 
23 
10 
10 
23 
10 
10 
80 
80 
80 
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 Baseline/Screening assessment, other assessments are Since Last Visit Additional C-SSRS measures may be conducted as clinically indicated. The site will utilize the MAPS-adapted C-SSRS.   
C Conducted pre- and post-IMP administration, and at phone calls every other day for 14 days starting 2 days 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.  
E Only scales D (combat experiences) and E (post-battle experiences) of the DRRI-II will be administered.  
F PCL-5 conducted pre-IMP administration.  
G BDI-II conducted pre-IMP administration. 


MAPS Public Benefit Corporation 
 
  
 
 
 
       MPVA6 Protocol  
IND #063384 
 
 
            Amendment 7 Version 1: 04 August 2022 
  
Page 51 of 94 
Table 8: Time and Events-Study Measures-Group 2 (2 Experimental Sessions) 
 
Screening 
Baseline & Enrollment 
Confirmation 
Treatment 1 
Treatment 2 
Post-Treatment Follow-Up & Study Termination 
 
Visit # 
Site A 
IR 
Screening 
V0 
V3 
V4 
V5 
V6 & 7 
V8 
V9 
V10 & 11 
V12 
V13 
V14 
V15 
V16 
Visit Description 
~Time to 
Complete 
Measure 
(minutes) 
Site 
Visit 
Tele- 
medicine 
Site 
Visit 
Baseline 
 CAPS-5 T1 
Prep. 3 & 
Enrollment 
Confirmation 
Exp. 1 
Int. 1.1 
& 1.2 
Int.  1.3 
Exp. 2 
Int.  2.1 & 
2.2 
Int. 
2.3 
CAPS-5 T2 
Outcome: 
Telemedicine 
Outcome 
Site Visit 
CAPS-5 T2.2: 
Outcome: 
Telemedicine 
Study 
Termination 
CAPS-5 
90 (Baseline) 
60 (all others) 
 


 

 
 
 
 
 
 
 

 
 
SDS 
5 
 
 


 
 
 
 
 
 
 


 
 
DSP-I 
15 
 
 


 
 
 
 
 
 
 


 
 
MINI 
15 
 
 



 
 
 
 
 
 



 
SCID-5-PD 
60 
 
 



 
 
 
 
 
 



 
SCID-5-SPQ 
20 
 




 
 
 
 
 
 



 
WHOQOL- BREF 
10 
 
 


 
 
 
 
 
 
 
 

 
 
AAQ-II 
3 
 
 


 
 
 
 
 
 
 
 

 
 
C-SSRS B 
10 




  
 C 
 
 
 C 
 
 

 

 
SCS 
6 
 
 


 
 
 
 
 
 
 
 

 
 
DDIS D 
5 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
BPAQ-SF 
12 
 
 


 
 
 
 
 
 
 
 

 
 
DRRI-II E 
11 
 
 


 
 
 
 
 
 
 
 
 
 
 
LEC-5 
5 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
PCL-5 
8 

 


 
 F 
 
 
 F 
 

 

 

MIES 
4 
 
 


 
 
 
 
 
 
 
 

 
 
ACE 
4 
 
 


 
 
 
 
 
 
 
 
 
 
 
BDI-II 
10 (Baseline) 
5 (all others) 
 
 


 
G 
 
 
G 
 
 
 

 
 
CPGS 
5 
 
 


 
 
 
 
 
 
 
 

 
 
PTGI 
8 
 
 


 
 
 
 
 
 
 
 

 
 
OSU-TBI 
5 
 
 


 
 
 
 
 
 
 
 
 
 
 
UFEC 
3 
 
 


 
 
 
 
 
 
 
 

 
 
AUDIT 
3 

 
 
 
 
 
 
 
 
 
 
 

 
 
DUDIT 
3 

 
 
 
 
 
 
 
 
 
 
 

 
 
~Total Time of Completing 
Measures (minutes) 
49 
90 
23 
100 
76 
23 
10 
10 
23 
10 
10 
80 
80 
80 
23 
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 Baseline/Screening assessment, other assessments are Since Last Visit. Additional C-SSRS measures may be conducted as clinically indicated. The site will use the MAPS-adapted C-SSRS.  
C Conducted pre- and post-IMP administration, and at phone calls every other day for 14 days starting 2 days 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.  
E Only scales D (combat experiences) and E (post-battle experiences) of the DRRI-II will be administered.  
F PCL-5 should be conducted pre-IMP administration.  
G BDI-II should be conducted pre-IMP administration. 


MAPS Public Benefit Corporation 
 
 MPVA6 Protocol  
IND #063384 
 
Amendment 7 Version 1: 04 August 2022 
  
Page 52 of 94 
7.1 Screening and Enrollment Period 
7.1.1 Screening 
Prospective participants will be pre-screened in person or 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 begin screening. Relevant medical and psychiatric records are required for the site 
physician to obtain a well-characterized medical history and assess eligibility. The physician may 
need to contact the prescribing physician to discuss the tapering of medications (see Section 11.0 
Concomitant Medications). 
 
Site staff (preferably the therapy pair 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. The signature may be 
obtained using an electronic 21 CFR Part 11 compliant system due to COVID-19. 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 Baseline/Screening C-SSRS to assess history of suicidal behavior and 
ideation. 
 
Review past and current medications and adherence to prescriptions. 


MAPS Public Benefit Corporation 
 
 MPVA6 Protocol  
IND #063384 
 
Amendment 7 Version 1: 04 August 2022 
  
Page 53 of 94 
 
Assess ability to become pregnant and discuss requirement for commitment to adequate 
contraception for the duration of the study. Perform urine pregnancy test for participants 
who are of able to become pregnant. 
 
Perform a urine drug test. 
 
Direct participant to complete self-reported Screening measures: 
o SCID-5-SPQ 
o AUDIT 
o DUDIT 
o PCL-5 
o LEC-5 
 
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 12.0 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 nuclear exercise testing by a cardiologist and for carotid 
ultrasound. If these tests fail to reveal evidence of significant vascular disease or other 
cardiac disease, the person may be enrolled if there are no other contraindications. 
Participants taking one or more antihypertensives may be enrolled in the study. The 
investigators will record and review medications used to control hypertension prior to 
enrollment. Per the Medical Monitor and site physician’s instruction, other tests of 


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cardiovascular health and function may be required during screening, such as an 
echocardiogram. These will only be completed on a case-by-case basis to confirm a 
participant’s cardiovascular eligibility. 
 
Additional visits (in person, by telephone, or via telemedicine) may be scheduled at the 
discretion of the study staff to collect more information for determining eligibility or to discuss 
study expectations with the potential participant. 
 
Once all results are obtained, the site team will review all medical assessments, notes from 
interviews and discussions, medical records, and measures against eligibility criteria. If, upon 
examination, there are questions raised about possible medical problems, the site physician will 
request additional tests, assessments, or measures as indicated. The site physician may also 
contact outside providers with participant permission as needed. If deemed initially eligible, the 
site staff will schedule the IR screening and send results of LEC-5 and SCID-5-SPQ to the IR.  
 
The study team will provide the participant with a location to complete the telemedicine visits at 
the study site. They will also provide technical support before the assessment and therapeutic 
support after, if needed. These assessments may be completed remotely with prior permission 
from the Medical Monitor and Independent Rater if it is deemed safe based on the participant’s 
medical history and current presentation. For all IR visits, participants should have adequate 
internet access and be in a private and quiet space where they are comfortable talking about 
personal matters. 
 
7.1.2 Independent Rater Screening Assessments 
If participants meet initial eligibility during Screening, a blinded IR will continue the 
eligibility assessment via telemedicine after reviewing the results of the LEC-5 and SCID-5-
SPQ. The blinded IR interview may be recorded to assess reliability of ratings. The potential 
participant should be present at the study site during this assessment unless the study team has 
received permission for the participant to complete the assessment remotely. In either case, the 
therapy pair will be available for support. If a participant reports suicidal ideation during this 
assessment, the IR will contact the therapy pair after the call and present any concerns. The 
therapy pair is then required to 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 personality disorders. Only appropriate modules will be 
completed. 
 
The IR will also ask relevant questions from the DDIS to identify dissociative disorders 
and administer the Since Last Visit C-SSRS to determine suicidal risk. 
 
The IR will complete MINI interview to assess psychiatric disorders. 
 
The results from the MINI, SCID-5-PD, DDIS, and C-SSRS will be provided to the therapy pair 
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 the results of any interview indicate an exclusionary psychological disorder diagnosis is 
present, the Senior IR reviewer will review the recording of the MINI and/or SCID-5-PD 
assessment. The Senior IR reviewer will invite the study team (including therapists, site 
physician, and Clinical Investigator) to provide any additional information that may inform the 
Senior IR reviewer’s opinion. The Senior IR reviewer will make the final judgment on whether 
or not the participant has an exclusionary diagnosis. Participants with exclusionary diagnoses 


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will not be enrolled. However, if any diagnosis is not present or uncertain according to any 
measure or interview, but the investigator believes the participant presents with a particular 
disorder, they may diagnose and deem the participant ineligible if appropriate. 
 
After the initial screening visit the Irs will be blinded to visit number, treatment assignment, 
number of treatments received, and any study data for the participant. IR visits will be assigned 
based on availability. 
 
7.1.3 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. The Sponsor will additionally perform eligibility review prior to enrollment at the site. 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 11.0 Concomitant Medications. 
 
At study onset, 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. If a participant is determined to be eligible to participate in the study, the participant 
will be notified of enrollment at Visit 0. A medication tapering plan will be discussed with the 
participant, if applicable. Medical history and medication information will be reviewed for 
completeness. If agreeable, the participant will be enrolled in the study. Once enrolled, AE 
collection requirements begin (refer to Section 10.0 Safety). Visit 0 should take place within 2 to 
14 days after Independent Rater Screening is completed. Visit 0 and Visit 1 may take place on the 
same day. 
 
For eligible participants at Enrollment (Visit 0), qualified site staff will: 
 
 
Administer the MAPS-Adapted C-SSRS (Since Last Visit). 
 
Support participants in the completion of the following pre-treatment measures.  
o DRRI-II  
o ACE  
o OSU-TBI 
o UFEC  
 
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 3.3 Lifestyle Modifications. 
 
7.2 Preparatory Period with Enrollment Confirmation 
7.2.1 Preparatory Sessions 
Participants will undergo three Preparatory Sessions (Visits 1, 2, and 4) lasting approximately 90 
minutes with the therapy pair prior to the first Experimental Session. The Preparatory Period will 
be initiated within 12 days of Visit 0. There must be at least 48 hours between Preparatory 
Sessions 1 (Visit 1) and 2 (Visit 2) and 72 hours between the Baseline CAPS-5-T1 (Visit 3) and 
Preparatory Session 3 (Visit 4). The minimum time to complete the Preparatory Period is 7 days. 
Adherence criteria for Preparatory Sessions should be followed per the Treatment Manual. In 
these visits the therapy pair will work with the participant to prepare for MDMA-assisted therapy, 


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begin building therapeutic alliance, and promote a safe set and setting for confronting trauma-
related memories, emotions, and thoughts. 
 
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. 
 
 
Preparatory Session 1 (Visit 1) will occur 0 to 12 days after Visit 0. 
 
Preparatory Session 2 (Visit 2) will occur at least 2 days after Visit 1 (depending on 
medication tapering). 
 
Preparatory Session 3 (Visit 4) will occur 3 to 6 days after the Baseline CAPS-5 (V3). 
 
At each 90-minute psychoeducation and therapy Preparatory Session, the therapy pair 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 10.0 Safety. 
 
Inquire about concomitant medication use and adherence. 
 
Discuss goals and expectations for the Experimental Session, following standard 
procedures and techniques described in the Treatment Manual [111]. 
 
If a participant would like a companion present during or after the Experimental Session, a 
meeting between the therapy pair and that individual will be scheduled prior to the first 
Experimental Session. There must be mutual agreement between the participant and therapy pair 
concerning the presence of the companion. 
 
At any time during the Preparatory Period, if a potential participant is deemed to be ineligible, the 
site team will classify them as a Pre-randomization Early Termination, notify the potential 
participant that they are not eligible for the study, and not schedule additional assessments. The 
site team will not randomize participants classified as Pre-randomization Early Terminations. 
 
During one of the Preparatory Sessions, if possible, the therapy pair will introduce the participant 
to the attendant who will remain with the participant during each overnight stay after each 
MDMA-assisted therapy session. The attendant will be an individual with previous training 
in caregiving. The site will make all attempts to have the same attendant for each Experimental 
Session for a given participant, but it is not guaranteed. 
 
7.2.2 Baseline CAPS-5 by Independent Rater 
At Baseline, an IR will measure the Baseline CAPS-5 (referred to as Baseline CAPS-5 T1) via 
telemedicine. This visit may be recorded to video to establish inter-rater reliability. The scores 
will be sent within 72 hours to the site staff. A CAPS-5 Total Severity Score of at least 28 is 
required to meet Enrollment Confirmation criteria. The IR will also administer the DSP-I and the 
SDS. 
 
7.2.3 Baseline Self-Reported Measures 
Qualified site staff will administer the MAPS-Adapted C-SSRS (Since Last Visit) and actively 
support participants in the completion of the following self-reported measures. These measures 
should be completed after the Baseline CAPS-5 and before the Treatment Period begins.  
o WHOQOL-BREF 
o AAQ-II 


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o SCS 
o BPAQ-SF 
o PCL-5 
o MIES 
o BDI-II 
o CPGS 
o PTGI 
 
7.2.4 Enrollment Confirmation 
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 with a Total Severity Score of 28 or greater, a total PCL-5 score of 36 or 
greater at Screening, continue to agree to all lifestyle modifications, and continue to meet all 
eligibility criteria.  
 
7.3 Treatment Period 
7.3.1 Experimental Sessions 
There will be two or three Experimental Sessions, depending on group (Visits 5 and 9 for 2-
session group; Visits 5, 9, and 13 for 3-session group). Procedures for MDMA-assisted therapy 
will remain the same across all sessions and all procedures regardless of assigned group. 
Experimental Sessions must be at least 6 to 8 hours long, measured from 30 minutes prior to IMP 
administration. 
 
 
Experimental Session 1 (Visit 5) will occur within 7 days after Preparatory Session 3 
(Visit 4). If the Baseline CAPS-5 assessment is completed outside of the allowed 
window, the investigator should consult the CRA and Medical Monitor to determine if 
the assessment should be repeated. The first Experimental Session will include an initial 
dose of 120 mg of MDMA followed by a supplemental dose of 40 mg 1.5 to 2 hours after 
the initial dose unless tolerability issues emerge with the first dose or it is refused by the 
participant. 
 
Experimental Session 2 (Visit 9) will occur 21 to 35 days after Experimental Session 1 
(Visit 5). An initial dose of 120 mg MDMA will be administered. A supplemental dose of 
40 mg will be administered 1.5 to 2 hours after the initial dose unless tolerability issues 
emerge with the first dose or it is refused by the participant. 
 
Group 1 only: Experimental Session 3 (Visit 13) will occur 21 to 35 days after the second 
Experimental Session (Visit 9). An initial dose of 120 mg will be administered. A 
supplemental dose of 40 mg will be administered 1.5 to 2 hours after the initial dose 
unless tolerability issues emerge with the first dose or it is refused by the participant.  


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Table 9: Schedule of Procedures for Experimental Sessions 
Approximate Time 
Procedure or Action 
8:30 
Urine drug screen and pregnancy test, concomitant 
medication information collected, self-reported measures 
and C-SSRS administered, participant acclimated to 
environment 
8:55 
Baseline BP, body temperature, pulse 
9:00 
IMP Administration, Begin video recording 
10:30 
BP, body temperature pulse 
Supplemental Dose Administration, unless tolerability issues 
emerge with the first dose or it is refused by the participant 
16:30 
C-SSRS, BP, body temperature, pulse 
 
Pre-IMP Administration 
 
24 to 48 hours prior to the first Experimental Session, the participant will be randomized. 
 
On the day of the Experimental Session, the participant will arrive approximately 30 to 
60 minutes prior to IMP administration. 
 
The therapy pair will direct the participant to complete the PCL-5 and BDI-II and will 
administer the C-SSRS. 
 
The site team will ensure the participant has not used caffeine or nicotine 2 hours prior 
and has fasted for 10 hours prior to IMP administration and complied with all other 
requirements per Section 3.3 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 10.0 
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 IMP administration. 
 
The site team will complete urine drug screen, pregnancy test, and concomitant 
medication review. 
o A positive drug screen will be reviewed by the site physician and may be cause 
for delaying IMP administration to a later time, rescheduling the session to a later 
date, or withdrawing the participant from the study, based on Medical Monitor 
review. 
o A positive pregnancy screen is cause for withdrawal from the protocol. 
 
The therapy pair 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. 
 
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 9:00 in the morning, a qualified staff 
member will administer the initial dose of IMP with an electrolyte-containing fluid. The 
participant will sit or recline on comfortable furnishings. Eyeshades and a program of 
music will be provided for the participant if they wish to use them. Whenever they wish, 
participants may speak to the therapy pair, who will provide guidance and support, as 
needed. 
 
After the first hour, if the participant has not spoken spontaneously, the therapy pair will 
check in with them about the nature of the experience. For the rest of the experience, as 
appropriate, the therapy pair will support and encourage the participant in emotional 


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processing and resolution of whatever psychological material is emerging, as described in 
the Treatment Manual. 
 
Water or Electrolyte-containing fluids will be provided throughout the session but not to 
exceed three liters overall. 
 
Blood pressure, body temperature, and pulse will be measured approximately 1.5 to 2 
hours after the initial dose, before the supplemental dose is administered. 
 
If the participant prefers not to have the supplemental dose, the therapy pair will 
document the reason. 
 
The site physician will be contacted with a brief description of how the session is 
progressing and the recent vital signs. The site physician will approve or deny the 
administration of the supplemental dose. If an AE requiring medical attention has 
occurred between the initial and supplemental dose, the site physician will determine 
whether the supplemental dose is recommended or not. If medical attention is needed, the 
site physician will provide further instruction or consult the Medical Monitor. 
 
A supplemental dose will be administered with a glass of electrolyte-containing fluid 
approximately 1.5 to 2 hours after the initial dose, unless tolerability issues emerge with 
the first dose or it is refused by the participant. 
 
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 pair brings them to the session room. 
Alternatively, the companion may arrive after the session has ended. 
 
End of Experimental Session 
 
The therapy pair will record Aes and concomitant medications. 
 
Blood pressure, body temperature, and pulse will be measured approximately 8 hours 
after the initial dose. 
 
The therapy pair will administer the C-SSRS. 
 
The session may be ended if all medical and psychiatric parameters are acceptable, 
elevations in vital signs have resolved to pre-IMP levels, the participant is alert, 
ambulatory, and emotionally stable, and the night attendant has arrived. 
 
The therapy pair or site physician shall remain available to participants via 24-hour 
cellular phone for support, as needed. 
 
Overnight Stay 
 
The participant will remain overnight with the therapy pair or a night attendant in 
accordance with site SOPs. 
 
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 pair, 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 caregiving and will be supportive but not intrusive. If there is 
an emergency or the participant needs additional support, the attendant can contact the 
therapy pair. 
 
The participant and a companion (if applicable) will receive information that will allow 
them to contact the therapy pair during the overnight stay in the case of an emergency or 
to request 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. 


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 
Participants may not drive until after the Integrative Session and cleared by therapist, as 
emotional processing may impair their attention and focus. 
 
7.3.2 Telephone Contact After Experimental Sessions 
The goal of the telephone contact is to assess health changes, ensure participant safety, and offer 
support. A member of the therapy pair will follow-up with the participant by telephone on every 
other day for 14 days after each Experimental Session (starting 2 days post-Experimental session) 
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 pair or participant. 
 
At each telephone contact, the member of the therapy pair 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 10.0 
Safety. 
 
Inquire about concomitant medication use and adherence. 
 
Offer support in accordance with the Treatment Manual. 
 
Administer the Since Last Visit C-SSRS. 
 
7.3.3 Integrative Sessions 
After each Experimental Session, three Integrative Sessions will take place. Each session will 
consist of 90 minutes of therapy.  
 
Treatment 1 
 
Integrative Session 1.1 (Visit 6): morning after Experimental Session 1 (Visit 5). 
 
Integrative Session 1.2 (Visit 7): ~1 week (3 to 14 days) after Experimental Session 1 
(Visit 5). 
 
Integrative Session 1.3 (Visit 8): ~2 weeks (10 to 21 days) after Experimental Session 1 
(Visit 5). This visit serves two purposes: to continue integration and to prepare for the 
next Experimental Session. 
Treatment 2 
 
Integrative Session 2.1 (Visit 10): morning after Experimental Session 2 (Visit 9). 
 
Integrative Session 2.2 (Visit 11): ~1 week (3 to 14 days) after Experimental Session 2 
(Visit 9). 
 
Integrative Session 2.3 (Visit 12): ~2 weeks (10 to 21 days) after Experimental Session 2 
(Visit 9) This visit serves two purposes: to continue integration and to prepare 
participants in Group 1 (3-Session Group) for the next Experimental Session. 
Treatment 3 (3-Session Group only) 
 
Integrative Session 3.1 (Visit 14): morning after Experimental Session 3 (Visit 13) 
 
Integrative Session 3.2 (Visit 15): ~1 week (3 to 14 days) after Experimental Session 3 
(Visit 13). 
 
Integrative Session 3.3 (Visit 16): ~2 weeks (10 to 21 days) after Experimental Session 3 
(Visit 13). This visit will be the final Integrative Session prior to entering the Post-
Treatment Period. 
 
During Integrative Sessions, the therapy pair will: 
 
 
Record the session. 


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 
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 10.0 
Safety. 
 
Inquire about concomitant medication use and adherence. 
 
Discuss and review events that occurred with the participant during the Experimental 
Session, including thoughts, feelings, and memories. If necessary, the therapy pair will 
help the participant to reduce any residual psychological distress they are experiencing. 
The therapy pairs 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 pairs will be supportive, 
validate the experience, and facilitate understanding and emotional clearing. 
 
Be accessible for additional support via phone or telemedicine if needed. 
 
7.4 Post-treatment Period and Study Termination 
7.4.1 Post-treatment Period 
After the last Integrative Session, participants will enter follow-up for approximately 4 weeks 
with no protocol required visits until the Outcome CAPS-5 T2 assessment. This assessment will 
also include the SDS and the DSP-I. Participants will have access to therapy pairs for support if 
needed, and additional visits via phone, telemedicine, or in person can be scheduled if requested. 
Participants will continue to comply with protocol requirements for concomitant medications 
until after Study Termination. 
 
Participants will be scheduled for an in-person visit within 1 to 7 days after the CAPS-5 T2, 
where qualified site staff will arrange the post-treatment blood draw, administer the MAPS-
Adapted C-SSRS (Since Last Visit), and actively support participants in the completion of the 
self-reported outcome measures.  
o WHOQOL-BREF 
o AAQ-II 
o SCS 
o BPAQ-SF 
o PCL-5 
o MIES 
o BDI-II 
o CPGS 
o PTGI 
o UFEC 
o AUDIT 
o DUDIT 
 
Participants in the two Experimental Session group will have a second outcome evaluation (T2.2, 
Visit 15) timed to be concurrent with those who completed three Experimental Sessions, 
approximately 4 weeks after their first post-treatment assessment at T2 (Visit 13). A blinded IR 
from the IR Pool will conduct the assessments via telemedicine. These assessments may be 
recorded to establish inter-rater reliability. Participants will be instructed to withhold from 
sharing with the IRs their progress in the study including how many visits or Experimental 
Sessions they have had. 
 
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 the SDS. 
 


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Following post treatment assessment, participants will engage in post treatment planning with the 
treatment team and are no longer required to comply with requirements related to concomitant 
medication or other forms of therapy. 
 
7.4.2 Study Termination 
Study Termination will take place 1 to 7 days after the final CAPS-5 assessment. 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 10.0 
Safety. 
 
Inquire about concomitant medication use and adherence. 
 
Measure weight (used to calculate BMI). 
 
Measure blood pressure. 
 
Administer the MAPS-Adapted C-SSRS (Since Last Visit). 
 
Support the participant in the completion of the PCL-5 and BDI-II (2-Session Group 
only). 
 
Provide and discuss a Post-Study Plan. 
 
Actively support participant in completion of Study Termination self-reported measures. 
 
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 a Post-Study Plan, which may include a referral for additional medical or 
therapeutic care, as described in Section 7.4.3 Post-Study Plan. 
 
7.4.3  Post-Study Plan 
At Study Termination, participants will be provided with a Post-Study Plan. This 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 a Post-Study Plan at their last contact. Screen Failures will be provided a referral if 
requested. 
 
8.0 Investigational Medicinal Product 
8.1 Description of Active Compounds 
The Active Pharmaceutical Ingredient (API) to be used in this protocol is MDMA (as 
hydrochloride salt). This ring-substituted phenethylamine has a complex pharmacology, but it 
acts most prominently as a monoamine releaser and re-uptake inhibitor. Its direct actions on 
serotonergic, adrenergic, and other receptors are considerably lower. Refer to the IB for a 
comprehensive review of the pharmacology effects and proposed mechanisms of action of the 
investigational Medicinal Product (IMP). Mannitol and magnesium stearate serve as inactive 
excipients. All capsules are HPMC. MDMA HCl is referred to throughout as MDMA. 


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8.1.1 Doses 
This study will compare the effects of two versus three manualized Experimental Sessions of 
therapy assisted by divided doses of MDMA. Initial doses per Experimental Session include 120 
mg MDMA HCl, followed 1.5 to 2 hours later by a supplemental dose (40 mg MDMA HCl). 
Total amounts of MDMA HCl to be administered per Experimental Session range from 120 to 
160 mg. Refer to Table 2: Dose Regimen of MDMA. 
 
8.1.2 Stability 
IMP was manufactured and packaged according to Good Manufacturing Practices (GMP). 
Stability studies for the IMP are ongoing. All required Chemistry Manufacturing and Control 
(CMC) submissions will be made to the IND. 
 
8.2 Handling 
8.2.1 Encapsulation, Packaging, and Labeling 
Each package will be an open-label container that will be used as bulk presentation at the study 
site. Each dose of MDMA can be dispensed by the Schedule I license holder or designee. 
Additional doses of MDMA that are not administered to a participant will be kept in the open-
label container for administration in future sessions or to other participants.   
 
All labels will comply with local, state, and federal regulations. Each Package will be labeled 
with a protocol number, IMP name, lot number, sponsor name and contact information. A 
statement that the IMP is restricted to clinical trial use only will be included on each package. All 
labels will comply with US regulations. 
 
8.2.2 Accountability 
Forms will be provided to track IMP accountability and administration throughout the study. 
Open-label IMP accountability and administration logs will be reviewed by the sponsor. MDMA 
will be accounted for per capsule dispensed, based on the doses to be administered at each 
Experimental Session for any given participant. IMP will be handled in accordance with all local, 
state, and federal regulations and forms pertaining to the use of Schedule I controlled substances, 
and forms will be maintained by the appropriate controlled substance license holder or delegate. 
 
8.2.3 Storage 
MDMA is a controlled substance and will be stored securely and handled in compliance with all 
relevant federal, state and local regulations. In accordance with these requirements, the 
appropriate license holder or designee will be responsible for storing, dispensing, and 
administering the MDMA.  
 
8.2.4 Administration 
IMP 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 withheld or 
declined. Each dose (initial and supplemental) will be administered with a glass of water. 
 


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A person at the site authorized to manage and administer controlled substances will dispense the 
appropriate number of capsules for each Experimental Session. 
 
Records pertaining to the use of scheduled, regulated compounds will be maintained in 
accordance with relevant federal, state, and local regulations. 
 
8.2.5 Treatment Compliance 
Compliance to protocol required doses will be guaranteed by the person licensed to manage and 
administer controlled substances for Experimental Sessions at each site. All administered doses 
will be recorded for IMP accountability. The IMP will be stored securely per regulations. 
 
8.3 Randomization and Participant Numbering 
Every potential participant who is prescreened by telephone according to the IRB-approved script 
will be assigned a Screening Number by the site. This Screening Number should be recorded on 
the Screening Log.  
 
Each participant who passes pre-screening and is scheduled to complete Screening assessments 
will be assigned a ten-digit alphanumeric Participant Number. Eligible participants will be 
enrolled in the study and sequentially assigned an identification number. One character of this 
Participant Number will be updated for participants who reach Enrollment Confirmation at Visit 
4. Please see the MPVA6 Study Operations Manual for taxonomy details. All participants will 
also be assigned a unique participant identifier within the database for use in analysis. 
 
Participants will be randomized in 1:1 allocation to two versus three sessions of MDMA-assisted 
therapy. 
 
8.4 Blinding and Bias Minimization 
Eligibility will be determined by review of screening by the PI, site team and Sponsor Medical 
Monitor prior to enrollment. 
 
To further minimize bias in measuring effectiveness, the sponsor will use an observer-blind, 
centralized, reliable IR pool to administer the Primary Outcome measure via live video 
interviews. The IR Pool will have no knowledge of AEs and will only evaluate participants at 
Baseline and at the assessments scheduled after each Experimental Session. The IR Pool is 
blinded to full study design, visit number, treatment assignment, number of treatments, and any 
data from the treating therapy pair after Baseline. IRs will be assigned to participants based on 
availability. Participants will be instructed to withhold study progress from IRs. Timing of CAPS- 
5 assessments are pre-specified in the study protocol within visit windows. 
 
To ensure that all participants regardless of group assignment are treated in a similar manner, the 
sites will be required to follow the protocol and Treatment Manual delineating minimum length 
of time per visit type and describing delivery of treatment. All Experimental Sessions are required 
to be at least 6 to 8 hours long. Adherence to the Treatment Manual will be randomly checked by 
review of video by blinded Adherence Raters. The sponsor will monitor data in real-time to 
ensure complete data collection for all participants, including those who discontinue treatment. 
Sites will be required to make and document a specific number of attempts to obtain follow-up 
data per protocol. All randomized participants who receive at least one dose of IMP and complete 
at least one follow-up assessment will be included in the final mITT set. 
 


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The Safety Review Committee will act in an advisory capacity to the site to monitor participant 
safety, data quality, and review outcomes to ensure the trial is conducted safely, ethically, and 
meets endpoint objectives. 
 
9.0 Risks 
9.1 Non-drug Related Risks 
9.1.1 Medical Assessments 
In preparation for MDMA-assisted therapy 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. 
 
9.1.2 PTSD, Suicide Risk, and Therapy 
During Screening, throughout MDMA-assisted therapy, 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 therapy sessions. Therapy is conducted as part of this study, and people 
undergoing therapy are expected to confront unpleasant thoughts, feelings, and memories in the 
process. Because therapy is an integral part of the research study design, the potential distress 
arising from therapy is unavoidable. Therapy pairs will provide emotional support to participants 
during any psychological distress. 
 
The therapy pair 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 pair, and Medical Monitor. 
 
A qualified individual will administer the C-SSRS according to the Time and Events-Study 
Measures Table, and as needed depending on clinical presentation of the participants, to monitor 
for development and intensity of suicidal ideation and/or behavior. The therapy pair will 
implement the following plan to assess elevated or imminent suicide risk. 
 
If the C-SSRS or other clinical information 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. 


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b. Regular check-ins via phone or in-person will be continued until the participant 
has stabilized or a new course of action is taken based on changes in C-SSRS 
score and/or ongoing clinical assessment. 
c. Notification of the sponsor within 24 hours of this event and provide a narrative 
for the AE for expedited reporting to FDA. Increases in suicidality will be 
captured as an AESI per Section 10.1.1 Adverse Events of Special Interest and 
evaluated for seriousness. SAEs will be reported per regulatory guidance. 
d. Treatment would be continued when deemed appropriate by the investigator and 
Medical Monitor, unless it is determined that treatment should be discontinued, 
in which case the participant will enter follow-up. 
2. If the participant has suicidal ideation, and a plan to commit suicide (Suicidal Ideation 
Score=5) or positive Suicidal Behavior (Score greater than or equal to 1), the individual 
administering the C-SSRS will assess whether the risk is imminent. A Suicidal Ideation 
score of five does not necessarily indicate an immediate risk if the thoughts are fleeting, 
fairly easily controlled, and deterrents are strong. If there is no imminent risk, the 
individual will follow the procedure described above. If there is imminent risk of suicidal 
behavior, the individual will ensure: 
a. Participants are evaluated by the investigator or site physician to determine an 
appropriate course of action, and the therapy pair 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 
pair will do one of the following: 
i. If on site with the participant, escort them to the ED; 
ii. If not on site with the participant (e.g., telephone or telehealth 
appointment), 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 
VA police if on site. Explain that the participant is in immediate danger of 
committing suicide. Provide a complete description of the participant and give 
any other needed details to ensure the participant’s safety. 
d. Notification of appropriate members of the study team and sponsor 
representatives within 24 hours, provide a narrative for the AE for expedited 
reporting to FDA. 
e. The event will be collected as an AESI per Section 10.1.1 Adverse Events of 
Special Interest and seriousness will be evaluated. SAEs will be reported per 
regulatory guidance. 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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9.1.3 Recorded Content 
All therapy 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. 
 
9.2 Risks of Receiving MDMA 
Study procedures and eligibility criteria have been developed based on Phase 2 and Phase 3 
PTSD clinical trials which exclude potential participants with pre-existing exclusionary medical 
conditions that would exacerbate risk. The therapy pairs and site physicians are available via 
telephone 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 should be immediately available by telephone, and based on assessment of the 
situation, they should make the decision to either evaluate the participant themselves at the site or 
arrange for transfer of the participant to the Emergency Department. 
 
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). 
 
9.2.1 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. 
 
9.2.2 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. 
 
9.2.2.1 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 and Phase 3 
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 and Phase 
3 studies of MDMA-assisted therapy detected a dose-dependent increase in systolic blood 


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pressure and to a lesser extent diastolic blood pressure. Characterization of sympathomimetic 
effects among participants with controlled hypertension is ongoing. 
 
Risks posed by elevated blood pressure are addressed by excluding people with pre-existing 
uncontrolled hypertension and monitoring blood pressure and pulse, as described in Section 3.2 
Exclusion Criteria. Before and after IMP administration in Experimental Sessions, the therapy 
teams monitor vital signs. The therapy teams should attend to clinical signs and symptoms of 
potential rare complications of the cardiovascular effects of MDMA, such as stroke or acute 
myocardial infarction (AMI). during Experimental Sessions. Any symptoms such as chest pain, 
shortness of breath, neurological deficit or confusion or other potential indicators of end organ 
effects should prompt additional vital sign measurements, and intervention if appropriate. 
Therapy teams should notify the site physician if this occurs for evaluation. 
 
If any participant has neurological deficits, as assessed by the site physician, whether or not they 
are associated with hypertensive crisis, they should be monitored (as described above) and a rapid 
response team should be called if medically indicated. If evaluation at the hospital reveals a 
nonhemorrhagic stroke, there will be sufficient time to administer recombinant tissue 
plasminogen within the 3-hour time frame recommended in the American Academy of 
Neurology/American Heart Association guidelines [112]. 
 
If a participant experiences ischemic type chest pain, whether or not it is associated with 
hypertensive crisis, the study physician will be contacted immediately, and a rapid response team 
will be called to assess the patient and act in accordance with the assessment of the expert on site 
supported by national and local/AHA and European Society of Cardiology (ESC) Guidelines. 
Pending transport to the hospital the site team may take any measures ordered by the site 
physician including administering medication such as aspirin or nitroglycerin or providing 
supplemental oxygen per local standards. 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, 
and will be followed up for safety. 
 
QT interval will be evaluated in the event of hospitalization for management of cardiovascular or 
cerebrovascular event. If at any time a participant develops a QT/QTc interval > 450 ms or of >30 
ms over Baseline during ECG evaluation, the participant should be discontinued from treatment. 
 
9.2.2.2 Psychological Risks and Mitigation 
MDMA may expose or exacerbate any underlying psychological distress, which could arise from 
the onset of MDMA effects until the last effects have dissipated, or even later. 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 clinical 
studies, these symptoms have been self-limiting and have responded well to reassurance from the 
therapy pair, with occasional use of benzodiazepines for anxiety. In this study, participants will 
have the intention of confronting and working through traumatic experiences. 
Accordingly, signs of psychological distress, panic, or other unpleasant psychological reactions 
are to be expected and may be considered an element of the psychotherapeutic process. 
 


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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 therapy 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 pair upon request or at the 
appearance of signs of a potential SAE. 
 
During the Preparatory Sessions, participants should be made aware of the fact that difficult 
emotions, including grief, rage, fear, or panic, may arise during Experimental Sessions. Every 
effort should 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 pair 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 therapy session, at least one 
member of the therapy pair will remain with the participant for at least 2 more hours. During this 
time, the therapy pair 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 pair will decide between the following options: 
 
1. If severe distress occurs at the end of an Experimental Session, a nurse, therapeutic 
assistant, physician, or therapy pair member should stay with the participant until the 
severe distress resolves or until the time of their Integrative Session appointment the 
following morning. The therapy pair should 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 site 
physician may prescribe a benzodiazepine (specifically, lorazepam) and/or sleep aid (e.g., 
zolpidem). The route, frequency, and dose should be determined by the site physician. If 
these medications are stocked on site, they should be stored according to applicable 
national and local regulations. This medication will be captured on the Concomitant 
Medications eCRF. The site physician should not prescribe an SSRI, SNRI, or 
monoamine oxidase inhibitor (MAOI) in this context, unless it has been determined that 
the participant will be withdrawn from the study. Residual symptoms will be addressed 
during the frequent follow-up therapy visits with the therapy pair. 
3. If a participant should become psychotic, arrangements should be made to stabilize them 
or transfer them to the Emergency Department if hospitalization is necessary. Any 
participant who is hospitalized after a severe psychological reaction will be suspended 


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from the protocol until after recovery or stabilization, at which time the investigator 
and/or site physician will carefully evaluate the participant’s emotional status. 
 
For those participants engaged in an ongoing therapeutic relationship with a therapist or 
psychiatrist, the participant’s outside therapist(s) should be involved in the management of any 
psychiatric complications. For those participants engaged in an ongoing therapeutic relationship 
with the investigator or member of the therapy pair, the management of any psychiatric 
complications should be undertaken by them in their capacity as the participant’s therapist. 
 
9.2.3 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. 
 
9.2.3.1 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 and Phase 3 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 should 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 
should 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 should be consulted for further evaluation and treatment. 
 
9.2.3.2 Osmoregulatory Risk and Mitigation 
MDMA administered in a controlled setting is not expected to have any risks of osmoregulatory 
changes. Participants are not allowed to drink more than three liters of water 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 should not receive another Experimental 
Session unless it is approved by the investigator, site physician, and the Medical Monitor. 
 
9.2.3.3 Genotoxicity Risk and Mitigation 
The standard genotoxicity battery for MDMA has demonstrated that MDMA is negative for in 
vitro and in vivo genotoxicity, both with and without metabolic activation. 
 
9.2.3.4 Reproductive and Developmental Risks and Mitigation 
There are no data from the use of MDMA in pregnant women. In the absence of these data, 
epidemiological studies of Ecstasy are the only source of human data. One of two studies of 
Ecstasy users suggests that use of Ecstasy and polydrug use during pregnancy may be associated 
with some abnormalities at birth while the other failed to find this association [115, 116]. 


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Studies in rats and rabbits have not shown direct or indirect harmful effects with respect to 
reproductive toxicity. Repeated dose toxicity studies of adequate duration, fertility, early 
embryonic development, and embryofetal development studies of MDMA with toxicokinetics 
have been completed. These studies established the “no-observed-adverse-effect level” (NOAEL) 
dose to be excluded the highest dose level evaluated at ≤10 mg/kg/day (supratherapeutic dose) in 
both sexes of the rat for fertility, reproductive performance, and for maternal and developmental 
toxicity in the rabbit. The NOAEL dose was the highest dose level evaluated at ≤15 mg/kg/day 
(supratherapeutic dose) for maternal and developmental toxicity in the rat. Due to the short half-
life and single-dose dosing regimen of MDMA, pre- and post-natal development studies are not 
considered necessary for assessment of risk to the unborn. Assessment of embryofetal risk based 
on all available non- clinical and clinical data supports unlikely human teratogenicity/fetotoxicity 
in early pregnancy. On the basis of male fertility studies, the embryofetal risk posed from 
treatment of male participants with MDMA is also unlikely. 
 
People who are able to become pregnant are included in the studies in this program, defined as 
those who are fertile, following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. Postmenopausal state is defined as no menses for 12 
months without an alternative medical cause. As a precautionary measure in clinical trials, 
participants who are able to become pregnant must have a negative pregnancy screen before 
undergoing each Experimental Session, which are conducted in monthly intervals, and must agree 
to use adequate contraception at least for the duration of the study during the Treatment Period 
which is 10 days post the last dose of MDMA. The end of relevant systemic exposure to MDMA 
is approximately 48 hours [117]. 
 
9.2.4 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. 
 
9.2.4.1 Common Expected AEs 
Common expected AEs were typically observed during Experimental Sessions, but were transient 
and typically diminished as the MDMA was metabolized and excreted over the next 72 hours 
after dosing. In the Phase 3 study MAPP1, the most common adverse events reported more 
frequently reported in the MDMA group were muscle tightness, decreased appetite, dizziness, 
nausea, hyperhidrosis, feeling cold, restlessness, mydriasis, dizziness (postural), bruxism, 
nystagmus, increased blood pressure, feeling jittery, chest pain (non-cardiac), dry mouth, vision 
blurred, pollakiuria, intrusive thoughts, vomiting, stress, and musculoskeletal chest pain. AEs 
were typically self-limiting. 
 
9.2.4.2 Neurotoxicity Risk 
It does not appear that MDMA-assisted therapy negatively impacts cognitive function based on 
data from Phase 2 studies sponsored by MAPS. 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. 
 


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9.2.4.3 Abuse Potential 
Despite its classification as a Schedule I drug, an examination of 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. There have been no AESIs reported in Phase 2 and Phase 3 studies 
that could be suggestive of abuse potential among research study participants treated with 
MDMA. Diversion is not an issue for sponsor-supported studies because MDMA is only 
administered under the supervision of the clinical investigator and no take-home doses are 
permitted. MDMA administration and handling follows all regulations pertaining to the use of 
controlled substances within research studies. 
 
Studies assessing prevalence of problematic Ecstasy use or dependence suggest that a small 
percentage of individuals, especially those with prior psychological difficulties, may develop 
problematic Ecstasy use or dependence. An observational long-term follow-up assessment 
conducted at least 12 months after participation in a MAPS-sponsored early Phase 2 PTSD study 
of MDMA-assisted therapy found that 8.7% (8 of 92) participants reported using Ecstasy 
subsequent to study participation, with 6 of these 8 participants having used Ecstasy prior to study 
enrollment. Several participants volunteered that they would not seek out MDMA outside of a 
psychotherapeutic setting. 
 
10.0 Safety 
10.1 Adverse Events 
In accordance with guidance for the specific study site, FDA Safety Reporting Requirements for 
INDs and BA/BE Studies, an Adverse Event (AE) is defined as any medical occurrence in a 
participant, including any abnormal sign (e.g., abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the participant’s involvement in the research, 
whether or not considered related to participation in the research. This definition includes 
concurrent illnesses or injuries and exacerbation of pre-existing conditions. 
 
Events related to planned treatments or physician visits for Baseline conditions collected in the 
medical history will not be collected, unless there is an exacerbation of the condition, in which 
case they will be actively followed until resolution. 
 
An unexpected AE is one that is not listed in the current IB or an event that is by nature more 
specific or more severe than a listed event. 
 
The site physician will be responsible for reviewing and confirming all AEs and SAEs collected 
during the study. The therapy pairs will collect AEs during study visits from Enrollment (Visit 0) 
through Study Termination. Participants will be asked directly how they are feeling during each 
contact, and AEs may be captured spontaneously during therapy 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 pair 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. 
 


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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 seriousness and relationship of study treatment to an AE will be determined by the 
Investigator based on the following definitions: 
 
1. “Not Related”: The AE is not related if exposure to the investigational product has not 
occurred, or the occurrence of the AE is not reasonably related in time, or the AE is 
considered unlikely to be related to use of the investigational product, i.e., there are no 
facts (evidence) or arguments to suggest a causal relationship, or the AE is more likely 
related to the subject’s pre-existing condition. 
2. “Related”: The administration of the investigational product and AE are considered 
reasonably related in time and the investigational product is more likely than other causes 
to be responsible for the AE or is the most likely cause of the AE. 
 
10.1.1 Adverse Events of Special Interest 
In accordance with the guidance Clinical Safety Data Management Definitions and Standards for 
Expedited Reporting ICH Topic E2A: Guidance for Industry or FDA Safety Reporting 
Requirements for INDs and BA/BE Studies, the sponsor will pay special attention to a subset of 
AEs. 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 cardiovascular risk for the IMP in the intended patient population that 
could be indicative of QT interval prolongation or cardiac arrhythmias, including Torsade de 
pointes, sudden death, ventricular extrasystoles, ventricular tachycardia, ventricular fibrillation 
and flutter, non-postural syncope, and seizures. 
 
The subset of AEs involving suicide risk under the following terms are also of special interest: 
 
 
Suicides 
 
Suicide attempts 
 
Self-injurious behavior associated with suicidal ideation 
 
Suicidal ideation scores of 4 or 5 on the C-SSRS 
 
Suicidal ideation judged to be serious or severe in the opinion of the investigator 
 
These AEs will be marked in the eCRF with the denotation “Adverse Event of Special Interest” 
(AESIs) whether serious or non-serious. 
 
In order to assess signals of abuse potential for the IMP in the intended patient population: 
 
 
AESIs involving the terms of Behavioral addiction, Drug abuser, Substance abuser, 
Dependence, Intentional product misuse, Overdose (accidental, intentional, or 
prescribed), or Drug diversion in cases that are related to MDMA or “Ecstasy” (material 
presented as MDMA) will be collected and coded as AESIs in the eCRF. 
 
Cases of noncompliance, protocol violations, participants lost to follow-up, and any other 
reasons why participants dropped out of the study will be assessed for presence of AESIs; 


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 
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 or if it involves suicide risk, it should be reported via the eCRF within 24 
hours of the site’s awareness of the event. 
 
10.1.2 Serious Adverse Events 
In accordance with guidance Clinical Safety Data Management Definitions and Standards for 
Expedited Reporting ICH Topic E2A: Guidance for Industry or FDA Safety Reporting 
Requirements for INDs and BA/BE Studies, an SAE is defined as any untoward medical 
occurrence that at any dose: 
 
 
Results in death. 
 
Is life-threatening (i.e., the participant was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
 
Requires or prolongs inpatient hospitalization. 
 
Results in persistent or significant disability/incapacity (i.e., the event causes substantial 
disruption of a person’s ability to conduct normal life functions). 
 
Results in a congenital anomaly/birth defect. 
 
Requires intervention to prevent permanent impairment or damage. 
 
Is an important and significant medical event that may not be immediately life- 
threatening or resulting in death or hospitalization, but based upon appropriate medical 
judgment, may jeopardize the participant or may require intervention to prevent one of 
the other outcomes listed above. 
 
AEs which do not fall into these categories are defined as non-serious. It should be noted that a 
severe Adverse Event need not be serious in nature and that a SAE need not, by definition, be 
severe. 
 
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 the time of informed consent through Study Termination. All 
SAEs which occur during the course of the trial, whether considered to be associated with IMP or 
not, must be reported to the sponsor within 24 hours of the site staff’s awareness of occurrence. 
Reporting procedures will be provided to the site. All SAEs will be assessed for relationship, 
expectedness and any required actions to address safety at the time of reporting of the event. 
SAEs will be evaluated by the site physician and Medical Monitor to determine if it is appropriate 
for the participant to continue treatment or enter follow-up. Any participant who experiences a 
SAE considered related to the IMP administration will be permanently discontinued from future 
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10.2 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. 
 
10.3 Pregnancy 
10.3.1 Definition of ‘Able to Become Pregnant’ 
A participant is considered able to become pregnant if they were assigned female at birth and are 
post-menarche. A participant is considered not able to become pregnant if they are premenarchal, 
surgically sterile (documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy, 
and/or tubal ligation), postmenopausal, or assigned male at birth. 
 
10.3.2 Contraception Guidelines 
Study participants who were assigned male at birth with partners who are able to become 
pregnant will not be required to practice contraception. Adequate contraception is required for all 
participants of who are able to become pregnant, regardless of sexual activity, sexual orientation, 
or the sex of their partner. Abstinence from penile-vaginal intercourse is not an adequate 
contraception plan by itself; participants must agree to a back-up method (e.g., condoms with 
spermicide) if they do choose to engage in penile-vaginal intercourse. It is recommended to stock 
condoms with spermicide at the study site to provide to participants if they need them. Adequate 
contraception methods 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 
 
For questions about acceptable contraception methods, contact the Medical Monitor. 
 
10.3.3 Follow-up Requirements 
Details of all pregnancies in study participants will be collected after Enrollment (Visit 0) and 
collected through 10 days after the last Experimental Session. Pregnancies should be reported to 
the sponsor via telephone or email within 24 hours of site staff awareness. 
 
In the event of a pregnancy, the participant will discontinue Experimental Sessions but may 
continue with non-drug Integrative Sessions, the next CAPS-5 assessment, and Study 
Termination procedures. At a minimum, prior to withdrawal from the study, efforts should be 
made to assess the final CAPS-5 immediately and complete Study Termination procedures. The 
participant will be emergency unblinded if the participant wishes as described in Section 8.4 
Blinding and Bias Minimization, after the final CAPS-5 assessment. 
 


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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. 
 
 
10.4 Medical Monitor 
The name and contact information for the Medical Monitor is:  
 
Kelly Green, PA-C, MPH 
Associate Medical Director, MAPS Public Benefit Corporation 
Email: kelly.green@mapsbcorp.com 
Phone number: 877-748-3767 
 
Medical Monitor contact information will also be provided in a separate contact list. 
 
11.0 Concomitant Medications 
11.1 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. 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 11.2 Allowed Concomitant Medications). The prescribing 
physician’s opinion about medication discontinuation will be documented either in writing from 
the prescribing physician, or in writing by the site physician documenting phone contact with the 
prescribing physician. Tapering will follow a time course appropriate for the medication based on 
its half-life, with the Baseline CAPS-5 T1 (Visit 3) scheduled to occur after complete washout for 
psychological medications and Experimental Session 1 (Visit 5) scheduled to occur after 
complete washout for medications with drug-drug interactions without a psychological concern 
(five half-lives plus at least 1 week for stabilization). 
 
The therapy pair 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. 
 


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Participants may return to taking psychiatric medications and discontinue contraception after the 
final Study Termination visit if necessary. 
 
11.2 Allowed Concomitant Medications 
The site physician may prescribe necessary and appropriate medications in accordance with local 
and state regulations during the study to treat AEs that do not respond to other management 
outlined in the Treatment Manual. Examples include concomitant benzodiazepines for 
uncontrolled anxiety (for example, lorazepam at modest doses and occasional use only to avoid 
withdrawal effects of discontinuation between Experimental Sessions) or sleep aids (excluding 
trazodone) in compliance with Section 11.3 Prohibited Medications. 
 
Gabapentin or certain opiates will be allowed when prescribed for pain management. The 
following opiates will be allowed during the study: hydrocodone, morphine, and codeine. Prior to 
randomization, participants who are taking opiates not included on this list will be cross-tapered 
to an allowable opiate under the care of their prescribing physician. Opiate medications may 
reduce the efficacy of MDMA and may prolong QT/QTc interval, but the opiates that are allowed 
during this trial have been selected because they have the lowest potential for QT/QTc interval 
prolongation. Individuals using opiates for pain management will be asked to decrease the dose 
leading up to the Experimental Session in order to avoid withdrawal effects when they are 
required to refrain from taking the medication from 12 hours before IMP administration at the 
Experimental Session to 24 hours after. During this period, the participant will be allowed to take 
the medication if needed for intolerable pain flare-ups or to prevent withdrawal symptoms. If a 
participant reports lack of analgesic effect during the sub-acute period following each 
Experimental Session, the site physician may approve taking an allowed opiate medication sooner 
than 24 hours after IMP administration. 
 
If the participant is on stimulants for Attention Deficit/Hyperactivity Disorder (ADHD) at 
Baseline, they can continue to use them at the same dose and frequency, as long as they 
discontinue five half-lives before each Experimental Session and do not restart for 10 days after 
each Experimental Session. 
  
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. 
 
11.3 Prohibited Medications 
To be enrolled in the study, participants must: 
 
 
Refrain from the use of any psychoactive medication not approved by the research team 
from Baseline through Study Termination (with the exception of gabapentin or certain 
opiates for pain control). 
 
Be willing to comply with all medication requirements per protocol. Medications will 
only be discontinued after enrollment per clinical judgment of the site physician in 
consultation with the prescribing physician. 
 
Agree that, for 1 week preceding each Experimental Session they will refrain from: 
o Taking any specified herbal supplement (except with prior approval of the 
research team). 
 
Agree that, for 5 half-lives of the medication preceding each Experimental Session they 
will refrain from: 


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o Taking any nonprescription medications (with the exception of non-steroidal 
anti-inflammatory medications or acetaminophen) unless with prior approval of 
the research team. 
o Taking any prescription medications (with the exception of birth control pills, 
thyroid hormones, or other medications approved by the research team). 
 
Use of Marijuana, St. John’s Wort, and other herbs and medicines with notable serotonergic 
effects are prohibited from Baseline to Study Termination. Any investigational treatments under 
study for PTSD treatment are prohibited from use concurrent with this study. 
 
Diphenhydramine is excluded from this study unless prior approval is granted by the site 
physician. 
 
If an SSRI, SNRI, MAOI, or other antidepressant is used between Experimental Session 1 (Visit 
5) and Study Termination, 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. Participants whose Experimental Sessions are 
delayed by the COVID-19 pandemic may start any of these medications during the delay, as 
clinically indicated. When study visits resume, they will be given the option to resume 
Experimental Sessions after tapering off of these medications, per the tapering plan described 
above. 
 
12.0 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 


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 
CBC 
o Hematocrit 
o Hemoglobin 
o Mean corpuscular volume (MCV) 
o Mean corpuscular hemoglobin (MCH) 
o Mean corpuscular hemoglobin concentration (MCHC) 
o Red cell distribution width (RDW) 
o Percentage and absolute differential counts 
o Red blood cell (RBC) count 
o White blood cell (WBC) count 
 
Urinalysis 
o Color 
o Appearance 
o Specific gravity 
o pH 
o Protein 
o Glucose 
o Ketones 
o Occult blood 
o Leukocyte esterase 
o Nitrite 
o Bilirubin 
o Urobilinogen 
 
Thyroid function 
o Thyroid-stimulating hormone (TSH) high sensitivity (if abnormal, free T3 and 
T4 will also be tested) 
 
HCV if indicated 
 
%Carbohydrate deficient transferrin (%CDT) to detect heavy alcohol use 
 
Urine-dip pregnancy test for participants who are able to become pregnant 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). 
 
13.0 Statistical Considerations 
Key personnel, MAPS, and the biostatistician will agree on a Statistical Analysis Plan prior to 
database lock, 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. 
 
13.1 Power and Sample Size Determination 
In this equivalence design the primary hypothesis is a comparison of 3 sessions of MDMA with 
therapy versus 2 sessions of MDMA with therapy. The internal validity of this study is predicated 
upon data already established and approved by the FDA showing that 3 sessions of MDMA with 
therapy has proven superiority over placebo in the treatment of PTSD. Therefore, it is appropriate 
to compare the effectiveness of the experimental arm of 2 sessions of MDMA to the effectiveness 
of the previously established 3 doses in order to test an equivalence hypothesis. If the null 
hypothesis is rejected, the alternative hypothesis will be accepted which states that 2 sessions of 


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MDMA shows equivalent efficacy as 3 sessions. The measure of effectiveness is the change from 
baseline in the CAPS-5 Total Severity Score. In this equivalency design the "zone" of 
equivalence is a pre-defined region above or below the difference in mean changes in the CAPS-5 
Total Severity Score in the arm given 3 sessions of MDMA. In a previous study, MP16, it was 
reported that the mean change in baseline among 29 participants with PTSD who were given 3 
sessions of MDMA experienced a mean reduction of 30.7 in the CAPS-5 Total Severity Score, 
with a standard deviation of 12.7. Therefore, the "zone" of equivalence in this study is defined as 
a mean change in the CAPS-5 Total Severity Score in the arm given 2 sessions of MDMA that is 
within 11 points of the mean change in that seen in the arm given 3 sessions. If similar results are 
observed as those seen from the sponsor’s 3 session MP16 study, we would conclude equivalence 
if the difference in mean changes in CAPS-5 Total Severity Score in the arm given 2 sessions of 
MDMA was as low as -19.7 to as high as -41.7. Assuming that in the population of PTSD 
patients there is no difference in the mean change in CAPS-5 Total Severity Score when given 2 
sessions of MDMA or 3 sessions of MDMA, with alpha level set at 5%, power set to 90%, the 
sample size of this study is 30 participants per arm. 
 
13.2 Statistical Analyses 
Descriptive statistics will be computed overall, as well as by MDMA-assisted session condition, 
for all available data from outcome measures, time course of onset of treatment effect and 
including minimum, maximum, average, median, and standard deviation. 
 
The following analysis sets are defined for this study: 
 
 
All Enrolled: all participants who sign informed consent and are initially enrolled 
 
mITT: all randomized participants who receive Investigational Product in at least one 
Experimental Session and have at least one follow-up CAPS-5 assessment 
 
Per Protocol (PP): all randomized participants who receive Investigational Product in 
assigned number of Experimental Sessions (depending on randomization group) and have 
completed post-treatment 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 IMP 
 
13.2.1 Primary Effectiveness Analysis 
The groups will be compared from T1 (Baseline) to T2 (Primary Outcome Visit) using post- 
treatment mean change in symptom severity, as assessed by the mean change in CAPS-5 Total 
Severity Score. The mean change from baseline to T2 (Primary Outcome Visit) will be 
summarized by treatment group along with confidence intervals.  If the primary null hypothesis is 
rejected, mean change in SDS score from Baseline to T2 (Primary Outcome Visit) will be 
analyzed. In a previous study, MAPP1, it was reported that the standard deviation of the mean 
change in baseline among 37 participants with PTSD who were given 3 sessions of MDMA 11.5. 
Recalculations of the equivalence zone with 90% power provide the "zone" of equivalence for the 
difference in means in this study will be [-10, 10]. 
 
The null hypothesis is formulated as: 
 
  
Ho: (µ1 − µ2 ) ≤  − 10 or (µ1 − µ2 ) ≥  10 
 
The alternative hypothesis is formulated as: 
 


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H1:   − 10 < (µ1 − µ2 ) <  10 
 
The null hypothesis will be tested using the two-one-sided-test (TOST [reference added at end]) 
procedure.  The 90% confidence interval around the difference of the means will be compared to 
the interval of equivalence.  If both of the bounds are inside the equivalence interval, we will 
reject the null hypothesis and conclude the effect of 3 sessions of MDMA with therapy is 
equivalent to the effect of 2 sessions.  If the primary effectiveness hypothesis is rejected, the 
secondary effectiveness hypothesis will be tested. 
 
13.2.2 Secondary Effectiveness Analysis  
The SDS will be analyzed in a similar manner to the primary analysis of the CAPS-5 using an 
equivalence zone of [-2.25, 2.25]. 
 
13.2.3 Exploratory Analyses 
An exploratory responder analysis will further characterize clinical significance of PTSD 
treatment effect in the mITT set after each Experimental Session based on the following 
categories: 
 
 
Treatment Response: 10-point or greater reduction in CAPS-5 Total Severity Score 
 
Loss of Diagnosis: 10-point or greater reduction in CAPS-5 Total Severity Score and no 
longer meeting PTSD diagnostic criteria on CAPS-5 
 
Remission: CAPS-5 Total Severity Score of 11 or less and no longer meeting PTSD 
diagnostic criteria on CAPS-5 
 
The primary effectiveness analysis will be performed in the same method above using the 
CAPS-5 measure from visit T2.2 in the 2 Session treatment group compared to the T2 
Session in the 3 Session treatment group. 
 
Exploratory analyses may be conducted, when possible, to evaluate effectiveness by assigned 
treatment group, actual exposure, and the impact of 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, diagnosis of comorbid depression, 
diagnosis of comorbid psychiatric diagnosis, and number of Experimental Sessions completed) on 
treatment effect. Further details of the exploratory analyses of secondary outcome measures will 
be provided in the Statistical Analysis Plan. 
 
13.2.4 Safety Analyses 
Safety analyses will confirm safety data with summary tables listing exposure to IMP, unsolicited 
AEs, concomitant medications, suicidal ideation and behavior, and vital signs overall and by 
group. If a participant has more than one AE mapped to the same PT, that AE will be reported 
once using the highest severity. AEs that occur on Day 0 (Experimental Session), Day 1, Day 2 
after IMP administration will be presented separately. Assess relative incidence of AEs during 
Experimental Sessions such as clinical signs and symptoms, such as chest pain, shortness of 
breath, or neurological symptoms or any other signs or symptoms that may be indicative of a 
medical complication of the IMP. 
 
Frequency and incidence of concomitant medications will be displayed by generic name, sorted 
by class, and summarized by treatment group, analysis set, and category. Concomitant 
medications taken on Day 0 (Experimental Session), Day 1, Day 2 after IMP administration will 


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be presented separately. Any psychiatric concomitant medications will be tabulated by period 
(Preparatory, Treatment Period, Follow-up Period). Frequency and incidence of positive or 
serious ideation and suicidal behavior will be presented using descriptive statistics of C-SSRS 
scores in tabular format. Vital signs (heart rate, blood pressure, and body temperature) for 
Experimental Sessions will be summarized using descriptive statistics in tabular format listing 
values at pre-IMP administration, prior to the supplemental dose, and at the end of each 
Experimental Session by treatment group. Additional details are available in the Statistical 
Analysis Plan. 
 
13.2.5 Interim Analysis 
An interim analysis may be performed before all participants in the mITT set have completed the 
final CAPS-5 assessment and terminated treatment, including early termination participants who 
have completed their final CAPS-5. The objective of the interim analysis is to assess whether the 
sponsor wants to add additional subjects to the study. Additional details and statistical 
methodology for the sample size re-estimation will be provided in the Statistical Analysis Plan. 
 
13.2.6 Safety Review Committee 
The sponsor will appoint a Safety Review Committee with appropriate expertise in the conduct of 
clinical trials to monitor subject safety information during this study, conduct the interim 
analysis, and make associated recommendations for all reviews. The Safety Review Committee is 
an advisory group commissioned and charged with the responsibility of periodically evaluating 
cumulative safety and other clinical trial data for evidence of safety concern and recommending 
study continuation, discontinuation, or modification. The composition of the Safety Review 
Committee will include clinician experts, MAPS PBC senior management and biostatistician. The 
Safety Review Committee will periodically review safety reports and data on safety outcome 
measures, to assess suitability of continuation of the study.  
 
14.0 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 MAPS PBC, including designing, initiating, managing, coordinating, continuing, and 
concluding the clinical trials within the Clinical Development Program. MAPS PBC is tasked 
with maintaining the quality of study conduct through ongoing monitoring of data and 
participating in writing study publications. MAPS PBC contracts with independent entities who 
represent clinical sites to accomplish these goals. Collectively, MAPS and MAPS PBC are 
referred to as sponsor throughout this document. 
 
14.1 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. 
 
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) before study start. 
Signed and dated documentation of approvals must be provided to the sponsor. Prior to study 
start, the investigator is required to sign a signature page confirming their agreement to conduct 
the study in accordance with these documents and all of the instructions and procedures found in 
this protocol and to give access to all relevant data and records to the sponsor. 


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14.1.1 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. 
 
14.1.2 Informed Consent 
The investigator and therapy pair 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 may be sent the ICF to review after the initial phone screen. Preferably, 
informed consent will be obtained by the therapy pair 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 pair 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 pair 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. Site staff (preferably the therapy 
pair who would be treating this potential participant) will explain and obtain written (or 
electronic) informed consent using the IRB-approved ICF. Written consent must be obtained 
prior to performing any tests or evaluations for the study. The signature may be obtained using an 
electronic 21 CFR Part 11 compliant system due to COVID-19. Discussion about the ICF may 
take place over a telemedicine visit or at the first in-person 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. The signature may 
instead be obtained using an electronic 21 CFR Part 11 compliant system due to COVID- 19.  
 
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 


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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. 
 
14.2 Study Monitoring, Auditing, and Documentation 
Investigators, therapy pairs, and all study staff will be trained prior study start for each site. Study 
sites will be monitored by site visits and telephone calls by representatives of the sponsor. In 
addition, critical data and systemic issues will be subject to centralized monitoring via the EDC 
system to develop and evaluate strategies for correction across sites. Sites will be monitored as 
appropriate for the rate of enrollment to comply with GCP guidelines and to ensure validity of 
study data. During each monitoring visit, source data verification will be performed to ensure 
compliance, including accurate and complete recording of data on eCRFs, source records, and 
IMP accountability records. An eCRF collation will be completed for each participant enrolled 
within the EDC system. 
 
Videos from selected sessions will be reviewed for adherence to the Treatment Manual as 
described in Section 5.4 Adherence to Therapeutic Method. Findings from video reviews may be 
discussed with therapy pairs 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. 
 
14.2.1 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. 
 
14.3 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. If past medical records are needed, participants will sign forms for the release 
of information upon consent to permit screening for protocol enrollment. In accordance with the 
guidance for a specific study site location, Clinical Trials (GUIDE-0068) or FDA E6(R2) Good 
Clinical Practice: Integrated Addendum to ICH E6(R1), all assessment records will be kept in a 
locked file drawer or cabinet in a locked office, and access to measures will be limited to 
regulatory agencies, researchers, and individuals analyzing data. Researchers, other than the 
investigators who are directly involved in the protocol, with access to data will not be provided 
with any information that would identify participants by name or by other means, such as social 


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security number. Only personnel listed on the MPVA-6 Site Responsibilities Log and the MAPS 
PBC Sponsor Delegation Log can have access to documents containing Protected Health 
Information (PHI). 
 
Maintaining data in a secure environment will prevent the accidental or deliberate examination or 
removal of data. The sponsor will utilize confidentiality procedures to assure participant privacy. 
Audiovisual recordings are necessary for sponsor oversight of therapy processes. Any requests 
for use of audiovisual recordings outside of research and training requests will result in 
participants receiving information on the request. Participants will have control over any 
presentation of audiovisual recordings beyond viewing by authorized researchers, sponsor staff, 
or regulatory agencies. The sponsor uses encrypted, secure technology to transfer and store 
recordings, but there is always a risk of a security breach. The sponsor is committed to taking 
preventative measures to avoid such an event. In the case of a security breach, the participant will 
be notified, and all efforts will be made to minimize the dissemination of recorded content. 
  
Clinical trial data other than audiovisual recordings 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. 
 
14.4 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. Participants who previously received therapy from a therapy pair 
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. 
 
14.5 Treatment and Compensation for Study Related Injury 
Some study-related emergencies can be treated by the site physicians. If the site physicians 
cannot treat a study-related emergency, then there are contingency plans for the transport of 
participants to the nearest hospital. Treatment of a study-related emergency would first be billed 
to a participant’s health insurance provider. If the participant's private or employer health 
insurance plan does not cover clinical trial-related claims, then the sponsor will cover any 
treatment costs directly related to the study. The sponsor will not cover costs of ongoing 
treatment unrelated to the study due to pre-existing conditions, or the cost of the participant's time 
spent obtaining treatment for pre-existing conditions before receiving treatment in the study. In 
the event of a suit against the sponsor, the sponsor carries third-party insurance that will cover 
bodily injury claims and will pay for applicable legal defense if needed/warranted. 


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14.6 Record Retention 
Investigators must retain all study records required by the sponsor and applicable ICH-GCP, 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. Medical records will be maintained according to the James J Peters 
VA medical center’s requirements. Research Investigator files at JJP VAMC will be destroyed six 
years after the end of the fiscal year when the research project has been completed per Records 
Schedule DAA-0015-2015-0004-0032. 
 
14.7 Publication Policy 
The sponsor recognizes the importance of communicating medical research and scientific data 
and their obligations to participants enrolled in a study and therefore, encourage publication of 
such material in reputable scientific journals and at professional and/or academic seminars or 
conferences. For multi-center studies, it is intended that the first publication of the study’s 
primary clinical data be co-authored by designated participating centers and the sponsor or 
designated representatives. Inclusion of Clinical Investigators in the authorship of any multi- 
center publication will be based upon substantial contribution to the design, analysis, 
interpretation of data, drafting and/or critically revising any manuscript(s) derived from the 
Study. All publications will follow ICMJE Recommendations for the Conduct, Reporting, 
Editing, and Publication of Scholarly Work in Medical Journals, unless other guidelines are 
required by the journal. It is understood by the Clinical Investigators that the information 
generated in this study will be used by the sponsor in connection with the development of the 
IMP and therefore may be disclosed to government agencies in various countries. To allow for 
the use of information derived from the study, it is understood that the investigators are obliged to 
provide the sponsor with complete test results, all study data, and access to all study records. It is 
mandatory that all data analysis is done on the official monitored sponsor database and that the 
analysis plan is agreed upon with the sponsor statistician. 
 
Any results of medical investigations with the sponsor and/or publication/lecture/manuscripts 
based thereon shall be exchanged and discussed by the investigator and sponsor prior to 
submission for publication or presentation. Due regard shall be given to the sponsor's legitimate 
interests, e.g., manuscript authorship, obtaining optimal patient protection, coordinating, and 
maintaining submissions to health authorities, and coordinating with other ongoing studies in the 
same field. The full details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this trial will be described in the Clinical Trial Agreement. 
 
 
 


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Bond, F.W., et al., Preliminary psychometric properties of the Acceptance and Action 
Questionnaire-II: a revised measure of psychological inflexibility and experiential 
avoidance. Behav Ther, 2011. 42(4): p. 676-88. 
107. 
Development of the World Health Organization WHOQOL-BREF quality of life 
assessment. The WHOQOL Group. Psychol Med, 1998. 28(3): p. 551-8. 
108. 
Skevington, S.M., et al., The World Health Organization's WHOQOL-BREF quality of 
life assessment: psychometric properties and results of the international field trial. A 
report from the WHOQOL group. Qual Life Res, 2004. 13(2): p. 299-310. 
109. 
Vogt, D., et al., Deployment risk and resilience inventory-2 (DRRI-2): an updated tool 
for assessing psychosocial risk and resilience factors among service members and 
veterans. J Trauma Stress, 2013. 26(6): p. 710-7. 
110. 
Corrigan, J.D. and J. Bogner, Initial reliability and validity of the Ohio State University 
TBI Identification Method. J Head Trauma Rehabil, 2007. 22(6): p. 318-29. 
111. 
Mithoefer, M., A Manual for MDMA-Assisted Psychotherapy in the Treatment of 
Posttraumatic Stress Disorder; Version 8.1. 2017: 
http://www.maps.org/research/mdma/mdma-research-timeline/4887-a-manual-for-mdma-
assisted-psychotherapy-in-the-treatment-of-ptsd. 
112. 
Powers, W.J., et al., Guidelines for the early management of patients With acute ischemic 
stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic 
stroke: A guideline for healthcare professionals from the American Heart 
Association/American Stroke Association. Stroke, 2019. 50(12): p. e344-e418. 
113. 
Ryan, T.J., et al., 1999 update: ACC/AHA guidelines for the management of patients with 
acute myocardial infarction. A report of the American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines (Committee on Management of 
Acute Myocardial Infarction). J Am Coll Cardiol, 1999. 34(3): p. 890-911. 
114. 
Liechti, M.E., A. Gamma, and F.X. Vollenweider, Gender differences in the subjective 
effects of MDMA. Psychopharmacology (Berl), 2001. 154(2): p. 161-8. 
115. 
McElhatton, P.R., et al., Congenital anomalies after prenatal ecstasy exposure [letter]. 
Lancet, 1999. 354(9188): p. 1441-2. 
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Bateman, D.N., et al., A case control study to examine the pharmacological factors 
underlying ventricular septal defects in the North of England. Eur J Clin Pharmacol, 
2004. 60(9): p. 635-41. 
117. 
Mueller, M., et al., Direct comparison of (+/-) 3,4-methylenedioxymethamphetamine 
("ecstasy") disposition and metabolism in squirrel monkeys and humans. Ther Drug 
Monit, 2009. 31(3): p. 367-73. 
 

SAP_001.pdf: 
 
 
MPVA6 Statistical Analysis Plan 
 
Version 1: 30 August 2021  
Version 2: 18 December 2023 
 
 
STUDY TITLE 
A Phase 2, Open-Label, Randomized Comparative 
Effectiveness Study for MDMA-Assisted Psychotherapy in 
U.S. Veterans with Chronic PTSD 
 
 
 
SPONSOR 
Multidisciplinary Association for Psychedelic Studies (MAPS) 
3141 Stevens Creek Blvd #40563 
San Jose, CA 95117 
 
SPONSOR 
REPRESENTATIVE 
Amy Emerson, CEO, MPBC 
 
 
MEDICAL MONITOR(S) 
Ian Schneider, NP 
 
STATISTICIAN(S) 
Scott Hamilton, Ph.D. 
 
PREPARED BY 
Scott Hamilton, Ph.D. 
 
USE 
In conjunction with relevant regulatory guidance 
 
 
 
 


MAPS Public Benefit Corporation 
 
MPVA6 Statistical Analysis Plan 
U.S. 
 
Version 2: 18 DEC 2023 
 
Page 2 of 11 
Table of Contents 
1.0 Introduction .............................................................................................................................. 3 
2.0 Study Objectives....................................................................................................................... 3 
2.1 Primary Objective .................................................................................................................. 3 
2.2 Secondary Objective .............................................................................................................. 3 
2.3 Safety Objectives ................................................................................................................... 3 
2.4 Exploratory Objectives .......................................................................................................... 4 
3.0 Measures ................................................................................................................................... 5 
3.1 Primary Measure .................................................................................................................... 5 
3.2 Secondary Outcome Measure ................................................................................................ 5 
3.3 Safety Measures ..................................................................................................................... 5 
3.4 Exploratory Measures ............................................................................................................ 5 
4.0 Study Design ............................................................................................................................. 5 
5.0 Randomization and Blinding .................................................................................................. 7 
6.0 Sample Size and Power Considerations ................................................................................. 8 
7.0 Analyses .................................................................................................................................... 8 
7.1 Analysis Sets .......................................................................................................................... 8 
7.2 Missing Data Handling .......................................................................................................... 8 
7.2.1 Partial or Missing Dates .................................................................................................. 8 
7.3 Protocol Deviations ................................................................................................................ 8 
7.4 Baseline Values ...................................................................................................................... 9 
7.5 Participant Disposition and Dosing Summary ....................................................................... 9 
7.6 Demographics and Baseline Characteristics .......................................................................... 9 
7.7 Efficacy Analyses .................................................................................................................. 9 
7.7.1 Primary Effectiveness Analysis ...................................................................................... 9 
7.7.2 Secondary Effectiveness Analysis ................................................................................ 10 
7.7.3 Exploratory Analyses .................................................................................................... 10 
7.8 Safety Analyses .................................................................................................................... 10 
7.8.1 Analysis of Exposure .................................................................................................... 10 
7.8.2 Analysis of Adverse Events .......................................................................................... 10 
7.8.3 Concomitant Medications ............................................................................................. 11 
7.8.4 Analysis of Suicidal Ideation and Behavior .................................................................. 11 
7.8.5 Summary of Vital Signs ................................................................................................ 11 
8.0 Timing of Analyses ................................................................................................................. 11 
 
 


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MPVA6 Statistical Analysis Plan 
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1.0 Introduction 
This document contains a Statistical Analysis Plan (SAP) for MPVA6 “A Phase 2, Open-Label, 
Randomized Comparative Effectiveness Study for MDMA-Assisted Therapy in U.S. Veterans 
with Chronic PTSD.” 
 
This open-label comparative effectiveness study was designed to explore the relative 
effectiveness of two vs. three randomly assigned active drug sessions in a sample of U.S. military 
veterans with at least moderate chronic PTSD. The Primary Outcome measure, the Clinician 
Administered PTSD Scale (CAPS-5), evaluates changes in PTSD symptom severity and  is 
assessed by a blinded centralized Independent Rater (IR) pool. 
 
Due to various administrative and non-safety related reasons, in May of 2023 MPBC decided to 
terminate this study with enrollment of approximately twenty participants.  Since the new sample 
size will not support efficacy conclusions, the focus of the analyses described herein has shifted 
from safety and efficacy to safety only.  Sections 2 through 6 state the study objectives, study 
measures, design, randomization, and sample size/power as described in the Protocol.  Section 7, 
analysis, has been modified to reflect the changes resulting from early termination of the study. 
 
2.0 Study Objectives 
2.1 Primary Objective  
The primary objective of this study is to compare the effectiveness of two versus three sessions of  
MDMA-assisted therapy in treatment of PTSD, based on mean change in CAPS-5 Total Severity 
Score from T1 (Baseline) to T2 (Primary Outcome). 
 
2.2 Secondary Objective 
The key secondary objective of this study is to compare the effectiveness of two versus three 
sessions of MDMA-assisted therapy in clinician-rated functional impairment, as measured by the 
mean change in Sheehan Disability Scale (SDS) item score from Baseline to T2 (Primary 
Outcome). 
 
2.3 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, and vital 
signs to support the package insert for MDMA-assisted therapy. The following safety objectives 
will evaluate the safety of MDMA-assisted therapy: 
 
1. Assess incidence of AEs during Experimental Sessions that may be indicative of a 
medical complication of the Investigational Medicinal Product (IMP), such as clinical 
signs and symptoms of chest pain, shortness of breath, or neurological symptoms or any 
other signs or symptoms that prompt additional vital sign measurements. 
2. 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 
through 2 days after IMP administration. 
5. Assess incidence of AESIs, defined as AEs specified in the protocol related to cardiac 
function and abuse liability.  


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6. Assess incidence of AEs by severity categorized as leading to discontinuation of IMP, 
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 through 2 days after IMP 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-IMP 
administration to end of each Experimental Session. 
 
2.4 Exploratory Objectives 
Exploratory objectives include analyses of baseline predictors of treatment outcome (e.g., adverse 
childhood experiences, history of mild TBI), and post-treatment changes in self report measures 
of clinical state, including depression, PTSD, and moral injury as assessed by: 
 
1. Explore changes between the two treatment groups 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 Baseline to Post-treatment and 
Follow-up. 
2. Explore trajectories of change and onset of treatment effectiveness within and between 
groups using multiple assessments with PCL-5 self-reports.  
3. Explore the effect of adverse childhood experiences (ACE) on the CAPS-5 Total Severity 
analyses.  
4. Explore differences between treatment groups using measures below regarding changes 
in clinical state associated with MDMA treatment, and regarding baseline predictors of 
outcome using the following measures: 
a. Acceptance and Action Questionnaire (AAQ-II)  
b. Dissociative Subtype of PTSD Interview (DSP-I) 
c. Columbia Suicide Severity Rating Scale (C-SSRS) 
d. Self Compassion Scale (SCS) 
e. Buss-Perry Aggression Questionnaire-Short Form (BPAQ-SF) 
f. Deployment Risk and Resilience Inventory 2 (DRRI-2) 
g. Life Events Checklist (LEC-5) 
h. PTSD Checklist for DSM-5 (PCL-5) 
i. 
Moral Injury (MIES) 
j. 
Depression (BDI-II) 
k. Posttraumatic Growth Inventory (PTGI) 
l. 
Chronic Pain Grade Scale (CPGS) 
m. World Health Organization Quality of Life-Brief Form (WHOQOL-BREF) 
n. Ohio State University Traumatic Brain Injury (OSU-TBI) 
o. The Utilization of Facility and Emergent Care (UFEC) 
p. Addictive behaviors including Alcohol Use Disorders Identification Test 
(AUDIT), Drug Use Disorders Identification Test (DUDIT) 
 
 


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Version 2: 18 DEC 2023 
 
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3.0 Measures 
3.1 Primary Measure 
• 
CAPS-5 (Clinician-Administered PTSD Scale for DSM-5) 
 
3.2 Secondary Outcome Measure 
• 
Sheehan Disability Scale (SDS) for MPBC 
 
3.3 Safety Measures 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
Adverse Events 
• 
Treatment-emergent Adverse Events 
• 
Serious Adverse Events 
• 
Adverse Events of Special Interest 
• 
Concomitant medication use 
• 
Vitals signs during MDMA sessions 
 
3.4 Exploratory Measures 
• 
DSP-I (The Dissociative Subtype of PTSD Interview) 
• 
ACE (Adverse Childhood Experience Questionnaire) 
• 
BDI-II (Beck Depression Inventory II) 
• 
CPGS (Chronic Pain Grade Scale)  
• 
SCS (Self-Compassion Scale) 
• 
AUDIT (Alcohol Use Disorders Identification Test) 
• 
DUDIT (Drug Use Disorders Identification Test) 
• 
MIES (Moral Injury Event Scale) 
• 
PTGI (Posttraumatic Growth Inventory) 
• 
BPAQ-SF (Buss Perry Aggression Questionnaire Short Form)  
• 
AAQ-II (Acceptance and Action Questionnaire)  
• 
WHOQOL-BREF (WHO Quality of Life-BREF) 
• 
DRRI-II (Deployment Risk and Resilience Inventory-2)  
• 
UFEC (Utilization of Facility-based and Emergent Care) 
• 
OSU-TBI-ID (Ohio State University Traumatic Brain Injury Identification Method)   
 
4.0 Study Design 
This open-label, randomized Phase 2 study will assess the relative safety and effectiveness of two 
versus three Experimental Sessions of MDMA-assisted therapy in treatment-seeking veterans 
diagnosed with at least moderate PTSD. 
 
The study was to be conducted in up to 60 participants, but the study was terminated early at 
approximately 20 participants. Randomization will occur in a 1:1 fashion. Randomization will be 
allocated to Group 1: 3 Experimental Sessions of MDMA-assisted therapy or Group 2: 2 
Experimental Sessions of MDMA-assisted therapy. 
 


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For each participant, the study will consist of: 
 
• 
Screening Period: Phone or in-person screen, informed consent, eligibility, and 
baseline  assessments 
• 
Study Inclusion and Randomization: Include eligible participants, randomize to 
group, complete baseline self-report measures, 
• 
Treatment Period: 3 Preparatory Sessions, followed by 2 or 3 Experimental 
Sessions, depending on group. Each Experimental Session is followed by 3 Integrative 
Sessions. 
• 
Post treatment: Clinical evaluation and self-report measures. 
o Note: the primary endpoint (T2) occurs approximately 1 month after the last 
experimental session. This means that the T2 occurs ~12 weeks after baseline 
for the 2-session group, and ~16 weeks after baseline for the 3-session group. 
▪ 
The 2-session group will have an additional clinical evaluation ~16 
weeks post-baseline (T2.2). 
• 
Study Termination: Clinical evaluation and self-report measures 
 
A divided-dose of MDMA (120 mg initial dose, followed by a supplemental 40 mg dose), is 
administered during the Treatment Period with manualized therapy in two or three open-label 
monthly Experimental Sessions. This ~ 8-12-week Treatment Period includes three Preparatory 
Sessions prior to the first MDMA-assisted session. Each Experimental Session is followed by 
three Integrative Sessions of non-drug therapy. Experimental Sessions are followed by an 
overnight stay. The Primary Outcome measure, the change in CAPS-5 from Baseline, is assessed 
by a centralized IR pool at 7 weeks following the final treatment session (post treatment). The IR 
pool will be blinded to treatment arm assignment, visit number, and number of treatments 
received, and will not have access to data collected by the sites during the active Treatment 
Period. Self-reported PTSD symptoms will be assessed at the start of each treatment visit by the 
PCL-5. 
 
 
 
 


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Page 7 of 11 
Table 1: CAPS-5 Data Collection by Visit 
 
CAPS 
Number 
Visit 
Description/Timing 
Target Timing 
Post Baseline 
Baseline 
CAPS-5 T1 
Screening 
Baseline 
2-9 days after initial eligibility 
met 
Not Applicable 
CAPS-5 T2 
V12 (2-session group) or 
V16 (3-session group) 
Post Treatment Primary Outcome 
28 to 35 days after last 
Experimental Session 
~12 wk (±7 days) or 
~16 wk (±7 days) 
CAPS-5 T2.2 
V13 (2-session group 
only) 
Secondary outcome for 2-session 
group only 
28 to 35 days weeks after T2 
~16 wk (±7 days) 
 
Dose Selection 
 
This study will compare the effects of two versus three open-label manualized Experimental 
Sessions of therapy assisted by set doses of MDMA HCl (referred to as MDMA throughout) 
as described in the table below, along with associated non-drug preparatory and integrative 
therapy. Similar MDMA doses to those proposed in this study have been safely used in 
previous Phase 2 and 3 studies sponsored by MAPS. 
 
Table 2: Dose Regimen of MDMA 
* Unless initial dose is not tolerated or refused by participant 
 
5.0 Randomization and Blinding 
Participants will be randomized in 1:1 allocation to two versus three sessions of MDMA-assisted 
therapy. 
 
To further minimize bias in measuring effectiveness, the sponsor will use an observer-blind, 
centralized, reliable IR pool to administer the Primary Outcome measure via live video 
interviews. The IR Pool will have no knowledge of AEs and will only evaluate participants at 
Baseline and at the assessments scheduled after each Experimental Session. The IR Pool is 
blinded to full study design, visit number, treatment assignment, number of treatments, and any 
data from the treating therapy pair after Baseline. IRs will be assigned to participants based on 
availability. Participants will be instructed to withhold study progress from IRs. Timing of 
CAPS-5 assessments are pre-specified in the study protocol within visit windows.   
 
Sites will be required to make and document a specific number of attempts to obtain follow-up 
data per protocol. All randomized participants who receive at least one dose of IMP and complete 
at least one follow-up assessment will be included in the final mITT set. 
 
Experimental 
Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative Dose 
1 
120 mg 
40 mg 
120 mg to 160 mg 
2 
120 mg 
40 mg 
120 mg to 160 mg 
3 
120 mg 
40 mg 
120 mg to 160 mg 
Total Cumulative Dose: 2 Session Group 
240 mg to 320 mg 
Total Cumulative Dose: 3 Session Group 
360 mg to 480 mg 


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6.0 Sample Size and Power Considerations 
Due to the early termination of this study, the initial power estimates are no longer valid, and the 
primary efficacy analysis will not be executed.   
 
7.0 Analyses 
7.1 Analysis Sets 
The following analysis sets are defined for this study: 
 
• 
All Enrolled: all participants who sign informed consent and are initially enrolled 
• 
Safety: all participants who receive any IMP 
 
7.2 Missing Data Handling 
Missing outcome data will not be imputed.  
 
7.2.1 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.  
4. In the event that an imputed start date is after a complete stop date, the start date will be 
set equal to the complete stop date. 
 
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. 
 
7.3 Protocol Deviations 
Protocol deviations will be classified as major/minor by the MPBC protocol deviations review 
committee.  The committee will determine the impact of the deviation on the study subjects’ 
safety and rights, study compliance, data quality, and the proposed analyses.  A subject level 
listing will report the description of the deviation and the impact.  
 


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A table of protocol deviations will summarize them by major/minor into the following categories: 
 
• 
Informed Consent 
• 
Inclusion/Exclusion 
• 
Study Treatment 
• 
Prohibited Concomitant Medication 
• 
Trial Procedures 
• 
Safety Reporting 
• 
Discontinuation 
• 
Miscellaneous 
 
7.4 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. 
 
7.5 Participant Disposition and Dosing Summary 
The All Enrolled Set will be used in the summary of participant disposition. The Safety Set will 
be included in the summary of 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.  
 
7.6 Demographics and Baseline Characteristics 
Participant demographic data and Baseline characteristics will be summarized descriptively for 
the Safety Set by treatment group and overall.  
 
7.7 Efficacy Analyses 
Due to the early termination of the study, the primary, secondary, and exploratory efficacy 
analyses specified in V1 of the SAP were removed.  For all primary and secondary endpoints 
descriptive statistics (n, mean, standard deviation, median, interquartiles, range, or counts and 
percentages where appropriate) by timepoint will be provided for the overall sample and by 
treatment received. 
 
7.7.1 Primary Effectiveness Analysis 
Because of early termination at 1/3 of the planned sample size, the primary effectiveness analysis 
is no longer valid and will not be executed. Ninety-five percent confidence intervals will be 
calculated for the CAPS-5 raw means and change from baseline at T2 and T2.2 (for the 2 session 
group). 
 


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7.7.2 Secondary Effectiveness Analysis  
The SDS will be presented in a similar manner to the CAPS-5 with descriptive statistics (n, mean, 
standard deviation, median, interquartile range, or counts and percentages where appropriate) by 
timepoint for the overall sample and by treatment received. Ninety-five percent confidence 
intervals will be calculated for the SDS raw means and change from baseline at T2 and T2.2 (for 
the 2 session group). 
 
7.7.3 Exploratory Analyses 
Data collected of the exploratory measures will be presented in by participant listings. 
 
7.8 Safety Analyses 
Safety analyses will confirm safety data with summary tables listing exposure to IMP, unsolicited 
AEs, concomitant medications, suicidal ideation and behavior, and vital signs overall and by 
treatment received. If a participant has more than one AE mapped to the same PT, that AE will be 
reported once using the highest severity. AEs that occur on Day 0 (Experimental Session), Day 1, 
Day 2 after IMP administration will be presented separately. Comparisons will be presented of 
relative incidence of AEs during experimental Sessions. 
 
Frequency and incidence of concomitant medications will be displayed by generic name, sorted 
by class, and summarized overall and by treatment group. Frequency and incidence of positive or 
serious ideation and suicidal behavior will be presented using descriptive statistics of C-SSRS 
scores in tabular format. Vital signs (heart rate, blood pressure, and body temperature) for 
Experimental Sessions will be summarized using descriptive statistics in tabular format listing 
values at pre-IMP administration, prior to the supplemental dose, and at the end of each 
Experimental Session by treatment group.  
 
7.8.1 Analysis of Exposure 
The total mg exposure of participants will be summarized. Data will be tabulated for the Safety 
Set. 
 
7.8.2 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 final study visit 
• 
AEs that occur one and two days after MDMA administration 
• 
AESIs are defined as AEs specified in the protocol related to cardiac function, serious 
suicidal ideation/behavior, 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 IMP 
• 
SAEs 
 
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 24.0 


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Frequency and incidence of AEs will be displayed by PT, sorted by SOC, 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 as determined by the Clinical Investigator  
• 
AEs that occur on day of Experimental Sessions and two days after IMP administration 
will be presented separately. 
 
7.8.3 Concomitant Medications 
Frequency and incidence of concomitant medications will be displayed by generic name, sorted 
by class, and summarized by treatment group.  
 
7.8.4 Analysis of Suicidal Ideation and Behavior 
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. 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-IMP), 
Integrative Sessions, and endpoints). Frequency and incidence of positive or serious ideation and 
suicidal behavior will be presented using descriptive statistics in tabular format. A Shift table of 
changes in suicide ideation since baseline will be presented. 
 
7.8.5 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-IMP, prior to the supplemental 
dose, and at the end of each Experimental Session.  
 
8.0 Timing of Analyses 
The final analysis will be conducted after the database is locked.