Clinical trial NCT03537014
Conditions: Posttraumatic Stress Disorder
Sponsor: Lykos Therapeutics
Start date: 2018-11-21; Completion date: 2020-08-21
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

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

Researchers will compare three sessions of MDMA-assisted therapy with an initial dose of 80 to 120 mg to three sessions of placebo with therapy.

Participants will undergo three preparatory sessions without any study drug, followed by three MDMA-assisted therapy or placebo with therapy sessions. Each medication session will be followed by three integrative therapy sessions without study drug.

Detailed description:
This multi-site, double-blind, placebo-controlled, randomized Phase 3 study will assess the efficacy and safety of MDMA-assisted therapy versus placebo with therapy in participants diagnosed with at least severe PTSD. The study will be conducted in N ≈ 100 participants. Participants will be randomized to one of two groups at a 1:1 ratio. An initial dose of midomafetamine HCl or placebo, followed by a supplemental half-dose unless contraindicated, is administered during the Treatment Period with manualized therapy in three monthly Experimental Sessions. This \~12-week Treatment Period is preceded by three Preparatory Sessions. During the Treatment Period, each Experimental Session is followed by three Integrative Sessions of non-drug psychotherapy. Initial doses per Experimental Session include 80 mg or 120 mg of midomafetamine HCl or placebo followed 1.5 to 2 hours later by a supplemental half-dose (40 or 60 mg). Total amounts of midomafetamine HCl to be administered per Experimental Session range from 80 mg to 180 mg.

The primary endpoint is change from baseline in Clinician Administered PTSD Scale for DSM-V (CAPS-5) to 18 weeks post-Baseline. Drug safety will be assessed by measuring blood pressure, heart rate and body temperature during Experimental Sessions, collecting adverse events and measuring suicidal thoughts or behaviors with the Columbia Suicide Severity Rating Scale (adapted C-SSRS).

Arms: arm 1: Administration of 80 or 120 mg midomafetamine HCl with a supplemental dose 1.5 to 2 hours later of 40 or 60 mg midomafetamine HCl, respectively, in combination with therapy during 3 experimental sessions scheduled 3-5 weeks apart. arm 2: Administration of inactive placebo in combination with therapy during 3 experimental sessions scheduled 3-5 weeks apart
Interventions: intervention 1: Therapy intervention 2: midomafetamine HCl intervention 3: Placebo
Intervention descriptions: intervention 1: Non-directive therapy performed by therapist team intervention 2: Administration of 80 to 120 mg midomafetamine HCl, followed by a supplemental dose 1.5 to 2 hrs later of 40 or 60 mg midomafetamine HCl, respectively, during three experimental sessions intervention 3: Administration of placebo during three experimental sessions

Protocol documents:
ICF_005.pdf: 
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[FOR CALIFORNIA SITES ONLY] 
 
California Experimental Subject’s Bill of Rights 
 
Any person who is requested to consent to participate in a research study involving a 
medical experiment, or who is requested to consent on behalf of another, has the right 
to: 
 
1. Learn the nature and purpose of the study (also called "experiment", "clinical 
trial" or "research"). 
2. Receive an explanation of the procedures to be followed in the medical study, 
and a description of any drug or device to be used. 
3. Be informed of any related discomforts and risks that can reasonably be 
expected from participating in the study.  
4. Learn about any benefits you might expect from the study, if applicable.  
5. Be told about any other procedures, drugs or services that might be helpful to 
you and the relative risks and benefits of these alternatives.  
6. Be informed of the medical treatment, if any, available to you if you are injured 
because of the study. 
7. Ask any questions about the study. 
8. Stop the study at any time without any effect on your healthcare benefits or 
medical care, even if you stop the study. 
9. Receive a copy of the signed and dated consent form when one is required. 
10. Decide to consent or not to consent to a medical study without feeling forced to 
participate. 
 
 
______________________________________________________________________ 
Printed Name of Subject 
 
 
______________________________________________________________________ 
Signature of Subject 
 
 
____________________________ 
Date  
 
<<CF-Main User Defined #2>> 
 


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PARTICIPANT INFORMATION AND CONSENT FORM  
AND HIPAA AUTHORIZATION 
 
TITLE:  
A Randomized, Double-Blind, Placebo-Controlled, Multi-Site 
Phase 3 Study of the Efficacy and Safety of Manualized 
MDMA-Assisted Psychotherapy for the Treatment of Severe 
Posttraumatic Stress Disorder 
 
PROTOCOL NO.:  
MAPP1 
 
IRB Protocol # 20180587 
 
SPONSOR:  
Multidisciplinary Association for Psychedelic Studies (MAPS) 
1115 Mission Street  
Santa Cruz, CA 95060 
 
CLINICAL  
INVESTIGATOR NAME: <<CF-Main Investigator Name>> 
 
<<CF-Main Header Block - Sites>> 
STUDY RELATED 
PHONE NUMBER(S): 
<<CF-Main User Defined #1>> 
 
You should keep a copy of this form. If you have any questions or problems during the 
study, call the phone number(s) above. 
 


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


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known as “Ecstasy” or “Molly” (which is supposed to contain MDMA, but often contains 
other drugs instead of or in addition to MDMA). MDMA is a chemical that is structurally 
similar to some stimulant chemicals, like methamphetamine, which is both a major drug 
of abuse and an FDA-approved treatment for Attention Deficit Disorder, and to some 
psychedelic (hallucinogenic) chemicals, like mescaline, which is found in peyote cactus. 
MDMA has already been used legally in research and illegally in uncontrolled 
environments, such as nightclubs. While much is known about MDMA and its risks, 
much remains unknown about this drug. 
 
The study is sponsored by a U.S.-based non-profit organization, the Multidisciplinary 
Association for Psychedelic Studies (MAPS, www.maps.org). MAPS has completed 
eight studies of MDMA-assisted psychotherapy in the U.S., Canada and Israel. 
 
Before MDMA became illegal in 1985, some psychologists and psychiatrists combined it 
with psychotherapy to help people with psychological problems or challenges, including 
PTSD and couples’ therapy. Though we do not know exactly why it may help people 
with PTSD, we know that MDMA may increase positive mood and changes the way we 
see and think about the world around us, making it easier to think about and recall 
things that happened to us that are upsetting. People say they feel caring and forgiving 
toward themselves and others during the MDMA experience. It is possible that these 
drug effects, when combined with psychotherapy, help people work through thoughts, 
memories and emotions related to PTSD and other past experiences. 
 
This study will test the safety of MDMA-assisted psychotherapy and whether it works. 
During MDMA-assisted psychotherapy sessions, you will receive a dose of MDMA or 
placebo and possibly a second dose equal to half the size of the first dose about two 
hours later. You will have either the same dose or a slightly higher dose for the second 
and third sessions, which will happen roughly one month apart.  
 
TYPE OF STUDY 
This study is double-blind, meaning neither you nor the study researchers will know if 
you get MDMA or placebo. You may get MDMA, or you may get a placebo (pills that do 
not contain MDMA). The drug you get will be decided at random, as if by tossing a coin. 
However, this information will be available if needed in case of an emergency. You will 
have a 50% chance of receiving MDMA and a 50% chance of receiving the placebo. 
Once the entire study is completed and all participants at all study centers have 
finished, you will find out what you received. There will be a total of at least 100 people 
in the study across multiple locations.  Whether you receive MDMA or placebo, you will 
receive psychotherapy as well. 
 
LENGTH OF STUDY 
The length of active participation in the study will be about 19 to 38 weeks, depending 
on the length of screening and the time in between your study visits. Participation in the 


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study requires a large time commitment from you over the active study period. To 
confirm that you are eligible for the study, there will be multiple in-person visits to the 
study location, lab, and doctor’s office, at least one online meeting with an evaluator, 
and phone calls from the study team. Then, there will be three preparatory visits, three 
day-long visits with overnight stays, and nine integrative (talk therapy) visits for you in a 
13 to 26-week period (depending on visit scheduling).  The audio and video of these 
visits will be recorded.  There will be two evaluation days where you will complete many 
questionnaires. There will also be four online meetings with an evaluator who will ask 
you questions about your PTSD symptoms.  You will meet also with the staff and 
therapy team about two months after your last Overnight Test Session. 
 
The timeline for starting treatment after enrollment is variable depending on availability 
of appointments and if you need to discontinue any medications. You may have your 
first Overnight Test Session as soon as 2 weeks, or as long as 11 weeks after your first 
visit. Overnight Test Sessions last all day and require an overnight stay at the clinic 
afterwards. After these overnight stays, you will have eight brief phone calls with the 
therapy team during the 14 days after the visit.  
 
You will be invited to enroll in a 12-month follow-up study at the end of your 
participation. This will be explained in another informed consent form. 
 
When the study is complete, if we learn that you received placebo and if you still meet 
all study criteria, you will be invited to enroll in another study where you will get MDMA-
assisted psychotherapy. This study would not start until all participants have completed 
this current study. This would be at a minimum a year and a half from the start of this 
study. 
 
TYPES OF VISITS AND DURATION: 
 
Screening Visits: Multiple visits at the study location, lab, and/or doctor’s office, an 
online meeting with an evaluator, and phone calls from the study team. 
 
Preparatory Visits (~90 minutes each): Three introductory sessions at the start of 
participation in the study, spaced about one week apart. 
 
Integration Sessions (~90 minutes each): Three sessions after each Overnight Test 
Session. These are approximately one to three weeks apart and will involve you talking 
to your therapists about your thoughts and feelings. Some of these visits may be done 
remotely. 
 
Telephone Calls after Integration Visits (~15-20 minutes each): Eight phone check-
ins will take place on days 2, 4, 6, 7, 8, 10, 12, 14 after each Overnight Test Session. 
 


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Overnight Test Sessions (~8 hours long plus an overnight stay): Three visits about a 
month apart. You will be given either MDMA or placebo during these visits along with 
psychotherapy. 
 
Online Meetings (60-90 minutes each): Four online video meetings where you will be 
interviewed about your PTSD symptoms.  You will need to come to the study site for 
these meetings unless your research team tells you otherwise. 
 
Evaluation and Testing Visits (90 to 120 minutes): Psychological testing and 
completing questionnaires two times, starting with the beginning of the study. 
 
You will need to be flexible about taking the appointments offered most of the time 
because there is a limited time frame for each type of visit.  
 
Please note that because of the COVID-19 pandemic, it may be necessary to delay 
some study activities, including the Experimental and Integrative sessions. 
 
PROCEDURES/WHAT WILL HAPPEN  
 
Screening/Evaluation and Beginning of Study 
If you agree to be in this study, you will first sign this form before any study-related 
procedures are done.  
 
Before you can be in the study, the study doctor must first make sure that you qualify for 
the study and that you are generally physically healthy.  This screening process can 
take up to six weeks, and there will be one or more office visits and online meetings with 
an evaluator during this time. The online meeting will be recorded, and you will need to 
come to the study site.  The study doctor may ask you for written permission to contact 
your doctors or psychotherapists to get information about your medical history. They 
may need to do this so that they will know whether you can be in the study or not.  
 
If there are other medical concerns during screening, you may be asked to do additional 
testing with your primary care physician or another doctor.  The study doctors will 
explain any tests they are asking you to do. 
 
Psychological and medical screening will be done by staff, doctors, or your therapy 
team. The tests will include the following: 
 
• Questions about your medical history, including questions about your emotional 
and psychiatric history. This may include any previous medical or psychiatric 
problems or treatment and may include questions about difficult experiences you 
may have had during childhood or at other times of your life. 


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• An interview about any psychological or psychiatric issues you may be 
experiencing, or that you have experienced in the past. 
• A brief interview about thoughts you might have about hurting or killing yourself.  
• Psychological questionnaires you fill out yourself. 
• A physical examination that will include measures of your blood pressure, pulse, 
temperature, and body weight. This information will also be used to calculate 
your Body Mass Index (BMI). 
• An ECG (electrocardiogram) and rhythm strip will also be taken, which are 
recordings of the electrical activity of your heart. 
• A sample of your blood (about 2 tablespoons) and a urine sample for routine 
laboratory testing, including tests of metabolism, liver function, and alcohol use. 
We will also test for the human immunodeficiency virus (HIV) and Hepatitis C 
virus (HCV). 
 
o If you have positive test results for HIV or Hepatitis C, we will notify you.  If 
the state we are practicing in requires that we notify state health authorities of 
positive results, we will do so.  If you test positive for Hepatitis C, you will only 
be able to participate if you currently don’t have symptoms of Hepatitis C 
(asymptomatic) and have been previously treated for it. If you do not want to 
be tested, you should not take part in this research study. 
 
• A urine test for drugs of abuse. Urine drug screen will be reviewed in order for 
you to take part in the study. We will not report findings of drugs to any 
authorities. 
• A urine pregnancy test if you are able to get pregnant. Your urine pregnancy test 
must be negative for you to take part in the study. 
 
If you pass the initial screening and choose to participate, you will be enrolled in the 
study. However, this does not mean you are guaranteed to be able to participate in 
Overnight Test Sessions. The screening process continues until Visit 4, when the 
therapists will let you know whether or not you are fully eligible to participate in the 
study. 
 
Beginning of Study 
Once you pass the initial screening, we will schedule your first preparatory 
psychotherapy session with the therapy team.  
 
If you are taking certain medications, you may need to stop taking them before you 
have your first online meeting to discuss your PTSD or your first Overnight Test 
Session. Your study doctor will discuss the medication plan with the doctor who 
prescribed the medications.  Only stop medications if the study doctor gives you specific 
instructions for how to stop. Some PTSD medications can cause thoughts about 
wanting to kill yourself if you stop taking them too quickly and without the care of a 


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doctor.  This is very important. Do not stop taking any medications before you are 
supposed to. 
 
You must let the therapy team know about any change in medicines or medical 
conditions or procedures, like surgery, within 48 hours of it happening.  
 
You will need to give the therapy team the name and contact information (telephone 
number, cell phone number or email) of a relative, spouse or close friend to contact in 
case of medical emergency, should you become at risk of hurting yourself or someone 
else, or if the study team cannot get in touch with you, so they can reach that person to 
let them know what is going on or find out if you are okay.  
 


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


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Preparatory Sessions 
The first two preparatory sessions will last approximately 90 minutes and the last 
preparatory session will last about 2.5hours. These visits will be recorded.  During each 
preparatory session, you will talk about the traumatic incidents that led to your PTSD, 
the ways PTSD symptoms are affecting your life, and what you would like to achieve 
during the study. You will be asked questions about thoughts or feelings you might have 
about hurting or killing yourself and complete psychological questionnaires in the third 
preparatory session. There will be four visits total during this period.  You will need to 
come to the study site for all four visits: Three therapy visits and an online meeting with 
a researcher who will ask you questions about your PTSD symptoms. This information 
will be used to learn how you are doing after the study treatment.  
 
At the third preparatory session, the staff will let you know whether you will continue on 
to the treatment part of the study. There are many reasons why you may not be eligible 
to continue in the study after the preparatory sessions. The study has very specific 
criteria. If you do not qualify for the study, this does not mean the study staff think you 
are not suffering from PTSD or that the treatment would not work for you in the future. If 
the study staff believe there is anything medically wrong with you, they will notify you so 
you can get follow-up care. 
 
Overnight Test Sessions 
If you qualify for the study after the preparatory sessions, you will be fully enrolled in the 
study.  There will be three day-long Overnight Test Sessions. These visits will happen 3 
to 5 weeks apart. These visits will be recorded.  The first Overnight Test Session will 
occur after you have had three preparatory sessions. During the Overnight Test 
Session, you will receive a dose of either MDMA or placebo (pills that do not contain 
MDMA) followed 1.5 to 2 hours later by a dose of half the first dose of MDMA or 
placebo. During the second and third Overnight Test Sessions, you and your therapy 
team can decide if you would like to take the same dose you took in your first Overnight 
Test Session, or if you would like to try a higher dose. Your therapy team will discuss 
the optimal dose of MDMA with you for the second Overnight Test Session. The goal 
will be to decide on the optimal dose for you. 
 
You must not eat any food or drink any alcohol after midnight on the night before each 
visit, though you can drink non-alcoholic liquids during this time, such as water or juice. 
You cannot use any psychoactive drug, with the exception of caffeine or nicotine, within 
24 hours of each Overnight Test Session (or longer depending on the specific drug – 
this should be discussed with the therapy team).  You cannot use caffeine or nicotine for 
2 hours before and 6 hours after you take the first dose during the Overnight Test 
Session. For 1 week before each Overnight Test Session, you cannot take any herbal 
supplements, nonprescription medications, or prescription medications that have not 
been discussed and approved with the therapy team and study doctor. 
 


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If you are taking certain opioid medications for pain management, you can stay on these 
medications during treatment, although we will ask you to reduce the dose before each 
Overnight Test Session and stop taking them for 12 hours before and at least 24 hours 
after the first dose in each Overnight Test Session. If your pain becomes too severe to 
handle during this period, you will be allowed to take your medication. 
 
First, you and the therapy team will discuss your goals for the Overnight Test Sessions 
and the therapy team will answer any other questions you may have. 
 
Before an Overnight Test Session: 
 
• Your urine will be tested for drugs of abuse, including stimulants, sedatives, 
opioids, and cannabis. 
• If you can become pregnant, you will take a urine pregnancy test. 
• Answer questions about thoughts you might have about hurting or killing yourself.  
 
After urine testing, you will receive a dose containing either MDMA or placebo. After 
taking the dose, you will then sit or lie down in a comfortable position. You can ask for 
eyeshades if you wish. You will listen to music during much of each Overnight Test 
Session, either through headphones or room speakers. During the session there will be 
times when you will be asked to talk to the therapy team. If you are wearing 
headphones, you may remove them yourself if you want to talk to the therapy team or 
have times of silence. Lying or sitting in a comfortable position and listening to music 
are meant to bring out thoughts and feelings, including thoughts and feelings about past 
traumatic experiences. The therapy team will remain with you, and they will help you if 
you need them to. They will speak with you and ask you to talk to them at least once an 
hour, but you can talk to them whenever you wish. There may be times when the 
therapy team will suggest that you stop talking for a while in order to pay attention to 
your thoughts and feelings. There will be beverages available, including juices or 
Gatorade® or similar sports drinks, and you will be encouraged to drink an adequate 
amount of fluid. You can drink it whenever you wish to do so, within the limits of the 
amount that is safe for your body. In the afternoon, food will also be provided. 
 
Approximately 2 hours after you take the first dose, you may take a second dose, after 
discussion with the study doctor. The second dose will contain half the amount of the 
first dose. The second dose may make the effects last longer. If you or the therapy team 
notice you have problems after the first dose, then you will not get the second dose. 
 
The therapy team will watch for any side effects (unwanted effects or health problems), 
which will be treated if necessary. If this happens, the therapy team will keep you fully 
informed about any concerns or treatment. Your blood pressure, temperature, and pulse 
will be measured before taking the first and second doses and at the end of the session. 
If you have any symptoms including confusion, light-headedness, dizziness, chest pain, 


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shortness of breath, tell your therapy team. More frequent measurements may be 
needed if this happens. 
 
If you are confused or upset 8 or more hours after the start of an Overnight Test 
Session, the therapy team will stay with you until you have fully recovered. If the therapy 
team thinks you are at risk of hurting yourself or others, they will either remain with you 
all night or admit you to a hospital until you are no longer at risk. The therapy team will 
ask you how you feel at the beginning and end of the Overnight Test Session and on 
several occasions during the phone follow-up period.  
 
You will be spending the night in a room at the office of the therapy team with an 
attendant who will be staying in another room nearby. You can use the kitchen if you 
want. If you find you need to talk with the therapy team or you are having other 
problems and need to contact the therapy team, the attendant will contact them 
immediately. 
 
The next day, you will have a non-drug therapy session with the therapy team. You 
must have someone drive you to wherever you are staying (home, hotel or another 
location), because we do not know how MDMA will affect your ability to drive and 
because some people report feeling tired, less alert, or having trouble concentrating a 
day after having taken MDMA. If you do not have anyone to take you home, the therapy 
team will find someone to drive you. 
 
After you return home from the therapy session, the therapy team will talk to you by 
phone on Days 2, 4, 6, 7, 8, 10, 12, and 14 after each Experimental Session to ask how 
you are feeling and see whether you should see the therapy team before your next 
scheduled non-drug therapy session. You and your therapy team can decide which days 
would be best to speak on the phone. The phone calls will take approximately 15 
minutes, though they can be as long as you need them to be. The therapy team will ask 
you about thoughts about killing or harming yourself during the second and seventh day 
of phone contact. You can call the therapy team at any time; except for a few times when 
they may be unavailable. At those times the study doctor will be on call and can be 
called at the 24-hour number provided on this consent form. 
 
The therapy team will give you a card with phone numbers for calling the emergency 
number and the IRB, which is an independent committee that protects the rights and 
welfare of study participants.  You can keep this card in your wallet to make it easier for 
you to contact the therapy team if you need to. 
 
If there are delays in following the usual study schedule, the therapy team will call you at 
least once a week to talk about how you’re doing. These calls will take about 15 minutes.  
You need to agree to call the study doctors if any of the following things happen:  
 


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• you have an increase in symptoms that you have taken medication for in the past  
• you have a new symptom or medical issue  
• you need to contact your outside therapist other than for the usual appointments  
• you start or stop taking a prescription medicine or an over-the-counter medicine 
that you have not previously cleared with the therapy team 
• you go to the hospital for any reason 
 
If you have very high blood pressure, get sick, or have an uncomfortable and strong 
lasting negative reaction (unwanted effect or health problem) during or after an Overnight 
Test Session, you or the therapy team may decide that you should not have the next 
Overnight Test Session. You may also make the decision to stop treatment in the study 
for any reason.  
 
If the therapy team decides to take you out of the study for medical reasons after you 
have taken the study drug, they will let you know that they are doing this and their reason 
for doing it. They will help you find a therapist who can continue to help you with your 
PTSD, if needed. If you are taken out of the study or decide you do not want to receive 
treatment in the study, the study researchers will ask you to complete some final 
questionnaires about your PTSD symptoms.  This is optional.  If you decide you do not 
want to continue in the study during an Overnight Test Session, you will still have to stay 
in the office until the therapy team thinks that you are stable enough to leave and that all 
the acute effects of the drug have worn off.  If this happens, you will also be asked to 
take part in some of the same interviews and questionnaires you completed at the 
beginning of the study.  This is optional.  
 
Integration Visits  
The day after each Overnight Test Session, and 2 to4 weeks afterward, you will have 
therapy visits to help you express, understand, bring together and connect any thoughts 
or feelings you may be having about your symptoms and their causes, and to think and 
talk about your experience during the Overnight Test Session. There will be three of 
these visits after every Overnight Test Session visit. These visits will be recorded. Some 
of these visits may happen remotely via telemedicine. These visits will last about 90 
minutes. The therapy team will ask you questions about thoughts about killing or harming 
yourself at these sessions. At the last integration therapy visit you will also complete a 
psychological questionnaire. 
 
Measuring PTSD After Sessions 
Within one month after the first two Overnight Test Sessions and two months after the 
last Overnight Test Session, you will meet with an evaluator online, which will be 
recorded. These meetings will happen at the study site unless the study team tells you 
otherwise.  The researcher will ask about your PTSD symptoms. You will also meet with 
your therapy team about 2 months after your last Overnight Test Sessions to fill out the 
same questionnaires from the start of the study. You will also be asked if you have had 


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any thoughts about hurting or killing yourself. The researchers will measure your blood 
pressure and weight. The tests will help the therapy team tell if your symptoms have 
changed or stayed the same over time. 
 
At or after this visit you will also be invited to participate in a long-term follow-up study 
for an additional visit 12 months from the last time you had an Overnight Test Session 
to see if the changes in people’s PTSD symptoms continue to improve, stay the same, 
or worsen over time after the study. There will be a separate consent form for this study. 
 
You and the therapy team will discuss how you will be notified of whether you received 
MDMA or placebo once the study concludes. At that point, if you received placebo, you 
will be invited to participate in an extension study where all participants will receive 
MDMA. This may happen up to 2 years after you finish this study. There will be a 
separate consent form for that study if you wish to participate. 
 
POSSIBLE RISKS OR DISCOMFORTS 
MDMA has not been widely tested in humans, but as of October 2019, 1,600 people have 
been given MDMA in clinical research settings. Some of the effects that have been 
observed are listed below.  
 
Side effects that are typically not severe but are more frequently reported at active doses of 
MDMA include: 
 
• Anxiety (about four-fifths – 80%) 
• Teeth grinding or tight jaw muscles (about two thirds - 66%) 
• Lack of appetite (about half - 50%) 
• Headache (about half – 50%) 
• Fatigue (about half – 50%) 
• Dizziness (about half – 50%) 
• Nausea (about half – 50%) 
• Sensitivity to cold (about two-fifths – 40%) 
• Muscle tension (about one-third – 33%) 
• Sweating (about one-third – 33%) 
• Insomnia (about one-third – 33%) 
• Restlessness (about one-third – 33%) 
• Thirst (about one-third – 33%) 
• Difficulty balancing or walking (about one-fourth – 25%) 
• Dry mouth (about one-fourth – 25%) 
 
One-fifth of participants or less reported (from most to least common) the following effects: 
low mood, difficulty concentrating, private worries, eye wiggling, heavy legs, tingling of 
hands or feet, drowsiness, irritability, weakness, need for more sleep. When these side 


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effects occur, they usually last less than four hours. However, some effects have been 
reported to last for more than 24 hours and (rarely) for as long as four days. 
 
There may be unknown side effects or risks from the use of MDMA. 
 
Other possible risks of MDMA may include the following: 
 
Serious problems: There have been some serious problems, and even deaths, 
associated with the use of Ecstasy outside of controlled clinical or research settings. These 
problems have included high fever, brain swelling associated with drinking too much liquid, 
convulsions, and liver damage. Some recreational users of ecstasy have become severely 
anxious, depressed or paranoid (thinking that other people are out to get them). Since you 
will be receiving moderate amounts of research grade MDMA in a controlled setting with a 
trained therapy team who will be closely monitoring your physical and psychological 
reactions, these problems are not expected to occur either during or after the Overnight 
Test Session. While this does not guarantee that they will not occur, it does mean that if 
they do occur, the study doctors are prepared to respond in a safe and professional 
manner. 
 
Changes in vision, hearing or other senses: In previous studies in which MDMA was 
given to volunteers, most participants reported experiencing temporary and minor changes 
in vision and hearing, such as sounds seeming closer or farther away than usual or objects 
seeming brighter than usual. These changes typically lasted two to three hours. People 
also reported unusual feelings in their bodies, such as tingling or numbness. 
 
Blood pressure and heart rate: The effects of MDMA usually last 6 to 8 hours with the 
first and second dose. At the dose in this experiment, the increases in blood pressure 
and heart rate are likely to be moderate. Average increase in systolic blood pressure is 
27.5 mmHg (measurement unit for blood pressure) and average diastolic blood 
pressure increase is 13.1 mmHg. Heart rate may increase by approximately 28.4 beats 
per minute (bpm) on average. 
 
In past studies supported by MAPS, blood pressure rose well above normal levels in 
about one-third participants after taking MDMA, but these participants did not report any 
discomfort and did not require any treatment. Although these increases in blood 
pressure are similar to what happens after heavy exercise, they could cause serious 
problems in individuals with pre-existing heart or blood vessel conditions. These serious 
problems could include an irregular heartbeat, heart attack or stroke. We will screen all 
potential participants for preexisting heart problems before they are allowed to be in this 
study. While this doesn't guarantee that no heart problems will occur, it does reduce the 
risk of this happening. 
 


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Anxious or jittery feeling: A little less than four-fifths (80%) of participants with PTSD 
in past studies who received MDMA reported feeling anxious. These feelings usually 
lasted less than 30 minutes.  Letting yourself accept and feel these emotions deeply can 
be part of the psychotherapy. If you are not able to deal with these experiences in a way 
that helps you, the therapy team will work with you to deal with these feelings. It is 
possible that if such periods of heightened emotion do not clear up or grow weaker 
during the session, you could be at increased risk for suicide or other self-harm 
afterwards. You will be encouraged to ask the attendant to call the therapy team 
immediately if you have any thoughts about hurting or killing yourself so they can safely 
help you. If needed, they may prescribe anti-anxiety medication or medication for sleep. 
 
The way MDMA affects the brain has the potential to cause mania in some people, 
although mania has not been reported in individuals receiving MDMA or ecstasy. 
 
Your PTSD symptoms may get worse during the study. 
 
If you are in immediate danger of hurting or killing yourself or hurting someone else, 
then the researchers may require you to be admitted to a hospital. 
 
Insomnia and drowsiness: In previous studies, participants have reported insomnia 
(difficulty sleeping) or feeling tired, irritable, or drowsy for as long as 3 days after taking 
MDMA. If needed, the study doctor may prescribe medication for sleep. You should 
not drive or use machinery immediately after Overnight Test Sessions (up to 24 
hours afterwards). This is because the study drug may cause drowsiness, lack of 
coordination or slower reaction time. 
 
Mood: Some after-effects of MDMA may be noticed up to two or three days later. While 
some participants feel that their mood is better, about one-fifth (20%) feel that it is 
worse. 
 
Immune system: You may have a less active immune system for two or three days 
after taking MDMA. This may make you more likely to become sick with a cold or other 
infection during this time. The study describing this finding did not report how many 
people in the study showed these changes. 
 
Addiction: There is a small chance that you will become dependent on (addicted to) 
MDMA. One study found that up to 6% of people using Ecstasy for recreational 
purposes were dependent on it. However, a study of people who had received MDMA 
for the first time in a legal laboratory setting found that they did not want to try MDMA 
again outside of the laboratory. 
 
People who have recently had problems with drug abuse should not be in this study. 
 


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


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Emotional openness: MDMA is considered an “empathogenic” drug. This means 
people who use it may experience increased empathy and sociability. After taking the 
study drug, you may feel more emotionally open, friendly, extroverted, or talkative. You 
may also feel closer to your therapists or more trusting of them, or you may even feel 
love and sexual feelings toward your therapist(s). This can happen with any 
psychotherapy but may be heightened by MDMA. Your therapists are aware of the 
effects of the drug. They have been through training on how to appropriately care for 
someone who has taken MDMA and on a code of ethics that prohibits any sexual 
relations between therapists and participants, including after participation in the study 
has ended. All of your therapy sessions are recorded. One of the reasons for this is to 
ensure your safety. Videos are randomly reviewed by a group of trained researchers. 
Your therapists also have supervisors who continue to oversee and train them 
throughout the study. 
 
RISKS OF BEING IN THE STUDY 
If you are tested for drugs of abuse within 3 days of each Overnight Test Session, you 
may test positive. The therapy team will provide you with an information card in case 
you are tested for drugs of abuse, and if you are tested for drugs of abuse while you are 
in this study, you can have the person(s) testing you call your therapy team to verify that 
you are in this study. This card may not protect you from discipline at work or loss of 
employment. The study doctors will discuss when and how to present the information 
card. The card will not prevent you from being stopped or cited if you are driving 
erratically or poorly, so you should not operate machinery or drive a car until you feel 
normal again.   
 
The psychotherapy and interviews you have during the study involve no specific risks or 
discomforts beyond those of a standard psychotherapy or a clinical interview situation. 
You may feel upset or increased symptoms at the review of your emotional experiences, 
or you may feel boredom or fatigue. Answering questions about your trauma or thoughts 
you might have of hurting or killing yourself may be upsetting. 
 
There is a risk of loss of privacy related to the conduct of audiovisual sessions during the 
study.  
 
The medical evaluation involves some blood tests. The risks of blood drawing include 
temporary discomfort from the needle stick, bruising and, rarely, infection at the site of the 
needle stick. Fainting could also happen. 
 
It is possible that after you stop taking certain psychiatric medicines (as for depression or 
anxiety) as part of the study, you may start to have symptoms again. There is also a risk 
that you may have thoughts of hurting or killing yourself when you stop taking medicine, 
especially if you have had these thoughts before.  If this happens, you should talk with 
your outside therapist and your therapy team. If you have to start taking medicine again, 


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then the study doctors will have to take you out of the study.  There are some allowable 
medicines on study; your doctors will discuss these with you. 
 
REPRODUCTIVE RISKS 
Effects of MDMA on the growth and development of an unborn baby are not known; 
therefore, you will not be allowed to be in the study if you are pregnant.  If you get 
pregnant after you have had at least one Overnight Test Session, the study doctors and 
the sponsor, MAPS, will ask you about and keep track of your pregnancy and will need to 
know about the outcome of your pregnancy.  If you become pregnant, you will be 
withdrawn from receiving additional study drug, but you will be able to continue in the talk 
therapy sessions if you want to. 
 
Those who are at risk of becoming pregnant must use one of the allowed birth control 
methods: intrauterine device (IUD), intrauterine hormone-releasing system (IUS), non-oral 
hormonal methods (including injected, intravaginal, implanted, or transdermal), 
abstinence, oral hormones plus a barrier contraception or double barrier contraception , or 
a vasectomized sole partner, during the study and for 10 days after the last Overnight 
Test Session. Two forms of contraception are required with any barrier method or oral 
hormones (i.e. condom + diaphragm, condom or diaphragm + spermicide, oral hormonal 
contraceptives + spermicide or condom). If you plan to be abstinent for the study, you will 
need to let the therapy team know what your back-up method will be.  Not being of 
childbearing potential is defined as permanent sterilization or postmenopausal or 
assigned male at birth. The therapy team will explain these methods to you and will help 
you decide which might be best for you, and they can suggest to you where you can get 
more information and advice. 
 
If you are of childbearing potential, you will be tested at the start of the study and again 
before each Overnight Test Session to see if you are pregnant.  If, at any time during 
the study, you think that you may be pregnant or are worried that you may become 
pregnant, you must tell your therapy team immediately. If you should become pregnant 
during the study, the study doctors will help you get proper advice and guide you to get 
proper care while you are pregnant. If you become pregnant, you will discontinue 
treatment but remain in the study for follow-up purposes. 
 
NEW FINDINGS 
If any new information becomes available about MDMA while you are in this study, the 
therapy team will tell you about it as soon as possible. You may be asked to sign a new 
consent form if this occurs. You may contact the therapy team at any time after your 
participation ends to find out if any new information about this study has become 
available. 
 


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POSSIBLE BENEFITS 
Your symptoms of PTSD may improve while taking part in this study. There is no 
guarantee that you will benefit from taking part in this research study. Information 
obtained from this study may help doctors and researchers to improve treatment for 
PTSD and relationships in the future. 
 
PAYMENT FOR PARTICIPATION 
In order to remove some financial barriers to participation, you may be reimbursed for 
direct costs of participation (travel or dependent care costs, for example) for certain 
study visits as they are completed. If you do not complete a visit, you may not be 
reimbursed for costs associated with it. As a nonprofit organization, MAPS has limited 
funds to reimburse participants for financial assistance, and you will have the option to 
decline funds if they aren’t needed. Options for reimbursement will be offered as 
outlined in the table below.  
 
Visit 
Payment 
Overnight Test Session 1 
Up to $70 
Overnight Test Session 2 
Up to $70 
Overnight Test Session 3 
Up to $70 
Visit 3 Psychological Testing 
Up to $70 
Visit 19 Psychological Testing 
Up to $70 
                                       TOTAL  
Up to $350 
 
<<CF-Main Payment for Part. Paragraph>> 
 
COSTS 
The Sponsor of this study, MAPS, will cover the costs that are directly related to the 
research. This includes the costs for all psychotherapy sessions that are a part of this 
study, for the psychological and laboratory testing, for medical examinations, including 
any extra tests you might have, solely to see if you can be in the study (if you are 
eligible), and for the study drug.  You, your private medical insurance (if any), or public 
health insurance plan will not be charged for any procedures done solely for the 
purpose of the study. You or your insurance company will remain responsible for on-
going treatment not included in the study.  
 
ALTERNATIVES 
One alternative to being in this study is to decide not to take part. You may decide to try 
other treatments for PTSD. There are approved medicines that may help treat your 
symptoms of PTSD and other forms of psychotherapy that you could try. Approved 
medications for PTSD are those called selective serotonin reuptake inhibitors (SSRIs 
named paroxetine (Paxil) and sertraline (Zoloft).  If you are currently having 
psychotherapy and/or taking medicine, you could continue with those for a longer period 


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of time. The therapy team can discuss the alternatives and their potential risks and 
benefits with you. 
 
CONFIDENTIALITY 
To ensure confidentiality, your information will be stored in secure electronic systems or 
in a locked office at the participating sites until securely transferred to a remote storage 
facility. These records will be stored for at least 25 years after the end of the study. 
Absolute confidentiality and security cannot be guaranteed, but every effort will be made 
to maintain your confidentiality. 
 
People outside of your therapy team will need access to your information to monitor the 
study and conduct further research and training. Any paperwork copied will have any 
information that could be used to identify you removed first, except for videos, which will 
still show your face and retain recordings of your voice. If records are copied, only your 
participant number and initials will identify you to the study Sponsor unless you give 
specific permission, (for example, if you sign a media release.  
 
Medical records, including audiovisual, which could identify you, and the consent form 
signed by you will be looked at and/or copied for research or regulatory purposes.  
These records may be looked at by: 
 
• The Sponsor, MAPS and the people they hire. 
• The FDA, Health Canada, the Israeli Ministry of Health, and similar agencies in 
other countries. 
• Copernicus Group Independent Review Board (CGIRB).  The IRB is a group of 
scientists and non-scientists who review the ethics of research. The goal of the 
IRB is to protect the rights and welfare of study participants 
• Members of the study team. 
 
<<CF-Main User Defined #4>> Your records may also be inspected by the Research 
Advisory Panel of California (RAPC) or by State and Federal regulatory agencies. 
**FOR CA SITES ONLY** 
 
You have the right to review any medical records related to this study, including lab 
results and cardiac testing. At the end of the study, your therapist team or study doctor 
will provide a summary of study procedures, side effects or other health issues on 
study, and medications taken. 
 
The results of this research study may be presented in meetings, presentations, or in 
publications, where your identity will not be disclosed. Audiovisual recordings of your 
sessions may be used in training sessions for research therapy teams or other 
researchers only in controlled settings as described below. 
 


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Audiovisual recordings: By signing this informed consent you are agreeing to the 
therapy team and evaluators audiovisual recording each visit. The reasons for recording 
the visits are: 
 
• So that the therapy team will have accurate records of the session. 
• So that trained raters working for the Sponsor can verify that the therapy and 
assessments are being carried out properly  
• For further research on the therapy and how it is performed.  
• For training other therapy teams to conduct MDMA-assisted psychotherapy and 
scientists to develop and work on additional research.  
 
For the above purposes, the trained raters, researchers and therapists who may be 
viewing these recordings will be selected by the Sponsor, and will sign confidentiality 
agreements to ensure they do not share the identifying information they may receive. If 
you ever want to withdraw consent from having your videos used at future trainings, you 
can let your study therapists know or send an email to video@mapsbcorp.com 
requesting this. Note: if you email video@mapsbcorp.com, you will be sending 
identifying information to MAPS (the sponsor of this study), including your name and 
email address. You will need to tell MAPS what study you were in, your initials or 
participant identification number, your therapists’ names, and where you took part in the 
study. To avoid sharing this information, you can have your study therapists contact 
MAPS on your behalf without sharing your name or email address. 
 
Information contained in recordings that could be used to identify you may include: 
 
• Your physical appearance 
• Your voice 
• Your name (if it is spoken on the recording) 
• Situations from your life that might be discussed 
 
These recordings will be stored in remote data storage centers. No personally 
identifying information will be used to label the audiovisual recordings. A copy will be 
transferred to the Sponsor for secure electronic storage on the web to allow for viewing 
purposes described above. Electronic systems used will include measures to protect 
confidentiality of your identity and protection of this audiovisual data. Total security 
cannot be guaranteed, but the Sponsor is consistently working to maintain and improve 
the security of its data systems. 
 
During your study sessions you may ask to stop the recording at any time, but your 
therapy team will ask your permission to turn it back on when you are ready. 
 
By signing this consent form, you consent to the collection, access, use and sharing of 
your information as described above.  


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TREATMENT AND COMPENSATION FOR INJURY 
In the event of a study-related injury, the doctor who treats you will bill your insurance 
company. If your insurance company denies coverage or insurance is not available, 
then the Sponsor will pay for any costs that arise from treating a study-related injury, 
including hospitalization. Neither the Sponsor nor the therapy team has a program in 
place to provide additional compensation in the event of an injury. 
 
Your health insurance may not be willing to pay for the costs of treating a study-related 
emergency. The study Sponsor will pay for any study-related procedure that your 
insurance will not cover. 
 
LEGAL RIGHTS 
The above section does not restrict your right to seek legal assistance. You do not 
waive any legal rights by signing this form. 
 
VOLUNTARY PARTICIPATION 
Your decision to take part in this research study is completely voluntary. There will not 
be any penalty or loss of benefits to you if you decide not to take part. 
 
In addition, you may withdraw from (leave, stop being in) the study at any time. There 
will be no penalty or loss of benefits if you decide to withdraw from the research study. 
Before withdrawing from this study, notify your study doctor that you wish to withdraw. 
This notice will allow your study doctor to inform you if there are any potential medical 
risks of withdrawal. You may be asked if you would be willing to return to the office for 
final tests. 
 
If you decide to stop being in the study or are removed from the study, the data 
collected about you up to that point will remain part of the study and will not be removed 
from the study database. 
 
WITHDRAWAL 
Your therapy team, the Sponsor, or the medicine agency in your country has the right to 
stop your participation in the study at any time, with or without your consent, for any of 
the following reasons:  
 
• if you have an adverse effect from the study drugs,  
• if you need a treatment not allowed in this study, such as restarting medication 
for depression or anxiety,  
• if you do not keep appointments or follow study procedures,  
• if you do not take the study drug as instructed,  
• if you become pregnant, or  


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• if the study is canceled by the FDA, Health Canada, Israeli Ministry of Health, 
IRB, or the Sponsor. 
 
The Sponsor, the FDA, Health Canada, Israeli Ministry of Health, or the IRB may decide 
to stop the study at any time. 
 
If the study is stopped, the data collected about you up to that point will remain part of 
the study and will not be removed from the study database. 
 
CONTACT FOR QUESTIONS 
If you have any questions, concerns, or complaints about your participation in this study 
or if you feel that you have experienced a study-related injury or reaction to the study 
drug, or have a complaint about the research study, contact the study doctor using the 
information found on page 1 of this form. 
 
You should contact the study doctor first if you have questions, complaints, or concerns 
about the study. 
 
This research is being overseen by an Institutional Review Board (“IRB”). You may talk 
to them at 888-303-2224, irb@cgirb.com, if: 
 
• You have questions, concerns, or complaints that are not being answered by the 
research team. 
• You are not getting answers from the research team. 
• You cannot reach the research team. 
• You want to talk to someone else about the research. 
• You have questions about your rights as a research participant. 
 
Do not sign this consent form unless you have had a chance to ask questions 
and have received satisfactory answers to all of your questions.  
 


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PARTICIPANT’S STATEMENT OF CONSENT 
 
“A Randomized, Double-Blind, Placebo-Controlled, Multi-Site Phase 3 Study of the 
Efficacy and Safety of Manualized MDMA-Assisted Psychotherapy for the Treatment of 
Severe Posttraumatic Stress Disorder” 
 
My participation in this study is voluntary. I may refuse to take part in or I may stop 
taking part in this study at any time. I will call the researchers if I decide to do this. My 
decision will not affect my current or future regular medical care or any benefits to which 
I am entitled at this site. The staff and/or the Sponsor may stop my participation in this 
study at any time without my consent if they decide it is in my best interest or if I do not 
follow their instructions. 
 
I agree to have my sessions audio and video-recorded during this study. 
 
I understand that this is a very demanding study that will take considerable time and 
attention between sessions. I agree to not take on any major activities or travel while I 
am in the study without discussion with the therapists. 
 
I have read the information in this consent form and it has been discussed with me. I 
have been given sufficient opportunity to consider whether to participate. All of my 
questions so far about the study and my participation in it have been answered. I freely 
consent to take part in this research study. 
 
By signing this consent form, I have not waived any of the legal rights which I otherwise 
would have as a participant in a research study. I have been told that I will be given a 
copy of this consent form<<CF-Main California Bill of Rights>>. 
 
 
 
Signature of Participant 
 
 
 
 
Date 
 
 
 
Printed Name of Participant 
 
 
 
 


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I certify that the information provided was given in language that was 
understandable to the participant. I attest to adhering to informed consent 
procedures. 
 
 
 
 
 
Signature of Person Obtaining Consent 
 
 
 
 
Date 
Printed Name of Person Obtaining Consent 
 
 
 


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ADDITIONAL CARDIAC TESTING 
 
You may need additional testing by a cardiologist if you have hypertension, diabetes, or 
another medical condition. The cardiologist will explain these tests in detail. They may 
include a nuclear exercise stress test and/or carotid ultrasound. These extra tests may 
occur over one or two visits to a cardiologist’s office. The visits will take between 1-3 
hours each. 
 
The study doctors will use the results of these tests to assess whether your heart is 
healthy enough to take MDMA in the study. 
 
In addition to the risks or discomforts listed here, there may be other risks that are 
currently not known. Also, the risks or discomforts described may occur more often or 
be more severe than has been seen before. 
 
Nuclear Exercise Stress Test 
Exercise testing is a way of learning how your heart responds to strenuous exercise. 
For this test, you will go to a doctor’s office that is specifically prepared for this kind of 
procedure. There are two parts to this test. The first you will receive a radiotracer 
followed by imaging (pictures) of your heart. You will then exercise on the treadmill or a 
stationary bicycle. About 2 minutes before stopping (or until signs of difficulty, such as 
shortness of breath or tension in your chest appear), you will receive a second 
radioactive tracer. Another set of imaging will be procured about 60 minutes later. The 
whole procedure will therefore take about 3 hours to complete. The exposure to 
radiation is very low. There are no known side effects to receiving the radioactive 
tracers.  
 
The cardiac tracer is introduced via a needle placed in an arm. This is a fine, small 
gauge needle; it could cause brief minor pain where it is inserted, possible bruising, and 
rarely, infection or fainting. 
 
The nuclear exercise testing may cause discomfort, fatigue, and shortness of breath. 
Rarely, more serious problems such as fainting, falling, or irregular heartbeat have been 
reported. In less than one in 10,000 cases, heart attacks have occurred. The doctor 
performing these testing procedures will monitor you continuously during the test and 
will stop the test if it appears that you are having problems or if you ask to stop the test. 
 
The radiotracer contains a small amount of radiation. This is not necessary for your 
medical care, is for research purposes only, and is necessary to obtain the desired 
information. The “effective” radiation dose you will receive during the rest portion of this 
scan is approximately 2.552 mSv. The “effective” dose from the stress portion is 
approximately 7.656 mSv. Therefore, your total “effective” dose is 10.208 mSv. 
“Effective” dose is a quantity that is used to relate the different doses received by each 


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organ to a single value and can be compared to environmental radiation. The organ 
receiving the highest dose in this test is the gallbladder wall. Both portions of this test 
will be carried out on the same day. The total “effective” dose you will receive is 
comparable to 3.3 times the yearly dose from environmental radiation in the US (3.1 
mSv), is allowed by the FDA for individuals participating in basic research studies and 
has not been shown to involve a risk of cancer 
 
Carotid Ultrasound 
A carotid ultrasound is a painless test that uses high-frequency sound waves to create 
pictures of the insides of your carotid arteries, which are inside your neck. The 
ultrasound will show the doctor if there is any buildup of plaque inside your carotid 
arteries. If there is too much plaque, it can cause blood clots, which can cause a stroke. 
 
There are no known risks associated with the carotid ultrasound procedure, because it 
uses harmless sound waves, similar to how doctors record pictures of fetuses in 
pregnant people. 
 
 


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PARTICIPANT’S STATEMENT OF CONSENT 
 
I consent to take part in this additional cardiovascular testing if it is required of me to 
screen for the study. The testing and the information in this consent form have been 
explained to me. I have read all pages of this form. I have had an opportunity to ask 
questions and they have been answered to my satisfaction. I have been told that I have 
not given up any legal rights. I will receive a copy of this signed and dated consent form. 
 
 
 
Signature of Participant 
 
 
 
 
Date 
 
 
 
Printed Name of Participant 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Authorization 
 
 
 
 
Date 
Printed Name of Person Obtaining Authorization 
 
 
 
 


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


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<<CF-Main User Defined #5>> Your records may also be inspected by the 
Research Advisory Panel of California (RAPC) or by State and Federal 
regulatory agencies. **FOR CA SITES ONLY** 
 
Your personal health information may be further shared by the groups 
above. If shared by them, the information will no longer be covered by the 
Privacy Rule. However, these groups are committed to keeping your 
personal health information confidential.  
 
You have the right to see and get a copy of your records related to the 
study for as long as the study doctor has this information. However, by 
signing this Authorization, you agree that you might not be able to review or 
receive some of your records related to the study until after the study has 
been completed. 
 
You may choose to withdraw this Authorization at any time, but you must 
notify the study doctor in writing. Send your written withdrawal notice to the 
study doctor using the contact information found on page 1 of this form. 
 
If you withdraw from the study and withdraw your Authorization, no new 
information will be collected for study purposes unless the information 
concerns an adverse event (a bad effect) related to the study. If an adverse 
event occurs, your entire medical record may be reviewed.  
 
All information that has already been collected for study purposes, and any 
new information about an adverse event related to the study, will be sent to 
the study Sponsor.  
 
If you withdraw from the study but do not withdraw your Authorization, new 
personal health information may be collected until this study ends.   
 
If you do not withdraw this Authorization, it will remain in effect. 
 
If the research site is located in California, Delaware, Illinois, Indiana, 
Washington, or Wisconsin, this authorization will expire on 31Dec2060. 
 


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There is no expiration of this authorization except for research conducted in 
the states listed above. 
 
<<CF-Main User Defined #3>> ***For IL Sites Only***You have the right 
to review any mental health information collected about you and shared 
with others.  
 
You have the right to review and copy your health information. However, 
your access to this information may be delayed until the study is complete. 
 
If you do not sign this Authorization, you cannot participate in this research 
study. If you withdraw this Authorization in the future, you will no longer be 
able to participate in this study. Your decision to withdraw your 
Authorization or not to participate will not involve any penalty or loss of 
access to treatment or other benefits to which you are entitled. 
 
Authorization 
I authorize the release of my medical records and personal health 
information related to this study to the Sponsor and its representatives, the 
IRB <<CF-Main User Defined #6>>, Research Advisory Panel of California 
(RAPC) **FOR CA SITES ONLY**, the FDA, and other regulatory agencies 
as described above.  I have been told that I will receive a signed and dated 
copy of this Authorization for my records. 
 
 
 
Signature of Participant 
 
 
 
 Date 
 
 
 
Printed Name of Participant 
 
  
 


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Signature of Person Obtaining Authorization 
 
 
 
 Date 
Printed Name of Person Obtaining Authorization 
  
 

SAP_002.pdf: 
MAPP1 Statistical Analysis Plan 
Version 1: 19 January 2017 
Version 2: 9 June 2017 
Version 3: 23 July 2017 
Version 4: 26 July 2017 
Version 5: 25 September 2017 
Version 6: 23 January 2018 
Version 7: 22 May 2020 
SPONSOR 
SPONSOR 
REPRESENTATIVE 
SPONSOR DELEGATE & 
TRIAL ORGANIZER 
SPONSOR DESIGNEE 
MEDICAL MONITOR(S) 
STATISTICIAN(S) 
PREPARED BY 
USE 
Multidisciplinary Association for Psychedelic Studies (MAPS) 
1115 Mission Street 
Santa Cruz, CA 95060 
Rick Doblin, Ph.D. 
Executive Director, MAPS 
MAPS Public Benefit Corporation (MPBC) 
1115 Mission Street 
Santa Cruz, CA 95060 
Amy Emerson 
Executive Director, MPBC 
Phone number: 510-393-7224 
Email: amy@mapsbcorp.com 
Michael Mithoefer, M.D. 
Scott Hamilton, Ph.D. 
Scott Hamilton, Ph.D. 
Berra Yazar-Klosinski, Ph.D. 
Julie Wang, MPh, Ph.D. 
In conjunction with relevant FDA, HC, MOH guidance 


MAPS Public Benefit Corporation 
 
MAPP1 SAP 
IND #063384 
 
Version 7: 22 May 2020 
 
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Table of Contents 
List of Tables ................................................................................................................................... 3 
List of Abbreviations ...................................................................................................................... 4 
1.0 Definitions of Terms ................................................................................................................. 6 
2.0 Introduction .............................................................................................................................. 7 
3.0 Study Objectives ....................................................................................................................... 7 
3.1 Primary Objective ................................................................................................................... 7 
3.2 Secondary Objective ............................................................................................................... 7 
3.3 Safety Objectives .................................................................................................................... 7 
3.4 Exploratory Objectives ........................................................................................................... 8 
4.0 Measures .................................................................................................................................... 9 
5.0 Study Design ............................................................................................................................ 11 
6.0 Randomization and Blinding ................................................................................................. 15 
7.0 Sample Size and Power Considerations ................................................................................ 15 
8.0 Analyses ................................................................................................................................... 16 
8.1 Analysis Sets ......................................................................................................................... 16 
8.2 Missing Data Handling ......................................................................................................... 16 
8.2.1 Partial or Missing Dates ................................................................................................ 17 
8.3 Protocol Deviations .............................................................................................................. 17 
8.4 Baseline Values .................................................................................................................... 17 
8.5 Participant Disposition and Dosing Summary ...................................................................... 18 
8.6 Demographics and Baseline Characteristics ......................................................................... 18 
8.7 Efficacy Analyses ................................................................................................................. 18 
8.7.1 Primary Efficacy Analyses ............................................................................................ 18 
8.7.2 Supportive Analyses: ..................................................................................................... 19 
8.7.3 Key Secondary Efficacy Analyses................................................................................. 22 
8.7.4 Responder Analyses....................................................................................................... 24 
8.8 Safety Analyses .................................................................................................................... 26 
8.8.1 Analysis of Exposure ..................................................................................................... 26 
8.8.2 Analysis of Adverse Events ........................................................................................... 26 
8.8.3 Concomitant Medications .............................................................................................. 26 
8.8.4 Analysis of Suicidal Ideation and Behavior .................................................................. 27 
8.8.5 Analysis of Vital Signs .................................................................................................. 27 
8.9 Administrative Interim Analysis........................................................................................... 27 
9.0 Data Monitoring Committee .................................................................................................. 29 
10.0 Timing of Analyses ............................................................................................................... 29 
 
 


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List of Tables 
 
Table 1: Protocol Objectives and Assessment Tools ........................................................................ 9 
Table 2: Phase 3 Dose Regimen of MDMA or Placebo ................................................................. 11 
Table 3: Time and Events ............................................................................................................... 12 
Table 4: Proposed Estimands and Key Attributes .......................................................................... 19 
Table 5: Inference of Treatment Effect for Missing Data from mITT Set Based on Reasons for 
Post-Randomization Withdrawal ............................................................................................ 21 
Table 6: Observed Effect Sizes and Corresponding Sample Size for 90% Conditional Power 
Guidance at the Interim Analysis (N=60) ............................................................................... 28 
 
 


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List of Abbreviations 
 
ACE 
 
Adverese Childhood Experiences Questionnaire 
AE  
 
Adverse Event 
AESI  
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
AUDIT  
Alcohol Use Disorders Identification Test 
BDI-II              Beck Depression Inventory-II 
BMI 
 
Body Mass Index 
BOCF  
Baseline Observation Carried Forward 
BP  
 
Blood Pressure 
CAPS-4 
Clinician Administered PTSD Scale for DSM-4 
CAPS-5 
Clinician Administered PTSD Scale for DSM-5 
CPGS  
Chronic Pain Grade Scale 
C-SSRS  
Columbia Suicide Severity Rating Scale  
DDIS  
Dissociative Disorders Interview Schedule 
DMC  
Data Monitoring Committee 
DSM-4  
Diagnostic and Statistical Manual of Mental Disorders, 4th edition 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
DSPI 
 
Dissociative Subtype of PTSD Interview 
DUDIT  
Drug Abuse Disorders Identification Test 
EAT-26 
Eating Attitudes Test 
EQ-5D-5L 
EuroQol Five Dimensions – Five Levels Questionnaire 
ES  
 
Effect Size 
GCP 
 
Good Clinical Practice 
HPQSF  
Health and Work Performance Absenteeism and Presenteeism Short Form 
IASC  
Inventory of Altered Self-Capacities 
 
IP 
 
Investigational Product 
IPF 
 
Inventory of Psychological Functioning 
IR 
 
Independent Rater 
ISG 
 
Independent Statistical Group 
IWRS  
Interactive Web Randomization System 
LEC-5  
Life Events Checklist 
LOCF  
Last Observation Carried Forward 
LS 
 
Least Squares 
MAPS  
Multidisciplinary Association for Psychedelic Studies 
MAR  
Missing at Random 
MDI 
 
Multiscale Dissociation Inventory 
MDMA 
3,4-methylenedioxymethamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities  
Mg 
 
Milligram 
mITT              Modified Intent-to-Treat 
MMRM 
Mixed Model Repeated Measure 
MNAR  
Missing Not at Random 
MPBC  
MAPS Public Benefit Corporation 
NPP 
 
Not Per Protocol 
PCL-5  
PTSD Checklist for DSM-5 
PMM  
Pattern Mixture Model 
PP  
 
Per Protocol 
PSQI   
Pittsburgh Sleep Quality Index 
PT 
 
Preferred Terms 
PTSD   
Posttraumatic Stress Disorder 


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IND #063384 
 
Version 7: 22 May 2020 
 
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REML  
Restricted Maximum Likelihood 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SCS 
 
Self-compassion Scale 
SDS 
 
Sheehan Disability Scale 
SEM 
 
Standard Error of Measurement 
SOC 
 
System Organ Class 
SRNU  
Self-reported Nicotine Use 
TEAE  
Treatment Emergent Adverse Event 
TAS-20 
Toronto Alexithymia Scale 
UFEC  
Utilization of Facility-based and Emergent Care 
WHO DDE 
WHO Drug Dictionary EnhancedTM 
WOCF  
Worst Observation Carried Forward 
 
 
 
 


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


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Tabular listing: list of each variable or item for each individual participant either in total or by 
treatment group in a table format 
 
2.0 Introduction 
This document contains a Statistical Analysis Plan (SAP) for the study, “A Randomized, Double-
Blind, Placebo-Controlled, Multi-Site Phase 3 Study of the Efficacy and Safety of Manualized 
MDMA-Assisted Psychotherapy for the Treatment of Severe Posttraumatic Stress Disorder.” 
 
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit research and 
educational organization working to obtain approval for the prescription use of 3,4-
methylenedioxymethamphetamine (MDMA) in conjunction with psychotherapy in persons with 
posttraumatic stress disorder (PTSD). MAPS has delegated trial organization activities to its 
wholly owned subsidiary, MAPS Public Benefit Corporation (MPBC). 
 
To confirm the efficacy and safety of this treatment for participants with severe PTSD, the 
sponsor is conducting this Phase 3 randomized, placebo-controlled, two-arm, double-blind, multi-
site study with three monthly Experimental Sessions of psychotherapy combined with either 
MDMA or placebo, along with 12 non-drug psychotherapy sessions including preparatory and 
integrative sessions. The Primary Outcome measure, the Clinician Administered PTSD Scale 
(CAPS-5), evaluates PTSD symptom severity and is assessed by a blinded centralized 
Independent Rater (IR) pool.  
 
3.0 Study Objectives 
3.1 Primary Objective  
The primary objective of this study is to evaluate the de jure efficacy of MDMA-assisted 
psychotherapy for PTSD compared to identical psychotherapy with inactive placebo, as measured 
by the reduction in CAPS-5 Total Severity Score from Visit 3 (Baseline) to Visit 19 (18 weeks 
post Baseline). 
 
3.2 Secondary Objective 
The key secondary objective of this study is to evaluate the efficacy of MDMA-assisted 
psychotherapy for PTSD compared to identical psychotherapy with inactive placebo in clinician-
rated functional impairment, as measured by the mean change in Sheehan Disability Scale (SDS) 
item scores from Visit 3 (Baseline) to Visit 19 (18 weeks post Baseline).  
 
3.3 Safety Objectives 
The overall safety objective is to assess differences between groups in severity, incidence and 
frequency of Adverse Events (AEs), Treatment Emergent AEs (TEAEs), AEs of Special Interest 
(AESIs), and Serious Adverse Events (SAEs), concomitant medication use, suicidal ideation and 
behavior, and vital signs to support the package insert for MDMA-assisted psychotherapy. The 
following safety objectives will evaluate the safety of MDMA-assisted psychotherapy compared 
to identical psychotherapy with inactive placebo:  
 
1. Compare relative incidence of AEs during Experimental Sessions that may be indicative 
of a medical complication of the Investigational Product (IP) such as clinical signs and 


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symptoms of chest pain, shortness of breath, or neurological symptoms or any other signs 
or symptoms that prompt additional vital sign measurements. 
2. Compare relative incidence of AEs by severity. 
3. Compare relative incidence of TEAEs, to determine relationship to the IP based on 
relative incidence in the MDMA group. 
4. Compare relative incidence of TEAEs by severity reported during an Experimental 
Session, 1 and 2 days after IP administration. 
5. Compare relative incidence of AESIs, defined as AEs specified in the protocol related to 
cardiac function and abuse liability. 
6. Compare relative incidence of AEs by severity categorized as leading to discontinuation 
of IP, resulting in death or hospitalization, and continuing at Termination 
7. Compare relative incidence of SAEs 
8. Compare relative incidence of concomitant medications taken during an Experimental 
Session, 1 and 2 days after IP administration. 
9. Compare relative incidence of psychiatric concomitant medications taken during the 
Treatment Period. 
10. Compare relative incidence of positive or serious ideation and suicidal behavior assessed 
with the Columbia Suicide Severity Rating Scale (C-SSRS) by treatment group. 
11. Compare mean changes in blood pressure, heart rate, and body temperature from pre-IP 
administration to end of each Experimental Session by treatment group. 
 
3.4 Exploratory Objectives 
The additional exploratory objectives of this study involve comparing participants receiving 
active dose MDMA to those receiving placebo to support the primary objective: 
 
• 
Assess differences between treatment groups in change of dissociative symptoms 
associated with PTSD, as measured by the de jure estimand of change in Dissociative 
Subtype of PTSD Interview (DSPI) Total Score from Baseline (Visit 3) after 18 weeks 
(Visit 19) post-randomization 
• 
Explore the correlation of dissociation symptoms as measured by the de jure estimand of 
change in DSPI with the change in CAPS-5 Total Severity scores from Baseline (Visit 3) 
after 18 weeks (Visit 19) post-randomization 
• 
Characterization of CAPS-5 Total Severity score at weeks 6, 10, and 18 to explore onset 
of treatment efficacy with a descriptive time course plot.  
• 
Explore the effect of adverse childhood experiences on treatment outcome, as measured 
by the Adverse Childhood Experiences Questionnaire (ACE) at screening, on the de jure 
estimand of change in CAPS-5 Total Severity scores from from Baseline (Visit 3) after 
18 weeks (Visit 19) post-randomization 
• 
Assess differences between treatment groups in change in depression symptoms, as 
measured by the de jure estimand of change in the Beck Depression Inventory-II (BDI-II) 
total score from Baseline (Visit 4) after 18 weeks (Visit 20) post-randomization 
• 
Assess differences between treatment groups in change of sleep quality, as measured by 
the de jure estimand of change in Pittsburgh Sleep Quality Index (PSQI) total score from 
Baseline (Visit 4) after 18 weeks (Visit 20) post-randomization 
• 
Assess differences between treatment groups in change in chronic pain, as measured by 
the de jure estimand of change in Chronic Pain Grade Scale (CPGS) total score from 
Baseline (Visit 4) after 18 weeks (Visit 20) post-randomization 
• 
Explore the effect of presence of secondary traumatic stressors during the last month on 
the CAPS-5 Total Severity analyses, as measured by the Life Events Checklist (LEC-5) 
from Baseline (Visit 4) after 18 weeks (Visit 20) post-randomization 


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• 
Explore changes within-participants in PTSD symptom clusters of re-experiencing, 
avoidance, negative alterations in cognition and mood, and hyperarousal, as measured by 
the de jure estimand of change in CAPS-5 subscale scores from Baseline (Visit 3) after 
18 weeks (Visit 19) post-randomization 
• 
Assess differences between treatment groups in change in functioning in relation to self 
and others, as measured by the de jure estimand of change in Inventory for Altered Self-
Capacities (IASC) subscale scores from Baseline (Visit 4) after 18 weeks (Visit 20) post-
randomization 
• 
Assess differences between treatment groups in change in alexithymia, as measured by 
the de jure estimand of change in Toronto Alexithymia Scale (TAS-20) total score from 
Baseline (Visit 4) after 18 weeks (Visit 20) post-randomization 
• 
Assess differences between treatment groups in change in self-compassion, as measured 
by the de jure estimand of change in Self-Compassion Scale (SCS) total score from 
Baseline (Visit 4) after 18 weeks (Visit 20) post-randomization 
• 
Assess differences between treatment groups in change in quality of life, as measured by 
the de jure estimand of change in EuroQol Five Dimensions – Five Levels Questionnaire 
(EQ-5D-5L) from Baseline (Visit 4) after 18 weeks (Visit 20) post-randomization 
• 
Assess differences between treatment groups in change in eating habits, as measured by 
the Eating Attitudes Test (EAT-26) from Baseline (Visit 4) after 18 weeks (Visit 20) 
post-randomization 
• 
Assess differences between treatment groups in change in drug use, as measured by the 
Drug Use Disorders Identification Test (DUDIT) total score from Screening to 18 weeks 
(Visit 20) post-randomization 
• 
Assess differences between treatment groups in change in alcohol use, as measured by 
the Alcohol Use Disorders Identification Test (AUDIT) total score from Screening to 18 
weeks (Visit 20) post-randomization 
• 
Assess differences between treatment groups in change in nicotine use, as measured by 
the Self-reported Nicotine Use (SRNU) from Baseline (Visit 4) after 18 weeks (Visit 20) 
post-randomization 
• 
Assess differences between treatment groups in change in workplace productivity, as 
measured by the Health and Work Performance Absenteeism and Presenteeism Short 
Form (HPQSF) from Baseline (Visit 4) after 18 weeks (Visit 20) post-randomization 
 
4.0 Measures 
Table 1: Protocol Objectives and Assessment Tools 
 
Objectives 
Measure 
Measure Type 
Administration 
Eligibility 
Assess psychiatric disorders 
 
 
MINI 
Eligibility 
Site 
Assess personality disorders 
SCID-5-PD 
with SCID-
5-SPQ 
Eligibility 
Telemedicine 
(IR)/ self-report 
measure at Site 
Confirm PTSD diagnosis and severity 
PCL-5 with 
LEC-5 
Eligibility 
Site 
Identify dissociative disorders  
 
DDIS 
Eligibility 
Site 


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Objectives 
Measure 
Measure Type 
Administration 
Primary 
Assess changes in PTSD symptom severity 
from Visit 3 to Visit 19 compared between 
groups 
 
CAPS-5 
Outcome 
Telemedicine 
(IR) 
Secondary 
Assess changes in clinician-rated functional 
impairment from Visit 3 to Visit 19 compared 
between groups 
 
SDS 
Outcome 
Telemedicine 
(IR) 
Safety 
Compare relative incidence of positive or 
serious ideation and suicidal behavior between 
groups 
C-SSRS 
Safety 
Site 
Exploratory 
Characterization of CAPS-5 Total Severity 
score at weeks 6, 10, and 18 to explore onset 
of treatment efficacy with a descriptive time 
course plot 
CAPS-5 
Outcome 
Telemedicine 
Explore changes in PTSD symptom clusters of 
re-experiencing, avoidance, negative 
alterations in cognition and mood, and 
hyperarousal as measured by changes in 
CAPS-5 subscale scores 
CAPS-5 
Outcome 
Telemedicine 
Assess changes in severity of dissociative 
symptoms associated with PTSD from Visit 3 
to Visit 19 compared between groups  
DSP-I 
Outcome 
Telemedicine 
(IR) 
Explore correlation of dissociative symptoms 
associated with PTSD with the CAPS-5 Total 
Severity analyses 
DSP-I 
CAPS-5 
Outcome 
Telemedicine 
(IR) 
Explore the effect of presence of secondary 
traumatic stressors during the assessment 
period as a covariate on the CAPS-5 Total 
Severity analyses  
LEC-5 
CAPS-5 
Outcome 
Site or 
Telemedicine 
Explore the effect of adverse childhood 
experiences on PTSD treatment outcomes as a 
covariate on the CAPS-5 Total Severity 
analyses 
ACE 
CAPS-5 
Outcome 
Site or 
Telemedicine 
Assess changes in depression symptoms from 
Visit 4 to Visit 20 compared between groups 
BDI-II 
Outcome 
Site or 
Telemedicine 
Assess changes in chronic pain from Visit 4 to 
Visit 20 compared between groups 
CPGS 
Outcome 
Site or 
Telemedicine 
Assess changes in quality of life from Visit 4 
to Visit 20 compared between groups 
EQ-5D-5L 
Outcome  
Site or 
Telemedicine 
Assess changes in functioning in relation to 
self and others from Baseline to Visit 20 
compared between groups 
IASC 
Outcome 
Site or 
Telemedicine 
Assess changes in self-reported psychosocial 
functioning from Visit 4 to Visit 20 compared 
between groups 
IPF 
Outcome 
Site or 
Telemedicine 
Assess changes in self-compassion from Visit 
4 to Visit 20 compared between groups 
SCS 
Outcome 
Site or 
Telemedicine 
Assess changes in alexithymia from Visit 4 to 
Visit 20 compared between groups 
TAS-20 
Outcome 
Site or 
Telemedicine 


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Objectives 
Measure 
Measure Type 
Administration 
Assess changes in alcohol use from Screening 
to Visit 20 compared between groups  
AUDIT 
Healthcare cost 
Site or 
Telemedicine 
Assess changes in drug use from Screening to 
Visit 20 compared between groups  
DUDIT 
Healthcare cost 
Site or 
Telemedicine 
Assess changes in nicotine use from Visit 4 to 
Visit 20 compared between groups 
SRNU 
Healthcare cost 
Site or 
Telemedicine 
Assess changes in disordered eating from Visit 
4 to Visit 20 compared between groups  
EAT-26 
Healthcare cost 
Site or 
Telemedicine 
Assess changes in workplace productivity 
from Visit 4 to Visit 20 compared between 
groups 
HPQSF 
Healthcare cost 
Site or 
Telemedicine 
Assess facility-based healthcare utilization at 
Screening 
UFEC 
Healthcare cost 
Site or 
Telemedicine 
 
5.0 Study Design 
Table 2: Phase 3 Dose Regimen of MDMA or Placebo 
 
Experimental Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative Dose 
1 
80 milligrams (mg) 
40 mg 
80 mg to 120 mg 
2 
80 or 120 mg 
40 or 60 mg 
80 mg to 180 mg 
3 
80 or 120 mg 
40 or 60 mg 
80 mg to 180 mg 
Total Cumulative Dose 
240 mg to 480 mg 
* Unless contraindicated 


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


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Treatment Period 
~12 weeks (+/-3 weeks) 
Follow-up Period & 
Study Termination 
(~4 wks) 
 
Treatment 1 
Treatment 2 
Treatment 3 
Primary 
Outcome 
Study 
Termi-
nation 
Visit 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
Visit Description 
Exp. 1 
Int. 1.1 
Int. 
1.2 G 
CAPS-5 
T2: 
Tele- 
medicin
e 
Int.  
1.3 G 
Exp. 2 
Int. 2.1 
Int. 
2.2 G 
CAPS-5 
T3: 
Tele- 
medicin
e 
Int.  
2.3 G 
Exp. 3 
Int. 3.1 
Int.  
3.2 G 
Int.  
3.3 G 
CAPS-5 T4 
Outcome: 
Tele-
medicine F 
Study 
Termi-
nation 
Visit Timing 
4 to 7 
days 
after 
V3; 1 
to 4 
days 
after 
V4 
Morn-
ing 
after 
V5 
3 to 
14 
days 
after 
V5  
18 to 30 
days 
after V5  
20 to 
34 days 
after 
V5; 1 
to7 
days 
before 
V10 
21 to 
25 
days 
after 
V5 
Morn-
ing 
after 
V10 
3 to 
14 
days 
after 
V10 
18 to 30 
days 
after 
V10 
20 to 
34 days 
after 
V10; 1 
to 7 
days 
before 
V15 
21 to 
35 
days 
after 
V10 
Morn-
ing 
after 
V15 
3 to 14 
days 
after 
V15 
21 to 
35 
days 
after 
V15  
105 to 147 
days after 
V3; 42 to 
70 days 
after V15 
105 to 
147 
days 
after 
V3; 1 to 
9 days 
after 
V19 
Past/Current 
Medication & 
Adherence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Screen  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All AEs A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Container 
Assignment B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer IMP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8-hour Exp. 
Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BP, Pulse, 
Temperature C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 D 
Overnight Stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
90-min Integrative 
Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Call 
Follow-up E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A  All Adverse Events (AEs) includes collecting Serious Adverse Events, AEs of Special Interest, AEs of Psychiatric Status, AEs requiring medical advice or attention, AEs that 
indicate withdrawal of a participant, and all other AEs 
B  Randomize 24 to 48 hours prior to first Experimental Session; obtain container assignment 24 to 48 hours prior to each Experimental Session 
C  During Experimental Sessions, vitals are measured before Investigational Product administration, immediately before the supplemental dose is administered (or would be, if 
supplemental dose not given), and approximately 8 hours after initial dose, and as needed 
D  At Study Termination, only blood pressure needs to be measured 


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E  14 days of phone call follow-up: Days 2, 4, 6, 7, 8, 10, 12, 14 after each Experimental Session 
F  All visits must be scheduled to ensure that the Primary Outcome CAPS-5 T4 assessment is within the overall window provided: 105 to 147 days post Visit 3 
G  All Integrative Sessions must be at least 2 days apart. An Integrative Session and CAPS-5 assessment may take place on the same day (in the appropriate order, per protocol).H  Four 
days of phone call follow-up: Day 2 and 7 after the Experimental Session, with two additional calls in between 
I    All visits must be scheduled to ensure that the CAPS-5 T4 assessment is within the window provided 
 
 
 
 
Screening 
Baseline & 
Enrollment 
Confirmation 
Treatment 1 
Treatment 2 
Treatment 3 
Follow-up & Study 
Termination 
Visit # 
Site A 
IR 
Screening 
IR 
V3 
V4 
V5 
V6&7 
IR 
V8 
V9 
V10 
V11&12 
IR 
V13 
V14 
V15 
V16&17 
V18 
IR 
V19 
V20 
Visit Description 
~Time to 
Complete 
Measure 
(minutes) 
Site Visit 
Tele-
medicine 
Tele-
medicine 
Site 
Visit 
Exp. 
Session 
1 
Int. 
Sessions 
1.1 & 
1.2 
CAPS-5 
T2: Tele-
medicine 
Int. 
Session 
1.3 
Exp. 
Session 2 
Int. 
Sessions 
2.1 & 
2.2 
CAPS-5 
T3: Tele- 
medicine 
Int. 
Session 
2.3 
Exp. 
Session 3 
Int. 
Sessions 
3.1 & 3.2 
Int. 
Session 
3.3 
CAPS-5 
T4: 
Outcome: 
Tele-
medicine 
Study 
Termi-
nation 
CAPS-5 
90 (Baseline) 
60 (all others)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SDS 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSP-I 
 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS B 
10 
 
 
 
 
C 
 
 
 
C 
 
 
 
C 
 
 
 
 
MINI 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-SPQ 
20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-PD 
60 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LEC-5 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PCL-5 
8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DDIS D 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACE 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI-II 
10 (Baseline) 
5 (all others) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPGS 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IASC 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IPF 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCS 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TAS-20 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUDIT 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DUDIT 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SRNU 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EAT-26 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HPQSF 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UFEC 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
~Total Time of Completing 
Measures (minutes) 
49 
90 
107 
85 
 
10 
10 
77 
15 
10 
10 
77 
15 
10 
10 
15 
77 
87 
 
A Ensure that LEC-5 and SCID-5-SPQ results are sent to the Independent Rater who will be conducting the SCID-5-PD 
B First C-SSRS is a Lifetime assessment, other assessments are Since Last Visit 
C Conducted pre- and post-Investigational Product administration, and at phone calls on Days 2, 4, 6, 7, 8, 10, 12, and 14 after Experimental Sessions 
D The relevant questions (117-130) from the DDIS will be asked by the Independent Rater during the SCID-5-PD assessment. The entire measure will never be administered. 


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6.0 Randomization and Blinding 
Eligible participants will be enrolled in the study and sequentially assigned an identification 
number. Participants will be assigned to MDMA or placebo treatment groups via an Interactive 
Web Randomization System (IWRS) based on a randomization schedule developed by an 
independent third-party vendor to maintain blinding. Randomization will be stratified by clinical 
site.  
 
To minimize bias, protect the study’s double-blind and to ensure data quality, the Sponsor plans to 
use a second Electronic Data Capture (EDC) database that is dedicated to the collection of critical 
primary and key secondary outcome measures, including the Total Severity Score on the CAPS-5 
and item scores on the Sheehan Disability Scale (SDS), administered by the centralized blinded 
Independent Rater (IR) Pool through live video. This second database is termed the Independent 
Rater Database (IRDB) and it will be separate from the blinded, clinical EDC database in order to 
ensure that site and sponsor staff engaged in study conduct are masked from study outcomes. The 
IRDB will only be accessible by: (1) qualified, observer-blind individuals who are in the established 
IR Pool, (2) the Senior IR responsible for oversight and data quality of the IR Pool, and (3) the IR 
Coordinator responsible for data entry based on paper Source Records completed by the IR Pool. 
All CAPS-5 and SDS scores and supporting documentation will be reviewed by the IR Coordinator 
prior to data entry.  
 
As a site-independent review method that evaluates and confirms diagnoses, symptom severity, 
and subject validity prior to randomization, the Senior IR will review endpoint data quality. Once 
data is entered into the IRDB, the Senior IR will oversee the data quality by centrally monitoring 
the critical data using a risk-based approach. The risk-based monitoring methodology will utilize 
the following strategies: 1) To perform remote, source data review of the IRDB to check logic and 
to confirm reliability between the IR’s, 2) To perform remote, source data verification to check the 
IRDB for administrative, data entry, or transcription errors made by the Independent Rater 
Coordinator, and 3) To perform systematic line listing reviews for data trends and/or to trigger 
implementation of pre-defined, risk-mitigation strategies when specific data thresholds are 
exceeded. 
 
7.0 Sample Size and Power Considerations 
The statistical power calculations were made by fitting an MMRM model to CAPS-4 data from 
the Phase 2 study MP1 data to obtain covariance parameter estimates. CAPS-4 data was also 
converted to the CAPS-5 scale, by dividing the CAPS-4 score by 34 and multiplying by 20 to 
obtain the CAPS-5 score, and both methods came up with the same level of statistical power. The 
following inputs created the 90% statistical power estimate using the PASS 14 Mixed Models 
Repeated Measures module. 
a. N=47 per group (allowing for 3 dropouts per treatment group) 
b. Alpha = 0.0499 
c. 1000 simulations 
d. Change from baseline means of 5.5, 12.8, and 20.5 for placebo. Change from baseline 
means of 17.2, 31.1, and 37.4, for MDMA at visits 1, 2, and 3, respectively 
e. Two levels of treatment factor (MDMA, Placebo) 
f. Three within subject levels (3 treatment visits) 
g. Subject level variance = 335 
h. Variance of R (diagonal elements) = 280 
i. Rho = 0.5 
j. Unstructured covariance 


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Additional participants may be added to the sample size at the recommendation of the Data 
Monitoring Committee (DMC) from the results of an administrative interim analysis (Section 8.9) 
occurring after 60% of the mITT participants have completed a final assessment of the Primary 
Outcome (Visit 19) and terminated treatment. 
 
8.0 Analyses 
Every effort will be made to ensure complete, accurate and timely data collection and to avoid 
missing data, to ensure the completeness of the data which can impact the integrity and accuracy 
of the final study analysis. The statistical analyses will be reported using summary tables, figures, 
and data listings. All analyses and tabulations will be performed using SAS® Version 9.4 or 
higher, and S-PLUS. In general, nominal variables will be described in terms of frequencies and 
percentages and analyzed using chi square analysis. Ordinal and non-normal continuous variables 
will be described using sample median and range and analyzed by non-parametric statistical tests. 
Approximately normal variables will be described using sample mean and standard deviations 
and analyzed by parametric statistical tests. Except for the primary efficacy analysis, all statistical 
tests will be two-sided and a difference resulting in a p-value of less than or equal to 0.05 will be 
considered statistically significant. All p-values will be rounded to and displayed in four 
decimals. If a p-value less than 0.0001 occurs it will be shown in tables as <0.0001. Data not 
subject to analysis according to this plan will not appear in any tables or graphs, but will be 
included in the data listings. Selected results may be presented graphically using standard 
graphical software. 
 
Post-hoc exploratory analyses not identified in this SAP may be performed to further examine the 
study data. These analyses will be clearly identified as such in the final clinical study report. 
 
8.1 Analysis Sets 
• 
Modified Intent-To-Treat (mITT): all randomized participants who receive IP in at least 
one blinded Experimental Session (Visit 5) and have at least one follow-up CAPS-5 
assessment post-treatment 
• 
Per Protocol (PP): all randomized participants who meet eligibility criteria, who receive 
IP in three Experimental Sessions, and have three follow-up CAPS-5 assessments post-
treatment 
• 
Not Per Protocol (NPP): all participants who are included in the mITT set but not the PP 
set 
• 
Safety: all participants who receive any IP  
• 
All Enrolled: all participants who sign informed consent and are initially enrolled 
 
8.2 Missing Data Handling 
All possible procedures within Good Clinical Practice (GCP) will be used to minimize Post-
randomization Early Termination. Based on Phase 2 data it is expected that up to 5% of enrolled 
and randomized participants will terminate early. Post-randomization Early Terminators will be 
compared to the Completers using baseline demographics and CAPS-5 Total Severity Score at 
baseline. For the Post-randomization Early Terminators, data collection by IRs will continue on 
the same schedule as planned through Study Termination visit procedures in order to limit 
missing data. All observed CAPS-5 data up to the point of discontinuation of treatment will be 
included in the MMRM model of the de jure estimand from Post-randomization Early 
Terminators. Participants will not be replaced, enrollment and treatments will continue until 
N=100 participants are obtained in the mITT set. All observed CAPS-5 data from Post-


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randomization Early Terminators collected prior to and after early termination will be included in 
the supportive effectiveness analysis of the de facto estimand. 
 
8.2.1 Partial or Missing Dates 
The following conventions will be used to impute missing portions of dates for AEs and 
concomitant medications. Note that the imputed values outlined here may not always provide the 
most conservative date. In those circumstances, the imputed value may be replaced by a date that 
will lead to a more conservative analysis. 
 
Start Dates: 
1. If the year is unknown, then the date will not be imputed and will be assigned a missing 
value.  
2. If the month is unknown, then: 
a. The month and day of the first dose date will be imputed if the year matches the 
first dose date year. 
b. Otherwise, ‘January’ will be assigned. 
3. If the day is unknown, then: 
a. The day of the first dose date will be imputed if the month and year match the 
first dose date month and year.  
b. Otherwise, the first day of the month will be assigned. 
 
Stop Dates: 
1. If the year is unknown, then the date will not be imputed and will be assigned a missing 
value. 
2. If the month is unknown, then ‘December’ will be assigned. 
3. If the day is unknown, then the last day of the month will be assigned. 
 
8.3 Protocol Deviations 
A major deviations will be defined as participants enrolled and randomized but did not meet 
eligibility critera during the course of the study. The number of participants in each protocol 
deviation category listed below will be summarized by analysis set and treatment group. 
Individual participants will appear in a listing. 
 
Possible protocol deviations include the following categories: 
 
• 
Participant entered study but did not meet criteria 
• 
Participant developed withdrawal criteria but was not withdrawn 
• 
Participant received excluded concomitant treatment 
• 
Protocol procedure not performed per protocol 
• 
Participant received incorrect treatment or incorrect dose 
• 
Protocol procedure performed out of range 
• 
Miscellaneous 
 
8.4 Baseline Values 
Baseline values are from Baseline Visits for all measures, except C-SSRS, AUDIT, DUDIT, 
resting blood pressure (BP), Body Mass Index (BMI). For C-SSRS, the initial screening visit will 
be conducted with the ‘Lifetime’ version of the measure. The Independent Rater Screening 
assessment of ‘Since Last Visit’ suicidal ideation and behavior will be used as ‘Baseline.’ For the 


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AUDIT and DUDIT measures and resting BP, BMI, results collected at Screening will be used as 
the Baseline value. 
 
8.5 Participant Disposition and Dosing Summary 
The All Enrolled Set will be included in the summary of participant disposition and 
accountability. The tabulation of number of participants in each treatment group and overall will 
be displayed for the Safety Set and in the mITT Set. The number and percent of participants who 
completed or discontinued the study will be displayed for each treatment group and overall 
together with reasons for early termination, where the percent is with respect to the total number 
of randomized participants in that treatment group. The timepoint of doses and total MDMA (mg) 
administered will be summarized by treatment group for the Safety and mITT Sets.  
 
8.6 Demographics and Baseline Characteristics 
Participant demographic data and Baseline characteristics will be summarized descriptively by 
treatment group and overall. The demographic data and baseline characteristics will be 
summarized for the mITT and Safety Sets.  
 
8.7 Efficacy Analyses 
For all primary, secondary, and exploratory endpoints descriptive statistics (n, mean, standard 
deviation, median, range, or counts and percentages where appropriate) will be provided by 
treatment group. Longitudinal CAPS-5 Total Severity Score and mean SDS item scores will be 
plotted across visits to characterize the onset of treatment effect. 
 
8.7.1 Primary Efficacy Analyses 
The de jure estimand of treatment efficacy will be used to estimate the causal effect of MDMA-
assisted psychotherapy on PTSD symptom severity in the intended population of patients with 
PTSD from any cause (Estimand 1 in Table 4). All efficacy analyses will be based on the mITT 
analysis set. The primary treatment comparison will be made at a 2-sided, 0.0499 level of alpha. 
The primary estimator of effects of initially randomized treatments will be the difference between 
groups in mean change in CAPS-5 Total Severity Scores from Baseline to 18 weeks after 
randomization (Visit 19). Least squares means from a restricted maximum likelihood (REML)-
based mixed model for repeated measures (MMRM) will be used to compare treatment groups at 
Visit 19. CAPS-5 data collected after treatment discontinuation will not be included in the de jure 
estimand. Missing data will not be imputed. The model is specified as follows: Let Yij be the 
change in the CAPS-5 score from the ith participant at the jth visit, i = 1, …, n and j = 1, 2, 3, 
corresponding to post-baseline visits 8, 13, and 19, respectively. The treatment variable Χi is the 
randomized treatment of the ith participant. The variables T1 and T2, are variables indicating if the 
data from that record are from visit 13, or 19, respectively. Covariates included in the MMRM 
model are the continuous baseline CAPS-5 Total Severity Score and the binary variable 
indicating dissociative subtype at baseline. Investigative site is included as a fixed effect.  The 
regression model is specified as follows: 
 
Yij = α + β1Xi + β21T1I(j=2) + β22T2I(j=3) + β31T1ΧiI(j=2) + β32T2Χi I(j=3) 
+ β4Baseline_CAPSi + β5DSi + φSitei + εij, 
 


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where I(j=J) is the indicator function that equals 1 if j=J and 0 otherwise. We assume that 
the Yij follow a Normal distribution with var(Yij) = σj2, and cov(Yij, Yij´) = σjj´=σj´j (unstructured 
correlation). The model above has been parameterized with reference cell coding where the 
coefficient estimate of β1 corresponding to the treatment variable, Χ, captures the mean difference 
in the change from baseline CAPS-5 for MDMA vs. placebo. The coefficient estimates of β21 and 
β22 corresponding to the visit variables, T1 and T2 capture the difference in mean change in the 
CAPS-5 at visits 13 and 19 from the mean scores at visit 8, respectively. The coefficient estimates 
of β31 and β32 corresponding to the interaction of the treatment variable and the visit variable 
capture the incremental mean difference in the change in CAPS-5 for the MDMA group at visits 
13 and 19 from visit 8 versus the placebo group. The coefficient estimate of β4 captures the effect 
on the change in CAPS-5 post baseline corresponding to the baseline level of CAPS-5 score. The 
coefficient estimate of β5 captures the effect on the change in CAPS-5 post baseline 
corresponding to dissociative subtype at baseline. The parameter φ captures the the differences in 
mean change in CAPS-5 due to site differences.  The following SAS code will implement this 
model and the statistical test for the MDMA vs. placebo comparison at Visit 19. 
 
proc mixed; 
  class ID X T Site DS; 
     model CAPS = X  T  X*T Baseline_CAPS DS Site / s  DDFM=SATTERTH ; 
     repeated T / subject=ID type=un; 
     estimate 'MDMA vs. Placebo at Visit 19'  X  1 -1  X*T  0 0 1 0 0 -1 / e; 
run; 
 
where, the CAPS variable is the change from baseline in the CAPS-5 total severity score at each 
visit, the ID variable uniquely identifies the participant, Baseline_CAPS is the baseline CAPS-5 
Total Severity Score for each participant, DS is the dummy variable indicating dissociative 
subtype at baseline, and Site indicates the clinical site where the participant was treated. There is 
a record for each visit for every participant. If the unstructured variance/covariance model 
assumption doesn’t allow the REML algorithm to converge, a heterogeneous Toeplitz structure 
will be used.  If the model doesn’t converge under heterogeneous Toeplitz, the homogeneous 
Toeplitz structure will be used.  If that fails to converge, the next variance/covariance attempted 
will be AR(1).  In the event AR(1) structure fails to converge, the compound symmetry 
assumption will be used. 
 
Table 4: Proposed Estimands and Key Attributes 
 
Estimand 
Hypothesis Inference 
Population Endpoint 
Use of data after 
early termination 
in analysis 
1 
de jure  
Initially 
randomized 
treatment 
mITT 
Planned 
endpoint 
Not included 
2 
de facto 
Treatment Policy 
mITT 
Planned 
endpoint 
Included 
 
 
8.7.2 Supportive Analyses: 
To support the need to provide information on treatment effectiveness in all randomized 
participants that could be expected in clinical practice, regardless of adherence to the 3-session 


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course of MDMA-assisted psychotherapy treatment, we propose a de facto estimand is included 
as an exploratory supportive analysis (Estimand 2 in Table 4).  
The de facto estimand will include all available CAPS-5 outcome data from all participants in the 
mITT set regardless of adherence to the treatment, including CAPS-5 data collected after 
treatment discontinuation in case of early termination. This will be estimated in the mITT set by a 
statistical comparison between treatment groups using the MMRM model with a weighted least 
squares estimate of the change in CAPS-5 scores from baseline to 18 weeks after randomization 
across all the post treatment CAPS-5 measures. The sponsor expects no more than 5% of the 
participants will discontinue treatment after the first experimental session and CAPS-5 outcome 
assessment, due to the highly-controlled treatment setting which is analogous to residential or in-
patient treatment settings. Additionally, some participants may choose to discontinue after the 
first experimental session because of strong and early positive response.  These participants are 
treatment successes and should not be modeled as treatment failures. Using the least squares 
estimate of the mean reduction in CAPS-5 scores across all treatment sessions will capture these 
early successes in the de facto estimand. It can be argued that because all participants in the study 
will have continued data collection and all observed post-treatment CAPS-5 scores included in 
the de facto estimand that there is no missing data in this analysis. Thus the de facto estimand will 
support the primary de jure estimand.  
1. The choice of primary estimand will be tested with a supportive analysis including a 
different estimand:  
a. To determine de facto effectiveness by comparing MDMA-assisted 
psychotherapy to identical psychotherapy with inactive placebo for PTSD, as 
measured by the estimand of change in CAPS-5 Total Severity Score from 
Baseline after 18 weeks post-randomization, including all observed data after 
early termination. 
2. The effect of departures from choices and assumptions made for the primary analysis 
will be tested as sensitivity analyses for the primary estimand. No sensitivity analyses 
will be performed for the secondary efficacy endpoints. Details of the sensitivity 
analyses with multiple imputation will be provided in the Final SAP. 
a. Distributional assumptions for the full data will be tested, if distribution found not to 
be normal, we will test a transformation of the data, such as the log transformation, to 
achieve normality. 
b. If outlying or influential observations are found: (1) a log transformation will be 
applied to the full data and (2) outliers will be excluded  
c. Effect of covariates will be tested by conducting the primary analysis with and 
without: (1) dissociative subtype of PTSD based on CAPS-5 and (2) Baseline CAPS-
5 Total Severity Score. 
d. To examine the pre and post COVID-19 effect on the treatment effect the full model 
will be fitted with an additional binary dummy variable indicating whether the 
CAPS-5 measure was taken pre or post COVID-19.  We chose to indicate the date of 
delineation between pre and post COVID-19 as March 11, 2020 – the day the World 
Health Organization declared COVID-19 a pandemic, and coincidently, the data 
cutoff date of the Interim Analysis.  The COVID-19 binary variable will be added to 
the full model specified for the primary analysis in a sensitivity analysis as a fixed 
effect along with an interaction term with the treatment variable.  If the interaction 
term is not significant at the alpha 0.05 level it will be dropped from the model.  The 
estimate of the COVID-19 dummy variable will be clinically interpreted and included 
in the interpretation and discussion of the primary efficacy results. 
e. A concordance analysis will be executed to examine the effect of not completing all 
three (3) treatment sessions (treatment dropouts) on the treatment effect as measured 
by CAPS-5 [1].  The objective of the concordance analysis will be to address what 


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the treatment effect would have been if all the treatment dropouts had completed the 
treatments and CAPS-5 measures.  This will be compared to a worst-case scenario.  
f. To examine the robustness of the inferences to the MAR assumption, Jump to 
Reference and Copy Reference multiple imputation methods will be employed to 
ensure the most appropriate methodology is selected to test assumptions about 
missing data mechanism [2, 3]. Residual treatment effects are likely to carry over 
from observed periods during the study to the unobserved period after data collection 
ends for a dropout in some cases.  Imputation method choice will depend on 
individual reasons for withdrawal (see Table 5). 1000 complete datasets will be 
generated; each of which will be analyzed using an ANCOVA model with effects for 
treatment arm, visit, and covariates. The final results will be obtained by combining 
the least squares (LS) means and LS mean differences from these 1000 analyses 
using standard multiple imputation methodology, and overall inference will be 
obtained by applying Rubin’s Rules on the estimates obtained from each 
imputed/complete data set [4].  
Table 5: Inference of Treatment Effect for Missing Data from mITT Set Based on 
Reasons for Post-Randomization Withdrawal  
Post-randomization Events 
Available Data Post-
Withdrawal 
Treatment 
Assignment  
Inference of Treatment Effect if Data is 
Missing (CAPS-5 Post Session 2 or 3) 
Discontinue Study, 
Withdraw Consent 
No data  
MDMA 
Assume treatment failure 
• 
Jump to Reference Placebo arm 
Placebo 
Assume treatment failure 
• 
Copy Reference Placebo arm 
Discontinue Intervention (or 
experiences long delay e.g., 
due to a pandemic) and does 
not receive Rescue 
Medication 
Data collection 
continues whenever 
possible via remote 
visits 
MDMA 
Assume treatment success if post-treatment 
CAPS and reason supports treatment response 
• 
Copy  Reference MDMA arm 
Assume lack of tolerability if post-treatment 
CAPS and reason for dropping out do not 
support treatment response 
• 
Jump to Reference Placebo arm 
Placebo 
Assume treatment failure 
• 
Copy reference Placebo arm 
Discontinue Intervention (or 
experiences long delay e.g., 
due to a pandemic) and 
receives Rescue Medication 
Data collection 
continues whenever 
possible via remote 
visits 
MDMA 
Assume treatment success if reason supports 
treatment response 
• 
Copy Reference MDMA arm 
 
Assume treatment failure if reason does not 
support treatment response 
• 
Jump to Reference Placebo arm 
Placebo 
Assume treatment failure 
• 
Copy Reference Placebo arm 
Death 
No data  
MDMA 
Assume treatment success if post-treatment 
CAPS supports treatment response 
• 
Copy Reference MDMA arm  
Assume lack of tolerability if post-treatment 
CAPS and reason for dropping out do not 
support treatment response 
• 
Jump to Reference Placebo arm 
Placebo 
Assume treatment failure 
• 
Copy reference Placebo arm 
Suicide 
No data  
MDMA 
Assume treatment failure 
• 
Jump to Reference Placebo arm 


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Post-randomization Events 
Available Data Post-
Withdrawal 
Treatment 
Assignment  
Inference of Treatment Effect if Data is 
Missing (CAPS-5 Post Session 2 or 3) 
Placebo 
Assume treatment failure 
• 
Copy Reference Placebo arm 
 
In exploratory analyses, additional baseline covariates (age, gender, ethnicity, index trauma, 
complexity and severity of trauma, medication tapering, diagnosis of comorbid depression, 
diagnosis of comorbid Axis 2 diagnosis, adverse childhood experiences) may be assessed for 
inclusion in the model at a p<0.05.  
 
8.7.3 Key Secondary Efficacy Analyses  
For the key secondary analysis of efficacy, the de jure estimand will be used to estimate the 
causal effect of MDMA-assisted psychotherapy on PTSD on the SDS in the intended population 
of patients with PTSD from any cause (Estimand 3 in Table 4). The SDS is a 3-item scale 
measuring the severity of disability in the domains of work, family life/home responsibilities and 
social/leisure activities. Each of these three domains is scored on a ten-point Likert scale, where a 
score of 0 is ‘not at all impaired’, 5 is ‘moderately impaired’ and 10 is ‘very severely impaired’. 
The summary measure used to analyze the treatment effect on SDS will be 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 will be scored as a 10 on item 1. In cases where participants did not work 
due to reasons unrelated to PTSD, the score for item 1 (work/school) will be imputed by 
averaging the scores of items 2 and 3. It is expected that no more than 5% of participants will 
have item 1 (work/school) imputed, based on prior studies of paroxetine with PTSD. To limit 
missing data and ensure standardized administration, the SDS will be administered in a clinician- 
rated format during the same visits as the CAPS-5 by the centralized Independent Rater Pool. The 
clinician-rated administration will be important in limiting misinterpretation of the Work/school 
Impairment item that could contribute to elevated rates of skipping out, which can also be 
completed in reference to school, unpaid or volunteer work, and may not immediately come to 
mind in a participant-reported format. 
 
If item 1 of the SDS is imputed in more than 5% of the participants, multiple imputation methods 
will be explored as an additional sensitivity analyses. If more than 5% of Item 1 data is missing, 
the frequency of participants not working due to reasons unrelated to PTSD and related to PTSD 
will be tabulated for both overall and within each visit. Additionally, a sensitivity analysis will be 
conducted to explore the effect of the different distributions for average SDS depending on 
whether the respective checkboxes for item 1 are checked or not. Separate MMRM models for the 
two types of responses to item 1 will be run and the treatment effect will be the weighted average 
of the two groups with the weights calculated as the frequency of checked item 1’s. 
 
A hierarchical testing strategy will be employed to control for type-I error. That is, the hypothesis 
for the Key Secondary Endpoint (SDS) will only be tested if the statistical test for the Primary 
Efficacy comparison rejects the null hypothesis. If the statistical test for the Primary Efficacy 
comparison does not reject the null hypothesis, the analysis of the Key Secondary Endpoint 
(SDS) will be exploratory. The treatment comparison will be made at a 2-sided, 0.0499 level of 
alpha. The key secondary estimator of effects of initially randomized treatments will be the 
difference between groups in mean change in the SDS summary measure from Baseline to 18 
weeks after randomization (Visit 19). Least squares means from a restricted maximum likelihood 
(REML)-based mixed model for repeated measures (MMRM) will be used to compare treatment 
groups at Visit 19. SDS data collected after treatment discontinuation will not be included in the 
de jure estimand. Missing data will not be imputed and will be considered missing at random. The 
model is specified as follows: Let Yij be the change in the SDS summary measure from the ith 


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participant at the jth visit, i = 1, ..., n and j = 1, 2, 3, corresponding to post-baseline visits 8, 13, 
and 19, respectively. The treatment variable Χi is the randomized treatment of the ith participant. 
The variables T1 and T2, are variables indicating if the data from that record are from visit 13, or 
19, respectively. Covariates included in the MMRM model are the continuous baseline SDS 
summary measure and the binary variable indicating dissociative subtype at baseline. 
Investigative site is included as a fixed effect. The regression model is specified as follows: 
 
Yij = α + β1Xi + β21T1I(j=2) + β22T2I(j=3) + β31T1ΧiI(j=2) + β32T2Χi I(j=3) 
+ β4Baseline_SDSi + β5DSi + φSitei + εij, 
 
where I(j=J) is the indicator function that equals 1 if j=J and 0 otherwise. We assume that the Yij 
follow a Normal distribution with var(Yij) = σj2, and cov(Yij, Yij ́) = σjj ́=σj ́j (unstructured 
correlation). The model above has been parameterized with reference cell coding where the 
coefficient estimate of β1 corresponding to the treatment variable, Χ, captures the mean 
difference in the change from baseline SDS measure for MDMA vs. placebo. The coefficient 
estimates of β21 and β22 corresponding to the visit variables, T1 and T2 capture the difference in 
mean change in the SDS summary measure at visits 13 and 19 from the mean scores at visit 8, 
respectively. The coefficient estimates of β31 and β32 corresponding to the interaction of the 
treatment variable and the visit variable capture the incremental mean difference in the change in 
the SDS summary measure for the MDMA group at visits 13 and 19 from visit 8 versus the 
placebo group. The coefficient estimate of β4 captures the effect on the change in the SDS 
summary measure post baseline corresponding to the baseline level of the SDS summary 
measure. The coefficient estimate of β5 captures the effect on the change in SDS summary 
measure post baseline corresponding to dissociative subtype at baseline. The parameter φ 
captures the the differences in mean change in SDS summary measure due to site differences. The 
following SAS code will implement this model and the statistical test for the MDMA vs. placebo 
comparison at Visit 19.  
 
proc mixed; 
  class ID X T Site DS; 
     model SDS = X  T  X*T Baseline_SDS DS Site / s  DDFM=SATTERTH ; 
     repeated T / subject=ID type=un; 
     estimate 'MDMA vs. Placebo at Visit 19'  X  1 -1  X*T  0 0 1 0 0 -1 / e; 
run; 
where, the SDS variable is the change from baseline in the SDS summary measure at each visit, 
the ID variable uniquely identifies the participant, Baseline_SDS is the baseline SDS summary 
measure for each participant, DS is the dummy variable indicating dissociative subtype at 
baseline, and Site indicates the clinical site where the participant was treated. In the data used to 
fit the model, there is a record for each visit for every participant. If the unstructured 
variance/covariance model assumption doesn’t allow the REML algorithm to converge, a 
heterogeneous Toeplitz structure will be used.  If the model doesn’t converge under 
heterogeneous Toeplitz, the homogeneous Toeplitz structure will be used.  If that fails to 
converge, the next variance/covariance attempted will be AR(1).  In the event AR(1) structure 
fails to converge, the compound symmetry assumption will be used. 


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


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score ranges to describe functional impairment severity for each of three items describing the 
functional domains of work, social life, and family life: No impairment (0), Mild impairment (1-
3), Moderate impairment (4-6), Marked impairment (7-9), Extreme impairment (10). Based on 
the psychometric development publication [5] and prior Paroxetine studies for treatment of 
PTSD, a 4-point mean reduction across SDS items would represent a clinically meaningful 
treatment response, as this would correspond to downward change from Extreme to Moderate, 
Marked to Moderate, or Moderate to Mild in severity of any domain of functional impairment. If 
a participant drops to a mean score of less than 3 across SDS items, this would be defined as a 
functional remission indicating Mild or No impairment.  
 
Figure 2: CONSORT for Functional Impairment Responder Analysis After 
Treatment 
 
[1] Response at T2, T3, and T4 will be in comparison to Baseline at T1. 
 
As an alternate definition of treatment response to assess clinical significance of study outcomes, 
the sponsor will conduct an exploratory responder analysis to support findings from the key 
secondary efficacy analysis, to explore the onset of clinically meaningful functional improvement 
(Figure 2). To further support the exploration of a clinically meaningful functional improvement 
in the PTSD population, results will be plotted in a cumulative distribution function plot to 
examine the magnitude of differences between treatment groups. Distribution-based methods 
including standard error of measurement (SEM) and one standard deviation away from the mean 
SDS scores at baseline will be reported. Ceiling effects will be assessed based on 40% of 
responses at most endorsing Extreme Impairment and floor effects will be assessed based on less 
than 5% of responses endorsing No Impairment on each item. 


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


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• 
Pretreatment medications are defined as medications taken prior to and after signing 
informed consent and those taken during the Preparatory Period prior to the first 
Experimental Session. A stop date is expected prior to the first Experimental Session for 
any medications requiring a change in dose, a skipped dose, or tapering.  
• 
Treatment Period concomitant medications are defined as those taken or continued during 
the Treatment Period from the first Experimental Session to the last Integrative Session. 
A stop date is expected prior to the each Experimental Session for any medications 
requiring a change in dose, a skipped dose, or tapering.  
• 
Concomitant medications with a start date of the day of and two days after IP 
administration 
• 
Follow-up Period concomitant medications are defined as those taken or continued 
during the Follow-up Period after the last Integrative Session through Termination 
• 
Any concomitant medications that are tapered 
• 
Any concomitant medications that are taken to treat an AE 
• 
Any concomitant medications that are taken to treat an SAE 
• 
Any excluded concomitant medications taken as a deviation from the protocol. 
 
Concomitant medications on case report forms will be classified using the WHO Drug Dictionary 
EnhancedTM (WHO DDE). Frequency and incidence of concomitant medications will be 
displayed by generic name, sorted by class, and summarized by treatment group, analysis set, and 
category as defined above. Concomitant medications will be analyzed and presented as follows: 
• 
Concomitant medications taken on the day of and two days after IP administration will be 
presented separately 
• 
Any psychiatric concomitant medications by period. 
 
8.8.4 Analysis of Suicidal Ideation and Behavior 
Suicidal ideation and behavior will be summarized according to suggestions made in the C-SSRS 
Scoring and Data Analysis Guide [6]. A positive response for suicidal ideation is counted when a 
participant answers “yes” to any one of the five suicidal ideation questions (Categories 1-5) on 
the C-SSRS (i.e., a score >0 for suicidal ideation). Serious suicidal ideation is a suicidal ideation 
score of 4 or 5. A positive response for suicidal behavior occurs when a participant answers “yes” 
to any one of the five suicidal behavior questions (Categories 6-10) on the C-SSRS (i.e., a score 
>0 for suicidal behavior). The number and percent of positive responses of Positive Ideation, 
Serious Ideation, and Positive Behavior will be tabulated by treatment group and time period 
(lifetime, screening, baseline, each Experimental Session (pre- and post-IP), Integrative Sessions, 
and endpoints). Frequency and incidence of positive or serious ideation and suicidal behavior will 
be presented using descriptive statistics in tabular format. 
 
8.8.5 Analysis of Vital Signs 
Vital signs (heart rate, BP, and body temperature) for Experimental Sessions will be summarized 
using descriptive statistics in tabular format listing values at pre-IP, prior to the supplemental 
dose, and at the end of each Experimental Session by treatment group. Change from Baseline in 
vital signs will be compared by treatment group with appropriate statistical techniques.   
 
8.9 Administrative Interim Analysis 
An unblinded administrative interim analysis is planned to be performed at a single time point 
after the first 60% of participants in the mITT set have completed the final CAPS-5 follow-up 
assessment and terminated treatment, including early termination participants who have 


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completed their final CAPS-5, and 100 participants have been enrolled. The objective of the 
administrative interim analysis is to conduct a sample size re-estimation. The key secondary 
endpoint will not be evaluated at the interim analysis. The detailed results of the interim analysis 
will not be revealed to the site staff, participants, IRs, or sponsor staff/designees except for a 
single designated sponsor representative from MAPS.  The independent DMC statistician will 
perform the unblinded administrative interim analysis as described in the DMC Charter. In 
addition, procedures will be developed to ensure the blinding of the participant level data for 
parties outside of the Independent Statistical Group (ISG).  
 
Sample size re-estimation:  Based on the result of calculating conditional power using the 
estimated effect size from the first 60% of participants in the mITT set, the sample size may be 
increased. The table below shows the range of possible effect sizes that could be observed at the 
interim analysis and what the guidance from the DMC could be for the adjusted sample size.  
 
Table 6: Observed Effect Sizes and Corresponding Sample Size for 90% 
Conditional Power Guidance at the Interim Analysis (N=60) 
[1] Conditional Power based on the alternative hypothesis effect size as observed in the first 60 subjects. 
 
For Table 6, the conditional power estimates and the numbers to increase the sample size to 
restore 90% conditional power were calculated in PASS version 14 using the module for two-
sample t-tests, which is based on the conditional power definitions from Jennison and Turnbull 
[7]. Since the minimum effect size for all possible scenarios where the sample size would be 
increased achieves greater than 50% conditional power for N=60, the type-I error rate is 
preserved with this administrative sample size re-estimation method [8]. However, the sponsor 
has chosen to allocate 2% of the alpha (0.0001) for this unblinded administrative interim analysis 
to account for any possible downward bias in the variance estimate.  At the time of the interim 
analysis, the independent unblinded statistician will fit the cleaned data on the first 60 participants 
to the primary analysis model to estimate the parameters.  These parameter estimates will be input 
to the PASS 14 Mixed Model Repeated Measures module to re-estimate the power.  If the power 
is less than 90% and more than 50%, the independent statistician will increase the sample size up 
to the point where the power reaches 90%.  These results will be provided by the unblinded 
independent statistician to the DMC. 
Effect Size 
≤ 0.32 
 0.32 
0.34 
0.36 
0.38 
0.40 
0.42 
0.44 
Mean Change 
- 
5.76 
6.12 
6.48 
6.84 
7.2 
7.56 
7.92 
Conditional Power[1] 
< 50% 
52% 
60% 
67% 
74% 
80% 
85% 
89% 
Increase in Sample 
Size to Restore 90% 
Conditional Power 
No 
increase 
 
240 
 
180 
 
140 
 
110 
 
70 
 
40 
 
10 


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The DMC will review the group-unblinded interim analysis results provided by the independent 
statistician and will give recommendations to the designated sponsor representative from MAPS. 
The designated sponsor representative from MAPS will provide written information to the trial 
organizer delegate of MPBC indicating how many participants, if any, to add to the IWRS but 
will not provide any information on the corresponding conditional power the additional 
participants are being added to achieve. Only the re-estimation of sample size will be completed 
at the interim analysis, this will not be used to drop or add treatment arms or doses, change entry 
criteria, change randomization ratio or change primary endpoint. The sponsor representative from 
MAPS will not be part of any trial decisions or administration after the sample size re-estimation 
has been communicated to MPBC who will continue to be the trial organizer. If the DMC reports 
a sample size increase to the independent statistician DMC member, they will increase the 
randomization cap from 100 to the new sample size within the IWRS accordingly. Thereafter, the 
IWRS will cap randomization at the increased sample size resulting from the interim analysis. If 
the interim analysis results in a sample size increase, it will not be revealed to the investigators, 
participants, or sponsor.  
 
9.0 Data Monitoring Committee  
A DMC with appropriate expertise in the conduct of PTSD clinical trials will act in an advisory 
capacity to monitor participant safety on a routine basis throughout the trial by reviewing safety 
and study data provided by an Independent Statistical Group. The DMC will also monitor 
individual participant tolerability. The composition of the DMC will include two clinician experts 
in PTSD clinical trials and a biostatistician. 
 
The DMC may: 
• 
Review the study protocol and informed consent documents, and plans for data 
monitoring 
• 
Evaluate the progress of the trial, study data quality, timeliness, participant recruitment, 
accrual and retention, participants’ risk versus potential benefit, and other factors that 
could affect the study outcome 
• 
Implement the adaptive design aspects of the study at the interim analysis by reviewing 
the interim analysis results and making the appropriate decision to the independent 
statistician on sample size re-estimation 
• 
Consider relevant information that may have an impact on the safety of the participants or 
the ethics of the study 
• 
Make other recommendations to MAPS concerning continuation, termination or other 
modifications of the study based on their observations of the study. 
 
A full description of the DMC duties will be detailed in the DMC Charter. 
 
10.0 Timing of Analyses 
The primary efficacy analysis will be conducted after all participants complete Visit 20 and the 
database is locked. 
 
 
 


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Carrasco, J.L., et al., Estimation of the concordance correlation coefficient for repeated 
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2. 
Tang, Y., An efficient monotone data augmentation algorithm for multiple imputation in 
a class of pattern mixture models. J Biopharm Stat, 2017. 27(4): p. 620-638. 
3. 
Molenberghs, G., et al., Analyzing incomplete longitudinal clinical trial data. 
Biostatistics, 2004. 5(3): p. 445-64. 
4. 
Rubin, D.B., Inference and missing data. Biometrika, 1976. 63(3): p. 581-592. 
5. 
Sheehan, K.H. and D.V. Sheehan, Assessing treatment effects in clinical trials with the 
discan metric of the Sheehan Disability Scale. Int Clin Psychopharmacol, 2008. 23(2): p. 
70-83. 
6. 
Nilsson, M.E., et al., Columbia Suicide Severity Rating Scale Scoring and Data Analysis 
Guide, in CSSRS Scoring Version 2.0. 2013: 
http://www.cssrs.columbia.edu/documents/ScoringandDataAnalysisGuide_Feb2013.pdf. 
p. 1-13. 
7. 
Jennison, C. and B.W. Turnbull, Group sequential methods with applications to clinical 
trials. 2000, Boca Raton, FL: Chapman & Hall/CRC Press. 
8. 
Chen, Y.H., D.L. DeMets, and K.K. Lan, Increasing the sample size when the unblinded 
interim result is promising. Stat Med, 2004. 23(7): p. 1023-38. 
 

Prot_004.pdf: 
CONFIDENTIAL 
 
 
 Protocol MAPP1 
IND #063384 
 
Original Protocol Version 1: 16 January 2017 
Original Protocol Version 2: 07 June 2017 
Amendment 1 Version 1: 26 February 2018 
Amendment 2 Version 1: 12 September 2019 
Amendment 3 Version 1: 13 November 2019 
Amendment 4 Version 1: 22 May 2020 
 
A Randomized, Double-Blind, Placebo-Controlled, Multi-Site Phase 3 Study of the 
Efficacy and Safety of Manualized MDMA-Assisted Psychotherapy for the 
Treatment of Severe Posttraumatic Stress Disorder 
 
 
SPONSOR 
Multidisciplinary Association for Psychedelic Studies (MAPS) 
1115 Mission Street 
Santa Cruz, CA 95060 
 
SPONSOR REPRESENTATIVE 
Rick Doblin, Ph.D. 
Executive Director 
MAPS 
SPONSOR DELEGATE  
&TRIAL ORGANIZER  
MAPS Public Benefit Corporation 
1115 Mission Street 
Santa Cruz, CA 95060 
 
SPONSOR DESIGNEE 
Amy Emerson 
Executive Director 
MAPS Public Benefit Corporation 
Phone number: 510-393-7224 
Email: amy@mapsbcorp.com 
 
CLINICAL INVESTIGATOR 
Multi-site Study 
 
MEDICAL MONITOR 
Michael C. Mithoefer, M.D. 
Email: michael@mapsbcorp.com 
Alia Lilienstein, M.D., M.P.H. 
Email: alia@mapsbcorp.com  
 
USE 
In conjunction with relevant Food and Drug Administration (FDA), 
Health Canada (HC), and Israeli Ministry of Health (MOH) guidance 
 


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


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


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


MAPS Public Benefit Corporation 
 
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IND #063384 
 
Amendment 4 Version 1: 22 May 2020 
 
Page 5 of 104 
Treatment Period 
From Randomization to Integrative Session 3.3 (Visit 18): 12 weeks (-3/+4) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Treatment 1 
Randomization 
.5 hours/ 
24 to 48 hours before 
V5 
Complete after enrollment and scheduling Visit 5. 
Enter demographics in Medrio for use in 
randomization. The participant does not need to be 
present for this. 
Experimental 
Session 1 
(Visit 5) 
8 hours + overnight/ 
4 to 7 days after V3; 
1 to 4 days after V4 
First Experimental Session is within 2 weeks of the 
Baseline CAPS-5 (Visit 3), it lasts 8 hours with 
overnight stay. Dose is 80 mg with supplemental 
half-dose of 40 mg unless contraindicated. 
Integrative 
Session 1.1 
(Visit 6) 
1.5 hours/ 
Morning after V5 
Visit 6 is a 90-minute Integrative Session the 
morning after Visit 5. Followed by phone check-ins 
that includes Since Last Visit C-SSRS assessment 
on Days 2, 4, 6, 7, 8, 10, 12, 14 post Visit 5.  
Integrative 
Session 1.2 
(Visit 7) 
1.5 hours/ 
3 to 14 days after V5; 
at least 2 days after V6 
Between 3 and 14 days after Visit 5, a 90-minute 
Integrative Session (Visit 7) is completed. 
CAPS-5 T2 
(Visit 8) 
1 hour 
18 to 30 days after V5; 
between V7 and V9 
(may be on same day as 
either) 
Between Visits 7 and 9 (may be same day as either), 
CAPS-5, SDS, and DSP-I assessment completed by 
an IR via telemedicine.  
Integrative 
Session 1.3 
(Visit 9) 
1.5 hours/ 
20 to 34 days after V5; 
at least 2 days after V7; 
1 to 7 days before V10  
90-minute Integrative Session post Visit 8 and in 
preparation for Visit 10. Can occur 1 to 7 days 
before Visit 10. Measures include LEC-5 and C-
SSRS. 
Treatment 2 
Experimental 
Session 2 
(Visit 10) 
8 hours + overnight/ 
21 to 35 days after V5 
21 to 35 days after Visit 5. The second 
Experimental Session lasts 8 hours with an 
overnight stay. Dose is 80 or 120 mg plus 
supplemental half-dose unless contraindicated. 
Integrative 
Session 2.1 
(Visit 11) 
1.5 hours/ 
Morning after V10 
 
Visit 11 is a 90-minute Integrative Session the 
morning after Visit 10. Followed by phone check-
ins that includes Since Last Visit C-SSRS 
assessment on Days 2, 4, 6, 7, 8, 10, 12, 14 post 
Visit 10.  
Integrative 
Session 2.2 
(Visit 12) 
1.5 hours/ 
3 to 14 days after V10; 
at least 2 days after V11 
Between 3 and 14 days after Visit 10, a 90-minute 
Integrative Session (Visit 12) is completed. 
CAPS-5 T3 
(Visit 13) 
1 hour/ 
18 to 30 days after V10; 
between V12 and V14 
(may be on same day as 
either) 
Between Visits 12 and 14 (may be on same day as 
either), CAPS-5, SDS, and DSP-I assessment 
completed by an IR via telemedicine. 
Integrative 
Session 2.3 
(Visit 14) 
1.5 hours/ 
20 to 34 days after V10; 
at least 2 days after 
Integrative Session 2.2 
(V12) 
1 to 7 days before V15 
90-minute Integrative Session post Visit 13 and in 
preparation for Visit 15. Can occur 1 to 7 days 
before Visit 15. Measures include LEC-5 and C-
SSRS. 
 
 


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


MAPS Public Benefit Corporation 
 
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IND #063384 
 
Amendment 4 Version 1: 22 May 2020 
 
Page 7 of 104 
Primary Outcome (CAPS-5) Data Collection by Visit 
CAPS Number 
Visit 
Description/Timing 
Target Timing 
Post Baseline (V3) 
Baseline CAPS-5 T1 
V3 
Baseline 
Between Visits 2 and 4 Preparatory Sessions 
0 days 
CAPS-5 T2 
V8 
Post Experimental Session 1 (~3 weeks) 
Between Visits 7 and 9 Integrative Sessions 
~6 weeks 
CAPS-5 T3 
V13 
Post Experimental Session 2 (~3 weeks) 
Between Visits 12 and 14 Integrative Sessions 
~10 weeks 
Primary Outcome  
CAPS-5 T4 
V19 
Post Experimental Session 3 (~8 weeks) 
~18 weeks 
 
Dose Selection 
 
This study will compare the effects of three blinded manualized Experimental Sessions of 
psychotherapy assisted by flexible doses of MDMA or placebo as described in the table below, 
along with associated non-drug preparatory and integrative psychotherapy. Similar MDMA doses 
to those proposed in this study have been safely used in previous Phase 2 studies sponsored by 
MAPS. 
 
Dose Regimen of MDMA or Placebo 
Experimental 
Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative Dose 
1 
80 mg 
40 mg 
80 mg to 120 mg 
2 
80 or 120 mg 
40 or 60 mg 
80 mg to 180 mg 
3 
80 or 120 mg 
40 or 60 mg 
80 mg to 180 mg 
Total Cumulative Dose 
240 mg to 480 mg 
* Unless contraindicated 
 
Protocol Objective 
 
The overall objective of this study is to use standard clinical measures to confirm the efficacy and 
safety of manualized MDMA-assisted psychotherapy with a flexible dose of MDMA in reducing 
PTSD and associated symptoms in comparison to the same psychotherapy combined with an 
inactive placebo control. 
 
Primary Objective 
 
The primary objective of this study is to evaluate the efficacy of MDMA-assisted psychotherapy 
for PTSD compared to the identical psychotherapy with inactive placebo, based on comparison of 
CAPS-5 Total Severity Score at Visit 3 (Baseline) to Visit 19 (18 weeks post Baseline). 
 
Secondary Objective 
 
The secondary objective of this study is to evaluate the efficacy of MDMA-assisted 
psychotherapy for PTSD compared with identical psychotherapy with inactive placebo in 
clinician-rated functional impairment, as measured by the mean change in Sheehan Disability 
Scale (SDS) item scores from Visit 3 (Baseline) to Visit 19 (18 weeks post Baseline).  
 


MAPS Public Benefit Corporation 
 
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IND #063384 
 
Amendment 4 Version 1: 22 May 2020 
 
Page 8 of 104 
Safety Objectives 
 
The overall safety objective is to assess differences between groups in severity, incidence and 
frequency of AEs, Treatment Emergent AEs (TEAEs), AEs of Special Interest (AESIs), and 
Serious Adverse Events (SAEs), concomitant medication use, suicidal ideation and behavior, and 
vital signs to support the package insert for MDMA-assisted psychotherapy.  
The following safety objectives will evaluate the safety of MDMA-assisted psychotherapy 
compared to identical psychotherapy with inactive placebo: 
 
1. Compare relative incidence of AEs during Experimental Sessions that may be indicative 
of a medical complication of the Investigational Medicinal Product (IMP), such as 
clinical signs and symptoms of chest pain, shortness of breath, or neurological symptoms 
or any other signs or symptoms that prompt additional vital sign measurements. 
2. Compare relative incidence of AEs by severity. 
3. Compare relative incidence of TEAEs, to determine relationship to the IMP based on 
relative incidence in the MDMA group. 
4. Compare relative incidence of TEAEs by severity reported during an Experimental 
Session, 1 day, and 2 days after IMP administration. 
5. Compare relative incidence of AESIs, defined as AEs specified in the protocol related to 
cardiac function and abuse liability. 
6. Compare relative incidence of AEs by severity categorized as leading to discontinuation 
of IMP, resulting in death or hospitalization, and continuing at Study Termination. 
7. Compare relative incidence of SAEs. 
8. Compare relative incidence of psychiatric concomitant medications taken during an 
Experimental Session, 1 day, and 2 days after IMP administration. 
9. Compare relative incidence of any psychiatric concomitant medications taken during the 
Treatment Period. 
10. Compare relative incidence of positive or serious suicidal ideation and positive suicidal 
behavior assessed with the Columbia Suicide Severity Rating Scale (C-SSRS) by 
treatment group. 
11. Compare mean changes in blood pressure, heart rate, and body temperature from pre-IMP 
administration to end of each Experimental Session by treatment group. 
 
Recruitment and Participant Population 
 
Approximately N≈100 participants with a confirmed diagnosis of at least severe PTSD will be 
enrolled. Participants will be recruited through print and internet advertisements, referrals from 
other treatment providers, and by word of mouth. The sponsor will monitor demographics on an 
ongoing basis and encourage diversity (representative of PTSD population) in enrollment of study 
participants by communicating with sites. Randomization will be stratified by clinical site.  
 
Participants will be persons aged 18 or older, with a confirmed diagnosis of at least severe PTSD 
per the PCL-5 (PTSD Checklist for DSM-5) at Screening with symptoms present for at least 6 
months. At Baseline, participants must qualify for a PTSD diagnosis per the CAPS-5 and have a 
Total Severity Score equal to or greater than 35 (severe). Participants would not be excluded for 
having more than one traumatic event or for having tried, not tolerated, or refused a selective 
serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) 
prescribed for PTSD. Participants with confirmed diagnosis of specific psychological and 
personality disorders will be excluded. Participants must be in good physical health and without 
major medical disorders that could affect the safety or tolerability of MDMA. 
 


MAPS Public Benefit Corporation 
 
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IND #063384 
 
Amendment 4 Version 1: 22 May 2020 
 
Page 9 of 104 
Statistical Analysis of Efficacy 
 
The statistical power calculations were made by fitting a Mixed-Effect Model Repeated Measure 
(MMRM) model to CAPS-4 (Clinician-Administered PTSD Scale for DSM-4) data from the 
Phase 2 study MP1 to obtain covariance parameter estimates. The Phase 2 MP1 study followed a 
similar design with outcomes measured by CAPS-4 outcome scores, which allowed for 
estimation of within-subject covariance parameters. With a sample size of 50 participants per 
treatment group in the modified Intent-to-Treat (mITT) population, this study has 90% power to 
detect a treatment effect, using a two-sided test with an alpha of 0.0499. Additional participants 
may be enrolled, depending on sample size re-estimation by an independent DMC, with 
conditional power analysis conducted at a group-unblinded interim analysis for efficacy when 
100 participants are enrolled and at least 60% of the blinded participants (N=60) have completed 
their final CAPS-5 assessment and terminated treatment. Under no circumstances will the number 
of participants enrolled (at V0) be reduced below the initial planned 100, in order to obtain 
additional safety data. 
 
Primary Efficacy Analysis 
 
All efficacy analyses will be based on the mITT analysis set. The primary treatment comparison 
will be made at a 2-sided, 0.0499 level of significance. The reduction from Visit 3 (Baseline) in 
CAPS-5 Total Severity Scores between groups will be compared at Visit 19 (Primary Outcome) 
with least squares means from an MMRM model. The mITT analysis set will include all 
randomized participants who receive IMP in at least one blinded Experimental Session and have 
at least one follow-up CAPS-5 assessment. 
 
 
 
 


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Amendment 4 Version 1: 22 May 2020 
 
Page 10 of 104 
Study Structure Overview
Prestudy
Treatment Period 
-
 
Treatment 1:
Approximately 4 weeks
Treatment 2:
Approximately 4 weeks
Treatment 3:
Approximately 4 weeks
 Medication Tapering
Preparatory Period and Enrollment 
Confirmation: Approximately 6 weeks 
Follow-Up Period:
Approximately 18 weeks post Baseline
Summary of Events
Primary 
Outcome
 
Medication Tapering
Preparatory Sessions
14 Day Phone 
Follow-up 
Experimental 
Session 1
Integrative Sessions
1.1, 1.2, 1.3
-
14 Day Phone 
Follow-up 
Experimental 
Session 2
Integrative Sessions 
2.1, 2.2, 2.3
14 Day Phone 
Follow-up 
Integrative Sessions 
3.1,3.2,3.3
 Screening     V0                    V1          V2        V3         V4                                      V5          V6                           V7         V8        V9                    V10        V11                         V12      V13      V14                   V15        V16                         V17        V18                               
                                    
Outcome  CAPS T4 (IR)
 
 
 
SCID-PD (IR)
 
SCID-PD (IR)
 
V19
Study 
Termination
V20
 
Baseline  CAPS T1 (IR)
 
Baseline  CAPS T1 (IR)
Medication Tapering
Enroll
Randomization
 
 CAPS T2 (IR)
 
 CAPS T2 (IR)
 
 CAPS T3 (IR)
 
 CAPS T3 (IR)
Experimental 
Session 3


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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Psychiatric History 
 
6. 
Have received Electroconvulsive Therapy (ECT) within 12 weeks of enrollment. 
7. 
Have a history of or a current primary psychotic disorder, bipolar disorder 1 assessed 
via MINI and clinical interview or dissociative identity disorder assessed via 
Dissociative Disorders Interview Schedule (DDIS) and clinical interview. 
8. 
Have a current eating disorder with active purging assessed via MINI and clinical 
interview. 
9. 
Have current major depressive disorder with psychotic features assessed via MINI. 
10. 
Have a current moderate (not in early remission in the 3 months prior to enrollment; 
meets 5 of 11 diagnostic criteria per DSM-5) or severe alcohol or cannabis use 
disorder within the 12 months prior to enrollment (meets at least 6 of 11 diagnostic 
criteria per DSM-5). 
11. 
Have an active illicit (other than cannabis) or prescription drug substance use 
disorder at any severity within 12 months prior to enrollment. 
12. 
Have current Personality Disorders Cluster A (paranoid, schizoid, schizotypal), 
Cluster B (antisocial, borderline, histrionic, narcissistic), or Cluster C (avoidant, 
dependent, obsessive-compulsive) assessed via SCID-5-PD (Structured Clinical 
Interview for DSM-5 Personality Disorders). 
13. 
Any participant presenting current serious suicide risk, as determined through 
psychiatric interview, responses to C-SSRS, and clinical judgment of the investigator 
will be excluded; however, history of suicide attempts is not an exclusion. Any 
participant who is likely to require hospitalization related to suicidal ideation and 
behavior, in the judgment of the investigator, will not be enrolled. Any participant 
presenting with the following on the Baseline C-SSRS will be excluded: 
a. 
Suicidal ideation score of 4 or greater within the last month of the assessment 
at a frequency of once a week or more 
b. 
Suicidal ideation score of 5 within the last 6 months of the assessment 
c. 
Any suicidal behavior, including suicide attempts or preparatory acts, within 
the last 6 months of the assessment. Participants with non-suicidal self-
injurious behavior may be included if approved by the Medical Monitor. 
14. 
Would present a serious risk to others as established through clinical interview and 
contact with treating psychiatrist. 
15. 
Require ongoing concomitant therapy with a psychiatric medication with exceptions 
described in Section 12.0: Concomitant Medications. 
 
Medical History 
 
16. 
Have a history of any medical condition that could make receiving a 
sympathomimetic drug harmful because of increases in blood pressure and heart rate. 
This includes, but is not limited to, a history of myocardial infarction, 
cerebrovascular accident, or aneurysm. Participants with other mild, stable chronic 
medical problems may be enrolled if the site physician, CI, and Medical Monitor 
agree the condition would not significantly increase the risk of MDMA 
administration or be likely to produce significant symptoms during the study that 
could interfere with study participation or be confused with side effects of the IMP. 
Examples of stable medical conditions that could be allowed include, but are not 
limited to Diabetes Mellitus (Type 2), Human Immunodeficiency Virus (HIV) 
infection, Gastroesophageal Reflux Disease (GERD), etc. Any medical disorder 
judged by the investigator to significantly increase the risk of MDMA administration 
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17. 
Have uncontrolled essential hypertension using the standard criteria of the American 
Heart Association (values of 140/90 milligrams of Mercury [mmHg] or higher 
assessed on three separate occasions). 
18. 
Have a history of ventricular arrhythmia at any time, other than occasional premature 
ventricular contractions (PVCs) in the absence of ischemic heart disease. 
19. 
Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not 
been successfully eliminated by ablation. 
20. 
Have a history of arrhythmia, other than occasional PVCs in the absence of ischemic 
heart disease, within 12 months of screening. Participants with a history of atrial 
fibrillation, atrial tachycardia, atrial flutter or paroxysmal supraventricular 
tachycardia or any other arrhythmia associated with a bypass tract may be enrolled 
only if they have been successfully treated with ablation and have not had recurrent 
arrhythmia for at least 1 year off all antiarrhythmic drugs, and confirmed by a 
cardiologist.  
21. 
Have a marked Baseline prolongation of QT/QTc interval (e.g., repeated 
demonstration of a QTc interval>450 milliseconds [ms] in males and>460 ms in 
females corrected by Bazett’s formula). For transgender or non-binary participants, 
QTc interval will be evaluated based on sex assigned at birth, unless the participant 
has been on hormonal treatment for 5 or more years. 
22. 
Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, 
hypokalemia, family history of Long QT Syndrome). 
23. 
Require use of concomitant medications that prolong the QT/QTc interval during 
Experimental Sessions. Refer to Section 12.0 Concomitant Medications. 
24. 
Have symptomatic liver disease or have significant liver enzyme elevations. 
25. 
Have history of hyponatremia or hyperthermia. 
26. 
Weigh less than 48 kilograms (kg). 
27. 
Are pregnant or nursing, or are of childbearing potential and are not practicing an 
effective means of birth control. 
28. 
Have engaged in ketamine-assisted therapy or used ketamine within 12 weeks of 
enrollment. 
 
4.3 Lifestyle Modifications 
All participants must agree to the following lifestyle modifications at enrollment and throughout 
the duration of the study. Participants are eligible to enroll in the study if they: 
 
• 
Are willing to commit to medication dosing, psychotherapy sessions, follow-up sessions, 
completing evaluation instruments, and all necessary telephone contact. 
• 
Agree to not participate in any other interventional clinical trials during the duration of 
this study. 
 
Leading up to Experimental Sessions 
 
• 
Agree to take nothing by mouth except alcohol-free liquids after 12:00 A.M. (midnight) 
the evening before each Experimental Session. 
• 
Refrain from the use of any psychoactive medication not approved by the research team 
from Baseline through Study Termination. 
• 
Agree not to use caffeine or nicotine for 2 hours before and at least 6 hours after the 
initial dose during each Experimental Session. 
• 
Are willing to comply with medication requirements per protocol (refer to Section 12.0 
Concomitant Medications). Medications will only be discontinued after enrollment per 
clinical judgment of the site physician in consultation with the prescribing physician. 


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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8.3.1 Experimental Sessions 
There will be three blinded Experimental Sessions (Visits 5, 10, 15). Procedures for MDMA-
assisted psychotherapy will remain the same across all sessions and all procedures regardless of 
dose received. Experimental Sessions must be at least 8 hours long, measured from 30 minutes 
prior to IMP administration.  
 
Experimental Sessions will be scheduled as follows: 
 
• 
Experimental Session 1 (Visit 5) will occur within 4 to 7 days after the Baseline CAPS-5 
(Visit 3) assessment; 1 to 4 days after Preparatory Session 3 and Enrollment 
Confirmation (Visit 4). Experimental Session 1 (Visit 5) must occur within 7 days of the 
Baseline CAPS-T1 (Visit 3) and after Preparatory Session 3 and Enrollment 
Confirmation (Visit 4). If the Baseline CAPS-5 assessment is completed outside of the 
allowed window, the investigator should consult the CRA and Medical Monitor to 
determine if the assessment should be repeated. The first Experimental Session will 
include 80 mg of IMP followed by a supplemental half-dose 1.5 to 2 hours after the 
initial dose unless contraindicated. 
• 
Experimental Session 2 (Visit 10) will occur 21 to 35 days after Experimental Session 1 
(Visit 5) and at least 1 day after Integrative Session 1.3. A dose of 80 or 120 mg MDMA 
or placebo will be administered. A supplemental half-dose will be administered 1.5 to 2 
hours after the initial dose unless contraindicated. 
• 
Experimental Session 3 (Visit 15) will occur 21 to 35 days after the second Experimental 
Session (Visit 10) and after Integrative Session 2.3. A dose of 80 or 120 mg MDMA or 
placebo will be administered. A supplemental half-dose will be administered 1.5 to 2 
hours after the initial dose unless contraindicated. 
 
Table 7: Schedule of Procedures for Experimental Sessions 
Approximate Time 
Procedure or Action 
9:30  
Urine drug screen and pregnancy test, concomitant medication 
information collected, participant acclimated to environment, C-SSRS 
9:55 
Baseline BP (Blood Pressure), body temperature, pulse 
10:00  
IMP Administration, Begin video recording  
11:30  
BP, body temperature pulse 
Supplemental Dose Administration, unless contraindicated  
17:30 
C-SSRS, BP, body temperature, pulse 
 
Pre-IMP administration 
 
• 
24 to 48 hours prior to the first Experimental Session, the participant will be randomized 
using a web-based randomization program.  
• 
24 to 48 hours prior to each Experimental Session, the site team will obtain the container 
assignment. 
• 
On the day of the Experimental Session, the participant will arrive approximately 30 to 
60 minutes prior to IMP administration. 
• 
The site team will ensure the participant has not used caffeine or nicotine 2 hours prior 
and has fasted for 10 hours prior to IMP administration and complied with all other 
requirements per Section 4.3 Lifestyle Modifications. 
• 
The site team will inquire about any possible changes in health to ensure the participant 
continues to meet all eligibility requirements and record AEs as described in Section 11.0 
Safety. 


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• 
The site team will instruct the participant that they will not be able to use caffeine or 
nicotine at least 6 hours after the IMP administration. 
• 
The site team will complete urine drug screen, pregnancy test, and concomitant 
medication review. 
o A positive drug screen will be reviewed by the site physician and may be cause for 
delaying IMP administration to a later time, rescheduling the session to a later date, 
or withdrawing the participant from the study, based on Medical Monitor review.  
o A positive pregnancy screen is cause for withdrawal from the protocol.  
• 
The therapy team will administer Since Last Visit C-SSRS. 
• 
The therapy team will review procedures for the Experimental Session with the 
participant and discuss the participant’s goals, intentions, and concerns and some of the 
commonly experienced effects of MDMA. The choice of whether to keep the dose the 
same or change it from the first Experimental Session will be made by the therapy team 
in consultation with the site physician based on observed response, tolerability to the 
previously administered dose, and discussion with the participant.  
• 
If the participant continues to be eligible, the session will proceed. 
• 
Baseline blood pressure, body temperature, and pulse will be measured just prior to 
administration of the initial dose. 
 
During the Experimental Session 
 
• 
After video recording has begun, at approximately 10:00 in the morning, a qualified staff 
member will administer the initial dose of IMP with an electrolyte-containing fluid. The 
participant will sit or recline on comfortable furnishings. Eyeshades and a program of 
music will be provided for the participant if they wish to use them. Whenever they wish, 
participants may speak to the therapy team, who will provide guidance and support, as 
needed.  
• 
After the first hour, if the participant has not spoken spontaneously, the therapy team will 
check in with them about the nature of the experience. For the rest of the experience, as 
appropriate, the therapy team will support and encourage the participant in emotional 
processing and resolution of whatever psychological material is emerging, as described in 
the Treatment Manual. 
• 
Electrolyte-containing fluids will be provided throughout the session but not to exceed 
three liters overall. 
• 
Blood pressure, body temperature, and pulse will be measured approximately 1.5 to 2 
hours after the initial dose, before the supplemental dose is administered. 
• 
If the participant prefers not to have the supplemental dose, the therapy team will 
document the reason. 
• 
The site physician will be contacted with a brief description of how the session is 
progressing and the recent vital signs. The site physician will approve or deny the 
administration of the supplemental dose. If an AE requiring medical attention has 
occurred between the initial and supplemental dose, the site physician will determine 
whether the supplemental dose is contraindicated. If medical attention is needed, the site 
physician will provide further instruction or consult the Medical Monitor. 
• 
A supplemental half-dose will be administered with a glass of electrolyte-containing fluid 
approximately 1.5 to 2 hours after the initial dose, unless contraindicated. 
• 
Food will be provided during the latter part of the session.  
• 
If there is an approved companion, that person may arrive as agreed upon but will wait in 
the waiting room until a member of the therapy team brings them to the session room. 
Alternatively, the companion may arrive after the session has ended. 
 


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


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


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


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


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


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


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


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a centralized randomization schedule developed by an independent third-party vendor to maintain 
blinding.  
 
9.4 Blinding and Bias Minimization 
Eligibility will be determined by review of screening by the PI, site team and as needed the 
sponsor Medical Monitor prior to randomization. Participants, site staff, and the sponsor will 
remain blinded to subject group assignment until after the database is locked.  
 
To further minimize bias in measuring efficacy, the sponsor will use an observer-blind, 
centralized, reliable IR pool to administer the Primary Outcome measure via live video 
interviews. The IR Pool will have no knowledge of AEs and will only evaluate participants at 
Baseline and at the assessments scheduled after each Experimental Session. The IR Pool is 
blinded to full study design, visit number, treatment assignment, number of treatments, and any 
data from the treating therapy team after Baseline. IRs will be assigned to participants based on 
availability. Participants will be instructed to withhold their opinion on treatment group 
assignment from IRs. The participants, sponsor, and site staff will not see the CAPS-5 results 
until the end of the study. Timing of CAPS-5 assessments are pre-specified in the study protocol 
within visit windows. Changes in study management and analysis, if any, will be made by 
sponsor personnel who are blinded to group assignment and CAPS-5 data.  
 
As a site-independent review method that evaluates and confirms diagnoses, symptom severity, 
and subject validity prior to randomization, the Senior IR will review video recordings of actual 
clinical interviews conducted by the IR Pool. The recordings of these interviews accompanied by 
digital notes will be electronically submitted for independent review and 'dual' scoring of key 
rating instruments. This site-independent Senior IR reviewer either affirms subject eligibility or 
identifies administrative and/or clinical issues that may preclude study eligibility (screen failure). 
The Senior IR reviewer will invite the study team (including therapists, site physician, and 
Clinical Investigator) to provide any additional information that may inform the Senior IR 
reviewer’s opinion. The Senior IR reviewer will make the final judgment on whether or not the 
participant has an exclusionary diagnosis. 
 
To minimize bias, protect the study's double-blind and to ensure data quality, the sponsor will use 
a second Electronic Data Capture (EDC) database that is dedicated to the collection of critical 
primary and key secondary outcome measures, including the Total Severity Score on the CAPS-5 
and item scores on the Sheehan Disability Scale (SDS), administered by the centralized blinded 
IR Pool through live video. This second database is termed the Independent Rater Database 
(IRDB) and it will be separate from the blinded, clinical EDC database in order to ensure that site 
and sponsor staff engaged in study conduct are masked from study outcomes. The IRDB will only 
be accessible by: (1) qualified, observer-blind individuals who are in the established IR Pool, (2) 
the Senior IR responsible for oversight and data quality of the IR Pool, and (3) the IR Coordinator 
responsible for data entry based on paper Source Records completed by the IR Pool. All CAPS-5 
and SDS scores and supporting documentation will be reviewed by the IR Coordinator prior to 
data entry. Frequent assessments of the CAPS-5 and timely entry into the EDC system will help 
ensure that data reviewed by the DMC is as accurate and free of bias as possible. 
 
Once data is entered into the IRDB, the Senior IR will oversee the data quality by centrally 
monitoring the critical data using a risk-based approach. The risk-based monitoring methodology 
will utilize the following strategies: 1) To perform remote, source data review of the IRDB to 
check logic and to confirm reliability between the IR's, 2) To perform remote, source data 
verification to check the IRDB for administrative, data entry, or transcription errors made by the 
Independent Rater Coordinator, and 3) To perform systematic line listing reviews for data trends 


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and/or to trigger implementation of pre-defined, risk-mitigation strategies when specific data 
thresholds are exceeded. 
 
To ensure that all participants regardless of group assignment are treated in a similar manner, the 
sites will be required to follow the protocol and Treatment Manual delineating minimum length 
of time per visit type and describing delivery of treatment. All Experimental Sessions are required 
to be at least 8 hours long. Adherence to the Treatment Manual will be randomly checked by 
review of video by blinded Adherence Raters. The sponsor will monitor data in real-time to 
ensure complete data collection for all participants, including those who discontinue treatment. 
Sites will be required to make and document a specific number of attempts to obtain follow-up 
data per protocol. All randomized participants who receive at least one dose of IMP and complete 
at least one follow-up assessment will be included in the final mITT primary efficacy analysis.  
 
The DMC will act in an advisory capacity to the sponsor to monitor participant safety, data 
quality, and review Phase 3 outcomes to ensure the trial is conducted safely, ethically, and meets 
endpoint objectives. The DMC will be the only group reviewing group-unblinded interim data. 
The DMC will not be able to recommend early Study Termination for efficacy at the interim 
analysis, which will be conducted after N=100 have been enrolled. A single representative within 
MAPS will be designated to receive written communication of recommendations following the 
interim DMC review of the trial. This communication will be limited to the results needed for the 
decision of sample size re-estimation. The sponsor representative within MAPS and DMC 
members will sign a written confidentiality agreement in order that the precise rules governing 
sample size re-estimation may not be disclosed to the outside community. No other adaptions to 
the study design will be made based on this interim analysis. The sponsor representative from 
MAPS will not be part of any trial decisions or administration after the sample size re-estimation 
has been communicated to MPBC who will continue to be the trial organizer. 
 
If there is an emergency requiring knowledge of a participant’s condition assignment, the blind 
may be broken for an individual participant through the IWRS. Upon database lock, the study 
will be unblinded and participants will be notified of treatment assignment. 
 
10.0 Risks 
10.1 Non-drug Related Risks 
10.1.1 Medical Assessments 
In preparation for MDMA-assisted psychotherapy sessions, blood draws and a full medical 
examination, including a physical examination, ECG, 1-minute rhythm strip, and laboratory tests, 
are required to establish eligibility for the study. Temporary discomfort, inflammation, or 
infection could arise as a result of sampling blood at the punctured vein. Submitting to a full 
medical examination may also cause discomfort or psychological distress. Since medical 
examinations and blood draws are required to establish eligibility for the study, they cannot be 
omitted from the protocol. 
 
10.1.2 PTSD, Suicide Risk, and Psychotherapy 
During Screening, throughout MDMA-assisted psychotherapy, and during assessment of study 
measures, participants will be asked to think about and discuss their thoughts and emotions 
relating to the traumatic event or events. They may experience intense emotional responses or 
suicidal ideation as a result of recalling and speaking about this material. Even in a therapeutic 
context, thinking about and discussing the trauma, symptoms related to the trauma or the effects 


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


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


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screening is adequate to eliminate or manage the risk in the patient population. No high level 
risks have been identified in this study. 
 
10.2.2 Medium Level Risks 
Medium Risk does not indicate the likelihood the event will occur but indicates per the RACT 
assessment that new or many procedures, which are not complex, are needed to ensure screening 
is adequate to eliminate or manage the risk in the patient population. 
 
10.2.2.1 Cardiovascular and Cerebrovascular Risks and Mitigation 
MDMA is known to transiently increase heart rate and blood pressure in a dose-dependent 
manner that is generally not problematic for physically healthy individuals. These changes should 
last no more than 8 hours. Participants with PTSD in MAPS-sponsored Phase 2 studies do not 
appear to differ from healthy individuals in this sympathomimetic, physiological response. Most 
people do not experience elevations in cardiovascular parameters that exceed those seen after 
moderate exercise. An examination of safety data drawn from Phase 2 studies of MDMA-assisted 
psychotherapy detected a dose-dependent increase in systolic blood pressure but not diastolic 
blood pressure. Characterization of sympathomimetic effects among participants with controlled 
hypertension is ongoing.  
 
Risks posed by elevated blood pressure will be addressed by excluding people with pre-existing 
uncontrolled hypertension and monitoring blood pressure and pulse, as described in Section 4.2 
Exclusion Criteria. Before and after IMP administration in Experimental Sessions, the therapy 
team will monitor vital signs. The therapy team will attend to clinical signs and symptoms of 
potential rare complications of the cardiovascular effects of MDMA, such as stroke or acute 
myocardial infarction (AMI) during Experimental Sessions. Any symptoms such as chest pain, 
shortness of breath, neurological deficit or confusion or other potential indicators of end organ 
effects will prompt additional vital sign measurements, and intervention if appropriate. The 
therapy team will notify the site physician for evaluation if this occurs.  
 
If any participant has neurological deficits, as assessed by the site physician, whether or not they 
are associated with hypertensive crisis, they will be monitored, as described above and 
transported to the hospital if medically indicated. If evaluation at the hospital reveals a 
nonhemorrhagic stroke, there will be sufficient time to administer recombinant tissue 
plasminogen within the 3-hour time frame recommended in the American Academy of 
Neurology/American Heart Association guidelines [107, 108]. 
 
If a participant experiences ischemic type chest pain, whether or not it is associated with 
hypertensive crisis, they will be given 0.4 mg of sublingual nitroglycerin every 5 minutes as 
needed for chest pain pending transport to the hospital, and the site physician will be promptly 
notified. Nitroglycerin should be stocked on site per applicable national and local regulations in 
order to respond promptly in case of need. If further evaluation at the hospital reveals that the 
participant has had an AMI, they will be well within the time frame required for definitive 
therapy. The American College of Cardiology/American Heart Association guidelines for the 
treatment of AMI recommend percutaneous transluminal coronary angioplasty (PTCA) as the 
treatment of choice when it can be performed within 90 minutes of arrival at the hospital in 
participants who present within 12 hours of an episode of chest pain lasting more than 30 minutes 
and who have ECG evidence of AMI [109]. Any participant who experiences such medical 
complications during an Experimental Session will not be given another Experimental Session, 
unless it is approved by the investigator, site physician, and the Medical Monitor.  
 


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


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


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participant. If at any time the temperature rises more than 1.5°C above Baseline despite these 
efforts, the site physician will be consulted for further evaluation and treatment.  
 
10.2.3.2 Osmoregulatory Risk and Mitigation 
MDMA administered in a controlled setting is not expected to have any risks of osmoregulatory 
changes. Participants will not be allowed to drink more than three liters of electrolyte-containing 
fluids over the course of the Experimental Session and fluid intake will be spread out 
appropriately during the session. If a participant exhibits any signs of toxicity or clinically 
significant dilutional hyponatremia despite these precautions after an Experimental Session, they 
will not receive another Experimental Session unless it is approved by the investigator, site 
physician, and the Medical Monitor. 
 
10.2.3.3 Genotoxicity Risk and Mitigation 
To reduce the risk of metabolic activation and formation of nitroso-derivatives of MDMA due to 
interactions with nitrates or nitrites in food, participants are required to have fasted (no intake 
other than alcohol-free liquids) for 10 hours prior to IMP administration at Experimental 
Sessions. 
 
10.2.3.4 Reproductive and Developmental Risks and Mitigation 
Risks posed by MDMA to pregnant people are not known. One of two studies of Ecstasy users 
suggests that use of Ecstasy and other drugs during pregnancy may be associated with some 
abnormalities at birth while the other failed to find this association [111, 112]. 
 
Pregnant and lactating people will be excluded from participation in the study. Participants who 
are able to become pregnant must have a negative pregnancy screen before undergoing each 
Experimental Session and must agree to use adequate birth control for the duration of the study 
during the Treatment Period. Paternal drug exposure studies show that exposure to MDMA was 
not a factor in adverse pregnancy outcomes, so partners of participants who were assigned male at 
birth will not be required to practice birth control. Due to the limited number of single-dose 
exposures being studied in this trial, the chance of birth defects are low. Procedures described in 
Section 11.3 Pregnancy have been put in place to mitigate risk of reproductive or developmental 
exposure to the IMP. 
 
10.2.4 Minimal Risks 
Minimum Level Risk does not indicate the likelihood the event will occur but indicates per the 
RACT assessment that no procedures are needed beyond basic monitoring to ensure screening is 
adequate to eliminate or manage the risk in the patient population. 
 
10.2.4.1 Common AEs 
Common AEs are typically observed during IMP administration, but are transient and diminish as 
the IMP is metabolized and excreted over the next 72 hours after dosing. Common AEs most 
frequently reported during Experimental Sessions include muscle tightness in the jaw, lack of 
appetite, dizziness, and nausea. During the week following treatment, lack of appetite, muscle 
tightness in the jaw, restlessness, weakness, dry mouth, thirst, impaired gait/balance, and 
sensitivity to cold may be reported. Severe anxiety, insomnia, fatigue, and depressed mood are 
commonly reported in PTSD studies in both placebo and MDMA groups. Common AEs are 
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acting low dose benzodiazepines (specifically, lorazepam) or sleep aids as needed, per clinical 
judgment of the site physician. 
 
10.2.4.2 Potential Neurotoxicity Associated with Ecstasy Use 
Some researchers believe that MDMA is neurotoxic in humans even at doses used in clinical 
trials [113]. However, these claims are based on studies that employed inappropriately high doses 
of MDMA utilized in animal studies and on human studies comparing the effects of repeated use 
of Ecstasy, often along with other drugs. Meanwhile, another recently published meta-analysis 
has taken careful steps to overcome methodological limitations in previous work and found only 
modest evidence of neurotoxicity [114]. The sponsor has carefully considered the risks of such 
neurotoxicity and conclude that they are minimal in the proposed study. This conclusion is 
supported by empirical and toxicokinetic evidence and is consistent with the lack of toxicity 
reported in previous clinical MDMA studies. It does not appear that MDMA-assisted 
psychotherapy negatively impacts cognitive function. Neurotoxicity and neurocognitive effects of 
MDMA were studied in the sponsor’s Phase 2 studies and provided sufficient data to conclude 
that limited exposures to MDMA allowed for adequate time for reversibility of any effects at the 
synaptic level. Furthermore, limited dosing of MDMA has shown to have no effect on 
neurocognitive functioning. 
 
10.2.4.3 Abuse Liability 
Findings in humans and animals suggests that MDMA possesses moderate abuse potential that is 
higher than that reported for “classic hallucinogens,” like psilocybin, but lower than that reported 
for psychostimulants, such as cocaine or methamphetamine. In sponsor-supported Phase 2 PTSD 
studies in 107 participants treated with MDMA-assisted psychotherapy in a controlled clinical 
setting, 29.9% (32 of 107) of participants had tried Ecstasy at least 6 months prior to enrollment, 
with U.S. samples demonstrating a higher prevalence of use than international studies. 
Participants reported using Ecstasy an average of 2.3 (SD:1.43) times. Due to the known 
association of substance use disorders and PTSD, this sample was likely not representative of the 
general healthy volunteer population but is congruent with the PTSD population. At long-term 
follow-up across Phase 2 studies, 8.7% of participants (eight of 92) reported “Ecstasy” use across 
studies, with five participants indicating single and not repeated use and three participants 
indicating two uses. Six of these eight subjects had used Ecstasy prior to study participation. Of 
these participants, most were attempting to recreate a therapeutic experience, and most did not 
indicate a desire to repeat this. In addition to self-report data, urine drug screens specific for 
MDMA were performed at random and 2, 6, and 12 months after the final Experimental Session 
during one study (MP2, N=12). All were negative, supporting the observation that study 
participants did not seek out MDMA or Ecstasy after taking part in the study [60]. In addition to 
data on Ecstasy use at follow-up, AEs were reviewed across Phase 2 studies, the sponsor found an 
absence of clinically significant AEs supporting drug dependence, intentional drug misuse, and 
substance abuse, and a low rate (<2%) of secondary terms that reflect acute intoxication.  
 
Based on current information, it does not appear that MDMA-assisted psychotherapy 
demonstrates signals associated with known abuse liability patterns in a PTSD population when 
administered in a therapeutic setting under continuous observation in three single-dose sessions. 
Any abuse potential and diversion is further limited since the IMP is not supplied to the 
participant to take home and is administered in a restrictive setting. Each investigator responsible 
for dispensing or administration of the IMP will maintain current registration with authorities 
with oversight of controlled substances. IMP will be handled following all regulations pertaining 
to the handling and dispensing of controlled substances within research studies. See Section 
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Within-participant elevation in self-reported Ecstasy use post-treatment will be clinically assessed 
for signals of abuse and will be monitored during the Long-term Follow-up extension study 
associated with this protocol.  
 
11.0 Safety 
11.1 Adverse Events 
In accordance with guidance for the specific study site, Health Canada Clinical Safety Data 
Management Definitions and Standards for Expedited Reporting International Conference on 
Harmonisation (ICH) Topic E2A: Guidance for Industry or FDA Safety Reporting Requirements 
for INDs and BA/BE Studies, an Adverse Event (AE) is defined as any medical occurrence in a 
participant, including any abnormal sign (e.g., abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the participant’s involvement in the research, 
whether or not considered related to participation in the research. This definition includes 
concurrent illnesses or injuries and exacerbation of pre-existing conditions.  
 
Events related to planned treatments or physician visits for Baseline conditions collected in the 
medical history will not be collected, unless there is an exacerbation of the condition, in which 
case they will be actively followed until resolution. 
 
An unexpected AE is one that is not listed in the current IB or an event that is by nature more 
specific or more severe than a listed event. 
 
The site physician will be responsible for reviewing and confirming all AEs and SAEs collected 
during the study. The therapy teams will collect AEs during study visits from Enrollment (Visit 0) 
through Study Termination (Visit 20). Participants will be asked directly how they are feeling 
during each contact, and AEs may be captured spontaneously during psychotherapy sessions, 
telephone calls, or other correspondence. Completed measures may create suspicion that an AE 
occurred; in this case, the site staff should follow-up with the participant. 
 
All AEs will be monitored by the therapy team until resolution or, if the AE becomes chronic, a 
cause can be identified. If an AE is unresolved when a participant terminates from the study, a 
clinical assessment will be made by the site physician, investigator, and/or Medical Monitor as to 
whether continued follow-up of the AE is warranted. 
 
The severity of events reported on the “Adverse Events” eCRF will be determined by the site 
physician as: 
 
• 
Mild: No limitation in normal daily activity 
• 
Moderate: Some limitation in normal daily activity 
• 
Severe: Unable to perform normal daily activity 
 
The relationship of each AE to the IMP will be determined via analysis and the opinion of the 
investigator will not be collected, with the exception of SAEs. 
 
11.1.1 Adverse Events of Special Interest  
In accordance with guidance for the specific study site, Health Canada Clinical Safety Data 
Management Definitions and Standards for Expedited Reporting ICH Topic E2A: Guidance for 
Industry or FDA Safety Reporting Requirements for INDs and BA/BE Studies, the sponsor will 


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pay special attention to a subset of AEs involving cardiac function that could be indicative of QT 
interval prolongation or cardiac arrhythmias, including Torsade de pointes, sudden death, 
ventricular extrasystoles, ventricular tachycardia, ventricular fibrillation and flutter, non-postural 
syncope, and seizures. The subset of AEs involving suicide risk under the following terms are 
also of special interest: suicides, suicide attempts, self-injurious behavior associated with suicidal 
ideation, and suicidal ideation judged to be serious or severe in the opinion of the investigator. 
These AEs will be marked in the eCRF with the denotation “Adverse Event of Special Interest” 
(AESIs) whether serious or non-serious. 
 
In order to assess signals of abuse potential for the IMP in the intended patient population: 
 
• 
AESIs involving the terms of Behavioral addiction, Drug abuser, Substance abuser, 
Dependence, Intentional product misuse, Overdose (accidental, intentional, or 
prescribed), or Drug diversion in cases that are related to MDMA or “Ecstasy” (material 
represented as MDMA) will be collected and coded as AESIs in the eCRF. 
• 
Cases of noncompliance, protocol violations, participants lost to follow-up, and any other 
reasons why participants dropped out of the study will be assessed for presence of AESIs. 
• 
Qualitative urine drug test data will be collected prior to each Experimental Session. Any 
positive findings that cannot be attributed to pre-approved concomitant medications or 
diet will be reviewed by the Medical Monitor to assess compliance with ongoing 
eligibility criteria and for presence of AESIs. 
 
If an AESI is a SAE (Serious Adverse Event ) or if it involves suicide risk, it should be reported 
to the sponsor with a narrative via the eCRF within 24 hours of the site’s awareness of the event. 
 
11.1.2 Serious Adverse Events 
In accordance with guidance for the specific study site, Health Canada Clinical Safety Data 
Management Definitions and Standards for Expedited Reporting ICH Topic E2A: Guidance for 
Industry or FDA Safety Reporting Requirements for INDs and BA/BE Studies, an SAE is defined 
as any untoward medical occurrence that at any dose: 
 
• 
Results in death. 
• 
Is life-threatening (i.e., the participant was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires or prolongs inpatient hospitalization. 
• 
Results in persistent or significant disability/incapacity (i.e. the event causes substantial 
disruption of a person’s ability to conduct normal life functions). 
• 
Results in a congenital anomaly/birth defect. 
• 
Requires intervention to prevent permanent impairment or damage. 
• 
Is an important and significant medical event that may not be immediately life-
threatening or resulting in death or hospitalization, but based upon appropriate medical 
judgment, may jeopardize the participant or may require intervention to prevent one of 
the other outcomes listed above. 
 
AEs which do not fall into these categories are defined as non-serious. It should be noted that a 
severe Adverse Event need not be serious in nature and that a SAE need not, by definition, be 
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In addition, a pre-existing event or condition that results in hospitalization should be recorded on 
the medical history. The hospitalization would not result in the event or condition being reported 
as a study-related SAE, unless, in the view of the site physician, hospitalization was prolonged as 
a result of participation in the clinical trial or was necessary due to a worsening of the pre-
existing condition. This is because the onset of the event (the reason for the procedure) occurred 
before the participant was entered in the trial. Hospitalization for cosmetics, non-emergency 
prophylaxis, or elective abortion does not result in an SAE report, unless, in the view of the site 
physician, hospitalization for these procedures was prolonged as a result of participation in the 
clinical trial. 
 
All SAEs will be collected from enrollment through Study Termination. All SAEs which occur 
during the course of the trial, whether considered to be associated with IMP or not, must be 
reported to the sponsor within 24 hours of the site staff’s awareness of occurrence. Reporting 
procedures will be provided to the site. All SAEs will be assessed for relationship, expectedness 
and any required actions to address safety at the time of reporting of the event. SAEs will be 
evaluated by the site physician and Medical Monitor to determine if it is appropriate for the 
participant to continue treatment or enter follow-up.  
 
11.2 Other Significant Events 
Significant life events that may occur during the course of the study, including death of a loved 
one, loss of employment, or other hardship, may have an impact on treatment outcome. The 
sponsor will capture these life events using the LEC-5 measure. Such events will be entered as 
Comments in the eCRF and if appropriate, described in the Case Study Report for data outliers, if 
any. 
 
11.3 Pregnancy 
11.3.1 Definition of Childbearing Potential 
A participant is considered of childbearing potential if they were assigned female at birth and are 
post-menarche. A participant is considered not of childbearing potential if they are premenarchal, 
surgically sterile (documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy, 
and/or tubal ligation), postmenopausal, or assigned male at birth.  
 
11.3.2 Contraception Guidelines 
Study participants who were assigned male at birth with partners of childbearing potential will 
not be required to practice birth control. Adequate birth control methods are required for 
participants of childbearing potential and include: 
 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Non-oral hormonal methods, including injected, intravaginal, implanted, transdermal 
• 
Oral hormones plus a barrier contraception (condom, diaphragm, or spermicide)  
• 
Double barrier method (at least two of the following: condom, diaphragm, and 
spermicide) 
• 
Vasectomized sole partner 
• 
Abstinence from penile-vaginal intercourse 
o The reliability of abstinence should be evaluated carefully with the participant in 
relation to their general lifestyle. An additional acceptable birth control method 


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


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


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


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


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


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


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


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


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


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


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


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


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16.0 References 
1. 
Lanius, R.A., et al., The dissociative subtype of posttraumatic stress disorder: rationale, 
clinical and neurobiological evidence, and implications. Depress Anxiety, 2012. 29(8): p. 
701-8. 
2. 
Lanius, R.A., et al., Emotion modulation in PTSD: Clinical and neurobiological evidence 
for a dissociative subtype. Am J Psychiatry, 2010. 167(6): p. 640-7. 
3. 
Nicholson, A.A., et al., The Dissociative Subtype of Posttraumatic Stress Disorder: 
Unique Resting-State Functional Connectivity of Basolateral and Centromedial 
Amygdala Complexes. Neuropsychopharmacology, 2015. 40(10): p. 2317-26. 
4. 
Hoge, C.W., et al., Combat duty in Iraq and Afghanistan, mental health problems, and 
barriers to care. N Engl J Med, 2004. 351(1): p. 13-22. 
5. 
Statement Of Jon A. Wooditch Acting Inspector General Department Of Veterans Affairs, 
in Committee On Veterans' Affairs Subcommittee On Disability Assistance And Memorial 
Affairs. 2005: Washington, DC. 
6. 
Solon, O., My therapist gave me a pill: Can MDMA help cure trauma? 
https://www.theguardian.com/society/2016/sep/16/mdma-ptsd-therapy-trauma-maps-
medical-study#comments, in The Guardian. 2016. 
7. 
Kemp, J. and R. Bossarte, Suicide Data Report 2012. 2013, US Department Of Veterans 
Affairs, Mental Health Services, Suicide Prevention Program 
http://www.va.gov/opa/docs/Suicide-Data-Report-2012-final.pdf%20. 
8. 
Brady, K., et al., Efficacy and safety of sertraline treatment of posttraumatic stress 
disorder: a randomized controlled trial. JAMA, 2000. 283(14): p. 1837-44. 
9. 
Davidson, J.R., et al., Multicenter, double-blind comparison of sertraline and placebo in 
the treatment of posttraumatic stress disorder. Arch Gen Psychiatry, 2001. 58(5): p. 485-
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10. 
Friedman, M.J., et al., Randomized, double-blind comparison of sertraline and placebo 
for posttraumatic stress disorder in a Department of Veterans Affairs setting. J Clin 
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11. 
Arikian, S.R. and J.M. Gorman, A Review of the Diagnosis, Pharmacologic Treatment, 
and Economic Aspects of Anxiety Disorders. Prim Care Companion J Clin Psychiatry, 
2001. 3(3): p. 110-117. 
12. 
Sidran Institute. Post traumatic stress disorder fact sheet. 2016; Available from: 
https://www.sidran.org/resources/for-survivors-and-loved-ones/post-traumatic-stress-
disorder-fact-sheet/ Accessed September 2016. 
13. 
Ursano, R.J., et al., Practice guideline for the treatment of patients with acute stress 
disorder and posttraumatic stress disorder. Am J Psychiatry, 2004. 161(11 Suppl): p. 3-
31. 
14. 
Foa, E.B., et al., Effective Treatments for PTSD, Practice Guidelines from the 
International Society for Traumatic Stress Studies. Second ed. 2009, New York, NY: 
Guilford Press. 
15. 
Benish, S.G., Z.E. Imel, and B.E. Wampold, The relative efficacy of bona fide 
psychotherapies for treating post-traumatic stress disorder: a meta-analysis of direct 
comparisons. Clin Psychol Rev, 2008. 28(5): p. 746-58. 
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Cukor, J., et al., Emerging treatments for PTSD. Clin Psychol Rev, 2009. 29(8): p. 715-
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Basoglu, M., E. Salcioglu, and M. Livanou, A randomized controlled study of single-
session behavioural treatment of earthquake-related post-traumatic stress disorder using 
an earthquake simulator. Psychol Med, 2007. 37(2): p. 203-13. 
18. 
Gerardi, M., et al., Virtual reality exposure therapy using a virtual Iraq: case report. J 
Trauma Stress, 2008. 21(2): p. 209-13. 


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19. 
Heresco-Levy, U., et al., Pilot-controlled trial of D-cycloserine for the treatment of post-
traumatic stress disorder. Int J Neuropsychopharmacol, 2002. 5(4): p. 301-7. 
20. 
Freudenmann, R.W., F. Oxler, and S. Bernschneider-Reif, The origin of MDMA (ecstasy) 
revisited: the true story reconstructed from the original documents. Addiction, 2006. 
101(9): p. 1241-5. 
21. 
Shulgin, A.T., The background and chemistry of MDMA. J Psychoactive Drugs, 1986. 
18(4): p. 291-304. 
22. 
Farre, M., et al., Pharmacological interaction between 3,4-
methylenedioxymethamphetamine (ecstasy) and paroxetine: pharmacological effects and 
pharmacokinetics. J Pharmacol Exp Ther, 2007. 323(3): p. 954-62. 
23. 
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Appendix A: Sub-study without Overnight Stays 
 
Rationale 
 
This sub-study to the MAPP1 protocol “A Randomized, Double-Blind, Placebo-Controlled, 
Multi-Site Phase 3 Study of the Efficacy and Safety of Manualized MDMA-Assisted 
Psychotherapy for the Treatment of Severe Posttraumatic Stress Disorder" allows participants to 
be discharged in the evening after the Experimental Session is over at two investigational study 
sites. In MAPS’ Phase 2 study MAA1, which tested the safety and efficacy of MDMA-assisted 
psychotherapy for social anxiety among autistic adults, an overnight stay was not required. There 
were no safety concerns due to travel to home or hotel, and this approach was found to be 
feasible. 
 
Study site and participants will follow all protocol procedures described in the main protocol, 
except those related to overnight stays as described below. The overnight stay is included in the 
main study protocol primarily as an opportunity for rest and integration in a relaxed and 
comfortable environment away from the distractions of home, and to facilitate the logistics of 
participation in the integrative visit at the site on the day following the Experimental Session. The 
overnight stay is not required for medical reasons, but in case of emergencies, the therapists and 
study physician are on-call for all sites. 
 
In the main study protocol, a Night Attendant accompanies the participant during the overnight 
stay. The Night Attendant’s primary function is to ensure the participant is comfortable and has a 
meal, to provide minimal support, and to alert qualified site staff in case of need expressed by the 
participant or determined by observation. All Night Attendants are interviewed, trained, and 
approved by therapy teams to ensure they are comfortable providing the necessary support and 
know whom to call if medical support is needed from the therapy team or study physician.  
 
Medically-trained Night Attendants have not been required for any of the five Phase 2 studies of 
MDMA-assisted psychotherapy for PTSD since MP-1 was completed. In MP-1, the first Phase 2 
study, the FDA required that the Night Attendant be a registered nurse. Since MP-1, Night 
Attendants were not required to have medical training in subsequent studies. Among 189 
participants treated under this IND, no medical complications have arisen during overnight stays 
under the watch of Night Attendants. 
 
The sponsor and investigators agree that allowing participants who are screened for stable 
domestic circumstances to return home will not increase the risks of participation in the study. 
The study protocol discusses the risk of psychological distress in a PTSD population and 
mitigation in Section 10.2.2.2. Therapists and site physicians are aware of these risks, including 
anxiety and depressed mood occasionally reported 1 to 3 days after MDMA administration. In 
previous Phase 1 and 2 studies, these reactions have been transient and have responded well to 
reassurance from the therapy team, with occasional use of benzodiazepines for anxiety. If needed, 
the study physician may prescribe a short-acting, low-dose benzodiazepine (specifically, 
lorazepam) or sleep aids (excluding trazodone) as needed. 
 
Consistent with the main study protocol and the sub-study, proper preparation and follow-up 
support will reduce the difficulties participants might have with acute or sub-acute reactions. The 
potential for destabilizing psychological distress will be minimized by: 
 
• 
Excluding people who might be more vulnerable to it (such as people diagnosed with 
bipolar affective disorder type 1 or with psychotic disorders) 
• 
Excluding people who do not have a stable living situation or supportive family/network 


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


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


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