Clinical trial NCT04077437
Conditions: Posttraumatic Stress Disorder
Sponsor: Lykos Therapeutics
Start date: 2020-09-02; Completion date: 2022-11-02
Enrollment: 121 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 moderate 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 psychotherapy versus psychotherapy with placebo control in participants diagnosed with at least moderate PTSD. The study will be conducted in N ≈ 100 participants. Participants will be randomized into one of two groups (MDMA or placebo) in a 1:1 ratio. An initial dose of MDMA or placebo, followed by a supplemental half-dose unless contraindicated, will be administered during the Treatment Period with manualized psychotherapy in three monthly Experimental Sessions. This \~12-week Treatment Period is preceded by three Preparatory Sessions. 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. Each Experimental Session will be followed by three Integrative Sessions of non-drug psychotherapy to help the participants process and understand their experiences during the Experimental Sessions.

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 change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) Total Severity Score from Visit 3 (Baseline) to Visit 19 (18 weeks post Baseline) (Blake et al., 1995). 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 change in Sheehan Disability Scale (adapted SDS) item scores from Visit 3 (Baseline) to Visit 19 (18 weeks post Baseline) (Leon et al., 1997).

Arms: arm 1: Administration of 80 to 120 mg midomafetamine HCl in combination with manualized psychotherapy, followed by a supplemental half-dose 1.5 to 2 hrs after the initial dose of 40 or 60 mg, respectively. arm 2: Administration of inactive placebo in combination with manualized psychotherapy.
Interventions: intervention 1: Therapy intervention 2: Midomafetamine intervention 3: Placebo
Intervention descriptions: intervention 1: Standardized non-directive therapy performed by therapist team. intervention 2: Administration of 80 to 120 mg midomafetamine HCl, followed by a supplemental half-dose 1.5 to 2 hrs after the initial dose of 40 or 60 mg, respectively, during three sessions of MDMA-assisted psychotherapy. intervention 3: Administration of placebo with therapy during three experimental sessions

Protocol documents:
ICF_003.pdf: 
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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 
Posttraumatic Stress Disorder of Moderate or Greater 
Severity 
 
PROTOCOL NO.: 
MAPP2 
 
IRB Protocol # 20193178 
 
SPONSOR: 
Multidisciplinary Association for Psychedelic Studies (MAPS) 
3141 Stevens Creek Blvd #40547 
San Jose, CA 95117 
 
<<CF-Main Header Block - Investigator>> 
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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Any person who is requested to consent to participate as a subject in a research study 
involving a medical experiment, or who is requested to consent on behalf of another has 
the right to: 
 
(a) Be informed of the nature and purpose of the experiment. 
(b) Be given an explanation of the procedures to be followed in the medical 
experiment and any drug or device to be used. 
(c) Be given a description of any attendant discomforts and risks reasonably to be 
expected from the experiment, if applicable. 
(d) Be given an explanation of any benefits to the subject reasonably to be expected 
from the experiment if applicable. 
(e) Be given a disclosure of any appropriate alternative procedures, drugs, or 
devices that might be advantageous to the subject, and their relative risks and 
benefits. 
(f) Be informed of the avenues of medical treatment, if any, available to the subject 
after the experiment or if complications should arise. 
(g) Be given an opportunity to ask any questions concerning the experiment or other 
procedures involved. 
(h) Be instructed that consent to participate in the medical experiment may be 
withdrawn at any time, and the subject may discontinue in the medical 
experiment without prejudice. 
(i) Be given a copy of a signed and dated written informed consent form when one 
is required. 
 
Be given the opportunity to decide to consent or not to consent to a medical experiment 
without the intervention of any element of force, fraud, deceit, duress, coercion or undue 
influence on the subject's decision. 
.


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Purpose of the Participant Information and Consent Form 
This consent form describes the 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. The form describes 
the purpose, procedures, benefits, risks, discomforts and your rights as a part of the 
study.   
 
If you sign the form, you are giving your permission to participate. Signing this form 
does not guarantee that you will be enrolled in the study or that you are obligated to 
participate or unable to withdraw from the study. You should participate only if you want 
to. Before you decide whether to participate, you should think about how the tests and 
study visits will affect your schedule, family, and work.  
 
You can review 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. 
 
The sponsor is paying for this research study. Your study doctor, research team and 
therapy pair 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.  
 
Signing this form will not result in you losing any of your rights. You may refuse to take 
part in this study or withdraw from this study at any time without penalty or loss of 
benefits to which you are otherwise entitled.  
 
Background 
You are being asked to participate because you have reported symptoms of 
posttraumatic stress disorder (PTSD) lasting for at least 6 months or longer. 
 
The purpose of this multi-center study is to provide information on whether the drug 3,4-
methylenedioxymethamphetamine (MDMA) combined with therapy is safe and helpful 
for people who have PTSD.  


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MDMA is an experimental drug, which means that it has not been approved by the Food 
and Drug Administration (FDA) for sale for medical use in the United States (U.S.). 
MDMA is also a controlled drug (illegal to use outside of research) and is sometimes 
known as “Ecstasy” or “Molly” (which is supposed to contain MDMA, but often contains 
other drugs instead of or in addition to MDMA). MDMA is a chemical that is structurally 
similar to some stimulant chemicals, like methamphetamine, which is both a major drug 
of abuse and an FDA-approved treatment for Attention Deficit Disorder. MDMA is also 
similar 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 
twelve studies of MDMA-assisted therapy in the U.S., Canada, and Israel for PTSD and 
other diagnoses. 
 
Before MDMA became illegal in 1985, some psychologists and psychiatrists combined it 
with therapy 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 change 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 distressing. 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 therapy, help people work through thoughts, 
memories and emotions related to PTSD and other past experiences. 
 
Study Information 
 
Type of Study 
This study is double-blind, meaning neither you nor the study researchers (including 
your therapists) will know if you get MDMA or placebo. You may get MDMA, or you may 
get a placebo (pills that looks like MDMA but 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 therapy as well. 
 


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Length of Study 
The length of active participation in the study will be about 27 weeks but may be more 
or less, depending on the length of screening, how long you need to safely stop your 
medications (as needed), and scheduling. Participation in the study requires a large 
time commitment from you over the active study period.  
 
Due to the COVID-19 pandemic or other unforeseen circumstances, there may be 
delays in your study schedule including visits and Study Drug Sessions. The Study 
team will be closely following federal and local safety guidelines regarding COVID-19 
and will keep you as informed as possible about any potential changes to the study 
schedule. 
 
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 are still 
eligible to participate, you will be invited to enroll in another study where you will get 
MDMA-assisted therapy. This study would not start until all participants have completed 
this current study. It may be at least a year before you are able to enroll in this study. 
 
Types of Visits and Duration 
Below are the planned visits for this study: 
 
• Screening Visits: Multiple visits at the study location, lab, and/or doctor’s office, 
an online meeting with an evaluator, and phone/video calls from the study team. 
 
• 3 Preparatory Visits (~90 minutes each): Three introductory therapy sessions 
at the start of participation in the study, spaced about one week apart. 
 
• 3 Study Drug Sessions (~8 hours long plus an overnight stay): Three visits 
about 1 month apart. You will be given either MDMA or placebo during these 
visits along with therapy. 
 
• 9 Integrative Sessions (~90 minutes each): Three sessions after each Study 
Drug Session. These are about 1 week apart and will involve you talking to your 
therapists about your thoughts and feelings. 
 
• 4 Online Meetings with an Evaluator (~120 minutes each): Four video 
meetings where you will be interviewed about your PTSD symptoms. These 
meetings may be conducted on-site or at your home.  
 
• Questionnaires (90 to 120 minutes): Completion of questionnaires at Visit 4 
(the third Preparatory Visit) and Visit 20 (Study Termination).  


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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. 


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Procedures/What Will Take Place in the Study  
 
Screening/Evaluation and Beginning of Study 
If you agree to be in this study, you will first sign this Informed Consent form before any 
study-related procedures are done.  
 
Before you can be enrolled in the study, the study team must first make sure that you 
qualify for the study and that you are generally physically healthy. This screening 
process can take up to 6 weeks. The order of assessments in screening may vary, but 
this form lists all the activities in the screening period. Some of these meetings may take 
place online or in-person. 
 
At the initial meeting, you will be asked to: 
• Provide information about yourself, including answering questions about difficult 
experiences you may have had during your childhood and other times in your life 
• Complete questionnaires about your past trauma(s), PTSD symptoms, substance 
use, and thought patterns 
• Answer questions about thoughts you might have had in your life about harming 
yourself or ending your life 
 
If you are initially eligible, screening will continue with the following medical 
assessments with a study doctor. There may be multiple visits or online meetings, 
where you will be asked to do the following: 
 
• Provide your medical and psychiatric history, including past medical records from 
the last 3 years 
• Provide information about past and current medications 
• A brief physical exam, including taking vital signs (blood pressure, heart rate, and 
body temperature) and measuring your height and weight 
• An electrocardiogram (ECG) and rhythm strip, which are recordings of the 
electrical activity of your heart  
• Provide a small sample of your blood (about 2 teaspoons) for the sole purpose of 
ensuring your safety and compatibility with the study, including tests of 
metabolism, liver function, and alcohol use. We also will test for the human 
immunodeficiency virus (HIV) and Hepatitis C virus (HCV). 
 
o If you have positive test results for HIV or HCV, 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. You may still be able to participate in the 
study after you have been evaluated (and potentially treated) by a doctor. 
If you do not want to be tested, you should not take part in this research 
study. 
 


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• A urine test for drugs that may be addictive. 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. 
 
You will also have an online meeting with an evaluator who will ask you questions 
about: 
 
• Your emotional and psychiatric history 
• Drug use 
• Thoughts you may have about harming yourself or ending your life 
• Other thought patterns you may have 
 
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.  
 
Due to COVID-19, your therapy pair and study doctor may ask you additional questions 
about your health in advance of any on-site visit. They may ask you to wear a mask or 
other protective equipment. They may take your temperature or ask for other 
precautions, such as COVID-19 testing. If there are any costs associated with COVID-
19 screening or protective equipment required by your therapy pair or study doctor, the 
sponsor will pay for those costs. 
 
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, echocardiogram 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 and 3 hours each. 
 
<<CF-Main User Defined #3>>The cardiologist may generate medical records with your 
name on them. 
 
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 in the following sections, 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. 
 


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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. First, you will receive a radiotracer 
(radioactive dye) in your blood followed by imaging (pictures) of your heart. You will 
then exercise on a treadmill or stationary bicycle. About 2 minutes before stopping (or 
until signs of difficulty appear, such as shortness of breath or tension in your chest), you 
will receive a second radiotracer. Another set of imaging will be done 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 radiotracers.  
 
The radiotracer is injected using a needle placed in a vein in the arm (similar to a blood 
draw). 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 
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. 
 
Stress Echocardiogram 
Your study doctor may order this type of exercise testing. This will depend on availability 
of the testing and your study doctor’s clinical opinion. For this test, you will also go to a 
doctor’s office that is specifically prepared for this kind of procedure. There are two 
parts to this test. In the first part of the test, a cardiac scientist performs an 
echocardiogram, using an ultrasound machine. An echocardiogram checks how your 
heart functions when resting. In order to obtain the image, you will be asked to lie on 
your left side. To ensure good contact between your skin and the probe, surgical jelly is 
placed at several different sites on your chest. In the second part of the test, your heart 


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is exercised or ‘stressed’. If you can walk easily, you can walk on the treadmill. The 
speed and slope of the treadmill will increase gradually. This makes your heart do more 
work. When your heart is working as hard as possible, you stop exercising and quickly 
lie down on the bed. More echocardiogram pictures are taken. The test will be stopped 
if you have chest pain, become very tired or very short of breath, or if you ask to stop. 
 
Echocardiogram 
An echocardiogram (echo) is a graphic outline of the heart's movement. During an echo 
test, ultrasound (high-frequency sound waves) from a hand-held wand placed on your 
chest provides pictures of the heart's valves and chambers and helps the sonographer 
evaluate the pumping action of the heart. Echo is often combined with Doppler 
ultrasound and color Doppler to evaluate blood flow across the heart's valves. 
 
There are no known risks associated with the echo procedure, because it uses 
harmless sound waves, similar to how doctors record pictures of fetuses in pregnant 
people. The gel may feel cold when it is first placed. Some people with sensitive skin 
can develop a rash from the gel. 
 
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. 
 
Beginning of Study 
If you pass the initial screening and choose to participate, you will be enrolled in the 
study and we will schedule your first preparatory session with your therapy pair. 
However, this does not mean you are guaranteed to be able to participate in Study Drug 
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. 
 
If you are taking certain medications, you may need to stop taking them before your first 
online meeting to discuss your PTSD or your first Study Drug Session. The study doctor 
will discuss the medication plan with your prescribing doctor. Only stop medications if 
the study doctor gives you specific instructions for how to stop. Your symptoms of PTSD 
may worsen with discontinuation of your current medications. Some PTSD medications 
can cause thoughts of harming yourself or ending your life if you stop taking them too 
quickly and without the care of a doctor. This is very important. Do not stop taking 
the medications before you are supposed to. 


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You must let your therapy pair know about any change in medicines or medical 
conditions or procedures, such as surgery, within 48 hours of it happening.  
 
You will need to give your therapy pair the name and contact information (phone 
number or email) of a relative, spouse, or close friend. Your therapy pair will contact this 
person only if you have a medical emergency, if you are at risk of hurting yourself or 
someone else, or if the study team cannot get in touch with you and need to know you 
are okay.  
 
Preparatory Sessions 
During the Preparatory Period, you will have the following sessions: 
 
• Visit 1: Preparatory Session 1 (90 minutes) 
• Visit 2: Preparatory Session 2 (90 minutes) 
• Visit 3: Online evaluation (90-120 minutes) 
• Visit 4: Preparatory Session 3 (90 minutes therapy + 90 minutes questionnaires) 
 
Most of these visits will take place in person at the study site; your therapy pair will let 
you know if any of the preparatory sessions can or will take place remotely on a 
computer.  
 
Preparatory Sessions are 90-minute therapy sessions. The third Preparatory Session 
has an additional 90 minutes of questionnaires. During each Preparatory Session, the 
therapists will get to know you and discuss with you 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.  
 
During Visit 3, the online evaluation, an evaluator will ask you questions about your 
PTSD symptoms. This information will be used to measure changes in your PTSD 
symptoms from before and after the study treatment. 
 
At the third Preparatory Session (Visit 4), the site staff will inform you of the outcome of 
screening and whether you are eligible to continue in the study. There are many 
reasons why you may not be eligible to continue in the study after the first two 
Preparatory Sessions. As a research protocol, this 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. To 
protect the reliability of the study, the study staff and therapists will not be able to share 
the outcome of all your evaluations or the reason you are not eligible for the study. If the 
study staff have medical concerns about your health, they will provide you with that 
information so you can get follow-up care. 
 


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If you are eligible to continue in the study at the third Preparatory Session, you will then 
be fully enrolled in the study. At that point you will proceed to the second portion of the 
visit, which includes about 90 minutes of psychological questionnaires. These 
questionnaires are an essential part of the research and will help establish the baseline 
data for your participation in the study. During the third Preparatory Session and several 
times throughout the study, you will be asked questions about thoughts or feelings you 
might have about harming yourself or ending your life. Your study therapists will ask 
these questions so that they can assess your safety and track any changes in suicidal 
thoughts or feelings throughout the study. While these questions may be difficult to 
respond to, it is important for you to answer them honestly. The study therapists will 
support you in processing any difficult emotions or reactions to these questions.  
 
The therapy pair will give you a card with contact information for the therapists, a study 
24-hour emergency phone number, and the Institutional Review Board (IRB), which is 
an independent committee that protects the rights and welfare of study participants. You 
can keep this card in your wallet to contact the therapy pair if you need to. 
 
Randomization 
This study is randomized, which means 50% of participants in this study receive 
placebo with therapy and 50% receive MDMA-assisted therapy. The therapists and 
study doctors will not know which group you are in until the end of the study at all sites. 
Some participants reported finding it challenging to think they are in the therapy-only 
group, including difficulty during study sessions or staying off their previous psychiatric 
medications. 
 
If this happens to you, please talk to your study therapists to get support. Although your 
therapists and study doctors will not know for sure what you received until the study 
ends and is unblinded, any feelings that come up for you around this are honored and 
welcomed. 
 
When the study is complete, if we learn that you received placebo and if you are still 
eligible to participate, you will be invited to enroll in another study where you will get 
MDMA-assisted therapy. This study would not start until all participants have completed 
this current study. It may be at least two years before you are able to enroll in this study. 
 
Study Drug Sessions 
After the Preparatory Sessions, the study team will discuss whether you are eligible to 
continue in the study and receive study drug sessions. 
 
There will be a total of 3 full-day Study Drug Sessions during the study which will occur 
3 to 5 weeks apart. The first Study Drug Session will occur after you have had three 
Preparatory Sessions. During the Study Drug Session, you will receive a dose of either 
MDMA or placebo (pills that do not contain MDMA). Both MDMA and placebo capsules 


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contain mannitol (a sweetener) and magnesium stearate (a lubricant). You will receive 
another dose (half of what you initially received) of MDMA or placebo 1.5 to 2 hours 
later, unless you or the therapy pair decide that it is not in your best interest to receive 
the second dose. During the second and third Study Drug Sessions, you and your 
therapy pair can decide if you would like to take the same dose you took in your first 
Study Drug Session, or if you would like to try a higher dose. The goal will be to decide 
on the optimal dose for you. 
 
We will ask you to make some lifestyle changes prior to the Study Drug Sessions.  
 
For 1 week before each Study Drug Session: 
 
• You cannot take any herbal supplements that have not been discussed and 
approved with the therapy pair and study doctor. 
• You may need to stop taking prescription and non-prescription medications 
before each Study Drug Session, which may require more or less time than one 
week. Your medications will be reviewed by the study doctor in advance and the 
requirements will be shared with you. Do not stop taking any medications 
without the study doctor instructing you when and how to do so. Ask the 
study doctor if you have any questions. 
 
After midnight before each Study Drug Session: 
 
• You must not eat any food or drink any alcohol. 
• You can drink non-alcoholic liquids during this time, such as water or juice. 
 
For 2 hours before each Study Drug Session: 
 
• You cannot use nicotine or caffeine. 
 
For 6 hours after the first dose of MDMA or placebo at each Study Drug Session: 
 
• You cannot use nicotine or caffeine. 
 
If you are taking certain opioid medications for pain management, you can stay on these 
medications during treatment, although the study team may ask you to reduce the dose 
before each Study Drug Session and stop taking them for 12 hours before and at least 
24 hours after the first dose in each Study Drug Session. If your pain becomes too 
severe to handle during this period, or you have side effects from not taking your 
medication. Please inform the study team of any symptoms you may have or any 
changes in the medications you are taking during your study participation so they can 
guide you as to which medications are safe to use during the study. 
 


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On the morning of the Study Drug Session, before the first dose of MDMA or placebo: 
 
• You will be asked to provide a urine sample to test for drugs of abuse and for 
pregnancy 
• You will be asked to answer questions about thoughts you might have about 
harming yourself or ending your life 
• You will be asked to discuss your goals with the therapy pair and get answers to 
any questions you may have. 
 
After urine testing, you will receive capsules containing a dose of 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 
Study Drug Session, either through headphones or room speakers. Lying or sitting in a 
comfortable position and listening to music are meant to bring out thoughts and feelings, 
including those about past traumatic experiences. The therapy pair 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 pair 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 sports drinks, and you will be encouraged to drink an adequate amount of fluid. 
You can drink whenever you wish to do so, within the limits of the amount that is safe 
for your body. In the afternoon, food will be provided. 
 
Approximately 2 hours after you take the first dose, you may take a second dose 
containing half the amount of the first dose if the study doctor thinks it is appropriate for 
you. The second dose may make the effects last longer. If you choose not to, or if you 
or the therapy pair decide that it is not in your best interest to receive the second dose, 
then you will not receive the second dose. 
 
The therapy pair will watch for any side effects (unwanted effects or health problems), 
which will be treated if necessary. If this happens, the therapy pair 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, 
or shortness of breath, tell your therapy pair. More frequent measurements may be 
needed if this happens. 
 
If you are confused or upset 8 or more hours after the start of a Study Drug Session, the 
therapy pair will stay with you until you have fully recovered. If the therapy pair 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 pair will ask you how 
you feel at the beginning and end of the Study Drug Session and on several occasions 
during the phone follow-up period.  


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You need to agree to call the study doctors if any of the following things happen while 
you are on study:  
 
• 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 pair 
• 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 a Study 
Drug Session, you or the therapy pair may decide that you should not have the next 
Study Drug Session. You may also make the decision to stop treatment in the study for 
any reason.  
 
If the therapy pair decides you can no longer participate in the study for medical 
reasons after you have taken the dose of MDMA or placebo, they will let you know that 
they are doing this and their reason. They will help you find a therapist who can 
continue to help you with your PTSD, if needed. If you can no longer participate in the 
study or decide you do not want to receive study drug in the study, the study 
researchers may ask you to complete some final questionnaires about your PTSD 
symptoms. If you decide you do not want to continue in the study during a Study Drug 
Session, you will still have to stay in the office until the therapy pair thinks that you are 
stable enough to leave and all the side 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.  
 
Overnight Stay 
You will spend the night after each Study Drug Session in a room at the study site with 
an attendant who will be staying in a room nearby. If you find you need to talk with the 
therapy pair or are having other problems and need to contact the therapy pair, you or 
the attendant can contact them immediately (some sites do not have an overnight stay). 
 
Integrative Sessions 
There will be three Integrative Sessions after each Study Drug session. The morning 
after each Study Drug Session, you will have a 90-minute non-drug therapy visit to help 
you express, understand, and connect any thoughts or feelings you may be having 
about your symptoms and their causes. The therapy pair will encourage you to think 
and talk about your experience during the Study Drug Session. You may not drive until 
after the Integrative Session. Do not drive if you are feeling tired, less alert, or 


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having difficulty concentrating.  If you do not have anyone to take you home, the 
therapy pair will find someone to drive you. 
 
After you return home from the therapy session, the therapy pair will talk to you by 
phone every other day for 14 days to ask how you are feeling. They will ask if you have 
had any thoughts of harming yourself or ending your life. They will also ask about 
medications you are taking. These calls will take about 5 to 15 minutes, though can be 
as long as you need them to be. You can call the therapy pair at any time. If they are 
unavailable, a study team member will be available at the 24-hour number provided on 
the contact card. 
 
After each Study Drug Session, you will have two more Integrative Sessions, about 1 
and 3 weeks after. Your therapy pair will let you know if any can be conducted remotely. 
At each, the therapy pair will ask you if you are having thoughts of harming yourself or 
ending your life. At each third Integrative Session, you will be asked to complete a 
questionnaire about stressful events in your life.  
 
If there are delays in following the usual study schedule, the therapy pair will call you at 
least once a week to talk about how you are doing. These calls will take about 15 
minutes. 
 
Measuring PTSD After Sessions 
Within 1 month after the first two Study Drug Sessions and 2 months after the last Study 
Drug Session, you will meet with an evaluator online. Your therapy pair will let you know 
if these evaluations can happen remotely or if you need to come to the study site. The 
evaluator will ask about your PTSD symptoms at each online meeting.  
 
You will also meet with your therapy pair about 2 months after your last Study Drug 
Session to fill out the same questionnaires from the start of the study. You will be asked 
if you have had any thoughts of harming yourself or ending your life. The researchers 
will measure your blood pressure and weight. The tests will help the therapy pair tell if 
your symptoms have changed or stayed the same over time. 
 
At or after this visit, you will be invited to participate in a long-term follow-up study for an 
additional visit at least 12 months from your last Study Drug Session to see if your 
PTSD symptoms 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 pair 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 and 
you are eligible for the study, you will be invited to participate in an extension study 
where all participants will receive MDMA. It may be at least a year before you are able 


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to enroll in this study. There will be a separate consent form for that study if you wish to 
participate. 
 
Possible Risks, Benefits or Alternatives 
You may have any changes in health while on the study, due to MDMA or placebo, 
therapy, or events in your own life not related to the study. Everyone in the study will be 
tended to carefully for any side effects. However, doctors do not know all the possible 
side effects. Side effects may be mild or very serious. You should talk to your study 
doctor about all changes in health you experience while taking part in the study, 
whether you think they are related to the study or not. 
 
Risks of MDMA 
MDMA has not been widely tested in humans, but as of October 01, 2020, 1,775 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 and at least twice as often as placebo include: 
 
Most Common (≥20% of patients): 
 
• Muscle Tightness (about 65%) 
• Lack of appetite (about 52%) 
• Nausea (about 30%) 
• Sweating (about 20%) 
 
Common (≥10% to 19% of patients): 
 
Feeling cold, restlessness, big pupils, dizziness, jaw clenching, eye wiggling, increased 
blood pressure, feeling jittery, chest pain not related to heart issues, dry mouth. 
 
Less Common (<5% to 9% of patients): 
 
Blurry vision, frequent urination, recurrent thoughts, vomiting, stress, muscle pain, 
increased body temperature, chills, substance use (cannabis use), urgent urination, 
muscle twitching, feeling sleepy, nervousness. 
 
There may be unknown side effects or risks from the use of MDMA. 
 
Serious problems 
Within all MAPS sponsored studies to date, only one serious reaction occurred in a 
participant, who had a medical history of pre-existing heart issues (irregular heart 


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rhythm) and who experienced an episode of changes in heart rhythm after receiving 
MDMA. 
 
Blood pressure and heart rate  
The effects of MDMA usually last 6 to 8 hours after the first dose, even if you take a 
second dose. At the dose in this experiment, the increases in blood pressure and heart 
rate are likely to be moderate. These increases are similar to what happens with 
moderate exercise. 
 
In past studies supported by MAPS, blood pressure rose well above normal levels in 
about one-third of 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 moderate 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. 
 
Anxiety or Suicidal Thoughts 
About 37% of participants with PTSD in past studies who received MDMA reported 
feeling anxious, and about 40% of participants who received only placebo also reported 
feeling anxious. These feelings usually lasted less than 30 minutes. Letting yourself 
accept and feel these emotions deeply can be part of the therapy. If you are not able to 
process these experiences in a way that helps you, the therapy pair will work with you to 
process these feelings. It is possible that if such periods of heightened emotion do not 
decrease or pass 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 
pair immediately if you have any thoughts about harming yourself or ending your life so 
they can safely help you. If needed, they may prescribe anti-anxiety medication or 
medication for sleep. 
 
The way MDMA affects the brain has the potential to cause mania in some people, 
although mania has not been reported in individuals receiving MDMA or Ecstasy. 
 
If you are in immediate danger of harming yourself or someone else, or ending your life, 
then the researchers may require you to be admitted to a hospital. 
 
Driving Limitation 
In past studies, participants have reported blurred vision (8.7%), eye wiggling (13), pupil 
dilation (15.2%), feeling tired/drowsy (6.5%) or dizzy (13%) after taking MDMA. You 
should not drive or use machinery immediately after MDMA Therapy Sessions (up to 24 
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Immune System and Risk of Respiratory Infection 
In a recent MAPS sponsored PTSD study with MDMA versus placebo there was no 
evidence of an effect of the immune system and there was no observed increase in 
respiratory tract infections in the participants that received MDMA compared to the 
participants that received placebo. 
 
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. 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 1 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. 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 those who are not anxious, 
depressed, or without other psychological issues. 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.  
 
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 negative changes in your brain, though this is not guaranteed. 
 
Studies involving healthy volunteers receiving one or two doses of MDMA have not 
found any lasting changes in memory or planning. Studies comparing people before and 


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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 in this study will not produce any lasting changes in memory or 
planning, though this cannot be guaranteed. 
 
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 therapy 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 
It is possible that you may experience some risks associated with being in the research 
study outside of the scope of MDMA. These potential risks are described in the 
following sections.  
 
Positive Drug Test 
If you are tested for drugs of abuse within 3 days of each Study Drug session, you may 
test positive. The therapy pair will provide you with an information card in case you are 
tested for drugs of abuse. 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 pair 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 
back to baseline again.  
 
Emotional Discomfort 
The interviews you have and questionnaires you complete during the study involve no 
specific risks or discomforts beyond those of a standard clinical interview situation. You 
may feel upset at the review of your emotional experiences, or you may feel boredom or 
fatigue. Answering questions about thoughts you might have of harming yourself or 
ending your life may be upsetting. 
 


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The medical tests done during health screening for the study may show something 
abnormal that needs further evaluation by the study doctors or your personal doctor. 
This testing is optional. You can decline any testing you do not want to complete, but we 
may not be able to enroll you in the study without medical confirmation for your safety. 
Abnormal test results and additional evaluations may cause you some stress or 
emotional discomfort. The study doctors will explain all test results to you and refer you 
to the appropriate medical providers, as needed. 
 
Trauma Therapy 
The treatment being tested in this study is a combination of a drug (MDMA) combined 
with therapy. Any therapy, including MDMA-assisted therapy, can be a challenging 
process when it addresses emotionally painful experiences, and symptoms may 
become more pronounced at times. During the study (and/or after) you could 
experience increased anxiety, sadness, or other difficult feelings and thoughts, including 
the possibility of suicidal thoughts. Tell your therapy pair if you are having any new or 
worsening symptoms. If your experience does worsen, it does not necessarily mean 
that the study will not help you. The study is designed to give you support. It is important 
that you understand this possibility before deciding whether or not to participate. 
 
COVID-19 Transmission 
Study participation will involve a number of several hour in-person visits with the therapy 
pair, including 8-hour Study Drug Sessions. This personal interaction may increase your 
risk of becoming infected with SARS-CoV-2 (coronavirus that causes COVID-19 
disease).  Some visits will be performed via telemedicine to reduce your possible 
exposure, and other precautions will be taken to try to reduce this risk (such as 
screening for symptoms before in-person visits, using face masks, cleaning surfaces, 
washing hands). For your safety and the safety of study staff, we recommend that you 
follow the local and federal safety guidelines for prevention of COVID-19, which may 
include wearing a face mask while in public, maintaining 6-feet distance between 
yourself and others outside of your household, and other physical distancing guidelines 
in order to reduce the potential for COVID-19 infection. The Study Team will ask you 
about your habits prior to in person visits, and together you will figure out a safe plan for 
reducing risk while attending in-person visits. This plan may include testing for the virus, 
isolating at home, or other changes to your habits. 
 
Remote Visits 
Some of the non-drug therapy sessions and online evaluations may be able to happen 
remotely rather than at the study site. There may be benefits to remote visits, such as 
convenience and reduced risk of COVID-19 transmission. There may be risks, including 
potential breach of security and technological difficulties or interruptions. It is critical that 
you do not share the links to online meetings with anyone unauthorized to attend. 
 


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Loss of Privacy 
There is a risk of loss of privacy related to the conduct of audiovisual sessions during 
the study. Absolute confidentiality and security cannot be guaranteed; however, every 
effort will be made to maintain your confidentiality. This is described more in the 
Confidentiality section. 
 
Discomfort During Blood Tests  
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. 
 
Symptoms of Depression, Anxiety, or PTSD 
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 harming yourself or ending your life when you stop 
taking medicine, especially if you have had these thoughts before. If this happens, talk 
with your prescribing doctor, your therapy pair, and your study doctor. If you need to 
start taking medicine again, the study doctors will need to re-evaluate your eligibility and 
there is a chance that you will not be able to continue in the study. Your safety takes 
priority over your continuation in the study. There are some allowable medicines on 
study; your doctors will discuss these with you if needed. 
 
Your pre-existing symptoms and diagnosis related to your PTSD may not improve and 
may become worse during the study or after. 
 
Reproductive Risks 
Effects of MDMA on the growth and development of an unborn baby or nursing children 
are not known. Therefore, you will not be allowed to be in the study if you are pregnant, 
planning to get pregnant, or are nursing. If you get pregnant after you have had at least 
one Study Drug Session the study doctors and the sponsor will ask you about and keep 
track of your pregnancy and will ask 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. 
 
Not being able to become pregnant is defined as permanent sterilization or 
postmenopausal or assigned male at birth. Those who are able to become pregnant 
must use one of the allowed contraception methods during the study and for 10 days 
after the last Study Drug Session:  
 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Non-oral hormonal methods (including injected, intravaginal, implanted, or 
transdermal) 


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• Abstinence from penile-vaginal intercourse 
• Oral hormones plus a barrier contraception or double barrier contraception  
• Vasectomized sole partner  
 
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). If you plan to be abstinent from penile-
vaginal intercourse during the study, you will need to let the therapy pair know what 
your back-up method will be. The study 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 able to become pregnant, you will be tested at the start of the study and again 
before each Study Drug Session to see if you are pregnant. If, at any time during the 
study, you think that you may be pregnant or may become pregnant, you must tell your 
therapy pair immediately. If you should become pregnant during the study, the study 
doctors will refer you to the appropriate medical providers, as needed. If you become 
pregnant, you will no longer receive study drug but remain in the study for follow-up 
purposes. 
 
Study Termination 
This is a time-limited study. You may require further treatment after you complete the 
study. This may be because the study treatment did not help you, or it was helpful but 
did not fully resolve your symptoms, or because the process of trauma therapy itself can 
worsen symptoms in the course of addressing trauma. This may mean more time and 
treatment are needed for resolution.  
 
You may feel increased feelings of distress at the termination of the study. Your 
therapists will support you by helping you find another therapist or by providing 
appropriate resources for further follow-up. 
 
New Findings  
If any new information becomes available about MDMA while you are in this study, the 
therapy pair 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 pair at any time after your 
participation ends to find out if any new information about this study has become 
available. 
 
Possible Benefits 
Your symptoms of PTSD may improve while taking part in this study. There is no 
guarantee that you will benefit from taking part in this research study. Information 
obtained from this study may help doctors and researchers to improve treatment for 
PTSD and other mental health conditions in the future.  


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Alternatives 
One alternative to being in this study is to decide not to take part. Your symptoms may 
get better, stay the same or get worse during the study. 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 therapy that you could try. Approved medications for PTSD 
are those called selective serotonin reuptake inhibitors (SSRIs) named paroxetine 
(Paxil) and sertraline (Zoloft). Evidence-based therapies for PTSD include Cognitive 
Processing Therapy (CPT), Cognitive Behavioral Therapy (CBT), Prolonged Exposure 
(PE), and Eye Movement Desensitization and Reprocessing (EMDR). If you are 
currently having therapy and/or taking medicine, you could continue with those for a 
longer period of time. The therapy pair can discuss alternatives and their potential risks 
and benefits with you. 
 
Your Rights as a Study Participant 
 
Confidentiality  
To ensure confidentiality, your information will be stored in secure electronic systems at 
the participating sites until securely transferred to a remote storage facility. These 
records will be stored after the end of the study in keeping with the regulatory and ethics 
board regulations governing your study site. Absolute confidentiality and security cannot 
be guaranteed, but every effort will be made to maintain your confidentiality. 
 
People outside of your therapy pair 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. 
• The Institutional Review Board (IRB) that reviewed this research. 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. .<<CF-Main 
SMO Company 1>><<CF-Main Affiliated IN Language 1>> 
• Members of the study team. 


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• (For CA sites only) Your records may also be inspected by the Research 
Advisory Panel of California (RAPC) or by State and Federal regulatory 
agencies.  
 
These people may look at your records to make sure the study has been done the right 
way. They also want to make sure that your health information has been collected the 
right way, or for other reasons that are allowed under the law. 
 
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. After the study is complete, you may request a summary 
of your data. 
 
The results of this research study may be presented in meetings, presentations, or in 
publications, where your identity will not be disclosed. To help make scientific 
knowledge accessible, the data collected in this study will be shared with other 
researchers.  
 
Audiovisual recordings 
By signing this document, you are agreeing to audio and video recording of your study 
visits and online evaluations. The purpose for recording study visits and online 
evaluations is: 
 
• To maintain accurate records of the study visits and online evaluations 
• To verify that the therapy, assessments, and evaluations are carried out properly, 
according to the protocol 
• To conduct further research on MDMA and MDMA-assisted therapy  
 
For the above purposes, authorized researchers and therapists may view these 
recordings. Researchers and therapists are selected by the sponsor and agree to 
protect the confidentiality of the recordings and all identifying information.  
 
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) 
• Your address and phone number (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 


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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. The sponsor takes 
data security seriously and works to consistently maintain and improve the security of its 
systems. Total security cannot be guaranteed. 
 
During your study sessions, you may ask to stop the recording at any time, and your 
therapists 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 videos and information as described above.  
 
After the study is complete at all locations, you may request access to view the video 
recordings from your study visits. You may contact the study site with any questions 
about video recording, or to request access to your records.  
 
Reimbursement for Study Participation 
In order to remove some financial barriers to participation, up to $100 in a stipend will 
be provided to you during screening. If you do not complete a part of screening, you will 
not receive the stipend for that visit. 
 
MAPS is a non-profit, and you have the option to decline funds if you choose. 
 
Screening Stipend: 
• ICF & Initial Measures: $20 
• Laboratory Tests: $20 
• Cardiac Testing (EKG): $20 
• Independent Rater Assessment: $20 
• Medical Records Collection & Physical Exam: $20 
 
Once you are enrolled in the study, you may be reimbursed for direct costs of 
participation (travel, eldercare, or childcare costs, for example). 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 have the option to decline funds if they are not needed. Options for 
reimbursement will be offered as outlined below: 
 
• Visits 1-5 (Preparatory Sessions through Study Drug Session 1): up to $400 
• Visits 6-10 (Integrative Session 1.1 through Study Drug Session 2): up to $400 
• Visits 11-15 (Integrative Session 2.1 through Study Drug Session 3): up to $400 
• Visits 16-20 (Integrative Session 3.1 through Study Termination): up to $300 
 


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The total possible amount of reimbursement is $1500. Your reimbursement will be 
provided to you by the study site within 30 days of your request, according to the 
schedule above. 
 
<<CF-Main Payment for Part. Paragraph>> 
 
COSTS 
The sponsor of this study, MAPS, will cover the costs that are directly related to the 
research and have been outlined in this document. This includes the costs for screening 
to see if you are eligible for the study, including medical and psychological testing. This 
also includes the Study Drug Sessions, including study drug, therapy, and psychological 
testing. 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 ongoing treatment not included in the 
study. You may talk to the study staff and your insurance company about what is 
covered. 
 
If there are any costs associated with COVID-19 screening or protective equipment 
required by your therapy pair or study doctor, the sponsor will pay for these costs. 
 
Treatment and Compensation for Study-Related Injury 
If you get sick or injured during this study, call the study doctor immediately.  Some 
study-related injuries or sickness can be treated by the study doctor. If the study doctor 
cannot treat a study-related emergency, they will arrange to transport you to the nearest 
hospital.  
 
Treatment of a study-related injuries, sickness, or emergency would first be billed to 
your health insurance provider, if you have health insurance. If your health insurance 
plan does not cover clinical trial-related claims that occurred during the course of the 
study, or you do not have health insurance, then the sponsor will cover any treatment 
costs directly related to the study. To cover those costs, the sponsor carries third-party 
insurance 
 
The sponsor will not cover costs of ongoing treatment unrelated to the study due to pre-
existing conditions, or the cost of your time spent getting treatment for pre-existing 
conditions before receiving treatment in the study. 
 
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. 
 


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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 which you are otherwise entitled 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 to which you are otherwise entitled 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 complete final assessments. 
 
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. Your video recordings will be retained. 
 
Withdrawal 
Your study team, the sponsor, or the government in your country have 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 serious reaction from the study drugs 
• If you need a treatment not allowed in this study, such as restarting a psychiatric 
medication 
• If you do not keep appointments or follow study procedures 
• If you do not take the study drug as instructed 
• If you become pregnant 
• If the study is canceled by the FDA, Health Canada, Israeli Ministry of Health, 
IRB, or the sponsor. 
 
The sponsor, the FDA, 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 questions, concerns, or complaints, or think this research has hurt you or 
made you sick, talk to the research team at the phone number(s) listed above on the 
first page. 
 
This research is being overseen by an Institutional Review Board (“IRB”). An IRB is a 
group of people who perform independent review of research studies. You may talk to 
them at (888)-303-2224 or (800) 562-4789, irb@cgirb.com if: 
 


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• 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 subject. 
 
Do not sign this consent form unless you have had a chance to ask questions and have 
received satisfactory answers to all of your questions.  
  


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PARTICIPANT’S STATEMENT OF CONSENT 
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 
signed and dated copy of this consent form. 
 
 
 
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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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 Institutional Review Board (IRB) 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. 
• The Institutional Review Board (IRB) <<CF-Main SMO Company 
2>><<CF-Main Affiliated IN Language 2>> 
• The U.S. Food and Drug Administration (FDA). 


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• Other regulatory agencies.  
• If you are a California resident, your records may also be inspected 
by the Research Advisory Panel of California (RAPC) or by State and 
Federal regulatory agencies. 
 
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. We may also share the data 
collected in this study with other researchers. Any data or recordings 
shared that could contain identifiable information will require the 
researchers to maintain a data use agreement with confidentiality 
parameters for your data. 
 
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.  
 
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. 
 


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If the research site is located in California, Delaware, Illinois, Indiana, 
Washington, or Wisconsin this authorization will expire on December 31, 
2070. 
 
There is no expiration of this authorization except for research conducted in 
the states listed above. 
 
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. 
 
You do not have to sign this form. 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 otherwise entitled. 
 
For IL Sites Only: [You have the right to review any mental health 
information collected about you and shared with others.]<<CF-Main User 
Defined #7>> 


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AUTHORIZATION  
HIPAA Authorization: I authorize the release of my medical records and 
personal health information related to this study to the IRB, the FDA, other 
regulatory agencies as described above, and (For CA sites only) The 
Research Advisory Panel of California (RAPC). However, as the sponsor 
(and its representatives) is not considered a covered entity, I waive my right 
to the HIPAA privacy rule and my health information may be shared 
between their representatives. The study site where you will complete 
study visits is/is not a covered entity. 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 
 
 
 

Prot_000.pdf: 
 
CONFIDENTIAL 
 
Protocol and Synopsis MAPP2 
IND #063384 
 
Original Protocol Version 1: 25 April 2019 
Amendment 1 Version 1: 12 September 2019
Amendment 2 Version 1: 12 November 2019 
Amendment 3 Version 1: 21 July 2020 
Amendment 4 Version 1: 23 March 2021 
 
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 Posttraumatic Stress Disorder of Moderate or Greater Severity
 
SPONSOR
 
 
 
Multidisciplinary Association for Psychedelic Studies 
(MAPS)
3141 Stevens Creek Blvd #40563
San Jose, CA 95117
SPONSOR  
REPRESENTATIVE 
Rick Doblin, Ph.D. 
Executive Director, MAPS
SPONSOR DELEGATE  
&TRIAL ORGANIZER
 
 
MAPS Public Benefit Corporation
3141 Stevens Creek Blvd #40547
San Jose, CA 95117 
SPONSOR DESIGNEE 
 
 
Amy Emerson
Chief Executive Officer
MAPS Public Benefit Corporation
Email: amy@mapsbcorp.com
CLINICAL 
INVESTIGATOR
Multi-site Study
MEDICAL MONITOR 
Alia Lilienstein, M.D., M.P.H. 
Medical Director
Phone number: 877-748-3767
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 
 
MAPP2 Protocol Synopsis  
IND #063384 
 
Amendment 4 Version 1: 23 March 2021 
Page 2 of 110 
MAPP2 Protocol Synopsis
Full protocol begins on Page 8.
Rationale
 
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit 
research and educational organization working as a clinical trial sponsor to obtain 
approval for the prescription use of 3,4-methylenedioxymethamphetamine (MDMA) as 
an adjunct to therapy in patients with posttraumatic stress disorder (PTSD). PTSD is a 
serious debilitating disorder that negatively impacts a person’s daily life, and can result in 
diminished cognitive and psychosocial functioning, fractured relationships, inability to 
maintain employment, substance abuse, high-cost healthcare utilization, increased 
depression, and suicide risk. People who suffer from PTSD relive their traumatic 
experience(s) through nightmares and flashbacks, have difficulty sleeping, and feel 
detached or estranged. Symptoms can be severe and long lasting. 
 
MDMA is a monoamine releaser and re-uptake inhibitor with indirect effects on 
neurohormone release. The combined neurobiological effects reduce defenses and fear of 
emotional injury, enhance communication and introspection, and increase empathy and 
compassion. MDMA may enhance fear extinction learning in humans. The subjective 
effects of MDMA create a productive psychological state that enhances the therapeutic 
process. Data from an international series of Phase 2 pilot studies of MDMA-assisted 
therapy conducted by the sponsor provide preliminary evidence that chronic PTSD, 
independent of cause, is treatable with two to three sessions of MDMA-assisted therapy 
and associated non-drug preparatory and integrative therapy. This Phase 3 study is 
intended to confirm the efficacy and safety of manualized MDMA-assisted therapy as a 
treatment for PTSD.
 
Study Design 
 
This multi-site, randomized, double-blind study assesses the efficacy and safety of 
MDMA-assisted therapy versus therapy with placebo control in participants diagnosed 
with at least moderate PTSD. A flexible dose of MDMA hydrochloride salt (referred to 
as MDMA throughout) or placebo, followed by a supplemental half-dose unless 
tolerability issues emerge, is administered during the Treatment Period with manualized 
therapy 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 therapy. 
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. 
 
Group 1: MDMA-assisted therapy or Group 2: placebo with therapy, with a planned 


MAPS Public Benefit Corporation 
 
MAPP2 Protocol Synopsis  
IND #063384 
 
Amendment 4 Version 1: 23 March 2021 
Page 3 of 110 
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, an open-label lead-in study was conducted following identical study procedures for 
Phase 3 therapy teams to receive clinical supervision from the sponsor. This study is an 
identical confirmatory Phase 3 study to the pivotal Phase 3 study,  
 MAPP1. 
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: at least 6 
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 therapy as in the initial study. Data will be included in the sponsor’s 
overall safety database.
 
Primary Outcome (CAPS-5) Data Collection by Visit
Qualified, blinded IRs selected based on availability from the IR Pool will perform the 
CAPS-5 assessments as described in the following table.
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 
therapy assisted by flexible doses of MDMA or placebo as described in the table below, 
along with associated non-drug preparatory and integrative therapy. Similar MDMA 


MAPS Public Benefit Corporation 
 
MAPP2 Protocol Synopsis  
IND #063384 
 
Amendment 4 Version 1: 23 March 2021 
Page 4 of 110 
doses to those proposed in this study have been safely used in previous Phase 2 and 3 
studies sponsored by MAPS.
 
Dose Regimen of MDMA 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 tolerability issues emerge with the first dose or it is refused by the participant.
 
Protocol Objective 
 
The overall objective of this study is to use standard clinical measures to confirm the 
efficacy and safety of manualized MDMA-assisted therapy with a flexible dose of 
MDMA in reducing PTSD and associated symptoms in comparison to the same therapy 
combined with an inactive placebo control. 
 
Primary Objective 
 
The primary objective of this study is to evaluate the efficacy of MDMA-assisted therapy 
for PTSD compared to the identical therapy 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 
therapy for PTSD compared with identical therapy 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).  
 
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 
therapy. The following safety objectives will evaluate the safety of MDMA-assisted 
therapy 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 


MAPS Public Benefit Corporation 
 
MAPP2 Protocol Synopsis  
IND #063384 
 
Amendment 4 Version 1: 23 March 2021 
Page 5 of 110 
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
 
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 
moderate PTSD per the PCL-5 at Screening with symptoms present for at least 6 months. 
At Baseline, participants must qualify for a PTSD diagnosis per the CAPS-5 and have a 
Total Severity Score equal to or greater than 28 (moderate). Participants would not be 
excluded for having more than one traumatic event or for having tried, not tolerated, or 
refused a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine 
reuptake inhibitor (SNRI) prescribed for PTSD. Participants with confirmed diagnosis of 
specific psychological and personality disorders will be excluded. Participants must be in 
good physical health and without major medical disorders that could affect the safety or 
tolerability of MDMA.
Statistical Analysis of Efficacy
The statistical power calculations were made by fitting a Mixed-Effect Model Repeated 
Measure (MMRM) model to Clinician-Administered PTSD Scale for DSM-4 (CAPS-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 


MAPS Public Benefit Corporation 
 
MAPP2 Protocol Synopsis  
IND #063384 
 
Amendment 4 Version 1: 23 March 2021 
Page 6 of 110 
least 60% of the blinded participants (N=60) have completed their final CAPS-5 
assessment and terminated treatment. The Sponsor does not plan to reduce the number of 
participants 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. 


MAPS Public Benefit Corporation
MAPP2 Protocol Synopsis 
IND #063384 
 
Amendment 4 Version 1: 23 March 2020 
Page 7 of 110
Study Structure Overview


 
CONFIDENTIAL 
 
Protocol and Synopsis MAPP2 
IND #063384 
 
Original Protocol Version 1: 25 April 2019 
Amendment 1 Version 1: 12 September 2019
Amendment 2 Version 1: 12 November 2019 
Amendment 3 Version 1: 21 July 2020 
Amendment 4 Version 4: 23 March 2021 
 
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 Posttraumatic Stress Disorder of Moderate or Greater Severity
 
SPONSOR
 
 
 
Multidisciplinary Association for Psychedelic Studies 
(MAPS)
3141 Stevens Creek Blvd #40563
San Jose, CA 95117
SPONSOR  
REPRESENTATIVE 
Rick Doblin, Ph.D. 
Executive Director, MAPS
SPONSOR DELEGATE  
&TRIAL ORGANIZER
 
 
MAPS Public Benefit Corporation
3141 Stevens Creek Blvd #40547
San Jose, CA 95117 
SPONSOR DESIGNEE 
 
 
Amy Emerson
Chief Executive Officer
MAPS Public Benefit Corporation
Email: amy@mapsbcorp.com
CLINICAL 
INVESTIGATOR
Multi-site Study
MEDICAL MONITOR 
Alia Lilienstein, M.D., M.P.H. 
Medical Director
Phone number: 510-708-4622 
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 
 
MAPP2 Protocol 
IND #063384 
 
Amendment 4 Version 1: 23 March 2021 
Page 9 of 110 
Table of Contents
List of Tables ........................................................................................................................... 13 
List of Figures ......................................................................................................................... 14 
List of Abbreviations .............................................................................................................. 15 
1.0 Introduction....................................................................................................................... 18 
1.1 Rationale ......................................................................................................................... 18 
1.2 Background ..................................................................................................................... 18 
1.2.1 PTSD ....................................................................................................................... 18 
1.2.2 MDMA .................................................................................................................... 20 
1.2.3 MDMA-Assisted Therapy for PTSD ......................................................................... 21 
1.2.4 Previous Clinical Experience with MDMA ............................................................... 22 
2.0 Protocol Objectives ........................................................................................................... 23 
2.1 Primary Objective ........................................................................................................... 23 
2.2 Key Secondary Objective ................................................................................................ 23 
2.3 Safety Objectives ............................................................................................................ 24 
2.4 Exploratory Objectives .................................................................................................... 24 
3.0 Eligibility Criteria ............................................................................................................. 25 
3.1 Inclusion Criteria ............................................................................................................. 25 
3.2 Exclusion Criteria ............................................................................................................ 26 
3.3 Lifestyle Modifications.................................................................................................... 28 
4.0 Protocol Design.................................................................................................................. 29 
4.1 Study Design Overview ................................................................................................... 29 
4.2 Planned Duration of Study ............................................................................................... 36 
4.3 Interruptions and Accommodations Due to COVID-19 Pandemic or Any Other Unforeseen 
Emergency at Clinic Locations .............................................................................................. 37 
4.4 Discontinuation and Completion Criteria ......................................................................... 37 
4.4.1 Complete or Evaluable Participants ........................................................................... 37 
4.4.2 Screen Failures ......................................................................................................... 38 
4.4.3 Pre-Randomization Early Terminations..................................................................... 38 
4.4.4 Early Termination from the Study ............................................................................. 39 
4.4.5 Lost to Follow-up ..................................................................................................... 39 
4.5 End of Study Definition and Premature Discontinuation .................................................. 40 
4.6 Rationale of Dose Selection ............................................................................................. 40
5.0 Therapy ............................................................................................................................. 42 
5.1 Description of Therapeutic Method.................................................................................. 42 
5.2 Therapy Team Qualifications........................................................................................... 42 
5.3 Training .......................................................................................................................... 42 
5.4 Adherence to Therapeutic Method ................................................................................... 42 
6.0 Measures and Reliability................................................................................................... 43 
6.1 Primary Outcome Measure and Reliability....................................................................... 44 
6.1.1 CAPS-5 (Clinician-Administered PTSD Scale for DSM-5) ....................................... 44 
6.2 Secondary Measure ......................................................................................................... 45 
6.2.1 SDS (Sheehan Disability Scale) ................................................................................ 45 
6.3 Safety Measures .............................................................................................................. 45 
6.3.1 C-SSRS (Columbia Suicide Severity Rating Scale) ................................................... 45 
6.4 Screening Measures and Reliability ................................................................................. 45 
6.4.1 MINI (Mini-International Neuropsychiatric Interview).............................................. 45 
6.4.2 SCID-5-PD (Structured Clinical Interview for DSM-5 for Personality Disorders)...... 46 
6.4.3 LEC-5 (Life Events Checklist for DSM-5) ................................................................ 46 
6.4.4 PCL-5 (PTSD Checklist) .......................................................................................... 46 
6.4.5 DDIS (Dissociative Disorders Interview Schedule for DSM-5) ................................. 46 


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6.5 Exploratory Measures......................................................................................................47
6.5.1 DSP-I (The Dissociative Subtype of PTSD Interview) .............................................. 47 
6.5.2 ACE (Adverse Childhood Experience Questionnaire) ............................................... 47 
6.5.3 BDI-II (Beck Depression Inventory II) ...................................................................... 47 
6.5.4 CPGS (Chronic Pain Grade Scale) ............................................................................ 48 
6.5.5 EQ-5D-5L (EuroQol Five Dimensions-Five Levels Questionnaire) ........................... 48 
6.5.6 IASC (Inventory of Altered Self Capacities) ............................................................. 48 
6.5.7 IPF (Inventory of Psychosocial Functioning) ............................................................ 49 
6.5.8 SCS (Self-Compassion Scale) ................................................................................... 49 
6.5.9 TAS-20 (Toronto Alexithymia Scale) ....................................................................... 49 
6.5.10 Blinding Survey Measure ........................................................................................ 49 
6.5.11 AUDIT (Alcohol Use Disorders Identification Test) ............................................... 50 
6.5.12 DUDIT (Drug Use Disorders Identification Test) .................................................... 50 
6.5.13 SRNU (Self-reported Nicotine Use) ........................................................................ 50 
6.5.14 EAT-26 (Eating Attitudes Test) .............................................................................. 50 
6.5.15 HPQSF (Health and Work Performance Absenteeism and Presenteeism Short Form)
 ......................................................................................................................................... 50 
6.5.16 UFEC (Utilization of Facility-based and Emergent Care) ........................................ 51 
7.0 Study Procedures .............................................................................................................. 51 
7.1 Screening Period ............................................................................................................. 55 
7.1.1 Pre-Screening and Informed Consent ........................................................................ 55 
7.1.2 Initial Eligibility Assessment .................................................................................... 55 
7.1.3 Meeting with Site Physician ...................................................................................... 56 
7.1.4 Independent Rater Screening .................................................................................... 57 
7.1.5 Enrollment ................................................................................................................ 58 
7.2 Preparatory Period with Enrollment Confirmation ........................................................... 59 
7.2.1 Preparatory Sessions 1 and 2 ..................................................................................... 59 
7.2.2 Baseline: CAPS-5 by Independent Rater ................................................................... 60 
7.2.3 Baseline: Preparatory Session 3 & Enrollment Confirmation ..................................... 60 
7.3 Treatment Period ............................................................................................................. 61 
7.3.1 Experimental Sessions .............................................................................................. 61 
7.3.2 Telephone Contact After Experimental Sessions ....................................................... 64 
7.3.3 Integrative Sessions .................................................................................................. 65
7.3.4 Independent Rater Assessments ................................................................................ 66 
7.4 Follow-up Period and Study Termination ........................................................................ 66 
7.4.1 Follow-up Period ...................................................................................................... 66 
7.4.2 Final Independent Rater Assessment ......................................................................... 66 
7.4.3 Study Termination .................................................................................................... 67 
7.4.3.1 Extension Studies ............................................................................................... 67 
7.4.3.2 Exit Plan ............................................................................................................ 68 
8.0 Investigational Product ..................................................................................................... 68 
8.1 Description of Active Compounds ................................................................................... 68 
8.1.1 Doses ....................................................................................................................... 68 
8.1.2 Dose Modifications................................................................................................... 69 
8.1.3 Stability .................................................................................................................... 69 
8.2 Handling ......................................................................................................................... 69 
8.2.1 Encapsulation, Packaging, and Labeling ................................................................... 69 
8.2.2 Accountability .......................................................................................................... 70 
8.2.3 Storage ..................................................................................................................... 70 
8.2.4 Administration .......................................................................................................... 70 
8.2.5 Treatment Compliance .............................................................................................. 71 
8.3 Randomization and Participant Numbering ...................................................................... 71 


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8.4 Blinding and Bias Minimization......................................................................................71
9.0 Risks .................................................................................................................................. 73 
9.1 Non-drug Related Risks................................................................................................... 73 
9.1.1 Medical Assessments ................................................................................................ 73 
9.1.2 PTSD, Suicide Risk, and Therapy ............................................................................. 74 
9.1.3 Recorded Content ..................................................................................................... 75 
9.2 Risks of Receiving MDMA ............................................................................................. 75 
9.2.1 High Level Risks ...................................................................................................... 76 
9.2.2 Medium Level Risks ................................................................................................. 76 
9.2.2.1 Cardiovascular and Cerebrovascular Risks and Mitigation.................................. 76 
9.2.2.2 Psychological Risks and Mitigation .................................................................... 77 
9.2.3 Low Level Risks ....................................................................................................... 79 
9.2.3.1 Thermoregulatory Risks and Mitigation ............................................................. 79 
9.2.3.2 Osmoregulatory Risk and Mitigation .................................................................. 79 
9.2.3.3 Genotoxicity Risk and Mitigation ....................................................................... 79 
9.2.3.4 Reproductive and Developmental Risks and Mitigation ...................................... 80 
9.2.4 Minimal Risks .......................................................................................................... 80 
9.2.4.1 Common Expected AEs ..................................................................................... 80 
9.2.4.2 Neurotoxicity Risk ............................................................................................. 81 
9.2.4.3 Abuse Potential .................................................................................................. 81 
10.0 Safety ............................................................................................................................... 81 
10.1 Adverse Events ............................................................................................................. 81 
10.1.1 Adverse Events of Special Interest .......................................................................... 82 
10.1.2 Serious Adverse Events .......................................................................................... 83 
10.2 Other Significant Events ................................................................................................ 84 
10.3 Pregnancy ..................................................................................................................... 84 
10.3.1 Definition of Able to Become Pregnant ................................................................... 84 
10.3.2 Contraception Guidelines ........................................................................................ 84 
10.3.3 Follow-up Requirements ......................................................................................... 85 
10.4 Medical Monitor ............................................................................................................ 85 
11.0 Concomitant Medications ............................................................................................... 85 
11.1 Tapering Instructions ..................................................................................................... 85 
11.2 Allowed Concomitant Medications ................................................................................ 86 
11.3 Prohibited Medications .................................................................................................. 87 
12.0 Clinical Laboratory Assessments .................................................................................... 88 
13.0 Statistical Considerations ................................................................................................ 89 
13.1 Power and Sample Size Determination .......................................................................... 89 
13.2 Statistical Analyses........................................................................................................ 90 
13.2.1 Efficacy Analyses ................................................................................................... 90 
13.2.1.1 Primary Outcome ............................................................................................. 90 
13.2.1.2 Secondary Outcome ......................................................................................... 91 
13.2.1.3 Exploratory Secondary Outcomes .................................................................... 91 
13.2.2 Safety Analyses ...................................................................................................... 91 
13.2.3 Administrative Interim Analysis ............................................................................. 92 
13.3 Data Monitoring Committee .......................................................................................... 92 
14.0 Study Governance ........................................................................................................... 93 
14.1 Ethics ............................................................................................................................ 93 
14.1.1 Financial Disclosure ............................................................................................... 94 
14.1.2 Informed Consent ................................................................................................... 94 
14.2 Study Monitoring, Auditing, and Documentation ........................................................... 95 
14.2.1 Source Records ....................................................................................................... 95 
14.3 Confidentiality .............................................................................................................. 96 


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14.4 Costs to Participants ......................................................................................................97
14.5 Treatment and Compensation for Study Related Injury .................................................. 97 
14.6 Record Retention ........................................................................................................... 97 
14.7 Publication Policy ......................................................................................................... 98 
Appendix A: Sub-study without Overnight Stays .................................................................. 99 


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List of Tables 
 
Table 1: Study Design Overview ............................................................................................... 32 
Table 2: Primary Outcome (CAPS-5) Data Collection by Visit .................................................. 36 
Table 3: Dose Regimen of MDMA or Placebo .......................................................................... 41 
Table 4: Protocol Objectives and Assessment Tools .................................................................. 43 
Table 5: Time and Events-Study Procedures ............................................................................. 52 
Table 6: Time and Events-Study Measures ................................................................................ 54 
Table 7: Schedule of Procedures for Experimental Sessions ...................................................... 62 


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List of Figures
 
Figure 1: Study Structure Overview .......................................................................................... 31 
Figure 2: Example Label ........................................................................................................... 70 


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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
AHA
American Heart Association
ALT
Alanine Aminotransferase 
AMI
Acute Myocardial Infarction
API
Active Pharmaceutical Ingredient
ASA
American Stroke Association 
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 


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GMP
Good Manufacturing Practice 
HCV
Hepatitis C Virus
HIV 
Human Immunodeficiency Virus
HIPAA 
Health Insurance Portability and Accountability 
HPA  
Hypothalamic-pituitary-adrenal 
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 
MPBC MAPS Public Benefit Corporation 
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 


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


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1.0 Introduction
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit 
research and educational organization working as a clinical trial sponsor to obtain 
marketing approval for the prescription use of 3,4-methylenedioxymethamphetamine 
(MDMA) as an adjunct to therapy in patients with posttraumatic stress disorder (PTSD). 
Controlled Phase 1 studies, nonclinical studies, and investigator-initiated studies formed 
the basis for the Clinical Development Program of MDMA under Investigational New 
Drug (IND) #063384. MAPS-sponsored studies are implemented through MAPS’ wholly 
owned subsidiary and delegate, the MAPS Public Benefit Corporation (MPBC). 
 
1.1 Rationale 
PTSD is a serious debilitating disorder that negatively impacts a person’s daily life. 
MDMA has been shown to reduce defenses and fear of emotional injury, enhance 
communication, and increase empathy. MDMA may enhance fear extinction learning in 
humans. These subjective effects of MDMA create a productive psychological state that 
enhances the therapeutic process for the treatment of PTSD and other anxiety disorders. 
This is supported by data from an international series of Phase 2 pilot studies of MDMA-
assisted therapy conducted by the sponsor that provide preliminary evidence that chronic 
PTSD, independent of cause, is treatable with two to three sessions of MDMA-assisted 
therapy and associated non-drug preparatory and integrative therapy. This confirmatory 
Phase 3 study is intended to confirm the efficacy and safety of manualized MDMA-
assisted therapy as a treatment for PTSD as an independent but identical study to the 
Phase 3 pivotal study, MAPP1. 
 
The results from multiple independent studies in Phase 2 efficacy analyses demonstrate 
superiority of MDMA-assisted therapy over therapy with placebo and low dose MDMA. 
The acceptable risk-benefit ratio in early trials justifies confirmation in a Phase 3 
program. To further assess the efficacy and safety of this treatment for participants with 
at least moderate 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 therapy combined with either a 
flexible dose of MDMA or inactive placebo, along with non-drug preparatory and 
integrative therapy. 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. 
 
1.2 Background 
1.2.1 PTSD 
PTSD is a serious debilitating disorder associated with increased mortality and 
cardiometabolic morbidity. PTSD is a stress-related psychiatric condition that may occur 
following a traumatic event such as war, disaster, sexual abuse, violence, terrorism, and 
accidents. The four main symptom categories described in the Diagnostic and Statistical 
Manual of Mental Disorders, 5th edition (DSM-5), include arousal and reactivity, 


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avoidance of triggers, negative thoughts and feelings, and intrusive thoughts and 
nightmares. PTSD negatively impacts a person’s daily life, resulting in fractured 
relationships, inability to maintain employment, diminished cognitive and psychosocial 
functioning, substance abuse, high-cost healthcare utilization, and increased depression 
and suicide risk. People who suffer from PTSD often relive the experience through 
nightmares and flashbacks, have poor sleep quality, and feel detached or estranged. 
Confronting overwhelming internal distress and frightening external environments can 
also lead to high levels of depersonalization and derealization, which led clinicians to 
identify a dissociative subtype of PTSD in the DSM-5. Adaptations in normal brain 
function have been observed in imaging studies of patients with PTSD that underlie 
alterations in emotional processing and regulation, cognition, and many aspects of 
behavior, though clinical symptoms and changes in brain activity are not homogenous 
across patients [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 therapy as routine first-line treatment by the 


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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 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 therapy 
is another such approach. 
 
1.2.2 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) 


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[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.
1.2.3 MDMA-Assisted Therapy for PTSD 
Many therapies for PTSD involve the induction and extinction of abnormal autonomic 
responses through revisiting traumatic experiences in therapy 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-
induced activation of the amygdala may be supported and enhanced by interacting with 
the therapy pair during and after the MDMA experience. The subjective effects of 
MDMA create a productive psychological state that enhances the therapeutic process. 
MDMA is capable of inducing unique psychopharmacological effects, including 
decreased fear and increased wellbeing, sociability, interpersonal trust, acceptance of self 
and others, and ability to address these issues without extreme disorientation or ego loss 
due to alert state of consciousness. These factors taken together can provide the 
opportunity for a corrective emotional experience.
 
A combined treatment of MDMA and therapy may be especially useful for treating PTSD 
because MDMA can attenuate the fear response of a perceived threat to one’s emotional 
integrity and decrease defensiveness without blocking access to memories or preventing a 
deep and genuine experience of emotion [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 therapy may enable the participants to restructure their intra-psychic 
realities and develop a wider behavioral and emotional repertoire with which to respond 
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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. 
 
1.2.4 Previous Clinical Experience with MDMA 
MDMA-assisted therapy is a novel treatment package that combines psychotherapeutic 
techniques with the administration of MDMA as a pharmacological adjunct intended to 
enhance certain aspects of therapy. Chemists Shulgin and Nichols were the first to report 
on the effects of MDMA in humans [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 therapy 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 [44, 45, 53]. An estimated 
500,000 doses of MDMA were administered during therapy and personal growth sessions 
in North America prior to its scheduling [44, 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 therapy without any safety concerns and with some PTSD 
symptom reduction [41]. These studies formed the basis of clinical experience with 
MDMA prior to studies subsequently conducted under a MAPS IND.
 
Under IND #063384, MAPS initiated an international series of Phase 2 clinical trials to 
develop the medical use of MDMA-assisted therapy for patients with chronic, at least 
moderate PTSD (CAPS-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 
therapy 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 therapy 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 


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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 therapy. Durable improvements were 
found at least 12 months after the last Experimental Session in 91 participants who 
received a therapeutically active dose of MDMA in these studies, and 67% did not meet 
PTSD diagnostic criteria per CAPS-4 assessment [63]. As of October 01, 2020, with 341 
individuals exposed to MDMA in the sponsor’s development program across various 
indications and at least 1,434 participants in MDMA research studies conducted without 
sponsor support (for a total of at least 1,775 individuals), the sponsor has observed an 
acceptable risk-benefit ratio for MDMA-assisted therapy.. 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.
 
2.0 Protocol Objectives 
The overall objective of this study is to use standard clinical measures to confirm the 
efficacy and safety of manualized MDMA-assisted therapy with a flexible dose MDMA 
in reducing PTSD and associated symptoms in comparison to the same therapy combined 
with an inactive placebo control. 
 
2.1 Primary Objective 
1. The primary objective of this study is to evaluate the efficacy of MDMA-assisted therapy 
for PTSD compared to identical therapy 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). 
 
2.2 Key Secondary Objective 
1. The key secondary objective of this study is to evaluate the efficacy of MDMA-assisted 
therapy for PTSD compared to identical therapy with inactive placebo in clinician-rated 
functional impairment, as measured by the mean change in Sheehan Disability Scale 
(SDS) item scores from Visit 3 (Baseline) to Visit 19 (18 weeks post Baseline).  
 


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2.3 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 therapy. The following safety objectives will evaluate the safety of 
MDMA-assisted therapy compared to identical therapy 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. 
2.4 Exploratory Objectives
These objectives may be explored to characterize participants receiving MDMA-assisted 
therapy in comparison to those receiving therapy 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 
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)  


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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)  
 
3.0 Eligibility Criteria 
3.1 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 28 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 therapy 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 able to become pregnant, must have a negative pregnancy test at study entry and prior 
to each Experimental Session, and must agree to use adequate 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, vasectomized sole 
partner, or double barrier contraception. Two forms of contraception are required with 
any barrier method or oral hormones (i.e. condom plus diaphragm, condom or diaphragm 
plus spermicide, oral hormonal contraceptives plus spermicide or condom). ‘Not able to 
become pregnant’ is defined as permanent sterilization, postmenopausal, or assigned 
male at birth. 
8. Agree to the following lifestyle modifications (described in more detail in Section 4.3 
Lifestyle Modifications): comply with requirements for fasting and refraining from 
certain medications prior to Experimental Sessions, not participate in any other 


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interventional clinical trials during the duration of this study without prior approval of the 
Medical Monitor, remain overnight at the study site after each Experimental Session and 
be driven home after, and commit to medication dosing, therapy, and study procedures. 
Medical History
 
1.
At Screening, meet DSM-5 criteria for current PTSD with a symptom duration of 6 
months or longer. 
2. At Screening, have at least moderate PTSD symptoms in the last month based on PCL-5 
total score of 40 or greater. 
3. 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. 
4. May have asymptomatic Hepatitis C virus (HCV) that has previously undergone 
evaluation and treatment as needed. 
5. At Baseline, have at least moderate PTSD per CAPS-5 and symptoms in the last month 
constituting a CAPS-5 Total Severity Score of 28 or greater. 
6. 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 4 or 5 of 11 diagnostic criteria per DSM-5).  
7. 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. 
8. May have hypothyroidism if taking adequate and stable thyroid replacement medication. 
9. May have a history of, or current, glaucoma if approval for study participation is received 
from an ophthalmologist. 
 
3.2 Exclusion Criteria 
Potential participants are ineligible to enroll in the protocol if they: 
 
1. Are not able to give adequate informed consent. 
2. Are currently engaged in compensation litigation whereby financial gain would be 
achieved from prolonged symptoms of PTSD or any other psychiatric disorders. 
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. 
 
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 DDIS and 
clinical interview. 
8. Have a current eating disorder with active purging assessed via MINI and clinical 
interview. 


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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 4 or 5 of 11 diagnostic criteria per DSM-5) or severe alcohol or cannabis use 
disorder within the 12 months prior to enrollment (meets at least 6 of 11 diagnostic 
criteria per DSM-5).  
11. Have an active illicit drug (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. 
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 11.0: Concomitant Medications. 
 
Medical History 
 
16. Have a history of any medical condition that could make receiving a sympathomimetic 
drug harmful because of increases in blood pressure and heart rate. This includes, but is 
not limited to, a history of myocardial infarction, cerebrovascular accident, or aneurysm. 
Participants with other mild, stable chronic medical problems may be enrolled if the site 
physician, CI, and Medical Monitor agree the condition would not significantly increase 
the risk of MDMA administration or be likely to produce significant symptoms during 
the study that could interfere with study participation or be confused with side effects of 
the IMP. Examples of stable medical conditions that could be allowed include, but are not 
limited to Diabetes Mellitus (Type 2), Human Immunodeficiency Virus (HIV) infection, 
Gastroesophageal Reflux Disease (GERD), etc. Any medical disorder judged by the 
investigator to significantly increase the risk of MDMA administration by any 
mechanism would require exclusion.  
17. Have a diagnosis of uncontrolled essential hypertension, which is assessed using the 
recommended criteria of the American Heart Association for Stage 2 hypertension
(values of 140/90 milligrams of Mercury [mmHg] or higher assessed on three separate 
occasions). 
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 


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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 11.0 Concomitant Medications. 
24. Have symptomatic liver disease or have significant liver enzyme elevation. 
25. Have history of hyponatremia or hyperthermia. 
26. Weigh less than 48 kilograms (kg). 
27. Are pregnant or nursing, or are able to become pregnant 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. 
 
3.3 Lifestyle Modifications 
All participants must agree to the following lifestyle modifications at enrollment and 
throughout the duration of the study. Participants are eligible to enroll in the study if they:
 
 
Are willing to commit to medication dosing, therapy sessions, follow-up sessions, 
completing evaluation instruments, and all necessary telephone contact. 
 
Agree to not participate in any other interventional clinical trials during the duration of 
this study without prior approval of the Medical Monitor.  
 
Leading up to Experimental Sessions
 
 
Agree to take nothing by mouth except alcohol-free liquids after 12:00 A.M. (midnight) 
the evening before each Experimental Session. 
 
Refrain from the use of any psychoactive medication not approved by the research team 
from Baseline through Study Termination. 
 
Agree not to use caffeine or nicotine for 2 hours before and at least 6 hours after the 
initial dose during each Experimental Session. 
 
Are willing to comply with medication requirements per protocol (refer to Section 11.0 
Concomitant Medications). Medications will only be discontinued after enrollment per 
clinical judgment of the site physician in consultation with the prescribing physician. 
 
Are able to decrease dose of allowable opiates (per Section 11.0 Concomitant 
Medications), if used for pain management, leading up to the Experimental Session in 
order to avoid taking the medication prior to the initial IMP administration and 24 hours 
after. During this period, the participant will be allowed to take the medication if needed 
for intolerable pain flare-ups or to prevent withdrawal symptoms. 
 
Agree that, for 1 week preceding each Experimental Session 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). 


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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. 
 
Agree not to drive after each Experimental Session until after the Integrative Session the 
next morning. 
4.0 Protocol Design 
4.1 Study Design Overview 
This multi-site, randomized, double-blind study assesses the efficacy and safety of 
MDMA-assisted therapy versus therapy with placebo control in participants diagnosed 
with at least moderate PTSD.  
 
Group 1: MDMA-assisted therapy or Group 2: placebo with therapy. 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.  
 
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: 6 months 
after last Experimental Session 
 
The treatment consists of a flexible dose of MDMA or placebo, followed by a 
supplemental half-dose unless tolerability issues emerge, administered with manualized 
therapy 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 therapy. 
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 


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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 therapy.  
  


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Figure 1: Study Structure Overview


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Table 1: Study Design Overview 
 
Screening Period
From Consent to Enrollment (Visit 0): ~4 weeks (±2 weeks)
Study Visit
Visit Duration/
Visit Timing 
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. Medication taper 
for psychoactive medications should occur prior to 
Visit 3. Medication taper for medications with drug-
drug interactions without a psychological concern 
should occur prior to Visit 5.
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 pair/CI. 
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 28 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 
tolerability issues emerge with the first dose 
or it is refused by the participant. C-SSRS 
administered pre- and post- Investigational 
Product administration.
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 every other day for 14 days post 
Visit 5. C-SSRS administered during 
Integrative Session 1.1 and phone calls.  
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 tolerability 
issues emerge with the first dose or it is 
refused by the participant. C-SSRS 
administered pre- and post- Investigational 
Product administration.
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 every other day for 14 days post 
Visit 5. C-SSRS administered during 
Integrative Session 2.1 and phone calls.  
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 Visit 12 and Visit 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 (Visit 12) 
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 tolerability 
issues emerge with the first dose or it is 
refused by the participant. C-SSRS 
administered pre- and post- Investigational 
Product administration.
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 every other day for 14 days post 
Visit 5. C-SSRS administered during 
Integrative Session 3.1 and phone calls.
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 (V12) 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 and42 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 must be 
completed within the overall window. Other visits 
should be scheduled to ensure the timing of the 
Primary Outcome CAPS-5 T4 assessment is 
appropriate.
Study Termination
Study 
Termination 
Visit 20 
2 hours 
~18 (±3) weeks (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. In the case of study 
interruption, Visit 19 should be scheduled 42 to 70 
days after Visit 15. Complete self-reported and 
safety measures; create an exit plan for participant. 
Complete blinding survey. 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.
 


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Qualified, blinded IRs selected based on availability from the IR Pool will perform the 
CAPS-5 assessments as described in table below. 
 
Table 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 
 
4.2 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 necessary to ensure an appropriate medication washout of at 
least five half-lives of pre-study psychiatric medications and active metabolites, and at 
least 7 days for stabilization prior to Baseline CAPS-5 T1 (Visit 3). Medication taper for 
psychological medications should occur prior to Visit 3. Medication taper for medications 
with drug-drug interactions without a psychological concern should occur prior to Visit 5. 
Enrollment Confirmation takes place at the completion of the Preparatory Period, at 
which time the Treatment period will commence. 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 dependent 
on medication tapering. 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. 


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All participants who complete the study will be asked to participate in an observational 
LTFU extension study with one visit at least 6 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 extension study of manualized MDMA-assisted therapy. This open-label safety 
extension study will take place at least 18 months after the first participant is enrolled in 
MAPP2 and will follow a design similar to this protocol. 
 
4.3 Interruptions and Accommodations Due to COVID-19 Pandemic or Any Other 
Unforeseen Emergency at Clinic Locations 
This clinical trial may be interrupted by the Coronavirus Disease 2019 (COVID-19) 
global pandemic. Accommodations may be required for study continuation and 
participant and study site staff safety due to this emergency or any other unforeseen 
emergency in the future. The following accommodations in the protocol will be allowed, 
captured, and noted in the Clinical Study Report as COVID-19 deviations: 
 
 
Integrative Sessions may be conducted by telemedicine 
 
Delaying the start of medication tapering after enrollment and the subsequent Treatment 
Period per Section 11.1 Tapering Instructions 
 
Delaying Experimental Sessions and associated Integrative Sessions 
 
Delaying Independent Rater assessments for participants who cannot complete them 
remotely off-site 
 
Use of prohibited medications and/or cannabis or initiation of new therapy for 
participants with significant study delays, which will be reviewed by the study team 
before each Experimental Session and re-tapered prior to resuming treatment per Section 
11.0 Concomitant Medications. 
 
For any participant with COVID-19 related illness, continued trial participation after full 
recovery of the disease may be appropriate after discussion between the site physicians 
and Medical Monitors on a case-by-case basis. 
 
4.4 Discontinuation and Completion Criteria 
4.4.1 Complete or Evaluable Participants 
A participant is considered ‘Evaluable’ and eligible for the mITT analysis if they have 
completed at least one Experimental Session and one CAPS-5 assessment beyond 
Baseline.  
 
A participant is considered ‘Evaluable and Completed Per Protocol’ if they have 
completed all Experimental Sessions and CAPS-5 assessments as planned. These 
participants will be included in the mITT analysis set and the Per Protocol analysis set. 
 


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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 pair, the participant was compliant with protocol 
requirements, even if they were unable to complete all study visits. 
 
4.4.2 Screen Failures
‘Screen Failures’ are defined as participants who pass phone screening but are deemed 
ineligible before successfully enrolling in the study at Visit 0. Screen failures may fail to 
meet all Inclusion Criteria and may meet one or more Exclusion Criteria or withdraw 
consent prior to Enrollment. All potential participants who begin Screening will be 
tracked on a Screening Log, and reasons for Screen Failure will be recorded. Screen 
Failures are not considered evaluable. 
 
Screen Failures may be identified through review of medical history, assessments, 
measures, laboratory results, or conversations with the participant. Medical assessments 
may be repeated for confirmation. At any time during Screening, if a potential participant 
is deemed to be ineligible, classify as a Screen Failure, notify the potential participant 
that they are unfortunately not eligible for the study, and do not schedule additional 
Screening assessments. Participants who fail Screening may be rescreened at a later date 
if deemed appropriate by the investigator but should sign a new copy of the Informed 
Consent Form (ICF). Screen Failures may request a referral to an outside therapist if 
needed. Screen Failures that were scheduled for an IR assessment will be entered into the 
Electronic Data Capture (EDC) system.
 
4.4.3 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 4.3.4 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 7.4.3.2 Exit Plan. 


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4.4.4 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 11.1 Tapering Instructions. Any time a participant 
terminates from the study early, the site team will attempt to obtain information about AE 
outcomes if appropriate, as determined by the site physician and Medical Monitor. The 
site team will provide the participant with an Exit Plan as described in Section 7.4.3.2 
Exit Plan.
 
 
Post-randomization Early Termination: Participants who discontinue study treatment 
but continue to participate in Independent Rater primary and secondary outcome 
assessments. Data collection by IRs will continue on the same schedule as planned 
through Study Termination visit procedures. 
 
Dropout: If a participant decides to withdraw consent completely, they will terminate 
without further follow-up. If the participant agrees, they will complete a final CAPS-5 
assessment. These participants are defined as dropouts who withdraw consent due to any 
reason after receiving at least one dose of IMP and no longer participate in the study (i.e., 
no further contact with investigators or site staff). Data collected on study participants up 
to the time of withdrawal of consent will remain in the trial database in order to maintain 
scientific validity. Removal of data from the database would undermine the scientific and 
ethical integrity of the research. 
 
4.4.5 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 


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considered evaluable. All participants with at least one Experimental Session will be 
included in the safety analysis. 
 
If a participant does not attend a scheduled visit, the site must attempt to contact the 
participant to reschedule the visit as soon as possible and emphasize the importance of 
complying with the protocol specified visit schedule. The staff should determine if the 
participant is willing to comply with future visits. 
 
If a participant does not respond to this initial contact, the site staff must make multiple 
efforts to contact the study participant and document each attempt in the source record. 
At least three attempts should be made via telephone, over the course of approximately 7 
days, with calls at different times of day. If telephone contact fails, an email should be 
sent if such contact information was provided. The emergency contact the participant 
provided should be contacted and asked to attempt contact with the participant. Lastly, a 
certified letter (or equivalent) should be sent to their last known mailing address. If the 
participant fails to respond to all of these contacts, they will be considered to have 
withdrawn from the study and are lost to follow-up. 
 
4.5 End of Study Definition and Premature Discontinuation 
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in Table 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.
4.6 Rationale of Dose Selection
Similar MDMA doses to those proposed in this study have been safely used in previous 
Phase 2 studies sponsored by MAPS. Phase 2 studies indicate that 75, 100 and 125 mg 
MDMA initial doses with the supplemental dose are active and effective in two to three 
Experimental Sessions. MDMA doses with an optimal risk-benefit ratio range from 75 
mg (Cohen’s d Independent Groups Pre-test Post-test [dIGPP]=2.73, N=7) to 125 mg 
(Cohen’s dIGPP=0.77, N=58) initial dose of MDMA with a 2-session treatment package. 
In Phase 2 studies, the sponsor observed a -36.4 point mean change in CAPS-4 scores 
among active dose participants receiving two Experimental Sessions (N=72) compared to 
a -44.2 point mean change after three Experimental Sessions (N=51). Although 
uncontrolled, the additional 7.8 point mean reduction observed after three Experimental 
Sessions compared to two, along with the observed favorable safety profile formed the 
basis for 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 


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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. A participant will receive a divided-dose of 
120 mg or 180 mg per Experimental Session. Initial doses per Experimental Session are 
80 mg or 120 mg of MDMA or placebo compounded with inactive excipients or equal 
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 tolerability 
issues emerge with the first dose or it is refused by the participant. Total amounts of 
MDMA to be administered per Experimental Session range from 80 mg to 180 mg. 
 
An inactive placebo has been selected as the control to allow differentiation of any 
additional MDMA effect from therapy alone. This pivotal study will generate 
unequivocal assessment of safety data and demonstration of efficacy of MDMA-assisted 
therapy compared to therapy 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 tolerability issues emerge with the first dose or it is refused by the participant.
 
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 tolerability issues emerge with the first dose or it is refused by 
the participant. The choice of whether to keep the dose the same or change it from the 
first Experimental Session will be made by the site team based on observed response, 
tolerability to the previously administered dose, and discussion with the participant. In 
each Experimental Session, 1.5 to 2 hours after the initial dose is given, the participant 
will be administered a supplemental half-dose unless tolerability issues emerge with the 
first dose or it is refused by the participant. 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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5.0 Therapy
5.1 Description of Therapeutic Method
The largely non-directive therapeutic method of MDMA-assisted therapy is described in 
detail in the Treatment Manual. All therapy 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. 
 
5.2 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 pairs, male/female preferred 
 
One person per therapy pair is required to be licensed to provide therapy according to 
state and local requirements 
 
If one person on the therapy pair is unlicensed, they will work under the direction of the 
licensed pair member 
 
5.3 Training
The sponsor’s Therapy Training Program is designed to teach competency in applying 
the essential elements of this method of MDMA-assisted therapy. Therapy team members 
will receive specific training in the MDMA-assisted therapy method, protocol, and latest 
version of the IB. Training in the therapy method consists of reading the Treatment 
Manual, completing an online training module, and participating in an in-person 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. 
5.4 Adherence to Therapeutic Method
Therapy sessions, including Experimental Sessions, may be recorded, with recordings 
preserved for research and training purposes. Adherence criteria and competence ratings 
will be conducted by qualified, trained, and blinded Adherence Raters who will analyze 
video data from specific and randomly selected Preparatory Sessions, Experimental 
Sessions, and Integrative Sessions. The elements included in adherence criteria are 
specific to each type of session and are defined in the Treatment Manual. These ratings 
will be collected, at minimum, for each therapy pair in the study. Ratings will be used to 


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provide feedback to new therapy teams, to further characterize the manualized therapy, 
and for future exploratory research.
 
6.0 Measures and Reliability
The following eligibility, outcome, exploratory, and safety measures will be used in the 
study, in accordance with Table 6: Time and Events-Study Measures.
 
Table 4: Protocol Objectives and Assessment Tools
 
Objectives
Measure
Measure Type 
Eligibility
Assess psychiatric disorders 
MINI 
Eligibility
Assess personality disorders 
SCID-5-PD with 
SCID-5-SPQ 
Eligibility
Confirm PTSD diagnosis and severity 
PCL-5 with LEC-5 
Eligibility
Identify dissociative disorders  
DDIS
Eligibility
Primary 
Assess changes in PTSD symptom severity from Visit 3 
to Visit 19 compared between groups 
CAPS-5 
Outcome 
Secondary
Assess changes in clinician-rated functional impairment 
from Visit 3 to Visit 19 compared between groups 
SDS 
Outcome 
Safety 
Compare relative incidence of positive or serious 
ideation and suicidal behavior between groups 
C-SSRS 
Safety
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 
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 
Assess changes in severity of dissociative symptoms 
associated with PTSD from Visit 3 to Visit 19 compared 
between groups 
DSP-I
Outcome 
Explore correlation of dissociative symptoms associated 
with PTSD with the CAPS-5 Total Severity analyses 
DSP-I
CAPS-5 
Outcome 
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 
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 
Assess changes in depression symptoms from Visit 4 to 
Visit 20 compared between groups 
BDI-II 
Outcome 
Assess changes in chronic pain from Visit 4 to Visit 20 
compared between groups
CPGS
Outcome 
Assess changes in quality of life from Visit 4 to Visit 20 
compared between groups
EQ-5D-5L
Outcome 


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Objectives
Measure
Measure Type
Assess changes in functioning in relation to self and 
others from Baseline to Visit 20 compared between 
groups
IASC
Outcome
Assess changes in self-reported psychosocial 
functioning from Visit 4 to Visit 20 compared between 
groups 
IPF
Outcome
Assess changes in self-compassion from Visit 4 to Visit 
20 compared between groups 
SCS
Outcome 
Assess changes in alexithymia from Visit 4 to Visit 20 
compared between groups
TAS-20 
Outcome 
Assess whether participant thinks they receive active 
drug or placebo at Visit 20 compared between groups. 
Blinding Survey
Outcome 
Assess changes in alcohol use from Screening to Visit 
20 compared between groups 
AUDIT
Healthcare cost
Assess changes in drug use from Screening to Visit 20 
compared between groups 
DUDIT
Healthcare cost
Assess changes in nicotine use from Visit 4 to Visit 20 
compared between groups
SRNU
Healthcare cost
Assess changes in disordered eating from Visit 4 to Visit 
20 compared between groups  
EAT-26 
Healthcare cost
Assess changes in workplace productivity from Visit 4 
to Visit 20 compared between groups 
HPQSF
Healthcare cost
Assess facility-based healthcare utilization at Screening
UFEC
Healthcare cost
 
6.1 Primary Outcome Measure and Reliability
6.1.1 CAPS-5 (Clinician-Administered PTSD Scale for DSM-5) 
The last month CAPS-5 is a semi-structured interview that assesses index history of 
DSM-5-defined traumatic event exposure [64], including the most distressing event, time 
since exposure, to produce a diagnostic score (presence vs. absence) and a PTSD Total 
Severity score [64]. The CAPS-5 rates intrusion symptoms (intrusive thoughts or 
memories), avoidance, cognitive and mood symptoms, arousal and reactivity symptoms, 
duration and degree of distress and dissociation. The CAPS-5 will be administered by a
blinded IR via telemedicine. Interviews will be conducted by the centralized remote IR 
pool to enhance quality control by reducing site-level variation in interview fidelity and 
quality. The IRs will be trained and supervised by a research reliable trainer and will be 
supervised by qualified personnel. Per the CAPS-5 Training Manual for the IR Pool, IRs 
will ensure that every single item-level score is collected in every CAPS-5 interview. The 
CAPS-5 is administered by the IR in a neutral, non-leading manner to minimize the 
chance for bias. Additionally, the IRs are trained to carefully assess trauma-relatedness of 
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 


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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.
 
6.2 Secondary Measure 
6.2.1 SDS (Sheehan Disability Scale)
The SDS is a clinician-rated assessment of functional impairment [65]. The reporting 
period for the SDS is the past month and this measure is administered by a member of the 
Independent Rater Pool. 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 [66]. 
The SDS takes 1 to 2 minutes to complete. 
 
6.3 Safety Measures 
6.3.1 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 [66]. 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 [67]. 
 
6.4 Screening Measures and Reliability
6.4.1 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 [68], 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 [70]. The MINI takes between 15 and 20 minutes to perform and addresses 
major psychiatric disorders. MINI items were highly reliable (interrater reliability 


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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 [69, 70] Testing on nonpsychiatric 
samples did not create false positives [68]. The IR pool will not assess the PTSD or 
Antisocial Personality Disorder modules.
 
6.4.2 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 [72]. Prior to the 
SCID-5-PD clinical interview, participants will complete a brief self-report questionnaire 
called the SCID-5 Self-report Personality Questionnaire (SCID-5-SPQ) as a self-report 
screening tool used to assess for personality disorders. Potential personality disorders that 
satisfy diagnostic thresholds will be further assessed via clinical interview during the 
SCID-5-PD. IRs will receive training on administering these measures from a research 
reliable trainer. Interviews may be recorded in as many instances as necessary to establish 
reliability of a random selection of interviews for accuracy. 
 
6.4.3 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 [73].
 
6.4.4 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 [74]. Participants indicate how much distress they have experienced due to 
symptoms such as "Repeated, disturbing memories, thoughts, or images of a stressful 
experience from the past," "Trouble remembering important parts of a stressful 
experience from the past," and "Feeling irritable or having angry outbursts" on a five-
point Likert-type scale (1=Not at all to 5=Extremely). A total PCL-5 score of 40 at 
Screening will be required for initial enrollment. 
 
6.4.5 DDIS (Dissociative Disorders Interview Schedule for DSM-5) 
Questions on the DDIS specifically addressing dissociative disorder symptoms (items 
117 to 130) will be assessed by a member of the Independent Rater Pool during 
Screening. These questions are part of an intensive interview that includes questions 
concerning somatic and psychiatric symptoms. The interview is intended to assess and 
potentially distinguish between dissociative disorders and other disorders and between 
Dissociative Identity Disorder (DID) and a dissociative disorder not otherwise specified 
[75]. Owing to overlap with items found between the DDIS and other screening 
measures, only questions specifically addressing DID will be assessed. 
 


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6.5 Exploratory Measures
6.5.1 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 [76]. Assessments of military veterans and civilians support the existence of a 
dissociative subtype of PTSD that is associated with PTSD severity and derealization and 
depersonalization [76-78]. The DSP-I takes approximately 5 to 15 minutes to complete
and will be assessed by a member of the Independent Rater Pool. It consists of two parts, 
only Part 1 will be administered. Part 1 contains five items addressing depersonalization, 
four items addressing derealization, and a section that is administered if dissociative 
episodes are endorsed that assesses duration and perceived cause of episodes (seven 
items) and observer items (three items) addressing interviewee demeanor, including 
evidence of dissociation, such as forgetfulness or giving a statement that is bizarre within 
the context of the interview. If two or more items within this section are endorsed, this 
indicates the presence of other dissociative symptoms beyond depersonalization and 
derealization. The DSP-I was first developed in 2016 and revised in 2017. 
 
6.5.2 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 [79]. 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 [80-83]. The 
scoring method has been used in archival research, finding an association between 
increased scores and health problems in several generations [83].  
 
6.5.3 BDI-II (Beck Depression Inventory II) 
The BDI-II is a revision of the BDI, a 21-item self-report measure [84, 85] that will serve 
as a measure of depression symptom severity over the prior two weeks [86]. 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 [86]. 
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 [86, 87]. Higher scores indicate more severe 
depressive symptoms.  
 


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6.5.4 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 regarding pain intensity in the past 6 months, and the response 
to the other item is made on a 10-point Likert scale regarding present-day pain [89]. 
Responses to questions are used to attain a rating (grade) for pain from 0 (no pain) to five 
(high disability, severely limiting). The instrument has three scale scores: pain severity, 
pain intensity, and pain-related disability. Estimated time to complete is 3 to 5 minutes. 
The CPGS is a validated scale with high internal consistency (Cronbach’s alpha=0.90) 
and correlated with other instruments assessing pain [90].
 
6.5.5 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 statement that best reflects their health on the day of measure 
completion, from the healthiest or fewest problems (e.g., “I have no trouble walking 
about”) to the most trouble (e.g., “I am unable to walk about”) [90, 91]. In the second part 
of the EQ-5D-5L, current degree of health (“your health today”) is indicated by marking 
a 20 cm line marked form one to 100, with 100 considered “the best health you can 
imagine” and one “the worst health you can imagine.” The EQ-5D-5L does not sum 
responses, but treats each response on a dimension as a scale score, and the VAS is the 
location of the mark in centimeters. The scale can permit comparison across groups on 
health profiles, and an index can be derived from matching the five dimension scores and 
the VAS response with nation-specific datasets and calculator software or statistical 
software syntax designed for the measure. The EQ-5D-5L began as part of the EuroQoL 
measure, published in 1990 [93]. The instrument has been validated in populations from 
eight countries. EQ-5D-5L index scores and VAS scores assessed in people with stroke 
varied with degree of recovery assessed via long-term observation. EQ-5D-5L index 
scores and VAS scores assessed in people with stroke varied with degree of recovery 
assessed via long-term observation [93]. The EQ-5D-5L takes about 3 minutes to 
complete.
 
6.5.6 IASC (Inventory of Altered Self Capacities) 
The IASC is a 63-item self-report measure of difficulties with relationships, identity, and 
affect regulation [95]. The measure is completed by rating the frequency that an event or 
experience has occurred in the last 6 months or last month (1=Never to 5=Very often) on 
a 
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 [95]. 
 


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6.5.7 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 [96]. The IPF is an 80-item measure that was developed for use 
among individuals with PTSD. It assesses current psychosocial functioning across seven 
domains: romantic relationships, family, work, friendships, parenting, education, and 
self-care. Responses are made on a six point Likert scale, (1=Never to 6=Always). 
Domain scores can be computed for each subscale, which possess positive correlations 
with similar scales or subscales on other measures. The IPF has excellent psychometric 
properties, with Cronbach’s alpha for the total scale computed at 0.93 and good internal 
consistency for subscales (ranging from 0.80 to 0.90) [97].  
 
6.5.8 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 [98]. 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 
more strongly associated with stable mood and less associated with self-rumination and 
anger [99]. 
 
6.5.9 TAS-20 (Toronto Alexithymia Scale) 
The TAS-20 is a 20-item measure of self-reported difficulties with recognizing and 
verbalizing emotions [99, 100]. 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).
 
6.5.10 Blinding Survey Measure  
The Blinding Survey Measure is a sponsor-developed measure assessing whether the 
participant thinks they receive active drug or placebo. The measure will be only collected 
at Study Termination (Visit 20) through participant direct report.  
 


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6.5.11 AUDIT (Alcohol Use Disorders Identification Test)
The AUDIT is a ten-item self-report test. Respondents answer on a 5-point scale 
(0=Never or none, 4=Daily or greatest number) [102]. The ninth item addresses 
occurrence of injury of self or other as a result of drinking and the tenth addresses others’ 
concerns about the respondent’s drinking, with only three responses provided (0=No, 
2=Yes, but not during the last year, 3=Yes, during the last year). The measure can readily 
detect alcohol abuse disorders in a wide array of individuals [103].
6.5.12 DUDIT (Drug Use Disorders Identification Test)
The DUDIT is an 11-item measure designed to assess presence of substance use disorders
within the past year [103]. 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% [103]. The English translation 
was developed from a Swedish-language original. Estimated time to complete is 2 to 4 
minutes.
 
6.5.13 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. 
 
6.5.14 EAT-26 (Eating Attitudes Test) 
The EAT-26 is a 26-item self-report measure that assesses attitudes about eating and food 
and is used to assess presence of eating disorders. Responses are made on a six-point 
scale (1=Always to 6=Never), and gathers information on gender, age, height, and
weight. The EAT-26 produces a total score and can be used to generate a “referral score.” 
The 27th item addresses the occurrence and frequency of specific eating behaviors, such 
as binge eating. Estimated time to complete is 4 to 8 minutes. Items on the EAT-26 have 
high reliability coefficients (Cronbach alpha of 0.83 to 0.90) and has concurrent validity 
[105]. 
 
6.5.15 HPQSF (Health and Work Performance Absenteeism and Presenteeism Short 
Form)
The HPQSF is a short form of a larger measure of health and work performance that has 
selected items referring to absenteeism and work performance [106]. The larger measure 
was created by the WHO as part of the Global Burden of Disease initiative. It consists of 
eight questions selected from the larger Health and Work Performance Questionnaire, 
with one question containing five additional items. Items include questions concerning 
hours worked during an average week, number of whole and partial days missed during a 
4-week period, and items that rate average coworker and self-work performance on a ten-


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point Likert scale (1=Worst performance to 10=Top performance). Hours spent in work 
over a 4-week period and over the last 7 days can be used to estimate absenteeism, and 
the HPQSF can also score presenteeism, a measure of actual performance in relation to 
possible performance. Self-reports on measure appear to match employer records of 
presence or absence [107], and the HPQSF appears to be reliable between one time point 
and another (reliability of 0.52) and is sensitive to change [106]. 
6.5.16 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. 
 
7.0 Study Procedures 
All assessments must be performed by qualified study staff delegated these duties on the 
Site Responsibilities Log. The Clinical Research Associate (CRA) should be notified of 
any delays or deviations to study procedures and Medical Monitor consulted if necessary. 
If there are delays of more than 7 days between visits or contact, the site should assess the 
need for additional telephone contact with the participant to ensure safety. 
 


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Table 5: Time and Events-Study Procedures
Screening Period
(up to 28 days)
Preparatory Period w/ Enrollment Confirmation
(At least 5 days, depending on medication tapering)
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
At least 2 days after
V1 (depending on 
medication tapering)
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- 
medicine
Int. 
1.3 G 
Exp. 
2 
Int. 
2.1 
Int. 
2.2 G 
CAPS-5 
T3: Tele- 
medicine 
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 to 
7 days 
before 
V10 
21 to 
35 
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
14-day Phone 
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
E Phone follow-up: every other day for 14 days 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
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
Blinding Survey
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
90 C
77
15
10
90 C
77
15
10
90 C
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 every other day for 14 days after Experimental Session
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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7.1 Screening Period
7.1.1 Pre-Screening and Informed Consent
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 begin screening. Relevant medical and psychiatric records are 
required for the site physician to obtain a well-characterized medical history and assess 
eligibility. The physician may need to contact the prescribing physician to discuss the 
tapering of medications (see Section 11.0 Concomitant Medications).
 
Site staff (preferably the therapy pair who would be treating this potential participant) or 
central screener will explain and obtain written (or electronic) informed consent using the 
IRB-approved ICF. Written consent must be obtained prior to performing any tests or 
evaluations for the study. The signature may be obtained using an electronic 21 CFR Part 
11 compliant system due to COVID-19. Discussion about the ICF may take place over a 
telemedicine visit or at the first in-person visit. 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, and/or over the telephone. All procedures must be completed but there can 
be some flexibility in timing and order of individual assessments. The sponsor suggests
the following order of assessments to minimize in-person screening in light of COVID-
19:
 
Initial Eligibility, including measures, in-person discussions, and review of medical 
records 
 
Medical Assessments, including labs, electrocardiogram (ECG), and physical exam 
 
Independent Rater Screening. 
 
7.1.2 Initial Eligibility Assessment
Qualified site staff or central screener will complete the following assessments in-person 
or via telemedicine: 
 
 
Collect demographics information 
 
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. 


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Direct participant to complete self-reported Screening measures: 
o SCID-5-SPQ 
o AUDIT 
o DUDIT 
 
Review results of all measures and discussions against eligibility criteria to assess initial 
eligibility. If deemed initially eligible, continue collection of information on source 
records, including past therapy and developmental trauma events, and schedule a meeting 
with a site physician. 
7.1.3 Meeting with Site Physician 
A site physician will meet with the participant over telemedicine, the phone, or in-person 
to perform the following assessments: 
In advance of meeting with the participant, review medical and psychiatric history via 
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. 
 
Review medical and psychiatric history with the participant via interview, confirming 
information collected in medical records. 
 
Review past and current medications and adherence to prescriptions. 
 
Assess ability to become pregnant and discuss requirement for commitment to adequate 
birth control for the duration of the study.  
 
If the physician deems the participant initially eligible based on these discussions and 
review of medical records, the site will make an assessment about the next step for 
screening, either IR screening (Section 7.1.4 Independent Rater Screening) or in-person 
medical assessments. The Sponsor suggests completing the IR Screening while the 
medical assessments are being scheduled.  
In-Person Medical Assessments
 
The physical exam must be performed by a qualified physician and lab assessments must 
be completed at a designated lab. Some or all of these assessments may be at outside 
facilities. Medical assessments will include:
 
Perform urine pregnancy test for participants who are able to become pregnant. 
 
Perform a urine drug test. 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. 


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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. Per the Medical Monitor and site physician's instruction, other tests of 
cardiovascular health and function may be required during screening, such as an 
echocardiogram. These will only be completed on a case-by-case basis to confirm a 
participant's cardiovascular eligibility. 
 
Additional visits (in person, by telephone, or via telemedicine) may be scheduled at the 
discretion of the study staff to collect more information for determining eligibility or to 
discuss study expectations with the potential participant.  
 
Once all results are obtained, the site team will review all medical assessments, notes 
from interviews and discussions, medical records, and measures against eligibility 
criteria. If, upon examination, there are questions raised about possible medical problems, 
the site physician will request additional tests, assessments, or measures as indicated. The 
site physician may also contact outside providers with participant permission as needed. 
7.1.4 Independent Rater Screening
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.
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 pair is needed for support. If a participant reports suicidal 


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ideation during this assessment, the IR will contact the therapy pair after the call and 
present any concerns. The therapy pair will follow-up with the participant to ensure 
safety, provide support, recommend treatment, or schedule a visit to the study site. 
 
 
Using the results of the SCID-5-SPQ to guide the interview, the IR will perform the 
SCID-5-PD to assess personality disorders. Only appropriate modules will be completed.  
 
The IR will also ask relevant questions from the DDIS to identify dissociative disorders 
and administer the Since Last Visit C-SSRS to determine suicidal risk. 
 
The IR will complete MINI interview to assess psychiatric disorders.  
The results from the MINI, SCID-5-PD, DDIS, and C-SSRS will be provided to the 
therapy pair at the site to review along with all other Screening information to determine 
eligibility. Items assessed by the IR at this visit will be confirmed in the Preparatory 
Period by clinical observation, but the measures will not be repeated. If 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 reviewer will invite the study team (including 
therapists, site physician, and Clinical Investigator) to provide any additional information 
that may inform the Senior IR reviewer’s opinion. The Senior IR reviewer will make the 
final judgment on whether or not the participant has an exclusionary diagnosis. 
Participants with exclusionary diagnoses will not be enrolled. However, if any diagnosis 
is not present or uncertain according to any measure or interview, but the investigator 
believes the participant presents with a particular disorder, they may diagnose and deem 
the participant ineligible if appropriate. 
 
After the initial screening visit the IRs will be blinded to visit number, treatment 
assignment, number of treatments received, and any study data for the participant. IR 
visits will be assigned based on availability.  
 
7.1.5 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 11.0 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. 


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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 10.0 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.
7.2 Preparatory Period with Enrollment Confirmation
Participants will undergo three Preparatory Sessions (Visits 1, 2, and 4) lasting 
approximately 90 minutes with the therapy pair prior to the first Experimental Session. 
The Preparatory Period will be initiated within 12 days of Visit 0 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 pair will work 
with the participant to prepare for MDMA-assisted therapy, begin building therapeutic 
alliance, and promote a safe set and setting for confronting trauma-related memories, 
emotions, and thoughts.  
 
7.2.1 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. These sessions will 
consist of: 
 
 
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.  
 
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 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 therapy Preparatory Session, the therapy pair 
will:
 
 
Record the therapy session. 
 
Inquire about any possible changes in health to ensure the participant continues to meet 
all eligibility requirements. Record AEs as described in Section 10.0 Safety. 
 
Inquire about concomitant medication use and adherence. 
 
Confirm that medication tapering is ongoing or complete, as appropriate. 


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Discuss goals and expectations for the Experimental Session, following standard 
procedures and techniques described in the Treatment Manual [108].
If a participant would like a companion present during or after the Experimental Session, 
a meeting between the therapy pair and that individual will be scheduled prior to the first 
Experimental Session. There must be mutual agreement between the participant and 
therapy pair concerning the presence of the companion.
 
During one of the Preparatory Sessions, if possible, the therapy pair will introduce the 
participant to the attendant who will remain with the participant during each overnight 
stay after each MDMA-assisted therapy session. The attendant will be an individual with 
previous training in caregiving. The site will make all attempts to have the same attendant 
for each Experimental Session for a given participant, but it is not guaranteed. 
 
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. 
 
7.2.2 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 28 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. 
 
7.2.3 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 28. 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. 
 


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For eligible participants at Visit 4, qualified site staff will:
 
Perform urine pregnancy test for participants who can become pregnant.
 
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. 
 
7.3 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.
7.3.1 Experimental Sessions
There will be three blinded Experimental Sessions (Visits 5, 10, 15). Procedures for 
MDMA-assisted therapy 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. The Experimental Sessions will 
consist of:
 
Experimental Session 1: (Visit 5) will occur 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 for the 


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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 MDMA or placebo followed by a supplemental half-dose 1.5 to 2 hours 
after the initial dose unless tolerability issues emerge with the first dose or it is refused by 
the participant. 
 
Experimental Session 2: (Visit 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 tolerability issues emerge with the first dose or it is 
refused by the participant. 
 
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 tolerability issues emerge with the first dose or 
it is refused by the participant. 
 
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 Blood Pressure (BP), body temperature, pulse 
10:00 
IMP Administration, Begin video recording 
11:30 
BP, body temperature pulse
Supplemental Dose Administration, unless tolerability issues emerge 
with the first dose or it is refused by the participant.
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 3.3 Lifestyle Modifications. 
 
The site team will inquire about any possible changes in health to ensure the participant 
continues to meet all eligibility requirements and record AEs as described in Section 10.0 
Safety. 
 
The site team will instruct the participant that they will not be able to use caffeine or 
nicotine at least 6 hours after the IMP administration. 
 
The site team will complete urine drug screen, pregnancy test, and concomitant 
medication review. 
o A positive drug screen will be reviewed by the site physician and may be cause 
for delaying IMP administration to a later time, rescheduling the session to a later 


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date, or withdrawing the participant from the study, based on Medical Monitor 
review.  
o A positive pregnancy screen is cause for withdrawal from the protocol.  
 
The therapy pair will administer Since Last Visit C-SSRS. 
 
The therapy pair will review procedures for the Experimental Session with the participant 
and discuss the participant’s goals, intentions, and concerns and some of the commonly 
experienced effects of MDMA. The choice of whether to keep the dose the same or 
change it from the first Experimental Session will be made by the therapy pair 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 pair, who will provide guidance and support, as 
needed.  
 
After the first hour, if the participant has not spoken spontaneously, the therapy pair will 
check in with them about the nature of the experience. For the rest of the experience, as 
appropriate, the therapy pair will support and encourage the participant in emotional 
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 pair will 
document the reason. 
 
The site physician will be contacted with a brief description of how the session is 
progressing and the recent vital signs. The site physician will approve or deny the 
administration of the supplemental dose. If an AE requiring medical attention has 
occurred between the initial and supplemental dose, the site physician will determine 
whether the supplemental dose is recommended or not. If medical attention is needed, the 
site physician will provide further instruction or consult the Medical Monitor. 
 
A supplemental half-dose will be administered with a glass of electrolyte-containing fluid 
approximately 1.5 to 2 hours after the initial dose, unless tolerability issues emerge with 
the first dose or it is refused by the participant. 
 
Food will be provided during the latter part of the session.  
 
If there is an approved companion, that person may arrive as agreed upon but will wait in 
the waiting room until a member of the therapy pair brings them to the session room. 
Alternatively, the companion may arrive after the session has ended. 
 
End of Experimental Session 
 
 
The therapy pair will administer Since Last Visit C-SSRS. 
 
The therapy pair will record AEs and concomitant medications. 


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The session may be ended if all medical and psychiatric parameters are acceptable, 
elevations in vital signs have resolved to pre-IMP levels, the participant is alert, 
ambulatory, and emotionally stable, and the night attendant has arrived. 
 
The therapy pair or site physician shall remain available to participants via 24-hour 
cellular phone for 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 pair, a companion may accompany the participant during the overnight stay.  
 
An attendant will check in periodically on the participant during the overnight stay, even 
if a companion is present. The attendant will monitor participant condition and will help 
participants relax during the overnight stay. The attendant will be an individual with 
some previous training in caregiving and will be supportive but not intrusive. If there is 
an emergency or the participant needs additional support, the attendant can contact the 
therapy pair.  
 
The participant and a companion (if applicable) will receive information that will allow 
them to contact the therapy pair during the overnight stay in the case of an emergency or 
to request 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. 
 
Participants may not drive until after the Integrative Session conducted on the day after the 
Experimental Session, as emotional processing may impair their attention and focus. 
 
7.3.2 Telephone Contact After Experimental Sessions
The goal of the telephone contact is to assess health changes, ensure participant safety, 
and offer support. The therapy pair 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 15 minutes but could be longer to address participant concerns and to 
adequately assess wellbeing. Additional telephone contact can be initiated at the request 
of the therapy pair or participant. 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 pair will:
 
Inquire about any possible changes in health, assess the participant’s mental health and 
the status of any previously recorded AEs, and record AEs as described in Section 10.0 
Safety. 
 
Inquire about concomitant medication use and adherence. 
 
Offer support in accordance with the Treatment Manual. 
 
Administer the Since Last Visit C-SSRS. 
 


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7.3.3 Integrative Sessions
After each Experimental Session, three Integrative Sessions will take place. Each session 
will consist of 90 minutes of therapy. 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 34 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 pair 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 pair will 
help the participant to reduce any residual psychological distress they are experiencing. 
The therapy pairs will also encourage the transfer of states of acceptance, feelings of 
intimacy, closeness, and reduced fear experienced in Experimental Sessions to 
emotionally threatening everyday situations. The therapy pairs will be supportive, 
validate the experience, and facilitate understanding and emotional clearing. 
 
Be accessible for additional support via phone or telemedicine if needed. 
 
At each third Integrative Session, direct the participants to complete the LEC-5. 
 


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7.3.4 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).
 
 
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). 
 
7.4 Follow-up Period and Study Termination
7.4.1 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 pairs for support if needed, and additional visits via phone, 
telemedicine, or in person can be scheduled if requested. Participants will continue to 
comply with protocol requirements for concomitant medications until after Study 
Termination. 
 
7.4.2 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, but if there are significant delays in 
the timing of Experimental Session 2 (Visit 10) and/or Experimental Session 3 (Visit 15), 
the alternative visit window is based on 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.
 


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7.4.3 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. 
 
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 least 6 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 Blinding Survey 
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 7.4.3.2 Exit Plan. Eligible 
participants will be asked to participate in the LTFU extension study, described in 
Section 7.4.3.1 Extension Studies. 
 
7.4.3.1 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 


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extension study. The ICF for this study will be provided to eligible participants at the 
Study Termination visit. This study will measure outcomes at least 6 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 therapy 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. 
 
Any sub-studies other than what is outlined in Appendix A will be detailed in separate 
documents. 
 
7.4.3.2 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.
 
8.0 Investigational Product
8.1 Description of Active Compounds
The Active Pharmaceutical Ingredient (API) to be used in this protocol is MDMA (as 
hydrochloride salt). This ring-substituted phenethylamine has a complex pharmacology, 
but it acts most prominently as a monoamine releaser and re-uptake inhibitor. Its direct 
actions on serotonergic, adrenergic, and other receptors are considerably lower. Refer to 
the IB for a comprehensive review of the pharmacology, effects and proposed 
mechanisms of action of the IMP. Mannitol and a lubricant, such as magnesium stearate,
will serve as inactive excipients.
8.1.1 Doses
This study will compare the effects of three blinded manualized Experimental Sessions of 
therapy assisted by flexible doses of MDMA or placebo. Initial doses per Experimental 
Session include 80 mg or 120 mg MDMA HCl 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. 


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8.1.2 Dose Modifications 
A participant will receive a divided-dose of 120 mg or 180 mg per Experimental Session.
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 tolerability issues emerge with the first dose or it is 
refused by the participant. The choice of whether to keep the dose the same or change it 
from the first Experimental Session will be made by the therapy pair 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 tolerability issues emerge with the first dose or it is refused 
by the participant. If an AE requiring medical attention occurs between the initial and 
supplemental dose this will be evaluated as a potential tolerability issue 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. 
 
8.1.3 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.
8.2 Handling
8.2.1 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.  
 
 
 


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Figure 2: Example Label
 
 
8.2.2 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 the Source Record and the IMP administration log. The web-based 
randomization system will enable tracking of blinded primary containers for 
accountability purposes.
8.2.3 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. 
8.2.4 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 
tolerability issues emerge with the first dose or it is refused by the participant. Each dose 
 Protocol #: MAPP2 
Kit Code/Container#: V 
Lot#: V 
Re-test date: V 
Experimental Session 1 
Storage Conditions: 15-25°C 
Contains: 3 capsules of MDMA HCl 40mg or Placebo 
Directions for use: Take by mouth and swallow with water 
Caution: New Drug-Limited by Federal (or United States) law 
to investigational use only by a qualified investigator.  
Multidisciplinary Association for Psychedelic Studies (MAPS) 
1115 Mission Street Santa Cruz, CA 95060 +1 (831) 429-6362 
IND #063384 
Site:_______________ Investigator:_____________________ 


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(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.  
 
8.2.5 Treatment Compliance 
Compliance to protocol required doses will be guaranteed by the person licensed to 
manage and administer controlled substances for Experimental Sessions at each site. All 
administered doses will be recorded for IMP accountability. The IMP will be stored 
securely per regulations. 
 
8.3 Randomization and Participant Numbering 
Every potential participant who is prescreened by telephone according to the IRB-
approved script will be assigned a seven-character alphanumeric Screening Number and 
recorded on the Screening Log. This number will begin with ‘S4’ 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 ‘401’. 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 S411401 and first Screening Number at Site 12 will 
be S412401. 
 
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 ‘22’. 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 
2212001. 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 therapy group and the placebo plus therapy group, stratified by clinical site. 
Randomization will be managed via an Interactive Web Randomization System (IWRS) 
based on a centralized randomization schedule developed by an independent third-party 
vendor to maintain blinding.  
 
8.4 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 


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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 pair 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, 


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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.
 
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.
 
9.0 Risks 
9.1 Non-drug Related Risks
9.1.1 Medical Assessments 
In preparation for MDMA-assisted therapy sessions, blood draws and a full medical 
examination, including a physical examination, ECG, 1-minute rhythm strip, and 
laboratory tests, are required to establish eligibility for the study. Temporary discomfort, 
inflammation, or infection could arise as a result of sampling blood at the punctured vein. 
Submitting to a full medical examination may also cause discomfort or psychological 
distress. Since medical examinations and blood draws are required to establish eligibility 
for the study, they cannot be omitted from the protocol. 


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9.1.2 PTSD, Suicide Risk, and Therapy 
During Screening, throughout MDMA-assisted therapy, and during assessment of study 
measures, participants will be asked to think about and discuss their thoughts and 
emotions relating to the traumatic event or events. They may experience intense 
emotional responses or suicidal ideation as a result of recalling and speaking about this 
material. Even in a therapeutic context, thinking about and discussing the trauma, 
symptoms related to the trauma or the effects of PTSD on life function can produce 
distress and exacerbate suicidal ideation during and immediately after therapy sessions. 
Therapy is conducted as part of this study, and people undergoing therapy are expected to 
confront unpleasant thoughts, feelings and memories in the process. Because therapy is 
an integral part of the research study design, the potential distress arising from therapy is 
unavoidable. Therapy pairs will provide emotional support to participants during any 
psychological distress. 
 
The therapy pair will minimize risks by carefully evaluating all participants to determine 
if there is a current risk of suicidal behavior. Participants with a history of suicide 
attempts will not be excluded unless significant risk of suicidal ideation and/or behavior 
is detected, per Exclusion Criteria described in Section 3.2. Participants will be enrolled 
according to the Eligibility Criteria based on the clinical judgment of the site physician, 
therapy pair, and Medical Monitor. 
 
A qualified individual will administer the C-SSRS according to 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 pair 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 Adverse Event of Special Interest (AESI) per Section 10.1.1 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. 


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2.
If the participant has suicidal ideation, and a plan to commit suicide (Suicidal Ideation 
Score=5) or positive Suicidal Behavior (Score greater than or equal to 1), the individual 
administering the C-SSRS will assess whether the risk is imminent. A Suicidal Ideation 
score of five does not necessarily indicate an immediate risk if the thoughts are fleeting, 
fairly easily controlled, and deterrents are strong. If there is no imminent risk, the 
individual will follow the procedure described above. If there is imminent risk of suicidal 
behavior, the individual will ensure: 
a. Participants are evaluated by the investigator or site physician to determine an 
appropriate course of action, and the therapy pair will contact their personal 
therapist, who will be invited to come to the study site to assist, depending on 
their location. 
b. If it is determined that the participant is at imminent risk of suicide, the therapy 
pair will do one of the following: 
i. Escort the participant to the emergency department (ED); 
ii. Escort the participant to an appropriate mental health services facility 
(e.g., hospital psychiatric unit); or  
iii. Call emergency medical services (EMS) and ensure that the participant is 
transferred to the responding medical personnel. 
c. If the participant will not comply and wishes to leave without consultation, call 
EMS. Explain that the participant is in immediate danger of committing suicide. 
Provide a complete description of the participant and give any other needed 
details to ensure the participant’s safety. 
d. Notification of appropriate members of the study team and sponsor 
representatives within 24 hours, provide a narrative for the AE for expedited 
reporting to FDA. 
e. The event will be collected as an AESI per Section 10.1.1 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. 
 
9.1.3 Recorded Content
All therapy sessions and IR assessments may be recorded for research and training 
purposes. Participants may feel uncomfortable with having their sessions recorded. The 
recordings are necessary for developing the experimental treatment and assessing 
adherence to the Treatment Manual. Any requests for use of video outside of research 
and training requests will result in participants receiving information on the request. They 
will have control over any presentation of this material beyond viewing by researchers or 
regulatory agencies.
The sponsor uses encrypted, secure technology to transfer and store recordings, but there 
is always a risk of a security breach. The sponsor is committed to taking preventative 
measures to avoid such an event. In the case of a security breach, the participant will be 
notified, and all efforts will be made to minimize the dissemination of recorded content.
9.2 Risks of Receiving MDMA 
Study procedures and eligibility criteria have been developed based on Phase 2 and Phase 
3 PTSD trials which exclude potential participants with pre-existing exclusionary medical 
conditions that would exacerbate risk. The therapy pairs and site physicians are available 


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via telephone throughout the study if any problem occurs when a participant is not at the 
site. In the event of a medical emergency or any other medical problem during an 
Experimental Session, the site physician should be immediately available by telephone, 
and based on assessment of the situation, they should make the decision to either evaluate 
the participant themselves at the site or arrange for transfer of the participant to the 
Emergency Department.  
 
Further information on the risks associated with MDMA can be found in the IB and risk 
mitigation procedures are described by risk category below. Risk Categories were 
determined by review of possible risks within the Risk Assessment and Categorization 
Tool (RACT).  
 
9.2.1 High Level Risks 
High Risk does not indicate an event is more likely to happen but indicates per the RACT 
assessment that new and or more complex procedures are required in the study to ensure 
screening is adequate to eliminate or manage the risk in the patient population. No high 
level risks have been identified based on the RACT assessment. 
 
9.2.2 Medium Level Risks 
Medium Risk does not indicate the likelihood the event will occur but indicates per the 
RACT assessment that new or many procedures, which are not complex, are needed to 
ensure screening is adequate to eliminate or manage the risk in the patient population. 
 
9.2.2.1 Cardiovascular and Cerebrovascular Risks and Mitigation 
MDMA is known to transiently increase heart rate and blood pressure in a dose-
dependent manner that is generally not problematic for physically healthy individuals. 
These changes should last no more than 8 hours. Participants with PTSD in MAPS-
sponsored Phase 2 and Phase 3 studies do not appear to differ from healthy individuals in 
this sympathomimetic, physiological response. Most people do not experience elevations 
in cardiovascular parameters that exceed those seen after moderate exercise. An 
examination of safety data drawn from Phase 2 and Phase 3 studies of MDMA-assisted 
therapy detected a dose-dependent increase in SBP and to a lesser extent DBP. 
Characterization of sympathomimetic effects among participants with controlled 
hypertension is ongoing.  
 
Risks posed by elevated blood pressure are addressed by excluding people with pre-
existing uncontrolled hypertension and monitoring blood pressure and pulse, as described 
in Section 3.2 Exclusion Criteria. Before and after IMP administration in Experimental 
Sessions, the therapy teams monitor vital signs. The therapy teams should attend to 
clinical signs and symptoms of potential rare complications of the cardiovascular effects 
of MDMA, such as stroke or acute myocardial infarction (AMI) during Experimental 
Sessions. Any symptoms such as chest pain, shortness of breath, neurological deficit or 
confusion or other potential indicators of end organ effects should prompt additional vital 
sign measurements, and intervention if appropriate. Therapy teams should notify the site 
physician if this occurs for evaluation.  


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If any participant has neurological deficits, as assessed by the site physician, whether or 
not they are associated with hypertensive crisis, they should be monitored, as described 
above and transported to the hospital if medically indicated. If evaluation at the hospital 
reveals an acute ischemic stroke, there will be sufficient time to administer recombinant 
tissue plasminogen within the 3-hour time frame recommended in the 2019 American 
Heart Association/American Stroke Association (AHA/ASA) guidelines [108].
If a participant experiences ischemic type chest pain, whether or not it is associated with 
hypertensive crisis, the study physician will be contacted immediately, and the participant 
will be taken to an emergency room by ambulance as expeditiously as possible to assess 
the patient and act in accordance with the assessment of the expert on site supported by 
national and local/AHA and European Society of Cardiology (ESC) Guidelines. Pending 
transport to the hospital the site team may take any measures ordered by the site 
physician including administering medication such as aspirin or nitroglycerin or 
providing supplemental oxygen per local standards. If further evaluation at the hospital 
reveals that the participant has had an AMI, they will be well within the time frame 
required for definitive therapy. 
 
Any participant who experiences such medical complications during an Experimental 
Session will not be given another Experimental Session. 
 
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 that is exclusionary per eligibility criteria or of >30 ms over Baseline during 
ECG evaluation, the participant should be discontinued from treatment.  
 
9.2.2.2 Psychological Risks and Mitigation 
Mild anxiety and depressed mood are occasionally reported 1 to 3 days after MDMA 
administration [49, 109]. 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 clinical studies, these symptoms have been self-limiting and have 
responded well to reassurance from the therapy pair, with occasional use of 
benzodiazepines for anxiety. In this study, participants will have the intention of 
confronting and working through traumatic experiences. Accordingly, signs of 
psychological distress, panic, or other unpleasant psychological reactions are to be 
expected and may be considered an element of the psychotherapeutic process. 
 
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). 


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Preparatory Sessions of non-drug therapy before the Experimental Session. 
 
Creating an atmosphere of trust during the Experimental Session. 
 
Close monitoring. 
 
Phone contact with participants during the week after the Experimental Session. 
 
Integrative Sessions. 
 
Overnight stays at the study site for the night of each Experimental Session. Qualified 
personnel will be available during the overnight stay to respond to the needs of the 
participant. Attendants will be instructed to contact the therapy pair upon request or at the 
appearance of signs of a potential SAE.  
 
During the Preparatory Sessions, participants should be made aware of the fact that 
difficult emotions, including grief, rage, fear, or panic, may arise during Experimental 
Sessions. Every effort should be made to help participants resolve difficult symptoms and 
to arrive at a more comfortable and relaxed state by the conclusion of the Experimental 
Session, including empathic listening on the part of the therapy pair and performance of 
diaphragmatic breathing by participants.  
 
If the participant is severely agitated, anxious, in danger of self-harm or suicide, or is 
experiencing any other severe psychological distress, at the end of a therapy session, at 
least one member of the therapy pair will remain with the participant for at least 2 more 
hours. During this time, the therapy pair will employ affect management techniques, will 
talk with the participant to help them gain cognitive perspective of their experiences, and 
will help the participant implement the self-soothing and stress inoculation techniques 
presented during the Preparatory Sessions. If the participant remains severely anxious, 
agitated, in danger of self-harm or suicide, or is otherwise psychologically unstable at the 
end of the 2-hour stabilization period, the site physician and therapy pair will decide 
between the following options:
 
1. If severe distress occurs at the end of an Experimental Session, a nurse, therapeutic 
assistant, physician, or therapy pair member should stay with the participant until the 
severe distress resolves or until the time of their Integrative Session appointment the 
following morning. The therapy pair should then meet with the participant daily until the 
period of destabilization has passed.  
2. If the participant experiences severe, persisting emotional distress, such as panic attacks, 
severe generalized anxiety, or insomnia following an Experimental Session, a site 
physician may prescribe a benzodiazepine (specifically, lorazepam) and/or sleep aid (e.g., 
zolpidem). The route, frequency, and dose should be determined by the site physician. If 
these medications are stocked on site, they should be stored according to applicable 
national and local regulations. This medication will be captured on the Concomitant 
Medications eCRF. The site physician should not prescribe an SSRI, SNRI, or 
monoamine oxidase inhibitor (MAOI) in this context, unless it has been determined that 
the participant will be withdrawn from the study. Residual symptoms will be addressed 
during the frequent follow-up therapy visits with the therapy pair. 
3. If a participant should become psychotic, arrangements should be made to stabilize them 
or transfer them to the Emergency Department if hospitalization is necessary. Any 
participant who is hospitalized after a severe psychological reaction will be suspended 
from the protocol until after recovery or stabilization, at which time the investigator 
and/or site physician will carefully evaluate the participant’s emotional status.  
 


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For those participants engaged in an ongoing therapeutic relationship with a 
psychotherapist or psychiatrist, the participant’s outside therapist(s) should 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 
pair, the management of any psychiatric complications should be undertaken by them in 
their capacity as the participant’s therapist. 
 
9.2.3 Low Level Risks 
Low Level Risk does not indicate the likelihood the event will occur but indicates per the 
RACT assessment that no new or complex procedures are needed to ensure screening is 
adequate to eliminate or manage the risk in the patient population. 
 
9.2.3.1 Thermoregulatory Risks and Mitigation 
MDMA administered in a controlled setting produces only a slight increase in body 
temperature [109]. Ambient temperature does not enhance or attenuate this slight 
elevation in humans. In data gathered from sponsor-supported Phase 2 and Phase 3 
studies, it was found that compared to placebo, a higher percentage of participants 
receiving MDMA had peak body temperatures greater than 1 degree Celsius (°C) above 
baseline. However, there was no strong relationship between dose of MDMA and peak 
body temperature or between MDMA dose and elevation above threshold of 1°C above 
baseline. 
 
Ambient temperature should be kept at a comfortable level during Experimental Sessions. 
If a participant’s temperature rises more than 1°C or the participant states that they feel 
hot, attempts should be made to decrease body temperature and increase comfort by 
removing blankets and layers of clothing, decreasing the ambient temperature, and, if 
necessary, directing a fan toward the participant. If at any time the temperature rises more 
than 1.5°C above baseline despite these efforts, the site physician should be consulted for 
further evaluation and treatment. 
9.2.3.2 Osmoregulatory Risk and Mitigation
MDMA administered in a controlled setting is not expected to have any risks of 
osmoregulatory changes. Participants are not allowed to drink more than three liters of 
water over the course of the Experimental Session and fluid intake will be spread out 
appropriately during the session. If a participant exhibits any signs of toxicity or 
clinically significant dilutional hyponatremia despite these precautions after an 
Experimental Session, they should not receive another Experimental Session unless it is 
approved by the investigator, site physician, and the Medical Monitor.
9.2.3.3 Genotoxicity Risk and Mitigation
The standard genotoxicity battery for MDMA has demonstrated that MDMA is negative 
for in vitro and in vivo genotoxicity, both with and without metabolic activation.


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9.2.3.4 Reproductive and Developmental Risks and Mitigation
There are no data from the use of MDMA in pregnant women. In the absence of these 
data, epidemiological studies of Ecstasy are the only source of human data. One of two 
studies of Ecstasy users suggest that use of Ecstasy and polydrug use during pregnancy 
may be associated with some abnormalities at birth while the other failed to find this 
association [110, 111]. 
Studies in rats and rabbits have not shown direct or indirect harmful effects with respect 
to reproductive toxicity. Repeated dose toxicity studies of adequate duration, fertility, 
early embryonic development, and embryofetal development studies of MDMA with 
toxicokinetics have been completed. These studies established the NOAEL dose to be 
excluded 
both sexes of the rat for fertility, reproductive performance, and for maternal and 
developmental toxicity in the rabbit. The NOAEL dose was the highest dose level 
evalua
toxicity in the rat. Due to the short half-life and single-dose dosing regimen of MDMA, 
pre- and post-natal development studies are not considered necessary for assessment of 
risk to the unborn. Assessment of embryofetal risk based on all available non-clinical and 
clinical data supports unlikely human teratogenicity/fetotoxicity in early pregnancy. On 
the basis of male fertility studies, the embryofetal risk posed from treatment of male 
participants with MDMA is also unlikely.  
 
PABP are included in the studies in this program, defined as those who are fertile, 
following menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. Postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. As a precautionary measure in clinical trials, 
participants who are able to become pregnant must have a negative pregnancy screen 
before undergoing each Experimental Session, which are conducted in monthly intervals,  
and must agree to use adequate contraception at least during the Treatment Period which 
is one month post the last dose of MDMA. The end of relevant systemic exposure to 
MDMA is approximately 48 hours [113].  
 
9.2.4 Minimal Risks 
Minimum Level Risk does not indicate the likelihood the event will occur but indicates 
per the RACT assessment that no procedures are needed beyond basic monitoring to 
ensure screening is adequate to eliminate or manage the risk in the patient population. 
 
9.2.4.1 Common Expected AEs 
Common expected AEs were typically observed during Experimental Sessions, but were 
transient and typically diminished as MDMA was metabolized and excreted over the next 
72 hours after dosing. In the Phase 3 study MAPP1, the most common adverse events 
reported more frequently in the MDMA group were muscle tightness, decreased appetite, 
dizziness, nausea, hyperhidrosis, feeling cold, restlessness, mydriasis, dizziness 
(postural), bruxism, nystagmus, increased blood pressure, feeling jittery, chest pain (non-


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cardiac), dry mouth, vision blurred, pollakiuria, intrusive thoughts, vomiting, stress, and 
musculoskeletal chest pain. AEs were typically self-limiting.  
 
9.2.4.2 Neurotoxicity Risk 
It does not appear that MDMA-assisted therapy negatively impacts cognitive function 
based on data from Phase 2 studies sponsored by MAPS. The sponsor has carefully 
considered the risks of such neurotoxicity and conclude that they are minimal in the 
proposed study. This conclusion is supported by empirical and toxicokinetic evidence and 
is consistent with the lack of toxicity reported in previous clinical MDMA studies.  
 
9.2.4.3 Abuse Potential 
Despite its classification as a Schedule I drug, an examination of findings in humans and 
animals suggests that MDMA possesses moderate abuse potential that is higher than that 
reported for “classic hallucinogens” like psilocybin, but lower than that reported for 
psychostimulants, such as cocaine or methamphetamine. There have been no AESIs 
reported in Phase 2 and Phase 3 studies that could be suggestive of abuse potential among 
research study participants treated with MDMA. Diversion is not an issue for sponsor-
supported studies because MDMA is only administered under the supervision of the 
clinical investigator and no take-home doses are permitted. MDMA administration and 
handling follows all regulations pertaining to the use of controlled substances within 
research studies. 
 
Studies assessing prevalence of problematic Ecstasy use or dependence suggest that a 
small percentage of individuals, especially those with prior psychological difficulties, 
may develop problematic Ecstasy use or dependence. An observational long-term follow-
up assessment conducted at least 12 months after participation in a MAPS-sponsored 
early Phase 2 PTSD study of MDMA-assisted therapy found that 8.7% (8 of 92) 
participants reported using Ecstasy subsequent to study participation, with 6 of these 8 
participants having used Ecstasy prior to study enrollment. Several participants 
volunteered that they would not seek out MDMA outside of a psychotherapeutic setting. 
10.0 Safety 
10.1 Adverse Events 
In accordance with guidance for the specific study site, Health Canada Clinical Safety 
Data Management Definitions and Standards for Expedited Reporting International 
Conference on Harmonization (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 
and clinically significant physical exam finding, laboratory finding, ECG result, or vital 
sign), 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.  
 


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Events related to planned treatments or physician visits for Baseline conditions collected 
in the medical history will not be collected, unless there is an exacerbation of the 
condition, in which case they will be actively followed until resolution.
 
An unexpected AE is one that is not listed in the current IB or an event that is by nature 
more specific or more severe than a listed event.
 
The site physician will be responsible for reviewing and confirming all AEs and SAEs 
collected during the study. The therapy pairs will collect AEs during study visits from 
Enrollment (Visit 0) through Study Termination (Visit 20). Participants will be asked 
directly how they are feeling during each contact, and AEs may be captured 
spontaneously during therapy sessions, telephone calls, or other correspondence. 
Completed measures may create suspicion that an AE occurred; in this case, the site staff 
should follow-up with the participant. 
 
All AEs will be monitored by the therapy pair until resolution or, if the AE becomes 
chronic, a cause can be identified. If an AE is unresolved when a participant terminates 
from the study, a clinical assessment will be made by the site physician, investigator, 
and/or Medical Monitor as to whether continued follow-up of the AE is warranted.
 
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. 
10.1.1 Adverse Events of Special Interest 
In accordance with the guidance for a specific study site location, 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 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  
 
suicidal ideation assessed as a 4 or 5 on the C-SSRS  
 
suicidal ideation judged to be serious or severe in the opinion of the investigator.  


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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 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.
 
10.1.2 Serious Adverse Events
In accordance with guidance for the specific study site, Health Canada Clinical Safety 
Data Management Definitions and Standards for Expedited Reporting ICH Topic E2A: 
Guidance for Industry or FDA Safety Reporting Requirements for INDs and BA/BE 
Studies, an SAE is defined as any untoward medical occurrence that at any dose:
 
Results in death. 
 
Is life-threatening (i.e., the participant was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
 
Requires or prolongs inpatient hospitalization. 
 
Results in persistent or significant disability/incapacity (i.e., the event causes substantial 
disruption of a person’s ability to conduct normal life functions). 
 
Results in a congenital anomaly/birth defect. 
 
Requires intervention to prevent permanent impairment or damage. 
 
Is an important and significant medical event that may not be immediately life-
threatening or resulting in death or hospitalization, but based upon appropriate medical 
judgment, may jeopardize the participant or may require intervention to prevent one of 
the other outcomes listed above. 
 
AEs which do not fall into these categories are defined as non-serious. It should be noted 
that a severe Adverse Event need not be serious in nature and that a SAE need not, by 
definition, be severe. 
 
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, 


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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. 
 
10.2 Other Significant Events
Significant life events that may occur during the course of the study, including death of a 
loved one, loss of employment, or other hardship, may have an impact on treatment 
outcome. The sponsor will capture these life events using the LEC-5 measure. Such 
events will be entered as Comments in the eCRF and if appropriate, described in the Case 
Study Report for data outliers, if any. 
 
10.3 Pregnancy 
10.3.1 Definition of Able to Become Pregnant
A participant is considered able to become pregnant if they were assigned female at birth 
and are post-menarche. A participant is considered not able to become pregnant if they 
are premenarchal, surgically sterile (documented hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy, and/or tubal ligation), permanently sterile by medical device 
such as Essure, postmenopausal, or assigned male at birth.  
 
10.3.2 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 


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o
The reliability of abstinence should be evaluated carefully with the participant in 
relation to their general lifestyle. An additional acceptable birth control method 
should be discussed with the participant in case they decide to engage in penile-
vaginal intercourse during the course of the study. 
 
For questions about acceptable birth control methods, contact the Medical Monitor.
 
10.3.3 Follow-up Requirements
Details of all pregnancies in study participants will be collected after Enrollment (Visit 0) 
and collected through 10 days after the last Experimental Session. Pregnancies should be 
reported to the sponsor via telephone or email within 24 hours of site staff awareness.
 
In the event of a pregnancy, the participant will discontinue Experimental Sessions but 
may continue with non-drug Integrative Sessions, the next CAPS-5 assessment, and 
Study Termination procedures. At a minimum, prior to withdrawal from the study, efforts 
should be made to assess the final CAPS-5 immediately and complete Study Termination 
procedures. The participant will be emergency unblinded if the participant wishes as 
described in Section 8.4 Blinding, 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. 
 
10.4 Medical Monitor
The name and contact information for the Medical Monitor is:  
 
Alia Lilienstein, M.D., M.P.H.
Medical Director
Email: alia@mapsbcorp.com
Telephone: 877-748-3767
Medical Monitor contact information will also be provided in a separate contact list. 
11.0 Concomitant Medications
11.1 Tapering Instructions
The site physician will record concomitant medications during Screening. If the 
prospective participant is being treated with psychiatric medications at enrollment, the 
prospective participant will be encouraged to discuss medication tapering with their 
outside treating physician, if any, and will be required to give the site physician 
permission to do so as well. Additionally, participants who are taking prohibited opiates 
will be cross-tapered to an allowable opiate (hydrocodone, morphine, and codeine) under 
the care of their prescribing physician.


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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 11.2 Allowable Concomitant Medications). The 
prescribing physician’s opinion about medication discontinuation will be documented 
either in writing from the prescribing physician, or in writing by the site physician 
documenting phone contact with the prescribing physician. Tapering will follow a time 
course appropriate for the medication based on its half-life, with the Baseline CAPS-5 T1 
(Visit 3) scheduled to occur after complete washout for psychoactive medications and 
Experimental Session 1 (Visit 5) scheduled to occur after complete washout for 
medications with drug-drug interactions without a psychological concern (five half-lives 
plus at least 1 week for stabilization).
 
The therapy pair will request information about any changes in medication at each 
contact. The site physician will be responsible for reviewing and confirming all 
medications collected during the study. 
 
All medications, non-prescription and prescription, will be collected from Screening 
through 7 days after the last Experimental Session. From 7 days after the last 
Experimental Session through Study Termination, only prescription or non-prescription 
medications taken to treat AEs will be collected. Throughout the protocol, all medications 
used to treat AEs will be collected, and all changes including discontinuations or 
additions to medications will be collected. The study team will also inquire about 
concomitant medication adherence and document all information on the Concomitant 
Medications eCRF. 
 
Participants may return to taking psychiatric medications and discontinue birth control 
after the final Study Termination visit if necessary. 
 
11.2 Allowed Concomitant Medications 
The site physician may prescribe necessary and appropriate medications in accordance 
with local and state regulations during the study to treat AEs that do not respond to other 
management outlined in the Treatment Manual. Examples include concomitant 
benzodiazepines for uncontrolled anxiety (for example, lorazepam at modest doses and 
occasional use only to avoid withdrawal effects of discontinuation between Experimental 
Sessions) or sleep aids (excluding trazodone) in compliance with Section 11.3 Prohibited 
Medications.  
 
Gabapentin or certain opiates will be allowed when prescribed for pain management. The 
following opiates will be allowed during the study: hydrocodone, morphine, and codeine. 
Prior to randomization, participants who are taking opiates not included on this list will 
be cross-tapered to an allowable opiate under the care of their prescribing physician. 
Opiate medications may reduce the efficacy of MDMA and may prolong QT/QTc 
interval, but the opiates that are allowed during this trial have been selected because they 
have the lowest potential for QT/QTc interval prolongation 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 


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administration at the Experimental Session to 24 hours after. During this period, the 
participant will be allowed to take the medication if needed for intolerable pain flare-ups 
or to prevent withdrawal symptoms. If a participant reports lack of analgesic effect during 
the sub-acute period following each Experimental Session, the site physician may 
approve taking an allowed opiate medication sooner than 24 hours after IMP 
administration. 
 
If the participant is on stimulants for attention deficit/hyperactivity disorder (ADHD) at 
Baseline, they can continue to use them at the same dose and frequency, as long as they 
discontinue five half-lives before each Experimental Session and do not restart for 10 
days after each Experimental Session.
 
All psychoactive medications, herbal supplements, nonprescription medications, and 
prescription medications must be reviewed by the research team 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.
 
11.3 Prohibited Medications
To be enrolled in the study, participants must: 
 
 
Refrain from the use of any psychoactive medication not approved by the research team 
from Baseline through Study Termination (with the exception of gabapentin or certain 
opiates for pain control). 
 
Be willing to comply with all medication requirements per protocol. Medications will 
only be discontinued after enrollment per clinical judgment of the site physician in 
consultation with the prescribing physician. 
 
Agree that, for 1 week preceding each Experimental Session they will refrain from: 
o Taking any specified herbal supplement (except with prior approval of the 
research team). 
 
Agree that, for 5 half-lives of the medication preceding each Experimental Session they 
will refrain from: 
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). 
 
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 


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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.
 
12.0 Clinical Laboratory Assessments
The site physician will confirm laboratory assessments gathered in screening for 
assessing eligibility. The site physician will use a list of normal ranges to conclude 
whether participants are eligible for the protocol and will indicate justification for 
admitting participants with abnormal values after consultation with the Medical Monitor. 
 
The following laboratory assessments will be performed as a part of Screening:  
 
 
Serum electrolytes and metabolic profile 
o Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) 
o Albumin:globulin (A:G) ratio 
o Albumin, serum 
o Alkaline phosphatase, serum 
o Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase 
(SGOT) 
o Bilirubin, total 
o Blood urea nitrogen (BUN): creatinine ratio 
o Calcium, serum 
o Carbon dioxide 
o Chloride, serum 
o Creatinine, serum 
o C-reactive protein (CRP) 
o Globulin, total 
o Glucose, serum 
o Potassium, serum 
o Protein, total, serum 
o Sodium, serum 
 
Complete Blood Count (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 


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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 who are able to become pregnant will be 
performed at the site 
 
Urinary drug test will be performed at the site 
 
Laboratory assessments, with the exception of urine pregnancy and drug tests, will be 
performed at the nearest clinical laboratory to the site. Clinical laboratories for each site 
will be specified in a separate document. Certificates and normal ranges will be stored in 
the site’s Investigator Site File (ISF).
 
13.0 Statistical Considerations 
Key personnel, MAPS, and the biostatistician will agree on a Statistical Analysis Plan 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.
13.1 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 


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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 13.2.3) occurring after 60% of the mITT participants have completed a final 
assessment of the Primary Outcome (Visit 19) and terminated treatment. 
13.2 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 
 
Not Per Protocol (NPP): all participants who are included in the mITT Set but not the 
PP Set 
 
Safety: all participants who receive any IMP  
 
13.2.1 Efficacy Analyses
13.2.1.1 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 therapy 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 
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13.2.1.2 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 in a similar manner to the primary endpoint. 
Details of analysis are described in the Statistical Analysis Plan.
 
13.2.1.3 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.
13.2.2 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 


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will be presented using descriptive statistics of C-SSRS scores in tabular format. Vital 
signs (heart rate, blood pressure, and body temperature) for Experimental Sessions will 
be summarized using descriptive statistics in tabular format listing values at pre-IMP 
administration, prior to the supplemental dose, and at the end of each Experimental 
Session by treatment group. Additional details are available in the Statistical Analysis 
Plan.
13.2.3 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). 
 
Following the DMC review of the MAPP1 results, the iDMC may recommend changes to 
the purpose and criteria of the interim analysis. For instance, the iDMC may recommend 
adding an efficacy interim analysis executed at a specific number of subjects with 
primary endpoint data. Regardless of the iDMCs suggested changes, overall type-I error 
will be preserved.    
 
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 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.
 
13.3 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 


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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 and make recommendations as necessary. The 
objective of the DMC safety review is to monitor the safety of the subjects enrolled and 
to be enrolled in the study. The DMC may also review the results of MAPP1 and make 
recommendations on updating the adaptive design elements to the study protocol, interim 
analysis, and/or data analysis of the MAPP2 study. 
 
A single representative within MAPS will be designated to receive written 
communication of recommendations following 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 the case that additional participants must 
be enrolled to ensure this is not disclosed to the outside community.
 
14.0 Study Governance 
The sponsor, MAPS, holds the IND for MDMA and is responsible for funding the 
Clinical Development Program. The sponsor has delegated the primary responsibility of 
trial organization to 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. 
 
14.1 Ethics
This clinical study was designed and shall be implemented and reported in accordance 
with the International Conference on Harmonisation (ICH) Guidelines for Good Clinical 
Practice (GCP), with applicable local regulations (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 


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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. 
 
14.1.1 Financial Disclosure 
Investigators will adequately and accurately disclose financial interests to the sponsor 
prior to study start, during the study if financial interests change, and 1 year after study 
completion. The sponsor will submit necessary disclosures to the appropriate regulatory 
bodies.
14.1.2 Informed Consent
The investigator and therapy 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 pair that will treat 
the participant. Information about the study must be given orally and in an 
understandable written ICF. The informed consent discussion must be conducted by a 
person who is qualified according to federal, state, or local regulations. The participant 
should have the opportunity to inquire about details of the study and to consider 
participation.
 
The therapy pair may meet with the potential participant via telemedicine for ICF review 
and signing prior to in person screening if necessary for scheduling of screening 
activities. If this is completed by telemedicine visit, the pair will ensure the ICF is 
thoroughly explained and reviewed just as it would be at an in-person visit. If the 
potential participant is still interested after review, they will sign the consent during that 
telemedicine visit. The participant will then bring their signed copy of the ICF to their 
next in person visit where study staff will then counter sign the ICF, copy the ICF for the 
participant and file the original at the site. The signature may instead be obtained using an 
electronic 21 CFR Part 11 compliant system due to COVID-19. 
 
In addition to the explanation of study visits, the information should include that access 
to original medical records and processing of coded personal information must be 
authorized. A written release is needed to give permission to site staff to request and view 
the participant’s medical records to assess protocol eligibility, if needed. Information 
necessary for protocol participation includes past medical history, psychiatric interview, 
physical examination, and clinical laboratory tests. 
 
Eligible participants may only be included in the study after signing the IRB approved 
ICF. Informed consent must be obtained before conducting any study-specific procedures 
(i.e., all of the procedures described in the protocol beyond phone screening). The 
process of obtaining informed consent should be documented in the participant’s source 
records. The study staff will provide a copy of the signed ICF to the participant and will 
maintain the original in the ISF. 
 


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The written ICF and any other written information to be provided to participants should 
be revised whenever important new information becomes available that may be relevant 
to the participant’s consent. Any revised ICF and written information should receive 
approval from an IRB before use. The participant should be informed in a timely manner 
if new information becomes available that may affect the decision to take part or continue 
in the study. The communication of this information should be documented. Participants 
can withdraw consent at any time without prejudice. If a participant withdraws consent 
but does not revoke the Health Insurance Portability and Accountability Act (HIPAA) 
authorization, the study team will have full access to their medical records, including 
termination visit information. If a participant revokes only the HIPAA authorization, the 
study team will have full access to all medical records prior to the date and time of 
revocation.
 
If a participant fails Screening and is rescreened at a later date, a new copy of the ICF 
should be signed.
14.2 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 5.4. 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.  
 
14.2.1 Source Records 
Source records contain all primary evidence of existence of the participant and document 
all study procedures. Source records include but are not limited to medical records, 
measures, checklists, notes, emails, and laboratory reports. All data reported in the eCRF 


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are transcribed from primary source documents and must be consistent. These documents 
are maintained at the study site securely. Source records of CAPS-5 assessments will be 
stored in dedicated limited access files during the study. 
 
14.3 Confidentiality
Every effort will be made to strictly safeguard the confidentiality of participants. Despite 
this, privacy cannot be guaranteed. Removing identifying information from data and 
restricting access to researchers directly involved in assessing the participants should 
prevent the dissemination of confidential data. 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. 
 
Maintaining data in a secure environment will prevent the accidental or deliberate 
examination or removal of data. The sponsor will utilize confidentiality procedures to 
assure participant privacy. Audiovisual recordings are necessary for sponsor oversight of 
therapy processes. Any requests for use of audiovisual recordings outside of research and 
training requests will result in participants receiving information on the request. 
Participants will have control over any presentation of audiovisual recordings beyond 
viewing by authorized researchers, sponsor staff, or regulatory agencies. The sponsor 
uses encrypted, secure technology to transfer and store recordings, but there is always a 
risk of a security breach. The sponsor is committed to taking preventative measures to 
avoid such an event. In the case of a security breach, the participant will be notified, and 
all efforts will be made to minimize the dissemination of recorded content. 
 
Clinical trial data other than audiovisual recordings will be hosted on an EDC system that 
is FDA-compliant. All data entered into this system will be de-identified. Participants 
will only be referred to by numbers and a secondary identifier code. Source Records and 
identifying information will be retained at clinical sites per GCP. The sponsor will train 
the study staff on EDC procedures. Each study staff member with access to the data will 
be given an individual password.
 
The sponsor has developed a feature that will allow participants to create a password and 
enter their self-report questionnaire data directly into Medrio using the electronic 
Participant Reported Outcome (ePRO) feature. Participants will be reminded by email to 
enter the data. Participant emails will be treated as Protected Health Information (PHI) in 


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the database. Participants will receive a welcome email and reminder emails to ensure 
that they provide all necessary data.
 
14.4 Costs to Participants
There will be no costs to the study participants for participation. The sponsor will cover 
all direct costs of study procedures required for participation, including any assessments 
or tests performed solely for the purpose of establishing eligibility for participation. 
Charges for treatment of a participant’s condition that are unrelated to the research study 
or any unrelated procedures will not be covered by the sponsor. 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.  
 
14.5 Treatment and Compensation for Study Related Injury 
If a participant becomes sick or injured during the study, they should call the site 
physician. Some study-related injuries or sickness 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 injury, sickness, or emergency would first be billed to a 
participant’s health insurance provider, if the participant has health insurance. If the 
participant's private or employer health insurance plan does not cover clinical trial-related 
claims that occurred during the course of the study, or the participant does not have 
health insurance, then the sponsor will cover any treatment costs directly related to the 
study. To cover these costs, the sponsor carries third-party insurance.  
 
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.  
 
 
14.6 Record Retention 
Investigators must retain all study records required by the sponsor and applicable ICH-
GCP, 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. 
 


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14.7 Publication Policy
The sponsor recognizes the importance of communicating medical research and scientific 
data and their obligations to participants enrolled in a study and therefore, encourage 
publication of such material in reputable scientific journals and at professional and/or 
academic seminars or conferences. For multi-center studies, it is intended that the first 
publication of the study’s primary clinical data be co-authored by designated 
participating centers and the sponsor or designated representatives. Inclusion of Clinical 
Investigators in the authorship of any multi-center publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or 
critically revising any manuscript(s) derived from the Study. All publications will follow 
ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of 
Scholarly Work in Medical Journals, unless other guidelines are required by the journal. 
It is understood by the Clinical Investigators that the information generated in this study 
will be used by the sponsor in connection with the development of the IMP and therefore 
may be disclosed to government agencies in various countries. To allow for the use of 
information derived from the study, it is understood that the investigators are obliged to 
provide the sponsor with complete test results, all study data, and access to all study 
records. It is mandatory that all data analysis is done on the official monitored sponsor 
database and that the analysis plan is agreed upon with the sponsor statistician. 
 
Any results of medical investigations with the sponsor and/or 
publication/lecture/manuscripts based thereon shall be exchanged and discussed by the 
investigator and sponsor prior to submission for publication or presentation. Due regard 
shall be given to the sponsor's legitimate interests, e.g., manuscript authorship, obtaining 
optimal patient protection, coordinating and maintaining submissions to health 
authorities, and coordinating with other ongoing studies in the same field. The full details 
of the processes of producing and reviewing reports, manuscripts, and presentations 
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Appendix A: Sub-study without Overnight Stays 
Rationale 
 
This sub-study to the MAPP2 protocol “A Randomized, Double-Blind, Placebo-
Controlled, Multi-Site Phase 3 Study of the Efficacy and Safety of Manualized MDMA-
Assisted therapy for the Treatment of Posttraumatic Stress Disorder of Moderate or 
Greater Severity" allows participants to be discharged in the evening after the 
Experimental Session is over at select investigational study sites. In MAPS’ Phase 2 
study MAA1, which tested the safety and efficacy of MDMA-assisted therapy 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 pair or study physician.  
 
Medically-trained Night Attendants have not been required for any of the five Phase 2 
studies of MDMA-assisted therapy 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 9.2.2.2. 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 pair, 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. 
 


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Consistent with the main study protocol and the sub-study, proper preparation and 
follow-up support will reduce the difficulties participants might have with acute or sub-
acute reactions. The potential for destabilizing psychological distress will be minimized 
by:
 
Excluding people who might be more vulnerable to it (such as people diagnosed with 
bipolar affective disorder type 1 or with psychotic disorders). 
 
Excluding people who do not have a stable living situation or supportive family/network. 
 
Preparatory Sessions of non-drug therapy before the Experimental Session. 
 
Creating an atmosphere of trust during the Experimental Session. 
 
Close monitoring. 
 
Phone contact with participants during the week after the Experimental Session. 
 
Conduct of Integrative Session on the morning after the Experimental Session. 
 
Specific to sub-study:
 
Therapist phone contact with participants on the night of the Experimental Session. 
 
A support person identified by the participant and agreed upon by the therapist must stay 
with the participant overnight on the evening following the Experimental Session. 
 
The therapists will meet with the support person prior to the first Experimental Session to 
assess their ability to act as an appropriate support person and to give them instructions 
about what to expect following Experimental Sessions and how to contact study 
personnel if needed. 
 
A support person must assist the participant during transfer from study site after the 
Experimental Session and to the study site on the following morning for the Integrative 
Session. This Integrative Session will start later in the day to allow for logistics of 
transportation. Participants can arrange their own transportation after the Integrative 
Session. 
  
Implementation of Sub-study
 
All eligibility criteria from the main study protocol will apply, except for the following 
inclusion criteria listed as a Lifestyle Modification:
Post Experimental Session
 
Are willing to remain overnight at the study site after each Experimental Session until 
after the Integrative Session the next morning (for exceptions see Appendix A sub-study) 
 
Agree not to drive after the Experimental Sessions until after the Integrative Session the 
next morning. 
 
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. The Integrative Session may happen remotely if approved by the research team. 
 


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Screening & Preparatory Periods
 
During the Screening and Preparatory Period, the participant will identify an appropriate 
support person to stay with the participant on the evening of the Experimental Session. 
Participants will be escorted to and from the study site after Experimental Sessions. The 
support person is not required to be the same as the escort for the participant. There may 
be more than one support person(s), and they will be responsible for providing 
companionship as needed overnight and contacting the study team with any questions or 
concerns. Any support person spending the night with the participant will meet the 
therapy pair, 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 therapy pair 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 therapy pair in person. The support 
person will receive printed instructions, including contact information of the study 
physician, therapists, investigator, and Study Coordinator and what to do in the case of an 
emergency.  
 
The support person will not provide therapy 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 pair 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. 
 


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End of Experimental Sessions 
 
Consistent with the main protocol, at the end of each Experimental Session, the therapy 
pair and site physician will assess the participant to decide if they are physically and 
emotionally stable. If the participant is not stable, the therapy pair 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 pair at the end of the Experimental Session, the participant will be escorted home 
via car, rideshare, or public transportation and will not remain overnight at the study site. 
The support person will be provided with an instruction sheet including how to contact 
the Clinical Investigator, Site Physician, and/or therapy pair 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 pair when they arrive where they 
will stay for the night. If the therapy pair 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 pair 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 pair 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 pair will also discuss this with the 
participant during the Preparatory and Experimental Sessions. The therapy pair 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 pair. The 
therapy pair 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 pair 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 pair in 
accordance with site SOPs. If the participant will not be leaving the site for the night, the 
therapy pair will call the support person(s) to inform them and arrange appropriate 
transportation following the Integrative Session on the following day if appropriate.
 


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Sub-Study Objective & Evaluation
 
The primary objective of this sub-study will be to evaluate the feasibility of conducting 
MDMA-assisted therapy 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 select 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.
 
 
 
 


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References
 
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IND #063384 
 
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35. 
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44. 
Stolaroff, M., The Secret Chief Revealed: Conversations with a pioneer of the 
underground therapy movement. 2004, Sarasota FL: Multidisciplinary 
Association for Psychedelic Studies. 
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Greer, G.R. and R. Tolbert, A method of conducting therapeutic sessions with 
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Shulgin, A.T. and D.E. Nichols, Characterization of three new psychotomimetics, 
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Vollenweider, F.X., et al., Psychological and cardiovascular effects and short-
term sequelae of MDMA ("ecstasy") in MDMA-naive healthy volunteers. 
Neuropsychopharmacology, 1998. 19(4): p. 241-51. 


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52. 
Grinspoon, L. and J.B. Bakalar, Can drugs be used to enhance the 
psychotherapeutic process? Am J Psychother, 1986. 40(3): p. 393-404. 
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Adamson, S., Through the gateway of the heart: Accounts of experiences  With 
MDMA and other empathogenic substances. 1985, San Francisco CA: Four Trees 
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Shulgin, A. and A. Shulgin, Pihkal: A Chemical Love Story. 1st ed. 1991, 
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Downing, J., The psychological and physiological effects of MDMA on normal 
volunteers. J Psychoactive Drugs, 1986. 18(4): p. 335-40. 
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Greer, G. and R. Tolbert, Subjective reports of the effects of MDMA in a clinical 
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Grob, C.S., et al., Psychobiologic effects of 3,4-methylenedioxymethamphetamine 
in humans: methodological considerations and preliminary observations. Behav 
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Grob, C., MDMA research: preliminary investigations with human subjects. Int J 
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Mithoefer, M.C., et al., Durability of improvement in post-traumatic stress 
disorder symptoms and absence of harmful effects or drug dependency after 3,4-
methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-
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61. 
Oehen, P., et al., A randomized, controlled pilot study of MDMA (+/- 3,4-
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resistant, chronic Post-Traumatic Stress Disorder (PTSD). J Psychopharmacol, 
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Chabrol, H. and P. Oehen, MDMA assisted psychotherapy found to have a large 
effect for chronic post-traumatic stress disorder. J Psychopharmacol, 2013. 27(9): 
p. 865-6. 
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Posner, K., et al., Columbia Classification Algorithm of Suicide Assessment (C-
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Posner, K., et al., The Columbia-Suicide Severity Rating Scale: initial validity and 
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Sheehan, D.V., et al., The Mini-International Neuropsychiatric Interview 
(M.I.N.I.): the development and validation of a structured diagnostic psychiatric 


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interview for DSM-IV and ICD-10. J Clin Psychiatry, 1998. 59 Suppl 20: p. 22-
33;quiz 34-57. 
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SAP_001.pdf: 
 
 
MAPP2 Statistical Analysis Plan 
 
Version 1: 1 May 2019 
Version 2: 22 Jan 2020 
Version 3: 10 Jun 2020 
 Version 4: 06 Sep 2022 
 
 
SPONSOR 
Multidisciplinary Association for Psychedelic Studies 
(MAPS) 
3141 Stevens Creek Blvd #40563 
San Jose, CA, 95117 
 
SPONSOR 
REPRESENTATIVE 
Rick Doblin, Ph.D. 
Executive Director, MAPS 
 
SPONSOR DELEGATE & 
TRIAL ORGANIZER 
MAPS Public Benefit Corporation (MPBC) 
3141 Stevens Creek Blvd #40547 
San Jose, CA, 95117 
 
SPONSOR DESIGNEE 
Amy Emerson 
Chief Executive Officer, MPBC 
Email: amy@mapsbcorp.com 
 
MEDICAL MONITOR(S) 
Sara Garcia Velaszquez, M.D.,  
STATISTICIAN(S) 
Scott Hamilton, Ph.D. 
PREPARED BY 
Scott Hamilton, Ph.D. 
Claire Le Lait, M.S. 
 
USE 
In conjunction with relevant FDA, HC, MOH guidance 


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IND #063384 
 
Version 4: 06 Sep 2022 
 
Page 2 of 31 
Table of Contents 
List of Tables ................................................................................................................................... 3 
List of Figures ................................................................................................................................. 4 
List of Abbreviations ...................................................................................................................... 5 
1.0 Definitions of Terms ................................................................................................................. 6 
2.0 Introduction .............................................................................................................................. 7 
3.0 Study Objectives ....................................................................................................................... 7 
3.1 Primary Objective ................................................................................................................... 7 
3.2 Secondary Objective ............................................................................................................... 8 
3.3 Safety Objectives .................................................................................................................... 8 
3.4 Exploratory Objectives ........................................................................................................... 9 
4.0 Measures .................................................................................................................................... 9 
5.0 Study Design .............................................................................................................................. 9 
6.0 Randomization and Blinding ................................................................................................. 13 
7.0 Sample Size and Power Considerations ................................................................................ 13 
8.0 Analyses ................................................................................................................................... 14 
8.1 Analysis Sets ......................................................................................................................... 14 
8.2 Missing Data Handling ......................................................................................................... 15 
8.2.1 Partial or Missing Dates ................................................................................................ 15 
8.3 Protocol Deviations .............................................................................................................. 16 
8.4 Baseline Values .................................................................................................................... 16 
8.5 Participant Disposition ......................................................................................................... 16 
8.6 Demographics and Baseline Characteristics ......................................................................... 16 
8.7 Medical History and Substance Use ..................................................................................... 16 
8.8 Efficacy Analyses ................................................................................................................. 16 
8.8.1 Primary Efficacy Analyses ............................................................................................ 17 
8.8.2 Supportive Analyses: ..................................................................................................... 18 
8.8.3 Key Secondary Efficacy Analyses................................................................................. 21 
8.8.4 Responder Analyses....................................................................................................... 22 
8.9 Safety Analyses .................................................................................................................... 25 
8.9.1 Analysis of Exposure ..................................................................................................... 25 
8.9.2 Analysis of Adverse Events ........................................................................................... 25 
8.9.3 Concomitant Medications .............................................................................................. 26 
8.9.4 Analysis of C-SSRS ....................................................................................................... 26 
8.9.5 Analysis of Vital Signs .................................................................................................. 27 
8.10 Administrative Interim Analysis......................................................................................... 28 
8.11 Subgroup Analysis .............................................................................................................. 30 
9.0 Data Monitoring Committee .................................................................................................. 30 
10.0 Timing of Analyses ............................................................................................................... 30 
11.0 References .............................................................................................................................. 31 
 
 


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Version 4: 06 Sep 2022 
 
Page 3 of 31 
List of Tables 
 
Table 1: Protocol Objectives and Assessment Tools ........................................................................ 9 
Table 2: Phase 3 Dose Regimen of MDMA or Placebo ................................................................... 9 
Table 3: Schedule of Events ........................................................................................................... 10 
Table 4: Proposed Estimands and Key Attributes .......................................................................... 18 
Table 5: Inference of Treatment Effect for Missing Data from mITT Set Based on Reasons for 
Post-Randomization Withdrawal ............................................................................................ 20 
Table 6: Shift Table Vital Sign Categories ..................................................................................... 28 
Table 7: Observed Effect Sizes and Corresponding Sample Size for 90% Conditional Power 
Guidance at the Interim Analysis (N=60) ............................................................................... 29 
 
 


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Version 4: 06 Sep 2022 
 
Page 4 of 31 
List of Figures 
 
Figure 1: CONSORT for PTSD CAPS-5 Responder Analysis After Treatment ........................... 23 
Figure 2: CONSORT for PTSD SDS Responder Analysis After Treatment ................................. 24 
 
 


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Version 4: 06 Sep 2022 
 
Page 5 of 31 
List of Abbreviations 
 
ACE  
Adverse Childhood Experiences Questionnaire 
AE  
 
Adverse Event 
AESI  
Adverse Event of Special Interest 
ATC  
Anatomical Therapeutic Chemical  
AUDIT 
Alcohol Use Disorders Identification Test 
BDI-II              Beck Depression Inventory-II 
BMI 
 
Body Mass Index 
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 
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 
IWRS  
Interactive Web Randomization System 
LEC-5  
Life Events Checklist 
LS 
 
Least Squares 
MAPS  
Multidisciplinary Association for Psychedelic Studies 
MAR  
Missing at Random 
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 
PP  
 
Per Protocol 
PSQI   
Pittsburgh Sleep Quality Index 
PT 
 
Preferred Terms 
PTSD   
Posttraumatic Stress Disorder 
REML  
Restricted Maximum Likelihood 
SAE 
 
Serious Adverse Event 


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Version 4: 06 Sep 2022 
 
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SAP 
 
Statistical Analysis Plan 
SCS 
 
Self-compassion Scale 
SDS 
 
Sheehan Disability Scale 
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 
 
 
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 Investigational Product 
 


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Page 7 of 31 
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 
 
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 Posttraumatic Stress 
Disorder of Moderate or Greater Severity.” 
 
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 therapy 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 moderate or 
greater severity of PTSD, the sponsor is conducting this Phase 3 randomized, placebo-
controlled, double-blind, multi-site study with three monthly Experimental Sessions of 
therapy combined with either MDMA or placebo, along with 12 non-drug therapy 
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 
therapy for PTSD compared to identical therapy with inactive placebo, as measured by 


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Page 8 of 31 
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 
therapy for PTSD compared to identical therapy 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 therapy. The following safety objectives will evaluate the safety of 
MDMA-assisted therapy compared to identical therapy 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 
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 Study 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 median changes in blood pressure, heart rate, and body temperature from pre-IP 
administration to end of each Experimental Session by treatment group 
 


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3.4 Exploratory Objectives 
The study protocol describes additional objectives that may be explored to characterize 
participants receiving MDMA-AT in comparison to those receiving therapy with inactive 
placebo to support the primary objective. These objectives may be assessed at future 
timepoints for post hoc analyses or exploratory publications and therefore will not be 
included in the present analysis plan. 
4.0 Measures 
Table 1: Protocol Objectives and Assessment Tools 
Objectives 
Measure 
Measure Type 
Administration 
Eligibility 
Assess Axis 1 psychiatric disorders 
MINI 
Eligibility 
Site 
Assess Axis 2 personality disorders 
SCID-5-PD 
with SCID-
5-SPQ 
Eligibility 
Telemedicine/ 
self-report 
measure at Site 
Confirm PTSD diagnosis and severity 
PCL-5 with 
LEC-5 
Eligibility 
Site 
Identify dissociative disorders  
 
 
 
 
Dissociative 
Disorders 
Interview 
Schedule 
(DDIS) 
Eligibility 
Site 
Primary 
Assess changes in PTSD symptom severity 
from Visit 3 to Visit 19 compared between 
groups 
CAPS-5 
Outcome 
Telemedicine 
Key Secondary 
Assess mean changes in clinician-rated 
functional impairment from Visit 3 to Visit 19 
compared between groups 
SDS 
Mean item 
scores 
Outcome 
Site 
Safety 
Compare relative incidence of positive or 
serious ideation and suicidal behavior 
between groups 
C-SSRS 
Safety 
Site 
 
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 tolerability issues emerge or the participant declines. 


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Table 3: Schedule of Events 
Study Procedures 
Screening Period 
(2-6 weeks) 
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 3 wks 
(-2/+1 wks) 
2 days post 
Screen 
(+7 days) 
2 days post SCID 
(+5 days) 
Within 1 wk 
of V0 (±5 
days) 
Within 3 wks 
of V1 
Post V2 & 
Taper 
Within 6 days of V3 
Initial Phone Screen 
 
 
 
 
 
 
 
 
Informed Consent 
Send Copy 
 
 
 
 
 
 
 
Follow-up Phone Screen 
 
 
 
 
 
 
 
 
Assess Eligibility 
 
 
 
 
 
 
 
 
Medical/Psychiatric History 
 A 
 
 
 
 
 
 
 
Past/Current Medication & Adherence 
 
 
 
 
 
 
 
 
Weight, Resting Vitals 
 
 
 
 
 
 
 
 
Physical Exam  
 
 
 
 
 
 
 
 
ECG & Rhythm Strip 
 
 
 
 
 
 
 
 
Clinical Lab Tests, BAC, HIV Test 
 
 
 
 
 
 
 
 
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 
18 weeks (±3 wks) 
post Baseline 
 
Treatment 1 
Treatment 2 
Treatment 3 
Primary 
Outcome 
Study 
Termi-
nation 
Visit 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
Visit Description 
Exp. 1 
Int. 1.1 
Int. 
1.2 
CAPS-5 
T2: Tele- 
medicine 
Int. 1.3 
Exp. 2 
Int. 2.1 
Int. 
2.2 
CAPS-5 
T3: Tele- 
medicine 
Int. 2.3 
Exp. 3 
Int. 3.1 
Int. 3.2 
Int. 3.3 
CAPS-5 
T4 
Outcome: 
Tele-
medicine I 
Study 
Termi-
nation 
Visit Timing 
Within 
1 wk of 
V3 
Morn-
ing 
after 
V5 
With-
in 2 
wks 
of V5 
Within 4 
wks of V5 
1-7 
days 
before 
V10 
Within 
4 wks 
of V5 
(±1 
wk) 
Morn-
ing 
after 
V10 
With-
in 2 
wks 
of 
V10 
Within 4 
wks of 
V10 
1-7 days 
before 
V15 
Within 
4 wks 
of V10 
(±1 
wk) 
Morn-
ing 
after 
V15 
Within 
2 wks 
of V15 
Within 
4 wks 
of V15 
8 wks 
post V15 
(±1 wk) 
2 days 
post 
V19 
(-1/+7 
days) 
Past/Current 
Medication & 
Adherence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Screen  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All AEs C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Container 
Assignment E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer IP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8-hour Exp. 
Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BP, Pulse, 
Temperature F 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 G 
Overnight Stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
90-min Integrative 
Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Call 
Follow-up H 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C  All Adverse Events (AEs) includes collecting Serious Adverse Events, AEs of Special Interest, AEs of Psychiatric Status, AEs requiring medical advice or attention, AEs that 
indicate withdrawal of a participant, and all other AEs  E  Randomize 24 to 48 hours prior to first Experimental Session; obtain container assignment 24 to 48 hours prior to each 
Experimental Session  F During Experimental Sessions, vitals are measured before Investigational Product administration, immediately before the supplemental dose is administered 
(or would be, if supplemental dose not given), and approximately 8 hours after initial dose, and as needed  G At Study Termination, only blood pressure needs to be measured            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 


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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 
 
 
✓ 
 
 
 
✓ 
 
 
 
✓ 
 
 
 
 
✓ 
 
C-SSRS B 
10 
✓ 
✓ 
 
 
C 
 
 
 
C 
 
 
 
C 
 
 
 
 
MINI 
15 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-SPQ 
20 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-PD 
60 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PCL-5 
8 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LEC-5 
5 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DDIS D 
 
5 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACE 
4 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI-II 
10 (Baseline) 
5 (all others) 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPGS 
5 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
DSP-I 
 
15 
 
 
✓ 
 
 
 
✓ 
 
 
 
✓ 
 
 
 
 
✓ 
 
EQ-5D-5L 
3 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
IASC 
15 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
IPF 
10 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSQI 
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 
95 
 
20 
10 
77 
15 
10 
10 
77 
15 
10 
10 
15 
77 
97 
 
A Ensure that LEC-5 and SCID-5-SPQ results are sent to the Independent Rater who will be conducting the SCID-5-PD   
B First C-SSRS is a Lifetime assessment, other assessments are Since Last Visit   
C Conducted pre- and post-Investigational Product administration, and at phone calls on Days 2 and 7 after Experimental Session   
D The relevant questions (117-130) from the DDIS will be asked by the Independent Rater during the SCID-5-PD assessment. The entire measure will never be administered.


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6.0 Randomization and Blinding 
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.  
 
Once data is entered into the IRDB, the Senior IR will oversee the data quality by 
centrally by reviewing the critical data. The monitoring conducted by the CRA 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, and 2) To perform remote source 
data verification to check the IRDB for administrative, data entry, or transcription errors 
made by the Independent Rater Coordinator. The IR Program Lead will review data 
listings for quality and completeness prior to database lock. 
 
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 (MMRM) 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, and 
e. Change from Baseline means of 17.2, 31.1, and 37.4, for MDMA at Experimental 
Session 1, 2, and 3, respectively 
f. Two levels of treatment factor (MDMA, Placebo) 
g. Three within subject levels (3 treatment visits) 
h. Subject level variance = 335 
i. 
Variance of R (diagonal elements) = 280 


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j. 
Rho = 0.5 
k. 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 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 R. In general, nominal variables will be described 
in terms of frequencies and percentages. Ordinal and non-normal continuous variables 
will be described using sample median and range. Approximately normal variables will 
be described using sample mean and standard deviations. A subset of demographic and 
baseline characteristics (age, sex, duration of PTSD, CAPS-5 at Baseline, SDS at 
Baseline, comorbid major depression, Adverse Childhood Experience Questionnaire 
[ACE] at Baseline, C-SSRS Lifetime Ideation Score, and prior MDMA use) will be 
tested formally using chi-squared tests for categorical variables and either Wilcoxon rank 
sum tests for non-normal continuous variables, t-tests for normal continuous variables 
with two categories. Except for the primary efficacy analysis (specified below), 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 of 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 
• 
All Screened: all participants who sign informed consent and are screened 
 


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Summaries of demographics, disposition, exposure and safety parameters will only be 
generated for the mITT Set if different from the Safety Set.  
 
8.2 Missing Data Handling 
All possible procedures within Good Clinical Practice (GCP) will be used to minimize 
Post-randomization Early Terminators. Based on MAPP1 data, it is expected that up to 5 
- 10% of enrolled and randomized participants will discontinue study treatment 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, and enrollment and treatments will continue until 
N=100 participants are obtained in the mITT set. All observed CAPS-5 data from Post-
randomization Early Terminators collected prior to and after treatment discontinuation 
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 or the month of study 
termination if December is later than the subject’s study termination date. 
3. If the day is unknown, then the last day of the month will be assigned or the day of study 
termination if the last day of the month is later than the subject’s study termination date. 
 


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8.3 Protocol Deviations 
The number of participants in each protocol deviation category will be summarized by 
analysis set, treatment group, and protocol deviation severity. Individual participants will 
appear in a listing. Protocol deviation severity is defined as:  
 
• 
Major: A type of deviation from the protocol that has the potential to significantly affect 
participant rights, safety, or well-being, or impact the primary or key secondary efficacy 
endpoint(s) for that subject. 
• 
Minor: A type of deviation from the protocol that does not have the potential to 
significantly affect subject rights, safety, or well-being, or does not have potentially 
significant impact on the primary or key secondary efficacy endpoint(s) for that subject. 
 
8.4 Baseline Values 
Baseline values are from Baseline Visits (Visit 3 or Visit 4) for all measures, except for 
vital signs. For height, weight and BMI, results collected at Screening will be used as the 
Baseline value. For blood pressure (BP), pulse, and temperature, baseline is assigned as 
the pre-dose timepoint of the first experimental session (Visit 5). 
 
8.5 Participant Disposition 
The All Screened 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 each analysis set and for the Overnight Stay and No 
Overnight Stay subgroups. 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 Study Termination, where the percent is with respect to the total number 
of screened participants in that treatment group.   
 
8.6 Demographics and Baseline Characteristics 
Participant demographic data and Baseline characteristics will be summarized for the 
mITT and Safety Sets descriptively by treatment group and overall. Trauma 
characteristics from the PCL-5 at screening will also be summarized by treatment group 
and overall. 
 
8.7 Medical History and Substance Use 
Medical history terms will be coded using MedDRA Version 24.0 and summarized by 
system organ class (SOC), preferred term (PT), and treatment group. Subjects with any 
history of prior therapy will also be summarized by treatment group and overall by the 
categories listing on the CRF. Substance use, ecstasy use history, and qualitative drug 
screening during the study will also be summarized by treatment group.  
 
8.8 Efficacy Analyses 
For all primary and secondary endpoints, descriptive statistics (n, mean, standard 
deviation, median, range, or counts and percentages where appropriate) will be provided 


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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. 
 
8.8.1 Primary Efficacy Analyses 
The de jure estimand of treatment efficacy will be used to estimate the causal effect of 
MDMA-assisted therapy 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 
(LS) means from a restricted maximum likelihood (REML)-based mixed model for 
repeated measures (MMRM) will be used to compare treatment groups at Visit 19. LS 
means, 95% confidence intervals (CI), LS mean difference, and 95% CI for the difference 
will be displayed for each treatment group at Visits 8, 13, and 19. The p-value for the LS 
mean difference in treatment groups will be displayed at Visit 19 only. CAPS-5 data 
collected after treatment discontinuation will be considered to be missing at random 
(MAR) and 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 from Baseline in 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 T2 and T3 are variables indicating if the data 
from that record are from Visit 13 or 19, respectively. Covariates included in the MMRM 
model are treatment, visit by treatment interaction, baseline CAPS-5 Total Severity 
Score, a binary variable indicating dissociative subtype at Baseline, and investigative site. 
The regression model is specified as follows: 
 
Yij = α + β1Xi + β22T2I(j=2) + β23T3I(j=3) + β32T2ΧiI(j=2) + β33T3Χi I(j=3) 
+ β4Baseline_CAPSi + β5DSi + β6Sitei + 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 in CAPS-5 for MDMA vs. 
placebo at Visit 8. The coefficient estimates of β22 and β23 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 β32 and β33, corresponding to the interaction of the treatment 
variable and the visit variable, capture the incremental mean difference in the change 
from Baseline 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 from 
Baseline in CAPS-5 corresponding to the baseline CAPS-5 score. The coefficient 
estimate of β5 captures the effect on the change from Baseline in CAPS-5, corresponding 
to dissociative subtype at Baseline. The coefficient estimate of β6 captures the difference 


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in mean change from Baseline 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; 
     lsmeans trtp trtp*avisitn / diff cl om alpha=.0499 ; 
     ods output tests3=tests3; 
     ods output Diffs=Diffs; 
run; 
 
where, the CAPS variable is the change from Baseline in the CAPS-5 Total Severity 
Score at Visit 8, 13, or 19, X is the randomized treatment assignment (MDMA or 
placebo), T is Visit (Visit 8, Visit 13, or Visit 19), Baseline_CAPS is the baseline CAPS-
5 Total Severity Score for each participant, DS is the dummy variable indicating 
dissociative subtype at Baseline, Site indicates the clinical site where the participant was 
treated, and ID uniquely identifies the 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. Cohen’s d and associated 
95% confidence intervals will also be presented to describe the difference in the mean 
change from Baseline between treatment groups.  
 
Table 4: Proposed Estimands and Key Attributes 
Estimand 
Endpoint 
Hypothesis 
Inference 
Population 
Endpoint 
Use of data after early 
treatment discontinuation 
in analysis 
1 
CAPS-5 
de jure  
Initially 
randomized 
treatment 
mITT 
Planned 
endpoint 
Not included 
2 
CAPS-5 
de facto 
Treatment 
Policy 
mITT 
Planned 
endpoint 
Included 
3 
SDS 
de jure 
Initially 
randomized 
treatment 
mITT 
Planned 
endpoint 
Not Included 
 
8.8.2 Supportive Analyses: 
To provide information on treatment effectiveness in all randomized participants that 
could be expected in clinical practice, regardless of adherence to the 3-session course of 
MDMA-assisted therapy treatment, a de facto estimand is included as a 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, including CAPS-5 data collected after 
treatment discontinuation for Post-randomization Early Terminators. This will be 
estimated in the mITT set by a statistical comparison between treatment groups using the 


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MMRM model with a least squares estimate of the change from Baseline in CAPS-5 to 
18 weeks after randomization.  No de facto sensitivity analyses will be performed for the 
key secondary efficacy endpoint.  
 
The effect of departures from choices and assumptions made for the primary analysis will 
also be tested as sensitivity analyses for the primary estimand. These are listed below.  
 
a. Distributional assumptions for the residuals of the model will be tested using 
Shapiro Wilks test and a Q-Q plot; if the distribution is found to be non-normal, 
we will test a transformation of the data, such as the log transformation, to achieve 
normality. 
b. 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. 
c. To examine the robustness of the inferences to the MAR assumption, a worst/best-
case imputation technique will be employed where each missing CAPS-5 measure 
from MDMA treated subjects from each visit will be replaced by the worst 
observed result among the MDMA subjects at that visit. Each missing CAPS-5 
measure from Placebo treated subjects at each visit will be replaced by the best 
observed measure among Placebo treated subjects at that visit. 1000 complete 
datasets will be generated by sampling from the data with missing CAPS-5 
measures replaced by worst/best case imputation using the MI procedure in SAS; 
each of which will be analyzed using the primary efficacy model with effects for 
treatment arm, visit, and covariates. The final results will be obtained by 
combining the LS means and LS mean differences from these 1000 analyses by 
applying Rubin’s rules [3].  
d. If the worst/best case imputation analysis results in the treatment effect estimate to 
have a p-value greater than 0.0499, a tipping point analysis will be executed. The 
tipping point analysis will be conducted to estimate the treatment difference in the 
CAPS-5 scores where model results become statistically non-significant. This 
sensitivity analysis assumes that all missing CAPS-5 data are Missing Not at 
Random (MNAR). This analysis will only be performed if the primary analysis 
results differ from the worst/best case sensitivity analysis. Multiple imputation 
will be used to impute missing CAPS-5 Visit 13 and/or Visit 19 data. If the data 
has monotone missingness pattern, then monotone regression procedure be used in 
SAS PROC MI [4] to impute missing Visit 13 CAPS-5, using Visit 8 CAPS-5, 
dissociative subtype, site, and treatment as covariates. Then, missing Visit 19 
CAPS-5 will be imputed in a similar manner, replacing Visit 8 CAPS-5 with Visit 
13 CAPS-5 as a predictor. If data does not have monotone missingness pattern, 
then fully conditionally specified (FCS) methods will be used for the imputation. 
The imputed MDMA-assisted therapy results will then be penalized by ∆ and 
estimates will be generated from these penalized datasets. Final results for ∆ 
penalized datasets will be combined from 1000 imputation datasets by applying 
Rubin’s Rules. Delta will be increased in increments of x until the final model 
result p-value crosses the threshold of 0.0499. 
e. An additional sensitivity analysis will address the effect of intercurrent events [1, 
2, 5], which are identified in this study as: 
• 
Discontinuation of study because subject withdrew consent 
• 
Post-Randomization Early Termination and does not take medication for 
PTSD after termination  


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• 
Post-Randomization Early Termination and does take medication for PTSD 
after termination  
• 
Death, not suicide 
• 
Suicide 
 
This analysis assesses the robustness of inferences from the primary model 
(which assumes missing data are MAR) by assuming each category of 
intercurrent events are MNAR. This is done by assigning missing CAPS-5 data 
to the estimated mean of the MDMA or placebo treatment groups (Table 5:).  
 
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  
Missing CAPS-5 Imputation  
Discontinue Study, 
Withdraw Consent 
No data  
MDMA 
Assume treatment failure 
• 
Assign missing value to Placebo 
estimated mean at corresponding visit  
Placebo 
Assume treatment failure 
• 
Assign missing value to Placebo 
estimated mean at corresponding visit  
Post-Randomization Early 
Termination (or >8 week 
delay between 
experimental sessions) 
and does not take  
medication for PTSD after 
discontinuing intervention 
Data collection 
continues whenever 
possible via remote 
visits 
MDMA 
Assume treatment success if data supports 
treatment response 
Assign missing value to MDMA estimated mean 
at corresponding Visit  
Assume treatment failure if data does not support 
treatment response 
• 
Assign missing value to Placebo 
estimated mean at corresponding Visit  
Placebo 
Assume treatment failure 
• 
Assign missing value to Placebo 
estimated mean at corresponding Visit  
Post-Randomization Early 
Termination (or >8 week 
delay between 
experimental sessions) 
and does take medication 
for PTSD after 
discontinuing intervention 
Data collection 
continues whenever 
possible via remote 
visits 
MDMA 
 Assume treatment success if data supports 
treatment response 
• 
Assign missing value to MDMA 
estimated mean at corresponding Visit  
  
Assume treatment failure if data does not support 
treatment response 
• 
Assign missing value to Placebo 
estimated mean at corresponding Visit  
Placebo 
Assume treatment failure 
• 
Assign missing value to Placebo 
estimated mean at corresponding Visit  
Death, not suicide 
No data  
MDMA 
Assume treatment success if last available data 
support treatment response 
• 
Assign missing value to MDMA 
estimated mean at corresponding Visit  
 
Assume treatment failure last available data does 
not support treatment response  
• 
Assign missing value to Placebo 
estimated mean at corresponding Visit  
Placebo 
Assume treatment failure 
• 
Assign missing value to Placebo 
estimated mean at corresponding Visit  
Suicide 
No data  
MDMA 
Assume treatment failure 
• 
Assign missing value to Placebo 
estimated mean at corresponding Visit  


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Post-randomization 
Events 
Available Data Post-
Withdrawal 
Treatment 
Assignment  
Missing CAPS-5 Imputation  
Placebo 
Assume treatment failure 
• 
Assign missing value to Placebo 
estimated mean at corresponding Visit  
 
Additional baseline covariates (including but not limited to: 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 primary efficacy model at a p<0.05 threshold. Each 
covariate and the corresponding treatment by covariate interaction term will be included 
in the primary efficacy analysis model one-at-a-time and the p-value of the term and its 
interaction with treatment with be reported. Covariates with either the estimate of the 
term or the covariate by interaction term will be included in a full model that includes all 
covariate/interaction terms that were significant in the primary efficacy model (i.e. the 
model with only covariate, covariate by treatment, treatment, and visit). Backward 
elimination will be used to compile a full model. 
 
8.8.3 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 therapy 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. If both items are checked for Item 1, it will be scored as a 10. 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 IR 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 more than 5% of item 1 data in a treatment group is missing at Visit 19, a sensitivity 
analysis will be conducted by using the sum of the items without imputing missing Item 1 
scores and compared to the results from the average SDS with imputation.  
 
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 


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the Primary Efficacy comparison does not reject the null hypothesis, the analysis of the 
Key Secondary Endpoint (SDS) will be exploratory. The key secondary estimator of 
effects of initially randomized treatments will be the difference between groups in mean 
change from Baseline in SDS summary measure at 18 weeks after randomization (Visit 
19). The key secondary efficacy analysis will be conducted using the same methodology 
as the primary efficacy measure, but replacing Baseline CAPS-5 with Baseline SDS as a 
covariate in the model.  
 
8.8.4 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. Four different 
responder categories will be derived and compared descriptively at each post 
Experimental Session visit using frequencies and percentages. The categories (Figure 1) 
are:  
 
• 
Non-responder: <10 point reduction in CAPS-5 Total Severity Score since Baseline 
• 
Response: 10 point or greater reduction in CAPS-5 Total Severity Score since Baseline 
• 
Loss of Diagnosis: 10 point or greater reduction in CAPS-5 Total Severity Score since 
Baseline 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 
 
Note that these groups are not independent. An exploratory analysis will also be 
conducted using a 12 point reduction in CAPS-5 scores.  
 
 


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Figure 1: CONSORT for PTSD CAPS-5 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 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 [4] 
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 


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functional remission indicating Mild or No impairment. Three different SDS responder 
categories will be derived and compared descriptively at each post Experimental Session 
visit using frequencies and percentages. The categories are:  
 
• 
Non-responder: <4 point reduction in the average SDS Total Score since Baseline 
• 
Response: 4 point or greater reduction in the average SDS Total Score since Baseline 
• 
Remission: average SDS Total Score is less than 3 at the visit 
 
Note that these groups are not independent. The exploratory responder analysis that was 
used for CAPS-5 will be conducted using the SDS measure and the thresholds described 
below (Figure 2). If more than 5% of item 1 data in a treatment group is missing at a 
visit, then SDS responder categories will also be derived using the sum of the items 
without imputation (see Section 8.8.3).  
 
Figure 2: CONSORT for PTSD SDS Responder Analysis After Treatment 
 
[1] Response at T2, T3, and T4 will be in comparison to Baseline at T1. 


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8.9 Safety Analyses 
Safety assessment analyses for this study will include summaries of drug exposure, 
unsolicited adverse events, concomitant medications, suicidal ideation, intensity, and 
behavior from the C-SSRS, and vital signs.  
 
8.9.1 Analysis of Exposure 
The frequencies and percentages of participants with exposure will be summarized 
overall and by treatment group. The total dose administered (either initial with no 
supplemental or initial plus supplemental) and elapsed time (minutes) from primary to 
supplemental dose (if applicable) will be produced along with summary statistics for each 
Experimental Session. The total dose administered over all Experimental Sessions and 
the average time from primary to supplemental dose for each subject across the 
Experimental Sessions will also be summarized. Data will be tabulated for the Safety Set. 
 
8.9.2 Analysis of Adverse Events 
The primary measure of safety will be the reporting of unsolicited AEs. All AEs collected 
from Enrollment to Study Termination will be categorized as follows: 
 
• 
Pretreatment AEs – AEs that occur during Preparatory Period prior to first dose in first 
Experimental Session 
• 
Treatment Emergent AEs – AEs that occur during Treatment Period from first 
Experimental Session to last Integrative Session. 
• 
AEs that occur on Days 0, 1 and 2 after MDMA or placebo administration 
• 
AESIs – AEs specified in the protocol related to cardiac function and abuse liability. 
• 
Follow-up Period AEs – AEs that occur during Follow-up Period after last Integrative 
Session through Study Termination. 
• 
AEs leading to discontinuation of IP 
• 
AEs resulting in death or hospitalization 
• 
SAEs 
• 
AEs continuing at Study 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 24.0. Frequency and incidence of AEs will be displayed and sorted by SOC then 
PT and summarized by treatment group, 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. 


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• 
AEs that occur on day of Experimental Sessions up to 2 days after IP administration will 
be presented separately. 
 
TEAEs with a preferred term of “Suicidal Ideation” will be summarized by history of 
suicidal ideation from the Lifetime C-SSRS at Screening (Yes or No). The time to onset 
(days post experimental session), duration of the events (days) will be summarized by 
treatment group. The number of events not resolved with also be presented.  
 
8.9.3 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: 
 
• 
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 each Experimental Session for any medications requiring 
a change in dose, a skipped dose, or tapering.  
• 
Concomitant medications include those with a start date of the day of and up to 2 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 Global (WHODrug Global). Frequency and incidence of concomitant 
medications will be summarized by treatment group, Anatomical Therapeutic Chemical 
(ATC) Class Level 1, ATC Class Level 3, preferred term, and indication. Concomitant 
medications will be analyzed and presented as follows: 
 
• 
Pretreatment medications 
• 
Prior and concomitant medications 
• 
Concomitant medications taken on the day of and up to 2 days after IP administration 
will be presented separately 
• 
Any central nervous system concomitant medications by period 
 
Other categories defined in this section will be presented in listings.  
 
8.9.4 Analysis of C-SSRS 
Suicidal ideation, ideation intensity, and behavior will be summarized according to 
suggestions made in the C-SSRS Scoring and Data Analysis Guide [8]. A positive 


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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 suicidal ideation, 
ideation intensity, and suicidal behavior will be presented by time period (listed above), 
treatment group and overall using descriptive statistics in tabular format. A shift table of 
suicidal ideation at Baseline (Visit 4) compared to the maximum post-treatment suicidal 
ideation score will be produced by treatment group.  
 
Additionally, the number of subjects with suicide-related treatment emergent (TE) 
suicidal ideation and behavior based on the C-SSRS during treatment will be compared 
by treatment group for categories below. Treatment-emergent is defined as any C-SSRS 
measurement taken after the first dose of IP. The difference the proportions between 
treatment groups will be compared using 2-sided Fisher’s exact tests and p-values will be 
presented for each category.  
 
• 
TE suicidal ideation (1-5) compared to recent history = number of subjects with post-
treatment C-SSRS score of 1-5 / number of subjects with at least one post-baseline 
suicidal ideation score where the baseline suicidal ideation score is < 5 
• 
TE serious suicidal ideation (0-3 to 4-5) compared to recent history = number of subjects 
with post-treatment C-SSRS score of 4-5 / number of subjects with at least one post-
baseline suicidal ideation score where the baseline suicidal ideation score is 0-3 
• 
Emergence of serious suicidal ideation (0 to 4-5) compared to recent history = number of 
subjects with post-treatment C-SSRS score of 4-5 / number of subjects with at least one 
post-baseline suicidal ideation score where the baseline suicidal ideation score is 0 
• 
Improvement in suicidal ideation at endpoint compared to baseline = number of subjects 
with post-treatment C-SSRS score is less than the baseline C-SSRS score / number of 
subjects with at least one post-baseline suicidal ideation score where the baseline 
suicidal ideation score is >0 
• 
Emergence of suicidal ideation (1-5) compared to all prior history = number of subjects 
with post-treatment C-SSRS score is greater than the Lifetime suicidal ideation score / 
number of subjects with at least one post-baseline suicidal ideation score where the 
Lifetime suicidal ideation score <5 
• 
Emergence of suicidal behavior (6-10) compared to all prior history = number of 
subjects with post-treatment suicidal behavior score of 6-10 / number of subjects with at 
least one post-baseline suicidal behavior score where the Lifetime suicidal behavior is 
less than 6 
 
8.9.5 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, interim 
(prior to the supplemental dose), and endpoint (at the end of each Experimental Session) 
by treatment group. Change from Baseline in vital signs will be described for each visit 


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and time point (predose, interim, and endpoint) by treatment group and overall. 
Summaries will also be produced by age group (< 65 years old and >= 65 years old). 
Shift tables will be generated by initial treatment dose (0 mg [placebo], 80 mg, and 120 
mg), and age group for pre-dose values compared to the maximum post-dose value using 
180 mmHg as a threshold for systolic blood pressure, 110 mmHg for diastolic blood 
pressure, and an increase of 1 degree C for temperature. The frequency and percent of 
subjects who had vital signs greater than or equal to the thresholds in the Observed Value 
and Change categories in Table 6 will also be summarized by age group and initial 
treatment dose.  
 
Table 6: Shift Table Vital Sign Categories 
Vital Sign 
Observed Value 
Change 
Systolic Blood Pressure 
>=180 mmHg 
<180 mmHg 
Increase of >=40 mmHg 
Diastolic Blood Pressure 
>=110 mmHg 
<110 mmHg 
Increase of >=25 mmHg 
Temperature 
>=38 degree C 
<38 degree C 
Increase >= 1 degree C 
 
8.10 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 treatment discontinuation 
participants who have completed their final CAPS-5, and N=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.  
 
Following the DMC review of the MAPP1 results, the DMC may recommend changes to 
the purpose and criteria of the interim analysis. For instance, the DMC may recommend 
adding an efficacy interim analysis executed at a specific number of subjects with 
Primary Endpoint data. Regardless of the DMCs suggested changes, overall Type-I error 
will be preserved.  
 
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 theoretical 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. Note that this table is an example of possible effect sizes 
and sample size increases based on a simpler model than the actual model that will be 
used in the interim analysis.  
 
 
 


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Table 7: Observed Effect Sizes and Corresponding Sample Size for 90% 
Conditional Power Guidance at the Interim Analysis (N=60) 
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 
[1] Conditional Power based on the alternative hypothesis effect size as observed in the first 60 subjects. 
Note: this table is theoretical and not based on the true efficacy model. It is an example based on a simplier 
modeling strategy based on theoretical effect sizes. 
 
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 [9]. 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 [10]. However, the sponsor has chosen to allocate 0.2% 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. 
 
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 


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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.  
 
8.11 Subgroup Analysis 
The primary efficacy analysis will be run on subgroups Overnight Stay/No Overnight 
Stay and Dissociative Subtype/No Dissociative Subtype (removing this as a covariate).If 
additional exploratory covariates are significant (Section 8.8.2), these will also be 
considered for subgroup analysis of the primary efficacy endpoint. Additionally, 
demographic and baseline characteristics, CAPS-5 responder analysis, and select adverse 
event tables will be produced by Overnight Stay/No Overnight Stay subgroups.  
 
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. 
• 
Review the results of MAPP1 and make recommendations on updating the adaptive 
design elements to the study protocol, interim analysis, and/or data analysis of the 
MAPP2 study. 
• 
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, Study 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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11.0 References 
1. 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. 
2. Molenberghs, G., et al., Analyzing incomplete longitudinal clinical trial data. Biostatistics, 
2004. 5(3): p. 445-64. 
3. Rubin, D.B., Inference and missing data. Biometrika, 1976. 63(3): p. 581-592. 
4. SAS Help Center: The MI Procedure. SAS/STAT ® 15.2 User's Guide Last updated October 
28, 2020. 
5. Iddrisu, AK., Gumedze, F. An application of a pattern-mixture model with multiple 
imputation for the analysis of longitudinal trials with protocol deviations. BMC Med Res 
Methodol 19, 10 (2019). https://doi.org/10.1186/s12874-018-0639-y 
6. An application of a pattern-mixture model with multiple imputation for the analysis of 
longitudinal trials with protocol deviations | BMC Medical Research Methodology | Full Text 
(biomedcentral.com) 
7. 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. 
8. 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. 
9. Jennison, C. and B.W. Turnbull, Group sequential methods with applications to clinical 
trials. 2000, Boca Raton, FL: Chapman & Hall/CRC Press. 
10. 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.