Clinical trial NCT04714359
Conditions: PTSD
Sponsor: Lykos Therapeutics
Start date: 2021-03-08; Completion date: 2023-11-06
Enrollment: 87 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical trial is to learn if MDMA-assisted therapy is safe and effective at reducing PTSD symptoms in people with PTSD who received placebo in a prior MDMA-assisted therapy study.

The main question it aims to answer is:

Do PTSD symptoms decrease in people who receive a flexible dose of MDMA (120 or 180 mg MDMA HCl) with therapy in three sessions?

Participants will undergo three preparatory therapy sessions without any study drug, then three MDMA-assisted therapy sessions with a flexible dose of 80 or 120 mg, followed by three integrative therapy sessions without study drug after each MDMA-assisted therapy session.

Detailed description:
This multi-site, open-label safety extension study assesses the efficacy and safety of MDMA-assisted psychotherapy versus psychotherapy in participants diagnosed with PTSD. The study will be conducted in N ≈ 100 participants. Participants who were randomized to the placebo arm in either of the two parent Phase 3 trials of MDMA-assisted psychotherapy and who meet all other entry criteria will be eligible and invited to participate in this study. In addition, participants in the parent Phase 3 trials who were unable to complete the study due to the COVID-19 pandemic or other unforeseen circumstances may participate in this study.

The treatment consists of an initial dose of midomafetamine HCl (80 or 120 mg), followed by a supplemental dose (40 or 60 mg) unless contraindicated, administered with manualized psychotherapy in three open-label Experimental Sessions each spaced approximately one month apart. During Experimental Session 1, participants will receive an initial dose of 80 mg of midomafetamine HCl, followed by a supplemental dose of 40 mg. During Experimental Sessions 2 and 3, participants will receive an initial dose of 80 or 120 mg of midomafetamine HCl, followed by a supplemental dose of 40 or 60 mg.

This Treatment Period is preceded by three Preparatory Sessions. During the Treatment Period, each Experimental Session is followed by three Integrative Sessions of non-drug psychotherapy. Experimental Sessions are followed by an overnight stay, with the exception of a subset of participants who will be invited to participate in a sub-study to assess the feasibility of Experimental Sessions without overnight stay. The primary study endpoint is the change from baseline in PCL-5 (PTSD Checklist for DSM-5) scores from Visit 3 to Visit 16.

Arms: arm 1: Three open-label sessions of MDMA-assisted therapy, each scheduled approximately 1 month apart, with initial dose of midomafetamine HCl of 80 or 120 mg and optional supplemental dose half that of initial dose (40 or 60 mg) 1.5 to 2 hours later
Interventions: intervention 1: Midomafetamine HCl
Intervention descriptions: intervention 1: Initial doses per Experimental Session include 80 mg or 120 mg midomafetamine HCl, followed 1.5 to 2 hours later by a supplemental dose unless tolerability issues emerge. For an initial dose of 80 mg, a 40 mg supplemental dose will be used. For an initial dose of 120 mg, a 60 mg supplemental dose will be used. Total amounts of midomafetamine HCl to be administered per Experimental Session range from 80 mg to 180 mg.

Protocol documents:
ICF_002.pdf: 
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PARTICIPANT INFORMATION AND CONSENT FORM AND HIPAA 
AUTHORIZATION 
 
TITLE: 
A Multi-Site Open-Label Safety Extension Study of 
Manualized MDMA-Assisted Therapy for the 
Treatment of Participants with Posttraumatic Stress 
Disorder 
 
PROTOCOL NO.: 
MAPPUSX 
 
WCG IRB Protocol # 20210317 
 
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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Experimental Subject’s Bill of Rights 
 
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 were previously involved in a 
Phase 3 clinical trial sponsored by the Multidisciplinary Association for 
Psychedelic Studies (MAPS, www.maps.org) and you were either randomized to 
placebo or you were unable to complete the study due to the Coronavirus 
Disease 2019 (COVID-19) global pandemic or other external circumstances.  
 


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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 post-traumatic stress disorder (PTSD). 
MDMA is an experimental drug, which means that it has not been approved by 
the Food and Drug Administration (FDA) for sale for medical use in the United 
States (U.S.). MDMA is also a controlled drug (illegal to use outside of research) 
and is sometimes known as “Ecstasy” or “Molly” (which is supposed to contain 
MDMA, but often contains other drugs instead of or in addition to MDMA). MDMA 
is a chemical that is structurally similar to some stimulant chemicals, like 
methamphetamine, which is both a major drug of abuse and an FDA-approved 
treatment for Attention Deficit/Hyperactivity 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, MAPS. MAPS 
has completed twelve studies of MDMA-assisted psychotherapy 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 open-label, meaning you will receive MDMA.  There will be 
approximately 100 participants enrolled in this study.  
 
Length of Study 
The length of active participation in the study will be about 22 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 


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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. 
 
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 (approximately 90 minutes each): Three 
introductory therapy sessions at the start of participation in the study, 
spaced about one week apart. 
• 3 Study Drug Sessions (approximately 8 hours long plus an 
overnight stay): Three visits about 1 month apart. You will be given 
MDMA during these visits along with therapy.  
• 9 Integrative Sessions (approximately 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. 
• Questionnaires (60 minutes): Completion of questionnaires at Visit 3 
(the third Preparatory Visit) and Visit 16 (Study Termination).  
 
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 and HIPAA 
Authorization 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 10 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 since 
your participation in the previous study 
• 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 may test for the Hepatitis C virus (HCV). 
o If you have positive test results for 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. 
• 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. 


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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. 
 
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. 
 
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.  


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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 
total “effective” radiation dose you will receive is comparable to 3.3 times the yearly dose 
from environmental radiation in the US, which 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, instead of the one mentioned 
above. 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 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 


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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. 
 
If you are taking certain medications, you may need to stop taking them before 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. 
 
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: Preparatory Session 3 (90 minutes therapy + 55 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 55 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.  
 
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 complete 
about 55 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 a group 
of scientists and non-scientists 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. 
 
Study Drug Sessions 
After you have met all of the inclusion criteria and none of the exclusion criteria of the study 
and if you qualify for the study after the Preparatory Sessions, you may be eligible to be 
enrolled in the study to receive study drug sessions. 
 
There will be a total of 3 full day Study Drug Sessions during the study which will occur 
about 4 weeks apart. The first Study Drug Session will occur after you have had three 
Preparatory Sessions. During the first Study Drug Session, you will receive an 80 mg dose 
of MDMA. MDMA capsules also contain mannitol (a sweetener) and magnesium stearate (a 
lubricant). You will receive another dose (40 mg) of MDMA 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 (120 mg). You will receive a supplemental dose of either 40 
mg or 60 mg of MDMA 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. 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. Examples of herbal supplements include milk 
thistle, gingko, ginseng, etc. Please talk to your study doctor about all herbal 
supplements and vitamins (such as multivitamins, Vitamin D, etc.) that you take. 
• 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 


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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. 
o Some prescription medications, such as birth control or blood pressure 
medication should be continued as normal. Talk to your study doctor to ensure 
you understand the requirements. 
o Non-prescription medications may include over-the-counter medicines like pain 
relievers, antacids, allergy medications, nasal sprays, etc. Talk to your study 
doctor about all over-the-counter medications you take to ensure you 
understand the requirements.  
 
After midnight before each Study Drug Session: 
• You must not eat any food, drink any alcohol, or use cannabis. 
• 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 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. 
 
On the morning of the Study Drug Session, before the first dose of MDMA: 
• 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 MDMA. 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 


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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 
about 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.  
 
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, they will let you know that they are doing this and 


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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. 
 
Integrative Sessions 
There will be three Integrative Sessions after each Study Drug session. Some or all of these 
visits may be conducted remotely. 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 having difficulty concentrating. 
 
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. 
 
Study Termination 
About 1 month after the last Study Drug Session and 2 months after the last Study Drug 
Session, you will meet with your therapy pair to end your study participation. Your therapy 
pair will let you know if this meeting can happen remotely or if you need to come to the study 


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site. You will fill out the same questionnaires from the start of the study (about 1 hour).  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. These tests will help the 
therapy pair tell if your symptoms have changed or stayed the same over time. 
 
Possible Risks, Benefits or Alternatives 
You may have changes in health while on the study, which could be due to MDMA or 
therapy, or events in your own life not related to the study. 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, 2022, 1,974 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 related to MDMA 
occurred in a participant who had a medical history of pre-existing heart issues (irregular 


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heart rhythm) and who experienced an episode of changes in heart rhythm after receiving 
MDMA. This participant recovered without any complications. 
 
Blood pressure and heart rate  
MDMA typically causes a transient increase in blood pressure and heart rate, similar to what 
happens with moderate exercise. These transient increases in blood pressure and heart rate 
usually have returned to normal by the end of the visit, approximately 6-8 hours after the first 
dose. 
 
In the Study Sponsor’s past studies, participants did not report any discomfort, nor did they 
require any treatment, due to increased blood pressure and heart rate after taking MDMA. 
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 test you for pre-existing heart problems before you 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. 
  
Driving Limitation 
Due to known potential risks described above, you should not drive of use machinery 
immediately after Study Drug Visits (up to 24 hours afterwards). 
Possible Negative Effects on the Brain 
Previous studies (conducted by the Study Sponsor) of brain scans of people before and 
after they got between one and three doses of MDMA did not show any changes or injury to 
the structure of the brain following MDMA. MDMA did decrease the reaction of the brain to 
challenging content in PTSD patients, which was an improvement. Findings from this study 
suggest that the amount of MDMA you will receive in this study will not produce any lasting 
negative changes in your brain. 
 
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 the 
Study Team or more trusting of them, or you may even feel loving or sexual feelings toward 
them. The Study Team is aware of the effects of the drug. They have been trained on how to 
appropriately care for someone who has taken MDMA and have signed a code of ethics that 
prohibits any sexual or romantic relations between researchers and participants in the study, 
including after participation in the study has ended. If you have any concerns that you are 
uncomfortable addressing with the Study Team, please contact the IRB via the phone 
number provided on this consent form. 
 
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 
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Positive Drug Test 
If you are given a drug test within three days of each Study Drug Visit, you may test positive 
for MDMA. The Study Team will provide you with an information card in case you are given 
a drug test. This card may not protect you from discipline at work or loss of employment. 
The Study Team 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 for 24 hours or more and until you feel back to 
your normal self. 
 
Emotional Discomfort 
The interviews you have and questionnaires you complete during the study may make you 
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. 
 
The medical tests done during health screening for the study may show something abnormal 
that needs further evaluation by the Study Doctor or your personal doctor, which may cause 
emotional discomfort. 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. 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 
study therapists 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. You should only 
continue in the study if you and the Study Therapists agree it is in your best interest.  The 
Study Therapists and doctor will provide you therapeutic support or alternative medications if 
needed. It is important that you understand this possibility before deciding whether or not to 
participate. 
 
Psychological Distress 
Both the therapeutic process and MDMA may expose underlying psychological distress. 
Psychological distress could arise following a Study Drug Visit or non-drug therapy visits or 
at the end of the study as a result of the process of integrating feelings, perspectives, 
insights, or may arise more generally around ending the study. 
 
The Study Therapists can discuss with you if you have any need for additional integration 
support during the study and can provide referrals at the end of the study for continuing 
integration support as needed. 


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Your pre-existing symptoms and diagnosis related to your PTSD may not improve and may 
become worse during the study or after. 
  
You may start Preparatory Visits but are not eligible to continue onto the Study Drug Visits 
due to the results of your screening evaluations. This may lead to disappointment and 
distress at not being able to participate in the research study. 
 
Temporarily Discontinuing your Regular Medications 
 
As you will be required to discontinue the use of psychiatric medicines (as for depression or 
anxiety, for example) as part of the study, you may start to have new or recurring symptoms. 
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 Study Therapists, 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 health and safety 
takes priority over your continued participation in the study. There are some allowable 
medicines on study; your doctors will discuss these with you if needed. 
 
COVID-19 Transmission 
Study participation will involve several consecutive overnight visits at the study site, 
including three 6-8 hour Study Drug Visits. This personal interaction may increase your risk 
of becoming infected with SARS-CoV-2 (coronavirus that causes COVID-19 disease). The 
Study Team will follow local and national COVID-19 prevention guidelines for healthcare 
workers and all precautions will be taken to reduce this risk, such as screening for 
symptoms before in-person visits, using face masks, cleaning surfaces, and washing hands. 
For your safety and the safety of Study Team, we recommend that you also follow the local 
and national 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 if exposed, or other 
changes to your habits. These recommendations may change as the impact of the COVID-
19 pandemic changes over time and your Study Team will update you as needed. 
 
Remote Visits 
Some of the non-Study Drug Visits, including Screening, Preparatory, and Integration visits, 
may be scheduled via telemedicine. The Study Team will discuss your options for 
telemedicine visits with you. 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 
Absolute confidentiality and security cannot be guaranteed; however, every effort will be 
made to maintain your confidentiality. This is described more in the section titled “Your 
Rights as a Study Participant.”  
 
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. 
 
 
Risks of ECG  
You may have skin irritation from the contacts used. 
 
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 are able to become pregnant, you will be tested at the start of the study, before 
each Study Drug Visit, and once after the final Study Drug Visit to see if you are 
pregnant. 
• If you are male assigned at birth and your female partner becomes pregnant during 
the study, we will request to follow-up with your partner’s pregnancy. If this is the 
case, we will provide a separate consent form for your partner. Taking part in the 
partner pregnancy follow-up is voluntary and will not affect your participation in the 
study.  
• If, at any time during the study, you think that you may be pregnant or may become 
pregnant, you must tell the Study Team immediately. 
• If you become pregnant after you have had at least one Study Drug Visit, the Study 
Doctors and the Study 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 no longer receive study drug but may remain in the 
study for follow-up purposes. 
If you should become pregnant during the study, the Study Doctors will refer you to 
the appropriate medical providers, as needed. 
 
Not being able to become pregnant is defined as permanent sterilization, 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 
Visit: 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Non-oral hormonal methods (including injected, intravaginal, implanted, or 
transdermal) 


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• Does not engage in sexual activities that could result in pregnancy 
• 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 do not engage in sexual activities that 
could result in pregnancy, you will still need to select a back-up method, in the case that you 
choose to while participating in this study. 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. 
 
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 
Study Team will tell you about it as soon as possible. 
 
Possible Benefits 
Your symptoms of PTSD may improve, stay the same, or get worse during or after 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.  
 
Alternatives 
One alternative to being in this study is to decide not to take part. You may decide to try 
other treatments for PTSD. In the U.S., the FDA  approved paroxetine (Paxil) and sertraline 
(Zoloft) for PTSD  Evidence-based psychotherapies 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 taking 
medication or doing therapy, you could continue those. There may also be other 
investigational therapies available. The Study Team can discuss alternatives with you. If you 
decide not to participate in this research, the Study Team will offer you referrals for other 
care which may be available to you. 
 
Your Rights as a Study Participant 


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Confidentiality  
All information collected will be treated and handled as confidentially as possible. 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. The information 
collected about you usually will not directly identify you (for example, by name, address, or 
social security number).  Instead, your initials and a code number will be used for your 
information. 
 
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. 
 
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.  


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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 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.  
 
Payment for Study Participation 
In order to remove some financial barriers to participation, you may be reimbursed for direct 
costs of participation (travel or dependent care costs, for example) at certain study visits as 
they are completed. If you do not complete a visit, you may not be reimbursed for costs 


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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 1-4 (Preparatory Sessions through Study Drug Session 1): $375 
• Visits 5-8 (Integrative 1.1 through Study Drug Session 2): $375 
• Visits 9-12 (Integrative 2.1 through Study Drug Session 3): $375 
• Visits 13-16 (Integrative Session 3.1 through Study Termination): $375 
 
OR You will not receive any payment for participating in this research study. 
 
<<CF-Main Payment for Part. Paragraph>> 
 
Cost 
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 has no plans to cover the 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 authority in your country (the FDA) 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, Health Canada, Israeli Ministry of Health, or the IRB may decide to 
stop the study at any time. If the study is stopped, the data collected about you up to that 
point will remain part of the study and will not be removed from the study database. 
 
Contact for Questions 
If you have 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, or 
contact the sponsor’s compliance hotline at 833-254-1732. 
 
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 1-
855-818-2289 or Researchquestions@wcgirb.com if: 
• You have questions, concerns, or complaints that are not being answered by the 
research team. 


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• 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. 
 
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 otherwise 
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 screening assessment audio and video-recorded during this study. 
 
I have read the information in this consent form and it has been discussed with me. I have 
been given sufficient opportunity to consider whether to participate. All of my questions so 
far about the study and my participation in it have been answered. I freely consent to take 
part in this research study. 
 
By signing this consent form, I have not waived any of the legal rights which I otherwise 
would have as a participant in a research study. I have been told that I will be given a signed 
and dated copy of this consent form<<CF-Main California Bill of Rights>>. 
 
 
Signature of Participant 
 
 
 
 Date 
 
 
 
Printed Name of Participant 
 
I certify that the information provided was given in language that was 
understandable to the participant. I attest to adhering to informed 
consent procedures. 
 
 
  
 
 
  
Signature of Person Obtaining Consent 
 
 
 
 Date 


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IRB Version 3.0 
Version Date 15MAR2023 
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, and audiovisual recordings. 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). 
• Other regulatory agencies.  
 


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IRB Version 3.0 
Version Date 15MAR2023 
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.] <<CF-Main User Defined #3>> 
 
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. 
 
If the research site is located in California, Delaware, Illinois, Indiana, 
Washington, or Wisconsin this authorization will expire on December 31, 2070. 
 


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Version Date 15MAR2023 
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 #4>> 
 
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 
 
 
 
 
 
 
 
Signature of Person Obtaining Authorization  
 
 
Date 
 


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Version Date 15MAR2023 
 
 
 
 
Printed Name of Person Obtaining Authorization  
 
 
 

Prot_000.pdf: 
 
 
 
Protocol and Synopsis MAPPUSX 
IND #063384 
 
A Multi-Site Open-Label Safety Extension Study of Manualized MDMA-Assisted Therapy for the 
Treatment of Participants with Posttraumatic Stress Disorder 
 
CURRENT APPROVED 
PROTOCOL 
AMENDED PROTOCOL 
Amendment 2, Version 1, 06 July 2021   
 
 
Amendment 3, Version 1, 15 March 2023 
 
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 
MAPS Public Benefit Corporation 
Phone number: +1 (877)-748-3767 
Additional contact information is available in the Study Operations 
Manual 
 
USE 
In conjunction with relevant Food and Drug Administration (FDA), 
Health Canada (HC), and Israeli Ministry of Health (MOH) guidance 


MAPS Public Benefit Corporation  
 
 
 
                       MAPPUSX Protocol Synopsis  
IND #063384 
 
 
 
 
 
                    Amendment 3 Version 1: 15 March 2023 
Page 2 of 90 
 
Protocol Amendment Summary of Changes 
 
DOCUMENT HISTORY 
Document 
Date 
MAPPUSX Original Protocol, Version 1 
27 July 2020 
MAPPUSX Amendment 1, Version 1 
19 January 2021 
MAPPUSX Amendment 2, Version 1 
06 July 2021 
 
Amendment 3, Version 3: 15 March 2023 
 
This amendment is considered to be substantial. 
 
Overall Rationale for the Amendment: 
 
The overall rationale for the changes implemented in the protocol amendment is to revise adverse event 
definitions and reporting, inclusion/exclusion criteria, and restructure the risk section to align with FDA 
guidance and the Investigator’s Brochure (IB), 15th Edition. 
 
 


MAPS Public Benefit Corporation  
 
 
 
                       MAPPUSX Protocol Synopsis  
IND #063384 
 
 
 
 
 
                    Amendment 3 Version 1: 15 March 2023 
Page 3 of 90 
 
MAPPUSX 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 and 3 studies of 
MDMA-assisted therapy conducted by the sponsor provide preliminary evidence that chronic PTSD, 
independent of cause, is treatable with two to three sessions of MDMA-assisted therapy and associated 
non-drug preparatory and integrative therapy. This open-label safety extension study is intended to 
explore the safety and effectiveness of MDMA-assisted therapy for the treatment of PTSD. 
 
Study Design 
 
This multi-site open-label safety extension study of MDMA-assisted therapy for the treatment of 
participants with PTSD will be conducted in N≈100 participants, by invitation only. 
 
The treatment consists of a flexible dose of MDMA, followed by a supplemental dose unless tolerability 
issues emerge, administered with therapy in three open-label approximately monthly Experimental 
Sessions. This 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 PCL-5 
(PTSD Checklist for DSM-5) from Visit 3 is assessed at Visit 16. An independent Data Monitoring 
Committee (DMC) will review safety data as described in the DMC charter and at any time a Serious 
Adverse Reaction (SAR) occurs (refer to Section 10.5 Data Monitoring Committee). 
 


MAPS Public Benefit Corporation  
 
 
 
                       MAPPUSX Protocol Synopsis  
IND #063384 
 
 
 
 
 
                    Amendment 3 Version 1: 15 March 2023 
Page 4 of 90 
For each participant, the study will consist of:  
 
• 
Screening Period: phone screen, informed consent, eligibility assessment, and enrollment of 
eligible participants  
• 
Preparatory Period: medication tapering, Preparatory Sessions 
• 
Treatment Period: three monthly Experimental Sessions over up to 4 months, followed by 
Integrative Sessions 
• 
Study Termination: Primary Outcome PCL-5 4 weeks after third Experimental Session 
• 
Invitation to participate in Long-term Follow-up (LTFU) extension study: at least 6 months 
after last Experimental Session 
 
Primary Outcome (PCL-5) Data Collection by Visit 
 
PCL-5 Number 
Visit 
Description/Timing 
Initial PCL-5 T0 
Screening 
Prior to enrollment and initiation of tapering 
Baseline PCL-5 T1 
V3 
Baseline 
After tapering and stabilization, at Preparatory Session 3 (Visit 3) 
PCL-5 T2 
V6 
10 to 18 days after Experimental Session 1 
At Integrative Session 1.2 (Visit 6) 
PCL-5 T3 
V10 
10 to 18 days after Experimental Session 2 
At Integrative Session 2.2 (Visit 10) 
PCL-5 T4 
V14 
10 to 18 days after Experimental Session 3 
At Integrative Session 3.2 (Visit 14) 
Primary Outcome  
PCL-5 T5 
V16 
24 to 32 days after Experimental Session 3 
At Study Termination (Visit 16) 
 
Dose Selection 
 
This open-label study will examine the safety and effectiveness of a flexible dose of MDMA administered 
in three Experimental Sessions, as described in the table below, along with associated non-drug 
preparatory and integrative therapy. Similar MDMA doses to those proposed in this study have been 
safely used in previous Phase 2 and Phase 3 studies sponsored by MAPS. 
 
Dose Regimen of MDMA 
Experimental 
Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative Dose 
1 
80 mg 
40 mg 
80 mg to 120 mg 
2 
80 or 120 mg 
40 or 60 mg 
80 mg to 180 mg 
3 
80 or 120 mg 
40 or 60 mg 
80 mg to 180 mg 
Total Cumulative Dose 
240 mg to 480 mg 
* Unless 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 explore the safety and 
effectiveness of MDMA-assisted therapy with a flexible dose of MDMA in reducing PTSD and 
associated symptoms.  
 


MAPS Public Benefit Corporation  
 
 
 
                       MAPPUSX Protocol Synopsis  
IND #063384 
 
 
 
 
 
                    Amendment 3 Version 1: 15 March 2023 
Page 5 of 90 
Primary Objective 
 
The primary objective of this study is to evaluate the effectiveness of MDMA-assisted therapy for PTSD, 
as measured by the reduction in PCL-5 total score from Visit 3 to Visit 16.  
 
Secondary Objective 
 
The key secondary objective of this study is to evaluate the effectiveness of MDMA-assisted therapy for 
PTSD in functional impairment, as measured by the mean change in Sheehan Disability Scale (SDS) item 
scores from Visit 3 to Visit 16.  
 
Safety Objectives 
 
The overall safety objective is to assess 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:  
 
1. Assess incidence of AEs during Experimental Sessions that may be indicative of a medical 
complication of the Investigational Medicinal Product (IMP) such as clinical signs and symptoms 
of chest pain, shortness of breath, or neurological symptoms or any other signs or symptoms that 
prompt additional vital sign measurements 
2. Assess incidence of AEs by severity 
3. Assess incidence of TEAEs by severity 
4. Assess incidence of TEAEs by severity reported during an Experimental Session, 1 day, and 2 
days after IMP administration 
5. Assess incidence of AESIs, defined as AEs specified in the protocol related to cardiac function, 
suicidality, and abuse liability 
6. Assess incidence of AEs by severity categorized as leading to discontinuation of IMP, resulting in 
death or hospitalization, and continuing at Study Termination 
7. Assess incidence of SAEs 
8. Assess incidence of concomitant medications taken during an Experimental Session, 1 day, and 2 
days after IMP administration 
9. Assess incidence of psychiatric concomitant medications taken during the Treatment Period 
10. Assess incidence of positive or serious suicidal ideation and positive suicidal behavior assessed 
with the Columbia Suicide Severity Rating Scale (C-SSRS) 
11. Assess changes in blood pressure (BP), heart rate, and body temperature from pre-IMP 
administration to end of each Experimental Session 
 
Recruitment and Participant Population 
 
Approximately N≈100 participants will be enrolled, by invitation only. Participants who were randomized 
to the placebo arm in the two parent Phase 3 trials and who meet all other entry criteria will be eligible 
and invited to participate in this open-label safety extension study. In addition, participants in the parent 
Phase 3 trials whose study participation was affected by the Coronavirus 2019 (COVID-19) global 
pandemic or other unforeseen circumstances, and were unable to complete the study (enrolled but not 
treated or enrolled, treated, but could not complete three Experimental Sessions prior to termination of the 
study) may participate in this open-label study if they meet all eligibility criteria and are approved by the 
Medical Monitor.  


MAPS Public Benefit Corporation  
 
 
 
                       MAPPUSX Protocol Synopsis  
IND #063384 
 
 
 
 
 
                    Amendment 3 Version 1: 15 March 2023 
Page 6 of 90 
 
Participants will be 18 years or older, considered in good standing with the study site at which they 
enrolled in a parent study, and able to agree to lifestyle modifications. 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 must be in good physical health and without major medical disorders that could affect 
the safety or tolerability of MDMA. 
 
Statistical Analyses 
 
This is a multi-site open-label safety extension study of MDMA-assisted therapy for the treatment of 
participants with PTSD. The effectiveness of MDMA-assisted therapy will be measured by the PCL-5 
and SDS. The sample size was not determined by statistical criteria. Every effort will be made to ensure 
(i) complete, accurate, and timely data collection and to avoid missing data, and (ii) 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. In general, nominal variables will be described in terms of 
frequencies and percentages. Ordinal and non-parametric continuous variables will be described using the 
sample median, 25th and 75th percentiles, and the interquartile range (IQR). 
 
The following analysis set is defined for this study: 
 
• 
All Enrolled: all participants who were enrolled in the study 
• 
Safety: all participants who received any IMP  
 
Primary Effectiveness Analysis 
 
The primary analysis of the effectiveness of MDMA-assisted therapy will be made using a Mixed Model 
Repeated Measure (MMRM) model to assess changes in PCL-5 scores throughout the study period from 
Baseline (Visit 3) through Visit 16. Baseline covariates (age, gender, ethnicity, index trauma, complexity 
and severity of trauma, diagnosis of comorbid depression, diagnosis of comorbid Axis 2 diagnosis, 
adverse childhood experiences collected in the parent study) may be assessed for inclusion in the final 
model with an alpha level set at 0.05. Details of the analysis are described in the Statistical Analysis Plan. 
 
Secondary Effectiveness Analysis 
 
The SDS will be analyzed in a similar manner to the primary analysis of the PCL-5. Please refer to the 
Statistical Analysis Plan for more details. 


MAPS Public Benefit Corporation  
 
 
 
         
                         
MAPPUSX Protocol 
IND #063384 
 
 
 
 
 
                  
 Amendment 3 Version 1: 15 March 2023 
Page 7 of 90 
Study Structure Overview 
 
 
Prestudy
Treatment Period 
-
 
Treatment 1:
Approximately 4 weeks
Treatment 2:
Approximately 4 weeks
Treatment 3:
Approximately 4 weeks
 Medication Tapering
Preparatory Period: 
At least 5 days, depending on
medication tapering length
Approximately 1 month after 
Experimental Session 3
Summary of Events
 
Medication Tapering
Preparatory Sessions
14 Day Phone 
Follow-up 
Experimental 
Session 1
Integrative Sessions
1.1, 1.2, 1.3
-
14 Day Phone 
Follow-up 
Experimental 
Session 2
Integrative Sessions 
2.1, 2.2, 2.3
14 Day Phone 
Follow-up 
Integrative Sessions 
3.1,3.2,3.3
 Screening     V0                    V1          V2        V3                                          V4          V5                           V6         V7                               V8          V9                          V10       V11                                V12        V13                          V14      V15                                     V16                     
                                    
 
 
 
MINI (IR) & PCL-5
 
MINI (IR) & PCL-5
 
Study 
Termination
Medication Tapering
Enroll
 
PCL-5
 
PCL-5
Experimental 
Session 3
 
PCL-5
 
 
PCL-5
 
 
PCL-5
 
 
PCL-5
 
 
PCL-5
 
PCL-5
 
PCL-5
 
PCL-5


 
 
 
Protocol and Synopsis MAPPUSX 
IND #063384 
 
A Multi-Site Open-Label Safety Extension Study of Manualized MDMA-Assisted Therapy for the 
Treatment of Participants with Posttraumatic Stress Disorder 
 
CURRENT APPROVED 
PROTOCOL 
AMENDED PROTOCOL 
Amendment 2, Version 1, 06 July 2021   
 
 
Amendment 3, Version 1, 15 March 2023 
 
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 
MAPS Public Benefit Corporation 
Phone number: +1 (877)-748-3767 
Additional contact information is available in the Study Operations 
Manual 
 
USE 
In conjunction with relevant Food and Drug Administration (FDA), 
Health Canada (HC), and Israeli Ministry of Health (MOH) guidance 


MAPS Public Benefit Corporation  
 
 
 
 
 
         MAPPUSX Protocol 
IND #063384 
 
 
 
 
 
 
      Amendment 3 Version 1: 15 March 2023 
Page 9 of 90 
Table of Contents 
Protocol Amendment Summary of Changes ............................................................................................ 2 
List of Tables ............................................................................................................................................. 12 
List of Figures ............................................................................................................................................ 13 
List of Abbreviations ................................................................................................................................ 14 
1.0 Introduction ......................................................................................................................................... 17 
1.1 Rationale ........................................................................................................................................... 17 
1.2 Background ....................................................................................................................................... 17 
1.2.1 PTSD .......................................................................................................................................... 17 
1.2.2 MDMA ....................................................................................................................................... 19 
1.2.3 MDMA-Assisted Therapy for PTSD ......................................................................................... 19 
1.2.4 Previous Clinical Experience with MDMA ............................................................................... 20 
2.0 Protocol Objectives ............................................................................................................................. 21 
2.1 Primary Objective ............................................................................................................................. 21 
2.2 Key Secondary Objective ................................................................................................................. 22 
2.3 Safety Objectives .............................................................................................................................. 22 
2.4 Exploratory Objectives ..................................................................................................................... 22 
3.0 Eligibility Criteria ............................................................................................................................... 23 
3.1 Inclusion Criteria .............................................................................................................................. 23 
3.2 Exclusion Criteria ............................................................................................................................. 24 
3.3 Lifestyle Modifications ..................................................................................................................... 26 
4.0 Protocol Design .................................................................................................................................... 27 
4.1 Study Design Overview .................................................................................................................... 27 
4.2 Planned Duration of Study ................................................................................................................ 31 
4.3 Interruptions and Accommodations Due to COVID-19 Pandemic or Any Other Unforeseen 
Emergency at Clinic Locations ............................................................................................................... 32 
4.4 Discontinuation and Completion Criteria ......................................................................................... 32 
4.4.1 Complete or Evaluable Participants ........................................................................................... 32 
4.4.2 Screen Failures ........................................................................................................................... 32 
4.4.3 Pre-Treatment Early Terminations ............................................................................................. 33 
4.4.4 Early Termination from the Study ............................................................................................. 33 
4.4.5 Lost to Follow-up ....................................................................................................................... 34 
4.5 End of Study Definition and Premature Discontinuation ................................................................. 34 
4.6 Rationale of Dose Selection .............................................................................................................. 34 
5.0 Therapy ................................................................................................................................................ 36 
5.1 Description of Therapeutic Method .................................................................................................. 36 
5.2 Therapy Team Qualifications............................................................................................................ 36 
5.3 Training and Supervision .................................................................................................................. 36 
5.4 Adherence to Therapeutic Method .................................................................................................... 36 
6.0 Measures and Reliability .................................................................................................................... 37 
6.1 Primary Outcome Measure ............................................................................................................... 37 
6.1.1 PCL-5 (PTSD Checklist) ........................................................................................................... 37 
6.2 Secondary Measure ........................................................................................................................... 38 
6.2.1 SDS (Sheehan Disability Scale) ................................................................................................. 38 
6.3 Safety Measures ................................................................................................................................ 38 
6.3.1 C-SSRS (Columbia Suicide Severity Rating Scale) .................................................................. 38 
6.4 Screening Measures .......................................................................................................................... 38 
6.4.1 MINI (Mini-International Neuropsychiatric Interview) ............................................................. 38 
6.5 Exploratory Measures ....................................................................................................................... 39 
6.5.1 LEC-5 (Life Events Checklist for DSM-5) ................................................................................ 39 


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IND #063384 
 
 
 
 
 
 
      Amendment 3 Version 1: 15 March 2023 
Page 10 of 90 
6.5.2 BDI-II (Beck Depression Inventory II) ...................................................................................... 39 
6.5.3 CPGS (Chronic Pain Grade Scale) ............................................................................................. 39 
6.5.4 EQ-5D-5L (EuroQol Five Dimensions-Five Levels Questionnaire) ......................................... 39 
6.5.5 AUDIT (Alcohol Use Disorders Identification Test) ................................................................. 40 
6.5.6 DUDIT (Drug Use Disorders Identification Test) ..................................................................... 40 
6.5.7 SRNU (Self-reported Nicotine Use) .......................................................................................... 40 
6.5.8 EAT-26 (Eating Attitudes Test) ................................................................................................. 40 
6.5.9 HPQSF (Health and Work Performance Absenteeism and Presenteeism Short Form) ............. 40 
6.5.10 UFEC (Utilization of Facility-based and Emergent Care) ....................................................... 41 
7.0 Study Procedures ................................................................................................................................ 41 
7.1 Screening Period ............................................................................................................................... 45 
7.1.1 Screening .................................................................................................................................... 45 
7.1.2 Initial Eligibility Assessment ..................................................................................................... 45 
7.1.3 Medical Assessments ................................................................................................................. 46 
7.1.4 Independent Rater Screening ..................................................................................................... 47 
7.1.5 Enrollment .................................................................................................................................. 48 
7.2 Preparatory Period ............................................................................................................................ 48 
7.2.1 Preparatory Sessions 1 and 2 ..................................................................................................... 49 
7.2.2 Preparatory Session 3 ................................................................................................................. 49 
7.3 Treatment Period ............................................................................................................................... 50 
7.3.1 Experimental Sessions ............................................................................................................... 50 
7.3.2 Telephone Contact After Experimental Sessions ....................................................................... 53 
7.3.3 Integrative Sessions.................................................................................................................... 54 
7.4 Study Termination ............................................................................................................................ 55 
7.4.1 Extension Studies ....................................................................................................................... 55 
7.4.2 Exit Plan/Plan for Moving Forward ........................................................................................... 55 
8.0 Investigational Product ...................................................................................................................... 56 
8.1 Description of Active Compounds .................................................................................................... 56 
8.1.1 Doses .......................................................................................................................................... 56 
8.1.2 Dose Modifications .................................................................................................................... 57 
8.1.3 Stability ...................................................................................................................................... 57 
8.2 Handling ............................................................................................................................................ 57 
8.2.1 Encapsulation, Packaging, and Labeling ................................................................................... 57 
8.2.2 Accountability ............................................................................................................................ 57 
8.2.3 Storage ....................................................................................................................................... 58 
8.2.4 Administration ........................................................................................................................... 58 
8.2.5 Treatment Compliance ............................................................................................................... 58 
8.3 Participant Numbering ...................................................................................................................... 58 
8.4 Bias Minimization ............................................................................................................................. 58 
9.0 Risks ..................................................................................................................................................... 59 
9.1 Risk Assessment ............................................................................................................................... 59 
10.0 Safety .................................................................................................................................................. 66 
10.1 Adverse Events, Serious Adverse Events, Adverse Events of Special Interest and Other Safety 
Reporting ................................................................................................................................................ 66 
10.1.1 AE Definition ........................................................................................................................... 66 
10.1.1.1 AE Severity Grading Criteria ............................................................................................ 67 
10.1.1.2 AE Causality Assessment ................................................................................................. 67 
10.1.2 Serious Adverse Events (SAE) ................................................................................................ 67 
10.1.2.1 SAE Definition .................................................................................................................. 68 
10.1.3 Adverse Events of Special Interest (AESI) ............................................................................... 68 
10.1.4 Other Reportable Information .................................................................................................. 69 


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IND #063384 
 
 
 
 
 
 
      Amendment 3 Version 1: 15 March 2023 
Page 11 of 90 
10.1.5 SAE and AESI Reporting ........................................................................................................ 69 
10.1.6 Pregnancy Reporting ................................................................................................................ 70 
10.1.7 Participant Discontinuation or Withdrawal from Study ........................................................... 70 
10.2 Other Significant Events ................................................................................................................. 71 
10.3 Pregnancy ........................................................................................................................................ 71 
10.3.1 Definition of Able to Become Pregnant ................................................................................... 71 
10.3.2 Contraception Guidelines ......................................................................................................... 71 
10.3.3 Follow-up Requirements .......................................................................................................... 72 
10.4 Data Monitoring Committee ........................................................................................................... 72 
11.0 Concomitant Medications................................................................................................................. 73 
11.1 Tapering Instructions ...................................................................................................................... 73 
11.2 Allowed Concomitant Medications ................................................................................................ 73 
11.3 Prohibited Medications ................................................................................................................... 74 
11.3.1 Prohibited Medications prior to the Experimental Sessions ........................................................ 75 
12.0 Clinical Laboratory Assessments .................................................................................................... 75 
13.0 Statistical Considerations ................................................................................................................. 76 
13.1 Power and Sample Size Determination ........................................................................................... 76 
13.2 Statistical Analyses ......................................................................................................................... 76 
13.2.1 Effectiveness Analyses ............................................................................................................ 77 
13.2.1.1 Primary Outcome .............................................................................................................. 77 
13.2.1.2 Secondary Outcome .......................................................................................................... 77 
13.2.2 Safety Analyses ........................................................................................................................ 77 
13.2.3 Concomitant Medications ........................................................................................................ 77 
13.2.4 Analysis of Exposure ............................................................................................................... 77 
14.0 Study Governance ............................................................................................................................. 77 
14.1 Ethics............................................................................................................................................... 78 
14.1.1 Financial Disclosure ................................................................................................................. 78 
14.1.2 Informed Consent ..................................................................................................................... 78 
14.2 Study Monitoring, Auditing, and Documentation........................................................................... 79 
14.2.1 Source Records ........................................................................................................................ 79 
14.3 Confidentiality ................................................................................................................................ 79 
14.4 Costs to Participants ........................................................................................................................ 80 
14.5 Treatment and Compensation for Study Related Injury ................................................................. 80 
14.6 Record Retention ............................................................................................................................ 81 
14.7 Publication Policy ........................................................................................................................... 81 
15.0 Appendix A: Sub-study without Overnight Stays .......................................................................... 82 
References .................................................................................................................................................. 86 
 
 


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List of Tables 
 
Table 1: Study Design Overview ................................................................................................................ 29 
Table 2: Primary Outcome (PCL-5) Data Collection by Visit .................................................................... 31 
Table 3: Dose Regimen of MDMA ............................................................................................................. 35 
Table 4: Protocol Objectives and Assessment Tools .................................................................................. 37 
Table 5: Time and Events-Study Procedures .............................................................................................. 42 
Table 6: Time and Events-Study Measures ................................................................................................ 44 
Table 7: Schedule of Procedures for Experimental Sessions ...................................................................... 51 
Table 8: Study Medication Intervention(s) Administered .......................................................................... 56 
Table 9: Risk Assessments .......................................................................................................................... 60 
 
 


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List of Figures 
 
Figure 1: Study Structure Overview ........................................................................................................... 28 
 
 


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List of Abbreviations 
 
°C 
 
Degrees Celsius 
A: G 
 
Albumin: Globulin 
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 
cGMP  
Good Manufacturing Practice 
CMC  
Chemistry Manufacturing and Control 
CPGS  
Chronic Pain Grade Scale 
CRA 
 
Clinical Research Associate 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DDIS  
Dissociative Disorders Interview Schedule 
DID 
 
Dissociative Identity Disorder 
dIGPP  
Cohen’s d Independent Groups Pre-test Post-test 
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 
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 
ESC 
 
European Society of Cardiology 
EQ-5D-5L 
EuroQol Five Dimensions-Five Levels Questionnaire 
FDA 
 
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
GERD  
Gastroesophageal Reflux Disease 
HCV 
 
Hepatitis C Virus 
HIPAA  
Health Insurance Portability and Accountability 
HIV 
 
Human Immunodeficiency Virus 


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HPA 
 
Hypothalamic-pituitary-adrenal 
HPMC  
Hydroxypropyl Methylcellulose 
HPQSF  
Health and Work Performance Absenteeism and Presenteeism Short Form 
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 
IR 
 
Independent Rater 
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
ITT 
 
Intent-to-Treat 
IUD 
 
Intrauterine Device 
IUS 
 
Intrauterine Hormone-releasing System 
IWRS  
Interactive Web Randomization System 
kg 
 
Kilogram 
LEC-5  
Life Events Checklist 
LTFU  
Long-term Follow-up 
MAPS  
Multidisciplinary Association for Psychedelic Studies 
MAOI  
Monoamine Oxidase Inhibitor 
MCH  
Mean Corpuscular Hemoglobin 
MCHC  
Mean Corpuscular Hemoglobin Concentration 
MCV  
Mean Corpuscular Volume 
MDMA 
3,4-methylenedioxymethamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
 
Milligram 
MINI  
Mini-International Neuropsychiatric Interview 
mITT   
Modified Intent-to-Treat  
 
 
mmHg  
Milligrams of Mercury 
MMRM 
Mixed Model Repeated Measure 
MPBC  
MAPS Public Benefit Corporation 
ms 
 
Millisecond 
PABP                Participant able to become pregnant 
PCL-5  
PTSD Checklist for DSM-5  
PHI 
 
Protected Health Information 
PTSD  
Posttraumatic Stress Disorder 
PVC 
 
Premature Ventricular Contraction 
RACT  
Risk Assessment and Categorization Tool  
RBC 
 
Red Blood Cell 
RDW  
Red Cell Distribution Width 
SAE 
 
Serious Adverse Event 
SDS 
 
Sheehan Disability Scale 
SGOT  
Serum Glutamic Oxaloacetic Transaminase 
SNRI  
Serotonin-norepinephrine Reuptake Inhibitor 
SRNU  
Self-reported Nicotine Use 
SSRI 
 
Selective serotonin reuptake inhibitor 
TEAE  
Treatment Emergent Adverse Event 
TSH 
 
Thyroid-stimulating Hormone 
UFEC  
Utilization of Facility-based and Emergent Care 
U.S. 
 
United States 


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


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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. 
 
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 justified 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 completed two Phase 3 
randomized, placebo-controlled, two-arm, double-blind, multi-site studies of three once-monthly 
Experimental Sessions of therapy combined with either a flexible dose of MDMA or placebo, along with 
non-drug preparatory and integrative therapy. 
 
Participants who were randomized to the placebo arm in either of the two parent Phase 3 trials and who 
meet all other entry criteria will be eligible and invited to participate in this open-label safety extension 
study. In addition, participants in the parent Phase 3 trials whose study participation was affected by the 
Coronavirus 2019 (COVID-19) global pandemic or other unforeseen circumstances and were unable to 
complete the study (enrolled but not treated or enrolled, treated, but could not complete three 
Experimental Sessions prior to termination of the study) may participate in this open-label study. This 
study will follow a similar schedule of events as the Phase 3 protocols but will measure PTSD severity 
using a self-report measure, the PTSD Checklist (for Diagnostic and Statistical Manual of Mental 
Disorders, 5th edition [DSM-5]) (PCL-5). 
 
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 [1]. The four main symptom categories 
described in the DSM-5, include arousal and reactivity, avoidance of triggers, negative thoughts and 
feelings, and intrusive thoughts and nightmares [2]. 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 [3-5]. People who suffer from PTSD often relive the experience through nightmares and 


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flashbacks, have poor sleep quality, and feel detached or estranged [6]. 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 [7]. 
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 [7]. 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 [8, 9]. 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 [10]. 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 [11]. 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 [12]. There are an estimated 20 to 22 suicides a day 
by veterans [13]. 
 
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 Clinician Administered PTSD Scale (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 [14-16]. PTSD rarely remits after 12 
weeks of SSRIs, and many patients who are placed on maintenance treatment experience partial relief of 
symptoms, which fully return upon discontinuation of treatment. Adverse effects of maintenance SSRI 
treatment that contribute to discontinuation include sexual dysfunction, weight gain, and sleep 
disturbance. Variable SSRI treatment outcomes have led to recommendations of trauma-focused 
psychotherapy as routine first-line treatment by the VA’s National Center for PTSD in the U.S., as well as 
by the World Health Organization (WHO). An extensive list of medications, namely antipsychotics, 
anxiolytics, antidepressants, and sleep aids, are frequently prescribed off-label but have only small effect 
sizes in reducing PTSD symptoms. PTSD brings a high public burden, both economically and socially, by 
increased use of health and social services, lost wages, and disability payments [17, 18]. Given the 
chronicity of PTSD, low compliance evidenced by high dropouts, and limited recovery with current 
medications contributing to serious outcomes, PTSD patients suffer from unmet medical need.  
 
One treatment approach is to develop medications and/or therapeutic treatments that may 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 


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movement desensitization and reprocessing (EMDR) have also proven to be effective in treating some 
symptoms of PTSD [19, 20], 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 [21]. 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 [22] for a review). Examples of this are virtual reality-assisted exposure 
therapy [23, 24] and D-cycloserine-assisted psychotherapy [25]. 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 [26, 27]. 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 [28-34]. 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, with most effects returning to 
baseline or near-baseline levels 6 hours after final drug administration [35-37]. 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) [38, 39]. Studies of regular or problematic Ecstasy 
users indicate that on average, regular use occurs no more often than once a week [40]. 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 psychotherapies for PTSD involve the induction and extinction of abnormal autonomic responses 
through revisiting traumatic experiences in psychotherapy with an appropriate level of emotional 
engagement [20]. To be effective, exposure must be accompanied by a degree of emotional engagement 
or “fear activation” while avoiding dissociation or overwhelming emotion [41]. This has been referred to 
as working within the “optimal arousal zone” or “window of tolerance” [42-44]. 
 
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 [45], and there is some 
indication that MDMA may increase activity in the prefrontal cortex [46]. Brain imaging after MDMA 
indicates less reactivity to angry facial expressions and greater reward in happy faces [45]. 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 [47-49]. 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 


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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 [50-53]. 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 [54]. 
Participants are able to experience and express fear, anger, and grief with less likelihood of feeling 
overwhelmed by these emotions. MDMA seems to engender internal awareness that even painful feelings 
that arise are an important part of the therapeutic process. In addition, feelings of empathy, love, and deep 
appreciation often emerge, along with a clearer perspective of the trauma as a past event, a more accurate 
perspective about its significance, and a heightened awareness of the support and safety that exists in the 
present. As a result, MDMA-assisted therapy may enable the participants to restructure their intra-psychic 
realities and develop a wider behavioral and emotional repertoire with which to respond to anxiogenic 
stimuli.  
 
The therapeutic method is described in further detail in the Treatment Manual of MDMA-Assisted 
Therapy, 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 therapeutic techniques with the 
administration of MDMA as a pharmacological adjunct intended to enhance certain aspects of therapy. 
Chemists Shulgin and Nichols were the first to report on the effects of MDMA in humans [55], with 80 to 
160 milligrams (mg) MDMA required to produce desired subjective effects in humans [55, 56]. MDMA 
was found to robustly influence human emotional status in a unique way [55] without adversely affecting 
physiological functions or perception, such as visual perception or cognition [35, 37, 57, 58]. In the 
1970s, psychotherapists used MDMA-assisted therapy to treat psychological disorders, including anxiety 
[59]. Legal therapeutic use continued until its placement on the U.S. list of Schedule I substances in 1985 
[51, 54, 60]. An estimated 500,000 doses of MDMA were administered during psychotherapy and 
personal growth sessions in North America prior to its scheduling [51, 61]. A few uncontrolled human 
studies of MDMA assessing safety in a therapeutic setting occurred in the 1980s [62, 63]. 
 
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 [64, 65]. 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 [53]. 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 (Clinician-
Administered PTSD Scale for DSM-4 [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. 


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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) [52, 66] 
and one in Switzerland (MP2) [67, 68]. 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 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 [69]. As of October 01, 2022, with 426 individuals exposed to MDMA in 
the sponsor’s development program across various indications and at least 1,548 participants in MDMA 
research studies conducted without sponsor support (for a total of at least 1,974 individuals), the sponsor 
has observed an acceptable risk-benefit ratio for MDMA-assisted therapy. Across Phase 2 studies, 75 mg-
125 mg MDMA was statistically superior to 0 mg to 40 mg MDMA based on a t-test of difference in 
CAPS-4 severity scores from Baseline, 2 months after two blinded Experimental Sessions (p<0.001). The 
dropout rate across studies was 7.5% (8 of 107). Large between-groups effect size estimates (0.9), initial 
indications of efficacy, and favorable safety outcomes support expanding the research initiative to 
encompass a larger sample of participants with PTSD in a Phase 3 program. The first randomized, 
double-blind, placebo-controlled multi-site Phase 3 study for MDMA-assisted therapy for severe PTSD in 
the United States, Canada and Israel had a total of 90 randomized participants (46 randomized to MDMA 
and 44 to placebo). 67% of the participants in the MDMA group no longer met the diagnostic criteria for 
PTSD after 3 experimental sessions as confirmed by the change in CAPS-5 total severity score [70]. An 
identical randomized, double-blind, placebo-controlled multi-site Phase 3 study confirming the efficacy 
and safety of MDMA-assisted therapy for the treatment of PTSD was recently concluded. 
 
A comprehensive review of MDMA research can be found in the IB supplied by the sponsor. This 
document should be reviewed prior to initiating the protocol. 
 
2.0 Protocol Objectives 
The overall objective of this study is to use standard clinical measures to explore the safety and 
effectiveness of MDMA-assisted therapy with a flexible dose of MDMA in reducing PTSD and 
associated symptoms. 
 
2.1 Primary Objective 
The primary objective of this study is to evaluate the effectiveness of MDMA-assisted therapy for PTSD, 
as measured by the reduction in PCL-5 total score from Visit 3 to Visit 16. 


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2.2 Key Secondary Objective 
The key secondary objective of this study is to evaluate the effectiveness of MDMA-assisted therapy for 
PTSD in functional impairment, as measured by the mean change in Sheehan Disability Scale (SDS) item 
scores from Visit 3 to Visit 16.  
 
2.3 Safety Objectives 
The overall safety objective is to assess 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:  
 
1. Assess incidence of AEs during Experimental Sessions that may be indicative of a medical 
complication of the Investigational Medicinal Product (IMP) such as clinical signs and symptoms 
of chest pain, shortness of breath, or neurological symptoms or any other signs or symptoms that 
prompt additional vital sign measurements 
2. Assess incidence of AEs by severity 
3. Assess incidence of TEAEs by severity 
4. Assess incidence of TEAEs by severity reported during an Experimental Session, 1 day, and 2 
days after IMP administration 
5. Assess incidence of AESIs, defined as AEs specified in the protocol related to cardiac function, 
suicidality, and abuse liability 
6. Assess incidence of AEs by severity categorized as leading to discontinuation of IMP, resulting in 
death or hospitalization, and continuing at Study Termination 
7. Assess incidence of SAEs 
8. Assess incidence of concomitant medications taken during an Experimental Session, 1 day, and 2 
days after IMP administration 
9. Assess incidence of psychiatric concomitant medications taken during the Treatment Period 
10. Assess incidence of positive or serious suicidal ideation and positive suicidal behavior assessed 
with the Columbia Suicide Severity Rating Scale (C-SSRS) 
11. Assess changes in blood pressure (BP), heart rate, and body temperature from pre-IMP 
administration to end of each Experimental Session 
 
2.4 Exploratory Objectives 
These objectives may be explored to characterize participants receiving MDMA-assisted therapy to 
support the primary objective: 
 
1. Explore the effect of presence of secondary traumatic stressors identified on the Life Events 
Checklist (LEC-5) on the PCL-5 total severity analysis 
2. Explore differences from Visit 3 to Visit 16 in:  
a. Depression (BDI-II)  
b. Chronic pain (CPGS) 
c. Quality of life (EQ-5D-5L) 
d. Nicotine use (SRNU)  
e. Eating habits (EAT-26) 
f. Workplace productivity (HPQSF) 
3. Explore differences from Screening to Visit 16 in alcohol use (AUDIT) and drug use (DUDIT) 


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3.0 Eligibility Criteria 
3.1 Inclusion Criteria 
At the completion of Screening, participants must meet all eligibility criteria and agree to all lifestyle 
modifications to be enrolled. Each participant will then enter the Preparatory Period which includes 
medication tapering, if needed, and non-drug Preparatory Sessions. 
 
In the below criteria, “parent study” refers to a MAPS-sponsored Phase 3 clinical trial of MDMA-assisted 
therapy, namely MAPP1 or MAPP2. 
 
Potential participants are eligible to enroll in the protocol if they: 
 
1. Were previously enrolled in a parent study, met all criteria in the parent study at the time of 
enrollment in the parent study, and (meet one of the following): 
a. At time of unblinding, their treatment assignment was to the placebo arm; or,  
b. Did not begin Experimental Sessions due to the COVID-19 global pandemic or other 
unforeseen circumstances; or, 
c. Completed fewer than three Experimental Sessions prior to Study Termination due to the 
COVID-19 global pandemic or other unforeseen circumstances. 
2. Are considered in good standing with the study site at which they enrolled in a parent study; if, in 
the opinion of the investigator, therapy team, and Medical Monitor, the participant was compliant 
with protocol requirements, even if they were unable to complete all study visits.  
3. Are at least 18 years old. 
4. Are fluent in speaking and reading the predominantly used or recognized language of the study 
site. 
5. Are able to swallow pills. 
6. Agree to have study visits recorded, including Experimental Sessions and non-drug therapy 
sessions. 
7. 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.  
8. Must agree to inform the investigators within 48 hours of any medical conditions and procedures. 
9. For participants assigned female sex at birth: 
• 
A participant is eligible to participate if not pregnant, and one of the following conditions 
applies: 
o Is not able to become pregnant as defined in Section 10.3.1 Definition of Able to Become 
Pregnant. 
OR 
o Is a person able to be pregnant (PABP) and using a contraceptive method that is highly 
effective, with a failure rate of <1%, as described in Section 10.3.2 Contraception 
Guidelines, during the study intervention period and for at least 10 days after the last dose  
of study intervention. The investigator should evaluate the potential for contraceptive 
method failure (e.g., noncompliance or drug interactions with oral contraception [e.g., 
antibiotics], recently initiated) in relationship to the first dose of study intervention. 
PABP who are taking oral contraception and antibiotics, or other medications known to 
decrease the effectiveness of oral contraception, should be counseled to use a barrier 
method of birth control as well as oral contraception for the duration of the antibiotic or 
other drug interaction and for 10 days thereafter. 
• 
A PABP must have a negative highly sensitive pregnancy test (urine or serum as required by 
local regulations) at study entry and prior to each experimental session. 


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• 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a participant with an early undetected 
pregnancy. 
10. Agree to the following lifestyle modifications (described in more detail in Section 3.3 Lifestyle 
Modifications): comply with requirements for fasting and refraining from certain medications 
prior to Experimental Sessions, not participate in any other interventional clinical trials during the 
duration of this study without prior approval of the Medical Monitor, remain overnight at the 
study site after each Experimental Session, and commit to medication dosing, therapy, and study 
procedures. 
 
Medical History 
 
11. At time of enrollment, met all inclusion and no exclusion criteria in parent study.  
12. 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. 
13. May have asymptomatic Hepatitis C virus (HCV) that has previously undergone evaluation and 
treatment as needed. 
14. May have current mild or moderate alcohol or cannabis use disorder (meets 3 to 5 of 11 
diagnostic criteria per DSM-5). 
15. May have a history of or current Diabetes Mellitus (Type 2) if additional screening measures rule 
out underlying cardiovascular disease, if the condition is judged to be stable on effective 
management, and with approval by the Medical Monitor. 
16. May have hypothyroidism if taking adequate and stable thyroid replacement medication. 
17. May have a history of, or current, glaucoma if approval for study participation is received from an 
ophthalmologist. 
 
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 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. 
3. Have any current problem which, in the opinion of the investigator or Medical Monitor, might 
interfere with participation. 
 
Psychiatric History 
 
4. Have received Electroconvulsive Therapy (ECT) within 12 weeks of enrollment. 
5. Have a history of or a current primary psychotic disorder, bipolar disorder 1 assessed via MINI 
and clinical interview. 
6. Have a current eating disorder with active purging assessed via MINI and clinical interview. 
7. Have current major depressive disorder with psychotic features assessed via MINI. 
8. Have a current severe alcohol or cannabis use disorder within the 12 months prior to enrollment 
(meets at least 6 of 11 diagnostic criteria per DSM-5). 
9. Have an active illicit (other than cannabis) or prescription drug substance use disorder at any 
severity within 12 months prior to enrollment. 
10. 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 


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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. 
11. Would present a serious risk to others as established through clinical interview and contact with 
treating psychiatrist. 
12. Require ongoing concomitant therapy with a psychiatric medication with exceptions described in 
Section 11.0 Concomitant Medications. 
 
Medical History 
 
13. 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 or Medical Monitor to significantly increase the risk 
of MDMA administration by any mechanism would require exclusion.  
14. 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). 
15. Have a history of ventricular arrhythmia at any time, other than occasional premature ventricular 
contractions (PVCs) in the absence of ischemic heart disease. 
16. Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been 
successfully eliminated by ablation. 
17. Have a history of arrhythmia, other than occasional PACs or PVCs in the absence of ischemic 
heart disease, within 12 months of screening. Participants with a history of atrial fibrillation, atrial 
tachycardia, atrial flutter or paroxysmal supraventricular tachycardia or any other arrhythmia 
associated with a bypass tract may be enrolled only if they have been successfully treated with 
ablation and have not had recurrent arrhythmia for at least 1 year off all antiarrhythmic drugs, or 
are under adequate and stable pharmacologic treatment for atrial fibrillation for at least a year, as 
confirmed by a cardiologist.  
18. Have a marked Baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a 
QTcF interval>450 milliseconds [ms] in males and>460 ms in females corrected by Fridericia’s 
formula). For transgender or non-binary participants, QTcF interval will be evaluated based on 
sex assigned at birth, unless the participant has been on hormonal treatment for five or more 
years. Participants whose QTcF exceeds this value during screening may be enrolled if a pre-
study concomitant medication is suspected to be prolonging the QT-interval. ECGs should be 
repeated after tapering off the pre-study concomitant medication to ensure the participant meets 
eligibility criteria prior to IMP dosing. 
Note: The QTcF is the QT interval corrected for heart rate according to Fridericia's formula. It 
is either machine-read or manually over-read.  


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19. Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, hypokalemia, 
family history of Long QT Syndrome). 
20. Require use of concomitant medications that prolong the QT/QTc interval during Experimental 
Sessions. Refer to Section 11.0 Concomitant Medications. 
21. Have symptomatic liver disease or have significant liver enzyme elevations. 
22. Have a recent history of clinically significant hyponatremia or hyperthermia. 
23. Weigh less than 48 kilograms (kg). 
24. Are pregnant or nursing or are able to become pregnant and are not practicing an effective means 
of contraception. 
 
3.3 Lifestyle Modifications 
All participants must agree to the following lifestyle modifications at enrollment and throughout the 
duration of the study. Participants are eligible to enroll in the study if they: 
 
• 
Are willing to commit to medication dosing, therapy sessions, follow-up sessions, completing 
evaluation instruments, and all necessary telephone contact. 
• 
Agree to not participate in any other interventional clinical trials during the duration of this study 
without prior approval of the Medical Monitor. 
 
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. 
• 
Agree not to use alcohol or cannabis after 12:00 A.M. (midnight) before 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 opioids (per Section 11.0 Concomitant Medications), if 
used for pain management, leading up to the Experimental Session in order to avoid taking the 
medication for at least 12 hours prior to the initial IMP administration and 24 hours after. During 
this period, the participant will be allowed to take the medication if needed for intolerable pain 
flare-ups 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). 
• 
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 contraception, thyroid 
hormones, anti-hypertensives, or other medications approved by the research team). 
 


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Post Experimental Session (for exceptions, see Appendix A) 
 
• 
Are willing to remain overnight at the study site after each Experimental Session until after the 
Integrative Session the next morning. 
• 
Agree to not drive after each Experimental Session until after the Integrative Session the next 
morning. 
 
4.0 Protocol Design 
4.1 Study Design Overview 
This multi-site open-label safety extension study of MDMA-assisted therapy for the treatment of 
participants with posttraumatic stress disorder will be conducted in N≈100 participants, by invitation 
only. 
 
For each participant, the study will consist of:  
 
• 
Screening Period: phone screen, informed consent, eligibility assessment, and enrollment of 
eligible participants  
• 
Preparatory Period: medication tapering, Preparatory Sessions 
• 
Treatment Period: three monthly Experimental Sessions over up to 4 months, followed by 
Integrative Sessions 
• 
Study Termination: Primary Outcome PCL-5 4 weeks after third Experimental Session 
• 
Invitation to participate in Long-term Follow-up (LTFU) extension study: at least 6 months 
after last Experimental Session 
 
The treatment consists of a flexible dose of MDMA, followed by a supplemental dose unless tolerability 
issues emerge, administered with therapy in three open-label approximately monthly Experimental 
Sessions. This 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 PCL-5 
from Visit 3, is assessed at Visit 16. 


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Figure 1: Study Structure Overview 
 
 
 
Prestudy
Treatment Period 
-
 
Treatment 1:
Approximately 4 weeks
Treatment 2:
Approximately 4 weeks
Treatment 3:
Approximately 4 weeks
 Medication Tapering
Preparatory Period: 
At least 5 days, depending on
medication tapering length
Approximately 1 month after 
Experimental Session 3
Summary of Events
 
Medication Tapering
Preparatory Sessions
14 Day Phone 
Follow-up 
Experimental 
Session 1
Integrative Sessions
1.1, 1.2, 1.3
-
14 Day Phone 
Follow-up 
Experimental 
Session 2
Integrative Sessions 
2.1, 2.2, 2.3
14 Day Phone 
Follow-up 
Integrative Sessions 
3.1,3.2,3.3
 Screening     V0                    V1          V2        V3                                          V4          V5                           V6         V7                               V8          V9                          V10       V11                                V12        V13                          V14      V15                                     V16                     
                                    
 
 
 
MINI (IR) & PCL-5
 
MINI (IR) & PCL-5
 
Study 
Termination
Medication Tapering
Enroll
 
PCL-5
 
PCL-5
Experimental 
Session 3
 
PCL-5
 
 
PCL-5
 
 
PCL-5
 
 
PCL-5
 
 
PCL-5
 
PCL-5
 
PCL-5
 
PCL-5


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Table 1: Study Design Overview 
Screening Period 
From Consent to Enrollment (Visit 0): 1 to 10 weeks 
Study Visit 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Screening 
Screening  
Multiple visits over 7 to 
70 days/ 
After phone screen 
 
At initial visit, obtain Informed Consent and assess all 
screening measures (including PCL-5 and Interim C-SSRS), 
interim medical history, and interim and current medications. 
Contact outside providers and order medical records (as 
needed), physical exam, labs (including pregnancy and drug 
tests), ECG, and 1-minute rhythm strip. Once all results are 
obtained, review along with notes from all screening visits and 
measures. If eligible, send results of LEC-5 & C-SSRS to IR. 
Independent 
Rater 
Screening 
1 hour/ 
After initial screening 
visit 
After initial eligibility is reviewed, an IR will conduct the 
MINI and C-SSRS via telemedicine. Results will be confirmed 
by clinical observation during the Preparatory Period, but the 
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, followed by five half-lives of drug or active metabolite 
(whichever is longer),  
(for stabilization prior to V3). For non-selective irreversible 
MAOIs, a 2-week washout period following the taper is 
required (3 weeks in the case of imipramine and clomipramine, 
tricyclic antidepressants with MAOI activity). 
 
Preparatory Period 
From Preparatory Session 1 (Visit 1) to Preparatory Session 3 (Visit 3): 1 to 11 weeks 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Preparatory Period 
Preparatory 
Session 1 
(Visit 1) 
1.5 hours/ 
0 to 14 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 or eligibility. 
Preparatory 
Session 2 
(Visit 2) 
1.5 hours/ 
2 to 75 days after V1 
90-minute Preparatory Session. 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 77 
days after V0 
If needed, confirm medication taper and stabilization is 
complete. 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. 
Preparatory 
Session 3 
Baseline 
PCL-5 T1 
(Visit 3) 
1.5 hours/ 
As soon as possible post 
V2 & Medication Taper; 
1 to 14 days before V4 
90-minute Preparatory Session. PCL-5, SDS, C-SSRS, and 
exploratory measures collected by study team.  
 


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Treatment Period 
From Experimental Session 1 (Visit 4) to Integrative Session 3.3 (Visit 15): 6 to 20 weeks 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Treatment 1 
Experimenta
l Session 1 
(Visit 4) 
At least 6 hours + 
overnight/ 
1 to 14 days after V3 
First Experimental Session occurs 1 to 14 days after 
Preparatory Session 3 (Visit 3), it lasts at least 6 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 5) 
1.5 hours/ 
Morning after V4 
90-minute Integrative Session the morning after Visit 4. 
Followed by phone check-ins every other day for 14 days. C-
SSRS administered during Integrative Session 1.1 and phone 
calls.  
Integrative 
Session 1.2 
(Visit 6) 
1.5 hours/ 
10 to 18 days after V4; 
at least 2 days after V5 
Between 10 and 18 days after Visit 4, a 90-minute Integrative 
Session is completed. C-SSRS, PCL-5, and LEC-5 are 
administered.  
Integrative 
Session 1.3 
(Visit 7) 
1.5 hours/ 
at least 2 days after V6; 
1 to 14 days before V8  
90-minute Integrative Session at least 2 days after Integrative 
Session 1.2 (Visit 6) and 1 to 14 days before Experimental 
Session 2 (Visit 8). C-SSRS administered. 
Treatment 2 
Experimenta
l Session 2 
(Visit 8) 
At least 6 hours + 
overnight/ 
21 to 56 days after V4;  
1 to 14 days after V7 
Second Experimental Session occurs 1 to 14 days after 
Integrative Session 1.3 (Visit 7), it lasts at least 6  hours with 
overnight stay. Dose is 80 or 120 mg plus supplemental 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 9) 
1.5 hours/ 
Morning after V8 
 
90-minute Integrative Session the morning after Visit 8. 
Followed by phone check-ins every other day for 14 days. C-
SSRS administered during Integrative Session 2.1 and phone 
calls. 
Integrative 
Session 2.2 
(Visit 10) 
1.5 hours/ 
10 to 18 days after V8; 
at least 2 days after V9 
Between 10 and 18 days after Visit 8, a 90-minute Integrative 
Session is completed. C-SSRS, PCL-5, and LEC-5 are 
administered. 
Integrative 
Session 2.3 
(Visit 11) 
1.5 hours/ 
at least 2 days after 
Integrative Session 2.2 
(Visit 10) 
1 to 14 days before V12 
90-minute Integrative Session at least 2 days after Integrative 
Session 2.2 (Visit 10) and 1 to 14 days before Experimental 
Session 3 (Visit 12). C-SSRS administered.  
Treatment 3 
Experimenta
l Session 3 
(Visit 12) 
At least 6 hours + 
overnight/ 
21 to 56 days after V8;  
1 to 14 days after V11 
Third Experimental Session occurs 1 to 14 days after 
Integrative Session 2.3 (Visit 11), it lasts at least 6 hours with 
overnight stay. Dose is 80 or 120 mg plus supplemental 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 13) 
1.5 hours/ 
Morning after V12 
90-minute Integrative Session the morning after Visit 12. 
Followed by phone check-ins every other day for 14 days. C-
SSRS administered during Integrative Session 3.1 and phone 
calls. 
Integrative 
Session 3.2 
(Visit 14) 
1.5 hours/ 
10 to 18 days after V12; 
at least 2 days after V13 
Between 10 and 18 days after Visit 12, a 90-minute Integrative 
Session is completed. C-SSRS, PCL-5, and LEC-5 are 
administered. 
Integrative 
Session 3.3 
(Visit 15) 
1.5 hours/ 
At least 2 days after V14 
90-minute Integrative Session at least 2 days after Integrative 
Session 3.2 (Visit 14). C-SSRS administered. 
 


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Study Termination 
From Experimental Session 3 (Visit 12) until Study Termination (Visit 16): 24 to 32 days  
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing 
Brief Description of Events  
Primary Outcome 
Study Termination 
Primary 
Outcome 
PCL-5 T5 
Study 
Termination 
(Visit 16) 
 
2 hours/ 
24 to 32 days after V12 
 
Primary Outcome PCL-5 and LEC-5 completed. Complete 
self-reported and safety measures. Create an exit plan for 
participant. Collect weight and final blood pressure. Invite 
participant to the extension study for LTFU.  
 
Table 2: Primary Outcome (PCL-5) Data Collection by Visit 
PCL-5 Number 
Visit 
Description/Timing 
Initial PCL-5 T0 
Screening 
Prior to enrollment and initiation of tapering 
Baseline PCL-5 T1 
V3 
Baseline 
After tapering and stabilization, at Preparatory Session 3 (Visit 3) 
PCL-5 T2 
V6 
10 to 18 days after Experimental Session 1 
At Integrative Session 1.2 (Visit 6) 
PCL-5 T3 
V10 
10 to 18 days after Experimental Session 2 
At Integrative Session 2.2 (Visit 10) 
PCL-5 T4 
V14 
10 to 18 days after Experimental Session 3 
At Integrative Session 3.2 (Visit 14) 
Primary Outcome  
PCL-5 T5 
V16 
24 to 32 days after Experimental Session 3 
At Study Termination (Visit 16) 
 
4.2 Planned Duration of Study 
Full screening may take 70 days after Informed Consent is obtained during the Informed Consent visit. 
The Preparatory Period begins at enrollment and can be as brief as 5 days but depending on medication 
tapering could be as long as necessary to ensure an appropriate medication washout. An appropriate 
psychoactive medication taper schedule should be defined by the treating physician. The taper will be 
followed by a washout period of five half-lives of drug or active metabolite (whichever is longer). For 
non-selective irreversible MAOIs, a 2-week washout period following the taper is required (3 weeks in 
the case of imipramine and clomipramine, tricyclic antidepressants with MAOI activity). The taper 
followed by washout should be completed for psychological stabilization prior to Baseline PCL-5 (Visit 
3). Medication taper for psychoactive medications should occur prior to Visit 3. Medication taper for 
medications with drug-drug interactions without a psychiatric concern should occur prior to Visit 4. The 
Treatment Period will consist of three Experimental Sessions 3 to 8 weeks apart with associated non-drug 
Integrative Sessions.  
 
Four weeks after the final Experimental Session 3 (Visit 12) and after the final Integrative Session 3.3 
(Visit 15), participants will complete Study Termination (Visit 16), including administration of the 
Primary Outcome PCL-5 assessment. 
 
The minimum time that a participant who completes all study visits from Screening to Study Termination 
will be in the clinical trial is 13 weeks, and the maximum is dependent on medication tapering. The 
average participant is expected to complete the study in 22 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 a LTFU extension study at least 6 
months after the last Experimental Session. 
 
4.3 Interruptions and Accommodations Due to COVID-19 Pandemic or Any Other 
Unforeseen Emergency at Clinic Locations 
This clinical trial may be impacted by the Coronavirus Disease 2019 (COVID-19) global pandemic. 
Special arrangements may be required for study continuation and participant and study site staff safety 
due to this 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 when 
applicable: 
 
• 
Preparatory and Integrative Visits 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 or initiating 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.  
 
4.4 Discontinuation and Completion Criteria 
4.4.1 Complete or Evaluable Participants 
A participant is considered ‘Evaluable’ and eligible for the Modified Intent-to-Treat (mITT) analysis if 
they have completed at least one Experimental Session and one PCL-5 assessment beyond Baseline.  
 
A participant is considered ‘Evaluable and Completed Per Protocol’ if they have completed all 
Experimental Sessions and PCL-5 assessments as planned. These participants will be included in the 
mITT analysis set and the Per Protocol analysis set. 
 
A participant is considered ‘Evaluable and Early Termination’ if they have completed at least one 
Experimental Session and one PCL-5 assessment beyond Baseline but terminated early from treatment. 
These participants will be included in the mITT analysis.  
 
4.4.2 Screen Failures 
‘Screen Failures’ are defined as participants who pass phone screening but are deemed ineligible before 
successfully enrolling in the study at Visit 0. Screen failures may fail to meet all Inclusion Criteria and 
may meet one or more Exclusion Criteria or withdraw consent prior to Enrollment. All potential 
participants who begin Screening will be tracked on a Screening Log, and reasons for Screen Failure will 
be recorded. Screen Failures are not considered evaluable.  
 
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, they will be classified as a 
Screen Failure. The site staff will notify the potential participant that they are unfortunately not eligible 
for the study and will not schedule additional Screening assessments. Participants who fail Screening may 


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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 will be entered into the Electronic Data Capture (EDC) system. 
 
4.4.3 Pre-Treatment Early Terminations 
‘Pre-Treatment 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. These participants 
may fail to meet all Inclusion Criteria and may meet one or more Exclusion Criteria or withdraw consent 
prior to the first Experimental Session or the site may withdraw the participant for reasons described in 
Section 4.4.4 Early Termination from the Study). All enrolled participants will be maintained in the EDC 
system. Pre-Treatment Early Terminations are not considered evaluable. 
 
Pre-Treatment 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, the site staff will classify as a Pre-Treatment 
Early Termination, notify the potential participant that they are unfortunately not eligible for the study, 
and not schedule additional assessments. Pre-Treatment Early Terminations will be provided an Exit 
Plan/Plan for Moving Forward as described in Section 7.4.2 Exit Plan/Plan for Moving Forward.  
 
4.4.4 Early Termination from the Study 
Participants who are removed from the study after they receive IMP but do not complete the study may 
fall into one of these categories: Post-Treatment Early Termination or Dropout. If the participant has 
received IMP in at least one Experimental Session and completed one PCL-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 Investigators, affects the safety of the 
participant, including psychiatric diagnosis, medical diagnosis, pregnancy, or requirement of use of 
prohibited medications, the participant will discontinue treatment in Experimental Sessions but remain in 
the study for the associated Integrative Sessions. Any time a participant terminates from the study early, 
the site team will attempt to obtain information about AE outcomes if appropriate, as determined by the 
site physician and Medical Monitor. The site team will provide the participant with an Exit Plan/Plan for 
Moving Forward as described in Section 7.4.2 Exit Plan/Plan for Moving Forward. 
 
Below are the definitions of the two types of participants who terminate the study after they receive IMP 
but before study completion: 
 
• 
Post-Treatment Early Termination: Participants who discontinue study treatment but continues 
to participate in primary and secondary outcome assessments. Data collection 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 PCL-5 assessment. These 
participants are defined as dropouts who withdraw consent due to any reason after receiving at 


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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 
PCL-5 assessment after the Experimental Session, they will be considered evaluable. All participants with 
at least one Experimental Session will be included in the safety analysis. 
 
If a participant does not attend a scheduled visit, the site must attempt to contact the participant to 
reschedule the visit as soon as possible and emphasize the importance of complying with the protocol 
specified visit schedule. The staff should determine if the participant is willing to comply with future 
visits. 
 
If a participant does not respond to this initial contact, the site staff must make multiple efforts to contact 
the study participant and document each attempt in the source record. At least three attempts should be 
made via telephone, over the course of approximately 7 days, with calls at different times of day. If 
telephone contact fails, an email should be sent if such contact information was provided. The emergency 
contact the participant provided should be contacted and asked to attempt contact with the participant. 
Lastly, a certified letter (or equivalent) should be sent to their last known mailing address. If the 
participant fails to respond to all of these contacts, they will be considered to have withdrawn from the 
study and are lost to follow-up. 
 
If at a later date it is determined that the participant was lost to follow-up due to an SAE, AESI or 
pregnancy, then the investigator should report this within 24 hours of discovery to the Sponsor. 
 
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/Plan for Moving Forward. 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 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 


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favorable safety profile formed the basis for selection of a 3-session treatment package. A flexible dosing 
regimen has been explored previously in Phase 2 studies, where participants who received doses of 0 mg 
to 75 mg MDMA in the blinded portion of the study crossed over to receive open-label 100 mg MDMA 
in the first Experimental Session with an option to increase to 125 mg MDMA in the second and third 
Experimental Sessions. Larger doses have been administered in MP2 (150 mg and 75 mg supplemental) 
and in Phase 1 studies (150 mg and 160 mg). The results of these Phase 2 studies led to the selection of 80 
mg and 120 mg MDMA as the initial active doses to be compared to inactive placebo in Phase 3 trials. In 
the first Phase 3 trial, participants received a single divided dose of 80-180mg of MDMA or placebo. In 
the first experimental session, an initial dose of 80 mg was followed by a supplemental half-dose of 40 
mg 1.5–2.5 h after the first dose. In the second and third experimental sessions, there was the option to 
increase to an initial dose of 120 mg was followed by a supplemental half-dose of 60 mg. This dosing 
regimen produced an appropriate response with no tolerability issues. 
 
This open-label study will examine the effectiveness of a flexible dose of MDMA administered in three 
Experimental Sessions. A participant will receive a divided-dose of 120 mg or 180 mg per Experimental 
Session. The dose regimen will match that of the parent studies. Initial doses per Experimental Session 
are 80 mg or 120 mg of MDMA compounded with inactive excipients, followed 1.5 to 2 hours later by a 
supplemental dose (40 mg or 60 mg). A flexible dosing regimen was chosen to mimic proposed clinical 
practice and better adapt to risk-benefit considerations. The initial active doses of 80 mg and 120 mg are 
expected to produce all commonly reported effects of MDMA. The supplemental 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.  
 
Table 3: Dose Regimen of MDMA 
Experimental Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative Dose 
1 
80 mg 
40 mg 
80 mg to 120 mg 
2 
80 or 120* mg 
40 or 60 mg 
80 mg to 180 mg 
3 
80 or 120* mg 
40 or 60 mg 
80 mg to 180 mg 
Total Cumulative Dose 
240 mg to 480 mg 
* Unless 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. In the second and third 
Experimental Sessions, the initial dose may be increased to 120 mg MDMA 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 dose unless tolerability issues emerge with the first dose or it is refused by the participant. If 
the participant received an initial dose of 80 mg, a 40 mg supplemental dose will be used. If the 
participant received an initial dose of 120 mg, a 60 mg supplemental dose will be used. If drug supply 
does not permit availability of 60 mg capsules, a reduced supplemental dose of 40 mg may be 
administered following the 120 mg initial dose.  
 


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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 eligibility at Screening  
• 
One or more two-person therapy pairs, male/female preferred 
• 
One person per therapy pair is required to be licensed to provide psychotherapy according to state 
or province and local requirements 
• 
If one person on the therapy team is unlicensed, they will work under the direction of the licensed 
team member 
 
5.3 Training and Supervision 
The sponsor’s Therapy Training Program is designed to teach competency in applying the essential 
elements of this method of MDMA-assisted therapy. Therapy team members will receive specific training 
in the MDMA-assisted therapy method, protocol, and latest version of the IB. Training in the therapy 
method consists of reading the Treatment Manual, completing an online training module, and 
participating in an in-person or online training program that includes watching and discussing videos of 
Experimental Sessions. The final part of training includes supervision from the training team during a 
MAPS-sponsored protocol of MDMA-assisted psychotherapy, including this protocol. The sponsor will 
provide clinical supervision for new therapists completing their clinical supervision requirement in this 
protocol, with supervision provided at dedicated time points during treatment of their first participant. All 
therapy pairs participating in the trial will receive clinical supervision as requested or deemed necessary 
by the pair’s assigned supervisor. 
 
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 ratings will be conducted by qualified, trained, and regularly-
calibrated adherence raters who will analyze video data from specific select Preparatory Sessions, 
Experimental Sessions, and Integrative Sessions conducted with individual participants. Adherence 
criteria assess adherence to overall aspects of the treatment modality, such as the creation and 


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nurturance of a safe therapeutic container and support of the participant’s inner-directed process, as well 
as constructs specific to each type of session (e.g., emotional and factual preparation of the participant 
for Experimental sessions during the Preparatory phase; appropriate use of silence, music, touch, and 
trauma processing in Experimental sessions; and support of the participant’s unfolding emotional, 
cognitive, and somatic experiences during the Integrative phases). The elements included in adherence 
criteria are specific to each type of session and are defined in the Adherence Manual. These ratings will 
be collected, at minimum, for each therapy pair in the study. Ratings will be used to provide feedback to 
new therapy pairs, to further characterize the manualized therapy, and for future exploratory research. 
6.0 Measures and Reliability 
The following eligibility, outcome, exploratory, and safety measures will be used in the study, in 
accordance with Table 6: Time and Events-Study Measures.  
 
Table 4: Protocol Objectives and Assessment Tools 
Objectives 
Measure 
Measure Type 
Eligibility 
Assess psychiatric disorders 
MINI 
Eligibility 
Primary 
Assess changes in PTSD symptom severity from Visit 3 to Visit 16  
PCL-5 
Outcome 
Secondary 
Assess changes in self-reported functional impairment from Visit 3 to 
Visit 16  
SDS 
Outcome 
Safety 
Compare relative incidence of positive or serious ideation and suicidal 
behavior  
C-SSRS 
Safety 
Exploratory 
Explore the effect of presence of secondary traumatic stressors during 
the assessment period as a covariate on the PCL-5 Total Severity 
analyses  
LEC-5 
PCL-5 
Outcome 
Assess changes in depression symptoms from Visit 3 to Visit 16 
BDI-II 
Outcome 
Assess changes in chronic pain from Visit 3 to Visit 16  
CPGS 
Outcome 
Assess changes in quality of life from Visit 3 to Visit 16  
EQ-5D-5L 
Outcome  
Assess changes in nicotine use from Visit 3 to Visit 16  
SRNU 
Healthcare cost 
Assess changes in eating habits from Visit 3 to Visit 16  
EAT-26 
Healthcare cost 
Assess changes in workplace productivity from Visit 3 to Visit 16 
HPQSF 
Healthcare cost 
Assess changes in alcohol use from Screening to Visit 16 
AUDIT 
Healthcare cost 
Assess changes in drug use from Screening to Visit 16  
DUDIT 
Healthcare cost 
Assess facility-based healthcare utilization at Screening 
UFEC 
Healthcare cost 
 
6.1 Primary Outcome Measure 
6.1.1 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 [71]. Participants indicate how 
much distress they have experienced in the last 2 weeks 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). 
 


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6.2 Secondary Measure 
6.2.1 SDS (Sheehan Disability Scale) 
The SDS is a 5-item measure of functional impairment [72]. The items indicate degree of impairment in 
the domains of work/school, social life, and home life, with response options based on a 10-point scale 
(0=not at all to 10=extremely), and five verbal tags (not at all, mildly, moderately, markedly, extremely). 
The SDS has high internal consistency and accurately identified 80% of a sample of primary care patients 
with mental disorders [73]. The Customized version of the SDS for PTSD for MAPS was developed 
utilizing the standard SDS. The first three items indicate degree of impairment in the domains of 
work/school, social life, and home life, with response options based on a 10-point scale (0=not at all to 
10=extremely), and five verbal tags (not at all, mildly, moderately, markedly, extremely). The remaining 
two items assess Days Lost and Days Unproductive during the reporting period. The SDS for PTSD for 
MAPS maintains the same scale conventions as the standard SDS. To limit missing data, the summary 
measure used to analyze the treatment effect on SDS is the mean of the 3 item responses at each visit. 
Any participant who did not work during the reporting period due to reasons related to PTSD is scored as 
maximal work-related impairment on item 1. Any participant who did not work during the reporting 
period due to reasons not related to PTSD reports on the reason for not working and Item 1 is skipped. 
The SDS for PTSD for MAPS has been approved by the author (Dr. David Sheehan) for use in MAPS 
Research and is referred to throughout the protocol as SDS. The SDS for PTSD for the MAPS takes 
approximately 5 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 [74]. In this study, the Since Last Visit version will be used. 
The first assessment will measure suicidality since the last administration in the parent study and for the 
previous two weeks. All subsequent administrations will assess suicidality since the last administration in 
this protocol. The C-SSRS assesses suicidal ideation, ideation intensity, and behavior and consists of a 
series of questions and can be administered during a face-to-face interview or over the telephone. 
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 [75]. The MAPS Adapted C-SSRS was 
developed utilizing Dr. Kelly Posner’s Columbia Suicide Severity Scale. The MAPS Adapted C-SSRS 
maintains the content and flow of the standard C-SSRS. The scale was adapted to modify formatting and 
add additional administrative guidance to reduce rater and data entry errors. The MAPS Adapted C-SSRS 
has been approved by Dr. Posner for use in MAPS Research and is referred to throughout the protocol as 
C-SSRS. The MAPS Adapted C-SSRS takes approximately 10 minutes to complete. 
 
6.4 Screening Measures 
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 [76], is now 
compatible with DSM-5 and will be administered by a member of the Independent Rater (IR) Pool to 
screen for psychiatric conditions per DSM-5. Each module of the MINI consists of two or three questions 


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where the answer is either “Yes” or “No,” and decision-tree logic is used to determine whether to ask 
additional questions [77]. The MINI takes around 75 minutes to perform and addresses major psychiatric 
disorders. MINI items were highly reliable (interrater reliability between kappa of 0.8 and 0.99; test-retest 
reliability between 0.6 and 0.9 for all scales save “current mania), and diagnosis via MINI was 
comparable to that made with the Composite Diagnostic Interview and the SCID [77, 78] Testing on 
nonpsychiatric samples did not create false positives [76]. The IR pool will not assess the PTSD or 
Antisocial Personality Disorder modules. 
6.5 Exploratory Measures 
6.5.1 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 as well as presence of other life stressors. The participant indicates whether each event listed 
has occurred since the last administration of the measure (in parent study), permitting the possibility of 
marking multiple events [79]. 
 
6.5.2 BDI-II (Beck Depression Inventory II) 
The BDI-II is a revision of the BDI, a 21-item self-report measure [80, 81] that will serve as a measure of 
depression symptom severity over the prior 2 weeks [82]. 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 [82]. 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 [82, 83]. Higher scores indicate more severe depressive 
symptoms.  
 
6.5.3 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 [84]. 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 [85]. 
 
6.5.4 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”) [86, 87]. 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 


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software syntax designed for the measure. The EQ-5D-5L began as part of the EuroQoL measure, 
published in 1990 [88]. 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 [89]. The EQ-5D-5L takes about 3 minutes to 
complete. 
 
6.5.5 AUDIT (Alcohol Use Disorders Identification Test) 
The AUDIT is a ten-item self-report test covering alcohol use habits over the past year. Respondents 
answer on a 5-point scale (0=Never or none, 4=Daily or greatest number) [90]. 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 [91]. 
 
6.5.6 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 [92]. 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% [92]. The English translation was developed 
from a Swedish-language original. Estimated time to complete is 2 to 4 minutes. 
 
6.5.7 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. 
 
6.5.8 EAT-26 (Eating Attitudes Test) 
The EAT-26 is a 26-item self-report measure that assesses attitudes about eating and food currently and is 
used to assess presence of eating disorders [93]. Responses are made on a 6-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 
[94].  
 
6.5.9 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 [95]. The larger measure was created by the WHO as part 
of the Global Burden of Disease initiative. It consists of eight questions selected from the larger Health 
and Work Performance Questionnaire, with one question containing five additional items. Items include 
questions concerning hours worked during an average week, number of whole and partial days missed 
during a 4-week period, and items that rate average coworker and self-work performance on a ten-point 
Likert scale (1=Worst performance to 10=Top performance). Hours spent in work over a 4-week period 


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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 [96], and the HPQSF appears to be reliable between one 
time point and another (reliability of 0.52) and is sensitive to change [95]. 
 
6.5.10 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 since termination from the parent study. 
 
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 
(1 to 6 weeks) 
Preparatory Period 
(At least 5 days, depending on medication tapering) 
 
Screening 
Preparatory 
 
Visit 
Phone Screening 
Screening 
IR Screening 
V0 
V1 
V2 
V3 
Visit Description 
Phone 
Calls 
In-person/Remote 
Visits & Labs 
Telemedicine 
Enrollment 
Prep. 1 
Prep. 2 
Prep. 3 
Visit Timing 
Prior to Initial 
Screening 
Over 7 to 70 days 
After initial 
screening visit 
2 to 14 days post 
IR Screening 
0 to 14 days after 
V0 
At least 2 days 
after V1 
(depending on 
tapering) 
Post V2 & Taper; 
1 to 14 days before 
V4 
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 
 
 
 
 
 
 
 
Independent Rater Assessment 
 
 
 
 
 
 
 
Medication Taper 
 
 
 
 
 
 
 
Study Enrollment  
 
 
 
 
 
 
 
All AEs B 
 
 
 
 
 
 
 
90-min Preparatory Session 
 
 
 
 
 
 
 
Phone Call Follow-up C 
 
 
 
 
 
 
 
Measures (ePRO or Clinician-
Administered D 
 
 
 
 
 
 
 
A  At Screening, collect data on previous hospitalizations and healthcare utilization. Site physician may request participants to obtain medical/psychiatric records generated since 
the end of the parent study as required for eligibility assessment 
B 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   
C If needed, call participant to confirm medication tapering and stabilization is complete prior to Visit 3   
D Refer to Table 6: Time and Events-Measures for details 


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Treatment Period 
8 to 20 weeks 
 
 
 
Treatment 1 
Treatment 2 
Treatment 3 
 
Study 
Termi-
nation 
Visit 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
Visit Description 
Exp. 1 
Int. 1.1 
Int. 1.2 F 
Int.  
1.3 F 
Exp. 2 
Int. 2.1 
Int. 2.2 F 
Int.  
2.3 F 
Exp. 3 
Int. 3.1 
Int.  
3.2 F 
Int.  
3.3 F 
Study  
Termination 
Visit Timing 
1 to 14 
days 
after V3 
Morning 
after V4 
10 to 18 
days after 
V4 
At least 2 
days after 
V6;  
1 to 14 days 
before V8 
21 to 
56 days 
after 
V4 
Morning 
after V8 
10 to 18 
days 
after V8 
At least 2 
days after 
V10; 
1 to 14 days 
before V12 
21 to 56 
days 
after V8 
Morning 
after V12 
10 to 18 
days after 
V12 
At least 
two 
days 
after 
V14  
24 to 32 
days after 
V12 
Past/Current 
Medication & 
Adherence 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screen 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Screen  
 
 
 
 
 
 
 
 
 
 
 
 
 
All AEs A 
 
 
 
 
 
 
 
 
 
 
 
 
 
Container 
Assignment B 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer IMP 
 
 
 
 
 
 
 
 
 
 
 
 
 
At least 6-hour 
Exp. Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
BP, Pulse, 
Temperature  
 C 
 H 
 
 
 C 
 H 
 
 
 C 
 H 
 
 
 D 
Potential 
Overnight Stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
90-min Integrative 
Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Call 
Follow-up E 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
Measures (ePRO 
or Clinician-
Administered G 
 
 E 
 
 
 
 E 
 
 
 
 E 
 
 
  
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 Obtain container assignment 24 to 48 hours prior to each Experimental Session  
C During Experimental Sessions, vitals are measured within 15 minutes before Investigational Product administration, immediately before the supplemental dose is administered 
(or would be, if supplemental dose not given), and approximately 6 hours after initial dose, and as needed. Additional measurements to be taken if clinically indicated (e.g., if 
blood pressure does not return to baseline).  
D At Study Termination, only blood pressure needs to be measured   
E 14 days of phone call follow-up: every other day after the Experimental Session; includes C-SSRS administration and AE collection   
F All Integrative Sessions must be at least 2 days apart   
G Refer to Table 6: Time and Events-Measures for details 
H If clinically indicated. 


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Table 6: Time and Events-Study Measures 
 
 
 
Screening 
Preparatory Period 
Treatment 1 
Treatment 2 
Treatment 3 
  
Study 
Termi
nation 
Visit # 
Screening 
IR 
Screening 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
Visit 
Description 
~Time to 
Complete 
Measure 
(minutes) 
Site Visit 
Tele-
medicine 
Prep. 
Session 
1 
Prep. 
Session 
2 
Prep. 
Session 
3 
Exp. 
Session 
1 
Int. 
Sessions 
1.1 
Int. 
Session 
1.2 
Int. 
Session 
1.3 
Exp. 
Session 
2 
Int. 
Sessions 
2.1  
Int. 
Session 
2.2 
Int. 
Session 
2.3 
Exp. 
Session 3 
Int. 
Sessions 
3.1  
Int. 
Session 
3.2 
Int. 
Sessi
on 
3.3 
Study 
Termi-
nation 
C-SSRS A 
10 
✓ 
✓ 


 
 B 
 
✓ 
 
 B 
 
✓ 
 
 B 
 
 
✓ 
 
MINI 
75 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LEC-5 
5 
✓ 
 
 
 
✓ 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
PCL-5 
8 
✓ 
 
 
 
✓ 
 
 
✓ 
 
 
 
 
 
 
 
✓ 
 
 
SDS 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI-II 
5 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPGS 
5 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
3 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
AUDIT 
3 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DUDIT 
3 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SRNU 
3 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
EAT-26 
6 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
HPQSF 
5 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
UFEC 
3 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
~Total Time 
of 
Completing 
Measures 
(minutes) 
139 
29 
85 
0 C 
0 C 
55 
90 B 
10 
23 
10 
90 B 
10 
23 
10 
90 B 
10 
23 
10 
 
61 
A All C-SSRS are Since Last Visit. The first assessment will measure suicidality since the last administration in the parent study and the last two weeks. All subsequent 
administrations will assess suicidality since the last administration in this protocol.  
B Conducted pre- and post-Investigational Product administration, and every other day for 14 days after Experimental Sessions.  
C No planned measures to be assessed at Visit 1 or Visit 2


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7.1 Screening Period 
7.1.1 Screening 
Participants will be identified and invited to screen based on participation in a parent Phase 3 study. 
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 recorded on the Screening Log using their Participant Number from the parent study. 
Data from potential participants who do not pass telephone screening will not be entered in the eCRF but 
reason of ineligibility will be documented on the Screening Log. At any time during Screening, if a 
potential participant is deemed ineligible, they will be classified as a Screen Failure, notified that they are 
not eligible for the study, and not be scheduled for any additional Screening assessments. 
 
If deemed potentially eligible, the potential participant will receive a copy of the ICF for review and 
invited to the site for in-person screening. Relevant medical and psychiatric records are required for the 
site physician to obtain a well-characterized medical history and assess eligibility. The physician may 
need to contact the prescribing physician to discuss the tapering of medications (see Section 11.0 
Concomitant Medications) or the treating therapist or psychiatrist to confirm eligibility. 
 
Site staff (preferably the therapy pair who would be treating this potential participant) will explain and 
obtain written informed consent using the IRB-approved ICF. Written (wet-ink or electronic) consent 
must be obtained prior to performing any tests or evaluations for the study. The signature may be obtained 
using an electronic 21 CFR Part 11 compliant system due to COVID-19. Discussion about the ICF may 
take place over a telemedicine visit or at the first in-person visit. If a participant fails Screening and is 
rescreened at a later date, a new copy of the ICF should be signed. 
 
Screening will take place over multiple visits and will be completed in-person, via telemedicine, or over 
the telephone, within 6 weeks of signing of the ICF. 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 (as 
needed) 
• 
Medical Assessments, including labs, electrocardiogram (ECG), and physical exam 
• 
Independent Rater screening 
 
7.1.2 Initial Eligibility Assessment 
Qualified site staff will: 
 
• 
Collect demographics information 
• 
Administer the Interim (Since Last Visit) C-SSRS to assess history of suicidal behavior and 
ideation. The first assessment will measure suicidality since the last administration in the parent 
study and within the last 2 weeks.  


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• 
Direct participant to complete self-reported Screening measures: 
o AUDIT  
o DUDIT  
o UFEC 
o LEC-5 
o PCL-5, under the direction of the therapy pair, who will remind them of the index trauma 
identified in the parent study to which PTSD symptoms should be anchored. 
• 
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 interim and current psychotherapy, and schedule a meeting with a site physician. 
 
7.1.3 Medical Assessments 
A site physician will meet with the participant over telemedicine, the phone, or in-person to perform the 
following assessments: 
• 
Collect data on hospitalizations and healthcare utilization. 
• 
Review interim medical and psychiatric history with the participant via interview. 
• 
Review past and current medications and adherence to prescriptions. 
• 
Assess ability to become pregnant and discuss requirement for commitment to adequate 
contraception for the duration of the study. 
 
The site physician may deem it appropriate to collect medical and/or psychiatric records depending on the 
participant’s medical history. Records may be requested to confirm information required for eligibility 
assessment or supplement a participant who does not have adequate recall of the period of time since the 
parent study. Records are not necessary to collect and review in all instances, but all records collected 
should be reviewed. 
 
If the physician deems the participant initially eligible based on these discussions and review of medical 
records (as needed), 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. 
• 
Collect blood pressure, pulse, and body temperature measurement. 
• 
Measure 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 12.0 Clinical Laboratory Assessments. The clinical 
laboratory values will not be captured in the eCRF but will be used to establish eligibility and will 
be kept with the participant’s source record. Clinically significant abnormal values will be 
captured as medical history. 


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• 
If there is evidence of liver disease by history, physical examination or laboratory testing, HCV 
serology will be performed. 
• 
If there is evidence of significant hepatic disease other than HCV, the potential participant will 
not be eligible for enrollment and will be advised to see their personal physician for further 
evaluation. If HCV serology is positive and the potential participant has not already been 
evaluated for possible treatment of HCV, they will be referred to a physician with expertise in 
evaluating and treating liver disease. After this evaluation and after completion of any 
recommended treatment, if the HCV is judged by this physician to be relatively stable and of mild 
severity, the participant may be enrolled, if there are no other contraindications. 
• 
If the potential participant has a condition such as controlled hypertension or Diabetes Mellitus 
(Type 2) that warrants additional testing to ensure they do not have evidence of significant 
vascular or other cardiac disease, they have no other evidence of significant 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 
stress 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 (as requested), and measures against eligibility criteria. If, upon 
examination, there are questions raised about possible medical problems, the site physician will request 
additional tests, assessments, or measures as indicated. The site physician may also contact outside 
providers with participant permission as needed. If deemed initially eligible, the site staff will schedule 
the IR screening and send results of LEC-5 and C-SSRS 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. The site can provide technical support before the assessment and therapeutic support after, 
if needed. For all IR visits, the site team will confirm with the participant that they should have adequate 
internet access and be in a private and quiet space where they are comfortable talking about personal 
matters. 
 
7.1.4 Independent Rater Screening 
An IR will continue the eligibility assessment via telemedicine after reviewing the results of the LEC-5 
and most recent C-SSRS. The IR interview may be recorded to assess reliability of ratings. If possible, the 
potential participant should be present at the study site during this assessment, in case the therapy pair is 
needed for support. The IR will perform a C-SSRS and contact the therapy pair after the call to 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. The IR will complete MINI interview to assess 
psychiatric disorders, skipping the modules for PTSD and Antisocial Personality Disorder.  
 
The results from the MINI 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 


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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 any interview indicate an exclusionary psychological disorder diagnosis is present, the 
Senior IR reviewer will review the recording of the MINI assessment. The Senior IR will invite the study 
team (including therapists, site physician, and Clinical Investigator) to provide any additional information 
that may inform the Senior IR reviewer’s opinion. The Senior IR reviewer will make the final judgment 
on whether or not the participant has an exclusionary diagnosis. Participants with exclusionary diagnoses 
will not be enrolled. However, if any diagnosis is not present or uncertain according to any measure or 
interview, but the investigator believes the participant presents with a particular disorder, they may 
diagnose and deem the participant ineligible if appropriate.  
 
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 (as requested), 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 request for enrollment, including medical history, for approval to enroll the potential 
participant. 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. 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 within 30 days after 
Independent Rater Screening is completed. Visit 0 and Visit 1 may take place on the same day. 
 
7.2 Preparatory Period 
Participants will undergo three Preparatory Sessions (Visits 1, 2, and 3) lasting approximately 90 minutes 
with the therapy pair prior to the first Experimental Session. 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 promoting a safe set 
and setting for confronting trauma-related memories, emotions, and thoughts in preparation for MDMA-
assisted therapy.  
 
Telephone calls may be scheduled between visits if indicated for tapering, safety, or any further questions 
about medical history. Each session may be recorded. With awareness of the therapy team, CI, and 
Medical Monitors, one or more Preparatory Sessions may be performed via telemedicine. 
 
The Preparatory Period will be initiated 0 to 14 days after Visit 0. The duration of the preparatory period 
will be at a minimum 5 days but can be as long as needed depending on duration of medication tapering. 
There must be at least 48 hours between Preparatory Sessions.  
 
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-Treatment Early Termination, notify the potential participant that they are 
unfortunately not eligible for the study, and not schedule additional assessments. 
 


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At each 90-minute psychoeducation and therapy Preparatory Session, the therapy pair will: 
 
• 
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. 
• 
Discuss goals and expectations for the Experimental Session, following standard procedures and 
techniques described in the Treatment Manual [97]. 
• 
At Visit 4, administer the Since Last Visit C-SSRS. 
 
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. 
 
7.2.1 Preparatory Sessions 1 and 2 
Preparatory Session 1 (Visit 1) will occur 0 to 14 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 75 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. If tapering is complete or not needed, the site 
team will confirm eligibility and schedule Preparatory Session 3 (Visit 3) as soon as possible.  
 
7.2.2 Preparatory Session 3 
Preparatory Session 3 (Visit 3) should take place as soon as possible after medication tapering and 
stabilization and 1 to 14 days prior to Experimental Session 1 (Visit 4). 
 
The site team will confirm eligibility and ensure that the participant continues to agree to all lifestyle 
modifications. If any requirements are not met before or during Visit 3, the participant will be considered 
a Pre-Treatment Early Termination. 
 
For eligible participants, qualified site staff will: 
 
• 
Perform urine pregnancy test for participants who are able to 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 PCL-5, under the direction of the therapy pair, who will remind them of the index trauma 
identified in the parent study to which PTSD symptoms should be anchored 


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o LEC-5 
o SDS 
o BDI-II 
o CPGS 
o EQ-5D-5L 
o SRNU 
o EAT-26  
o HPQSF 
• 
Complete the third 90-minute Preparatory Session with the purpose of confirming all enrollment 
eligibility 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 3.3 Lifestyle Modifications.  
 
7.3 Treatment Period 
During the Treatment Period, which occurs over a duration of 8 to 20 weeks, participants will complete 
three Experimental Sessions, followed by Integrative Sessions. Each treatment consists of an 
Experimental Session, followed the morning after by an Integrative Session, phone follow-ups over the 
next 14 days, and two additional Integrative Sessions. The Experimental Sessions will be scheduled 3 to 8 
weeks apart. The PCL-5 will be assessed at three visits during the Treatment Period: Integrative Session 
1.2 (Visit 6), Integrative Session 2.2 (Visit 10), and Integrative Session 3.2 (Visit 14). The Primary 
Outcome PCL-5 will be assessed at Study Termination (Visit 16).  
 
7.3.1 Experimental Sessions 
There will be three open-label Experimental Sessions (Visits 4, 8, 12). 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 6 hours long, measured from 30 minutes prior to IMP 
administration. The Experimental Sessions will consist of: 
 
• 
Experimental Session 1 (Visit 4) will occur 1 to 14 days after Preparatory Session 3 (Visit 3). The 
first Experimental Session will include 80 mg of MDMA 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 8) will occur 21 to 56 days after Experimental Session 1 (Visit 4) 
and 1 to 14 days after Integrative Session 1.3 (Visit 7). A dose of 80 or 120 mg MDMA will be 
administered. A supplemental dose (40 mg or 60 mg) will be administered 1.5 to 2 hours after the 
initial dose unless tolerability issues emerge with the first dose or it is refused by the participant. 
If the participant received an initial dose of 80 mg, a 40 mg supplemental dose will be used. If the 
participant received an initial dose of 120 mg, a 60 mg supplemental dose will be used. If drug 
supply does not permit availability of 60 mg capsules, a reduced supplemental dose of 40 mg may 
be administered following the 120 mg initial dose.  
• 
Experimental Session 3 (Visit 12) will occur 21 to 56 days after the second Experimental Session 
(Visit 8) and 1 to 14 days after Integrative Session 2.3 (Visit 11). A dose of 80 or 120 mg MDMA 
will be administered. A supplemental dose (40 mg or 60 mg) will be administered 1.5 to 2 hours 
after the initial dose unless tolerability issues emerge with the first dose or it is refused by the 
participant. If the participant received an initial dose of 80 mg, a 40 mg supplemental dose will be 
used. If the participant received an initial dose of 120 mg, a 60 mg supplemental dose will be 
used. If drug supply does not permit availability of 60 mg capsules, a reduced supplemental dose 
of 40 mg may be administered following the 120 mg initial dose.  


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Table 7: Schedule of Procedures for Experimental Sessions 
Approximate Time during 
an 8 hour session 
Procedure or Action 
9:30  
Urine drug screen and pregnancy test, concomitant medication information 
collected, participant acclimated to environment, C-SSRS. Begin video 
recording. 
9:55 
Baseline BP, body temperature, pulse 
10:00  
IMP Administration 
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 
 
In the hours before IMP administration, the following procedures will take place: 
 
• 
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 and not used cannabis or alcohol since 12:00 AM (midnight) prior to IMP administration 
and complied with all other requirements per Section 3.3 Lifestyle Modifications. 
• 
The site team will inquire about any possible changes in health to ensure the participant continues 
to meet all eligibility requirements and record AEs as described in Section 10.0 Safety. 
• 
The site team will instruct the participant that they will not be able to use caffeine or nicotine at 
least 6 hours after the IMP administration. 
• 
The site team will complete urine drug screen, pregnancy test, and concomitant medication 
review. 
o A positive drug screen will be reviewed by the site physician and may be cause for 
delaying IMP administration to a later time, rescheduling the session to a later date, or 
withdrawing the participant from the study, based on Medical Monitor review.  
o A positive pregnancy test that has been confirmed 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 (initial dose will be administered within 15 minutes of baseline 
blood pressure, body temperature, and pulse). 
 


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During the Experimental Session 
 
• 
At approximately 10:00 A.M., 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 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. 
• 
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. 
• 
Participants with persistent elevations in blood pressure at the end of Experimental Sessions will 
have additional blood pressure assessments after the session and the next morning during the 
integration session.  If deemed necessary, the blood pressure will be monitored until the pressure 
returns to baseline or an acceptable pressure is reported as determined by the study physician. 
Any changes in antihypertensive therapy will be recorded on the Concomitant Medication log and 
the event will be reported on the Adverse Event eCRF.  
• 
The therapy pair or site physician shall remain available to participants via 24-hour cellular phone 
for integration, as needed. 
 
At the end of each Experimental Session, the therapy pair (in consultation with site physician, if 
necessary) 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. 


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Overnight Stay 
 
If a participant is deemed medically and psychologically stable by the therapy pair at the end of the 
Experimental Session, the session will be ended and participant care transferred to the Night Attendant. 
 
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).  
 
The following procedures will take place at overnight stays: 
 
• 
Participants will remain overnight in an appropriately furnished room at or near the study site 
until after the Integrative Session the morning after each Experimental Session. With prior 
approval of the therapy pair, a companion may accompany the participant during the overnight 
stay.  
• 
An attendant will check in periodically on the participant during the overnight stay, even if a 
companion is present. The attendant will monitor participant condition and will help participants 
relax during the overnight stay. The attendant will be an individual with some previous training in 
caregiving and will be supportive but not intrusive. If there is an emergency or the participant 
needs additional support, the attendant can contact the therapy pair.  
• 
The participant and a companion (if applicable) will receive information that will allow them to 
contact the therapy pair during the overnight stay in the case of an emergency or to request 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 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 every other day for 14 days after each 
Experimental Session. If an Integrative Session falls on the date of a planned phone call, the phone call 
does not need to be performed. Each call will last on average 5 to 20 minutes but could be longer to 
address participant concerns and to adequately assess wellbeing. Additional telephone contact can be 
initiated at the request of the therapy pair or participant. 
 
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. 
• 
Administer the Since Last Visit C-SSRS. 
• 
Inquire about concomitant medication use and adherence. 
• 
Offer support in accordance with the Treatment Manual. 
 


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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. The therapy pair may 
record the sessions. Integrative Sessions 1.2, 1.3, 2.2, 2.3, 3.2, and 3.3 may be performed via 
telemedicine. 
 
Treatment 1 
 
• 
Integrative Session 1.1 (Visit 5): morning after Experimental Session 1 (Visit 4). 
• 
Integrative Session 1.2 (Visit 6): 10 to 18 days after Experimental Session 1 (Visit 4). The 
participant will complete the PCL-5 and LEC-5.  
• 
Integrative Session 1.3 (Visit 7): at least 2 days after Integrative Session 1.2 (Visit 6) and 1 to 14 
days in advance of Experimental Session 2 (Visit 8). This visit serves two purposes: to continue 
integration and to prepare for the next Experimental Session.  
 
Treatment 2 
 
• 
Integrative Session 2.1 (Visit 9): morning after Experimental Session 2 (Visit 8). 
• 
Integrative Session 2.2 (Visit 10): 10 to 18 days after Experimental Session 2 (Visit 8). The 
participant will complete the PCL-5 and LEC-5.  
• 
Integrative Session 2.3 (Visit 11): at least 2 days after Integrative Session 2.2 (Visit 10) and 1 to 
14 days in advance of Experimental Session 3 (Visit 12). This visit serves two purposes: to 
continue integration and to prepare for the next Experimental Session.  
 
Treatment 3 
 
• 
Integrative Session 3.1 (Visit 13): morning after Experimental Session 3 (Visit 12). 
• 
Integrative Session 3.2 (Visit 14): 10 to 18 days after Experimental Session 3 (Visit 12). The 
participant will complete the PCL-5 and LEC-5.  
• 
Integrative Session 3.3 (Visit 15): at least 2 days after Integrative Session 3.2 (Visit 14). 
 
During Integrative Sessions, 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. Record AEs as described in Section 10.0 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 pair 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 pair 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 second Integrative Session, participants will complete the LEC-5 and PCL-5, under the 
direction of the therapy pair, who will remind them of the index trauma listed in the parent study 
to which PTSD symptoms should be anchored. 
 


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7.4 Study Termination 
Study Termination (Visit 16) will take place 24 to 32 days after the Experimental Session 3 (Visit 12) and 
after the last Integrative Session 3.3 (Visit 15). Participants who have withdrawn from treatment but have 
continued for follow-up will also complete this assessment immediately upon withdrawal. 
 
The site team will: 
 
• 
Inquire about any possible changes in health. Assess the participant’s mental health and the status 
of any previously recorded AEs. Record AEs as described in Section 10.0 Safety. 
• 
Inquire about concomitant medication use and adherence. 
• 
Administer Since Last Visit C-SSRS. 
• 
Measure weight (used to calculate BMI). 
• 
Measure blood pressure. 
• 
Perform urine pregnancy test for participants who are able to become pregnant. 
• 
Provide and discuss a study Exit Plan/Plan for Moving Forward. 
• 
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. 
• 
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 PCL-5, under the direction of the therapy pair, who will remind them of the index trauma 
listed in the parent study to which PTSD symptoms should be anchored 
o SDS 
o BDI-II 
o CPGS 
o EQ-5D-5L 
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. 
 
7.4.1 Extension Studies 
Upon completion of the study, defined as completing at least one Experimental Session and one PCL-5 
assessment beyond Baseline and terminating participation, participants will be asked to join the LTFU 
extension study to observe long-term effects. This study will not involve any additional Experimental 
Sessions or administration of IMP. The ICF for this study will be provided to eligible participants at the 
Study Termination visit if available. This study will measure outcomes at least 6 months after the last 
Experimental Session. 
 
Any sub-studies will be detailed in separate documents. 
 
7.4.2 Exit Plan/Plan for Moving Forward 
At Study Termination, participants will be provided with an Exit Plan/Plan for Moving Forward. This 
Exit Plan/Plan for Moving Forward will summarize treatments completed, current medications, and 


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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/Plan for Moving Forward 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 
[HCl]). 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. The IMP will be compounded with inactive 
excipients such as mannitol and magnesium stearate. 
 
Table 8: Study Medication Intervention(s) Administered 
Intervention Label  
Active Intervention 
Intervention Name 
3,4-methylenedioxymethamphetamine (MDMA) as a hydrochloride salt (HCl) 
Intervention Description 
Initial doses (per Experimental Session) include 80 mg or 120 mg MDMA HCl, 
followed 1.5 to 2 hours later by a supplemental dose of 40 mg or 60 mg MDMA 
HCl. 
Type  
Drug 
Dose Formulation 
hydroxypropylmethylcellulose (HPMC) capsule 
Unit Dose Strength(s) 
40 mg or 60 mg MDMA HCl 
Dosage Level(s) 
Initial dose: 80 mg MDMA HCl for first session and 80 mg or 120 mg MDMA 
HCl for following sessions 
 
Supplemental dose: 40 mg or 60 mg MDMA HCl 
Inactive Ingredients 
Mannitol and magnesium stearate 
Route of Administration 
Oral 
Use 
Experimental 
IMP and NIMP/AxMP. 
IMP 
Sourcing 
Provided centrally by the sponsor 
Packaging and Labeling 
Study intervention will be provided in an open-label container. Each container 
will be labeled as required per country and federal, state, and local regulations. 
This will include the following: 
 
Caution: New Drug – Limited by Federal (or United States) law to 
investigational use. 
 
8.1.1 Doses 
This study will explore the effectiveness of three Experimental Sessions of therapy assisted by flexible 
doses of MDMA. Initial doses per Experimental Session include 80 mg or 120 mg MDMA HCl 
compounded with mannitol and magnesium stearate, followed 1.5 to 2 hours later by a supplemental dose 
(40 mg or 60 mg MDMA HCl). If the participant received an initial dose of 80 mg, a 40 mg supplemental 
dose will be used. If the participant received an initial dose of 120 mg, a 60 mg supplemental dose will be 
used. If drug supply does not permit availability of 60 mg capsules, a reduced supplemental dose of 40 
mg may be administered following the 120 mg initial dose. Total amounts of MDMA HCl to be 


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administered per Experimental Session range from 80 mg to 180 mg. All drug is encapsulated with 
hydroxypropyl methylcellulose (HPMC) capsules. 
 
Refer to Table 3: Dose Regimen of MDMA.  
 
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. In the second and third Experimental 
Sessions, the initial dose may be increased to 120 mg MDMA HCl 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 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. If the participant 
received an initial dose of 80 mg, a 40 mg supplemental dose will be used. If the participant received an 
initial dose of 120 mg, a 60 mg supplemental dose will be used. If drug supply does not permit 
availability of 60 mg capsules, a reduced supplemental dose of 40 mg may be administered following the 
120 mg initial dose.  
 
8.1.3 Stability 
IMP will be manufactured and packaged according to current Good Manufacturing Practices (cGMP). 
Six-month accelerated stability studies will be completed for the IMP along with an ambient stability 
study that will continue 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 
Each package will be an open-label container that will be used as bulk presentation at each study site. 
Each dose of MDMA may be dispensed by the Schedule I license holder (or equivalent) or designee. 
Additional doses of MDMA that are not administered to a participant, will be kept in the open-label 
containers for administration in future sessions or to other participants.  
 
All labels will comply with local, state/provincial, and national regulations. Each package will be labeled 
with a unique container number, protocol number, IMP name, lot number, sponsor name and contact 
information, dosage form, route, directions for administration, and storage conditions. A statement that 
the IMP is restricted to clinical trial use only will be included on each package. 
 
8.2.2 Accountability 
Forms will be provided to track IMP accountability and administration throughout the study. IMP 
accountability and administration logs will be reviewed during routine monitoring visits. MDMA will be 
handled in accordance with all local, state, and federal regulations and forms pertaining to the use of 
controlled substances, and required forms will be maintained by the appropriate controlled substance 
license holder or delegate.  


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Each container label will contain a unique container number. The container numbers will be used to track 
IMP administration in the Source Record and the IMP administration log. 
 
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 local, state/provincial, and national 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 (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 IMP for each Experimental Session. If a supplemental dose is not administered, the unused 
IMP will be retained securely.  
 
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 Participant Numbering 
Every participant will be tracked using the same participant number used in the parent study.  
 
8.4 Bias Minimization 
Eligibility will be determined by review of screening by the PI, site team and as needed the sponsor 
Medical Monitor prior to enrollment confirmation. Participants, site staff, and the sponsor will be aware 
that each participant in MAPPUSX will be receiving open-label MDMA.  
 
To ensure that all participants are treated in a similar manner, the sites will be required to follow the 
protocol and Treatment Manual delineating minimum length of time per visit type and describing delivery 
of treatment. All Experimental Sessions are required to be at least 6 hours long. The sponsor will monitor 
data in real-time to ensure complete data collection for all participants, including those who discontinue 
treatment. Sites will be required to make and document a specific number of attempts to obtain follow-up 
data per protocol. All participants who receive at least one dose of IMP and complete at least one follow-
up assessment will be included in the final mITT primary effectiveness analysis. 
 


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9.0 Risks 
More detailed information about the known and expected benefits and risks and reasonably expected 
adverse events (AEs) of MDMA may be found in the IB and Informed Consent Form (ICF). 
 
9.1 Risk Assessment 
Potential risks, summaries, rationale, and mitigation strategy can be found in Table 9: Risk Assessments.  


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Table 9: Risk Assessments 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Risk of IMP 
Cardiovascular 
and 
Cerebrovascular 
Events 
MDMA transiently increases heart 
rate and blood pressure in a dose-
dependent manner that is generally not 
clinically concerning for physically 
healthy individuals. These changes 
typically last no more than 6 hours. 
Most people do not experience 
elevations in cardiovascular 
parameters that exceed those seen 
after moderate exercise. An 
examination of safety data drawn from 
Phase 2 and Phase 3 studies of 
MDMA-assisted therapy detected a 
dose-dependent increase in systolic 
BP and to a lesser extent diastolic BP. 
Characterization of sympathomimetic 
effects among participants with 
controlled hypertension is ongoing. 
MDMA is not likely to increase risk 
of QTc interval prolongation based on 
a definitive hERG study and had no 
effect on qualitative or quantitative 
ECG parameters in an in vivo dog 
cardiovascular study, see IB. 
• 
Participants with documented significant cardiovascular risk factors, including 
uncontrolled hypertension will be excluded, see Section 3.2 Exclusion Criteria. 
• 
ECG and a 1-minute rhythm strip will be completed at screening to assess for undiagnosed 
cardiac conduction abnormalities. 
• 
Participants with controlled hypertension or other cardiac risk factors (e.g., diabetes 
mellitus) will undergo a cardiovascular evaluation and risk mitigation per the local 
standard of care to assess cardiac function and risk of cerebrovascular events. 
• 
Before and after IMP administration in Experimental Sessions, the therapy teams monitor 
vital signs. The therapy team should attend to clinical signs and symptoms of potential 
rare complications of the cardiovascular effects of MDMA, such as stroke or acute 
myocardial infarction during Experimental Sessions. In the unlikely event any such 
situation arise, study teams will seek immediate emergency medical attention. 
• 
Participants with persistent elevations in blood pressure at the end of Experimental 
Sessions will have additional blood pressure assessments after the session and the next 
morning during the integration session. If deemed necessary the blood pressure will be 
monitored until the pressure returns to baseline or an acceptable pressure is reported as 
determined by the study physician. Any changes in antihypertensive therapy will be 
recorded on the concomitant medication log and the event will be reported on the adverse 
event eCRF. 
Negative 
Psychological 
Impact 
MDMA may expose or exacerbate any 
underlying psychological distress, 
which could arise from the onset of 
MDMA effects until the last effects 
have dissipated, or even later. In 
addition, psychological distress could 
arise following an Experimental 
Session as a result of participants 
integrating their experience after the 
MDMA effect has subsided. 
• 
MDMA is only administered as an adjunct to supportive psychotherapy. 
• 
Non-drug preparatory sessions will be conducted before experimental sessions. 
• 
Three non-drug integrative sessions will be conducted after each experimental session. 
• 
Participants who may be more vulnerable to destabilizing reactions (such as people 
diagnosed with bipolar affective disorder Type 1 or psychotic disorders) will be excluded. 
• 
Phone contact with participants will be arranged during the week following the 
Experimental Sessions.  
• 
An escort to and from the clinical site following each experimental session is required. 


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Thermoregulatory 
Events 
In MAPS-sponsored Phase 2 and 
Phase 3 studies, MDMA administered 
in a controlled setting can produce a 
slight increase in body temperature 
(up to approximately 1 C). 
• 
Participants with a known history of drug-induced hyperthermia will be excluded. 
• 
During experimental sessions, ambient temperature should be kept at a comfortable level. 
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 body temperature rises more than 1.5° C above baseline despite these efforts, the site 
clinician should be consulted. 
Osmolarity 
Changes 
MDMA causes AVP release, which 
can cause changes in osmolality under 
certain circumstances.  
• 
Participants with a recent history of clinically significant hyponatremia will be excluded. 
• 
Serum electrolytes are assessed during screening, and participants with clinically 
significant hyponatremia will be excluded. 
• 
Participants will be limited to a maximum of 3 liters of fluid consumption during 
experimental sessions. 
Reproductive and 
Developmental 
Risks 
MDMA has been demonstrated to be 
negative for genotoxicity, both in vitro 
and in vivo, with and without 
metabolic activation. While there are 
no clinical data on the use of MDMA 
in pregnant individuals, repeated dose 
toxicity studies of adequate duration, 
fertility, early embryonic 
development, and embryofetal 
development studies of MDMA in rats 
and rabbits have not found direct or 
indirect harmful effects with respect to 
reproductive toxicity, see IB. 
• 
Participants who are pregnant will be excluded from participation. 
• 
Urine pregnancy tests will be conducted during screening and immediately prior to any 
experimental session. Any positive urine pregnancy test may be followed by a 
confirmatory serum analysis. 
• 
A final urine pregnancy test will be conducted after the end of systemic exposure. 
• 
Participants who are able to become pregnant will be required to adhere to contraceptive 
measures with a <1% failure rate, as described in Section 10.3.2 Contraception 
Guidelines. 
• 
Information on all pregnancies in participants and their partners will be collected after the 
start of study intervention and until the participant’s final visit. Pregnancies will be 
followed until the outcome of the pregnancy is known. Live births will be followed for 30 
days after delivery. 
 
Abuse Potential 
Because the medication is considered 
a controlled substance in the U.S. with 
known abuse potential, the FDA has 
requested that patients are consistently 
monitored for adverse events that 
could be suggestive of abuse potential 
among research participants treated 
with MDMA.  
• 
Participants with current severe alcohol and/or substance use disorders which could pose a 
safety concern or interfere with the therapeutic process will not be eligible for the study, 
see Section 3.2 Exclusion Criteria.  
• 
MDMA is only administered under the supervision of the clinical investigator and no take-
home doses are administered. MDMA administration and handling follows all regulations 
pertaining to the use of controlled substances within research studies. 
• 
Use of alcohol and other recreational drugs will be monitored in the study. 
• 
Behavior suggestive of abuse potential will be recorded as an AESI and reported in the 
same manner as an SAE, refer to Section 10.1.3 Adverse Events of Special Interest 
(AESI). 


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Risk of Other Study Procedures 
Discomfort with 
Medical 
Assessments 
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. 
Medical examinations and blood 
sampling are required to establish 
eligibility for the study and cannot be 
omitted from the protocol. 
• 
Medical examinations and blood sampling will be completed by staff with appropriate 
training and expertise.  
• 
Investigators will be trained to counsel participants on their laboratory findings. 
Loss of privacy 
due to video 
recording of 
sessions 
Many of the visits with participants 
are required to be video recorded to 
ensure reliability between IR 
assessments and adherence to the 
Treatment Manual. Video recordings 
also enable clinical supervision of site 
therapists. Should these recordings be 
accessed by unauthorized individuals, 
there is a risk of loss of privacy. 
Should the participant provide 
information to the sponsor either 
directly, or through one of the 
sponsor’s electronic systems, and 
against recommended process, this 
may result in unintended identification 
of the participant. Because of the 
nature of the study (providing therapy) 
and need for supervision and 
adherence rating, there is no way to 
conceal the participant’s name, 
physical appearance, voice, or 
personal health information relating to 
life events and trauma history. 
Video procedures are designed to meet privacy, data protection, and security standards that 
constitute best practices expected of facilities providing medical care and to comply with legal 
requirements. MAPS PBC contracts with service providers (Processors) through Data 
Processing Agreements to carry out personal data processing activities in accordance with US 
privacy laws. MAPS PBC conducts periodic data privacy impact assessments and audits to 
mitigate the risk of loss of privacy. Participants may ask to stop the recording at any time, and 
therapists will ask for participant permission to resume recording when the participant signals 
they are ready. 
 


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Discomfort 
related to therapy 
 
 
 
During both non-drug and MDMA-
assisted therapy sessions, participants 
are asked to think about and discuss 
their experiences, thoughts, and 
emotions related to their condition. 
They may experience intense 
emotional responses to recalling and 
speaking about this material. As 
MDMA is only administered in 
combination with therapy, the 
discomfort associated with therapy is 
unavoidable and is considered a 
necessary part of the therapeutic 
process that requires proper 
facilitation and support from 
therapists. 
• 
Therapy teams support participants as they bring conscious awareness to difficult feelings, 
memories, or body sensations during the course of treatment. This is supported through 
empathic presence and establishment of a strong therapeutic alliance, a safe container, and 
a comfortable setting in which the therapeutic process takes place. 
• 
Therapy teams may also support participants through discomfort related to therapeutic 
processing of trauma through a variety of practices including, but not limited to, use of 
music, breathwork, and sensorimotor and somatic psychotherapy practices. 
• 
Therapy teams assess participants’ support networks and help participants to consider 
ways in which their support system can be of help during the time between therapy 
sessions. 
• 
During MDMA-assisted therapy sessions, MDMA may catalyze therapeutic processing by 
allowing participants to stay emotionally engaged while revisiting traumatic experiences 
without being overwhelmed by anxiety or other painful emotions. Frequently, participants 
are able to experience and express fear, anger, and grief as part of the therapeutic process 
with less likelihood of either feeling overwhelmed by these emotions or of avoiding them 
by dissociation or emotional numbing.  
• 
At times, a participant may experience strong “negative” emotional reactions, including 
feelings of loss of control. When the therapists see that the participant’s distress is 
interfering with their ability to stay focused on the inner experience, they intervene, 
encouraging the participant to stay present with deeper levels of emotion, including 
distressing feelings, and to trust that it is safe to face the experience. The empathic 
presence of the therapy team can support a participant to tolerate and titrate the discomfort 
of addressing challenging emotions and memories in service of healing. 


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Tapering off 
psychiatric 
medications may 
result in increase 
in severity of 
underlying 
psychiatric 
symptoms or 
other adverse 
events 
Previously published data indicated 
some psychiatric medications may 
blunt the effects of MDMA-assisted 
therapy. Therefore, ongoing 
psychiatric medications must be 
tapered and stopped at least  five half-
lives of parent drug or active 
metabolite (whichever is longer)  
prior to Visit 3. For non-selective 
irreversible MAOIs, a 2-week 
washout period following the taper is 
required (3 weeks in the case of 
imipramine and clomipramine, 
tricyclic antidepressants with MAOI 
activity) prior to the Visit 3. The 
tapering and withdrawal of such 
medications can lead to new or a 
return of symptoms these medications 
were initially prescribed to treat and 
has been known to induce suicidal 
ideation or behavior in some people.  
• 
Participants will be informed of the potential risks associated with medication taper and 
cessation, and will be encouraged to discuss this with the prescribing clinician. 
• 
Study clinicians are encouraged to contact the prescribing clinician (with participant 
consent) and discuss the tapering plan. 
• 
Participants will be closely monitored during the medication tapering and AEs will be 
recorded. 
• 
Should a participant be unable to successfully taper off any prohibited medication, the 
participant will be withdrawn from the study and referred back to the prescribing clinician 
for evaluation and possible restart of psychiatric medication.  
• 
Participants are informed at screening that they should not initiate tapering themselves or 
with their prescribing clinician for study participation to ensure that the tapering plan is 
monitored by the site clinician and Medical Monitor. 


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Other 
Suicide and Risk 
of Self-Harm 
Suicidal ideation and behavior are 
disease related events with high 
incidence in populations of people 
with PTSD, especially those suffering 
from chronic PTSD. Due to the nature 
of the therapeutic method, wherein a 
person may re-experience emotions 
associated with the traumatic event in 
order to reprocess the memory in a 
new, therapeutic way, thoughts of 
ending one’s life may surface during 
the process. In previous MAPS-
sponsored clinical trials C-SSRS 
scores have escalated during the 
Preparatory Sessions, which is thought 
to be a result of preparatory discussion 
of traumatic experiences, and/or 
participants concomitant tapering off 
long-prescribed medications, such as 
SSRIs and benzodiazepines. 
During both non-drug and MDMA-
assisted therapy sessions, participants 
are asked to think about and discuss 
their experiences, thoughts, and 
emotions related to their condition. 
Participants are also asked to report on 
their suicidality in these sessions and 
follow-up phone calls through C-
SSRS administration. They may 
experience intense emotional 
responses to recalling and speaking 
about this material. As MDMA is only 
administered in combination with 
therapy, the distress associated with 
therapy is unavoidable and is 
considered a necessary part of the 
therapeutic process that requires 
proper facilitation and support from 
therapists. 
• 
Therapy teams minimize risks by carefully evaluating all participants to determine if there 
is a current risk of suicidal behavior. Participants with current, severe suicidal ideation or 
a suicide attempt within the past six months are excluded from the trial, see Section 3.2 
Exclusion Criteria. However, participants with a history of suicide attempts are not 
excluded unless significant risk of suicidal behavior is present at the time of Screening, as 
this would result in enrolling a non-representative sample of the population.  
• 
If positive serious ideation or behavior occurred after study enrollment, the investigators 
are to make additional follow-up C-SSRS observations to ensure participant safety and to 
track scores until they returned to non-serious levels.  
• 
Should a participant be at serious risk to themselves, then the therapy team and site staff 
will intervene appropriately, consistent with professional practice standards. In extreme 
circumstances, this may involve summoning external crisis management teams for further 
assessment which may lead to involuntary hospitalization. 
• 
Attempted suicide or adverse event associated with an increase in suicidal ideation to a 4 or 
5 on the C-SSRS will be reported as an AESI by the PI within 24 hours of discovery and 
will be followed until the outcome of the event(s) is known, refer to Section 10.1.3 Adverse 
Events of Special Interest (AESI). 


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10.0 Safety 
10.1 Adverse Events, Serious Adverse Events, Adverse Events of Special Interest and Other 
Safety Reporting 
The investigator and any qualified designees are responsible for detecting, documenting, and recording 
events that meet the definition of an Adverse Event (AE), Serious Adverse Event (SAE), or Adverse 
Event of Special Interest (AESI), and remain responsible for following up on all AEs. 
 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). The collection period of AEs is from the time of signed 
ICF until the completion of the study termination visit (+/- 2 days). Medical occurrences that begin before 
the start of Visit 0, but after obtaining informed consent may be recorded as medical history or a current 
medical conditions, unless the event occurs as a result of a study requirement in which case the event 
would be reported as an AE. All AEs should be recorded regardless of the cause of the event, whether the 
event is deemed positive, negative or neutral by the investigator, reporter or qualified designee. The 
investigator will elicit information through non-leading open-ended questioning and examination of the 
participant about the occurrence of the AE. For each event, the following information will be recorded in 
the participant’s record and transcribed into the AE section of the eCRF and SAE form when appropriate 
according to the instructions below: 
 
• 
Classification of the event: serious or non-serious 
• 
Classification of the event as an adverse event of special interest (AESI) 
• 
Description of signs and/or symptoms. Whenever possible, the specific diagnosis for the 
event will be recorded. If a diagnosis cannot be made, each sign or symptom will be 
recorded separately (e.g., nausea and vomiting would be recorded as two separate events). 
• 
Severity of event: mild, moderate or severe 
• 
Relationship to study medication: related or not related 
• 
Action taken with study medication: dose maintained, dose not changed, dose reduced, 
interruption of dose, drug withdrawn/discontinued, unknown, or not applicable 
• 
Adverse event outcome: resolved without sequelae, resolved with sequelae (describe 
sequelae), resolving, not resolved, fatal, or unknown (lost to follow-up) 
• 
Event onset date. If a laboratory event is reported as an AE, record the start date as the date 
of collection of the first lab sample that shows the change. 
• 
Event stop date: date the event resolved 
 
10.1.1 AE Definition 
An AE is any untoward medical occurrence in a clinical study participant which does not necessarily have 
a causal relationship with the treatment. An AE can therefore be any unfavorable unintended sign, 
including an abnormal laboratory symptom or disease temporally associated with the use of IMP, whether 
or not related to the IMP.  
 
Note: For the purpose of this study, an adverse event will be considered any event that occurs within the 
study, whether deemed positive, negative, or neutral by the investigator, qualified designee or reporter. 
Examples of positive or neutral events may include, but are not limited to: 
 
• 
Positive mood, calmness, talkative, elevated mood, dizziness, feeling abnormal, feeling drunk, 
feeling of relaxation, thinking abnormal, inappropriate affect, somnolence, mood disorders and 
disturbances, confusion and disorientation. 


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The investigator or qualified designee should carefully record any AE that occurs. Whenever possible, a 
diagnosis rather than a list of signs and symptoms is preferred. Treatment or intervention of an AE should 
not be reported as an event. The event necessitating the treatment or intervention should be reported. AEs 
should be followed until the events have subsided, returned to baseline or in case of permanent 
impairment, until the condition stabilizes.   
 
10.1.1.1 AE Severity Grading Criteria 
The investigator will make an assessment of severity for each AE and SAE reported during the study and 
assign it to one of the following categories:  
 
• 
Mild: No limitation in normal daily activity. Minor event requiring no specific medical 
intervention, asymptomatic laboratory findings only, marginal clinical relevance. 
• 
Moderate: Some limitation in normal daily activity. Minimal intervention, local intervention, 
non-invasive intervention, transfusion, elective interventional radiological procedure, therapeutic 
endoscopy or operation. 
• 
Severe: Unable to perform normal daily activity. Significant symptoms, which may require 
hospitalization or invasive intervention, elective interventional radiological procedure, therapeutic 
endoscopy or operation, life threatening or disabling events, events resulting in death. 
 
Note: The terms serious and severe are NOT synonymous. The general term severe is often used to 
describe the intensity (severity) of a specific event. The event itself may be of relatively minor medical 
significance (e.g., severe headache). A severe headache does not necessarily need to be considered serious 
unless it meets the criteria of a serious adverse event.   
 
10.1.1.2 AE Causality Assessment 
The investigator will assess the relationship between the AE and the study treatment or the study 
procedure using a binary causality assessment. Causality will be reported separately for each study 
treatment received by the participant. 
 
• 
Related: There is a reasonable possibility that the study treatment, study drug, or study protocol 
caused the event. 
• 
Not Related: There is no reasonable possibility that the study treatment caused the event.  There 
may be other plausible alternative causes for the event which may include but are not limited to: 
medical history, lack of efficacy, worsening of treated condition, other treatment, concomitant 
medications, withdrawal of study treatment, or erroneous administration of treatment.   
 
10.1.2 Serious Adverse Events (SAE) 
All SAEs that occur from the time of signed ICF through the study termination visit (+/- 2 days) should 
be reported. Any SAE that is continuing at the time of the study termination visit will be followed until 
the outcome of the event is known. Whenever possible the investigator should report the overall diagnosis 
of the event(s) rather than the signs and symptoms associated with the event(s). Treatment or intervention 
of an event should not be reported as an SAE. The event necessitating treatment or intervention should be 
reported. 
 


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10.1.2.1 SAE Definition 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria 
listed: 
 
1. Results in death. 
2. Is life threatening. 
3. Requires inpatient hospitalization or prolongation of an existing hospitalization. 
4. Results in persistent or significant disability/incapacity. 
5. Is a congenital anomaly or birth defect. 
6. Is an important medical event (event does not result in death or is life threatening, but based on 
medical judgement may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed above).   
 
Life Threatening: is an event that in the view of the investigator places the participant at immediate risk 
of death from the event as it occurred (e.g., anaphylaxis, ventricular fibrillation, respiratory arrest). This 
does not include events which hypothetically might have caused death if it were more severe. 
 
Hospitalization or Prolongation of Existing Hospitalization:  An event that requires hospitalization or 
prolongation of an existing hospitalization. Hospitalization does not include the following: emergency 
room visit (< 24 hour) or same day surgeries (as outpatient/same day/ambulatory procedures, if the 
surgery was preplanned prior to entering the study). If during a preplanned hospitalization, an event 
occurs that was not part of the preplanned hospital admission (e.g., thromboembolic event), then the event 
prolonging the hospitalization and not the diagnosis or event associated with the preplanned 
hospitalization should be reported.   
 
10.1.3 Adverse Events of Special Interest (AESI) 
An adverse event of special interest (AESI) is a serious or non-serious event of scientific and medical 
concern specific to the study intervention. The event may require further investigation and depending on 
the nature of the event, submission to the FDA or other applicable regulatory authorities. For the purpose 
of this trial, AESIs have been predefined. 
 
AESIs will be reported on the SAE/AESI report form within 24 hours of discovery. Any AESI that also 
meets the criteria of a SUSAR (suspected unexpected serious adverse reaction) will be emergently 
reported to FDA and other appropriate regulatory agencies, PIs, IRBs and IECs. AESIs will be followed 
until the outcome of the event is determined. 
 
AESIs will include the following:  
 
• 
Cardiac arrhythmias, or AEs that are indicative of QT interval prolongation, including (but not 
limited to) Torsade de pointes, sudden death, ventricular extrasystoles, ventricular tachycardia, 
ventricular fibrillation and flutter, palpitations, and non-postural syncope 
• 
Cardiac disorders (e.g., acute MI, angina pectoris, ischemic chest pain) 
• 
Drug diversion, drug abuse and drug accountability (e.g., accidental poisoning, behavioral 
addiction, dependence, drug abuser, drug diversion, overdose, intentional overdose, intentional 
product misuse, poisoning deliberate, prescribed overdose, substance abuser, euphoria-like 
response, hallucination dissociative state, psychosis, aggression, drug tolerance, habituation, drug 
withdrawal syndrome, substance related disorders)  


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• 
Central nervous system vascular disorders (e.g., ischemic central nervous system vascular 
conditions) 
• 
Seizures 
• 
Hypertensive crisis 
• 
Suicide, suicidal behavior (e.g., intentional overdose, intentional self-injury, suicide attempt, 
suicide threat, suspected suicide, suspected suicide attempt), C-SSRS Suicidal Ideation score of 4 
or 5, and/or suicidal ideation judged to be serious or severe in the opinion of the investigator 
 
10.1.4 Other Reportable Information 
Other reportable AEs include but are not limited to the following: 
 
• 
Any clinically significant worsening of a pre-existing condition 
• 
An AE occurring from an overdose (i.e., a dose higher than that indicated in the protocol) of 
study drug whether accidental or intentional 
• 
An AE occurring from abuse (e.g., use for nonclinical reasons of a study medication) 
• 
An AE that has been associated with the discontinuation of the use of a study medication 
• 
A medication error such as an inadvertent or accidental exposure with or without an AE 
 
Any event meeting the abovementioned listing should be reported on an SAE/AESI report form and sent 
to the sponsor or designee within 24 hours of discovery. These events should be followed until the events 
have subsided, returned to baseline or in the case of permanent impairment, until the condition stabilizes.  
 
10.1.5 SAE and AESI Reporting 
In the event of an SAE or AESI, the investigator must fill in the SAE/AESI Report form. The form should 
be signed and dated.  The SAE form should be sent to the sponsor or designee within 24 hours of 
awareness of the event. Each event should have a separate SAE/AESI form. 
 
The investigator should include the minimum reportable criteria on the SAE/AESI report form. The 
minimum criteria include: a product, a participant, a reportable event, and a site/investigator. If any of the 
reportable criteria are missing, the Principal Investigator (PI) should acquire the information prior to 
submitting the SAE/AESI form. 
 
It is not necessary to send source documentation to the sponsor as part of the SAE/AESI reporting 
function but the documentation should be available on site. However, the sponsor may request source 
documentation associated with the event (e.g., hospital admission, relevant tests, and labs, discharge 
summary, autopsy report) and the site should be able to supply the documentation when requested. 
 
If source documentation is requested, all source documentation must be de-identified, redacted, or 
pseudonymized in all attached documents before being sent to the sponsor or designee. Any follow-up 
information should be provided on a new SAE/AESI report form with a sequential follow-up number 
starting with follow-up #1. The SAE/AESI report form should be used for any changes, revisions or 
additional report to the event. 
 
The sponsor assumes responsibility for appropriate reporting of any suspected unexpected serious adverse 
reaction (SUSAR) to the regulatory authorities and governing bodies according to the local regulations. 
 


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The investigator (or sponsor where required) must report these events to the appropriate Institutional 
Review Board (IRB) and/or IEC (Independent Ethics Committee) that approved the protocol unless 
otherwise required and documented by the IRB/IEC. 
 
All SAEs and AESIs should be followed until resolved, returned to baseline or stabilized to a level 
satisfactory to the investigator. 
 
10.1.6 Pregnancy Reporting 
• 
Details of all pregnancies in participants and their partners will be collected after the start of study 
intervention and until the participant's final visit. 
• 
If a pregnancy is reported, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the pregnancy. 
• 
Pregnancies should be reported on a pregnancy form. 
• 
Pregnancies will not be considered SAEs. However, any pregnancy that meets the criterial of an 
SAE (e.g., still birth, spontaneous abortion) should be reported on both a pregnancy and 
SAE/AESI report form. The SAE form is due to the sponsor or designee within 24 hours of 
awareness of the event. 
• 
Pregnancies will be followed until the outcome of the pregnancy is known.   
• 
Live births will be followed for 30 days after delivery. 
 
Any participant who becomes pregnant while participating in the study will not undergo any additional 
MDMA-assisted therapy sessions, though in some cases may continue participation in non-drug therapy 
sessions. Prior to continuation of non-drug study interventions following pregnancy, the following must 
occur: 
 
• 
The sponsor and the relevant IRB/IEC give written approval. 
• 
The participant and/or their partner gives signed informed consent. 
• 
The investigator agrees to monitor the outcome of the pregnancy and the status of the participant 
and/or their partner and their offspring. 
 
10.1.7 Participant Discontinuation or Withdrawal from Study 
Reasons why a participant may discontinue or be withdrawn from the study may include but are not 
limited to: 
• 
Development of toxicity which in the investigator's judgment precludes further therapy 
• 
Participants request 
• 
Participant non-compliance 
• 
Intercurrent illness 
• 
At the discretion of the investigator 
• 
Pregnancy 
• 
Study termination by the sponsor 
• 
Protocol violation 
 
When a participant is withdrawn, the investigator will notify the sponsor and clearly document in the 
medical record and appropriate case report form the reason for withdrawal from study. When possible, the 
investigator will perform the procedures indicated for the final visits within 30 days after the last 
medication dose.  
 


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10.2 Other Significant Events 
Significant life events that may occur during the course of the study, including death of a loved one, loss 
of employment, or other hardship, may have an impact on treatment outcome. The sponsor will capture 
these life events using the LEC-5 measure. Such events will be entered as Comments in the eCRF and if 
appropriate, described in the Case Study Report for data outliers, if any. 
 
10.3 Pregnancy 
10.3.1 Definition of Able to Become Pregnant 
Participants in the following categories are considered a person able to become pregnant (PABP), i.e., 
fertile: 
 
1. Following menarche 
2. From the time of menarche until becoming postmenopausal unless permanently sterile (see 
below) 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
o PABP on HRT and whose menopausal status is in doubt will be required to use one of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
• 
Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented non-surgical hysteroscopic sterilization (Essure) 
o Documented bilateral oophorectomy 
o For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry. 
 
Note: Documentation can come from the site personnel’s review of the participant’s medical records, 
medical examination, or medical history interview. 
 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
 
10.3.2 Contraception Guidelines 
Study participants who were assigned male at birth with partners able to become pregnant will not be 
required to practice contraception. Adequate contraceptive methods are required for participants able to 
become pregnant 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 


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• 
Abstinence from penile-vaginal intercourse 
o The reliability of abstinence should be evaluated carefully with the participant in relation 
to their general lifestyle. An additional acceptable contraceptive 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 contraceptive methods, contact the Medical Monitor. 
 
10.3.3 Follow-up Requirements 
Details of all pregnancies in study participants and their partners 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, PCL-5 assessments, and Study Termination procedures. At a minimum, 
prior to withdrawal from the study, efforts should be made to assess the final PCL-5 immediately and 
complete Study Termination procedures.  
 
The investigator will collect follow-up information on the participant or their partner 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 Data Monitoring Committee 
The sponsor will appoint a DMC with appropriate expertise in the conduct of clinical trials to 
independently monitor participant safety information during the study and make associated 
recommendations for all reviews. The DMC is an independent expert advisory group commissioned and 
charged with the responsibility of periodically evaluating cumulative safety and other clinical trial data 
for evidence of safety concern and recommending study continuation, discontinuation, or modification. 
The composition of the DMC will include clinician experts and at least one biostatistician. 
 
The objective of the DMC Charter is to outline the specific purposes and functions of the DMC. In 
addition, it describes the procedures for data abstraction and data delivery conventions to and from the 
DMC members for review purposes. Access to the DMC charter will be restricted to the DMC and only 
limited specified sponsor staff who were involved in the trial design. 
 
The DMC will periodically receive safety reports as described in the DMC charter and at any time a 
Serious Adverse Reaction (SAR) occurs 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 participants enrolled and to be enrolled in the study. The DMC will also 
review the results of other trials specified in their charter and make recommendations on updating the 
adaptive design elements of the study protocol or data analysis. 
 
The DMC will communicate their recommendations to the sponsor study staff, who will implement 
accordingly. 
 


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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 opioids 
will be cross-tapered to an allowable opioid (hydrocodone, morphine, and codeine) under the care of their 
prescribing physician. 
 
The site physician will consult the prescribing physician to initiate medication tapering for participants, as 
they must refrain from taking psychiatric medications throughout the study, with some exceptions (see 
Section 11.2 Allowed Concomitant Medications). The prescribing physician’s opinion about medication 
discontinuation will be documented either in writing from the prescribing physician, or in writing by the 
site physician documenting phone contact with the prescribing physician. Tapering will follow a time 
course appropriate for the medication based on its half-life or activity, with the Baseline PCL-5 at 
Preparatory Session 3 (Visit 3) scheduled to occur after complete washout for psychoactive medications 
and Experimental Session 1 (Visit 4) scheduled to occur after complete washout for medications with 
drug-drug interactions without a psychological concern (5 half-lives of parent drug or active metabolite, 
whichever is longer, 2 weeks for MAOIs, and 3 weeks for imipramine and clomipramine).  
 
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 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, to avoid withdrawal effects of discontinuation 
between Experimental Sessions) or sleep aids (excluding trazodone) in compliance with Section 11.3 
Prohibited Medications. Sublingual nitroglycerin will be available on site in the case of emergency. 
 
Gabapentin or certain opioids will be allowed when prescribed for pain management. The following 
opioids will be allowed during the study: hydrocodone, morphine, and codeine. Prior to randomization, 
participants who are taking opioids not included on this list will be cross-tapered to an allowable opioid 
under the care of their prescribing physician. Opioid medications may reduce the effectiveness of MDMA 
and may prolong QT/QTc interval, but the opioids 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 opioids for pain management will be asked to decrease the dose leading up to 


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the Experimental Session in order to avoid withdrawal effects when they are required to refrain from 
taking the medication from 12 hours before IMP administration at the Experimental Session to 24 hours 
after. During this period, the participant will be allowed to take the medication if needed for intolerable 
pain flare-ups or to prevent withdrawal symptoms. If a participant reports lack of analgesic effect during 
the sub-acute period following each Experimental Session, the site physician may approve taking an 
allowed opioid medication sooner than 24 hours after IMP administration. 
 
If the participant is on stimulants for Attention Deficit/Hyperactivity Disorder (ADHD) at Baseline, they 
can continue to use them at the same dose and frequency, as long as they discontinue five half-lives 
before each Experimental Session and do not restart for 10 days after each Experimental Session. 
 
All psychoactive medications, herbal supplements, nonprescription medications, and prescription 
medications must be reviewed by the research team. Failure to comply with protocol requirements for 
concomitant medications may result in withdrawal from treatment, depending on the investigator and 
Medical Monitor judgment. 
 
11.3 Prohibited Medications 
There are medications that should be discontinued prior to enrolling in the study. These medications 
should not be restarted until study termination unless previously discussed with the MPBC medical 
monitor.   
 
 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 opioids for pain 
control). 
• 
Agree to follow an appropriate tapering initiated at enrollment visit, defined by the treating 
physician, and to respect a subsequent washout period of 5 half-lives of the medication 
(calculation based on parent or active metabolite half-life, whichever is longer) preceding Visit 3. 
o For specific medications, including antidepressants and most antipsychotics, refer to the 
Allowed and Prohibited Medication List (if a drug is not in the list, it will be discussed with 
the Medical Monitor).  
o For non-selective irreversible MAOIs, a 2-week washout period following the taper is required 
(three weeks in the case of imipramine and clomipramine, tricyclic antidepressants with 
MAOI activity) prior to Experimental Session. 
 
Use of St. John’s Wort, and other herbs and medicines with notable serotonergic effects are prohibited 
from Baseline to Study Termination.  
 
Ketamine must be discontinued 1 month prior to Preparatory Session 3 (Visit 3) and is prohibited until 
Study Termination. 
 
If an SSRI, SNRI, MAOI (including non-psychiatric medications with MAOI activity, e.g. rasagiline, 
selegiline, linezolid), or other antidepressant (including antipsychotics used for depression, e.g. clozapine, 
risperidone, aripiprazole, ziprasidone, olanzapine) is used between Experimental Session 1 (Visit 4) and 
Study Termination (Visit 16), the participant will be withdrawn from treatment and continue in follow-up. 
 
Opioids other than hydrocodone, morphine, and codeine are prohibited from Enrollment Confirmation to 
Study Termination. Participants taking prohibited opioids will be cross-tapered to an allowable opioid 
during the Preparatory Period. 


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11.3.1 Prohibited Medications prior to the Experimental Sessions 
There are medications that can be used during the protocol but should be held prior to the Experimental 
Sessions. The participant should agree to the following: 
• 
Agree 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 for 5 half-lives of the medication (calculation based on parent or active metabolite half-
life, whichever is longer) 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 contraception, thyroid 
hormones, anti-hypertensives, or other medications approved by the research team). 
 
12.0 Clinical Laboratory Assessments 
The site physician will confirm laboratory assessments gathered in screening for assessing eligibility. The 
site physician will use a list of normal ranges to conclude whether participants are eligible for the protocol 
and will indicate justification for admitting participants with abnormal values after consultation with the 
Medical Monitor. 
 
The following laboratory assessments will be performed as a part of Screening:  
 
• 
Serum electrolytes and metabolic profile 
o Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) 
o Albumin: Globulin (A:G) ratio 
o Albumin, serum 
o Alkaline phosphatase, serum 
o Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) 
o Bilirubin, total 
o Blood urea nitrogen (BUN): creatinine ratio 
o Calcium, serum 
o Carbon dioxide 
o Chloride, serum 
o Creatinine, serum 
o Globulin, total 
o Glucose, serum 
o Potassium, serum 
o Protein, total, serum 
o 
Sodium, serum 
• 
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  


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• 
Urinalysis 
o Color 
o Appearance 
o Specific gravity 
o pH 
o Protein 
o Glucose 
o Ketones 
o Occult blood 
o Leukocyte esterase 
o Nitrite 
o Bilirubin 
o 
Urobilinogen 
• 
Thyroid function 
o 
Thyroid-stimulating hormone (TSH) high sensitivity (if abnormal, free T3 and T4 will 
also be tested) 
• 
HCV if indicated 
• 
Urine-dip pregnancy test for participants able to become pregnant will be performed at the site. 
Serum human chorionic gonadotropin (hCG) pregnancy test (if urine test is positive; for PABP 
only). 
• 
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 during the 
beginning of the study, which will provide more detail about analyses than provided in this protocol. A 
brief overview of the statistical analyses that will be performed is provided in the following sections. 
 
13.1 Power and Sample Size Determination 
This is a multi-site open-label safety extension study of MDMA-assisted therapy for the treatment of 
participants with PTSD. The effectiveness of MDMA-assisted therapy will be measured by the PCL-5 
and SDS. The sample size is not determined by statistical criteria. 
 
13.2 Statistical 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. In general, nominal variables will be 
described in terms of frequencies and percentages. Ordinal and non-normal continuous variables will be 
described using the sample median, 25th and 75th percentiles, and interquartile range (IQR). 
 
The following analysis set is defined for this study: 
 
• 
All Enrolled: all participants who are enrolled in the study 
• 
Safety: all participants who receive any IMP  


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13.2.1 Effectiveness Analyses 
13.2.1.1 Primary Outcome 
The primary analysis of the effectiveness of MDMA will be made using a Mixed Model Repeated 
Measure (MMRM) model to assess changes in PCL-5 scores throughout the study period from Baseline 
(Visit 3) through Visit 16. Baseline covariates (age, gender, ethnicity, index trauma, complexity and 
severity of trauma, diagnosis of comorbid depression, diagnosis of comorbid Axis 2 diagnosis, adverse 
childhood experiences collected in the parent study) may be assessed for inclusion in the final model with 
an alpha level set at 0.05. Details of analyses are described in the Statistical Analysis Plan.  
 
13.2.1.2 Secondary Outcome 
The SDS will be analyzed in a similar manner to the primary analysis of the PCL-5. Details of analysis 
are 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, 
TEAEs, 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 positive or serious ideation and suicidal behavior will be presented using descriptive 
statistics of C-SSRS scores in tabular format. Vital signs (heart rate, blood pressure, and body 
temperature) for Experimental Sessions will be summarized using descriptive statistics in tabular format 
listing values at pre-IMP administration, prior to the supplemental dose, and at the end of each 
Experimental Session by treatment group. 
 
13.2.3 Concomitant Medications 
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). Additional details are available in the Statistical Analysis Plan. 
 
13.2.4 Analysis of Exposure 
The frequencies and percentages of participants with exposure will be summarized overall and by visit. 
 
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 


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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 ICH 
Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European 
Directive 2001/20/EC, US Code of Federal Regulations Title 21) and with the ethical principles laid 
down in the Declaration of Helsinki.  
 
The protocol and the ICF must be reviewed and approved by a properly constituted institutional review 
board (IRB) or ethics committee and national regulatory agency (FDA, Health Canada, or Israeli Ministry 
of Health) before study start. Signed and dated documentation of approvals must be provided to the 
sponsor. Prior to study start, the investigator is required to sign a signature page confirming their 
agreement to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to the sponsor. 
 
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 an electronic ICF platform is available, it may be used. If no electronic ICF platform 
is available or there are technical difficulties, the participant will sign a paper copy of the ICF during that 
telemedicine visit. The participant will then submit a scan or image of the ICF to the site and 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 


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described in the protocol beyond phone screening). The process of obtaining informed consent should be 
documented in the participant’s source records. The study staff will provide a copy of the signed ICF to 
the participant and will maintain the original in the ISF. 
 
The written ICF and any other written information to be provided to participants should be revised 
whenever important new information becomes available that may be relevant to the participant’s consent. 
Any revised ICF and written information should receive approval from an IRB before use. The participant 
should be informed in a timely manner if new information becomes available that may affect the decision 
to take part or continue in the study. The communication of this information should be documented. 
Participants can withdraw consent at any time without prejudice. If a participant withdraws consent but 
does not revoke the Health Insurance Portability and Accountability Act (HIPAA) authorization, the study 
team will have full access to their medical records, including termination visit information. If a participant 
revokes only the HIPAA authorization, the study team will have full access to all medical records prior to 
the date and time of revocation. 
 
If a participant fails Screening and is rescreened at a later date, a new copy of the ICF should be signed. 
 
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 remote monitoring and/or 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.  
 
During or after the study, the regulatory authorities, the IRB, and/or representatives of the sponsor may 
request access to all source documents, eCRFs, and other protocol documentation for on-site audit or 
inspection. Monitoring and auditing procedures will be supplied in a separate document.  
 
14.2.1 Source Records 
Source records contain all primary evidence of existence of the participant and document all study 
procedures. Source records include but are not limited to medical records, measures, checklists, notes, 
emails, and laboratory reports. All data reported in the eCRF are transcribed from primary source 
documents and must be consistent. These documents are maintained securely at the study site and the 
sponsor may be given view only access through a secure electronic document storage system to facilitate 
remote monitoring. 
 
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 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 


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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 or 
secure electronic document storage system, and access to measures will be limited to regulatory agencies, 
researchers, and individuals analyzing data. Researchers, other than the investigators and sponsor staff 
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 helpful for sponsor oversight of therapy processes. Any requests for use of audiovisual 
recordings outside of research and training requests will result in participants receiving information on the 
request. Participants will have control over any presentation of audiovisual recordings beyond viewing by 
authorized researchers, sponsor staff, or regulatory agencies. The sponsor uses encrypted, secure 
technology to transfer and store recordings, but there is always a risk of a security breach. The sponsor is 
committed to taking preventative measures to avoid such an event. In the case of a security breach, the 
participant will be notified, and all efforts will be made to minimize the dissemination of recorded 
content.  
 
Clinical trial data other than video data will be hosted on an EDC system that is FDA-compliant. All data 
entered into this system will be de-identified. Participants will only be referred to by numbers and a 
secondary identifier code. Source Records and identifying information will be retained at clinical sites per 
GCP. The sponsor will train the study staff on EDC procedures. Each study staff member with access to 
the data will be given an individual password. 
 
The sponsor has developed a feature that will allow participants to create a password and enter their self-
report questionnaire data directly into Medrio using the electronic Participant Reported Outcome (ePRO) 
feature. Participants will be reminded by email to enter the data. Participant emails will be treated as 
Protected Health Information (PHI) in the database. Participants will receive a welcome email and 
reminder emails to ensure that they provide all necessary data. 
 
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 ICF.  
 
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 emergencies can be treated by the site physicians. If the site physicians cannot treat a study-related 
emergency, then there are contingency plans for the transport of participants to the nearest hospital.  
 


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


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15.0 Appendix A: Sub-study without Overnight Stays 
Rationale 
 
This sub-study to the MAPPUSX protocol “A Multi-Site Open-Label Safety Extension Study of 
Manualized MDMA-Assisted Therapy for the Treatment of Participants with Posttraumatic Stress 
Disorder" 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. This 
approach was also tested in the Phase 2 study MP16 and Phase 3 study MAPP1 with no safety concerns 
due to travel to home or hotel; this approach was found to be comparable in safety to participants who had 
an overnight stay. The sub-study has also been tested in the Phase 3 study MAPP2. The accumulation of 
these sub-study samples will enable a sample size to permit an integrated analysis of safety for this 
protocol variant compared to participants with an overnight stay. 
 
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 
Psychological Risks and Mitigation. 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. 
 
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). 


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• 
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. The Integrative Session may 
happen remotely if approved by the research team. 
  
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. 
 
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 


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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. 
 
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. 


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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. 
 
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. 
 
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 clinical sites and to support 
generalizability of potentially delivering this treatment to varied treatment settings post-approval. 
 


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References 
 
1. 
Yehuda, R., et al., Post-traumatic stress disorder. Nat Rev Dis Primers, 2015. 1: p. 15057. 
2. 
APA, Clinical practice guideline for the treatment of posttraumatic stress disorder (PTSD) in 
adults. 2017. 
3. 
Burg, M.M. and R. Soufer, Post-traumatic Stress Disorder and Cardiovascular Disease. Curr 
Cardiol Rep, 2016. 18(10): p. 94. 
4. 
Koenen, K.C., et al., Posttraumatic stress disorder in the World Mental Health Surveys. Psychol 
Med, 2017. 47(13): p. 2260-2274. 
5. 
Nichter, B., et al., Psychological burden of PTSD, depression, and their comorbidity in the U.S. 
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SAP_001.pdf: 
MAPPUSX Statistical Analysis Plan 
Version 1: 13 April 2021 
SPONSOR 
Multidisciplinary Association for Psychedelic Studies (MAPS)
1115 Mission Street 
Santa Cruz, CA 95060 
SPONSOR 
REPRESENTATIVE 
Rick Doblin, Ph.D. 
Executive Director, MAPS 
SPONSOR DELEGATE & 
TRIAL ORGANIZER 
Multidisciplinary Association for Psychedelic Studies (MAPS)
3141 Stevens Creek Blvd #40563 
San Jose, CA 95117 
SPONSOR DESIGNEE 
Amy Emerson 
Chief Executive Officer 
MAPS Public Benefit Corporation 
MEDICAL MONITOR(S) 
Alia Lilienstein, M.D. 
STATISTICIAN(S) 
Scott Hamilton, Ph.D. 
PREPARED BY 
Scott Hamilton, Ph.D. 
USE 
In conjunction with relevant regulatory guidance 
• • • 
. .. .. . 
•• • •• • ••• 
• • • • •• 
• • 
.. . . .. . •· ········ 
. . : : : ...... •:....... . 
e • • • : : l l .••:....... •• e 
. 
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. .. . ...... :.•· ... :: : . . . 
.. •······· .• .. . . . .. 
• 
••• • • • • • 
······· .. ..... . 
••• • •• • • ••• 
..... .. ..... 
•• •• •• •• 
• ••• • 
MAPS 
Public Benefit 
Corporation 


MAPS Public Benefit Corporation 
 
MAPPUSX Statistical Analysis Plan 
U.S.
Version 1: 13 April 2021
Page 2 of 19 
Table of Contents 
List of Tables .................................................................................................................................. 3
List of Abbreviations ..................................................................................................................... 4
1.0 Definitions of Terms ................................................................................................................ 7
2.0 Introduction .............................................................................................................................. 8
3.0 Study Objectives....................................................................................................................... 8
3.1 Primary Objective .................................................................................................................. 8
3.2 Secondary Objective .............................................................................................................. 8
3.3 Safety Objectives ................................................................................................................... 8
3.4 Exploratory Objectives .......................................................................................................... 9
4.0 Measures ................................................................................................................................... 9
4.1 Primary Measure .................................................................................................................... 9
4.2 Secondary Outcome Measure ................................................................................................ 9
4.3 Safety Measures ..................................................................................................................... 9
4.4 Exploratory Measures .......................................................................................................... 10
5.0 Study Design ........................................................................................................................... 10
6.0 Randomization and Blinding ................................................................................................ 15
7.0 Sample Size and Power Considerations ............................................................................... 15
8.0 Analyses .................................................................................................................................. 15
8.1 Analysis Sets ........................................................................................................................ 15
8.2 Missing Data Handling ........................................................................................................ 15
8.2.1 Partial or Missing Dates ................................................................................................ 15
8.3 Protocol Deviations .............................................................................................................. 16
8.4 Baseline Values .................................................................................................................... 16
8.5 Participant Disposition and Dosing Summary ..................................................................... 16
8.6 Demographics and Baseline Characteristics ........................................................................ 17
8.7 Efficacy Analyses ................................................................................................................ 17
8.7.1 Primary Effectiveness Analysis .................................................................................... 17
8.7.2 Secondary Effectiveness Analysis ................................................................................ 17
8.7.3 Exploratory Analyses .................................................................................................... 17
8.8 Safety Analyses .................................................................................................................... 17
8.8.1 Analysis of Exposure .................................................................................................... 18
8.8.2 Analysis of Adverse Events .......................................................................................... 18
8.8.3 Concomitant Medications ............................................................................................. 18
8.8.4 Analysis of Suicidal Ideation and Behavior .................................................................. 19
8.8.5 Summary of Vital Signs ................................................................................................ 19
9.0 Timing of Analyses ................................................................................................................. 19
 
 


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Version 1: 13 April 2021
Page 3 of 19 
List of Tables 
 
Table 1: Dose Regimen of MDMA................................................................................................ 10
Table 2: Time and Events  Study Procedures .............................................................................. 11
 
 
-


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


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


MAPS Public Benefit Corporation 
 
MAPPUSX Statistical Analysis Plan 
U.S.
Version 1: 13 April 2021
Page 6 of 19 
UFEC
Utilization of Facility-based and Emergent Care
U.S. 
 
United States 
VA 
 
U.S. Department of Veterans Affairs 
VAS 
 
Visual Analog Scale 
WBC  
White Blood Cell 
WHO  
World Health Organization 
WHO DDE 
WHO Drug Dictionary EnhancedTM 
 
 


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MAPPUSX Statistical Analysis Plan 
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Version 1: 13 April 2021
Page 7 of 19 
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 PCL-5 outcome assessment atVisit 16. 
 
Descriptive data: includes mean, median, standard deviation, minimum, and maximum of 
numerical data used as needed to describe the sample 
 
Difference scores: consist of scores computed by subtracting one value from another, as 
subtracting Baseline from follow-up score, used to test for differences between and within groups 
to determine change as a function of experimental treatment over time 
 
Dropouts: are defined as participants who withdraw consent due to any reason after dosing and 
no longer participate in the study, i.e. no further contact with investigators or site staff. 
 
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-dosing Early Terminators: are defined as participants who discontinue study treatment but 
continue to participate in study evaluations and outcome assessments. 
 
Pre-dosing Early Terminators: are defined as participants who discontinue participation after 
enrollment but before randomization during the Preparatory Period and never receive study drug. 
 
Process measures: study measures or qualitative observations collected during the study that may 
increase depth of understanding of the condition and treatment, although not necessarily related to 
safety or 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 blinding, measurement techniques, data workflow, and 
statistical analysis 
 


MAPS Public Benefit Corporation 
 
MAPPUSX Statistical Analysis Plan 
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Version 1: 13 April 2021
Page 8 of 19 
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 
Thi
-Site Open-
Label Safety Extension Study of Manualized MDMA-Assisted Therapy for the Treatment of 
 
 
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 
 
Corporation (MPBC). 
 
This multi-site open-label safety extension study of manualized MDMA-assisted therapy for the 
treatment of participants with PTSD will be con
 
 
The treatment consists of a flexible dose of MDMA, followed by a supplemental dose unless 
tolerability issues emerge administered with manualized therapy in three open-label 
approximately monthly Experimental Sessions. This Treatment Period is preceded by three 
Preparatory Sessions. During the Treatment Period, each Experimental Session is followed by 
threeIntegrative Sessions of non-drug therapy. Experimental Sessions are followed by an 
overnight stay; a sub-study will assess feasibility of Experimental Sessions without an overnight 
stay. The Primary Outcome measure, the change in PCL-5 (PTSD Checklist for DSM5) from 
Visit 3 is assessed at Visit 16. An independent Data Monitoring Committee (DMC) will 
review safety data as described in the DMC charter and at any time a Serious Adverse Reaction 
(SAR) occurs. 
 
3.0 Study Objectives 
3.1 Primary Objective  
The primary objective of this study is to evaluate the effectiveness of MDMA-assisted therapy for 
PTSD, as measured by the reduction in PCL-5 total score from Visit 3 to Visit 16. 
 
3.2 Secondary Objective 
The key secondary objective of this study is to evaluate the effectiveness of MDMA-assisted 
therapy for PTSD in functional impairment, as measured by the mean change in Sheehan 
Disability Scale (SDS) item scores from Visit 3 to Visit 16. 
 
3.3 Safety Objectives 
The overall safety objective is to assess 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: 
s document contains a Statistical Analysis Plan (SAP) for MAPPUSX "A Multi 
Participants with Posttraumatic Stress Disorder." 
implemented through MAPS' wholly owned subsidiary and delegate, the MAPS Public Benefit 
ducted in N::::100 participants, by invitation only. 


MAPS Public Benefit Corporation 
 
MAPPUSX Statistical Analysis Plan 
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Version 1: 13 April 2021
Page 9 of 19 
1.
Assess incidence of AEs during Experimental Sessions that may be indicative of a
medical complication of the Investigational Medicinal Product (IMP) such as clinical 
signs and symptoms of chest pain, shortness of breath, or neurological symptoms or any 
other signs or symptoms that prompt additional vital sign measurements 
2. Assess incidence of AEs by severity 
3. Assess incidence of TEAEs by severity 
4. Assess incidence of TEAEs by severity reported during an Experimental Session, 1 day, 
and 2 days after IMP administration 
5. Assess incidence of AESIs, defined as AEs specified in the protocol related to cardiac 
function, suicidality, and abuse liability 
6. Assess incidence of AEs by severity categorized as leading to discontinuation of IMP, 
resulting in death or hospitalization, and continuing at Study Termination 
7. Assess incidence of SAEs 
8. Assess incidence of concomitant medications taken during an Experimental Session, 1 
day, and 2 days after IMP administration 
9. Assess incidence of psychiatric concomitant medications taken during the Treatment 
Period 
10. Assess incidence of positive or serious suicidal ideation and positive suicidal behavior 
assessed with the Columbia Suicide Severity Rating Scale (C-SSRS) 
11. Assess changes in blood pressure (BP), heart rate, and body temperature from pre-IMP 
administration to end of each Experimental Session 
 
3.4 Exploratory Objectives 
These objectives may be explored to characterize participants receiving MDMA-assisted therapy 
to support the primary objective: 
1. Explore the effect of presence of secondary traumatic stressors identified on the Life 
Events Checklist (LEC-5) on the PCL-5 total severity analysis 
2. Explore differences from Visit 3 to Visit 16 in: 
a. Depression (BDI-II) 
b. Chronic pain (CPGS) 
c. Quality of life (EQ-5D-5L) 
d. Nicotine use (SRNU) 
e. Eating habits (EAT-26) 
f. Workplace productivity (HPQSF) 
3. Explore differences from Screening to Visit 16 in alcohol use (AUDIT) and drug use 
(DUDIT) 
 
4.0 Measures 
4.1 Primary Measure 
 
PCL-5 (PTSD Checklist) 
 
4.2 Secondary Outcome Measure 
 
Sheehan Disability Scale (SDS) 
 
4.3 Safety Measures 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Adverse Events 
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Treatment-emergent Adverse Events 
 
Serious Adverse Events 
 
Adverse Events of Special Interest 
 
Concomitant medication use 
 
Vitals signs during MDMA sessions 
 
4.4 Exploratory Measures 
 
Life Events Checklist (LEC-5) 
 
Beck Depression Inventory II (BDI-II)  
 
Chronic Pain Grade Scale (CPGS) 
 
EuroQol Five Dimensions  Five Levels Questionnaire (EQ-5D-5L) 
 
Alcohol Use Disorders Identification Test (AUDIT) 
 
Drug Use Disorders Identification Test (DUDIT) 
 
Self-reported Nicotine Use (SRNU) 
 
EAT-26 (Eating Attitudes Test) 
 
HPQSF (Health and Work Performance Absenteeism and Presenteeism Short Form) 
 
Utilization of Facility-based and Emergent Care (UFEC)  
 
5.0 Study Design 
Table 1: Dose Regimen of MDMA 
 
Experimental 
Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative Dose 
1 
80 mg 
40 mg 
80 to 120 mg 
2 
80 or 120 mg 
40 or 60 mg 
80 to 180 mg 
3 
80 or 120 mg 
40 or 60 mg 
80 to 180 mg 
Total Cumulative Dose
240 to 480 mg 
* Unless contraindicated 
 
 
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• 
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• 
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Table 2: Time and Events  Study Procedures 
 
Screening Period 
(1 to 6 weeks) 
Preparatory Period 
(At least 5 days, depending on medication tapering) 
 
Screening 
Preparatory 
 
Visit 
Phone Screening 
Screening 
IR Screening 
V0 
V1 
V2 
V3 
Visit Description 
Phone 
Calls 
In-person Visits & 
Labs 
Telemedicine 
Enrollment 
Prep. 1 
Prep. 2 
Prep. 3 
Visit Timing 
Prior to Initial 
Screening 
Over 7 to 42 days 
2 to 9 days after 
initial eligibility 
met 
2 to 14 days post 
IR Screening 
0 to 14 days after 
V0 
At least 2 days after 
V1 (depending on 
tapering) 
Post V2 & Taper, 
1 to 14 days before 
V4 
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 
 
 
 
 
 
 
Independent Rater Assessment 
 
 
 
 
 
Medication Taper 
 
 
 
 
Study Enrollment  
 
 
 
 
 
 
All AEs B 
 
 
 
90-min Preparatory Session 
 
 
 
 
Phone Call Follow-up C 
 
 
 
 
 
 
Measures (ePRO or Clinician-
Administered D 
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A  At Screening, collect data on previous hospitalizations and healthcare utilization. Request participants to obtain medical/psychiatric records generated since the end of the parent 
study to bring to the in-person screening   
B 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   
C If needed, call participant to confirm medication tapering and stabilization is complete prior to Visit 3   
D Refer to Table 6: Time and Events-Measures for details 
 
Treatment Period 
8 to 20 weeks 
 
 
 
Treatment 1 
Treatment 2 
Treatment 3 
 
Study 
Termi-
nation 
Visit 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
Visit Description 
Exp. 1 
Int. 1.1 
Int. 1.2 F 
Int.  
1.3 F 
Exp. 2 
Int. 2.1 
Int. 2.2 F 
Int.  
2.3 F 
Exp. 3 
Int. 3.1 
Int.  
3.2 F 
Int.  
3.3 F 
Study  
Termination 
Visit Timing 
1 to 14 
days 
after V3 
Morning 
after V4 
10 to 18 
days after 
V4 
At least 2 
days after 
V6;  
1 to 14 days 
before V8 
21 to 56 
days 
after V4 
Morning 
after V8 
10 to 18 
days 
after V8 
At least 2 
days after 
V10; 
1 to 14 days 
before V12 
21 to 56 
days 
after V8 
Morning 
after V12 
10 to 18 
days after 
V12 
At least 
two days 
after 
V14  
24 to 32 days 
after V12 
Past/Current 
Medication & 
Adherence 
Drug Screen 
 
 
 
 
 
 
 
 
 
 
Pregnancy Screen  
 
 
 
 
 
 
 
 
 
 
All AEs A 
Container 
Assignment B 
 
 
 
 
 
 
 
 
 
 
Administer IMP 
 
 
 
 
 
 
 
 
 
 
8-hour Exp. Session 
 
 
 
 
 
 
 
 
 
 
BP, Pulse, 
Temperature  
 C 
 
 
 
 C 
 
 
 
 C 
 
 
 
 D 
Potential Overnight 
Stay 
 
 
 
 
 
 
 
 
 
 
90-min Integrative 
Session 
 
 
 
 
Phone Call 
Follow-up E 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Draw (CRP) 
 
 
 
 
 
 
 
 
 
 
 
 
Measures (ePRO or 
Clinician-
Administered G 
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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 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  
DAt Study Termination, only blood pressure needs to be measured   
E 14 days of phone call follow-up: every other day after the Experimental Session; includes C-SSRS administration and AE collection   
F All Integrative Sessions must be at least 2 days apart   
G Refer to Table 6: Time and Events-Measures for details 
 
 
 
Screening 
Preparatory Period 
Treatment 1 
Treatment 2 
Treatment 3 
  
Study 
Termi
nation 
Visit # 
Screeni
ng 
IR 
Screeni
ng 
V1 
V2 
V3 
V4 
V5 
V6 
 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
Visit 
Description 
~Time to 
Complete 
Measure 
(minutes) 
Site 
Visit 
Tele-
medici
ne 
Prep. 
Session 
1 
Prep. 
Session 
2 
Prep. 
Sessi
on 3 
Exp. 
Sessio
n 1 
Int. 
Sessi
ons 
1.1 
Int. 
Sessi
on 
1.2 
Int. 
Sessio
n 1.3 
Exp. 
Sessi
on 2 
Int. 
Sessi
ons 
2.1  
Int. 
Sessi
on 
2.2 
Int. 
Sessi
on 
2.3 
Exp. 
Sessio
n 3 
Int. 
Sessi
ons 
3.1  
Int. 
Sessi
on 
3.2 
Int. 
Sessi
on 
3.3 
Study 
Termi-
nation 
C-SSRS A 
10 
 B 
 B 
 B 
MINI 
75 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LEC-5 
5 
 
 
 
 
 
 
 
 
 
 
PCL-5 
8 
 
 
 
 
 
 
 
 
 
 
SDS 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI-II 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CPGS 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUDIT 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DUDIT 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SRNU 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EAT-26 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HPQSF 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UFEC 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
~Total 
Time of 
Completin
g Measures 
(minutes) 
121 
29 
70 
0 C 
0 C 
55 
90 B 
10 
23 
10 
90 B 
10 
23 
10 
90 B 
10 
23 
10 
 
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Version 1: 13 April 2021 
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A All C-SSRS are Since Last Visit. The first assessment will measure suicidality since the last administration in the parent study. All subsequent administrations will assess 
suicidality since the last administration in this protocol.  
B Conducted pre- and post-Investigational Product administration, and every other day for 14 days after Experimental Sessions.  
C No planned measures to be assessed at Visit 1 or Visit 2 
 
 
 


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6.0 Randomization and Blinding 
This is an open-label study with no randomization or blinding. 
 
7.0 Sample Size and Power Considerations 
This is a one-arm open-label study. Thus, no power nor sample size calculations are required. 
 
8.0 Analyses 
Every effort will be made to ensure complete, accurate and timely data collection and to avoid 
missing data, to ensure the completeness of the data which can impact the integrity and accuracy 
of the final study analysis. The statistical analyses will be reported using summary tables, figures, 
and data listings. All analyses and tabulations will be performed using SAS® Version 9.4 or 
higher, and S-PLUS. In general, nominal variables will be described in terms of frequencies and 
percentages. Ordinal and non-normal continuous variables will be described using sample median 
and range.  
 
Approximately normally distributed continuous variables will be described using sample mean 
and standard deviations and analyzed by parametric statistical tests. Otherwise, Wilcoxon rank-
sum tests will be used.  Categorical variable will be displayed by counts and percentages and 
analyzed by chi-squared tests.  Except for the primary efficacy analysis, all statistical tests will be 
two-sided and a difference resulting in a p-value of less than or equal to 0.05 will be considered 
statistically significant. All p-values will be rounded to and displayed in four decimals. If a p-
value less than 0.0001 occurs it will be shown in tables as <0.0001. Data not subject to analysis 
according to this plan will not appear in any tables or graphs, but will be included in the data 
listings. Selected results may be presented graphically using standard graphical software. 
 
8.1 Analysis Sets 
 
Safety: all participants who receive any IP  
 
 
All Enrolled:  all participants who signed informed consent 
 
 
8.2 Missing Data Handling 
All possible procedures within Good Clinical Practice (GCP) will be used to minimize Post-
dosing Early Termination. All participants who receive IP in at least one Experimental Session 
will be included in all safety analyses.  
 
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. 
 
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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. 
 
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. 
 
3. If the day is unknown, then the last day of the month will be assigned. 
 
8.3 Protocol Deviations 
Protocol deviations will be classified as major/minor by the MPBC protocol deviations review 
committee.  The committee will determine the impact of the deviation on the study subject  
safety and rights, study compliance, data quality, and the proposed analyses.  A subject level 
listing will report the description of the deviation and the impact.  
 
A table of protocol deviations will summarize them by major/minor into the following categories: 
 
 
Informed Consent 
 
Inclusion/Exclusion 
 
Study Treatment 
 
Prohibited Concomitant Medication 
 
Trial Procedures 
 
Safety Reporting 
 
Discontinuation 
 
Miscellaneous 
 
8.4 Baseline Values 
Baseline values are from Baseline Visits for all measures, except C-SSRS, AUDIT, DUDIT, 
resting blood pressure (BP), Body Mass Index (BMI). For C-SSRS, the initial screening visit will 
AUDIT and DUDIT measures and resting BP, BMI, results collected at Screening will be used as 
the Baseline value. 
 
8.5 Participant Disposition and Dosing Summary 
The Safety Set will be included in the summary of participant disposition and accountability 
summarized. The number and percent of participants who completed or discontinued the study 
will be displayed with reasons for early termination, where the percent is with respect to the total 
number of participants. The timepoint of doses and total MDMA (mg) administered will be 
summarized for the Safety Set.  
• • • • • • • • 
Otherwise, 'January' will be assigned. 
If the month is unknown, then 'December' will be assigned. 
s' 
be conducted with the 'Lifetime' version of the measure. The Independent Rater Screening 
assessment of' Since Last Visit' suicidal ideation and behavior will be used as 'Baseline.' For the 


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8.6 Demographics and Baseline Characteristics 
Participant demographic data and Baseline characteristics will be summarized descriptively.  
 
8.7 Efficacy Analyses 
For all primary, secondary, and exploratory endpoints descriptive statistics (n, mean, standard 
deviation, median, range, or counts and percentages where appropriate) will be provided. 
Longitudinal PCL-5 and SDS item scores will be plotted across visits to characterize the onset of 
treatment effect. 
 
8.7.1 Primary Effectiveness Analysis 
The primary analysis of the effectiveness of MDMA-assisted psychotherapy will be made using a 
Mixed Model Repeated Measure (MMRM) model to assess changes in PCL-5 scores throughout 
the study period from Baseline (Visit 3) through Visit 16. Baseline covariates (baseline PVL-5, 
age, gender, ethnicity, index trauma, complexity and severity of trauma, diagnosis of comorbid 
depression, diagnosis of comorbid Axis 2 diagnosis, adverse childhood experiences collected in 
the parent study) may be assessed for inclusion in the final model with an alpha level set at 0.05. 
 
8.7.2 Secondary Effectiveness Analysis  
The SDS will be analyzed in a similar manner to the primary analysis of the PCL-5. 
 
8.7.3 Exploratory Analyses 
Post-hoc exploratory analyses not identified in this SAP may be performed to further examine the 
study data. In particular, MMRM models, linear regression, and/or ANCOVA models may be 
utilized to analyze the effect of MDMA in conjunction with psychotherapy on the following 
exploratory endpoints: 
 
Presence of secondary traumatic stressors identified on the Life Events Checklist (LEC-
5) on the PCL-5 total severity analysis
 
Depression (BDI-II)
 
Chronic pain (CPGS)
 
Quality of life (EQ-5D-5L)
 
Nicotine use (SRNU)
 
Eating habits (EAT-26)
 
Workplace productivity (HPQSF)
 
Alcohol use (AUDIT) 
 
Drug use (DUDIT)
 
These analyses will be clearly identified as exploratory in the final clinical study report. 
 
 
8.8 Safety Analyses 
Safety analyses will confirm safety data with summary tables listing exposure to IMP, unsolicited 
AEs, TEAEs, 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 
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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. 
 
8.8.1 Analysis of Exposure 
The total mg exposure of participants will be summarized. Data will be tabulated for the Safety 
Set. 
 
8.8.2 Analysis of Adverse Events 
The primary measure of safety will be the reporting of unsolicited AEs. All AEs collected from 
Enrollment to Termination will be categorized as follows: 
 
Pretreatment AEs are defined as AEs that occur during the Preparatory Period prior to the 
first dose in the first Experimental Session 
 
Treatment Emergent AEs are defined as AEs that occur during the Treatment Period from 
the first Experimental Session to the last Integrative Session 
 
AEs that occur on and two days after MDMA administration 
 
AESIs are defined as AEs specified in the protocol related to cardiac function and abuse 
liability 
 
Follow-up Period AEs are defined as AEs that occur during the Follow-up Period after 
the last Integrative Session through Termination 
 
AEs leading to discontinuation of IP 
 
AEs resulting in death or hospitalization. 
 
SAEs 
 
AEs continuing at Termination. 
 
Verbatim terms on case report forms will be mapped to preferred terms (PT) and system organ 
class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) Version 24.0 
Frequency and incidence of AEs will be displayed by PT, sorted by SOC, severity, and 
seriousness. AEs will be analyzed and presented as follows: 
 
If a participant has more than one AE mapped to the same PT, that AE will be reported 
once using the highest severity 
 
Relationship will be determined by the Clinical Investigator 
 
AEs that occur on day of Experimental Sessions and two days after IP administration will 
be presented separately. 
 
8.8.3 Concomitant Medications 
Frequency and incidence of concomitant medications will be displayed by generic name, sorted 
by class, and summarized by treatment group, analysis set, and category. Concomitant 
medications taken on Day 0 (Experimental Session), Day 1, Day 2 after IMP administration will 
be presented separately. Any psychiatric concomitant medications will be tabulated by period 
(Preparatory, Treatment Period, Follow-up Period). Frequency and incidence of positive or 
serious ideation and suicidal behavior will be presented using descriptive statistics of C-SSRS 
scores in tabular format. Vital signs (heart rate, blood pressure, and body temperature) for 
Experimental Sessions will be summarized using descriptive statistics in tabular format listing 
values at pre-IMP administration, prior to the supplemental dose, and at the end of each 
Experimental Session. 
 
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MAPS Public Benefit Corporation 
MAPPUSX Statistical Analysis Plan 
U.S.
Version 1: 13 April 2021
Page 19 of 19 
8.8.4 Analysis of Suicidal Ideation and Behavior 
Suicidal ideation and behavior will be summarized according to suggestions made in the C-SSRS 
Scoring and Data Analysis Guide [1]. A positive response for suicidal ideation is counted when a 
ny 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 an
to any one of the five suicidal behavior questions (Categories 6-10) on the C-SSRS (i.e., a score 
>0 for suicidal behavior). The number and percent of positive responses of Positive Ideation,
Serious Ideation, and Positive Behavior will be tabulated by treatment group and time period
(lifetime, screening, baseline, each Experimental Session (pre- and post-IP), Integrative Sessions,
and endpoints). Frequency and incidence of positive or serious ideation and suicidal behavior will
be presented using descriptive statistics in tabular format.
8.8.5 Summary of Vital Signs 
Vital signs (heart rate, BP, and body temperature) for Experimental Sessions will be summarized 
using descriptive statistics in tabular format listing values at pre-IP, prior to the supplemental 
dose, and at the end of each Experimental Session. Change from Baseline in vital signs will be 
presented by study.   
9.0 Timing of Analyses 
Preliminary analyses and listing reviews will be ongoing throughout the studies to inform 
therapist supervision and assumptions made for other and ongoing trials. For clinical study 
reports and publications, only locked database files will be used. The final analysis will be 
conducted after all participants complete Visit 20 and the database is locked. 
References 
1.
Nilsson, M.E., et al., Columbia Suicide Severity Rating Scale Scoring and Data Analysis
Guide, in CSSRS Scoring Version 2.0. 2013:
http://www.cssrs.columbia.edu/documents/ScoringandDataAnalysisGuide_Feb2013.pdf.
p. 1-13.
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