Clinical trial NCT04030169
Conditions: PTSD
Keywords: MDMA methylenedioxymethamphetamine psychotherapy PTSD Posttraumatic Stress Disorder
Sponsor: MAPS Europe B.V.
Start date: 2020-06-24; Completion date: 2023-12-15
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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

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

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

Detailed description:
This multi-site, open-label, Phase 2, lead-in study conducted in Europe assesses the safety and efficacy of MDMA-assisted therapy in participants diagnosed with at least severe posttraumatic stress disorder (PTSD). This study additionally provides an opportunity for clinical supervision to planned Phase 3 therapy teams. Select sites will also participate in an optional fMRI (brain imaging) sub-study.

This study compares the effects of two open-label manualized Experimental Sessions of psychotherapy assisted by flexible doses of MDMA HCl. Initial doses per Experimental Session include 80 mg or 120 mg of MDMA HCl, followed 1.5 to 2 hours later by a supplemental half-dose (40 mg or 60 mg). Total amounts of MDMA to be administered per Experimental Session range from 80 mg to 180 mg. This \~8-week Treatment Period is preceded by three non-drug Preparatory Sessions. During the Treatment Period, each Experimental Session is followed by three Integrative Sessions of non-drug psychotherapy.

The primary endpoint is the change in Clinician Administered PTSD Scale for DSM 5 (CAPS-5) from Baseline to 13 weeks post-baseline (Visit 14). The secondary endpoint is the change in Sheehan Disability Scale (adapted SDS) item scores from Baseline to 13 weeks post-baseline (Visit 14).

Arms: arm 1: Administration of 80 to 120 mg midomafetamine (MDMA) HCl followed by a supplemental half-dose 1.5 to 2 hrs after the initial dose of 40 or 60 mg, respectively, in combination with manualized psychotherapy.
Interventions: intervention 1: Midomafetamine HCl
Intervention descriptions: intervention 1: Non-directive psychotherapy conducted during MDMA-assisted psychotherapy session

Protocol documents:
ICF_003.pdf: 
 
 
 
 
 
 
 
 
 MP18 Master Informed Consent Form 
EudraCT # 2018-001718-13 
 
ICF Version: Version 6,  22 November 2022 
 
 
An Open-Label, Phase 2, Multicenter Feasibility Study of Manualized MDMA-Assisted 
Psychotherapy with an Optional fMRI Sub-Study Assessing Changes in Brain Activity 
in Subjects with Posttraumatic Stress Disorder 
 
SPONSOR 
MAPS Europe B.V. 
 
 
SPONSOR DESIGNEE 
Amy Emerson 
Chief Executive Officer 
 
MAPS Europe B.V. 
Email: amy@mapsbcorp.com 
 
COORDINATING 
PRINCIPAL INVESTIGATOR 
Prof. Dr. H.G.J.M. (Eric) Vermetten 
Leiden University Medical Center 
Email: e.vermetten@lumc.nl 
 
MEDICAL MONITOR 
Aurélien Viaccoz 
MAPS Europe B.V. 
Email: medicalmonitor@mapseurope.eu  
USE 
 
In conjunction with relevant regulatory and ethical guidance 
 
 
 


 
 
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Participant Information Sheet and Informed Consent Form 
 
Study short title: MDMA-Assisted Psychotherapy for the Treatment of PTSD 
Study official title: An Open-Label, Phase 2, Multicenter Feasibility Study of Manualized MDMA-
Assisted Psychotherapy with an optional fMRI sub-study Assessing Changes in Brain Activity in 
Subjects with Posttraumatic Stress Disorder 
Sponsor: MAPS Europe B.V. 
Sponsor protocol number: MP18  
 
 
Introduction 
Dear Sir, Dear Madam, 
You are being invited to take part in this medical research to find out if the experimental drug MDMA 
combined with psychotherapy (talk therapy) is safe and helpful for people who have posttraumatic 
stress disorder (PTSD). You have been asked to participate because you have been diagnosed with 
severe PTSD with symptoms lasting for at least six months. Please read this information carefully before 
you decide whether you want to participate in this study. Please ask the study doctor or research team 
for an explanation if you have any questions. You may also discuss it with your partner, friends, family 
or general practitioner (GP). Participation in this study is voluntary and you will need to give written 
consent in order to take part.  
 
1.  General information 
MAPS Europe B.V. has prepared this study. MAPS Europe is owned by the Multidisciplinary Association 
for Psychedelic Studies (MAPS) a charity organisation that funds this study. MAPS Europe is the Study 
Sponsor. Approximately forty (40) participants from various research centres in Europe will be asked to 
be in this study and about [insert number of participants planned within the country] participants are 
expected to participate in [insert country].  
The researchers involved in conducting this study do not receive any financial incentives for including 
you in this study and do not benefit financially from this study. However, the sponsor will pay the study 
doctor and/ or institution for his/ her expenses, time, and effort to conduct this study. 
Ethics Committee [insert country Ethics Committee name and list other local bodies that will review and 
approve the study] has approved this study. The goal of the Ethics Committee is to protect the rights 
and welfare of study participants. 
 
2. Purpose of the study 
The purpose of this study is to find out if the drug MDMA combined with psychotherapy is safe and 
helpful for people who have PTSD. [Add for countries participating in the fMRI sub-study:  
The study sponsor also wants to find out how MDMA affects brain function]. There have been many 
studies that suggest MDMA-assisted psychotherapy can have a positive impact on PTSD symptoms.  
How it helps is not yet fully understood. With the results from this study, we aim to better understand 


 
 
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the effects of MDMA-assisted psychotherapy on PTSD. [Add for countries participating in the fMRI sub-
study: We aim to explore the effects of MDMA-assisted psychotherapy including two brain scans, before 
and after the course of therapy]. 
 
This study is open-label, meaning that you and the study researchers will know that you will get MDMA. 
During first MDMA-assisted psychotherapy session you will receive a dose of MDMA (80 milligrams 
(mg)) and possibly two hours later a second dose equal to half the size (40 mg) of the first dose. During 
the second session, about one month after your first session, you will receive either the same or a 
slightly higher dose (80 + 40 mg or 120 + 60 mg). Effects of MDMA usually last 6 to 8 hours after you 
take the capsule. 
 
[Add for countries participating in the fMRI sub-study:  
This study will also include two brain scans. During the brain scans, we will observe you as you complete 
different tasks. In one of the tasks we will observe how you respond to pictures of different faces and 
how you respond to a script of your own neutral and traumatic experience that you will prepare together 
with your study therapist. In other tasks you will be asked to close your eyes and be still. In between 
the tasks you will be asked how upset or bothered you are at the moment. Looking at your brain while 
you do these things will help us understand which regions of the brain are activated and how this effects 
things such as remembering positive and negative emotional memories].   
 
3. Background of the study 
MDMA is an experimental drug, which has not been approved by health authorities for medical use and 
can be used only within clinical studies. MDMA is similar to the stimulant methamphetamine, and a 
popular recreational drug, sometimes referred to as “Ecstasy” (which is supposed to contain MDMA, 
but often contains other drugs instead of or in addition to MDMA). The MDMA used in this study is 
produced by a pharmaceutical drug supplier licensed to manufacture the medicine under strict quality 
controls. MDMA is an illegal drug to use outside of research.  
 
Before MDMA became illegal, some psychologists and psychiatrists combined it with psychotherapy to 
help people with psychological problems including PTSD. MDMA may increase positive mood and 
changes the way we see and think about the world around us, making it easier to think about and recall 
things that happened to us that are upsetting. People say they feel caring and forgiving toward 
themselves and others during the MDMA experience. It is possible that these drug effects, when 
combined with psychotherapy, help people work through thoughts, memories and emotions related to 
PTSD and other past experiences.  
 
MAPS PBC has completed studies of MDMA-assisted psychotherapy in the United States, Canada, 
Israel and Switzerland; 358 participants have received MDMA across studies in the clinical development 
program, as of October 01, 2021. Data from six Phase 2 studies indicated that MDMA-assisted 
psychotherapy is safe and effective for patients with moderate to severe PTSD when administered in a 
controlled clinical setting, with 54.2% of participants (39 of 72) no longer meeting criteria for PTSD after 
two experimental sessions. In the long-term follow-up to Phase 2 studies, 67% (61 of 91) of participants 
still did not meet the criteria for PTSD at least 12 months after last exposure to MDMA.  


 
 
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[Add for countries participating in the fMRI sub-study: There have been a limited number of brain 
scanning studies exploring how MDMA affects the brain in people with PTSD. This study will address 
this knowledge gap by using the brain imaging technique known as functional magnetic resonance 
imaging (fMRI). A fMRI records a magnetic signal detected from blood flow in the brain, which is linked 
to changes in brain activity.] 
 
4. What participation involves report 
If you are enrolled into the study your participation will last at least 14 weeks and at most 27 weeks. 
Full screening may take 2 to 6 weeks after completing phone screening. Screening includes a visit to 
the study site where you will be asked to complete psychological questionnaires, have a physical 
examination, provide urine samples for drug and when appropriate pregnancy tests, undergo a heart 
test and provide a blood sample for laboratory tests.  If your pregnancy test is positive, you cannot 
participate in the study. It is also possible that the study doctor may determine that it is necessary to 
include a Hepatitis C test at screening, or that you need additional tests of your heart (such as an 
exercise test to evaluate your heart function). Additional at-home tests, like checking your blood 
pressure, may also be requested. A urine drug test and pregnancy test (when appropriate) will be 
repeated before each MDMA-assisted psychotherapy session (“MDMA-therapy session”). You will need 
to tell your doctor about all the medications you are currently taking, as certain medications (including 
but not limited to antidepressants) will be slowly reduced and stopped before you can start the study 
treatment according to the plan with your study doctor. It is important that you do not stop any 
medication before the study doctor tells you to. 
 
Non-drug psychotherapy sessions begin after you pass initial screening. The duration of these sessions 
can be as brief as 2 weeks but can last up to 11 weeks depending on what medications you are currently 
taking. Enrollment confirmation for the treatment will happen after 3 initial non-drug psychotherapy 
sessions and, if confirmed, the treatment period will begin. Some participants complete the non-drug 
therapy sessions but then are not eligible to continue with the MDMA-therapy sessions. The research 
team can explain the reasons why this might happen. 
 
The treatment period will last about 8 weeks with 2 MDMA-psychotherapy sessions including 2 over-
night stays 3-5 weeks apart. The MDMA-psychotherapy sessions are always preceded by non-drug 
psychotherapy sessions. Your participation in the study will end about 8 weeks after your last MDMA 
session. Detailed information about types of visit and assessment duration is described in Appendix 
A. Please read this information carefully.  
 
Your participation also involves audio and video recordings of your study visits and online evaluations, 
and written transcripts of these recordings, from now on called video recording. The purpose of video 
recording study visits and online evaluations is as follows: 
• 
To verify that the assessments and evaluations are carried out properly, according to the 
research protocol, and ensure reliability of the measures and results 


 
 
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• 
To verify that the therapy is carried out according to the training manual and for your therapists 
to be able to review the videos with their supervisors to receive feedback and improve their 
delivery of MDMA-assisted therapy 
You may ask to stop the video recording at any time. The therapy team will ask your permission to turn 
it back on when you are ready. 
 
To be added for countries where companion presence during the therapy sessions is allowed following 
site specific SOPs: [If you would like, a companion (a friend or family member) may be present during 
part of the therapy sessions or part of MDMA- therapy sessions. Before the session, the therapy team 
will meet with you and your companion to discuss the most suitable arrangement. There must be mutual 
agreement between you and the therapy team concerning the presence of your companion.] 
 
5. What is expected from you 
In order to carry out the study properly and for your own safety, it is important that you follow the study 
instructions:  
• 
Do not participate in another research study during the duration of this study.  
• 
Stop taking those medications or recreational drugs that your study doctor has said are prohibited 
during this study.  
• 
Report any changes to your health to the research team. 
• 
Keep appointments and be flexible about taking the appointments offered. 
• 
Agree not to begin a new form of mental healthcare during the study, without first speaking with 
the study team. 
• 
Carry your participant card with you. This card states that you are participating in this study and 
who to contact in case of an emergency. Show this card if you visit any other doctor. 
• 
You will need to give the therapy team the name and contact information (phone number or email) 
of a relative, spouse or close friend to contact in case of medical emergency, should you become 
at risk of hurting yourself or someone else, or if the study team cannot get in touch with you to let 
them know what is going on or find out if you are okay. 
• 
Once you have swallowed the study medication on the dosing day, you will be required to remain 
in the clinical research facility at the hospital until the study team tells you that you can leave. 
You must understand that the study team may, in the least restrictive manner, prevent you from 
leaving the Clinical Research Facility if they think you would be a risk to yourself or others. Steps 
will be taken in your best interests, if necessary. 
 
It is important that you contact the investigator as soon as possible: 
• 
before you take any other medicines. 
• 
if you are admitted to hospital or are going there for treatment.  
• 
if you suddenly develop any health problems. 
• 
if you no longer want to participate in the study. 
• 
if your contact information changes. 
 


 
 
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6. Possible side effects and discomforts  
MDMA has not been widely tested in humans. As of 01 October 2021, 1799 people have been given MDMA 
in clinical research settings, of which 358 were enrolled in the MAPS clinical development program.  
 
The recently completed MDMA Phase 3 trial in the US shows the following frequent side effects 
related to MDMA:  
• 
Muscle tightness (65%) 
• 
Lack of appetite (52%) 
• 
Nausea (30%) 
• 
Sweating (20%) 
 
Twenty percent or less of participants reported (from most to least common) the following effects: feeling 
cold, restlessness, big pupils, dizziness, jaw clenching, eye wiggling, increased blood pressure, feeling 
jittery, chest pain not related to heart issues, dry mouth, blurry vision, frequent urination, recurrent 
thoughts, vomiting, stress, muscle pain, increased body temperature, chills, substance use (cannabis 
use), urgent urination, muscle twitching, feeling sleepy, and nervousness. When these side effects 
occur, they usually last less than four hours. However, some effects have been reported to last for more 
than 24 hours and up to several days after the study drug session. In addition, there may be unknown 
side effects or risks from the use of MDMA. 
 
Possible risks of MDMA may include: 
Serious problems: There have been some serious problems, and even deaths, associated with the 
use of Ecstasy outside of controlled clinical or research settings. These problems have included high 
fever, brain swelling associated with drinking too much liquid, convulsions, and liver damage. Some 
recreational users of Ecstasy have become severely anxious, depressed or paranoid (thinking that other 
people are out to get them). These problems have not been observed in controlled clinical research 
settings. Since you will be receiving moderate amounts of research-grade MDMA in a controlled setting 
with a trained therapy pair who will be closely monitoring your physical and psychological reactions, 
these problems are not expected to occur either during or after the MDMA-therapy session. While this 
does not guarantee that they will not occur, it does mean that if they do occur, the study doctors are 
prepared to respond in a safe and professional manner. This may include transporting you to a hospital 
if necessary. 
 
Other Risks 
Blood pressure and heart rate: The effects of MDMA usually last 6 to 8 hours after the first dose, 
even if you take a second dose. At the dose in this clinical trial, the increases in blood pressure and 
heart rate are likely to be moderate. These increases are similar to what happens with moderate 
exercise. In past studies supported by MAPS, blood pressure rose well above normal levels in about 
one-third of participants after taking MDMA, but these participants did not report any discomfort and did 
not require any treatment. Although these increases in blood pressure are similar to what happens after 
moderate exercise, they could cause serious problems in individuals with pre-existing heart or blood 
vessel conditions. These serious problems could include an irregular heartbeat, heart attack or stroke. 


 
 
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We will evaluate you for pre-existing heart problems before you are allowed to be in this study. While 
this does not guarantee that no heart problems will occur, it does reduce the risk of this happening. 
If you have stable hypertension (controlled blood pressure) that requires medication, or if you have 
stable chronic disease (for example, diabetes) which is a cardiovascular risk factor, you will be referred 
to a cardiologist for further investigation, such as a carotid ultrasound and an echocardiogram, or other 
non-invasive imaging, as recommended by the study doctor or cardiologist. You may continue with the 
study enrollment if the study doctor and Sponsor deem you at low risk of cardiovascular harm from 
taking MDMA. 
 
Feeling Anxious: Participating in a clinical trial can cause you to feel anxious. In a recently completed 
Phase 3 trial of MDMA-assisted therapy for PTSD, approximately 37% of participants who received 
MDMA reported feeling anxious, and 41% of participants who received a placebo reported feeling 
anxious. These feelings usually lasted less than 30 minutes. Letting yourself accept and feel these 
emotions deeply can be part of the psychotherapy. If you are not able to process these emotions in a 
way that helps you, your study therapist will work with you to process these feelings. If needed, the 
study doctor may prescribe you anti-anxiety medication or medication to help you sleep.  
 
It is possible that if such periods of heightened emotion do not decrease or pass during the session you 
could be at increased risk for suicidal thoughts or other self-harm afterwards. If you have any thoughts 
about hurting or killing yourself you should call the study doctor or therapy team immediately, so they 
can help you.  
If you are in immediate danger of harming yourself or someone else, or ending your life, you may be 
required to be admitted to a hospital. 
 
Driving Limitations: In past studies, participants have reported blurred vision (8.7%), eye wiggling 
(13%), pupil dilatation (15.2%), feeling tired/drowsy (13%) or dizzy (13%) after taking MDMA. You 
should not drive or use machinery immediately after MDMA-therapy session (up to 24 hours 
afterwards).  
 
Immune System: Studies have demonstrated changes in immune cells with MDMA, but a controlled 
study on change in infection risk in a patient population has not been published. It is currently not known 
whether MDMA impacts your body’s ability to fight infections. 
 
Pregnancy: Effects of MDMA on the growth and development of an unborn baby are not known. 
Therefore, if you are pregnant or breast-feeding you cannot participate in this study. People able to 
have children must not become pregnant during the study. It is important for you to tell your partner 
about your participation. The study doctor or researchers will talk to you about which contraceptives are 
approved for use in the study. If, at any time during the study, you think that you may be pregnant or 
are worried that you may become pregnant, you must tell your study doctor immediately. If you still 
become pregnant during the study, you must immediately inform the study doctor. If your partner 
becomes pregnant during the study, please ask her for permission to inform the study doctor.  If you 
should become pregnant during the study, the study doctors will help you get proper advice. If you 
become pregnant, you will discontinue treatment but remain in the study for follow-up purposes. 


 
 
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You can find more information in Appendix B. 
 
7. Side effects and discomforts of study tests 
Blood tests: Taking blood may be painful or cause some bruising at the needle puncture site. In rare 
cases, you could get an infection. Fainting could also happen. In total, we will take 10 ml (approximately 
two teaspoons) of blood from you. This amount is small enough to not cause you any problems. To 
compare: a blood donation involves 500 ml of blood being taken each time.  
 
Risks not related to the study drug  
It is possible that you may experience some risks just from being in a research study, not related to 
MDMA. These potential risks are described below: 
 
Emotional Discomfort 
The medical tests done during screening for the study may show something abnormal that needs further 
evaluation by the study doctors or your general practitioner. Abnormal test results and additional 
evaluations may cause you some stress or emotional discomfort. The study doctors will explain all test 
results to you and refer you to the appropriate medical providers, as needed. You can decline any 
testing you do not want to complete, but you may not be able to enroll in the study. 
 
Trauma Therapy 
The treatment being tested in this study is a combination of a drug (MDMA) combined with 
psychotherapy. Any psychotherapy, including MDMA-assisted psychotherapy, can be a challenging 
process when it addresses emotionally painful experiences, and symptoms may become more 
pronounced at times. During the study (and/or after) you could experience increased anxiety, sadness, 
or other difficult feelings and thoughts, including the possibility of suicidal thoughts. Tell your therapy 
pair if you are having any new or worsening symptoms. If your experience does worsen, it does not 
necessarily mean that the study will not help you. The study is designed to give you support. It is 
important that you understand this possibility before deciding whether or not to participate. 
 
COVID-19 Transmission 
Study participation will involve a number of several hour in-person visits with the therapy pair, including 
8-hour MDMA-psychotherapy session. This personal interaction may increase your risk of becoming 
infected with SARS-CoV-2 (coronavirus that causes COVID-19 disease).  Some visits will be performed 
via teleassessment (online video meetings) and other precautions will be taken to try to reduce this risk 
such as screening for symptoms before in-person visits, using face masks, cleaning surfaces and 
washing hands. For your safety and the safety of study staff, we recommend that you follow the local 
safety guidelines for prevention of COVID-19, which may include wearing a face mask while in public, 
maintaining physical distance between yourself and others outside of your household, and other 
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 agree a safe plan for reducing risk 
while attending in-person visits. This plan may include testing for the virus, isolating at home, or other 
changes to your habits. 


 
 
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Remote Visits 
Some of the non-drug psychotherapy sessions and online evaluations may be able to happen remotely, 
via teleassessment, rather than at the study site. There may be benefits to remote visits, such as 
convenience and reduced risk of COVID-19 transmission. There may be risks, including potential 
breach of security and technological difficulties or interruptions. It is critical that you do not share the 
links to online meetings with anyone unauthorized to attend and that you have a private space where 
you will not be interrupted during the visit. 
 
[Add for countries participating in the fMRI sub-study:  
MRI scan:  During the MRI scan you will be invited to lay on a table which is moved slowly into the MRI 
tunnel. The front and back of the tunnel are open.  If you are claustrophobic, lying in the tunnel may feel 
unpleasant. You will not feel the magnetic waves but taking brain scans is associated with a loud 
thumping noise. Therefore, you will be given hearing protection, which is mandatory to wear. 
 
It is important that you lie still. The researchers will try to make you as comfortable as possible, they will 
be monitoring and speaking to you throughout the scan session. If you experience anything unpleasant 
you can always reach the researcher by pressing an alarm button. The MRI scan will last approximately 
1 hour. 
 
Besides possible discomfort, there are no known harmful side-effects associated with temporary 
exposure to the strong magnetic field used by MRI scanners. However, there are important safety 
concerns to consider before performing or undergoing an MRI scan: 
• 
The magnet may cause medical devices and implants that contain metal to malfunction or heat 
up during the session. 
• 
Any loose metal object may cause damage or injury if it gets pulled towards the magnet. 
• 
Dyes from tattoos or tattooed eyeliner can cause skin or eye irritation. 
• 
Medication patches can cause a skin burn. 
• 
Prolonged exposure to radio waves during the scan could lead to slight warming of the body. 
Therefore, before lying down in the scanner, all participants will be screened for the above prior to MRI 
scanning.]  
 
8. Possible advantages and disadvantages 
It is important that you properly weigh the possible benefits and disadvantages before you decide to 
participate in this study. 
 
Possible benefits: 
Your symptoms of PTSD may improve while taking part in this study. Information obtained from this 
study may help doctors and researchers to improve treatment for PTSD in the future.  
Possible disadvantages: 
- 
Possible side effects/complications of the treatment 
- 
Possible adverse effects/discomforts of the evaluations in the study 
- 
There is no guarantee that you will benefit from taking part in this research study 


 
 
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- 
There may be side effects or risks from receiving MDMA that we are not yet aware of 
 
[Add for countries participating in the fMRI sub-study:  
- 
Incidental findings: for example, during the MRI scan, the investigator may find out about other 
illnesses that you may have.] 
 
Participation in the study also means: 
- 
Additional time you have to dedicate to the study 
- 
Additional visits to the clinic and overnight stay 
- 
Additional tests 
- 
Instructions you need to follow 
All these aspects have been described above under points 4, 5 and 6. 
 
Media interest: 
Because of the history of MDMA, it is quite likely that journalists will be interested in the trial. The media 
will not be informed that you are involved in the study. If somebody from the media approaches you, 
we ask that you do not talk to them. Please refer them to the Investigator [name, contact details]. 
 
9. Withdrawing consent - If you do not want to participate or you want to stop participating in 
the study 
Participation in this study is voluntary. If you do not want to participate, you will be treated as usual for 
PTSD. There are approved medicines that may help treat your symptoms of PTSD and other forms of 
psychotherapy that you could try. If you are currently having psychotherapy and/or taking medicine, you 
could continue with those for a longer period of time. The therapy team can discuss the alternatives and 
the potential risks and benefits with you. 
 
If you choose to participate in the study, you can always decide to stop at any time during the study. 
You can withdraw from treatment (stop treatment) or withdraw (take away) your consent to the use of 
your personal data at any time for any reason. You do not have to explain why you are stopping 
treatment or withdrawing consent, there will be no penalty or impact on your care if you decide to not 
participate or withdraw from the study after enrolling. But before withdrawing you must tell the study 
doctor or therapy team. This will allow your study doctor to let you know about any potential medical 
risks of withdrawal at that time. You may be asked to return to the study site for tests. 
 
Also, the investigator can stop your study participation and discontinue treatment if it is judged as best 
for you, or if you cannot comply with parts of the study that are critical for your safety or for the purpose 
of the study. For example, if you become pregnant or require use of prohibited medications, you may 
be asked to stop MDMA treatment, but will be asked to remain in the study for the integration visits 
and/or other assessments. 
 
The data collected until you stop participating (withdraw your consent) will still be used for the study.  
 


 
 
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During the study, you will be notified of changes to study procedures, newly discovered side effects or 
significant findings which may affect your health or willingness to participate. You may be asked to sign 
a new consent form that shows that you have been informed of new information relating to this study. 
 
Right to erase data 
Under the European data protection regulations (General Data Protection Regulation, or GDPR), you 
have the right to ‘be forgotten’, meaning to have the right to request the deletion of your personal data, 
including video recordings. The sponsor and the local research institute are obliged to consider your 
request and grant it, if it is appropriate according to the regulations.  
 
You should understand that the sponsor and the local research institute may be subject to laws that 
require them to retain certain data. For example, the sponsor is typically required to retain data which 
is used to support the approval of a new medicine (marketing authorization) for up to 25 years after the 
end of the trial or for at least 2 years after the granting of the last approval. In those cases, deletion will 
only occur once those retention requirements have elapsed.. 
 
10. End of the study 
Your participation in the study stops when: 
• You have completed all the visits according to the schedule (Appendix A) 
• You choose to stop 
• The end of the entire study has been reached  
• The investigator considers it best for you to stop (for example, if you become pregnant or if you 
experience unwanted side effects)   
• The sponsor, the government or [enter name of the local Ethics Committee], decides to stop the 
study. 
 
The study is concluded once all the participants have completed the study. The medication you have 
used during the study will not be available once the study has ended. Your therapy team will discuss 
the options for further medical care with you. After analyzing the data, the researchers will inform you 
about the most important results of the study.   
 
11. Usage and storage of your data  
Your personal data will be collected, used and stored for this study. This concerns data such as your 
name, address, date of birth, race, ethnic origin, marital status, data about your education, 
occupation/veteran status, employment, disability, income and data about your health. For this study, 
personal data is processed on the basis of your consent in accordance with the EU  General Data 
Protection (Regulation (EU) 2016/679 of the European Parliament and of the Council Directive 
95/46/EC, (Art. 6 (1) (a) and Art. 9 (2) (a)).   
The organizations responsible for your personal data are MAPS Europe, MAPS PBC and the  research 
institute where you will participate. You can contact them at any time if you have questions about how 
they are handling your data or wish to exercise your GDPR rights. 
 


 
 
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Sponsor’s office for data protection, personal data and data privacy: 
Email address: dataprivacy@mapseurope.eu or dataprivacy@mapsbcorp.com  
 
Video recordings 
The therapy sessions will be recorded and stored in a system called Valis, while the online evaluations 
will be recorded by and stored in a system called WebEx.  
Who is viewing these video recordings:  
• 
The system administrators (only as needed) 
• 
MPBC staff (only as needed) 
• 
Senior Independent Raters and Lead Independent Raters (who specifically review the online 
evaluations to ensure reliability),  
• 
the adherence raters (specifically for the psychotherapy recordings  
the supervisors of the therapy pair (specifically for the psychotherapy recordings).. 
Where are these video recordings located: The videos are stored for a limited amount of time in the 
Valis or WebEx servers, all of which are based in Europe. 
 
How is the video data being transmitted: When the video recordings are being reviewed, the video 
data is encrypted and streamed from WebEx or Valis data centers (depending on storage location) to 
the viewer’s browser, it is never downloadable.  
 
 
The video recordings from your therapy sessions will be used for the purposes explained in section 4. 
The adherence raters, as well as the supervisors of the therapy team who may be viewing these video 
recordings will be selected by the Sponsor and will sign confidentiality agreements to ensure they do 
not share any identifying information, for example: 
• 
Your physical appearance 
• 
Your voice 
• 
Your name (if it is spoken on the recording) 
• 
Identifying situations from your life that might be discussed 
 
Other data 
The bodily material (blood and urine samples) collected from you during the screening period will be 
sent for the analysis to the central laboratory. Once samples are analyzed, the bodily material will be 
destroyed at the lab.  
 
The collection, use and storage of your personal data is required to answer the questions asked in this 
study and to publish the results. It is also required to make the medication we are studying (MDMA) 
available on prescription to potential patients in Europe and abroad if these studies have positive 
results.  
 
We therefore ask your permission for the use of your personal data and bodily material. By signing this 
consent form, you consent (agree) to the collection, access, use, sharing and storage of your 


 
 
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information in the data center as described above. You have the right to request information about what 
data is stored about you at any time. 
 
Confidentiality of your data  
To protect your privacy and confidentiality, your personal data and your bodily material will be given a 
code. Your name and other information that can directly identify you, will be removed. Data can only be 
traced back to you with the code key. The code will be stored securely in the local research institute. 
The data and bodily material that is sent to the sponsor or sponsor delegates will only contain the code, 
not your name. This process is known as “pseudonymization”, meaning no person can be identified 
from the coded information.  
 
Study sponsor and other third-party companies working for the sponsor will take all reasonable 
measures to keep any information they receive confidential. The sponsor has agreements with the third 
parties to secure adequate protection of your data, biological samples and video recordings. 
 
Electronic systems for recording audio and video data include measures to protect the confidentiality of 
your identity and data. Those systems were chosen as they are GDPR compliant. The data cannot be 
traced back to you in reports and publications about the study.   
 
Site therapists, study doctors, investigators or other site staff may have to report abuse, for example 
child abuse or elder abuse if required by local law or professional code in your country. The sponsor 
and site staff will keep any information they receive to the same standard of confidentiality according to 
applicable local law.  
 
Access to your data for verification  
Some qualified and authorized people independent of the therapy team can access your data (including 
the data without a code) at the research location. This is necessary to check whether the study is being 
conducted in a good and reliable manner. 
 
Study documentation that is copied will not have any information that could be used to identify you. If 
records are copied, only your participant number will identify you to the study. People who will have 
access to your directly identifiable data (medical records, including video and the consent form signed 
by you), are as follows: 
• 
Auditors/data monitors working for the sponsor of the study 
• 
National and international regulatory authorities, for example, European Medicines agency 
(EMA) 
 
They will keep your data confidential. We ask you to consent to this access.  
 
The results of this research study may be presented in meetings, presentations, or in publications, 
where your identity will not be disclosed.  
 
Passing on to countries outside your country and outside the European Union (EU)  


 
 
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In this study, your encoded data will be sent in an encrypted way to countries outside the European 
Union where personal data protection laws might be less strict. These countries include the United 
States for coded data and health data. Other countries may receive coded data and health data as well, 
however, the study Sponsor will ensure that your personal information is protected at all times. 
 
More information about your rights when processing data 
For general information about your rights when processing your personal data, you can consult the local 
research institute’s data protection officer or the Local Data Protection Authority. The Sponsor’s data 
protection office will not know if you are a participant in the study or not, so if you have specific questions 
about the Sponsor’s role, please ask the research institute’s data protection office who will liaise with 
Sponsor as necessary at email address: dataprivacy@mapseurope.eu.  
 
Retention period of your data  
Study data and video recordings will be kept for only as long as necessary for the purposes for which 
the data is being collected. This generally means that non-video data will be retained for up to 25 
years unless the Sponsor is legally required to retain it for longer. Video and audio recordings of both 
therapy sessions and IR assessments will be deleted within 90 days after a participant’s last study 
visit, unless there is a concern noted through the supervisor review, in which case the video must be 
retained for the length of the investigation, or longer where legal privilege applies.  
 
Information about unexpected findings 
If, during this study, something is found by chance that is not important to the study but may be important 
for your health, you will be informed by the study doctor. You can then discuss with your doctor what 
needs to be done. You also consent to this by signing this form.  
 
Registration of the study 
A description of this clinical study, MP18 protocol, will be available on 
https://clinicaltrials.gov/ct2/show/NCT04030169 (identified by NCT04030169) and 
https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-001718-13 (identified by EudraCT 
Number 2018-001718-13). 
These databases do not contain any information that can identify you. After the study ends, the website 
may display a summary of the results of this study.  
 
12. Study participant insurance 
Insurance has been taken out for everyone participating in this study. This insurance covers damage 
caused by the study. If you are injured as a direct result of a study related procedure or because you 
received the study drug, appropriate medical care for the treatment of the illness or injury will be 
discussed with you.  
Appendix C contains more information about the insurance and the exclusions. It also tells you who to 
report potential claims to.   
 


 
 
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13. Will my GP and/or treating specialist and/or pharmacist be informed if I participate? 
[Please update as per country specific regulations and check if it is required to inform GP] We will 
always send your General Practitioner (GP) and/or treating specialist a letter or email to let them know 
that you are participating in the study. This is for your own safety. If you do not agree to this, you cannot 
participate in this study. We may contact your GP/other doctor about your medical history or about the 
medicines you use, and in some cases, to discuss how best to stop certain medication prior to the 
MDMA-therapy sessions.  
 
14. Costs and compensation  
There will be no cost to you for participating in this study. The study sponsor will cover the costs that 
are directly related to the research. This includes the costs for all psychotherapy sessions, for the 
psychological and laboratory testing, for medical examinations to see if you can be in the study and for 
the study drug. You or your insurance company will remain responsible for on-going treatment not 
included in the study. You will not be paid for your participation in this study. You will be reimbursed for 
travel costs. 
 
15. Questions or concerns 
If you have any questions or if you have any unusual reaction while in the study, or in case of an 
emergency, you should contact the study doctor/research team.  
If you have any complaints about the study, you can discuss this with the investigator. Contact Principal 
Investigator: [add email and phone here] Contact study doctor: [add email and phone here]  
 
16. Signing the consent form  
When you have had enough time to decide on participation in this study, we will ask you to give your 
consent in writing on the attached consent form (Appendix D). By signing this consent, you indicate 
that you have understood the information and agree to participation in the study. You will receive a 
signed copy of the consent form to keep with you. Thank you for reading this document and considering 
taking part in the study. 
 
17. Appendices to this information 
A. Overview/description of study procedures 
B. Additional Information on side effects  
C. Insurance information  
D. Informed Consent Form 


 
 
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Appendix A: Overview of study procedures 
Please see the description of study procedures below.  
 
Screening: Multiple visits at the study location, lab, and/or doctor’s office, and teleassessments/phone 
calls. 
 
Psychological and medical screening will be done by the study researchers and research site staff, 
doctors, and your therapy team. The tests will include the following: 
 
• 
Questions about your medical history. This may include any previous medical, psychological or 
psychiatric problems or treatment and may include questions about difficult experiences you 
may have had during childhood, at other times of your life, or currently. 
• 
Psychological questionnaires you fill out yourself and an interview about any psychological or 
psychiatric issues you may be experiencing, or that you have experienced in the past. 
• 
A brief interview about thoughts you might have about hurting or killing yourself.  
• 
A physical examination including measures of your blood pressure, pulse, temperature, 
height, and body weight and Body Mass Index (BMI). In addition, you may be asked to 
measure your blood pressure at home.  
• 
An ECG (electrocardiogram) and rhythm strip, which are recordings of the electrical activity of 
your heart. If you have high blood pressure, or other cardiovascular risk factors, you may be 
asked to undergo additional tests of your heart. This may include a stress echocardiogram (an 
ultrasound of your heart during or after exercise or medication to make your heart beat quickly) 
and a carotid ultrasound (measurement of blood flow in your neck). 
• 
A sample of your blood (about 2 teaspoons) and urine for laboratory testing, including tests of 
metabolism, liver function, and alcohol use. As part of the study, we may also test for the 
Hepatitis C virus (HCV). 
o 
If you have abnormal test results that could impact your health, we will notify you. If you 
do not want to know, you cannot participate in this study. 
o 
If you test positive for Hepatitis C you will only be able to participate if you currently 
don’t have symptoms of Hepatitis C and have been previously treated for it. 
• 
Urine drug tests will be done during screening and repeated before each MDMA-therapy 
session. We will not report findings of drugs to any authorities, but a positive drug test may 
impact your eligibility to continue in the study. 
• 
A urine pregnancy test is required if you are able to get pregnant. This test must be negative 
for you to take part in the study and will be repeated before each MDMA-therapy session and 
again towards the end of the study.  
 
The screening process continues after you start the preparatory session.  At Visit 3, you will have 
additional psychological testing by an online video meeting. You will not know for sure whether you will 
get MDMA treatment until after Visit 3. 
 
Beginning of Study (Visit 0): Once you have completed all screening procedures, your first 
preparatory psychotherapy session will be scheduled. You must let the therapy team know about any 
change in medicines or medical conditions or procedures, like surgery, within 48 hours of it happening. 
You should not stop taking your current medication until you are instructed by the study physician. 


 
 
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Preparatory Sessions (Visits 1 through 4): at the start of participation in the study, the first two 
preparatory sessions will last approximately 90 minutes and the last preparatory session will last about 
3 hours, which includes completion of questionnaires and therapy session. Preparatory sessions are 
paced about one week apart. 
 
During each session, you will talk about the traumatic incidents that led to your PTSD, the ways PTSD 
symptoms are affecting your life, and what you would like to achieve during the study. You will be asked 
questions about thoughts or feelings you might have about hurting or killing yourself and complete 
psychological questionnaires in the 3rd preparatory session. There will be four visits total during this 
period: three therapy visits and an online meeting with a researcher who will ask you questions about 
your PTSD symptoms. After the online video meeting (Visit 3), the staff will let you know whether you 
will continue to the treatment part of the study. 
 
During this time, you may be asked to slowly stop taking certain medications, such as antidepressants 
or certain pain management medications. This “tapering plan” will be agreed between the study doctor, 
the doctor who normally prescribes your medications, and yourself. The length of time it takes to taper 
medications will be different for each study participant. Ask the study doctor if you are ever unclear 
about which medications to take, and when. 
 
Please note, until you have completed all the Preparatory Sessions and tapered any required 
medications, the study team will not be able to confirm if you are eligible to participate in the MDMA-
therapy session.   
 
MDMA-assisted psychotherapy sessions (MDMA-therapy session) with overnight stay (Visits 5 
and 10): (~8 hours plus an overnight stay): two visits about a month apart. You will be given MDMA 
during these visits along with psychotherapy. There will be two day-long MDMA-therapy sessions with 
overnight stays. These visits will happen 3-5 weeks apart. The first MDMA-therapy session will occur 
after you have had three preparatory sessions. During the day of your MDMA-therapy session, you will 
receive a dose of MDMA followed 1.5 to 2 hours later by a dose of half the first dose of MDMA. During 
the second MDMA-therapy session, you, the study doctor and therapy team can decide if you should 
take the same dose you took in your first MDMA-therapy session, or if you would like to try a higher 
dose. Your therapy team will discuss the optimal dose of MDMA with you for the second MDMA-therapy 
session.  
 
You must not eat any food or drink any alcohol after midnight on the night before each MDMA-therapy 
session visit, though you can drink non-alcoholic liquids during this time, such as water or juice. There 
will be beverages available at the study site, including juices, and you will be encouraged to drink an 
adequate amount of fluid. You can drink it whenever you wish to do so, within the limits of the amount 
that is safe for your body. Later on, food will also be provided. You cannot use any psychoactive drug, 
with the exception of caffeine or nicotine, within 24 hours of each MDMA-therapy session (or longer 
depending on the specific drug – this should be discussed with the therapy team). You cannot use 
caffeine or nicotine for two hours before and six hours after you take the first dose during the MDMA-
therapy sessions. For one week before each MDMA-therapy session, you cannot take any herbal 


 
 
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supplements, non-prescription medications, or prescription medications that have not been discussed 
with and approved by the study doctor and the therapy team. 
 
If you are taking certain opioid medications for pain management, you can continue to take these 
medications during treatment, although we will ask you to reduce the dose before each MDMA-therapy 
session and stop taking them for 12 hours before and at least 24 hours after the first dose in each 
MDMA-therapy session. If your pain becomes too severe to handle during this period, you will be 
allowed to take your medication after talking with the study physician about it. 
 
 
Before an MDMA-therapy session with overnight stay: 
 
• 
Your urine will be tested for drugs of abuse, including stimulants, sedatives, opioids, and 
cannabis. 
• 
If you can become pregnant, you will take a urine pregnancy test before each MDMA-therapy 
session. 
• 
Answer questions about thoughts you might have about hurting or killing yourself (before and 
at the end of the MDMA-therapy session).   
 
After urine testing, you will receive a capsule containing MDMA. After taking the capsule, you will sit or 
lie down in a comfortable position. You can ask for an eyeshade if you wish. You will listen to music 
during much of each MDMA-therapy session, either through headphones or room speakers. During the 
session there will be times when you will be asked to talk to the therapy team. If you are wearing 
headphones, you may remove them yourself if you want to talk to the therapy team or have times of 
silence. Lying or sitting in a comfortable position and listening to music are meant to bring out thoughts 
and feelings, including thoughts and feelings about past traumatic experiences. The therapy team will 
remain with you, and they will help you if you need them to. They will speak with you and ask you to 
talk to them at least once an hour, but you can talk to them whenever you wish. There may be times 
when the therapy team will suggest that you stop talking for a while in order to pay attention to your 
thoughts and feelings.  
 
Approximately two hours after you take the first dose, you may take a second dose, after discussion 
with the study doctor and therapy team. The thought behind taking the second dose is that it is supposed 
to make the session last longer. If you, the study doctors or the therapy team notice you have problems 
after the first dose, then you will not get the second dose. 
 
The therapy team will watch for any side effects (unwanted effects or health problems), which will be 
treated if necessary. If this happens, the therapy team will keep you fully informed about any concerns 
or treatment. Your blood pressure, temperature, and pulse will be measured before taking the first and 
second doses and at the end of the session. At the same time, you will be asked to complete a 
questionnaire about how you feel at that moment. If you have any symptoms including confusion, light-
headedness, dizziness, chest pain or shortness of breath, please tell the therapy team. More frequent 
measurements may be needed if this happens. 
 


 
 
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If you are confused or upset 8 or more hours after the start of a MDMA-therapy session, the therapy 
team will stay with you until you have fully recovered. If the therapy team thinks you are at risk of hurting 
yourself or others, they will either remain with you all night or have you admitted to a hospital until you 
are no longer at risk. The therapy team will ask you how you feel at the beginning and end of the MDMA-
therapy session and on several occasions during the phone follow-up period.  
 
You will be spending the night in a room at the research facility with an attendant who will be staying in 
another room nearby. You can use the kitchen or may take a short walk around both outside of the 
room and into the immediate hospital grounds, if agreed and accompanied by your therapist or night 
attendant. If you find you need to talk with the therapy team or you are having problems and need to 
contact the therapy team, the attendant will contact them immediately. 
 
The day after each MDMA-therapy session, you will have a non-drug therapy session (also known as 
an integration session, Visit 6 and Visit 11). After this session, you will need to have someone drive you 
(to home or wherever you are staying), because MDMA may affect your ability to drive. If you do not 
have anyone available to take you home, the therapy team will find someone to drive you. 
 
After you return home from the therapy session, the therapy team will talk to you by phone four days 
out of the following week to ask how you are feeling and see whether you should see the therapy team 
before your next scheduled non-drug psychotherapy session. You and your therapy team can decide 
which days would be best to speak on the phone. The phone calls will take approximately 5 to 15 
minutes, though they can be as long as you need them to be. The therapy team will ask you about 
thoughts about hurting or killing yourself during the second and seventh day of phone contact. You can 
call the therapy team at any time; except for a few times when they may be unavailable. At those times 
the study doctor or therapy team will be on call and can be called at the 24-hour number provided on 
this consent form. If there are delays in following the usual study schedule, the therapy team will call 
you at least once a week to talk about how you’re doing. These calls will take about 15 minutes.   
 
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 MDMA-therapy session, you or the 
therapy team may decide that you should not have the next MDMA-therapy session. You may also 
make this decision to stop treatment in the study for any reason. If the therapy team decides to take 
you out of the study, they will let you know that they are doing this and their reason for doing it. They 
will help you find a therapist who can continue to help you with your PTSD, if needed. If you are taken 
out of the study or decide you do not want to receive treatment in the study, the study researchers will 
ask you to complete some final questionnaires about your PTSD symptoms. If you decide you do not 
want to continue in the study during a MDMA-therapy session, you will still have to stay in the office 
until the therapy team thinks that you are stable enough to leave and that all the short-lived 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.  
 


 
 
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Integration Visits (Visits 6, 7, 9, 11, 12, 13; ~90 minutes each): You will receive 3 psychotherapy 
sessions after each MDMA-therapy session. These visits will last about 90 minutes. These will usually 
be 1-3 weeks apart and will involve you talking to your therapists about your thoughts and feelings. 
The day after each MDMA-therapy session, and 2-4 weeks afterward, you will have therapy visits to 
help you express, understand, bring together and connect any thoughts or feelings you may be having 
about your symptoms and their causes, and to think and talk about your experience during the MDMA-
therapy session. The therapy team will ask you questions about thoughts about hurting or killing yourself 
at these sessions. At the last integration therapy visit you will also complete a psychological 
questionnaire and do a final pregnancy test if applicable. 
 
Measuring the severity of your PTSD symptoms 
 
Online Meetings (Visits 3, 8, and 14; 60-90 minutes each): There will be 3 online video meetings. 
During these meetings, the study researcher will ask about your PTSD symptoms and you will complete 
the same online interview about your PTSD symptoms. You will also be asked if you have had any 
thoughts about hurting or killing yourself. 
During these meetings, you must be in a quiet place with a stable internet connection. Your device can 
be a phone, computer, or tablet. Your device must have a camera and you must be in a location in 
which you feel comfortable to discuss personal information. These meetings will be video recorded. If 
needed, we can arrange for these online visits to occur in the research facility. 
 
Study Termination (Visit 15; 120 minutes): this final visit will take place after the online meeting at 
Visit 14. You will meet with your therapy team and the study physician to complete a physical exam 
(including weight, blood pressure, pulse and temperature). You will fill in the study questionnaires. The 
results from Visit 14 and 15 will help the therapy team to understand if your symptoms have changed 
or stayed the same during the study. Your therapy team will discuss the options for further medical care 
with you, including the possible restart of any medications that you stopped for this study. 
 
Table 1 and Figure 1 below shows the type of in-person visits and online sessions you will have. Time 
periods are counted from the first study visit after you are selected to participate in the study.  


 
 
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Table 1: Schedule of Events 
 
 
  Screening 
(2-6 weeks) 
Screening, Preparation 
(2-11 weeks) 
Treatment Period 1 
(about 4 weeks) 
Treatment Period 2 
(about 4 weeks) 
Evaluation 
Study 
Termination 
(±4 weeks) 
Visit # 
 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Participant Information and 
Consent at site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Screening including 
weight, height 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Pressure, Pulse, 
Temperature 



 
 
 
 
 
 
 
 
 
 
 
 
 
Medical tests (bloodwork, 
urinalysis, ECG) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed physical 
exam 

 
 
 
 

 
 
 
 

 
 

 
 
Drug and/or Pregnancy Test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interview PTSD Symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychological Testing and 
Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Non-drug Psychotherapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MDMA-therapy session with 
overnight stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Four phone calls during a 
week  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overnight Stay 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brain scan session [Add for 
countries participating in the fMRI sub-
study] 
 
 
 
 
 
V4.1 
 
 
 
 
 
 
 
 
 
  
V14.1 
 


 
 
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Figure 1: Overview Study Structure 
 
 


 
 
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Figure 1: Overview Study Structure with fMRI Sub-study 
 
 
 
 


 
 
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Appendix B: Additional information on side effects 
Possible Brain Damage 
Experiments in rats and monkeys show that high and repeated doses of MDMA can change certain 
brain cells that release a chemical called serotonin. The changes include loss of the parts of the cell 
(called “axons”) that connect different brain areas. Rodents given repeated, high doses of MDMA are 
less sensitive to a later dose of MDMA, are more likely to become overheated when placed in a warm 
room, and some studies find they perform worse in difficult memory tests. Recent studies in monkeys 
and rodents suggest that the doses used in these studies are far higher than those typically taken by 
humans in either recreational or laboratory settings. 
 
Many studies found that people who had used Ecstasy many times in recreational contexts were not 
able to recall words, pictures or patterns as well as people who did not use Ecstasy and they performed 
less well on tests of planning and impulse control. These differences are not great, but they have lasted 
for at least 1 year after people had stopped taking Ecstasy.  Not all studies have found Ecstasy users 
to have difficulty recalling words or pictures or to have impulse control problems. At least two studies 
found that people who are anxious, depressed, or have psychological problems before taking any drugs 
are more likely to take Ecstasy than those who are not anxious, depressed, or without other 
psychological issues. When compared with people who do not use Ecstasy, studies found Ecstasy users 
were more likely to report feeling generally anxious or depressed. Many of these studies found that 
using alcohol or other drugs was also associated with feeling anxious or depressed. 
 
Only one study has looked at brain scans of people before they got MDMA and then again after they 
have received one or two moderate doses of MDMA. This study did not show any changes in the brain 
following MDMA, though it is possible that there were changes that were too small to notice. Other 
studies looked at people before and after they decided to take a few tablets of Ecstasy in a recreational 
setting and found one small change in the amount of blood flow in a specific part of the brain but did not 
show signs of brain injury. The decrease in blood volume might be from temporary lowering of a type of 
brain receptor, or it might be a sign of reduced function in this area. Findings from these studies suggest 
that the amount of MDMA you will receive in this study will not produce any lasting negative changes in 
your brain, though this is not guaranteed. 
 
Studies of people receiving one or two doses of MDMA in a laboratory setting have not found any lasting 
changes in memory or planning. Studies comparing people before and after they decided to take a few 
tablets of Ecstasy in a recreational setting with people who did not take them found less improvement 
in memory in the people who took ecstasy, and no other changes in thinking or planning ability. It is 
believed that the amount of MDMA you will receive will not produce any lasting changes in memory or 
planning ability, though this cannot be guaranteed. 
 
Symptoms of Depression, Anxiety, or PTSD 
It is possible that after you stop taking certain psychiatric medicines (for depression or anxiety) as part 
of the study, you may start to have symptoms again. There is also a risk that you may have thoughts of 
harming yourself or ending your life when you stop taking medicine, especially if you have had these 
thoughts before. If this happens, talk with your prescribing doctor, your therapist, and your study doctor. 
If you need to start taking medicine again, the study doctors will need to re-evaluate your eligibility and 


 
 
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there is a chance that you will not be able to continue in the study. Your safety takes priority over your 
continuation in the study. There are some allowable medicines on study; your doctors will discuss these 
with you if needed. Your pre-existing symptoms and diagnosis related to your PTSD may not improve 
and may become worse during the study or after. 
 
Emotional Openness 
MDMA is considered an “empathogenic” drug. This means people who use it may experience increased 
empathy and sociability. After taking the study drug, you may feel more emotionally open, friendly, 
extroverted, or talkative. You may also feel closer to your therapists or more trusting of them, or you 
may even feel love and sexual feelings toward your therapist(s). This can happen with any 
psychotherapy but may be heightened by MDMA. Your therapists are aware of the effects of the drug. 
They have been through training on how to appropriately care for someone who has taken MDMA and 
on a code of ethics that prohibits any sexual relations between therapists and participants, including 
after participation in the study has ended. All of your therapy sessions are recorded. One of the reasons 
for this is to ensure your safety. Videos are randomly reviewed by a group of adherence raters, who are 
trained to ensure the visits are conducted appropriately.  Your therapists also have supervisors who 
continue to oversee and train them throughout the study. 
 
Reproductive risks  
Effects of MDMA on the growth and development of an unborn baby are not known; therefore, you will 
not be allowed to be in the study if you are pregnant.  If you get pregnant after you have had at least 1 
MDMA-therapy session, the study doctors and the sponsor, MAPS Europe B.V., will ask you about and 
keep track of your pregnancy and will need to know about the outcome of your pregnancy. 
 
Those who are able to become pregnant and are engaging in penile-vaginal intercourse (male-female 
sex) must use one of the allowed birth control methods: intrauterine device (IUD), non-oral hormonal 
methods (injected, intravaginal, implanted, or transdermal [skin patch]),, oral hormones plus a barrier 
contraception (for example, condoms), or abstinence if this is your normal lifestyle. Condoms alone are 
not an acceptable form of contraception for this study. Not being able to become pregnant is defined as 
permanent sterilization or postmenopausal if no menses for more than 12 months or assigned male at 
birth. The therapy team will explain these methods to you and will help you decide which might be best 
for you, and they can suggest to you where you can get more information and advice. 
 
Other risks 
If you are tested for drugs of abuse within three days of each MDMA-therapy session, e.g., by your 
employer, you may test positive. The therapy team will provide you with an information card in case you 
are tested for drugs of abuse, and if you are tested for drugs of abuse while you are in this study, you 
can have the person(s) testing you call your therapy team to verify that you are in this study. We cannot 
guarantee that this card will protect you from discipline at work or loss of employment. The study doctors 
will discuss when and how to present the information card. The card will not prevent you from being 
stopped or cited if you are driving erratically or poorly.  
 


 
 
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The interviews you have during the study involve no specific risks or discomforts beyond those of a 
standard clinical interview situation. You may feel upset at the review of your emotional experiences, or 
you may feel boredom or fatigue. Answering questions about thoughts you might have of hurting or 
killing yourself may be upsetting. 


 
 
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Appendix C: Insurance information 
Insurance has been taken out by sponsor for everyone participating in this study. The insurance covers 
damage due to participation in the study. [If needed by country specific regulations provide additional 
details] 
 
In the event of damage please contact the insurance company directly.  
 
The insurance company for the study is: 
Name: 
… 
Address: 
… 
Telephone number:  
… 
E-mail: 
… 
(Policy number: 
...) 
(Contact person:  …) 
 


 
 
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Appendix D: Participant Consent Form 
Sponsor protocol number: MP18 
 
Study short title: MDMA-Assisted Psychotherapy for the Treatment of Severe PTSD  
• 
I have read the participant information form and understand the information it contains. I was able 
to ask questions. My questions have been answered to my satisfaction. I have had enough time to 
decide whether to participate. 
• 
I know that participation is voluntary. I know that I may decide at any time not to participate or to 
withdraw from the study. I do not need to give a reason for this. I am also aware that withdrawing 
will not affect my medical care or legal rights or the continued processing of my coded data. 
• 
I give permission for my GP / treating specialist(s) to be informed that I am participating in this study 
and I give permission for information to be requested from them about my medical history. 
• 
I give permission to the Sponsor and its authorized representatives (such as monitors and auditors, 
governmental, regulatory health authorities, and ethics committee) to have direct access to my 
medical records for the purposes of the study. 
• 
I give permission for the collection and use of my personal data / body material to answer the 
research questions in this study.  
• 
I understand that my anonymized data may be used to support future scientific research in the public 
interest and may be shared with other researchers. 
• 
I consent that my personal data as set out in this consent form, including data relating to my physical 
or mental health or condition, race or ethnic origin may be used by the sponsor and study center to 
answer the research questions of this study.  
• 
I give permission to have my sessions video-recorded during this study, and for them to be stored 
for a limited amount of time in the data centers located in Europe, understanding that my personal 
information will be protected as mentioned above 
• 
I agree that my GP and/or treating specialist will be informed of coincidental findings that (may) be 
of interest for my health. In relation to this, I also agree that the contact details I have provided may 
be used to contact me in order to provide this information about my health. 
• 
I know that I should not become pregnant during the study. 
• 
The investigator has discussed with me the most suitable contraception for me.  
• 
I consent to being contacted again after this study for a follow-up study  yes  no 
• 
I agree to take part in this study. 
 
Name of Participant (Please print): _______________________________________________ 
 
 
 
Signature of Participant: _______________________________________________________ 
 
 
 
 
 
 
Date (dd/MMM/yyyy): __ __ / __ __ __ / __ __ __ __ 
 
Time: __ __:__ __ 
 
 
 
 


 
 
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Researcher taking consent: 
I hereby declare that I have fully informed this study participant about this study and, to the best of my 
knowledge, they clearly understand the nature, risks and benefits of taking part in this study. 
 
If information comes to light during the course of the study that could affect the study participant's 
consent, I will inform him/her of this in a timely fashion. 
 
Name and signature of researcher taking consent:  
Name: ___________________________________ 
Signature: ________________________________ 
 
 
 
 
 
 
 
Date (dd/MMM/yyyy): __ __ / __ __ __ / __ __ __ __ 
 
Time: __ __:__ __ 
 
----------------------------------------------------------------------------------------------------------------- 
 
The participant will receive the full information sheet, together with a signed copy of the consent form. 
The second signed copy will be kept at the research site.  
 
 

Prot_000.pdf: 
Protocol MP18 
EudraCT # 2018-001718-13 
NCT # NCT04030169 
Protocol Version 1.0: 20 September 2018 
Protocol Version 2.0: 12 December 2018 
Protocol Version 3.0: 10 June 2019 
Protocol Version 4.0: 19 August 2019 
Protocol Version 5.0: 16 December 2019 
Protocol Version 6.0: 29 March 2021 
Protocol Version 7.0:  22 November 2022 
An Open-Label, Phase 2, Multicenter Feasibility Study of Manualized MDMA-
Assisted Psychotherapy with an Optional fMRI Sub-Study Assessing Changes in 
Brain Activity in Subjects with Posttraumatic Stress Disorder 
SPONSOR 
MAPS Europe B.V. 
SPONSOR DESIGNEE 
Amy Emerson 
Chief Executive Officer 
MAPS Europe B.V. 
Email: amy@mapsbcorp.com 
COORDINATING 
PRINCIPAL INVESTIGATOR 
Prof. Dr. H.G.J.M. (Eric) Vermetten 
Leiden University Medical Center 
Email: e.vermetten@lumc.nl 
MEDICAL MONITOR 
Aurélien Viaccoz 
MAPS Europe B.V. 
Email: medicalmonitor@mapseurope.eu 
USE 
In conjunction with relevant regulatory and ethical guidance 
CONFIDENTIAL 


MAPS Europe B.V. 
 
MP18 Protocol Synopsis  
EudraCT #2018-001718-13 
 
Version 7.0: 22 November 2022 
Page 2 of 116 
 
Protocol Amendment Summary of Changes  
 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment Version #7 
16Nov2022 
Amendment Version #6 
 
29March2022 
Amendment Version #5 
14Oct2019 
Amendment Version #4 
19Aug2019 
Amendment Version #3 
10June2019 
Amendment Version #2 
12Dec2018 
Original Protocol Version 1 
20Sep2018 
 
 
 


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Page 3 of 116 
 
MP18 Protocol Synopsis  
Full protocol begins on Page 20 
Rationale 
MAPS Europe B.V. is a small or medium-sized enterprise (SME) organization working as a 
clinical trial sponsor to obtain approval for the prescription use of 3,4-
methylenedioxymethamphetamine (MDMA) as an adjunct to psychotherapy in patients with 
posttraumatic stress disorder (PTSD). MAPS Europe B.V. is a wholly owned subsidiary of the 
Multidisciplinary Association for Psychedelic Studies (MAPS), a tax-exempt charity providing 
funding for the clinical development program. The Multidisciplinary Association for Psychedelic 
Studies (MAPS) Data from a series of Phase 2 studies of MDMA-assisted psychotherapy 
sponsored by MAPS provide preliminary evidence that chronic PTSD, independent of cause, is 
treatable with two to three sessions of MDMA-assisted psychotherapy and associated non-drug 
preparatory and integrative psychotherapy. This open-label Phase 2 study will serve as the lead-in 
to the planned Phase 3 study in Europe and to validate assumptions made for statistical power 
calculations supporting the planned Phase 3 clinical trial. This study will also provide cross-
cultural validation data on the updated version of the Primary Outcome measure, the Clinician 
Administered PTSD Scale for DSM-5 (CAPS-5), which will be used in the Phase 3 study. In 
addition, the study will gather supportive data on the safety and effectiveness of manualized 
MDMA-assisted psychotherapy while providing an opportunity for clinical supervision to 
planned Phase 3 therapy teams. This study will be the first multicenter study of MDMA-assisted 
psychotherapy for PTSD in Europe and will explore reproducibility of findings from FDA-
regulated Phase 2 trials to confirm the Phase 3 study design. 
 
PTSD is a serious, debilitating disorder that negatively impacts a person’s daily life, and can 
result in diminished cognitive and psychosocial functioning, fractured relationships, inability to 
maintain employment, substance abuse, high-cost healthcare utilization, increased depression, 
and suicide risk. People who suffer from PTSD may relive the traumatic experience through 
nightmares and flashbacks, have difficulty sleeping, and feel detached or estranged. Symptoms 
can be severe and long lasting. MDMA is a monoamine releaser and re-uptake inhibitor with 
indirect effects on neurohormone release. The combined neurobiological effects reduce defenses 
and fear of emotional injury, enhance communication and introspection, and can increase 
empathy and compassion. MDMA may enhance fear extinction learning in humans. The 
subjective effects of MDMA create a productive psychological state that enhances the therapeutic 
process.  
 
Study Design 
This multicenter, open-label, lead-in study assesses the safety and effectiveness of MDMA-
assisted psychotherapy in participants diagnosed with at least severe PTSD. All safety data will 
be included in the global safety database for MDMA maintained by MAPS. The study will be 
conducted in up to 40 participants who will complete the study in multiple countries in Europe. 
Some sites will participate in the imaging sub-study (see Appendix A).  
 
A flexible dose of MDMA, followed by a supplemental half-dose unless tolerability issues 
emerge, is administered during the Treatment Period with manualized psychotherapy in two 
open-label Experimental Sessions spaced approximately a month apart. This 8-week Treatment 
Period is preceded by three Preparatory Sessions. During the Treatment Period, each 
Experimental Session is followed by three Integrative Sessions of non-drug psychotherapy. The 
Primary Outcome measure, the change in CAPS-5 Total Severity Score from Baseline (V3) to 
Visit 14, is assessed by a centralized Independent Rater (IR) pool at 13 weeks post Baseline 
(V14). The CAPS-5 is also administered as an exploratory measure after Treatment 1 (V8). The 


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Version 7.0: 22 November 2022 
Page 4 of 116 
 
IR pool will be blinded to visit number and number of treatments received and will not have 
access to data collected by the sites during the active treatment period.  
 
For each participant, the study will consist of the following periods: 
 
• 
Screening Period: phone screen (where permitted), informed consent, eligibility 
assessment, and enrollment of eligible participants  
• 
Preparatory Period with Enrollment Confirmation: medication tapering, Preparatory 
Sessions and Baseline assessments leading to Enrollment Confirmation 
• 
Treatment Period: two monthly Experimental Sessions and associated Integrative 
Sessions over ~8 weeks plus one CAPS-5 assessment  
• 
Follow-up Period and Study Termination: ~4 weeks with no study visits, followed by 
Primary Outcome CAPS-5 and Study Termination visit 
 
The imaging sub-study (Appendix A) will include Magnetic Resonance Imaging (MRI) scanning 
to explore the effects of two experimental sessions, consisting of a baseline scan (one week 
before the first experimental session at MRI-1 V4.1), and the second scan will be conducted after 
the CAPS-5 outcome measure (at MRI-2 V14.1). 
 
Study Design Overview 
 
 
Screening Period 
From Consent to Enrollment (Visit 0): ~4 weeks (+/-2 weeks) 
Study Visit 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Screening 
Screening  
Multiple visits over 3 
weeks (-2 weeks/+1 
week) 
 
7 to 28 days total 
At initial visit, obtain Informed Consent and assess 
all screening measures (including LEC-5, PCL-5, 
Lifetime C-SSRS, AUDIT, DUDIT), medical 
history, and pre-study medications. Contact outside 
providers and order medical records, physical exam, 
labs (including pregnancy and drug tests), ECG, and 
1-minute rhythm strip. Once all results and records 
are obtained, review along with notes from all 
screening visits and measures. If eligible, send 
results of LEC-5 & CIPD-SR to IR. Screening may 
take place over 3 weeks at multiple visits. 
Independent 
Rater Screening 
1 hour/ 
2 days after initial 
eligibility established in 
Screening 
(+7 days) 
 
2 to 9 days after initial 
eligibility established 
After PCL-5, and initial eligibility are reviewed, an 
IR will conduct the Since Last Visit C-SSRS, CIPD, 
DDIS, and MINI via tele-assessment. Results will be 
confirmed by clinical observation during the 
Preparatory Period, but the CIPD, DDIS, and MINI 
will not be repeated. 
Enrollment 
Enrollment 
(Visit 0) 
1.5 hours/ 
2 days after (+12 days) 
Independent Rater 
Screening 
 
2 to 14 days after IR 
Screening 
Prior to enrolling: review all screening measures, 
medical history, discussion with outside providers 
and sponsor, and any clarification phone calls with 
participant. Visit is 1.5 hours to review eligibility 
and medical tapering plan. If enrolled, begin taper, 
(5 half-lives plus 1 week for stabilization). Adverse 
Event (AE) collection begins. 


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Preparatory Period with Enrollment Confirmation  
From Preparatory Session 1 (Visit 1) to Preparatory Session 3 (Visit 4): ~6 weeks (+5/-4 weeks) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Preparatory Period 
Preparatory 
Session 1 
(Visit 1) 
1.5 hours/ 
Within 1 week (-7/+5 
days) after Enrollment 
(V0) 
 
0 to 12 days after 
Enrollment (V0) 
90-minute Preparatory Session. Target visit timing 
on tapering needs. If needed, schedule calls between 
V1 and V2 if indicated for tapering, safety, or further 
questions about medical history. 
Preparatory 
Session 2 
(Visit 2) 
 
1.5 hours/ 
At least 2 days after 
Preparatory Session 1 
(V1); within 3 weeks of 
Preparatory Session 1 
(V1) 
 
2 to 21 days after 
Preparatory Session 1 
(V1) 
 
90-minute Preparatory Session/ongoing assessment. 
If tapering is complete or not needed, check 
eligibility and schedule V3 and V4. If tapering is 
ongoing, schedule post taper call for ongoing 
assessment. 
Phone Call 
End Taper 
 
1 hour/ 
Within 1 week of 
planned taper end & 
stabilization off 
medications; before 
Baseline CAPS T1 
(V3); within 8 weeks of 
V0 
 
0 to 56 days after 
Enrollment (V0); 
within 7 days of the end 
of tapering and 
stabilization; prior to 
baseline CAPS T1 (V3) 
If needed, confirm medication taper and stabilization 
is complete and participant is eligible for Baseline 
CAPS-5. Schedule V3 and V4. 
 
 
Baseline & Enrollment 
Confirmation  
Baseline 
CAPS-5 T1 
(Visit 3) 
1.5 hours/ 
Post Preparatory 
Session 2 (V2) & 
confirmation of 
Medication Taper and 
stabilization; before V4  
 
At least 7 days after 
Preparatory Session 2 
(V2) 
CAPS-5, SDS, and DSP-I completed by an IR via 
tele-assessment after taper is complete. CAPS-5 
scores sent ASAP to the therapy team/Principal 
Investigator. 


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Preparatory 
Session 3 
& Enrollment  
Confirmation 
(Visit 4) 
3 hours: (90 minutes of 
measures, 90-minute 
therapy) 
Within 6 days of 
Baseline CAPS T1 
(V3); within 4 days 
prior to Experimental 
Session 1 (V5) but not 
on the same day. 
 
3 to 6 days after 
Baseline CAPS T1 
(V3); 1 to 4 days before 
Experimental Session 1 
(V5). Both Baseline 
CAPS T1 (V3) and 
Preparatory Session 3 
and Enrollment 
Confirmation (V4) 
must take place within 
7 days prior to 
Experimental Session 1 
(V5). 
Prior to visit, ensure CAPS-5 confirms PTSD 
diagnosis and Total Severity Score of ≥35 and 
confirm enrollment by reassessing specified 
eligibility criteria. Complete Baseline self-report 
measures. Complete 3-hour Preparatory Session 
(~90-minute measures, 90-minute therapy) and 
schedule V5. If enrollment is not confirmed do not 
perform visit, complete termination.  


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Treatment Period 
From Experimental Session 1 (Visit 5) to Integrative Session 2.3(Visit 13): 8 weeks (-3/+4) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Treatment 1 
Experimental 
Session 1 
(Visit 5) 
8 hours + overnight/ 
Within 1 week of 
Baseline CAPS-5 T1 
(V3) and Preparatory 
Session 3 and 
Enrollment 
Confirmation (V4) 
 
4 to 7 days after 
Baseline CAPS-5 T1 
(V3); 1 to 4 days after 
Preparatory Session 3 
and Enrollment 
Confirmation (V4). 
Experimental Session 1 
(V5) must occur within 
7 days of the Baseline 
CAPS-5 T1 (V3) and 
after Preparatory 
Session 3 and 
Enrollment 
Confirmation (V4) 
 
At least 14 days after 
Preparatory Session 2 
(V2); after Therapist 
Supervision Meeting 
 
First Experimental Session is within 1 week of the 
Baseline CAPS-5 (V3) and 2 weeks after 
Preparatory Session 2 (V2); it lasts 8 hours with 
overnight stay. Dose is 80 mg with supplemental 
half-dose of 40 mg unless tolerability issues emerge 
with the first dose or the participant declines. 
Negative pregnancy test and drug test must be 
confirmed prior to dosing. 
Integrative 
Session 1.1 
(Visit 6) 
1.5 hours/ 
Morning after 
Experimental Session 1 
(V5) 
 
1 day after 
Experimental Session 1 
(V5) 
V6 is a 90-minute Integrative Session the morning 
after V5. Followed by 4 phone check-ins over the 7 
days post V5.  
Integrative 
Session 1.2 
(Visit 7) 
1.5 hours/ 
At least 3 days after 
Experimental Session 1 
(V5); at least 2 days 
after Integrative 
Session 1.1 (V6); 
within 2 weeks after 
Experimental Session 1 
(V5) 
 
3 to 14 days after 
Experimental Session 1 
(V5); at least 2 days 
after Integrative 
Session 1.1 (V6) 
 
Approximately 2 weeks after V5, a 90-minute 
Integrative Session (V7) is completed. 


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CAPS-5 T2 
(Visit 8) 
1 hour/ 
3 weeks (-3/+9 days) 
after Experimental 
Session 1 (V5); after 
Integrative Session 1.2 
(V7) and before 
Integrative Session 1.3 
(V9) 
 
18 to 30 days after 
Experimental Session 1 
(V5); between 
Integrative Sessions 1.2 
and 1.3 (V7 & V9) but 
may be same day as 
either. 
 
Between V7 and V9, CAPS-5, SDS, and DSP-I 
assessment completed by an IR via tele-assessment. 
Integrative 
Session 1.3 
(Visit 9) 
1.5 hours/ 
3 to 5 weeks after 
Experimental Session 1 
(V5); at least 2 days 
after Integrative 
Session 1.2 (V7); may 
be the same day as 
CAPS-5 T2 (V8); 1 to 7 
days before 
Experimental Session 2 
(V10) 
 
20 to 34 days after 
Experimental Session 1 
(V5); at least 2 days 
after Integrative 
Session 1.2 (V7); 1 to 7 
days before 
Experimental Session 2 
(V10) 
90-minute Integrative Session post V8 and in 
preparation for V10. Can occur 1 to 7 days before 
V10. Measures include LEC-5, PCL-5, and Since 
Last Visit C-SSRS. 
 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Treatment 2 
Experimental 
Session 2 
(Visit 10) 
8 hours + overnight/ 
3 to 5 weeks after 
Experimental Session 1 
(V5); at least 2 weeks 
after Integrative 
Session 1.3 (V9)  
 
21 to 35 days after 
Experimental Session 1 
(V5) 
 
At least 14 days after 
Integrative Session 1.2 
(V7); after Therapist 
Supervision Meeting 
3 to 5 weeks after V5, and 2 weeks after Integrative 
Session 1.1 (V6). The second Experimental Session 
lasts 8 hours with an overnight stay. Dose is 80 or 
120 mg plus supplemental half-dose (80 mg + 
supplemental 40 mg -OR- 120 mg + supplemental 
60 mg) unless tolerability issues emerge with the 
first dose or the participant declines. Negative 
pregnancy test and drug test must be confirmed prior 
to dosing. 


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Integrative 
Session 2.1 
(Visit 11) 
1.5 hours/ 
Morning after 
Experimental Session 2 
(V10) 
 
1 day after 
Experimental Session 2 
(V10) 
V11 is a 90-minute Integrative Session the morning 
after V10. Followed by 4 phone check-ins over 7 
days post V10.  
Integrative 
Session 2.2 
(Visit 12) 
1.5 hours/ 
At least 3 days after 
Experimental Session 2 
(V10); at least 2 days 
after Integrative 
Session 2.1 (V11); 
within 2 weeks after 
Experimental Session 2 
(V10) 
 
3 to 14 days after 
Experimental session 2 
(V10); at least 2 days 
after Integrative 
Session 2.1 (V11) 
Approximately 2 weeks after V10, a 90-minute 
Integrative Session (V12) is completed. 
Integrative 
Session 2.3 
(Visit 13) 
1.5 hours/ 
3 to 5 weeks after 
Experimental Session 2 
(V10) 
 
20 to 34 days after 
Experimental Session 2 
(V10); at least 2 days 
after Integrative 
Session 2.2 (V12) 
90-minute Integrative Session post V12. Measures 
include LEC-5, PCL-5 and Since Last Visit C-SSRS. 
Follow-up Period and Study Termination 
From Integrative Session 2.3 (Visit 13) until Study Termination (Visit 15): 4 weeks (+/-2). 
After Integrative Session 2.3 (Visit 13), ~4 weeks with no scheduled study visits until the Primary 
Outcome is completed. 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Primary Outcome 
Primary 
Outcome 
CAPS-5 T3 
(Visit 14) 
1 hour/ 
~13 (+/-3) weeks after 
Baseline CAPS-5 T1 
(V3) & 
8 weeks (+/-2) after 
Experimental Session 2 
(V10)  
 
67 to 112 days post 
Baseline CAPS-5 T1 
(V3); 42 to 70 days 
after Experimental 
Session 2 (V10) 
Primary Outcome CAPS-5, SDS, and DSP-I 
assessment completed by an IR via tele-assessment. 
Although there are allowable windows for all visits 
throughout the protocol, this visit must be completed 
within the overall window. Other visits should be 
scheduled to ensure the timing of the Primary 
Outcome CAPS-5 T3 assessment is appropriate. 


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Study Termination 
Study 
Termination 
(Visit 15) 
2 hours  
~13 (-3/+4) weeks after 
Baseline CAPS-5 T1 
(V3) & 
2 days (-1/+7 days) 
after Primary Outcome 
CAPS-5 T3 (V14) 
 
68 to 121 days after 
Baseline CAPS-5 T1 
(V3); 1 to 9 days after 
Primary Outcome 
CAPS-5 T3 (V14) 
Complete self-reported and safety measures; create 
an exit plan for participant.  
 
Qualified IRs selected based on availability from the IR Pool will perform the CAPS-5 
assessments as described in the following table.  
 
Primary Outcome (CAPS-5) Data Collection by Visit 
CAPS 
Number 
Visit 
Description/Timing 
Target 
Timing 
Post 
Baseline 
(V3) 
Baseline 
CAPS-5 T1 
V3 
Baseline; between V2 and confirmation of end of tapering and 
stabilization of medications 
0 days 
CAPS-5 T2 
V8 
Post Experimental Session 1 (3 weeks -3/+9 days); between 
Integrative Sessions 1.2 and 1.3 (V7 & V9) 
~6 weeks 
Primary 
Outcome 
CAPS-5 T3 
V14 
Post Experimental Session 2 (8 weeks +/-2) after Experimental 
Session 2 (V10); after Integrative Session 2.3 (V13) (4 weeks +/-
2). 
~13 weeks 
 
This study will compare the effects of two open-label manualized Experimental Sessions of 
psychotherapy assisted with a flexible divided-dose of MDMA as described in the table below, 
along with associated non-drug preparatory and integrative psychotherapy sessions. MDMA dose 
ranges proposed in this study have been safely used in previous Phase 2 studies sponsored by 
MAPS. 
 
Dose Regimen of MDMA 
Experimental Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative Dose 
1 
80 mg 
40 mg 
80 mg to 120 mg 
2 
80 or 120 mg 
40 or 60 mg 
80 mg to 180 mg 
Total Cumulative Dose 
160 mg to 300 mg 
* Unless tolerability issues emerge with the first dose or the participant declines 
 
Protocol Objective 
The overall objective of this study is to use standard clinical measures to explore the safety and 
effectiveness of open-label manualized MDMA-assisted psychotherapy with a flexible dose of 
MDMA in participants with severe PTSD and to serve as an opportunity for training and 
supervision of therapy teams selected to conduct Phase 3 MDMA-assisted psychotherapy 
research. 
 


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Primary Objective 
The primary objective of this study is to evaluate the effectiveness of MDMA-assisted 
psychotherapy for treatment of PTSD, as measured by the estimand of change in CAPS-5 Total 
Severity Score from Baseline (Visit 3) to 13 weeks post Baseline (Visit 14). 
 
Secondary Objective 
 
The secondary objective is to evaluate the effectiveness of MDMA-assisted psychotherapy for 
PTSD in clinician-rated functional impairment, as measured by the mean change in Sheehan 
Disability Scale (SDS) item scores from Visit 3 (Baseline) to Visit 14 (13 weeks post Baseline).  
Safety Objectives 
The overall safety objective is to assess severity, incidence and frequency of AEs, AEs of Special 
Interest (AESIs), and Serious Adverse Events (SAEs), concomitant medication use, suicidal 
ideation and behavior, and vital signs to support the package insert for MDMA-assisted 
psychotherapy. The following safety objectives will evaluate the safety of MDMA-assisted 
psychotherapy: 
 
1. Assess incidence of AEs during Experimental Sessions that may be indicative of a 
medical complication of the Investigational Product (IP), such as clinical signs and 
symptoms of chest pain, shortness of breath, or neurological symptoms or any other signs 
or symptoms that prompt additional vital sign measurements. 
2. Assess incidence of AEs by severity. 
3. Assess incidence of Treatment Emergent AEs (TEAEs) by severity. 
4. Assess incidence of TEAEs by severity taken during an Experimental Session and 
through 2 days after IP administration. 
5. Assess incidence of AESIs, defined as AEs specified in the protocol related to cardiac 
function and abuse liability. 
6. Assess incidence of AEs by severity categorized as leading to discontinuation of IP, 
resulting in death or hospitalization, and continuing at Study Termination. 
7. Assess incidence of SAEs. 
8. Assess incidence of psychiatric concomitant medications taken during an Experimental 
Session and through 2 days after IP administration. 
9. Assess incidence of any psychiatric concomitant medications taken during the Treatment 
Period. 
10. Assess incidence of serious suicidal ideation and positive suicidal behavior assessed with 
the Columbia Suicide Severity Rating Scale (C-SSRS). 
11. Assess mean changes in blood pressure, heart rate, and body temperature from pre-IP 
administration to end of each Experimental Session. 
 
Exploratory Objectives 
These objectives may be explored to characterize participants receiving MDMA-assisted 
psychotherapy to support the primary objective: 
 
1. Explore the effect of presence of secondary traumatic stressors (LEC-5) on the CAPS-5 
Total Severity analyses 
2. Explore changes within-participants in PTSD symptom clusters of re-experiencing, 
avoidance, negative alterations in cognition and mood, and hyperarousal, as measured by 
changes in CAPS-5 subscale scores from Visit 3 (Baseline) to Visit 14 (13 weeks post 
Baseline) 


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3. Explore the effect of adverse childhood experiences (ACE) on the CAPS-5 Total Severity 
analyses 
4. Explore changes in:  
• 
Dissociative symptoms associated with PTSD (DSP-I) 
• 
Depression (BDI-II)  
• 
Chronic pain (CPGS) 
• 
Quality of life (EQ-5D-5L) 
• 
Self-compassion (SCS) 
• 
Addictive behaviors including alcohol use (AUDIT), drug use (DUDIT), and 
nicotine use (SRNU)  
• 
Eating habits (EAT-26) 
• 
Healthcare utilization (UFEC) and economic productivity 
• 
Subjective effects (SE) 
 
Recruitment and Participant Population 
Therapy teams that have been identified to work on the sponsor’s planned Phase 3 study will treat 
at least one participant with open-label MDMA. Up to 40 participants with a confirmed diagnosis 
of at least severe PTSD will be enrolled. Participants will be recruited through referrals from 
other psychiatrists, psychotherapists, or physicians, print and internet advertisements, and by 
word of mouth. The sponsor will monitor demographics on an ongoing basis and encourage 
diversity in enrollment by communicating with sites.  
 
Participants will be persons aged 18 or older, with a confirmed diagnosis of at least severe PTSD 
per the PTSD Checklist for DSM-5 (PCL-5) at Screening with symptoms present for at least 6 
months. At Baseline, participants must qualify for a PTSD diagnosis per the CAPS-5 and have a 
Total Severity Score equal to or greater than 35 (severe). Participants would not be excluded for 
having more than one traumatic event or for having tried, not tolerated, or refused a selective 
serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) 
prescribed for PTSD. Participants with confirmed diagnosis of specific psychological and 
personality disorders will be excluded. Participants must be in good physical health and without 
major medical disorders that could affect the safety or tolerability of MDMA. 
 
Eligibility Criteria 
At the completion of Screening, participants must meet all eligibility criteria (except Inclusion 
Criterion #13 listed below) and agree to all lifestyle modifications to be enrolled. Each participant 
will then enter the Preparatory Period which includes medication tapering, if needed, and non-
drug Preparatory Sessions. The Preparatory Period ends with Enrollment Confirmation. A 
participant’s enrollment will be confirmed once they have completed medication tapering, have a 
confirmed PTSD diagnosis per the CAPS-5 assessment and a Total Severity Score of 35 or 
greater, continue to agree to all lifestyle modifications, and continue to meet all eligibility criteria.  
 
Inclusion Criteria 
1. Are at least 18 years old. 
2. Are fluent in speaking and reading the predominantly used or recognized language of the 
study site. 
3. Are able to swallow pills. 
4. Agree to have study visits video-recorded, including Experimental Sessions, Independent 
Rater assessments, and non-drug psychotherapy sessions. 


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5. Must provide a contact (relative, spouse, close friend or other support person) who is 
willing and able to be reached by the investigators in the event of a participant becoming 
suicidal or unreachable. 
6. Must agree to inform the investigators within 48 hours of any medical treatments and 
procedures. 
7. People able to become pregnant (PABP) (i.e., assigned female at birth, fertile, following 
menarche and until becoming post-menopausal unless permanently sterile), must have a 
highly sensitive negative pregnancy test at study entry and prior to each Experimental 
Session, and must agree to use adequate birth control through 10 days after the last 
Experimental Session. Adequate birth control methods include intrauterine device (IUD), 
injected or implanted hormonal methods, abstinence, oral hormones plus a barrier 
contraception, vasectomized sole partner (described in more detail in Section 10.3.2 
Contraception Guidelines).  
8. Agree to the following lifestyle modifications (described in more detail in Section 3.3 
Lifestyle Modifications): comply with requirements for fasting and refraining from 
certain medications prior to Experimental Sessions, not enroll in any other interventional 
clinical trials during the duration of the study, remain overnight at the study site after 
each Experimental Session and be driven home after, and commit to medication dosing, 
therapy, and study procedures. 
 
Medical History 
 
9. At Screening, meet DSM-5 criteria for current PTSD with a symptom duration of 6 
months or longer. 
10. At Screening, have at least severe PTSD symptoms in the last month based on PCL-5 
total score of 46 or greater. 
11. May have well-controlled hypertension that has been successfully treated with anti-
hypertensive medicines, if they pass additional screening to rule out underlying 
cardiovascular disease. 
12. May have asymptomatic Hepatitis C virus (HCV) that has previously undergone 
evaluation and treatment as needed. 
13. At Baseline, have a confirmed diagnosis of PTSD per CAPS-5 and at least severe 
symptoms in the last month constituting a CAPS-5 Total Severity Score of 35 or greater. 
14. May have alcohol or substance use disorder if participant is not in withdrawal or 
requiring detox. Participants must have a plan, agreed upon by investigator, therapy team, 
and Medical Monitor, to reduce use of alcohol or other substances and to manage 
symptoms without self-medicating. Enrollment will require that, in the judgment of the 
investigator, therapy team, and Medical Monitor, the plan for decreasing substance use is 
realistic and has a good chance of succeeding in order to prevent substance use from 
impacting the safety or efficacy of the investigational treatment. 
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.  


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Exclusion Criteria 
Potential participants are ineligible to enroll in the protocol if they: 
 
1. Are not able to give adequate informed consent. 
2. Are currently engaged in compensation litigation whereby financial gain would be 
achieved from prolonged symptoms of PTSD or any other psychiatric disorders. 
3. Are likely, in the investigator’s opinion and via observation during the Preparatory 
Period, to be re-exposed to their index trauma or other significant trauma, lack social 
support, or lack a stable living situation. 
4. Have used Ecstasy (material represented as containing MDMA) more than 10 times 
within the last 10 years or at least once within 6 months of the first Experimental Session; 
or have previously participated in a MAPS-sponsored MDMA clinical trial. 
5. Have any current problem which, in the opinion of the investigator or Medical Monitor, 
might interfere with participation.  
6. Have hypersensitivity to any ingredient of the IMP (Investigational Medicinal Product).  
 
Psychiatric History 
 
7. Have received Electroconvulsive Therapy (ECT) within 12 weeks of enrollment. 
8. Have a history of, or a current primary psychotic disorder, bipolar affective disorder type 
1 assessed via MINI and clinical interview or dissociative identity disorder assessed via 
DDIS and clinical interview. 
9. Have a current eating disorder with active purging assessed via MINI and clinical 
interview. 
10. Have current major depressive disorder with psychotic features assessed via MINI. 
11. Have a current alcohol or substance use disorder other than caffeine or nicotine that the 
investigators, therapy team, and/or Medical Monitor judge to be a safety concern for 
enrollment in the study or that could interfere with the therapeutic process or with other 
aspects of study participation. Any participant who is not able to agree or adhere to a plan 
to reduce use and manage symptoms will not be enrolled. 
12. Have current Personality Disorders (paranoid, schizoid, schizotypal, antisocial, 
borderline, histrionic, narcissistic, avoidant, dependent, obsessive-compulsive) assessed 
via CIPD. Diagnoses will be confirmed via clinical interview. 
13. Any participant presenting current serious suicide risk, as determined through psychiatric 
interview, responses to C-SSRS, and clinical judgment of the investigator will be 
excluded; however, history of suicide attempts is not an exclusion. Any participant who 
is likely to require hospitalization related to suicidal ideation and behavior, in the 
judgment of the investigator, will not be enrolled. Any participant presenting with the 
following on the Baseline C-SSRS will be excluded: 
• 
Suicidal ideation score of 4 or greater within the last month of the assessment at a 
frequency of once a week or more. 
• 
Suicidal ideation score of 5 within the last 6 months of the assessment. 
• 
Any suicidal behavior, including suicide attempts or preparatory acts, within the 
last 6 months of the assessment. Participants with non-suicidal self-injurious 
behavior may be included if approved by the Medical Monitor. 
14. Would present a serious risk to others as established through clinical interview and 
contact with treating psychiatrist. 
15. Require ongoing concomitant therapy with a psychiatric medication with exceptions 
described in Section 11.0: Concomitant Medications. 
 
 
Medical History 


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16. Have a history of any medical condition that could make receiving a sympathomimetic 
drug harmful because of increases in blood pressure and heart rate. This includes, but is 
not limited to, a history of myocardial infarction, cerebrovascular accident, or aneurysm. 
Participants with other mild, stable chronic medical problems may be enrolled if the site 
physician, PI, and Medical Monitor agree the condition would not significantly increase 
the risk of MDMA administration or be likely to produce significant symptoms during 
the study that could interfere with study participation or be confused with side effects of 
the IMP. Examples of stable medical conditions that could be allowed include, but are not 
limited to Diabetes Mellitus (Type 2), Human Immunodeficiency Virus (HIV) infection, 
Gastroesophageal Reflux Disease (GERD), etc. Any medical disorder judged by the 
investigator to significantly increase the risk of MDMA administration by any 
mechanism would require exclusion.  
17. Have a diagnosis of uncontrolled hypertension, defined as repeated readings of ≥140 
millimeters of mercury [mmHg] systolic or ≥90 mmHg diastolic. The diagnosis may be 
confirmed by repeated clinic measurements or home blood pressure monitoring if 
clinically indicated per European Society of Cardiology (ESC) guidelines. 
18. Have a history of ventricular arrhythmia at any time, other than occasional premature 
ventricular contractions (PVCs) in the absence of ischemic heart disease. 
19. Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been 
successfully eliminated by ablation.  
20. Have a history of arrhythmia, other than premature atrial contractions (PACs) or 
occasional PVCs in the absence of ischemic heart disease, within 12 months of screening. 
Participants with a history of atrial fibrillation, atrial tachycardia, atrial flutter or 
paroxysmal supraventricular tachycardia or any other arrhythmia associated with a 
bypass tract may be enrolled only if they have been successfully treated with ablation and 
have not had recurrent arrhythmia for at least one year off all antiarrhythmic drugs, and 
confirmed by a cardiologist. 
21. Have a marked Baseline prolongation of QT/QTc interval (For purposes of eligibility, 
this is defined as repeated demonstration of a QT interval corrected using Fridericia’s 
formula [QTcF] >450 milliseconds [ms]). 
22. Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, 
hypokalemia, family history of Long QT Syndrome). 
23. Require use of concomitant medications that prolong the QT/QTc interval during 
Experimental Sessions. Refer to Section 11.0 Concomitant Medications. 
24. Have symptomatic liver disease or have significant liver enzyme elevation. 
25. Have history of hyponatremia (defined as outside of the normal range of 135 to 145 
mmol/L) or hyperthermia. 
26. Weigh less than 48 kilograms (kg). 
27. Are pregnant or nursing or are able to become pregnant and are not practicing an 
approved means of birth control. 
28. Have engaged in ketamine-assisted therapy or used ketamine within 12 weeks of 
enrollment. 


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Lifestyle Modifications 
All participants must agree to the following lifestyle modifications at time of signing the 
informed consent form and throughout the study. Participants are eligible to enroll in the study if 
they: 
 
• 
Are willing to commit to medication and MDMA dosing, psychotherapy sessions, 
follow-up sessions, completing evaluation instruments, and all necessary telephone 
contact. 
• 
Agree to not participate in any other interventional clinical trials during the duration of 
this study, without prior approval of the Medical Monitor. 
• 
Agree to not begin a new form of mental healthcare during the screening or treatment 
phases of the trial, without first discussing with the PI in consultation with the Medical 
Monitor.  
o It is acceptable for participants to continue ongoing mental healthcare, if it is not 
increased in frequency or specifically excluded by the study protocol.  
o All ongoing therapies should be documented by the site and discussed with the 
Medical Monitor prior to enrollment to avoid confounding treatment effects. In 
some instances, the Medical Monitor may request that the participant delay 
enrollment until their planned course of therapy is complete and an integration 
period has elapsed. 
 
Leading up to Experimental Sessions 
 
• 
Agree to take nothing by mouth except alcohol-free liquids after 12:00 A.M. (midnight) 
the evening before each Experimental Session. 
• 
Refrain from the use of any psychoactive medication not approved by the research team 
from Baseline through Study Termination. 
• 
Agree not to use caffeine or nicotine for 2 hours before and at least 6 hours after the 
initial dose during each Experimental Session. 
• 
Are willing to comply with medication requirements per protocol (refer to Section 11.0 
Concomitant Medications). Medications will only be discontinued after enrollment per 
clinical judgment of the site physician in consultation with the prescribing physician. 
• 
Are able to decrease dose of allowable opiates (per Section 11.0 Concomitant 
Medications), if used for pain management, leading up to the Experimental Session in 
order to avoid taking the medication for at least 12 hours prior to the initial IP 
administration and 24 hours after. During this period, the participant will be allowed to 
take the medication if needed for intolerable pain flare-ups. 
• 
Agree that, for 1 week preceding each Experimental Session to refrain from: 
o Taking any herbal supplement (except with prior approval of the research team) 
o Taking any nonprescription medications (with the exception of non-steroidal 
anti-inflammatory medications or acetaminophen unless with prior approval of 
the research team). 
o Taking any prescription medications (with the exception of birth control pills, 
thyroid hormones, or other medications approved by the research team). 
 
Post Experimental Session 
 
• 
Are willing to remain overnight at the study site after each Experimental Session until 
after the Integrative Session the next morning. 
• 
Are willing to be driven home on the morning after the Experimental Sessions after the 
Integrative Session, either by a driver arranged by the participant, site personnel or taxi. 


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Statistical Analysis  
The primary and key secondary endpoint analyses will be based on the mITT analysis set.  
The primary estimator of effectiveness will be the mean change in CAPS-5 Total Severity Scores 
from Baseline to 14 weeks after start of dosing (Visit 14). Least squares means from a restricted 
maximum likelihood (REML)-based mixed model for repeated measures (MMRM) will be used 
to estimate the change in CAPS-5 from baseline to each visit. The mITT analysis set will include 
all participants who receive IP in at least one Experimental Session and have at least one follow-
up CAPS-5 assessment. Additional details of statistical analyses are described in the Statistical 
Analysis Plan (SAP). 
 


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Study Structure Overview 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
Protocol MP18 
EudraCT # 2018-001718-13 
 
Protocol Version 1.0: 20 September 2018 
Protocol Version 2.0: 12 December 2018 
Protocol Version 3.0: 10 June 2019 
Protocol Version 4.0: 19 August 2019 
Protocol Version 5.0: 16 December 2019 
Protocol Version 6.0: 29 March 2021  
Protocol Version 7.0: 22 November 2022 
 
An Open-Label, Phase 2, Multicenter Feasibility Study of Manualized MDMA-
Assisted Psychotherapy with an Optional fMRI Sub-Study Assessing Changes in 
Brain Activity in Subjects with Posttraumatic Stress Disorder 
 
SPONSOR 
MAPS Europe B.V. 
 
 
SPONSOR DESIGNEE 
 
Amy Emerson 
Director  
MAPS Europe B.V. 
Email: amy@mapsbcorp.com 
 
COORDINATING 
PRINCIPAL INVESTIGATOR 
Prof. Dr. H.G.J.M. (Eric) Vermetten 
Leiden University Medical Center 
Email: e.vermetten@lumc.nl 
 
MEDICAL MONITOR 
Aurélien Viaccoz 
MAPS Europe B.V. 
Email: medicalmonitor@mapseurope.eu 
 
USE 
In conjunction with relevant regulatory and ethical guidance 
 
CONFIDENTIAL 
 
 
 
 
 
 


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Table of Contents 
Eligibility Criteria ......................................................................................................................... 12 
Inclusion Criteria ........................................................................................................................ 12 
Exclusion Criteria ....................................................................................................................... 14 
Lifestyle Modifications ............................................................................................................... 16 
List of Tables ................................................................................................................................. 22 
List of Figures ............................................................................................................................... 22 
List of Abbreviations .................................................................................................................... 23 
1.0 Introduction ............................................................................................................................. 26 
1.1 Rationale ............................................................................................................................... 26 
1.2 Background ........................................................................................................................... 27 
1.2.1 PTSD .............................................................................................................................. 27 
1.2.2 MDMA .......................................................................................................................... 28 
1.2.3 MDMA-Assisted Psychotherapy for PTSD ................................................................... 29 
1.2.4 Previous Clinical Experience with MDMA ................................................................... 30 
2.0 Protocol Objectives ................................................................................................................. 31 
2.1 Primary Objective and Primary End Point ........................................................................... 31 
2.2 Secondary Objective and Secondary End Point ................................................................... 31 
2.3 Safety Objectives .................................................................................................................. 31 
2.4 Exploratory Objectives ......................................................................................................... 32 
3.0 Eligibility Criteria ................................................................................................................... 32 
3.1 Inclusion Criteria .................................................................................................................. 33 
3.2 Exclusion Criteria ................................................................................................................. 34 
3.3 Lifestyle Modifications ......................................................................................................... 36 
4.0 Protocol Design ....................................................................................................................... 37 
4.1 Study Design Overview ........................................................................................................ 37 
4.2 Planned Duration of Study .................................................................................................... 45 
4.3 Discontinuation and Completion Criteria ............................................................................. 46 
4.3.1 Complete or Evaluable Participants ............................................................................... 46 
4.3.2 Screen Failures ............................................................................................................... 46 
4.3.3 Pre-Dosing Early Terminations ..................................................................................... 46 
4.3.4 Early Termination from the Study ................................................................................. 47 
4.3.5 Lost to Follow-up .......................................................................................................... 48 
4.4 End of Study Definition and Premature Discontinuation ..................................................... 48 
4.5 Rationale of Dose Selection .................................................................................................. 48 
5.0 Psychotherapy ......................................................................................................................... 49 
5.1 Description of Therapeutic Method ...................................................................................... 49 
5.2 Therapy Team Qualifications ............................................................................................... 50 
5.3 Training ................................................................................................................................. 50 
5.3.1 Therapy Training Program ............................................................................................ 50 
5.4 Adherence to Therapeutic Method ....................................................................................... 50 
6.0 Measures and Reliability ........................................................................................................ 50 
6.1 Primary Outcome Measure and Reliability .......................... Error! Bookmark not defined. 
6.2 Secondary Outcome Measure ............................................................................................... 53 
6.3 Safety Measures .................................................................................................................... 53 
6.4 Screening Measures and Reliability ..................................................................................... 53 
6.5 Exploratory Measures ........................................................................................................... 54 
7.0 Study Procedures .................................................................................................................... 57 
7.1 Screening Period ................................................................................................................... 61 
7.1.1 Screening ....................................................................................................................... 61 
7.1.2 Remote Visits ................................................................................................................. 63 


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7.1.3 Interruptions and Arrangements Due to COVID-19 Pandemic or Any Other 
Unforeseen Emergency at Clinic Locations ........................................................................... 63 
7.1.4 Independent Rater Screening ......................................................................................... 64 
7.1.5 Enrollment ..................................................................................................................... 64 
7.2 Preparatory Period with Enrollment Confirmation ............................................................... 65 
7.2.1 Preparatory Session 1 and Preparatory Session 2 .......................................................... 65 
7.2.2 Baseline: CAPS-5 by Independent Rater ....................................................................... 66 
7.2.3 Baseline: Preparatory Session 3 and Enrollment Confirmation .................................... 66 
7.3 Treatment Period .................................................................................................................. 67 
7.3.1 Experimental Sessions ................................................................................................... 68 
 Psychotherapy Session ............................................................................................ 68 
7.3.2 Telephone Contact After Experimental Sessions .......................................................... 70 
7.3.3 Integrative Sessions ....................................................................................................... 71 
7.3.4 Independent Rater Assessments .................................................................................... 72 
7.4 Follow-up Period and Study Termination ............................................................................ 72 
7.4.1 Follow-up Period ........................................................................................................... 72 
7.4.2 Final Independent Rater Assessment ............................................................................. 72 
7.4.3 Study Termination ......................................................................................................... 72 
7.4.4 Exit Plan ......................................................................................................................... 73 
8.0 Investigational Medicinal Product ........................................................................................ 73 
8.1 Description of Active Compounds ....................................................................................... 73 
8.1.1 Doses .............................................................................................................................. 74 
8.1.2 Dose Modifications ........................................................................................................ 74 
8.2 Handling ............................................................................................................................... 74 
8.2.1 Encapsulation, Packaging, and Labeling ....................................................................... 74 
8.2.2 Accountability ................................................................................................................ 74 
8.2.3 Storage ........................................................................................................................... 75 
8.2.4 Administration ............................................................................................................... 75 
8.2.5 Treatment Compliance ................................................................................................... 75 
8.3 Participant Numbering .......................................................................................................... 75 
8.4 Bias Minimization ................................................................................................................ 76 
9.0 Risks ......................................................................................................................................... 76 
9.1 Non-drug Related Risks ........................................................................................................ 76 
9.1.1 Medical Assessments ..................................................................................................... 76 
9.1.2 PTSD, Suicide Risk, and Psychotherapy ....................................................................... 77 
9.1.3 Recorded Content .......................................................................................................... 78 
9.2 Risks of Receiving MDMA .................................................................................................. 78 
9.2.1 High Level Risks ........................................................................................................... 79 
9.2.2 Medium Level Risks ...................................................................................................... 79 
 Cardiovascular and Cerebrovascular Risks and Mitigation .................................... 79 
 Psychological Risks and Mitigation ....................................................................... 80 
9.2.3 Low Level Risks ............................................................................................................ 81 
 Thermoregulatory Risks and Mitigation ................................................................. 81 
 Osmoregulatory Risk and Mitigation ..................................................................... 82 
 Genotoxicity Risk and Mitigation .......................................................................... 82 
 Reproductive and Developmental Risks and Mitigation ........................................ 82 
9.2.4 Minimal Risks ................................................................................................................ 82 
 Common Expected AEs .......................................................................................... 83 
 Neurotoxicity Risk .................................................................................................. 83 
 Abuse Potential ....................................................................................................... 83 
10.0 Safety ...................................................................................................................................... 83 
10.1 Adverse Events ................................................................................................................... 83 


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10.1.1 Adverse Events of Special Interest .............................................................................. 84 
10.1.2 Serious Adverse Events ............................................................................................... 85 
10.1.3 Suspected unexpected serious adverse reaction .......................................................... 86 
10.2 Other Significant Events ..................................................................................................... 86 
10.3 Pregnancy ........................................................................................................................... 87 
10.3.1 Definition of People Able to Become Pregnant .......................................................... 87 
10.3.2 Contraception Guidelines ............................................................................................ 87 
10.3.3 Follow-up Requirements ............................................................................................. 87 
11.0 Concomitant Medications .................................................................................................... 88 
11.1 Tapering Instructions .......................................................................................................... 88 
11.2 Allowed Concomitant Medications .................................................................................... 88 
11.3 Prohibited Medications ....................................................................................................... 89 
12.0 Clinical Laboratory Assessments ........................................................................................ 90 
13.0 Statistical Considerations ..................................................................................................... 91 
13.1 Statistical Analyses ............................................................................................................. 92 
13.1.1 Effectiveness Analyses ................................................................................................ 92 
 Primary Outcome Analyses .................................................................................. 92 
 Secondary Outcome Analyses .............................................................................. 92 
 Exploratory Analyses ............................................................................................ 92 
13.1.2 Safety Analyses ........................................................................................................... 93 
14.0 Study Governance ................................................................................................................. 93 
14.1 Ethics .................................................................................................................................. 93 
14.1.1 Financial Disclosure .................................................................................................... 94 
14.1.2 Informed Consent ........................................................................................................ 94 
14.2 Study Monitoring, Auditing, and Documentation .............................................................. 95 
14.2.1 Source Records ............................................................................................................ 95 
14.3 Confidentiality and Data Protection ................................................................................... 96 
14.4 Costs to Participants ........................................................................................................... 96 
14.5 Treatment and Compensation for Study Related Injury ..................................................... 97 
14.6 Record Retention ................................................................................................................ 97 
14.7 Publication Policy ............................................................................................................... 97 
Appendix A: Imaging Sub-Study .............................................................................................. 108 
 
List of Tables 
 
 Study Design Overview .................................................................................................... 39 
 Primary Outcome (CAPS-5) Data Collection by Visit ..................................................... 45 
 Dose Regimen of MDMA ................................................................................................ 49 
 Protocol Objectives and Assessment Tools ...................................................................... 51 
 Time and Events – Screening and Preparatory Study Procedures ................................... 58 
 Time and Events – Treatment and Follow-up Period ....................................................... 59 
 Time and Events – Study Measures ................................................................................. 60 
 Schedule of Procedures for Experimental Sessions ......................................................... 68 
 
List of Figures 
 
Figure 1: Study Structure Overview ............................................................................................... 38 


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List of Abbreviations 
A:G 
 
Albumin:Globulin 
ACE 
 
Adverse Childhood Events 
ADHD  
Attention Deficit Hyperactivity Disorder 
AE(s)  
Adverse Event(s) 
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 
°C 
 
Degrees Celsius 
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 
CIPD  
Clinical Interview for Personality Disorders 
CIPD-SR 
Clinical Interview for Personality Disorders Self-Report 
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 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
DSM-4  
Diagnostic and Statistical Manual of Mental Disorders, 4th 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 
EDC 
 
Electronic Data Capture 
EMA  
European Medicines Agency  
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 
GDPR  
General Data Protection Regulation 
GERD  
Gastroesophageal Reflux Disease 
GMP 
 
Good Manufacturing Practice 


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HCV 
 
Hepatitis C Virus 
HIV 
 
Human Immunodeficiency Virus 
HPA 
 
Hypothalamic-pituitary-adrenal 
HPMC  
Hydroxypropyl Methylcellulose  
IB 
 
Investigator’s Brochure 
ICD 
 
International Classification of Disease 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonisation 
ICD-10  
International Classification of Disease, 10th edition  
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 
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  
MINI  
Mini-International Neuropsychiatric Interview 
mg 
 
Milligram 
mITT   
Modified Intent-to-Treat  
 
 
mmHg  
Milligrams of Mercury 
MMRM 
Mixed Model Repeated Measure 
MPBC  
MAPS Public Benefit Corporation 
ms 
 
Millisecond 
PABP  
People Able to Become Pregnant 
PAC 
 
Premature atrial contraction 
PCL-5  
PTSD Checklist for DSM-5  
PTCA  
Percutaneous Transluminal Coronary Angioplasty 
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 
SCID-5-PD  
Structured Clinical Interview for DSM-5 Personality Disorders 
SCID-4-PD 
Structured Clinical Interview for DSM-4 Personality Disorders 
SCS 
 
Self-compassion Scale 
SDS 
 
Sheehan Disability Scale 
SE 
 
Subjective Effects 
SGOT  
Serum Glutamic Oxaloacetic Transaminase 
SME 
 
Small or Medium-sized Enterprise 
SNRI  
Serotonin-norepinephrine Reuptake Inhibitor 


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SPGT  
Serum Glutamic Pyruvic Transaminase 
SRNU  
Self-reported Nicotine Use 
SSRI 
 
Selective Serotonin Reuptake Inhibitor 
SUDS  
Subjective Unit of Distress Scale 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBI  
 
Traumatic Brain Injury 
TEAE  
Treatment Emergent Adverse Event 
TSH 
 
Thyroid-stimulating Hormone 
UFEC  
Utilization of Facility-based and Emergent Care 
US 
 
United States 
VAS 
 
Visual Analog Scale 
WBC  
White Blood Cell 
WHO  
World Health Organization 
 
  
 


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1.0 Introduction 
MAPS Europe B.V. is a small or medium-sized enterprise (SME) organization working as a 
clinical trial sponsor to obtain approval for the prescription use of 3,4-
methylenedioxymethamphetamine (MDMA) as an adjunct to psychotherapy in patients with 
posttraumatic stress disorder (PTSD). MAPS Europe B.V. is a wholly owned subsidiary of the 
Multidisciplinary Association for Psychedelic Studies (MAPS), a tax-exempt charity providing 
funding for the clinical development program. Controlled Phase 1 studies, nonclinical studies, 
and investigator-initiated studies formed the basis for the Clinical Development Program of 
MDMA.  
 
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 novel treatment package consists of 
up to three Experimental Sessions spaced a month apart of psychotherapy combined with a 
flexible dose of MDMA, along with non-drug preparatory and integrative psychotherapy. This 
study design is supported by data from an international series of Phase 2 pilot studies of MDMA-
assisted psychotherapy conducted by the sponsor that provide preliminary evidence that chronic 
PTSD, independent of cause, is treatable with two to three sessions of MDMA-assisted 
psychotherapy and associated non-drug preparatory and integrative psychotherapy sessions. The 
results from multiple independent studies in Phase 2 efficacy analyses demonstrate superiority of 
MDMA-assisted psychotherapy over psychotherapy with placebo or low dose MDMA. The 
acceptable risk-benefit safety ratio in early trials justifies further study.  
 
This open-label, lead-in Phase 2 study is intended to gather supportive data on the safety and 
effectiveness of manualized MDMA-assisted psychotherapy as a treatment for PTSD. The 
Primary Outcome measure, the change in Clinician Administered PTSD Scale for DSM-5 
(CAPS-5) from Baseline to V14, evaluates changes in PTSD symptom severity and is assessed by 
a centralized Independent Rater (IR) pool in this study and in planned Phase 3 clinical trials [1]. 
This will be the first study of MDMA-assisted psychotherapy in Europe using the CAPS-5 as a 
primary outcome measure to confirm assumptions made for statistical power calculations using 
the Clinician-Administered PTSD Scale for DSM-4 (CAPS-4) which support planned Phase 3 
clinical trials. This study will gather supportive data on the safety and effectiveness of 
manualized MDMA-assisted psychotherapy as a treatment for PTSD and provide clinical 
supervision to planned Phase 3 therapy teams. This study will also be the first multi-site study of 
MDMA-assisted psychotherapy for PTSD in Europe and will explore reproducibility of findings 
from FDA-regulated trials in a multi-site format to further confirm the Phase 3 study design. 
 
In this Phase 2 study, therapy teams without previous experience on a MAPS-sponsored MDMA-
assisted psychotherapy study will have the opportunity for training and clinical supervision from 
the sponsor prior to participating in Phase 3 studies. The sponsor conducts training programs to 
teach therapy team members about techniques and procedures for conducting MDMA-assisted 
therapy for PTSD based on the MDMA-assisted therapy Treatment Manual. These programs are 
designed to support and expand the knowledge and skills of therapy team members who will be 
working on MDMA research studies. 
 
 


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1.2 Background 
1.2.1 PTSD 
PTSD is a serious debilitating disorder associated with increased mortality and cardiometabolic 
morbidity. PTSD is a stress-related psychiatric condition that may occur following a traumatic 
event such as war, disaster, sexual abuse, violence, terrorism, and accidents. The four main 
symptom categories described in the Diagnostic and Statistical Manual of Mental Disorders, 5th 
edition (DSM-5), include arousal and reactivity, avoidance of triggers, negative thoughts and 
feelings, and intrusive thoughts and nightmares. PTSD negatively impacts a person’s daily life, 
resulting in fractured relationships, inability to maintain employment, diminished cognitive and 
psychosocial functioning, substance abuse, high-cost healthcare utilization, and increased 
depression and suicide risk. People who suffer from PTSD often relive the experience through 
nightmares and flashbacks, have poor sleep quality, and feel detached or estranged. Confronting 
overwhelming internal distress and frightening external environments can also lead to high levels 
of depersonalization and derealization, which led clinicians to identify a dissociative subtype of 
PTSD in the DSM-5. Adaptations in normal brain function have been observed in imaging studies 
of patients with PTSD that underlie alterations in emotional processing and regulation, cognition, 
and many aspects of behavior, though clinical symptoms and changes in brain activity are not 
homogenous across patients [2]. The dissociative subtype occurs in 12 to 30% of people with 
PTSD and is characterized by detachment and emotional numbing and visualized in the brain as 
overmodulation of affect mediated by midline prefrontal inhibition of limbic regions, while the 
non-dissociative subtype presents symptoms of hyperarousal and re-experiencing, an emotional 
under modulation mediated by the failure of prefrontal inhibition of the same limbic regions [3, 
4]. 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. 
 
In Europe, lifetime PTSD prevalence ranges from 0.56% to 6.67% in the general population. The 
Netherlands was shown to be amongst the countries with the highest lifetime prevalence of PTSD 
next to the United Kingdom (UK), France and Germany [5]. The lifetime PTSD prevalence in the 
general population in the Netherlands is 7.4% [6], in the UK adult population, the lifetime 
prevalence is between 1.9 and 8.8% [7]. Occupational exposure to dangerous and high-risk 
situations increases the risk for PTSD. This applies to military personnel and police officers. In 
Dutch veterans the risk of developing PTSD is increased in the first 2 years after deployment [8] 
and the need for medical care is also increased [9]. In the UK, the cost of PTSD to the National 
Health Service and society is substantial, with a recent study in Northern Ireland estimating 150 
million euro per year [10].  
 
Available PTSD treatments, including medications and therapy, effectively treat only a fraction of 
people who try them for adequate dose and duration. This indicates a need to develop treatments 
targeting durable remission of PTSD. The Food and Drug Administration (FDA) has approved 
only two pharmacotherapies for PTSD, both of which are selective serotonin reuptake inhibitors 
(SSRIs). Paroxetine and sertraline (Paxil and Zoloft) both demonstrated statistically significant 
superiority over placebo on the CAPS in 12-week confirmatory clinical trials with daily dosing, 
but some studies were less effective in treating combat-related PTSD and sertraline demonstrated 
gender differences with minimal efficacy in men [11-13]. 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 


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the U.S., as well as by the World Health Organization (WHO). Currently, there is evidence that 
the antidepressants paroxetine, venlafaxine, sertraline and fluoxetine can be effective in post-
traumatic stress disorder, but the magnitude of effect is, unfortunately, small to medium 
[14](Cohen’s d 0.13 – 0.43) and there is no evidence for augmenting trauma-focused 
psychotherapy (TFPT) with drugs, such as D-cycloserine, that have evidence for enhancing 
exposure therapy in other disorders [15]. An extensive list of medications, namely antipsychotics, 
anxiolytics, antidepressants, and sleep aids, are frequently prescribed off-label but are minimally 
effective in reducing PTSD symptoms. PTSD carries a high public burden, both economically 
and socially, by increased use of health and social services, lost wages, and disability payments 
[16, 17]. Given the chronicity of PTSD, low treatment compliance evidenced by high dropouts, 
and limited recovery with current medications contributing to serious outcomes, PTSD patients 
exhibit an unmet medical need.  
 
One treatment approach is to develop medications and/or psychotherapeutic treatments that may 
indirectly decrease or eliminate the neurochemical irregularities underlying 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 [18]. Other methods such as 
psychodynamic therapy and eye movement desensitization and reprocessing (EMDR) have also 
proven to be effective in reducing symptoms of PTSD for some people [19, 20], although many 
patients 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 for PTSD [21]. In the past decade, there has been a growing amount of 
research into medications and other methods that may augment psychotherapy for PTSD (see [22] 
for a review). For example, virtual reality-assisted exposure therapy [23] and D-cycloserine 
combined with psychotherapy are under investigation [24]. MDMA-assisted psychotherapy is 
another novel approach. 
 
1.2.2 MDMA 
MDMA is a ring-substituted phenylisopropylamine derivative invented by Merck pharmaceutical 
company in 1912 [25, 26]. Similar to SSRIs, MDMA binds to the monoamine transporters, with 
the greatest affinity for the serotonin transport (SERT). MDMA also enhances synaptic levels of 
serotonin, and to a lesser extent norepinephrine and dopamine, by vesicular carrier-mediated 
release and reuptake inhibition of these neurotransmitters [27-33]. MDMA increases levels of 
affiliative neurohormones oxytocin and vasopressin, which is associated with increased trust and 
attenuation of reactivity to threatening cues, and cortisol and prolactin. The indirect effects of 
MDMA on central and peripheral neurohormone release contribute to a novel mechanism that 
may help regulate the HPA axis, which would treat the core psychopathology of PTSD for a 
durable remission. 
 
Onset of MDMA effects occurs ~0.5 to 1 hour after oral administration, and peak effects occur 
1.25 to 2 hours after the initial dose. Effects of the initial dose last 3 to 6 hours, which is extended 
to 5 to 8 hours with a supplemental half-dose administered 1.5 to 2 hours post initial dose. Orally 
administered MDMA has 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 work 
through different mechanisms than anxiolytics and SSRIs. Furthermore, there is no evidence that 
limited doses of MDMA in controlled clinical settings creates a physical dependence or drug 
seeking behavior. Previous studies of polydrug users have found a small percentage of people 
exhibit problematic use of Ecstasy (material represented as containing MDMA) [34, 35]. Studies 
of regular or problematic Ecstasy users indicate that on average, regular use occurs no more often 


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than once a week [36]. Hence, MDMA is said to have moderate abuse potential in non-medical 
settings, and low abuse potential in clinical settings. See the Investigator’s Brochure (IB) for a 
more detailed explanation. 
 
1.2.3 MDMA-Assisted Psychotherapy for PTSD 
Many psychotherapies for PTSD involve the induction and extinction of abnormal autonomic 
responses through revisiting traumatic experiences in psychotherapy with an appropriate level of 
emotional engagement [20]. To be effective, exposure must be accompanied by a degree of 
emotional engagement or “fear activation” while avoiding dissociation or overwhelming emotion 
[37]. This has been referred to as working within the “optimal arousal zone” or “window of 
tolerance” [38-40]. 
 
The combined neurobiological effects of MDMA increase compassion for self and others, 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 decreases blood flow in the prefrontal cortex. In contrast, MDMA acutely 
decreases activity in the amygdala [41], and there is some indication that MDMA may increase 
activity in the prefrontal cortex (PFC) [42]. Another study showed increased functional 
connectivity between the amygdala and hippocampus, and decreased connectivity between the 
amygdala and PFC [43]. Brain imaging after MDMA indicates less reactivity to angry facial 
expressions and greater reward in happy faces [41], compatible with its reported reduction in fear 
or defensiveness, and counteracts the stimulation of the amygdala observed in animal models of 
conditioned fear, a state similar to PTSD [44-46]. The reduction in stress-induced activation of 
the amygdala may be supported and enhanced by interacting with the therapy team during and 
after the MDMA experience. The subjective effects of MDMA create a productive psychological 
state that enhances the therapeutic process. MDMA enhances perceived self-authenticity [47] and 
a naturalistic study suggests that it can increase self-compassion [48], effects that may support 
and contribute to the therapeutic process. MDMA is capable of inducing unique 
psychopharmacological effects, including decreased fear and increased wellbeing, sociability, 
interpersonal trust, acceptance of self and others, and ability to address these issues without 
extreme disorientation or ego loss due to alert state of consciousness. These factors taken together 
can provide the opportunity for a corrective emotional experience. 
 
A combined treatment of MDMA and psychotherapy may be especially useful for treating PTSD 
because MDMA can attenuate the fear response of a perceived threat to one’s emotional integrity 
and decrease defensiveness without blocking access to memories or preventing a deep and 
genuine experience of emotion [49-52]. 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 [53]. Participants are able to experience and express fear, anger, and grief 
with less likelihood of feeling overwhelmed by these emotions. In healthy controls, MDMA 
reduces reactivity to unpleasant memories [54]. MDMA seems to engender internal awareness 
that even painful feelings that arise are an important part of the therapeutic process. In addition, 
feelings of empathy, love, and deep appreciation often emerge, along with a clearer perspective of 
the trauma as a past event, a more accurate perspective about its significance, and a heightened 
awareness of the support and safety that exists in the present. As a result, MDMA-assisted 
psychotherapy may enable participants to restructure their intra-psychic realities and develop a 
wider behavioral and emotional repertoire with which to respond to anxiogenic stimuli.  
 
The therapeutic method is described in further detail in the Treatment Manual of MDMA-
Assisted Psychotherapy, which the sites and therapy teams will be trained on prior to the study. 


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1.2.4 Previous Clinical Experience with MDMA 
MDMA-assisted psychotherapy is a novel treatment package that combines psychotherapeutic 
techniques with the administration of MDMA as a pharmacological adjunct intended to enhance 
certain aspects of psychotherapy. Chemists Shulgin and Nichols were the first to report on the 
effects of MDMA in humans [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 [57-60]. In the 1970s, psychotherapists used 
MDMA-assisted psychotherapy to treat psychological disorders, including anxiety, even though 
the drug had not been studied controlled clinical trials [61]. Legal therapeutic use continued until 
its placement on the U.S. list of Schedule 1 substances in 1985 [50, 53, 62]. An estimated 
500,000 doses of MDMA were administered during psychotherapy and personal growth sessions 
in North America prior to its scheduling [50, 63]. A few uncontrolled human studies of MDMA 
assessing safety in a controlled setting occurred in the 1980s [64, 65]. 
 
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 [66, 67]. Starting in 
2000 in Spain, MAPS funded a Phase 2 investigator-initiated dose-response effect and safety pilot 
study in participants with PTSD that was terminated early due to political pressure. This study 
enrolled six participants, with four receiving a single session of MDMA-assisted psychotherapy 
without any safety concerns and with some PTSD symptom reduction [52]. These studies formed 
the basis of clinical experience with MDMA prior to studies subsequently conducted under a 
MAPS IND with FDA. 
 
MAPS initiated an international series of Phase 2 clinical trials to develop the medical use of 
MDMA-assisted psychotherapy for patients with chronic, at least moderate PTSD (CAPS-4 
score: 50+), with at least 6 months of symptoms. Participants were not excluded for having more 
than one traumatic event, or for having tried, not tolerated, or refused an SSRI or serotonin-
norepinephrine reuptake inhibitor (SNRI) prescribed for PTSD. Outcomes from six Phase 2 
studies with evaluable data have been promising and have generated a range of methodological 
information for the design of future studies. 
 
Results from two Phase 2 studies have been published: one study in the U.S. with a long-term 
follow-up (LTFU) conducted an average of 3.8 years after the final MDMA-assisted 
psychotherapy session (MP1) [51, 68] and one in Switzerland (MP2) [69, 70]. MP1 was followed 
by a small open-label extension study examining the treatment of relapse in three participants 
with a single MDMA-assisted psychotherapy treatment and a 12-month follow-up (MP1E2). 
Three additional studies have completed treatments (MP8, MP9, MP12) and two international 
studies were terminated early for logistical reasons with partial datasets (MP3, MP4). These 
studies tested a range of designs, such as a placebo control (MP1, MP4), low dose MDMA 
comparator control (MP2, MP9), and three-arm dose response studies (MP8, MP12). Findings 
from a dose-comparison study at the same site in military veterans, firefighters and police officers 
(MP8) have now been published and confirm findings reported in the initial studies [71]. 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 


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of 107 blinded participants with chronic PTSD was completed in 2016. In these studies, PTSD, 
independent of cause, appears treatable with a two- t three-session treatment package of MDMA-
assisted psychotherapy. As of 01 October 2021 with 358 individuals exposed to MDMA in the 
sponsor’s development program across various indications and at least 1799 participants in 
MDMA research studies conducted without sponsor support, the sponsor has observed an 
acceptable risk-benefit ratio for MDMA-assisted psychotherapy. Across Phase 2 studies initial 
doses of 75 mg-125 mg MDMA were statistically superior to 0 mg to 40 mg MDMA based on a 
t-test of difference in CAPS-4 severity scores from Baseline to 1 to 2 months after two to three 
blinded experimental sessions (p<0.001). The dropout rate across studies was 7.5% (8 of 107). 
Large placebo-subtracted effect sizes (Cohen’s d 0.9), initial indications of efficacy, and favorable 
safety outcomes support expanding the research initiative to encompass a larger sample of 
participants with PTSD in a Phase 3 program. 
 
A comprehensive review of MDMA research can be found in the IB supplied by the sponsor. 
This document should be reviewed prior to initiating the protocol. 
 
2.0 Protocol Objectives 
The overall objective of this study is to use standard clinical measures to explore the safety and 
effects of open-label manualized MDMA-assisted psychotherapy with a flexible dose of MDMA 
in participants with severe PTSD, and to serve as an opportunity for supervision of therapy teams 
selected to conduct Phase 3 MDMA-assisted psychotherapy research.  
 
2.1 Primary Objective and Primary End Point  
The primary objective of this study is to evaluate the effect of MDMA-assisted psychotherapy on 
PTSD, as measured by the estimand of change in CAPS-5 Total Severity Score from Baseline 
(Visit 3) to 13 weeks post Baseline (Visit 14).  
 
The primary endpoint is the change in CAPS-5 Total Severity Score from Baseline (Visit 3) to 13 
weeks post Baseline (Visit 14). 
 
2.2 Secondary Objective and Secondary End Point 
The secondary objective is to evaluate the effect of MDMA-assisted psychotherapy for PTSD in 
clinician-rated functional impairment, as measured by the mean change in Sheehan Disability 
Scale (SDS) item scores from Visit 3 (Baseline) to 13 weeks post Baseline (Visit 14).  
The secondary endpoint is the mean change in Sheehan Disability Scale (SDS) item scores from 
baseline (Visit 3) to 13 weeks post Baseline (Visit 14). 
2.3 Safety Objectives 
The overall safety objective is to assess severity, incidence and frequency of AEs, AEs of Special 
Interest (AESIs), and Serious Adverse Events (SAEs), concomitant medication use, suicidal 
ideation and behavior, and vital signs to support the package insert for MDMA-assisted 
psychotherapy. The following safety objectives will evaluate the safety of MDMA-assisted 
psychotherapy. 
 
1. Assess incidence of AEs during Experimental Sessions that may be indicative of a 
medical complication of the Investigational Product (IP), such as clinical signs and 


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symptoms of chest pain, shortness of breath, or neurological symptoms or any other signs 
or symptoms that prompt additional vital sign measurements. 
2. Assess incidence of AEs by severity. 
3. Assess incidence of Treatment Emergent AEs (TEAEs) by severity. 
4. Assess incidence of TEAEs by severity taken during an Experimental Session and 
through 2 days after IP administration. 
5. Assess incidence of AESIs, defined as AEs specified in the protocol related to cardiac 
function and abuse liability. 
6. Assess incidence of AEs by severity categorized as leading to discontinuation of IP, 
resulting in death or hospitalization, and continuing at Study Termination. 
7. Assess incidence of SAEs. 
8. Assess incidence of psychiatric concomitant medications taken during an Experimental 
Session and through 2 days after IP administration. 
9. Assess incidence of any psychiatric concomitant medications taken during the Treatment 
Period. 
10. Assess incidence of serious suicidal ideation and positive suicidal behavior assessed with 
the Columbia Suicide Severity Rating Scale (C-SSRS). 
11. Assess mean changes in blood pressure, heart rate, and body temperature from pre-IP 
administration to end of each Experimental Session. 
 
2.4 Exploratory Objectives 
These objectives may be explored to characterize participants receiving MDMA-assisted 
psychotherapy to support the primary objective: 
 
1. Explore the effect of presence of secondary traumatic stressors (LEC-5) on the CAPS-5 
Total Severity analyses 
2. Explore changes within-participants in PTSD symptom clusters of re-experiencing, 
avoidance, negative alterations in cognition and mood, and hyperarousal, as measured by 
changes in CAPS-5 subscale scores from Visit 3 (Baseline) to Visit 14 (13 weeks post 
Baseline) 
3. Explore the effect of adverse childhood experiences (ACE) on the CAPS-5 Total 
Severity analyses 
4. Explore changes in:  
• 
Dissociative symptoms associated with PTSD (DSP-I) 
• 
Depression (BDI-II)  
• 
Chronic pain (CPGS) 
• 
Quality of life (EQ-5D-5L) 
• 
Self-compassion (SCS) 
• 
Addictive behaviors including: Alcohol use (AUDIT), Drug use (DUDIT) and 
Nicotine use (SRNU)  
• 
Eating habits (EAT-26) 
• 
Healthcare utilization (UFEC) and economic productivity 
• 
Subjective effects (SE)  
 
3.0 Eligibility Criteria 
At the completion of Screening, participants must meet all eligibility criteria (except Inclusion 
Criterion #13 listed below) and agree to all lifestyle modifications to be enrolled. Each participant 
will then enter the Preparatory Period which includes medication tapering, if needed, and non-
drug Preparatory Sessions. The Preparatory Period ends with Enrollment Confirmation. A 
participant’s enrollment will be confirmed once they have completed medication tapering, have a 


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confirmed PTSD diagnosis per the CAPS-5 assessment and a Total Severity Score of 35 or 
greater, continue to agree to all lifestyle modifications, and continue to meet all eligibility criteria.  
3.1 Inclusion Criteria 
Potential participants are eligible to enroll in the protocol if they: 
 
1. Are at least 18 years old. 
2. Are fluent in speaking and reading the predominantly used or recognized language of the 
study site. 
3. Are able to swallow pills. 
4. Agree to have study visits video-recorded, including Experimental Sessions, Independent 
Rater assessments, and non-drug psychotherapy sessions. 
5. Must provide a contact (relative, spouse, close friend or other support person) who is 
willing and able to be reached by the investigators in the event of a participant becoming 
suicidal or unreachable. 
6. Must agree to inform the investigators within 48 hours of any medical treatments and 
procedures. 
7. People able to become pregnant (PABP) (i.e., assigned female at birth, fertile, following 
menarche and until becoming post-menopausal unless permanently sterile), must have a 
highly sensitive negative pregnancy test at study entry and prior to each Experimental 
Session, and must agree to use adequate birth control through 10 days after the last 
Experimental Session. Adequate birth control methods include intrauterine device (IUD), 
injected or implanted hormonal methods, abstinence, oral hormones plus a barrier 
contraception, vasectomized sole partner (described in more detail in Section 10.3.2 
Contraception Guidelines).  
8. Agree to the following lifestyle modifications (described in more detail in Section 3.3 
Lifestyle Modifications): comply with requirements for fasting and refraining from 
certain medications prior to Experimental Sessions, not enroll in any other interventional 
clinical trials during the duration of the study, remain overnight at the study site after 
each Experimental Session and be driven home after, and commit to medication dosing, 
therapy, and study procedures. 
 
Medical History 
 
9. At Screening, meet DSM-5 criteria for current PTSD with a symptom duration of 6 
months or longer. 
10. At Screening, have at least severe PTSD symptoms in the last month based on PCL-5 
total score of 46 or greater. 
11. May have well-controlled hypertension that has been successfully treated with anti-
hypertensive medicines, if they pass additional screening to rule out underlying 
cardiovascular disease. 
12. May have asymptomatic Hepatitis C virus (HCV) that has previously undergone 
evaluation and treatment as needed. 
13. At Baseline, have a confirmed diagnosis of PTSD per CAPS-5 and at least severe 
symptoms in the last month constituting a CAPS-5 Total Severity Score of 35 or greater. 
14. May have alcohol or substance use disorder if participant is not in withdrawal or 
requiring detox. Participants must have a plan, agreed upon by investigator, therapy team, 
and Medical Monitor, to reduce use of alcohol or other substances and to manage 
symptoms without self-medicating. Enrollment will require that, in the judgment of the 
investigator, therapy team, and Medical Monitor, the plan for decreasing substance use is 
realistic and has a good chance of succeeding in order to prevent substance use from 
impacting the safety or efficacy of the investigational treatment. 


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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 currently engaged in compensation litigation whereby financial gain would be 
achieved from prolonged symptoms of PTSD or any other psychiatric disorders. 
3. Are likely, in the investigator’s opinion and via observation during the Preparatory 
Period, to be re-exposed to their index trauma or other significant trauma, lack social 
support, or lack a stable living situation. 
4. Have used Ecstasy (material represented as containing MDMA) more than 10 times 
within the last 10 years or at least once within 6 months of the first Experimental Session; 
or have previously participated in a MAPS-sponsored MDMA clinical trial. 
5. Have any current problem which, in the opinion of the investigator or Medical Monitor, 
might interfere with participation.  
6. Have hypersensitivity to any ingredient of the IMP (Investigational Medicinal Product).  
 
Psychiatric History 
 
7. Have received Electroconvulsive Therapy (ECT) within 12 weeks of enrollment. 
8. Have a history of, or a current primary psychotic disorder, bipolar affective disorder type 
1 assessed via MINI and clinical interview or dissociative identity disorder assessed via 
DDIS and clinical interview. 
9. Have a current eating disorder with active purging assessed via MINI and clinical 
interview. 
10. Have current major depressive disorder with psychotic features assessed via MINI. 
11. Have a current alcohol or substance use disorder other than caffeine or nicotine that the 
investigators, therapy team, and/or Medical Monitor judge to be a safety concern for 
enrollment in the study or that could interfere with the therapeutic process or with other 
aspects of study participation. Any participant who is not able to agree or adhere to a plan 
to reduce use and manage symptoms will not be enrolled. 
12. Have current Personality Disorders (paranoid, schizoid, schizotypal, antisocial, 
borderline, histrionic, narcissistic, avoidant, dependent, obsessive-compulsive) assessed 
via CIPD. Diagnoses will be confirmed via clinical interview. 
13. Any participant presenting current serious suicide risk, as determined through psychiatric 
interview, responses to C-SSRS, and clinical judgment of the investigator will be 
excluded; however, history of suicide attempts is not an exclusion. Any participant who 
is likely to require hospitalization related to suicidal ideation and behavior, in the 
judgment of the investigator, will not be enrolled. Any participant presenting with the 
following on the Baseline C-SSRS will be excluded: 
• 
Suicidal ideation score of 4 or greater within the last month of the assessment at a 
frequency of once a week or more. 
• 
Suicidal ideation score of 5 within the last 6 months of the assessment. 


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• 
Any suicidal behavior, including suicide attempts or preparatory acts, within the 
last 6 months of the assessment. Participants with non-suicidal self-injurious 
behavior may be included if approved by the Medical Monitor. 
14. Would present a serious risk to others as established through clinical interview and 
contact with treating psychiatrist. 
15. Require ongoing concomitant therapy with a psychiatric medication with exceptions 
described in Section 11.0: Concomitant Medications. 
 
Medical History 
 
16. Have a history of any medical condition that could make receiving a sympathomimetic 
drug harmful because of increases in blood pressure and heart rate. This includes, but is 
not limited to, a history of myocardial infarction, cerebrovascular accident, or aneurysm. 
Participants with other mild, stable chronic medical problems may be enrolled if the site 
physician, PI, and Medical Monitor agree the condition would not significantly increase 
the risk of MDMA administration or be likely to produce significant symptoms during 
the study that could interfere with study participation or be confused with side effects of 
the IMP. Examples of stable medical conditions that could be allowed include, but are not 
limited to Diabetes Mellitus (Type 2), Human Immunodeficiency Virus (HIV) infection, 
Gastroesophageal Reflux Disease (GERD), etc. Any medical disorder judged by the 
investigator to significantly increase the risk of MDMA administration by any 
mechanism would require exclusion.  
17. Have a diagnosis of uncontrolled hypertension, defined as repeated readings of ≥140 
millimeters of mercury [mmHg] systolic or ≥90 mmHg diastolic. The diagnosis may be 
confirmed by repeated clinic measurements or home blood pressure monitoring if 
clinically indicated per European Society of Cardiology (ESC) guidelines. 
18. Have a history of ventricular arrhythmia at any time, other than occasional premature 
ventricular contractions (PVCs) in the absence of ischemic heart disease. 
19. Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been 
successfully eliminated by ablation.  
20. Have a history of arrhythmia, other than premature atrial contractions (PACs) or 
occasional PVCs in the absence of ischemic heart disease, within 12 months of screening. 
Participants with a history of atrial fibrillation, atrial tachycardia, atrial flutter or 
paroxysmal supraventricular tachycardia or any other arrhythmia associated with a 
bypass tract may be enrolled only if they have been successfully treated with ablation and 
have not had recurrent arrhythmia for at least one year off all antiarrhythmic drugs, and 
confirmed by a cardiologist. 
21. Have a marked Baseline prolongation of QT/QTc interval (For purposes of eligibility, 
this is defined as repeated demonstration of a QT interval corrected using Fridericia’s 
formula [QTcF] >450 milliseconds [ms]). 
22. Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, 
hypokalemia, family history of Long QT Syndrome). 
23. Require use of concomitant medications that prolong the QT/QTc interval during 
Experimental Sessions. Refer to Section 11.0 Concomitant Medications. 
24. Have symptomatic liver disease or have significant liver enzyme elevation. 
25. Have history of hyponatremia (defined as outside of the normal range of 135 to 145 
mmol/L) or hyperthermia. 
26. Weigh less than 48 kilograms (kg). 
27. Are pregnant or nursing or are able to become pregnant and are not practicing an 
approved means of birth control. 
28. Have engaged in ketamine-assisted therapy or used ketamine within 12 weeks of 
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3.3 Lifestyle Modifications 
All participants must agree to the following lifestyle modifications at time of signing the 
informed consent form and throughout the study. Participants are eligible to enroll in the study if 
they: 
 
• 
Are willing to commit to medication and MDMA dosing, psychotherapy sessions, 
follow-up sessions, completing evaluation instruments, and all necessary telephone 
contact. 
• 
Agree to not participate in any other interventional clinical trials during the duration of 
this study, without prior approval of the Medical Monitor. 
• 
Agree to not begin a new form of mental healthcare during the screening or treatment 
phases of the trial, without first discussing with the PI in consultation with the Medical 
Monitor.  
o It is acceptable for participants to continue ongoing mental healthcare, if it is not 
increased in frequency or specifically excluded by the study protocol.  
o All ongoing therapies should be documented by the site and discussed with the 
Medical Monitor prior to enrollment to avoid confounding treatment effects. In 
some instances, the Medical Monitor may request that the participant delay 
enrollment until their planned course of therapy is complete and an integration 
period has elapsed. 
 
Leading up to Experimental Sessions 
 
• 
Agree to take nothing by mouth except alcohol-free liquids after 12:00 A.M. (midnight) 
the evening before each Experimental Session. 
• 
Refrain from the use of any psychoactive medication not approved by the research team 
from Baseline through Study Termination. 
• 
Agree not to use caffeine or nicotine for 2 hours before and at least 6 hours after the 
initial dose during each Experimental Session. 
• 
Are willing to comply with medication requirements per protocol (refer to Section 11.0 
Concomitant Medications). Medications will only be discontinued after enrollment per 
clinical judgment of the site physician in consultation with the prescribing physician. 
• 
Are able to decrease dose of allowable opiates (per Section 11.0 Concomitant 
Medications), if used for pain management, leading up to the Experimental Session in 
order to avoid taking the medication for at least 12 hours prior to the initial IP 
administration and 24 hours after. During this period, the participant will be allowed to 
take the medication if needed for intolerable pain flare-ups. 
• 
Agree that, for 1 week preceding each Experimental Session to refrain from: 
o Taking any herbal supplement (except with prior approval of the research team) 
o Taking any nonprescription medications (with the exception of non-steroidal 
anti-inflammatory medications or acetaminophen unless with prior approval of 
the research team). 
o Taking any prescription medications (with the exception of birth control pills, 
thyroid hormones, or other medications approved by the research team). 
 
Post Experimental Session 
 
• 
Are willing to remain overnight at the study site after each Experimental Session until 
after the Integrative Session the next morning. 


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• 
Are willing to be driven home on the morning after the Experimental Sessions after the 
Integrative Session, either by a driver arranged by the participant, site personnel or taxi. 
 
4.0 Protocol Design 
4.1 Study Design Overview 
This multi-site, open-label study assesses the safety and effectiveness of MDMA-assisted 
psychotherapy in participants diagnosed with at least severe PTSD. This study will also serve as 
an experiential training opportunity for therapy teams who will be participating in the upcoming 
Phase 3 study. The sponsor will provide clinical supervision through the adherence raters and the 
therapy pair supervisors, who will review the therapy session videos to ensure adherence to the 
therapeutic method, consistency between sites and therapy pairs, and provide support and advice 
to the therapy pair.. 
 
The study will be conducted in up to 40 participants in multiple countries in Europe. Some sites 
will participate in the imaging sub-study (see Appendix A for additional details). This study will 
be conducted in compliance with the protocol, GCP and applicable regulatory requirement(s). 
All data will be included in the sponsor’s safety database. 
 
For each participant, the study will consist of: 
  
• 
Screening Period: phone screen, informed consent, eligibility assessment, and enrollment 
of eligible participants  
• 
Preparatory Period with Enrollment Confirmation: medication tapering, Preparatory 
Sessions and Baseline assessments leading to Enrollment Confirmation 
• 
Treatment Period: two Experimental Sessions spaced a month apart and associated 
Integrative Sessions over ~8 weeks plus one CAPS-5 assessment 
• 
Follow-up Period and Study Termination: ~4 weeks with no study visits, followed by 
Primary Outcome CAPS-5 and Study Termination visit 
 
The treatment consists of a flexible dose of MDMA, followed by a supplemental half-dose unless 
tolerability issues emerge with the first dose or the participant declines, administered with 
manualized psychotherapy in two open-label Experimental Sessions spaced a month apart. This 
~8-week Treatment Period is preceded by three Preparatory Sessions. During the Treatment 
Period, each Experimental Session is followed by three Integrative Sessions of non-drug 
psychotherapy. Experimental Sessions are followed by an overnight stay. Study design overview 
is shown in Table 1 and Figure 1.  
 
Participants will have tele-assessment visits conducted by an Independent Rater (IR) from the IR 
Pool. All CAPS-5, SDS, MINI, DDIS, DSPI, and CIPD/SCID-PD assessments will be performed 
by an IR. All ratings will be video recorded. The Primary Outcome measure, the change in 
CAPS-5 from Baseline (V3), is assessed  at 13 weeks post Baseline (V14). The CAPS-5 is also 
administered as an exploratory measure after Treatment 1 (V8). The IR pool will be blinded to 
visit number and number of treatments received and will not have access to data collected by the 
sites during the active treatment period.  


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Figure 1: Study Structure Overview 
 


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 Study Design Overview 
 
Screening Period 
From Consent to Enrollment (Visit 0): ~4 weeks (+/-2 weeks) 
Study Visit 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Screening 
Screening  
Multiple visits over 3 
weeks (-2 weeks/+1 
week) 
 
7 to 28 days total 
At initial visit, obtain Informed Consent and assess 
all screening measures (including LEC-5, PCL-5, 
Lifetime C-SSRS, AUDIT, DUDIT), medical 
history, and pre-study medications. Contact outside 
providers and order medical records, physical exam, 
labs (including pregnancy and drug tests), ECG, and 
1-minute rhythm strip. Once all results and records 
are obtained, review along with notes from all 
screening visits and measures. If eligible, send 
results of LEC-5 & CIPD-SR to IR. Screening may 
take place over 3 weeks at multiple visits. 
Independent 
Rater Screening 
1 hour/ 
2 days after initial 
eligibility established in 
Screening 
(+7 days) 
 
2 to 9 days after initial 
eligibility established 
After PCL-5, and initial eligibility are reviewed, an 
IR will conduct the Since Last Visit C-SSRS, CIPD, 
DDIS, and MINI via tele-assessment. Results will be 
confirmed by clinical observation during the 
Preparatory Period, but the CIPD-SR, DDIS, and 
MINI will not be repeated. 
Enrollment 
Enrollment 
(Visit 0) 
1.5 hours/ 
2 days after (+12 days) 
Independent Rater 
Screening 
 
2 to 14 days after IR 
Screening 
Prior to enrolling: review all screening measures, 
medical history, discussion with outside providers 
and sponsor, and any clarification phone calls with 
participant. Visit is 1.5 hours to review eligibility 
and medical tapering plan. If enrolled, begin taper, 
(5 half-lives plus 1 week for stabilization). Adverse 
Event (AE) collection begins. 


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Preparatory Period with Enrollment Confirmation  
From Preparatory Session 1 (Visit 1) to Preparatory Session 3 (Visit 4): ~6 weeks (+5/-4 weeks) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Preparatory Period 
Preparatory 
Session 1 
(Visit 1) 
1.5 hours/ 
Within 1 week (-7/+5 
days) after Enrollment 
(V0) 
 
0 to 12 days after 
Enrollment (V0) 
 
90-minute Preparatory Session. Target visit timing 
on tapering needs. If needed, schedule calls between 
V1 and V2 if indicated for tapering, safety, or further 
questions about medical history. 
Preparatory 
Session 2 
(Visit 2) 
 
1.5 hours/ 
At least 2 days after 
Preparatory Session 1 
(V1); within 3 weeks of 
Preparatory Session 1 
(V1) 
 
2 to 21 days after 
Preparatory Session 1 
(V1) 
 
90-minute Preparatory Session/ongoing assessment. 
If tapering is complete or not needed, check 
eligibility and schedule V3 and V4. If tapering is 
ongoing, schedule post taper call for ongoing 
assessment. 
Phone Call 
End Taper 
 
1 hour/ 
Within 1 week of 
planned taper end & 
stabilization off 
medications; before 
Baseline CAPS T1 
(V3); within 8 weeks of 
V0 
 
0 to 56 days after 
Enrollment (V0); 
within 7 days of the end 
of tapering and 
stabilization; prior to 
baseline CAPS T1 (V3) 
If needed, confirm medication taper and stabilization 
is complete and participant is eligible for Baseline 
CAPS-5. Schedule V3 and V4. 
 
 
Baseline & Enrollment 
Confirmation  
Baseline 
CAPS-5 T1 
(Visit 3) 
1.5 hours/ 
Post Preparatory 
Session 2 (V2) & 
confirmation of 
Medication Taper and 
stabilization; before V4  
 
At least 7 days after 
Preparatory Session 2 
(V2) 
CAPS-5, SDS, and DSP-I completed by an IR via 
tele-assessment after taper is complete. CAPS-5 
scores sent ASAP to the therapy team/Principal 
Investigator. 


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Preparatory 
Session 3 
& Enrollment  
Confirmation 
(Visit 4) 
3 hours: (90 minutes of 
measures, 90-minute 
therapy) 
Within 6 days of 
Baseline CAPS T1 
(V3); within 4 days 
prior to Experimental 
Session 1 (V5) but not 
on the same day 
 
3 to 6 days after 
Baseline CAPS T1 
(V3); 1 to 4 days before 
Experimental Session 1 
(V5). Both Baseline 
CAPS T1 (V3) and 
Preparatory Session 3 
and Enrollment 
Confirmation (V4) 
must take place within 
7 days prior to 
Experimental Session 1 
(V5). 
Prior to visit, ensure CAPS-5 confirms PTSD 
diagnosis and Total Severity Score of ≥35 and 
confirm enrollment by reassessing specified 
eligibility criteria. Complete Baseline self-report 
measures. Complete 3-hour Preparatory Session 
(~90-minute measures, 90-minute therapy) and 
schedule V5. If enrollment is not confirmed do not 
perform visit, complete termination.  


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Treatment Period 
From Experimental Session 1 (Visit 5) to Integrative Session 2.3(Visit 13): 8 weeks (-3/+4) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Treatment 1 
Experimental 
Session 1 
(Visit 5) 
8 hours + overnight/ 
Within 1 week of 
Baseline CAPS-5 T1 
(V3) and Preparatory 
Session 3 and 
Enrollment 
Confirmation (V4) 
 
4 to 7 days after 
Baseline CAPS-5 T1 
(V3); 1 to 4 days after 
Preparatory Session 3 
and Enrollment 
Confirmation (V4). 
Experimental Session 1 
(V5) must occur within 
7 days of the Baseline 
CAPS-5 T1 (V3) and 
after Preparatory 
Session 3 and 
Enrollment 
Confirmation (V4) 
 
At least 14 days after 
Preparatory Session 2 
(V2); after Therapist 
Supervision Meeting 
 
First Experimental Session is within 1 week of the 
Baseline CAPS-5 (V3) and 2 weeks after 
Preparatory Session 2 (V2); it lasts 8 hours with 
overnight stay. Dose is 80 mg with supplemental 
half-dose of 40 mg unless tolerability issues emerge 
with the first dose or the participant declines. 
Negative pregnancy test and drug test must be 
confirmed prior to dosing. 
Integrative 
Session 1.1 
(Visit 6) 
1.5 hours/ 
Morning after 
Experimental Session 1 
(V5) 
 
1 day after 
Experimental Session 1 
(V5) 
V6 is a 90-minute Integrative Session the morning 
after V5. Followed by 4 phone check-ins over the 7 
days post V5.  
Integrative 
Session 1.2 
(Visit 7) 
1.5 hours/ 
At least 3 days after 
Experimental Session 1 
(V5); at least 2 days 
after Integrative 
Session 1.1 (V6); 
within 2 weeks after 
Experimental Session 1 
(V5) 
 
3 to 14 days after 
Experimental Session 1 
(V5); at least 2 days 
after Integrative 
Session 1.1 (V6) 
 
Approximately 2 weeks after V5, a 90-minute 
Integrative Session (V7) is completed. 


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CAPS-5 T2 
(Visit 8) 
1 hour/ 
3 weeks (-3/+9 days) 
after Experimental 
Session 1 (V5); after 
Integrative Session 1.2 
(V7) and before 
Integrative Session 1.3 
(V9) 
 
18 to 30 days after 
Experimental Session 1 
(V5); between 
Integrative Sessions 1.2 
and 1.3 (V7 & V9) but 
may be same day as 
either. 
 
Between V7 and V9, CAPS-5, SDS, and DSP-I 
assessment completed by an IR via tele-assessment. 
Integrative 
Session 1.3 
(Visit 9) 
1.5 hours/ 
3 to 5 weeks after 
Experimental Session 1 
(V5); at least 2 days 
after Integrative 
Session 1.2 (V7); may 
be the same day as 
CAPS-5 T2 (V8); 1 to 7 
days before 
Experimental Session 2 
(V10) 
 
20 to 34 days after 
Experimental Session 1 
(V5); at least 2 days 
after Integrative 
Session 1.2 (V7); 1 to 7 
days before 
Experimental Session 2 
(V10) 
90-minute Integrative Session post V8 and in 
preparation for V10. Can occur 1 to 7 days before 
V10. Measures include LEC-5, PCL-5, and Since 
Last Visit C-SSRS. 
 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Treatment 2 
Experimental 
Session 2 
(Visit 10) 
8 hours + overnight/ 
3 to 5 weeks after 
Experimental Session 1 
(V5); at least 2 weeks 
after Integrative 
Session 1.3 (V9)  
 
21 to 35 days after 
Experimental Session 1 
(V5) 
 
At least 14 days after 
Integrative Session 1.2 
(V7); after Therapist 
Supervision Meeting 
3 to 5 weeks after V5, and 2 weeks after Integrative 
Session 1.1 (V6). The second Experimental Session 
lasts 8 hours with an overnight stay. Dose is 80 or 
120 mg plus supplemental half-dose (80 mg + 
supplemental 40 mg -OR- 120 mg + supplemental 
60 mg) unless tolerability issues emerge with the 
first dose or the participant declines. Negative 
pregnancy test and drug test must be confirmed prior 
to dosing. 


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Integrative 
Session 2.1 
(Visit 11) 
1.5 hours/ 
Morning after 
Experimental Session 2 
(V10) 
 
1 day after 
Experimental Session 2 
(V10) 
V11 is a 90-minute Integrative Session the morning 
after V10. Followed by 4 phone check-ins over 7 
days post V10.  
Integrative 
Session 2.2 
(Visit 12) 
1.5 hours/ 
At least 3 days after 
Experimental Session 2 
(V10); at least 2 days 
after Integrative 
Session 2.1 (V11); 
within 2 weeks after 
Experimental Session 2 
(V10) 
 
3 to 14 days after 
Experimental session 2 
(V10); at least 2 days 
after Integrative 
Session 2.1 (V11) 
Approximately 2 weeks after V10, a 90-minute 
Integrative Session (V12) is completed. 
Integrative 
Session 2.3 
(Visit 13) 
1.5 hours/ 
3 to 5 weeks after 
Experimental Session 2 
(V10) 
 
20 to 34 days after 
Experimental Session 2 
(V10); at least 2 days 
after Integrative 
Session 2.2 (V12) 
90-minute Integrative Session post V12. Measures 
include LEC-5, PCL-5 and Since Last Visit C-SSRS. 
Follow-up Period and Study Termination 
From Integrative Session 2.3 (Visit 13) until Study Termination (Visit 15): 4 weeks (+/-2). 
After Integrative Session 2.3 (Visit 13), ~4 weeks with no scheduled study visits until the Primary 
Outcome is completed. 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Primary Outcome 
Primary 
Outcome 
CAPS-5 T3 
(Visit 14) 
1 hour/ 
~13 (+/-3) weeks after 
Baseline CAPS-5 T1 
(V3) & 
8 weeks (+/-2) after 
Experimental Session 2 
(V10)  
 
67 to 112 days post 
Baseline CAPS-5 T1 
(V3); 42 to 70 days 
after Experimental 
Session 2 (V10) 
Primary Outcome CAPS-5, SDS, and DSP-I 
assessment completed by an IR via tele-assessment. 
Although there are allowable windows for all visits 
throughout the protocol, this visit must be completed 
within the overall window. Other visits should be 
scheduled to ensure the timing of the Primary 
Outcome CAPS-5 T3 assessment is appropriate. 


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Study Termination 
Study 
Termination 
(Visit 15) 
2 hours  
~13 (-3/+4) weeks after 
Baseline CAPS-5 T1 
(V3) & 
2 days (-1/+7 days) 
after Primary Outcome 
CAPS-5 T3 (V14) 
 
68 to 121 days after 
Baseline CAPS-5 T1 
(V3); 1 to 9 days after 
Primary Outcome 
CAPS-5 T3 (V14) 
Complete self-reported and safety measures; create 
an exit plan for participant.  
 
Qualified IRs selected based on availability from the IR Pool will perform the CAPS-5 
assessments as described Table 2.  
 
 Primary Outcome (CAPS-5) Data Collection by Visit 
 
CAPS 
Administration 
Visit 
Description/Timing 
Target 
Timing 
Post 
Baseline 
(V3) 
Baseline 
CAPS-5 T1 
V3 
Baseline; between V2 and confirmation of end of tapering and 
stabilization of medications 
0 days 
CAPS-5 T2 
V8 
Post Experimental Session 1 (3 weeks -3/+9 days); between 
Integrative Sessions 1.2 and 1.3 (V7 & V9) 
~6 weeks 
Primary Outcome 
CAPS-5 T3 
V14 
Post Experimental Session 2 (8 weeks +/-2) after Experimental 
Session 2 (V10); after Integrative Session 2.3 (V13) (4 weeks 
+/-2).  
~13 weeks 
 
4.2 Planned Duration of Study 
Full screening may take 2 to 6 weeks after completion of phone screening, where performed. The 
Preparatory Period begins at enrollment and can be as brief as 2 weeks. Depending on medication 
tapering could be as long as 11 weeks to ensure an appropriate medication washout of at least five 
half-lives of pre-study psychiatric medications and active metabolites, and at least one additional 
week for stabilization. 
 
Enrollment Confirmation takes place at the completion of the Preparatory Period, at which time 
the Treatment period will commence. The approximate 8-week Treatment Period will consist of 
two Experimental Sessions 3 to 5 weeks apart with associated non-drug Integrative Sessions and 
CAPS-5 assessment.  
 
After the final Integrative Session 2.3 (Visit 13), participants will enter follow-up with no study 
visits for approximately 4 weeks, after which the Primary Outcome CAPS-5 T3 assessment will 
take place (Visit 14). Although there are allowable windows for all visits throughout the protocol, 
the overall timelines should comply with the target timing of the Primary Outcome CAPS-5 T3 
assessment, which must be completed 13 weeks (+/-3 weeks) post Baseline, even if the maximum 
possible visit windows were used between visits. Other visits should be scheduled to ensure the 
timing of the Primary Outcome CAPS-5 T3 assessment is appropriate. The Study Termination 
visit follows 1 to 9 days after the final CAPS-5 assessment. 
 


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The minimum time that a participant who completes all study visits from Screening to Study 
Termination will be in the clinical trial is 14 weeks and the maximum is 27 weeks. The average 
participant is expected to complete the study in 17 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.  
 
4.3 Discontinuation and Completion Criteria 
4.3.1 Complete or Evaluable Participants 
A participant is considered ‘Evaluable’ and eligible for the mITT analysis if they have completed 
at least one Experimental Session and one CAPS-5 assessment beyond Baseline.  
 
A participant is considered ‘Evaluable and Completed Per Protocol’ if they have completed all 
Experimental Sessions and CAPS-5 assessments as planned. These participants will be included 
in the mITT analysis set and the Per Protocol analysis set. 
 
A participant is considered ‘Evaluable and Early Termination’ if they have completed at least one 
Experimental Session and one CAPS-5 assessment beyond Baseline but terminated early. These 
participants will be included in the mITT analysis.  
 
A participant is considered to be in good standing with the clinical site if, in the opinion of the 
investigator and/or therapy team, the participant was compliant with protocol requirements, even 
if they were unable to complete all study visits. 
 
4.3.2 Screen Failures 
‘Screen Failures’ are defined as participants who pass phone screening but are deemed ineligible 
before successfully enrolling in the study at Visit 0. Screen failures may fail to meet all Inclusion 
Criteria and may meet one or more Exclusion Criteria or withdraw consent prior to Enrollment. 
All potential participants who begin Screening will be tracked on a Screening Log, and reasons 
for Screen Failure will be recorded. Screen Failures are not considered evaluable.  
 
Screen Failures may be identified through review of medical history, assessments, measures, 
laboratory results, or conversations with the participant. Medical assessments may be repeated for 
confirmation. At any time during Screening, if a potential participant is deemed to be ineligible, 
classify as a Screen Failure, notify the potential participant that they are not eligible for the study, 
and do not schedule additional Screening assessments.  
 
Participants who fail Screening may be rescreened at a later date if deemed appropriate by the 
investigator but should sign a new copy of the Informed Consent Form (ICF). Screen Failures 
may request a referral to an outside therapist if needed. Screen Failures that were scheduled for an 
IR assessment will be entered into the Electronic Data Capture (EDC) system. 
 
4.3.3 Pre-Dosing Early Terminations 
‘Pre-Dosing Early Terminations’ are defined as participants who were deemed eligible and 
enrolled in the study at Visit 0, but are deemed ineligible prior to the first Experimental Session 
and do not have enrollment confirmed at Visit 4. These participants may fail to meet all Inclusion 
Criteria and may meet one or more Exclusion Criteria or withdraw consent prior to Enrollment 
Confirmation or the site may withdraw the participant for reasons described in Section 5.3.4 Early 
Termination from the Study). Participants who fail Enrollment Confirmation may not be re-


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enrolled into this study at a later date. All enrolled participants, even those failing Enrollment 
Confirmation, will be maintained in the EDC system. Pre-Dosing Early Terminations are not 
considered evaluable. 
 
Pre-Dosing Early Terminations may be identified through review of medical history, assessments, 
measures, laboratory results, or conversations with the participant. At any time during the 
Preparatory Period, if a potential participant is deemed to be ineligible, classify as a Pre-Dosing 
Early Termination, notify the potential participant that they are not eligible for the study, and do 
not schedule additional assessments. Do not perform the next visit. Pre-Dosing Early 
Terminations will be provided an Exit Plan as described in Section 7.4.4 Exit Plan.  
 
4.3.4 Early Termination from the Study 
Participants who are removed from the study after they are enrolled and receive IP but do not 
complete the study may fall into one of these categories: Post-Dosing Early Termination or 
Dropout. If the participant has received IP in at least one Experimental Session and completed 
one CAPS-5 assessment beyond Baseline, they will be considered evaluable. All participants who 
receive IP in at least one Experimental Session will be included in all safety analyses.  
 
Participants can withdraw from treatment or withdraw consent at any time for any reason without 
judgment. The site team can withdraw a participant if, in their clinical judgment, it is in the best 
interest of the participant or if the participant cannot comply with elements of the protocol that 
are critical for safety or for the scientific integrity of the study. If the site team makes the decision 
to terminate the participant from treatment or the study, they will explain the reason for 
withdrawal and document in the participant’s source records and eCRF. If a participant develops 
any Exclusion Criteria that, in the opinion of the Medical Monitor or Site, affects the safety of the 
participant, including psychiatric diagnosis, pregnancy, or requiring use of prohibited 
medications, the participant will discontinue treatment in Experimental Sessions but remain in the 
study for the associated Integrative Sessions. Any time a participant terminates from the study 
early, the site team will attempt to obtain information about AE outcomes if appropriate, as 
determined by the site physician and Medical Monitor. The site team will provide the participant 
with an Exit Plan as described in Section 7.4.4 Exit Plan. 
 
• 
Post-Dosing Early Termination: Participants who discontinue study treatment but 
continue to participate in study evaluations and outcome assessments. Data collection by 
Irs will continue on the same schedule as planned through Study Termination visit 
procedures. 
 
• 
Dropout: If a participant decides to withdraw consent, they will terminate without further 
follow-up. If the participant agrees, they will complete a final CAPS-5 assessment at that 
time and complete Study Termination visit procedures. These participants are defined as 
dropouts who withdraw consent due to any reason after receiving at least one dose of IP 
and no longer participate in the study, i.e. no further contact with investigators or site 
staff. Data collected on study participants up to the time of withdrawal of consent will 
remain in the trial database in order to maintain scientific validity. Removal of data from 
the database would undermine the scientific and ethical integrity of the research. 
 
 
• 
Participants who dropped out or are lost to follow up may be replaced depending on 
timing of the discontinuation and whether sufficient video was gathered to provide 
clinical supervision.  
 


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4.3.5 Lost to Follow-up 
A participant will be considered lost to follow-up if they fail to attend scheduled visits and are 
unable to be contacted by the site staff. If the participant has completed at least one Experimental 
Session and one CAPS-5 assessment beyond Baseline, they will be considered evaluable. All 
participants with at least one Experimental Session will be included in the safety analysis. 
 
If a participant does not attend a scheduled visit, the site must attempt to contact the participant to 
reschedule the visit as soon as possible and emphasize the importance of complying with the 
protocol specified visit schedule. The staff should determine if the participant is willing to 
comply with future visits. 
 
If a participant does not respond to this initial contact, the site staff must make an effort to contact 
the study participant and document each attempt in the source record. At least three attempts 
should be made via telephone, over the course of approximately 1 week, with calls at different 
times of day. If telephone contact fails, an email should be sent if such contact information was 
provided. In addition, site shall reach out to the contact person (relative, spouse, close friend or 
other support person) provided by the participant. Lastly, a certified letter (or equivalent) should 
be sent to their last known mailing address. If the participant fails to respond to all of these 
contacts, they will be considered to have withdrawn from the study and are lost to follow-up. 
 
4.4 End of Study Definition and Premature Discontinuation 
The end of the trial is defined as the date of the last patient last visit (LPLV) for the last 
participant globally. LPLV for this study is scheduled at Visit 15 (study termination) as shown in 
Table 7: Time and Events – Study Measures. 
 
The sponsor has the right to discontinue this study at any time. If the trial is prematurely 
terminated, the investigator is to promptly inform participants and will ensure they receive 
appropriate therapy, follow-up, and Exit Plan. If the study is prematurely discontinued, all 
procedures and requirements pertaining to retention and storage of documents will be observed. 
All other study materials will be returned to the sponsor and will be treated in accordance with 
country regulations. 
 
In addition, the study may be halted or terminated early if the extent (incidence and/or severity) 
of emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population is 
unacceptable. 
 
4.5 Rationale of Dose Selection 
Similar MDMA doses to those proposed in this study have been safely used in previous Phase 2 
studies sponsored by MAPS. Phase 2 studies indicate that 75, 100 and 125 mg MDMA initial 
doses with the supplemental dose are active and effective in two to three Experimental Sessions. 
MDMA doses with an optimal risk-benefit ratio range from 75 mg (Cohen’s d Independent 
Groups Pre-test Post-test [dIGPP]=2.73, N=7) to 125 mg (Cohen’s dIGPP=0.77, N=58) initial dose of 
MDMA with a 2-session treatment package. In Phase 2 studies, the sponsor observed a -36.4 
point mean change in CAPS-4 scores among active dose (75 to 125 mg) participants receiving 
two Experimental Sessions (N=72). Larger doses have been safely administered in MP2 (150 mg 
and 75 mg supplemental) and in Phase 1 studies (150 mg and 160 mg). The results of these Phase 
2 studies led to the selection of 80 mg and 120 mg MDMA as the initial active doses. 
 


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This open-label study will examine the effects of a flexible divided-dose of 80 mg to 180 mg 
MDMA administered in two Experimental Sessions. Initial doses per Experimental Session range 
from 80 mg to 120 mg MDMA, followed 1.5 to 2 hours later by a supplemental half-dose (40 mg 
or 60 mg). The initial active doses of 80 mg and 120 mg are expected to produce all commonly 
reported effects of MDMA. The supplemental half-dose will prolong subjective effects of 
MDMA without producing physiological effects much greater than peak effects occurring after 
the initial dose and will be administered unless there is a reason to withhold. Total amounts of 
MDMA to be administered per Experimental Session range from 80 mg to 180 mg (Table 3).  
 
 Dose Regimen of MDMA 
* Unless tolerability issues emerge with the initial dose or the participant declines 
 
In the first Experimental Session, the initial dose will be 80 mg MDMA. In the second 
Experimental Session, the initial dose may be increased to 120 mg MDMA unless tolerability 
issues emerge with the initial dose or the participant declines. The choice of whether to keep the 
dose the same or increase 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. If a participant experiences a severe adverse event, soon after administration of 
MDMA during an experimental session, or they experience clinical signs and symptoms that may 
suggest end organ effects, the dose may not be escalated, or a supplemental dose may not be 
administered. Examples of these symptoms include chest pain, shortness of breath, neurological 
deficit or confusion, or other potential indicators of end organ effects that will prompt additional 
vital sign measurements, and intervention if appropriate. Please refer to the section 9.2 for 
additional details. In each Experimental Session, 1.5 to 2 hours after the initial dose is given, the 
participant will be administered a supplemental half-dose unless tolerability issues emerge or the 
participant declines. Examples of tolerability issues include: if a patient experiences a severe 
adverse event after administration of MDMA during an experimental session, or they experience 
clinical signs and symptoms that may suggest end organ effects as specified in the protocol, the 
dose may not be escalated or a supplemental dose may not be administered. Examples of these 
symptoms include chest pain, shortness of breath, neurological deficit or confusion, or other 
potential indicators of end organ effects that will prompt additional vital sign measurements, and 
intervention if appropriate. 
 
5.0 Psychotherapy 
5.1 Description of Therapeutic Method 
The largely non-directive therapeutic method of MDMA-assisted psychotherapy is described in 
detail in the Treatment Manual. All therapy teams will be extensively trained in a 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. 
 
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 
Total Cumulative Dose 
160 mg to 300 mg 


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5.2 Therapy Team Qualifications 
Therapy teams will be trained by the sponsor. Sites must ensure that the minimum requirements 
below are met: 
• 
One person licensed to manage and administer controlled substances for each site  
• 
A physician to assess participant safety at Screening 
• 
One or more male/female therapy teams 
• 
One person per therapy team is required to be licensed to provide psychotherapy 
according to national requirements 
• 
If one person on the therapy team is unlicensed, they must work under the direct 
supervision of the licensed team member 
 
5.3 Training 
5.3.1 Therapy Training Program 
The MDMA Therapy Training Program is designed to teach competency in applying 
the essential elements of this method of MDMA-assisted psychotherapy. Therapy 
team members will receive specific training in the MDMA-assisted psychotherapy 
method, protocol, and latest version of the IB.  
 
Training in the psychotherapy method consists of reading the Treatment Manual, 
completing online training modules, and participating in an in-person training that 
includes watching and discussing videos of Experimental Sessions recorded in 
previous clinical trials. The required elements of the therapy are defined in the Treatment 
Manual, and teams will be trained on visit-specific sets of adherence criteria. The final part of 
training includes supervision provided by the sponsor at three dedicated time points during 
treatment of each therapy team member’s first subject, and additionally as needed in subsequent 
cases. 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 
Psychotherapy sessions, including Experimental Sessions, will be videorecorded. Adherence 
rating and commentary will be conducted by qualified, trained, and reliable adherence raters who 
will analyze video data from select Preparatory Sessions, Experimental Sessions, and Integrative 
Sessions. The elements included in adherence criteria are specific to each type of session and are 
defined in the Treatment Manual. These ratings will be collected, at minimum, for each therapy 
team in the study. Ratings will be used to provide feedback to therapy teams through each team’s 
supervisors. 
 
6.0 Measures and Reliability 
The following eligibility, outcome, exploratory, and safety measures will be used in the study, in 
accordance with Protocol Objectives and Assessment Tools (Table 4) and Time and Events Study 
Measures (Table 7).  
 


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 Protocol Objectives and Assessment Tools 
Objectives 
Measure 
Measure 
Type 
Administration 
Eligibility 
Assess Axis 1 psychiatric disorders 
MINI 
Eligibility 
Tele-assessment (IR)/  
Assess personality disorders 
CIPD 
Eligibility 
Tele-assessment (IR) and 
Self-report measure at Site 
Confirm PTSD diagnosis and severity 
PCL-5 with 
LEC-5 
Eligibility 
Site 
Identify Dissociative Identity Disorder  
DDIS 
Eligibility 
Site 
Primary 
Assess changes in PTSD symptom 
severity from Visit 3 to Visit 14  
CAPS-5 
Outcome 
Tele-assessment (IR) 
Secondary 
 
 
 
 
Assess changes in clinician-rated 
functional impairment from Visit 3 to 
Visit 14  
SDS 
Outcome 
Tele-assessment (IR) 
Safety 
Assess incidence of positive or serious 
ideation and suicidal behavior  
C-SSRS 
Safety 
Tele-assessment (IR 
screening) and Site 
Exploratory 
Characterization of CAPS-5 Total 
Severity score at weeks 3, 8, and 14 to 
explore onset of treatment efficacy with 
a descriptive time course plot 
CAPS-5 
Outcome 
Tele-assessment  
Explore changes in PTSD symptom 
clusters of re-experiencing, avoidance, 
negative alterations in cognition and 
mood, sleep and hyperarousal as 
measured by changes in CAPS-5 
subscale scores 
CAPS-5 
subscale 
scores 
Outcome 
Tele-assessment  
Assess overall changes in clinician-rated 
functional impairment through item 
scores from Visit 3 to Visit 14  
SDS 
item scores 
Outcome 
Tele-assessment 
Assess changes in severity of 
dissociative symptoms associated with 
PTSD from Visit 3 to Visit 14  
DSP-I 
Outcome 
Tele-assessment 
Explore correlation of dissociative 
symptoms associated with PTSD with 
the CAPS-5 Total Severity analyses 
DSP-I 
CAPS-5 
Outcome 
Tele-assessment  
Explore the effect of presence of 
secondary traumatic stressors during the 
assessment period as a covariate on the 
CAPS-5 Total Severity analyses  
LEC-5 
CAPS-5 
Outcome 
Site and Tele-assessment 
Explore the effect of adverse childhood 
experiences on PTSD treatment 
outcomes as a covariate on the CAPS-5 
Total Severity analyses 
ACE 
CAPS-5 
Outcome 
Site and Tele-assessment 
Explore changes in PTSD symptom 
clusters of re-experiencing, avoidance, 
negative alterations in cognition and 
mood, and hyperarousal as measured by 
changes in CAPS-5 subscale scores 
CAPS-5 
Outcome 
Tele-assessment  


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Objectives 
Measure 
Measure 
Type 
Administration 
Assess changes in depression symptoms 
from Visit 4 to Visit 15  
BDI-II 
Outcome 
Site 
Assess changes in chronic pain from 
Visit 4 to Visit 15  
CPGS 
Outcome 
Site 
Assess changes in quality of life from 
Visit 4 to Visit 15  
EQ-5D-5L 
Outcome  
Site 
Assess changes in self-compassion from 
Visit 4 to Visit 15  
SCS 
Outcome 
Site 
Assess changes in subjective effects 
from prior to drug intake, peak and at the 
end of the experimental session 
SE 
Subjective 
effects 
Self-report measure at Site 
Assess changes in alcohol use from 
Screening to Visit 15  
AUDIT 
Healthcare 
cost 
Site 
Assess changes in drug use from 
Screening to Visit 15  
DUDIT 
Healthcare 
cost 
Site 
Assess changes in nicotine use from 
Visit 4 to Visit 15  
SRNU 
Healthcare 
cost 
Site 
Assess changes in disordered eating 
from Visit 4 to Visit 15  
EAT-26 
Healthcare 
cost 
Site 
Assess facility-based healthcare 
utilization and economic productivity at 
Screening 
UFEC 
Healthcare 
cost 
Site 
 
6.1  
 
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)  
 
The last month CAPS-5 is a semi-structured interview that assesses index history of DSM-5-
defined traumatic event exposure [72], including the most distressing event, time since exposure, 
to produce a diagnostic score (presence vs. absence) and a PTSD Total Severity score [72]. The 
CAPS-5 rates intrusion symptoms (intrusive thoughts or memories), avoidance, cognitive and 
mood symptoms, arousal and reactivity symptoms, duration and degree of distress and 
dissociation. The CAPS-5 will be administered by a blinded IR via tele-assessment. Interviews 
will be conducted by the centralized remote IR pool to enhance quality control by reducing site-
level variation in interview fidelity and quality. The IRs will be trained and supervised by senior 
independent raters (SIRs)fluent in the local language. Per the CAPS-5 Training Manual for the IR 
Pool, IRs will ensure that every single item-level score is collected in every CAPS-5 interview. 
The CAPS-5 is administered by the IR in a neutral, non-leading manner to minimize the chance 
for bias. Avoiding a biased administration can be achieved by adhering to administration 
guidelines verbatim and only deviating from the script to clarify, re-direct, or query further if 
behavioral examples are needed to determine the appropriate symptom intensity rating. Avoiding 
building therapeutic/clinical rapport beyond the basic level of rapport needed to conduct the 
interview in the research setting also minimizes the chance for bias. Remote assessment assures 
that the rater who is collecting the Primary Outcome will not witness Experimental Sessions and 
the acute effects of IP. Interviews may be recorded in as many instances as necessary to establish 
reliability of a random selection of interviews for accuracy. After the initial screening visit, the Irs 
will be blinded to visit number, number of treatments received, and any study data for the 
participant. IR visits will be assigned based on availability. 


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6.2 Secondary Outcome Measure 
Sheehan Disability Scale (SDS) 
 
The SDS is a clinician-rated assessment of functional impairment [73]. The items indicate degree 
of impairment in the domains of work/school, social life, and home life, with response options 
based on an eleven-point scale (0=not at all to 10=extremely), and five verbal tags (not at all, 
mildly, moderately, markedly, extremely). For participants who are not able to work for reasons 
related to PTSD, the functional impairment item will be scored as a 10. The SDS takes 1 to 2 
minutes to complete [73, 74].  
 
6.3 Safety Measures 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS is a clinician-administered measure of suicidal behavior devised to detect potential 
suicidal thoughts or behaviors during a clinical trial [75]. It consists of a Lifetime version and a 
Since Last Visit version that assess suicidal ideation, ideation intensity, and behavior. The C-
SSRS consists of a series of questions, and can be administered during a face-to-face interview or 
over the telephone. The Lifetime version will only be administered at the initial Screening visit. 
All subsequent administrations will utilize the Since Last Visit version. Participants who are 
discontinuing medications to participate in the study will complete the C-SSRS before and after 
medication washout. The C-SSRS Intensity scale for Lifetime obtained a Cronbach’s alpha of 
0.93 and 0.94 for the Since Last Visit form, and Last Visit C-SSRS severity scores were 
positively correlated with the BDI “suicide thoughts” item [76]. 
 
6.4 Screening Measures and Reliability 
Mini-International Neuropsychiatric Interview (MINI) 
 
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 [77], is now compatible with DSM-5 and will be administered by a member of the 
Independent Rater Pool to screen for all psychiatric conditions other than personality disorders. 
Each module of the MINI consists of two or three questions where the answer is either “Yes” or 
“No,” and decision-tree logic is used to determine whether to ask additional questions [78]. The 
MINI takes between 1-1.5 hours 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 [78, 79] Testing 
on non-psychiatric samples did not create false positives [77].  
 
Clinical Interview for Personality Disorders (CIPD)  
 
A clinical interview for personality disorders (CIPD) will be conducted using either the Structured 
Clinical Interview for Personality Disorders DSM-5 (SCID-5-PD) or DSM-4 (SCID-4-PD) [80] or 
any other diagnostic measure approved by the sponsor and the responsible Ethics Committee and 
Competent Authority, as applicable per country.  
 
Prior to the CIPD participants will complete a brief self-report (SR) questionnaire SCID-5-PD or 
SCID-4-PD or any other SR measure as applicable per country as a self-screening tool for 
personality disorders. Potential personality disorders that satisfy diagnostic thresholds will be 


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further assessed via clinical interview by a blinded IR via tele-assessment. IRs will receive training 
on administering these measures from a trainer. Interviews may be recorded as necessary to 
establish reliability of a random selection of interviews for accuracy. 
 
Life Events Checklist for DSM-5 (LEC-5) 
 
The LEC-5 is a 17-item self-report instrument designed to determine the presence of traumatic 
life events in the assessment and diagnosis of PTSD. It is a companion measure to the PCL-5 and 
will be used to assess PTSD. The participant indicates whether each event listed has occurred 
during their lifetime, permitting the possibility of marking multiple events [81]. 
 
PTSD Checklist for DSM-5 (PCL-5) 
 
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 [82]. Participants 
indicate how much distress they have experienced due to symptoms such as “Repeated, disturbing 
memories, thoughts, or images of a stressful experience from the past,” “Trouble remembering 
important parts of a stressful experience from the past,” and “Feeling irritable or having angry 
outbursts” on a five-point Likert-type scale (1=Not at all to 5=Extremely). A total PCL-5 score of 
46 or greater at Screening will be required for initial enrollment. 
 
Dissociative Disorders Interview Schedule for DSM-5 (DDIS) 
 
Questions on the DDIS specifically addressing dissociative disorder symptoms (items 117 to 132) 
will be asked by an IR during Screening. These questions are part of an intensive interview that 
includes questions concerning somatic and psychiatric symptoms. The interview is intended to 
assess and potentially distinguish between dissociative disorders and other disorders and between 
Dissociative Identity Disorder (DID) and a dissociative disorder not otherwise specified [83]. 
Owing to overlap with items found between the DDIS and other screening measures, only 
questions specifically addressing DID will be assessed. 
 
6.5 Exploratory Measures 
The Dissociative Subtype of PTSD Interview (DSP-I) 
 
The DSP-I is a clinician-administered interview designed by an international team of PTSD 
researchers to detect and assess severity of the dissociative type of PTSD and recommended for 
use as an additional or complementary measure (“add-on”) to the CAPS-5 [84-87]. Assessments 
of military veterans and civilians support the existence of a dissociative subtype of PTSD that is 
associated with PTSD severity and derealization and depersonalization. The DSP-I takes 
approximately 5 to 15 minutes to complete. It consists of two parts, only Part 1 will be 
administered. Part 1 contains five items addressing depersonalization, four items addressing 
derealization, and a section that is administered if dissociative episodes are endorsed that assesses 
duration and perceived cause of episodes (seven items) and observer items (three items) 
addressing interviewee demeanor, including evidence of dissociation, such as forgetfulness or 
giving a statement that is bizarre within the context of the interview. If two or more items within 
this section are endorsed, this indicates the presence of other dissociative symptoms beyond 
depersonalization and derealization. The DSP-I was first developed in 2016 and revised in 2017. 
 


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Adverse Childhood Experience Questionnaire (ACE) 
 
The ACE is a 10-item checklist measure assessing number and types of adverse childhood 
experiences, including neglect and emotional, physical, and sexual abuse. Respondents are asked 
if an experience happened “often” and if so, to write “1”. The total score reflects the number of 
adverse childhood experiences. The measure was first used in the context of a study investigating 
the relationship between childhood adverse experiences and health outcomes in adulthood [88]. 
Number of frequent adverse childhood experiences is associated with adverse health outcomes in 
adulthood, including greater likelihood of heart disease, chronic pain, and poor work performance 
[89-92]. The scoring method has been used in archival research, finding an association between 
increased scores and health problems in several generations [91].  
 
In addition, developmental trauma events (DTE) during childhood and adolescence, including 
description and frequency of the events will be evaluated at screening and throughout the trial. 
 
Beck Depression Inventory II (BDI-II) 
 
The BDI-II is a revision of the BDI, a 21-item self-report measure [93, 94] that will serve as a 
measure of depression symptom severity [95]. 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 [95]. 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 [95, 96]. 
Higher scores indicate more severe depressive symptoms.  
 
Chronic Pain Grade Scale (CPGS) 
 
The CPGS is a seven-item measure of pain. Responses to six of the seven items are made on a 10-
point Likert scale, and a response on the other item is the number of days in the past 3 to 6 
months when pain prevented the respondent from carrying out everyday activities [97]. 
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 [98]. 
 
EuroQol Five Dimensions – Five Levels Questionnaire (EQ-5D-5L) 
 
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”) [99, 100]. In the second part of the EQ-5D-5L, current degree of health (“your 
health today”) is indicated by marking a 100 mm line, 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 (Visual 
Analogue Scale) is the location of the mark. The scale can permit comparison across groups on 
health profiles, and an index can be derived from matching the five-dimension scores and the 
VAS response with nation-specific datasets and calculator software or statistical software syntax 
designed for the measure. The EQ-5D-5L began as part of the EuroQoL measure, published in 


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1990 [101]. 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 [102]. The EQ-5D-5L takes about 3 minutes to complete. 
 
Self-Compassion Scale (SCS) 
 
The SCS is a 26-item self-report measure of self-compassion, or responding to one’s own failure, 
suffering or inadequacies with kindness and compassion and recognizing one’s own flaws and 
suffering as part of common human experience [103]. Respondents complete the SCS by 
indicating how typical they feel on each item on a five-point Likert scale (1=Almost never and 
5=Almost always). It is estimated to take between 4 to 8 minutes to complete. The scale has six 
sub-scales: Self-Kindness, Self-Judgment, Common Humanity, Isolation, Mindfulness, and Over-
Identified. The mean of subscale scores serves as a total score. Analysis of SCS response 
indicated that subscales are all related to a higher order factor of self-compassion, and the 
measure has high test-test reliability at a level of 0.93. Neff et al. reported an inverse relationship 
between SCS total scores and scores on measures of depression and anxiety. Self-compassion and 
global self-esteem are both related to positive mood and optimism, but self-compassion may be 
more strongly associated with stable mood and less associated with self-rumination and anger 
[104]. 
 
Alcohol Use Disorders Identification Test (AUDIT) 
 
The AUDIT is a ten-item self-report test. Respondents answer on a 5-point scale (0=Never or 
none, 4=Daily or greatest number) [105]. 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 [106]. 
 
Drug Use Disorders Identification Test (DUDIT) 
 
The DUDIT is an 11-item measure designed to assess presence of substance use disorders [107]. 
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% [107]. The 
English translation was developed from a Swedish-language original. Estimated time to complete 
is 2 to 4 minutes. 
 
Self-reported Nicotine Use (SRNU) 
 
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. 
 
Eating Attitudes Test (EAT-26) 
 
The EAT-26 is a 26-item self-report measure that assesses attitudes about eating and food and is 
used to assess presence of eating disorders. Responses are made on a six-point scale (1=Always 
to 6=Never), and gathers information on gender, age, height, and weight. The EAT-26 produces a 
total score and can be used to generate a “referral score.” The 27th item addresses the occurrence 


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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 [108].  
 
Utilization of Facility-based and Emergent Care (UFEC) and Economic Productivity  
 
The UFEC is a sponsor-developed measure assessing participant health events, including 
hospitalization and use of healthcare facilities, including in-patient hospitalization, rehabilitation 
facilities and other health care facilities for a set period prior to study entry.  
 
In addition, participants employment/disability status and income level will be collected in order 
to assess economic productivity.  
 
Subjective Effects (SE) 
Subjective effects on 15 items (negative mood, body perception changes, confusion, difficulty 
concentrating, compassion for self, compassion for others, euphoria, positive mood, intellectual 
efficiency, social, calmness, talkative, open to new experiences, meaningful experience, 
emotional distress) will be collected using the VAS at three time points: initial dose of MDMA, 
prior to supplemental dose of MDMA and at the end of the experimental session (see Table 8). 
VAS items are rated on a series of 100 mm long lines, marked from ‘not at all’ on the left to 
‘extremely’ on the right. The subjective effects chosen for the scales are based on literature 
reviews of subjective effects of MDMA among healthy volunteers in controlled studies [109, 
110].  
 
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 (Table 5 and 6) and Medical Monitor consulted if necessary. If 
there are delays of more than a week between visits or contact, the site should assess the need for 
additional telephone contact with the participant to ensure safety. 


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 Time and Events – Screening and Preparatory Study Procedures 
 
Screening Period 
(2 to 6 weeks) 
Preparatory Period w/ Enrollment Confirmation 
(2 to 11 weeks) 
Screening 
Enrollment 
Preparatory 
Baseline 
CAPS-5 T1 
Baseline & 
Enrollment 
Confirmation 
Visit 
Phone 
Screening 
Screening 
IR 
Screening 
V0 
V1 
V2 
V3 
V4 
Visit Description 
Phone 
Calls 
In-person 
Visits & 
Labs 
Tele-
assessment  
Enrollment 
Prep. 1 
Prep. 2 
Tele-
assessment  
Prep. 3 & 
Enrollment 
Confirmation 
Visit Timing 
Prior to 
Initial 
Screening 
Over 3 
weeks 
(-2 /+1 
weeks) 
2 days after 
initial 
eligibility 
met 
(+7 days) 
2 days post IR 
Screening 
(+12 days) 
Within 1 
week of 
V0 (0 to 
12 days) 
2 to 21 
days of 
V1  
Post V2 & 
Taper 
3 to 6 days after V3; 
1 to 4 days before 
V5 
Initial Phone Screen 
 PA 
 
 
 
 
 
 
 
Informed Consent 
Send Copy 
P 
 
 
 
 
 
 
Follow-up Phone Screen 
P 
 
 
 
 
 
 
 
Assess Eligibility 
P 
P 
 
P 
P 
P 
 
P 
Medical/Psychiatric History 
 P B 
P 
 
 
P 
P 
 
P 
Past/Current Medication & 
Adherence 
P 
P 
 
 
P 
P 
 
P 
Weight, Blood Pressure, 
Pulse, Temperature 
 
P 
 
 
 
 
 
 
Physical Exam  
 
P 
 
 
 
 
 
 
ECG C & Rhythm Strip 
 
P 
 
 
 
 
 
 
Clinical Lab Tests 
 
P 
 
 
 
 
 
 
Drug Test D 
 
P 
 
 
 
 
 
P 
Pregnancy Test E 
 
P 
 
 
 
 
 
P 
Digital Recording of Visit 
 
 
P 
 
P 
P 
P 
P 
Medication Taper 
 
 
 
P 
P 
P 
 
 
Study Enrollment  
 
 
 
P 
 
 
 
P Confirmed 
AE Assessment F 
 
 
 
P 
P 
P 
 
P 
90-min Preparatory Session 
 
 
 
 
P 
P 
 
P 
Phone Call Follow-up G 
 
 
 
 
 
P 
 
 
A In Germany phone screening is not permitted 
B At Screening, collect data on previous hospitalizations, healthcare utilization and economic productivity. Request participants to obtain medical/psychiatric records to 
bring to the next in-person screening visit. 
C ECG to be conducted at any time if clinically indicated. 
D In the UK, also includes testing for alcohol. 
E PABP Only. Urine or serum (UK: serum only).  
F Adverse Events (Aes) Assessment 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 
G If needed, call participant to confirm medication tapering and stabilization is complete prior to Visit 3 
 
 


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 Time and Events – Treatment and Follow-up Period 
 
Treatment Period 
~8 weeks (+/-3 weeks) 
Follow-up Period & Study 
Termination 
(~4 weeks) 
13 weeks (+/-3 weeks) post 
baseline 
 
Treatment 1 
Treatment 2 
Primary 
Outcome 
Study 
Termination 
Visit 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Visit Description 
Exp. 1 
Int. 1.1 
Int. 1.2 
CAPS-5 
T2: Tele- 
assessme
nt 
Int. 1.3 
Exp. 2 
Int. 2.1 
Int. 2.2 
Int. 2.3 
CAPS-5 T3 
Outcome:  
Tele-
assessment A 
Study  
Termination 
Visit Timing 
Within 1 
week of 
V3 
Mornin
g after 
V5 
3 to 14 
days 
after V5 
18 to 30 
days after 
V5 
20 to 34 
days after 
V5 
21 to 35 
days after 
V5 
Morning 
after V10 
3 to 14 
days after 
V10 
20 to 34 
days after 
V10 
13 weeks post 
V5 
(+/-3 weeks) 
2 days post 
V14 
(-1/+7 days) 
Concomitant 
medication review 
P 
P 
P 
 
P 
P 
P 
P 
P 
 
P 
Symptom-directed 
Physical Exam 
P 
 
 
 
 
P 
 
 
 
 
PB 
Drug Test C 
P 
 
 
 
 
P 
 
 
 
 
 
Pregnancy Test D 
P 
 
 
 
 
P 
 
 
P  
 
 
Digital Recording of 
Visit 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
 
AE Assessment E 
P 
P 
P 
 
P 
P 
P 
P 
P 
 
P 
Administer IP 
P 
 
 
 
 
P 
 
 
 
 
 
8-hour Exp. Session 
P 
 
 
 
 
P 
 
 
 
 
 
Blood Pressure, 
Pulse, Temperature F 
P 
 
 
 
 
P 
 
 
 
 
P  
Overnight Stay 
P 
 
 
 
 
P 
 
 
 
 
 
90-min Integrative 
Session 
 
P 
P 
 
P 
 
P 
P 
P 
 
 
Phone Call 
Follow-up G 
 
P 
 
 
 
 
P 
 
 
 
 
A All visits must be scheduled to ensure that the Primary Outcome CAPS-5 T3 assessment is within the overall window provided: 13 weeks (+/-3 weeks) post V5 
B  At Study Termination, includes weight. A symptom-directed physical exam to be conducted only if clinically indicated. 
C  In the UK, also includes testing for alcohol. Must be completed prior to IMP dosing. 
D  PABP only. At Visit 5 and Visit 10, a negative urine pregnancy test must be confirmed prior to IMP dosing. 
E Adverse Events (Aes) Assessment 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. 
F During Experimental Sessions, vitals are measured before Investigational Product administration, immediately before the supplemental dose is administered (or would 
be, if supplemental dose not given), approximately 8 hours after initial dose, and as needed. 
G 4 days of phone call follow-up: Day 2 and 7 after the Experimental Session, with two additional calls in between. 
 


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 Time and Events – Study Measures 
 
 
 
Screening 
Baseline & 
Enrollment 
Confirmation 
Treatment 1 
Treatment 2 
Follow-up & Study 
Termination 
Visit # 
Site A 
IR 
Screening 
IR 
V3 
V4 
V5 
V6&7 
IR 
V8 
V9 
V10 
V11&12 
V13 
IR 
V14 
V15 
Visit 
Description 
~Time to Complete 
Measure (minutes) 
Site Visit 
Tele-
assessment  
Tele-
assessment  
Site 
Visit 
Exp. 
Session 1 
Int. 
Sessions 
1.1 & 1.2 
CAPS-5 T2: 
Tele-
assessment  
Int. 
Session 
1.3 
Exp. 
Session 2 
Int. 
Sessions 
2.1 & 2.2 
Int. 
Session 
2.3 
CAPS-5 
T3: 
Outcome: 
Tele-
assessment  
Study 
Termi-
nation 
CAPS-5 
90 (Baseline) 
60 (all others) 
 
 
ü 
 
 
 
P 
 
 
 
 
P 
 
SDS 
2 
 
 
ü 
 
 
 
ü 
 
 
 
 
ü 
 
DSP-I 
15 
 
 
ü 
 
 
 
ü 
 
 
 
 
ü 
 
C-SSRS B 
10 
ü 
ü 
 
P 
PC 
P 
 
P 
PC 
P 
P 
 
P 
MINI 
90 
 
ü 
 
 
 
 
 
 
 
 
 
 
 
CIPD-SR 
20 
ü 
 
 
 
 
 
 
 
 
 
 
 
 
CIPD 
60 
 
ü 
 
 
 
 
 
 
 
 
 
 
 
LEC-5 
5 
ü 
 
 
ü 
 
 
 
P 
 
 
P 
 
P 
PCL-5 
8 
ü 
 
 
ü 
 
 
 
ü 
 
 
ü 
 
ü 
DDIS D 
 
5 
 
ü 
 
 
 
 
 
 
 
 
 
 
 
ACE 
4 
 
 
 
ü 
 
 
 
 
 
 
 
 
 
BDI-II 
10 (Baseline) 
5 (all others) 
 
 
 
ü 
 
 
 
 
 
 
 
 
P 
CPGS 
5 
 
 
 
ü 
 
 
 
 
 
 
 
 
P 
EQ-5D-5L 
3 
 
 
 
ü 
 
 
 
 
 
 
 
 
ü 
SCS 
6 
 
 
 
ü 
 
 
 
 
 
 
 
 
ü 
AUDIT 
3 
ü 
 
 
 
 
 
 
 
 
 
 
 
P 
DUDIT 
3 
ü 
 
 
 
 
 
 
 
 
 
 
 
P 
SRNU 
3 
 
 
 
ü 
 
 
 
 
 
 
 
 
P 
EAT-26 
6 
 
 
 
ü 
 
 
 
 
 
 
 
 
P 
UFEC 
3 
 
 
 
ü 
 
 
 
 
 
 
 
 
 
SE 
2 
 
 
 
 
ü 
 
 
 
ü 
 
 
 
 
~Total Time of Completing 
Measures (minutes) 
49 
165 
107 
50 
 
12 
10 
77 
23 
12 
10 
23 
77 
57 
 
A Ensure that LEC-5 and CIPD-SR results are sent to the Independent Rater  
B First C-SSRS is a Lifetime assessment, other assessments are Since Last Visit 
C Conducted pre- and post-IP administration, and at phone calls on Days 2 and 7 after Experimental Session 
D The relevant questions (117 to 132) from the DDIS will be asked by the Independent Rater during the IR Screening visit. The entire measure will 
never be administered. 


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7.1 Screening Period 
7.1.1 Screening 
Prospective participants will be pre-screened by telephone (except in Germany) according to an 
EC/HA-approved script to ascertain if they meet basic eligibility criteria. All individuals who are 
pre-screened should be assigned a Screening Number and recorded on the Screening Log. Data 
from potential participants who do not pass telephone screening will not be entered in the eCRF, 
but reason of ineligibility will be documented on the Screening Log. At any time during 
Screening, if a potential participant is deemed ineligible, they will be classified as a Screen 
Failure, notified that they are not eligible for the study, and not be scheduled for any additional 
Screening assessments. 
 
Site staff (preferably one of the therapists who would be treating this potential participant) will 
explain and obtain written informed consent using the EC/HA-approved informed consent form 
(ICF). If deemed eligible, the potential participant will receive a copy of the ICF for review and 
will be invited to the site for in-person discussion and screening. The ICF will always be 
thoroughly explained and signed during the in-person visit at site.  
Written consent must be obtained prior to performing any tests or evaluations for the study.  
 
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). 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 tele-
assessment, or over the telephone. All procedures must be completed but there can be some 
flexibility in timing and order of individual assessments within the Initial Eligibility and Medical 
Assessments categories below: 
 
• 
Initial Eligibility, including measures, in-person discussions, and review of medical 
records 
• 
Medical Assessments, including labs, electrocardiogram (ECG), and physical exam 
• 
The site staff will schedule the IR assessment and send IR the results of initial measures. 
 
The sponsor recommends the following order of assessments: 
 
Initial Eligibility 
 
Qualified site staff will: 
 
• 
Review medical and psychiatric history with the participant via interview and review of 
provided records. If no records were provided or those provided are not sufficient, 
request additional records. Collect data on previous hospitalizations, healthcare 
utilization and economic productivity.  
• 
Assess depersonalization (out of body experiences) and derealization (unreal 
experiences) history.  


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• 
Support the participant during completion of the LEC-5 with PCL-5 to confirm PTSD 
diagnosis and severity. Support is needed to ensure proper identification of the index 
trauma on the PCL-5. Symptom severity is assessed in relation to the index trauma.  
• 
Administer the Lifetime C-SSRS to assess history of suicidal behavior and ideation. 
• 
Review past and current medications and adherence to prescriptions. 
• 
Assess ability to become pregnant and discuss requirement for commitment to adequate 
birth control for the duration of the study. Collect sample for pregnancy test from PABP 
(serum in UK; serum or urine for all other countries). 
• 
Perform a urine drug test. 
• 
Perform alcohol test (UK only). 
• 
Direct participant to complete self-reported Screening measures: 
o CIPD-SR 
o AUDIT  
o DUDIT  
• 
Review results of all measures and discussions against eligibility criteria to assess initial 
eligibility. If deemed initially eligible, potential participant will be provided with 
instructions (and appointments, if applicable) for a physical exam, laboratory 
assessments, an electrocardiogram (ECG), and 1-minute rhythm strip. Some or all of 
these assessments may be at outside facilities, except in Germany where all assessments 
will be conducted within study site facilities. 
 
Medical Assessments 
 
The physical exam must be performed by a qualified physician and laboratory assessments must 
be completed at a designated laboratory. Medical assessments will include: 
 
• 
Blood pressure, pulse, and body temperature measurement 
• 
Height and weight, which will be used to calculate Body Mass Index (BMI) 
• 
Examination of head, eyes, ears, nose, throat, skin, heart, lungs, abdomen, and 
extremities 
• 
Brief neurological exam (cranial nerves 2-12, sensory, motor, reflexes, and cerebellar 
function) 
• 
TBI assessment with residual neurological signs or symptoms on the 
neurological part of the physical exam  
• 
ECG and 1-minute rhythm strip 
• 
Clinical laboratory assessments, per Section 12.0 Clinical Laboratory Assessments. The 
clinical laboratory values will not be captured in the eCRF but will be used to establish 
eligibility and will be kept with the participant’s source record. Clinically significant 
abnormal values will be captured as medical history. 
• 
If there is evidence of liver disease by history, physical examination or laboratory testing, 
HCV serology will be performed. 
• 
If there is evidence of significant hepatic disease other than HCV, the potential 
participant will not be eligible for enrollment and will be advised to see their personal 
physician for further evaluation. If HCV serology is positive and the potential participant 
has not already been evaluated for possible treatment of HCV, they will be referred to a 
physician with expertise in evaluating and treating liver disease. After this evaluation and 
after completion of any recommended treatment, if the HCV is judged by this physician 
to be relatively stable and of mild severity, the participant may be enrolled, if there are no 
other contraindications. 


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• 
If the potential participant has well-controlled hypertension and no other evidence of 
cardiovascular or cerebrovascular disease by history, physical exam or ECG, and if the 
investigator judges their overall health and other cardiovascular risk factors to be 
acceptable (family history, smoking, lipid levels, body weight, level of physical activity), 
they will be referred for stress test with either echocardiography or nuclear imaging, 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. Additional cardiovascular testing to confirm eligibility may be 
performed in consultation with Medical Monitor. Participants taking one or more 
antihypertensives may be enrolled in the study. The investigators will record and review 
medications used to control hypertension prior to enrollment. 
 
Additional visits or repeat assessments (in person, at home, by telephone, or via tele-assessment) 
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. For instance, at home 
blood pressure measurements may be required to corroborate or rule out undiagnosed 
hypertension or to determine if an ongoing diagnosis of hypertension is controlled per the ESC 
guidelines, and as required per the eligibility criteria of this protocol. 
 
Once all results are obtained, the site team will review all medical assessments, notes from 
interviews and discussions, medical records, and measures against eligibility criteria. If, upon 
examination, there are questions raised about possible medical problems, the site physician will 
request additional tests, assessments, or measures as indicated. The site physician may also 
contact outside providers with participant permission as needed. If deemed initially eligible, the 
site staff will schedule the IR screening and send results of LEC-5 and CIPD-SR to the IR. 
Although the IR visit is by tele-assessment, the participant will be provided a location to complete 
the tele-assessment visits at the study site if needed. For the first IR assessment, the site can 
provide technical support before the assessment and therapeutic support after, if needed. The site 
staff will instruct the participant on how to access the tele-assessment visits going forward. For all 
IR visits discuss with the participants that they should have adequate internet access and be in a 
private and quiet space where they are comfortable talking about personal matters. 
 
7.1.2 Remote Visits  
Some of the non-drug psychotherapy sessions and online evaluations may be permitted remotely, 
via tele-assessment (online video meetings), rather than at the study site. Remote visits if deemed 
appropriate may be permitted based on prior experience or in the context of local regulation due 
to a pandemic. 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.  
 
7.1.3 Interruptions and Arrangements 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 emergency or any other unforeseen emergency in the future. The 
following accommodations in the protocol will be allowed, captured, and noted in the Clinical 
Study Report as COVID-19 deviations when applicable: 
• 
Integrative Sessions may be conducted by tele-medicine 


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• 
Delaying the start of medication tapering after enrollment and the subsequent Treatment 
Period per Section 11.1 Tapering Instructions 
• 
Delaying Experimental Sessions and associated Integrative Sessions 
• 
Delaying Independent Rater assessments for participants who cannot complete them 
remotely off-site 
• 
Use of prohibited medications and/or cannabis or initiation of new therapy for 
participants with significant study delays, which will be reviewed by the study team 
before each Experimental Session and re-tapered prior to resuming treatment per Section 
11.0 Concomitant Medications. 
 
For any participant with COVID-19 related illness, continued trial participation after full recovery 
of the disease may be appropriate after discussion between the site physicians and Medical 
Monitors on a case-by-case basis. 
 
7.1.4 Independent Rater Screening 
If participants meet initial eligibility during Screening, an IR will continue the eligibility 
assessment via tele-assessment after reviewing the results of the LEC-5 and CIPD-SR. The IR 
interview will be recorded to assess reliability of ratings. If possible, the potential participant 
should be present at the study site during this assessment, in case the therapy team is needed for 
support. If a participant reports suicidal ideation during this assessment, the IR will contact the 
therapy team after the call and present any concerns. The therapy team will follow-up with the 
participant to ensure safety, provide support, recommend treatment, or schedule a visit to the 
study site. 
 
• 
Using the results of the CIPD-SR to guide the interview, the IR will perform the CIPD to 
assess personality disorders. Only appropriate modules will be completed.  
• 
The IR will also ask relevant questions from the DDIS to identify dissociative disorders 
and administer the Since Last Visit C-SSRS to determine suicidal risk. 
• 
The IR will complete MINI interview to assess Axis I psychiatric disorders.  
 
The results from the MINI, CIPD, DDIS, and C-SSRS will be provided to the therapy team at the 
site to review along with all other Screening information to determine eligibility. Items assessed 
by the IR at this visit will be confirmed in the Preparatory Period by clinical observation, but the 
measures will not be repeated. If site staff deem the participant eligible, schedule Enrollment 
(Visit 0). 
 
If the results of the any measure or interview indicate a diagnosis is present, the investigator is not 
permitted to use their clinical judgment to question the diagnosis. However, if a diagnosis is not 
present or uncertain according to any measure or interview, but the investigator believes the 
participant presents with a particular disorder, they may diagnose and deem the participant 
ineligible for the trial.  
 
7.1.5 Enrollment 
In advance of Visit 0, the site team will review all notes from Screening visits, medical 
assessments, IR assessments, notes, discussions, medical records, and measures against eligibility 
criteria. If the participant is eligible, medication tapering and concomitant medications dose 
adjustments will be discussed, if applicable. The site physician will consult the prescribing 
physician to initiate medication tapering for participants. For all details on concomitant 


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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 to discuss the medical history and screening data available for review to confirm 
the potential participant is eligible for enrollment.  
 
If a participant is confirmed as eligible for enrollment, the participant will be notified of 
enrollment at Visit 0 in-person, via tele-assessment, or by telephone.  
 
Medical history and medication information will be reviewed for completeness. A medication 
tapering plan will be discussed with the participant, if applicable. If agreeable, the participant will 
be enrolled in the study. Once enrolled, AE collection requirements begin (refer to Section 10.0 
Safety). V0 should take place 2 days (+12 days) after Independent Rater Screening is completed. 
Visit 0 and Visit 1 may take place on the same day. 
 
7.2 Preparatory Period with Enrollment Confirmation 
Participants will undergo three Preparatory Sessions (Visits 1, 2, and 4) lasting approximately 90 
minutes with the therapy team prior to the first Experimental Session. The Preparatory Period will 
be initiated within 12 days of Visit 0 and last 2-11 weeks, depending on duration of medication 
tapering. There must be at least 48 hours between Preparatory Sessions. The minimum time to 
complete the Preparatory Period is 2 weeks. The Preparatory Period will also include the Baseline 
CAPS-5 assessment (Visit 3), which will be assessed by an IR.  
 
Adherence criteria for Preparatory Sessions should be followed per the Treatment Manual. In 
these visits, the therapy team will work with the participant to prepare for MDMA-assisted 
psychotherapy, begin building therapeutic alliance, and promote a safe set and setting for 
confronting trauma-related memories, emotions, and thoughts.  
 
7.2.1 Preparatory Session 1 and Preparatory Session 2 
Preparatory Sessions during the Preparatory Period will focus on psychoeducation about PTSD, 
building safety for the therapeutic relationship, developing the therapeutic alliance, obtaining the 
background for the trauma, and preparing the participant for the first Experimental Session. 
Telephone calls may be scheduled between visits if indicated for tapering, safety, or any further 
questions about medical history.  
 
• 
Preparatory Session 1 (Visit 1) will occur within 1 week (0 to 12 days) of Visit 0. The 
visit timing should take into account appropriate times for monitoring medication 
tapering.  
• 
Preparatory Session 2 (Visit 2) will occur within 3 weeks of Visit 0 and at least 2 days 
after Visit 1. The visit timing should take into account appropriate times for monitoring 
medication tapering. Visit 2 must take place at least 2 days after and within 3 weeks of 
Preparatory Session 1 (Visit 1)  


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• 
If tapering is ongoing at Preparatory Session 2 (Visit 2), the site team will schedule a 
telephone call after tapering and stabilization are complete to confirm that the participant 
is eligible for the Baseline CAPS-5 assessment. If tapering is complete or not needed, the 
site team will confirm eligibility and schedule Baseline CAPS-5 T1 (Visit 3) and 
Preparatory Session 3 (Visit 4) as soon as possible.  
 
At each 90-minute psychoeducation and psychotherapy Preparatory Session, the therapy team 
will: 
 
• 
Record the therapy session. 
• 
Inquire about any possible changes in health to ensure the participant continues to meet 
all eligibility requirements. Record AEs as described in Section 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 [111]. 
 
If a participant would like a companion present during or after the Experimental Session, a 
meeting between the therapy team and that individual will be scheduled prior to the first 
Experimental Session. There must be mutual agreement between the participant and therapy team 
concerning the presence of the companion and companion should receive study information to 
read and to sign informed consent form before joining therapy or experimental sessions. 
 
During one of the Preparatory Sessions, if possible, the therapy team will introduce the 
participant to the attendant who will remain with the participant during each overnight stay after 
each MDMA-assisted psychotherapy session. The attendant will be an individual with previous 
training in managing psychological distress. The site will make all attempts to have the same 
attendant for each Experimental Session for a given participant, but it is not guaranteed. 
 
At any time during the Preparatory Period, if a potential participant is deemed to be ineligible, the 
site team will classify them as an Enrollment Confirmation Failure, notify the potential 
participant that they are unfortunately not eligible for the study, and not schedule additional 
assessments.  
 
7.2.2 Baseline: CAPS-5 by Independent Rater  
At Visit 3, an IR will measure the Baseline CAPS-5 (referred to as Baseline CAPS-5 T1) via tele-
assessment as soon as possible after medication tapering, stabilization, and two Preparatory 
Sessions are complete. This visit will be recorded to video to establish inter-rater reliability. The 
scores will be sent as soon as possible to the site staff. A CAPS-5 Total Severity Score of at least 
35 is required to meet Enrollment Confirmation criteria. The IR will also administer the DSP-I 
and SDS. 
 
7.2.3 Baseline: Preparatory Session 3 and Enrollment Confirmation 
Prior to Visit 4, the site team will review the results of the IR visit to ensure that the CAPS-5 
Total Severity Score is at least 35. Visit 4 should be scheduled within 6 days of the Baseline 
CAPS-5 assessment but ideally will take place as close to Experimental Session 1 (Visit 5) as 
possible, but not on the same day.  
 


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At Visit 4, the site team will confirm eligibility by reassessing specified eligibility criteria and 
ensuring that the participant continues to agree to all lifestyle modifications. If the participant 
continues to be eligible for the study, enrollment will be confirmed (after approval from the 
Medical Monitor for the initial participants until confidence is established). If any requirements 
are not met before or during Visit 4, the participant will be considered a Pre-Dosing Early 
Termination. 
 
For eligible participants at Visit 4, qualified site staff will ensure at least 3 hours are scheduled for 
the visit and: 
 
• 
Collect urine sample for pregnancy test from PABP. 
• 
Perform urine drug test. 
• 
Perform alcohol test (UK only). 
• 
Administer Since Last Visit C-SSRS to determine suicidal risk. 
• 
Actively support participant in the completion of Baseline self-reported measures: 
o PCL-5- ensure assessment is in relation to index trauma 
o ACE 
o BDI-II 
o CPGS 
o EQ-5D-5L 
o SCS 
o SRNU 
o EAT-26  
o UFEC and economic productivity 
 
Completion of the measures does not need to be recorded. 
 
• 
Complete the third 90-minute Preparatory Session (as described in Section 7.2.1 
Preparatory Sessions 1 and 2) with the purpose of confirming all enrollment is met and 
completing final preparation for the first Experimental Session. 
• 
Remind the participants of lifestyle modifications, including fasting and refraining from 
using psychoactive or non-approved medications, pertinent prior to the Experimental 
Session per Section 3.3 Lifestyle Modifications.  
• 
Schedule Visit 5. 
 
7.3 Treatment Period 
During the Treatment Period, which occurs over a duration of 5 to 12 weeks (Visits 5 to 13), 
participants will complete two treatments. Each treatment consists of an Experimental Session, 
followed the morning after by an Integrative Session, phone follow-ups over the next week, a 
second Integrative Session within 2 weeks, and a third Integrative Session within 3 to 5 weeks. 
The Experimental Sessions will be scheduled 3 to 5 weeks apart. The CAPS-5 will be assessed at 
one time point during the Treatment Period: CAPS-5 T2 after Integrative Session 1.2 (Visit 7). 
The Primary Outcome CAPS-5 T3 will be assessed after the last Experimental Session during the 
Follow-up Period. 
 


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7.3.1 Experimental Sessions 
 Psychotherapy Session 
There will be two open-label Experimental Sessions (Visits 5 and 10). Procedures for MDMA-
assisted psychotherapy will remain the same across all sessions and all procedures regardless of 
dose received (Table 7). Experimental Sessions must be at least 8 hours long, measured from 30 
minutes prior to IP administration. 
 
• 
Experimental Session 1 (Visit 5) will occur within 1 week of the Baseline CAPS-5 (Visit 
3) assessment. If the Baseline CAPS-5 assessment is completed outside of the allowed 
window, the investigator should consult the CRA and Medical Monitor to determine if 
the assessment should be repeated. The first Experimental Session will include 80 mg of 
IP followed by a supplemental half-dose 1.5 to 2 hours after the initial dose unless 
tolerability issues emerge with the first dose or the participant declines.  
• 
Experimental Session 2 (Visit 10) will occur within 3 to 5 weeks of Experimental Session 
1 (Visit 5) and after Integrative Session 1.3 (Visit 9). A dose of 80 or 120 mg MDMA 
will be administered. A supplemental half-dose will be administered 1.5 to 2 hours after 
the initial dose unless tolerability issues emerge with the first dose or the participant 
declines. 
 
 Schedule of Procedures for Experimental Sessions 
 
Pre-IP administration 
 
• 
On the day of the Experimental Session, the participant will arrive approximately 30 to 
60 minutes prior to IP administration. 
• 
The site team will ensure the participant has not used caffeine or nicotine 2 hours prior 
and fasted for 10 hours prior to IP administration and complied with all other 
requirements per Section 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 IP administration. 
• 
The site team will complete symptom-directed physical exam, urine drug screen, 
pregnancy test, and concomitant medication review.  
a. A positive drug screen will be reviewed by the site physician and may be cause 
for delaying IP administration to a later time, rescheduling the session to a later 
date, or withdrawing the participant from the study, based on Medical Monitor 
review.  
Approximate Time 
Procedure or Action 
9:30  
Urine drug screen, alcohol test (UK only), pregnancy test, Symptom-
directed Physical Exam, concomitant medication information collected, 
participant acclimated to environment, C-SSRS  
9:55 
Baseline BP, body temperature, pulse, SE 
10:00  
IP Administration, Begin video recording  
11:30  
BP, body temperature pulse, SE  
Supplemental Dose Administration, unless tolerability issues emerge 
with the first dose or the participant declines 
17:30 
C-SSRS, BP, body temperature, pulse, SE 


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b. A positive pregnancy screen is cause for withdrawal from the protocol.  
• 
The therapy team will administer Since Last Visit C-SSRS. 
• 
The therapy team will review procedures for the Experimental Session with the 
participant and discuss the participant’s goals, intentions, and concerns and some of the 
commonly experienced effects of MDMA. The choice of whether to keep the dose the 
same or change it from the first Experimental Session will be made by the therapy team 
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. Participant subjective effects (SE) self-rated VAS 
measures on 15 items (negative mood, body perception changes, confusion, difficulty 
concentrating, compassion for self, compassion for others, euphoria, positive mood, 
intellectual efficiency, social, calmness, talkative, open to new experiences, meaningful 
experience, emotional distress) will be collected at three time points: prior to initial dose 
of MDMA, prior to supplemental dose of MDMA and at the end of the experimental 
session (see Table 8). A symptom-directed physical examination will be conducted at any 
time if clinically indicated. 
 
During the Experimental Session 
 
• 
After video recording has begun, at approximately 10:00 in the morning, a qualified staff 
member will administer the initial dose of IP with water. The participant will sit or 
recline on comfortable furnishings. Eyeshades and a program of music will be provided 
for the participant if they wish to use them. Whenever they wish, participants may speak 
to the therapy team, who will provide guidance and support, as needed.  
• 
After the first hour, if the participant has not spoken spontaneously, the therapy team will 
check in with them about the nature of the experience. For the rest of the experience, as 
appropriate, the therapy team will support and encourage the participant in emotional 
processing and resolution of whatever psychological material is emerging, as described in 
the Treatment Manual. 
• 
Fluids will be provided throughout the session but not to exceed three liters overall. 
• 
Blood pressure, body temperature, pulse and SE will be measured approximately 1.5 to 2 
hours after the initial dose, before the supplemental dose is administered. 
• 
The site physician (if not part of the therapy team) will be contacted with a brief 
description of how the session is progressing and the recent vital signs. The site physician 
will approve or deny the administration of the supplemental dose. If medical attention is 
needed, the site physician will provide further instruction or consult the Medical Monitor. 
• 
A supplemental half-dose will be administered with a glass of water approximately 1.5 to 
2 hours after the initial dose, unless the participant experiences tolerability issues. 
• 
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 remain 
in the waiting room until a member of the therapy team brings them to the session room. 
Alternatively, the companion may arrive after the session has ended. 
 
End of Experimental Session 
 
• 
The therapy team will administer Since Last Visit C-SSRS. 
• 
The therapy team will record AEs and concomitant medications. 


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• 
Blood pressure, body temperature, pulse and SE will be measured including a symptom-
directed physical exam if clinically indicated. 
• 
The session may be ended if all medical and psychiatric parameters are acceptable, 
elevations in vital signs have resolved to pre-IP levels, the participant is alert, 
ambulatory, and emotionally stable, and the night attendant has arrived. 
• 
The therapy team or site physician shall remain available to participants via 24-hour 
cellular phone for integration, as needed. 
 
Overnight Stay  
 
• 
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. If in 
line with country specific regulations and site standard operation procedures, with prior 
approval of the therapy team, a companion may accompany the participant during the 
overnight stay.  
• 
An attendant will check in periodically on the participant during the overnight stay, even 
if a companion is present. The attendant will monitor participant condition and will help 
participants relax during the overnight stay. The attendant will be an individual with 
previous training in managing psychological distress and will be supportive but not 
intrusive. If there is an emergency or the participant needs additional support, the 
attendant can contact the therapy team.  
• 
The participant and a companion (if applicable) will receive information that will allow 
them to contact the therapy team during the overnight stay in the case of an emergency or 
to request for additional support.  
• 
Participants will be encouraged to use much of the time during their overnight stay for 
rest and as a period of reflection and integration in a quiet atmosphere. 
• 
The participant will be driven home after the integration session by either a driver 
arranged by the participant, by site personnel or taxi. 
 
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 team will follow-up with the participant by telephone on the second and 
seventh day after each Experimental Session, with two additional telephone contacts in between. 
Each call will last on average five to 15 minutes but could be longer to address participant 
concerns and to adequately assess wellbeing. Additional telephone contact can be initiated at the 
request of the therapy team or participant. 
 
At each telephone contact, the therapy team will: 
 
• 
Inquire about any possible changes in health, assess the participant’s mental health and 
the status of any previously recorded AEs, and record AEs as described in Section 10.0 
Safety 
• 
Inquire about concomitant medication use and compliance 
• 
Offer support in accordance with the Treatment Manual 
• 
On the second and seventh contact day after an Experimental Session the therapy team 
will administer the Since Last Visit C-SSRS. 
 


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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 psychotherapy. 
 
Treatment 1 
 
• 
Integrative Session 1.1 (Visit 6): morning after Experimental Session 1 (Visit 5)  
• 
Integrative Session 1.2 (Visit 7): 3 to 14 days after Experimental Session 1 (Visit 5) and 
at least 2 days after Integrative Session 1.1 (Visit 6)  
• 
Integrative Session 1.3 (Visit 9): within 3 to 5 weeks after Experimental Session 1 (Visit 
5) and 1 to 7 days in advance of Experimental Session 2 (Visit 10). At least two days 
after Integrative Session 1.2 (Visit 7). This visit serves two purposes: to continue 
integration and to prepare for the next Experimental Session. The participant will 
complete the LEC-5 and PCL-5 self-report measures. 
 
Treatment 2 
 
• 
Integrative Session 2.1 (Visit 11): morning after Experimental Session 2 (Visit 10) 
• 
Integrative Session 2.2 (Visit 12): approximately 2 weeks after Experimental Session 2 
(Visit 10) 
• 
Integrative Session 2.3 (Visit 13): within 3 to 5 weeks of Experimental Session 2 (Visit 
10). This visit serves to continue integration. The participant will complete the LEC-5 
and PCL-5 self-report measures. For PABP, a final urine pregnancy test will be 
conducted at this visit, Visit 14 or Visit 15 (representing the end of the relevant systemic 
exposure, 5 half-lives after the last IMP dose, and at least 2 weeks after the last MDMA 
experimental session).   
 
During Integrative Sessions, the therapy team will: 
 
• 
Record the session.  
• 
Inquire about any possible changes in health. Assess the participant’s mental health and 
the status of any previously recorded AEs. Record AEs as described in Section 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 team will 
help the participant to reduce any residual psychological distress they are experiencing. 
The therapy teams will also encourage the transfer of states of acceptance, feelings of 
intimacy, closeness, and reduced fear experienced in Experimental Sessions to 
emotionally threatening everyday situations. The therapy teams will be supportive, 
validate the experience, and facilitate understanding and emotional clearing. 
• 
Be accessible for additional support via telephone or tele-assessment if needed. 
• 
At each third Integrative Session, direct the participants to complete the LEC-5. 
• 
At each third Integrative Session, direct the participants to complete the PCL-5. 
 


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7.3.4 Independent Rater Assessments 
Participants will have one CAPS-5 assessment during the first treatment period of the study 
(Visits 8). An IR from the IR Pool will conduct the assessments via tele-assessment. These 
assessments may be recorded to establish inter-rater reliability. The results may be shared with 
site staff, but the IR Coordinator will enter the data. The IR will also administer the DSP-I and 
SDS at these time-points: 
 
• 
Baseline CAPS-5 T1 (Visit 3): At least 7 days after Preparatory Session 2 (Visit 2) and 
confirmation of end of tapering and stabilization off medications and eligibility is 
confirmed. 
• 
CAPS-5 T2 (Visit 8): 3 weeks (-3/+9 days) after Experimental Session 1 (Visit 5) or 18 
to 30 days after Experimental Session 1 (Visit 5), between Integrative Session 1.2 (Visit 
7) and Integrative Session 1.3 (Visit 9) 
• 
CAPS-5 T3 (Visit 14): 8 weeks (+/-2 weeks) after Experimental Session 2 (Visit 10), 
after last Integrative Session 2.3 (Visit 13)  
 
7.4 Follow-up Period and Study Termination 
7.4.1 Follow-up Period 
After the last Integrative Session 2.3 (Visit 13), participants will enter follow-up for 
approximately 4 weeks (+/- 2 weeks) with no protocol required visits until the final CAPS-5 
assessment (Visit 14) followed by a Study Termination (Visit 15). Participants will have access to 
therapy teams for support if needed, and additional visits via telephone, tele-assessment, or in 
person can be scheduled if requested. Participants will continue to comply with protocol 
requirements for concomitant medications until after Study Termination. 
 
7.4.2 Final Independent Rater Assessment 
Participants will have a final CAPS-5 assessment at the completion of the follow-up period (Visit 
14). An IR from the IR Pool will conduct the assessments via tele-assessment. These assessments 
may be recorded to establish inter-rater reliability. The IR Coordinator will enter the data in 
stand-alone database. The results may be shared with site staff during supervision by the therapy 
training team. Although there are allowable windows for all visits throughout the protocol, the 
Primary Outcome CAPS-5 T3 assessment must be completed 13 weeks (+/- 3 weeks) after the 
Baseline CAPS-5 assessment and within 8 weeks (+/-2 weeks) of Experimental Session 2 (Visit 
10). Participants who have withdrawn from treatment will also complete a final CAPS-5 
assessment immediately upon withdrawal. The IR will also administer the DSP-I and SDS. 
 
7.4.3 Study Termination 
Study Termination (Visit 15) will take place 2 (-1/+7) days after the final CAPS-5 assessment 
(Visit 14). Participants who have withdrawn from treatment but have continued for follow-up will 
also complete this assessment immediately upon withdrawal. 
 
The site team will: 
 


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• 
Inquire about any possible changes in health. Assess the participant’s mental health and 
the status of any previously recorded AEs. Record AEs as described in Section 10.0 
Safety. 
• 
Inquire about concomitant medication use and adherence. 
• 
Administer Since Last Visit C-SSRS. 
• 
Conduct symptom-directed physical examination if clinically indicated. 
• 
Conduct pregnancy test (at Visit 13, 14 or 15, or earlier if early withdrawal). 
• 
Measure weight (used to calculate BMI). 
• 
Measure blood pressure. 
• 
Provide and discuss a study exit plan. 
• 
Actively support participant in completion of Study Termination self-reported measures: 
o LEC-5  
o PCL-5, ensure assessment is in relation to index trauma 
o BDI-II 
o CPGS 
o EQ-5D-5L 
o SCS 
o AUDIT  
o DUDIT  
o SRNU 
o EAT-26 
 
Completion of the measures do not need to be recorded. 
 
After all Study Termination measures and assessments are completed, the participant is 
considered terminated from the study. The participant can resume normal everyday life. The 
study team will provide an Exit Plan, which may include a referral for additional medical or 
therapeutic care, as described in Section 7.4.4 Exit Plan. Eligible participants will be asked 
whether they are interested in participating in the LTFU extension study. 
 
7.4.4 Exit Plan 
At Study Termination, participants will be provided with an Exit Plan. This Exit Plan will 
summarize treatments completed, current medications, and contact information for more 
information about the study if needed. Participants may request a referral for further therapeutic 
or medical care if appropriate. Enrolled participants who terminate the study early will be 
provided an Exit Plan at their last contact. Screen Failures will be provided a referral if requested. 
 
8.0 Investigational Medicinal Product 
8.1 Description of Active Compounds 
The Active Pharmaceutical Ingredient (API) to be used in this protocol is MDMA. This ring-
substituted phenethylamine has a complex pharmacology, but it acts most prominently as a 
monoamine releaser and re-uptake inhibitor. Its direct actions on serotonergic, adrenergic, and 
other receptors are considerably lower. Refer to the IB for a comprehensive review of the 
pharmacology, effects and proposed mechanisms of action of the IMP. Mannitol and magnesium 
stearate will serve as inactive excipients. 
 


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8.1.1 Doses 
This study will compare the effects of two open-label manualized Experimental Sessions of 
psychotherapy assisted by flexible doses of MDMA. Initial doses per Experimental Session 
include 80 mg or 120 mg MDMA compounded with mannitol and magnesium stearate, followed 
1.5 to 2 hours later by a supplemental half-dose (40 mg or 60 mg). Total amounts of MDMA to 
be administered per Experimental Session range from 80 mg to 180 mg (Table 3). All drug is 
encapsulated with HPMC capsules. 
 
8.1.2 Dose Modifications 
In the first Experimental Session, the initial dose will be 80 mg MDMA. In the second 
Experimental Sessions, the initial dose may be increased to 120 mg MDMA unless tolerability 
issues emerge with the first dose or the participant declines. The choice of whether to keep the 
dose the same or change it from the first Experimental Session will be made by the therapy team 
in consultation with the site physician based on observed response, tolerability of the previously 
administered dose, and discussion with the participant. In each Experimental Session, 1.5 to 2 
hours after the initial dose is given, the participant will be administered a supplemental half-dose 
unless tolerability issues emerge with the first dose or the participant declines. Tolerability issues 
include: if a patient experiences a severe adverse event after administration of MDMA during an 
experimental session, or they experience clinical signs and symptoms that may suggest end organ 
effects as specified in the protocol, the dose may not be escalated or a supplemental dose may not 
be administered. Examples of these symptoms include chest pain, shortness of breath, 
neurological deficit or confusion, or other potential indicators of end organ effects that will 
prompt additional vital sign measurements, and intervention if appropriate. 
 
8.1.3 Stability 
IMP will be manufactured and packaged according to Good Manufacturing Practices (GMP). Six-
month accelerated stability studies will be completed for the IMP along with an ambient stability 
study that will remain ongoing throughout the duration of the study. All required Chemistry 
Manufacturing and Control (CMC) submissions will be made to the IND. 
 
8.2 Handling 
8.2.1 Encapsulation, Packaging, and Labellingc 
The IMP is packaged in 40 mg and 60 mg containers. All container labels will comply with 
country and EMA regulations. Each container will be labelled with a unique container number, 
protocol number, IMP name, lot number, sponsor name and contact information, investigator, 
dosage form, route and directions for administration, storage conditions, retest date, and 
strength/potency and a statement that the IMP is restricted to clinical trial use only.  
 
8.2.2 Accountability 
Forms will be provided to track IMP accountability and administration throughout the study. 
Open-label IMP accountability and administration logs will be reviewed during routine 
monitoring visits. IMP will be handled in accordance with country regulations and forms 
pertaining to the use of controlled substances, and forms will be maintained by the appropriate 
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Each container label will contain a unique container number for the IMP assigned to a single 
Experimental Session. The container numbers will be used to track IMP administration in the 
Source Record and the IMP administration log. 
 
 
8.2.3 Storage 
MDMA is a controlled substance and will be stored securely and handled in compliance with all 
relevant country regulations. In accordance with these requirements, the appropriate license 
holder or designee will be responsible for storing, dispensing, and administering the MDMA.  
 
8.2.4 Administration 
IMP will only be removed from storage 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 the participant declines. Each dose (initial and supplemental) will be 
administered with a glass of water. 
 
A person at the site authorized to manage and administer controlled substances will dispense the 
appropriate container for each Experimental Session. If a supplemental dose is not administered, 
the unused IMP will be kept for accountability.  
 
Records pertaining to the use of scheduled, regulated compounds will be maintained in 
accordance with relevant local country regulations.  
 
8.2.5 Treatment Compliance 
Compliance of doses required per protocol 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. 
 
8.3 Participant Numbering 
Every potential participant who is prescreened by telephone according to the IRB/EC-approved 
script will be assigned a seven-character alphanumeric Screening Number and recorded on the 
Screening Log. This number will begin with ‘S8’ to identify that it is a Screening Number. The 
next two digits represent the site number (e.g., ‘17’), followed by a three-digit screening identifier 
starting with ‘801’. The screening identifier will be assigned to each prescreened participant at a 
site sequentially. For example, the first Screening Number at Site 17 will be S817801 and first 
Screening Number at Site 18 will be S818801. 
 
Each participant who passes Screening and is enrolled in the trial at Visit 0 will be assigned a 
seven-digit Participant Number. The first digits will be ‘18’. The next two digits represent the site 
number (e.g., ‘17’), followed by a three-digit participant identifier starting with ‘001’. The 
participant identifier will be assigned to each enrolled participant at a site sequentially. For 
example, the first Participant Number at Site 17 will be 1817001. 
 


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Eligible participants will be enrolled in the study and sequentially assigned an identification 
number. All participants will also be assigned a unique participant identifier within the database 
for use in analysis.  
 
8.4 Bias Minimization 
Before a participant is deemed eligible and enrolled into the study, participant’s medical history 
and screening assessments will be reviewed by the Principal Investigator and therapy team. If 
needed, Medical Monitor will be consulted. 
 
Two different processes exist to ensure bias minimization: the primary and secondary outcome 
assessments performed by the IR team will be recorded and then reviewed by a senior (local) IR, 
and all psychotherapy study visits (including the experimental sessions) will be reviewed by 
adherence raters to ensure adherence to the Treatment Manual, and consistency among therapy 
pairs and sites. The paragraphs below describe these processed in more detail. 
 
To minimize bias in measuring effect, the sponsor will use an observer-blind, centralized, reliable 
IR pool to administer the Primary Outcome measure via live video interviews. The IR Pool will 
have no knowledge of participant’s study data or AEs and will only evaluate participants at 
Baseline and at the assessments scheduled after each Experimental Session. The IR Pool is 
blinded to study design, visit number, number of treatments, and any data from the treating 
therapy team after Baseline. IRs will be assigned to participants based on availability. Data will 
be entered into a dedicated IR Database by the IR Coordinator who is not part of the study 
assessments or procedures. Timing of CAPS-5 assessments are provided in Table 2.  
 
To ensure that all participants are treated in a similar manner, the sites will be required to follow 
the protocol and Treatment Manual delineating minimum length of time per visit type and 
describing delivery of treatment. All Experimental Sessions are required to be at least 8 hours 
long. Adherence to the Treatment Manual will be checked by review of video by adherence 
raters. The sponsor will monitor data in real-time to ensure complete data collection for all 
participants, including those who discontinue treatment. Sites will be required to make and 
document a specific number of attempts to obtain follow-up data per protocol. All participants 
who receive at least one dose of IP and complete at least one follow-up assessment will be 
included in the final mITT analysis. 
 
9.0 Risks 
9.1 Non-drug Related Risks 
9.1.1 Medical Assessments 
In preparation for MDMA-assisted psychotherapy sessions, blood draws and a full medical 
examination, including a physical examination, ECG, 1-minute rhythm strip, and laboratory tests, 
are required to establish eligibility for the study. See Section 7.1.1 for the list of medical 
assessments to be performed within the screening visit in order to confirm participant’s eligibility.  
 
Temporary discomfort, inflammation, or infection could arise as a result of sampling blood at the 
punctured vein. Submitting to a full medical examination may also cause discomfort or 
psychological distress. Since medical examinations and blood draws are required to establish 
eligibility for the study, they cannot be omitted from the protocol. 
 


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9.1.2 PTSD, Suicide Risk, and Psychotherapy 
During Screening, throughout MDMA-assisted psychotherapy, and during assessment of study 
measures, participants will be asked to think about and discuss their thoughts and emotions 
relating to the traumatic event or events. They may experience intense emotional responses or 
suicidal ideation as a result of recalling and speaking about this material. Even in a therapeutic 
context, thinking about and discussing the trauma, symptoms related to the trauma or the effects 
of PTSD on life function can produce distress and exacerbate suicidal ideation during and 
immediately after psychotherapy sessions. Psychotherapy is conducted as part of this study, and 
people undergoing psychotherapy are expected to confront unpleasant thoughts, feelings and 
memories in the process. Because psychotherapy is an integral part of the research study design, 
the potential distress arising from psychotherapy is unavoidable. Therapy teams will provide 
emotional support to participants during any psychological distress. 
 
The therapy team will minimize risks by carefully evaluating all participants to determine if there 
is a current risk of suicidal behavior. Participants with a history of suicide attempts will not be 
excluded unless significant risk of suicidal behavior is present at the time of Screening. 
Participants will be enrolled according to the Eligibility Criteria based on the clinical judgment of 
the site physician, therapy team, and Medical Monitor. 
 
A qualified individual will administer the C-SSRS according to Table 7: Time and Events – 
Study Measures, and as needed depending on clinical presentation of the participants, to monitor 
for development and intensity of suicidal ideation and/or behavior. The therapy team will 
implement the following plan to assess elevated or imminent suicide risk. 
 
If the Since Last Visit C-SSRS reveals current serious Suicidal Ideation (scores of four or 
greater), indicating risk at the time of the assessment, or positive Suicidal Behavior, the 
participant will be referred for further management as described below. 
 
1. If the participant has current suicidal ideation, but no specific plan to commit suicide 
(Suicidal Ideation Score=4), the individual administering the C-SSRS will ensure: 
a. The participant is evaluated by the investigator and/or site physician to determine 
an appropriate course of action. Findings will be discussed with the participant 
and their personal therapist, if applicable. 
b. Regular check-ins via phone or in-person will be continued until the participant 
has stabilized or a new course of action is taken based on changes in C-SSRS 
score and/or ongoing clinical assessment. 
c. Increases in suicidality will be captured as an AE. 
d. Treatment would be continued when deemed appropriate by the investigator and 
Medical Monitor, unless it is determined that treatment should be discontinued, 
in which case the participant will enter follow-up. 
 
2. If the participant has suicidal ideation, and a plan to commit suicide (Suicidal Ideation 
Score=5) or positive Suicidal Behavior, the individual administering the C-SSRS will 
assess whether the risk is imminent. A Suicidal Ideation score of five does not necessarily 
indicate an immediate risk if the thoughts are fleeting, fairly easily controlled, and 
deterrents are strong. If there is no imminent risk, the individual will follow the procedure 
described above. If there is imminent risk of suicidal behavior, the individual will ensure: 
a. Participants are evaluated by the investigator or site physician to determine an 
appropriate course of action, and the therapy team will contact their personal 


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therapist, who will be invited to come to the study site to assist, depending on 
their location. 
b. If it is determined that the participant is at imminent risk of suicide, the therapy 
team will do one of the following: 
i. 
Escort the participant to the ED; 
ii. 
Escort the participant to an appropriate mental health services facility 
(e.g., hospital psychiatric unit); or  
iii. 
Call EMS and ensure that the participant is transferred to the 
responding medical personnel. 
c. If the participant will not comply and wishes to leave without consultation, call 
EMS. Explain that the participant is in immediate danger of committing suicide. 
Provide a complete description of the participant and give any other needed 
details to ensure the participant’s safety. 
d. Notify appropriate members of the study team and sponsor representatives. 
e. The event will be collected as an AE and the seriousness will be evaluated. SAEs 
will be reported per local regulatory guidance. 
f. Treatment would be continued when deemed appropriate by the investigator and 
Medical Monitor, unless it is determined that treatment should be discontinued, 
in which case the participant will enter follow-up. 
 
9.1.3 Recorded Content 
All psychotherapy sessions and IR assessments will be video recorded . There is a risk that 
participants may feel uncomfortable with having their sessions recorded. The recordings are 
necessary for participant safety, for assessing adherence to the Treatment Manual, as well as 
providing clinical supervision to therapy teams that will be trained as a part of this study. Both 
types of videos will be deleted after the appropriate reviews are performed. 
 
The sponsor uses encrypted, secure technology to store recordings. In the case of a confidentiality 
breach, the participant will be notified and all efforts will be made to minimize the dissemination 
of recorded content. The sponsor is committed to taking preventative measures to avoid such an 
event. 
 
9.2 Risks of Receiving MDMA  
Study procedures and eligibility criteria have been developed based on Phase 2 and Phase 3 
PTSD trials which exclude potential participants with pre-existing exclusionary medical 
conditions that would exacerbate risk. The therapy teams and site physicians are available via 
telephone throughout the study if any problem occurs when a participant is not at the site. In the 
event of a medical emergency or any other medical problem during an Experimental Session, the 
site physician should be immediately available by telephone, and based on assessment of the 
situation, they should make the decision to either evaluate the participant themselves at the site or 
arrange for transfer of the participant to the Emergency Department. 
 
Further information on the risks associated with MDMA can be found in the IB and risk 
mitigation procedures are described by risk category below. Risk Categories were determined by 
review of possible risks within the Risk Assessment and Categorization Tool (RACT).  
 


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9.2.1 High Level Risks 
High Risk does not indicate an event is more likely to happen but indicates per the RACT 
assessment that new and or more complex procedures are required in the study to ensure 
screening is adequate to eliminate or manage the risk in the patient population. No high-level 
risks of MDMA have been identified based on the RACT assessment. 
 
9.2.2 Medium Level Risks 
Medium Risk does not indicate the likelihood the event will occur but indicates per the RACT 
assessment that new or many procedures, which are not complex, are needed to ensure screening 
is adequate to eliminate or manage the risk in the patient population. 
 
 Cardiovascular and Cerebrovascular Risks and Mitigation 
MDMA is known to transiently increase heart rate and blood pressure in a dose-dependent 
manner that is generally not problematic for physically healthy individuals. These changes should 
last no more than 8 hours. Participants with PTSD in MAPS-sponsored Phase 2 and Phase 3 
studies do not appear to differ from healthy individuals in this sympathomimetic, physiological 
response. Most people do not experience elevations in cardiovascular parameters that exceed 
those seen after moderate exercise. An examination of safety data drawn from Phase 2 and Phase 
3 studies of MDMA-assisted psychotherapy detected a dose-dependent increase in SBP and to a 
lesser extent DBP. Characterization of sympathomimetic effects among participants with 
controlled hypertension is ongoing.  
 
Risks posed by elevated blood pressure are addressed by excluding people with pre-existing 
uncontrolled hypertension and monitoring blood pressure and pulse, as described in Section 4.2 
Exclusion Criteria. Before and after drug 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 (AMI) during Experimental Sessions. Any symptoms such as chest pain, 
shortness of breath, neurological deficit or confusion other potential indicators of end organ 
effects of hypertension should prompt additional vital sign measurements and intervene if 
appropriate. Therapy teams should notify the site physician if this occurs for evaluation. If any 
participant has neurological deficits, as assessed by the site physician, whether or not they are 
associated with hypertensive crisis, they should be monitored as described above and transported 
to the hospital if medically indicated. If evaluation at the hospital reveals an acute ischemic 
stroke, there should be sufficient time to administer recombinant tissue plasminogen within the 3-
hour time frame recommended in the 2019 American Heart Association/American Stroke 
Association (AHA/ASA) guidelines [112] ,.  
 
If a participant experiences ischemic type chest pain, whether or not it is associated with 
hypertensive crisis, the study physician should be contacted immediately, and the participant 
should be taken to an emergency room by ambulance as expeditiously as possible to assess the 
patient and act in accordance with the assessment of the expert on site supported by local and/or 
European Society of Cardiology (ESC) Guidelines [113]. Pending transport to the hospital the site 
team may take any measures ordered by the site physician including administering medication 
such as aspirin or nitroglycerin or providing supplemental oxygen per local standards. If further 
evaluation at the hospital reveals that the participant has had an AMI, they should be well within 
the time frame required for definitive therapy. Any participant who experiences such medical 
complications during an Experimental Session should not be given another Experimental Session.  


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QT interval may be evaluated in the event of hospitalization for management of cardiovascular or 
cerebrovascular event. If at any time a participant develops a QT/QTcF interval >450 ms or of 
>30 ms over baseline during ECG evaluation, the participant should be discontinued from 
treatment.  
 
 Psychological Risks and Mitigation 
Mild anxiety and depressed mood are occasionally reported 1 to 3 days after MDMA 
administration [58, 114]. Psychological distress from MDMA could arise from the first 
indications of MDMA effects until the last effects have dissipated or even later. Anxiety or 
distress during the session may last for as little as 5 minutes or for as long as 5 hours or more. In 
addition, psychological distress could arise following an Experimental Session as a result of 
participants having difficulty integrating their experience after the MDMA effect has subsided. In 
clinical studies, these symptoms have been self-limiting and have responded well to reassurance 
from the therapy team, with occasional use of benzodiazepines for anxiety. In this study, 
participants will have the intention of confronting and working through traumatic experiences. 
Accordingly, signs of psychological distress, panic, or other unpleasant psychological reactions 
are to be expected and may be considered an element of the psychotherapeutic process.  
 
Proper preparation and follow-up support will reduce the difficulties participants might have with 
acute or sub-acute reactions. The potential for destabilizing psychological distress will be 
minimized by: 
 
• 
Excluding people who might be more vulnerable to it (such as people diagnosed with 
bipolar affective disorder type 1 or with psychotic disorders) 
• 
Preparatory Sessions of non-drug psychotherapy before the Experimental Session 
• 
Creating an atmosphere of trust during the Experimental Session 
• 
Close monitoring 
• 
Phone contact with participants during the week after the Experimental Session 
• 
Integrative Sessions 
• 
Overnight stays at the study site for the night of each Experimental Session. Qualified 
personnel will be available during the overnight stay to respond to the needs of the 
participant. Attendants will be instructed to contact the therapy team upon request or at 
the appearance of signs of a potential SAE.  
 
During the Preparatory Sessions, participants should be made aware of the fact that difficult 
emotions, including grief, rage, fear, or panic, may arise during Experimental Sessions. Every 
effort should be made to help participants resolve difficult symptoms and to arrive at a more 
comfortable and relaxed state by the conclusion of the Experimental Session, including empathic 
listening on the part of the therapy team and performance of diaphragmatic breathing by 
participants. 
 
If the participant is severely agitated, anxious, in danger of self-harm or suicide, or is 
experiencing any other severe psychological distress, at the end of a psychotherapy session, at 
least one member of the therapy team will remain with the participant for at least 2 more hours. 
During this time, the therapy team will employ affect management techniques, will talk with the 
participant to help them gain cognitive perspective of their experiences, and will help the 
participant implement the self-soothing and stress inoculation techniques presented during the 
Preparatory Sessions. If the participant remains severely anxious, agitated, in danger of self-harm 


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or suicide, or is otherwise psychologically unstable at the end of the 2-hour stabilization period, 
the site physician and therapy team will decide between the following options: 
 
1. If severe distress occurs at the end of an Experimental Session, a nurse, therapeutic 
assistant, physician, or therapy team member should stay with the participant until the 
severe distress resolves or until the time of their Integrative Session appointment the 
following morning. The therapy team should then meet with the participant daily until the 
period of destabilization has passed.  
2. If the participant experiences severe, persisting emotional distress, such as panic attacks, 
severe generalized anxiety, or insomnia following an Experimental Session, the site 
physician may prescribe a benzodiazepine (specifically, lorazepam) and/or sleep aid (e.g., 
zolpidem). This medication will be captured on the Concomitant Medications eCRF. The 
site physician should not prescribe an SSRI, SNRI, or monoamine oxidase inhibitor 
(MAOI) in this context, unless it has been determined that the participant will be 
withdrawn from the study. Residual symptoms will be addressed during the frequent 
follow-up psychotherapy visits with the therapy team. 
3. If a participant should become psychotic, arrangements should be made to stabilize them 
or transfer them to the Emergency Department if hospitalization is necessary. Any 
participant who is hospitalized after a severe psychological reaction will be suspended 
from the protocol until after recovery or stabilization, at which time the investigator 
and/or site physician will carefully evaluate the participant’s emotional status.  
 
For those participants engaged in an ongoing therapeutic relationship with a psychotherapist or 
psychiatrist, the participant’s outside therapist(s) should be involved in the management of any 
psychiatric complications. For those participants engaged in an ongoing psychotherapeutic 
relationship with the investigator or member of the therapy team, the management of any 
psychiatric complications should be undertaken by them in their capacity as the participant’s 
therapist. 
 
9.2.3 Low Level Risks 
Low Level Risk does not indicate the likelihood the event will occur but indicates per the RACT 
assessment that no new or complex procedures are needed to ensure screening is adequate to 
eliminate or manage the risk in the patient population. 
 
 Thermoregulatory Risks and Mitigation 
MDMA administered in a controlled setting produces only a slight increase in body temperature 
[114]. Ambient temperature does not enhance or attenuate this slight elevation in humans. In data 
gathered from sponsor-supported Phase 2 and Phase 3 studies, it was found that compared to 
placebo, a higher percentage of participants receiving MDMA had peak body temperatures 
greater than 1 degree Celsius (°C) above baseline. However, there was no strong relationship 
between dose of MDMA and peak body temperature or between MDMA dose and elevation 
above threshold of 1°C above baseline.  
 
Ambient temperature should be kept at a comfortable level during Experimental Sessions. If a 
participant’s temperature rises more than 1° C or the participant states that they feel hot, attempts 
should be made to decrease body temperature and increase comfort by removing blankets and 
layers of clothing, decreasing the ambient temperature, and, if necessary, directing a fan toward 
the participant. If at any time the temperature rises more than 1.5° C above baseline despite these 
efforts, the site physician should be consulted for further evaluation and treatment.  


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 Osmoregulatory Risk and Mitigation 
MDMA administered in a controlled setting is not expected to have any risks of osmoregulatory 
changes. Participants are not allowed to drink more than three liters of water over the course of 
the Experimental Session and fluid intake will be spread out appropriately during the session. If a 
participant exhibits any signs of toxicity or clinically significant dilutional hyponatremia despite 
these precautions after an Experimental Session, they should not receive another Experimental 
Session unless it is approved by the investigator, site physician, and the Medical Monitor. 
 
 Genotoxicity Risk and Mitigation 
 The standard genotoxicity battery for MDMA has demonstrated that MDMA is negative for in 
vitro and in vivo genotoxicity, both with and without metabolic activation. 
 
 Reproductive and Developmental Risks and Mitigation 
There are no data from the use of MDMA in pregnant women. In the absence of these data, 
epidemiological studies of Ecstasy are the only source of human data. One of two studies of 
Ecstasy users suggest that use of Ecstasy and polydrug use during pregnancy may be associated 
with some abnormalities at birth while the other failed to find this association [115, 116]. 
 
Studies in rats and rabbits have not shown direct or indirect harmful effects with respect to 
reproductive toxicity. Repeated dose toxicity studies of adequate duration, fertility, early 
embryonic development, and embryofetal development studies of MDMA with toxicokinetics 
have been completed. These studies established the NOAEL dose to be the highest dose level 
evaluated at ≤10 mg/kg/day (supratherapeutic dose) in both sexes of the rat for fertility, 
reproductive performance, and for maternal and developmental toxicity in the rabbit. The 
NOAEL dose was the highest dose level evaluated at ≤15 mg/kg/day (supratherapeutic dose) for 
maternal and developmental toxicity in the rat. Due to the short half-life and single-dose dosing 
regimen of MDMA, pre- and post-natal development studies are not considered necessary for 
assessment of risk to the unborn. Assessment of embryofetal risk based on all available non-
clinical and clinical data supports unlikely human teratogenicity/fetotoxicity in early pregnancy. 
On the basis of male fertility studies, the embryofetal risk posed from treatment of male 
participants with MDMA is also unlikely.  
 
PABP are included in the studies in this program, defined as those who are fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
Postmenopausal state is defined as no menses for 12 months without an alternative medical cause. 
As a precautionary measure in clinical trials, participants who are able to become pregnant must 
have a negative pregnancy screen before undergoing each Experimental Session, which are 
conducted at approximately monthly intervals, and must agree to use adequate contraception at 
least during the Treatment Period which is one month post last dose of MDMA. The end of 
relevant systemic exposure to MDMA is approximately 48 hours [117]. 
 
9.2.4 Minimal Risks 
Minimum Level Risk does not indicate the likelihood the event will occur but indicates per the 
RACT assessment that no procedures are needed beyond basic monitoring to ensure screening is 
adequate to eliminate or manage the risk in the patient population. 


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 Common Expected AEs 
Common expected AEs were typically observed during Experimental Sessions but were transient 
and typically diminished as MDMA was metabolized and excreted over the next 72 hours after 
dosing. In the Phase 3 study MAPP1, the most common adverse events reported more frequently 
in the MDMA group were muscle tightness, decreased appetite, nausea, hyperhidrosis, feeling 
cold, restlessness, mydriasis, dizziness (postural), bruxism, nystagmus, increased blood pressure, 
feeling jittery, chest pain (non-cardiac), dry mouth, vision blurred, pollakiuria, intrusive thoughts, 
vomiting, stress, and musculoskeletal chest pain. AEs were typically self-limiting.  
 
 Neurotoxicity Risk 
 
It does not appear that MDMA-assisted psychotherapy negatively impacts cognitive function 
based on data from Phase 2 studies sponsored by MAPS. The sponsor has carefully considered 
the risks of neurotoxicity and concludes that they are minimal in the intended clinical dosing 
regimen. This conclusion is supported by empirical and toxicokinetic evidence and is consistent 
with the lack of CNS toxicity reported in nonclinical MDMA studies.  
 
 Abuse Potential 
Despite its classification as a Schedule I drug, an examination of findings in humans and animals 
suggests that MDMA possesses moderate abuse potential that is higher than that reported for 
“classic hallucinogens” like psilocybin, but lower than that reported for psychostimulants, such as 
cocaine or methamphetamine. There have been no AESIs reported in Phase 2 and Phase 3 studies 
that could be suggestive of abuse potential among research study participants treated with 
MDMA. Diversion is not an issue for sponsor-supported studies because MDMA is only 
administered under the supervision of the clinical investigator and no take-home doses are 
permitted. MDMA administration and handling follows all regulations pertaining to the use of 
controlled substances within research studies. 
 
Studies assessing prevalence of problematic Ecstasy use or dependence suggest that a small 
percentage of individuals, especially those with prior psychological difficulties, may develop 
problematic Ecstasy use or dependence. An observational long-term follow-up assessment 
conducted at least 12 months after participation in a MAPS-sponsored early Phase 2 PTSD study 
of MDMA-assisted psychotherapy found that 8.7% (8 of 92) participants reported using Ecstasy 
subsequent to study participation, with 6 of these 8 participants having used Ecstasy prior to study 
enrollment. Several participants volunteered that they would not seek out MDMA outside of a 
psychotherapeutic setting.  
 
10.0 Safety 
10.1 Adverse Events 
An Adverse Event (AE) is defined as any medical occurrence in a participant, including any 
abnormal sign (e.g., abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with the participant’s involvement in the research, whether or not 
considered related to participation in the research. This definition includes concurrent illnesses or 
injuries and exacerbation of pre-existing conditions.  


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Events related to planned treatments or physician visits for Baseline conditions collected in the 
medical history will not be collected, unless there is an exacerbation of the condition, in which 
case they will be actively followed until resolution. 
 
An unexpected AE is one that is not listed in the current IB or an event that is by nature more 
specific or more severe than a listed event. 
 
The site physician will be responsible for reviewing and confirming all AEs and SAEs collected 
during the study. The therapy teams will collect AEs during study visits from Enrollment (Visit 0) 
through Study Termination (Visit 15). All SAEs will be collected from the time of informed 
consent signed through Study Termination (Visit 15). Participants will be asked directly how they 
are feeling during each contact, and AEs may be captured spontaneously during psychotherapy 
sessions, telephone calls, or other correspondence. Completed measures may create suspicion that 
an AE occurred; in this case, the site staff should follow-up with the participant. 
 
All AEs will be monitored by the therapy team until resolution or, if the AE becomes chronic, a 
cause can be identified. If an AE is unresolved when a participant terminates from the study, a 
clinical assessment will be made by the site physician, investigator, and/or Medical Monitor as to 
whether continued follow-up of the AE is warranted. 
 
The severity of events reported on the “Adverse Events” eCRF will be determined by the site 
physician as: 
• 
Mild: No limitation in normal daily activity 
• 
Moderate: Some limitation in normal daily activity 
• 
Severe: Unable to perform normal daily activity 
 
The seriousness and relationship of study treatment to an AE will be determined by the 
Investigator based on the following definitions:  
1. “Not Related”: The AE is not related if exposure to the investigational product has not 
occurred, or the occurrence of the AE is not reasonably related in time, or the AE is 
considered unlikely to be related to use of the investigational product, i.e., there are no facts 
(evidence) or arguments to suggest a causal relationship, or the AE is more likely related to 
the subject’s pre-existing condition.  
2. “Related”: The administration of the investigational product and AE are considered 
reasonably related in time and the investigational product is more likely than other causes 
to be responsible for the AE or is the most likely cause of the AE. 
 
 
10.1.1 Adverse Events of Special Interest  
The sponsor will pay special attention to a subset of AEs involving psychological distress, 
including Low Mood (occurring up to 5 days after Experimental Sessions), suicidal ideation and 
suicidal behavior, as well as cardiac function that could be indicative of QT interval prolongation 
or cardiac arrhythmias, including Torsade de pointes, sudden death, ventricular extrasystoles, 
ventricular tachycardia, ventricular fibrillation and flutter, syncope (non-postural), and seizures. 
These AEs will be marked in the eCRF with the denotation “Adverse Event of Special Interest” 
(AESIs) whether serious or non-serious. 
 
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• 
AESIs involving the terms of Behavioral addiction, Drug abuser, Substance abuser, 
Dependence, Intentional product misuse (including facilitation of product use outside of 
research setting), Overdose (accidental, intentional, or prescribed), or Drug diversion will 
be collected and coded as AESIs in the eCRF if noted in relation to MDMA or Ecstasy. 
• 
Cases of noncompliance, protocol violations, participants lost to follow-up, and any other 
reasons why participants dropped out of the study will be assessed for presence of AESIs. 
• 
Qualitative urine drug test data will be collected prior to each Experimental Session. Any 
positive findings that cannot be attributed to pre-approved concomitant medications or 
diet will be reviewed by the Medical Monitor to assess compliance with ongoing 
eligibility criteria and for presence of AESIs. 
 
If an AESI is a SAE, it should be reported via the eCRF within 24 hours of the site’s awareness of 
the event. 
 
10.1.2 Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose: 
 
• 
Results in death. 
• 
Is life-threatening (i.e., the participant was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires or prolongs inpatient hospitalization. 
• 
Results in persistent or significant disability/incapacity (i.e., the event causes substantial 
disruption of a person’s ability to conduct normal life functions). 
• 
Results in a congenital anomaly/birth defect. 
• 
Requires intervention to prevent permanent impairment or damage. 
• 
Is an important and significant medical event that may not be immediately life-
threatening or resulting in death or hospitalization, but based upon appropriate medical 
judgment, may jeopardize the participant or may require intervention to prevent one of 
the other outcomes listed above. 
 
AEs which do not fall into these categories are defined as non-serious. It should be noted that a 
severe Adverse Event need not be serious in nature and that a SAE need not, by definition, be 
severe. In addition, SAE’s will be evaluated by the Sponsor or designee for “expectedness.” An 
unexpected SAE is one that is not listed in the current IB or an event that is by nature more 
specific or more severe than a listed event. 
 
In addition, a pre-existing event or condition that results in hospitalization should be recorded on 
the medical history. The hospitalization would not result in the event or condition being reported 
as a study-related SAE, unless, in the view of the site physician, hospitalization was prolonged as 
a result of participation in the clinical trial or was necessary due to a worsening of the pre-
existing condition. This is because the onset of the event (the reason for the procedure) occurred 
before the participant was entered in the trial. Hospitalization for cosmetics, non-emergency 
prophylaxis, or elective abortion does not result in an SAE report, unless, in the view of the site 
physician, hospitalization for these procedures was prolonged as a result of participation in the 
clinical trial. 
 


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All SAEs will be collected from the time of informed consent through Study Termination. All 
SAEs which occur during the course of the trial, whether considered to be associated with IP or 
not, must be reported to the sponsor within 24 hours of the site staff’s awareness of occurrence. 
Reporting procedures will be provided to the site. All SAEs will be assessed for relationship, 
expectedness and any required actions to address safety at the time of reporting of the event. 
SAEs will be evaluated by the site physician and Medical Monitor to determine if it is appropriate 
for the participant to continue treatment or enter follow-up. Any participant who experiences a 
SAE considered related to the IMP administration will be permanently discontinued from future 
IMP treatments. All SAE’s must be reported by the investigator to his/her corresponding EC or 
applicable regulatory authorities in accordance with institutional policy/regulatory requirements 
and adequate documentation of this notification must be provided to the Sponsor. 
 
10.1.3 Suspected unexpected serious adverse reaction 
A suspected unexpected serious adverse reactions (SUSAR) is defined as any untoward and 
unintended response to a study drug, which is not expected, and meets one of the following 
serious criteria: 
• 
Results in death. 
• 
Is life threatening (i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires or prolongs inpatient hospitalization. 
• 
Results in persistent or significant disability/incapacity (i.e., the event causes substantial 
disruption of a person’s ability to conduct normal life functions). 
• 
Results in a congenital anomaly/birth defect. 
• 
Requires intervention to prevent permanent impairment or damage. 
• 
Is an important and significant medical event that may not be immediately life-
threatening or resulting in death or hospitalization, but based upon appropriate medical 
judgment, may jeopardize the participant or may require intervention to prevent one of 
the other outcomes listed above. 
 
 
All SUSARs will be collected from enrollment through Study Termination. All SUSARs must be 
reported to the sponsor immediately, within 24 hours of the site staff’s awareness of occurrence. 
MAPS or its designee will comply with Directive 2001/20/EC or with the applicable regulatory 
requirement(s) related to the reporting of suspected unexpected serious adverse reactions 
(SUSARs) to the regulatory authority(ies) and the EC.  
 
If a SUSAR or other safety signal relating to use of the IP is reported to MAPS or its designee, 
the Sponsor will communicate the information to the investigator and the investigator will be 
responsible for submitting this information to the EC and other relevant authorities. 
 
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. 
 


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10.3 Pregnancy 
10.3.1 Definition of People Able to Become Pregnant  
A participant is considered able to become pregnant if they were assigned female at birth and are 
post-menarche. A participant is considered not able to become pregnant if they are premenarchal, 
surgically sterile (documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy, 
and/or tubal ligation), postmenopausal, or assigned male at birth.  
 
10.3.2 Contraception Guidelines 
Adequate and only highly effective birth control methods are required for participants who are 
able to become pregnant (PABP), i.e. fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilisation methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy.  
 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in participants assigned female sex at birth not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required.  
 
Acceptable birth control methods include:   
 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Non-oral hormonal methods, including injected, intravaginal, implanted, transdermal 
• 
Oral hormones plus a barrier contraception (condom, diaphragm, or spermicide)  
• 
Vasectomized partner, if partner is the sole sexual partner of the PABP trial participant 
and that the vasectomised partner has received medical assessment of the surgical 
success.  
• 
Abstinence from penile-vaginal intercourse, defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. 
o The reliability of abstinence should be evaluated carefully with the participant in 
relation to their general lifestyle and will be evaluated in relation to the duration 
of the clinical trial.  
• 
Note: Hormonal contraception must be associated with inhibition of ovulation. 
 
For questions about acceptable birth control methods, contact the Medical Monitor. 
 
10.3.3 Follow-up Requirements 
Details of all pregnancies in study participants will be collected after Enrollment (Visit 0) and 
collected through 10 days after the last Experimental Session. Pregnancies should be reported to 
the sponsor via telephone or email within 24 hours of site staff awareness. 
 
    
In the event of a pregnancy, the participant will discontinue Experimental Sessions but may 
continue with non-drug Integrative Sessions, the next CAPS-5 assessment, and Study 
Termination procedures. At a minimum, prior to withdrawal from the study, efforts should be 
made to assess the final CAPS-5 immediately and complete Study Termination procedures. 


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The investigator will collect follow-up information on the participant and neonate and forward to 
the sponsor until the outcome of the pregnancy, which will be reported in the Pregnancy eCRF. 
Any termination, elective or spontaneous, will be reported. Abnormal pregnancy outcomes, such 
as spontaneous abortion, fetal death, stillbirth, congenital abnormalities, or ectopic pregnancy, 
will be reported as SAEs. 
 
11.0 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. The medications will 
then be tapered in an appropriate fashion to avoid withdrawal effects and discontinued at least 
five half-lives plus one additional week for stabilization before the first Experimental Session to 
avoid the possibility of any interaction. Additionally, participants who are taking prohibited 
opiates will be cross-tapered to an allowable opiate (hydrocodone, morphine, and codeine) under 
the care of their prescribing physician.  
 
The site physician will consult the prescribing physician to initiate medication tapering for 
participants, as they must refrain from taking psychiatric medications throughout the study, with 
some exceptions (see Section 11.2 Allowable Concomitant Medications). The prescribing 
physician’s opinion about medication discontinuation will documented either in writing from the 
prescribing physician, or in writing by the site physician documenting phone contact with the 
prescribing physician. Tapering will follow a time course appropriate for the medication based on 
its half-life, with the first Experimental Session scheduled to occur after complete washout (five 
half-lives plus at least 1 week for stabilization). If the health of the participant worsens after 
tapering, the participant will be withdrawn from the study and will be treated according to 
standard clinical practice. This will be recorded in the eCRF. 
 
The therapy team will request information about any changes in medication at each contact. The 
site physician will be responsible for reviewing and confirming all medications collected during 
the study.  
 
All medications, non-prescription and prescription, will be collected from Screening through 7 
days after the last Experimental Session. From 7 days after the last Experimental Session through 
Study Termination, only prescription or non-prescription medications taken to treat AEs will be 
collected. Throughout the protocol, all medications used to treat AEs will be collected, and all 
changes including discontinuations or additions to medications will be collected. The study team 
will inquire and document all information about withdrawal and tapering of medications, 
concomitant medication and medication adherence in the eCRF Concomitant Medications. 
 
Participants may return to taking psychiatric medications and discontinue birth control after the 
final Study Termination visit if necessary. 
 
11.2 Allowed Concomitant Medications 
The site physician may prescribe necessary and appropriate medications in accordance with local 
country regulations during the study to treat AEs that do not respond to other management 


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outlined in the Treatment Manual. Examples include concomitant benzodiazepines for 
uncontrolled anxiety (specifically, lorazepam at modest doses and occasional use only to avoid 
withdrawal effects of discontinuation between Experimental Sessions) or sleep aids (excluding 
trazodone) in compliance with Section 11.3 Prohibited Medications.  
 
Gabapentin or certain opiates will be allowed when prescribed for pain management. The 
following opiates will be allowed during the study: hydrocodone, morphine, and codeine. Prior to 
receiving study drug, participants who are taking opiates not included on this list will be cross-
tapered to an allowable opiate under the care of their prescribing physician. Opiate medications 
may reduce the efficacy of MDMA and may prolong QT/QTc interval, but the opiates that are 
allowed during this trial have been selected because they have the lowest potential for QT/QTc 
interval prolongation. Individuals using opiates for pain management will be asked to decrease 
the dose leading up to the Experimental Session in order to avoid withdrawal effects when they 
are required to refrain from taking the medication from 12 hours before IP administration at the 
Experimental Session to 24 hours after. If a participant reports lack of analgesic effect during the 
sub-acute period following each Experimental Session, the site physician may cross-taper to a 
different allowed opiate medication. 
 
If the participant is on stimulants for attention deficit/hyperactivity disorder (ADHD) at Baseline, 
they can continue to use them at the same dose and frequency, as long as they discontinue five 
half-lives before each Experimental Session and do not restart for 10 days after each 
Experimental Session. 
 
All psychoactive medications, herbal supplements, nonprescription medications, and prescription 
medications must be reviewed by the research team. Failure to comply with protocol 
requirements for concomitant medications may result in withdrawal from treatment, depending on 
the investigator and Medical Monitor judgment. 
 
11.3 Prohibited Medications 
To be enrolled in the study participants must: 
 
• 
Refrain from the use of any psychoactive medication not approved by the research team 
from Baseline through Study Termination (with the exception of gabapentin or certain 
opiates for pain control). 
• 
Be willing to comply with all medication requirements per protocol. Medications will 
only be discontinued after enrollment per clinical judgment of the site physician in 
consultation with the prescribing physician. 
• 
Agree that, for 1 week preceding each Experimental Session to refrain from: 
o Taking any specified herbal supplement (except with prior approval of the 
research team). 
o Taking any nonprescription medications (with the exception of non-steroidal 
anti-inflammatory medications or acetaminophen) unless with prior approval of 
the research team. 
o Taking any prescription medications (with the exception of birth control pills, 
thyroid hormones, or other medications approved by the research team). 
 
The research team should only approve medications that clearly would not be expected to have 
any interactions with MDMA, including, but not limited to, any drugs with sympathomimetic 


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activity or activity on the serotonin or other monoamine systems, and any other drugs that would 
be contraindicated with or have any interaction with monoamine oxidase inhibitors (MAOIs). 
 
The following medications are prohibited as they would present potential confounds for 
interpretation of the data collected from this study as they have notable serotonergic effects or are 
under potential or available treatments for PTSD: 
 
Use of Marijuana, St. John’s Wort, and other herbs and medicines with notable serotonergic 
effects are prohibited from Baseline to Study Termination. Any investigational treatments under 
study for PTSD treatment are prohibited from use concurrent with this study. 
 
Diphenhydramine is excluded from this study unless prior approval is granted by the site 
physician. 
 
If an SSRI, SNRI, or other antidepressant is used between Experimental Session 1 (Visit 4) and 
Study Termination (Visit 15), the participant will be withdrawn from treatment and continue in 
follow-up. 
 
Opiates other than hydrocodone, morphine, and codeine are prohibited from Enrollment 
Confirmation to Study Termination. Participants taking prohibited opiates will be cross-tapered to 
an allowable opiate during the Preparatory Period. 
 
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 
• 
CBC 
o Hematocrit 


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o Hemoglobin 
o Mean corpuscular volume (MCV) 
o Mean corpuscular hemoglobin (MCH) 
o Mean corpuscular hemoglobin concentration (MCHC) 
o Red cell distribution width (RDW) 
o Percentage and absolute differential counts 
o Red blood cell (RBC) count  
o White blood cell (WBC) count  
• 
Urinalysis 
o Color 
o Appearance 
o Specific gravity 
o pH 
o Protein 
o Glucose 
o Ketones 
o Occult blood 
o Leukocyte esterase 
o Nitrite 
o Bilirubin 
o Urobilinogen 
• 
Thyroid function 
o Thyroid-stimulating hormone (TSH) high sensitivity (if abnormal, free T3 and 
T4 will also be tested) 
• 
HCV antibody if indicated, with reflexive RNA test 
• 
%Carbohydrate deficient transferrin (%CDT) to detect heavy alcohol use 
• 
Pregnancy test 
o A highly sensitive pregnancy test for PABP will be performed at the site or by 
the central lab at screening, and at the site before each experimental session.   
o A serum or urine sample may be used. 
§ 
In the UK, screening pregnancy test must use serum only. 
o A final urine pregnancy test should be completed at Visit 13 (or at Visit 14 or 15, 
if Visit 13 is done remotely) for PABP.  
• 
Qualitative drugs test 
o To be performed at the site during screening and before each experimental 
session. 
§ 
In the UK, also includes alcohol. 
 
Laboratory assessments, with the exception of urine pregnancy and drug tests, will be performed 
by a central laboratory in Europe. Certificates and normal ranges will be stored in the site’s 
Investigator Site File (ISF). 
 
Additional laboratory assessments may be ordered by the Principal Investigator if indicated, in 
consultation with the Medical Monitor. 
 
13.0 Statistical Considerations  
Key personnel, MAPS, and the biostatistician will agree on a Statistical Analysis Plan at the 
beginning of the study, which will provide more detail about analyses than provided in this 


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protocol. An overview of the statistical analyses that will be performed is provided in the 
following sections. 
 
13.1 Statistical Analyses 
Descriptive statistics will be computed overall, as well as by initial MDMA dose received, for all 
available data from outcome measures, including minimum, maximum, average, median, and 
standard deviation.  
 
The following analysis sets are defined for this study: 
 
• 
All Enrolled: all participants who sign informed consent and are initially enrolled 
• 
mITT: all participants who receive investigational product in at least one Experimental 
Session and have at least one follow-up CAPS-5 assessment 
• 
Per Protocol (PP): all participants who receive investigational product in two 
Experimental Sessions and have three CAPS-5 assessments 
• 
Not Per Protocol (NPP): all participants who are included in the mITT Set but not the PP 
Set 
• 
Safety: all participants who receive the IP  
 
13.1.1 Effectiveness Analyses 
 Primary Outcome Analyses 
The primary analysis will be conducted after all participants complete Study Termination (Visit 
14) and the study database has been locked. All outcome analyses will be based on the mITT 
analysis set. The de jure estimand of treatment effectiveness is of the most relevance to measure 
the effect of two experimental sessions, given actual adherence to treatment of MDMA-assisted 
psychotherapy in a controlled clinic setting on PTSD symptom severity in the intended 
population of patients with PTSD from any cause. The primary estimator of effectiveness will be 
the mean change in CAPS-5 Total Severity Scores from Baseline to 14 weeks after start of dosing 
(Visit 14). Least squares means from a restricted maximum likelihood (REML)-based mixed 
model for repeated measures (MMRM) will be used to estimate the change in CAPS-5 from 
baseline to each visit. Ninety-five percent confidence intervals will be calculated for the estimated 
mean change from baseline CAPS-5 scores at each visit. Missing data will not be imputed and 
will be considered missing at random. 
 
 Secondary Outcome Analyses 
Sheehan Disability Scale (SDS), the secondary outcome measure, will be analyzed in the same 
manner as the Primary Outcome. The secondary estimator of effectiveness will be the mean 
change in SDS Mean Item Scores from Baseline to 14 weeks after start of dosing (Visit 14). Least 
squares means from a REML-based MMRM will be used to estimate the change from Baseline to 
each visit. SDS data collected after treatment discontinuation will not be included in the de jure 
estimand.  
 
 Exploratory Analyses 
One-group pretest-posttest Cohen’s d effect size will be estimated. Exploratory sub-group 
analyses may be conducted when possible to evaluate effects and by individual demographic 


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characteristics (e.g., age, gender, ethnicity, index trauma, ACE score, presence of secondary 
traumatic stressors during the assessment period with LEC-5, medication tapering, diagnosis of 
comorbid depression, diagnosis of comorbid diagnosis, and number of experimental sessions 
completed). Post-hoc exploratory analyses not described in the protocol or Statistical Analysis 
Plan may be performed to further examine the study data. These analyses will be clearly 
identified as such in the final clinical study report.  
 
13.1.2 Safety Analyses 
Safety data will be summarized by exposure to IP, unsolicited AEs, concomitant medications, 
suicidal ideation and behavior, and vital signs overall. If a participant has more than one AE 
mapped to the same PT, that AE will be reported once using the highest severity. AEs that occur 
on Day 0 (Experimental Session), Day 1, Day 2 after IP administration will be presented 
separately. Report incidence of AEs during Experimental Sessions such as clinical signs and 
symptoms, such as chest pain, shortness of breath, or neurological symptoms or any other signs or 
symptoms that may be indicative of a medical complication of the IP.  
 
Frequency and incidence of concomitant medications will be displayed by generic name, sorted 
by class, and summarized by analysis set and category. Concomitant medications taken on Day 0 
(Experimental Session), Day 1, Day 2 after IP administration will be presented separately. Any 
psychiatric concomitant medications will be tabulated by period (Preparatory, Treatment Period, 
Follow-up Period). Frequency and incidence of positive or serious ideation and suicidal behavior 
will be presented using descriptive statistics of C-SSRS scores in tabular format. Vital signs 
(heart rate, blood pressure, and body temperature) for Experimental Sessions will be summarized 
using descriptive statistics in tabular format listing values at pre-IP administration, prior to the 
supplemental dose, and at the end of each Experimental Session. Additional details are available 
in the Statistical Analysis Plan. 
 
14.0 Study Governance 
MAPS Europe B.V. is a small/medium-sized enterprise that is a wholly owned subsidiary of the 
Multidisciplinary Association for Psychedelic Studies (MAPS), a non-profit research and 
educational organization based in the United States. The sponsor, MAPS Europe B.V., is 
developing MDMA for treatment of PTSD in Europe and is responsible for trial organization, 
including designing, initiating, managing, coordinating, continuing, and concluding the clinical 
trials within the Clinical Development Program. Funding for the trials is provided by MAPS. The 
sponsor is tasked with maintaining the quality of study conduct through ongoing monitoring of 
data. The sponsor has delegated the design, systems infrastructure, and retention of Essential 
Documents to the MAPS Public Benefit Corporation (MPBC). The sponsor contracts with 
independent entities who represent clinical sites to accomplish these goals.  
 
14.1 Ethics 
This clinical study was designed and shall be implemented and reported in accordance with the 
International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP), 
with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal 
Regulations Title 21) and with the ethical principles laid down in the Declaration of Helsinki 
[118, 119].  
 
The protocol, the ICF and other study documents must be reviewed and approved by a properly 
constituted institutional review board (IRB) or ethics committee (EC) and country regulatory 


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agency before study start. Signed and dated documentation of approvals must be provided to the 
sponsor. Prior to study start, the investigator is required to sign a signature page confirming her or 
his agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to the 
sponsor. 
 
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 
"Informed consent" is the voluntary agreement of an individual to participate in research. Consent 
must be given with free will of choice, and without undue inducement. The individual must have 
sufficient knowledge and understanding of the nature of the proposed research, the anticipated 
risks and potential benefits, and the requirements of the research to be able to make an informed 
decision. 
 
The investigator and therapy team are responsible for obtaining informed consent in adherence to 
protocol, GCP and according to applicable local regulations prior to entering the participant into 
the trial. Potential participants may be sent the Informed Consent Form (ICF) to review after the 
initial phone screen. Preferably, informed consent will be obtained by the one of the therapists 
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 local country regulations. The participant should have the opportunity to 
inquire about details of the study and should be given sufficient time to read and consider 
participation. Potential participants will be given approximately two weeks to read the 
information and decide whether they are interested in participating in the study. 
 
Discussion about the study and informed consent may take place either at site or via tele-
assessment/video call. However, the informed consent form (ICF) should be signed in the 
presence of the investigator or delegate at the first in-person visit at the site. The study staff will 
counter sign the ICF, copy the ICF for the participant and file the original at the site in the ISF. 
 
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/EC approved ICF. 
Informed consent must be obtained before conducting any study-specific procedures (i.e., all of 
the procedures described in the protocol beyond phone screening). The process of obtaining 
informed consent should be documented in the participant’s source records.  
 
The 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 


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participant’s consent. Any revised ICF and written information should receive approval from an 
IRB/EC 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 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. Study sites will 
be monitored by site visits and telephone calls by representatives of the sponsor. In addition, 
critical data and systemic issues will be subject to centralized monitoring via the EDC system to 
develop and evaluate strategies for correction across sites. Sites will be monitored as appropriate 
for the rate of enrollment, to comply with GCP guidelines and local regulations and to ensure 
validity of study data. During each monitoring visit, source data verification will be performed to 
ensure compliance, including accurate and complete recording of data on eCRFs, source records, 
and IP accountability records. An eCRF collation will be completed for each participant enrolled 
within the EDC system.  
CAPS-5 results may be shared with site staff. The IR Coordinator will be responsible for review 
and data entry of the CAPS-5 source records into CAPS-5 eCRFs.  
 
Videos from selected sessions will be reviewed for adherence to the Treatment Manual as 
described in Section 6.4. Findings from video reviews may be discussed between the therapy 
team and their supervisor as needed to ensure continued adherence to the protocol. 
 
During or after the study, the regulatory authorities, the IRB, and/or representatives of the 
sponsor may request access to all source documents, eCRFs, and other protocol documentation 
for on-site audit or inspection.  
 
14.2.1 Source Records 
Prior to start of the study the site staff participating in the study conduct will be trained on what 
documents will be required for review as source documentation. The kind of documentation that 
will serve as source documents will be specified on the Source Document Agreement and this 
agreement will be finalized before the first participant’s first visit at each site.  
 
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, MRI scans (if applicable) and laboratory reports. The participant must 
also allow access to their medical records if available. Each participant must be informed of this 
prior to the start of the study and consent for access to medical records may be required in 
accordance with local regulations.  
 
All data reported in the eCRF are transcribed from primary source documents and must be 
consistent. These documents are to be maintained at the study site securely. Source records of 
CAPS-5 assessments will be stored in dedicated limited access files during the study.  
 


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14.3 Confidentiality and Data Protection 
Every effort will be made to strictly safeguard the confidentiality of participants. Removing 
identifying information from data and restricting access to researchers directly involved in 
assessing the participants should prevent the dissemination of confidential data. Except for the 
Screening Log, the Informed Consent, previous medical records, emails with the participant, and 
a Contact Information Sheet that will be stored separately from other study documents, all source 
data will be identified only by the participant number and the participant’s identifier code. All 
source documents will be kept in a locked file drawer or cabinet in a locked office, and access to 
measures will be limited to regulatory agencies, researchers, and individuals analyzing data. 
Researchers with access to data, other than the investigators who are directly involved in the 
protocol, will not be provided with any information that would identify participants by name or 
by other means, such as social security number.  
 
Maintaining data in a secure environment will prevent the accidental or deliberate examination or 
removal of data. The sponsor will utilize confidentiality procedures to assure participant privacy. 
Data will be securely transferred to remote and secure servers. Clinical trial data other than video 
data will be hosted on an EDC system compliant with Title 21 Part 11 policies of the Code of 
Federal Regulations in the US and with applicable EU Directives. The data system includes 
password protection and internal quality checks. The EDC system will be designed and validated 
by the Sponsor prior to activation for data entry by sites. The investigator or designated delegate 
must review data entered and electronically sign the eCRFs to verify their accuracy. 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.  
 
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. 
ePRO will be only used by the participants enrolled in the United Kingdom.  
 
The sponsor respects the participants’ rights to privacy and will ensure the confidentiality of their 
medical information in accordance with all applicable laws and regulations. With regards to any 
personal data processed in the context of this study, the sponsor and MAPS PBC serve as joint 
data controllers according to the General Data Protection Regulation (GDPR). The sponsor is 
responsible for exercising the rights of data subjects. The legal basis for data transfer between the 
sponsor and MAPS PBC, including responsibilities related to cross-border data transfers, is 
described in a controller-to-controller agreement with Standard Contractual Clauses. 
 
 
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 


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reimbursed for reasonable expenses incurred for study participation, such as local travel expenses. 
This is specified in each site’s informed consent. 
 
Participants will not receive monetary compensation for taking part in the study.  
 
14.5 Treatment and Compensation for Study Related Injury 
Some study-related emergencies can be treated by the site physicians. If the site physicians 
cannot treat a study-related emergency, then there are contingency plans for the transport of 
participants to the nearest hospital. Treatment of a study-related emergency would first be billed 
to a participant’s health insurance provider. If the participant's private health insurance plan does 
not cover clinical trial-related claims, then the sponsor will cover any treatment costs directly 
related to the study. The sponsor will not cover costs of ongoing treatment unrelated to the study 
due to pre-existing conditions, or the cost of the participant's time spent obtaining treatment for 
pre-existing conditions before receiving treatment in the study. In the event of a suit against the 
sponsor, the sponsor carries third-party insurance that will cover bodily injury claims and will pay 
for applicable legal defense if needed/warranted.  
 
 
14.6 Record Retention 
Investigators must retain all study records required by the sponsor and applicable ICH-GCP and 
local country regulations in a secure and safe facility. The Investigator must consult a 
representative of the sponsor before disposal of any study records and must notify the sponsor of 
any change in the location, disposition, or custody of the study files. “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.  
 
Essential documents should be retained in the sponsor Trial Master File until at least 2-years after 
the last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2-years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period however if required by the applicable regulatory 
requirement(s) or if needed by the sponsor (ICH E6 (R2))[120]. 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 PIs 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 Principal Investigators that the information generated in this study will be used by the sponsor 
in connection with the development of the IP and therefore may be disclosed to government 


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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 PIs 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 Master Service Agreement 
and Clinical Trial Agreements.  
 
 


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References 
 
1. 
Weathers, F.W., et al., The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5): 
Development and Initial Psychometric Evaluation in Military Veterans. Psychol Assess, 
2017. 
2. 
Lanius, R.A., et al., The dissociative subtype of posttraumatic stress disorder: rationale, 
clinical and neurobiological evidence, and implications. Depress Anxiety, 2012. 29(8): p. 
701-8. 
3. 
Lanius, R.A., et al., Emotion modulation in PTSD: Clinical and neurobiological evidence 
for a dissociative subtype. Am J Psychiatry, 2010. 167(6): p. 640-7. 
4. 
Nicholson, A.A., et al., The Dissociative Subtype of Posttraumatic Stress Disorder: 
Unique Resting-State Functional Connectivity of Basolateral and Centromedial 
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stress disorder. Arch Gen Psychiatry, 2005. 62(3): p. 273-81. 


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Felmingham, K., et al., Changes in anterior cingulate and amygdala after cognitive 
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Lindauer, R.J., et al., Effects of psychotherapy on regional cerebral blood flow during 
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Lanius, R.A., et al., Neural correlates of trauma script-imagery in posttraumatic stress 
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Etkin, A. and T.D. Wager, Functional neuroimaging of anxiety: a meta-analysis of 
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Stein, M.B., et al., Increased amygdala and insula activation during emotion processing 
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Bush, G., P. Luu, and M.I. Posner, Cognitive and emotional influences in anterior 
cingulate cortex. Trends Cogn Sci, 2000. 4(6): p. 215-222. 
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Whalen, P.J., et al., Masked presentations of emotional facial expressions modulate 
amygdala activity without explicit knowledge. J Neurosci, 1998. 18(1): p. 411-8. 
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Hamner, M.B., J.P. Lorberbaum, and M.S. George, Potential role of the anterior 
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Pitman, R.K., L.M. Shin, and S.L. Rauch, Investigating the pathogenesis of posttraumatic 
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Milad, M.R. and G.J. Quirk, Neurons in medial prefrontal cortex signal memory for fear 
extinction. Nature, 2002. 420(6911): p. 70-4. 
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Shin, L.M., et al., Regional cerebral blood flow during script-driven imagery in 
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Kim, M.J., et al., Diminished rostral anterior cingulate activity in response to threat-
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McGaugh, J.L., The amygdala modulates the consolidation of memories of emotionally 
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Corcoran, K.A. and S. Maren, Hippocampal inactivation disrupts contextual retrieval of 
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Astur, R.S., et al., Hippocampus function predicts severity of post-traumatic stress 
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Peres, J.F., et al., Cerebral blood flow changes during retrieval of traumatic memories 
before and after psychotherapy: a SPECT study. Psychol Med, 2007. 37(10): p. 1481-91. 
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Bluhm, R.L., et al., Alterations in default network connectivity in posttraumatic stress 
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social reward. Psychopharmacology, 2009. 207(1): p. 73-83. 
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Hysek, C.M., et al., MDMA enhances emotional empathy and prosocial behavior. Social 
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Wardle, M.C. and H. de Wit, MDMA alters emotional processing and facilitates positive 
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Kirkpatrick, M.G., et al., MDMA effects consistent across laboratories. 
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Baumgartner, T., et al., Oxytocin Shapes the Neural Circuitry of Trust and Trust 
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173. 
Petrovic, P., et al., Oxytocin Attenuates Affective Evaluations of Conditioned Faces and 
Amygdala Activity. The Journal of Neuroscience, 2008. 28(26): p. 6607-6615. 
174. 
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Appendix A: Imaging Sub-Study 
This sub-study to the MP18 protocol “An Open-Label, Phase 2, Multicenter Feasibility Study of 
Manualized MDMA-Assisted Psychotherapy with an Optional fMRI Sub-Study Assessing Changes 
in Brain Activity in Subjects with Posttraumatic Stress Disorder” allows participants to participate in 
pre and post treatment imaging (Visits 4.1 and 14.1) and will be performed at pre-selected study sites. 
 
Study site and participants will follow all protocol procedures described in the main protocol, with the 
addition of imaging visits as described below.  
 
1.0 Neurocircuitry of PTSD  
 
Neuroimaging of individuals with PTSD has demonstrated structural and functional abnormalities in brain 
regions such as the amygdala, insula, medial prefrontal cortex (mPFC), and hippocampus [121]. These 
regions are associated with fear conditioning, fear extinction and the regulation of emotions [122]. Some 
brain abnormalities may predispose to the development of PTSD, whilst others are a sequela of PTSD [123]. 
For instance, non-trauma exposed twins of sufferers may show smaller hippocampal volumes [124] and 
increased resting metabolic activity in the anterior cingulate cortex [122], whilst PTSD sufferers acquire 
further secondary loss of hippocampal volumes [125]and lower grey matter density of the pregenual ACC 
[126]. 
 
A common functional brain imaging task involves script driven imagery, whereby individuals are prompted 
to relive their trauma [127]. This task closely replicates reactions that would be seen during imaginal 
exposure in TFPT, and would therefore be a useful tool in exploring the therapeutic mechanism of a new 
drug that could augment therapy. Another task involves presenting individuals with non-trauma related 
emotional stimuli which may replicate hypervigilance within the therapeutic relationship[128]. 
 
The amygdala is a medial temporal lobe structure that plays an important role in fear conditioning and threat 
detection [129]. PTSD is characterized by hyperactivity in the amygdala, which may account for the failure 
of fear extinction and exaggerated startle response observed [130]. Increases in amygdala activation have 
been reported in several task based functional imaging studies of PTSD, where symptoms are provoked 
using traumatic memory cues such as combat images, sounds and smells [121].  
 
The neurocircuitry model of PTSD hypothesizes that the amygdala, medial prefrontal cortex (mPFC) and 
hippocampus are dysfunctional [131]. Specifically, the amygdala is hyperactive in response to threat-related 
stimuli [127], and this accords with both an exaggerated fear response and overgeneralized fear conditioning 
[131]. Additionally, compared to traumatized controls, people with PTSD show a relative failure to activate 
the mPFC (hypoactivation) when engaged in trauma imagery [127] and the mPFC fails to exert top-down 
control over the amygdala [131], leading to both emotional dysregulation and impaired fear extinction. 
Lastly, impaired hippocampal activity may underlie deficits in recognizing present contexts as safe during 
fear extinction [131]. 
 
Combat veterans with PTSD show more physiological reactivity, including increased heart rate and blood 
pressure in response to combat related stimuli than combat veterans without PTSD [132]. Neuroimaging 
studies have demonstrated that the amygdala is hyperactive when personalized trauma scripts are used [133, 
134]. Increased amygdala activation also extends to emotional, non-trauma related stimuli. Exposure to 
emotional faces has been an especially effective probe of amygdala function [135]. There is increased 
amygdala activity in individuals with PTSD in response to fearful versus happy faces [125, 130, 136, 137] 
and this increased amygdala activation has been positively correlated with PTSD symptom severity [121, 
138]. Successful exposure therapy has been associated with decreased amygdala activation during fear 
conditioning [139].  


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The insula is structurally interconnected with the amygdala and specifically sensitive to salient 
environmental stimuli, marking such stimuli for further processing [140]. Several studies have reported 
hyperactivity of the insula in PTSD using trauma script symptom provocation [141, 142] as well as increased 
activity when processing fearful versus happy facial expressions [143]). A positive correlation has been 
reported between insula activation and PTSD severity [121] as well as in other anxiety disorders [135, 144, 
145].  
 
PTSD sufferers describe persistent re-experiencing symptoms and difficulty suppressing thoughts related to 
their trauma when performing unrelated cognitive tasks. The anterior cingulate cortex is involved in 
recruiting cognitive control over emotional processes [146], by decreasing the significance of affective 
information [147].The rostral subdivision plays an important role in regulating amygdala activity, with 
impairment of rACC leading to hyperactivity of the amygdala [148, 149]. The medial prefrontal cortex, 
including the rACC and vmPFC, acts in functional opposition to the amygdala, by extinguishing fear 
conditioning and retaining extinction [150]. 
 
Individuals with PTSD show reduced activation or greater deactivation in regions of the medial prefrontal 
cortex in response to traumatic-script driven imagery[127, 132, 151]. Diminished rACC and mPFC 
activation was also seen in response to fearful versus happy facial expressions, with rACC activation being 
negatively correlated with PTSD severity [136]. Likewise, there is diminished rACC activity in response to 
trauma-related and unrelated emotional interference [152] with a negative correlation between rACC 
activation and PTSD symptom severity. Poor response to cognitive behavioural therapy has been predicted 
by deficient pre-treatment rACC activation [137], whilst successful exposure therapy has been associated 
with increased rACC activation and decreased amygdala activation during fear processing [139]. Taken 
together, this suggests that the amygdala and mPFC are part of an emotional regulation circuit, and that 
mPFC inhibition of the amygdala-mediated fear response is required for fear extinction. 
 
PTSD sufferers experience disturbances in memory with symptoms such as intrusive recollections, 
dissociative flashbacks and psychogenic amnesia[138]. The hippocampus is involved in consolidating the 
memories of emotionally arousing experiences and modulating memories according to context during fear 
conditioning [153, 154]. There have been conflicting reports as to whether the hippocampus is hyperactive 
or hypoactive in PTSD but a meta-analysis suggested that overall there is reduced activity in PTSD [144]. 
In particular, individuals with PTSD have demonstrated reduced hippocampal activation in response to 
traumatic script provocation [132]. Reduced hippocampal activation in a virtual Morris water task (designed 
to test learning, memory and spatial navigation) predicted symptom severity in participants with PTSD 
[155]. Successful treatment with psychotherapy in patients with subthreshold PTSD has found increased 
hippocampal activation in response to traumatic scripts [156].  
 
The findings described above illustrate functional changes in task-based conditions. Similar changes have 
also been demonstrated in spontaneous, resting brain activity and functional connectivity [157]. A functional 
MRI study of non-provocation, resting state activity in veterans with PTSD found increased magnitudes of 
spontaneous brain activity in the left amygdala, as well as the right anterior insula, ventral anterior cingulate 
and orbital frontal cortex. Veterans also showed decreased spontaneous activity in the precuneus, dorsal 
lateral prefrontal cortex and thalamus [158], with a negative correlation between resting thalamic activity 
and severity of re-experiencing symptoms [152, 158]Interestingly, a case study has described a veteran who 
developed PTSD symptoms following a thalamic infarct [159].  
 
Certain brain regions, including the mPFC, posterior cingulate cortex (PCC), precuneus and lateral parietal 
cortices, are more active and temporally synchronised with each other when an individual is in a state of 
wakeful rest. This has been termed the default mode network [160]. The default mode network may reflect 
a brain state that is involved in processing self-referential thought and is temporarily suspended during goal 


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directed activity [161]. Alterations in the resting state functional connectivity (RSFC) of the default mode 
network have been discovered for individuals with PTSD and may be associated with disturbances in self-
referential processing and dissociative symptoms [157]. Individuals with PTSD have been found to have 
increased positive RSFC between the amygdala and insula[162] and reduced positive connectivity between 
the amygdala and hippocampus. Additionally, there are negative correlations between the amygdala and the 
mPFC, rACC and dorsal ACC, supporting the hypothesis of an inhibitory role of the mPFC in relation to 
the amygdala. 
 
In the first resting state fMRI investigation of MDMA in healthy participants, the intensity of the euphoric 
effect correlated with reductions of cerebral blood flow (CBF) in the amygdala and hippocampus. 
Amygdalar response to angry faces was reduced in people given MDMA [163]. Moreover, a decreased 
RSFC was found between the hippocampus and vmPFC, whilst an increased RSFC was seen between the 
hippocampus and amygdala. The magnitude of the former correlated with the intensity and euphoria of the 
MDMA experience, suggesting that MDMA may exert some of its therapeutic effect by decreasing the 
coupling between the mPFC and hippocampus [54].  
 
MDMA administration in healthy participants has been shown to produce changes in regional blood flow, 
including increases in ventromedial frontal and occipital cortex, inferior temporal lobe and cerebellum; and 
decreases in the motor and somatosensory cortex, temporal lobe including left amygdala, cingulate cortex, 
insula and thalamus [42].This has the potential to reverse some of those abnormalities seen in participants 
with PTSD. 
 
A recent study showed that participants given MDMA are more likely to use words relating to friendship, 
support and intimacy, in comparison to the drug methamphetamine, which by contrast reduced participants’ 
discussions about compassion [163]. MDMA appears to enhance the quality of social interactions and 
thereby improve relationships, recently tested using a simulated experimental paradigm of social exclusion 
by Frye et al, 2014, showing how participants taking MDMA exhibited reduced social exclusion phenomena 
[164]. Another recent study showed similarly that MDMA enhances levels of shared empathy and pro-social 
behavior compared with placebo [165]. Furthermore, Wardle showed how MDMA can facilitate a faster 
detection of happy faces, and reduces the detection of negative facial expressions, which leads participants 
to view their social interaction partner as more caring [166]. Additionally, a recent study by comparing 
MDMA against intranasal oxytocin demonstrated the former produced the greater improvements in pro-
social communication [167]. And the positive effects of MDMA appear consistent across different 
environments, with participants examined in San Francisco, Chicago and Basel demonstrating broadly 
similar pro-social outcomes [167].  
 
Emotional numbing is a characteristic feature of PTSD, where sufferers find it difficult to benefit from the 
positive effects of social contact (DSM-5). There is a strong link between the strength of the therapeutic 
alliance and positive outcome in PTSD therapy [168]. MDMA induces the release of oxytocin and produces 
robust pro-social feelings, the strength of which is strongly correlated to the level of oxytocin released [169]. 
 
Oxytocin has been found to markedly dampen fear related amygdala activity, causing a decreased stress 
response, decreased social anxiety [170-172] and alters negative evaluations of aversive conditioned stimuli 
such as fearful faces [173]. The amygdala is required for accurate social judgements of others based on their 
facial expression [174]. Healthy volunteers given MDMA were better able to detect positive facial 
expressions than negative ones [165]. As described above, the vmPFC plays an inhibitory role opposing the 
amygdala and is essential for fear extinction learning. MDMA causes increased vmPFC activation and 
decreased amygdala activation when given to healthy controls [42] and in response to observing angry faces 
[163]. 
 


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Possible biological correlates of response to treatment in PTSD will be assessed by MRI. We aim to 
investigate pre-post effects of MDMA-assisted psychotherapy on brain function and connectivity as 
measured by functional magnetic resonance imaging (fMRI), including response to trauma-unrelated 
emotional stimuli (emotional faces), response to trauma symptom provocation (personal trauma narrative).  
 
This sub-study will measure changes in brain activity at rest, and in response to stressful or threatening 
stimuli in the form of an emotional eliciting task and personalized trauma script. Conclusions concerning 
the efficacy of MDMA-assisted therapy may be further supported if changes in PTSD symptoms are 
accompanied by changes in brain activity and alterations in brain metabolites. 
 
2.0 Implementation of Sub-Study 
 
All eligibility criteria from the main study protocol will apply, except for the following inclusion criteria: 
 
• 
Absence of Traumatic Brain Injury 
• 
Absence of metal implants or metal fragments in the body 
• 
Absence of claustrophobia 
• 
Absence of tattoos in the head/neck or permanent eye makeup 
 
3.0 Sub-Study Design Overview 
 
The sub-study visits are presented below in relation to preceding visits from the main study. 
 
Preparatory Period with Enrollment Confirmation  
From Preparatory Session 1 (Visit 1) to Preparatory Session 3 (Visit 4): ~6 weeks (+5/-4 weeks) 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Baseline & 
Enrollment 
Confirmation & 
MRI 
Baseline 
CAPS-5 T1 
(Visit 3) 
1.5 hours/ 
Post Preparatory 
Session 2 (V2) & 
confirmation of 
Medication Taper and 
stabilization; before 
V4 
CAPS-5, SDS, and DSP-I completed by an IR via 
tele-assessment after taper is complete. CAPS-5 
scores sent ASAP to the therapy team/PI. 


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Preparatory 
Session 3 
& 
Enrollment  
Confirmation 
(Visit 4) 
3h30min: (~30 min 
trauma script paradigm 
preparation, 90 
minutes of measures, 
90-minute therapy) 
within 6 days of 
Baseline CAPS-5 T1 
(V3); within 4 days 
prior to Experimental 
Session 1 (V5) but not 
same day 
 
3 to 6 days after 
Baseline CAPS T1 
(V3); 1 to 4 days 
before Experimental 
Session 1 (V5). Both 
Baseline CAPS T1 
(V3) and Preparatory 
Session 3 and 
Enrollment 
Confirmation (V4) 
must take place within 
7 days prior to 
Experimental Session 
1 (V5) 
Prior to visit, ensure CAPS-5 confirms PTSD 
diagnosis and Total Severity Score of ≥35 and 
confirm enrollment by reassessing specified 
eligibility criteria. Complete Baseline self-report 
measures. Complete Preparatory Session 3 (~30 
min trauma script paradigm preparation, 90-
minute measures, 90-minute therapy) and schedule 
V5. If enrollment is not confirmed, do not perform 
visit; complete termination. 
 
Baseline 
MRI session 
(Visit 4.1) 
~1.5 hours/After 
Preparatory Session 3 
& Enrollment 
Confirmation (V4) and 
within 6 days of 
Experimental Session 
1 (V5) 
30 min MRI preparatory session; ~63 min MRI 
scanning session including three paradigms: 
response to non-trauma-related stimuli, trauma-
script provocation. 
 
Follow-up Period and Study Termination 
From Integrative Session 2.3 (Visit 13) until Study Termination (Visit 15): 4 weeks (+/-2). 
After Integrative Session 2.3 (Visit 13), ~4 weeks with no scheduled study visits until the Primary 
Outcome is completed. 
Study Visit/ 
Visit # 
Visit Duration/ 
Visit Timing/ 
(Scheduling Window) 
Brief Description of Events  
Primary 
Outcome 
Primary 
Outcome 
CAPS-5 T3 
(Visit 14) 
1 hour/ 
~13 (+/-3) weeks post 
Baseline CAPS-5 T1 
(Visit 3) & 
8 weeks (+/-2) after 
Experimental Session 2 
(V10)  
 
Primary Outcome CAPS-5, SDS, and DSP-I 
assessment completed by an IR via tele-assessment. 
Although there are allowable windows for all visits 
throughout the protocol, this visit must be completed 
within the overall window. Other visits should be 
scheduled to ensure the timing of the Primary 
Outcome CAPS-5 T3 assessment is appropriate. 
MRI post- 
therapy 
MRI-2 (Visit 
14.1)  
~63 min/ 
~13 (+/-3) weeks post 
Baseline & 
8 (+/-2) weeks post 
V10. After CAPS-5 T3 
~63 min MRI scanning session including three 
paradigms: response to non-trauma-related stimuli, 
trauma-script provocation. 
 
4.0 Sub-Study Methods 


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4.1 MRI Experimental Session  
 
Table 1: Schedule of Procedures for MRI Session 
 
 
 
 
 
 
Pre-Scan Session 
• 
On the day of the scan sessions, participants will arrive at the scan facilities 30 minutes prior to 
the scan session. 
• 
The participant will be asked to fill out any documents required for the session and will ensure 
that they are MR compatible (i.e., have removed all free metals including piercings, are wearing 
suitable clothing). 
• 
The participant will be informed of all activities during the scan session and will have time to ask 
questions. 
• 
If available, the participant will have the option to briefly lay down in a mock scanner in order to 
become more familiarized with the real scanner environment. If unavailable, a detailed description 
of the scanner environment will be verbally explained. 
 
Scan Session – Set Up 
• 
The participant will be invited to lay down in the scanner, and will be given necessary equipment 
(ear plugs; padding; alarm button; MR compatible glasses if necessary) 
• 
During the first 8 minutes, preliminary scans will be taken (fieldmap; localizer; anatomical scan). 
During this time the participant will be instructed to relax and remain still. A neutral image (e.g., 
nature picture) will be displayed on the screen for participants to focus on. 
 
Scan Session – Resting State 
• 
During the resting state scan, participants will be asked to relax with eyes closed. During this 
time, participants will be instructed to empty their mind. 
 
Scan Session – Emotional Faces Task  
• 
Participants will be presented with stimuli consisting of either picture of faces in various 
emotional states (angry, fearful, sad, happy and neutral) or scrambled faces (control). In the 
emotion condition, participants have to indicate the gender of the face. In the control condition, 
participants have to press the corresponding button as indicated on the screen, i.e., an arrow 
pointing left or right. 
 
 
 
Approximate 
Time 
(minutes) 
Cumulated time 
Procedure or Action 
8 
 
Set up (fieldmap; localizer; anatomical scan) 
12 
20’ 
Resting state scan 
 
21’ 
SUDS-1 
12 
33’ 
Emotional faces task 
  
34’ 
SUDS-2 
8 
40’ 
Neutral Audio Script   
 
41’ 
SUDS-3 neutral script 
6 
49’ 
Traumatic Audio Script 
 
50’ 
SUDS-4 traumatic script 


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Scan Session – Traumatic Audio Script Cue Paradigm 
• 
This task will closely replicate the imaginal exposure technique, which is a characteristic feature 
of trauma-focused psychotherapy. A neutral and a traumatic event will be collected during 
preparatory session and condensed into audio recording of approximately 30 seconds. During the 
scanning session, each participant will be instructed to lie still, breathe through his/her nose, and 
allow himself/herself to begin focusing on the neutral script as soon as the script is played. As 
soon as the participant has heard the script, he/she is encouraged to remember all sensations that 
are associated with the event for 60 seconds. The neutral script will be followed by the traumatic 
condition. The procedure will be as follows: 
60 sec Rest 
30 sec Neutral script > 60 sec time to remember all sensations > 120 sec break 
30 sec Neutral script > 60 sec time to remember all sensations > 120 sec break 
60 sec SUDS-neutral script  
30 sec Traumatic script > 60 sec time to remember all sensations > 120 sec break 
30 sec Traumatic script > 60 sec remember all sensations 
60 sec SUDS-traumatic script   
 
Scan Session – Subjective Units of Distress Scale (SUDS) 
• 
Participants will be asked to rate how distressed they feel after preparation of neutral and 
traumatic script at preparatory session 3.  
• 
Participants will be asked to rate how distressed they feel at set times throughout the scan session 
as explained in Table 1 above: Schedule of Procedures for MRI Session. 
 
 
5.0 Sub-Study Objectives and Evaluation 
 
The primary objective of this sub-study will be to explore possible biological correlates of treatment 
outcomes obtained from MDMA-assisted psychotherapy among participants with PTSD.  
• 
To investigate pre-post effects of MDMA-assisted psychotherapy on brain function and 
connectivity as measured by functional magnetic resonance imaging (fMRI), including 
response to trauma-unrelated emotional stimuli (emotional faces), response to trauma 
symptom provocation (personal trauma narrative). The outcome variables will be compared 
between timepoints (Baseline scan V 4.1 and post-treatment scan V 14.1). 
• 
To examine the relationship between fMRI outcome variables and the primary outcome 
variable, namely change in CAPS-5 Total Severity Score from Baseline (Visit 3) to 13 weeks 
post Baseline (Visit 14). 
 
6.0 Methods, Data Analysis, and Hypothesis 
 
All measures will be performed on a 3-Tesla MRI machine (Siemens or Philips, depending on site) 
equipped with a standard head coil. The measurements will remain the same for both scan 1 (pretreatment) 
and scan 2 (posttreatment). The impact of MDMA-assisted psychotherapy (scan 2) on the outcome 
measures will be compared with those at baseline (scan 1). 
 
fMRI sub-study data may be analyzed at the later stage and presented in an addendum to the clinical study 
report.   
 
 
 


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7.0 Resting State  
 
During resting state, participants will be instructed to relax with eyes closed. During this time, they will be 
instructed to empty their mind. 
 
8.0 Data analysis: Resting State 
 
Resting state images will be analyzed via functional connectivity. Functional connectivity data will be 
produced with the MATLAB toolbox DPARSF. Sphere regions of interest (ROI) will be created that are 
located in key areas of the fear circuitry system. Average time courses will be obtained for each sphere 
ROI and correlational analysis will be performed voxel wise to generate FC maps for each sphere ROI. 
Finally, the correlation coefficient map will be converted into z-maps by Fisher’s r-to-z transform to 
improve normality.  
 
 
9.0 Hypothesis: Resting State 
 
We hypothesize that upon completion of the treatment (post-treatment scan vs. baseline scan), there will 
be decreased BOLD activity in the amygdala and hippocampus. Additionally, there will be decreased 
coupling between the vmPFC and hippocampus and increased coupling between the amygdala and 
hippocampus, and that these changes will positively correlate with subjective effects ratings of the 
MDMA experience. 
 
 
10.0 Emotional Faces Task 
 
The experimental paradigm during functional MRI scanning consists of a blocked design, including an 
emotion condition with angry, fearful, sad, happy and neutral face stimuli known to reliably activate the 
anterior medial temporal lobe including the amygdala [128], and a control condition with scrambled faces. 
Twenty-four stimuli were selected for each of five facial expressions, comprising 12 female and 12 male faces. 
Each face will not be presented more than four times. The control condition (scrambled faces) will be presented 
80 times. To reduce anticipatory effects, an event-related design was used that involved a pseudo-random 
presentation of a total of 200 stimuli against a black background. Each photograph will be shown on the screen 
for 2.5 s, with an interstimulus (black screen) interval varying between 0.5 and 1.5 s. Participants have to indicate 
each face’s gender by pressing one of two buttons with the index finger of the left or right hand on two magnet-
compatible button boxes. During the presentation of scrambled faces, participants have to press left or right 
buttons in conformity with the instruction presented on the screen (i.e., an arrow pointing to the left or to the 
right). The reaction time will be recorded. 
 
 
11.0 Data Analysis: Emotional Face-Matching Task  
 
Image analysis will be performed with SPM12 (http://www.fil.ion.ucl.ac.uk/spm). The first five EPI-
volumes will be discarded, and the remaining images will be realigned to the first volume. Images will be 
then co-registered to the anatomical scan, corrected for differences in slice acquisition time, spatially 
normalized to the MNI T1 template, resampled into 2 ´ 2 ´ 2 mm3 voxels, and spatially smoothed (8 mm 
FWHM). Statistical analysis will be performed within the framework of the general linear model. To assess 
the influence of MDMA-assisted psychotherapy on neural responsivity, the two experimental conditions 
(posttreatment scan; baseline scan) will be modeled as box-car regressors convolved with the canonical 
hemodynamic response function of SPM12. In addition, the realignment parameters will be included to 


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     MP18 Protocol Appendix A: Imaging Sub-Study  
EudraCT #2018-001718-13 
                                Version 7.0: 22 November 2022                                 
 
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model potential movement artifacts, as well as a constant. Furthermore, a high-pass filter (cut-off 1/128 Hz) 
will be included, and temporal autocorrelation will be modeled with an AR (1) process. Contrast images 
subtracting the visuo-motor control condition from the emotion condition will be obtained and analyzed in 
subsequent random effects models. 
 
12.0 Hypothesis: Emotional Face-Matching Task 
 
We hypothesize that upon completion of the treatment (post-treatment scan vs. baseline scan) participants 
will display a reduced amygdala response to fearful vs. angry faces. 
 
13.0 Traumatic Audio Script Paradigm 
 
The script-driven imagery procedure is based on previously published fMRI methods [127]. A neutral and 
a traumatic event will be collected during preparatory session 3 and condensed into an audio recording of 
30 seconds. Patient will be asked to rate how distressed they feel (SUDS) after collection of the neutral 
event and after the collection of the traumatic event. During the paradigm, participants will be instructed to 
lie still, breathe through his/her nose, and allow themselves to begin focusing on the script, as soon as the 
audio recording is played. As soon as the participant has heard the script, they will be encouraged to 
remember all sensations that were associated with the event for approximately 60 seconds. Both the neutral 
and the traumatic script will be played two times. The total task time is of approximately 14 minutes. The 
heart rate will be measured during the entire Traumatic Audio Script Paradigm period. 
 
 
14.0 Data Analysis: Traumatic Audio Script Paradigm 
 
Brain activation during the recall of the neutral event will be calculated by using the average activation 
patterns during the final 30 seconds of each period of recollection of the neutral event. Brain activation 
during the recall of the traumatic event will be calculated on the basis of the average activation patterns 
during the final 30 seconds of each period of recollection of the traumatic event. The difference in brain 
activation between these two conditions will be compared between baseline scan and post-treatment scan. 
 
Functional maps of the activated pixels will be constructed by pixel-by-pixel comparisons of the  
signal intensity in the baseline and task-related images. Statistical parametric mapping methods (SPM12 
software) will be used. Basis functions representing epochs of interest will be entered into SPM12. 
Variability in scans attributed to each basis function relative to SPM12’s implicit baseline will be revealed 
by using contrasts. Fixed-effects analyses will be performed by modeling each group’s evoked blood-
oxygen-level-dependent (BOLD) response with hemodynamically convolved boxcar basis functions. The 
regions of interest will be defined on the basis of T1-weighted images and Talairach coordinates. 
 
 
15.0 Hypothesis: Traumatic Audio Script Paradigm 
 
We hypothesize that upon completion of the treatment (post-treatment scan vs. baseline scan), participants 
will rate their traumatic script as less emotionally overwhelming and more tolerable to imagine. This will 
correlate with decreased activation of the amygdala and insula, and increased activation of the mPFC and 
hippocampus and the strength will correlate with reductions in Subjective Units of Distress (SUDS) ratings. 

SAP_001.pdf: 
 
 
MP18 Statistical Analysis Plan 
 
 
Version 1: 05 September 2019 
 
 
SPONSOR 
MAPS Europe B.V. 
 
SPONSOR DESIGNEE 
Amy Emerson 
Director  
MAPS Europe B.V. 
Phone number: +1 510-393-7224 
Email: amy@mapsbcorp.com 
 
MEDICAL MONITOR(S) 
Michael Mithoefer, M.D. 
STATISTICIAN(S) 
Scott Hamilton, Ph.D. 
 
PREPARED BY 
Scott Hamilton, Ph.D. 
Allison Feduccia, Ph.D. 
Berra Yazar-Klosinski, Ph.D. 
Ilsa Jerome, Ph.D. 
 
USE 
In conjunction with relevant FDA, EMA guidance 
 


MAPS Europe B.V. 
 
MP18 SAP  
EudraCT: 2018-001718-13 
 
Version 1: 05 September 2019 
 
Page 2 of 20 
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 ................................................................................................................... 9 
3.4 Exploratory Objectives ........................................................................................................... 9 
4.0 Measures ................................................................................................................................. 10 
4.1 Primary Measure .................................................................................................................. 10 
4.2 Secondary Outcome Measure .............................................................................................. 10 
4.3 Safety Measures ................................................................................................................... 10 
4.4 Exploratory Measures .......................................................................................................... 10 
5.0 Study Design ........................................................................................................................... 10 
6.0 Randomization and Blinding ................................................................................................ 14 
7.0 Sample Size and Power Considerations ............................................................................... 14 
8.0 Analyses ................................................................................................................................... 14 
8.1 Analysis Sets ........................................................................................................................ 14 
8.2 Missing Data Handling ........................................................................................................ 14 
8.2.1 Partial or Missing Dates ................................................................................................ 15 
8.3 Protocol Deviations .............................................................................................................. 15 
8.4 Baseline Values .................................................................................................................... 16 
8.5 Participant Disposition and Dosing Summary ..................................................................... 16 
8.6 Demographics and Baseline Characteristics ........................................................................ 16 
8.7 Effectiveness Analyses ......................................................................................................... 16 
8.7.1 Primary Effectiveness Analyses .................................................................................... 16 
8.7.2 Key Secondary Effectiveness Analyses ........................................................................ 17 
8.7.3 Exploratory Analyses .................................................................................................... 17 
8.7.4 Responder Analyses ...................................................................................................... 18 
8.8 Safety Analyses .................................................................................................................... 18 
8.8.1 Analysis of Exposure .................................................................................................... 18 
8.8.2 Analysis of Adverse Events .......................................................................................... 19 
8.8.3 Concomitant Medications ............................................................................................. 19 
8.8.4 Analysis of Suicidal Ideation and Behavior .................................................................. 20 
8.8.5 Summary of Vital Signs ................................................................................................ 20 
9.0 Timing of Analyses ................................................................................................................. 20 
 
 


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EudraCT: 2018-001718-13 
 
Version 1: 05 September 2019 
 
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List of Tables 
 
Table 1: Dose Regimen of MDMA ................................................................................................ 10 
Table 2: Time and Events – Study Procedures .............................................................................. 11 
Table 3: Time and Events – Study Measures ................................................................................. 13 
 
 


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EudraCT: 2018-001718-13 
 
Version 1: 05 September 2019 
 
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List of Abbreviations 
° C                     Degrees Celsius 
A:G 
 
Albumin:Globulin 
ACE 
 
Adverse Childhood Experiences Questionnaire 
ADHD  
Attention Deficit/Hyperactivity Disorder 
AE 
 
Adverse Event 
AED 
 
Automatic External Defibrillator 
AESI  
Adverse Event of Special Interest 
ALT 
 
Alanine Aminotransferase 
AMI 
 
Acute Myocardial Infarction 
API 
 
Active Pharmaceutical Ingredient 
AST 
 
Aspartate Aminotransferase 
AUDIT  
Alcohol Use Disorders Identification Test 
BDI-II  
Beck Depression Inventory-II 
BLS 
 
Basic Life Support 
BMI 
 
Body Mass Index 
BP 
 
Blood Pressure 
BUN 
 
Blood Urea Nitrogen 
CAPS-4 
Clinician-Administered PTSD Scale for DSM-4 
CAPS-5 
Clinician-Administered PTSD Scale for DSM-5 
CBC 
 
Complete Blood Count 
%CDT  
%Carbohydrate-deficient Transferrin 
CMC  
Chemistry Manufacturing and Control 
CPGS  
Chronic Pain Grade Scale 
CRA 
 
Clinical Research Associate 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DDIS  
Dissociative Disorders Interview Schedule 
DID 
 
Dissociative Identity Disorder 
dIGPP  
Cohen’s d Independent Groups Pre-test Post-test 
DMF 
 
Drug Master File 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
DSP-I  
Dissociative Subtype of PTSD Interview 
DUDIT  
Drug Abuse Disorders Identification Test 
EAT-26 
Eating Attitudes Test 
 
ECG 
 
Electrocardiogram 
EEA  
 
European Economic Area  
eCRF  
Electronic Case Report Form 
ECT 
 
Electroconvulsive Therapy 
ED 
 
Emergency Department 
EDC 
 
Electronic Data Capture 
EMDR  
Eye Movement Desensitization and Reprocessing 
EMS 
 
Emergency Medical Services 
ePRO  
Electronic Participant Reported Outcome 
EQ-5D-5L 
EuroQol Five Dimensions – Five Levels Questionnaire 
FDA 
 
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
GMP 
 
Good Manufacturing Practice 
HCV 
 
Hepatitis C Virus 
HIV 
 
Human Immunodeficiency Virus 
HIPAA  
Health Insurance Portability and Accountability 
HPA 
 
Hypothalamic-pituitary-adrenal 
HPMC  
Hydroxypropyl Methylcellulose 
HPQSF  
Health and Work Performance Absenteeism and Presenteeism Short Form 


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EudraCT: 2018-001718-13 
 
Version 1: 05 September 2019 
 
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IASC  
Inventory of Altered Self-Capacities 
IB 
 
Investigator’s Brochure 
ICD 
 
International Classification of Disease 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonisation 
IP 
 
Investigational Product 
IPF 
 
Inventory of Psychosocial Functioning 
IR 
 
Independent Rater 
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
ITT 
 
Intent-to-Treat 
IUD 
 
Intrauterine Device 
IUS 
 
Intrauterine Hormone-releasing System 
kg 
 
Kilogram 
LEC-5  
Life Events Checklist 
LTFU  
Long-term Follow-up 
MAPS  
Multidisciplinary Association for Psychedelic Studies 
MAOI  
Monoamine Oxidase Inhibitor 
MCH  
Mean Corpuscular Hemoglobin 
MCHC  
Mean Corpuscular Hemoglobin Concentration 
MCV  
Mean Corpuscular Volume 
MDMA 
3,4-methylenedioxymethamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
 
Milligram 
mITT   
Modified Intent-to-Treat  
 
 
mmHg  
Milligrams of Mercury 
MMRM 
Mixed Model Repeated Measure 
MPBC  
MAPS Public Benefit Corporation 
ms 
 
Millisecond 
PCL-5  
PTSD Checklist for DSM-5  
PTCA  
Percutaneous Transluminal Coronary Angioplasty 
PTSD  
Posttraumatic Stress Disorder 
RACT  
Risk Assessment and Categorization Tool  
RBC 
 
Red Blood Cell 
RDW  
Red Cell Distribution Width 
SAE 
 
Serious Adverse Event 
SCID-5-PD 
Structured Clinical Interview for DSM-5 Personality Disorders 
SCID-5-SPQ 
SCID-5 Self-report Personality Questionnaire 
SCS 
 
Self-compassion Scale 
SDS 
 
Sheehan Disability Scale 
SGOT  
Serum Glutamic Oxaloacetic Transaminase 
SNRI  
Serotonin-norepinephrine Reuptake Inhibitor 
SPGT  
Serum Glutamic Pyruvic Transaminase 
SRNU  
Self-reported Nicotine Use 
SSR 
 
Sample size re-estimation 
SSRI 
 
Selective serotonin reuptake inhibitor 
SUBJID 
Subject Identifier 
TAS-20 
Toronto Alexithymia Scale 
TEAE  
Treatment Emergent Adverse Event 
TSH 
 
Thyroid-stimulating Hormone 
UFEC  
Utilization of Facility-based and Emergent Care 
VA 
 
U.S. Department of Veterans Affairs 
VAS 
 
Visual Analog Scale 


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Version 1: 05 September 2019 
 
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WBC  
White Blood Cell 
WHO  
World Health Organization 
WHO DDE 
WHO Drug Dictionary EnhancedTM 
 
 


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Version 1: 05 September 2019 
 
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1.0 Definitions of Terms 
Categorical data: refers to discrete (indivisible) variables, such as gender or ethnicity; data will 
be presented as total numbers of each category as needed to describe the sample 
 
Completers: are defined as participants who complete all two planned experimental sessions and 
the CAPS-5 outcome assessment 14 weeks after enrollment (Visit 14). 
 
Descriptive data: includes mean, median, standard deviation, minimum, and maximum of 
numerical data used as needed to describe the sample 
 
Difference scores: consist of scores computed by subtracting one value from another, as 
subtracting Baseline from follow-up score, used to test for differences between and within groups 
to determine change as a function of experimental treatment over time 
 
Dropouts: are defined as participants who withdraw consent due to any reason after dosing and 
no longer participate in the study, i.e. no further contact with investigators or site staff. 
 
Effectiveness: type of analysis used to assess therapeutic effects or benefits 
 
Exploratory analyses: inferential or descriptive analysis of the data to determine trends that might 
lead to hypotheses for further study 
 
Frequency listing: tabular listing of numbers and/or percentages of events used as needed to 
describe the sample or data characteristics 
 
Outcome measures: primary and secondary study measures that are used to test the study 
hypotheses 
 
Post-dosing Early Terminators: are defined as participants who discontinue study treatment but 
continue to participate in study evaluations and outcome assessments. 
 
Pre-dosing Early Terminators: are defined as participants who discontinue participation after 
enrollment but before randomization during the Preparatory Period and never receive study drug. 
 
Process measures: study measures or qualitative observations collected during the study that may 
increase depth of understanding of the condition and treatment, although not necessarily related to 
safety or effectiveness 
 
Protocol deviation: event that represents significant divergence from the intended study design as 
described in the protocol 
 
Safety: assessment of indicators of potential risks and adverse events  
 
Safety measures: study measures that assess safety of  the Investigational Product (IP), such as 
heart rate monitoring, blood pressure, body temperature 
 
Study design: all elements of a research project that define the study question, experimental 
methods, study procedures including enrollment, measurement techniques, data workflow, and 
statistical analysis 
 


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Version 1: 05 September 2019 
 
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Tabular listing: list of each variable or item for each individual participant either in total or by 
treatment group in a table format 
 
2.0 Introduction 
This document contains a Statistical Analysis Plan (SAP) for an open-label study (MP18), “An 
Open-Label, Phase 2, Multicenter Feasibility Study of Manualized MDMA-Assisted 
Psychotherapy with an Optional fMRI Sub-Study Assessing Changes in Brain Activity in 
Subjects with Posttraumatic Stress Disorder.” A separate SAP for the Optional fMRI Sub-Study 
is to be prepared.  
 
This study is similar in study design, objectives, and protocols to MP16 and MP17, which are 
open-label three-session studies. The differences are the number of sessions (2 sessions in MP18, 
3 sessions in MP16 and MP17), the number of subjects enrolled in each study, location of sites 
(MP18 at EU sites, MP16 at USA and MP17 at Canada sites) and the source and dose of MDMA. 
MDMA used in all studies have similar purity and drug properties. MP18 tests a flexible dosing 
regimen of 80mg MDMA in Session 1, and 80mg or 120mg MDMA in Sessions 2, each followed 
by a supplemental half-dose. MP16 tests a flexible dosing regimen of 80 mg MDMA in Session 
1, and 80 mg or 120 mg MDMA in Sessions 2 and 3, each followed by a supplemental half-dose. 
MP17 tests a flexible dosing regimen of 100mg MDMA in Session 1, and 100mg or 120mg 
MDMA in Sessions 2 and 3, each followed by a supplemental half-dose.  
 
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit research and 
educational organization working to obtain approval for the prescription use of 3,4-
methylenedioxymethamphetamine (MDMA) in conjunction with psychotherapy in persons with 
posttraumatic stress disorder (PTSD). MAPS Europe B.V. has delegated statistical analysis to 
MAPS Public Benefit Corporation (MPBC). 
 
The open-label Phase 2 MP18 study will serve as the lead-in to the sponsor’s planned Phase 3 
study in the European Economic Area (EEA). Only sites planned for Phase 3 will participate in 
these studies. These open-label lead-in Phase 2 studies will serve to validate assumptions made 
for statistical power calculations supporting planned Phase 3 clinical trials and will provide 
crosscultural verification data on the updated version of the instrument for the Primary Outcome 
measure, the Clinician Administered PTSD Scale for DSM-5 (CAPS-5), which will be used in 
Phase 3. In addition, these studies will gather supportive data on the safety and effect of 
manualized MDMA-assisted psychotherapy while providing an opportunity for clinical 
supervision to planned Phase 3 therapy teams. These studies will explore reproducibility of 
findings in a multi-site format to confirm the Phase 3 study design in the EEA region. 
 
3.0 Study Objectives 
3.1 Primary Objective  
The primary objective of this study is to evaluate the effectiveness of MDMA-assisted 
psychotherapy for treatment of PTSD, as measured by the estimand of change in CAPS-5 Total 
Severity Score from Baseline (Visit 3) to 13 weeks post Baseline (Visit 14). 
 
3.2 Secondary Objective 
The secondary objective is to evaluate the effectiveness of MDMA-assisted psychotherapy for 
PTSD in clinician-rated functional impairment, as measured by the mean change in Sheehan 
Disability Scale (SDS) item scores from Visit 3 (Baseline) to Visit 14 (13 weeks post Baseline). 


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Version 1: 05 September 2019 
 
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3.3 Safety Objectives 
The overall safety objective is to assess severity, incidence and frequency of AEs, AEs of Special 
Interest (AESIs), and Serious Adverse Events (SAEs), concomitant medication use, suicidal 
ideation and behavior, and vital signs to support the package insert for MDMA-assisted 
psychotherapy. The following safety objectives will evaluate the safety of MDMA-assisted 
psychotherapy: 
 
1. Assess incidence of AEs during Experimental Sessions that may be indicative of a 
medical complication of the Investigational Product (IP), such as clinical signs and 
symptoms of chest pain, shortness of breath, or neurological symptoms or any other signs 
or symptoms that prompt additional vital sign measurements. 
2. Assess incidence of AEs by severity. 
3. Assess incidence of Treatment Emergent AEs (TEAEs) by severity. 
4. Assess incidence of TEAEs by severity taken during an Experimental Session and 
through 2 days after IP administration. 
5. Assess incidence of AESIs, defined as AEs specified inthe protocol related to cardiac 
function and abuse liability. 
6. Assess incidence of AEs by severity categorized as leading to discontinuation of IP, 
resulting in death or hospitalization, and continuing at Study Termination. 
7. Assess incidence of SAEs. 
8. Assessincidence of psychiatric concomitant medications taken during an Experimental 
Session and through 2 days after IP administration. 
9. Assess incidence of any psychiatric concomitant medications taken during the Treatment 
Period. 
10. Assess incidence of serious suicidal ideation and positive suicidal behavior assessed with 
the Columbia Suicide Severity Rating Scale (C-SSRS). 
11. Assess mean changes in blood pressure, heart rate, and body temperature from pre-IP 
administration to end of each Experimental Session. 
 
3.4 Exploratory Objectives 
These objectives may be explored to characterize participants receiving MDMA-assisted 
psychotherapy to support the primary objective: 
1. Explore the effect of presence of secondary traumatic stressors (LEC-5) on the CAPS-5 
Total Severity analyses 
2. Explore changes within-participants in PTSD symptom clusters of re-experiencing, 
avoidance, negative alterations in cognition and mood, and hyperarousal, as measured by 
changes in CAPS-5 subscale scores from Visit 3 (Baseline) to Visit 14 (13 weeks post 
Baseline) 
3. Explore the effect of adverse childhood experiences (ACE) on the CAPS-5 Total Severity 
analyses 
4. Explore changes in:  
• 
Dissociative symptoms associated with PTSD (DSP-I) 
• 
Depression (BDI-II)  
• 
Chronic pain (CPGS) 
• 
Quality of life (EQ-5D-5L) 
• 
Self-compassion (SCS) 
• 
Addictive behaviors including: alcohol use (AUDIT), drug use (DUDIT), and 
nicotine use (SRNU)  
• 
Eating habits (EAT-26) 


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MP18 SAP  
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Version 1: 05 September 2019 
 
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• 
Healthcare utilization (UFEC) and economic productivity 
• 
Subjective effects (SE) 
 
4.0 Measures 
4.1 Primary Measure 
• 
Clinician Administered PTSD Scale for DSM-5 (CAPS-5) 
 
4.2 Secondary Outcome Measure 
• Sheehan Disability Scale (SDS) 
 
4.3 Safety Measures 
• 
Treatment-emergent Adverse events 
• 
Concomitant medication use 
• 
Vitals signs during MDMA sessions 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
4.4 Exploratory Measures 
• 
Life Events Checklist (LEC-5) 
• 
Adverse Childhood Experience Questionnaire (ACE) 
• 
Dissociative symptoms associated with PTSD (DSP-I) 
• 
Depression (BDI-II)  
• 
Chronic pain (CPGS) 
• 
Quality of life (EQ-5D-5L) 
• 
Self-compassion (SCS) 
• 
Addictive behaviors including: alcohol use (AUDIT), drug use (DUDIT), and nicotine 
use (SRNU)  
• 
Eating habits (EAT-26) 
• 
Healthcare utilization (UFEC)  
• 
Subjective effects (SE) 
 
5.0 Study Design 
Table 1: Dose Regimen of MDMA 
 
Experimental 
Session 
Initial Dose 
Supplemental Dose* 
Min-Max Cumulative Dose 
1 
80 milligrams (mg) 
 
40 mg 
 
80 mg to 120 mg 
 
2 
80 or 120* mg 
 
40 or 60 mg 
 
80 mg to 180 mg 
 
Total Cumulative Dose 
160 mg to 300 mg 
 
* Unless contraindicated


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Table 2: Time and Events – Study Procedures 
 
 
Screening Period 
(2 to 6 weeks) 
Preparatory Period w/ Enrollment Confirmation 
(2 to 11 weeks) 
Screening 
Enrollment 
Preparatory 
Baseline 
CAPS-5 T1 
Baseline & 
Enrollment 
Confirmation 
Visit 
Phone 
Screening 
Screening 
IR Screening 
V0 
V1 
V2 
V3 
V4 
Visit Description 
Phone 
Calls 
In-person 
Visits & 
Labs 
Tele-
assessment  
Enrollment 
Prep. 1 
Prep. 2 
Tele-
assessment  
Prep. 3 & Enrollment 
Confirmation 
Visit Timing 
Prior to Initial 
Screening 
Over 3 
weeks 
(-2 /+1 
weeks) 
2 days after 
initial 
eligibility 
met 
(+7 days) 
2 days post IR 
Screening 
(+12 days) 
Within 1 
week of V0 
(0 to 12 
days) 
2 to 21 days 
of V1  
Post V2 & 
Taper 
3 to 6 days after V3; 
1 to 4 days before V5 
Initial Phone Screen 
P 
 
 
 
 
 
 
 
Informed Consent 
Send Copy 
P 
 
 
 
 
 
 
Follow-up Phone Screen 
P 
 
 
 
 
 
 
 
Assess Eligibility 
P 
P 
 
P 
P 
P 
 
P 
Medical/Psychiatric History 
P A 
P 
 
 
P 
P 
 
P 
Past/Current Medication & 
Adherence 
P 
P 
 
 
P 
P 
 
P 
Weight, Resting Vitals 
 
P 
 
 
 
 
 
 
Physical Exam  
 
P 
 
 
 
 
 
 
ECG & Rhythm Strip 
 
P 
 
 
 
 
 
 
Clinical Lab Tests 
 
P 
 
 
 
 
 
 
Drug Screen 
 
P 
 
 
 
 
 
P 
Pregnancy Screen  
 
P 
 
 
 
 
 
P 
Enter Participant in eCRF B 
 
P 
 
 
 
 
 
 
Record 
 
 
P 
 
P 
P 
P 
P 
Medication Taper 
 
 
 
P 
P 
P 
 
 
Study Enrollment  
 
 
 
P 
 
 
 
P
 Confirmed 
All AEs C 
 
 
 
P 
P 
P 
 
P 
90-min Preparatory Session 
 
 
 
 
P 
P 
 
P 
Phone Call Follow-up D 
 
 
 
 
 
P 
 
 
A  At Screening, collect data on previous hospitalizations, healthcare utilization and economic productivity. Request participants to obtain medical/psychiatric records 
to bring to the in-person screening. 
B  Participants will be entered into the eCRF after the IR visit is scheduled 
C  All Adverse Events (AEs) includes collecting Serious Adverse Events, AEs of Special Interest, AEs of Psychiatric Status, AEs requiring medical advice or 
attention, AEs that indicate withdrawal of a participant, and all other AEs 
D  If needed, call participant to confirm medication tapering and stabilization is complete prior to Visit 3 
 
 
 


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Treatment Period 
~8 weeks (+/-3 weeks) 
Follow-up Period & Study 
Termination 
(~4 weeks) 
13 weeks (+/-3 weeks) post baseline 
 
Treatment 1 
Treatment 2 
Primary 
Outcome 
Study 
Termination 
Visit 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Visit Description 
Exp. 1 
Int. 1.1 
Int. 1.2 
CAPS-5 
T2: Tele- 
assessmen
t 
Int. 1.3 
Exp. 2 
Int. 2.1 
Int. 2.2 
Int. 2.3 
CAPS-5 T3 
Outcome:  
Tele-
assessment I 
Study  
Termination 
Visit Timing 
Within 1 
week of 
V3 
Morning 
after V5 
3 to 14 
days 
after V5 
18 to 30 
days after 
V5 
20 to 34 
days after 
V5 
21 to 35 
days after 
V5 
Morning 
after V10 
3 to 14 
days after 
V10 
20 to 34 
days 
after 
V10 
13 weeks post 
V5 
(+/-3 weeks) 
2 days post V14 
(-1/+7 days) 
Past/Current 
Medication & 
Adherence 
P 
P 
P 
 
P 
P 
P 
P 
P 
 
P 
Drug Screen 
P 
 
 
 
 
P 
 
 
 
 
 
Pregnancy Screen  
P 
 
 
 
 
P 
 
 
 
 
 
Record 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
 
All AEs E 
P 
P 
P 
 
P 
P 
P 
P 
P 
 
P 
Administer IP 
P 
 
 
 
 
P 
 
 
 
 
 
8-hour Exp. Session 
P 
 
 
 
 
P 
 
 
 
 
 
BP, Pulse, 
Temperature F 
P 
 
 
 
 
P 
 
 
 
 
P G 
Overnight Stay 
P 
 
 
 
 
P 
 
 
 
 
 
90-min Integrative 
Session 
 
P 
P 
 
P 
 
P 
P 
P 
 
 
Phone Call 
Follow-up H 
 
P 
 
 
 
 
P 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
P 
 
E  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 
F During Experimental Sessions, vitals are measured before Investigational Product administration, immediately before the supplemental dose is administered (or 
would be, if supplemental dose not given), and approximately 8 hours after initial dose, and as needed 
G At Study Termination, only blood pressure needs to be measured 
H  4 days of phone call follow-up: Day 2 and 7 after the Experimental Session, with two additional calls in between 
I  All visits must be scheduled to ensure that the Primary Outcome CAPS-5 T3 assessment is within the overall window provided: 13 weeks (+/-3 weeks) post V5 
 
 
 
 
 
 


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Table 3: Time and Events – Study Measures  
 
 
 
 
Screening 
Baseline & 
Enrollment 
Confirmation 
Treatment 1 
Treatment 2 
Follow-up & Study 
Termination 
Visit # 
Site A 
IR 
Screening 
IR 
V3 
V4 
V5 
V6&7 
IR 
V8 
V9 
V10 
V11&12 
V13 
IR 
V14 
V15 
Visit 
Description 
~Time to Complete 
Measure (minutes) 
Site Visit 
Tele-
assessment  
Tele-
assessment  
Site 
Visit 
Exp. 
Session 1 
Int. 
Sessions 
1.1 & 1.2 
CAPS-5 T2: 
Tele-
assessment  
Int. 
Session 
1.3 
Exp. 
Session 2 
Int. 
Sessions 
2.1 & 2.2 
Int. 
Session 
2.3 
CAPS-5 T3: 
Outcome: 
Tele-
assessment  
Study 
Termi-
nation 
CAPS-5 
90 (Baseline) 
60 (all others) 
 
 
ü 
 
 
 
P 
 
 
 
 
P 
 
SDS 
2 
 
 
ü 
 
 
 
ü 
 
 
 
 
ü 
 
DSP-I 
15 
 
 
ü 
 
 
 
ü 
 
 
 
 
ü 
 
C-SSRS B 
10 
ü 
ü 
 
P 
PC 
P 
 
P 
PC 
P 
P 
 
P 
MINI 
15 
 
ü 
 
 
 
 
 
 
 
 
 
 
 
CIPD-SR 
20 
ü 
 
 
 
 
 
 
 
 
 
 
 
 
CIPD 
60 
 
ü 
 
 
 
 
 
 
 
 
 
 
 
LEC-5 
5 
ü 
 
 
ü 
 
 
 
P 
 
 
P 
 
P 
PCL-5 
8 
ü 
 
 
ü 
 
 
 
ü 
 
 
ü 
 
ü 
DDIS D 
 
5 
 
ü 
 
 
 
 
 
 
 
 
 
 
 
ACE 
4 
 
 
 
ü 
 
 
 
 
 
 
 
 
 
BDI-II 
10 (Baseline) 
5 (all others) 
 
 
 
ü 
 
 
 
 
 
 
 
 
P 
CPGS 
5 
 
 
 
ü 
 
 
 
 
 
 
 
 
P 
EQ-5D-5L 
3 
 
 
 
ü 
 
 
 
 
 
 
 
 
ü 
SCS 
6 
 
 
 
ü 
 
 
 
 
 
 
 
 
ü 
AUDIT 
3 
ü 
 
 
 
 
 
 
 
 
 
 
 
P 
DUDIT 
3 
ü 
 
 
 
 
 
 
 
 
 
 
 
P 
SRNU 
3 
 
 
 
ü 
 
 
 
 
 
 
 
 
P 
EAT-26 
6 
 
 
 
ü 
 
 
 
 
 
 
 
 
P 
UFEC 
3 
 
 
 
ü 
 
 
 
 
 
 
 
 
 
SE 
2 
 
 
 
 
ü 
 
 
 
ü 
 
 
 
 
~Total Time of Completing 
Measures (minutes) 
49 
105 
107 
50 
 
12 
10 
77 
23 
12 
10 
23 
77 
57 
 
A Ensure that LEC-5 and CIPD-SR results are sent to the Independent Rater  
B First C-SSRS is a Lifetime assessment, other assessments are Since Last Visit 
C Conducted pre- and post-IP administration, and at phone calls on Days 2 and 7 after Experimental Session 
D The relevant questions (117 to 132) from the DDIS will be asked by the Independent Rater during the IR Screening visit. The entire measure will never be 
administered. 
 
 
 


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6.0 Randomization and Blinding 
MP18 is an open-label study with no randomization or blinding of treatment.  
 
7.0 Sample Size and Power Considerations 
MP18 is a one-arm interventional study. Thus, no power nor sample size calculations were 
required. 
 
8.0 Analyses 
Every effort will be made to ensure complete, accurate and timely data collection and to avoid 
missing data, to ensure the completeness of the data which can impact the integrity and accuracy 
of the final study analysis. The statistical analyses will be reported using summary tables, figures, 
and data listings. All analyses and tabulations will be performed using SAS® Version 9.4 or 
higher, and S-PLUS. In general, nominal variables will be described in terms of frequencies and 
percentages. Ordinal and non-normal continuous variables will be described using sample median 
and range.  
 
Approximately normal variables will be described using sample mean and standard deviations 
and analyzed by parametric statistical tests. Except for the primary effectiveness analysis, all 
statistical tests will be two-sided and a difference resulting in a p-value of less than or equal to 
0.05 will be considered statistically significant. All p-values will be rounded to and displayed in 
four decimals. If a p-value less than 0.0001 occurs it will be shown in tables as <0.0001. Data not 
subject to analysis according to this plan will not appear in any tables or graphs, but will be 
included in the data listings. Selected results may be presented graphically using standard 
graphical software. 
 
 
8.1 Analysis Sets 
• 
Safety: all participants who receive any IP  
 
• 
All Enrolled:  all participants who signed informed consent 
 
• 
Modified Intent-To-Treat (mITT): all enrolled participants who receive IP in at least one 
blinded Experimental Session (Visit 5) and have at least one follow-up CAPS-5 
assessment post-treatment  
• 
Per Protocol (PP): all randomized participants who meet eligibility criteria, who receive 
IP in two Experimental Sessions, and have two follow-up CAPS-5 assessments post- 
treatment  
• 
Not Per Protocol (NPP): all participants who are included in the mITT set but not the PP 
set  
 
8.2 Missing Data Handling 
All possible procedures within Good Clinical Practice (GCP) will be used to minimize Post-
dosing Early Termination. Based on the US Phase 2 data it is expected that up to 5% of enrolled 


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and randomized participants will terminate early. Post-dosing Early Terminators will be 
compared to the Completers using baseline demographics and CAPS-5 Total Severity Score at 
baseline. Participants who are removed from the study after they are enrolled and receive IP but 
do not complete the study may fall into one of these categories: Post-Dosing Early Termination or 
Dropout. If the participant has received IP in at least one Experimental Session and completed 
one CAPS-5 assessment beyond Baseline, they will be considered evaluable. All participants who 
receive IP in at least one Experimental Session will be included in all safety analyses. Post-
Dosing Early Termination are participants who discontinue study treatment but continue to 
participate in study evaluations and outcome assessments. Data collection by IRs will continue on 
the same schedule as planned through Study Termination visit procedures. Dropouts are defined 
as a participant who decides to withdraw consent. They will terminate without further follow-up. 
If the participant agrees, they will complete a final CAPS-5 assessment and Study Termination 
visit procedures. These participants are defined as dropouts who withdraw consent due to any 
reason after receiving at least one dose of IP and no longer participate in the study, i.e. no further 
contact with investigators or site staff. Data collected on study participants up to the time of 
withdrawal of consent will remain in the trial database in order to maintain scientific validity. All 
observed CAPS-5 data up to the point of discontinuation of treatment will be included in the 
MMRM model of the de jure estimand from Post-dosing Early Terminators. Participants will not 
be replaced. All observed CAPS-5 data from Post-dosing Early Terminators and Dropouts 
collected prior to and after early termination will be included in the supportive effectiveness 
analysis of the de facto estimand. 
 
8.2.1 Partial or Missing Dates 
The following conventions will be used to impute missing portions of dates for AEs and 
concomitant medications. Note that the imputed values outlined here may not always provide the 
most conservative date. In those circumstances, the imputed value may be replaced by a date that 
will lead to a more conservative analysis. 
 
Start Dates: 
1. If the year is unknown, then the date will not be imputed and will be assigned a missing 
value.  
2. If the month is unknown, then: 
a. The month and day of the first dose date will be imputed if the year matches the 
first dose date year. 
b. Otherwise, ‘January’ will be assigned. 
3. If the day is unknown, then: 
a. The day of the first dose date will be imputed if the month and year match the 
first dose date month and year.  
b. Otherwise, the first day of the month will be assigned. 
 
Stop Dates: 
1. If the year is unknown, then the date will not be imputed and will be assigned a missing 
value. 
2. If the month is unknown, then ‘December’ will be assigned. 
3. If the day is unknown, then the last day of the month will be assigned. 
 
8.3 Protocol Deviations 
A major deviation will be defined as participants enrolled but did not meet eligibility criteria 
during the course of the study, or any deviations that affect safety or overall data integrity, 
particularly if it relates to study endpoints. The number of participants in each protocol deviation 


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category listed below will be summarized by analysis set. Individual participants will appear in a 
listing. 
 
Possible protocol deviations include the following categories: 
 
• 
Participant entered study but did not meet criteria 
• 
Participant developed withdrawal criteria but was not withdrawn 
• 
Participant received excluded concomitant treatment 
• 
Protocol procedure not performed per protocol 
• 
Participant received incorrect treatment or incorrect dose 
• 
Protocol procedure performed out of range 
• 
Miscellaneous 
 
8.4 Baseline Values 
Baseline values are from Baseline Visits for all measures, except C-SSRS, AUDIT, DUDIT, 
resting blood pressure (BP), Body Mass Index (BMI). For C-SSRS, the initial screening visit will 
be conducted with the ‘Lifetime’ version of the measure. The Independent Rater Screening 
assessment of ‘Since Last Visit’ suicidal ideation and behavior will be used as ‘Baseline.’ For the 
AUDIT and DUDIT measures and resting BP, BMI, results collected at Screening will be used as 
the Baseline value. 
 
8.5 Participant Disposition and Dosing Summary 
The Safety Set will be included in the summary of participant disposition and accountability 
summarized overall. The number and percent of participants who completed or discontinued the 
study will be displayed with reasons for early termination, where the percent is with respect to the 
total number of participants. The timepoint of doses and total MDMA (mg) administered will be 
summarized for the Safety Set.  
 
8.6 Demographics and Baseline Characteristics 
Participant demographic data and Baseline characteristics will be summarized descriptively. The 
demographic data and baseline characteristics will be summarized for the Safety Set and overall.  
 
8.7 Effectiveness Analyses 
For all primary, secondary, and exploratory endpoints descriptive statistics (n, mean, standard 
deviation, median, range, or counts and percentages where appropriate) will be provided overall. 
Longitudinal CAPS-5 Total Severity Score and SDS item scores will be plotted across visits to 
characterize the onset of treatment effect. 
 
8.7.1 Primary Effectiveness Analyses 
The de jure estimand of treatment effectiveness will be used to estimate the change in CAPS-5 
score from baseline due to MDMA-assisted psychotherapy on PTSD symptom severity in the 
intended population of patients with PTSD from any cause. The primary estimator of 
effectiveness will be the mean change in CAPS-5 Total Severity Scores from Baseline to 14 
weeks after start of dosing (Visit 14). Least squares means from a restricted maximum likelihood 
(REML)-based mixed model for repeated measures (MMRM) will be used to estimate the change 


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in CAPS-5 from baseline to each visit. CAPS-5 data collected after treatment discontinuation will 
not be included in the de jure estimand. Missing data will not be imputed.  
 
8.7.2 Key Secondary Effectiveness Analyses  
For the key secondary analysis of effectiveness, the de jure estimand will be used to estimate the 
change from baseline due to MDMA-assisted psychotherapy on PTSD on the SDS in the intended 
population of patients with PTSD from any cause.  The SDS is a 3-item scale measuring the 
severity of disability in the domains of work, family life/home responsibilities and social/leisure 
activities. Each of these three domains is scored on a ten-point Likert scale, where a score of 0 is 
‘not at all impaired’, 5 is ‘moderately impaired’ and 10 is ‘very severely impaired’. For each 
study participant at each visit, the responses on the 3 items of the SDS will be summarized with a 
mean.  In cases where the response on item 1 is not applicable, it will not be considered missing 
data.  Thus, missing data assumptions and methodologies are not required when item 1 is not 
answered.  Whereas when all 3 items have a response, the summary measure is the mean of the 3 
item responses, in the cases where item 1 is not answered the summary measure will consist of 
the mean of items 2 and 3.  It is expected that no more than 20% participants will have not have 
an applicable score for item 1, based on prior studies of paroxetine with PTSD. To limit missing 
data and ensure standardized administration, the SDS will be administered in a clinician-rated 
format during the same visits as the CAPS-5 by the centralized Independent Rater Pool.  
 
A secondary estimator of effectiveness will be the mean change in SDS Mean Scores from 
Baseline to 14 weeks after start of dosing (Visit 14). Least squares means from a restricted 
maximum likelihood (REML)-based mixed model for repeated measures (MMRM) will be used 
to estimate the change from baseline to each visit.  SDS data collected after treatment 
discontinuation will not be included in the de jure estimand. Missing data will not be imputed and 
will be considered missing at random.  
 
8.7.3 Exploratory Analyses 
Post-hoc exploratory analyses not identified in this SAP may be performed to further examine the 
study data. These analyses will be clearly identified as such in the final clinical study report or in 
the clinical study report addendum.  
 
In exploratory analyses, additional baseline covariates (age, gender, ethnicity, index trauma, 
complexity and severity of trauma, medication tapering, diagnosis of comorbid depression, 
diagnosis of comorbid Axis 2 diagnosis, adverse childhood experiences) may be assessed for 
inclusion in the model at a p<0.05. One-group pretest-posttest Cohen’s d effect size will be 
estimated. 
 


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8.7.4 Responder Analyses 
The CAPS-5 produces a Total Severity Score based on severity of PTSD symptom domains 
described in the DSM-5, as well as a categorical rating indicating whether a participant meets 
PTSD diagnostic criteria. A psychometric validation study found the following severity score 
ranges for the CAPS-5: Asymptomatic (0-10), Mild (11-22), Moderate (23-34), Severe (35-46), 
Extreme (47+). Based on these data, a 10-point reduction in CAPS-5 Total Severity Score is 
clinically meaningful. As an alternate definition of treatment response to assess clinical 
significance of study outcomes, the sponsor will conduct a responder analysis to support findings 
from the primary effectiveness analysis, and to explore how many single-dose treatments are 
needed to achieve response (See Figure 1).  
 
Figure 1: CONSORT for PTSD Responder Analysis After Treatment 
 
[1] Response at T2, and T3 will be in comparison to Baseline at T1. 
 
8.8 Safety Analyses 
Safety assessment analyses for this study will include summaries of unsolicited adverse events, 
concomitant medications, suicidal ideation and behavior, and vital signs. Qualitative safety 
analyses will examine safety data with summary tables listing drug exposure, concomitant 
medications/therapies, unsolicited AEs, and percentages tabulated overall.  
 
8.8.1 Analysis of Exposure 
The frequencies and percentages of participants with exposure will be summarized. Data will be 
tabulated for the Safety Set. 
 
 
Compare frequency of degree of response between 
groups based on CAPS-5  
i Response: ≥ 10-point reduction  
i Loss of diagnosis:  Does not meet Diagnostic 
Criteria + ≥ 10-point reduction 
i Remission: Does not meet Diagnostic Criteria + 
CAPS-5 Total Score  d 11 
Compare frequency of response between groups 
based on CAPS-5  
i Non-responders: < 10-point reduction  
Response 
After 
Session 1 
CAPS-5 T2 
Evaluable mITT  
 
Compare frequency of degree of response between 
groups based on CAPS-5  
i Response: ≥ 10-point reduction  
i Loss of diagnosis:  Does not meet Diagnostic 
Criteria + ≥ 10-point reduction 
i Remission: Does not meet Diagnostic Criteria + 
CAPS-5 Total Score  d 11 
Compare frequency of response between groups 
based on CAPS-5  
i Non-responders: < 10-point reduction 
Response 
After 
Session 2 
CAPS-5 T3 


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8.8.2 Analysis of Adverse Events 
The primary measure of safety will be the reporting of unsolicited AEs. All AEs collected from 
Enrollment to Termination will be categorized as follows: 
• 
Pretreatment AEs are defined as AEs that occur during the Preparatory Period prior to the 
first dose in the first Experimental Session 
• 
Treatment Emergent AEs are defined as AEs that occur during the Treatment Period from 
the first Experimental Session to the last Integrative Session 
• 
AEs that occur on and two days after MDMA or placebo administration 
• 
AESIs are defined as AEs specified in the protocol related to cardiac function and abuse 
liability 
• 
Follow-up Period AEs are defined as AEs that occur during the Follow-up Period after 
the last Integrative Session through Termination 
• 
AEs leading to discontinuation of IP 
• 
AEs resulting in death or hospitalization. 
• 
SAEs 
• 
AEs continuing at Termination. 
 
Verbatim terms on case report forms will be mapped to preferred terms (PT) and system organ 
class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) Version 20.0 
(Hierarchy), WHO DRUG Enhanced Mar-2018 B3 (Hierarchy and Ingredients).   
 
Frequency and incidence of AEs will be displayed by PT, sorted by SOC, and summarized by 
treatment group, analysis set, category (as defined above), severity, and seriousness. AEs will be 
analyzed and presented as follows: 
• 
If a participant has more than one AE mapped to the same PT, that AE will be reported 
once using the highest severity 
• 
Relationship will be determined based on relative incidence of TEAEs with at least two-
fold difference between MDMA vs. placebo 
• 
Compare relative incidence of AEs during Experimental Sessions such as clinical signs 
and symptoms, such as chest pain, shortness of breath, or neurological symptoms or any 
other signs or symptoms that may be indicative of a medical complication of the 
investigational product 
• 
AEs that occur on day of Experimental Sessions and two days after IP administration will 
be presented separately. 
 
8.8.3 Concomitant Medications 
A secondary measure of safety will be the reporting of concomitant medications. All concomitant 
medications collected from Screening to Study Termination will be categorized as follows: 
• 
Pretreatment medications are defined as medications taken prior to and after signing 
informed consent and those taken during the Preparatory Period prior to the first 
Experimental Session. A stop date is expected prior to the first Experimental Session for 
any medications requiring a change in dose, a skipped dose, or tapering.  
• 
Treatment Period concomitant medications are defined as those taken or continued during 
the Treatment Period from the first Experimental Session to the last Integrative Session. 
A stop date is expected prior to the each Experimental Session for any medications 
requiring a change in dose, a skipped dose, or tapering.  
• 
Concomitant medications with a start date of the day of and two days after IP 
administration 


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• 
Follow-up Period concomitant medications are defined as those taken or continued 
during the Follow-up Period after the last Integrative Session through Termination 
• 
Any concomitant medications that are tapered 
• 
Any concomitant medications that are taken to treat an AE 
• 
Any concomitant medications that are taken to treat an SAE 
• 
Any excluded concomitant medications taken as a deviation from the protocol. 
 
Concomitant medications on case report forms will be classified using the WHO Drug Dictionary 
EnhancedTM (WHO DDE). Frequency and incidence of concomitant medications will be 
displayed by generic name, sorted by class, and summarized by treatment group, analysis set, and 
category as defined above. Concomitant medications will be analyzed and presented as follows: 
• 
Concomitant medications taken on the day of and two days after IP administration will be 
presented separately 
• 
Any psychiatric concomitant medications by period. 
 
8.8.4 Analysis of Suicidal Ideation and Behavior 
Suicidal ideation and behavior will be summarized according to suggestions made in the C-SSRS 
Scoring and Data Analysis Guide [1]. A positive response for suicidal ideation is counted when a 
participant answers “yes” to any one of the five suicidal ideation questions (Categories 1-5) on 
the C-SSRS (i.e., a score >0 for suicidal ideation). Serious suicidal ideation is a suicidal ideation 
score of 4 or 5. A positive response for suicidal behavior occurs when a participant answers “yes” 
to any one of the five suicidal behavior questions (Categories 6-10) on the C-SSRS (i.e., a score 
>0 for suicidal behavior). The number and percent of positive responses of Positive Ideation, 
Serious Ideation, and Positive Behavior will be tabulated by treatment group and time period 
(lifetime, screening, baseline, each Experimental Session (pre- and post-IP), Integrative Sessions, 
and endpoints). Frequency and incidence of positive or serious ideation and suicidal behavior will 
be presented using descriptive statistics in tabular format. 
 
8.8.5 Summary of Vital Signs 
Vital signs (heart rate, BP, and body temperature) for Experimental Sessions will be summarized 
using descriptive statistics in tabular format listing values at pre-IP, prior to the supplemental 
dose, and at the end of each Experimental Session.   
 
9.0 Timing of Analyses 
Preliminary analyses and listing reviews will be ongoing throughout the study to inform therapist 
supervision and assumptions made for the upcoming Phase 3 trial. For clinical study reports and 
publications, only locked database files will be used. The primary effectiveness analysis will be 
conducted after all participants complete Visit 15 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.