Clinical trial NCT01958593
Conditions: Posttraumatic Stress Disorder
Keywords: PTSD Posttraumatic stress disorder MDMA psychotherapy therapy
Sponsor: Lykos Therapeutics
Start date: 2014-10-14; Completion date: 2016-10-17
Enrollment: 6 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical trial is to compare full dose MDMA-assisted therapy to placebo with therapy in participants with chronic, treatment-resistant PTSD. The main question it aims to answer is: Does MDMA-assisted therapy versus placebo with therapy reduce PTSD symptoms?

Participants will receive either MDMA-assisted therapy or placebo with therapy during two blinded experimental sessions spaced three to five weeks apart. During experimental sessions, participants receive an initial dose of 125 mg of MDMA HCl, or placebo, followed by a dose of 62.5 mg of MDMA HCl, or placebo. During this treatment period, participants will also undergo non-drug preparatory therapy sessions and non-drug integration sessions.

Researchers will compare PTSD symptoms in the MDMA-assisted therapy group to the placebo with therapy group to see if there is a reduction in symptoms after the treatment period. Safety measures will also be assessed between groups.

Detailed description:
This randomized, double-blind, placebo-controlled clinical study will assess the safety and efficacy of MDMA-assisted therapy in treating chronic, treatment-resistant PTSD. In Stage 1, participants will be randomized to either MDMA-assisted therapy or placebo with therapy during two blinded experimental sessions, spaced three to five weeks apart. During experimental sessions, participants receive an initial dose of 125 mg of MDMA HCl, or placebo, followed by a dose of 62.5 mg of MDMA HCl, or placebo. During this treatment period, participants will also undergo non-drug preparatory therapy sessions and non-drug integration sessions. After this treatment period, participants will complete the primary endpoint assessment and the study will become unblinded.

Participants who were assigned to receive MDMA-assisted therapy will receive a third session of MDMA-assisted therapy that is open-label and participants assigned to receive placebo with therapy will have the option to enter Stage 2. Stage 2 will explore the optimal therapeutic dose of MDMA in a clinical titration dosing strategy. Participants will receive MDMA-assisted with an initial dose of 100 mg followed by a dose of 50 mg of MDMA HCl for the first experimental session. In the second and third experimental sessions, participants will have the option to increase the dose to an initial dose of 125 mg followed by a dose of 62.5 mg.

A blinded independent rater will assess PTSD symptoms via the CAPS-IV as well as other secondary outcome measures and safety measures.

Arms: arm 1: Participants will receive placebo with therapy during each of two experimental sessions. arm 2: Participants will receive MDMA (initial dose of 125 mg midomafetamine HCl followed by a supplemental dose of 62.5 mg midomafetamine HCl) with therapy during each of two experimental sessions.
Interventions: intervention 1: Placebo intervention 2: Midomafetamine HCl intervention 3: Psychotherapy
Intervention descriptions: intervention 1: Placebo with therapy administered in two blinded experimental sessions. Participants in this group in Stage 1 may take part in Stage 2. intervention 2: Participants will receive MDMA-assisted therapy during two blinded experimental sessions. After unblinding, may receive a third session of open-label MDMA-assisted therapy. intervention 3: Psychotherapy before and after experimental sessions.

Protocol documents:
ICF_002.pdf: 


 
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Please ask the study personnel to explain any words or information in this consen  
 
you do not clearly understand.  You may take home an unsigned copy of this co
 
form to think about or discuss with family or friends before making your decision.   
 
PURPOSE AND BACKGROUND 
This small study is designed to provide information on whether MDMA-assisted 
psychotherapy is safe and helpful for subjects with PTSD.  The study therapists plan to 
use the results of this study to design future studies of MDMA-assisted psychotherapy. 
 
The study is sponsored by a US-based non-profit organization, the Multidisciplinary 
Association for Psychedelic Studies (MAPS, www.maps.org). MAPS’ first small study of 
MDMA-assisted psychotherapy in 21 people with PTSD is finished in the U.S. MAPS 
has completed another MDMA/PTSD pilot study in 12 people in Switzerland.  Three 
studies are currently enrolling, two in the U.S. and one in Israel.  
 
MDMA is experimental, which means it has not been approved by Health Canada for 
medical use, except within research studies like this one. MDMA is illegal to use outside 
of research and is sometimes known as "Ecstasy" (which is supposed to contain MDMA 
but can often contain other drugs instead of or in addition to MDMA).  
 
Before it became illegal, some psychotherapists combined MDMA with psychotherapy 
(“talk therapy”) to help people with psychological problems, sometimes including PTSD. 
Though we do not know if it helps people with PTSD, we know that MDMA increases 
positive mood and also changes the way we see and think about the world around us, 
making it easier to think about and recall upsetting experiences, and people say they 
feel caring and forgiving toward themselves and others after MDMA. Most types of 
therapy that treat PTSD involve facing the trauma and PTSD symptoms and going over 
trauma-related emotions. Doing this reduces fear, defensiveness, avoiding things, 
places or feelings that trigger unwanted feelings or thoughts, and feeling emotionally 
numb or distant from relationships. If MDMA can temporarily decrease fear and 
avoidance and increase trust and connection between the person with PTSD and their 
therapist, then MDMA may make the therapy stronger and more likely to work. It is 
possible that these effects, when combined with psychotherapy, help people confront 
and go through the thoughts, memories and emotions related to PTSD.  
 
During the study you will interact with a therapy team consisting of one doctor and one 
therapist. You will see the same study therapy team for the whole study. You will have 
your symptoms measured by an independent researcher. Study personnel will contact 
you to schedule your visits. Some of the visits may be conducted by phone or 
telemedicine. Telemedicine involves the use of electronic communications. 
 
This study will compare full dose MDMA with a comparator dose, meaning a dose that 
may or may not contain MDMA in it. During experimental sessions participants will 
receive full dose of MDMA or a comparator, possibly followed one and a half to two and 
a half hours later by a second dose equal to half the size of the first dose. 
 


 
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Length of Study 
The length of the study depends on your group assignment to the active dose grou  
 
the comparator dose group.  Participation in the study will require a significant time 
commitment on your part. Neither you nor the study team will know what group you are 
being assigned to. 
 
• Active Dose Group: This study can take up to 15 months or 18 visits if you 
are assigned to one of the active doses of MDMA in “Stage 1.” This time 
period includes active participation for up to 3.5 months and a long-term 
follow-up visit 12 months after the last experimental session. 
 
• Comparator Dose Group: If you receive the comparator dose in Stage 1 the 
study can take up to 23 months or 28 visits to complete both stage 1 and 2 
plus the long term follow up visit.  If you are in the comparator group you will 
have 12 visits in stage 1 and you can choose to have an additional 12 visits in 
Stage 2 where you receive the active dose of MDMA over an additional 3.5 
months. This time period includes 6 months of active participation plus a long-
term follow-up visit 12 months after the last experimental session. 
 
The timeline for starting treatment can move fast or slow depending on availability of 
open appointments. You may start therapy at enrollment or it may take as long as two 
months if time is needed for medication to leave your body. Depending on your group 
you will meet with the therapist approximately once a week during the active period of 
the study. Experimental sessions last all day and require an overnight stay.  After these 
overnight stays, you will also have a brief daily phone call with one of the therapists for 
7 days and you will have 3 psychotherapy sessions in person or on the phone or by 
telemedicine. You will have testing visits 4-5 times during the study. After active 
participation is complete, you will have a follow up visit one year later. 
 
Types of visits and duration: 
Psychotherapy sessions (90 minutes each): 3 introductory sessions at the start of 
participation and 3 sessions after each experimental session. 
 
Experimental sessions (8 hours long plus an overnight stay): 3 sessions for each 
person in the active dose group and 2 sessions plus 3 optional sessions for each 
person in the comparator dose group.  
 
Evaluation Testing Visits (Up to 2 and a half hours): Testing and completing 
questionnaires 4-5 times, starting with the beginning of the study. 
 
With very few exceptions you will need to take the appointments we schedule because 
there is a limited time frame for each type of event.  
 
 
 


 
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Subject Responsibilities 
If you and the study doctor agree that you can and want to be in the study, you will 
 
to come to all study visits. You will have to avoid taking any psychiatric medications 
from the beginning of the study up until your last study visit unless the study doctor 
make a specific exception, such as giving you medication for sleep or anxiety if needed 
temporarily between experimental sessions. If you are taking psychiatric medication, 
you will need to give the study doctor permission to talk with your doctor about how best 
to stop taking your medication. If you are taking certain medications to manage pain, 
you will need to decrease the dose of medication you are taking right before 
experimental sessions.  
 
If you are currently seeing a psychotherapist, you may not begin any new 
psychotherapy or change the frequency or length of visits with your psychotherapist 
until after the final evaluation session. 
 
For your safety, it is very important to tell the study doctor about all medications you are 
taking, including herbal or “natural” remedies, and to check with the study doctor before 
you begin taking a new medication while in this study.  
 
Any study visit you have may be audio and/or video recorded for research and training 
purposes to help the researchers understand and learn about this type of therapy.  The 
study personnel can give you access to these recordings to watch. 
 
PROCEDURES/WHAT WILL HAPPEN TO YOU 
SCREENING/EVALUATION AND BEGINNING OF STUDY 
If you agree to take part in this study, you will first sign this form before any study-
related procedures are performed. Before you can be in the research study, the study 
doctor must first make sure that you qualify for the study and that you are generally 
physically healthy. The screening process will take about 6 hours and may be done over 
multiple visits in person and on the phone. 
 
The tests will include the following: 
• An interview about your PTSD symptoms and how you deal with them in your 
everyday life.  Your score on this interview will be used to decide if you can be in the 
study. This interview may be video recorded for research purposes.  
• A questionnaire about your personality. 
• A questionnaire about the quality of your sleep. 
• A questionnaire about any detachment symptoms. 
• A questionnaire about feelings of depression or other symptoms or feelings you 
might experience. 
• A questionnaire about your mental health. 
• Questions about your medical history, including questions about your emotional and 
psychiatric history. This may include any previous medical or psychiatric problems or 
treatment and may include questions about difficult experiences you may have had 
during childhood or at other times of your life. 


 
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• Questions about thoughts and feelings you might have about hurting or 
 
yourself. 
• Two different tests of attention, memory and different types of problem solving.  
These are not tests of intelligence. 
• A visual scale of pain and/or tinnitus (ringing in your ears) levels if you have these 
symptoms.     
• A physical examination that will include measures of your blood pressure, pulse, 
temperature, and body weight.     
• An ECG (electrocardiogram) will also be taken, which is a recording of the electrical 
activity of your heart.   
• A sample of your blood (about 2 tablespoons, or about 30 mL) and a urine sample 
for routine laboratory testing, including tests of metabolism and liver function.  An 
HIV test will also be run. 
• A urine test for drugs of abuse. Your urine drug screen must be negative before 
experimental sessions. 
• A urine pregnancy test if you are a woman and are able to get pregnant.  Your urine 
pregnancy test must be negative for you to take part in the study.  
 
BEGINNING OF STUDY 
If you have decided that you want to be in the study and if the study therapists find that 
you are eligible, you will schedule your first introductory psychotherapy session with one 
of the study therapist teams. If you were taking psychiatric medicines when the study 
therapists first checked to see if you could be in the study, you may have your PTSD 
and other symptoms measured again after you have stopped taking your medication.  
Your first experimental session will be between 4 and 8 weeks after your baseline PTSD 
symptoms are measured. The time will depend on scheduling and on the time it takes 
for any medication to clear from your body. 
 
You must let the study therapists know about any medical conditions or procedures that 
you had or are having, like surgery, within 48 hours of their occurrence.  
 
You will need to give the study therapists the name and contact information (telephone 
number, cell phone number or email) of a relative, spouse or close friend to contact in 
case of medical emergency, as when you might be at risk of hurting yourself, or 
someone else, so they can reach that person to let them know what is going on. 
 
SCHEDULE OF EVENTS   
The types of visits in the study consist of screening, preparatory visits, experimental 
sessions, integrative visits, and follow up visits. Time is counted from the first study visit 
after you are selected to be in the study. The tables below show the type of visits you 
will have in Stage 1 and Stage 2 (if you are in the comparator group) 




 
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INTRODUCTORY PSYCHOTHERAPY SESSIONS: 
Once screening is complete and you are enrolled in the study you will meet wit  
 
study therapists three separate times before the first experimental session.  These visits 
will last about 90 minutes. During each introductory 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 these sessions.  You will be asked 
questions about thoughts or feelings you might have about hurting or killing yourself 
during one of these preparatory sessions. You will also learn more about what to expect 
during experimental sessions. The introductory session may be recorded to audio and 
video, so that the study therapists will have accurate records of the session and so that 
they can gather more information about drug-assisted psychotherapy sessions.  You 
can ask the study therapists to let you hear or see these recordings if you wish.  
 
SELECTION OF DRUG – FULL DOSE OR COMPARATOR DOSE? 
This study is double blind, meaning that neither you nor the study researchers will know 
what you will get.  However, in the event of an emergency the researchers can find out. 
The drug you get will be decided at random, as if by tossing a coin.  Seven people will 
receive the full dose and five people will receive the comparator.  You will have a 58% 
chance of receiving full dose MDMA and a 42% chance of receiving the comparator.  
You will find out what you received about 1 month after your second experimental 
session is complete. There will be 12 participants in this study. 
 
Neither you, the person measuring your PTSD symptoms, nor the study therapists will 
know who is getting the high dose of MDMA and who is getting the low dose (known as 
“double blinded”) until after the study is completed.  However, this information is 
available if needed in an emergency.  
 
EXPERIMENTAL SESSIONS: 
 
After you have completed three introductory therapy sessions, you will have two day-
long experimental sessions with psychotherapy. During both sessions, you will have full 
dose MDMA or comparator dose. The sessions will happen three to five weeks apart.  
Each experimental session will last about eight hours, though one or both study 
therapists will remain with you for a longer time if needed. 
 
One week before each of the experimental sessions, you will need to avoid taking: 
 
• Any herbal supplement (except with prior permission);  
• Any non-prescription medications, unless you have permission (with the exception of 
non-steroidal anti-inflammatory drugs or acetaminophen [Tylenol]); 
• Any prescription medications, unless you have permission (with the exception of 
birth control pills, thyroid hormones or other medications).  You will need to talk to 
the study therapists about which medications are okay to keep taking. 
 
You must not eat after midnight on the night before each session, but you can drink 
non-alcoholic liquids during this time, such as water or juice. You cannot use nicotine or 


 
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caffeine for 2 hours before and 6 hours after receiving the capsule. The study ther
 
will give you a paper with these instructions before your first experimental session. 
 
First, you and the study therapists will discuss your goals for the experimental session, 
and the study therapists will answer any questions you still have about your 
experimental session.   
 
Before an experimental session: 
• Your urine will be tested for drugs of abuse. 
• If you are a woman who can become pregnant, a urine pregnancy test will be done. 
 
Throughout an experimental session: 
• Your blood pressure and pulse will be measured every 30 minutes. 
• Your temperature will be measured every 60 to 90 minutes. 
• You will also complete a very short, simple test of how comfortable or upset you feel 
by marking a number on a sheet of paper that shows the way you feel at that 
moment. You will complete it every 60 to 90 minutes during each experimental 
session.  
• About an hour before taking the capsule and about 6 hours afterward, you will 
answer questions about thoughts you might have about hurting or killing yourself. 
• The study therapists will check in on you every hour or so to see how you are doing. 
 
The experimental session may be audiotaped and videotaped, so that the study 
therapists will have accurate records of the session and so that they can gather more 
information about drug-assisted psychotherapy sessions. The study therapists can give 
you access to these recordings for you to watch or hear if you want them. 
 
After urine test results come back, you will be given a capsule containing either the 
comparator dose or full dose MDMA. After taking the capsule, you will sit or lie down in 
a comfortable position. You can ask for an eye-shade if you wish. You will be able to 
listen to music through headphones during much of each experimental session. You 
might be asked to remove the headphones to talk to the study therapists, and you may 
also remove them yourself if you want to talk to the study therapists or for periods 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 the trauma. Both 
study therapists will stay with you, and they will help you if you need them to do so. 
They will talk to 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 study therapists will suggest 
that you stop talking for a while in order to pay attention to your thoughts and feelings. 
There will be water, juices or drinks containing electrolytes available to drink whenever 
you like within the limits of what is safe for your body. Later on, food will also be 
provided. 
 
About one and a half to two and a half hours later, you and the study therapists will talk 
about taking a second capsule. The second dose will be half the amount of the first 


 
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dose. If you and the study therapists agree, then you will take the second dose. If y
 
 
the study therapists notice problems after the first capsule, then you will not get the 
second capsule. 
 
The study therapists will continue to measure blood pressure, pulse and temperature, 
and they will watch for any side effects (unwanted effects or health problems), which will 
be treated if they occur. If this happens, the study therapists will let you know what they 
are doing. 
 
If you are still confused or very upset eight or more hours after the start of the 
experimental session, the study therapists will stay with you until you have recovered 
more fully. If the study therapists think you are at risk for hurting yourself or someone 
else, they will either stay with you all night or have you stay in a nearby hospital until 
they are certain you are not at risk. If the study therapists decide that the effects of the 
drug have worn off and you are in an okay frame of mind, they will leave the office with 
the attendant in charge. The study therapists will ask you about thoughts of killing or 
harming yourself before and after taking the first capsule.  
 
You will spend the night in a comfortably furnished room in the offices of the 
Investigator. If you request and the study therapists agree, you may also have a 
companion stay with you at the office during or after an experimental session. An 
attendant will stay in another room at the same location from the time after you are done 
with the experimental session until the non-drug session on the next day. The attendant 
will offer dinner and breakfast, help you with any physical needs if requested, and 
contact the study therapists to speak with them or to have them return to the office at 
your request or if the attendant thinks it is needed.  
 
On the next day, you will have a non-drug therapy session with the study therapists.  
You will need to arrange ahead of time to have someone take you home from this 
session, because we don’t know how the experimental session will affect you and some 
people report feeling tired or less alert. If you cannot find anyone to take you home, the 
study therapists will either call a taxi or make arrangements for someone to drive you 
home. 
 
After you return home, one of the study therapists will telephone you every day for a 
week to ask about how you are feeling and decide whether you should see them for 
your next non-drug (integrative) psychotherapy session. These telephone calls will take 
approximately 5 to 15 minutes, though they can last as long you need them to. You may 
schedule additional meetings with the study therapists besides those that are scheduled 
as part of the study.  
 
You can contact the study therapists at any time. The study therapists will give you a 
card with telephone numbers for reaching them, the organization sponsoring the study, 
or the Institutional Review Board – IRB Services (an independent committee that 
reviewed the ethical parts of this study to help protect the rights and welfare of study 


 
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participants). At least one of the study therapists will be on call (reachable by teleph
 
or pager) 24 hours a day throughout the research study.  
 
If there are delays in following the usual study schedule, the study therapists will 
telephone you at least once a week to talk about how you're doing. These telephone 
calls will take approximately 15 minutes, and you should call the study therapists if any 
of the following things happens: you have an increase in symptoms for which you were 
previously took medication, you need to contact your outside therapist other than for the 
usual appointments, you start or stop taking prescribed medication, and/or you go to the 
hospital for any reason. 
 
If you have very high blood pressure, get sick, or have a significant lasting unwanted 
effect or health problem after the first experimental session, you or the study doctor may 
decide that you should not participate in the second experimental session.  If the study 
doctor decides to take you out of the study, they will let you know that they are doing 
this and their reason for doing this.  If you are taken out of the study or decide you do 
not want to be in the study, the study researcher will ask you to complete final 
questionnaires about your PTSD and other symptoms and tests of memory and problem 
solving. If you decide you do not want to continue in the study during an experimental 
session, you will still have to stay in the office until the study doctor thinks that you are 
well enough to go and that all the effects of the drug have worn off.  
 
The experimental sessions will occur two to five weeks apart. The experimental 
sessions will all be carried out in an identical manner. 
 
At this time MDMA is not available for use outside of research studies. The study 
therapist will discuss treatment options with you at your last study visit. 
 
PSYCHOTHERAPY AFTER EXPERIMENTAL SESSIONS : 
 
After the experimental sessions, you will have regular psychotherapy to help you 
express, understand and integrate (bring together and connect to your life) any thoughts 
or feelings you may be having about your symptoms and their causes and about your 
experiences during experimental sessions. You will have psychotherapy with the study 
therapists the morning of the day after each experimental session and then during two 
additional sessions after each experimental session. These sessions will last 60 to 90 
minutes. You and the study therapists will also discuss ways to use what you learned to 
help work on treating your PTSD, face and solve difficulties you may have faced during 
the experimental sessions and gain maximum benefit and understanding from 
experimental sessions. Some of these visits may be done by telephone or telemedicine.  
Each regular psychotherapy session may be recorded to audio and video and you can 
hear or see these recordings if you wish.  
 
Before starting psychotherapy on the day after each experimental session, you will be 
asked to guess whether you received MDMA. You will not be told if your guess is 


 
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correct. After you finish psychotherapy on the day after an experimental session  
 
will answer questions about thoughts and feelings you might have about h
 
yourself. The study therapists will ask you these same questions about hurting or killing 
yourself during each psychotherapy session, and during the second and seventh day of 
telephone contact with the study therapist.  This is so the study therapists can have 
another way of making sure you are no in danger of hurting yourself. 
 
You will complete a questionnaire about your PTSD symptoms on the third 
psychotherapy session after an experimental session. If you had tinnitus or chronic pain 
before the study and mention any changes in these symptoms the study therapists will 
help you to record the changes. 
 
MEASURING PTSD, DEPRESSION AND OTHER TESTS AFTER EXPERIMENTAL SESSIONS 
 
Approximately three months after the start of the study (six weeks after the third 
experimental session), the study researcher will ask you about your PTSD and other 
symptoms. You will also have the same tests of attention, memory and different types of 
problem solving that you had at the beginning of the study. This visit should last about 
two and a half hours, and some of the tests may be done by telemedicine or telephone. 
These tests are so we can tell if your symptoms have changed or stayed the same over 
time.  
 
After you complete these tests, you will meet with the study therapists and they will ask 
you about thoughts about hurting or killing yourself. You and the study therapists will 
learn whether you got the comparator dose or full dose MDMA. The study researcher 
that measured your PTSD symptoms will not find out.  
 
If you learn that you got the comparator dose, then you will have the option to go on to 
the next part of the study without finishing Stage 1, described below (Stage 2).  
 
If you will not go on to Stage 2, then you will complete a questionnaire about your 
experience as a research subject. The study therapists will give you a memory aid card. 
This is for you to keep track of your health during the months in between your last visit 
with the researchers and the 12-month follow up visit, described below. The card will 
help you to remember to tell the researchers about any new problems or medical 
conditions, or changes in medication that happened during this time. You may have 
your regular doctor fill out this card for you. Your next study assessment will be the 12-
month long-term follow-up. 
 
OPEN-LABEL MDMA SESSION FOR PEOPLE WHO RECEIVED FULL DOSE 
 
If you are one of the seven participants in the full dose group, you will have a third day-
long experimental session with the same dose MDMA in Stage 1. After learning that you 
were in the full dose condition, you will schedule and complete your last experimental 
session, which will be “open label,” meaning you will receive MDMA, but this time you 


 
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will know. You will have the same regular psychotherapy visits after this last 
experimental session. 
 
Approximately six months after the start of the study (two months after the third 
experimental session), you will meet with the study researcher again. The researcher 
will ask about your PTSD symptoms and you will fill out a questionnaire on feelings of 
depression, a sleep quality questionnaire, a dissociation symptoms questionnaire, and a 
PTSD symptom questionnaire. You will complete the two tests of memory, attention and 
problem solving. You will also be asked if you have had any thoughts about hurting or 
killing yourself. This visit should last about 2.5 and 3.5 hours.  
 
OPEN-LABEL MDMA SESSIONS FOR PEOPLE WHO RECEIVED COMPARATOR DOSE  (STAGE 2) 
 
If you are one of the five subjects who got the comparator dose, you can take part in 
three open-label MDMA-assisted sessions scheduled 3 to 5 weeks apart as part of 
Stage 2.  In this part of the study, you will receive an active dose of MDMA during each 
session. Signing this consent form means you agree to take part in the second part of 
the study. The seven people who receive a full dose of MDMA during Stage 1 
cannot take part in Stage 2. 
 
If you take part in Stage 2, you will have 12 more visits with the study therapists. These 
sessions will be like experimental sessions you had during the first part of the study, 
except that you will know you are getting an active dose of MDMA. You will also only 
have one preparatory session rather than three sessions. The study timing and 
procedures will be similar to Stage 1. In the first experimental session, you will receive 
an active dose of 100mg MDMA with an optional supplemental dose. If this dose feels 
optimal you have the option to receive the same dose in the second and third 
experimental sessions in Stage 2. If it does not feel optimal, you can discuss increasing 
the dose to 125mg MDMA in either one of the experimental sessions with your study 
therapists. The study therapists will make the final decision about the dose you will 
receive in the second and third experimental sessions.  
 
You will have the same tests of your PTSD and other symptoms, personality and mental 
health two months after the third open-label experimental session, and some of these 
tests may be done by telemedicine or telephone. You will have the tests of memory, 
attention and problem solving in person with the study researcher. You will complete a 
questionnaire about your PTSD symptoms on every third psychotherapy session after 
the first and third experimental sessions. You will complete the scale of pain and tinnitus 
levels if you had them before the study. You will complete a questionnaire about your 
experience as a research subject.  
 
At the two-month follow-up after your second experimental session, you will receive a 
memory aid card to help you keep track of your health in between your last visit and a 
follow up visit 12 months after the final experimental session. The card will help you to 
remember to tell the researchers about any new problems or medical conditions, or 


 
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changes in medication that happened during this time. You may have your re
 
doctor fill out this card for you. 
 
 
LONG-TERM FOLLOW-UP 12 MONTHS AFTER LAST EXPERIMENTAL SESSION 
 
About 12 months after your last experimental session, you will either complete 
measurements of your PTSD symptoms over the phone, by telemedicine, or in person. 
You will complete questionnaires about your other symptoms and you will fill out a 
questionnaire on the positive and negative effects of being in the study. If you were only 
in Stage 1, then this will happen 12 months after your third experimental session, and if 
you were in Stage 2, then this will happen 12 months after the third experimental 
session in Stage 2.  
 
The same study researcher who asked you about your PTSD symptoms will do so 
again, either in person or over the telephone. You will also answer the questionnaire 
about feelings of depression or other symptoms you might have, and questionnaires 
about your personality, any changes in your PTSD symptoms, any thoughts you have 
about the good and bad points of MDMA-assisted therapy, and your thoughts about 
taking MDMA. The study therapists will ask you questions about thoughts or feelings 
about killing yourself. If you completed the visual scale of pain and tinnitus before the 
12-month follow-up, then you will complete it at 12-month follow up to measure changes 
in tinnitus and chronic pain symptoms if you had them before the study. There are no 
right or wrong answers to these questions. 
 
The questionnaires may be mailed to you for you to fill out.  It will come with an 
envelope that is already stamped and has only the researcher’s address on it.  Do not 
put your name on the questionnaires. 
 
A researcher who is part of the study may ask you about any changes in medication or 
your mental health, including any benefits or harms, during the follow-up period 
between your last visit and the 12-month follow-up visit in person or over the phone. 
 
The researchers will use your answers to these questionnaires to see if there are any 
long-lasting effects of being in the study, such as changes in PTSD symptoms or other 
life events.  
 
POSSIBLE RISKS OR DISCOMFORTS 
 
MDMA has not been widely tested in humans but as of March 2014 about 960 people 
have received MDMA in clinical research settings, without any serious unexpected 
problems happening. 
 
 


 
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Side effects during the MDMA experience that are less severe but more frequ
 
reported, are:  
 
• Lack of appetite (68%) 
• Dry mouth (64%) 
• Teeth grinding or tight jaw muscles (60%)  
• Decreased concentration (53%) 
• Thirst (48%) 
• Restlessness (46%) 
 
In two studies of MDMA in a total of 37 people with PTSD, these reactions were 
commonly reported after a full dose of MDMA: 
 
• Fatigue (77%) 
• Anxiety (74%) 
• Muscular tightness/tight jaw (62%) 
• Insomnia (61%) 
• Headache (51%) 
• Lack of appetite (48%) 
 
Forty eight to 77% of subjects in previous studies and in a placebo-controlled study of 
MDMA-assisted psychotherapy in people with PTSD reported nausea, low mood, 
feeling cold, dizziness, impaired balance, disturbance in attention, restlessness, 
perspiration, thirst, feeling weak, and need for more sleep (from most to least commonly 
reported).  When any of these side effects occur, they usually last less than four hours, 
though some people report that some of these side effects can last for more than 
twenty-four hours, and rarely longer, but no more than four days. 
 
Risks from MDMA   
 
Changes in vision, hearing or other senses:  In other studies where MDMA was given to 
volunteers, most people reported experiencing minor changes in vision and hearing, 
such as sounds seeming closer or farther away than usual, or objects seeming brighter 
than usual, with these changes lasting 2 to 3 hours. People also reported unusual 
feelings in their bodies, such as tingling or numbness (12%-33% in healthy controls, 7% 
of people with PTSD given full dose MDMA). These studies did not report exactly how 
many people experienced perceptual changes. 
 
Blood pressure and heart rate.  These effects of MDMA usually last 4 to 6 hours.  At the 
dose in this experiment, the increases in blood pressure and heart rate are likely to be 
moderate. Average increase in systolic blood pressure is 35 mmHg (measurement unit 
for blood pressure) and average diastolic blood pressure increase is 20 mmHg. Heart 
rate may increase by 20 beats per minute (BPM). 
 


 
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Blood pressure rose well above normal levels in a few people (a little less than 5%) 
 
MDMA was given in previous studies, but these people did not report any disco
 
and did not require any treatment. Although these increases in blood pressure are 
similar to what happens after heavy exercise, they could cause serious problems in 
people with pre-existing heart or blood vessel defects. These serious problems could 
include irregular heart beat, heart attack or stroke.  We will screen all potential 
participants for preexisting heart problems before they are allowed to be in this study.  
This doesn't guarantee that no heart problems will occur, but it does greatly reduce the 
risk of this happening. 
 
Anxious or jittery feeling: Some people in previous studies (16%) felt over-stimulated or 
anxious. It usually lasted less than 30 minutes. Due to your PTSD, you may be more 
likely to have severe anxiety or panic attacks. Panic attack was reported by 4% of 
participants with PTSD. Letting yourself accept and feel those emotions deeply can be 
part of the psychotherapy. If you are not able to deal with these experiences in a way 
that helps you, the study therapists will work with you to deal with these feelings. It is 
possible that if such periods of heightened emotion do not clear up or grow weaker 
during the session, you could be at increased risk for suicide or other self-harm 
afterwards. You will be encouraged to ask the attendant to call the study therapists 
immediately if you have any thoughts about hurting or killing yourself so they can help 
you resolve them safely. If necessary, they may prescribe anti-anxiety medication or 
medication for sleep. 
 
If you are in immediate danger of hurting or killing yourself or hurting someone else, 
then the study therapists may require you to stay in a nearby hospital. 
   
Serious problems and death: There have been some serious problems, and even 
deaths, associated with the use of Ecstasy, an illegal substance that may contain some 
MDMA, outside of controlled clinical or laboratory settings.  Serious problems have 
included high fever, 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 against them). Since you will be taking moderate 
amounts of uncontaminated MDMA in a controlled setting with trained therapists who 
will be closely monitoring your physical and psychological reactions, these problems are 
not expected to occur during or after the experimental session, but this does not 
guarantee that they could not occur. If they do occur, the study therapists are prepared 
to respond to these problems. There has been one case of irregular heartbeat in a 
controlled, clinical study of MDMA in a person with PTSD. 
 
Insomnia & drowsiness:  In previous studies, less than 23% of subjects without PTSD 
have reported insomnia (difficulty sleeping), and feeling tired, irritable, or drowsy for as 
long as 3 days after MDMA. Sixty-one percent of people with PTSD reported some 
insomnia, and 4% of people in two completed and one ongoing study in people with 
PTSD reported insomnia lasting more than 7 days. 
 


 
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Mood:  Some after-effects of MDMA may be noticeable up to 2 or 3 days later. In p
 
with PTSD, 39% reported low mood and 17% reported some rumination (p
 
worries). In healthy people, a few people feel that their mood is better, but 14% feel it is 
worse. 
 
Immune System: You will probably have a less active immune system for 2 or 3 days 
after MDMA. This may make you more likely to become sick with a cold or other 
infection during this time. The study describing this finding did not say how many people 
in the study showed these changes. 
 
Addiction:  There is a small chance that you could become addicted to MDMA. One 
study found that up to 6% of people using Ecstasy for recreational purposes were 
dependent on it.  However, a study of people who had received MDMA for the first time 
in a legal laboratory setting found that they did not want to try MDMA again outside of 
the laboratory, and in two completed studies in 37 people with PTSD, only one person 
reported trying ecstasy after being in the study. People who have had problems with 
drug abuse in the last 6 months should not take part in this study. 
 
There may be unknown side effects or risks from the use of MDMA. 
 
Possible Brain Damage  
Experiments in rats and monkeys show that high and repeated doses of MDMA can 
change brain cells that release a chemical called serotonin; in mice only, the affected 
cells release dopamine. The changes include loss of the part of the cell (called "axons") 
that connects 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 tests of 
memory. Recent studies in monkeys and rodents suggest that the doses in studies 
finding damaged axons are too high to reflect typical human doses of ecstasy or MDMA 
used in studies.   
 
Many studies found that people who had used Ecstasy many times in recreational 
contexts were not able to recall words, pictures or patterns as well as people who did 
not use Ecstasy and performed less well on tests of planning and impulse control. 
These differences are not big, but they have lasted for at least a year after people had 
stopped taking Ecstasy.  Not all studies have found Ecstasy users to have difficulty 
recalling words or pictures or to have impulse control problems.  When compared with 
people who do not use Ecstasy, studies found Ecstasy users were more likely to report 
feeling generally anxious or depressed. Many of these studies found that using alcohol 
or other drugs was also associated with feeling anxious or depressed.  At least two 
studies found that people who are anxious, depressed or have psychological problems 
before taking any drugs are more likely to take Ecstasy than people without these 
problems. 
 


 
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Only one study has looked at brain scans of people before they got MDMA and 
 
again after they have received one or two moderate doses of MDMA, and did no  
 
any changes in the brain, 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 only saw one small change in the 
amount of blood found in a specific part of the brain, and did not see signs of brain 
injury. The decrease in blood volume might be from temporary lowering of a type of 
brain receptor, or it might be a sign of reduced function in this area. Findings from these 
studies suggest that the amount of MDMA you will receive in this study will not produce 
any lasting changes in your brain, though this is not guaranteed.   
 
Studies of people receiving one or two doses of MDMA in a medical laboratory setting 
have not found any lasting changes in memory or planning. Studies comparing people 
before and after they decided to take a few Ecstasy tablets 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. A study of MDMA-assisted 
psychotherapy in the US found that memory and learning were the same in people who 
got MDMA and people who got placebo. It is believed that the amount of MDMA you will 
receive will not produce any lasting changes in memory or planning ahead, though this 
cannot be guaranteed. You will not get a second dose of MDMA if they believe you are 
showing signs of memory problems. 
 
Other Risks: 
You should not drive or use machinery immediately after each experimental 
session (up to 24 hours afterwards).  This is because the study medication may 
cause drowsiness, lack of co-ordination or slower reaction time. 
 
If you are tested for drugs of abuse within three days of each experimental session, you 
may test positive. The study therapists 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 the study therapists to verify 
that you are in this study. 
 
The interviews you will have during the course of 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. The 
medical evaluations involve some blood tests. The risks of blood drawing include 
temporary discomfort from the needle stick, bruising and, rarely, infection at the site of 
the needle stick. Fainting could also occur. 
 
It is possible that after you stop taking psychiatric medication (as for depression or 
anxiety) as part of the study, you may start to have symptoms again. If this happens, 
you should talk with your outside therapist and the study therapists. If you have to start 
taking medication again, then the study therapists will have to take you out of the study. 
 
As with any medical procedure, there are potential risks associated with the use of 


 
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telemedicine. These risks include, but may not be limited to: 
·  In rare cases, information transmitted may not be good or clear enough (e.g. poo  
resolution or choppy video connection) to allow for appropriate medical decision making 
by your therapy team or the researchers; 
·  Delays in medical evaluation and treatment could occur due to problems or failures of 
the equipment or internet service; 
·  In very rare instances, security protocols (the computer software and settings that 
maintain security) could fail, causing a breach of privacy of personal medical 
information; 
 
Reproductive Risks: 
Effects of MDMA on the growth and development of an unborn baby are not known, 
therefore you will not be allowed to enter the study if you are pregnant.  
 
Women who are able to become pregnant must use one of the allowed birth control 
methods, such as birth-control pills or shots, IUD, and diaphragm used along with 
spermicide and with partner use of condom while they are in the study. The study 
doctors 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. 
 
You will be tested at the start of the study and again before each experimental session 
to see if you are pregnant.  If, at any time during the study, you suspect that you may be 
pregnant or are concerned that you may become pregnant, you must advise the study 
therapists immediately. If you should become pregnant during the study, the study 
therapists will help you get proper advice while you are pregnant and you will need to let 
them know about the health of your baby when he or she is born. 
 
NEW FINDINGS 
If any new information becomes available about MDMA while you are participating in 
this study, the study therapists will tell you about it as soon as possible. 
 
POSSIBLE BENEFITS 
Your symptoms of PTSD may improve while taking part in this study. There is no 
guarantee that you will benefit from being in this research study. Information learned 
from this study may help researchers to improve treatment for PTSD in the future. 
 
COSTS 
The sponsor of this study, Multidisciplinary Association for Psychedelic Studies (MAPS), 
will cover the costs that are directly related to this study. This includes the costs for all 
psychotherapy sessions, for the psychological and laboratory testing, for medical 
examinations, and for the experimental drug.  You, your private medical insurance (if 
any), and the public health insurance plan will not be charged for any procedures done 
solely for the purpose of the study. 
 
You or your insurance will remain responsible for on-going treatment unrelated to the 
study. 


 
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REIMBURSEMENT FOR PARTICIPATION 
The Sponsor, MAPS, will not pay for meals and lodgings or travel expenses.  
 
The sponsor is paying your study therapists and study researchers for the time, effort 
and expenses to conduct this study.   
 
ALTERNATIVES 
One alternative to being in this study is to decide not to participate. You may decide to 
try other treatments for PTSD. There are other medications, such as Paxil (paroxetine) 
or Zoloft (sertraline) and anti-anxiety medications such as Xanax (alprazolam) and other 
forms of psychotherapy that you could try. If you are currently receiving psychotherapy 
and/or medication, you could continue with these. 
 
CONFIDENTIALITY 
All information collected will be treated and handled as confidentially as possible, except 
where disclosure is required by law. Although complete confidentiality is something the 
study team will try for, absolute confidentiality cannot be guaranteed.  
 
As part of this research, the study doctors will collect the results of your study-related 
tests and procedures and may also access your personal medical records for health 
information such as past medical history and test results.  When not in use, information 
will be stored in a locked office and will be kept for 25 years after study completion, as 
required by Canadian clinical trial regulations. Audio and video recordings will be stored 
for up to 25 years after their creation. 
 
Some people need access to the information to monitor the study. Any paperwork 
copied will have any information that could be used to identify you removed first. 
Session recordings will not have your name or initials printed on them, only a number. 
 
Medical records, including audio and video recordings, which identify you and the 
consent form signed by you will be looked at and/or copied for research or regulatory 
purposes. 
 
Medical records may be looked at, at the study site, by 
• Representatives of the sponsor, MAPS 
• Health Canada and similar agencies in other countries, as the U.S. Food and Drug 
Administration (FDA) 
• Governmental agencies in other countries; and 
• IRB Services 
 
Information from this study will be submitted to the sponsor, and to Health Canada and 
to governmental agencies in other countries (e.g. U.S. FDA). Information sent from the 
study site will not contain your name. 
 


 
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Results from this study may be presented in meetings or in publications. Your id
 
will not be disclosed in those presentations, which will mostly give averages of data  
 
All records in 
 are subject to subpoena by a court of law. 
 
Audio and video recordings: Any information that could directly identify you will be 
withheld from recordings (except unique voice or image identity). Access to recordings 
will be limited to research purposes. 
 
Telemedicine: Some of the study visits may be conducted by telemedicine or telephone 
from different locations for the purpose of improving your access to care and making 
scheduling more efficient. The information may be used for diagnosis, therapy, follow-up 
and measuring symptoms, and may include any of the following: 
·  Live two-way audio and video that may be recorded 
·  Sending recorded audio and video of therapy sessions or assessments 
 
Electronic systems used will include measures to protect confidentiality of your 
identification and video data. 
 
You will be asked to give an additional consent at the end of the study in order for your 
audio or video recordings to be viewed by others, such as researchers working with the 
sponsor or therapists learning how to perform MDMA-assisted psychotherapy, but you 
do not have to agree to this in order to participate in the study. You may request to hear 
or see these recordings.  
 
You have the right to check your study records and request changes if the information is 
not correct. 
 
By signing this information and consent form, you consent to the collection, access, use 
and disclosure of your information as described above. 
  
TREATMENT AND COMPENSATION FOR INJURY 
In the event of a study-related injury, the Sponsor will cover any costs that arise from 
treating the injury that is not covered by the provincial health plan or your private 
medical insurance (if any).  Injuries that are not related to participation in the study will 
not be covered.  
 
LEGAL RIGHTS 
The above section does not restrict your right to seek legal assistance.  You do not 
waive any legal rights by signing this Subject Information and Consent Form. 
 
VOLUNTARY PARTICIPATION 
Your decision to take part in this research study is completely voluntary.  There will not 
be any penalty or loss of benefits to you if you decide not to participate. 
 




 
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·have concerns, complaints or general questions about the research, or 
·wish to provide input about the research study 
 
You can do so in the following ways: 
 
In writing: 300-372 Hollandview Trail, Aurora, ON L4G 0A5 
By phone: 1-866-449-8591 
By email: subjectinquiries@irbservices.com 
Do not sign this consent form unless you have had a chance to ask questions and have 
received satisfactory answers to all of your questions. 
 
SUBJECT’S STATEMENT OF CONSENT 
 
Your participation in this study is voluntary.  You may refuse to take part in or you may 
stop taking part in this study at any time.  You should call the study doctors if you decide 
to do this.  Your decision will not affect your current or future regular medical care or 
any benefits to which you are entitled at this site. The study doctors and/or the sponsor 
may stop your participation in this study at any time without your consent if they decide 
it is in your best interest or if you do not follow the study doctors’ instructions.   
 
You will need to have someone drive you home on the day after the experimental 
session.  If you cannot find anyone to take you home, the study doctors will find 
someone to drive you.   
 
You have read the information in this consent form and it has been discussed with you.  
All of your questions so far about the study and your participation in it have been 
answered.  You freely consent to participate in this research study. 
 
You will not donate blood while you are in the study and for at least 30 days after.  
 
By signing this consent form, you have not waived any of the legal rights which you 
otherwise would have as a subject in a research study.  You will be given a copy of 
the consent form signed by you and the person administering this consent. 
 
The study therapists have my permission to tell my regular doctor about my being in this 
study:  
! YES          ! NO 


 
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SUBJECT 
 
 
Printed name 
 
 
 
Signature 
 
 
 
Date 
 
 
PERSON ADMINISTERING CONSENT 
 
 
Printed name 
 
 
 
Signature 
 
 
 
Date 
 
 
 
 
 

Prot_003.pdf: 




MAPS Study MP-4 
 
Protocol Synopsis Amendment 2 Version 3 
Canada 
 
June 20, 2014 
 
Page 1 of 7 
A Randomized, Double-Blind, Controlled Phase 2 Pilot Study of Manualized 
3,4-methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy in 12 Subjects 
with Treatment-Resistant Posttraumatic Stress Disorder (PTSD) – Canada 
 
Amendment 2 Version 3: June 20, 2014 
 
Study Code:  
MP-4 
 
Sponsor:  
Multidisciplinary Association for Psychedelic Studies (MAPS) 
1215 Mission St. 
Santa Cruz, CA 95060, USA 
Qualified  
Investigator:  
Ingrid Pacey MBBS FRCP[C]  
Research Affiliate, CARBC 
University of Victoria 
Tel:  604-732-9309 
 
Sub-Investigator:   Donna Dryer, MD, FRCP[C]  
Clinical Assistant Professor, Department of Psychiatry,  
University of British Columbia 
Medical Director, Orenda Institute 
Psychiatrist, Connect Health Centre for Integrative Medicine 
Cell: 778-938-6926 
Voice/FAX: 250-935-0037 
 
Site: 
3369 West 4th Avenue  
Vancouver BC Canada 
V6R 1N6 
Tel:  604-336-4822 
 
Medical Monitor:  Michael C. Mithoefer M.D. 
Assistant Clinical Professor of Psychiatry 
Medical University of South Carolina 
208 Scott Street 
Mount Pleasant, SC 29464-4345 
Tel:  843-849-6899 
 
Study Description: This is a Phase 2 randomized, double-blind, placebo controlled study to 
assess safety and efficacy of manualized MDMA-assisted psychotherapy in treating chronic, 
treatment-resistant PTSD. Seven subjects will be randomized to receive full dose MDMA (full 
dose condition) and five subjects will receive a comparator dose (comparator condition), with an 
optional supplemental half-dose available 1.5 to 2.5 hours after the initial dose.  
 
A team consisting of a male and female therapist will conduct psychotherapy according the 
treatment manual provided. There are two teams involved with this study. One team will consist 
of the Qualified Investigator and a co-therapist, and the second team will consist of a co-therapist 
and a Sub-investigator who have been delegated the authority to conduct therapy by the 


MAPS Study MP-4 
 
Protocol Synopsis Amendment 2 Version 3 
Canada 
 
June 20, 2014 
 
Page 2 of 7 
Qualified Investigator. Information will be collected regarding consistency and response of these 
teams by reviewing adherence criteria in selected blinded videos of therapy sessions. All study 
procedures, including administration of the Investigational Product, will be done by the 
Investigator or designated qualified study personnel. 
 
In Stage 1, all subjects will have two blinded experimental sessions of manualized MDMA-
assisted psychotherapy scheduled at a three to five week interval, within a moderate course of 
non-drug psychotherapy (preparatory and integrative sessions), after which they will complete 
the primary endpoint assessment. Integrative sessions may be completed via telemedicine, 
telephone or in person. After the primary endpoint assessment, the subject and the therapists will 
be unblinded. Subjects assigned to receive full dose MDMA will receive a third open-label 
experimental session and complete Stage 1. Subjects assigned to receive comparator dose will 
have the option to cross over, without completing Stage 1, to an open-label study segment 
following similar procedures, referred to as Stage 2. Stage 2 will be used to explore the optimal 
therapeutic dose of MDMA using a clinical titration dosing strategy. Stage 2 follows similar 
procedures and visit schedule as Stage 1 using varied active doses of MDMA, in which each 
initial dose may be followed by a supplemental dose that will be half of the initial dose. In Stage 
2, subjects will receive an initial dose of 100 mg MDMA during the first experimental session. 
The co-therapists, in consultation with the subject, will decide whether to administer an initial 
dose of 100 mg or 125 mg MDMA in the second and third experimental sessions.  
 
A blinded Independent Rater (IR) will assess PTSD symptoms, general function, and 
psychological symptoms. These symptoms will be assessed at baseline, the primary endpoint, 
and two months after the third experimental session in Stage 1 and equivalent timepoints in 
Stage 2. Outcome measures after baseline may be completed via telemedicine or in person. 
Neurocognitive measures must be done in person. Symptoms and long-term benefits and harms 
will be assessed again twelve months after the final experimental session. This study will provide 
an estimate of effect size based on dose comparison of PTSD symptoms to MDMA-assisted 
psychotherapy. This study will also permit the refinement of the treatment manual through 
blinded review of adherence criteria assessed by rating videos of psychotherapy sessions. 


MAPS Study MP-4 
 
Protocol Synopsis Amendment 2 Version 3 
Canada 
 
June 20, 2014 
 
Page 3 of 7 
Dose Selection: This study will compare the effects of psychotherapy sessions assisted by 
comparator dose or full dose MDMA. The comparator dose will be 0 mg MDMA followed 1.5 to 
2.5 hours later by 0 mg MDMA. The full dose will be 125 mg MDMA followed 1.5 to 2.5  hours 
later by 62.5 mg MDMA. 
 
Table 1. Stage 1 Drug Doses  
Experimental 
Session 
Dose 
Initial 
Dose 
Optional 
Supplemental 
Dose 
Min-Max 
Cumulative 
Dose 
1 and 2 
Comparator Dose 
0 mg 
0 mg 
0 mg 
1, 2, and 3 
Full Dose 
125 mg 
62.5 mg 
125-187.5 mg 
 
Table 2. Stage 2 Drug Doses  
Experimental 
Session 
Dose 
Initial 
Dose 
Optional 
Supplemental 
Dose 
Min-Max 
Cumulative 
Dose 
Min-Max 
Cumulative 
Dose with 
Titration 
1 
Active Dose 
100 mg 
50 mg 
100-150 mg 
 
Active Dose 
100 mg 
50 mg 
100-150 mg 
 
2 and 3 
+ Optional 
Titration Dose 
25 mg 
12.5 mg 
 
125-187.5 mg 
 
The MDMA doses to be used in this study have been used in previous studies sponsored by 
MAPS. The initial full dose is expected to produce all the commonly reported effects of MDMA. 
The supplemental dose will prolong subjective drug effects without producing physiological 
effects any greater than peak effects occurring after the initial dose.  The comparator dose is not 
expected to produce effects associated with MDMA.   
 
Protocol Objectives: The overall objective of this study is to examine whether the full dose of 
MDMA versus the comparator used in conjunction with manualized psychotherapy will reduce 
or attenuate PTSD symptoms as evaluated by standard clinical measures and to collect safety 
data.  
 
 
Primary Objective: Assess changes in PTSD symptoms in subjects receiving the full dose of 
MDMA compared to the comparator dose as measured by Global CAPS scores at baseline and 
the primary endpoint, one month after the second experimental session. 
 
Primary Outcome Measure: Clinician-Administered PTSD scale (CAPS) administered by a 
blinded Independent Rater. With the exception of the Screening/Baseline visit this measure can 
be administered via telemedicine or in person. 
 
Secondary Outcome Measures: Posttraumatic Diagnostic Scale (PDS), Global Assessment of 
Function (GAF), Beck Depression Inventory-II (BDI-II), Neuroticism Extroversion Openness 
Personality Inventory (NEO-PI), Pittsburgh Sleep Quality Index (PSQI), Posttraumatic Growth 
Inventory (PTGI), and Dissociation Scale II (DES-II) 


MAPS Study MP-4 
 
Protocol Synopsis Amendment 2 Version 3 
Canada 
 
June 20, 2014 
 
Page 4 of 7 
 
Safety Measures: Columbia Suicide Severity Rating Scale (C-SSRS), Repeatable Battery for 
Assessment of Neuropsychological Status (RBANS), Paced Auditory Serial Addition Task 
(PASAT), Vital signs, Subjective Units of Distress (SUD), Adverse Events and Spontaneously 
Reported Reactions, Concomitant Medications, Visual analog scales assessing pain and tinnitus, 
in participants with medical history of chronic pain and/or tinnitus  
 
Process Measures: Belief of condition assignment, States of Consciousness Questionnaire 
(SOCQ), Perceptions of Experimental Sessions, Reactions to Research Participation 
Questionnaire (RRPQ), Adherence to Treatment Manual 
 
Recruitment and Subject Population:  Subjects may be male or female, aged 21 or older, with a 
confirmed diagnosis of chronic PTSD, who have undergone at least one treatment of adequate 
dose/duration for PTSD without achieving remission. Prior treatment can include 
psychotherapeutic or pharmacological treatments, and people who have undergone one or more 
prior treatments are eligible for study participation. Subjects would not be excluded for having 
more than one traumatic event. Subjects must have a CAPS score equal to or greater than 60 and 
must meet all protocol inclusion criteria and no exclusion criteria at baseline. Subjects must be in 
good physical health and without major medical disorders that might affect the safety or 
tolerability of MDMA. Subjects will be recruited through printed ads, internet ads, referrals from 
other psychiatrists, psychotherapists or physicians, and through word of mouth. 
 
Study Procedures: After giving written informed consent, prospective subjects will be screened 
for eligibility, and twelve subjects meeting study criteria will be enrolled. In consultation with 
their prescribing physician, any individuals taking psychiatric medications will taper off these 
medications, allowing for a washout period of at least five times the medication half-life plus one 
week for stabilization before the first experimental session. Subjects taking psychostimulants for 
ADHD or gabapentin for pain management may continue to take these medications so long as 
they discontinue use for five half lives prior to each experimental session and resume use of 
psychostimulants ten days after an experimental session. During the study, benzodiazepines or 
zolpidem or other anxiolytic or sedative may be used as rescue medications if needed as 
approved by the qualified investigator responsible for the study. Any subjects who are in 
psychotherapy with an outside therapist at the time of enrollment may continue that therapy 
during the study without increasing the number or type of sessions or changing psychotherapists 
or type of psychotherapy.  
 
Symptoms of PTSD, perceived positive changes or growth after trauma, general psychological 
function, depression, sleep quality and dissociative experiences will be assessed at baseline in all 
subjects. The RBANS and PASAT will be administered to all subjects at baseline. The CAPS 
interviews may be recorded to audio and video to assess reliability of CAPS ratings. The first 
experimental session will be preceded by three preparatory sessions and followed by three 
integrative psychotherapy sessions. During preparatory sessions, subjects will learn what to 
expect during experimental sessions, and during integrative sessions they will receive support in 
integrating their experiences and insights from the experimental sessions. Preparatory, 
experimental and integrative sessions will be audio and video recorded for research purposes. 
Video data will be evaluated for adherence to the therapy manual using adherence criteria 
ratings. 


MAPS Study MP-4 
 
Protocol Synopsis Amendment 2 Version 3 
Canada 
 
June 20, 2014 
 
Page 5 of 7 
 
Seven subjects will be randomized to receive a full dose of MDMA and five will be randomized 
to receive comparator dose during two experimental psychotherapy sessions scheduled three to 
five weeks apart. After each experimental session, subjects will spend the night at the treatment 
facility with an attendant on duty. Subjects will complete the SOCQ in the time between an 
experimental session and the integrative session on the day after. Subjects and therapists will 
report their beliefs on their condition assignment at the integrative session on the day after each 
experimental session. There will be daily phone contact with one of the therapists for seven days 
after each experimental session. Throughout the study, changes in symptom severity of tinnitus 
and/or chronic pain will be collected as needed when subjects who have a medical history of 
these conditions report a change in symptoms using a simple visual analog scale. The PDS will 
be completed on the third integrative session after the first and third experimental sessions and 
during IR visits. Symptoms of PTSD, depression, sleep quality, dissociation, and perceived 
growth, general psychological function and cognitive function will be repeated for each subject 
at the primary endpoint, after which the blind will be broken. Subjects who learn they were 
assigned to full dose will have a third and final open-label experimental session with full dose 
MDMA, two months after which their psychological symptoms will be assessed again. Subjects 
who learn they were assigned to receive comparator dose will have the opportunity to enroll in 
Stage 2. Stage 2 consists of a similar series of procedures and visits except that subjects receive 
one preparatory visit and three open-label experimental sessions. Subjects will receive 100 mg 
MDMA possibly followed by 50 mg during the first open-label session. The decision to titrate 
the dose in the second and third experimental sessions in Stage 2 will be based on the experience 
of the first session. If 100mg MDMA does not seem to be the optimal therapeutic dose based on 
the first experimental session in Stage 2, the dosage may be increased by an increment of 25mg 
in order to achieve the optimal therapeutic dose. The supplemental doses for each experimental 
session will be half of the initial dose, respectively. Cognitive function will be assessed via 
RBANS and PASAT again at the primary endpoint and two months after the third Stage 1/Stage 
2 experimental sessions. 
 
There will be a long-term follow-up with repeated outcome measures for symptoms of PTSD, 
depression, dissociation, posttraumatic growth, sleep quality, pain and/or tinnitus, if applicable, 
twelve months after the subjects’ final experimental session.  The study therapists will maintain 
communication with the referring physician or therapist and any other healthcare providers 
requested by the subject.  
 
Subjects discontinuing treatment prior to the primary endpoint will be replaced until complete 
data has been collected from twelve subjects.  
 
Safety: The safety of subjects will be assured during and after the experimental sessions by 
assessing physiological effects, psychological distress, adverse events (AEs), spontaneously 
reported reactions, and suicidality.   
 
• 
Suicidality will be assessed with the Columbia Suicide Severity Rating Scale (C-SSRS) 
during visits prior to experimental sessions, twice during experimental sessions, and 
several times after each experimental session. 
• 
Subjective Units of Distress (SUD) scores and vital signs including blood pressure, heart 
rate and temperature will be measured during each experimental session. 


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• Serious Adverse Events (SAEs) will be collected through termination.  
• All AEs and spontaneously reported reactions will be collected on the day of drug 
administration and for seven days after each experimental session. 
• AEs requiring medical attention will be collected from the first experimental session 
through the subject’s last two-month follow-up. 
• AEs 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. 
• Any AE leading to withdrawal from the protocol will be collected throughout the study. 
• All AEs related to changes in psychiatric status will be collected throughout the study. 
• Changes in pre-existing tinnitus and/or chronic pain symptoms will be collected using a 
visual analog scale, specifically in subjects with a medical history of tinnitus and/or 
chronic pain. 
• Changes in memory, attention, speed of information processing and problem solving will 
be measured with RBANS and PASAT at the primary endpoint and two months after the 
final Stage 1 or Stage 2 experimental session. 
 
Statistical Analysis: This is a pilot study intended to collect estimates of effect size of full dose 
MDMA (125 mg) versus placebo comparator dose. The study is underpowered for detection of 
differences of a small or moderate effect size, but it may detect differences if the effect size is 
large. The Sponsor will judge the clinical and statistical significance of the study based on a 
comparison of observer-blind data collected at baseline and the primary endpoint using the 
primary outcome measure, which is the CAPS. Descriptive statistics will be computed overall 
and within the two conditions for all available data from outcome measures. Effect sizes will be 
estimated for all outcome measures using Cohen’s techniques. RBANS and PASAT scores at 
baseline and primary endpoint will be compared across conditions using difference scores and 
independent-sample t-tests, with p value set at 0.05. Descriptive statistics will be computed for 
each adherence scale within a specific given session. The sponsor will explore the factors and 
structure of the measures of adherence to assist in further development of adherence and 
competence measures. If sufficient data is available, the sponsor will correlate the mean 
adherence ratings for adherence scale and session type with Global CAPS scores to investigate 
the effects of adherence to the treatment manual on reduction in PTSD symptoms.  
 


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Figure 1. Study Structure Overview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outcome Measure 
Unblinding 
Stage 2 for 
comparator 
dose subjects 
Screening 
Measures 
Integrative 
Sessions 
Open Label 
Experimental 
Session for full 
dose subjects 
Experimental 
Session 
Experimental 
Session  
Integrative 
Sessions 
Integrative 
Sessions 
Outcome Measure 
 
Outcome Measure 
Long-term Follow-up 
Preparatory  
Sessions 


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PROTOCOL MP-4 
IND #63,384 
Original Protocol: March 17, 2009 
Amendment 1 Version 1: October 27, 2010 
Amendment 1 Version 2: June 20, 2013 
Amendment 2 Version 1: February 4, 2014 
Amendment 2 Version 2: June 02, 2014 
Amendment 2 Version 3: June 20, 2014 
 
A Randomized, Double-Blind, Controlled Phase 2 Pilot Study of Manualized 
3,4-methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy in 12 
Subjects with Treatment-Resistant Posttraumatic Stress Disorder (PTSD) - Canada 
 
SPONSOR 
Multidisciplinary Association for Psychedelic 
Studies (MAPS)  
1215 Mission St. 
Santa Cruz, CA 95060 
SPONSOR DESIGNEE 
Amy Emerson 
Phone number: 510-393-7224 
 
QUALIFIED 
INVESTIGATOR 
 
 
 
Ingrid Pacey, M.B.B.S., F.R.C.P.[C]  
Research Affiliate, CARBC 
University of Victoria 
Tel: 604-732-9309 
SUB-INVESTIGATOR 
 
 
 
 
 
 
 
SITE 
Donna Dryer, M.D., F.R.C.P.[C]  
Clinical Assistant Professor,  
Department of Psychiatry, UBC 
Medical Director, Orenda Institute 
Cell: 778-938-6926 
Voice/FAX: 250-935-0037 
 
3369 West 4th Avenue  
Vancouver, BC Canada 
V6R 1N6 
Tel:  604-336-4822 
 
MEDICAL MONITOR 
Michael C. Mithoefer, M.D. 
Assistant Clinical Professor of Psychiatry 
Medical University of South Carolina 
208 Scott Street  
Mount Pleasant SC, 29464-4345 
Tel: 843-849-6899 
 
For trial related emergencies, call: 650-248-4647


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Table of Contents 
 
1.0 List of Abbreviations ............................................................................................................................. 4!
2.0 Introduction............................................................................................................................................ 6!
3.0 Background............................................................................................................................................. 7!
3.1 Posttraumatic Stress Disorder......................................................................................................7!
3.2 MDMA ........................................................................................................................................9!
3.3 Previous Clinical Experience with MDMA.................................................................................9!
3.4 MDMA-assisted Psychotherapy for PTSD................................................................................11!
3.5 Purpose ......................................................................................................................................13!
4.0 Ethics..................................................................................................................................................... 13!
5.0 Informed Consent ................................................................................................................................ 14!
6.0 Study Objectives................................................................................................................................... 15!
6.1 Primary Objective......................................................................................................................15!
6.2 Secondary Objectives ................................................................................................................15!
6.3 Safety Objectives.......................................................................................................................16!
7.0 General Investigational Plan............................................................................................................... 17!
7.1 Recruitment and Subject Population .........................................................................................17!
7.2 Enrollment Criteria ....................................................................................................................18!
7.2.1 Inclusion Criteria ..............................................................................................18!
7.2.2 Exclusion Criteria .............................................................................................19!
7.3 Planned Duration of Study and Visit Windows.........................................................................20!
8.0 Drug Description and Dosage ............................................................................................................. 20!
8.1 Drug Compounding, Doses, and Labeling ................................................................................22!
8.2 MDMA Accountability..............................................................................................................24!
8.3 MDMA Storage and Handling...................................................................................................25!
9.0 Method .................................................................................................................................................. 25!
9.1 Randomization...........................................................................................................................26!
9.2 Subject Numbering ....................................................................................................................26!
9.3 Assessments and Measures........................................................................................................30!
9.3.1 Outcome Measures............................................................................................30!
9.3.2 Safety Measures................................................................................................32!
9.3.3 Process Measures..............................................................................................34!
9.4 Visit Descriptions ......................................................................................................................35!
9.4.1 Prescreening, Screening, and Baseline Evaluation (Pre-study)........................35!
9.4.2 Preparatory Psychotherapy Sessions - Visits 1, 2, 3 (Stage 1), 18 (Stage 2)....38!
9.4.3 Experimental Sessions - Visits 4, 8 (Stage 1), 13, (Full Dose Group Stage 1), 
19 23, 28 (Stage 2).....................................................................................................39!
9.4.4 Integrative Sessions 24 Hours after Experimental Session - Visits 5, 9 (Stage 
1), 14 (Full Dose Group Stage 1), 20, 24, 29 (Stage 2) .............................................43!
9.4.5 A Week of Daily Contact..................................................................................44!
9.4.6 Integrative Psychotherapy Between Experimental Sessions - Visits 6, 7, 10, 
11,  (Stage 1), 15, 16, (Full Dose Group Stage 1), 21, 22, 25, 26, 30, 31 (Stage 2)..44!
9.4.7 Evaluation at Primary Endpoint and Unblinding - Visit 12 (Stage 1)..............45!
9.4.8 End of Stage 1 - Visit 17 (Full Dose Group Stage 1) .......................................46!
9.4.9 Open-label Stage 2 (Comparator Dose Subjects from Stage 1)........................47!
9.4.9 Long-term Follow-up........................................................................................48!
10.0 Removal of Subjects from Therapy or Assessment ........................................................................ 49!
11.0 Premature Discontinuation of the Study ......................................................................................... 50!
12.0 Data Analysis...................................................................................................................................... 50!
12.1 Statistical Power ......................................................................................................................52!


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13.0 Risk Mitigation................................................................................................................................... 53!
13.1 Medical Emergencies...............................................................................................................53!
14.0 Adverse Events ................................................................................................................................... 54!
14.1 Serious Adverse Events ...........................................................................................................55!
14.2 Adverse Event Collection........................................................................................................56!
14.3 Spontaneously Reported Reactions .........................................................................................57!
14.4 Collection of Concomitant Medications and Tapering Instructions........................................57!
14.5 Clinical Laboratory Assessments ............................................................................................60!
15.0 Study Monitoring, Auditing, and Documentation .......................................................................... 61!
16.0 Risks of Participation......................................................................................................................... 62!
16.1 Risks and Discomforts Associated with Psychotherapy Sessions and Assessment of 
Measures..........................................................................................................................................62!
16.2 Risks of Receiving MDMA.....................................................................................................62!
16.2.1 Cardiovascular and Sympathomimetic Effects...............................................63!
16.2.2 Psychological Distress ....................................................................................64!
16.2.3 Body Temperature ..........................................................................................67!
16.2.4 Reproductive and Developmental Risks.........................................................67!
16.2.5 Potential Neurotoxicity Associated with Ecstasy Use....................................67!
16.3 Abuse Liability ........................................................................................................................67!
16.4 Risks and Discomforts of Receiving the Comparator Dose of Study Drug ............................68!
17.0 Alternative Treatments and Procedures.......................................................................................... 68!
18.0 Confidentiality.................................................................................................................................... 69!
19.0 Costs to Subjects................................................................................................................................. 70!
20.0 Record Retention................................................................................................................................ 70!
21.0 Publication Policy............................................................................................................................... 70!
22.0 References........................................................................................................................................... 72!
 


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1.0 List of Abbreviations 
 
AE(s)  
Adverse Event(s) 
AED  
Automated External Defibrillator 
A:G 
 
Abumin : Globulin ratio 
ALT/SGPT 
Alanine Aminotransferase 
AMI   
Acute Myocardial Infarction 
AST/SGOT 
Aspartate Aminotransferase 
BDI-II  
Beck Depression Inventory II 
BP 
 
Blood Pressure 
BT 
 
Body Temperature 
BUN  
Blood Urea Nitrogen 
C 
 
Celsius 
CAPS  
Clinician Administered PTSD Scale 
CI 
 
Clinical Investigator(s) (e.g. therapists, Sub-Investigator(s)) 
CPK 
 
Creatine phosphokinase 
CPT 
 
Cognitive Processing Therapy 
CRA  
Clinical Research Associate 
CRF(s) 
Case Report Form(s) 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DBP 
 
Diastolic Blood Pressure 
DEA  
Drug Enforcement Administration 
DES-II  
Dissociation Experiences Scale II 
DMF  
Drug Master File 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders IV 
ECG/EKG 
Electrocardiogram 
ED 
 
Emergency Department 
EMDR  
Eye Movement Desensitization and Reprocessing 
EMS  
 
Emergency Medical Services 
F 
 
Fahrenheit 
FDA  
Food and Drug Administration  
GAF   
Global Assessment of Functioning 
GCP 
 
Good Clinical Practice 
HCl 
 
Hydrochloride 
HIPA   
Health Information Protection Act 
HIV 
 
Human Immunodeficiency Virus  
HPLC  
High Performance Liquid Chromatography 
IB 
 
Investigator’s Brochure 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
IND 
 
Investigational New Drug  
IR 
 
Independent Rater 
IRB 
 
Institutional Review Board 
ISF 
 
Clinical Investigator Site File 
IV 
 
Intra-venous 
LSD 
 
d-Lysergic acid diethylamide 


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MAOI  
Monoamine oxidase Inhibitor 
MAPS  
Multidisciplinary Association for Psychedelic Studies 
MCH  
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV   
Mean Corpuscular Volume  
MDMA 
3,4-Methylenedioxymethamphetamine 
MP-1  
MAPS’ First Clinical Trial of MDMA-assisted Psychotherapy for PTSD 
MP-2 
MAPS’ Second Clinical Trial of MDMA-assisted Psychotherapy for PTSD 
NEO-PI 
Neuroticism Extroversion Openness Personality Inventory  
OT 
 
Oxytocin 
PASAT  
Paced Auditory Serial Addition Test 
PDS 
 
PTSD Diagnostic Scale 
PI 
 
Principal Investigator 
PRN 
 
As Needed 
PSQI  
Pittsburgh Sleep Quality Index 
PTSD  
Posttraumatic Stress Disorder 
PTCA   
Percutaneous Transluminal Coronary Angioplasty 
PTGI  
Posttraumatic Growth Inventory 
PTSD  
Posttraumatic Stress Disorder 
PTT 
 
Partial Thromboplastin Time 
RBANS  
Repeatable Battery for the Assessment of Neuropsychological Status  
RBC  
Red Blood Cell Count 
RDW  
Red Cell Distribution Width 
RRPQ  
Reactions to Research Participation Questionnaire 
SAE(s) 
Serious Adverse Event(s) 
SBP 
 
Systolic Blood Pressure 
SCID-RV 
Structured Clinical Interview for Diagnoses Research Version 
SERT   
Serotonin Transporter 
SL 
 
Sublingual 
SNRI  
Serotonin Norepinephrine Reuptake Inhibitor 
SOP(s)  
Standard Operating Procedure(s) 
SSRI  
Selective Serotonin Reuptake Inhibitor  
SUD   
Subjective Units of Distress 
T3 
 
Triiodothyronine 
T4 
 
Thyroxine 
TSH 
 
Thyroid Stimulating Hormones 
U.S. 
 
United States of America 
WBC   
White Blood Cell Count 


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2.0 Introduction 
 
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)-assisted psychotherapy in 
patients with chronic treatment-resistant posttraumatic stress disorder (PTSD). This 
study, seeking to test MDMA-assisted psychotherapy in Canadian residents with chronic 
treatment-resistant PTSD, is part of an international series of Phase 2 clinical trials. 
Ongoing and planned Phase 2 studies are laying the groundwork for a possible End-of-
Phase 2 meeting with FDA and Phase 3 multi-site studies. 
 
MAPS has published results indicating sustained improvements in PTSD severity after 
MDMA-assisted psychotherapy [1-3].  MAPS is currently conducting a U.S.-based 
Phase 2 trial treating U.S. military veterans, firefighters, and police officers with service-
related, chronic, treatment-resistant PTSD, a U.S. Phase 2 pilot study in 12 subjects in 
Boulder, Colorado, and an Israeli Phase 2 pilot study in 10 subjects. Taken together, 
these pilot studies will help to gather preliminary data about the safety and efficacy of 
MDMA-assisted psychotherapy that will inform the design of possible Phase 3 multi-site 
studies. 
 
This Canadian pilot study is a randomized, double-blind, placebo-controlled evaluation 
of MDMA-assisted psychotherapy in 12 patients with chronic, treatment-resistant PTSD. 
PTSD must be of at least 6 months duration without remission from prior treatment with 
either pharmacotherapy or psychotherapy of adequate dose/duration or where treatment 
was discontinued due to lack of tolerability.  This study is designed to obtain estimates 
of effect size for safety and efficacy. The data will be combined with ongoing Phase 2 
dose response studies in a meta-analysis. 
 
This pilot study will be the first study of the therapeutic potential of MDMA to be 
conducted in Canada. In this study, seven of 12 people will receive a dose of MDMA 
expected to be fully therapeutic (full dose) and five of 12 will receive a comparator dose 
of 0 mg (inactive placebo) during the blinded part of the study, referred to as Stage 1.  
PTSD and associated symptoms will be assessed at baseline and one month after the 
second double-blind MDMA-assisted (experimental) psychotherapy session. Cognitive 
function will also be assessed at baseline and again one month after the second 
experimental session. Study subjects will receive psychotherapy before and after each 
experimental session.  
 
Unblinding will take place after the primary endpoint assessments. Full dose subjects 
will continue in Stage 1 and receive a third MDMA-assisted (experimental) 
psychotherapy session. The benefit of three vs. two full dose sessions will be assessed. 
Subjects who received the comparator dose during Stage 1 will have the opportunity to 
cross over and take part in a second study segment, referred to as Stage 2, with three 
experimental sessions. Stage 2 will be used to explore the optimal therapeutic dose of 
MDMA using a clinical titration dosing strategy. Stage 2 follows similar procedures and 
visit schedule as Stage 1 using varied active doses of MDMA, in which each initial dose 


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may be followed by a supplemental dose that will be half of the initial dose. In Stage 2, 
subjects will receive an initial dose of 100 mg MDMA during the first experimental 
session. The co-therapists, in consultation with the subject, will decide whether to 
administer an initial dose of 100 mg or 125 mg MDMA in the second and third 
experimental sessions.  
 
3.0 Background 
 
3.1 Posttraumatic Stress Disorder 
 
PTSD is a debilitating psychiatric disorder arising after a traumatic life event. PTSD 
severely reduces quality of life and may directly or indirectly lead to or exacerbate other 
psychiatric and medical problems. A complex biopsychosocial condition, PTSD is 
characterized by a combination of three types of symptoms: 
 
1. Hyperarousal symptoms such as hypervigilance, anxiety, and sleep disturbance. 
2. Intrusive re-experiencing of traumatic experiences, such as intrusive memories, 
nightmares, or flashbacks. 
3. Avoidance symptoms, including emotional numbing and withdrawal [4, 5].  
 
The DSM-IV criteria for PTSD include:  
 
• Exposure to a significant traumatic event accompanied by an intense, acute 
emotional response.   
• Persistent re-experiencing of the event or aspects of the experience.   
• Persistent avoidance of stimuli associated with the event and/or withdrawal from 
some aspects of life.   
• Persistent symptoms of increased arousal.   
• The above symptoms must last for more than one month for Acute PTSD and 
more than three months for Chronic PTSD.  
 
The lifetime prevalence of PTSD in the U.S. general population is between 6% and 10% 
[6-10], but it is common in other countries as well [11-14]. According to some estimates, 
PTSD appears to be less prevalent in the general population of Europe at 1.9% [13]. In 
U.S. military personnel returning from combat in the Iraq war, the incidence of PTSD is 
as high as 18% [15]. It is estimated that the number of service members returning home 
with PTSD will ultimately be between 75,000 and 225,000 [16]. In countries with 
endemic armed conflict, the incidence of PTSD in civilians is often far greater [14, 17, 
18].  
 
Although presently we are not aware of any national surveys of lifetime PTSD 
prevalence in Canada, it is likely that the percentage of Canadians experiencing PTSD is 
similar to the 8% to 11% listed in samples from the United States and Europe. Likewise, 
a large prospective, longitudinal epidemiological study of adolescents and young adults 
in Germany showed a lifetime prevalence of PTSD, including sub-threshold cases, at 
baseline of 5.6%; by the end of the follow-up period (35-50 months) this had increased 


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to 10.3% [19]. A survey of 3062 women in Ontario reported a 10.7% lifetime prevalence 
rate [20]. A study of Canadian peacekeepers reported higher rates of prevalence, with 
peacekeepers with single deployment diagnosed with PTSD at a rate of 10.9% and a 
14.8% rate in peacekeepers that were deployed more than once [21]. These findings 
suggest that Canadians have PTSD at rates comparable to the US and Europe and that as 
expected, certain populations will experience higher rates of PTSD. 
 
PTSD is clearly a serious public health problem and contributes substantially to 
healthcare costs [5, 8, 9]. PTSD is typically a chronic illness [6, 22] associated with high 
rates of psychiatric and medical comorbidity, disability, suffering, and suicide [7-10, 
23]. People suffering from PTSD face challenges in relationships and work productivity 
[24]. Despite the sheer number of individuals suffering from PTSD and its devastating 
effects, questions remain concerning the best possible treatments [25]. Two selective 
serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, which are known to 
affect the serotonergic components of PTSD, are currently marketed as PTSD 
medications in the U.S. [26, 27]. SSRIs must be used every day in order to be effective 
for PTSD symptoms [28]. However, SSRIs are associated with a high rate of 
discontinuation due to lack of tolerability caused by treatment-emergent side effects that 
may be under-reported [29, 30]. 
  
A wider array of effective treatments are needed for PTSD. At least a third of PTSD 
patients fail to respond to established PTSD psychotherapies or do not respond in a 
clinically significant manner [31-33]. In the U.S. National Comorbidity Study, the 
median time to remission for PTSD was 36 months with treatment and 64 months 
without treatment. In both subgroups, more than a third of the patients still had 
symptoms several times per week after 10 years [34].  Forty to 60% of PTSD patients 
were found to be resistant to treatment in this study. In a comparison of two types of 
psychotherapy for women with PTSD after sexual assault in 2002, 47% of each 
treatment group still satisfied diagnostic criteria for PTSD based on Clinician 
Administered PTSD Scale (CAPS) scores, an outcome which was considered highly 
efficacious [35]. At least one study of paroxetine indicated that men with PTSD did not 
respond to this drug [26] and another randomized, double-blind study found no 
difference between sertraline and placebo in the treatment of PTSD [36]. These findings 
suggest that there is still a substantial need for innovative treatments for PTSD. 
 
Another treatment approach is to develop drugs and/or psychotherapeutic treatments that 
may indirectly decrease or eliminate the neurochemical pathologies underlying the 
chronic hyperarousal associated with PTSD. Cognitive behavioral therapies, particularly 
prolonged exposure and cognitive processing therapy, are considered among the most 
effective psychotherapies [37-39]. Other methods such as psychodynamic therapy and 
eye movement desensitization and reprocessing (EMDR) have also proven to be 
effective in treating some symptoms of PTSD [40, 41], although some patients may need 
more than one type of treatment to reduce or resolve those symptoms [28]. A recent 
meta-analysis concluded that all “bona fide” psychotherapies, including those listed 
above, are similarly effective with PTSD [42]. In recent years, there has been a growing 
amount of research into drugs and other methods that may augment the effectiveness of 


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psychotherapy for PTSD (see [43] for a review).  Examples of this are virtual reality-
assisted exposure therapy [44-47] and D-cycloserine-assisted psychotherapy [48]. 
MDMA-assisted psychotherapy is another such approach. 
 
3.2 MDMA 
 
MDMA is a ring-substituted phenylisopropylamine derivative. Chemists at the Merck 
pharmaceutical company first synthesized it in 1912 [49, 50], though its clinical effects 
were not subject to formal investigation until the 1980s. MDMA is a potent monoamine 
releaser that has its greatest effects on serotonin, followed by norepinephrine and 
dopamine [51-56].  
 
MDMA acutely decreases activity in the left amygdala [57], a brain region involved in 
interpretation of negative cues, and attenuates amygdalar response to angry faces [58]. 
This action of MDMA is compatible with its reported reduction in fear of emotional 
injury or defensiveness [59]. Brain imaging after MDMA indicates less reactivity to 
angry facial expressions and greater reward in happy faces [58]. A recent study in 
healthy volunteers found correlations between oxytocin (OT) levels, amygdalar volume, 
and extraverted personality [60].  
 
OT is a neuropeptide associated with pair bonding and social affiliation in mammals that 
also attenuates amygdalar response to anxiogenic stimuli [61, 62]. OT administration is 
associated with increased interpersonal trust and changes in social perception, including 
attenuated reactivity to threatening faces [63-66]. MDMA elevates OT in peripheral 
blood [67-69], which is an imperfect but somewhat reliable indicator of elevated OT in 
the brain [62]. Findings of an association between elevated OT and detectable MDMA 
in peripheral blood were first reported in a naturalistic study of London nightclub 
attendees with and without detectable serum MDMA levels [67]. Dumont and 
colleagues reproduced these results in humans and found that MDMA significantly 
elevated peripheral plasma OT levels in a placebo-controlled study in healthy volunteers 
[68], in addition to a positive association between elevated levels of OT and prosocial 
feelings. Hysek and colleagues replicated these results and reported that administering a 
serotonin reuptake inhibitor, but not a norepinephrine uptake inhibitor nor several 
adrenergic antagonists, attenuated the effects of MDMA on OT levels, suggesting a 
serotonergic mechanism in producing elevated OT [69]. The effects of MDMA on OT 
may influence empathy or compassion for self and others, decrease defensiveness, and 
strengthen therapeutic alliance. The multi-level effects of MDMA on monoaminergic 
signaling and OT, combined with a therapeutic setting, are more likely to provide the 
opportunity for a corrective emotional experience than OT alone, and could be useful in 
the treatment of PTSD. 
 
3.3 Previous Clinical Experience with MDMA 
 
Classification as a Schedule I drug in the United States has hampered research into the 
medical uses of MDMA. In recent years, clinical investigation of the safety and efficacy 
of MDMA-assisted psychotherapy has become more feasible due to an open IND with 


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the FDA [70]. The first double-blind, placebo-controlled U.S. Phase 1 study sanctioned 
by the FDA was conducted at Harbor-UCLA Medical Center in 1994, with findings that 
suggested MDMA may cause a statistically significant increase in body temperature, 
heart rate, and blood pressure in some healthy volunteers [71]. However, these increases 
were found to be transient and generally tolerable in a controlled clinical setting. 
Subsequent trials confirmed that MDMA produced significant increases in heart rate and 
blood pressure that were likely to be well tolerated by healthy individuals [68, 71-76]. 
The elevation in body temperature noted in healthy volunteers was not clinically 
significant in sponsor-supported studies at normal ambient temperatures [1, 77]. As of 
May 2013, MDMA has been administered to more than 845 research subjects, in both 
Phase 1 and Phase 2 studies, and the sponsor has not been informed of or seen published 
reports of any unexpected MDMA-related Serious Adverse Events (SAEs) in research 
studies [1, 51, 54, 58, 59, 68, 69, 71, 72, 74, 76-108]. 
 
The potentially therapeutic effects of MDMA were initially investigated in a dose 
response pilot study funded by MAPS in Spain, in six female survivors of sexual assault 
with treatment-resistant PTSD [78, 109]. In this study, doses ranging from 50 mg to 75 
mg demonstrated mild signs of improvement without any adverse events (AEs) or signs 
of deteriorating mental health [109].  
 
MAPS sponsored the first U.S. Phase 2 randomized, placebo-controlled study of 
MDMA-assisted psychotherapy for the treatment of chronic, treatment resistant PTSD, 
designated as MP-1. MP-1 demonstrated promising results in a sample of 20 subjects 
[77]. This study employed the CAPS as a primary outcome measure, with PTSD 
symptoms measured by a blinded Independent Rater (IR) at baseline, three to five days 
after each experimental session, and at two-month follow-up. Data from this 
randomized, placebo-controlled pilot study suggests that MDMA is associated with 
significantly greater improvement in PTSD than placebo (N=20) [77]. Two months after 
treatment with MDMA-assisted psychotherapy, 83.3% (8 of 12) of the subjects no 
longer had a PTSD diagnosis and exhibited a 68% drop in CAPS global severity scores. 
Twenty five percent (two of eight) of the subjects in the placebo and psychotherapy 
group no longer had a PTSD diagnosis and exhibited a 26% drop in CAPS global 
severity scores. Seven of the eight subjects receiving placebo went through the treatment 
program again to receive full dose MDMA. The crossover subjects experienced a 48% 
drop in CAPS scores and none of these subjects qualified for a PTSD diagnosis at the 
end of the study, establishing that subjects receiving placebo were not more resistant to 
treatment. Evaluation of subjects on an average of 45.4 months after receiving MDMA-
assisted psychotherapy indicates that the therapeutic benefits have been sustained over 
time on average, although two subjects experienced a relapse in PTSD symptoms [3]. 
PTSD symptom severity in subjects who completed the CAPS at long-term follow-up 
(mean CAPS scores 23.7±22.8, N=16) were statistically equivalent on average to the end 
of the treatment program (mean CAPS scores 24.6±18.6, N=16) [3].  
 
The sponsor also supported a randomized, double-blind pilot study in 12 subjects with 
chronic, treatment-resistant PTSD in Switzerland with three experimental sessions, 
designated as MP-2. The study results suggested a trend toward significant improvement 


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in subjects receiving full dose MDMA, when compared to a 25 mg active placebo 
MDMA at two-month follow-up [1]. The improvement continued to increase during the 
12-month follow-up [1]. 
 
In addition, the sponsor supported an initial pilot study with two experimental sessions 
comparing full dose to 25 mg active placebo MDMA in Israel that enrolled five subjects, 
with no drug-related Serious Adverse Events (SAEs).  
 
Overall, the results of these studies suggest that MDMA-assisted psychotherapy may be 
safe and effective in these subjects regardless of trauma etiology.  
 
3.4 MDMA-assisted Psychotherapy for PTSD 
 
MDMA-assisted psychotherapy is an innovative mode of treatment that combines 
therapeutic techniques with the administration of MDMA, a pharmacological adjunct 
that may enhance or amplify certain aspects of therapy. MDMA possesses unique 
pharmacological properties that may make it especially well suited to use as an adjunct 
to therapy. MDMA is capable of inducing unique psychopharmacological effects, 
including: 
 
• Decreased feelings of fear. 
• Increased feelings of wellbeing. 
• Increased sociability and extroversion. 
• Increased interpersonal trust. 
• Alert state of consciousness. 
 
Early observers noted increased acceptance of self and others, increased tolerance of 
emotionally upsetting materials, and the ability to address these issues without extreme 
disorientation or ego loss [110-113]. In the U.S., MDMA was used as an adjunct to 
psychotherapy by a considerable number of psychiatrists and other therapists in the 
treatment of neuroses, relationship problems, and PTSD [110, 111, 114, 115] before it 
was placed in Schedule I in 1985, as a result of extensive non-medical use [59, 113, 
116]. Placement in Schedule I prohibited it for use, except in a federally approved 
research setting in the U.S.  
 
In contrast to daily administrations of SSRIs, MDMA-assisted psychotherapy consists of 
several drug-assisted sessions interspersed with a moderate course of non-drug 
psychotherapy. Thus the effects of MDMA are distinct from and go well beyond those 
of anti-anxiety drugs such as benzodiazepines. Furthermore, there is no evidence that 
MDMA creates a physical dependency, as benzodiazepines do. Previous studies of 
polydrug users have found a small percentage of people exhibit problematic use of 
Ecstasy (material represented as containing MDMA) [117, 118]. Studies of regular or 
problematic Ecstasy users indicate that on average, regular use occurs no more often 
than once a week [119]. Hence, MDMA may have moderate abuse potential. See the 
Investigator’s Brochure (IB) for a more detailed explanation. 
 


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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 [5].  To be effective, exposure must be 
accompanied by a degree of emotional engagement or “fear activation” while avoiding 
dissociation or overwhelming emotion [120].  This has been referred to as working 
within the “optimal arousal zone” or “window of tolerance” [121-123]. When given in 
an appropriate setting, MDMA produces increased positive mood, facilitates recall and 
imagination, changes in emotion perception, and social affiliation [58, 68, 69, 103, 124]. 
These effects are thought to permit revisiting of trauma-associated memories, thoughts, 
and feelings while maintaining the window of tolerance.  
 
In the context of psychotherapy, MDMA has been noted to reduce defenses and fear of 
emotional injury while enhancing communication and capacity for introspection [59]. 
MDMA-assisted psychotherapy is an innovative mode of treatment that combines 
psychotherapeutic techniques with the administration of MDMA as a pharmacological 
adjunct. MDMA possesses unique pharmacological properties that may make it 
especially well suited to use as an adjunct to psychotherapy in PTSD patients, as it 
appears to stimulate spontaneous engagement in elements of conventional therapies, 
such as exposure therapy, psychodynamic therapy, and internal family systems therapy 
in the therapeutic context. Treatment goals of MDMA-assisted psychotherapy for PTSD 
include alleviating symptoms, interrupting and counteracting the stress-induced 
neurobiological abnormalities that may be associated with the condition. The biologic 
and therapeutic approaches are intended to overlap and reinforce each other.  
 
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 [77, 109, 111, 113]. 
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 
[110]. Subjects are able to experience and express fear, anger, and grief with less 
likelihood of feeling overwhelmed by these emotions. MDMA seems to engender 
internal awareness that even painful feelings that arise are an important part of the 
therapeutic process. In addition, feelings of empathy, love, and deep appreciation often 
emerge, along with a clearer perspective of the trauma as a past event, a more accurate 
perspective about its significance, and a heightened awareness of the support and safety 
that exists in the present. As a result, MDMA-assisted psychotherapy may enable the 
subjects to restructure their perspective and develop a wider behavioral and emotional 
repertoire with which to respond to anxiogenic stimuli.  
 
Based on these data and on an extensive review of the MDMA literature, we conclude 
that MDMA-assisted psychotherapy may have the potential to serve as an innovative 
treatment for PTSD, particularly in people who fail to respond to currently available 
therapies, and that the modest risks of administering MDMA within a therapeutic 
context are outweighed by the possibility that this treatment may offer significant 


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benefits. A comprehensive review of MDMA research is included in the IB supplied by 
the sponsor. This document should be reviewed prior to initiating the protocol. 
 
3.5 Purpose 
 
This Phase 2 pilot study is a randomized, double-blind, placebo controlled study in 12 
subjects that will estimate the effect sizes of full dose and comparator dose MDMA as 
an adjunct to manualized psychotherapy. Seven subjects will be randomized to the full 
dose condition and five subjects will be randomized to the comparator dose condition. 
Stage 1 will consist of two blinded experimental sessions and one open-label 
experimental session of manualized MDMA-assisted psychotherapy, each lasting six to 
eight hours and scheduled three to five weeks apart, within a moderate course of non-
drug psychotherapy. The study will be unblinded one month after the second 
experimental session in Stage 1, after completion of outcome measures, which 
constitutes the primary endpoint assessment.  
 
After unblinding, full dose subjects will continue in Stage 1 and receive a third MDMA-
assisted psychotherapy session. The benefit of three vs. two full dose sessions will be 
assessed. Subjects who received the comparator dose during Stage 1 will have the 
opportunity to cross over to Stage 2 with three experimental sessions. Stage 2 will be 
used to explore the optimal therapeutic dose of MDMA using a clinical titration dosing 
strategy. 
 
A blinded IR will assess the severity of PTSD symptoms at baseline, at the primary 
endpoint one month after the second experimental session, two months after the third 
open-label experimental session and at equivalent time points in Stage 2. All subjects 
will complete a long-term follow-up visit 12 months after their final experimental 
session in either Stage 1 or Stage 2.  
 
Two therapy teams will conduct psychotherapy visits according the treatment manual 
provided. One team will consist of the Qualified Investigator and a co-therapist, and the 
second team will consist of a co-therapist and a Sub-investigator who have been 
delegated the authority to conduct therapy by the Qualified Investigator. All study 
procedures, including administration of the Investigational Product, will be done by the 
Investigator or designated qualified study personnel according to the Site Responsibility 
Log. 
 
4.0 Ethics 
 
The trial will not be initiated until appropriate Health Canada and Institutional Review 
Board (IRB) approval of the protocol and the informed consent document has been 
obtained. All documents will be submitted to other authorities in compliance with local 
jurisdictions. The IRB and, if applicable, other authorities must be informed of protocol 
amendments in accordance with local legal requirements. The protocol will also be 
submitted to FDA under U.S. IND #63,384. 
 


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This trial will be conducted in accordance with the most recently acceptable version of 
the Declaration of Helsinki, Good Clinical Practice (GCP) according to International 
Conference on Harmonization (ICH) guidelines, and applicable Standard Operating 
Procedures (SOPs). The trial will be conducted under a protocol reviewed and approved 
by an IRB.  The trial will be conducted by scientifically and medically qualified persons.  
The benefits of the study will be considered in proportion to the risks.  The rights and 
welfare of the subjects will be respected.  The physicians conducting the trial do not find 
the hazards to outweigh the potential benefits.  Each subject will give his or her written 
informed consent before any protocol-driven tests or evaluations are performed. 
 
5.0 Informed Consent 
 
The Investigator is responsible for overseeing informed consent is obtained in adherence 
to GCP and according to applicable regulations prior to entering the subject into the trial. 
The informed consent discussion must be conducted by a person who is qualified 
according to regulations. Written information about the trial will be provided in an 
understandable Informed Consent Form (ICF).  Written consent must be given by the 
subject.  The ICF document must be explained and the subjects’ questions must be 
answered. The subject should have the opportunity to inquire about details of the 
MDMA-assisted session and to consider participation.  
 
The ICF will state the probability of random assignment to the full dose group or the 
comparator dose group, however there will be a level of obfuscation, which makes it 
unclear that there is only one comparator dose, and that it is an inactive placebo. The 
ICF will indicate the comparator dose may or may not contain MDMA. If subjects ask 
about the composition of investigational product in the comparator dose group, the exact 
contents of the comparator dose will be said to include lactose and may or may not 
include MDMA, however everyone assigned to the comparator dose group will have the 
opportunity to receive active dose MDMA during Stage 2. For all subjects in the 
comparator dose group, the content of the comparator dose will be disclosed after the 
primary endpoint visit when unblinding occurs. Unblinding and debriefing at the 
primary endpoint will take place with the co-therapist team and the subject. During the 
debriefing, subjects will be informed of the contents of the investigational product they 
received during the blinded experimental sessions in Stage 1. 
 
In addition to the explanation of study visits, the ICF should include that access to 
original medical records and processing of coded personal information must be 
authorized. Written consent to take part in the study includes giving the Investigator 
permission to view the subject’s recent 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 subjects may only be included in the study after signing the IRB approved ICF. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. 
all of the procedures described in the protocol, including screening activities). The 
process of obtaining informed consent should be documented in the subject source 


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records. The therapists will provide a copy of the signed ICF to the subject and will 
maintain the original in the ISF. 
 
The written ICF and any other written information to be provided to subjects should be 
revised whenever important new information becomes available that may be relevant to 
the subject’s consent. Any revised ICF and written information should receive approval 
from an IRB before use. The subject should be informed in a timely manner if new 
information becomes available that might affect the decision to take part in the MDMA-
assisted session. The communication of this information should be documented.  
 
Subjects can withdraw consent at any time without prejudice. If a subject withdraws 
consent but does not revoke Health Information Protection Act (HIPA), the Investigator 
will have access to the subject’s study related medical records and data will be used. If a 
subject revokes consent and HIPA, the Investigator will have access to the subject’s 
medical records prior to the date and time of revocation but the data will not be used.  
 
6.0 Study Objectives 
 
The overall objective of this study is to examine whether the full dose of MDMA versus 
the comparator dose used in conjunction with manualized psychotherapy will reduce or 
attenuate PTSD symptoms as evaluated by standard clinical measures and to collect 
safety data. 
 
6.1 Primary Objective 
 
• Assess changes in PTSD symptoms in subjects receiving the full dose of MDMA 
compared to the comparator dose as measured by Global CAPS scores at 
baseline and the primary endpoint, one month after the second experimental 
session. 
 
6.2 Secondary Objectives 
 
The following objectives will compare full dose subjects to comparator dose subjects in 
Stage 1: 
 
• Assess changes in self-reported PTSD symptoms as measured with the PTSD 
Diagnostic Scale (PDS) at baseline, after each experimental session and/or the 
primary endpoint. 
• Assess depression symptoms with the Beck Depression Inventory (BDI-II) at 
baseline and the primary endpoint. 
• Assess global functioning with the Global Assessment of Functioning (GAF) at 
baseline and the primary endpoint. 
• Assess changes in personality with the Neuroticism Extroversion Openness 
Personality Inventory (NEO-PI) at baseline and the primary endpoint. 
• Assess self-reported sleep quality with the Pittsburgh Sleep Quality Index (PSQI) 
at baseline and the primary endpoint. 


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• Assess self-reported dissociation symptoms with the Dissociation Experiences 
Scale II (DES-II) at baseline and the primary endpoint. 
• Assess self-reported posttraumatic growth with the Posttraumatic Growth 
Inventory (PTGI) at baseline and the primary endpoint. 
 
The following objectives will compare effects in specified subjects: 
 
• Assess PTSD symptoms via CAPS and PDS, depression symptoms via BDI-II, 
global functioning via GAF, sleep quality via PSQI, posttraumatic growth via 
PTGI, changes in personality via NEO-PI and dissociation symptoms via the 
DES-II, throughout Stage 2 in comparison to Stage 1 in crossover subjects. 
• Assess long-term effects of MDMA-assisted psychotherapy on symptoms of 
PTSD, depression, global function, sleep quality, posttraumatic growth, and 
dissociation symptoms via CAPS, PDS, BDI-II, GAF, PTGI, PSQI, PTGI (in 
reference to start of the study), DES-II, and changes in personality via NEO-PI 
one year after the final experimental session for each subject. 
 
The following objectives will include exploratory analyses intended to inform protocol 
design: 
 
• Explore the effects of each experimental session upon self-reported changes in 
consciousness, as those associated with a transformational or mystical experience 
via the States of Consciousness Questionnaire (SOCQ). 
• Assess the effect of the third experimental session for full dose subjects in Stage 
1 and Stage 2 using CAPS, PDS, BDI-II, GAF, PSQI, PTGI, NEO-PI, and DES-
II.  
• Assess the ability of the therapists and subjects to accurately guess condition 
assignment in Stage 1. 
• Correlate adherence to the treatment manual with Global CAPS scores using 
adherence criteria ratings to assess videos of psychotherapy sessions. 
 
6.3 Safety Objectives 
 
The study will monitor and ensure safety in subjects enrolled in the study by assessing 
physiological effects, psychological distress, spontaneously reported reactions, and 
suicidality. 
 
• Vital signs (blood pressure, heart rate, and temperature) and Subjective Units of 
Distress (SUD) will be measured during each experimental session. Comparisons 
will be made for SUD scores and vital signs between each condition.  
• SAEs, AEs, and spontaneously reported reactions will be collected during the 
study according to protocol Section 14.0.  
• Suicidality will be assessed with the Columbia Suicide Severity Rating Scale (C-
SSRS) during visits prior to and after experimental sessions, twice during 
experimental sessions, and several times after each experimental session. 


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Comparisons will be made for C-SSRS scores for subjects in each condition. The 
same schedule of assessment will be followed during Stage 2. 
• Assess cognitive function with the Paced Auditory Serial Addition Test 
(PASAT) and the Repeatable Battery for the Assessment of Neuropsychological 
Status (RBANS) at baseline and the primary endpoint by condition, and end of 
Stage 1/end of Stage 2 for maximal exposure. 
• Collect changes to pre-existing tinnitus and/or chronic pain symptoms using a 
visual analog scale, specifically in subjects with a medical history of tinnitus 
and/or chronic pain.  
 
7.0 General Investigational Plan 
 
7.1 Recruitment and Subject Population 
 
Subjects may be men or women aged 21 or older with a confirmed diagnosis of chronic, 
treatment-resistant PTSD who have undergone psychotherapeutic or 
psychopharmacological treatment for PTSD of adequate dose/duration without 
achieving remission. Subjects who discontinued PTSD treatment due to inability to 
tolerate psychotherapy (e.g. due to persistent “over-engagement”) or 
psychopharmacology due to treatment-emergent side effects would not be excluded. 
Subjects will also not be excluded for having more than one traumatic event. Subjects 
must have a CAPS score equal to or greater than 60 and meet all inclusion criteria and 
no exclusion criteria at baseline. They must be in good physical health and without 
major medical disorders that might affect the safety or tolerability of MDMA Seven of 
12 subjects will be randomly assigned to receive the full dose and five subjects will be 
randomly assigned to receive the comparator dose.  
 
Study subjects will be Canadian residents recruited by letters of referral sent to 
psychiatrists and psychotherapists, written advertisements, announcements placed on 
appropriate Internet sites and the sponsor site, and through word of mouth. Site staff will 
interview prospective subjects by telephone to learn if they meet basic eligibility criteria. 
If the prospective subject is interested in taking part in the study, the Study Coordinator 
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7.2 Enrollment Criteria 
 
7.2.1 Inclusion Criteria 
 
Individuals eligible to be enrolled into this protocol are subjects who: 
 
1. Meet DSM-IV criteria for current PTSD, with a CAPS score of 60 or higher, 
indicating moderate to severe PTSD symptoms; 
2. Have chronic PTSD, defined as PTSD persisting for longer than 6 months; 
subjects may have experienced one or more traumatic event; 
3. Have treatment-resistant PTSD, who were unable to achieve remission despite 
receiving adequate dose/duration of psychotherapy or psychopharmacology with 
an SSRI, mirtazapine, or MAOI, or who discontinued treatment due to either:  
a. Inability to tolerate psychotherapy for PTSD (e.g. persistent “over-
engagement” when attempting Prolonged Exposure Therapy). 
b. Inability to tolerate psychopharmacology for PTSD due to treatment-
emergent side effects; 
4. Are at least 21 years old; 
5. Are willing to commit to medication dosing, experimental sessions, follow-up 
session and completion of evaluation instruments; 
6. Are willing to refrain from taking any psychiatric medications during the study 
period, with the exception of gabapentin when prescribed for pain control. If the 
subject is on stimulants for 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 ten days after each experimental 
session. Any psychiatric drugs will be tapered in an appropriate fashion to avoid 
withdrawal effects. Medications will only be discontinued after consultation with 
the prescribing physician; 
7. If in ongoing psychotherapy at the time of recruitment, are able to continue to see 
their outside therapist during the course of the study. Subjects must sign a release 
permitting the Investigator or Sub-Investigator to communicate directly with 
their therapist. Subjects may not change therapists, increase the frequency of 
therapy, or commence any new type of therapy until after the evaluation session 
at the end of Stage 1 or Stage 2, as applicable; 
8. Agree to refrain from taking, for one week preceding each experimental session: 
a. Any herbal supplement (except with prior approval of the research 
team).  
b. Any nonprescription medications (with the exception of non-steroidal 
anti-inflammatory drugs or acetaminophen unless with prior approval of 
the research team). 
c. Any prescription medications (with the exception of birth control pills, 
thyroid hormones or other medications approved by the research team). 
Note: Must have physician’s approval; 
9. Agree to take nothing by mouth except alcohol-free liquids after midnight the 
evening before the experimental session. Subjects must also refrain from the use 
of any psychoactive drug, with the exception of caffeine or nicotine, within 24 


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hours of each experimental session. They must agree not to use caffeine or 
nicotine for 2 hours before and 6 hours after each experimental session; 
10. Are willing to remain overnight at the clinic after each experimental session until 
the integrative session occurring the next morning. An attendant with previous 
training in managing psychological distress will be present to assist with personal 
needs if requested and offer dinner and breakfast; 
11. Are willing to locate an individual to drive them home the morning after the 
experimental sessions, after the integrative session. If a subject is unable to 
locate someone to transport them home, the therapists will assist the subject in 
obtaining transport from the clinic to the subject’s home or any other location 
where he or she is staying temporarily; 
12. Are willing to be contacted via telephone on a daily basis by one of the therapists 
for a week after each experimental session; 
13. Are willing to provide a contact (relative, spouse, close friend, or other 
caregiver) who is willing and able to be reached by the therapists in the event of 
a subject becoming suicidal; 
14. Agree to inform the therapists within 48 hours of any planned medical 
interventions; 
15. Have a negative pregnancy test and must agree to use an effective form of birth 
control, if the participant is a female of childbearing potential; 
16. Are literate and proficient in reading documents written in English and speaking 
English; 
17. Agree to have all clinic visit sessions recorded to audio and video; 
18. Agree not to participate in any other interventional clinical trial for the duration 
of this clinical trial, including the follow-up period. 
 
7.2.2 Exclusion Criteria 
 
Individuals not eligible to be enrolled into this protocol are those who: 
 
1. Are pregnant or nursing, or of child bearing potential and not practicing an 
effective means of birth control; 
2. Have a history of, or current primary psychotic disorder or bipolar affective 
disorder type 1 or borderline personality disorder; 
3. Have dissociative identity disorder or an eating disorder with active purging; 
4. Have evidence or history of significant hematological, endocrine, 
cerebrovascular, cardiovascular, cardiac, coronary, pulmonary, renal, 
gastrointestinal, immunocompromising, or neurological disease, including 
seizure disorder, or any other medical disorder judged by the Investigator or Sub-
Investigator to significantly increase the risk of MDMA administration (Subjects 
with hypothyroidism who are on adequate and stable thyroid replacement will 
not be excluded); 
5. Have hypertension using the standard criteria of the American Heart Association  
of values of 140/90 or higher assessed on three separate occasions, peripheral 
vascular disease, hepatic disease (with or without abnormal liver enzymes), or 
history of hyponatremia or hyperthermia; 


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6. Weigh less than 48 kg; 
7. Have used “Ecstasy” (illicit drug preparations purported to contain MDMA) 
more than five times in the last 10 years or at least once within six months of 
enrollment;  
8. Would present a serious suicide risk, or who are likely to require hospitalization 
during the course of the study, as determined through psychiatric interview, 
responses to C-SSRS and through clinical judgment of the Investigator or Sub-
Investigator; 
9. Require ongoing concomitant therapy with a psychiatric drug, including but not 
limited to SSRIs, SNRIs, or MAOIs; 
10. Meet DSM-IV criteria for active substance abuse or dependence for any 
substance other than caffeine or nicotine in the past 6 months; 
11. Are not able to give adequate informed consent; 
12. Have any current problem, which in the opinion of the Investigator, Sub-
Investigator, or Medical Monitor, might interfere with participation in the study. 
 
7.3 Planned Duration of Study and Visit Windows 
 
Subjects enrolled in this study will fall into two categories that will determine the 
duration of the study. These include the follow-up portion of the study, which 
encompasses 12 months after the final experimental session. 
 
• Full dose subjects completing Stage 1 only: 15 months  
• Comparator dose subjects who complete Stage 2: 18 months 
 
Screening may take up to two months, with the baseline CAPS being conducted 4 to 8 
weeks before the first experimental session, in order to allow for appropriate medication 
washout of at least 5 half-lives of pre-study psychiatric medications and active 
metabolites, and one additional week for stabilization. For example, the maximum 
washout would be 7 weeks for subjects tapering off of fluoxetine plus one week for 
stabilization. Tapering off high doses of benzodiazepines may take a comparable period 
of time. Scheduling of preparatory sessions must be between screening and the first 
experimental session at intervals that suite the scheduling needs of participants and the 
research team, with the first experimental session taking place 3-5 weeks after 
enrollment, and at most 5 weeks after the baseline CAPS. The maximum window from 
the start of screening to the first experimental session is 13 weeks. The optimal timing 
for Stage 2 is within one month after the primary endpoint visit in Stage 1, with a 
maximum allowable window of five months. Any delay between visits would result in a 
corresponding extension of study duration. 
 
8.0 Drug Description and Dosage 
 
Subjects assigned to the full dose condition will receive three experimental sessions with 
an initial dose of 125 mg possibly followed 1.5 to 2.5 hours later by an optional 
supplemental dose of 62.5 mg MDMA. Subjects in the comparator dose condition will 
be assigned to receive two experimental sessions with an initial dose of 0 mg MDMA 


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possibly followed 1.5 to 2.5 hours later by an optional supplemental dose of 0 mg 
MDMA. Seven of 12 subjects, or 58%, will be assigned to the full dose condition, and 
five of 12, or 42%, will be assigned to the comparator dose condition.  
 
Subjects in the comparator dose condition during Stage 1 will have the opportunity to 
cross over to Stage 2. Stage 2 will be used to explore the optimal therapeutic dose using 
a clinical titration dosing strategy using varied active doses of MDMA. In Stage 2 
subjects will receive an initial dose of 100 mg followed 1.5 to 2.5 hours later by an 
optional supplemental dose of 50 mg MDMA during the first experimental session. In 
the second and third session they will receive an initial dose of 100 mg or 125 mg 
MDMA followed 1.5 to 2.5 hours later by an optional supplemental dose of 50 mg or 
62.5mg as appropriate to the initial dose of MDMA. The decision to titrate the dose in 
the second and third session will be based on the experience of the first session, if 
100mg MDMA does not seem to be the optimal therapeutic dose based on the first 
experimental session in Stage 2, the dosage may be increased by an increment of 25mg 
in order to achieve the optimal therapeutic dose. The supplemental doses for each 
experimental session will be half of the initial dose, respectively. 
 
The initial and supplemental doses of 125 mg MDMA and 62.5 mg used in the full dose 
condition are identical to those in use in other sponsor-supported studies of MDMA-
assisted psychotherapy. Previous researchers have also used doses within this range [71, 
72, 74, 75, 124, 125]. Doses equal to or exceeding 125 mg have been employed in 
previous uncontrolled and controlled studies of MDMA [74, 75, 91, 126-128]. Prior to 
the time MDMA was placed in Schedule I in the U.S., identical or similar doses and 
regimens were used in psychotherapy [59, 111, 113]. The initial full dose is expected to 
produce all the common effects of MDMA, including changes in affect (mood) and 
cognition and changes in feelings of interpersonal closeness and trust. The supplemental 
dose will prolong subjective drug effects without producing physiological effects any 
greater than peak effects occurring after the initial dose. In this study, the 100mg 
MDMA initial dose will be administered in the first experimental session in Stage 2. The 
co-therapists, in consultation with the subject, will have the option to explore whether 
this dose or the clinical titration of an additional 25mg initial dose, with corresponding 
supplemental doses, would constitute the optimal therapeutic dose for the second and/or 
third experimental sessions.   
 
The doses to be compared in this study have been chosen on the basis of the Sponsor’s 
ongoing initiative to develop MDMA-assisted psychotherapy as a treatment for PTSD 
and in Stage 2 to develop a dose-response curve for the treatment. The Stage 1 
comparator dose of 0 mg MDMA is not expected to produce the therapeutic or 
physiological effects of MDMA. The goal of this study is to estimate the effect size of 
comparator and full dose MDMA for safety and efficacy. The placebo dose will provide 
clear adverse event, neurocognitive and efficacy data. 
 


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Table 1. Stage 1 Drug Doses  
 
Experimental 
Session 
Dose 
Initial 
Dose 
Optional 
Supplemental 
Dose 
Min-Max 
Cumulative 
Dose 
1 and 2 
Comparator Dose 
0 mg 
0 mg 
0 mg 
1, 2, and 3 
Full Dose 
125 mg 
62.5 mg 
125-187.5 mg 
 
Table 2. Stage 2 Drug Doses  
 
Experimental 
Session 
Dose 
Initial 
Dose 
Optional 
Supplemental 
Dose 
Min-Max 
Cumulative 
Dose 
Min-Max 
Cumulative 
Dose with 
Titration 
1 
Active Dose 
100 mg 
50 mg 
100-150 mg 
 
Active Dose 
100 mg 
50 mg 
100-150 mg 
 
2 and 3 
+ Optional 
Titration Dose 
25 mg 
12.5 mg 
 
125-187.5 mg 
 
8.1 Drug Compounding, Doses, and Labeling 
 
The investigational product (IP) for the study is MDMA. Bulk IP will be received at the 
pharmacy via a secure delivery system in accordance with all local regulations. A receipt 
will be kept on file at the pharmacy and at the site. Seven strengths of IP will be created: 
125 mg, 100 mg, 62.5 mg, 50 mg, 25 mg, 12.5 mg and 0 mg (placebo only).  Each of 
these batches will be created with the bulk MDMA and varied amounts of lactose during 
the compounding process. A “packing stat” will be created by filling 10 capsules with 
lactose to calibrate the amount of compounded IP per capsule. Once encapsulated, the 
total number of capsules will be recorded on the drug accountability log.  
 
The encapsulation will be performed by a pharmacist who has the appropriate skills. The 
MDMA will be weighed out (calculated as the weight of the hydrochloride salt) into 
gelatin capsules in combination with lactose used to ensure that all capsules have similar 
weights. The placebo capsule will consist of lactose only. Capsules for all experimental, 
double-blind sessions will be prepared in such a way as to prevent therapists and 
subjects from distinguishing contents of full dose and comparator dose capsules. Dosage 
for open-label sessions will be clearly indicated in the packaging. 
 
The IP for each experimental session will be packaged in one primary container, labeled 
with a unique container number, protocol number, drug name, lot number, sponsor 
name, experimental session number, stage, and a statement that the drug is restricted to 
clinical trial use only. All drug labels will comply with local regulations and will be 
provided in English. The initial and supplemental dose will be packaged in separate 
labeled “inner envelopes” within the primary container. There will be one primary 
container per subject per experimental session. The sponsor randomization monitor will 
oversee the process of blinded drug packaging conducted by the pharmacist according to 


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Page 23 of 83 
the randomization list. This list will not be shared with any blinded site or sponsor staff. 
The pharmacist and randomization monitor will be the only staff who are unblinded.  
  
Figure 1. Examples of Drug Labels  
 
 
 
 
 
 
 
Stage 1 Primary Container Labels 
       Blinded 
 
 
Open Label Session 3 
Primary Container 
MAPS 1215 Mission St, Santa 
Cruz, CA USA 95060 
Study # MP-4 
Stage 1 Blinded 
Experimental Session #___  
Container # XXX  
Lot # XXX 
Expiry date: XXX 
Store at 22
oC 
 
Subject #____________  
Restricted drug for clinical trial 
use by Qualified investigator only 
 
Primary Container 
MAPS 1215 Mission St, Santa Cruz, 
CA USA 95060 
Study # MP-4 
Stage 1 Open Label 
Experimental Session #3  
Container # XXX 
125mg & 62.5mg MDMA 
Lot # XXX 
Expiry date: XXX 
Store at 22
oC 
Subject #____________  
Restricted drug for clinical trial use 
by Qualified investigator only 
 
Stage 1 Inner Envelope Labels 
                Blinded 
 
 
 
 
Blinded 
Inner Envelope 
MAPS Study # MP-4 
Stage 1 
Container # XXX 
Initial Dose  
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
Inner Envelope 
MAPS Study # MP-4 
Stage 1 
Container # XXX 
Supplemental Dose  
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
Open Label Session 3 
 
 
Open Label Session 3 
Inner Envelope 
MAPS Study # MP-4 
Stage 1 Open Label 
Container # XXX 
Initial Dose 125mg MDMA 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
Inner Envelope 
MAPS Study # MP-4 
Stage 1 Open Label 
Container # XXX 
Supplemental Dose 62.5mg MDMA 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
 
 
 
 
Holding Box Labels 
 
Holding Box Label 
MAPS Study# MP-4 
Investigational Product: MDMA  
Dose: XXmg 
Lot #: XXX 
Restricted drug for clinical trial use by Qualified investigator only 


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June 20, 2014 
  
 
 
Page 24 of 83 
Stage 2 Primary Container Labels 
       Open Label 
 
 
  Open Label  
               Open Label 
Primary Container 
MAPS 1215 Mission St, Santa 
Cruz, CA USA 95060 
Study # MP-4 
Stage 2 
Experimental Session # 1  
Container # XXX 
100mg & 50mg MDMA 
Lot #: XXX 
Expiry date: XXX 
Store at 22
oC 
Subject #____________  
Restricted drug for clinical trial 
use by Qualified investigator only 
 
Primary Container 
MAPS 1215 Mission St, Santa 
Cruz, CA USA 95060 
Study # MP-4 
Stage 2 
Experimental Session # 2  
Container # XXX 
100+25mg & 50+12.5mg MDMA 
Lot #: XXX 
Expiry date: XXX 
Store at 22
oC 
Subject #____________  
Restricted drug for clinical trial 
use by Qualified investigator only 
 
Primary Container 
MAPS 1215 Mission St, Santa Cruz, 
CA USA 95060 
Study # MP-4 
Stage 2 
Experimental Session # 3  
Container # XXX 
100+25mg & 50+12.5mg MDMA 
Lot #: XXX 
Expiry date: XXX 
Store at 22
oC 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
Stage 2 Inner Envelope Labels 
 
Unblinded Session 1  
 
Unblinded Session 1 
Inner Envelope 
MAPS Study # MP-4 
Stage 2 Open Label 
Experimental Session # 1  
Container # XXX 
Initial Dose 100mg MDMA 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
Inner Envelope 
MAPS Study # MP-4 
Stage 2 Open Label 
Experimental Session # 1 
Container # XXX 
Supplemental Dose  
50mg MDMA 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
Unblinded Session 2 or 3 
 
 
Unblinded Session 2 or 3 
 
Inner Envelope 
MAPS Study # MP-4 
Stage 2 Open Label 
Experimental Session #___ 
Container # XXX 
Initial Dose 100mg MDMA 
Open Label 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
Inner Envelope 
MAPS Study # MP-4 
Stage 2 Open Label 
Experimental Session #__  
Container # XXX 
Initial Dose increment 
25mg MDMA 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
8.2 MDMA Accountability 
 
Forms will be provided to track drug accountability and administration throughout the 
study. Blinded drug accountability and administration logs will be reviewed during 
routine monitoring visits. MDMA will be handled in accordance with all provincial and 
national regulations and forms pertaining to the use of controlled substances in Canada, 
and forms will be maintained by the pharmacist.  
 
Each primary container label will contain a unique container number for the drug 
assigned to a single experimental session. The container numbers will be used to track 
drug administration in the Source Record and the drug administration log. The web-
based randomization system will enable tracking of blinded primary containers for drug 
accountability purposes. 
 


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8.3 MDMA Storage and Handling 
 
MDMA is a Schedule III compound in Canada and the pharmacist will store and handle 
it in compliance with relevant Federal and Province regulations. The pharmacist will be 
responsible for storing and dispensing the MDMA in accordance with all regulatory 
requirements. The IP will be stored at room temperature in a locked safe at the pharmacy 
and only the pharmacist will have access to it.  
 
IP will only be removed for a single experimental session at a time and will be 
administered orally at the site by the Investigator or Sub-Investigator. 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 are provided for each experimental session but are optional to use. In addition, the 
clinical titration doses with corresponding supplemental dose are provided in Stage 2 
session 2 and 3 and are optional to use. 
 
The pharmacist will dispense one primary container with the appropriate container 
number to the Investigator or Sub-Investigator before each experimental session. If the 
Investigator or Sub-Investigator decides not to administer the optional supplemental 
dose and/or the optional clinical titration dose in a given experimental session, the 
unused capsules will be kept in their respective inner envelopes inside of the primary 
container until the end of the experimental session. Within 24 hours of the end of the 
experimental session (as soon as possible within the working hours of the pharmacy), 
the Investigator or Sub-Investigator will return the container and any remaining unused 
capsules to the Pharmacist for return to the pharmacy safe. At the end of the study, the 
Sponsor will be consulted to determine the course of action if there is any unused IP 
remaining. 
 
9.0 Method 
 
This Phase 2 pilot study is a randomized, double-blind, controlled study in 12 subjects 
comparing the effect size of comparator dose to full dose MDMA as an adjunct to 
manualized MDMA-assisted psychotherapy. Two therapy teams will conduct 
psychotherapy visits according to the treatment manual provided. The teams will consist 
of two therapists who will work together, with a physician on each team. Seven subjects 
will be randomized to the full dose condition and five subjects will be randomized to the 
comparator dose condition. Stage 1 of the study will consist of two blinded experimental 
sessions for all subjects and one open-label experimental session for full dose subjects, 
each lasting six to eight hours and scheduled three to five weeks apart, within a 
moderate course of non-drug psychotherapy. Each subject will be unblinded after 
completion of outcome measures at the primary endpoint, one month after the second 
experimental session in Stage 1. A blinded IR will assess the severity of PTSD 
symptoms at baseline, at the primary endpoint one month after the second experimental 
session, two months after the third open-label experimental session as well as the 
equivalent time points in Stage 2. After unblinding, full dose subjects will have one 
more full dose session in Stage 1 and comparator dose subjects will have the opportunity 


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Page 26 of 83 
to cross over to open-label Stage 2, which will be used to explore the optimal therapeutic 
dose for cross over subjects. All subjects will complete a long-term follow-up visit 12 
months after their final experimental session in either Stage 1 or Stage 2.  This study will 
provide an estimate of effect size based on a dose comparison of PTSD symptoms to 
MDMA-assisted psychotherapy.  
 
9.1 Randomization 
 
In total, 12 subjects will be enrolled in the study. The randomized portion of the study 
will be blinded and there will be a 7:5 ratio between subjects in the full dose and 
comparator dose conditions. An unblinded randomization monitor will generate the 
randomization list prior to enrollment of subjects. Subjects will be assigned sequential 
subject numbers upon enrollment for randomization assignment in a blinded fashion. 
Upon enrollment, the randomization monitor will provide the Investigator or Sub-
Investigator or designated study personnel with the randomization enrollment code 
corresponding to that subject’s sequential subject number. A unique container number 
will be pre-printed on the container labels corresponding to doses for each experimental 
session. The Investigator or Sub-Investigator or designated study personnel will enter 
the randomized enrollment code into the web-based randomization program to obtain the 
container number based on the condition assignment for each blinded experimental 
session. Blinded personnel will conduct all study evaluations in the randomized portion 
of the study until the blind is broken for each subject at the primary endpoint per 
protocol via the web-based randomization program. Detailed instructions will be 
provided to the site in a separate document. 
 
The therapists, the IR, and all site personnel except the pharmacist will remain blind to 
condition assignment. If there is an adverse event or other emergency requiring 
knowledge of the subject’s condition assignment, the blind may be broken for an 
individual subject by contacting the Sponsor’s Randomization Monitor. In most cases it 
should be sufficient to inform the treating physician for the emergency that the subject 
had received a minimum of 0 mg MDMA and a maximum of 125mg MDMA with a 
supplemental dose of 62.5mg MDMA. 
 
9.2 Subject Numbering 
 
Prior to enrollment, subjects will be tracked with a secondary identifier number and a 
screening number assigned sequentially starting at “001”. Subjects who meet the 
enrollment criteria will be enrolled in the study and assigned a 5-digit subject number. 
The first two digits identify the study site. The next three digits identify the subject 
within the site and will be assigned sequentially, with 01 corresponding to the first 
subject enrolled, e.g. the first enrolled subject will be 04001, second 04002, etc. 


MAPS Study MP-4 
 
 
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MAPS Study MP-4 
 
 
Amendment 2 Version 3 
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June 20, 2014 
  
 
Table 3. Time & Events Stage 1 
 
Study Phase 
Screen/ 
Baseline 
Preparatory 
Sessions 
Experimental 
Session 1 
Experimental 
Session 2 
Primary 
Endpoint 
Experimental 
Session 3 
End of 
Stage 1 
Visit # 
Prior to enrollment
V1,2,3 
V4 
V5,6,7 
V8 
V9,10,11 
V12 
V13 N 
V14,15,16N 
V17N 
Type of Visit 
Screening/Baseline
Preparatory 
Experimental 
Integrative 
Experimental 
Integrative 
Outcome 
Experimental 
Integrative 
Outcome 
Visit Timing – see Section 7.3 for visit 
windows 
Up to 2 months 
prior to V1 
Between 
baseline and V4 
within 13 weeks 
post  CAPS 
Between 
V4 and V8 
2-5 weeks 
post V4 
Between 
V8 and V12 
3-5 weeks 
post V8 
3-5 weeks 
post V8 
Between 
V13 and V17 
7-10 weeks 
post V13 
Initial Phone Screen 
! 
 
 
 
 
 
 
 
 
 
Informed Consent 
! 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric History  
! 
 
 
 
 
 
 
 
 
 
General Physical Exam, ECG 
! 
 
 
 
 
 
 
 
 
 
Brief Neurological Exam 
! 
 
 
 
 
 
 
 
 
 
SCID-RV (IR) 
! 
 
 
 
 
 
 
 
 
 
Clinical Lab Tests with HIV test 
! 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
! 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Medication Taper (if applicable) 
 
! 
 
 
 
 
 
 
 
 
Study Enrollment (if eligible) 
 
!O 
 
 
 
 
 
 
 
 
Record to Audio/Video 
 
! 
! 
! 
! 
! 
 
! 
! 
 
General Wellbeing 
 
! 
! 
! 
! 
! 
! 
! 
! 
 
Drug Screen 
! 
 
! 
 
! 
 
 
! 
 
 
Pregnancy Screen (if applicable) 
! 
 
! 
 
! 
 
 
! 
 
 
Obtain Container Assignment  
 
 
!B 
 
!B 
 
 
 
 
 
CAPS, GAF, BDI-II, NEO-PI, PSQI, 
PTGI, DES-II 
! 
 
 
 
 
 
!L 
 
 
! Q 
RBANS/PASAT 
! 
 
 
 
 
 
! 
 
 
! 
PDS  
! 
 
 
!M 
 
 
! 
 
!M 
! 
C-SSRS 
! 
!G 
!C, D, E 
!I 
!C, D, E 
!I 
! 
!C, D, E 
!I 
! 
Administer Drug + Therapy 
 
 
! 
!
! 
!
!
! 
 
 
Monitoring of BP, Pulse, and Temp.  
 
 
! 
!
! 
!
!
! 
 
 
SUD 
 
 
!F, E 
!
!F, E 
!
!
!F, E 
 
 
Belief of Condition Assignment 
 
 
 
!K 
 
!K 
 
 
 
 
Overnight Stay, SOCQ 
 
 
! 
 
! 
 
 
! 
 
 
Integrative Therapy Session 
 
 
 
!A 
 
!A 
 
 
!A 
 
7 Days Integrative Telephone Contact 
 
 
 
! 
 
! 
 
 
! 
 
AEs Requiring Medical Attention 
 
 
! 
! 
! 
! 
! 
! 
! 
! 
Spont. Reported Reactions & All AEs 
 
 
!J 
! 
!J 
! 
! 
!J 
! 
 
Changes in Tinnitus and/or Pain 
!P 
 
!E,P 
!E,P 
!E,P 
!E,P 
!P 
!E,P 
!E,P 
!P 
AEs of Psychiatric Status or Withdrawal 
 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Serious Adverse Events 
 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Issue Memory Aid Card  
 
 
 
 
 
 
 
 
 
!H 
Unblinding
  
 
 
 
 
 
 
! 
 
 
!
Perception of Experimental Sessions 
 
 
 
 
 
 
!N 
 
 
!N 
RRPQ 
 
 
 
 
 
 
 
 
 
!H 
A = First Integrative session is one day after experimental session; B = At least 24 hours prior to experimental session; C = Approximately six hours post MDMA; D = At the beginning of the session; E = As needed;  
F  = Approximately every 60 minutes; G = Given on 2nd preparatory session after washout; H = Only for subjects starting LTFU; I = Every face to face visit and Day 2 and Day 7 phone calls only; J = Reactions collected for 
seven days post experimental session; K = On the day of the first integrative session following the experimental session; L = One month after the second experimental session but before the third experimental session; M = 
On the day of the third integrative session; N = After unblinding for full dose subjects only; O = Only on Visit 1; P = Only in subjects with pre-existing tinnitus and/or chronic pain; Q = All measures listed except for the 
NEO-CI. 


MAPS Study MP-4 
 
 
Amendment 2 Version 3 
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June 20, 2014 
  
 
Table 4. Time & Events Stage 2 
 
Study Phase 
Preparatory 
Sessions 
Experimental 
Session 1 
Experimental 
Session 2 
Secondary 
Endpoint 
Experimental 
Session 3 
End of 
Stage 2 
 
Long-term 
Follow-up 
Visit # 
V18* 
V19 
V20,21,22 
V23 
V24,25,26 
V27 
V28 
V29,30,31 
V32 
LTFU 
Type of Visit 
Preparatory 
Experimental 
Integrative 
Experimental 
Integrative 
Outcome 
Experimental  
Integrative 
Outcome 
Follow-up 
Visit Timing – See Section 7.3 for visit 
windows 
Within 1 month 
post V12* 
+/_1 week 
post V18 
Between 
V19 and V23 
2-5 weeks 
post V19 
Between 
V23 and V27 
3-5 weeks 
post V23 
3-5 weeks 
post V23 
Between 
V28 and V32 
7-10 Weeks 
post V28 
1 year 
post V13 or V28 
Confirm Informed Consent 
! 
 
 
 
 
 
 
 
 
 
Confirm Inclusion/Exclusion 
! 
 
 
 
 
 
 
 
 
 
Enrollment in Stage 2 
! 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
! 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Record to Audio/Video 
! 
! 
! 
! 
! 
 
! 
! 
 
 
General Wellbeing 
! 
! 
! 
! 
! 
! 
! 
! 
 
 
Drug Screen 
 
! 
 
! 
 
 
! 
 
 
 
Pregnancy Screen (if applicable) 
 
! 
 
! 
 
 
! 
 
 
 
CAPS, GAF, BDI-II, NEO-PI, PSQI, 
PTGI, DES-II 
Use V12* 
 
 
 
 
!H 
 
 
! 
! 
RBANS/PASAT 
 
 
 
 
 
 
 
 
! 
 
PDS 
Use V12* 
 
!I 
 
 
! 
 
!I 
! 
! 
C-SSRS 
! 
!B, C, D 
!
G 
!B, C, D 
!
G 
! 
!B, C, D 
!
G 
! 
! 
Administer Drug + Therapy 
 
! 
!
! 
!
!
! 
 
 
 
Monitoring of BP, Pulse, and Temp.  
 
! 
!
! 
!
!
! 
 
 
 
SUD 
 
!D, E 
!
!D, E 
!
!
!D, E 
 
 
 
Overnight Stay, SOCQ 
 
! 
 
! 
 
 
! 
 
 
 
Integrative Therapy Session 
 
 
! A 
 
!A 
 
 
!A 
 
 
7 Days Integrative Telephone Contact 
 
 
! 
 
! 
 
 
! 
 
 
AEs Requiring Medical Attention 
! 
! 
! 
! 
! 
! 
! 
! 
! 
 
Spont. Reported Reactions and All AEs 
 
! 
!
F 
! 
!
F 
 
! 
!
F 
 
 
Changes in Tinnitus and/or Pain 
 
!J,D 
!J,D 
!J,D 
!J,D 
!J,D 
!J,D 
!J,D 
!J, D 
!J 
AEs of Psychiatric Status or Withdrawal 
! 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Serious Adverse Events 
! 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Perception of Experimental Sessions 
 
 
 
 
 
! 
 
 
! 
!
Complete Stage 2, Go to Follow-up 
 
 
 
 
 
 
 
 
! 
!
RRPQ 
 
 
 
 
 
 
 
 
! 
!
Issue Memory Aid Card 
 
 
 
 
 
 
 
 
! 
!
Follow-up Questionnaire 
 
 
 
 
 
 
 
 
!
! 
Termination Visit 
 
 
 
 
 
 
 
 
!
 
! 
* If Visit 18 is more than 8 weeks after Visit 12, then subjects will need to repeat measures prior to starting Stage 2 with the exception of NEO-PI.  
 
A = First session is one day after experimental session; B = Approximately six hours post MDMA; C = At the beginning of the session; D = As needed; E = Approximately every 60 minutes; F = Reactions collected for seven 
days post experimental session; G = Every face to face visit and Day 2 and Day 7 phone calls only; H = One month after the second experimental session but before the third experimental session; I = On the day of the third 
integrative session; J = Only in subjects with pre-existing tinnitus and/or chronic pain; K = All measures listed except for the NEO-PI 
 


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   June 20, 2014   
 
 
 
Page 30 of 83 
 
 
9.3 Assessments and Measures 
 
Screening and outcome measures were chosen to be well recognized in the literature and 
because of prior use in other sponsor-supported studies of MDMA-assisted 
psychotherapy in people with PTSD.  
 
Eligibility for the study will be determined based on psychiatric diagnoses confirmed 
during screening through medical history, the Structured Clinical Interview for Diagnoses 
(SCID-RV) and the CAPS. 
 
9.3.1 Outcome Measures 
 
The primary outcome measure will be the CAPS, a clinician-administered measure for 
PTSD diagnosis and assessment of symptom intensity and frequency. A qualified, 
blinded IR will perform the CAPS at baseline and outcome measurement time points 
according to the Time and Events Table. The baseline CAPS will be administered by the 
IR during a face-to-face visit, with administration of the CAPS being conducted via 
telemedicine or in person at subsequent visits.  The IR will not be present during the 
subject’s experimental sessions nor have any information regarding the experimental 
sessions. Subjects will be instructed not to inform the IR of any beliefs they or others 
have concerning their condition assignment during the evaluation session. The CAPS 
provides a standardized method to evaluate the frequency and intensity dimensions of 
each symptom, impact of symptoms on the subject’s social and occupational functioning, 
overall severity of the symptom complex and global improvement since baseline and the 
validity of the ratings obtained. The CAPS interview takes approximately one hour to 
complete. All assessments, including those at baseline, will use the CAPS assessment of 
symptoms over the last month. The CAPS interviews have been determined to have good 
internal consistency, concurrent validity, and test/retest reliability [129, 130].   
 
The secondary measure of PTSD symptoms will be the PDS, a self-report measure 
designed to follow DSM-IV criteria for assessing PTSD. The measure is derived from the 
Posttraumatic Symptom Scale – Self Report (PSS-SR), a measure also intended to tap 
into diagnostic criteria for PTSD. The PDS contains 49 items, with responses made on a 
four-point scale, ranging from 0 (“not at all”) to 3 (“five or more times a week”). The 
PDS consists of a list of 12 potential traumatic events, 12 items addressing elements of 
the traumatic event, of 17 symptom items, and nine items assessing impact on areas of 
life function [131]. Items addressing elements of the traumatic event and life function are 
answered as either present or not present (Yes or No). The 17 items are summed to create 
a symptom severity scale. Cronbach’s alpha for the symptom severity scale is 0.92. The 
PDS has test-retest reliability of 0.74 after a two-week and one-month interval, and 
subscales are inter-correlated, with correlations ranging from 0.73 to 0.82, and PDS 
scores have a moderate to good correlation with SCID-RV diagnosis, with kappa = 0.65 
[131]. Subjects will complete the PDS questionnaire at baseline, after the first and third 
experimental sessions, at the primary endpoint, at the end of Stage 1, and equivalent time 
points in Stage 2 and at the Long Term Follow-up, as specified in the Time and Events 
Table. 


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The Global Assessment of Function (GAF) is a measure of general function made 
through clinical observation. The GAF consists of a single score, ranging from 0 to 100, 
with 100 reflecting superior function and 0 reflecting serious risk of causing harm to the 
self or others. The IR administering the CAPS will perform the GAF assessment with the 
baseline GAF being administered during a face-to-face visit. Administration of the GAF 
at subsequent visits will be conducted in person or via telemedicine. The GAF will serve 
as a measure of global functioning and will be performed at the same times the CAPS is 
administered.   
 
The Post Traumatic Growth Inventory (PTGI) is a 21-item self-report measure of 
perceived growth or benefits occurring after a traumatic event. It contains five subscales; 
relationship to others, new possibilities, personal strength, spiritual change, and 
appreciation of life [132, 133]. In this study, subjects will complete the PTGI in reference 
to the time since the trauma at baseline, but will respond in reference to the beginning of 
their participation in the study on all subsequent occasions. Subjects will complete the 
PTGI according to the Time and Events table.  
 
The BDI-II is a 1996 revision of the BDI, a 21-item self-report measure [134, 135], that 
will serve as a measure of depression according to DSM-IV criteria [136]. 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 five to 10 minutes to complete 
[136]. Score cutoffs indicate: 0-13 minimal depression, 14-19 mild depression, 20-28 
moderate depression, and 29-63 severe depression. Higher scores indicate more severe 
depressive symptoms. Subjects will complete the BDI-II according to the Time and 
Events table. 
 
The NEO-PI will serve as a measurement of personality [137, 138]. The NEO-PI is a 
240-item self-report assessment that takes between 30 and 40 minutes to complete. It is a 
well-established measure of five personality traits with sound properties of reliability and 
validity that operationally define personality structure according to a five-factor model. 
Subjects will complete the NEO-PI according to the Time and Events table. 
 
The Pittsburgh Sleep Quality Index (PSQI) is a 19-item measure of self-reported sleep 
quality over a one-month period. The PSQI was designed to be a reliable, standardized 
measure able to distinguish between good and poor sleepers. Possible responses range 
from 0 to 4 on a five-point scale [139]. The PSQI consists of seven sub-scales; sleep 
quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of 
sleeping medications, and daytime dysfunction. These are all summed to produce a single 
global scale. Global scores can range from 0 to 21, with higher scores reflecting poorer 
sleep quality, and a score below 5 indicative of good sleep. It takes five to 10 minutes to 
complete. Test-retest reliability ranges from 0.85 to 0.87, and it is internally consistent, 
with a Cronbach’s alpha of 0.83[139, 140]. Global scores correlate with other measures 
of alertness and self-reported sleep quality [141]. Subjects will complete the PSQI 
according to the Time and Events table. 
 


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   June 20, 2014   
 
 
 
Page 32 of 83 
 
 
The DES-II is a 28-item self-report measure of dissociation, defined as a lack of normal 
integration of an individual’s thoughts, feelings, or experiences into the stream of 
consciousness or memory [142, 143].  It is an established measure of dissociative 
symptoms. The scale consists of statements describing facets of dissociation. 
Respondents indicate how often the specific experience happens to them, from “never” to 
“always.” Responses on the original scale were made via visual analog scales. The DES-
II uses the same items but with responses made on a 10-point scale from “0%” to “100%” 
of the time. The scale is scored by treating percentages as single digits to produce a total 
score. The DES-II can also be used to produce scores for three factors, amnesia, 
depersonalization, and derealization. The scale differentiated between respondents 
without psychiatric disorders or with psychiatric disorders with few dissociative 
symptoms and respondents with psychiatric disorders associated with dissociative 
symptoms [142]. Reliability of the DES-II is high (ranging from 0.79 to 0.96 in an early 
review), and a reported Cronbach’s alpha of 0.95 [143, 144]. There may be a relationship 
between experiencing dissociation and occurrence of chronic PTSD [143, 145]. Subjects 
will complete the DES-II according to the Time and Events table. 
 
9.3.2 Safety Measures 
 
Safety measures will be applied as described below to minimize risks associated with 
drug-assisted psychotherapy sessions. The therapists will be available via mobile phone 
or pager throughout the study to ensure subject safety.  
 
Safety measures, including vital signs and a measurement of psychological distress, will 
be assessed during all experimental sessions. Subjects will rate their current degree of 
subjective distress with the SUD scale, which is a single-item self-report scale. The SUD 
will be completed repeatedly during the experimental sessions, with the degree of distress 
marked along seven points. Results of the SUD are intended to assist therapists in 
maintaining subject safety during experimental sessions. 
 
The therapists will assess general wellbeing during each preparatory session, on each 
integrative session and during telephone calls for seven days. Results of this scale are 
intended to assist therapists in maintaining subject safety throughout the study. 
 
During the course of each MDMA-assisted psychotherapy session, the Subjective Units 
of Distress (SUD) scale will be used to assess degree of psychological distress 
experienced at various points during the session. Subject and therapists’ beliefs 
concerning subject condition assignment (either full dose or comparator) will be assessed 
during the non-drug psychotherapy session occurring on the day after each experimental 
session. Neither the SUD scale nor condition assignment beliefs measures are outcome 
measures.  
 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a clinician-administered 
measure of suicidal behavior devised to detect potential suicidal thoughts or behaviors 
during a clinical trial [146]. It assesses lifetime suicidal ideation, ideation intensity and 
behavior, and a form for assessing current suicidal ideation and behavior. The C-SSRS 


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consists of a series of questions, and can be administered during face-to-face interview or 
over the telephone. C-SSRS scores are sensitive to changes in suicidal ideation or 
behavior over time, and the measure demonstrates good convergent validity with other 
measures of suicidality [147]. The C-SSRS will be performed by the therapists or 
designated qualified study personnel at baseline, and repeated throughout the protocol to 
assess suicidality. See the Time and Events Table for a detailed schedule. 
 
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
[148] is a relatively brief battery of assessments for cognitive function. It consists of 12 
subtests that cover verbal and visual memory and attention and takes approximately 30 
minutes to administer. Tasks include recall of lists, figures and stories, picture naming, 
semantic fluency, copying a figure, digit span and coding, and line orientation. Scores on 
the RBANS subtests can be used to obtain a total score and five index scores; attention, 
immediate memory, delayed memory, language and visuospatial/constructional scores. 
Factor analyses of the RBANS and samples of veterans and people with schizophrenia 
suggest that the RBANS possesses two factors rather than five [149, 150]. The RBANS 
has alternate forms, allowing repeated administration. Test performance by healthy 
controls were distinguishable from performance by people with probable Alzheimer’s 
disease or the neurodegenerative condition Huntington’s disease [151], and the test has 
high split-half reliability, with coefficients ranging from 0.80 to 0.88 [148]. Test-retest 
reliability is good for total RBANS scores in healthy controls and psychiatric patients 
[152]. The RBANS has been used in community-based and psychiatric samples [149, 
153] and in a prospective investigation of the effects of chemotherapy upon cognitive 
function [154]. Each administration of the RBANS will use one of parallel forms of 
RBANS, and each participant will not complete the same form twice. This measure was 
employed as a means of assessing safety after two sessions of MDMA-assisted 
psychotherapy for PTSD [77]. See Time and Events Table for a detailed schedule. 
 
The Paced Auditory Serial Addition Test (PASAT) is a measure of psychomotor speed, 
auditory information processing and computation ability [155]. The PASAT was 
originally designed to assess recovery after traumatic brain injury, and has been used 
subsequently to assess cognitive function in other populations [155, 156]. It takes 
approximately ten to 15 minutes to administer. The measure involves the addition of a 
series of digits presented at a three or two second interval, with responses made by 
adding each number to the prior digit. The PASAT consists of two alternate forms, 
permitting repeated administration. PASAT scoring includes collecting number of correct 
and incorrect responses, time to response (latency of response) and any failure to 
respond. There was a positive correlation between responses on the PASAT and a non-
numerical paced measure. The measure is internally consistent (Cronbach’s alpha of 
0.90), and it has high test-retest reliability, with reliability ranging from 0.90 to 0.97 
[156-158]. The first administration of the PASAT will use one of the two alternate forms, 
and the second administration will use the other. This measure was employed as a means 
of assessing safety after two sessions of MDMA-assisted psychotherapy for PTSD [77]. 
See Time and Events Table for a detailed schedule. 
 


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Cardiovascular effects will be assessed via blood pressure and pulse measurement.  
Blood pressure and heart rate will be assessed periodically during each experimental 
session by an automatic blood pressure (BP) and pulse monitor. Blood pressure and pulse 
will be measured at the outset of the experimental session, and once approximately every 
30 minutes for the first four hours of the experimental session, and once every hour, or as 
needed, thereafter. More frequent measures will be taken if the established thresholds of 
160 systolic, 110 diastolic, or pulse of 110 are exceeded. Blood pressure will also be 
measured more frequently if there are symptoms, such as chest pain, shortness of breath 
or neurological symptoms that may be indicative of hypertension. The therapists will 
measure subject body temperature approximately every 60 to 90 minutes. Cardiovascular 
effects will be assessed via BP measurement. The timing of these measurements will be 
adjusted so they do not interfere with the therapeutic process.  
 
A 100-millimeter visual analog scale will be used to assess changes in symptoms of pre-
existing tinnitus and/or chronic pain [159-161].  The changes in Tinnitus and/or Pain 
visual analog scale will allow rating of symptom severity from “None” to “Worst Case 
Imaginable”. This exploratory measure will enable quantification of subjective somatic 
symptoms that are known to be associated with PTSD [160, 162-164]. Presence of 
chronic pain is associated with PTSD, possibly as a result of psychological response to 
traumatic stress as reflected in brain activity, such as increased amygdalar activity in 
response to pain and transmitter systems involved in the stress response [160, 163, 164]. 
 
All AEs and spontaneously reported reactions will be collected, as described in Section 
14.0. AEs and spontaneously reported reactions may be collected during face-to-face 
visits or over the telephone. Common reactions that are spontaneously reported are 
collected for seven days after each experimental session on a separate CRF page and will 
be categorized as mild, moderate, or severe. 
 
9.3.3 Process Measures 
 
All sessions after enrollment may be recorded to audio and video, including introductory, 
integrative and experimental sessions for research and training purposes. These 
recordings will be used for further development of the manual of standard procedures for 
performing MDMA-assisted psychotherapy in people with PTSD. 
 
Adherence criteria and competence ratings will be conducted by qualified, trained 
blinded adherence raters who will analyze video data from selected preparatory, 
experimental and integrative sessions. The elements included in adherence criteria are 
specific to each type of session. These ratings will be collected, at minimum, for each 
therapist team in the study. The goal of these ratings will be to correlate therapist 
adherence to the treatment manual with outcome as a part of the sponsor’s ongoing 
efforts to standardize treatment methods of MDMA-assisted psychotherapy for PTSD.  
 
The SOCQ is a 100-item questionnaire based on the “Peak Experience Profile” designed 
by Pahnke and colleagues [165, 166].  Subjects respond to the SOCQ using a six-point 
Likert-type scale anchored at 0=none at all and 5=extreme (more than ever before in my 


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life). It has seven subscale scores; internal unity, external unity, transcendence of time 
and space, ineffability and paradoxicality (claim of difficulty in describing the experience 
in words), sense of sacredness, noetic quality, and deeply felt positive mood. The 
measure is a self-report instrument and takes approximately 20 to 30 minutes to 
complete. Subjects will complete the SOCQ after each experimental session, at any time 
between the end of an experimental session and prior to leaving the treatment facility the 
next day. 
 
Response to study participation and perceived degree of choice in taking part in the study 
will be assessed with the Reactions to Research Participation Questionnaire (RRPQ) 
[167]. Subjects will complete this measure during their final study visit, roughly six 
weeks after the last experimental session. The RRPQ is intended to assess the subject’s 
experience as a research subject, perceived reasons for consenting to be a research subject 
and perceived freedom to take part in the study, and is a process measure.  
 
Questions regarding the belief of condition assignment and certainty of the belief will be 
asked of the therapists and subjects at the integrative session on the day after each 
blinded experimental session in Stage 1. Each therapist responsible for treating the 
subject will indicate their belief of condition assignment and certainty based on the full 
dose (125mg) and comparator dose (0 mg) groups. In line with informed consent 
obfuscation, where the comparator dose is not revealed, subjects will initially be asked if 
they believe they received MDMA or not during this assessment. If they believe they 
received MDMA, they will be asked about what dose they think they received. These 
beliefs are collected as a part of the sponsor’s ongoing initiative to optimize the double-
blind as a part of dose response studies.  
 
Perceptions of the experimental sessions will be collected from each full dose subject 
during the primary endpoint visit after unblinding and from Stage 2 subjects during the 
secondary endpoint visit in Stage 2 before the third experimental session in Stage 1/Stage 
2. Perceptions will be collected again at the end of Stage 1/Stage 2 according to the Time 
and Events Table. These perceptions are collected as a part of the sponsor’s ongoing 
initiative to assess the therapeutic value of the third experimental session and information 
on the optimal therapeutic dose of MDMA. 
 
The long-term follow-up questionnaire has been developed internally by the Sponsor to 
assess long-term benefits and harms of MDMA-assisted psychotherapy at the long-term 
follow-up visit.   
  
9.4 Visit Descriptions 
 
9.4.1 Prescreening, Screening, and Baseline Evaluation (Pre-study) 
 
Prospective subjects will be prescreened by telephone according to an IRB-approved 
script to learn if they meet basic eligibility criteria. All individuals who are prescreened 
should be assigned a screening number and recorded on the Subject Screening Log where 
information on the selection of potential subjects in the trial should be collected.  


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Upon signing the IRB-approved informed consent form (ICF), the potential subject may 
commence study-related screening activities. The screening number should also be 
recorded on the signed ICF. If a subject is enrolled, the study staff should record the 
enrollment date and assign a subject number. If a subject is not enrolled, an explanation 
should be recorded on the Screening Log. A CRF will not be completed for subjects who 
are not enrolled. These subjects will only be documented on the Screening Log and 
source records. It is the responsibility of the Investigator and study coordinator to file the 
Screening Log in the Investigator Site File (ISF) to be readily available for on-site 
monitoring and/or inspection by relevant authorities.  
 
Screening may take place over more than one day and should be complete by up to two 
months prior to enrollment. Screening may take up to two months, with the baseline 
CAPS being conducted no more than 5 – 8 weeks before the first experimental session, 
leaving room for appropriate medication washout of at least 5 half-lives of pre-study 
psychiatric medications and active metabolites, plus one week for stabilization.  A 
window of up to 8 weeks is allowed if needed for medication tapering. If the CAPS is 
completed outside of this window for a subject, the Investigator  or Sub-Investigator 
should consult the Sponsor CRA and Medical Monitor to determine if the baseline CAPS 
should be repeated. The maximum window from the start of screening to the first 
experimental session is 13 weeks. If, after reviewing all information, the Investigator or 
Sub-Investigator concludes that a subject is eligible, they will enroll the subject in the 
study. Visits will be scheduled consecutively as described in the Time and Events Table. 
During the screening visit: 
 
a. Explain and obtain written informed consent from the subject. Written informed 
consent must be obtained prior to performing any tests or evaluations for the study. 
The Investigator or Sub-Investigator and qualified designated staff may all participate 
in conducting the informed consent. 
b. Assign the subject a screening number. Complete the Screening Log.  
c. Review the ability of females of childbearing potential to become pregnant and their 
commitment to practice appropriate birth control as determined by the CI for the 
treatment period of the study. 
d. Obtain medical and psychological history by interview. 
e. Collect information on pre-study and current medications. 
f. Tinnitus and chronic pain symptom severity will be collected using a visual analog 
scale in subjects with a medical history of these conditions. 
g. Administer the C-SSRS to assess past and current suicide risk.  
h. A physician will perform a general physical examination. The examination will 
involve the following procedures:  
 
• Blood pressure. 
• Pulse. 
• Height. 
• Weight. 
• Body temperature. 
• Examination of head, eyes, ears, nose, throat, skin, heart, lungs, abdomen and 


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extremities. 
• Brief neurological exam (cranial nerves 2-12, sensory, motor, reflexes and 
cerebellar function). 
• Electrocardiogram (ECG). 
• Serum electrolytes, metabolic profile, urinalysis and complete blood count 
• Thyroid stimulating hormone (TSH), free T3, and free T4. 
• Human Immunodeficiency Virus (HIV) serology. 
• Urine-dip pregnancy test on females with childbearing potential.  
• Urinary drug test. 
 
Results of HIV serology will be kept confidential, and appropriate referral for counseling 
may be necessary in accordance with local law. The clinical laboratory values will not be 
captured in the CRF, but will be used to establish eligibility and will be kept with the 
subject’s source record. Clinically significant abnormal values will be captured as 
medical history in the CRF. If, upon examination, there are questions raised about 
possible medical problems, the Investigator or Sub-Investigator will request a review of 
subject medical records and request additional tests or assessments as indicated. 
 
• A blinded IR who will not be present during any of the therapy sessions will 
administer the following during a face-to -face interview: 
• Structured Clinical Interview for Diagnoses Research Version (SCID-RV) to 
assess eligibility based on diagnoses, which includes a self-report questionnaire to 
focus on modules to use based on symptoms. 
• Last month’s CAPS to assess PTSD symptoms and eligibility, which may be 
recorded to video in as many instances as necessary to establish inter-rater 
reliability. 
• GAF to assess general psychological function. 
• PASAT to assess cognitive function. 
• RBANS to assess cognitive function. 
 
The subject will complete the following self-report measures: 
• PTGI (in reference to time since the trauma) 
• PDS to assess self-reported PTSD symptoms 
• BDI-II to assess depression symptoms 
• NEO-PI to assess changes in personality 
• PSQI to assess changes in sleep quality 
• DES-II to assess dissociation symptoms 


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9.4.2 Preparatory Psychotherapy Sessions - Visits 1, 2, 3 (Stage 1), 18 (Stage 2) 
 
Subjects who do not complete all screening activities will not be enrolled. Eligibility may 
be discussed by phone after screening is complete and at the time Visit 1 is scheduled but 
the final confirmation will occur at Visit 1. If all inclusion criteria and no exclusion 
criteria are met, the subject will be enrolled and issued a subject number.  
 
During Visit 1: 
a. Complete a final review of Inclusion/exclusion criteria. 
b. Assess general wellbeing. 
c. Confirm eligibility and willingness to participate in study. 
d. Assess general wellbeing. 
e. Ensure medical history and medication history is complete. After enrollment new 
events will be collected as AEs and new medications will be collected as 
described in Section 14.0 of the protocol. 
f. Discuss medication tapering, if applicable. Upon confirmation of eligibility, the 
Investigator or Sub-Investigator will consult the prescribing physician to initiate 
medication tapering for subjects who must refrain from taking a psychiatric 
medication for the study. Tapering will follow a time course appropriate for the 
medication as specified in the Medication Tapering Table in Section 14.4 of the 
protocol, with the first experimental session scheduled to occur one week after 
complete washout. 
 
The subjects will undergo three preparatory sessions lasting 90 minutes with their 
therapist team, prior to their first experimental session. The first preparatory session will 
take place at Visit 1 after enrollment confirmation. Three preparatory sessions should be 
scheduled prior to the first experimental session  The preparatory sessions should be 
completed in time to ensure the experimental session occurs within 5 -8 weeks (plus any 
additional time needed for longer drug tapering) after the baseline CAPS. In Stage 2 (for 
comparator dose crossover subjects), only one preparatory session will take place prior to 
their first full dose open-label experimental session, as described in the Time and Events 
Table.  
 
Adherence criteria for preparatory sessions should be completed as a part of one of the 
three sessions. These elements do not have to be accomplished in any specific order or in 
every preparatory session. Generally, adherence criteria for these sessions include that the 
therapists will work with the subject to prepare for MDMA-assisted psychotherapy. The 
therapists and subject will seek to form a strong working relationship with each other, 
and they will help the subject prepare for upcoming experimental sessions. Preparatory 
sessions will promote a safe set and setting for confronting trauma-related memories, 
emotions, and thoughts, which is intended to develop therapeutic alliance.  
 
During the preparatory sessions: 
 
a. Therapists may record all sessions to audio and video. Subjects may review 
recordings from these sessions upon request.  


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b. Collect AEs and Medications as described in Section 14.0 of the protocol. 
c. The therapists will inquire about any possible changes in the subject’s health to 
ensure that subject continues to meet eligibility criteria and if applicable, will confirm 
that the subject has appropriately tapered off of medications.  
d. If subjects who have pre-existing tinnitus or chronic pain mention any changes, use 
the visual analog scale to collect the changes in symptoms. 
e. The subject and therapists will discuss goals for the experimental session and will 
review what will happen during the experimental session, following standard 
procedures and techniques discussed in the treatment manual.  
f. Prior to the experimental session, the therapists will introduce the subject to the 
attendant that will remain with the subject during each overnight stay after each 
MDMA-assisted psychotherapy session. The attendant will be an individual with 
previous training in managing psychological distress.  
g. If a subject would like a companion present during or after the experimental session, 
a meeting between the therapists and that individual will be scheduled prior to the 
first experimental session. There must be mutual agreement between the subject and 
therapists concerning the presence of the companion. 
h. The therapists or qualified study personnel will administer the C-SSRS just prior to 
beginning the second preparatory session, unless a subject is still undergoing 
medication washout. Subjects still undergoing medication washout will complete the 
C-SSRS during the second preparatory session or at a point after washout is complete 
prior to the first experimental session.  
i. Assess general wellbeing at each preparatory session. 
j. During the third and last preparatory session, give the Reminder of Study Rules to the 
subject, which includes instructions and restrictions for conduct prior to receiving the 
drug. Subjects must agree to: 
 
• Ingest only alcohol-free liquids after 24:00 (midnight) the evening before the 
experimental session.  
• Refrain from the use of any psychoactive drug, with the exception of caffeine or 
nicotine, within twenty-four hours of each experimental session. 
• Not use caffeine or nicotine for two hours before and six hours after ingesting the 
drug, or until therapists deem it safe to do so. 
 
9.4.3 Experimental Sessions - Visits 4, 8 (Stage 1), 13, (Full Dose Group Stage 1), 19 
23, 28 (Stage 2) 
 
Experimental sessions of MDMA-assisted psychotherapy should be scheduled 
approximately 4 weeks apart (2-5 weeks) . Procedures for MDMA-assisted 
psychotherapy will remain the same across all sessions. The dose of the drug and 
blinding procedures will vary based on the stage of the study.  
 
Adherence criteria for experimental sessions should be completed as a part of each 
experimental session. These elements do not have to be accomplished in any specific 
order. Generally, adherence criteria for these sessions include that the therapists will 
create and communicate a setting of safety and support the subject during periods of inner 


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focus. Therapists will use a largely nondirective approach, following the lead of the 
subject’s inner healing intelligence. Therapists will provide encouragement for staying 
present with difficult experiences. Therapists may occasionally offer gentle guidance or 
redirection as a choice to encourage collaborative exploration if the subject repeatedly 
avoids trauma related material. Therapists will inquire about somatic symptoms and if 
necessary encourage release of tension through movement, in whatever way feels 
appropriate to the subject. Therapists will use music to support the experience without 
being intrusive.  
 
Pre-drug: 
 
a. At least 24 hours prior to the first experimental session the subject will be 
randomized. The Investigator or Sub-Investigator or designated study personnel will 
obtain the container assignment using a web-based randomization program prior to 
the blinded sessions.  
b. On the day of the experimental session, the subject will arrive approximately 60 to 90 
minutes prior to drug administration.  
c. Confirm continuing eligibility by reviewing inclusion/exclusion criteria. 
d. Perform a urine drug screen. A positive drug screen will be reviewed by the 
Investigator or Sub-Investigator and may be cause for delaying drug administration to 
a later time, rescheduling the session to a later date, or withdrawing the subject from 
the study. 
e. If a woman is of childbearing potential, perform a urine pregnancy test. A positive 
pregnancy screen is cause for withdrawal from the protocol. 
f. If the subject continues to meet criteria and the subject reports that they followed 
appropriate rules and restrictions, the session will proceed. 
g. Review procedures for the experimental session with the subject. 
h. Record the entire session to video and audio if possible. Subjects may review audio or 
video recordings of their experimental sessions upon request. 
i. The session will last for approximately eight hours or longer, followed by an 
overnight stay at the study site. 
j. The therapists or qualified study personnel will administer the C-SSRS prior to drug 
administration. 
k. Before drug administration, discuss and review the subject’s goals, intentions and 
concerns and some of the commonly experienced effects of MDMA. 
l. Instruct the subject not to use caffeine or nicotine two hours before or six hours after 
the dose of drug. 
m. Subject body temperature will be measured at baseline prior to initial dose 
administration and approximately every hour after that. Measurements can be done 
more frequently if body temperature exceeds more than 1oC above baseline. 
n. Subjects will complete the SUD at baseline prior to initial dose administration. 
Subjects will complete the SUD every 60 to 90 minutes, until the session is over, 
allowing a window of up to 30 minutes to fit into the psychotherapy process where a 
natural break occurs. If necessary, the therapists can make a greater number of 
measurements as their clinical judgment dictates. 
o. Measure blood pressure and pulse at baseline prior to the experimental session, and 


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once every half-hour throughout the experimental session if the established thresholds 
for normal blood pressure and pulse have not been exceeded for the duration of the 
experimental session. More frequent measures will be taken if the established 
thresholds of 160 systolic, 110 diastolic, or pulse 110 are exceeded. Measurements 
should be taken more frequently until the values fall below these levels or until they 
have been decreasing for 15 minutes or have stabilized at a level judged by the 
Investigator or Sub-Investigator to be safe. The therapists may also make more 
frequent measurements if a subject exhibits symptoms indicative of hypertension. 
 
During: 
 
p. At approximately 10:00 in the morning, subjects will receive the initial dose of drug 
along with a glass of water. This will be administered by the Investigator or Sub-
Investigator. 
q. The subject will sit or recline on comfortable furnishings. Eyeshades and a program 
of music will be provided if the subject wishes to use them. Subjects may speak to the 
therapists whenever they wish, who will provide guidance and support as needed.  
r. After the first hour, if the subject has not spoken spontaneously, check in with 
him/her about the nature of the experience. For the rest of the experience, as 
appropriate, the therapists will support and encourage the subject in emotional 
processing and resolution of whatever psychological material is emerging as 
described in the treatment manual. 
s. Record any spontaneously reported reactions during the session. 
t. If subjects who have pre-existing tinnitus or chronic pain mention any changes, use 
the visual analog scale to collect the changes in symptoms. 
u. Provide water and electrolyte containing fluids throughout the session but not to 
exceed 3L overall. 
v. An optional supplemental dose half the size of the initial dose may be administered 
approximately 1.5 to 2.5 hours after the initial dose unless contraindicated. 
w. Provide food during the latter part of the session.  
x. If there is a companion who has previously been asked and has agreed to be present 
during part or all of the MDMA-assisted session, that person may arrive during the 
session at whatever time has been agreed upon, but will wait in the waiting room until 
brought back to the session room by one of the therapists.  Alternatively, the support 
person may arrive after the session has ended. 
y. If it is appropriate to do so, initiate the first question of the C-SSRS at any point in the 
session if the subject is experiencing significant psychological distress that does not 
respond readily to processing with the therapists according to the methods described 
in the treatment manual. The C-SSRS is required at least once during the session. It is 
preferable to administer it towards the end of the session at about six hours after the 
initial dose.  
z. End the session if all medical and psychiatric parameters are acceptable and the 
subject is alert, ambulatory, and emotionally stable. 
 


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Table 5. Example Schedule of Procedures and Measures for Experimental Sessions  
Approximate Time 
Procedure or Action 
9:00  
Urine drug screen, pregnancy test, C-SSRS 
 9:45  
Baseline BP, pulse, SUD 
 9:55  
2nd Baseline BP, pulse, BT, SUD 
10:00  
Drug Administration, begin recording to audio and video 
10:30  
BP, pulse 
11:00  
BP, pulse, SUD, BT 
11:30  
BP, pulse, May administer supplemental dose  
12:00  
BP, pulse, BT 
12:30  
BP, pulse, SUD 
13:00  
BP, pulse 
13:30  
BP, pulse, BT 
14:00  
BP, pulse, SUD 
Every hour, and as needed 
BP, pulse 
Every 60 to 90 minutes 
SUD, temperature 
Approximately six hours 
after administration 
C-SSRS, General Wellbeing 
 
 
Post-drug: 
 
aa. Give the subject the SOCQ to be completed after the end of the experimental session 
and prior to leaving the treatment facility the next day. 
bb. The therapists will depart the site when they have concluded that the subject is 
emotionally and medically stable. Therapists shall remain available to subjects during 
the experimental session and for one week after via twenty-four-hour cellular phone 
for integration as needed. 
cc. If the Investigator or Sub-Investigator decides not to administer any optional 
supplemental or clinical titration doses, as described in Section 8.3, in a given 
experimental session, the unused capsules will be kept in their respective inner 
envelopes inside of the primary container until the end of the experimental session. At 
the end of the experimental session, the Investigator or Sub-Investigator will return 
the container and any remaining unused capsules to the pharmacy safe. 
dd. Spontaneously reported reactions, AEs, and Medications will be collected as 
described in Section 14.0 of the protocol.  
  
Subjects will remain overnight in an appropriately furnished room at the study site. With 
the approval of the therapists, a companion may accompany the subject during the 
overnight stay. An attendant will check in periodically on the subject during the overnight 
stay, even if a companion is present. The attendant will monitor subject condition and 
will help subjects relax during the overnight stay. The attendant will be an individual 
with some previous training in managing psychological distress. If there is an emergency 
or the subject needs additional support, the attendant can contact the therapists. The 
subject and a companion (if applicable) will receive information that will allow them to 
contact the therapists during the overnight stay in the case of an emergency or request for 


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additional support. Subjects will be encouraged to use much of the time during their 
overnight stay for rest and for a period of reflection and integration in a quiet atmosphere. 
 
9.4.4 Integrative Sessions 24 Hours after Experimental Session - Visits 5, 9 (Stage 1), 
14 (Full Dose Group Stage 1), 20, 24, 29 (Stage 2) 
 
On the morning after each experimental session, both of the therapists from the subject’s 
team will meet with the subject during a 60 to 90-minute integrative therapy session.  
 
Adherence criteria for integrative sessions should be completed as a part of one of the 
three sessions following each experimental session. These elements do not have to be 
accomplished in any specific order or all in each and every integrative session. Generally, 
adherence criteria for these sessions include discussing material that emerged during 
experimental sessions and helping subjects integrate their experiences both internally and 
into daily life. Therapists will validate the choices of the subject about how much they 
wish to communicate their thoughts, feelings and experiences at this time, but will elicit 
enough information to be able to assess the subject’s level of emotional stability and state 
of emotional and physical wellbeing. Therapists will emphasize their commitment to 
support the subject during the integration period and will be available via phone for 
additional meetings if needed. Subjects will be encouraged to relax and rest as much as 
possible for several days after the experimental session. 
 
During integrative psychotherapy sessions: 
 
a. The integrative psychotherapy session may be recorded to audio and video. Subjects 
may review these data upon request. 
b. The therapists will administer the C-SSRS during each integrative session.  
c. Prior to integrative psychotherapy, the subject and both therapists will indicate their 
beliefs concerning subject condition assignment.  
d. Discuss and review events that occurred with the subject during the experimental 
session, including thoughts, feelings, and memories. If necessary, the therapists will 
help the subject to reduce any residual psychological distress he or she is 
experiencing. The therapists 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 therapists will be 
supportive, validating the experience and facilitating understanding and emotional 
clearing.  
e. The therapists will remain accessible any time the subject needs support outside the 
scheduled integration sessions.  
f. Assess the subject’s mental health, general wellbeing and the presence of any 
remaining reactions during integrative psychotherapy immediately after each 
experimental session.  
g. Integrative psychotherapy sessions can also serve as an opportunity for the therapists 
to gather information about the effects of the drug on the subject in an unstructured 
manner.  
h. If subjects who have pre-existing tinnitus or chronic pain mention any changes, use 


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the visual analog scale to collect the changes in symptoms. 
i. After the integrative psychotherapy session following the experimental session, a 
person previously selected by the subject will provide a ride home to the subject. If 
the subject is unable to locate an individual willing or able to take him or her home, 
or if the designated person is unable to assist the subject due to unforeseen events, the 
therapists will assist the subject in finding an alternative means of returning home. 
j. Spontaneously reported reactions, AEs, and Medications will be collected as 
described in 14.0 of the protocol.  
k. Remind the subjects that they will have daily phone contact for the next seven days. 
 
9.4.5 A Week of Daily Contact 
 
During daily phone contact:  
 
a. Therapists will follow the most recent version of the treatment manual in all matters 
relating to follow-up subsequent to the experimental psychotherapy sessions. 
b. Starting on the day of the integrative psychotherapy session following each 
experimental session, one of the therapists will contact the subject via telephone or in 
person on a daily basis for one week. The goal of daily contact is assessment of 
changes in general wellbeing, safety of the subjects, and offering support for subjects.  
c. The integrative phone contact will be for a brief check-in lasting five to 15 minutes, 
or as long as necessary to address any subject’s concerns and to assess subject’s 
wellbeing. Additional telephone contact can be initiated at the request of the 
therapists or subject. 
d. On the second and seventh day of phone contact after the experimental session, the 
therapists will administer the C-SSRS. 
e. General wellbeing will be assessed at each phone call. 
f. Spontaneously reported reactions, AEs, and Medications will be collected as 
described in Section 14.0 of the protocol. 
 
9.4.6 Integrative Psychotherapy Between Experimental Sessions - Visits 6, 7, 10, 11,  
(Stage 1), 15, 16, (Full Dose Group Stage 1), 21, 22, 25, 26, 30, 31 (Stage 2) 
 
In addition to the session the morning after each experimental session, the subject will 
have two additional integrative psychotherapy sessions with the therapists lasting 90 
minutes with the therapists between each experimental session and in the month 
following the last experimental session. The therapists may conduct more sessions if they 
and the subject deem it necessary. Some of these sessions may be done via telemedicine 
or phone calls. 
 
Adherence criteria for integrative sessions should be completed as a part of one of the 
three sessions following each experimental session. These elements do not have to be 
accomplished in any specific order or in each integrative session. Generally, adherence 
criteria for these sessions include integration of material that emerged as a part of 
experimental sessions and afterward into daily life. Therapists will emphasize their 
commitment to support the subject during the integration period and will be available via 


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phone or pager. Subjects will be encouraged to relax and rest as much as possible for 
several days after the experimental session. 
 
During integrative psychotherapy sessions: 
 
a. Record each integrative session to audio and video if possible. Subjects may 
review these recordings upon request. 
b. The C-SSRS will be administered just prior to beginning each integrative session.  
c. General wellbeing will be assessed at each integrative session. 
d. If subjects who have pre-existing tinnitus or chronic pain mention any changes, 
use the visual analog scale to collect the changes in symptoms. 
e. The subject will complete the PDS questionnaire on the third integrative session 
after the first and third experimental sessions, according to the Time and Events 
Table. 
f. The subject and therapists will continue to work on supporting the subject as she 
or he considers his or her experiences during experimental sessions.  
g. The therapists will use clinical judgment to assess the subject’s psychological 
wellbeing during this period of time. If there are any indications of continuing 
anxiety or distress, the therapists may arrange to work on reducing the distress at 
a specially scheduled integrative therapy session, through continuing contact, or at 
the next regularly scheduled integrative therapy session. The subject may also 
initiate contact with the therapists at any time throughout the study.  
h. Collect AEs and medications as described in Section 14.0 of the protocol. 
i. NOTE: If an integrative session falls within the period of telephone contact and 
additional phone call is not required that day, all data normally collected during 
the telephone call will be completed in person. 
 
9.4.7 Evaluation at Primary Endpoint and Unblinding - Visit 12 (Stage 1) 
 
The primary endpoint evaluation in Stage 1 will occur one month (within a window of 3-
5 weeks) after the second blinded experimental session. This visit will consist of two 
meetings that may be completed on separate days, one with the IR and the other with the 
therapists. Subjects who have withdrawn from treatment but have continued for follow-
up will also complete this time point one month after their last experimental session. 
 
At the primary endpoint: 
 
a. Subjects will complete the following assessments in person:  
• PASAT to assess cognitive function. 
• RBANS to assess cognitive function. 
b. The GAF to assess general psychological function, and CAPS to assess PTSD will be 
administered by the blinded IR in person or via telemedicine. CAPS interviews may 
be recorded to video in as many instances as necessary to establish inter-rater 
reliability. 
 
c. The subject will complete the following self-report measures: 


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• PTGI to assess post-traumatic growth (in reference to start of the study) 
• PDS to assess PTSD symptoms. 
• BDI-II to assess depression symptoms. 
• NEO-PI to assess changes in personality. 
• PSQI to assess changes in sleep quality. 
• DES-II to assess dissociation symptoms. 
d. After completing all assessments and measures, the subject will meet with the 
therapists for approximately 30 minutes. 
e. The therapists or qualified study personnel will assess suicidality with the C-SSRS. 
f. General wellbeing will be assessed. 
g. The visual analog scale will be used to collect changes in pre-existing tinnitus and 
chronic pain symptoms.  
h. The blind will be broken for the subject’s condition assignment. Only the IR will 
remain blind to condition assignment at this time.  
i. If the subject was assigned to receive the comparator dose, the therapists will discuss 
continuation to Stage 2. Comparator dose subjects will not complete the third 
experimental session and associated integrative sessions in Stage 1. 
j. Collect perceptions of experimental sessions from full dose subjects after unblinding. 
k. Collect AEs and medications as described in Section 14.0 of the protocol. 
l. If the subject was assigned to receive full dose MDMA, the subject will complete a 
third open-label experimental session, with associated daily phone calls and 
integrative sessions in Stage 1.  
9.4.8 End of Stage 1 - Visit 17 (Full Dose Group Stage 1) 
 
Full dose subjects will repeat outcome measures and meet with the therapists again two 
months (within a window of plus or minus two weeks) after their final open-label 
experimental session, which will be their final visit in Stage 1. This visit will consist of 
two meetings that may be completed on separate days, one with the IR and the other with 
the therapists. 
 
At the end of Stage 1: 
 
a. The IR will administer the CAPS in person or via telemedicine, the RBANS and 
PASAT will be administered in a face-to-face visit. 
b. Subjects will complete the PDS, BDI-II, DES-II and PSQI, PTGI (in reference to start 
of the study). 
c. Full dose subjects who complete Stage 1 and comparator dose subjects who elect not 
to participate in Stage 2 will complete the RRPQ and continue on to the Long-term 
Follow-up.  
d. The visual analog scale will be used to collect changes in pre-existing tinnitus and 
chronic pain symptoms.  
e. The therapists or qualified study personnel will assess suicidality with the C-SSRS. 
f. Collect perceptions of experimental sessions. 
g. Subjects who will continue on to the Long-term Follow-up may return to taking 
psychiatric medications after the End of Stage 1 if necessary.  


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h. Subjects who will continue on the Long-term Follow-up will receive a memory aid 
card for use between their End of Stage 1 visit and the 12-month follow-up. Subjects 
will use this card to record AEs, medications, and changes in psychiatric status that 
they will be asked about at the termination visit. Memory Aids will not be collected.  
i. Collect AEs and medications as described in Section 14.0 of the protocol. 
 
9.4.9 Open-label Stage 2 (Comparator Dose Subjects from Stage 1) 
 
During Stage 2: 
 
a. Subjects will be reminded that participation in Stage 2 is voluntary and optional. 
b. Subjects who elect to cross over to Stage 2 will undergo the same course of therapy 
and evaluation as in Stage 1, with the exception that the subject will complete a single 
preparatory psychotherapy session instead of three (see Section 9.4.2), and varied 
active doses of MDMA will be administered in an open-label context to explore the 
optimal therapeutic dose (e.g. without unblinding). Visits will be scheduled 
consecutively according to the Time and Events Table. 
c. Assessment of PTSD symptoms at the primary endpoint will serve as baseline 
assessments in Stage 2. If the start of Stage 2 is delayed for more than 8 weeks from 
the primary endpoint (Visit 12) to the first preparatory session in Stage 2 (Visit 18), 
the IR will re-administer the CAPS and GAF. The subjects will complete the PDS, 
BDI-II, PSQI, PTGI (in reference to start of the study), and the DES-II. These scores 
will be used as the baseline for comparison to assessment at the secondary endpoint 
and end of Stage 2.   
d. Experimental sessions will be conducted according to procedures described in Section 
9.4.3.  
1. During the first experimental session, subjects will receive a 100mg initial 
dose of MDMA and may receive a 50mg optional supplemental dose of 
MDMA. 
2. At the beginning of the second and third experimental sessions, the therapists, 
in consultation with the subject, will decide whether to administer an initial 
dose of 100 mg or 125 mg initial dose of MDMA. If a 100mg initial dose of 
MDMA is selected, an optional supplemental dose of 50 mg MDMA may be 
administered. If a 125mg initial dose of MDMA is selected, an optional 
supplemental dose of 62.5mg MDMA may be administered 
3. If the Investigator or Sub-Investigator decides not to administer the optional 
supplemental dose and/or the optional clinical titration dose in a given 
experimental session, the unused capsules will be kept in their respective inner 
envelopes inside of the primary container until the end of the experimental 
session. The Investigator or Sub-Investigator will return the container and any 
remaining unused capsules to the pharmacy for storage in the safe. 
e. Integrative sessions will be conducted according to procedures described in Sections 
9.4.4 and 9.4.6. 
f. Phone calls will be conducted according to procedures described in Section 9.4.5. 
g. At the secondary endpoint based on procedures described in Section 9.4.7, the IR will 
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(in reference to start of the study), and DES-II as described in the Time and Events 
Table.  
h. At the end of Stage 2 based on procedures described in Section 9.4.8, the IR will 
administer the CAPS, GAF, RBANS and PASAT. Subjects will complete the PDS, 
BDI-II, DES-II, PSQI, PTGI (in reference to start of the study), and NEO-PI as 
described in the Time and Events Table. 
i. The End of Stage 2 will be completed in the same manner as the End of Stage 1 as 
described in Section 9.4.8.  
j. Therapists will follow the most recent treatment manual in all matters relating to the 
psychotherapy sessions. 
 
9.4.9 Long-term Follow-up  
 
All subjects will be evaluated for long-term effects 12 months (within a visit window of 
plus or minus one month) after their last MDMA-assisted psychotherapy session.  This 
visit will consist of two meetings, one with the IR and the other with the therapists. 
Subjects who have withdrawn from treatment but have continued for follow-up will also 
complete this time point.  This visit may be audio and video recorded. 
 
At the Long-term Follow-up visit:  
 
a. The IR will administer the CAPS and GAF via telemedicine or in person.  
b. Subjects will complete the PDS, BDI-II, NEO-PI, PSQI, PTGI (in reference to start of 
the study), and DES-II. 
c. Subjects will have a final meeting with at least one of the therapists to review 
specified AEs and medications since the last visit. Subjects should bring the Memory 
Aid Cards to this visit, to be used as aids in recollection. These cards will not be 
collected. AEs and Medications will be collected as described in Section 14.0 of the 
protocol. 
d. The therapists or qualified study personnel will assess suicidality with the C-SSRS.  
e. Subjects will complete a questionnaire assessing positive and negative long-term 
effects of the study.   
f. A researcher who is a part of the study team may ask the subject questions about 
positive or negative effects about the study in person or on the phone. 
g. The visual analog scale will be used to collect changes in pre-existing tinnitus and 
chronic pain symptoms. 
h. Subjects will complete the termination visit at this time. 


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10.0 Removal of Subjects from Therapy or Assessment 
 
Subjects can withdraw consent at any time without prejudice. The Investigator or Sub-
Investigator can withdraw a subject if, in his or her clinical judgment, it is in the best 
interest of the subject or if the subject cannot comply with elements of the protocol that 
are critical for safety and/or for the scientific integrity of the study. If the Investigator or 
Sub-Investigator withdraws a subject from the study, the Investigator or Sub-Investigator 
will explain the reason for withdrawing the subject. The reason for early termination will 
be recorded in the subject’s source records and CRF. 
 
Subjects will be clinically monitored after withdrawal, the cause of which will be re-
corded in the subject’s source records and CRF. Whenever possible, the tests and 
evaluations listed for the termination and outcome visits will be carried out. Efforts will 
be made to obtain information about AE outcomes, if deemed necessary by the 
Investigator or Sub-Investigator and/or sponsor. 
 
If the subject develops any exclusion criteria, which in the opinion of the Medical 
Monitor, affects the safety of the subjects (including psychiatric diagnosis, pregnancy or 
excluded medications), the subject will discontinue treatment but remain in the study for 
follow-up purposes. Whenever possible, the tests and evaluations listed for the primary 
endpoint and 12-month follow-up will be carried out. Efforts will be made to obtain 
information about AE outcomes, if deemed necessary by the Investigator or Sub-
Investigator, Medical Monitor and/or Sponsor. 
 
Subjects who discontinue treatment prior to the primary endpoint will be replaced. 
Individuals who replace these subjects will be assigned the next available subject 
number. Subjects who discontinue treatment after the primary endpoint in Stage 1 or after 
continuation to Stage 2 will not be replaced. If Stage 1 subjects discontinue treatment 
before the primary endpoint, the site should contact the randomization monitor for 
replacement instructions. Detailed instructions will be provided to the site in a separate 
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11.0 Premature Discontinuation of the Study 
 
The sponsor or the Investigator (following consultation with the sponsor) has the right to 
discontinue this study at any time. If the trial is prematurely terminated, the Investigator  
or Sub-Investigator are to promptly inform the study subjects and will assure appropriate 
therapy and follow-up. If the trial or study is prematurely discontinued, all procedures 
and requirements pertaining to the archiving of the documents will be observed. All other 
study materials will be returned to the sponsor and will be treated in accordance with 
national and provincial regulations. 
 
12.0 Data Analysis  
 
The sponsor will judge the clinical and statistical significance of the study based on a 
comparison of observer-blind data collected at baseline and the primary endpoint using 
the primary outcome measure, which is the CAPS. Descriptive statistics will be computed 
overall and within the two dose conditions for all available data from outcome measures, 
including minimum, maximum, average, and standard deviation. Distributional 
characteristics will be examined for outliers and extreme values and, if either is evident, 
nonparametric statistics will be utilized in the analysis. Cohen’s techniques will be used 
to estimate effect sizes between conditions for all outcome measures for Stage 1, Stage 2, 
and 12-month follow-up.  
 
The sponsor will examine full dose and comparator dose groups for homogeneity through 
comparing demographic characteristics. There is no expectation that conditions will 
differ in composition by gender, race or ethnicity, duration of PTSD diagnosis or 
presence versus absence of other permitted psychiatric disorders, as depression. 
However, owing to small sample size, such variations may arise by chance. 
 
The sponsor will examine CAPS scores for the primary outcome analysis at baseline and 
the primary endpoint in full dose and comparator dose conditions using difference scores, 
and independent sample t-tests will be used to test for significance between groups, with 
p value set at 0.05.  
 
For exploratory purposes, the sponsor will examine PDS, BDI-II, GAF, PSQI, PTGI, 
NEO-PI, and DES-II scores at baseline and the primary endpoint in full dose and 
comparator dose conditions using difference scores, and independent sample t-tests will 
be used to test for significance between groups, with p value set at 0.05. Changes in 
outcome measures from the primary/secondary endpoint to the 2-month follow-up in 
Stage 1/Stage 2 will be compared for a within-subject analysis with p value set at 0.05 to 
see whether a third session produces further decline in symptoms.  
 
An exploratory repeated measures analysis of variance (ANOVA) will be performed 
upon PDS scores at baseline, after each experimental session, at the primary endpoint, 
and at the end of Stage 1 with p value set at 0.05. Condition will serve as a between-
subjects factor. Results of ANOVA analysis will be used to examine the effects of each 
experimental session on self-reported PTSD symptom severity. PDS and CAPS scores 


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may be correlated via Pearson’s product moment correlation at baseline and the primary 
endpoint to provide a comparison of a self-report measure with a clinician-administered 
measure of PTSD symptoms.   
 
Formal statistical comparisons between Stage 1 and Stage 2 scores may only occur if, at 
minimum, three subjects complete Stage 2. Data from the open-label third experimental 
session in Stage 1 will be compared statistically to Stage 2 data, and data from this 
session will only be utilized if they are equivalent to Stage 2 data.  
 
The sponsor will compare CAPS, PDS, GAF, BDI-II, PSQI, PTGI, and DES-II, scores at 
the final assessment prior to the 12 month follow-up to the 12-month follow-up using 
difference scores in an independent t-test for a within-subject analysis with p value set at 
0.05. 
 
The sponsor will compare baseline and primary endpoint RBANS and PASAT scores in 
full dose and comparator dose conditions using difference scores in an independent 
sample t-test to test for significance between groups, with p value set at 0.05. The sponsor 
will examine the effects of maximal exposure to MDMA on neurocognitive function 
using the RBANS and PASAT by performing a within-subject repeated measures 
ANOVA with time of administration as a within-subjects factor and with p. set at 0.05.  
 
The sponsor will collect Changes in Tinnitus and/or Pain visual analog scale scores from 
any subject reporting tinnitus or chronic pain during each point of administration, 
including baseline, experimental and integrative sessions, the primary endpoint, and two-
month follow-up. The sponsor will plot out and examine all Changes in Tinnitus and/or 
Pain visual analog scale scores across both groups and in the full dose and comparator 
dose groups for trends. Formal analysis of Changes in Tinnitus and/or Pain visual analog 
scale scores will only occur if three or more subjects complete Changes in Tinnitus 
and/or Pain visual analog scale at baseline and primary endpoint. Likewise, formal 
between-groups analyses will not be performed if all primary endpoint scores are from 
subjects assigned to the same condition. The sponsor will perform an independent t-test 
on the difference between baseline and primary endpoint Changes in Tinnitus and/or Pain 
visual analog scale scores in the full dose and comparator dose conditions, with p. set at 
0.05. If the only scores available are for subjects in a single condition, then a paired t-test 
will be performed comparing baseline and primary endpoint Changes in Tinnitus and/or 
Pain visual analog scale scores, with p. set at 0.05.    
 
Descriptive statistics will be computed for vital signs and subjective distress during each 
experimental or open-label session. The sponsor will compare peak blood pressure, heart 
rate, and body temperature for subjects after sessions with full dose MDMA or 
comparator dose MDMA whenever possible. Frequency tables will be produced on 
prevalence of spontaneously reported reactions and AEs. 
 
The sponsor will collect ratings of adherence to the treatment manual from specifically 
selected types of sessions. Descriptive statistics will be computed for each adherence 
scale within a specific type session. The sponsor will explore the factors and structure of 


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the measures of adherence to assist in further development of adherence and competence 
measures. If sufficient data is available, the sponsor will correlate the mean adherence 
ratings for adherence scale and session type with Global CAPS scores to investigate the 
effects of adherence to the treatment manual on reduction in PTSD symptoms. If it is 
found that there are specific factors within the adherence scales, then the factor will be 
correlated with global CAPS score. 
 
The sponsor will compute descriptive statistics for SOCQ scores from after each MDMA-
assisted psychotherapy session, and average SOCQ scores for blinded experimental 
sessions will be compared between conditions. The data will be explored for effects of 
condition on domain scores in the SOCQ. 
 
Perception of experimental sessions will be examined during Stage 1 and Stage 2, before 
and after subjects have undergone a third experimental session. The results of this 
analysis will inform the sponsor of expectancies and the value of the third session for 
future protocol development. These data may be correlated with difference scores 
calculated from the primary/secondary endpoint CAPS data compared to end of Stage 
1/Stage 2 CAPS data to assess the potential contribution of expectation and self-reported 
response to changes in PTSD symptoms.  
 
Subjects who discontinue treatment prior to the primary endpoint will be asked to 
complete an outcome assessment prior to continuing to the long-term follow-up. The data 
from these subjects will be tested for equivalence to data from subjects completing the 
study per protocol. If found to be equivalent, data from these subjects will be presented as 
an exploratory intent-to-treat analysis to examine results without bias towards subjects 
more likely to complete the study per protocol.  
 
An interim analysis may be completed when all subjects have completed Stage 1 and 
Stage 2, but not all subjects have completed the 12-month follow-up evaluation. 
Additionally, an interim analysis may be performed after all subjects have completed 
Stage 1 but not necessarily before all eligible subjects complete Stage 2. This analysis 
will address safety, efficacy and process measures. Results of the interim analysis will 
have no effect on study conduct. 
 
12.1 Statistical Power 
 
This study is a pilot investigation intended to estimate effect sizes of the safety and 
efficacy of MDMA-assisted psychotherapy in people with PTSD. Because of their 
exploratory nature, pilot studies are often underpowered for detecting the desired effect. 
Because it is a pilot study in a small sample, statistical power is difficult to assess but it is 
likely to be low. Analyses of MAPS’ completed US study of MDMA-assisted 
psychotherapy in 20 people with PTSD found an effect size of 1.24 for treatment 
efficacy, as represented by changes in CAPS score [77]. The estimated effect size for this 
study may be lower as a result of employing a smaller sample size. The sponsor intends 
to combine effect size estimates to develop a dose response curve as a meta-analyses of 
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The sponsor used Java applications created by Lenth and posted on the website listed 
below to calculate estimated statistical power for this study, assuming an effect size of 
1for the impact of two sessions of MDMA-assisted psychotherapy on symptoms [168], 
reducing the effect size to account for the hypothesized effects of using a comparator 
dose. The software calculated an estimated power of 0.34, indicating an underpowered 
study. Had we used the higher effect size of 1.1, power analysis still indicates that this 
study is underpowered, with an estimated effect size of 0.37. Statistical power estimates 
were not available for secondary and exploratory measures, as they were previously not 
used in sponsor-supported studies. 
 
13.0 Risk Mitigation 
 
Careful review of medical screening data will be utilized to exclude potential subjects 
with pre-existing exclusionary medical conditions from the study. Study procedures have 
been developed to mitigate the risks of receiving MDMA described in detail in the IB. 
Ambient temperature will be kept at a comfortable level during experimental sessions. 
Subjects will not be allowed to drink more than 3L of fluids over the course of the 
experimental session, and fluid intake will be spread out appropriately during the session. 
Fluids administered will include electrolytes. If a subject exhibits any signs of toxicity or 
clinically significant dilutional hyponatremia despite these precautions after an 
experimental session, the subject will not receive another experimental session unless it is 
approved by the Investigator and the Medical Monitor.   
 
13.1 Medical Emergencies 
 
Psychotherapy sessions will take place in the offices of the Investigator. Subjects may sit 
or lie on a couch or bed. The offices are furnished with beds that allow for two people to 
remain overnight. They can be heated or cooled with fans. One therapist can reach the 
offices within five to 10 minutes of contact if necessary. The study site will contain 
equipment for assessing blood pressure, pulse, and body temperature and there will be an 
automatic external defibrillator (AED) on site. The therapists will maintain basic life 
support (BLS) certification or its equivalent in Canada in cardiopulmonary resuscitation 
(CPR) including training in using an AED. The site is five minutes from the University of 
British Columbia emergency department and eight to 15 minutes away from St. Paul’s 
Hospital emergency department. In the event of a medical emergency paramedics will be 
summoned and study subjects will be transported to either hospital as appropriate.   This 
is an adequate level of emergency backup based on experience with previous Phase 2 
studies in the U.S. and Switzerland during which there have been no adverse events 
during experimental sessions requiring emergency treatment.   
 
The first U.S. Phase 2 trial with MDMA was conducted in an outpatient setting with a 
“crash cart” of emergency equipment on hand and an emergency physician and nurse in 
the building. The estimated transport time from this site to the nearest hospital emergency 
department was approximately 10 minutes with an estimated response time for an 
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MDMA was administered on 51 different occasions at a dose of either 125 mg by mouth 
or 125 mg followed in 2 to 2.5 hours by an additional 62.5 mg. Blood pressure, pulse, and 
temperature were closely monitored but never reached levels that required intervention 
nor were there any other medical problems requiring treatment during the MDMA-
assisted sessions. Subsequently, a similar study was completed in Switzerland and was 
conducted in an outpatient psychiatry office, approximately five minutes from the nearest 
hospital without a crash cart or emergency personnel on site.  The Swiss therapists have 
administered 125 mg followed by 62.5 mg MDMA on 39 occasions and administered 150 
mg MDMA on four occasions without medical incident. 
 
14.0 Adverse Events 
 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
This definition includes concurrent illnesses or injuries and exacerbation of pre-existing 
conditions. 
 
An unexpected adverse event 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. All AEs will be monitored 
until resolution or, if the AE becomes chronic, a cause identified. If an AE is unresolved 
at the conclusion of the study, a clinical assessment will be made by the Investigator or 
Sub-Investigator and Medical Monitor as to whether continued follow-up of the AE is 
warranted. 
 
The severity of events reported on the “Adverse Events” CRF will be determined by the 
Investigator or Sub-Investigator as: 
 
• Mild: No limitation in normal daily activity. 
• Moderate: Some limitation in normal daily activity. 
• Severe: Unable to perform normal daily activity. 
 
The relationship of the study treatment to an AE will be determined by the Investigator or 
Sub-Investigator based on the following definitions: 
 
• “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. 
 


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• “Possibly Related”: The administration of the investigational product and AE are 
considered reasonably related in time and the AE could be explained by causes 
other than exposure to the investigational product. 
 
• “Probably Related”: Exposure to the investigational product and AE are 
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. 
 
14.1 Serious Adverse Events 
 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose: 
 
• Results in death. 
• Is life threatening (i.e., the subject was, in the opinion of the Investigator or Sub-
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 a 
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 patient/subject or may require intervention 
to prevent one of the other outcomes listed above. 
 
Adverse events 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 
serious adverse event need not, by definition, be severe. 
 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the medical history. The hospitalization would not result in the event or 
condition being reported as an on study SAE unless, in the view of the Investigator or 
Sub-Investigator, 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 subject was 
entered in the trial. Hospitalization for cosmetics, non-emergency prophylaxis, or 
abortion does not result in an SAE report unless, in the view of the Investigator or Sub-
Investigator, hospitalization for these procedures was prolonged as a result of 
participation in the clinical trial. 
 


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14.2 Adverse Event Collection 
 
The Investigator or Sub-Investigator will be responsible for reviewing and confirming all 
AEs and SAEs collected during the study. The Investigator or Sub-Investigator and/or 
qualified study personnel will collect AEs during study visits after enrollment.  
 
All SAEs will be collected for the duration of the protocol. All SAEs which occur during 
the course of the trial, whether considered to be associated with the study drug or not, 
have to be reported within 24 hours of the Investigator’s awareness of their occurrence.  
All SAE reports should be faxed to the Sponsor. A fax number will be provided to the 
site in separate site-specific instruction for SAE reporting. In addition to the fax, the 
Investigator, or designee should call the CRA during normal working hours and verbally 
inform the CRA of the SAE. During off business hours or if medical advice is needed 
immediately please call the Sponsor Medical Monitor. An SAE reporting instruction with 
all contact numbers will be provided to the site prior to study start.   
 
SAE Reporting: 
MAPS Office 
 
Telephone: 831-429-6362, ext. 104 
Fax: 831-429-6370     
 
Medical Monitor: 
Michael C. Mithoefer, M.D. 
Email: mmithoefer@mac.com  
Telephone: 843-849-6899 (office) 843-566-4252 (cell) 
Fax number: 843-278-9188 
 
Study Monitor contact information will be provided in a separate contact list. 
 
Adverse events that will be collected for the duration of the protocol are: 
 
• All SAEs will be collected through subject termination. 
• All AEs and spontaneously reported reactions will be collected on the day of drug 
administration and for seven days after each experimental session. 
• Events requiring medical attention will be collected from enrollment through the 
subject’s last two-month follow-up. 
• 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. 
• Any Adverse Event leading to withdrawal from the protocol will be collected 
throughout the study. 
• All AEs related to changes in psychiatric status will be collected throughout the 
study. 
 
A Memory aid card will be provided to the subject on the last visit prior to the 12-month 
follow-up to record information on medications taken to treat SAEs, AEs leading to 


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withdrawal and psychiatric AEs during the follow-up period between the end of Stage 
1/Stage 2 and the 12-month follow-up evaluation. The memory aid card will not be 
collected, but information from the card will be used to aid the subjects in providing 
information to the Investigator or Sub-Investigator. This information may be collected by 
phone. 
 
14.3 Spontaneously Reported Reactions 
 
Commonly expected spontaneously reported reactions are collected on a separate CRF 
page and will be categorized as mild, moderate, or severe. Common, expected reactions 
are defined as those most frequently reported in the literature and include:  Anxiety, 
Diarrhea, Difficulty Concentrating, Dizziness, Drowsiness, Dry Mouth, Fatigue, 
Headache, Heavy Legs, Impaired Gait/Balance, Impaired Judgment, Increased 
Irritability, Insomnia, Jaw Clenching or Tight Jaw, Lack of Appetite, Low Mood, Muscle 
Tension, Nausea, Need More Sleep, Nystagmus, Parasthesias, Perspiration, Restlessness, 
Rumination (increased private worries), Sensitivity to Cold, Thirst, and Weakness. 
Spontaneously reported reactions will be collected during the experimental session and 
the seven days of telephone contact following the integrative session that occurs on the 
day after each experimental session. Each reported reaction will be followed during 
follow-up phone calls or visits until resolution. 
 
14.4 Collection of Concomitant Medications and Tapering Instructions 
 
The Investigator, Sub-Investigator, or designated study personnel will record concomitant 
medications during screening. If the subject is being treated with psychiatric drugs at the 
time he or she is recruited into the study, the prospective subject will be encouraged to 
discuss medication tapering with his or her outside treating physician, if any, and will be 
required to give the Investigator, Sub-Investigator or qualified study personnel 
permission to do so as well. The drugs will then be tapered in an appropriate fashion to 
avoid withdrawal effects. They will be discontinued long enough before the first MDMA 
session to avoid the possibility of any drug-drug interaction (the interval will be at least 
five times the particular drug’s and active metabolites half-life).  
 
If a subject is taking opiates for pain control they may continue them if necessary in the 
opinion of the Investigator or Sub-Investigator and Medical Monitor, but will be asked to 
taper to the lowest dose possible by the day of the experimental sessions. The dose and 
method of tapering should be agreed upon by the subject, the investigator or Sub-
Investigator and the prescribing physician.  If the subject is using opiates as needed 
(PRN) but not every day they should be asked to refrain from taking them the morning of 
the experimental session.   
 
The therapists or designated study personnel will request information about any changes 
in medication just prior to each experimental session. The Investigator or Sub-
Investigator will be responsible for reviewing and confirming all medications collected 
during the study.  
 


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All medications, over the counter (OTC) and prescription will be collected from 
screening through seven days after the last MDMA session. From seven days after the 
last MDMA session through study termination only prescription or OTC medications 
taken to treat AEs will be collected. Throughout the protocol all medications used to treat 
AEs will be collected, as described in Section 14.0, and all changes including 
discontinuations or additions to psychiatric medications will be collected. Medications 
will be recorded on the concomitant medications CRF.   
 
Subjects must be willing to refrain from taking any psychiatric medications during Stage 
1 and Stage 2, with the exception of gabapentin when prescribed for pain control. If the 
subject is on stimulants for ADHD at baseline, they can continue to use them at the same 
dose and frequency as long as they discontinue five half-lives before each experimental 
session and do not restart for 10 days after each experimental session. 


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Table 6. Medication Tapering Table 
Generic Name Brand Name 
Half-life (hours) 
including active metabolites 
Days for Washout 
alprazolam 
Xanax 
11 
3 
aripiprazole 
Abilify 
75 
16 
atomoxetine 
Strattera 
5-24 
5 
bupropion 
Wellbutrin 
21 
5 
citalopram 
Celexa 
35 
8 
clonazepam 
Klonopin 
30-40 
8 
diazepam 
Valium 
20-70 
15 
duloxetine 
Cymbalta 
12 
3 
escitalopram 
Lexapro 
32 
7 
fluoxetine 
Prozac 
7-9 (days) 
45 
imiprimine 
Tofranil 
6-18 
4 
lamotrigine 
Lamictal 
25 
6 
lorazepam 
Ativan 
12 
3 
mirtazapine 
Remeron 
20-40 
8 
olanzapine 
Zyprexa 
21-54 
11 
paroxetine 
Paxil 
21 
5 
prazosin 
Minipress 
2-3 
1 
quetiapine 
Seroquel 
6 
2 
risperidone 
Risperdal 
3-20 
4 
sertraline 
Zoloft 
26 
6 
temazepam 
Restoril 
8-12 
3 
trazodone 
Desyrel 
9 
2 
venlafaxine 
Effexor 
12 
3 
ziprazidone 
Geodon 
7 
2 
zolpidem 
Ambien 
2.5 
<1 
 
The Investigator or Sub-Investigator may prescribe a designated rescue medication in the 
event of symptoms that require it during or after the experimental session (e.g. insomnia 
or severe anxiety that does not respond to other management outlined in the treatment 
manual). Rescue medications may be a benzodiazepine, zolpidem or other anxiolytic or 
sedative according to the physician's clinical judgment. SSRIs, SNRIs, and MAOIs 
should not be used as rescue medications.  
 
Subjects must agree that, for one week preceding the MDMA session: 
 
a. They will refrain from taking any herbal supplement (except with prior approval 
of the research team).  
b. They will refrain from taking any prescription or nonprescription medications 
(with the exception of non-steroidal anti-inflammatory drugs, acetaminophen, 
birth control pills, thyroid hormones, or other medications approved by the 
research team).  
 


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Subjects will receive a memory aid card for use between the end of Stage1/Stage 2 visit 
and the 12-month follow-up. Subjects will use this card to record changes in psychiatric 
medications that they will be asked about at the termination visit. Memory aids will not 
be collected. Subjects may return to taking psychiatric medications and discontinue birth 
control after the final two-month assessment if necessary. 
 
14.5 Clinical Laboratory Assessments 
 
The Investigator or Sub-Investigator will examine laboratory assessments gathered in 
screening for assessing subject eligibility. The Investigator or Sub-Investigator will use a 
list of normal ranges to conclude whether subjects are eligible for the protocol, and will 
indicate justification for admitting subjects 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 ALT/SGPT 
o Albumin:globulin (A:G) ratio 
o Albumin, serum 
o Alkaline phosphatase, serum 
o AST/SGOT 
o Bilirubin, total 
o BUN:creatinine ratio 
o Calcium, serum 
o Carbon dioxide 
o Chloride, serum 
o Creatinine, serum 
o Glucose, serum 
o Potassium, serum 
o Protein, total, serum 
o Sodium, serum 
• CBC 
o Hematocrit 
o Hemoglobin 
o MCV 
o MCH 
o MCHC 
o RDW 
o Percentage and absolute differential counts 
o RBC 
o Red blood cell count 
o White blood cell count 
• Urinalysis 
o Color 
o Appearance 


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o Specific gravity 
o pH 
o Protein 
o Glucose 
o Ketones 
o Blood in urine 
o Leukocyte esterase 
o Nitrite 
• Thyroid function. 
o TSH high sensitivity 
o Free T4 
o Free T3 
• HIV serology. 
• Urine-dip pregnancy test for females of childbearing potential. 
• Urinary drug test will be performed.  
 
The clinical lab assessments and ECG will be performed by: 
  
LifeLabs Medical Laboratory Services 
 
 
 
15.0 Study Monitoring, Auditing, and Documentation 
 
The Investigator, Sub-Investigator, therapists, and their study staff will be trained prior to 
the start of the study.  The clinical study site will be monitored by site visits and regular 
contact with the Investigator and qualified study personnel by representatives of the 
sponsor. The site will be monitored as appropriate for the rate of enrollment. During each 
monitoring visit, source data verification will be performed by a Clinical Research 
Associate to ensure compliance, including accurate and complete recording of data in 
CRFs, source documents, and drug accountability records, while maintaining the blind 
during Stage 1. CRFs will be supplied by the sponsor will be completed for each subject 
enrolled. Monitoring and auditing procedures of the sponsor will be followed in order to 
comply with GCP guidelines and to ensure validity of the study data. Monitoring and 
auditing procedures will be supplied in a separate document. 
 
The sponsor will review the study documentation used for planning, conduct, and 
monitoring of the study in order to ensure compliance with GCP and local regulations. 
This documentation includes as a minimum: the IB, the Protocol, the CRFs, and the 
Subject Information and Consent Form. 
 
During or after the clinical study, the regulatory authorities, the IRB, and/or 
representatives of the sponsor may request access to all source documents, CRFs, and 
other protocol documentation for on-site audit or inspection. 
 


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16.0 Risks of Participation 
 
16.1 Risks and Discomforts Associated with Psychotherapy Sessions and Assessment 
of Measures 
 
In preparation for drug-assisted psychotherapy sessions, blood draws and a full medical 
examination are required to establish eligibility for the study. Temporary discomfort, 
inflammation, or infection could arise as a result of sampling blood at the punctured vein. 
Submitting to a full medical examination may also cause discomfort or psychological 
distress. Since medical examinations and blood draws are required to establish eligibility 
for the study, they cannot be omitted from the protocol. 
 
During screening, non-drug and drug-assisted psychotherapy sessions and assessment of 
study measures, subjects 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 to 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 during and immediately after non-
drug psychotherapy, experimental, and open-label sessions. Psychotherapy is conducted 
as part of the research study, including the experimental intervention, and people 
undergoing psychotherapy are expected to confront unpleasant thoughts, feelings, and 
memories in the process of therapy. Because psychotherapy is an integral part of the 
research study design, the potential distress arising from psychotherapy is unavoidable.   
 
All psychotherapy sessions may be recorded to audio and video for research and training 
purposes. Subjects may feel uncomfortable with having their sessions recorded. Subjects 
may have access to recordings if they request them. The recordings are necessary for 
developing the experimental treatment and assessing adherence to the treatment manual. 
Subjects will receive information on who will have access to any of their recordings and 
will have control over any presentation of this material beyond viewing by researchers or 
regulatory agencies.  
 
As with any medical procedure, there are potential risks associated with the use of 
telemedicine. In rare cases, information transmitted may not be sufficient (e.g. poor 
resolution or choppy video connection) to allow for appropriate medical decision making 
by your therapy team or the researchers. Delays in medical evaluation and treatment 
could occur due to deficiencies or failures of the equipment or internet service. In very 
rare instances, security protocols could fail, causing a breach of privacy of personal 
medical information. 
 
16.2 Risks of Receiving MDMA 
 
Spontaneously reported reactions and common adverse effects of MDMA are modest and 
have generally not been associated with serious discomfort by healthy volunteers in 
previous studies. Common reactions include lack of appetite, insomnia, dizziness, tight 
jaw or bruxism (tooth-grinding), difficulty concentrating, impaired gait or balance, dry 


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mouth, ruminations, and thirst. Other slightly less common reactions include restlessness, 
parasthesias (odd somatic feelings, such as tingling, feeling hot or cold), impaired 
judgment, perspiration, drowsiness, and nystagmus (eye-wiggling). While anxiety, 
headache, fatigue, insomnia and lack of appetite were spontaneously reported by 40% to 
80% of subjects in both conditions in MAPS study MP-1 (N=23), tight jaw, nausea, 
impaired gait/balance, and sensitivity to cold were more often reported by subjects in the 
MDMA than the placebo condition, and irritability was slightly more likely to be reported 
in the placebo condition. Additionally, subjects in the MDMA condition were more likely 
to report muscle tension in various body parts and diarrhea.  
 
These effects are transient and diminish as drug effects wane. Sub-acute effects that may 
either continue for the next 24 hours or appear later include insomnia, fatigue, needing 
more sleep, weakness, heavy legs, dry mouth, low mood or irritability. Sub-acute effects 
are reported less often than acute effects. More information on spontaneously reported 
reactions is described in the IB.  
 
MDMA may produce mild alterations in sensory perception and altered perception of 
time [74, 169, 170]. Women may be more sensitive to these effects [124].  MDMA 
acutely affects attention, information processing, and memory. MDMA acutely impairs 
verbal memory and recall for object location without affecting recall of complex scene 
changes [171]. For this reason, subjects will stay at the site overnight and will not be 
permitted to drive after experimental sessions.  
 
MDMA may produce modest changes in immune functioning, lasting up to 48 hours. 
Because of their limited duration, these changes are not likely to have clinical 
significance beyond several days of possible increased risk of viral upper respiratory 
infection or similar illness.  
 
Further information on the risks associated with MDMA, including information drawn 
from case reports and studies of ecstasy users, can be found in the sponsor’s IB.  
 
16.2.1 Cardiovascular and Sympathomimetic Effects 
 
The full dose of 125 mg, followed by a supplemental dose of 62.5 mg after 1.5 to 2.5 
hours, is expected to produce significant but transient, self-limited increases in blood 
pressure and heart rate. These changes should last no more than six hours. In less than 5% 
of volunteers in Phase 1 studies, peak blood pressure values were higher than 140/90 
mmHg. Clinical intervention was not required in any of these cases. Nonetheless, careful 
monitoring of subjects and predefined contingency plans will allow the researchers to 
rapidly identify and manage any related toxicity. For more information, see the sponsor’s 
IB. 
 
Risks posed by elevated blood pressure will be addressed by excluding people with pre-
existing hypertension and monitoring blood pressure and pulse, as described in Section 
5.1.2. During experimental sessions the co-therapists will continually evaluate the patient 
for increasing blood pressure and signs or symptoms of a developing hypertensive or 


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other cardiovascular emergency. Subjects reporting chest pain, shortness of breath or 
neurological symptoms or other potential indicators of hypertension will have more 
frequent measurements and assessment by the Investigator or Sub-Investigator. Any 
subject who experiences medical complications during an experimental session will not 
be given another experimental session unless it is approved by the Investigator or Sub-
Investigator and the Medical Monitor.   
In case of need, subjects will be transferred to the emergency room at the closest hospital, 
as described in Section 13.1. Reasons for moving a patient to an Emergency Department 
(ED) would include, but not be limited to, severe headache in the setting of hypertension, 
angina, or neurological deficits regardless of blood pressure. The Investigator or Sub-
Investigator may, at any time, make a clinical judgment to transfer the patient to the ED 
for closer monitoring and additional treatment.  
 
The Investigator or Sub-Investigator will be prepared to respond to rare complications of 
cardiovascular effects, such as stroke or acute myocardial infarction (AMI). The 
therapists will attend to any signs or symptoms of neurological deficit or confusion that is 
more extensive than might be expected from MDMA or from psychological distress, and 
will notify the Investigator or Sub-Investigator if this occurs for on-site evaluation or a 
decision to initiate transfer to the ED. If any subject has neurological deficits, as assessed 
by the Investigator or Sub-Investigator, whether or not they are associated with 
hypertensive crisis, paramedics will be summoned to initiate the applicable protocols for 
further evaluation and stabilization and if necessary, they will be transported to the 
emergency department at the closest hospital for further management. If evaluation at the 
hospital reveals a nonhemorrhagic stroke, there will be time to administer recombinant 
tissue plasminogen within the three-hour time frame recommended in the American 
Academy of Neurology/American Heart Association guidelines [172, 173]. 
 
The Investigator or Sub-Investigator will observe the subject and note any complaints of 
chest pain. If a subject experiences ischemic type chest pain, whether or not it is 
associated with hypertensive crisis, paramedics will be summoned to initiate the 
applicable protocols for further evaluation and stabilization and, if necessary, he or she 
will be transported to the ED or a location in the hospital where appropriate care can be 
given. He or she will be given nitroglycerin 0.4 mg SL q 5 minutes PRN chest pain 
pending transport to the hospital. If further evaluation at the hospital reveals that the 
subject has had an AMI, they will be well within the time frame required for definitive 
therapy. The American College of Cardiology/ American Heart Association guidelines 
for the treatment of AMI recommend percutaneous transluminal coronary angioplasty 
(PTCA) as the treatment of choice when it can be performed within 90 minutes of arrival 
at the hospital in patients who present within 12 hours of an episode of chest pain lasting 
more than 30 minutes and who have ECG evidence of AMI [174]. 
 
16.2.2 Psychological Distress 
 
Mild anxiety and depressed mood are occasionally reported one to three days after 
MDMA administration [72, 124, and see the IB]. Psychological distress from MDMA 
could arise from the first indications of drug effects until the last effects have dissipated 


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(approximately three to five hours after drug administration), or even later. Anxiety or 
distress during the session may last for as little as five minutes or for as long as five hours 
or more. In addition, psychological distress could arise following an MDMA session as a 
result of subjects having difficulty integrating their experience after the MDMA effect 
has subsided. In previous Phase 1 and Phase 2 studies, these symptoms have been self-
limiting, and have responded well to reassurance from the therapists, with occasional use 
of benzodiazepines for anxiety. In this study, subjects will have the intention of 
confronting and working through traumatic experiences. Hence 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 subjects 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-1 or with psychotic disorders). 
• Preparatory non-drug psychotherapy sessions before the experimental session. 
• Creating an atmosphere of trust during the experimental session. 
• Close monitoring. 
• Daily contact with subjects for the period of a week after the experimental session 
• Providing non-drug integrative psychotherapy sessions. 
• Subjects will remain at the study site for the night of each experimental session to 
further reduce psychological distress. Qualified personnel will be available during 
the overnight stay to respond to the needs of the subject. Attendants will be 
instructed to contact the therapists upon request or at the appearance of signs of a 
potential serious adverse event.  
 
During the preparatory sessions, subjects will be made aware of the fact that difficult 
emotions, including grief, rage and fear or panic, may arise during experimental sessions. 
Every effort will be made to help subjects 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 therapists and performance of 
diaphragmatic breathing by subjects.  
 
At the end of the six to eight hour experimental session, if the subject is still severely 
agitated or experiencing any other severe psychological distress, the following measures 
will be taken:  
 


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• If the subject is anxious, agitated, in danger of any self-harm or is suicidal at the 
end of the experimental session, one or both of the therapists will remain with the 
subject for at least two more hours. During this time, the therapists will employ 
affect management techniques, will talk with the subject to help him or her gain 
cognitive perspective of their experiences, and will help them implement the self- 
soothing and stress inoculation techniques presented during the preparatory 
session. If this situation should occur during an integrative therapy session, at 
least one of the therapists will be available to stay (in person or on the phone if 
the visit is a phone visit) with the subject for at least two additional hours. 
• If a subject remains severely anxious, agitated or in danger of self-harm or 
suicide, or is otherwise psychologically unstable at the end of this two-hour 
stabilization period, the Investigator or Sub-Investigator will decide between the 
following options: 
1. A psychiatric nurse, therapeutic assistant, physician, or therapist will stay with 
the subject until the time of his or her appointment with the therapists the next 
day. The therapists will then meet with the subject daily until the period of 
destabilization has passed.  
2. If a subject experiences severe, persisting emotional distress, such as panic 
attacks, severe generalized anxiety, or insomnia following an MDMA session, 
the Investigator or Sub-Investigator may prescribe a rescue medication such as 
a benzodiazepine, zolpidem or other anxiolytic or sedative according to the 
physician's clinical judgment. This medication will be captured on the 
concomitant medications CRF page. The physician should not prescribe an 
SSRI, SNRI or MAOI in this context unless it has been determined that the 
subject will be withdrawn from the study. Residual symptoms will be 
addressed during the frequent follow-up psychotherapy visits with the 
therapists. 
3. Hospitalization for stabilization. If a subject should become psychotic 
arrangements will be made to stabilize them and transfer them to the ED if 
necessary. 
 
Subjects hospitalized after a severe panic reaction will be suspended from the protocol 
until after recovery or stabilization, at which time the Investigator or Sub-Investigator 
will carefully evaluate the subject’s emotional status.   
 
For those subjects engaged in an ongoing therapeutic relationship with a psychotherapist 
or psychiatrist, the subject’s outside therapists will be involved in the management of any 
psychiatric complications. For those subjects engaged in an ongoing psychotherapeutic 
relationship with the Investigator or Sub-Investigator, the management of any psychiatric 
complications will be undertaken by them in their capacity as therapists.   
 


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16.2.3 Body Temperature 
 
MDMA administered in a controlled setting produces only a slight increase in body 
temperature [124] and ambient temperature does not enhance or attenuate this slight 
elevation in humans [75].   
 
If temperature rises more than 1°C, attempts will be made to lower it by removing 
blankets and layers of clothing, decreasing the ambient temperature and, if necessary, 
directing a fan toward the subject. If at any time the temperature rises more than 1.5°C 
above baseline despite these efforts, the Investigator or Sub-Investigator will be consulted 
for further evaluation and treatment.   
 
16.2.4 Reproductive and Developmental Risks 
 
Risks posed by MDMA to pregnant women are not known. One of two studies of Ecstasy 
users suggests that use of Ecstasy and other drugs during pregnancy may be associated 
with some abnormalities at birth while the other failed to find this association [175, 176],  
and a third reported some developmental delays in mothers reporting use of ecstasy and 
other drugs during pregnancy [177].   
 
Pregnant and lactating women will be excluded from participation in the study, and 
women who are able to become pregnant must have a negative pregnancy screen before 
undergoing each experimental session and must agree to use birth control for the 
treatment portion of the study. 
 
16.2.5 Potential Neurotoxicity Associated with Ecstasy Use 
 
Some researchers believe that MDMA is neurotoxic in humans even at doses used in 
clinical trials [178].  However, they are basing their case on studies that employed 
inappropriately high doses of MDMA utilized in animal studies, and on human studies 
comparing the effects of repeated use of ecstasy, often along with other drugs. 
Meanwhile, another recently published meta-analysis has taken careful steps to overcome 
methodological limitations in previous work, and found only modest evidence of 
neurotoxicity [179]. We have carefully considered the risks of such neurotoxicity and 
conclude that they are minimal in the proposed study. This conclusion is supported by 
empirical and toxicokinetic evidence and is consistent with the lack of toxicity reported 
in previous clinical MDMA studies. More information on the potential neurotoxicity of 
MDMA can be found in the IB.  
 
16.3 Abuse Liability 


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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. 
More information on abuse liability is provided in the IB. 
 
Whether MDMA-assisted psychotherapy will cause PTSD patients to develop symptoms 
of abuse is an open question that the sponsor is addressing on an ongoing basis. Based on 
long-term follow-up data from two sponsor-supported studies (N=32), only one subject 
took Ecstasy after completing the study and failed to reproduce the experience from the 
study, and a number of subjects volunteered that they would never seek out Ecstasy 
outside a legal, controlled, therapeutic setting. In addition, negative results from MDMA-
specific drug testing data obtained from the Swiss study MP-2 (N=12) supports that none 
of these subjects took Ecstasy outside of the study during the long-term follow-up period.   
 
Diversion is not an issue in this protocol because MDMA will only be administered a few 
times under the supervision of the Investigator or Sub-Investigator and no take-home 
doses will be permitted. MDMA will be handled following all regulations pertaining to 
the handling and dispensing of controlled substances within research studies. 
 
16.4 Risks and Discomforts of Receiving the Comparator Dose of Study Drug 
 
Receiving the comparator dose of 0mg MDMA may be associated with less reduction in 
anxiety and a smaller drop in PTSD symptoms than after full dose MDMA. The 
comparator is not expected to produce the therapeutic effects of MDMA. However, it is 
notable participants receiving placebo in the first sponsor-supported study exhibited some 
reduction in PTSD symptoms after undergoing two experimental sessions [77, 180].  The 
comparator dose of MDMA is not expected to produce most or all of the potentially 
therapeutic effects of the drug, such as increased positive mood, facilitated recall, 
changed perception of meaning, and increased feelings of closeness to others. All 
participants receiving the comparator may enroll in Stage 2 and receive active doses of 
MDMA. 
 
17.0 Alternative Treatments and Procedures 
 
The alternative to participating in the research study is to decide not to take part in the 
study. The decision not to participate in this research study will not in any way alter or 
compromise the care offered to individuals receiving therapy from the Investigator or 
Sub-Investigator or any physician involved in this research study.   
  
The Investigator or Sub-Investigator will discuss alternatives to study participation, 
including other available treatments, with all potential subjects. There are a number of 
recognized treatments for PTSD. Treatment often includes both psychotherapy and 
medication. Most commonly recommended psychotherapeutic treatments for PTSD 
include anxiety management (stress inoculation training), cognitive therapy, exposure 


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therapy, and psychoeducation. Psychodynamic psychotherapy and Eye Movement 
Desensitization and Reprocessing are also used to treat PTSD. 
 
Drugs available in Canada for treating PTSD include paroxetine, and in the US, sertraline 
and paroxetine are approved for use in treatment of PTSD. Sertraline has been shown to 
decrease the hyperarousal and avoidance symptoms, but not the re-experiencing 
symptoms, of PTSD. Paroxetine has been shown to have an effect on all three categories 
of symptoms in approximately 62% of patients. Other medications commonly used are 
other SSRIs, nefazedone, venlafaxine, tricyclic antidepressants, benzodiazepines, 
buspirone, zolpidem, and mood stabilizers. 
 
18.0 Confidentiality 
 
Every effort will be made to strictly safeguard the confidentiality of subjects in their role 
as research subjects. Removing identifying information from data and restricting access 
to researchers directly involved in assessing the subjects should prevent the dissemination 
of confidential data, with or without identifying information. Except for the screening 
log, the ICF, and a subject contact information sheet that will be stored separately from 
other documents, all data will be identified only by the subject’s secondary identifier 
number on the source document and five-digit subject number.  If past medical records 
are needed, subjects will sign forms for the release of information upon consent to permit 
screening for protocol enrollment.  
 
All psychotherapy sessions and the 12-month follow-up may be recorded to video and 
audio. In addition the CAPS assessment may also be recorded to audio and video to 
establish inter-rater reliability. These recordings will be used for manual development 
and potentially for training therapists to perform MDMA-assisted psychotherapy. They 
are intended to record the events occurring during therapy, and will not serve as outcome 
measures. Full names and addresses will not appear in these recordings. Audio and video 
recordings will only be marked with the subject’s subject number. Video data will be 
stored on a HIPA-compliant remote server with encryption and authentication in place to 
ensure confidentiality. Study subjects will only be able to view their own video data by 
logging in to a secure HIPA-compliant server. Only HIPA-certified researchers who have 
signed a Data Confidentiality Agreement, completed Good Clinical Practice training, and 
received approval from the Investigator  will be permitted to access video data for 
research and training purposes.  
 
Any materials mailed to subjects will be sent along with stamped return envelopes using 
the office address of the Investigator  both as main and return address. All assessment 
records will be kept in a locked file drawer or cabinet in a locked office, and access to 
measures will be limited to regulatory agencies, researchers, and individuals analyzing 
data. Researchers, other than the Investigator or Sub-Investigator directly involved in the 
protocol, with access to data will not be provided with any information that would 
identify subjects by name or by other means, such as social security number.  
 
 


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19.0 Costs to Subjects 
 
There will be no costs to subjects for any study-related procedures. Only Canadian 
residents with Canadian health insurance will be enrolled in the study. The sponsor 
(MAPS) will pay for all assessments, laboratory work, or physical examinations needed 
to determine study eligibility. The sponsor will also cover costs of the study drug and 
remaining at the study site on the night after each experimental session. The sponsor will 
pay for all study drugs and study procedures. The sponsor will not reimburse subjects for 
travel, food, and lodging.  Subjects will not be paid for their participation in this study. 
 
Charges for treatment of the subject’s condition that are unrelated to the research study or 
any of its procedures will continue to be billed to the health insurance provider of the 
subject or to the subject him or herself. It is anticipated that there will not be any charges 
for treatment that is unrelated to the study except in the case of subjects who previously 
received therapy from the Investigator or Sub-Investigator and who will continue to 
receive ongoing treatment that is not related to participating in the study.   
 
20.0 Record Retention 
 
The Investigator must retain all study records required by MAPS and by the applicable 
regulations in a secure and safe facility for 25 years in accordance with Health Canada 
regulations. The Investigator must consult a MAPS representative before disposal of any 
study records. “Essential documents” are defined as documents that individually and 
collectively permit evaluation of the conduct of a trial and the quality of the data 
produced. It is the responsibility of the sponsor to inform the Investigator as to when 
these documents no longer need to be retained. 
 
21.0 Publication Policy 
 
The sponsor recognizes the importance of communicating medical study data and 
therefore encourages publications in reputable scientific journals and presentations at 
seminars or conferences. It is understood by the Investigator that the information 
generated in this study will be used by the sponsor in connection with the development of 
the investigational product and therefore may be disclosed to government agencies in 
various countries. To allow for the use of information derived from the study, it is 
understood that the Investigator and Sub-Investigator 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 products and/or publications/ 
lectures/manuscripts based thereon, shall be exchanged and discussed by the Investigator 
or Sub-Investigator and the sponsor clinical research representative(s) 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 studies in 


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the same field. 
The full details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this trial will be described in the Clinical Trial 
Agreement. 


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22.0 References 
 
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2. 
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Mithoefer, M.C., et al., Durability of improvement in post-traumatic stress 
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16. 
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32. 
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33. 
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victims. J Consult Clin Psychol, 1992. 60(5): p. 748-56. 


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34. 
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Survey. Arch Gen Psychiatry, 1995. 52(12): p. 1048-60. 
35. 
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36. 
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37. 
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38. 
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disorder in women: a randomized controlled trial. Jama, 2007. 297(8): p. 820-30. 
39. 
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40. 
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41. 
Ursano, R.J., et al., Practice guideline for the treatment of patients with acute 
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42. 
Benish, S.G., Z.E. Imel, and B.E. Wampold, The relative efficacy of bona fide 
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43. 
Cukor, J., et al., Emerging treatments for PTSD. Clin Psychol Rev, 2009. 29(8): p. 
715-26. 
44. 
Basoglu, M., E. Salcioglu, and M. Livanou, A randomized controlled study of 
single-session behavioural treatment of earthquake-related post-traumatic stress 
disorder using an earthquake simulator. Psychol Med, 2007. 37(2): p. 203-13. 
45. 
Gerardi, M., et al., Virtual reality exposure therapy using a virtual Iraq: case 
report. J Trauma Stress, 2008. 21(2): p. 209-13. 
46. 
McLay, R.N., et al., A randomized, controlled trial of virtual reality-graded 
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47. 
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48. 
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49. 
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(ecstasy) revisited: the true story reconstructed from the original documents. 
Addiction, 2006. 101(9): p. 1241-5. 


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50. 
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1986. 18(4): p. 291-304. 
51. 
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52. 
Liechti, M.E. and F.X. Vollenweider, The serotonin uptake inhibitor citalopram 
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53. 
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54. 
Tancer, M. and C.E. Johanson, The effects of fluoxetine on the subjective and 
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humans. Psychopharmacology (Berl), 2007. 189(4): p. 565-73. 
55. 
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57. 
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58. 
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66. 
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67. 
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98. 
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101. 
Kuypers, K.P., et al., Inhibition of MDMA-induced increase in cortisol does not 
prevent acute impairment of verbal memory. Br J Pharmacol, 2013. 168(3): p. 
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102. 
Hernandez-Lopez, C., et al., 3,4-Methylenedioxymethamphetamine (ecstasy) and 
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103. 
Bedi, G., D. Hyman, and H. de Wit, Is ecstasy an "empathogen"? Effects of +/-
3,4-methylenedioxymethamphetamine on prosocial feelings and identification of 
emotional states in others. Biol Psychiatry, 2010. 68(12): p. 1134-40. 
104. 
Lawton, G., A real fMRI high: My ecstasy brain scan, in New Scientist. 2012. p. 
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105. 
Peiro, A.M., et al., Human pharmacology of 3,4-
methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 2 
h apart. Psychopharmacology (Berl), 2013. 225(4): p. 883-93. 
106. 
Hysek, C., et al., Carvedilol inhibits the cardiostimulant and thermogenic effects 
of MDMA in humans. Br J Pharmacol, 2012. 166(8): p. 2277-88. 
107. 
Wardle, M.C., C.G. Frye, and H. De Wit, MDMA buffers against cues of social 
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Stolaroff, M., The Secret Chief Revealed: Conversations with a pioneer of the 
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Tedeschi, R.G. and L.G. Calhoun, The Posttraumatic Growth Inventory: 
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Randolph, C., Repeatable Battery for the Assessment of Neuropsychological 
Status manual. 1998, San Antonio, TX: The Psychological Corporation. 
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Carlozzi, N.E., et al., Factor analysis of the Repeatable Battery for the 
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King, L.C., et al., Is the repeatable battery for the assessment of 
neuropsychological status factor structure appropriate for inpatient psychiatry? 
An exploratory and higher-order analysis. Arch Clin Neuropsychol, 2012. 27(7): 
p. 756-65. 


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Randolph, C., et al., The Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp 
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Wilk, C.M., et al., Test-retest stability of the Repeatable Battery for the 
Assessment of Neuropsychological Status in schizophrenia. Am J Psychiatry, 
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Duff, K., et al., Test-retest stability and practice effects of the RBANS in a 
community dwelling elderly sample. J Clin Exp Neuropsychol, 2005. 27(5): p. 
565-75. 
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Jansen, C.E., et al., A prospective longitudinal study of chemotherapy-induced 
cognitive changes in breast cancer patients. Support Care Cancer, 2011. 19(10): 
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concussion. Percept Mot Skills, 1977. 44(2): p. 367-73. 
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McCaffrey, R.J., H.J. Westervelt, and R.F. Haase, Serial neuropsychological 
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Crawford, J.R., M.C. Obonsawin, and K.M. Allan, PASAT and components 
ofWAIS-R performance: Convergent and discriminant validity. 
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Adamchic, I., et al., Psychometric evaluation of visual analog scale for the 
assessment of chronic tinnitus. Am J Audiol, 2012. 21(2): p. 215-25. 
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memory networks. Proc Natl Acad Sci U S A, 2011. 108(20): p. 8075-80. 
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disorder. Am J Audiol, 2007. 16(2): p. 107-17. 
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disorder - review of clinical and experimental evidence. Neuropharmacology, 
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response systems into a biopsychosocial model. Psychosom Med, 2005. 67(5): p. 
783-90. 
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Griffiths, R.R., et al., Psilocybin can occasion mystical-type experiences having 
substantial and sustained personal meaning and spiritual significance. 
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1969. 5(4): p. 149-62. 
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Newman, E., et al., Empirically supported ethical research practice: the costs and 
benefits of research from the participants' view. Account Res, 2001. 8(4): p. 309-
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Lenth, R.V. Java Applets for Power and Sample Size (Computer software).  2006  
[cited 2012 June]; Software allowing computation of power under various 
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http://www.stat.uiowa.edu/~rlenth/Power. 
169. 
Dumont, G.J. and R.J. Verkes, A review of acute effects of 3,4-
methylenedioxymethamphetamine in healthy volunteers. J Psychopharmacol, 
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Vollenweider, F.X., et al., Psychological and cardiovascular effects and short-
term sequelae of MDMA ("ecstasy") in MDMA-naive healthy volunteers. 
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Kuypers, K.P. and J.G. Ramaekers, Transient memory impairment after acute 
dose of 75mg 3.4-Methylene-dioxymethamphetamine. J Psychopharmacol, 2005. 
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Adams, H.P., Jr., et al., Guidelines for the early management of adults with 
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Ryan, T.J., et al., 1999 update: ACC/AHA guidelines for the management of 
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(Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol, 
1999. 34(3): p. 890-911. 
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[letter]. Lancet, 1999. 354(9188): p. 1441-2. 
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factors underlying ventricular septal defects in the North of England. Eur J Clin 
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Singer, L.T., et al., Neurobehavioral outcomes of infants exposed to MDMA 
(Ecstasy) and other recreational drugs during pregnancy. Neurotoxicol Teratol, 
2012. 34(3): p. 303-10. 
178. 
McCann, U.D. and G.A. Ricaurte, Caveat emptor: editors beware. 
Neuropsychopharmacology, 2001. 24(3): p. 333-6. 
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Rogers, G., et al., The harmful health effects of recreational ecstasy: a systematic 
review of observational evidence. Health Technol Assess, 2009. 13(6): p. iii-iv, 
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Mithoefer, M.C., et al., Safety, Efficacy and Durability of MDMA-Assisted 
Psychotherapy in Subjects with Chronic, Treatment-Resistant Posttraumatic 
Stress Disorder: Completed and Ongoing Randomized, Controlled, Triple-blind 


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Phase 2 Pilot Studies, in Military medical research across the continuum of care. 
2012: Fort Lauderdale, FL. 
 
 

SAP_001.pdf: 
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MP-4 Statistical Analysis Plan 
Version 1: 31 May 2016 
 
 
SPONSOR 
 
 
 
Multidisciplinary Association for Psychedelic Studies 
(MAPS)  
1115 Mission Street 
Santa Cruz, CA 95060 
SPONSOR DESIGNEE 
 
Amy Emerson 
Executive Director and Director of Clinical Research 
MAPS Public Benefit Corporation (MPBC) 
1115 Mission Street 
Santa Cruz, CA 95060 
USE 
In conjunction with relevant FDA guidance 
STUDY TITLE 
 
 
 
 
 
A Randomized, Double-Blind, Controlled Phase 2 Pilot 
Study of Manualized 
3,4-methylenedioxymethamphetamine (MDMA)-
assisted Psychotherapy in 12 Subjects with Treatment-
Resistant Posttraumatic Stress Disorder (PTSD) - 
Canada 
LATEST PROTOCOL  
Amendment 2 Version 3, June 20, 2014 
 
INVESTIGATOR 
 Ingrid Pacey, M.B.B.S., F.R.C.P.[C] 
 
MEDICAL MONITOR 
 
Michael C. Mithoefer, M.D. 
 
STATISTICIAN 
 
Scott Hamilton, Ph.D. 
 
PLAN PREPARED BY 
 
Scott Hamilton, Ph.D. 
Allison Feduccia, Ph.D. 
Berra Yazar-Klosinski, Ph.D. 


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Table of Contents 
1.0 
List of Abbreviations ............................................................................................ 3 
2.0 
Introduction ........................................................................................................... 4 
3.0 
Background ........................................................................................................... 4 
4.0 
Study Objectives.................................................................................................... 5 
4.1 
Primary Objective ........................................................................................................ 5 
4.2 
Secondary Objectives ................................................................................................... 5 
4.3 
Safety Objectives .......................................................................................................... 6 
5.0 
Study Design .......................................................................................................... 7 
6.0 
Randomization and Blinding ............................................................................. 11 
7.0 
Sample Size and Power Considerations ............................................................ 11 
8.0 
Measures .............................................................................................................. 11 
8.1 
Outcome Measures ..................................................................................................... 11 
8.2 
Safety Measures .......................................................................................................... 11 
8.3 
Process Measures ........................................................................................................ 12 
9.0 
Analyses ............................................................................................................... 12 
9.1 
Analysis Populations .................................................................................................. 13 
9.2 
Handling of Dropouts, Missing Data ........................................................................ 13 
9.3 
Protocol Deviations ..................................................................................................... 14 
9.4 
Pooling of Investigator Centers ................................................................................. 14 
9.5 
Baseline Values ........................................................................................................... 14 
9.6 
Subject Disposition and Dosing Summary ............................................................... 14 
9.7 
Demographics and Baseline Characteristics ............................................................ 15 
9.8 
Prior and Concomitant Medications ........................................................................ 15 
9.9 
Efficacy Analyses ........................................................................................................ 15 
9.9.1 
Primary Efficacy Analyses ....................................................................................... 15 
9.9.2 
Secondary Efficacy Analyses ................................................................................... 15 
9.9.3 
Exploratory Analyses ............................................................................................... 16 
9.9.4 
Safety Analyses ........................................................................................................ 17 
9.10 
Timing of Analyses ..................................................................................................... 19 
10.0 
Statistical Software ............................................................................................. 19 
11.0 
References ............................................................................................................ 19 
 
 
 


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1.0   List of Abbreviations  
 
AE(s)  
Adverse Event(s) 
ANOVA   
Analysis of Variance 
BDI-II 
Beck Depression Inventory-II 
BP 
Blood Pressure 
BT  
Body Temperature 
CAPS-4 
Clinician Administered PTSD Scale-4 
C-SSRS  
Columbia Suicide Severity Rating Scale  
DBP  
Diastolic Blood Pressure 
DES-II 
Dissociative Experiences Scale-II 
GAF 
Global Assessment of Functioning 
GWB 
General Well-being 
HR  
Heart Rate 
mITT  
Modified Intent To Treat  
MAPS 
Multidisciplinary Association for Psychedelic Studies 
MDMA 
3,4-methylenedioxymethamphetamine 
MPBC 
MAPS Public Benefit Corporation  
NEO PI 
Neuroticism-Extroversion-Openness Personality 
Inventory 
PASAT 
Paced Auditory Serial Addition Test 
PDS 
PTSD Diagnostic Scale 
PP  
Per Protocol 
PTSD  
Posttraumatic Stress Disorder 
PSQI  
Pittsburgh Sleep Quality Index 
PTGI 
Post Traumatic Growth Inventory 
RBANS 
Repeatable Battery for the Assessment of 
Neuropsychological Status 
RCT  
Randomized Controlled Trial 
RRPQ 
Reactions to Research Participation Questionnaire 
SBP  
Systolic Blood Pressure 
SOCQ 
States of Consciousness Questionnaire 
SUD 
Subjective Units of Distress 
 
 
 
 


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2.0   Introduction 
 
This document presents a Statistical Analysis Plan (SAP) for MAPS study protocol MP-
4, a Phase 2 pilot clinical trial designed to evaluate the safety and effect of MDMA-
assisted psychotherapy in treating chronic, treatment-resistant PTSD.  Though the 
protocol states 12 subjects will be enrolled, the study concluded with 6 subjects treated. 
 
Due to the reduction in sample size from 12 to 6, the planned statistical analyses 
described in the protocol were not executed. This document presents a revised plan 
appropriate for the 6 subjects enrolled.  The background provided in sections 3-5 below 
are based on information in the last approved protocol, they have not been adjusted based 
on the change in enrollment which was discontinued at N=6 subjects. This SAP will be 
finalized prior to any unblinded, inferential or descriptive analyses of data pertaining to 
the MAPS MP-4 study. SAS programming may occur as study data accumulate in order 
to have analysis programs ready at the time of unblinding of the clinical team. In such an 
event, arbitrary treatment group assignments must be randomly linked to subjects, 
effectively rendering any output of programs meaningless. For the reasons stated here the 
conduct of the study in the field is considered to be independent of any study outcome 
that might materialize upon enactment of the currently proposed statistical plan. 
3.0   Background 
 
This Phase 2 pilot study will examine the safety and effect of manualized MDMA-
assisted psychotherapy in subjects with chronic, treatment-resistant PTSD of at least six 
months duration who were unable to achieve remission despite having received prior 
treatment with either pharmacotherapy or psychotherapy of adequate dose/duration or 
who discontinued treatment due to lack of tolerability. MDMA (125 mg) and an inactive 
placebo (0 mg) will be assessed in two Stage 1 sessions. Subjects who received the 
inactive placebo during Stage 1 will have the opportunity to cross over and take part in a 
second study segment, referred to as Stage 2, with three open-label experimental 
sessions. Subjects that receive 125 mg MDMA in Stage 1 will have one additional open-
label active dose session. Co-therapist teams will conduct the study.  
 
This study is designed to obtain estimates of effect size and collection of safety data. This 
study is also intended to continue the development of a manualized psychotherapeutic 
approach to this potential treatment. 


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4.0   Study Objectives 
4.1   Primary Objective  
 
• Assess changes in PTSD symptoms in subjects receiving the full dose of MDMA 
compared to the comparator dose as measured by Global CAPS scores at baseline 
and the primary endpoint, one month after the second experimental session. 
4.2   Secondary Objectives 
 
• Assess changes in self-reported PTSD symptoms as measured with the PTSD 
Diagnostic Scale (PDS) at baseline, after each experimental session and/or the 
primary endpoint. 
• Assess depression symptoms with the Beck Depression Inventory (BDI-II) at 
baseline and the primary endpoint. 
• Assess global functioning with the Global Assessment of Functioning (GAF) at 
baseline and the primary endpoint. 
• Assess changes in personality with the Neuroticism Extroversion Openness 
Personality Inventory (NEO-PI) at baseline and the primary endpoint. 
• Assess self-reported sleep quality with the Pittsburgh Sleep Quality Index (PSQI) 
at baseline and the primary endpoint. 
• Assess self-reported dissociation symptoms with the Dissociation Experiences 
Scale II (DES-II) at baseline and the primary endpoint. 
• Assess self-reported posttraumatic growth with the Posttraumatic Growth 
Inventory (PTGI) at baseline and the primary endpoint. 


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The following objectives will compare effects in specified subjects: 
 
• Assess PTSD symptoms via CAPS and PDS, depression symptoms via BDI-II, 
global functioning via GAF, sleep quality via PSQI, posttraumatic growth via 
PTGI, changes in personality via NEO-PI and dissociation symptoms via the 
DES-II, throughout Stage 2 in comparison to Stage 1 in crossover subjects. 
• Assess long-term effects of MDMA-assisted psychotherapy on symptoms of 
PTSD, depression, global function, sleep quality, posttraumatic growth, and 
dissociation symptoms via CAPS, PDS, BDI-II, GAF, PTGI, PSQI, PTGI (in 
reference to start of the study), DES-II, and changes in personality via NEO-PI 
one year after the final experimental session for each subject. 
 
The following objectives will include exploratory analyses intended to inform protocol 
design: 
 
• Explore the effects of each experimental session upon self-reported changes in 
consciousness, as those associated with a transformational or mystical experience 
via the States of Consciousness Questionnaire (SOCQ). 
• Assess the effect of the third experimental session for full dose subjects in Stage 1 
and Stage 2 using CAPS, PDS, BDI-II, GAF, PSQI, PTGI, NEO-PI, and DES-II.  
• Assess the ability of the therapists and subjects to accurately guess condition 
assignment in Stage 1. 
• Correlate adherence to the treatment manual with Global CAPS scores using 
adherence criteria ratings to assess videos of psychotherapy sessions. 
 
4.3   Safety Objectives 
 
The safety objectives of the study are to monitor and assure the safety of subjects during 
and after the experimental sessions by assessing physiological effects, psychological 
distress, adverse events, spontaneously reported reactions and suicidality.  
 
• Vital signs (blood pressure, heart rate, and temperature) and Subjective Units of 
Distress (SUD) will be measured during each experimental session. Comparisons 
will be made for SUD scores and vital signs between each condition.  
• SAEs, AEs, and spontaneously reported reactions will be collected during the 
study according to protocol Section 14.0.  
• Suicidality will be assessed with the Columbia Suicide Severity Rating Scale (C-
SSRS) during visits prior to and after experimental sessions, twice during 
experimental sessions, and several times after each experimental session. 
Comparisons will be made for C-SSRS scores for subjects in each condition. The 
same schedule of assessment will be followed during Stage 2. 
• Assess cognitive function with the Paced Auditory Serial Addition Test (PASAT) 
and the Repeatable Battery for the Assessment of Neuropsychological Status 
(RBANS) at baseline and the primary endpoint by condition, and end of Stage 
1/end of Stage 2 for maximal exposure. 


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• Collect changes to pre-existing tinnitus and/or chronic pain symptoms using a 
visual analog scale, specifically in subjects with a medical history of tinnitus 
and/or chronic pain.  
5.0   Study Design 
 
As background for the statistical methods presented below, this section provides an 
overview of the study design. This overview is a summary only. The protocol is the 
definitive reference for all matters discussed in what follows. 
 
This randomized, double-blind, active placebo controlled study of MDMA-assisted 
psychotherapy in subjects diagnosed with chronic, treatment-resistant PTSD of at least 
six-months duration. The schedule will include two blinded MDMA-assisted 
psychotherapy sessions in Stage 1 scheduled approximately one month apart with a 
male/female co-therapist team. Subjects will remain with only one team for the entirety 
of the study. Upon enrollment, subjects will meet with their therapist team for 3 
preparatory sessions. Each MDMA-assisted psychotherapy session will be followed by 
an overnight stay at the clinic, an integrative psychotherapy session the next day, and 
daily telephone calls for the next seven days. Experimental sessions will be followed by 
two additional integrative sessions. PTSD symptoms will be assessed throughout Stage 1. 
For subjects continuing on to Stage 2, PTSD symptoms will be assessed throughout Stage 
2. All subjects will be evaluated for long-term effects 12 months after their last 
experimental session (See Table 2 Time and Events). 
 
In Stage 1, subjects will be randomly assigned to receive two blinded experimental 
psychotherapy sessions assisted by either inactive placebo or full dose MDMA.  The 
blind will be broken for all subjects in Stage 1 after completing the primary endpoint 
assessment, 1-month after the second experimental session in Stage 1. After unblinding, 
active dose subjects will continue in Stage 1 and receive a third MDMA-assisted 
psychotherapy session.  Subjects who receive the placebo dose of MDMA will be offered 
the option to enroll in the open-label Stage 2 unless they meet any exclusion criteria for 
study participation. In Stage 2, subjects will receive full dose MDMA and the three 
experimental sessions will otherwise follow the same sequence of events after a single 
preparatory session (See Time and Events Table). All subjects will complete a follow-up 
occurring 2 months after their last experimental session in Stage 1 and Stage 2, as 
applicable. In addition, all subjects will complete a visit 12 months after their final 
experimental session where outcome measures and a questionnaire on any lasting 
benefits or harms of the treatment will be administered.  
 
 
 
 
 
 
 
 


MAPS Public Benefit Corporation                                                                        MP-4 Statistical Analysis Plan  
US 
 
       Version 1: 31 May 2016 
 
 
                                                                                                               Page 8 of 19 
 
Table 1: Dose Regimen 
Stage 1 
Experimental 
Sessions 
Dose 
Initial 
Dose 
Optional 
Supplemental 
Dose 
Min-Max 
Cumulative 
Dose 
Min-Max 
Cumulative 
Dose with 
Titration 
1 and 2 
Comparator Dose 
0 mg 
0 mg 
0 mg 
 
1, 2, and 3 
Full Dose 
125 mg 
62.5 mg 
125-187.5 mg 
 
Stage 2 
Experimental 
Sessions 
 
 
 
 
 
1 
Active Dose 
100 mg 
50 mg 
100-150 mg 
 
2 and 3 
Active Dose 
100 mg 
50 mg 
100-150 mg 
 
 
+ Optional 
Titration Dose 
25 mg 
12.5 mg 
 
125-187.5 mg 
 


MAPS Study MP-4 
 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
 
 
A = First Integrative session is one day after experimental session; B = At least 24 hours prior to experimental session; C = Approximately six hours post MDMA; D = At the beginning of the session; E = As needed;  
F  = Approximately every 60 minutes; G = Given on 2nd preparatory session after washout; H = Only for subjects starting LTFU; I = Every face to face visit and Day 2 and Day 7 phone calls only; J = Reactions collected for 
seven days post experimental session; K = On the day of the first integrative session following the experimental session; L = One month after the second experimental session but before the third experimental session; M = 
On the day of the third integrative session; N = After unblinding for full dose subjects only; O = Only on Visit 1; P = Only in subjects with pre-existing tinnitus and/or chronic pain; Q = All measures listed except for the 
NEO-CI. 
 
 
Table 2. Time and Event Stage 1 
Screen/ 
Baseline 
Preparatory 
Sessions 
Experimental 
Session 1 
Experimental 
Session 2 
Primary 
Endpoint 
Experimental 
Session 3 
End of 
Stage 1 
Visit # 
Prior to enrollment 
V1,2,3 
V4 
V5,6,7 
V8 
V9,10,11 
V12 
V13 N 
V14,15,16N 
V17N 
Type of Visit 
Screening/Baseline
Preparatory 
Experimental 
Integrative 
Experimental 
Integrative 
Outcome 
Experimental 
Integrative 
Outcome 
Visit Timing – see Section 7.3 for visit 
windows 
Up to 2 months 
prior to V1 
Between 
baseline and V4 
within 13 weeks 
post  CAPS 
Between 
V4 and V8 
2-5 weeks 
post V4 
Between 
V8 and V12 
3-5 weeks 
post V8 
3-5 weeks 
post V8 
Between 
V13 and V17 
7-10 weeks 
post V13 
Initial Phone Screen 
ü 
 
 
 
 
 
 
 
 
 
Informed Consent 
ü 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric History  
ü 
 
 
 
 
 
 
 
 
 
General Physical Exam, ECG 
ü 
 
 
 
 
 
 
 
 
 
Brief Neurological Exam 
ü 
 
 
 
 
 
 
 
 
 
SCID-RV (IR) 
ü 
 
 
 
 
 
 
 
 
 
Clinical Lab Tests with HIV test 
ü 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
Medication Taper (if applicable) 
 
ü 
 
 
 
 
 
 
 
 
Study Enrollment (if eligible) 
 
üO 
 
 
 
 
 
 
 
 
Record to Audio/Video 
 
ü 
ü 
ü 
ü 
ü 
 
ü 
ü 
 
General Wellbeing 
 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
 
Drug Screen 
ü 
 
ü 
 
ü 
 
 
ü 
 
 
Pregnancy Screen (if applicable) 
ü 
 
ü 
 
ü 
 
 
ü 
 
 
Obtain Container Assignment  
 
 
üB 
 
üB 
 
 
 
 
 
CAPS, GAF, BDI-II, NEO-PI, PSQI, 
PTGI, DES-II 
ü 
 
 
 
 
 
üL 
 
 
ü Q 
RBANS/PASAT 
ü 
 
 
 
 
 
ü 
 
 
ü 
PDS  
ü 
 
 
üM 
 
 
ü 
 
üM 
ü 
C-SSRS 
ü 
üG 
üC, D, E 
üI 
üC, D, E 
üI 
ü 
üC, D, E 
üI 
ü 
Administer Drug + Therapy 
 
 
ü 
 
ü 
 
 
ü 
 
 
Monitoring of BP, Pulse, and Temp.  
 
 
ü 
 
ü 
 
 
ü 
 
 
SUD 
 
 
üF, E 
 
üF, E 
 
 
üF, E 
 
 
Belief of Condition Assignment 
 
 
 
üK 
 
üK 
 
 
 
 
Overnight Stay, SOCQ 
 
 
ü 
 
ü 
 
 
ü 
 
 
Integrative Therapy Session 
 
 
 
üA 
 
üA 
 
 
üA 
 
7 Days Integrative Telephone Contact 
 
 
 
ü 
 
ü 
 
 
ü 
 
AEs Requiring Medical Attention 
 
 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
Spont. Reported Reactions & All AEs 
 
 
üJ 
ü 
üJ 
ü 
ü 
üJ 
ü 
 
Changes in Tinnitus and/or Pain 
üP 
 
üE,P 
üE,P 
üE,P 
üE,P 
üP 
üE,P 
üE,P 
üP 
AEs of Psychiatric Status or Withdrawal 
 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
Serious Adverse Events 
 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
Issue Memory Aid Card  
 
 
 
 
 
 
 
 
 
üH 
Unblinding
  
 
 
 
 
 
 
ü 
 
 
 
Perception of Experimental Sessions 
 
 
 
 
 
 
üN 
 
 
üN 
RRPQ 
 
 
 
 
 
 
 
 
 
üH 


MAPS Study MP-4 
 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
 
Time and Events Stage 2 
Preparatory 
Sessions 
Experimental 
Session 1 
Experimental 
Session 2 
Secondary 
Endpoint 
Experimental 
Session 3 
End of 
Stage 2 
 
Long-term 
Follow-up 
Visit # 
V18* 
V19 
V20,21,22 
V23 
V24,25,26 
V27 
V28 
V29,30,31 
V32 
 
LTFU 
Type of Visit 
Preparatory 
Experimental 
Integrative 
Experimental 
Integrative 
Outcome 
Experimental  
Integrative 
Outcome 
Follow-up 
Visit Timing – See Section 7.3 for visit 
windows 
Within 1 month 
post V12* 
+/_1 week 
post V18 
Between 
V19 and V23 
2-5 weeks 
post V19 
Between 
V23 and V27 
3-5 weeks 
post V23 
3-5 weeks 
post V23 
Between 
V28 and V32 
7-10 Weeks 
post V28 
1 year 
post V13 or V28 
Confirm Informed Consent 
ü 
 
 
 
 
 
 
 
 
 
Confirm Inclusion/Exclusion 
ü 
 
 
 
 
 
 
 
 
 
Enrollment in Stage 2 
ü 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
Record to Audio/Video 
ü 
ü 
ü 
ü 
ü 
 
ü 
ü 
 
 
General Wellbeing 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
 
 
Drug Screen 
 
ü 
 
ü 
 
 
ü 
 
 
 
Pregnancy Screen (if applicable) 
 
ü 
 
ü 
 
 
ü 
 
 
 
CAPS, GAF, BDI-II, NEO-PI, PSQI, 
PTGI, DES-II 
Use V12* 
 
 
 
 
üH 
 
 
ü 
ü 
RBANS/PASAT 
 
 
 
 
 
 
 
 
ü 
 
PDS 
Use V12* 
 
üI 
 
 
ü 
 
üI 
ü 
ü 
C-SSRS 
ü 
üB, C, D 
ü
G 
üB, C, D 
ü
G 
ü 
üB, C, D 
ü
G 
ü 
ü 
Administer Drug + Therapy 
 
ü 
 
ü 
 
 
ü 
 
 
 
Monitoring of BP, Pulse, and Temp.  
 
ü 
 
ü 
 
 
ü 
 
 
 
SUD 
 
üD, E 
 
üD, E 
 
 
üD, E 
 
 
 
Overnight Stay, SOCQ 
 
ü 
 
ü 
 
 
ü 
 
 
 
Integrative Therapy Session 
 
 
ü A 
 
üA 
 
 
üA 
 
 
7 Days Integrative Telephone Contact 
 
 
ü 
 
ü 
 
 
ü 
 
 
AEs Requiring Medical Attention 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
 
Spont. Reported Reactions and All AEs 
 
ü 
ü
F 
ü 
ü
F 
 
ü 
ü
F 
 
 
Changes in Tinnitus and/or Pain 
 
üJ,D 
üJ,D 
üJ,D 
üJ,D 
üJ,D 
üJ,D 
üJ,D 
üJ, D 
üJ 
AEs of Psychiatric Status or Withdrawal 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
Serious Adverse Events 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
ü 
Perception of Experimental Sessions 
 
 
 
 
 
ü 
 
 
ü 
 
Complete Stage 2, Go to Follow-up 
 
 
 
 
 
 
 
 
ü 
 
RRPQ 
 
 
 
 
 
 
 
 
ü 
 
Issue Memory Aid Card 
 
 
 
 
 
 
 
 
ü 
 
Follow-up Questionnaire 
 
 
 
 
 
 
 
 
 
ü 
Termination Visit 
 
 
 
 
 
 
 
 
 
ü 
 
* If Visit 18 is more than 8 weeks after Visit 12, then subjects will need to repeat measures prior to starting Stage 2 with the exception of NEO-PI.  
 
A = First session is one day after experimental session; B = Approximately six hours post MDMA; C = At the beginning of the session; D = As needed; E = Approximately every 60 minutes; F = Reactions collected for seven 
days post experimental session; G = Every face to face visit and Day 2 and Day 7 phone calls only; H = One month after the second experimental session but before the third experimental session; I = On the day of the third 
integrative session; J = Only in subjects with pre-existing tinnitus and/or chronic pain; K = All measures listed except for the NEO-PI 


MAPS Study MP-4 
 
 
Canada 
 
 
 
 
 
 
 
 
6.0   Randomization and Blinding 
 
The protocol states in total, 12 subjects will be enrolled and randomized in Stage 1. The 
randomized portion of the study will be blinded and there will be a 7:5 ratio between subjects in 
the Full Dose and Comparator dose groups. Subjects will be assigned subject numbers, and 
subjects will be randomized in a blinded fashion. At the conclusion of enrollment, six subjects 
were enrolled in a 4:2 ratio between subjects in the Full Dose and Comparator Dose groups. 
7.0   Sample Size and Power Considerations 
 
This study is a pilot investigation intended to gather preliminary data on the safety and effect of 
MDMA in subjects with chronic, treatment-resistant PTSD. Because of their exploratory nature, 
pilot studies are often not powered for detecting the desired effect. Because it is a pilot study in a 
small sample, results will be used to collect effect size estimates for statistical power calculations 
for adequately powered subsequent studies. 
8.0   Measures 
 
8.1   Outcome Measures 
 
Clinician-Administered PTSD Scale (CAPS-4) Global Severity Score, Diagnostic Criteria Met 
score, Associated Features  
 
PTSD Diagnostic Scale (PDS), total score 
 
Global Assessment of Functioning (GAF), total score 
 
Post Traumatic Growth Inventory (PTGI), total score 
 
Beck Depression Inventory-II (BDI-II), total score 
 
Pittsburgh Sleep Quality Index (PSQI), total score 
 
Dissociative Experiences Scale-II (DES-II), total  
 
NEO Personality Inventory (NEO PI), five factors 
 
8.2   Safety Measures 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 


MAPS Study MP-4 
 
 
Canada 
 
 
 
 
 
 
 
Subjective Units of Distress (SUD) 
 
General Well-being (GWB) 
 
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
 
Paced Auditory Serial Addition Test (PASAT) 
 
Visual analog scale for Tinnitus and/or Pain visual analog scale 
 
Vital signs (systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), body 
temperature (BT))  
 
Adverse Events (AE), including Spontaneously Reported Reactions (SRR) 
 
8.3   Process Measures 
 
Belief of Condition Assignment 
 
Therapist Adherence Criteria 
 
Subject perceptions of experimental sessions 
 
States of Consciousness Questionnaire (SOCQ), total and composite scores 
 
Reactions to Research Participation Questionnaire (RRPQ) 
 
Long-term Follow-up Questionnaire (LTFU Questionnaire) 
9.0   Analyses 
 
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, and 
approximately normal variables will be described using sample mean and standard deviations. 
Although the protocol plan specifies parametric t-tests and ANOVAs, the small group sizes (n=2 
and n=4) are insufficient for analysis. Therefore, this statistical analysis plan acts to amend the 
data analysis plan in the protocol to use group descriptives and subject listings.  
 
Clinical data will be presented in tabular format. 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. Analyses 
will be carried out with SAS Version 9.3 or higher. Selected results may be presented graphically 
using standard graphical software. 
 
Post-hoc exploratory analyses not identified in this SAP may be performed to further examine 
the study data. These analyses will be clearly identified as such in the final clinical study report. 


MAPS Study MP-4 
 
 
Canada 
 
 
 
 
 
 
 
 
9.1   Analysis Populations 
 
Modified Intent-to-treat (mITT): all subjects who were randomized, received at least one 
experimental session and completed at least one outcome assessment 
 
Crossover: all subjects who completed Stage 2 in addition to completing Stage 1 
 
Safety: all subjects who receive any study treatment 
 
9.2   Handling of Dropouts, Missing Data 
 
Early termination visit data for mITT and Safety variables will be analyzed at the closest 
scheduled visit after the last experimental session completed. If the closest visit has valid data, 
the early termination data will be assigned to the next available visit. If a subject discontinues 
and does not participate in an early termination visit, data from the last available visit will be 
used to replace the missing early termination visit data.  
Partial or Missing Dates:  
The following conventions will be used to impute missing portions of dates for adverse events 
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. 
A. 
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: 
i) If the year matches the first dose date year, then impute the month and day of 
the first dose date. 
ii) Otherwise, assign ‘January.’  
3) 
 If the day is unknown, then: 
i) If the month and year match the first dose date month and year, then impute the 
day of the first dose date. 
ii) Otherwise, assign the first day of the month. 


MAPS Study MP-4 
 
 
Canada 
 
 
 
 
 
 
 
B. 
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 assign ‘December.’ 
3) 
If the day is unknown, then assign the last day of the month. 
 
9.3   Protocol Deviations 
All protocol deviations will be included as a categorized listing. Safety and mITT analyses will 
include all enrolled subjects with all available data. Subjects with major deviations will be 
excluded from the per protocol analyses. Major deviations will be defined as anyone who was 
enrolled and has completed at least one experimental session but found to not meet 
inclusion/exclusion criteria during the course of the study. The number of subjects in each 
protocol deviation category listed below will be summarized by group, and individual subjects 
will be listed in the appendix. 
Possible protocol deviations include the following seven categories: 
• 
Subject entered study but did not meet criteria 
• 
Subject developed withdrawal criteria but was not withdrawn 
• 
Subject received excluded concomitant treatment 
• 
Protocol procedure not performed per protocol 
• 
Subject received incorrect treatment or incorrect dose 
• 
Protocol procedure performed out of range 
• 
Miscellaneous 
9.4   Pooling of Investigator Centers 
 
All subjects in this study come from one investigational center.  
 
9.5   Baseline Values 
 
Baseline values are from screening/baseline visit for all measures, except C-SSRS. For C-SSRS, 
pre-enrollment scores will be used as a measure of ‘lifetime’ suicidal ideation and behavior, and 
preparatory session 2 (visit 2) prior to drug administration will used as ‘baseline.’ If a subject 
was not administered the C-SSRS at preparatory session 2 (visit 3), then ‘baseline’ scores will be 
visit 4 pre-drug C-SSRS observation. 
9.6   Subject Disposition and Dosing Summary 
All subjects enrolled in the study (i.e., who sign informed consent and complete 
inclusion/exclusion criteria) will be included in the summary of subject disposition and 
accountability. No inferential statistical tests will be performed. The tabulation of number of 
subjects in each treatment group and overall will be displayed for all subjects in the Safety 
Population, in the mITT Population, and in the PP Population. The number and percent of 


MAPS Study MP-4 
 
 
Canada 
 
 
 
 
 
 
 
subjects who completed or discontinued the study will be displayed for each treatment group and 
overall together with reasons for early termination, where the percent is with respect to the total 
number of randomized subjects in that treatment group. The timepoint of doses and total MDMA 
(mg) administered will be summarized by treatment group for the Safety, mITT and PP 
Populations.  
 
9.7   Demographics and Baseline Characteristics 
 
Subject demographic data and baseline characteristics will be summarized descriptively by 
treatment group and overall. The demographic data and baseline characteristics will be 
summarized for the mITT and Crossover Populations.  
9.8   Prior and Concomitant Medications  
The number and percent of subjects who took medications prior to and after enrollment will be 
summarized descriptively for each treatment group. Concomitant medications will be 
summarized similarly. Prior and concomitant medications will be summarized for the Safety 
Population. Psychiatric medications will be coded to common drug classes and terms. 
9.9    Analyses of Effect 
For all primary, secondary and exploratory endpoints descriptive statistics (n, mean, standard 
deviation, median, range, or counts and percentages where appropriate) will be provided by 
treatment group.  
Since the study ended with insufficient group sizes (n=2 and n=4), no formal analyses will be 
performed. 
9.9.1   Primary Analyses of Effect 
 
Clinician Administered PTSD Scale-4 (CAPS-4) 
 
The primary evaluation is the change from baseline to the primary outcome timepoint (visit 12) 
in the CAPS-4 Global Severity score of PTSD (difference score). Data will be presented with 
descriptive statistics and subject listings. 
 
9.9.2   Secondary Analyses of Effect 
 
The secondary analyses will be presented as change from baseline (Baseline) to primary 
endpoint (visit 12) of all the secondary measures, following the same methodology used for the 
primary endpoint.  
 


MAPS Study MP-4 
 
 
Canada 
 
 
 
 
 
 
 
PTSD Diagnostic Scale (PDS) total scores will be summarized in the same manner as the CAPS-
4 global scale primary analysis. 
 
Global Assessment of Functioning (GAF) total score will be summarized in the same manner as 
the CAPS-4 global scale primary analysis. 
 
Post Traumatic Growth Inventory (PTGI) total will be analyzed in the same manner as the 
CAPS-4 global scale primary analysis. 
 
Beck Depression Inventory-II (BDI-II) total score will be summarized in the same manner as the 
CAPS-4 global scale primary analysis. 
 
Pittsburgh Sleep Quality Index (PSQI) global scores will be summarized in the same manner as 
the CAPS-4 global scale primary analysis. 
 
Dissociative Experiences Scale-II (DES-II) total will be summarized in the same manner as the 
CAPS-4 global scale primary analysis. 
 
NEO Personality Inventory (NEO PI) five factor scores will be analyzed in the same manner as 
the CAPS-4 global scale primary analysis. 
 
9.9.2.1 Secondary Analyses of Effect at Secondary Endpoints 
 
Crossover Subject Analyses  
Formal statistical comparisons between Stage 1 and Stage 2 scores may only occur if all three 
eligible participants enroll in Stage 2. As only two subjects completed Stage 2, no formal 
statistical comparisons will be conducted within-subjects. 
 
Long-term Follow-up 
For the CAPS, PDS, GAF, PTGI, BDI-II, PSQI, and DES-II the absolute changes in the 
measures from baseline to the long-term follow-up visit (one year post final experimental 
session) will be summarized. The absolute changes in scores on measures from long-term 
follow-up to End of Stage 1 (full dose group) or long-term follow-up compared to End of Stage 2 
(comparator group) will be presented. 
 
9.9.3   Exploratory Analyses 
 
Clinician Administered PTSD Scale-4 (CAPS-4) 
 
• The percentage of subjects who achieve a 30% drop in CAPS-4 global score at the 
primary endpoint (visit 12), end of Stage 1, and end of Stage 2 will be an indirect 
measure of clinical significance. Descriptive statistics will be computed and displayed 
by Stage 1 treatment groups.  
 


MAPS Study MP-4 
 
 
Canada 
 
 
 
 
 
 
 
• The percentage of subjects who no longer meet PTSD diagnostic criteria according to 
the CAPS-4 at the primary endpoint (visit 12), end of Stage 1, and end of Stage 2 will be 
an indirect measure of clinical significance. Descriptive statistics will be computed and 
displayed by Stage 1 treatment groups.  
 
9.9.3.1 Process Measures  
 
States of Consciousness Questionnaire (SOCQ)  
Descriptive statistics will be computed for SOCQ scores completed after each MDMA-assisted 
psychotherapy session, and SOCQ scores will be presented by treatment group.  
 
Long-term Follow-up Questionnaire (LTFU Questionnaire) 
The LTFU Questionnaire nominal variables will be described in terms of frequencies and 
percentages, while ordinal and non-normal continuous variables will be described using sample 
mean, standard deviations, and range.  
 
Belief of Condition Assignment 
In order to compare the therapists’ and subjects’ belief of treatment group to dose received in 
each blinded session, the number and frequency of correct guesses will be calculated and 
depicted by dose group and study role (subject and each therapist). 
 
Reactions to Research Participation Questionnaire (RRPQ) 
Frequency of response will be tabulated for ‘reasons for participation’ across Stage 1 treatment 
groups. Descriptive statistics will be computed for total scores for subscales and displayed by 
Stage 1 conditions.  
 
Subject’s Perceptions of Experimental Sessions 
Descriptive statistics will be calculated for subject's perceptions of experimental sessions. Mean, 
standard deviation and range of individual responses and sum of items #1-4 will be examined. 
No formal analyses will be conducted due to small sample size. 
 
Adherence to the Treatment Manual 
The sponsor will collect ratings of adherence to the treatment manual from specifically selected 
types of sessions. Descriptive statistics will be computed for each adherence scale within a given 
session. Due to insufficient sample size, the sponsor will not correlate the mean adherence 
ratings for adherence scale and session type with Global CAPS scores from the closest available 
endpoint assessment to investigate the effects of adherence to the treatment manual on reduction 
in PTSD symptoms.  
 
9.9.4   Safety Analyses 
 
The primary measure of safety will be the reporting of adverse events. The Adverse events 
considered are Treatment Emergent Adverse Events (TEAE) defined as those AE’s that occurred 
after dosing and existing medical history diagnoses that worsened during the study. Verbatim 
terms on case report forms will be mapped to preferred terms and system organ classes using the 


MAPS Study MP-4 
 
 
Canada 
 
 
 
 
 
 
 
MedDRA dictionary. For incidence reporting if a subject has more than one AE mapped to the 
same preferred term, that AE will be reported only once using the highest severity and closest 
relationship to study drug. Subject incidence of AEs will be displayed by treatment group by 
stage and by system organ class. AEs will also be summarized by severity and relationship to 
study drug. Subject incidence of SAEs by treatment group will also be displayed. In addition to 
the listing of all AEs, a listing of SAEs and a listing of AEs leading to discontinuation of study 
drug will be included.  
 
Summary tables of frequency listings of commonly reported AEs (Spontaneously Reported 
Reactions) mapped to preferred terms will be displayed during and after each experimental 
session by Stage 1 treatment group. 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Suicidal ideation and behavior will be summarized according to suggestions made in the 
Columbia-Suicide Severity Rating Scale Scoring and Data Analysis Guide [1]. A positive 
response for suicidal ideation is counted when a subject 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 
score. Serious suicidal ideation is a suicidal ideation score of 4 or 5. A positive response for 
suicidal behavior occurs when a subject 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 score. The 
number and percent of positive responses of Positive Ideation, Serious Ideation, and Positive 
Behavior will be tabulated by Stage I treatment group and time period. Compare lifetime serious 
suicidal ideation and positive behavior frequencies to cumulative frequencies anytime during the 
study until end of Stage 1 and Stage 2. 
 
Subjective Units of Distress (SUD) 
 
Descriptive statistics for SUD scores will be calculated by Stage 1 treatment group and time 
period with counts and percentages.  
 
Vital signs  
 
Vital signs (heart rate, body temperature, systolic and diastolic blood pressure) will be 
summarized using descriptive statistics at baseline and at each post-baseline time point. 
Occurrences of systolic and diastolic blood pressure, heart rate, and body temperature readings 
above the pre-determined cutoff will be displayed with numbers and percentages by timepoint. 
 
Visual analog scale for Tinnitus and/or Pain visual analog scale 
 
Changes in Tinnitus and/or Pain visual analog scale scores will presented with descriptive 
statistics at each endpoint. 
 
Paced Auditory Serial Addition Test (PASAT) and Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS) 
 


MAPS Study MP-4 
 
 
Canada 
 
 
 
 
 
 
 
RBANS and PASAT scores at baseline and primary endpoint will be summarized by the active 
and comparator dose groups using descriptive statistics.  
 
9.10   Timing of Analyses 
 
The primary analysis may be conducted after all eligible subjects complete Stage 2, but before all 
long-term follow-up data have been collected. Subsequent analyses on this data set will not be 
conducted after initial analyses are performed, unless for further exploratory post-hoc analyses. 
Changes to the protocol will not occur after primary analysis.  
10.0   Statistical Software 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.3 or higher) for 
Windows. If the use of other software is warranted, the final clinical study report will detail what 
software was used and for what purposes. 
11.0   References 
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.