Conditions: Posttraumatic Stress Disorder
Keywords: MDMA Therapy Veterans Posttraumatic Stress Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 26
Healthy volunteers: no

Brief summary:
The goal of this clinical trial is to learn if MDMA-assisted therapy is safe and effective and reducing PTSD symptoms in veterans with chronic PTSD. The main question it aims to answer is: Do three doses of MDMA reduce PTSD symptoms?

Researchers will compare 30, 75, and 125 mg of MDMA HCl with therapy to see which dose best reduces PTSD symptoms.

Participants will undergo three preparatory non-drug therapy sessions with a male and female co-therapist team, then undergo three day-long MDMA-assisted therapy sessions after receiving an initial dose of 30, 75, or 125 mg MDMA HCl. After each MDMA-assisted therapy session, participants will undergo three integrative therapy sessions.

Detailed description:
This study is a randomized, double-blind, dose comparison study with an open-label cross-over segment that will assess the safety and efficacy of MDMA-assisted therapy in veterans with chronic PTSD. Twelve of 24 participants will receive the full dose of 125 mg, six will receive 75 mg and six will receive 30 mg (active placebo dose) of MDMA HCl. An independent rater blind to condition will assess symptoms of PTSD and depression, general quality of life and posttraumatic growth prior to any therapy sessions one month after the second experimental session.

After undergoing three 90-minute non-drug introductory therapy sessions with a male/female co-therapist team, study participants will undergo two eight-hour long experimental sessions scheduled three to five weeks apart, prior to which they will be randomized to receive an initial dose of 30, 75 or 125 mg MDMA HCl , followed by a supplemental dose of half the initial dose 1.5 to 2.5 hours later. Participants will undergo integrative therapy in between each experimental session, including on the day after each session. Vital signs and psychological distress will be measured throughout each experimental session, and suicidality will be assessed throughout the course of the study. Spontaneously reported side effects will be collected on the day of each experimental session, and for six days afterward. PTSD symptoms, symptoms of depression, general psychological function, posttraumatic growth and quality of sleep will be assessed one month after the second experimental session, and the blind will be broken.

Participants who received 125 mg MDMA HCl will continue to have a third experimental session, and they will be assessed two months after the third experimental session.

Participants who received 30 or 75 mg MDMA HCl may take part in an open-label crossover segment that will follow nearly identical procedures, except that there will only be one introductory session prior to the first experimental session. There will be three experimental sessions. Symptoms of PTSD, depression and posttraumatic growth will be assessed at the start of the study. They will also be assessed one month after the second and two months after the third experimental session.

All participants will be assessed 12 months after their final experimental session. PTSD and depression symptoms and posttraumatic growth will be assessed, and participants will complete a questionnaire concerning the costs and benefits of being in the study.

Arms:
arm 1: Participants will receive 30 mg midomafetamine HCl (MDMA) with therapy during each of two blinded experimental sessions. arm 2: Participants will receive 75 mg midomafetamine HCl (MDMA) with therapy on each of two blinded experimental sessions. arm 3: Participants will receive 125 mg midomafetamine HCl (MDMA) with therapy during each of two blinded experimental sessions, followed by a third open label session.

Interventions: intervention 1: Low dose MDMA-assisted therapy intervention 2: Medium dose MDMA-assisted therapy intervention 3: Full dose MDMA-assisted therapy intervention 4: Therapy
Intervention descriptions: intervention 1: 30 mg midomafetamine HCl administered p.o. once at start of an experimental session. Upon mutual agreement, this may be followed by a supplemental dose of 15 mg 1.5 to 2 hours later intervention 2: 75 mg midomafetamine HCl administered p.o. once at start of an experimental session. Upon mutual agreement, this may be followed by a supplemental dose of 37.5 mg 1.5 to 2 hours later intervention 3: 125 mg midomafetamine HCl administered p.o. once at start of an experimental session. Upon mutual agreement, this may be followed by a supplemental dose of 62.5 mg 1.5 to 2 hours later intervention 4: Non-directive therapy during each session

Protocol document:
ICF_002.pdf: 
 
 
 
 
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SUBJECT INFORMATION AND CONSENT FORM AND AUTHORIZATION TO USE 
AND DISCLOSE PERSONAL HEALTH INFORMATION FOR RESEARCH 
 
Study Title: 
A Randomized, Triple-Blind Phase 2 Pilot Study 
Comparing 3 Different Doses of MDMA in conjunction 
with manualized psychotherapy in 24 Veterans, 
Firefighters, and Police Officers with Chronic, Treatment-
resistant Posttraumatic Stress Disorder (PTSD) 
 
Protocol #: 
MP8 Amendment 5 
 
Study Sponsor: 
 
Multidisciplinary Association for Psychedelic Studies 
(MAPS) 
309 Cedar Street, #2323 
Santa Cruz, CA 95060 
 
Principal Investigator Name: 
 
 
Research Site Address(es): 
  
 
 
 
 
Daytime telephone number(s): 
 
 
24-hour contact number(s): 
 
 
Cellular number(s): 
 
  
 
PURPOSE OF THE SUBJECT INFORMATION AND CONSENT FORM 
This consent form describes a research study and your role as a participant.  Please read this form 
carefully before you decide to take part in this study. You may ask the study doctors anything 
about the information provided. You are being asked to participate in this research study because 
you are a military veteran, firefighter or police officer and you have been diagnosed with 
posttraumatic stress disorder (PTSD) related to your service, and because your symptoms have 
not gone away after psychotherapy, medicines, or both, or you stopped your treatment because 
you could not tolerate it. 
 
Please ask the study therapists to explain any words or information in this consent that you do 
not clearly understand.  You may take home an unsigned copy of this consent form to think 
about or discuss with family or friends before making your decision.


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PURPOSE AND BACKGROUND 
This small (“pilot”) study is designed to provide information on whether psychotherapy (“talk 
therapy”) combined with the drug MDMA is safe and helpful for subjects with posttraumatic 
stress disorder (PTSD).  The researchers plan to use the results of this study to design further 
studies. 
 
MDMA is an experimental drug, which means that it has not been approved by the United States 
Food and Drug Administration (FDA) for medical use except in research studies. MDMA is also 
a controlled drug (illegal to use outside of research) and is sometimes known as “Ecstasy” 
(which is supposed to contain MDMA but often contains other drugs instead of or in addition to 
MDMA).  MDMA has already been used legally in research and illegally in uncontrolled 
environments, such as nightclubs.  While much is known about MDMA and its risks, much 
remains unknown about this drug. 
 
The study is sponsored by a 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 US, with promising results.  MAPS has 
other MDMA/PTSD pilot studies in Switzerland and is planning new studies in the US, Canada, 
and Israel. 
 
Before it became illegal in 1985, some psychologists and psychiatrists combined MDMA with 
psychotherapy to help people with psychological problems, including PTSD. Though we do not 
know why it may help people with PTSD, we know that MDMA increases positive mood and 
changes the way we see and think about the world around us, making it easier to think about and 
recall things that happened to us that are upsetting. People say they feel caring and forgiving 
toward themselves and others during the MDMA experience. It is possible that these drug 
effects, when combined with psychotherapy, help people work through thoughts, memories and 
emotions related to PTSD. 
 
This study will compare three doses of MDMA: 30, 75 and 125 mg, possibly followed one and a 
half to two and a half hours later by a second dose half the size of the first dose. 
 
LENGTH OF STUDY 
This study can take up to 1.5 years or 20 visits if you receive 125 mg MDMA in “Stage 1.”  It 
can last for an additional three months or 15 more visits if you receive 30 or 75 mg MDMA in 
“Stage 1,” and decide to go on to have an active dose of MDMA in the second part of the study, 
“Stage 2.” This time period includes a long-term follow-up visit 12 months after the last 
experimental or open-label session. 
 
TYPE OF STUDY 
This study is double blind, meaning that neither you nor the study researchers will know what 
dose of MDMA you get. The dose of MDMA you get will be decided at random, as if by tossing 
a coin. Each person in this study has a 50% chance of getting 125 mg, a 25% chance of getting 
30 mg and a 25% chance of getting 75 mg. You will find out what dose of MDMA you received 
approximately 1 month after your second experimental session. There will be approximately 24 
subjects in this study. 


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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 Subject Information and Consent 
Form before any study-related procedures are performed.  You will not be asked to stop taking 
any of your current medications until you are enrolled in the study.  If you are taking psychiatric 
medications when you are enrolled you will be required to slowly stop taking them under the 
supervision of your prescribing physician or the study doctor.  It is possible that stopping some 
medications could lead to recurrent or new symptoms, including thoughts of wanting to kill 
yourself 
 
Before you can be in the study, the study doctor must first make sure that you qualify for the 
study and that you are generally physically healthy.  The screening process can take up to 4 
months, and there will be one or more office visits during this time.  The study therapists may 
ask your permission to contact your doctor or psychotherapist to get information about your 
medical history. They may need to do this so that they will know if you can be in the study or 
not. 
 
The tests will include the following: 
 
 A questionnaire about your PTSD symptoms and how you deal with them in your everyday 
life.  Your score on this questionnaire will be used to decide if you can be in the study. The 
person asking you these questions will be a different person from the therapists.  This session 
may be recorded to video. 
 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. The study doctor will rate how well you are doing in 
general. 
 A questionnaire about feelings of depression or other symptoms or feelings you might 
experience. 
 A questionnaire about thoughts or feelings you might have about hurting or killing yourself.  
 A questionnaire about your personality. 
 A questionnaire about your quality of sleep. 
 Another questionnaire about your PTSD and its effects on your life 
 A questionnaire about any dissociation symptoms. 
 A visual scale of pain and tinnitus (ringing in the 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) and a urine sample for routine laboratory 
testing, including tests of metabolism and liver function.  Laboratory tests will also include 
testing for the human immunodeficiency virus (HIV) and hepatitis C virus (HCV). 
 A urine test for drugs of abuse. Your urine drug screen must be negative to take part in the 
study. 


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 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. 
 
You may have to have extra medical tests to make sure you can be in the study. People who 
control their high blood pressure with medication may have to see a cardiologist (heart doctor) 
for more tests, and people with a liver disease called hepatitis C may have to visit a liver 
specialist. If you have hepatitis C, you will have to complete treatment the liver specialist or your 
physician (your doctor) prescribes for HCV. If the tests find out that you test positive for HCV or 
HIV, then the study doctors will have to tell the South Carolina department of Health and 
Environmental Control within seven days, as stated by law.  If you live outside South Carolina, 
the study doctors may need to report the results according to the laws of the state you live in.  
 
You may be asked if you want to participate in another study while you are in this study. If 
you are interested in learning more about this study, you will receive information about it 
separately and it will involve additional tests. 
 
BEGINNING OF STUDY 
Once you are in the study, you will schedule your first introductory (preparatory) psychotherapy 
session with the study therapists.  It may happen that the first preparatory session will be done at 
the Screening visit, after you have signed this consent form.  You will need to be enrolled in the 
study before the second psychotherapy session.  If you were taking psychiatric medicines before 
enrolling in the study, you will have to stop taking them after you are enrolled. The study doctors 
and your physician will help you do this.  If it takes over a month between when you stop taking 
your medication and your first MDMA session, then you may have to answer questions about 
your PTSD symptoms again.  You must let the study therapists know about any medical 
conditions or procedures, like surgery, within 48 hours of their occurrence. 
 
You will have to give the study therapists the name and contact information (as 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  
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 low or 
medium dose groups). 
Stage 1 
Screening 
Start study 
Intro and 
Preparati
on 
MDMA 
and Non-
Drug 
Therapy 1 
MDMA and 
Non-Drug 
Therapy 2 
Evaluation 
MDMA and 
Non-Drug 
Therapy 3  
Evaluation 
Long Term 
Evaluation
For All Groups 
For full dose group only 
Study Visit #
 
1 
Enroll
2* 3
4 
5
6
7
8
9
10 11 12 13 14 15 16 17 18 
 




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EXPERIMENTAL SESSIONS: 
There will be two day-long experimental sessions, when you will have MDMA (30, 75 or 125 
mg) and psychotherapy, each happening three to five weeks apart. The first experimental session 
will occur after you have had three introductory sessions.  If you are in the 125mg or Full Dose 
Group, you will have a third day-long experimental session with 125 mg MDMA.  If you 
received 30 or 75 mg (low or medium dose MDMA), you will be offered one of two active doses 
of MDMA sessions during the Stage 2 experimental sessions. Your therapists will discuss the 
optimal dose of MDMA with you for the second and third experimental sessions. 
 
One week before each of the MDMA sessions you will need to avoid taking: 
 
 any herbal supplement (except with prior permission);  
 any nonprescription 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 must not eat or drink any alcohol after midnight on the night before each session, though 
you can drink non-alcoholic liquids during this time, such as water or juice. You cannot use any 
psychoactive drug, with the exception of caffeine or nicotine, within 24 hours of each MDMA 
session.  You cannot use nicotine or caffeine for two hours before and six hours after MDMA 
treatments.   
 
First, you and the study therapists will discuss your goals for the experimental session, and the 
study therapists will answer any other questions you may have. 
 
Before an experimental session: 
 
 Your urine will be tested for drugs of abuse, including stimulants, sedatives, opiates and 
cannabis. 
 If you are a woman who can become pregnant, you will take a urine pregnancy test. 
 
Throughout an experimental session: 
 
 Your blood pressure and pulse will be measured periodically (every 15 to 30 minutes). 
 Your temperature will be measured every hour. 
 You will also complete a very brief, simple test of how comfortable or distressed you feel by 
marking a number on a sheet of paper that matches the way you feel at that moment. You 
will complete it every 60 to 90 minutes throughout each experimental session. 
 About an hour before receiving the drug and about six hours afterward, you will complete the 
questionnaire 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 will 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 copies of these recordings for 
you to keep and watch if you want them. 


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After urine test results come back, you will receive a capsule containing MDMA mixed with some 
lactose to make all capsules appear and weigh the same. The capsule can contain either 30, 75, or 
125 mg MDMA. After taking the capsule, you will then sit or lie down in a comfortable position. 
You can ask for an eye shade if you wish. You will listen to music during much of each 
experimental session, either through headphones or room speakers. Periodically you will be asked 
to talk to the study therapists. If you are wearing headphones, you may remove them yourself if you 
want to talk to the study therapists or have 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 remain with you, and they will help you if you 
need them to do so. They will speak with you and ask you to talk to them at least once an hour, but 
you can talk to them whenever you wish. There may be times when the study therapists will suggest 
that you stop talking for a while in order to pay attention to your thoughts and feelings. There will 
be beverages available, including water, juices and Gatorade or similar sports drinks, and you will 
be encouraged to drink an adequate amount of fluid. You can drink it whenever you wish to do so, 
within the limits of the amount that is safe for your body.  Later on, food will also be provided. 
 
Approximately one and a half to two and a half hours after you took the first capsule, you and the 
study therapists will talk about taking a second dose of MDMA. The second dose will contain half 
the amount MDMA of the first dose. If you and the study therapists agree, you will take the second 
dose. If you or the study therapists notice problems after the first dose of MDMA, then you will not 
get the second dose of MDMA. 
 
The study therapists will keep measuring blood pressure, pulse and temperature, and the study 
therapists will watch for any side effects (unwanted effects or health problems), which will be 
treated if they see them. If this happens, the study therapists will let you know what they are doing. 
 
If you are confused or upset eight or more hours after the start of an experimental session, the 
researchers will stay with you until you have fully recovered. If the researchers think you are at risk 
of hurting yourself or others, they will either remain with you all night or have you admitted to a 
hospital until you are no longer at risk of hurting yourself or others. The researchers will ask you 
about thoughts of killing or harming yourself before and after MDMA administration and 
throughout the follow-up period.  You will also be asked to complete a questionnaire about 
thoughts, feelings or other things you might have experienced during the experimental session. You 
can complete this questionnaire at any time between the end of the experimental session and you 
leave the study site the next day. 
 
If you request it and the study therapists agree to it, you can have a person of your choosing stay 
with you during some or all of the experimental session, starting at an agreed-upon time, or when 
you stay at the office of the study doctors after the session. When he or she arrives, this person will 
stay in the waiting room until there is a good time for them to come into the session. 
 
You will be spending the night in a room at the office of 
 
with an attendant who will be staying in another room nearby.  You can use the kitchen or walk 
around outside if you want.  If you find you need to talk with the researchers or you are having 
other problems and need to contact the researchers, the attendant will contact them immediately. 
 


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On the next day, you will have a non-drug (integrative) therapy session with the study therapists.  
You will need to have someone drive you to wherever you are staying (home, hotel or another 
location) from the non-drug therapy session on the day after the experimental session because we 
do not know how MDMA will affect your ability to drive, and because some people report 
feeling tired, less alert or having trouble concentrating a day after having taken MDMA. If you 
cannot find anyone to take you home, the researchers will find someone to drive you. 
 
After you return from the non-drug therapy session, the researchers will telephone you every day 
for a week to inquire about how you are feeling and determine whether you should see the study 
doctors before your next scheduled non-drug psychotherapy session.  These telephone calls will 
take approximately 5 to 15 minutes, though they can be as long as you need them to be. 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 be 
reachable by telephone 24 hours a day throughout the research study, except on occasions when 
he is out of town. At those times another psychiatrist familiar with the study will be on call and 
can be reached through his phone number which will be given to you as well. 
 
The researchers will give you a card with telephone numbers for reaching 
 
 and the Copernicus Group Independent Review Board (IRB), which 
is an independent committee that protects the rights and welfare of study participants.  You can 
keep this card in your wallet to make it easier for you to contact the researchers if you need to do 
so. 
 
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 agree to call the investigators if any of these things happen: 
you have an increase in symptoms for which you previously took medicine, you need to contact 
your outside therapist other than for the usual appointments, and/or you start or stop taking 
prescribed medicine. 
 
If you have very high blood pressure, get sick, or have an important and strong lasting negative 
reaction (unwanted effect or health problem) after the first experimental session, you or the study 
therapists may decide that you should not participate in the second experimental session.  You 
may make this decision to stop being in the study for any reason. If the study therapists decide 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 doctor will ask you to complete some final questionnaires about your PTSD symptoms. If 
you decide you do not want to continue in the study during an experimental session, you will still 
have to stay in the office until the study therapists think that you are well enough to leave and 
that all the effects of the drug have worn off. 
 
The experimental sessions will occur three (3) to five (5) weeks apart. All experimental sessions 
will be carried out in an identical manner to the first session. 
 
 
 


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PSYCHOTHERAPY AFTER EXPERIMENTAL SESSIONS 
You will have regular psychotherapy to help you express, understand, bring together and connect 
any thoughts or feelings you may be having about your symptoms and their causes, and to think 
and talk about your experience during experimental sessions. You will have psychotherapy with 
the study therapists the morning of the day after each experimental session and then two more 
visits during the next three to five weeks after each experimental session. These sessions will last 
60 to 90 minutes. You and the study therapists will also talk about 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. 
Each regular psychotherapy session will be recorded to audio and video, just like the 
introductory and experimental sessions, and you can hear, see, or have a copy of these 
recordings. 
 
Before starting psychotherapy on the day after each experimental session, you will be asked to 
guess whether you got 30, 75 or 125 mg MDMA. You will not be told if your guess is correct. 
The researchers will ask you about thoughts about killing or harming yourself during each 
follow-up session, and during the second and seventh day of telephone contact with the study 
doctors. 
 
MEASURING PTSD AFTER EXPERIMENTAL SESSIONS 
Approximately four months after the start of the study (one month after the second 
experimental session), you will meet with a study researcher who is not one of the study 
therapists.  You will be asked not to tell this researcher what your guess is about what dose of 
MDMA you think you received.  The study researcher will ask you questions about your PTSD 
symptoms, (which may be videotaped with your permission). You will also complete a 
questionnaire on feelings of depression, dissociation symptoms, a questionnaire on your sleep 
quality, a personality questionnaire, and one more questionnaire related to your PTSD. This visit 
should last up to two hours. The researchers will ask you about thoughts about killing or harming 
yourself.  You will also complete the scale of pain and tinnitus levels if you had these problems 
before the study. 
 
After you complete these tests, you will meet with the study therapists and all of you will find 
out if you received 30, 75 or 125 mg MDMA. The study researcher who measured your PTSD 
symptoms will not find out. 
 
If you learn that you had the low (30 mg) or medium (75 mg) dose of MDMA, you can then 
enroll in “open label” study sessions, or “Stage 2,” described below. If you decide not to 
participate in Stage 2, then you will complete a questionnaire about your experience as a research 
subject before you leave the first part of the study.  
 
If you are in the full dose group (125 mg), you will be asked about your thoughts on having a 
third experimental session. 
 
Full Dose (125 mg) Group Only – 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 (which may be videotaped, with your 
permission), and you will fill out a questionnaire on feelings of depression, another questionnaire 


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on PTSD, a dissociation symptoms questionnaire, and a sleep quality questionnaire. 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.  
 
The tests will help the study therapists tell if your symptoms have changed or stayed the same 
over time. 
 
You will complete a questionnaire about your experience as a research subject before you leave 
the first part of the study.  You will be asked about your thoughts on having a third experimental 
session. The study therapists will give you a memory aid card. This card is to help you to 
remember any new problems or medical conditions, or changes in medication during the months 
between this visit and your last visit, the 12-month follow-up visit.  On this card you will record 
any new important health problems, changes to your mental health, hospitalizations and 
medications to treat these problems. 
 
OPEN-LABEL MDMA SESSIONS FOR PEOPLE WHO RECEIVED 30 OR 75 MG MDMA (STAGE 2) 
If you are one of the twelve subjects who received 30 or 75 mg MDMA, you can take part in 
three open-label MDMA-assisted sessions scheduled 3 to 5 weeks apart as part of Stage 2.  In 
this study segment, you will receive an active dose of MDMA (either 100 mg possibly followed 
by 50mg or 125 mg possibly followed by 62.5 mg) , with the 125 and 62.5 doses possible during 
the second and third sessions. . Stage 2 can start any time after you learn what dose of MDMA 
you received but not later than five months after that point. Signing this consent form means you 
agree to take part in the second part of the study though you can change your mind at any time 
and still take part in the 12 month follow up without participating in Stage 2. The twelve people 
who receive a full dose of MDMA during the first stage of the study cannot take part in 
Stage 2.  
 
If more than 8 weeks pass between Stage 1 and Stage 2, you will need answer questions about 
your PTSD symptoms, and the questionnaires about depression, dissociation, and sleep quality 
again before you start Stage 2. If you take part in Stage 2, you will have 15 more visits. These 
sessions will be like the experimental ones you had during the first part of the study, except that 
you will know you are getting an active dose of MDMA and will have 3 experimental sessions 
instead of only two. You will also only have one review and introductory session instead of 
three. Otherwise, you will have three experimental sessions scheduled three weeks apart 
followed by an overnight stay and non-drug integrative therapy afterwards. You will complete 
the scale of pain and tinnitus levels if you notice changes in your symptoms that you had before 
the study. You will have tests of your PTSD symptoms and complete a questionnaire on 
symptoms of depression, dissociation symptoms, and sleep quality one and two months after the 
third open-label session, and a personality questionnaire two months after the third session. You 
will also be asked if you had any thoughts about hurting or killing yourself during that time.  
You will be asked about your thoughts on the experimental sessions before and after your third 
session.  At the 2-month follow-up, you will complete a questionnaire about your experience as a 
research subject.  The study therapists will give you a memory aid card. This card is to help you 
to remember any new problems or medical conditions, or changes in medication during the 
months between this visit and your last visit, the 12-month follow-up visit. On this card you will 
record any new important health problems, changes to your mental health, hospitalizations and 
medications to treat these problems 


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LONG-TERM FOLLOW-UP 12 MONTHS AFTER LAST EXPERIMENTAL SESSION FOR ALL PARTICIPANTS 
Approximately 12 months after your last MDMA-assisted session, you will answer questions 
about your PTSD symptoms, dissociation symptoms, feelings of depression and sleep quality, 
and a personality questionnaire, and you will fill out a questionnaire on the positive and negative 
effects of being in the study.  You will complete the scale of pain and tinnitus levels if you had 
them before 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 open-label session. 
 
The same study researcher who asked you about your PTSD symptoms will do so again, either in 
person or over the telephone. The study therapists will ask you about any changes in medications 
or your psychiatric health, including any benefits or harms, during the follow-up period between 
your last visit and the 12-month follow-up visit. 
 
You will also answer the questionnaire about feelings of depression, your personality, your sleep 
quality and another PTSD-related questionnaire. The questionnaires will include questions about 
any thoughts, feelings or events that happened after being in the study. You will also answer a 
questionnaire about your attitudes and feelings about being in the study, any thoughts you have 
about the good and bad points of MDMA-assisted therapy, and your thoughts about taking 
MDMA. There are no right or wrong answers to these questions. 
 
A researcher who is a part of the study team will ask you about any changes in medication or 
your psychiatric health, including any benefits or harms, during the follow-up period between 
your last visit and the 12-month follow-up visit. 
 
The questionnaires will 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 
questionnaire. 
 
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. They may 
be able to learn what happens to people who started out receiving full dose MDMA versus 
people who received lower doses of MDMA first, and then received full dose MDMA. 
 
POSSIBLE RISKS OR DISCOMFORTS 
MDMA has not been widely tested in humans, but as of May 2013 approximately 845 people 
have received MDMA in clinical research settings, without any serious problems happening. 
 
There may be unknown side effects or risks from the use of MDMA. 
 
Side effects during the MDMA experience that are less severe but more frequently reported, are:  
 
 Lack of appetite (68%) 
 Dry mouth (64%) 
 Teeth grinding or tight jaw muscles (60%)  
 Decreased concentration (53%) 
 Thirst (48%) 
 Restlessness (46%) 


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Subject’s Initials _______ 
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%) 
 
In previous studies and in a placebo-controlled study of MDMA-assisted psychotherapy in 
people with PTSD, 48% to 77% of subjects reported  
 
 Nausea,  
 Low mood,  
 Feeling cold,  
 Dizziness,  
 Impaired balance,  
 Disturbance in attention,  
 Restlessness,  
 Perspiration,  
 Thirst,  
 Feeling weak, and  
 Need for more sleep (listed 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. 
 
There may be unknown side effects or risks from the use of MDMA. 
 
Other possible risks of MDMA may include the following: 
 
Serious problems: There have been some serious problems, and even deaths, associated with the 
use of Ecstasy outside of controlled clinical or laboratory settings.  These problems have 
included high fever, brain swelling associated with drinking too much liquid, convulsions, and 
liver damage.  Some recreational users of Ecstasy have become severely anxious, depressed or 
paranoid (thinking that other people are out to get them).  Since you will be receiving moderate 
amounts of 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 either during or after the experimental session.  While this does not guarantee that they 
will not occur, it does mean that if they do occur, the study doctors are prepared to respond in a 
safe and professional manner. 
 


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Subject’s Initials _______ 
Changes in vision, hearing or other senses:  Most subjects that participated in previous MDMA 
studies reported experiencing temporary and minor changes in vision and hearing, such as 
sounds seeming closer or farther away than usual or objects seeming brighter than usual. . These 
changes typically lasted 2 to 3 hours. Between 12% and 33% of people who took MDMA also 
reported unusual feelings in their bodies, such as tingling or numbness. 
 
Blood pressure and heart rate:  The 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 approximately 
30 beats per minute (BPM). 
 
In previous studies, blood pressure rose well above normal levels in a few subjects (a little less 
than 5%) after receiving MDMA, but these subjects did not report any discomfort and did not 
require any treatment. Although these increases in blood pressure are similar to what happens 
after heavy exercise, they could cause serious problems in individuals with pre-existing heart or 
vessel conditions. These serious problems could include heart attack or stroke.  We will screen 
all potential subjects for preexisting heart problems before they are allowed to be in this study. 
While this doesn't guarantee that no heart problems will occur, it does reduce the risk of this 
happening. 
 
Anxious or jittery feeling: Some subjects in previous studies (16%) reported feeling over-
stimulated or anxious. These feelings usually lasted less than 30 minutes.  Letting yourself accept 
and feel these emotions deeply can be part of the psychotherapy. If you are not able to deal with 
these experiences in a way that helps you, the study doctors 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 
researchers may require you to be admitted to a hospital. 
 
Insomnia & drowsiness:  In previous studies, between 17% and 23% of subjects have reported 
insomnia (difficulty sleeping) or feeling tired, irritable, or drowsy for as long as 3 days after 
receiving MDMA.  You should not drive or use machinery immediately after each 
experimental session (up to 24 hours afterwards).  This is because the study drug may cause 
drowsiness, lack of coordination or slower reaction time. 
 
Mood:  Some after-effects of MDMA may be noticeable up to 2 or 3 days later. While some 
subjects feel that their mood is better, 14% feel that it is worse. 
 
Immune System: You may have a less active immune system for 2 or 3 days after receiving 
MDMA. This may make you more likely to become sick with a cold or other infection during 
this time. The study describing this finding did not report how many people in the study showed 
these changes. 


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Addiction:  There is a small chance that you will become dependent on (addicted to) MDMA. 
One study found that up to 6% of people using Ecstasy for recreational purposes were dependent 
on it.  However, a study of people who had received MDMA for the first time in a legal 
laboratory setting found that they did not want to try MDMA again outside of the laboratory. 
 
People who have recently (in the last 2 months) had problems with drug abuse should not take 
part in this study. 
 
Possible Brain Damage: Experiments in rats and monkeys show that high and repeated doses of 
MDMA can change certain brain cells that release a chemical called serotonin; in mice (though 
not in humans), the affected cells release dopamine. The changes include loss of the parts of the 
cell (called "axons") that connect different brain areas. Rodents given repeated, high doses of 
MDMA are less sensitive to a later dose of MDMA, are more likely to become overheated when 
placed in a warm room, and some studies find they perform worse in difficult memory tests. 
Recent studies in monkeys and rodents suggest that the doses used in these studies are far higher 
than those typically taken by humans in either recreational or laboratory settings. 
 
Many studies found that people who had used Ecstasy many times in recreational contexts were 
not able to recall words, pictures or patterns as well as people who did not use Ecstasy, and 
performed less well on tests of planning and impulse control. These differences are not great, but 
they have lasted for at least a year after people had stopped taking Ecstasy.  Not all studies have 
found Ecstasy users to have difficulty recalling words or pictures or to have impulse control 
problems.  When compared with people who do not use Ecstasy, studies found Ecstasy users 
were more likely to report feeling generally anxious or depressed. Many of these studies found 
that using alcohol or other drugs was also associated with feeling anxious or depressed.  At least 
two studies found that people who are anxious, depressed or have psychological problems before 
taking any drugs are more likely to take Ecstasy than people without these problems, but there is 
no proof that MDMA might not cause these problems in some people. 
 
Only one study has looked at brain scans of people before they got MDMA and then again after 
they have received one or two moderate doses of MDMA. This study did not show any changes 
in the brain following MDMA, though it is possible that there were changes that were too small 
to notice. Other studies looked at people before and after they decided to take a few tablets of 
Ecstasy in a recreational setting, and found one small change in the amount of blood flow in a 
specific part of the brain, but did not show signs of brain injury. The decrease in blood volume 
might be from temporary lowering of a type of brain receptor, or it might be a sign of reduced 
function in this area. Findings from these studies suggest that the amount of MDMA you will 
receive in this study will not produce any lasting changes in your brain, though this is not 
guaranteed. 
 
Studies of people receiving one or two doses of MDMA in a laboratory setting have not found 
any lasting changes in memory or planning. Studies comparing people before and after they 
decided to take a few tablets of Ecstasy in a recreational setting with people who did not take 
them found less improvement in memory in the people who took Ecstasy, and no other changes 
in thinking or planning. It is believed that the amount of MDMA you will receive will not 
produce any lasting changes in memory or planning, though this cannot be guaranteed. 
 


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Subject’s Initials _______ 
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 hospital.  
 
Other Risks of Being in the Study: 
 
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 
 to verify that you are in 
this study. 
 
The interviews you have during the study involve no specific risks or discomforts beyond those of 
a standard clinical interview situation. You may feel upset at the review of your emotional 
experiences, or you may feel boredom or fatigue. Answering questions about thoughts you might 
have of hurting or killing yourself may be upsetting. 
 
The medical evaluation involves some blood tests. The risks of blood drawing include temporary 
discomfort from the needle stick, bruising and, rarely, infection at the site of the needle stick. 
Fainting could also happen. 
 
It is possible that after you stop taking psychiatric medicine (as for depression or anxiety) as part 
of the study, you may start to have symptoms again. There is also a risk that you may have 
thoughts of hurting or killing yourself when you stop taking medicine and are in psychotherapy, 
especially if you have had these thoughts before.  If this happens, you should talk with your 
outside therapist and 
 If you have to start taking 
medicine again, then the study doctors will have to take you out of the study. 
 
REPRODUCTIVE RISKS 
Effects of MDMA on the growth and development of an unborn baby are not known. Birth defects 
could include physical deformities, mental retardation and premature birth; therefore you will not 
be allowed to enter the study if you are pregnant.  If you become pregnant after you have had at 
least one experimental session, the study doctors and the sponsor (MAPS) will ask you about and 
keep track of the pregnancy and will need to know about the outcome of your pregnancy. 
 
Women who are able to become pregnant must use one of the allowed birth control methods, such 
as birth-control pills or shots, IUDs, and diaphragms used along with spermicide and with partner 
use of condoms, or sexual abstinence while they are in the study and for at least one month 
afterward. The study therapists will explain these methods to you and will help you decide which 
might be best for you, and they can suggest to you where you can get more information and 
advice. 
 
If you are a woman of childbearing potential, you will be tested at the start of the study and again 
before each MDMA session to see if you are pregnant.  If, at any time during the study, you think 
that you may be pregnant or are worried that you may become pregnant, you must contact 
 
 immediately.  If you should become pregnant during the 
study, the study doctors will help you get proper advice and help you and your unborn baby get 
proper care while you are pregnant. 
 


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Subject’s Initials _______ 
NEW FINDINGS 
If any new information becomes available about MDMA while you are taking part in this study, 
the study therapists will tell you about it as soon as possible. You may contact the study doctor at 
any time after your participation ends to find out if any new information about this study has 
become available. 
 
POSSIBLE BENEFITS 
Your symptoms of PTSD may improve while participating in this study. There is no guarantee 
that you will benefit from taking part in this research study, however, information obtained from 
this study may help doctors and 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 that are a part of this study, for the psychological and laboratory testing, for medical 
examinations, including any extra tests you might have solely to see if you can be in the study (if 
you are eligible) and for the study drug.  You, your private medical insurance (if any), 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 company will remain responsible for on-going treatment 
unrelated to the study. 
 
PAYMENT FOR PARTICIPATION 
The Sponsor, MAPS, will reimburse you for travel related expenses as follows: 
 
Subjects who drive to the study site: 
If you must drive more than 50 miles round trip for visits, you will be reimbursed at a rate of 
$0.25 per mile.  If you live far enough away that it is not practical or desirable to make the round 
trip in one day, MAPS will pay up to $150.00 a night for all motel bills and up to $50.00 per day 
for meals. 
 
Subjects who fly to the study site: 
MAPS will pay for all travel expenses submitted by you for reimbursement.  MAPS will pay up 
to $150.00 a night for all motel bills and up to $50.00 per day for meals. 
 
If you must pay for travel or parking, the researchers will pay you back the costs of travel or 
parking. 
 
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 medicines, 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 having psychotherapy and/or taking medicine, you could 
continue with those for a longer period of time. The study doctor can discuss the alternatives and 
their potential risks and benefits with you. 
 
 


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Subject’s Initials _______ 
CONFIDENTIALITY 
To ensure confidentiality, only subject numbers will be provided to the study sponsor. 
When not in use, subject information will be stored in a locked office. Absolute confidentiality 
cannot be guaranteed. 
 
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. 
 
Medical records, including audiotapes and videotapes, which identify you and the consent form 
signed by you will be looked at and/or copied for research or regulatory purposes.  First any 
information that could directly identify you will be removed.  Medical records may be looked at 
by: 
 
 the sponsor, MAPS; 
 the FDA and similar agencies in other countries; 
 the Department of Health and Human Services (DHHS) agencies; 
 governmental agencies in other countries; and 
 the Copernicus Group Independent Review Board (IRB). 
 
The results of this research study may be presented in meetings or in publications.  Your identity 
will not be disclosed in those presentations. 
 
All records in 
 are subject to subpoena by a court of law. 
 
Audiotapes and videotapes:  The study therapists will listen to or watch these recordings, as well 
MAPS staff and other researchers seeking to better understand the principles of MDMA-assisted 
psychotherapy.  No identifying information will be written or otherwise attached to the tape 
recordings.  You may listen to or watch the recording if you wish, but you do not have to.  You 
will not automatically receive a copy of the recordings of your experimental session, but if you 
wish, you may receive a copy of the recording. 
 
You have the right to check your study records and ask for 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 physician who treats you will bill your insurance 
company.  If your insurance company denies coverage or insurance is not available, then MAPS 
will pay for any costs that arise from treating a study-related injury, including hospitalization.  
Neither the Sponsor nor the study doctor has a program in place to provide additional 
compensation in the event of an injury. 
 


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Subject’s Initials _______ 
Your health insurance may not be willing to pay for the costs of treating a study-related 
emergency.  The study sponsor (MAPS) will pay for any study-related procedure that your 
insurance will not cover. 
 
LEGAL RIGHTS 
The above section does not restrict your right to seek legal assistance. You do not waive any 
legal rights by signing this 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 take part. 
 
In addition, you may withdraw from (leave, stop being in) the study at any time. There will be no 
penalty if you decide to withdraw from the research study. Before withdrawing from this study, 
notify your study doctor that you wish to withdraw. This notice will allow your study doctor to 
inform you if there are any potential medical risks of withdrawal. You may be asked to return to 
the clinic for tests. 
 
WITHDRAWAL 
Your doctor, the sponsor company, or the FDA has the right to stop your participation in the 
study at any time, with or without your consent, for any of the following reasons: if you have an 
adverse effect from the study drugs, if you need a treatment not allowed in this study, such as 
restarting medication for depression or anxiety, if you do not keep appointments, if you do not 
take the study drug as instructed, if you become pregnant, or if the study is canceled by the FDA 
or the sponsor company. 
 
CONTACT FOR QUESTIONS 
If you have any questions or concerns about your participation in this research study or if you 
feel that you have experienced a research-related injury or reaction to the study drug, or have a 
complaint about the research study, contact: 
 
Investigator Name: 
 
 
Daytime telephone number(s): 
 
 
24-hour contact number(s): 
 


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Subject’s Initials _______ 
If you have any questions or concerns about your rights as a research subject or want to discuss a 
problem, get information or offer input, you may contact Copernicus Group Independent Review 
Board (IRB) at 1-888-303-2224 (toll free).  An IRB is a group of scientific and non-scientific 
individuals who perform the initial and ongoing ethical review of the research study with the 
study subject’s rights and welfare in mind.  Copernicus Group IRB has reviewed and approved 
the research study described in this Subject Information and Consent Form.  If you have study-
related comments, complaints or concerns, you should first contact the study investigator.  Please 
call the IRB if you want to talk to someone other than the study investigator or have difficulty 
reaching the study investigator.  For further information regarding the clinical trials process and 
your role as a research subject, you may visit the Copernicus Group IRB website at 
www.cgirb.com. 
 
The researchers will give you a wallet card containing contact information for the researchers, 
the sponsor and the IRB. 
 
Do not sign this consent form unless you have had a chance to ask questions and have 
received satisfactory answers to all of your questions.


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SUBJECT’S STATEMENT OF CONSENT 
 
“A Randomized, Triple-Blind Phase 2 Pilot Study Comparing 3 Different Doses of MDMA in 
conjunction with manualized psychotherapy in 24 Veterans, Firefighters, and Police Officers 
with Chronic, Treatment-resistant Posttraumatic Stress Disorder (PTSD)” 
 
My participation in this study is voluntary.  I may refuse to take part in or I may stop taking part 
in this study at any time.  I will call the researchers if I decide to do this.  My decision will not 
affect my current or future regular medical care or any benefits to which I am entitled at this site. 
The researchers and/or the sponsor may stop my participation in this study at any time without 
my consent if they decide it is in my best interest or if I do not follow the researchers’ 
instructions. 
 
I agree to have my sessions audio and video taped during this study. 
 
I have read the information in this consent form and it has been discussed with me.  I have been 
given sufficient opportunity to consider whether to participate in this study. All of my questions 
so far about the study and my participation in it have been answered.  I freely consent to 
participate in this research study. 
 
By signing this consent form, I have not waived any of the legal rights which I otherwise would 
have as a subject in a research study.  I have been told that I will be given a copy of this consent 
form signed by you and the investigator. 
 
 
SUBJECT 
 
INVESTIGATOR 
Printed Name 
 
 
Signature 
 
 
Date 
 
 


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Subject Initials ______ 
AUTHORIZATION TO USE AND DISCLOSE 
PERSONAL HEALTH INFORMATION FOR RESEARCH 
 
The United States government has issued a privacy rule to protect the privacy rights of patients.  
This rule was issued under a law called the Health Insurance Portability and Accountability Act 
of 1996 (HIPAA).  The Privacy Rule is designed to protect the confidentiality of your personal 
health information.  The document you are reading, called an “Authorization”, describes your 
rights and explains how your health information will be used and disclosed (shared). 
 
In working with the sponsor, the study doctor, 
, will use and share 
personal health information about you.  This is information about your health that also includes 
your name, address, telephone number or other facts that could identify the health information as 
yours.  This includes information in your medical record and information created or collected 
during the study.  This information may include your medical history, physical exam and 
laboratory test results.  Some of these tests may have been done as part of your regular care.  The 
study doctor will use this information about you to complete this research. 
 
In most cases, the study doctor will use your initials and assign a code number to your 
information that is shared with the sponsor.  The sponsor and its representatives may review or 
copy your personal health information at the study site.  Regulatory authorities and the 
Copernicus Group Independent Review Board may also review or copy your information to 
make sure that the study is done properly or for other purposes required by law. 
 
By signing this Authorization, you allow the study doctor to use your personal health 
information to carry out and evaluate this study.  You also allow the study doctor to share your 
personal health information with: 
 
 the sponsor and its representatives 
 the Copernicus Group Independent Review Board 
 the U.S. Food and Drug Administration (FDA) 
 other regulatory agencies 
 
Your personal health information may be further shared by the groups above.  If shared by them, 
the information will no longer be covered by the Privacy Rule.  However, these groups are 
committed to keeping your personal health information confidential. 
 
You have the right to see and get a copy of your records related to the study for as long as the 
study doctor has this information.  However, by signing this Authorization you agree that you 
might not be able to review or receive some of your records related to the study until after the 
study has been completed. 
 


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You may choose to withdraw this Authorization at any time, but you must notify the study 
doctor in writing.  Send your written withdrawal notice to: 
 
 
  
 
 
If you withdraw from the study and withdraw your Authorization, no new information will be 
collected for study purposes unless the information concerns an adverse event (a bad effect) 
related to the study.  If an adverse event occurs, your entire medical record may be reviewed.  
All information that has already been collected for study purposes, and any new information 
about an adverse event related to the study, will be sent to the study sponsor. 
 
If you withdraw from the study but do not withdraw your Authorization, new personal health 
information may be collected until this study ends. 
 
This Authorization does not have an expiration date.  If you do not withdraw this Authorization 
in writing, it will remain in effect indefinitely.  Your study doctor will keep this Authorization 
for at least 6 years. 
 
If you do not sign this Authorization, you cannot participate in this research study or receive 
study drug.  If you withdraw this Authorization in the future, you will no longer be able to 
participate in this study.  Your decision to withdraw your Authorization or not to participate will 
not involve any penalty or loss of access to treatment or other benefits to which you are entitled. 
 
AUTHORIZATION 
I authorize the release of my medical records and personal health information related to this 
study to the sponsor and its representatives, the Copernicus Group Independent Review Board, 
the FDA, and other regulatory agencies as described above.  I have been told that I will receive a 
signed and dated copy of this Authorization for my records. 
 
 
SUBJECT 
 
INVESTIGATOR 
Printed Name 
 
 
Signature 
 
 
Date 
 
 
 

Prot_003.pdf: 
MAPS Study # MP8 
1 of 79 
Amendment 5 Version 1  
US 
 
August 16, 2013 
PROTOCOL MP-8 
IND #63,384 
 
Original: December 17, 2009 
Amendment 1 Version 2: March 3, 2010  
Amendment 2 Version 1: August 31, 2010 
Amendment 3 Version 1: July 25, 2011 
Amendment 4 Version 1:  February 6, 2012 
Amendment 5 Version 1:  August 14, 2013 
 
 
A Randomized, Triple-Blind, Phase 2 Pilot Study Comparing 3 Different Doses of 
MDMA in Conjunction with Manualized Psychotherapy in 24 Veterans, 
Firefighters, and Police Officers with Chronic, Treatment-Resistant Posttraumatic 
Stress Disorder (PTSD) 
SPONSOR 
Multidisciplinary Association for Psychedelic 
Studies (MAPS) 
309 Cedar Street, #2323 
Santa Cruz, CA 95060 
SPONSOR DESIGNEE 
Amy Emerson 
Phone number: 510-393-7224 
 
CLINICAL INVESTIGATOR 
Michael C. Mithoefer, M.D. 
Assistant Clinical Professor of Psychiatry 
Medical University of South Carolina 
208 Scott Street 
Mount Pleasant, SC 29464 
Phone number:  843-849-6899 
MEDICAL MONITOR 
Julie Holland MD  
200 East 33rd Street, Suite 16H 
New York, NY 10016 
Voice mail: 212-358-5808 
  
STUDY MONITOR 
Berra Yazar-Klosinski PhD 
Phone number: 831-429-6362 ext. 104 
Fax number: 831-429-6370 
 
 
For trial related emergencies:  Phone number 650-248-4647 


MAPS Study # MP8 
2 of 79 
Amendment 5 Version 1  
US 
 
August 16, 2013 
Table of Contents 
 
1.0 List of Abbreviations _________________________________________________ 4!
2.0 Background Information______________________________________________ 6!
2.1 Introduction ____________________________________________________________ 6!
2.2 Protocol Purpose_________________________________________________________ 7!
2.3 Supporting Information___________________________________________________ 7!
3.0  Protocol Objectives __________________________________________________ 9!
3.2 Secondary Objectives ________________________________________________ 10!
4.0 Investigational Product ______________________________________________ 11!
4.1 MDMA Activity Related to Proposed Action ________________________________ 11!
4.2 MDMA Description _____________________________________________________ 12!
4.3 MDMA Doses, Compounding, and Labeling_________________________________ 12!
4.4 MDMA Accountability___________________________________________________ 14!
4.5 MDMA Storage and Handling ____________________________________________ 16!
4.6 MDMA Stability ________________________________________________________ 16!
5.0 Protocol Design ____________________________________________________ 17!
5.1 Planned Duration of Protocol _____________________________________________ 18!
5.2 Randomization and Subject Numbering ____________________________________ 19!
5.3 Recruitment and Subject Population _______________________________________ 19!
6.0 Methods __________________________________________________________ 23!
6.1 Assessments and Measures _______________________________________________ 25!
6.1.1 Outcome Measures ____________________________________________________ 25!
6.2 Visit Descriptions _______________________________________________________ 32!
6.3 Removal of Participants from the Study ____________________________________ 42!
6.4 Premature Discontinuation of the Study ____________________________________ 43!
7.0  Risks Of Study Participation _________________________________________ 43!
7.1 Screening ______________________________________________________________ 43!
7.2 Risks and Discomforts Associated with Drawing Blood________________________ 43!
7.3 Risks and Discomforts Associated with Non-Experimental and Experimental 
Psychotherapy_____________________________________________________________ 44!
7.4 Risks of Receiving MDMA _______________________________________________ 44!
8.0 Adverse Events _____________________________________________________ 51!


MAPS Study # MP8 
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August 16, 2013 
8.1 Common Expected Reactions _____________________________________________ 52!
8.2 Serious Adverse Events __________________________________________________ 52!
8.3 Adverse Event Collection_________________________________________________ 53!
9.0 Collection of Concomitant Medications _________________________________ 54!
10.0  Clinical Laboratory Assessments _____________________________________ 56!
11.0 Study Monitoring, Auditing and Documentation_________________________ 57!
12.0 Data Analysis _____________________________________________________ 58!
12.1 Statistical power _______________________________________________________ 60!
13.0  Informed Consent _________________________________________________ 60!
13.1 Confidentiality ________________________________________________________ 61!
13.2 Costs to Participants ___________________________________________________ 62!
13.3 Treatment and Compensation of Study Related Injury _______________________ 62!
14.0 Record Retention __________________________________________________ 62!
15.0 References _______________________________________________________ 64!
Appendix A: Prevention and Response to Possible Serious Adverse Events_____ Error! 
Bookmark not defined.!
Appendix B: Audio and Video Recording___________________________________ 79!
 


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August 16, 2013 
1.0 List of Abbreviations 
ACLS  
Advanced cardiac life support 
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 
BLS 
 
Basic Life Support 
BP 
 
Blood Pressure 
BT 
 
Body Temperature 
BUN  
Blood Urea Nitrogen 
C 
 
Celsius 
CAPS  
Clinician Administered PTSD Scale 
CPK 
 
Creatine Phosphokinase 
CRA  
Clinical Research Associate 
CRF(s) 
Case Report Form(s) 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DEA  
Drug Enforcement Administration 
DES-II  
Dissociative Experiences Scale II 
DBP 
 
Diastolic Blood Pressure 
DMF  
Drug Master File 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders - IV 
ECG  
Electrocardiogram 
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 
HCV  
Hepatitis C Virus 
HIPAA  
Health Insurance Portability and Accountability 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  
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
LSD 
 
d-lysergic acid diethylamide 


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MAPS  
Multidisciplinary Association for Psychedelic Studies  
MCH  
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV   
Mean Corpuscular Volume 
MDMA 
3,4-methylenedioxymethamphetamine 
NEO PI 
Neuroticism-Extroversion-Openness Personality Inventory 
NK 
 
Natural Killer 
OTC  
Over the counter (non-prescription) 
PSQI  
Pittsburgh Sleep Quality Index 
PT 
 
Prothrombin Time 
 
PTCA   
Percutaneous Transluminal Coronary Angioplasty 
PTGI  
Post Traumatic Growth Inventory 
PTSD  
Posttraumatic Stress Disorder 
PTT 
 
Partial Thromboplastin Time 
RBC  
Red Blood Cell Count 
RDW  
Red Cell Distribution Width 
RCT 
 
Randomized clinical trial 
RRPQ  
Reactions to Research Participation Questionnaire 
SAE(s) 
Serious Adverse Event(s) 
SBP 
 
Systolic Blood Pressure 
SCID-I-RV 
Structured Clinical Interview for Diagnoses Axis I Research Version 
SERT   
Serotonin Transporter 
SOCQ  
States of Consciousness Questionnaire 
SOP(s)  
Standard Operating Procedure(s) 
SSRI  
Selective Serotonin Reuptake Inhibitor  
Stage 1 
Randomized, double blind study arm 
Stage 2 
Open-label, partial crossover study arm 
SUD   
Subjective Units of Distress 
TSH 
 
Thyroid Stimulating Hormones 
U.S. 
 
United States of America 
WBC   
White Blood Cell Count 


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2.0 Background Information 
2.1 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 posttraumatic stress disorder (PTSD). 
 
Encouraging data has been obtained and submitted to the FDA from MAPS’ recently 
completed United States (U.S.) pilot study, IND #63-384 (MP1).  MAPS is currently 
sponsoring another Phase 2 study in Switzerland. An additional Phase 2 study is planned 
to start in the near future in Canada, with approval from Health Canada and a Canadian 
Institutional Review Board (IRB) already obtained.  Ongoing and planned Phase 2 
studies, along with the study described in this protocol, are laying the groundwork for an 
eventual End-of-Phase 2 meeting with FDA and possible Phase 3 multi-site 
MDMA/PTSD research studies.  
 
The proposed pilot study will examine the safety and efficacy of MDMA-assisted 
psychotherapy in twenty-four veterans, firefighters or police officers with service related 
PTSD, and will seek to enroll roughly equal numbers of men and women. This study will 
include those with chronic PTSD of at least six months duration who satisfy PTSD 
diagnostic criteria despite having received prior treatment with either medication or 
psychotherapy.  Full, medium and low dose MDMA will be assessed in Stage 1, as well 
as the benefit of three vs. two full dose sessions. Subjects who received the medium and 
low 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 open-label experimental sessions. Stage 
2 will be used to explore the optimal therapeutic dose of MDMA using a clinical titration 
dosing strategy. 
 
MAPS’ initial U.S. pilot study enrolled 21 subjects, a majority (17) of whom were 
women suffering from PTSD related to sexual assault and/or childhood sexual abuse[1, 
2] . Only two subjects had PTSD from war-related trauma (U.S. veterans of the Iraq War) 
and both were male. According to the European Medicines Agency (EMEA) Guideline 
for the Development of Medicinal Products for the Treatment of PTSD, it is desirable to 
examine treatment response in homogenous samples, conducting separate trials for 
different populations.  The findings from this proposed study in veterans, firefighters and 
police officers with service related trauma will be compared with results from our initial 
U.S. pilot study, mostly in women survivors of sexual abuse and assault.  
 
In order to refine our triple-blind methodology, the proposed study will also evaluate 
three different doses of MDMA to determine their relative success in achieving blinding 
of therapists, subjects, and independent raters.  
 


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In addition, this will be the first study of MDMA-assisted psychotherapy to permit the 
enrollment of subjects with two medical conditions that were exclusion criteria in the 
previous trial; Hepatitis-C, and controlled hypertension. Should any subjects with these 
conditions seek enrollment in the study, they will be required to go through additional 
specified screening procedures and additional monitoring for safety during the 
experimental sessions. 
 
A review of the published, peer-reviewed MDMA research literature is contained in the 
Investigator’s Brochure supplied by the sponsor.  This document should be reviewed by 
the investigator prior to initiating the protocol. 
 
2.2 Protocol Purpose 
 
2.3 Supporting Information 
 
2.3.1 Posttraumatic Stress Disorder 
PTSD is a serious, worldwide public health problem for which a wider array of effective 
treatments is needed. In the U.S., the lifetime prevalence of PTSD in the general  
population is between 6 and 10% [3].  Combat exposure can produce a form of PTSD 
that is “chronic, disabling and highly comorbid.” [4, 5], and that can be especially 
resistant to pharmacotherapy with Selective Serotonin Reuptake Inhibitors (SSRIs) [6]. 
PTSD is common in other countries as well [7-11]. In U.S. soldiers returning from 
combat in the Iraq war, the incidence of PTSD is as high as 18% [12], and it is estimated 
that the number of service members returning home from the Iraq and Afghanistan wars 
with PTSD will be between 75,000 and 225,000 [13]. In 2004, the U.S. Veterans 
Administration spent $4.3 billion on PTSD disability payments to approximately 215,000 
veterans, most of them from the Vietnam War [14].  Due to the Iraq and Afghanistan 
wars, the number of veterans disabled by PTSD, and the cost of providing disability 
payments, has increased substantially since 2004.  In countries where there is endemic 
armed conflict, the incidence of PTSD in civilians is often far greater [15-17].  PTSD is 
typically a chronic illness [18, 19], associated with high rates of psychiatric and medical 
co-morbidity, disability, suffering and suicide [9, 18, 20, 21]. During an appearance at a 
gathering of mental health professionals on October 26, 2009, U.S. Secretary of Defense 
Robert Gates stated that “Beyond waging the wars we are in, treatment of our wounded, 
their continuing care, and eventual reintegration into everyday life is my highest priority. 
... I consider this a solemn pact between those who have suffered and the nation that owes 
them its eternal gratitude." [22] 
 
An array of psychotherapeutic options exists for treating PTSD and two SSRIs (sertraline 
and paroxetine) are approved as PTSD treatments by the FDA. However, a significant 
minority of PTSD patients fail to respond adequately to established PTSD 
psychotherapies [23, 24], or respond in ways that are statistically significant but clinically 
inadequate. At least one study of paroxetine indicated that men with PTSD did not 


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respond to this drug [25].  These findings suggest that there is still substantial need for 
innovative treatments for PTSD.  
 
There is limited data about whether or not patients with war related PTSD are more 
difficult to treat than those with PTSD from other causes.  A recent comprehensive 
review stated that, “Most, but not all, randomized clinical trials (RCTs) with combat 
(mostly Vietnam War) veterans showed less treatment efficacy than RCTs with 
nonveterans whose PTSD was related to other traumatic experiences. … Therefore, some 
experts believe that combat veterans with PTSD are less responsive than survivors of 
other traumas to treatment.  Such a conclusion is premature. … More clinical trials with 
combat veterans would be important and welcome additions to this literature” [26].   
 
In recent years, there has been growing research into drugs or other methods that may 
augment the effectiveness of psychotherapy for PTSD.  Examples of this are virtual 
reality-assisted exposure therapy [27, 28] and D-cycloserine-assisted psychotherapy [29].  
MDMA-assisted psychotherapy is another such approach that is being rigorously tested.  
 
2.3.2 MDMA-Assisted Psychotherapy for PTSD 
To date psychotherapy has been the mainstay of treatment for PTSD and has a larger 
effect size than that of psychopharmacologic treatment. Cognitive behavioral therapies, 
particularly prolonged exposure and cognitive processing therapy, are considered among 
the most effective psychotherapies. Other methods such as psychodynamic therapy and 
eye movement desensitization and reprocessing (EMDR) have also proved to be effective 
in treating some aspects of PTSD symptoms [30]. Some people may have to undergo 
more than one treatment to reduce or resolve PTSD symptoms [31].  However, a recent 
meta-analysis concluded that all “bona fide” psychotherapies, including all those listed 
above, are similarly effective for PTSD and had an average effect size of 0.25 [32].  
 
One innovative avenue of treatment is MDMA-assisted psychotherapy, which uses 
psychotherapy in combination with a pharmacological adjunct intended to amplify and 
enhance particular aspects of psychotherapy. MDMA possesses unique pharmacological 
and psychological properties that may make it especially well suited for use as an adjunct 
to psychotherapy with PTSD patients [33-38]. This treatment consists of several 
administrations of MDMA-assisted psychotherapy within the context of a time limited 
course of non-drug psychotherapy over three to four months. MDMA-assisted 
psychotherapy is hypothesized to reduce symptoms from all three symptom clusters 
experienced by individuals diagnosed with PTSD: re-experiencing, hyperarousal and 
avoidance. 
 
Anecdotal accounts, data from MAPS’ recently completed U.S. clinical trial, and 
preliminary data from MAPS’ Swiss MDMA/PTSD study, all suggest that MDMA may 
provide unique benefits to people with PTSD when administered in combination with 
psychotherapy. It may assist people in confronting memories, thoughts and feelings 
related to the trauma without increasing either fear or avoidance in response to this 


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confrontation. An increase in self-acceptance and increased feelings of closeness to 
others may also assist people with PTSD in forming a therapeutic alliance with 
psychotherapists. 
 
Treatment goals for PTSD include alleviating symptoms and interrupting the stress-
induced neurochemical abnormalities produced by the condition. One approach is to 
discover drugs that directly counteract these neurobiological changes. Paroxetine (Paxil) 
and sertraline (Zoloft) are the only two drugs approved by the FDA in the U.S. for 
treating PTSD, and are known to act largely via serotonin reuptake inhibition. They may 
also block the down-regulation of brain-derived neurotrophic factor, but it is not known 
whether they can arrest and reverse the hippocampal atrophy found in PTSD patients 
[39]. Another approach to treatment of PTSD is to develop drugs and/or 
psychotherapeutic treatments that will indirectly interrupt the destructive neurobiological 
changes by decreasing or eliminating the stress reactions to triggers and the chronic 
hyperarousal of PTSD. Reports of past experience with MDMA-assisted psychotherapy 
suggest that it may be effective in this way. In fact, the biologic and psychotherapeutic 
approaches overlap and re-enforce each other. Knowledge about the connections between 
the neurobiological and the therapeutic effects of MDMA is far from complete, but it has 
been observed that MDMA acutely decreases activity in the left amygdala [40]. This 
action is compatible with its reported reduction in fear or defensiveness, and is in contrast 
to the stimulation of the amygdala observed in animal models of conditioned fear, a state 
similar to PTSD [41, 42].  
 
2.4 Previous MDMA Research 
 
As of June 2011, MDMA has been administered to approximately 540 research 
participants, in both Phase 1 and Phase 2 studies, without any occurrences of drug-related 
Serious Adverse Events (SAEs) [43-56]. 
 
The highest initial and supplemental doses to be used in this study are 125 mg and 62.5 
mg respectively, the same doses used in previous studies taking place in the U.S., Canada 
and Israel. The lowest initial and supplemental doses (30 and 15 mg) are only five 
milligrams above the lowest dose (25 mg) used in some of these studies. Researchers 
have administered 75 mg of MDMA in a number of studies, including a study of 
MDMA-assisted psychotherapy in people with PTSD in Spain [33] and a series of basic 
research studies occurring in the Netherlands [e.g. 51, 57]. The addition of a 
supplemental dose half the size of the initial 75 mg dose produces a total dose of 112.5 
mg, which is below the dose used in the first U.S. investigation of MDMA-assisted 
psychotherapy.  
3.0 Protocol Objectives 
The overall objective of this study is to explore the safety and estimate the effect size of 
efficacy for MDMA-assisted psychotherapy in veterans, firefighters and police officers 
with PTSD, a group with a different index trauma from most subjects in prior 


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investigations of this experimental treatment.  
3.1 Primary Objective 
• Assess changes in PTSD symptoms via Clinician-Administered PTSD Scale 
(CAPS) global scores in participants receiving by condition in the randomized 
study arms at baseline and the primary endpoint, one month after the second 
experimental session.  
3.2 Secondary Objectives 
 
The following objectives will compare full, medium and low dose subjects in the blinded 
portion of Stage 1: 
 
• Assess changes in posttraumatic growth via Post Traumatic Growth Inventory 
(PTGI) scores from baseline to the primary endpoint.   
• Assess changes in global functioning via Global Assessment of Functioning 
(GAF) scores from baseline to the primary endpoint.   
• Assess changes in symptoms of depression via Beck Depression Inventory-II 
(BDI-II) scores from baseline to the primary endpoint.  
• Assess changes in self-reported sleep quality via the Pittsburgh Sleep Quality 
Index (PSQI) from baseline to the primary endpoint. 
• Assess self-reported dissociation symptoms with the Dissociative Experiences 
Scale II (DES-II) from baseline to the primary endpoint. 
• Assess changes in Neuroticism-Extroversion-Openness Personality Inventory 
(NEO PI) scores from baseline to the primary endpoint. 
The following objectives will compare effects in specified subjects: 
 
• Assess PTSD symptoms via CAPS, posttraumatic growth via PTGI, depression 
symptoms via BDI-II, global functioning via GAF, sleep quality via PSQI, 
dissociation symptoms via DES-II, and personality via NEO PI throughout Stage 
2 in comparison to Stage 1 in crossover subjects. 
• Assess long-term effects of receiving active dose MDMA on PTSD symptoms 
via CAPS, posttraumatic growth via PTGI, personality changes via NEO PI, 
depression symptoms via BDI-II, global functioning via GAF, and sleep quality 
via PSQI one year after the final experimental session for each participant. 
 
The following objectives will include exploratory analyses intended to inform protocol 
design: 
 
• Explore the effects of each MDMA-assisted psychotherapy 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 effects of a third active dose experimental session by comparing 
Global CAPS, BDI-II, GAF, PSQI, PTGI (in reference to start of the study), and 


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DES-II scores at the primary/secondary endpoint and end of Stage 1/ Stage 2 in 
subjects receiving a third experimental session in Stage 1 and Stage 2.  
• Assess the ability of the investigators and participants to accurately guess 
condition assignment when asked to do so after each blinded experimental 
session. 
• Assess value of third experimental session in Stage 1/Stage 2 by collecting each 
active dose subject's perception of experimental sessions at the 
primary/secondary endpoint and end of Stage 1/ Stage 2. 
• Correlate adherence to the Treatment Manual with Global CAPS scores using 
adherence criteria ratings to assess videos of psychotherapy sessions. 
 
3.3 Safety Objective 
To monitor and ensure safety of participants during and after experimental sessions by 
assessing physiological effects, psychological effects, adverse events, spontaneously 
reported reactions and suicidality. 
 
• Suicidality will be assessed with the Columbia Suicide Severity Rating Scale (C-
SSRS) before, during and after experimental sessions and on selected days of 
telephone or face-to-face contact, with comparisons made between subjects in 
each condition. 
• 
Subjective Units of Distress (SUD) and vital signs (blood pressure, heart rate and 
temperature) will be measured during each experimental session, and comparisons 
will be made for vital signs between conditions.  
• 
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.  
• 
Serious adverse events, adverse events and spontaneously reported reactions will 
be collected during the study according to Section 8. 
 
4.0 Investigational Product  
The investigational product that will be used in this study is MDMA HCl manufactured 
by David Nichols, Ph.D., Dept. of Medicinal Chemistry and Pharmacology, Purdue 
University in 1985.  See Section 4.6 below for more information. 
4.1 MDMA Activity Related to Proposed Action 
MDMA has a unique profile of psychopharmacological effects making it well suited to 
intensive psychotherapy.  In the context of psychotherapy, MDMA has been noted to 
reduce defenses and fear of emotional injury while enhancing communication and 
capacity for introspection [58, 59].  In the first completed study of MDMA-assisted 
psychotherapy in people with PTSD, the Clinical Investigator of this protocol reported a 
significantly greater reduction in PTSD symptoms, as assessed by an independent rater, 
in people who received MDMA with psychotherapy compared to those who received 
placebo and the same psychotherapy [1].  Placebo-controlled clinical trials have 
confirmed that MDMA produces an easily-controlled intoxication characterized by 


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euphoria, increased well being, sociability, self-confidence, and extroversion [60-67].  
Effects in samples of largely drug-naïve individuals are similar to those reported by 
people with previous experience with Ecstasy (see for example [60] versus [68]).  An 
increase in positive mood, increased access to emotionally intense material, increased 
interpersonal trust and compassion for the self and others, and anxiolysis likely all 
contribute to the therapeutic effects of MDMA.  It is significant that MDMA reduces 
anxiety without depressing the sensorium or inhibiting patients' capacity to experience 
and reflect upon intense emotions. Increased interpersonal closeness may permit patients 
to explore upsetting thoughts, memories or feelings. Facilitated recall and unusual and 
potentially innovative shifts in thinking and perception may contribute to generating new 
perspectives about past or current thoughts, feelings and experiences.  
 
4.2 MDMA Description  
The compound to be used in this protocol is MDMA.  This ring-substituted 
phenylisopropylamine has a complex pharmacology, but it acts most prominently as a 
monoamine releaser and uptake inhibitor [69-71].  Its direct actions on serotonergic, 
adrenergic and other receptors are considerably weaker.  
 
4.3 MDMA Doses, Compounding, and Labeling 
The study will employ three different dosage levels, with the lowest dosage considered 
low dose and the highest dosage level considered a full dose. All participants will receive 
an initial dose, and may upon agreement of the investigators, receive a supplemental dose 
half the size of the initial dose administered 1.5 to 2.5 hours after the initial dose.  
This protocol will follow a randomized, triple-blind, dose response design that will 
compare three doses of MDMA. The initial doses are 30 mg for low dose, a medium dose 
of 75 mg, and a full dose of 125 mg.  Twelve participants will receive an initial dose of 
125 mg of MDMA followed by an optional supplemental dose of 62.5 mg.  Six 
participants will receive an initial dose of 75 mg MDMA followed by an optional 
supplemental dose of 37.5 mg, and six participants will receive an initial dose of 30 mg 
followed by an optional supplemental dose of 15 mg.  
 
 
 
Table 1. Stage 1 Blinded Drug Doses for MP-8 
Condition 
Number of 
Subjects 
Initial Dose 
Supplemental 
Dose  
Min-Max 
Cumulative Dose 
Low Dose 
6 
30 mg 
15 mg 
30-45 mg 
Medium Dose 
6 
75 mg 
37.5 mg 
75-112.5 mg 
Full Dose 
12 
125 mg 
62.5 
125-187.5 mg 
 


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Table 2. Stage 2 Drug Doses for MP-8 
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 full MDMA dose to be used in this study is identical to those used in previous 
studies in the U.S., Switzerland, and Israel. Previous researchers have also used doses 
within this range [44, 51, 60-62, 65, 72-75]. Prior to the scheduling of MDMA, similar 
doses and regimens were used in psychotherapy [36, 37, 58]. The doses to be compared 
in this study have been chosen on the basis of the Sponsor’s ongoing initiative to develop 
a dose response curve of MDMA-assisted psychotherapy in the treatment of PTSD.  
The initial full dose is expected to produce all the commonly reported 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.  
 
The 100mg MDMA initial dose will be administered in the first experimental session in 
Stage 2 to enable a comparison of subjective and therapeutic effects to full dose MDMA. 
Prior to both the second and 3rd experimental sessions in Stage 2 the co-therapists, in 
consultation with the subject, will decide whether the same dose or an initial dose of 
125mg (each with the corresponding optional supplemental dose) would be more likely to 
constitute the optimal therapeutic dose for each of these experimental sessions. 
 
MDMA in bulk will be sent from Organix Inc., in Woburn, MA, to the Clinical 
Investigator, who has been issued the Schedule 1 license by the Drug Enforcement 
Agency (DEA). The Clinical Investigator and unblinded Randomization Monitor will 
oversee compounding by a pharmacist in a manner that will maintain the blind for the 
Clinical Investigator. The pharmacist will provide bulk lactose for compounding MDMA 
capsules.  The pharmacist will weigh the MDMA into doses of 125, 100, 75, 62.5, 50, 
37.5, 30, 25 and 12.5 mg (calculated as the weight of the hydrochloride salt) and placed 
in gelatin capsules in combination with lactose used to ensure that all blinded capsules 
have similar appearance and weight. Capsules for the initial dose will be a different color 
from capsules used for the supplemental dose. All capsules will be compounded so that 
they weigh the same amount, but contain varying amounts of MDMA and lactose. 
Capsules for all experimental, triple-blind sessions will be prepared in such a way as to 
prevent Clinical Investigators and subjects from distinguishing contents of blinded 
capsules. Dosage for open-label sessions will be clearly indicated in the packaging. 


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Doses of MDMA for each experimental session will be stored in separate primary 
containers labeled with the protocol number, drug name, lot number, unique container 
number, sponsor name and a statement that the drug is for clinical trial use only.  Labels 
for each container of MDMA will be provided by the sponsor and applied by the 
pharmacist. The contents of the blinded primary containers will be hidden from the 
investigator to assure blinding. 
 
Figure 1. Examples of Blinded Labels 
 
Holding Box Labels 
 
 
 
 
 
 
 
Stage 1 Primary Container Labels 
 
Blinded Labels 
Open Label Session 3 Labels 
MAPS Study MP-8 
Experimental Session #__ 
Container # XXX  
Subject #____________  
Administer as per protocol 
Investigational Use Only   
MAPS Study # MP-8 
Experimental Session #____ 
125 & 62.5mg 
Container # XXX  
Subject #____________  
Administer as per protocol  
Investigational Use Only  
Stage 1 Inner Envelope Labels 
                Blinded 
 
 
 
 
Blinded 
Stage 1                    Container # XXX 
INITIAL DOSE 
Subject #_________Ex. Ses # ______ 
 
Stage 1                    Container # XXX 
SUPPLEMENTAL DOSE 
Subject #_________Ex. Ses # ______ 
 
Open Label Session 3 
 
 
Open Label Session 3 
Stage 1                    Open Label 125mg 
INITIAL DOSE 
Subject #_________Ex. Ses # ______ 
 
Stage 1                     Open Label 62.5mg 
SUPPLEMENTAL DOSE 
Subject #_________Ex. Ses # ______ 
 
Stage 2 Primary Container Labels 
       Open Label Session 1 
 
 
         Open Label Session 2 or 3 
 
         
Box Label 
MAPS Study# MP-8 
Investigational Product: MDMA  
Dose: XXXmg 
Lot #: XXXXX 
Administer as per protocol 
Caution-Limited by Law to Investigational Use Only 


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MAPS Study # MP-8 
Stage 2 
100mg & 50mg MDMA 
Lot # XXX 
Container # XXX  
 
Subject #____________  
Experimental Session #1 
Administer as per protocol Investigational Use Only 
 
MAPS Study # MP-8 
Stage 2 
100+25mg & 50+12.5mg MDMA 
Lot # XXX 
Container # XXX  
 
Subject #____________  
Experimental Session #___  
Administer as per protocol Investigational Use Only 
 
Stage 2 Inner Envelope Labels 
              Open Label Session 1 
 
 
Open Label Session 1  
Stage 2                    Open Label 100mg 
INITIAL DOSE 
Subject #_________Ex. Ses # 1 
 
Stage 2                   Open Label 50mg 
SUPPLEMENTAL DOSE 
Subject #_________Ex. Ses # 1 
Open Label Session 2 or 3 
 
Open Label Session 2 or 3 
Stage 2                    Open Label 100mg 
INITIAL DOSE 
Subject #_________Ex. Ses # ___ 
 
Stage 2                   Open Label 50mg 
SUPPLEMENTAL DOSE 
Subject #_________Ex. Ses # ___ 
Stage 2                    Open Label 25mg 
INITIAL DOSE 
Subject #_________Ex. Ses # ___ 
 
Stage 2                   Open Label 12.5mg 
SUPPLEMENTAL DOSE 
Subject #_________Ex. Ses # ____ 
 
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 federal and state 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 
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.  
 
4.4 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 state and federal 
regulations and forms pertaining to the use of controlled substances, and forms will be 
maintained by the Schedule 1 License Holder.  
 
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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4.5 MDMA Storage and Handling 
MDMA is a Schedule 1 compound and will be stored and handled in compliance with 
relevant Federal and State regulations.  In accordance with DEA requirements, the 
Clinical Investigator will be responsible for storing and dispensing the MDMA.  It will be 
stored in a safe mounted to the floor that has been inspected and approved by the DEA 
for this purpose.  Only the Clinical Investigator with the Schedule 1 license will have the 
combination to the safe.  The room in which the safe is mounted has an alarm system and 
will be locked whenever the CI or his staff are not present.   
 
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 their use is optional. 
 
The Schedule 1 License Holder will dispense the appropriate container number for each 
experimental session. If an optional dose is not administered the unused capsules will be 
kept in their respective inner envelopes inside of the primary container in the safe for 
drug accountability. 
 
Investigational product will only be removed from the safe for one subject at a time at the 
time of the session and the MDMA will not leave the premises. MDMA will be 
administered orally with a glass of water.  All doses administered will be recorded on the 
appropriate accountability logs. Records pertaining to the use of Schedule 1 compounds 
will be maintained in accordance with relevant Federal and State Regulations.  They will 
be kept separate from other records and will be maintained in a locked cabinet in a locked 
office with an alarm system. 
 
4.6 MDMA Stability 
Complete details on the chemistry, manufacturing and control of the MDMA to be used 
are described in Drug Master file (DMF) # 6293.  As described in that file, MDMA was 
prepared for human consumption in 1985 by David Nichols, Ph.D., Dept. of Medicinal 
Chemistry and Pharmacology, Purdue University.  The identity and purity of this MDMA 
was confirmed using High Performance Liquid Chromatography (HPLC) in 1997 as 
described in DMF # 6293 and was found to be 99.87% pure. On August 12, 2002, 
Chemic Laboratories reanalyzed the MDMA at the request of the sponsor prior to starting 
MAPS’ first U.S. pilot study of MDMA-assisted psychotherapy in people with PTSD. 
The analysis found the MDMA to be more than 99.7% pure. A more recent analysis 
performed by Nichols at the request of researcher Dr. Carl Hart on February, 2006, 
continued to find a high degree of purity. This analysis found the MDMA in question to 
be 99.9% pure.  This MDMA was used in an investigation of MDMA-assisted 
psychotherapy that took place in the U.S. with drug administration ending in 2008, and it 
was also used in non-sponsor supported study in 2006[76]. 


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5.0 Protocol Design 
This randomized, triple-blind study will examine the safety and efficacy of MDMA-
assisted psychotherapy with 30, 75 or 125 mg MDMA in twenty-four veterans, 
firefighters and police officers diagnosed with chronic, treatment-resistant PTSD arising 
from their service. These participants will ideally, but not necessarily, include twelve 
men and twelve women. Supplemental doses of half the initial dose may be administered 
between 1.5 and 2.5 hours after the initial dose was administered.  
 
Prior to undergoing the first MDMA-assisted (experimental) session, all participants will 
undergo three 90-minute preparatory non-drug psychotherapy sessions with a male and 
female co-therapist team.  Stage 1 of the study will consist of two blinded experimental 
sessions and, for the full dose group, one open-label experimental session, each lasting 
six to eight hours and scheduled three to five weeks apart. The study will be unblinded 
after the second experimental session in Stage 1, which constitutes the primary endpoint 
assessment. After unblinding, medium dose and low dose subjects will have the 
opportunity to continue to open-label Stage 2, unless they meet any exclusion criteria for 
study participation and full dose subjects will complete the third open-label experimental 
session. All subjects will complete a long-term follow-up visit 12 months after their final 
experimental session. All psychotherapy sessions may be recorded to audio and video.  In 
the first open-label experimental session in Stage 2, subjects will receive 100mg with an 
optional supplemental dose of 50mg. In the second and third open-label experimental 
session in Stage 2, subjects will receive one of two active doses of MDMA that are 
clinically titrated by the CI. Experimental sessions will otherwise follow the same 
sequence of events after a single preparatory session. (See Time and Events Table). 
 
A co-therapist team will perform all non-drug and MDMA-assisted psychotherapy 
sessions in their outpatient office. Participants will complete the SOCQ, a measure of 
alterations in consciousness related to mystical experiences, during the period of time 
between the end of each MDMA-assisted psychotherapy session and before they leave 
the treatment facility the next day. Participants will remain at the study site overnight 
accompanied by an attendant. Participants will undergo three integrative psychotherapy 
sessions after each experimental session, with the first integrative session occurring on 
the day after the experimental session.  
 
A blinded independent rater, who will not be present during any psychotherapy sessions, 
will assess participant PTSD symptoms with CAPS, symptoms of depression with BDI-
II, posttraumatic growth with PTGI, global functioning with GAF, sleep quality with 
PSQI, and dissociation with the DES-II. Changes in personality traits will be assessed via 
NEO-PI. Outcome assessments will be done at baseline, at the primary endpoint one 
month after the second experimental session, two months after the third open-label 
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When each subject completes the evaluation at the primary endpoint, the blind will be 
broken for that subject. Participants who had been assigned to receive low dose or 
medium dose MDMA will subsequently have the opportunity to enroll in the open-label 
study arm, or “Stage 2.” Stage 2 must start within a maximum of 5 months after the 
participant finishes Stage 1. The open-label study arm will follow a similar sequence of 
events and procedures, except that there will be a single preparatory session, and all three 
MDMA-assisted psychotherapy sessions will be open-label. Subjects will receive an 
initial dose of 100 mg MDMA in the first experimental session, and one of two active 
doses of MDMA that are clinically titrated by the CI during the second and third open-
label experimental sessions that will otherwise follow the same sequence of events (See 
Time and Events Table). Outcome measures except for the NEO PI will be repeated one 
month after the second Stage 2 experimental session, and all outcome measures will be 
repeated at the end of Stage 2. 
 
The study will conclude with a one-year follow-up occurring 12 months after the final 
experimental session of Stage 1 for participants who received full dose MDMA or who 
elected not to enroll in Stage 2 after receiving either the medium or low doses in Stage 1. 
Subjects who enrolled in Stage 2 will have their final follow-up 12 months after the final 
open-label experimental session. Outcome measures will be repeated at the 12-month 
follow-up, as well as a questionnaire concerning self-reported long-term effects of study 
participation. 
 
An interim analysis may be performed before all participants have completed the 12-
month follow-up. The interim data analysis may be conducted for safety and efficacy. 
 
Sub-studies in a select group of subjects in this study may be conducted for exploratory 
purposes. Subjects will complete a separate consent process if they chose to participate in 
these studies. 
 
5.1 Planned Duration of Protocol   
Stage 1 will take up to six months (full dose group) or four months (medium and low 
dose groups) to complete after screening and baseline evaluation. The screening and 
baseline evaluation can take up to 4 months.  In addition, if the length of time between 
the end of tapering and the first experimental session is longer than a month, the CAPS 
should be repeated to show consistency between this score and the baseline CAPS. The 
open-label study segment for participants initially assigned to receive low dose or 
medium-dose MDMA (Stage 2) will last an additional five months from the single 
introductory and review psychotherapy session until the evaluation two months after the 
final open-label MDMA-assisted psychotherapy session. The time period between the 
end of Stage 1 and the start of Stage 2 should not exceed 5 months for any participant 
with CAPS re-assessment done if there is an interval of greater than 8 weeks between the 
end of Stage 1 and the beginning of Stage 2. The 12-month follow-up will occur a year 
after the final experimental session for all participants who complete Stage 1 only, and a 
year after the final open-label session for any participants who enroll in and complete 


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Stage 2. For each participant who enrolls only in Stage 1, the entire study duration will be 
up to 1.5 years including the 12-month long-term follow-up, and for the participants that 
complete both Stage 1 and Stage 2 follow-ups, the study may take about two years. 
 
5.2 Randomization and Subject Numbering 
This is a randomized, triple-blind, dose comparison study with an open-label cross-over 
segment. For Stage 1, a randomization list will be prepared at the beginning of the study. 
Another list will be created to replace subjects who withdraw from the study and are 
unblinded. Each participant will be assigned to one of the three dose conditions; 30 mg 
(low dose), 75 mg (medium- dose) or 125 mg (full dose). Twelve participants will be 
assigned to the full-dose condition, six participants to the 75 mg condition and six 
participants to the 30 mg low dose condition. The study will employ a blinded 
randomization procedure that will maintain the 2:1:1 ratio while maintaining the blind 
and ensuring that each subsequent condition assignment is not predicated on the previous 
assignment. Drug containers will be assigned a unique random number. At least 24 hours 
before each experimental session, container assignments to each subject will be 
performed on a per experimental session basis, and the container will contain the initial 
and supplemental capsules for a single experimental session. This will be done by 
contacting the Randomization Monitor or logging into the web-based randomization 
system. The unblinded Randomization Monitor will also oversee drug encapsulation and 
labeling of drug bottles. Replacement doses for subjects who replace dropouts that retain 
the same ratio of condition assignment will also be created. The Randomization Monitor 
will provide the investigators with sealed envelopes that will permit emergency 
unblinding for an individual subject if required. In all other cases, the blind will be 
maintained up through the primary endpoint assessment. The participant, independent 
rater and both investigators conducting psychotherapy will be blind to condition 
assignment, until that point. Participants who drop out of the study or are withdrawn by 
the Clinical Investigator prior to the primary endpoint will be replaced until blinded data 
has been collected from 24 participants. Subjects who withdraw during Stage 2 or during 
the long-term follow-up portion of the study will not be replaced. 
 
Prior to enrollment, subjects will be tracked with their initials and a screening number 
assigned sequentially starting at “001”. Subjects who meet the study admission criteria 
will be enrolled into the study and will be assigned a 4-digit subject number.  The first 
two digits identify the study number (08). The next two digits identify the subject within 
the site and will be assigned sequentially, with 01 corresponding to the first subject 
enrolled, e.g. the first subject enrolled in study number 08 will be 0801, second 0802, etc.  
 
5.3 Recruitment and Subject Population 
Candidates for participation will be 24 veterans, firefighters or police officers with 
chronic, treatment-resistant, PTSD arising from their service. Treatment resistance is 
defined as PTSD of at least six months duration where patients 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 


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tolerability. Of the 24 subjects to be enrolled in this study, at least 18 must have PTSD of 
less than 10 years duration (from Iraq and Afghanistan Wars) while up to 6 may have 
PTSD of more than 10 years (including the Vietnam War). A subject would not be 
excluded for having more than one traumatic event, but would be excluded if a traumatic 
event not related to military, fire or police service was the major contributor to the PTSD 
symptoms. Participants must be at least 18 years old with a diagnosis of PTSD and a 
screening CAPS score equal to or greater than 50 at baseline evaluation. Ideally, subjects 
will include twelve men and twelve women. Subjects of each sex who qualify and agree 
to participate will be accepted into the study in chronological order until twelve subjects 
of either sex have been enrolled.  Enrollment will then be limited to members of the 
opposite sex until twelve male and twelve female subjects have been enrolled.  If, 
however, attempts to recruit equal numbers of male and female subjects turns out to 
result in undue delay in proceeding with the study, the investigators may, after discussion 
with the sponsor, revert to enrolling subjects of either sex in order to reach the goal of 24 
participants.  
 
Participants will be recruited via letters of referral sent to psychiatrists and 
psychotherapists, contact with veterans’ organizations, written advertisements, 
announcements placed on appropriate internet sites and the sponsor website, and word of 
mouth. Candidates may also be individuals who had previously contacted the 
investigators expressing interest in taking part in the initial study of MDMA-assisted 
psychotherapy for PTSD after that study had closed enrollment. 
 
One of the investigators or their assistant will interview prospective participants by 
telephone to learn if they meet basic eligibility criteria. If the prospective participant is 
interested in taking part in the study, the investigators will provide her or him with 
consent materials for review and consideration through postal mail or electronically. If, 
after review, a potential participant remains interested in taking part in the study, then he 
or she will meet with the investigators to complete the consent process. Participants will 
complete a quiz to assess their understanding of the consent forms.  Investigators will 
then review the quiz responses with the prospective participant to ensure that he or she 
correctly understands study procedures, risks and benefits. 
 
5.3.1 Inclusion Criteria 
Individuals eligible to be enrolled into this protocol are participants who: 
1. Meet DSM IV criteria for current PTSD with a duration of 6 months or longer 
resulting from traumatic experience during military service;  
2. Have a CAPS score of 50 or higher, indicating moderate to severe PTSD 
symptoms; 
3. Have had at least one unsuccessful attempt at treatment for PTSD with 
medication, such as an SSRI, SNRI, or mirtazapine, or one unsuccessful treatment 
with any form of psychotherapy for which there exists a controlled trial indicating 
efficacy in the treatment of PTSD. This includes cognitive-behavioral therapy 


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(including exposure therapy), stress inoculation training, including anxiety 
management, insight-oriented psychotherapy, and EMDR.  
OR who discontinued treatment due to either:  
• Inability to tolerate psychotherapy for PTSD (e.g. persistent “over-
engagement” when attempting Prolonged Exposure Therapy) or  
• Inability to tolerate psychopharmacology for PTSD due to treatment-emergent 
side effects;  
Treatment will be deemed to have been unsuccessful if the participant continues 
to meet criteria for current PTSD following the treatment. 
4. Are at least 18 years old; 
5. If in ongoing psychotherapy at the time subjects are recruited into the study, 
participants may continue to see their outside therapist during the course of the 
study. Participants must sign a release for the investigators 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 2 months after the final experimental session. Subjects who do 
not live within reasonable driving distance of the study site (equal to or less than 
an estimated two hours’ drive from the study site) must have a therapist in the 
area in which they live whom they can call on for support and evaluation if 
necessary; 
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 5 half lives before each 
MDMA session and do not restart for 10 days after each MDMA administration. 
Any psychoactive drugs, including stimulants, will be tapered in an appropriate 
fashion to avoid withdrawal effects.  Medications will only be discontinued after 
consultation with the prescribing physician;   
7. Agree that, for one week preceding the MDMA session will refrain from: 
a. taking any herbal supplement (except with prior approval of the research 
team);  
b. taking any nonprescription medications (with the exception of non-
steroidal anti-inflammatory drugs or acetaminophen unless with prior 
approval of the research team); 
c. taking any prescription medications, with the exception of birth control 
pills, thyroid hormones or other medications approved by the research 
team);  
8. Agree to take nothing by mouth except alcohol-free liquids after 12:00 A.M. 
(midnight) the evening before the experimental session;  
9. Refrain from the use of any psychoactive drug, with the exception of caffeine or 
nicotine, within 24 hours of each MDMA session;  
10. Agree not to use caffeine or nicotine for 2 hours before and 6 hours after the dose 
of MDMA; 
11. Are willing to remain overnight at the study site; 


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12. Agree to have transportation other than driving themselves home or to where the 
participants are staying after the integrative session on the day after the MDMA 
session; 
13. Are willing to be contacted via telephone for all necessary telephone contacts;  
14. Must have a negative pregnancy test if able to bear children, and agree to use an 
effective form of birth control; 
15. Must provide a contact (relative, spouse, close friend or other caregiver) who is 
willing and able to be reached by the investigators in the event of a participant 
becoming suicidal; 
16. Must agree to inform the investigators within 48 hours of any medical conditions 
and procedures; 
17. Are proficient in speaking and reading English; 
18. Agree to have all clinic visit sessions recorded to audio and video; 
19. Agree to not participate in any other interventional clinical trials during the 
duration of this study. 
 
5.3.2 Exclusion Criteria 
Individuals not eligible to be enrolled into this protocol are those who: 
1. Are pregnant or nursing, or are women of child bearing potential who are not 
practicing an effective means of birth control; 
2. Have a history of, or a current primary psychotic disorder, bipolar affective 
disorder type 1 or, dissociative identity disorder;   
3. Have evidence or history of coronary artery disease or cerebral or peripheral 
vascular disease, hepatic disease with abnormal liver enzymes, or any other 
medical disorder judged by the investigator to significantly increase the risk of 
MDMA administration; 
4. Have hypertension using the standard criteria of the American Heart Association 
(values of 140/90 or higher assessed on three separate occasions  [77]), unless 
their hypertension has been successfully treated and is currently well-controlled 
on antihypertensive medicines,  In this case subjects with well-controlled 
hypertension may be enrolled if they pass additional screening to rule out 
underlying cardiovascular disease (see “Methods”); 
5. Have liver disease with the exception of asymptomatic subjects with Hepatitis C 
who have undergone additional evaluation (see “Methods”).  Subjects with 
Hepatitis C may be enrolled if they have received appropriate screening (see 
“Methods”);    
6. Have history of hyponatremia or hyperthermia; 
7. Weigh less than 48 kg;   
8. Would present a serious suicide risk, as determined through psychiatric interview, 
responses to C-SSRS and through the clinical judgment of the investigator, or 
who, in the judgment of the investigator, are likely to require hospitalization 
during the course of the study; 


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9. Would present a serious risk to others as established through clinical interview 
and contact with treating psychiatrist; 
10. Have used “Ecstasy” (material represented as containing MDMA) more than five 
times within the last 10 years or at least once within 6 months of the MDMA 
session; 
11. Require ongoing concomitant therapy with a psychotropic drug; 
12. Meet Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria 
for active substance abuse or dependence for any substance save caffeine or 
nicotine in the past 60 days; 
13. Are not able to give adequate informed consent; 
14. Have any current problem or a history of substance abuse which, in the opinion of 
the investigator or medical monitor, might interfere with participation in the 
protocol. 
 
6.0 Methods 
The following outcome, safety and process measures will be used in the study. 
Investigators will follow the most recent version of the Treatment Manual in all matters 
relating to the psychotherapy sessions and follow-up.  All psychotherapy sessions, 
including experimental sessions, may be recorded to audio and video, with all recordings 
preserved for research and training purposes.  
 
After consenting to take part in the study, participants will be screened by a physician 
who will obtain medical and psychological history by interview and perform a general 
physical examination, brief neurological exam and clinical laboratory assessments.  
 
Additional screening for specific conditions: 
If there is evidence of liver disease by history, physical examination or laboratory testing, 
hepatitis serology will be performed.  If there is evidence of significant hepatic disease 
other than Hepatitis C the person will not be eligible for enrollment, and will be advised 
to see their personal physician for further evaluation.  If Hepatitis C serology is positive 
and the potential subject has not already been evaluated for possible treatment of 
Hepatitis C, he or she will be referred to a physician with expertise in evaluating and 
treating liver disease. After this evaluation and after completion of any recommended 
treatment, if the Hepatitis C is judged by this physician to be relatively stable and of mild 
severity the person may be enrolled if there are no other contraindications.   
 
If the potential subject has well-controlled hypertension and no other evidence of 
cardiovascular or cerebrovascular disease by history, physical exam or electrocardiogram  
(ECG), and if the Clinical Investigator judges their overall health and other 
cardiovascular risk factors to be acceptable (family history, smoking, lipid levels, body 
weight, level of physical activity), they will be referred for exercise testing by a 
cardiologist and for carotid ultrasound.  If these tests fail to reveal evidence of significant 
vascular disease or other cardiac disease, the person may be enrolled if there are no other 


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contraindications. Participants taking one or more antihypertensives may be enrolled in 
the study. The investigators will record and review medications used to control 
hypertension prior to enrollment. 
 
 
Participants will also undergo the Structured Clinical Interview for Diagnoses I Research 
Version (SCID-I-RV) to assess eligibility based on Axis I diagnoses, and relevant parts of 
the Axis 2 SCID, which includes a self-report questionnaire to focus on modules to use 
based on symptoms and assessment via CAPS for psychiatric diagnosis and to determine 
participant eligibility. If, after reviewing all information, the investigators conclude that a 
participant is eligible, they will enroll the subject in the study. Visits will be scheduled 
consecutively as described in the Time and Events Table.  
 
After undergoing three 90-minute non-drug introductory psychotherapy sessions with a 
male/female co-therapist team, study participants will undergo eight-hour long 
experimental sessions scheduled approximately three to five weeks apart, during which 
they will randomly receive either the low dose, medium-dose or full-dose MDMA on all 
three occasions. Participants will undergo one non-drug integrative psychotherapy 
session the day after each experimental session and at least two additional 90 minute non-
drug integrative psychotherapy sessions between experimental sessions.  
 
PTSD symptoms will be assessed by an independent rater who will be blind to condition 
assignment and will not be present during any of the psychotherapy sessions. Subjects 
will be instructed not to reveal to the independent rater their own opinion about which 
dose of MDMA they believe they received. The rater will assess PTSD symptoms, global 
functioning, dissociative symptoms, sleep quality, symptoms of depression and post-
traumatic growth prior to MDMA-assisted psychotherapy at baseline, one month after the 
second experimental session and, for full dose subjects, two months after the third 
experimental session. Personality will be assessed at baseline, at the primary endpoint, at 
the end of Stage 2, and at 12-month follow-up.  Alterations in consciousness and 
elements of a mystical experience will be assessed after each MDMA-assisted 
psychotherapy session before the subject leaves the treatment facility the following day. 
All psychotherapy sessions, including MDMA-assisted experimental sessions, may be 
recorded to audio and video, with all recordings preserved for research purposes.  
Participants may receive any session recordings upon request. Participants will be asked 
to read a brief script for a computer program that will enable transcription of audio 
recordings from these sessions. 
 
As safety measures, vital signs and a measurement of psychological distress will be 
assessed during the MDMA sessions. Level of psychological distress will be measured 
with the 7 point Subjective Units of Distress (SUD) scale immediately before MDMA 
administration and approximately every 90 minutes thereafter for the duration of the 
MDMA sessions. Suicidality will be assessed throughout the course of the study with the 
clinician-administered C-SSRS. The C-SSRS will be administered during nearly every 


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visit involving face to face contact with the investigators conducting psychotherapy, and 
on two of six days of telephone contact. 
 
6.1 Assessments and Measures 
The following outcome and safety measures will be employed in Stage 1 and Stage 2, 
following a similar sequence of events to the full dose subject group in Stage 1, except 
that participants in Stage 2 will have one and not three preparatory (introductory) 
sessions.  
 
6.1.1 Outcome Measures 
The primary outcome measure will be the CAPS, a clinician-scored measure for PTSD 
diagnosis and measure of symptom intensity and severity. The CAPS provides a means to 
evaluate the frequency and intensity dimensions of each symptom, impact of symptoms 
on the patient'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 takes approximately one hour to complete. The CAPS interviews have been 
determined to have good internal consistency, concurrent validity, and test/retest 
reliability [78, 79]. An independent rater will assess all participants according to the Time 
and Events table. 
 
The Global Assessment of Functioning (GAF) is a measure of global functioning and 
general function made through observations. The GAF consists of a single score, with 
scores ranging from 0 to 100, with 100 reflecting superior function and zero reflecting 
serious risk of causing harm to the self or others. The GAF will be recorded by the 
independent rater according to the Time and Events table. 
 
The Beck Depression Inventory-II (BDI-II) is a 21-item a self-report measure of 
depressive symptoms [80] that will serve as a measure of depression. It takes five to ten 
minutes to complete. Participants will complete the BDI-II according to the Time and 
Events table. 
 
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. In this study, participants 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. Participants will complete the 
PTGI according to the Time and Events table.  
 
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 [81, 82]. 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 


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on the original scale were made via visual analog scales. The DES-II uses the same items 
but with responses made on a ten-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 [81]. 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 [82, 83]. There may be a relationship between experiencing dissociation and 
occurrence of chronic PTSD [82, 84]. 
 
The Pittsburgh Sleep Quality Index (PSQI) is a 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. It consists of 19 items, with possible 
responses ranging from 0 to 4 on a five-point scale [85]. 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 ten 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[85, 86]. Global scores correlate 
with other measures of alertness and self-reported sleep quality [87]. PSQI will be 
administered according to the Time and Events table. 
 
The NEO PI will serve as a measurement of personality [88]. 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. 
Participants will complete the NEO PI according to the Time and Events table. 
 
The States of Consciousness Questionnaire (SOCQ) is a 100-item questionnaire based on 
the “Peak Experience Profile” designed by Pahnke and colleagues [89, 90]. Participants 
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 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. Participants will complete the SOCQ after 
each experimental session in accordance with the Time and Events table, completing the 
measure at any time between the end of an experimental session and prior to leaving the 
treatment facility the next day. 
 


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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 12 month 
follow up visit. This questionnaire takes between five and ten minutes to complete. 
 
6.1.2 Safety Measures 
Safety measures will be applied as described below to minimize risks associated with 
drug-assisted psychotherapy sessions. 
 
Participants will rate their current degree of subjective distress with a single-item, self-
report scale, the SUD scale, repeatedly during the MDMA session, with the degree of 
distress marked along seven points.  Subjective psychological distress will be measured 
periodically throughout each experimental session. 
 
Cardiovascular effects will be assessed via blood pressure and pulse measurement.   
Blood pressure, heart rate (as pulse) and temperature will be measured periodically 
during each experimental session. Blood pressure and pulse will be measured at the 
outset of the experimental session, once every 15 minutes for the first four hours of the 
MDMA-assisted session and every 30 minutes for another two hours. Participants with 
controlled hypertension will have blood pressure and pulse assessed every 15 minutes for 
the first five hours and every thirty minutes for the next three hours. More frequent 
measurements will be taken as per the judgment of the Clinical Investigator. Blood 
pressure and pulse will be assessed via an automatically inflating cuff. Body temperature 
will be assessed via tympanic thermometer every 60-90 minutes. For subjects with a 
diagnosis of pre-existing controlled hypertension, the results of blood pressure and pulse 
measurements will be viewed by the investigators as the measurements occur. For 
subjects without a diagnosis of controlled hypertension, after viewing baseline values at 
the beginning of the session, the investigators will only view the blood pressure or pulse 
values in the case of a medical indication in order to improve the effectiveness of 
condition blinding. The night attendant will print out the blood pressure and pulse results 
after the session, make a back-up copy, and will seal both copies together in an envelope 
and write their initials over the seal. This envelope will be part of the source record and 
will be kept sealed until after unblinding occurs for that subject. In the event of any 
medical indication, such as signs or symptoms that could be related to either hypertension 
or hypotension, the investigators have the option to print out the results during the 
session. 
 
The C-SSRS is a clinician-administered measure of suicidal behavior devised to detect 
potential suicidal thoughts or behaviors during a clinical trial [91]. It consists of a 
“Baseline” form that assesses lifetime suicidal ideation, ideation intensity and behavior, 
and a form for assessing current suicidal ideation, and intensity. The C-SSRS consists of 
a series of questions, and can be administered during face-to-face interview or over the 
telephone. The C-SSRS will be administered by the investigators in accordance with the 
Time and Events table. The measure will be administered at baseline, during the second 


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preparatory session, twice during experimental sessions (once before and once after drug 
administration), on two days of telephone contact, during each integrative psychotherapy 
session and at the evaluation at the end of Stage 1, end of Stage 2 and the 12-month 
follow-up.  Participants undergoing medication washout will complete the C-SSRS 
before and after medication washout.   
 
A 100-millimeter visual analog scale will be used to assess changes in symptoms of pre-
existing tinnitus and/or chronic pain [92-94]. 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 [93, 95-97]. 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 [93, 96, 97]. 
 
All adverse events (AEs) and spontaneously reported reactions will be collected during 
each experimental session and for 7 days after each session. Commonly expected 
reactions that are spontaneously reported 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, difficulty 
concentrating, dizziness, drowsiness, dry mouth, fatigue, headache, heavy legs, impaired 
judgment, impaired gait/balance, increased irritability, increased personal worries or 
rumination, insomnia, jaw clenching, tight jaw, lack of appetite, low mood, nausea, need 
more sleep, nystagmus, parasthesias, perspiration, restlessness, sensitivity to cold, thirst 
and weakness. Serious adverse events (SAEs), adverse events leading to subject 
withdrawal from the study, and changes to psychiatric status will be collected throughout 
the protocol. Medications used to treat the specified AEs will be collected during the 
study, and all changes to psychiatric medications will be collected throughout the study. 
 
6.1.3 Process Measures 
Adherence criteria and competence ratings will be conducted by qualified, trained 
blinded adherence raters who will analyze audio/video data from selected preparatory, 
experimental and integrative sessions. Participants will be asked to read a brief script for 
a computer program that will enable transcription of audio recordings from these 
sessions. The elements included in adherence criteria are specific to each type of session. 
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.  
 
Belief of condition assignment and certainty will be collected from each therapist 
responsible for treating the subject and the subject at the integrative session on the day 
after each blinded experimental session in Stage 1. At the primary endpoint, the 
Independent Rater for the study will also provide their guess and certainty of condition 


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assignment prior to unblinding. These beliefs are collected as a part of the sponsor’s 
ongoing initiative to optimize the triple-blind as a part of dose response studies.  
 
Subject opinions about having three versus two experimental sessions will be collected 
from each subject at the Primary Endpoint after unblinding and the 2-month follow-up in 
Stage 1. Stage 2 subjects will complete the same measure at the Secondary Endpoint and 
the 2-month follow-up in Stage 2. These opinions (referred to as “perceptions” in the 
Time and Events Table) are collected as a part of the sponsor’s ongoing initiative to 
assess the therapeutic value of the third experimental session and to gather information 
on the optimal therapeutic dose for MDMA. 
 
The Reactions to Research Participation Questionnaire (RRPQ) [98] is an assessment of 
causes for taking part in research and responses to the experience of being a research 
subject. Subjects will complete this measure during their 2-month follow-up, with exact 
time of completion varying in accordance with participation in the third open label 
experimental session in Stage 1 or in Stage 2. 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. 


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A =First Integrative session is 1 day after exp session B = At least 24 hrs prior to 1st exp. session C =Approximately 6 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 meds are tapered (V3) H = Only for subjects starting Long term Follow up and not going to Stage 2 I =For 7 days post Exp. Session, C-SSRS D2 and D7 of calls only, 
General well being for all 7 days J =Subjects in the medium or low dose group will not have visits 14-18, but will instead move onto Stage 2. K= On the day of the 1st integrative session following the Exp. Session 
L=CAPS may be videotaped M=First preparatory session (V2) may happen at the time of screening, before enrollment. N= Full dose subjects only. O= Only in subjects with pre-existing tinnitus and/or chronic pain.
Table 3.Stage 1 Time&Events 
Screen/Baseline 
Preparatory Experimental Session 1 
Experimental Session 2 
Experimental Session 3 
Follow-Up 
Visit # 
Pre-Study 
V1 
V 2,3,4 
V5 
V 6,7,8 
V9 
V 10,11,12 
V13 
V14 
V 15,16,17 
V18 
Type of Visit 
Screening may take place 
over more than one day 
Enrollme
nt 
Preparatory 
Sessions 
Experimental 
Session 1 
Integrative 
Sessions 
Experimental 
Session 2 
Integrative 
Sessions 
Primary 
Endpoint 
Experimental 
Session 3  
Integrative 
Sessions 
End of Stage 1 & 
Outcome 
Visit Timing or Study day or Window 
Up to 2 months prior to  
Visit 1 
 
Prior to V5 M Up to 7 weeks 
post V1 
Before V9 A 
3-5 weeks 
post V5 
Before 
V13A 
1 month 
post V9 
3-5 weeks 
post V9 N 
Before V18 
A, N 
May happen over 
> 1 day. 2 mo. 
post V14 N 
Initial Phone Screen 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric History  
X 
 
 
 
 
 
 
 
 
 
 
General Phys. Exam (BP, Pulse, Temp) 
X 
 
 
 
 
 
 
 
 
 
 
Brief Neurological Exam 
X 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
SCID-I-RV 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Lab Tests, w/ HIV, HCV test 
X 
 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Taper (if applicable) 
X 
X 
 
 
 
 
 
 
 
 
 
Study Enrollment after meeting I/E 
 
X 
 
 
 
 
 
 
 
 
 
Record to Audio/Video 
XL 
 
X 
X 
X 
X 
X 
X L 
X 
X 
X L 
General Well-Being 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Drug Screen 
X 
 
 
X 
 
X 
 
 
X 
 
 
Pregnancy Screen (if applicable) 
X 
 
 
X 
 
X 
 
 
X 
 
 
Complete Randomization Procedure 
 
 
 
X B 
 
 
 
 
 
 
 
CAPS, GAF, BDI-II, PTGI, PSQI, 
DES-II (IR) 
X  
 
 
 
 
 
 
X 
 
 
X 
NEO PI (Ind. Rater) 
X 
 
 
 
 
 
 
X 
 
 
 
C-SSRS 
 
X 
X 
X C, D, E 
XI 
X C, D, E  
XI 
X 
X C, D, E  
XI 
X 
Administer IP Drug + Therapy, SOCQ 
 
 
 
X 
 
X 
 
 
X 
 
 
Monitoring of BP, Pulse and Temp.  
 
 
 
X 
 
X 
 
 
X 
 
 
SUD 
 
 
 
X F, E 
 
X F, E 
 
 
X F, E 
 
 
Beliefs of Condition Assignment 
 
 
 
 
XK 
 
XK 
 
 
XK 
 
Overnight Stay 
 
 
 
X 
 
X 
 
 
X 
 
 
Integrative Therapy Session 
 
 
 
 
X 
 
X 
 
 
X 
 
7 days Integrative Telephone Contact 
 
 
 
 
X I 
 
X I 
 
 
X I 
 
AEs Requiring Medical Attention 
 
 
 
X 
X 
X 
X 
X 
X 
X  
X 
Spont. Reported Reactions and all AEs 
 
 
 
X 
X 
X 
X 
 
X 
X 
 
Changes in Tinnitus and/or Pain 
X O 
 
X E, O 
X E, O 
X E, O 
X E, O 
X E, O 
XO 
X E, O 
X E, O 
XO 
AEs of psychiatric status or withdrawal  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Issue Memory Aid Card H 
 
 
 
 
 
 
 
 
 
 
X 
Unblinding J 
 
 
 
 
 
 
 
X 
 
 
 
Perception of Third Session 
 
 
 
 
 
 
 
XN 
 
 
XN 
RRPQ 
 
 
 
 
 
 
 
 
 
 
X H 


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* If Visit 19 is more then 8 weeks after V13 then the measures from V13 will need to be repeated prior to starting Stage 2 A =First session is 1 day after Exp session B =Approximately 6 hours post 
MDMA C =At the beginning of the session D =As needed E =Approximately every 60 minutes F = Given on 2nd integrative session only G = For 7 days post Exp. Session, C-SSRS D2 and D7 of calls 
only, General well being for all 7 days H=CAPS may be videotaped I= Only in subjects with pre-existing tinnitus and/or chronic pain. 
Table4.Stage2Time&Events 
Preparatory Experimental Session 1 
Experimental Session 2 
Experimental Session 3 
Follow-Up 
Long Term Follow-Up  
 Visit # 
V19* 
V20 
V 21,22,23 
V24 
V 25,26,27 
V28 
V29 
V 30,31,32 
V33 
1 Year Follow-up 
Type of Visit 
Preparatory 
Session 
Experimental 
Session 1 
Integrative 
Sessions 
Experimenta
l 
Session 2 
Integrative 
Sessions 
Secondary 
endpoint 
Experiment
al Session 3 
Integrative 
Sessions 
End of Stage 2 & 
Outcome 
Follow-Up & Outcome 
Visit Timing or Study day or 
Window 
Within maximum 
of 5 months of 
V13* 
After V19 Before V24 A 3-5 weeks 
post V20 
Before V28 A 
1 month 
post V24, 
beforeV29 
3-5 weeks 
post V24 
Before V33 
A 
May happen over > 
1 day 2 months post 
V29 
May happen over > 1 day. 
One Year post V14 or V29 
Confirm Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Confirm Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
Enrollment in Stage 2 
X 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record to Audio/Video 
X 
X 
X 
X 
X 
XH 
X 
X 
XH 
 
General Well-Being 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Drug Screen 
 
X 
 
X 
 
 
X 
 
 
 
Pregnancy Screen (if applicable) 
 
X 
 
X 
 
 
X 
 
 
 
CAPS, GAF, BDI-II, PTGI, PSQI, 
DES-II  (IR) 
Use V13* 
 
 
 
 
X 
 
 
X 
X 
NEO PI with Ind. Rater 
Use V13* 
 
 
 
 
 
 
 
X 
X 
C-SSRS 
X 
X C, D, E 
X G 
X C, D, E 
X G 
 
X C, D, E 
X G 
X 
X 
Administer IP Drug + Therapy, 
SOCQ 
 
X 
 
X 
 
 
X 
 
 
 
Monitoring of BP, Pulse and Temp.  
 
X 
 
X 
 
 
X 
 
 
 
SUD 
 
X D, F 
 
X D, F 
 
 
X D, F 
 
 
 
Overnight Stay 
 
X 
 
X 
 
 
X 
 
 
 
Integrative Therapy Session 
 
 
X 
 
X 
 
 
X 
 
 
7 days Integrative Telephone Contact 
 
 
X G 
 
X G 
 
 
X G 
 
 
AEs Requiring Medical Attention 
X 
X 
X 
X 
X 
X 
X 
X  
X 
 
Spont. Reported ReactionsG and all 
AEs 
 
X 
X G 
X 
X G 
 
X 
X G 
 
 
Changes in Tinnitus and/or Pain 
 
XD, I 
XD, I 
XD, I 
XD, I 
XI 
XD, I 
XD, I 
XI 
XI 
AEs of psychiatric status or 
withdrawal  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Perception of Third Session 
 
 
 
 
 
X 
 
 
X 
 
Complete Stage 2, go to 1yr F/U 
 
 
 
 
 
 
 
 
X 
 
RRPQ 
 
 
 
 
 
 
 
 
X 
 
Issue Memory Aid Card 
 
 
 
 
 
 
 
 
X 
 
Follow-up Questionnaire 
 
 
 
 
 
 
 
 
 
X 
Termination Visit 
 
 
 
 
 
 
 
 
 
Long Term Follow up after Stage 1 or Stage 2 
X 


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6.2 Study Procedure, Visit Descriptions and Adherence 
To ensure consistency of the manualized therapy, each type of visit described below must 
follow the Treatment Manual. Adherence to the manualized therapy will be reviewed by 
monitoring of data and or rating videos of these visits as part of the data review process.  
All criteria for a visit type should be completed as a part of the visit series, which may 
take place over more than one day. 
 
6.2.1 Prescreening, Screening and Baseline Evaluation (Pre-study, Visit 1) 
All individuals who are prescreened, as defined in this section, 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. Prospective participants 
will be prescreened by telephone according to an IRB-approved script to learn if they 
meet basic eligibility criteria.  
 
After telephone screening is completed, each potential participant will be given the 
informed consent form (ICF). The screening number will be used on all subject records 
prior to enrollment, including the ICF. After signing the ICF, participants will provide a 
medical and psychological history through interview and will undergo a general physical 
examination, performed by a physician who is not the Clinical Investigator.  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 extremities, brief neurological exam (cranial nerves 2-12, sensory, motor, 
reflexes and cerebellar function), ECG, clinical laboratory assessments to determine 
study eligibility (see Section 10.0 for list of laboratory tests).  Tinnitus and chronic pain 
symptom severity will be collected using a visual analog scale in subjects with a medical 
history of these conditions. In addition, Human Immunodeficiency Virus (HIV) and, if 
indicated, Hepatitis C Virus (HCV) serology will be performed.  If there is a confirmed 
positive HIV serology, it will be kept confidential with the exception of reporting to the 
South Carolina Department of Health and Environmental Control as required by law, 
with the Department of Health informing the home state of any individual not residing in 
South Carolina. Likewise HCV serology will be kept confidential except for reporting to 
the South Carolina Department of Health and Environmental Control within seven days 
of discovery as required by law. Appropriate referral for counseling and treatment will be 
made as necessary. The clinical laboratory values will not be captured in the Case Report 
Form (CRF), but will be used to establish eligibility and will be kept with the subject’s 
source record.  A urine-dip pregnancy test for females of childbearing potential and the 
drug screen will be performed as well.  If, upon examination, there are questions raised 
about possible medical problems, the investigators will request a review of participant 
medical records and request additional tests or assessments as indicated. If it is 
determined that the participant has Hepatitis C or well-controlled hypertension, further 
evaluation will be performed as described in Section 6.0. 
 
A blinded independent rater who will not be present during any of the therapy sessions 
will administer the CAPS and assess the participant on the GAF. To establish 
independent rater reliability, the investigators will have the option to video record the 
screening CAPS interview in as many instances as necessary. The C-SSRS will also be 


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administered at screening to assess suicide risk. Suicide risk will also be assessed via 
psychiatric interview. The Clinical investigator and independent rater will use medical 
records, communication with the participant’s treating psychiatrist or therapist if 
applicable and psychiatric interview to assess potential risk to others. The participant will 
complete the BDI-II, PTGI (in reference to time since the trauma), PSQI, DES-II and 
NEO-PI. The entire visit should take between 1.5 and 2.5 hours.  Screening may take 
place over more than one day and up to four months prior to Visit 1 (enrollment). The 
participant may also have the first preparatory session (Visit 2) prior to enrollment.  
 
If eligibility is confirmed, the participant will be enrolled and will be issued a subject 
number and contacted to schedule introductory non-drug psychotherapy sessions and first 
experimental session.  Any participant who must discontinue a medication will, after 
consultation with the prescribing physician, be given a schedule to begin tapering off that 
medication so washout will be completed before the first experimental session, with the 
interval between the start of washout (the last day the medication was taken) and the first 
experimental session being at least five times the drug and active metabolites’ half-life, 
plus one week for stabilization. The first experimental session will be scheduled to occur 
after washout is complete, if applicable. 
 
6.2.2 Preparatory Sessions (Visits 2-4) 
The investigator will inquire about any possible changes in the participant’s health to 
ensure that the subject continues to meet eligibility criteria and if applicable, will confirm 
that they have adhered to the schedule for tapering off medications.  In subjects who have 
pre-existing tinnitus or chronic pain, the visual analog scale will be used to collect the 
severity of symptoms. 
 
The participant will undergo three 90-minute preparatory non-drug psychotherapy 
sessions with the investigators at their offices. During these sessions the investigators will 
gather more detailed history, answer any questions the participant may have, and work 
toward forming a strong therapeutic alliance. The participant and investigators will 
discuss goals for the MDMA sessions. They will review the procedures and therapeutic 
approach, following standard procedures and techniques discussed in the sponsor-
developed treatment manual. The investigators will prepare the participant for the 
upcoming experimental sessions and promote an atmosphere of safety in which to 
confront traumatic experiences and powerful emotions. 
 
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.  
 


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The first preparatory session (Visit 2) may take place at the time of the screening and 
before enrollment. All eligible participants must be enrolled prior to the second 
preparatory session (Visit 3) and in maximum four months after the screening starts. 
 
During the third and last introductory session the investigators will supply the participant 
with a set of instructions and restrictions for conduct 24 hours prior to receiving MDMA, 
including restrictions on food and alcohol consumption.  Participants must agree to take 
nothing by mouth except alcohol-free liquids after 12:00 A.M. (midnight) the evening 
before the MDMA session.  Participants must also refrain from the use of any 
psychoactive drug, with the exception of caffeine or nicotine, within 24 hours of each 
MDMA session.  Participants must not use caffeine or nicotine for 2 hours before and 6 
hours after the dose of MDMA.  
 
Unless a participant is still undergoing medication washout, participants will complete 
the C-SSRS just prior to beginning the second preparatory session. Participants 
undergoing medication washout will repeat the C-SSRS at a point after washout is 
complete but before the first experimental session. 
 
The attendant, described below, will remain with the participant during each overnight 
stay after each MDMA-assisted psychotherapy session. He or she will have a healthcare 
background and will undergo specific training for the role. If a participant would like 
another individual present during the MDMA session, a meeting between the 
investigators and that individual will be scheduled during the introductory session. Such 
an individual will not replace the night-time attendant. Introductory sessions may be 
recorded to audio and video, and participants can receive copies of one or more 
introductory sessions upon request.  All SAEs will be recorded from the time the 
participant is enrolled at Visit 1.  
 
Adverse Events and medications will be collected as described in Sections 8 and 9 of the 
protocol. 
 
6.2.3 MDMA Sessions [Visits 5, 9, and 14 (Visit 14 for full dose group only)]  
Subjects in Stage 1 will receive two experimental sessions of MDMA-assisted 
psychotherapy blinded with respect to dose, scheduled approximately 3-5 weeks apart. 
Subjects in the open label third experimental session in Stage 1 will receive experimental 
sessions with the full dose of MDMA.  
 
Each experimental session will last approximately eight hours followed by an overnight 
stay at the study site. Experimental sessions will be conducted by the male and female co-
therapist team. Procedures for MDMA-assisted psychotherapy will remain the same 
across all sessions, and all procedures except drug dose will be the same for participants 
assigned to the full, medium and low dose conditions.  
 
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 


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create and communicate a setting of safety and support the subject during periods of inner 
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.  
 
On the day of the MDMA session, the participant will arrive approximately one hour 
prior to the MDMA session.  Continuing eligibility will be confirmed, with confirmation 
of eligibility including a urine drug screening and, if appropriate, a urine pregnancy test.  
If the subject continues to meet criteria and the participant reports that he/she followed 
appropriate rules and restrictions, the session will proceed; a positive pregnancy screen is 
cause for withdrawal from the protocol, a positive drug screen will be reviewed by the 
investigator and may be cause for delaying drug administration to a later time, 
rescheduling the session to a later date, or withdrawing the participant from the study. 
The sponsor and Clinical investigator will follow any pregnancy detected after the 
occurrence of an experimental session to outcome. 
 
Before MDMA is administered, the therapists and participant will discuss and review the 
participant’s goals, intentions and concerns and some of the commonly experienced 
effects of MDMA. Participants will complete the SUD just prior to initial dose 
administration. 
 
At approximately 10:00 A.M., participants will receive the initial dose of MDMA along 
with a glass of water.  The participant will sit or recline on comfortable furnishings, and 
there will be eyeshades and headphones if the participant wishes to use them.  They will 
listen to a program of music designed to support their experience by initially aiding 
relaxation and later evoking and supporting deep emotions and the emergence of 
unconscious material [99, 100]. They may also request periods of music if they wish. The 
investigators will also encourage periods of time in which the participant remains silent 
with eyes closed and with attention focused inward in order to allow for the further 
unfolding of their inner experience, in accordance with the principles of MAPS’ 
treatment manual [101].  Water and electrolyte containing fluids will be available ad lib 
throughout the session within the limits described in Appendix A.  Food will be available 
during the latter part of the session. The investigators may record the entire session to 
video and audio. Participants may receive a copy of audio or video recordings of at least 
one experimental session upon request. The participant will be encouraged to spend much 
of the time focusing attention on their inner experience without talking, but may speak to 
the investigators whenever they wish, and will receive guidance and support as needed.  
After the first hour, if the participant has not spoken spontaneously, the investigators will 
check in with him/her about the nature of the experience. For the rest of the experience, 
as appropriate, the investigators will support and encourage the participant in emotional 
processing and resolution of whatever psychological material is emerging. 


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Suicidality will be assessed with the C-SSRS twice during each experimental session 
(approximately one hour before and five to six hours after drug administration). 
 
Blood pressure and pulse will be measured at the outset of the experimental session, once 
every 15 minutes for the first 4 hours of the MDMA-assisted session and every 30 
minutes for another 2 hours.  More frequent measures will be taken as described in 
section 6.1.2 if the established thresholds are exceeded, or if the subject has a diagnosis 
of hypertension. For subjects without a diagnosis of controlled hypertension, after 
viewing baseline values at the beginning of the session, the investigators will only view 
the blood pressure or pulse values in the case of a medical indication in order to improve 
the effectiveness of condition blinding. More frequent measures will be taken if the 
participant exhibits symptoms that could be related to hypertension, hypotension 
tachycardia or bradycarida.  In the event of any medical indication, such as signs or 
symptoms that could be related to either hypertension or hypotension, the investigators 
have the option to print out the results during the session. 
 
Participant body temperature will be measured via tympanic thermometer every 60-90 
minutes. Participants will complete the SUD every 90 minutes, until the session is over, 
allowing a window of plus/minus 30 minutes to fit into the psychotherapy process where 
a natural break occurs.  If necessary, the investigators can make a greater number of SUD 
measurements as their clinical judgment dictates.  The investigators will record any 
spontaneously reported reactions during the session.  If subjects who have pre-existing 
tinnitus or chronic pain mention any changes, the visual analog scale will be used to 
collect the changes in symptoms. 
 
A supplemental dose half the size of the initial dose may be administered 1.5 to 2.5 hours 
after the initial dose upon mutual agreement between the investigators and the 
participant.  
 
Approximately six hours after drug administration, the investigators will administer the 
C-SSRS.  
 
If there is a support-individual who has previously been asked and has agreed to be 
present during part or all of the MDMA 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. 
 
The investigators will remain with the participant until the physical and psychological 
effects of the session have substantially subsided and the subject is judged to be in a  
stable condition and appears to have returned to baseline mental status. The investigators 
will end recording to audio and video when they have established that the participant has 
returned to baseline function or is very close to doing so. Both of the investigators 
conducting psychotherapy reside near the study site and one or both can quickly return to 
the site if necessary. Throughout the study, at least one of the investigators, or a physician 
who is covering for them if they are not available, will remain available to participants 
via 24-hour cellular telephone. 


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The participant will complete the SOCQ after the end of the experimental session and 
prior to leaving the treatment facility the next day.  
 
The participant will remain at the study site overnight, in a comfortably furnished suite 
that allows for accompaniment by a significant other, and the attendant. The attendant 
will remain in the building during the overnight stay, even if a significant other is present. 
The attendant will attend to the subject's needs such as food and fluids during the 
overnight stay. The attendant will be an individual with previous training or experience in 
supporting individuals in psychological distress. The attendant may be anyone with some 
training or background in health care, particularly in psychiatric care. If there is an 
emergency or the participant needs additional support, the attendant can contact the 
investigators. The participant and if applicable, his or her significant other, will also 
receive contact information for the investigators during the overnight stay in the case of 
an emergency or request for additional support. Participants 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.    
 
Participants will be instructed not to use caffeine or nicotine for 6 hours after the dose of 
MDMA. Spontaneously reported reactions, Adverse Events and Medications will be 
collected as described in Section 8 and 9 of the protocol. 
 
6.2.4 Integrative Sessions 24 Hours after Experimental Session [Visits 6, 10, 15 (15 
for full dose group only)]  
On the morning after the MDMA session, the participant will meet with both 
investigators during a 90-minute integrative psychotherapy 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 participants integrate their experiences both internally 
and into daily life. Therapists will emphasize their commitment to support the subject 
during the integration period and will be available via phone or pager. Subjects will be 
encouraged to relax and rest as much as possible for several days after the experimental 
session. 
 
Participants will complete the C-SSRS during each integrative session. At the beginning 
of this session, the participant and both investigators conducting psychotherapy will 
indicate their beliefs concerning participant condition assignment. The participant and 
investigator will then discuss and review events, thoughts, feelings and memories that 
occurred during the experimental session. If necessary, the investigators will help the 
participant to reduce any residual psychological distress he or she may be experiencing. 
The therapists will also encourage exploration of any new insights and perspectives 
resulting from states of acceptance, feelings of intimacy, and reduced fear that may have 
occurred during MDMA sessions and that may be applicable to emotionally distressing 


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situations in everyday life. The investigators will be supportive, validating the MDMA 
experience and facilitating understanding and emotional clearing. The investigators will 
assess participant mental health and the presence of any remaining reactions during 
integrative psychotherapy sessions. Integrative psychotherapy sessions can also serve as 
an opportunity for the investigators to gather information in an unstructured manner 
about the effects of MDMA on the participant.  If subjects who have pre-existing tinnitus 
or chronic pain mention any changes, the visual analog scale will be used to collect the 
changes in symptoms. 
 
After this psychotherapy session, a person previously selected by the subject will provide 
a ride home. If the participant is unable to locate an individual to take him or her home, 
the investigators will arrange an alternative means of transportation. The entire 
integrative psychotherapy session may be recorded to audio and video. Participants may 
receive copies of this session upon request. Therapists will be accessible if the participant 
needs support outside the scheduled integration sessions. 
 
Adverse Events and medications will be collected as described in Sections 8 and 9 of the 
protocol. 
 
6.2.5 Daily Telephone Contact for Seven days after an Experimental Session 
Investigators will follow the most recent version of the Treatment Manual in all matters 
relating to follow-up subsequent to the experimental psychotherapy sessions. 
Starting on the day of the non-drug integrative psychotherapy session following each 
experimental session, one of the investigators will contact the participant via telephone 
daily for one week. The telephone contact will be for a brief check-in lasting 5 to 15 
minutes, or as long as necessary to address any participant’s concerns or difficulties 
integrating their experience and to assess participant well-being. Additional telephone 
contact can be initiated at the request of the investigators or participant. On the second 
and seventh day of telephone contact, the C-SSRS will be administered to monitor for 
suicide risk. 
 
Adverse Events and medications will be collected as described in Sections 8 and 9 of the 
protocol. 
 
If the investigators are unable to reach a subject by telephone despite repeated attempts, 
every effort will be made to contact their outside physician or a family member to be sure 
they receive any support needed. If the investigators eventually contact the person, this 
participant would be permitted to remain enrolled in the study only if measures could be 
put in place to assure that such a problem would not recur. 
 
6.2.6 Integrative Psychotherapy between Experimental Sessions 
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 between experimental sessions and in the month following the last experimental 
session in each stage. The therapists may conduct more sessions if they and the subject 
deem it necessary. (See Time and Events Table). The purpose of these sessions is to 


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provide continued support for the participant as she or he considers his or her experiences 
during the experimental sessions and strives to integrate them into their lives. If subjects 
who have pre-existing tinnitus or chronic pain mention any changes, the visual analog 
scale will be used to collect the changes in symptoms. 
 
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 integration of material that emerged as a part 
of experimental sessions and afterward into daily life. Therapists will validate the choices 
of the subject to communicate or not on these thoughts, feelings and experiences.  
Therapists will emphasize their commitment to support the subject during the integration 
period and will be available via phone or pager. Subjects will be encouraged to relax and 
rest as much as possible for several days after the experimental session. 
 
The investigators will use clinical judgment to assess the participant’s psychological 
well-being during this period of time. Suicidality will be assessed with the C-SSRS. Each 
integrative session may be recorded to audio and video, and participants may receive a 
copy of one or more integrative sessions upon request. If there are any indications of 
continuing anxiety or distress, the investigators may arrange to address it in a specially 
scheduled additional non-drug therapy session, through continuing telephone contact, or 
at the next regularly scheduled non-drug therapy session. The participant may also 
initiate contact with the investigators at any time throughout the study.  
 
Adverse Events and medications will be collected as described in Sections 8 and 9 of the 
protocol. 
 
If an integrative session falls within the seven-day period of telephone contact, it will 
replace the day of telephone contact, and spontaneously reported reactions will be 
recorded as reported during the session.  
 
6.2.7 Evaluation at Primary Endpoint & Unblinding (Visit 13) 
The primary endpoint evaluation in Stage 1 will occur one month after the second blinded 
experimental session. This visit will consist of two meetings that may be completed on 
separate days, one with the independent rater and the other with the therapists. 
The blinded independent rater will administer:  CAPS to assess PTSD symptoms, BDI-II 
to assess depression symptoms, GAF to assess general psychological function, PTGI to 
assess post-traumatic growth (in reference to start of the study), PSQI to assess sleep 
quality, DES-II to assess dissociation symptoms and NEO PI to assess personality.  The 
blinded independent rater will provide their belief of the subject’s condition assignment.   
 
After completing all assessments and measures with the independent rater, the subject 
will meet with the therapists for approximately 30 minutes. Following the visit with the 
independent rater the blind will be broken for the subject’s condition assignment. The 
independent rater will remain blind to condition assignment at this time. The therapists 
will assess suicidality with the C-SSRS. The visual analog scale will be used to collect 


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changes in subjects who have pre-existing tinnitus and chronic pain symptoms.  
 
If the subject had been assigned to receive medium dose or low dose MDMA, the 
therapists will discuss continuation to Stage 2.  Low and medium dose subjects will not 
complete the third experimental session and associated integrative sessions in Stage 1. 
Participants who decline continuing to Stage 2 will complete the Responses to Research 
Participation Questionnaire (RRPQ). If participants had been assigned to the full dose 
condition in Stage I, they will provide their perceptions of experimental sessions at this 
point. The therapists will discuss scheduling the third open label full dose experimental 
session and integrative sessions.  
 
Adverse Events and medications will be collected as described in Sections 8 and 9 of the 
protocol. 
 
6.2.8 Evaluation Two Months after the Third Experimental Session (Visit 18- 
Full dose subjects only, End of Stage 1) 
The final evaluation for full dose subjects in Stage 1 will occur two months after the third 
experimental session. Participants will meet the independent rater for 90 to 120 minutes. 
The independent rater will administer the CAPS, BDI-II, PTGI (in reference to the start 
of the study), DES-II and the PSQI. The independent rater will assess participants on the 
GAF. Administration of CAPS may be recorded to video.  
 
After completing all assessments and measures at the evaluation at the end of Stage 1 
with the independent rater, the full dose subjects will meet with the investigators for 
approximately one hour. The investigators will administer the C-SSRS, and the subjects 
will indicate their perceptions of a third experimental session. Subjects will complete the 
RRPQ.  The visual analog scale will be used to collect changes in pre-existing tinnitus 
and chronic pain symptoms.  
 
Subjects will receive a memory aid card for use between this 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. Subjects may return to taking psychiatric medications from this point 
onward if necessary.  
 
6.2.9 Opportunity for Participants in Low Dose and Medium Dosage Condition to 
Enroll in Open-Label Study Segment ("Stage 2")  
Low dose and medium dose participants who elect to enroll in Stage 2 will undergo a 
course of therapy and evaluation nearly identical to the full dose group in Stage 1, but 
given in an open-label context. 
 
6.2.10 Open-Label Study Segment for Low Dose and Medium Dosage Participants 
(“Stage 2”) 
Participants assigned to receive low dose or medium dose MDMA during Stage 1 will 
undergo three open-label MDMA-assisted psychotherapy sessions that follow a course 
and schedule similar to Stage 1 for the full dose group except that participants will 


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undergo one instead of three introductory sessions. After confirming consent and 
eligibility criteria, participants continuing to Stage 2 will meet with both investigators 
conducting psychotherapy for a single review and preparatory psychotherapy session 
before the first open-label MDMA-assisted psychotherapy session. If more than 8 weeks 
have passed since the primary endpoint, all measures will be repeated for a new baseline 
prior to the first open-label experimental session. Experimental sessions will be 
conducted according to procedures described in Section 6.2.3.  During the first 
experimental session, subjects will receive a 100 mg initial dose of MDMA and may 
receive a 50mg optional supplemental dose of MDMA.  At the beginning of each of the 
second and third experimental sessions, the co-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 
50mg MDMA may be administered. If a 125mg initial dose of MDMA is selected, an 
optional supplemental dose of 62.5mg MDMA may be administered.  If the PI 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 in the safe.    
 
Integrative sessions will be conducted according to procedures described in Sections 
6.2.4 and 6.2.6. Phone calls will be conducted according to procedures described in 
Section 6.2.5.At the secondary endpoint based on procedures described in Section 6.2.7, 
the Independent Rater will administer the CAPS and GAF. Subjects will complete the 
BDI-II, PSQI, PTGI (in reference to the start of the study), and DES-II.Administration of 
the CAPS may be recorded to video. 
 
 Investigators will follow the most recent treatment manual in all matters relating to the 
Open-Label Stage 2 experimental psychotherapy sessions 
 
Spontaneously reported reactions, SAEs, AEs and medications will be collected and 
reported in the same manner as during Stage 1.  The visual analog scale will be used to 
collect changes in subjects who have pre-existing tinnitus and chronic pain symptoms as 
in Stage 1.  
 
6.2.11 Assessment Two Months after Third Open-Label Session (End of Stage 2) 
 
All participants in Stage 2 will be assessed by the independent rater two months after 
their final open-label session. At that visit, the independent rater will administer the 
CAPS, which may be recorded to video, and assess participants on the GAF, and 
participants will complete the BDI-II, PTGI (in reference to the start of the study), PSQI, 
DES-II, and NEO-PI. Participants will also complete C-SSRS and RRPQ with the 
therapists. Participants will provide their perception of the experimental sessions. 
Adverse Events and medications will be collected as described in Sections 8 and 9 of the 
protocol.  The visual analog scale will be used to collect changes in pre-existing tinnitus 
and chronic pain symptoms.  
 
 


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Subjects will receive a memory aid card for use between this 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. Subjects may return to taking psychiatric medications from this point 
onward if necessary. 
 
6.2.12 Evaluation 12 Months after Final Experimental Session 
All participants who completed Stage 1 only will be evaluated 12 months after their third 
experimental session, and all participants who completed Stage 2 will be evaluated 12 
months after their third open-label MDMA-assisted psychotherapy session. The 
independent rater will administer the CAPS and assess participants on GAF, and 
participants will complete the PTGI (in reference to the start of the study), BDI-II, PSQI, 
DES-II and NEO PI. Suicidality will be assessed with the C-SSRS. Participants will also 
complete a questionnaire assessing positive and negative long-term effects of the study. 
Outcome measures will either be completed over the telephone or at the study site.  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 and the participant will return 
self-report questionnaires in envelopes supplied by the investigators with the study site 
listed both as the mailing and return address. The visual analog scale will be used to 
collect changes in subjects who have pre-existing tinnitus and chronic pain symptoms.   
Subjects will complete the termination visit at this time. 
 
Adverse Events and medications will be collected as described in Sections 8 and 9 of the 
protocol. 
 
6.3 Removal of Participants from the Study 
Participants can withdraw consent at any time without prejudice.  The investigator can 
withdraw a participant if, in his or her clinical judgment, it is in the best interest of the 
participant or if the participant cannot comply with elements of the protocol that are 
critical for safety or necessary for the scientific integrity of the study. If the investigator 
withdraws a participant from the study, the investigators will explain the reason for 
withdrawing the participant.  
 
If a subject develops any exclusion criteria that in the opinion of the Medical Monitor, 
affects the safety of the subject, including psychiatric diagnosis, pregnancy or excluded 
medications, the subject will discontinue treatment.  
 
Subjects will be clinically monitored after discontinuation of treatment by at least one of 
the therapists.  The cause of discontinuation will be recorded in the subject’s source 
records and CRF.  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 investigators, 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 


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number. Subjects who discontinue treatment after the primary endpoint in Stage 1 will 
not be replaced. If Stage 1 subjects discontinue treatment before the primary endpoint, 
the site should contact the randomization monitor for replacement instructions. If there is 
an emergency requiring knowledge of subject's condition assignment, the blind may be 
broken for an individual subject. The investigator will be provided with sealed 
emergency unblinding envelopes corresponding to each Enrollment Code.  These sealed 
envelopes will be stored in a secure limited access area and should remain sealed if there 
are no emergency unblinding events during the study. The therapists, independent rater, 
and subject will remain blind to condition assignment until unblinding at the primary 
endpoint. Unblinding at the primary endpoint will be done using the web-based 
randomization program. Detailed instructions will be provided to the site in a separate 
document.  
 
6.4 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 
is to promptly inform the study subjects and will arrange appropriate therapy and follow-
up. If the 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 federal and local 
regulations. Participants will still receive recordings of sessions if they request them. 
 
7.0 Risks of Study Participation 
 
7.1 Screening 
Medical data will be collected via history and physical examination and measurement of 
vital signs, laboratory tests, and ECG. If indicated, additional procedures such as exercise 
tests and ultrasound imaging will be administered. Submitting to a full medical 
examination may be time consuming, and may be distressing or uncomfortable for some.  
Because medical examinations are part of the screening procedure, they cannot be 
omitted from the study design.   
 
Psychological assessments will be obtained through interviews.  Because these interviews 
require individuals to discuss their condition, they may prove upsetting for some.  
Because psychiatric interviews and discussion of PTSD symptoms are used during 
screening, they cannot be avoided. The investigators have experience working with 
people with PTSD, and they will seek to reduce anxiety and distress during these 
interviews. 
 
7.2 Risks and Discomforts Associated with Drawing Blood  
Prior to enrollment, blood will be drawn as part of screening to assess eligibility.  
Temporary discomfort may arise as a result of sampling blood.  Participants may 
experience temporary discomfort at the blood-draw site.  There is also a remote 
possibility of inflammation or infection at the blood-draw site.  


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7.3 Risks and Discomforts Associated with Non-Experimental and Experimental 
Psychotherapy 
During non-drug and MDMA-assisted psychotherapy sessions, participants will be asked 
to think about and discuss their thoughts and emotions relating to the traumatic event or 
events.  They may experience intense emotional responses 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 and experimental 
sessions.  Psychotherapy is conducted as part of the research study, including the 
experimental intervention (MDMA-assisted psychotherapy), and people undergoing 
psychotherapy are expected to confront unpleasant thoughts, feelings and memories in 
the process of therapy. Since psychotherapy is an integral part of the research study 
design, the potential distress arising from psychotherapy is unavoidable, and requires 
proper facilitation and support from the therapists. Discontinuing PTSD medications and 
the acute and sub-acute effects of MDMA-assisted psychotherapy can produce shifts in 
mood and activation, which may increase likelihood of suicidal ideation or behavior. 
 
Participants may discuss emotionally distressing or embarrassing issues during their 
MDMA session.  This may cause psychological distress. 
 
All psychotherapy sessions may be recorded to audio and video and participants may 
have access to recordings if they request them. Participants may feel uncomfortable with 
having their sessions recorded. The recordings will be used for developing a manualized 
form of MDMA-assisted psychotherapy to be used in future research. The recordings are 
necessary for developing the experimental treatment. Participants 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 investigators, trainees or regulatory 
agencies. 
 
7.4 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 volunteers in previous 
studies in non-psychiatric or psychiatric populations. Spontaneously reported reactions 
may include anxiety, reduced appetite, dizziness, tight jaw or bruxism (tooth-grinding), 
difficulty concentrating, impaired gait or balance, dry mouth, and thirst. Other slightly 
less common reactions include drowsiness, impaired judgment, headache, restlessness, 
nausea, parasthesias (odd somatic feelings, such as tingling, feeling hot or cold), changes 
in thought, perspiration, drowsiness, nystagmus (eye-wiggling) and sensitivity to cold.  
These effects are transient and wane as drug effects wane. Sub-acute effects that may 
either continue for the next 24 hours or appear later include insomnia, fatigue, weakness, 
heavy legs, dry mouth, low mood or irritability. Other spontaneously reported reactions 
include increased private worries (rumination) and needing more sleep. Sub-acute effects 
are reported less often than acute effects.  Other common reactions in preliminary data 
from the initial study of MDMA-assisted psychotherapy in people with PTSD include 
muscle tension in approximately 20% and gastrointestinal discomfort or diarrhea in 


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approximately 3.3% participants receiving MDMA. More information on drug side-
effects is contained in the Investigator's Brochure (IB).  
 
MDMA may produce mild alterations in sensory perception and altered perception of 
time [43, 60, 68].  Women may be more sensitive to these effects than men [62].  MDMA 
acutely affects attention, information processing and memory.  MDMA acutely impairs 
verbal memory and recall for object location without affecting recall of scene change 
[49].  
 
7.4.1 Cardiovascular 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. Participants enrolled in controlled trials with MDMA 
(approximately 5% per trial) have had elevations in blood pressure of above 140/90 
mmHg or higher, but none of these individuals needed clinical intervention and blood 
pressure returned to normal as drug effects waned [68, 75].  Table 2 shows the degree of 
increase in vital-sign measurements in the investigators’ recently completed clinical trial.  
No subjects in other clinical trials using MDMA have required any clinical interventions 
for elevated blood pressure, pulse or temperature, and all values returned to normal 
spontaneously.  
 
The degree of additional blood pressure and pulse elevation after a second dose of 
MDMA that is half the original dose and given 1.5 to 2.5 hours after the first dose is 
minimal. Preliminary data gathered by Dr. Michael Mithoefer, the Clinical Investigator 
who recently conducted a study of MDMA-assisted psychotherapy in 21 participants 
PTSD, demonstrates that elevation in blood pressure and heart rate after the supplemental 
dose does not exceed elevations seen after the initial dose.  
                                                                                                                                        
Table 2. Physiologic Data: Mean Increases in Vitals over Baseline and Range of 
Values per Experimental Session 
 
 
MDMA 
Placebo 
 
Mean increase (St. Dev.) 
[Range of values] 
Mean increase (St. Dev.) 
[Range of values] 
Systolic blood 
pressure, mmHg 
28.21 (14.11) 
[96-179] 
13.38 (10.40) 
[83-157] 
Diastolic blood 
pressure, mmHg 
15.38 (6.85) 
[56-113] 
10.94 (6.93) 
[60-102] 
Heart rate, 
beats/minute 
28.13 (11.87) 
[60-141] 
16.69 (12.35) 
[68-107] 
Temperature,  °C 
0.72 (0.52) 
[36.6-37.83] 
0.42 (0.32) 
[36.39-37.76] 
 


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Group comparisons of vital signs were tested for change pre-session (15 minutes prior) to 
highest recorded and pre-session to post-session (6 hours post) using t-tests.  There was a 
significantly greater increase in all physiologic measures from pre-session to highest 
recorded value during experimental sessions for the MDMA group than for the placebo 
group (p < .05). There were no significant differences when comparing changes from  
pre-session to post session (p>.05).  All values returned to pre-session norms by six hours 
after session completion. 
 
7.4.2 Psychological Distress 
Psychological distress from MDMA could arise at any time from the first indications of 
drug effects until the last effects have dissipated (approximately 3 to 5 hours after drug  
administration).  Anxiety or distress during the session may last for as little as 15 minutes 
or for as long as 5 hours.  In addition, psychological distress could arise following an 
MDMA session as a result of participants having difficulty integrating their experience 
after the MDMA effect has subsided.  In previous Phase 1 and Phase 2 studies, these 
symptoms have been self-limiting, and have responded well to reassurance from the 
investigator, with occasional use of benzodiazepines for anxiety. In the proposed study, 
participants will have volunteered for the sessions with the intention of confronting and 
working through traumatic experiences. Hence signs of psychological distress, anxiety, or 
other unpleasant psychological reactions are to be expected and may be considered an 
element of the psychotherapeutic process. Investigator responses to psychological distress 
are discussed in detail in Appendix A. 
 
Less commonly, mild anxiety and depressed mood are reported 1–3 days after MDMA  
administration [61, 62, and see the IB]. At least some of the physiological or 
psychological reactions listed above are very likely to occur. Proper preparation and 
follow-up support will reduce the impact of acute or sub-acute effects, so that participants 
are not likely to be unduly troubled by them. 
 
7.4.3 Body Temperature 
MDMA administered in a controlled setting produces only a slight increase in body  
Temperature [62], and ambient temperature does not enhance or attenuate this slight  
elevation in humans [44].  Maximum body temperature could rise above normal 
temperature, as with the maximum peak of 100° Fahrenheit (F), or 37.7 Celsius (C) 
during the first experimental session in the sponsor’s recent Phase 2 trial (n = 23, MDMA 
and placebo conditions combined), but body temperature returned to normal without 
treatment other than simply lowering the ambient temperature, which may or may not 
have been necessary. 
 
7.4.4 Immunological Changes 
MDMA may produce modest changes in immune functioning, lasting up to 48 hours. 
A research team in Spain has studied the acute immunological effects of one or two doses 
of 100 mg MDMA [102-104].  Findings included a decline in CD4 cells, smaller 
CD4/CD8 ratio, attenuated lymphocyte proliferation in response to mitogen, and an 
increase in natural killer (NK) cells, with effects diminishing but still detectable 24 hours 
after drug administration.  These researchers also found that MDMA decreased 


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production of pro-inflammatory cytokines, including IL-2 and interferon-Gamma and 
increased production of anti-inflammatory cytokines, including IL-4 and IL-10.  
Generally, MDMA appeared to decrease the concentration of Th1 (immunostimulating 
and pro-inflammatory) cytokines and increase the amount of Th2 (immunsuppressive and 
anti-inflammatory) cytokines measured in blood.  Research in rodents confirms these 
findings [105-107]. Changes of similar magnitude and duration have been previously 
noted after ingestion of other psychoactive agents, such as alcohol or cocaine [104, 108].  
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.  Immunological changes seen after an initial dose of MDMA 
are enhanced by a second dose of identical size given four hours after the first dose [109, 
110], and a second dose of identical size given 24 hours after the first dose produced the 
same immunological effects over the same time course, but with greater intensity than 
after the first dose [110]. Given this data, it is possible that administering a smaller 
supplemental dose 1.5 to 2.5 hours after the first dose will slightly enhance the 
immunological effects set in motion by the first dose.  Previous Phase 1 studies have not 
reported any indication of increased risk of illness occurring after MDMA administration. 
 
7.4.5 Abuse Liability 
MDMA was classified as a Schedule 1 compound in 1985, largely on the basis of its 
growing popularity at nightclubs and parties in the early to mid-1980s.  The DEA placed 
MDMA in Schedule 1, a category defined to include drugs with high abuse potential and 
no known medical use [111].  Despite its classification as a Schedule 1 drug, self-
administration studies in nonhuman animals and findings concerning prevalence of 
ecstasy abuse and dependence do not suggest that its abuse liability is high.  Rats, mice 
and monkeys will self-administer MDMA [112-114]. However, monkeys will “pay” 
higher prices in lever presses for psychostimulants than they will for MDMA [115, 116].  
Studies assessing prevalence of problematic ecstasy use or dependence suggest that a 
small percentage of individuals, especially those with prior psychological difficulties, 
may develop ecstasy use or dependence [117, 118], though studies of non-representative 
samples have reported higher rates of dependence [119].  Most regular ecstasy users 
report taking ecstasy no more often than once a week [120].  Taken together, an 
examination of findings in humans and nonhuman 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. 
 
When reviewing the effects of MDMA in a sample of 74 largely drug-naïve participants, 
Liechti and colleagues stated that “none of the participants expressed any interest in 
taking MDMA as a recreational drug” after receiving MDMA in a controlled research 
setting, [62]. People with PTSD undergoing MDMA-assisted psychotherapy are likely to 
experience painful and frightening emotions during these sessions in conjunction with 
memories related to the original traumatic incident in addition to or even instead of 
increased positive mood or euphoria. As a result, it seems unlikely that people with PTSD 
undergoing this emotionally challenging experimental intervention will find the 
experience pleasurable or safe enough to pursue MDMA use in unsupervised and 


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uncontrolled settings. Mithoefer reported that few participants in the study of MDMA-
assisted psychotherapy in people with PTSD reported desiring to take MDMA in an 
unsupervised setting.  
 
In the currently proposed protocol, diversion is not an issue because MDMA will only be 
administered under the supervision of the Clinical 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. 
 
7.4.6 Toxicity 
The toxicity of MDMA has been investigated in numerous animal and in-vitro studies 
published in peer-reviewed journals.  In addition, hundreds of published case reports 
describe adverse events in illicit ecstasy users.  Finally, 28-day toxicity studies in canines 
and rodents have been performed [121], and are included in the MDMA Drug Master File 
(DMF #6293).  Thus, the toxicity of MDMA is well characterized. 
 
Serious MDMA toxicity is rare even in uncontrolled settings, considering the millions of 
users taking ecstasy of unknown identity, potency, and purity [122-124], with many users 
consuming estimated MDMA doses that are several times higher than those used in the 
proposed program, without any apparent toxicity.  Under unsupervised and nonmedical 
conditions, the most common SAE involves hyperthermia, described in Appendix A.  In 
addition to hyperthermic syndromes, other rare AEs include dysphoric, panic or 
psychotic response, hepatotoxicity and hyponatremia, and these are described in more 
detail in the Investigator’s Brochure.  The majority of ecstasy users visiting emergency 
departments do so because of anxiety or panic [125, 126]. In the proposed clinical 
protocol, study eligibility is intended to reduce the likelihood of many serious adverse 
events. Participants will be carefully monitored for signs and symptoms of these events 
and will be offered supportive psychotherapy and other forms of support determined to 
be necessary by the Clinical Investigator.  Contingency plans for responding to these 
events are described in Appendix A.  
 
7.4.7 Potential Neurotoxicity Associated with Ecstasy Use 
Extensive studies in animals indicate that high or repeated doses of MDMA can damage 
serotonergic axons originating in the brainstem dorsal raphe nucleus, probably as a result 
of oxidative stress, and this damage is associated with decreases in serotonin, serotonin 
metabolites, and serotonin transporter site density [127-129], with a study in squirrel 
monkeys suggesting long-lasting effects on brain serotonin [130].  Similar changes can 
be induced by methamphetamine and other psychostimulants [131-133].  Previous studies 
in nonhuman primates overestimated human-equivalent doses [134], and previous studies 
in rodents may also have overestimated human-equivalent doses [135].  Studies in 
rodents and monkeys that employed lower or fewer doses of MDMA, or that involved 
self-administration, have failed to find some or all of the markers of serotonin 
neurotoxicity listed above [112, 136-138].  Some researchers believe that MDMA is 
neurotoxic in humans even at doses used in clinical trials [139].  However, they are 
basing their case on studies that employed inappropriately high doses of MDMA, and 


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studies comparing the effects of repeated use of ecstasy, often along with other drugs, as 
discussed below.   
 
There is controversy as to whether analogous changes in brain serotonin occur in humans, 
and a wealth of literature exists that compares ecstasy users to non-users [140].  Earlier 
studies were retrospective and possessed a number of methodological flaws, particularly 
in relation to appropriate matching of ecstasy users with controls.  Later research 
employed longitudinal study designs, allowing for comparisons over time.  Retrospective 
and longitudinal imaging studies have detected decreased estimated serotonin transporter 
(SERT) sites in current heavy ecstasy users when compared with controls [141-143], but 
with estimated SERT sites returning to normal or increasing in numbers with period of 
abstinence.  Likewise, studies have detected impaired memory and executive function in 
ecstasy users [140, 144, 145].  A number of these studies reported impaired cognitive 
function only in heavy users, and not in moderate users, and some recent studies suggest 
that use of other drugs may contribute to impaired cognition [146-149], though other 
studies also reported that abstinence from ecstasy did not attenuate memory impairment 
in heavy users [143, 150].  
 
There is also some evidence that ecstasy users are more likely to report symptoms of 
anxiety or depression, and to exhibit more behavioral impulsivity than non-ecstasy user 
controls[151-154].  Findings from prospective and longitudinal studies suggest that 
young people with existing psychological problems are more likely to try ecstasy than 
people without these problems [117, 118], and it appears that polydrug use may 
contribute to this association [151, 155].  Findings from retrospective studies are of 
limited value in estimating the potential risk of neurotoxicity from two doses of MDMA, 
as average cumulative dose and frequency of use in most of these studies is considerably 
higher than doses in human trials of MDMA.  A better estimate of the potential risk of 
neurotoxicity can be found from prospective studies comparing people before and after 
their first use of ecstasy.  
  
Starting in the early 2000s, a team of researchers in the Netherlands has examined  
samples of people before and after reporting their first uses of ecstasy.  These researchers 
have assessed estimated SERT sites, chemical markers of neuronal injury, changes in 
cerebral blood flow, performance and brain activity related to a working memory task, 
and cognitive function in samples of ecstasy users reporting an average use of 1 to 3 
tablets [156-159]. The team also performed studies expressly in heavy ecstasy users [160-
163]. They failed to find reductions in SERT sites, signs of neuronal injury or changes in 
performance on or brain activity during a working memory task in samples reporting use 
of no more than six ecstasy tablets [156, 157].  They found slight changes in cerebral 
blood flow in the dorsolateral prefrontal cortex but nowhere else, and they failed to find 
any markers of neuronal injury [156].  Low use of ecstasy also failed to alter brain 
activity or performance on a measure of working memory [116].  When comparing 
cognitive function in people before and after their first use of an average of 3.2 tablets, 
with non-user controls at similar points in time, ecstasy users showed less improvement 
on a memory task than non-users [156].  It is notable that the study examining SERT sites 
and cerebral blood flow did not employ non-user controls, that all participants in the 


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study of cognitive function performed within the normal range, and that one individual 
had reportedly used ecstasy on 30 occasions rather than the limit of 10 occasions set for 
the other studies.  Furthermore, there are some findings that women who decided to use 
ecstasy had higher impulsivity scores prior to use [164].  Taken together, their findings 
fail to confirm serotonergic neurotoxicity after low ecstasy use, yet found some possible 
indications of impaired memory.  
 
The risks of neurotoxicity are minimal in the proposed protocol.  This is supported by 
empirical and toxicokinetic evidence and is consistent with the lack of toxicity reported 
in previous clinical MDMA studies.  Nevertheless, the risks of neurotoxicity arising from 
MDMA administration will be described and noted in application materials prior to and 
during the completion of the application, and the investigators will informally monitor for 
any signs of changes in cognition after each MDMA-assisted psychotherapy session. 
 
7.4.8 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, 
[165, 166]. A survey reported that in women interviewed on their drug use during 
pregnancy, there was a link between self-reported extent of prenatal MDMA exposure 
and delays in infant development at 12 months [167].  Pregnant and lactating women will 
be excluded from participation in the proposed protocol, 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 during the period of the 
protocol. If any participant becomes pregnant after the occurrence of at an experimental 
session, the sponsor and Clinical investigator will follow the pregnancy to outcome. 
 
7.5 Medical Emergencies 
The preparatory session, MDMA session and integrative session, will be conducted in the 
psychiatric offices of the investigators.  The offices are located 2.6 miles from the nearest 
emergency room.  The office will be equipped with a "crash cart" containing the  
emergency drugs and equipment necessary to respond to any complications.  Intravenous 
fluids, antiarrhythmic drugs, antihypertensive drugs (such as nitroprusside and labetolol), 
injectable epinephrine and other pressor agents, and other standard emergency drugs and 
equipment will be available on-site as a means of treating any potential allergic reactions 
or other medical emergencies. In addition to drugs, the crash cart will contain a 
defibrillator (with rhythm monitoring capability), an oxygen tank, a suction device, a 
pulse oxometer, an IVAC pump and intubation equipment (including laryngoscope, and 
endotracheal tubes).  As is now common practice in emergency departments, an 
automatic blood pressure cuff will be used in place of intraarterial blood pressure 
monitoring equipment. For a recently completed Phase 2 trial, the researchers have 
established (in communication with the FDA) contingency plans for responding to those 
AEs that appear most likely, based on a comprehensive review of case reports of toxicity 
in illicit MDMA users reported by Baggott and colleagues in 2001 and in the current 
Investigator’s Brochure.  The same contingency plans and equipment will be used in this 
protocol, with the exception of the fact that there will not be an additional nurse on site 


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for this study. In the unlikely event of cardiac arrest, the researchers will follow the 
American Heart Association guidelines for 2-person BLS for Healthcare Providers 
(including defibrillation with an automated external defibrillator (AED) until the arrival 
of Emergency Medical Services (EMS), at which time Advanced Cardiac Life Support 
(ACLS) procedures will be instituted. With these personnel and equipment, the 
researchers, in conjunction with EMS if necessary would be able to begin treatment in the 
office and then transport the participant by ambulance if hospital admission were 
required. 
 
8.0 Adverse Events 
An Adverse Event (AE) is defined as any untoward or unfavorable medical occurrence in 
a clinical research study participant, including any abnormal sign (e.g. abnormal physical 
exam or laboratory finding), symptom, or disease, temporally associated with the 
participants' involvement in the research, whether or not considered related to 
participation in the research. This definition includes concurrent illnesses or injuries and 
exacerbation of pre-existing conditions.  
 
An unexpected adverse event is one that is not listed in the current Investigator’s 
Brochure or an event that is by nature more specific or more severe than a listed event. 
All AEs will be monitored by the investigators until resolution or, if the AE becomes 
chronic, a cause identified.  If an AE is unresolved at the conclusion of the protocol, a 
clinical assessment will be made by the investigator and/or Medical Monitor as to 
whether continued follow-up of the AE is warranted. 
 
The severity of events reported on the “Adverse Events” CRF will be determined by the 
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 
based on the following definitions: 
 
1. Not Related 
 
The AE is not related if exposure to the investigational product has not occurred, or the 
occurrence of the AE is not reasonably related in time, or the AE is considered unlikely 
to be related to use of the investigational product, i.e. there are no facts (evidence) or 
arguments to suggest a causal relationship, or the AE is more likely related to the 
subject’s pre-existing condition. 
 
2. 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  


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investigational product. 
 
3. 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. 
 
The relationship of the study treatment to an AE will be determined by the investigator. 
 
8.1 Common Expected Reactions 
Commonly expected reactions that are spontaneously reported are collected on a separate 
CRF page and will be categorized as mild, moderate or severe.  Spontaneously reported 
reactions may include reduced appetite, dizziness, tight jaw or bruxism (tooth-grinding), 
difficulty concentrating, impaired gait or balance, dry mouth, and thirst. Other slightly 
less common reactions include drowsiness, impaired judgment, headache, restlessness, 
nausea, parasthesias (odd somatic feelings, such as tingling, feeling hot or cold), changes 
in thought, perspiration, drowsiness, nystagmus (eye-wiggling) and sensitivity to cold. 
These effects are transient and wane as drug effects wane. Sub-acute effects that may 
either continue for the next 24 hours or appear later include insomnia, fatigue, weakness, 
heavy legs, dry mouth, low mood or irritability. Sub-acute effects are reported less often 
than acute effects.  Other spontaneously reported reactions include increased private 
worries (rumination) and needing more sleep. Sub-acute effects are reported less often 
than acute effects. Other common reactions in preliminary data from the initial study of 
MDMA-assisted psychotherapy in people with PTSD include muscle tension in 
approximately 20% and gastrointestinal discomfort or diarrhea in approximately 3.3% 
participants receiving MDMA. Spontaneously reported reactions will be collected during 
the experimental session and during the seven days of telephone contact beginning the 
day after each experimental session. 
 
8.2 Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose: 
 
• Results in death 
• Is life-threatening (i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event 
which hypothetically might have caused death if it were more severe 
• Requires or prolongs inpatient hospitalization 
• Results in persistent or significant disability/incapacity (i.e., the event causes 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 


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AEs which do not fall into these categories are defined as non-serious.  It should be noted 
that a severe adverse event need not be serious in nature and that a SAE need not, by  
definition, be severe. 
 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the medical history.  The hospitalization would not result in the event or  
condition being reported as a study-related SAE unless, in the view of the 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, hospitalization for these 
procedures was prolonged as a result of participation in the clinical trial. 
 
8.3 Adverse Event Collection 
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 or at the latest on the following working day by 
telephone or fax to either of the following: 
 
Medical Monitor:  
Julie Holland, M.D. 
NYU School of Medicine 
200 East 33rd Street, Suite 16H 
New York, NY 10016 
Cell number: 917-608-6200 
Voice mail: 212-358-5808  
Fax number: 212-679-2623 
Email: jholland@inch.com 
 
Study Monitor:  
Berra Yazar-Klosinski, Ph.D. 
Phone number: 831-429-6362 ext. 104 
Fax number: 831-429-6370 
Email: berra@maps.org 
 
Adverse events (AEs) that will be collected for the duration of the protocol are: 
 
• All SAEs will be collected from enrollment through termination. 
• All AEs and common expected reactions will be collected on the day of MDMA 
administration and for seven days after each experimental session. 
• Events requiring medical attention will be collected from the first experimental 
session through the subject’s final assessment at the end of Stage 1 or Stage 2 (as 
appropriate). 


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• Events related to planned treatments or physician visits for baseline conditions 
collected in the Medical History will not be collected unless there is an 
exacerbation of the condition. 
• 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. 
 
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 
withdrawal and psychiatric AEs during the period between the end of Stage 1 or end of 
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. This information may be collected by phone. 
 
9.0 Collection of Concomitant Medications and Tapering Instructions 
All medications, over the counter (OTC) and prescription will be collected from 
screening through 7 days after the final experimental session.  From 7 days after the final 
experimental session through study termination only medications taken to treat SAEs and 
psychiatric AEs will be collected. 
 
Concomitant medications will be recorded during screening. Any psychoactive drugs will 
be tapered in an appropriate fashion to avoid withdrawal effects. They will be 
discontinued long enough before the experimental session to avoid the possibility of drug 
interactions (the interval will be at least 5 times the half-life of the particular drug or its 
active metabolites, plus one week for stabilization). If necessary, the investigators will 
make plans for tapering off and discontinuing any contraindicated medication upon 
enrollment, in consultation with the prescribing physician.   
 
The investigators will request information about any changes in medication. Medications 
taken during the course of the protocol, including medications taken to treat AEs, will be 
recorded on a concomitant medications CRF.  Participants must be willing to refrain from 
taking any psychiatric medications until after the end of Stage 1 or Stage 2, with the 
exception of gabapentin when prescribed for pain control or stimulants for ADHD taken 
at baseline provided that they are discontinued 5 half lives before each MDMA session 
and are not restarted until 10 days after each MDMA administration. The investigators 
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).   
 
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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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 CI 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.  
 
Participants must agree that, for one week preceding the MDMA session: 
 
a. 
Subjects will refrain from taking any herbal supplement (except with prior 
approval of the research team).  
b. 
Subjects will not take any nonprescription medications (with the exception of 
non-steroidal anti-inflammatory drugs or acetaminophen unless with prior 
approval of the research team). 


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c. 
With the permission of their physician subjects will not take any prescription 
medications (with the exception of birth control pills, thyroid hormones or 
other medications approved by the research team).  
 
10.0 Clinical Laboratory Assessments 
The Clinical Investigator will examine laboratory assessments gathered in screening for 
assessing participant eligibility.  The investigator will use a list of normal ranges to  
conclude whether participants are eligible for the protocol, and will indicate justification 
for admitting participants with abnormal values.  
 
The following laboratory assessments will be performed as a part of screening: 
 
Serum electrolytes and the metabolic profile, which includes: 
ALT/SGPT;  
albumin:globulin (A:G) ratio;  
albumin, serum;  
alkaline phosphatase, serum;  
AST/SGOT;  
bilirubin, total;  
BUN;  
BUN:creatinine ratio;  
calcium, serum;  
carbon dioxide;  
chloride, serum;  
creatinine, serum;  
globulin, total;  
glucose, serum;  
potassium, serum;  
protein, total, serum;  
sodium, serum;  
 
CBC, which includes:  
Hematocrit;  
hemoglobin;  
MCV;  
MCH;  
MCHC;  
RDW;  
percentage and absolute differential counts;  
RBC;  
red cell count;  
WBC; 
 
Urinalysis, which includes:  
Color; 


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appearance; 
specific gravity;  
pH;  
protein;  
glucose;  
ketones;  
occult blood;  
leukocyte esterase;  
nitrite;  
bilirubin;  
urobilinogen; 
 
Thyroid function, which includes:  
TSH high sensitivity; 
Free T4; 
Free T3. 
 
In addition, HIV and, if indicated, Hepatitis C serology will be performed.   
 
A urine-dip pregnancy test for females of childbearing potential and a urinary drug screen 
will be performed as well.  
 
The laboratory assessments other than the urine drug screen and pregnancy test will be 
performed at: 
 
Laboratory Corporation of America 
1280 Johnnie Dodds Blvd, Ste 108 
Mount Pleasant, SC 29464 
 
The urine drug screen and pregnancy test will be performed at the study site. 
11.0 Study Monitoring, Auditing and Documentation 
Investigators and/or their study staff will be trained prior to the start of the protocol.  The 
clinical study site will be monitored by site visits and telephone calls to the investigator 
by representatives of the sponsor.  The site will be monitored as appropriate for the rate 
of enrollment in order to comply with GCP guidelines and to ensure validity of the study 
data. From the start of the study, videos from selected sessions will be reviewed for 
adherence to the Treatment Manual and therapeutic alliance. Adherence will be checked 
by monitoring and by review of selected video data. During each monitoring visit, source 
data verification will be performed by a Clinical Research Associate (CRA) to ensure 
compliance, including accurate and complete recording of data on CRFs, source 
documents, and drug accountability records.  A CRF collation supplied by the sponsor 
will be completed for each participant enrolled.   Monitoring and auditing procedures of 
the sponsor will be followed, in order to comply with Good Clinical Practice (GCP) 
guidelines and to ensure validity of the study data. 
 
The sponsor will review the study documentation used for planning, conduct and  


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monitoring of the study in order to ensure compliance with GCP and local regulations. 
This documentation includes as a minimum: the Investigator’s Brochure, the Study  
Protocol, the Case Report Forms and the Subject Information and Consent Form. 
 
During or after the clinical protocol, 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. 
12.0 Data Analysis  
The Sponsor will judge the clinical and statistical significance of the study and estimate 
effect size and statistical power based on a comparison of observer-blind data collected at 
baseline and the primary endpoint using the primary outcome measure, which is the 
CAPS.  
The sample selection is expected to produce acceptably homogeneous groups due to their 
diagnosis of with PTSD with CAPS scores of at least 50 who have not responded to 
treatment. There is no expectation that conditions will differ significantly in composition 
by gender, race or ethnicity, duration of PTSD diagnosis or presence versus absence of 
other permitted psychiatric disorders, as depression. 
 
The sponsor will examine individual CAPS, BDI-II, PTGI, PSQI, DES-II and GAF 
scores at baseline and the primary endpoint, in low dose, medium dose and full dose 
conditions. Descriptive statistics will be calculated for all measurements overall and by 
condition. Distributional characteristics will be examined for outliers and extreme values 
and, if either is evident. If outliers are found in primary or secondary outcome measures, 
the sponsor will perform analyses with and without the outlying data. Effect sizes for all 
outcome measures for primary endpoint, Stage 1, secondary endpoint, end of Stage 2, and 
12-month follow-up will be estimated using Cohen's techniques.  
 
All analyses of data from the primary endpoint will contain blinded data. Analysis of 
variance will be used to compare Global CAPS scores by dose condition at the primary 
endpoint. 
Analysis of variance, or nonparametric analysis if assumptions are not met, will be used 
to compare the dose conditions for change in BDI-II, PTGI, PSQI, GAF, DES-II and 
NEO PI scores separately. If scores cannot be examined sufficiently in this model, then 
analyses will compare available data through the use of difference scores.  
 
The sponsor will examine open-label data collected two months after the third Stage 1 
experimental session. The sponsor will perform a within-subject analysis of full dose 
participants.  
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 


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an exploratory intent to treat analysis to examine results without bias towards subjects 
more likely to complete the study per protocol. 
 
Descriptive statistics will be computed for vital signs and subjective distress during each 
experimental or open-label session. The sponsor will informally or formally compare 
peak blood pressure, heart rate and body temperature for participants after sessions after 
low, medium or full dose MDMA. Frequency tables will be produced on prevalence of 
spontaneously reported reactions and AEs. 
 
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 and examine all Changes in Tinnitus and/or Pain 
visual analog scale scores across all three groups and within the 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 SOCQ scores completed after each MDMA-
assisted psychotherapy session, and SOCQ scores will be compared across each of the 
three MDMA dose conditions and after full dose given during Stage 2. The data will be 
explored for effects of condition on responses to the SOCQ.  
 
Descriptive statistics will be calculated for subject's perceptions of experimental sessions. 
Mean, standard deviation and range of individual responses will be examined. 
Perceptions of experimental sessions will be examined during Stage 1 and Stage 2, before 
and after participant have undergone a third experimental session and will be compared 
within subjects. 
 
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. 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. If it is 
found that there are specific factors within the adherence scales, then the factor will be 
correlated with Global CAPS score. 
 


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Qualitative interviews conducted by a researcher who is part of the study team during the 
12-month follow-up visit will be transcribed to text. A computer-assisted qualitative data 
analysis software package will be utilized to assist in thematic content analysis of the 
interview transcripts. A member of the research team will code the interviews for content, 
to identify emerging themes and organize data into thematic constructs utilizing a 
grounded theory approach. Descriptive statistics will be calculated for emerging themes. 
 
There may be an interim analysis of the data that will not affect study conduct for safety 
and efficacy before all participants have completed the 12-month follow-up.  
 
12.1 Statistical power 
The literature does not provide an estimate of the effect size for change in CAPS after 
sessions using an low dose or medium -dose MDMA. The proposed study will provide 
these important estimates. With the current amendment, the sponsor is increasing the 
group size in each condition, and all subjects will complete the primary endpoint. This 
may increase statistical power in this study, and will provide important estimates of effect 
size that can be used to develop a dose response model. 
 
13.0 Informed Consent 
The investigator is responsible for obtaining informed consent in adherence to GCP and 
according to applicable regulations prior to entering the subject into the trial. Information 
about the study must be given in an understandable form.  Written information about the 
trial will also be provided.  In addition to the explanation of evaluation, preparatory, 
MDMA and integrative psychotherapy sessions, the information should include that 
access to original medical records and processing of coded personal information must be 
authorized.  The informed consent discussion must be conducted by a person who is 
qualified according to applicable local regulations. The subject should have the 
opportunity to inquire about details of the MDMA session and to consider participation. 
 
The informed consent form (ICF) must be signed and dated by the subject and must be 
countersigned by the investigator. The investigator will provide a copy of the signed ICF 
to the subject, and will maintain the original in the investigator’s study file. 
 
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 written ICF, and written information should receive 
approval from an IRB before use. 
 
Written consent to take part in the study session includes giving the investigators 
permission to view the participant'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. 
 
The subject should be informed in a timely manner if new information becomes available 
that may affect the decision to take part in the MDMA session.  The communication of 
this information should be documented.  


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Participants can withdraw consent for participation in the protocol at any time without 
prejudice.  If a subject withdraws consent but does not revoke the Health Insurance 
Portability and Accountability Act (HIPAA) authorization, MAPS will have full access to 
the subject’s medical records, including termination visit information.  If a participant 
revokes only the HIPAA authorization, MAPS will have full access to all of the 
participant’s medical records prior to the date and time of revocation. 
 
13.1 Confidentiality 
Every effort will be made to strictly safeguard the confidentiality of participants in their 
role as research participants.  Removing identifying information from data and restricting 
access to researchers directly involved in assessing the participants should prevent the 
dissemination of confidential data, with or without identifying information.  Despite this, 
privacy cannot be guaranteed.  Except for the screening log, the informed consent and a 
subject contact information sheet that will be stored separately from other documents, all 
data will be identified only by the participant's initials on the source document and four-
digit subject number.  If past medical records are needed, participants will sign forms for 
the release of information upon consent to permit screening for protocol enrollment. 
Copies of audio and video recordings intended for sharing with participants will only be 
marked with the participant’s subject number.  Any materials mailed to participants will 
be sent along with stamped return envelopes using the office address of the Clinical 
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 investigators directly involved in the protocol, with access to data will not be 
provided with any information that would identify participants by name or by other 
means, such as social security number.  
 
All psychotherapy sessions may be recorded to video and audio. 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. CAPS assessments may also be recorded to 
video to establish inter-rater reliability. Full names and addresses will not appear in these 
recordings.  
 
Any use of recordings for purposes other than research or training (e.g. a documentary 
film) may occur only with separate written informed consent of the participant obtained 
after study participation is complete.   
 
Maintaining data in a secure environment will prevent the accidental or deliberate 
examination or removal of data by unauthorized persons.  While it is possible that 
individuals may be identified on audiotape or video recording through means other than 
their names, restricting access to audio recordings or video recordings to researchers or 
trainees greatly reduces the risk of a breach of confidentiality.  
   


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13.2 Costs to Participants  
There will be no costs to the study participants for any study-related procedures.  The 
sponsor will cover all costs of study participation, including any assessments or tests 
performed solely for the purpose of establishing eligibility for participation.  Charges for 
treatment of the participant’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 participant 
or to the participant 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 participants who previously 
received therapy from the Clinical Investigator and who will continue to receive ongoing 
treatment that is not related to participating in the study.  
 
13.3 Treatment and Compensation of Study Related Injury 
Treatment of a study-related emergency would first be billed to a participant’s health 
insurance provider.  The sponsor will cover any direct costs relating to the treatment of a 
study-related emergency that are not covered by a participant’s health insurance. Some 
study-related emergencies can be treated by the investigators as described under 
“Medical Emergencies” (Section 7.5) and within Appendix A.  If the investigator cannot 
treat a study-related emergency, then there are contingency plans for the transport of 
participants to the nearest hospital, East Cooper Medical Center.   
 
14.0 Record Retention 
Investigators must retain all study records required by MAPS and by the applicable     
regulations in a secure and safe facility.  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. These documents will be filed according to ICH-
GCP regulations in the Investigator Site File (ISF).  It is the responsibility of the sponsor 
to inform the investigator/institution as to when these documents no longer need to be 
retained.  
 
15.0 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 PI 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 PI is 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 PI and the 
sponsor clinical research representative(s) prior to submission for publication or 


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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 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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48. 
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108. 
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Exp Ther, 2001. 296(1): p. 207-15. 
109. 
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mediated immune response in humans. Life Sci, 2001. 69(24): p. 2931-41. 
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111. 
Beck, J. and M. Rosenbaum, In Pursuit of Ecstasy: The MDMA Experience. 1994, 
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112. 
Fantegrossi, W.E., et al., Behavioral and neurochemical consequences of long-
term intravenous self-administration of MDMA and its enantiomers by rhesus 
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113. 
Schenk, S., et al., Development, maintenance and temporal pattern of self-
administration maintained by ecstasy (MDMA) in rats. Psychopharmacology 
(Berl), 2003. 169(1): p. 21-7. 
114. 
Trigo, J.M., et al., A reliable model of intravenous MDMA self-administration in 
naive mice. Psychopharmacology (Berl), 2006. 184(2): p. 212-20. 


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115. 
Lile, J.A., J.T. Ross, and M.A. Nader, A comparison of the reinforcing efficacy of 
3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") with cocaine in rhesus 
monkeys. Drug Alcohol Depend, 2005. 78(2): p. 135-40. 
116. 
Wee, S. and W.L. Woolverton, Self-administration of mixtures of fenfluramine 
and amphetamine by rhesus monkeys. Pharmacol Biochem Behav, 2006. 84(2): p. 
337-43. 
117. 
Huizink, A.C., et al., Symptoms of anxiety and depression in childhood and use of 
MDMA: prospective, population based study. Bmj, 2006. 332(7545): p. 825-8. 
118. 
Lieb, R., et al., Mental disorders in ecstasy users: a prospective-longitudinal 
investigation. Drug Alcohol Depend, 2002. 68(2): p. 195-207. 
119. 
Cottler, L.B., et al., Ecstasy abuse and dependence among adolescents and young 
adults: applicability and reliability of DSM-IV criteria. Hum Psychopharmacol, 
2001. 16(8): p. 599-606. 
120. 
von Sydow, K., et al., Use, abuse and dependence of ecstasy and related drugs in 
adolescents and young adults-a transient phenomenon? Results from a 
longitudinal community study. Drug Alcohol Depend, 2002. 66(2): p. 147-59. 
121. 
Frith, C.H., et al., Toxicity of methylenedioxymethamphetamine (MDMA) in the 
dog and the rat. Fundam Appl Toxicol, 1987. 9(1): p. 110-9. 
122. 
Baggott, M., et al., Chemical analysis of ecstasy pills. Jama, 2000. 284(17): p. 
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123. 
Baggott, M.J., Preventing problems in Ecstasy users: reduce use to reduce harm. 
J Psychoactive Drugs, 2002. 34(2): p. 145-62. 
124. 
Cole, J.C., et al., The content of ecstasy tablets: implications for the study of their 
long-term effects. Addiction, 2002. 97(12): p. 1531-6. 
125. 
Liechti, M.E., I. Kunz, and H. Kupferschmidt, Acute medical problems due to 
Ecstasy use. Case-series of emergency department visits. Swiss Med Wkly, 2005. 
135(43-44): p. 652-7. 
126. 
Williams, H., et al., "Saturday night fever": ecstasy related problems in a London 
accident and emergency department. J Accid Emerg Med, 1998. 15(5): p. 322-6. 
127. 
Cole, J.C. and H.R. Sumnall, The pre-clinical behavioural pharmacology of 3,4-
methylenedioxymethamphetamine (MDMA). Neurosci Biobehav Rev, 2003. 27(3): 
p. 199-217. 
128. 
Green, A.R., et al., The pharmacology and clinical pharmacology of 3,4-
methylenedioxymethamphetamine (MDMA, "ecstasy"). Pharmacol Rev, 2003. 
55(3): p. 463-508. 
129. 
O'Callaghan, J.P. and D.B. Miller, Neurotoxicity profiles of substituted 
amphetamines in the C57BL/6J mouse. J Pharmacol Exp Ther, 1994. 270(2): p. 
741-51. 
130. 
Hatzidimitriou, G., U.D. McCann, and G.A. Ricaurte, Altered serotonin 
innervation patterns in the forebrain of monkeys treated with (+/-)3,4-
methylenedioxymethamphetamine seven years previously: factors influencing 
abnormal recovery. J Neurosci, 1999. 19(12): p. 5096-107. 
131. 
Miller, D.B. and J.P. O'Callaghan, Neurotoxicity of d-amphetamine in the 
C57BL/6J and CD-1 mouse. Interactions with stress and the adrenal system. Ann 
N Y Acad Sci, 1996. 801: p. 148-67. 


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132. 
Molliver, M.E., et al., Neurotoxicity of MDMA and related compounds: anatomic 
studies. Ann N Y Acad Sci, 1990. 600: p. 649-61; discussion 661-4. 
133. 
Sabol, K.E., et al., Amphetamine analogs have differential effects on DRL 36-s 
schedule performance. Psychopharmacology (Berl), 1995. 121(1): p. 57-65. 
134. 
Mechan, A., et al., Pharmacokinetic profile of single and repeated oral doses of 
MDMA in squirrel monkeys: relationship to lasting effects on brain serotonin 
neurons. Neuropsychopharmacology, 2006. 31(2): p. 339-50. 
135. 
Baumann, M.H., X. Wang, and R.B. Rothman, 3,4-
Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of 
past and present findings. Psychopharmacology (Berl), 2007. 189(4): p. 407-24. 
136. 
Banks, M.L., et al., Effects of Cocaine and MDMA Self-Administration on 
Serotonin Transporter Availability in Monkeys. Neuropsychopharmacology, 
2008. 33(2): p. 219-25. 
137. 
Wang, J., et al., Respondent-driven sampling to recruit MDMA users: a 
methodological assessment. Drug Alcohol Depend, 2005. 78(2): p. 147-57. 
138. 
Wang, X., et al., 3,4-methylenedioxymethamphetamine (MDMA) administration 
to rats decreases brain tissue serotonin but not serotonin transporter protein and 
glial fibrillary acidic protein. Synapse, 2004. 53(4): p. 240-8. 
139. 
McCann, U.D. and G.A. Ricaurte, Caveat emptor: editors beware. 
Neuropsychopharmacology, 2001. 24(3): p. 333-6. 
140. 
Cole, J.C. and H.R. Sumnall, Altered states: the clinical effects of Ecstasy. 
Pharmacol Ther, 2003. 98(1): p. 35-58. 
141. 
McCann, U.D., et al., Quantitative PET studies of the serotonin transporter in 
MDMA users and controls using [11C]McN5652 and [11C]DASB. 
Neuropsychopharmacology, 2005. 30(9): p. 1741-50. 
142. 
Reneman, L., et al., Neuroimaging findings with MDMA/ecstasy: technical 
aspects, conceptual issues and future prospects. J Psychopharmacol, 2006. 20(2): 
p. 164-75. 
143. 
Thomasius, R., et al., Mood, cognition and serotonin transporter availability in 
current and former ecstasy (MDMA) users: the longitudinal perspective. J 
Psychopharmacol, 2006. 20(2): p. 211-25. 
144. 
Laws, K.R. and J. Kokkalis, Ecstasy (MDMA) and memory function: a meta-
analytic update. Hum Psychopharmacol, 2007. 
145. 
Zakzanis, K.K., Z. Campbell, and D. Jovanovski, The neuropsychology of ecstasy 
(MDMA) use: a quantitative review. Hum Psychopharmacol, 2007. 22(7): p. 427-
35. 
146. 
Gouzoulis-Mayfrank, E., et al., Memory impairment suggests hippocampal 
dysfunction in abstinent ecstasy users. Prog Neuropsychopharmacol Biol 
Psychiatry, 2003. 27(5): p. 819-27. 
147. 
Halpern, J.H., et al., Residual neuropsychological effects of illicit 3,4-
methylenedioxymethamphetamine (MDMA) in individuals with minimal exposure 
to other drugs. Drug Alcohol Depend, 2004. 75(2): p. 135-47. 
148. 
Hoshi, R., et al., Neurocognitive function in current and ex-users of ecstasy in 
comparison to both matched polydrug-using controls and drug-naive controls. 
Psychopharmacology (Berl), 2007. 194(3): p. 371-9. 


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149. 
Roiser, J.P., R.D. Rogers, and B.J. Sahakian, Neuropsychological function in 
ecstasy users: a study controlling for polydrug use. Psychopharmacology (Berl), 
2007. 189(4): p. 505-16. 
150. 
Gouzoulis-Mayfrank, E., et al., Memory performance in polyvalent MDMA 
(ecstasy) users who continue or discontinue MDMA use. Drug Alcohol Depend, 
2005. 78(3): p. 317-23. 
151. 
Daumann, J., et al., Self-reported psychopathological symptoms in recreational 
ecstasy (MDMA) users are mainly associated with regular cannabis use: further 
evidence from a combined cross-sectional/longitudinal investigation. 
Psychopharmacology (Berl), 2004. 173(3-4): p. 398-404. 
152. 
Morgan, M.J., et al., Elevated impulsivity and impaired decision-making in 
abstinent Ecstasy (MDMA) users compared to polydrug and drug-naive controls. 
Neuropsychopharmacology, 2006. 31(7): p. 1562-73. 
153. 
Sumnall, H.R. and J.C. Cole, Self-reported depressive symptomatology in 
community samples of polysubstance misusers who report Ecstasy use: a meta-
analysis. J Psychopharmacol, 2005. 19(1): p. 84-92. 
154. 
Sumnall, H.R., G.F. Wagstaff, and J.C. Cole, Self-reported psychopathology in 
polydrug users. J Psychopharmacol, 2004. 18(1): p. 75-82. 
155. 
Scholey, A.B., et al., Increased intensity of Ecstasy and polydrug usage in the 
more experienced recreational Ecstasy/MDMA users: a WWW study. Addict 
Behav, 2004. 29(4): p. 743-52. 
156. 
Jager, G., et al., Incidental use of ecstasy: no evidence for harmful effects on 
cognitive brain function in a prospective fMRI study. Psychopharmacology (Berl), 
2007. 193(3): p. 403-14. 
157. 
de Win, M.M., et al., A Prospective Cohort Study on Sustained Effects of Low-
Dose Ecstasy Use on the Brain in New Ecstasy Users. 
Neuropsychopharmacology, 2007. 32(2): p. 458-470. 
158. 
De Win, M., Jager, G., Reneman, L., Booij, J., van den Brink, W., Den Heeten, 
G., et al., Ecstasy: Is It Safe for the Brain? First Prospective Study on Effects of 
Low Doses of Ecstasy on the Brain in New Ecstasy Users, Using a Combination 
of Advanced MR Imaging Techniques and [123I]ß-CIT SPECT, in Radiological 
Society of North America (RSNA). 2006: Chicago, IL. 
159. 
Schilt, T., et al., Cognition in novice ecstasy users with minimal exposure to other 
drugs: a prospective cohort study. Arch Gen Psychiatry, 2007. 64(6): p. 728-36. 
160. 
Jager, G., et al., Assessment of cognitive brain function in ecstasy users and 
contributions of other drugs of abuse: results from an FMRI study. 
Neuropsychopharmacology, 2008. 33(2): p. 247-58. 
161. 
Reneman, L., et al., Memory function and serotonin transporter promoter gene 
polymorphism in ecstasy (MDMA) users. J Psychopharmacol, 2006. 20(3): p. 389-
99. 
162. 
de Win, M.M., et al., Mood disorders and serotonin transporter density in ecstasy 
users--the influence of long-term abstention, dose, and gender. 
Psychopharmacology (Berl), 2004. 173(3-4): p. 376-82. 
163. 
Schilt, T., et al., Specific effects of ecstasy and other illicit drugs on cognition in 
poly-substance users. Psychol Med, 2008. 38(9): p. 1309-17. 


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164. 
Schilt, T., et al., Decision making as a predictor of first ecstasy use: a prospective 
study. Psychopharmacology (Berl), 2009. 203(3): p. 519-27. 
165. 
McElhatton, P.R., et al., Congenital anomalies after prenatal ecstasy exposure 
[letter]. Lancet, 1999. 354(9188): p. 1441-2. 
166. 
Bateman, D.N., et al., A case control study to examine the pharmacological 
factors underlying ventricular septal defects in the North of England. Eur J Clin 
Pharmacol, 2004. 60(9): p. 635-41. 
167. 
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. 
168. 
Adamson, S., Through the gateway of the heart: Accounts of experiences  With 
MDMA and other empathogenic substances. 1985, San Francisco CA: Four Trees 
Publications. 
169. 
Gasser, P., Psycholytic therapy with MDMA and LSD in Switzerland. MAPS 
Bulletin, 1994. 5(3): p. 3-7. 
170. 
Ryan, T.J., et al., 1999 update: ACC/AHA guidelines for the management of 
patients with acute myocardial infarction. A report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines 
(Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol, 
1999. 34(3): p. 890-911. 
171. 
Practice advisory: thrombolytic therapy for acute ischemic stroke--summary 
statement. Report of the Quality Standards Subcommittee of the American 
Academy of Neurology. Neurology, 1996. 47(3): p. 835-9. 
172. 
Adams, H.P., Jr., et al., Guidelines for the early management of adults with 
ischemic stroke: a guideline from the American Heart Association/American 
Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular 
Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular 
Disease and Quality of Care Outcomes in Research Interdisciplinary Working 
Groups: the American Academy of Neurology affirms the value of this guideline 
as an educational tool for neurologists. Stroke, 2007. 38(5): p. 1655-711. 
 
  


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Appendix A: Prevention and Response to Possible Serious Adverse Events 
Risk Mitigation  
Information from a considerable body of research indicates that the likelihood of 
significant toxicity from the doses of MDMA used in a therapeutic setting is very low 
[43], see also the “Investigator’s Brochure.”  Psychiatrists in the U.S. and Europe 
reported administering MDMA to at least a thousand patients before the drug was made 
illegal without any drug-related SAEs occurring during sessions [36, 38, 59, 168, 169].  
There have been no unexpected drug-related SAEs during the course of a study of 
MDMA-assisted psychotherapy in people with PTSD under the direction of the Clinical 
Investigator for the proposed protocol, nor in any other ongoing sponsor-supported study 
of MDMA-assisted psychotherapy in people with PTSD.   
 
Although serious untoward reactions are unlikely, the researchers will closely and 
continuously monitor participants during an experimental session.  Throughout all 
sessions, participants will be attended by the investigators, a psychiatrist who is board-
certified in internal medicine as well as psychiatry and who maintains ACLS 
certification, and a psychiatric nurse or licensed therapist who will maintain Basic Life 
Support (BLS) certification.  The Clinical Investigator and assisting investigator will thus 
provide a team that is prepared to respond in the unlikely event of a medical 
emergency.  In the unlikely event of cardiac arrest, they will follow the American Heart 
Association guidelines for 2-person BLS for Healthcare Providers [including 
defibrillation with an automated external defibrillator (AED)] until the arrival of EMS, at 
which time ACLS procedures will be instituted.  
 
The listed means of minimizing the likelihood of any of the SAEs that are reported to  
occur in ecstasy users will be similar to the procedures and strategies employed in the  
current study of MDMA-assisted psychotherapy in people with PTSD. 
 
Psychological Distress 
Reports of MDMA-assisted psychotherapy conducted prior to the scheduling of MDMA 
indicate that some people receiving MDMA in a therapeutic context experienced periods 
of increased anxiety and even panic.  In the proposed study, participants will have the 
intention of confronting and working on their traumatic experiences and accepting and 
working through difficult and painful emotions.  Hence, signs of psychological distress, 
panic or other unpleasant psychological reactions are possible.  Psychological distress 
could arise at any time after the onset of the effects of MDMA until the last effects have 
dissipated (approximately 3 to 5 hours after drug administration), with anxiety or distress 
potentially lasting for as little as 15 minutes to as long as 5 hours.   
 
The potential for destabilizing psychological distress will be minimized in several ways. 
During the preparatory sessions, participants 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 participants resolve difficult symptoms and to arrive at 
a more comfortable and relaxed state by the conclusion of the session, including empathic 


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listening on the part of the investigators and performance of diaphragmatic breathing by 
participants.  Risks will be reduced by excluding people who might be more vulnerable to 
destabilizing psychological distress (such as people diagnosed with bipolar affective 
disorder - 1 or with psychotic disorders), by preparing people before the experimental 
session, by creating an atmosphere of trust during the experimental session, by close 
monitoring, by daily contact with subjects for the period of a week after the experimental 
session, and by providing non-drug integrative psychotherapy sessions.  Subjects will 
remain in the offices of the Clinical Investigator for the evening and night immediately 
following each experimental session.  The study site will be staffed by a trained attendant 
to respond to the needs of the subject. The investigators will offer specialized training for 
all attendants to prepare them for being supportive but not intrusive as subjects rest and 
reflect on the day's experience. The attendant will be instructed to contact the investigator 
upon request or at the appearance of signs of a potential adverse event.  The overnight 
stay in a private room in the study site and the presence of the attendant should further 
reduce psychological distress. There is also the possibility of psychological distress 
during the integration period following experimental sessions unrelated to direct effects 
of the experimental compound. Such distress occurs commonly in Prolonged Exposure, 
EMDR and other therapies for PTSD. 
 
At the end of the 6–8 hour experimental session, if the participant is still severely agitated 
or experiencing any other severe psychological distress, the following measures will be 
taken:  
- If the participant is anxious, agitated, in danger of any self-harm or is suicidal at 
the end of the MDMA session, the investigators will remain with the participant 
for at least two more hours.  During this time, the investigators will employ affect 
management techniques, will talk with the participant to help them express their 
feelings or gain cognitive perspective of their experiences, and will help them 
implement the self- soothing and stress inoculation techniques presented during 
the introductory session.  If this situation should occur during an integrative 
therapy session, at least one of the investigators will be available to stay with the 
participant for at least two additional hours. 
 
- If a participant 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 Clinical Investigator will decide between one of two  
options: 
 
A.  A psychiatric nurse, therapeutic assistant or therapist will stay with the 
subject until the time of his or her appointment with investigators the 
next day.  The investigators will then meet with the subject daily until 
the period of destabilization has passed.  At any time during this 
process, the Clinical Investigator may make the clinical judgment to 
proceed to option B. 
 
B. Hospitalization for stabilization. 
 


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Participants hospitalized after a severe panic reaction will be suspended from the protocol 
until after recovery or stabilization, at which time the investigator will carefully evaluate 
the participant’s emotional status.  The investigators will submit an SAE report to the 
IRB and the FDA in cases of drug-related hospitalization. 
 
For those subjects engaged in an on-going therapeutic relationship with a psychotherapist 
or psychiatrist, the participant’s outside therapists will be involved in the management of 
any psychiatric complications.   
 
The investigators have developed a contingency plan for responding to suicidal intent. 
They will evaluate the degree of suicidal intent and take steps to alleviate psychological 
distress.  
 
Seriousness of suicidal intent would first be evaluated by the investigators both clinically 
and through administrations of the C-SSRS. Depending upon what is learned from 
evaluation, the investigator might increase support for and discussion with the 
participant, increase frequency of contact, or if during an experimental session, remain 
with the subject.  Hospitalization would be considered in some situations as described in 
Appendix A.  
 
If the participant exhibits signs of suicidality the investigators will also call the contact 
person designated by the subject. 
 
The investigators will use the same procedures for all participants. Increased telephone 
contact could be used if additional appointments were not a viable option for a participant 
not within easy driving distance of the site. The treating therapist of any participant living 
outside reasonable driving distance would be enlisted to provide evaluation and support 
for the participant. 
 
In the event of a participant’s experiencing severe, persisting emotional distress, such as 
panic attacks, severe generalized anxiety or insomnia following an MDMA session, the 
investigator may prescribe a benzodiazepine or zolpidem as a “rescue medication.”  This 
medication will be captured on a concomitant medications CRF page.   Residual 
symptoms will be addressed during the frequent follow-up psychotherapy visits with the 
investigators.   
 
Means of monitoring for and preventing possible risks of MDMA other than the  
cardiovascular risks and psychological distress are described in detail below.  
 
Angina or Myocardial infarction  
If a participant experiences ischemic type chest pain, whether or not it is associated with 
hypertensive crisis, he or she will receive oxygen and an IV and will be monitored as  
described above.  He or she will be given 162 mg of chewable aspirin once 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 participant has had an acute myocardial 
infarction (AMI), he or she will be well within the time frame required for definitive 


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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 individuals who present within 12 hours of an episode of chest pain 
lasting more than 30 minutes and who have ECG evidence of AMI [170]. 
 
Stroke 
If any participant has neurologic deficits, whether or not they are associated with 
hypertensive crisis, he or she will receive oxygen and an IV and will be monitored as 
described above.  He or she will be transported to the hospital for a head CT scan and 
further management.   If evaluation at the hospital reveals a non-hemorrhagic stroke, 
there will be time to administer recombinant tissue plasminogen within the 3 hour time 
frame recommended in the American Academy of Neurology/American Heart 
Association guidelines [171, 172].  
 
Hyponatremia 
History of hyponatremia or detection of hyponatremia on initial laboratory examination 
will be cause for exclusion from the proposed protocol.  Participants will be given  
primarily electrolyte solutions such as Gatorade instead of water in order to decrease the 
likelihood of dilutional hyponatremia.  They will not be allowed to drink more than 3 L. 
of fluids, and fluid intake will be appropriately spread out across the session.  If there are 
any signs or symptoms of hyponatremia, a stat serum sodium will be drawn and fluids 
will be withheld until the results are obtained.  If the serum sodium is less than 
125mEq/L, serum and urine osmolality and sodium will be measured, and the subject will 
be transported to the East Cooper Medical Center, where further intervention can be  
provided.  
 
Hyperthermia 
Body temperature will be taken every 60 to 90 minutes throughout each experimental 
session.  If temperature rises more than 1° Celsius (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, ice packs will be used, blood will be 
drawn for stat CBC, electrolytes, BUN, creatinine, glucose, creatine phosphokinase  
(CPK), prothrombin time (PT), partial thromboplastin time (PTT), platelets and liver  
enzymes, and urine will be collected for urinalysis.  If there are significant abnormalities 
in these tests, if the temperature continues to rise, or if an elevated temperature is  
associated with delirium or muscle rigidity the participant will be transferred to the 
intensive care unit at the East Cooper Medical Center.   


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Appendix B: Audio and Video Recording 
 
Recording to video for psychotherapy sessions will be done with two cameras operated 
remotely by the investigators for the experimental and non-drug psychotherapy sessions.  
One camera will be adjusted to capture a fairly tight shot of the subject, including full-
face shots and partial or full body shots.  The other will capture a wider view including 
the subject and the two investigators. Two copies of the video will be made routinely, one 
to be stored by the investigators, and the other by the sponsor. Both will be kept in secure 
locations. A third copy of video recording of any experimental or non-drug 
psychotherapy session can be made for any subject who requests it.   
 
Participants will be asked to read a brief script for a computer program that will enable 
transcription of audio recordings. Audio recording of experimental and non-drug 
psychotherapy sessions will be done using a digital recording device controlled by one of 
the investigators, with control allowing him to stop or start recording.  The recordings 
will be transferred to an external hard drive that will be kept in a locked cabinet. The 
recordings will then be burned onto CDs. One copy will be stored by the investigators in 
a locked cabinet, another copy will be sent to the sponsor and will also be stored in a 
secure location. An additional audio recording can be made of any psychotherapy 
session.  The purpose of this is to enable the participants to have a recording for 
themselves at the end of each experimental session, rather than having to wait until the 
CDs are made by the investigators.  Part or all of these recordings may be viewed by 
people training to perform or analyze MDMA-assisted psychotherapy for sponsor-
supported studies. 
 
Recording to video of CAPS assessment by the independent rater will be done in the 
office of one of the raters. 
 
Full names and addresses will not appear in video or audio recordings. Facial images will 
not be removed from the copy of the video recording to be viewed by the sponsor or 
investigators for review of the therapeutic process and for manual development. 
 

SAP_001.pdf: 
MAPS Public Benefit Corporation                                                                               MP-8 Statistical Analysis Plan 
US                                                                                                                                      Version 1: 06 October 2015 
 
 
 
 
 
MP-8 Statistical Analysis Plan 
 
Version 1: 06 October 2015 
 
 
CORPORATION 
 
 
 
MAPS Public Benefit Corporation (MPBC) 
1115 Mission Street 
Santa Cruz, CA 95060 
 
CORPORATION DESIGNEE 
 
Amy Emerson 
Executive Director and Director of Clinical Research 
USE 
In conjunction with relevant FDA guidance 
STUDY TITLE 
 
 
 
 
 
A Randomized, Triple-Blind, Phase 2 Pilot Study 
Comparing 3 Different Doses of MDMA in Conjunction 
with Manualized Psychotherapy in 24 Veterans, 
Firefighters, and Police Officers with Chronic, 
Treatment-Resistant Posttraumatic Stress Disorder 
(PTSD) 
LATEST PROTOCOL  
Amendment 5 Version 1, August 14, 2013 
 
INVESTIGATORS 
Michael C. Mithoefer, M.D. 
 
MEDICAL MONITORS 
 
Julie Holland M.D. 
 
STATISTICIAN 
 
Scott Hamilton, Ph.D. 
 
PLAN PREPARED BY 
 
Scott Hamilton, Ph.D. 
Allison Feduccia Ph.D. 
Berra Yazar-Klosinski, Ph.D. 


MAPS Public Benefit Corporation                                                                               MP-8 Statistical Analysis Plan 
US                                                                                                                                      Version 1: 06 October 2015 
 
Table of Contents 
1.0 List of Abbreviations and Definitions of Terms ................................................................ 3 
2.0 Introduction .......................................................................................................................... 5 
3.0 Study Objectives................................................................................................................... 6 
3.1 Primary Objective ............................................................................................................ 6 
3.2 Secondary Objectives ....................................................................................................... 6 
3.3 Safety Objectives .............................................................................................................. 7 
4.0 Study Design ......................................................................................................................... 7 
4.1 Time and Events Tables ................................................................................................. 10 
5.0 Randomization and Blinding ............................................................................................ 13 
6.0 Sample Size and Power Considerations ........................................................................... 13 
7.0 Measures ............................................................................................................................. 13 
7.1 Outcome Measures ......................................................................................................... 13 
7.2 Safety Measures .............................................................................................................. 14 
7.3 Process Measures ............................................................................................................ 14 
8.0 Analyses .............................................................................................................................. 14 
8.1 Analysis Populations ...................................................................................................... 15 
8.2 Handling of Dropouts, Missing Data ............................................................................ 15 
8.3 Protocol Deviations......................................................................................................... 16 
8.4 Pooling of Investigator Centers ..................................................................................... 16 
8.5 Baseline Values ............................................................................................................... 16 
8.6 Subject Disposition and Dosing Summary ................................................................... 17 
8.7 Demographics and Baseline Characteristics ................................................................ 17 
8.8 Prior and Concomitant Medications ............................................................................ 17 
8.9 Efficacy Analyses ............................................................................................................ 17 
8.9.1 Primary Efficacy Analyses ........................................................................................ 17 
8.9.2 Secondary Efficacy Analyses .................................................................................... 18 
8.9.3 Exploratory Analyses ................................................................................................ 19 
8.9.4 Safety Analyses ......................................................................................................... 21 
8.10 Timing of Analyses ....................................................................................................... 22 
9.0 References ........................................................................................................................... 22 
 
 
 
 
 
 
 
 
 
 
 


MAPS Public Benefit Corporation                                                                               MP-8 Statistical Analysis Plan 
US                                                                                                                                      Version 1: 06 October 2015 
 
 
1.0   List of Abbreviations and Definitions of Terms 
 
Definitions of Terms 
 
Categorical data: refers to discrete (indivisible) variables, such as gender or ethnicity; data will 
be presented as total numbers of each category as needed to describe the sample 
Descriptive data: includes mean, median, standard deviation, minimum and maximum of 
numerical data used as needed to describe the sample 
Difference scores: consist of scores computed by subtracting one value from another, as 
subtracting baseline from End of Stage 1 score, used to test for differences between and within 
groups to determine change as a function of experimental treatment over time 
Efficacy: type of analysis used to assess therapeutic effects or benefits 
Exploratory analyses: inferential or descriptive analysis of the data to determine trends that 
might lead to hypotheses for further study 
Frequency listing: tabular listing of numbers and/or percentages of events used as needed to 
describe the sample or data characteristics 
Outcome measures: primary and secondary study measures that are used to test the study 
hypotheses 
Process measures: study measures or qualitative observations collected during the study that 
may increase depth of understanding and that are not necessarily related to safety or efficacy 
Protocol deviation: event that represents significant divergence from the intended study design 
as described in the protocol 
Safety: assessment of the condition of study subjects that examines potential risks, adverse 
events, and reactions 
Safety measures: study measures that assess safety, such as heart rate monitoring, that are used to 
assess safety of the study drug 
Spontaneously reported reactions, reactions: specific expected reactions gathered from the 
literature on MDMA 
Study design: all elements of a research project that define the study question, experimental 
methods, study procedures including blinding and randomization, measurement techniques, flow 
sheet of data, and statistical analysis 
Tabular listing: list of each variable or item for each individual subject either in total or by 
condition in a table format 
 


MAPS Public Benefit Corporation                                                                               MP-8 Statistical Analysis Plan 
US                                                                                                                                      Version 1: 06 October 2015 
 
List of Abbreviations 
 
AE  
Adverse Event 
ANOVA   
Analysis of Variance 
BDI-II 
Beck Depression Inventory-II 
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 
ES  
Effect Size 
GAF 
Global Assessment of Functioning 
GWB 
General Well-being 
HR  
Heart Rate 
ITT  
Intent To Treat  
MAPS 
Multidisciplinary Association for Psychedelic Studies 
NEO PI 
Neuroticism-Extroversion-Openness Personality Inventory 
PP  
Per Protocol 
PTSD  
Posttraumatic Stress Disorder 
PSQI  
Pittsburgh Sleep Quality Index 
PTGI 
Post Traumatic Growth Inventory 
RCT  
Randomized Controlled Trial 
RRPQ 
Reactions to Research Participation Questionnaire 
SBP  
Systolic Blood Pressure 
SOCQ 
States of Consciousness Questionnaire 
 
  
 
 
 
 


MAPS Public Benefit Corporation                                                                               MP-8 Statistical Analysis Plan 
US                                                                                                                                      Version 1: 06 October 2015 
 
2.0   Introduction 
 
This document contains a Statistical Analysis Plan for the study, “A Randomized, Triple-Blind, 
Phase 2 Pilot Study Comparing 3 Different Doses of MDMA in Conjunction with Manualized 
Psychotherapy in 24 Veterans, Firefighters, and Police Officers with Chronic, Treatment-
Resistant Posttraumatic Stress Disorder (PTSD).” 
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 persons with 
posttraumatic stress disorder (PTSD). 
 
Encouraging data has been obtained from MAPS’ completed United States (U.S.) pilot studies, 
MP1 and MP2. MAPS is currently sponsoring other Phase 2 studies in the U.S., Israel, and 
Canada. Ongoing and planned Phase 2 studies are laying the groundwork for an eventual End-of-
Phase 2 meeting with FDA and possible Phase 3 multi-site MDMA/PTSD research studies.  
 
This study, MP-8, will examine the safety and efficacy of MDMA-assisted psychotherapy in 24 
veterans, firefighters or police officers with service-related PTSD, and will seek to enroll roughly 
equal numbers of men and women. This study will include those with chronic PTSD of at least 
six months duration who satisfy PTSD diagnostic criteria despite having received prior treatment 
with either medication or psychotherapy. Full, medium and low dose MDMA will be assessed in 
Stage 1, as well as the benefit of three vs. two full dose sessions. Subjects who received the 
medium and low 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 open-label experimental sessions. Stage 
2 will be used to explore the optimal therapeutic dose of MDMA using a clinical titration dosing 
strategy.  
 
MAPS’ initial U.S. pilot study, conducted at the same site as this study, enrolled 23 subjects, of 
which 20 were evaluable, with a majority of whom were women suffering from PTSD related to 
sexual assault and/or childhood sexual abuse (N=18) [1, 2]. Only two subjects had PTSD from 
war-related trauma (U.S. veterans of the Iraq War) and both were male. According to the 
European Medicines Agency (EMA) Guideline for the Development of Medicinal Products for 
the Treatment of PTSD, it is desirable to examine treatment response in homogenous samples, 
conducting separate trials for different populations. The findings from this study in veterans, 
firefighters and police officers with service related trauma will be compared with results from 
our initial U.S. pilot study, mostly in women survivors of sexual abuse and assault.  
 
In order to refine our triple-blind methodology, MP-8 will evaluate three different doses of 
MDMA to determine their relative success in achieving blinding of therapists, subjects, and 
independent raters.  
 
In addition, this will be the first study of MDMA-assisted psychotherapy to permit the 
enrollment of subjects with two medical conditions that were exclusion criteria in the previous 
trial: Hepatitis-C, and controlled hypertension. Should any subjects with these conditions seek 
enrollment in the study, they will be required to go through additional specified screening 
procedures and additional monitoring for safety during the experimental sessions. 
 


MAPS Public Benefit Corporation                                                                               MP-8 Statistical Analysis Plan 
US                                                                                                                                      Version 1: 06 October 2015 
 
3.0   Study Objectives 
 
3.1   Primary Objective  
 
 Assess changes in PTSD symptoms via Clinician-Administered PTSD Scale (CAPS-4) 
global scores in subjects receiving by condition in the randomized study arms at baseline 
and the primary endpoint, one month after the second experimental session.  
3.2   Secondary Objectives 
The following objectives will compare full, medium and low dose subjects in the blinded portion 
of Stage 1: 
 
 Assess changes in posttraumatic growth via Post Traumatic Growth Inventory (PTGI) 
scores from baseline to the primary endpoint.  
 Assess changes in global functioning via Global Assessment of Functioning (GAF) 
scores from baseline to the primary endpoint.  
 Assess changes in symptoms of depression via Beck Depression Inventory-II (BDI-II) 
scores from baseline to the primary endpoint.  
 Assess changes in self-reported sleep quality via the Pittsburgh Sleep Quality Index 
(PSQI) from baseline to the primary endpoint. 
 Assess self-reported dissociation symptoms with the Dissociative Experiences Scale-II 
(DES-II) from baseline to the primary endpoint. 
 Assess changes in Neuroticism-Extroversion-Openness Personality Inventory (NEO PI) 
scores from baseline to the primary endpoint. 
 
 
The following objectives will include exploratory analyses intended to inform protocol design: 
 
 Explore the effects of each MDMA-assisted psychotherapy 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 effects of a third active dose experimental session by comparing Global 
CAPS, BDI-II, GAF, PSQI, PTGI (in reference to start of the study), and DES-II scores 
at the primary/secondary endpoint and end of Stage 1/ Stage 2 in subjects receiving a 
third experimental session in Stage 1 and Stage 2.  
 Assess the ability of the investigators and subjects to accurately guess condition 
assignment when asked to do so after each blinded experimental session. 
 Assess value of third experimental session in Stage 1/Stage 2 by collecting each active 
dose subject's perception of experimental sessions at the primary/secondary endpoint 
and end of Stage 1/ Stage 2. 
 Correlate adherence to the Treatment Manual with Global CAPS scores using adherence 
criteria ratings to assess videos of psychotherapy sessions. 
 Assess PTSD symptoms via CAPS, posttraumatic growth via PTGI, depression 
symptoms via BDI-II, global functioning via GAF, sleep quality via PSQI, dissociation 
symptoms via DES-II, and personality via NEO PI throughout Stage 2 in comparison to 
Stage 1 in crossover subjects. 
 Assess long-term effects of receiving active dose MDMA on PTSD symptoms via 
CAPS, posttraumatic growth via PTGI, personality changes via NEO PI, depression 


MAPS Public Benefit Corporation                                                                               MP-8 Statistical Analysis Plan 
US                                                                                                                                      Version 1: 06 October 2015 
 
symptoms via BDI-II, global functioning via GAF, and sleep quality via PSQI one year 
after the final experimental session for each subject. 
 
3.3   Safety Objectives 
 
 Suicidality will be assessed with the Columbia Suicide Severity Rating Scale (C-SSRS) 
before, during and after experimental sessions and on selected days of telephone or face-
to-face contact, with comparisons made between subjects in each condition. 
 
Subjective Units of Distress (SUD) and vital signs (blood pressure, heart rate and 
temperature) will be measured during each experimental session, and comparisons will be 
made for vital signs between conditions.  
 
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.  
 
Serious adverse events, adverse events and spontaneously reported reactions will be 
collected during the study according to Section 8.3 
4.0   Study Design 
 
This randomized, triple-blind study will examine the safety and efficacy of MDMA-assisted 
psychotherapy with 30, 75 or 125 mg MDMA in twenty-four veterans, firefighters and police 
officers diagnosed with chronic, treatment-resistant PTSD arising from their service. These 
subjects will ideally, but not necessarily, include twelve men and twelve women. Supplemental 
doses of half the initial dose may be administered between 1.5 and 2.5 hours after the initial dose 
was administered.  
 
Prior to undergoing the first MDMA-assisted (experimental) session, all subjects will undergo 
three 90-minute preparatory non-drug psychotherapy sessions with a male and female co-
therapist team. Stage 1 of the study will consist of two blinded experimental sessions and, for the 
full dose group, one open-label experimental session, each lasting six to eight hours and 
scheduled three to five weeks apart. Experimental sessions will follow a similar sequence of 
events. (See Time and Events Table). A co-therapist team will perform all non-drug and 
MDMA-assisted psychotherapy sessions in their outpatient office. Subjects will complete the 
SOCQ, a measure of alterations in consciousness related to mystical experiences, during the 
period of time between the end of each MDMA-assisted psychotherapy session and before they 
leave the treatment facility the next day. Subjects will remain at the study site overnight 
accompanied by an attendant. Subjects will undergo three integrative psychotherapy sessions 
after each experimental session, with the first integrative session occurring on the day after the 
experimental session. All psychotherapy sessions may be recorded to audio and video. 
 
A blinded independent rater, who will not be present during any psychotherapy sessions, will 
assess subject PTSD symptoms with CAPS, symptoms of depression with BDI-II, posttraumatic 
growth with PTGI, global functioning with GAF, sleep quality with PSQI, and dissociation with 
the DES-II. Changes in personality traits will be assessed via NEO-PI. Outcome assessments will 
be done at baseline, at the primary endpoint one month after the second experimental session, 
two months after the third open-label experimental session and at the 12-month follow-up and at 
equivalent points in Stage 2. 
 


MAPS Public Benefit Corporation                                                                               MP-8 Statistical Analysis Plan 
US                                                                                                                                      Version 1: 06 October 2015 
 
When each subject completes the evaluation at the primary endpoint, the blind will be broken for 
that subject. Subjects who had been assigned to receive low dose or medium dose MDMA will 
subsequently have the opportunity to enroll in the open-label study arm, or “Stage 2.” Stage 2 
must start within a maximum of 5 months after the subject finishes Stage 1. The open-label study 
arm will follow a similar sequence of events and procedures, except that there will be a single 
preparatory session, and all three MDMA-assisted psychotherapy sessions will be open-label. 
Subjects will receive an initial dose of 100 mg MDMA in the first experimental session, and one 
of two active doses of MDMA that are clinically titrated by the CI during the second and third 
open-label experimental sessions that will otherwise follow the same sequence of events (See 
Time and Events Table). Outcome measures except for the NEO PI will be repeated one month 
after the second Stage 2 experimental session, and all outcome measures will be repeated at the 
end of Stage 2. 
 
The study will conclude with a one-year follow-up occurring 12 months after the final 
experimental session of Stage 1 for subjects who received full dose MDMA or who elected not 
to enroll in Stage 2 after receiving either the medium or low doses in Stage 1. Subjects who 
enrolled in Stage 2 will have their final follow-up 12 months after the final open-label 
experimental session. Outcome measures will be repeated at the 12-month follow-up, as well as a 
questionnaire concerning self-reported long-term effects of study participation. 
 
Sub-studies in a select group of subjects in this study may be conducted for exploratory 
purposes. Subjects will complete a separate consent process if they chose to participate in these 
studies. 
 
Table 4.0-1: Stage 1 Blinded Drug Doses  
Condition 
Number of 
Subjects 
Initial Dose 
Supplemental 
Dose  
Min-Max 
Cumulative Dose 
Low Dose 
6 
30 mg 
15 mg 
30-45 mg 
Medium Dose 
6 
75 mg 
37.5 mg 
75-112.5 mg 
Full Dose 
12 
125 mg 
62.5 
125-187.5 mg 
 
Table 4.0-2: Stage 2 Drug Doses  
Experiment
al Session 
Dose 
Initial 
Dose 
Optional 
Supplement
al Dose 
Min-Max 
Cumulative 
Dose 
Min-Max 
Cumulativ
e Dose 
with 
Titration 
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 
 
For further details please refer to the protocol Section 5.0 Protocol.


MAPS Public Benefit Corporation                                                                               MP-8 Statistical Analysis Plan 
US                                                                                                                                      Version 1: 06 October 2015 
 
Table 4.1: Stage 1 Time & 
Events  
Screen/Baseline 
Preparator
y 
Experimental Session 
1 
Experimental Session 2 
Experimental Session 
3 
Follow-Up 
Visit # 
Pre-Study 
V1 
V 2,3,4 
V5 
V 6,7,8 
V9 
V 
10,11,12 
V13 
V14 
V 
15,16,17 
V18 
Type of Visit 
Screening may 
take place over 
more than one day 
Enrollm
ent 
Preparatory 
Sessions 
Experiment
al 
Session 1 
Integrativ
e Sessions 
Experimen
tal 
Session 2 
Integrati
ve 
Sessions 
Primary 
Endpoi
nt 
Experiment
al Session 
3  
Integrati
ve 
Sessions 
End of Stage 1 
& Outcome 
Visit Timing or Study day or 
Window 
Up to 2 months 
prior to  
Visit 1 
 
Prior to V5 
M 
Up to 7 
weeks post 
V1 
Before V9 
A 
3-5 weeks 
post V5 
Before 
V13A 
1 
month 
post V9 
3-5 weeks 
post V9 N 
Before 
V18 A, N 
May happen 
over > 1 day. 2 
mo. post V14 
N 
Initial Phone Screen 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric History  
X 
 
 
 
 
 
 
 
 
 
 
General Phys. Exam (BP, Heart 
rate, Temp) 
X 
 
 
 
 
 
 
 
 
 
 
Brief Neurological Exam 
X 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
SCID-I-RV 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Lab Tests, w/ HIV, HCV 
test 
X 
 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Taper (if applicable) 
X 
X 
 
 
 
 
 
 
 
 
 
Study Enrollment after meeting 
I/E 
 
X 
 
 
 
 
 
 
 
 
 
Record to Audio/Video 
XL 
 
X 
X 
X 
X 
X 
X L 
X 
X 
X L 
General Well-Being 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Drug Screen 
X 
 
 
X 
 
X 
 
 
X 
 
 
Pregnancy Screen (if applicable) 
X 
 
 
X 
 
X 
 
 
X 
 
 
Complete Randomization 
Procedure 
 
 
 
X B 
 
 
 
 
 
 
 
CAPS, GAF, BDI-II, PTGI, 
PSQI, DES-II (IR) 
X  
 
 
 
 
 
 
X 
 
 
X 
NEO PI (Ind. Rater) 
X 
 
 
 
 
 
 
X 
 
 
 
C-SSRS 
 
X 
X 
X C, D, E 
XI 
X C, D, E  
XI 
X 
X C, D, E  
XI 
X 
Administer IP Drug + Therapy, 
SOCQ 
 
 
 
X 
 
X 
 
 
X 
 
 
Monitoring of BP, Heart rate and 
Temp.  
 
 
 
X 
 
X 
 
 
X 
 
 
SUD 
 
 
 
X F, E 
 
X F, E 
 
 
X F, E 
 
 
Beliefs of Condition Assignment 
 
 
 
 
XK 
 
XK 
 
 
XK 
 


MAPS Public Benefit Corporation                                                                               MP-8 Statistical Analysis Plan 
US                                                                                                                                      Version 1: 06 October 2015 
 
 
4.1   Time and Events Tables 
 
A =First Integrative session is 1 day after exp session B = At least 24 hrs prior to 1st exp. session C =Approximately 6 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 meds are tapered (V3) H = Only for subjects starting Long term Follow up and not going to Stage 2 I =For 7 days post 
Exp. Session, C-SSRS D2 and D7 of calls only, General well being for all 7 days J =Subjects in the medium or low dose group will 
not have visits 14-18, but will instead move onto Stage 2. K= On the day of the 1st integrative session following the Exp. Session 
L=CAPS may be videotaped M=First preparatory session (V2) may happen at the time of screening, before enrollment. N= Full 
dose subjects only. O= Only in subjects with pre-existing tinnitus and/or chronic pain. 
 
 
Overnight Stay 
 
 
 
X 
 
X 
 
 
X 
 
 
Integrative Therapy Session 
 
 
 
 
X 
 
X 
 
 
X 
 
7 days Integrative Telephone 
Contact 
 
 
 
 
X I 
 
X I 
 
 
X I 
 
AEs Requiring Medical Attention 
 
 
 
X 
X 
X 
X 
X 
X 
X  
X 
Spont. Reported Reactions and all 
AEs 
 
 
 
X 
X 
X 
X 
 
X 
X 
 
Changes in Tinnitus and/or Pain 
X O 
 
X E, O 
X E, O 
X E, O 
X E, O 
X E, O 
XO 
X E, O 
X E, O 
XO 
AEs of psychiatric status or 
withdrawal  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Issue Memory Aid Card H 
 
 
 
 
 
 
 
 
 
 
X 
Unblinding J 
 
 
 
 
 
 
 
X 
 
 
 
Perception of Third Session 
 
 
 
 
 
 
 
XN 
 
 
XN 
RRPQ 
 
 
 
 
 
 
 
 
 
 
X H 


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US                                                                                                                                      Version 1: 06 October 2015 
 
 
                                                                                                               Page 11 of 23 
 
Table 4.1: Stage2 Time & 
Events 
Preparatory 
Experimental 
Session 1 
Experimental Session 2 
Experimental Session 
3 
Follow-Up 
Long Term Follow up after Stage 1 or Stage 2 
Long Term Follow-
Up  
 Visit # 
V19* 
V20 
V 21,22,23 
V24 
V 
25,26,27 
V28 
V29 
V 
30,31,32 
V33 
1 Year Follow-up 
Type of Visit 
Preparatory 
Session 
Experimen
tal 
Session 1 
Integrative 
Sessions 
Experime
ntal 
Session 2 
Integrative 
Sessions 
Seconda
ry 
endpoin
t 
Experim
ental 
Session 3 
Integrative 
Sessions 
End of Stage 2 
& Outcome 
Follow-Up & 
Outcome 
Visit Timing or Study day or 
Window 
Within 
maximum of 5 
months of 
V13* 
After V19 
Before 
V24 A 
3-5 weeks 
post V20 
Before 
V28 A 
1 month 
post 
V24, 
beforeV
29 
3-5 
weeks 
post V24 
Before 
V33 A 
May happen 
over > 1 day 2 
months post 
V29 
May happen over > 1 
day. One Year post 
V14 or V29 
Confirm Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Confirm Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
Enrollment in Stage 2 
X 
 
 
 
 
 
 
 
 
 
Collect Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record to Audio/Video 
X 
X 
X 
X 
X 
XH 
X 
X 
XH 
 
General Well-Being 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Drug Screen 
 
X 
 
X 
 
 
X 
 
 
 
Pregnancy Screen (if 
applicable) 
 
X 
 
X 
 
 
X 
 
 
 
CAPS, GAF, BDI-II, PTGI, 
PSQI, DES-II  (IR) 
Use V13* 
 
 
 
 
X 
 
 
X 
X 
NEO PI with Ind. Rater 
Use V13* 
 
 
 
 
 
 
 
X 
X 
C-SSRS 
X 
X C, D, E 
X G 
X C, D, E 
X G 
 
X C, D, E 
X G 
X 
X 
Administer IP Drug + 
Therapy, SOCQ 
 
X 
 
X 
 
 
X 
 
 
 
Monitoring of BP, Heart rate 
and Temp.  
 
X 
 
X 
 
 
X 
 
 
 
SUD 
 
X D, F 
 
X D, F 
 
 
X D, F 
 
 
 
Overnight Stay 
 
X 
 
X 
 
 
X 
 
 
 
Integrative Therapy Session 
 
 
X 
 
X 
 
 
X 
 
 
7 days Integrative Telephone 
Contact 
 
 
X G 
 
X G 
 
 
X G 
 
 
AEs Requiring Medical 
Attention 
X 
X 
X 
X 
X 
X 
X 
X  
X 
 


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US                                                                                                                                      Version 1: 06 October 2015 
 
 
                                                                                                               Page 12 of 23 
* If Visit 19 is more then 8 weeks after V13 then the measures from V13 will need to be repeated prior to starting Stage 2 A =First session is 1 day 
after Exp session B =Approximately 6 hours post MDMA C =At the beginning of the session D =As needed E =Approximately every 60 minutes F = 
Given on 2nd integrative session only G = For 7 days post Exp. Session, C-SSRS D2 and D7 of calls only, General well being for all 7 days H=CAPS 
may be videotaped I= Only in subjects with pre-existing tinnitus and/or chronic pain.
Spont. Reported ReactionsG 
and all AEs 
 
X 
X G 
X 
X G 
 
X 
X G 
 
 
Changes in Tinnitus and/or 
Pain 
 
XD, I 
XD, I 
XD, I 
XD, I 
XI 
XD, I 
XD, I 
XI 
XI 
AEs of psychiatric status or 
withdrawal  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Perception of Third Session 
 
 
 
 
 
X 
 
 
X 
 
Complete Stage 2, go to 1yr 
F/U 
 
 
 
 
 
 
 
 
X 
 
RRPQ 
 
 
 
 
 
 
 
 
X 
 
Issue Memory Aid Card 
 
 
 
 
 
 
 
 
X 
 
Follow-up Questionnaire 
 
 
 
 
 
 
 
 
 
X 
Termination Visit 
 
 
 
 
 
 
 
 
 
X 


MAPS Public Benefit Corporation                                                                    MP-8 Statistical Analysis Plan  
US 
 
Version 1: October 6, 2015 
 
 
                                                                                                               Page 13 of 23 
 
5.0   Randomization and Blinding 
 
This is a randomized, triple-blind, dose response study with an open-label cross-over 
segment. For Stage 1, a randomization list will be prepared at the beginning of the study. 
If needed, subsequent randomization lists will be created to replace subjects who 
withdraw from the study to ensure that replacement subjects are not added to the end of 
the initial list. Each subject will be assigned to one of the three dose conditions; 30 mg 
(low dose), 75 mg (medium dose) or 125 mg (full dose). Twelve evaluable subjects will 
be assigned to the full dose condition, six evaluable subjects to the 75 mg condition and 
six evaluable subjects to the 30 mg low dose condition. The study will employ a blinded 
randomization procedure that will maintain the 2:1:1 ratio while maintaining the blind 
and ensuring that each subsequent condition assignment is not predicated on the previous 
assignment.  
6.0   Sample Size and Power Considerations 
 
This study is a pilot investigation intended to gather preliminary data on the safety and 
efficacy of MDMA in 24 evaluable veterans, firefighters, or police officers 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 used to collect effect size estimates for statistical power calculations for 
adequately powered subsequent studies. 
7.0   Measures 
 
7.1   Outcome Measures 
 
Clinician-Administered PTSD Scale (CAPS-4) Global Severity Score, Diagnostic 
Criteria Met score 
 
Global Assessment of Functioning (GAF), total score 
 
Beck Depression Inventory-II (BDI-II), total score 
 
Post Traumatic Growth Inventory (PTGI), total  
 
Dissociative Experiences Scale-II (DES-II), total  
 
Pittsburgh Sleep Quality Index (PSQI), total score 
 
NEO Personality Inventory (NEO PI), five factors 


MAPS Public Benefit Corporation                                                                    MP-8 Statistical Analysis Plan  
US 
 
Version 1: October 6, 2015 
 
 
                                                                                                               Page 14 of 23 
 
States of Consciousness Questionnaire (SOCQ), total and composite scores 
 
Long-term Follow-up Questionnaire (LTFU Questionnaire) 
 
7.2   Safety Measures 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Subjective Units of Distress (SUD) 
 
General Well-being (GWB) 
 
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) 
 
7.3   Process Measures 
 
Therapist Adherence Criteria 
 
Belief of Condition Assignment 
 
Subject perceptions of experimental sessions 
 
Reactions to Research Participation Questionnaire (RRPQ) 
8.0   Analyses 
 
In general, nominal variables will be described in terms of frequencies and percentages 
and analyzed using chi square analysis. Ordinal and non-normal continuous variables will 
be described using sample median and range, and analyzed by non-parametric statistical 
tests, and approximately normal variables will be described using sample mean and 
standard deviations and analyzed by parametric statistical tests. All statistical tests will be 
two-sided and a difference resulting in a p-value of less than or equal to 0.05 will be 
considered statistically significant. All p-values will be rounded to and displayed in four 
decimals. If a p-value less than 0.0001 occurs it will be shown in tables as <0.0001. 
 
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. 


MAPS Public Benefit Corporation                                                                    MP-8 Statistical Analysis Plan  
US 
 
Version 1: October 6, 2015 
 
 
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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. 
 
8.1   Analysis Populations 
 
Intent-to-treat (ITT): all subjects who were randomized 
 
Per protocol (PP): all subjects who completed Stage 1, underwent assessment of PTSD 
symptoms, and did not experience a major protocol deviation 
 
Crossover: all subjects who completed Stage 2 in addition to completing Stage 1 
 
Safety: all subjects who receive any study treatment 
 
8.2   Handling of Dropouts, Missing Data 
 
Early termination visit data for ITT and Safety variables will be analyzed at the closest 
scheduled visit. 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. 
Subjects who discontinue treatment prior to completing the second experimental session 
prior to the primary endpoint will be replaced. These subjects will be asked to complete 
an outcome assessment prior to continuing to the long-term follow-up. These subjects 
will be included in the ITT population. 
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: 


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US 
 
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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. 
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. 
 
8.3   Protocol Deviations 
All protocol deviations will be included as a categorized listing. Safety and Intent to 
Treat 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 complete through the primary endpoint and anyone who was 
enrolled 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 MDMA group, and individual subjects will be listed in the appendix. 
Possible protocol deviations include the following five 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 
8.4   Pooling of Investigator Centers 
 
All subjects in this study come from one investigational center.  

8.5   Baseline Values 
 


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US 
 
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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 3) pre-drug Since Last Visit C-SSRS scores 
will used as ‘baseline.’ If a subject was not administered the C-SSRS at preparatory 
session 2 (visit 3), then ‘baseline’ scores will be from preparatory session 3 (visit 4). 
8.6   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 who are 
randomized and had any treatment exposure, in the Safety Population, in the ITT 
Population, and in the PP Population. The number and percent of 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, ITT and PP 
Populations.  
 
8.7   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 ITT and Crossover Populations.  
8.8   Prior and Concomitant Medications  
The number and percent of subjects who took medications prior to and after signing 
informed consent 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. 
8.9   Efficacy Analyses 
 
For all primary, secondary and exploratory endpoints descriptive statistics (n, mean, 
standard deviation, median, range, or counts and percentages where appropriate) will be 
provided by treatment group.  
8.9.1   Primary Efficacy Analyses 
 
Clinician Administered PTSD Scale-4 (CAPS-4) 


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US 
 
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The primary efficacy evaluation is the change from baseline to the primary outcome 
timepoint (visit 13) in the CAPS-4 Global Severity score of PTSD (difference score). The 
primary efficacy comparison will be made with ANOVA at an alpha level of 0.05. If the 
null hypothesis rejects, pairwise comparisons among the treatment groups will be made 
with t-tests. If the parametric assumptions for the ANOVA analyses are not met, the 
analogous nonparametric methods will be used (Kruskall-Wallis, Wilcoxon Rank-Sum).  
 
8.9.2   Secondary Efficacy Analyses 
 
8.9.2.1 Secondary Efficacy Analyses at Primary Endpoint 
The secondary efficacy analyses will be made with ANOVA comparing change from 
baseline (visit 1) to the primary outcome timepoint (visit 13) of all the secondary 
measures. If the parametric assumptions for the ANOVA analyses are not met, the 
analogous nonparametric methods will be used (Kruskall-Wallis, Wilcoxon Rank-Sum).  
 
Clinician Administered PTSD Scale-4 (CAPS-4) global scores will also be analyzed for 
effect size with the Cohen’s d analysis. 
 
Global Assessment of Functioning (GAF) total score 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 analyzed 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. 
 
Dissociative Experiences Scale-II (DES-II) total will be analyzed in the same manner as 
the CAPS-4 global scale primary analysis. 
 
Pittsburgh Sleep Quality Index (PSQI) global scores will be analyzed 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. 
 
8.9.2.2 Secondary Efficacy Analyses at Secondary Endpoints 
 
Assess 3 vs. 2 experimental MDMA sessions 
For the CAPS, PTGI, BDI-II, GAF, PSQI, DES-II, and NEO PI, the absolute changes in 
the measures from the primary endpoint to end of Stage 1 for the 125 mg group will be 
compared with t-tests.  In the crossover subjects (30 mg and 75 mg group) the absolute 


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US 
 
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changes in the measures from the secondary endpoint to end of Stage 2 will be compared 
with t-tests.  
 
Crossover Subject Analyses  
Data from subjects assigned to the low and medium dose groups, i.e. ‘crossover 
population,’ will be analyzed by within-subject t-tests comparing difference scores from 
primary endpoint in Stage 1 to secondary endpoint in Stage 2 (Table 3 and 4). The 
following measures total scores will be analyzed in this fashion: CAPS, PTGI, BDI-II, 
GAF, PSQI, DES-II, and NEO PI. 
 
Long-term Follow-up 
For the CAPS, PTGI, BDI-II, GAF, PSQI, DES-II, and NEO PI, the absolute changes in 
the measures from baseline to the long-term follow-up visit (one year post final 
experimental year) will be compared with t-tests. The absolute changes in the measures 
from long-term follow-up to End of Stage 1 (visit 18, 125 mg) or long-term follow-up 
compared to End of Stage 2 (visit 33, 30 and 75 mg) will be compared with within-
subject t-tests.   
 
8.9.3   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 will be an indirect measure of clinical significance.  
Descriptive statistics will be computed and displayed by Stage 1 conditions.  
 
 The percentage of subjects who no longer meet PTSD diagnostic criteria at the 
primary endpoint will be an indirect measure of clinical significance. Descriptive 
statistics will be computed and displayed by Stage 1 conditions.  
 
 CAPS-4 Subscale Scores (B, C, D, F) at the primary endpoint will be analyzed in 
the same manner as the primary analysis of the global score. Descriptive 
statistics will be computed and displayed by Stage 1 conditions.  
 
 Distributional characteristics will be examined for outliers and extreme values 
and, if either is evident. If outliers are found in primary or secondary outcome 
measures, the sponsor will perform analyses with and without the outlying data 
 
 


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US 
 
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8.9.3.1 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 compared by initial dose using 
ANOVA for overall differences and t-tests for pairwise comparisons for each 
experimental session. The data will be explored for effects of dose on composite and total 
SOCQ scores. 
 
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’, independent raters’, and subjects’ belief of condition 
to actual MDMA dose received in each blinded session, the frequency of correct guesses 
will be calculated and depicted by dose condition and study role (subject, therapist, or 
independent rater). 
 
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. For the 125 mg group, within-subjects t-tests will be performed on 
subject’s perceptions at Stage 1 primary and secondary endpoints. The same analysis will 
be performed for 30 mg and 75 mg groups, but data will be from Stage 2 primary and 
secondary endpoint. 
 
Reactions to Research Participation Questionnaire (RRPQ) 
Frequency of response will be tabulated for ‘reasons for participation’ across Stage 1 
conditions. Descriptive statistics will be computed for total scores for subscales and 
displayed by Stage 1 conditions.  
 
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. If sufficient data is available, the sponsor will 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.  
 


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Qualitative Interviews 
Qualitative interviews conducted by a researcher who is part of the study team during the 
12-month follow-up visit will be transcribed to text. A computer-assisted qualitative data 
analysis software package will be utilized to assist in thematic content analysis of the 
interview transcripts. A member of the research team will code the interviews for content, 
to identify emerging themes and organize data into thematic constructs utilizing a 
grounded theory approach. Descriptive statistics will be calculated for emerging themes. 
 
8.9.4   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 those existing AEs that worsened during the study. 
Verbatim terms on case report forms will be mapped to preferred terms and system organ 
classes using the MedDRA dictionary. For incidence reporting if a subject has more than 
one adverse event mapped to the same preferred term, that adverse event will be reported 
only once using the highest severity and closest relationship to study drug. In separate 
columns, the overall frequency of AE's will be reported.  Subject incidence of adverse 
events will be displayed by treatment group and by system organ class. Adverse events 
will also be summarized by severity and relationship to study drug. Subject incidence of 
serious adverse events by treatment group will also be displayed. In addition to the listing 
of all adverse events, a listing of serious adverse events and a listing of adverse events 
leading to discontinuation of study drug will be included.  
 
Summary tables of frequency listings of expected adverse events (Spontaneously 
Reported Reactions) mapped to preferred terms will be displayed during and after each 
experimental session by condition. 
 
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 [3]. 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 treatment group 
and time period. P-values will be calculated using the chi-squared test for overall 
treatment group differences and Fisher’s exact test will be used for pairwise testing. 
Compare lifetime serious suicidal ideation and positive behavior frequencies to 
cumulative frequencies anytime during the study until end of stage 1 and stage 2 using 
chi-squared test for overall treatment group differences and Fisher’s exact test for 
pairwise testing. 
 


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Subjective Units of Distress (SUD) 
 
Descriptive statistics for SUD scores will be calculated by treatment group and time 
period with counts and percentages.  
 
Visual analog scale for Tinnitus and/or Pain visual analog scale 
 
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. T-tests will be performed 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. 
 
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. 
For experimental sessions, mean peak heart rate, blood pressure, and body temperature 
will be analyzed by condition with ANOVA, with t-tests for pairwise comparisons. 
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. A within-subjects t-tests for pre- and post-drug endpoints will be conducted 
for each session for heart rate, blood pressure, and body temperature. 
 
8.10   Timing of Analyses 
 
The primary efficacy analysis will be conducted after all subjects complete Stage 2, but 
before all long-term follow-up data has 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 protocol will not occur after primary analysis. 
The final analysis of secondary endpoints will include only data not analyzed in the 
primary efficacy analysis, i.e. data will not be analyzed twice.  
9.0   References 
 
1. 
Mithoefer, M.C., et al., The safety and efficacy of {+/-}3,4-
methylenedioxymethamphetamine-assisted psychotherapy in subjects with 
chronic, treatment-resistant posttraumatic stress disorder: the first randomized 
controlled pilot study. J Psychopharmacol, 2011. 25(4): p. 439-52. 


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2. 
Mithoefer, M.C., et al., Durability of improvement in post-traumatic stress 
disorder symptoms and absence of harmful effects or drug dependency after 3,4-
methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-
term follow-up study. J Psychopharmacol, 2013. 27(1): p. 28-39. 
3. 
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_Feb20
13.pdf. p. 1-13.