Clinical trial NCT02876172
Conditions: Posttraumatic Stress Disorder
Keywords: PTSD therapy MDMA dyad cognitive behavioral therapy
Sponsor: Lykos Therapeutics
Start date: 2016-07-03; Completion date: 2018-05-29
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical trial is to learn if cognitive-behavioral conjoint therapy (CBCT) in combination with MDMA-assisted therapy is safe and effective in people with chronic PTSD and their partners.

The main question it aims to answer is: Does MDMA-assisted CBCT reduce PTSD symptoms in people with chronic PTSD?

Participants (chronic PTSD patients and their partners) will undergo three non-drug preparatory therapy sessions, followed by two MDMA-assisted therapy sessions. Each MDMA-assisted therapy session will be followed by five non-drug integrative therapy using CBCT.

Detailed description:
Cognitive-Behavioral Conjoint Therapy (CBCT) for PTSD is a three-phase, 15-session, manualized treatment. This Phase 1/2 open-label study will combine methods for conducting MDMA-assisted therapy with methods from the CBCT for PTSD in order to treat 10 participants with chronic PTSD and their partners (intimate or non-intimate significant other who does not have a current diagnosis of PTSD) in order to explore whether combined treatment is effective.

Each therapy team will have one therapist trained and experienced in MDMA-assisted therapy and one therapist trained and experienced in CBCT. During the first experimental session, both participants will receive 75 mg of midomafetamine HCl followed 1.5 to 2 hours later by an optional supplemental half-dose of 37.5 mg. During the second experimental session, an initial dose of either 100 or 75 mg of midomafetamine HCl will be administered to both participants followed by an optional supplemental half-dose of either 50 mg or 37.5 mg. The primary objective of this study is to assess changes in PTSD symptoms from Baseline to Primary Endpoint in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity scores in PTSD participants.

Arms: arm 1: Cognitive-behavioral conjoint therapy and 2 sessions of MDMA-assisted therapy.
Interventions: intervention 1: MDMA intervention 2: CBCT intervention 3: Therapy
Intervention descriptions: intervention 1: Two sessions of MDMA-assisted therapy, one with an initial dose of 75 mg midomafetamine HCl (and optional supplemental dose of 37.5 mg) and the second with 75 or 100 mg midomafetamine HCl (with optional supplemental dose of either 37.5 mg or 50 mg respectively) given to the participant with PTSD and their significant other. intervention 2: A three-phase, 15-session, manualized treatment from the CBCT manual intervention 3: Manualized MDMA-assisted therapy

Protocol documents:
ICF_002.pdf: 


 
 
 
 
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Table of Contents 
List of Tables .............................................................................................................................................................. 3 
1.0 Purpose of the PTSD+ Participant Information and Consent Form ............................................ 3 
2.0 Length of Study.................................................................................................................................................. 3 
3.0 Type of Study ..................................................................................................................................................... 4 
4.0 Procedures/What Will Happen .................................................................................................................. 4 
4.1 Screening/Evaluation and Beginning of Study ............................................................................... 4 
4.2 Beginning of Study ...................................................................................................................................... 5 
4.3 Schedule of Events ...................................................................................................................................... 5 
4.4 Preparatory Psychotherapy Sessions ................................................................................................. 7 
4.5 Experimental Sessions .............................................................................................................................. 7 
4.6 Psychotherapy (Talk Therapy) After Experimental Sessions ................................................. 10 
4.7 Measuring PTSD After Experimental Sessions .............................................................................. 10 
5.0 Possible Risks or Discomforts ................................................................................................................... 11 
6.0 Risks of Being in the Study ......................................................................................................................... 14 
7.0 Reproductive Risks ........................................................................................................................................ 14 
8.0 New Findings.................................................................................................................................................... 15 
9.0 Possible Benefits ............................................................................................................................................. 15 
10.0 Payment for Participation ........................................................................................................................ 15 
11.0 Costs .................................................................................................................................................................. 15 
12.0 Alternatives .................................................................................................................................................... 15 
13.0 Confidentiality ............................................................................................................................................... 16 
14.0 Treatment and Compensation for Injury ........................................................................................... 17 
15.0 Legal Rights .................................................................................................................................................... 17 
16.0 Voluntary Participation ............................................................................................................................. 17 
17.0 Withdrawal ..................................................................................................................................................... 18 
18.0 Contact for Questions ................................................................................................................................. 18 
19.0 Authorization ................................................................................................................................................ 21 


 
 
 
 
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List of Tables 
 
Table 1: Schedule of Events ............................................................................................................ 6 
 
1.0 Purpose of the PTSD+ Participant Information and Consent Form 
 
This consent form describes a research study and your role as a study participant.  This consent 
form may have words in it you do not clearly understand.  Please read this form carefully before 
you decide to be in this study. You may ask the study therapists anything about the information 
provided.  
 
The purpose of this form is to give you information about the research study and, if signed, gives 
your permission to be in the study.  The form describes the purpose, procedures, benefits, risks, 
discomforts and precautions of the research study.  You should be in the study only if you want 
to.  You may refuse to take part or withdraw from this study at any time without penalty or loss of 
benefits to which you are otherwise entitled. You may take home an unsigned copy of this 
consent form to think about or discuss with family or friends before making your decision.  You 
should not sign this form if you have any questions that have not been answered to your 
satisfaction. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website at any time.  
 
If you would like to review the information for this study, or a summary of the results, ask the 
study team doctor for the ClinicalTrials.gov study registration number. 
 
Your study therapists will be paid for their time to conduct this research study 
 
2.0 Length of Study 
 
The length of the study will be about 6 to 7 months. Participation in the study requires a big time 
commitment from you and your partner for 1 month.  There will be 4 in person visits, 2 over 
night visits and 10 videoconferencing visits for you and your partner in a 30-day period. After 
that you will have videoconferencing visits 3 and 6 months after your last video CBCT therapy 
visit. 
 
The timeline for starting treatment after enrollment is variable depending on availability of open 
appointments. You may start therapy as soon as one week or as long as two months after your 
first visit. Experimental sessions last all day and require an overnight stay for you and your 
partner. After these overnight stays, you will each have a brief daily phone call with the therapists 
for 7 days. Of the visits listed above, 4-5 of them will be longer interviews.  
 
Types of visits and duration: 
 
Psychotherapy sessions (90-minutes each): Two introductory sessions at the start of 
participation and 5 sessions after each Experimental Session. These are approximately two days 
apart; most of these visits will be over videoconference. 
 


 
 
 
 
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Experimental sessions (8-hours long plus an overnight stay): Two sessions for you and your 
partner together. These are about 2 weeks apart. 
 
Evaluation and Testing Visits (Up to 4 hours): Testing and completing questionnaires 5 times, 
starting with the beginning of the study. 
 
You will need to be flexible about taking the appointments offered most of the time because there 
is a limited time frame for each type of visit.  
 
3.0 Type of Study 
 
This study is open label, meaning you and the study researchers will know what dose of MDMA 
you and your partner will get. There will be up to 10 pairs/20 people total in this study at this 
location, which is the only location in which this study is being done. 
 
4.0 Procedures/What Will Happen  
 
4.1 Screening/Evaluation and Beginning of Study 
 
If you agree to be in this study, you will first sign this form before any study-related procedures 
are done.  You need to stay on any current medications until you are confirmed to be enrolled in 
the study. Only stop medications if you are officially enrolled under the care of the study doctor.  
Some PTSD medications can cause thoughts about wanting to kill yourself if you stop taking 
them too quickly and without the care of a doctor. This is very important. 
 
Before you can be in the study, the study doctor must first make sure that you and your partner 
qualify for the study and that you are generally physically healthy.  This screening process can 
take up to one month, and there will be one or more office visits or videoconferencing visits 
during this time. The study doctor may ask you and your partner for written permission to contact 
your doctors or psychotherapists to get information about your medical history. They may need to 
do this so that they will know whether or not you both can be in the study.  
 
Psychological and medical screening will be done by a study researcher and a physician other 
than your study therapists. The tests will include the following: 
 
• 
An interview about your PTSD symptoms and how you deal with them in your everyday 
life.  Your score on this interview will be used to decide if you can be in the study. This 
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 that you fill out yourself about your PTSD symptoms. 
• 
A questionnaire about feelings of depression or other symptoms or feelings you might 
experience. 
• 
Answer questions about thoughts you might have about hurting or killing yourself.  
• 
A questionnaire about your quality of sleep. 
• 
A questionnaire about any dissociation symptoms (level of detachment from immediate 
surroundings or from what you feel). 
• 
A visual scale of chronic body pain and tinnitus (ringing in the ears) levels if you have 






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4.4 Preparatory Psychotherapy Sessions 
 
You will meet with the study therapists on two separate occasions before the first Experimental 
Session.  One of these meetings will be by videoconference.  These visits will last 90 minutes. 
During each introductory session, you and your partner will talk about the traumatic incidents that 
led to your PTSD, the ways PTSD symptoms are affecting your life together and what you would 
like to achieve during these sessions. You will be asked the same questions about thoughts or 
feelings you might have about hurting or killing yourself during one of these Preparatory 
Sessions. You will also both learn more about what to expect during Experimental Sessions. The 
introductory sessions will be recorded to audio and video so that the study therapists will have 
accurate records of the sessions and so that they can gather more information about drug-assisted 
psychotherapy sessions. You can ask the study therapists to let you hear or see these recordings if 
you wish. 
 
4.5 Experimental Sessions 
 
There will be two day-long MDMA (experimental) sessions, when you and your partner will have 
an active dose of MDMA and talk therapy including CBCT therapy.  These visits will happen two 
weeks apart.  The first Experimental Session will occur after you have had two introductory 
sessions. Your therapists will discuss the optimal dose of MDMA with you and your partner for 
the second Experimental Session. 
 
One week before each of the Experimental Sessions, you and your partner will need to avoid 
taking: 
 
• 
Any herbal supplement (except with prior permission). 
• 
Any non-prescription medications, unless you have permission from the study therapists 
(with the exception of non-steroidal anti-inflammatory drugs or acetaminophen 
[Tylenol]). 
• 
Any prescription medications, unless you have permission from the study therapists (with 
the exception of birth control pills, thyroid hormones or other medications approved by 
the study therapists). 
 
You must not eat any food 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 
Experimental Session (or longer depending on the specific drug – this should be discussed with 
the study therapists).  You cannot use nicotine or caffeine for two hours before and six hours after 
drug administration.  
 
If you are taking opiate medications for pain management, you can stay on these medications, 
although we may ask you to reduce the dose or stop taking them for at least 24 hours before the 
Experimental Sessions, because these medications may reduce the effectiveness of MDMA. If 
your pain becomes too severe to handle during this period, you will be allowed to take your 
medication. 
 
First, you, your partner and the study therapists will discuss your goals for the Experimental 
Session and the study therapists will answer any other questions you may have. 
 


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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. 
 
During the Experimental Session: 
 
• 
Your blood pressure, temperature, and pulse will be measured before taking the first and 
second capsules of MDMA and at the end of the session. If you have any symptoms 
including confusion, light-headedness, dizziness, chest pain, shortness of breath, tell your 
study therapists. More frequent measurements may be needed if this happens. 
• 
You will also complete a very brief, simple test of how comfortable or distressed you feel 
by picking a number that best matches the level of any distress you may feel. You will 
complete it every 60 to 90 minutes during the Experimental Sessions. 
• 
About an hour before receiving the drug and about six hours afterward, you will answer 
questions about thoughts you might have about hurting or killing yourself. 
• 
The study therapists will talk to you at least every hour or so to see how you and your 
partner are doing. 
• 
If you had tinnitus or chronic pain before the study and mention any changes in these 
symptoms, the therapists will note the changes. 
 
The Experimental Session will be recorded to audio and video so that the study therapists will 
have accurate records of the session and so that they can gather more information about drug-
assisted psychotherapy sessions. You can ask to see or hear these recordings if you would like. 
 
After urine testing, you will receive a capsule containing an active dose of MDMA. After taking 
the capsule, you and your partner will then sit or lie down in a comfortable position. You can ask 
for an eyeshade if you wish. You will listen to music during much of each Experimental Session, 
either through headphones or room speakers. During the session there will be times when 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 times of silence. Lying or sitting 
in a comfortable position and listening to music are meant to bring out thoughts and feelings, 
including thoughts and feelings about the trauma. Both study therapists will remain with you, and 
your partner and they will help you if you need them to. They will speak with you and ask you to 
talk to them at least once an hour, but you can talk to them whenever you wish. There may be 
times when the 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 take the first capsule, you and 
your partner will take a second capsule. The second dose will contain half the amount of the first 
capsule. The thought behind taking the second capsule is that it is not supposed to make the 
MDMA stronger, just make it last longer. If you or the study therapists notice problems after the 
first capsule, then you or your partner will not get the second capsule. 
 
The study therapists will watch for any side effects (unwanted effects or health problems), which 
will be treated if necessary. If this happens, the study therapists will keep you fully informed 
about any concerns or treatment. 
 


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If you are confused or upset eight or more hours after the start of an Experimental Session, the 
therapists will stay with you until you have fully recovered. If the therapists 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 therapists will ask you 
about thoughts of killing or harming yourself before and after drug administration and on several 
occasions during the phone follow-up period.  You will also be asked to complete homework 
assignments during the study.  These should be completed and returned at 11 out of 19 visits. 
 
You and your partner will be spending the night in a room at the office of the therapist 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 therapists or you are having other 
problems and need to contact the therapists, the attendant will contact them immediately. 
 
On the next day, you and your partner will have a non-drug talk therapy session with the study 
therapists.  You will need to have someone drive you and your partner 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 therapists will find 
someone to drive you. 
 
After you return back home from the talk therapy session, the therapists will talk to you and your 
partner either by phone or videoconferencing every day for a week to ask how you are feeling and 
see whether you should see the study therapists before your next scheduled non-drug 
psychotherapy session.  The phone calls will take approximately 5 to 15 minutes, though they can 
be as long as you need them to be. The therapists will ask you about thoughts about killing or 
harming yourself during the second and seventh day of phone contact. You can call the study 
therapists at any time. The study therapists may be called 24 hours a day during the research 
study; except for a few times they may be out of town. At those times the study doctor will be on 
call and can be called at a number that will be given to you. 
 
The therapists will give you and your partner a card with phone numbers for calling your study 
therapist 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 therapists if you need to. 
 
If there are delays in following the usual study schedule, the study therapists will call you at least 
once a week to talk about how you’re doing. These calls will take about 15 minutes.  You need to 
agree to call the study doctors if any of these things happen: you have an increase in symptoms 
that you have taken medication for in the past, you need to contact your outside therapist other 
than for the usual appointments, and/or you start or stop taking a prescription medicine or an 
over-the-counter medicine that you have not previously cleared with the study therapists. 
 
If you have very high blood pressure, get sick, or have an important and strong lasting reaction 
(unwanted effect or health problem) during or after an Experimental Session, you or the study 
therapists may decide that you should not have the next Experimental Session.  You may make 
this decision to stop treatment in the study for any reason. If either you or your partner needs to 
quit the study, you will both need to quit the study at the same time.  
 
If the study therapists decide to take you or your partner out of the study, they will let you both 
know that they are doing this and their reason for doing it.  If you are taken out of the study or 
decide you do not want to receive treatment in the study, the study researchers will ask you to 


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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 acute effects of the 
drug have worn off.  If this happens, you will also be asked to take part in some of the same 
interviews and questionnaires you completed at the beginning of the study. You will also be 
expected to take part in the 6-month long-term follow-up. 
 
4.6 Psychotherapy (Talk Therapy) 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 and your partner will have 
psychotherapy with the study therapists the morning after each Experimental Session. These 
sessions will last 60 to 90 minutes. You and your partner will have 2 longer videoconference calls 
about 2 days apart during the week after the MDMA session for CBCT/ talk therapy. You and 
your partner will have 2 additional videoconference calls about 2 days apart during the second 
week for CBCT therapy. You may schedule more meetings with the study therapists besides 
those that are scheduled as part of the study if you, your partner and/or the therapists think they 
are needed.  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 with your partner and gain maximum benefit and understanding from 
Experimental Sessions. Each regular psychotherapy session will be recorded to audio and video, 
just like the preparatory and Experimental Sessions, and you can hear or see these recordings if 
you wish. 
 
If you had tinnitus or chronic pain before the study and mention any changes in these symptoms, 
the visual analog scale will be used to collect the changes. 
 
The therapists will ask you about thoughts about killing or harming yourself at these visits. 
Questions about your PTSD symptoms and the way you connect with others will also be asked 
during each of these visits. 
 
4.7 Measuring PTSD After Experimental Sessions 
 
Approximately two weeks after each Experimental Session you will meet with the study 
researcher again, which may be recorded. The researcher will ask about your PTSD symptoms. 
You will also meet with your study therapists two weeks after each Experimental Session to fill 
out the same questionnaires from the start of the study. You will also be asked if you have had 
any thoughts about hurting or killing yourself. You will also complete the scale of pain and 
tinnitus levels if you had these problems before the study. 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 participant 2 weeks after 
your second Experimental Session. The study therapists will give you and your partner 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 6-month 
follow-up videoconference visit.  On this card you will record any new important health 
problems, changes to your mental health, hospitalizations and medications to treat these 
problems. 
 
Three and 6 months after your second Experimental Session, you will meet with the study 
researcher by video conference again, which may be recorded. The researcher will ask about your 


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PTSD symptoms. The questionnaires will be given to you or mailed for you to fill out for your 3-
month and 6-month follow-up videoconference visit.  If mailed to you, it will come with an 
envelope that is already stamped and have 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.  
 
5.0 Possible Risks or Discomforts 
 
MDMA has not been widely tested in humans, but as of December 2015 more than 1185 people 
have been given MDMA in clinical research settings, without any serious unexpected problems 
happening. 
 
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%) 
 
In two studies of MDMA in a total of 37 people with PTSD, these reactions were commonly 
reported after a 125 mg active 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 participants reported: 
 
• 
Nausea 
• 
Low mood 
• 
Feeling cold 
• 
Dizziness 
• 
Impaired balance 
• 
Disturbance in attention 
• 
Restlessness 
• 
Perspiration 
• 
Thirst 
• 
Feeling weak 
• 
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. 
 


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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. 
 
Changes in vision, hearing or other senses: Most participants that took part in past 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 about 30 beats 
per minute (BPM), sometimes more. 
 
In past studies supported by MAPS and published studies, blood pressure rose well above normal 
levels in a few participants (a little less than 5%) after taking MDMA, but these participants did 
not report any discomfort and did not require any treatment. Although these increases in blood 
pressure are similar to what happens after heavy exercise, they could cause serious problems in 
individuals with pre-existing heart or blood vessel conditions. These serious problems could 
include an irregular heartbeat, heart attack or stroke.  We will screen all potential participants for 
preexisting heart problems before they are allowed to be in this study. While this doesn't 
guarantee that no heart problems will occur, it does reduce the risk of this happening. 
 
Anxious or jittery feeling: Some participants in past 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 safely help you. If needed, 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. 
 


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Insomnia & drowsiness: In previous studies, between 17% and 23% of participants have 
reported insomnia (difficulty sleeping) or feeling tired, irritable, or drowsy for as long as 3 days 
after taking MDMA.  You should not drive or use machinery immediately after 
Experimental Sessions (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 noticed up to 2 or 3 days later. While some 
participants 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 taking 
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. 
 
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 be 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 


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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. 
 
6.0 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 your study therapist 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, especially if you have had 
these thoughts before.  If this happens, you should talk with your outside therapist and your study 
therapist. If you have to start taking medicine again, then the study doctors will have to take you 
out of the study. 
 
7.0 Reproductive Risks 
 
Effects of MDMA on the growth and development of an unborn baby are not known; therefore, 
you will not be allowed to be in the study if you are pregnant.  If you get pregnant after you have 
had at least one Experimental Session, the study doctors and the sponsor, MAPS, will ask you 
about and keep track of your 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, 
intrauterine device (IUD), injected or implanted hormonal methods, abstinence, oral hormones 
plus a barrier contraception or double barrier contraception. Two forms of contraception are 
required with any barrier method or oral hormones (i.e. condom + diaphragm, condom or 
diaphragm + spermicide, oral hormonal contraceptives + spermicide or condom). Not of 
childbearing potential is defined as permanent sterilization or postmenopausal females until 10 
days after the second Experimental Session. 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. 
 


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If you are a woman of childbearing potential, you will be tested at the start of the study and again 
before each Experimental Session to see if you are pregnant.  If, at any time during the study, you 
think that you may be pregnant or are worried that you may become pregnant, you must tell your 
study therapist 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. 
 
8.0 New Findings 
 
If any new information becomes available about MDMA while you are in this study, the study 
therapists will tell you about it as soon as possible. You may contact the study therapist at any 
time after your participation ends to find out if any new information about this study has become 
available. 
 
9.0 Possible Benefits 
 
Your symptoms of PTSD and relationships may improve while taking part in this study. There is 
no guarantee that you will benefit from taking part in this research study.  Information obtained 
from this study may help doctors and researchers to improve treatment for PTSD and 
relationships in the future. 
 
10.0 Payment for Participation 
 
There will be no payment for taking part in this study.  
 
11.0 Costs 
 
The sponsor of this study, MAPS, will cover the costs that are directly related to the research. 
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), or public health insurance plan will not be charged 
for any procedures done solely for the purpose of the study. You or your insurance company will 
remain responsible for on-going treatment not included in the study. 
 
If you live over 165 miles away from the research site (which assumes a 3-hour car ride), you will 
be reimbursed for up to two nights in a hotel room at a hotel close to the study site that will be 
comfortable for you and your partner for each visit you attend in person per study protocol.  
 
12.0 Alternatives 
 
One alternative to being in this study is to decide not to take part. 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 therapist can discuss the alternatives 
and their potential risks and benefits with you. 
 


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13.0 Confidentiality 
 
To ensure confidentiality, only participant numbers will be provided to the study sponsor unless 
you give specific permission, for example at a time when you sign a media release. When not in 
use, your information will be stored in a locked office. Absolute confidentiality cannot be 
guaranteed, but every effort will be made to maintain your confidentiality. 
 
Some people need access to your 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.  Medical 
records may be looked at by: 
 
• 
The sponsor, MAPS and the people they hire to over-see the study. 
• 
The FDA and similar agencies in other countries. 
• 
The Department of Health and Human Services (DHHS) agencies. 
• 
Governmental agencies in other countries. 
• 
The Copernicus Group Independent Review Board (IRB). 
 
All records in 
 are participant to subpoena by a court of law. 
 
The results of this research study may be presented in meetings, presentations, or in publications, 
where your identity will not be disclosed. Videotapes of your sessions may be used in training 
sessions for research therapists or other researchers only in controlled settings as described below 
 
Audio and video recordings: The study therapists will audio and video record each visit after 
enrollment. The purposes for this recording that you are agreeing to by signing this informed 
consent are: 
 
1. So that you will have access to review your own therapy sessions. 
2. So the study therapists will have accurate records of the session. 
3. So that trained raters working for the sponsor can verify that the therapy is being carried 
out according to the protocol and the methods described in the Treatment Manual. The 
raters watch randomly selected video sessions through an online portal that requires 
strictly controlled, time-limited password access.  
4. For further research on the therapy and how it is performed.  
5. For training other therapists and scientists to develop and work on additional research.  
For this purpose, your videos may be viewed in online trainings, requiring strictly 
controlled time-limited password access, or in in-person trainings. 
 
For the above purposes the adherence raters, researchers and therapists who may be viewing these 
recordings will be selected by the sponsor, and will sign confidentiality agreements to ensure they 
do not share the identifying information they may receive.  
 
You may listen to or watch the recordings if you wish, but you do not have to. Due to processing 
time required, they will not be available immediately after your visit. Once the recordings are 
processed you may request a unique password to allow you to access your own recordings, which 
will be identified only by your study participant number. No identifying information will be 
written or otherwise attached to the video recordings. 
 
It is also possible that the investigators and/or Sponsor may wish to use portions of your videos to 


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educate a broader audience at medical conferences or other settings. In these settings the audience 
will not be specifically screened and selected, and confidentiality agreements will not be obtained 
from the audiences.  By signing this consent, you are not agreeing to the use of your video in 
these kinds of settings where confidentiality cannot be carefully guarded, and you are not 
required to agree to use of your video in these settings in order to participate in the study. At the 
end of the CBCT therapy (Visit 16) when you have completed all of the questionnaires and 
measures, you can make a decision about whether or not you wish to grant this additional 
consent.  
 
These recordings will be stored on encrypted back-up hard-drives stored in a locked and secure 
location when not in use. A copy will be transferred to electronic secure storage on the web to 
allow for viewing purposes described above. Electronic systems used will include measures to 
protect confidentiality of your identity and video data. Your videos may be viewed in online 
trainings or in in-person trainings with pre-screened therapists. People viewing these videos will 
be asked to sign a confidentiality agreement. No identifying information will be written or 
otherwise attached to the video recordings.  
 
During your study sessions you may ask to stop the recording at any time, but your therapists will 
ask your permission to turn it back on when you are ready. 
 
By signing this consent form, you consent to the collection, access, use and sharing of your 
information as described above. You have the right to check your study records. 
 
14.0 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 therapist has a program in place to provide additional 
compensation in the event of an injury. 
 
Your health insurance may not be willing to pay for the costs of treating a study-related 
emergency.  The study sponsor will pay for any study-related procedure that your insurance will 
not cover. 
 
15.0 Legal Rights 
 
The above section does not restrict your right to seek legal assistance. You do not waive any legal 
rights by signing this form. 
 
16.0 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 office for tests. 
 




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Participant’s Statement of Consent 
 
“A Phase 2 Open Label Treatment Development Study of MDMA-Assisted Cognitive-Behavioral 
Conjoint Therapy (CBCT) in Dyads in which 1 Member has Chronic 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-recorded during this study. 
 
I have read the information in this consent form and it has been discussed with me.  I have been 
given sufficient opportunity to consider whether to take part in this study. All of my questions so 
far about the study and my participation in it have been answered.  I freely consent to take part in 
this research study. 
 
By signing this consent form, I have not waived any of the legal rights which I otherwise would 
have as a participant in a research study.  I have been told that I will be given a copy of this 
consent form after it has been signed and dated.  
 
 
 
 
 
Signature of Participant 
 
 
 
 
Date 
 
 
 
Printed Name of Participant 
 
 
 
 
I certify that the information provided was given in language that was understandable to the 
participant. 
 
 
 
 
 
Signature of Person Obtaining Consent 
 
 
 
 
Date 
Printed Name of Person Obtaining Consent 
 
 
 
 
 
 
 
 
 
 
  
 
 




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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.  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.   
  
19.0 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. 
 
 
 
 
 
 
Signature of Participant 
 
 
 
 
Date 
 
 
 
Printed Name of Participant 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent 
 
 
 
 
Date 
Printed Name of Person Obtaining Consent 
 
 
 
 

Prot_003.pdf: 
Study Synopsis 
 
A Phase 1/2 Open-Label Treatment Development Study of MDMA-Assisted 
Cognitive-Behavioral Conjoint Therapy (CBCT) in Dyads in which 1 Member has 
Chronic Posttraumatic Stress Disorder (PTSD) 
Amendment 4 Version 1 
May 8, 2017 
 
Study Code: MPVA-1 
 
Sponsor: Multidisciplinary Association for Psychedelic Studies (MAPS) 
 
1115 Mission Street 
 
Santa Cruz, CA 95060, USA 
 
Investigator: Michael C. Mithoefer, M.D.  
 
Sub-Investigator: Candice Monson, Ph.D.  
 
Medical Monitor: Julie Holland, M.D. 
 
 
Study Description: This is a small pilot Phase 1/2 open-label experimental medicine 
study exploring Cognitive-Behavioral Conjoint Therapy (CBCT) integrated with 
MDMA-assisted psychotherapy for treatment of chronic Posttraumatic Stress Disorder 
(PTSD). This study is not intended to lead to a registration study. This study will enroll 
10 dyads, consisting of a participant diagnosed with PTSD (PTSD+ participant), and a 
Concerned Significant Other participant (CSO participant) who does not have a current 
diagnosis of PTSD, but is experiencing problems associated with psychosocial 
circumstances related to the PTSD+ participant’s diagnosis, assessed per the V-codes in 
the DSM-5. The primary outcome measure is the Clinician Administered PTSD Scale 
according to DSM-5 (CAPS-5) administered to the PTSD+ participant. Additional 
measures evaluate various qualities of the relationship between PTSD+ participant and 
CSO participant and psychological distress in the CSO participant. 
 
Eligible and enrolled participants will undergo a 2-month course of psychotherapy as a 
dyad that includes CBCT integrated with MDMA-assisted psychotherapy. Treating both 
members of the dyad is integral to CBCT therapy, as described in Monson and Fredman’s 
(2012) manual [1], which  will be integrated with elements of the Treatment Manual for 
MDMA-assisted Psychotherapy in order to modify CBCT to incorporate MDMA as a 
catalyst for the therapeutic process [2]. The integration of these treatments will provide 
the researchers with a consistent psychotherapy approach and test an experimental form 
of drug-assisted psychotherapy. This study is designed to obtain estimates of effect size 
for safety and efficacy. Since this is the first time that CBCT for PTSD is being combined 
with MDMA-assisted psychotherapy for PTSD, the researchers are interested in 
gathering preliminary information about the blending of these two therapeutic 
approaches.  
 
CBCT for PTSD is a three-phase, 15-session, manualized treatment described with the 
acronym “R.E.S.U.M.E. Living” to convey the sequential treatment phases and to signify 


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the recovery-focused nature of the therapy. The “R” and “E” (Rationale for treatment and 
Education about PTSD and relationships) capture the overall goals of Phase 1, which are 
to provide a rationale for treatment and to educate the couple about PTSD and associated 
interpersonal problems. The “S” and “U” (Satisfaction enhancement and Undermining 
avoidance) stand for the overall goals of Phase 2, which are to enhance relationship 
satisfaction and undermine avoidance that maintains PTSD and relationship issues. The 
“M” and “E” (Making meaning of the trauma and End of therapy) represent the overall 
goals of Phase 3, which are to make meaning of the traumatic event(s) and the end of 
therapy (but not the end of using the skills). Content from sessions 6 and 7 of Phase 2, 
and 8 and 9 of Phase 3 of CBCT for PTSD will be completed in 4 phone or 
videoteleconferencing sessions during the three weeks between the Experimental 
Sessions. All of the CBCT Sessions are 75 minutes each and include within-session 
practice and out-of-session assignments to facilitate the couple’s skill acquisition outside 
of session.  Each therapy team will have one therapist trained and experienced in 
MDMA-assisted psychotherapy and one therapist trained and experienced in CBCT.  
Whenever possible both therapists will have had training in both methods. It is believed 
that MDMA may hold promise to catalyze the effects of CBCT for PTSD. Given the 
properties of MDMA, specifically in inducing empathy and interpersonal openness, these 
psychopharmacological effects are especially relevant to the purported mechanisms of 
CBCT for PTSD. 
 
There are several important reasons to include significant others in PTSD treatment, and 
to treat them as clients versus “support persons”, in addition to the data supporting the 
efficacy of CBCT for PTSD noted above. First, four studies have been published showing 
that pre-treatment interpersonal functioning affects individual treatment outcomes [3-6]. 
These studies consistently document that poorer pre-treatment intimate relationship 
functioning and social support are associated with worse individual treatment outcomes 
for those receiving front-line individual treatments for PTSD. Second, loved ones of 
those with PTSD consistently document their own psychological distress, caregiver 
burden, and relationship distress associated with being in relation to someone with PTSD 
[7]. Thus, one cannot assume a psychologically healthy significant other to be 
participating in therapy with someone who is diagnosed with PTSD. Third, loved ones 
may engage in well-meaning behaviors, but in fact may exacerbate or at least maintain 
individual psychopathology. This phenomenon has been termed “partner 
accommodation” [8, 9], and has been shown to be associated with poorer outcomes for 
CBCT for PTSD. Fourth, in addition to interventions aimed at intrapsychic mechanisms, 
the communication and connection between loved ones is a target of intervention. 
MDMA is expected to facilitate this communication and connection, given MDMA’s 
purported mechanisms of action. For these reasons, CBCT for PTSD was developed to be 
a true interpersonal treatment for PTSD, and explains the choice to administer MDMA to 
both members of the dyad. 
 
This study will combine methods described in the Treatment Manual for conducting 
MDMA-assisted psychotherapy with methods from the CBCT for PTSD manual. The 
MDMA-assisted psychotherapy manual is not intended to define all interactions that 
occur in the therapy.  It provides a structure within which the therapy is expected to occur 
and allows individual therapist teams to include therapeutic interventions based on their 
own training, experience, intuition, and clinical judgment, provided the interventions are 


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compatible with the tenor of the method and appropriate to the participant’s unfolding 
experience. The therapists will carefully work with the both participants to establish a 
sense of safety, trust, and openness to create an environment supportive of healing.   
 
Dose Selection: This study will assess the effects of psychotherapy sessions assisted by 
two therapeutic doses. The first experimental dose will use 75 mg of MDMA followed 
1.5 to 2 hours later by an optional dose of 37.5 mg.  During the second Experimental 
Session an initial dose of either 100 mg or 75 mg will be administered followed by an 
optional supplemental half-dose 1.5 to 2 hours after the initial MDMA dose. The default 
dose for the second session will be 100 mg (followed by an optional supplemental half-
dose), however if, after discussion with the Clinical Investigators, each participant may 
be permitted to stay at 75 mg (followed by an optional supplemental half-dose) for the 
second session.    
  
Table i: Dose Selection 
Initial  
MDMA Dose  
Optional Supplemental  
MDMA Dose  
Cumulative (Initial + Optional)  
MDMA Dose  
75 mg 
37.5 mg 
112.5 mg 
100 mg 
50 mg 
150 mg 
 
MDMA appears to temporarily reduce fear and increase interpersonal trust, without 
clouding the sensorium or inhibiting access to emotions. MDMA may catalyze 
therapeutic exposure by enhancing the ability to tolerate negative or threatening 
emotional states and allowing patients to stay emotionally engaged without being 
overwhelmed by the intense emotions surrounding their condition. 
 
The active dose of MDMA to be used in this study is similar to the full dose of 125mg 
followed by a supplemental half dose of 62.5mg used in previous studies in the U.S., 
Switzerland, and Israel. Previous researchers have also used doses within this range [10-
19]. Prior to the scheduling of MDMA, similar doses and regimens were used in 
psychotherapy [20-22]. The MDMA doses to be used in this study have been used in 
previous studies sponsored by MAPS.  
 
The initial active doses are 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.  
 
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 conjunction 
with CBCT on PTSD symptoms in PTSD+ participants and relationship functioning in 
both participants. 
 
Primary Objective: The primary objective of the study is to assess changes in PTSD 
symptoms from baseline as measured by CAPS in PTSD+ participants at the Primary 
Endpoint. 
 


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Primary Outcome Measure: Clinician-Administered PTSD scale (CAPS) administered 
by a blinded Independent Rater. 
 
Secondary Outcome Measures: Posttraumatic Stress Disorder Checklist for the DSM-5 
(PCL-5), Beck Depression Inventory-II (BDI-II), Pittsburgh Sleep Quality Index (PSQI), 
Posttraumatic Growth Inventory (PTGI), Revised Conflict Tactics Scale (CTS-2), 
Emotion Regulation Questionnaire (ERQ), Interpersonal Reactivity Index (IRI), Toronto 
Alexithymia Scale-20 (TAS-20), Quality of Relationships Inventory (QRI), Significant 
Others’ Responses to Trauma Scale (SORTS), Miller Social Intimacy Scale (MSIS), 
Inventory of Psychosocial Functioning (IPF), Trauma and Attachment Beliefs Scale 
(TABS), Multiscale Dissociation Inventory (MDI), 
Interpersonal Closeness Measure (IPC) and Couples Satisfaction Index (CSI). 
 
Safety Measures: Columbia Suicide Severity Rating Scale (C-SSRS), Subjective Units of 
Distress (SUD), and vital signs including blood pressure, heart rate, and body 
temperature, Serious Adverse Events (SAEs), Adverse Events (AEs), spontaneously 
reported reactions, General Wellbeing, medications and changes to psychiatric 
medications, and changes in pre-existing chronic pain and/or tinnitus symptoms will be 
collected throughout the study using a Visual Analog Scale in any members of the dyad 
reporting these symptoms. 
 
Process Measures: Reaction to Research Participation Questionnaire with the (RRPQ), 
Long-term Follow-up Questionnaire (LTFU).  
 
Recruitment and Participant Population: Participants may be persons aged 18 or older 
including a PTSD+ participant who has been diagnosed with PTSD for at least 6 months 
and a CSO participant (i.e., intimate or non-intimate person) who does not have a current 
diagnosis of PTSD but is experiencing associated psychological distress as assessed by 
V-codes in the DSM-5. There is no upper age limit designated in this protocol as age 
alone does not put participants at increased risk and is a less specific exclusion criterion 
when compared with direct assessment of general health.  Participants with medical 
conditions that would have contraindications to receiving MDMA would be excluded 
according to the Inclusion and Exclusion Criteria. Participants with a history of suicide 
attempts will not be excluded unless risk of suicidal behavior is present at the time of the 
screening assessment.  All participants will be evaluated by the CI to determine if there is 
a current risk of suicidal behavior.  Participants will be enrolled according to the 
Inclusion and Exclusion Criteria based on the clinical judgment of the CI. 
 
The dyad members will be referred to individually as the PTSD+ participant and the CSO 
participant. PTSD+ participants would not be excluded for having more than one 
traumatic event. PTSD+ participants must have a past month CAPS score indicating at 
least moderate PTSD symptoms and must meet all Inclusion Criteria and no Exclusion 
Criteria at Baseline. CSO participants must also meet Inclusion Criteria and no Exclusion 
Criteria. Both participants must be in good physical health and without major medical 
disorders that might affect the safety or tolerability of MDMA. Dyads will be recruited 
through printed ads, Internet ads, referrals from other psychiatrists, psychotherapists, or 
physicians, and through word of mouth. Recruitment will continue until 10 dyads that 


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meet all inclusion criteria without meeting any exclusion criteria are enrolled. Only IRB-
approved recruitment materials and advertisements will be used for the study. 
 
Study Procedures: After giving written informed consent, prospective dyads will be 
screened for eligibility. At screening, the PTSD+ participant and the CSO participant will 
sign separate Informed Consent Forms.  Both must give written informed consent in 
order for the dyad to be enrolled. Dyads must consist of people who are in a significant 
ongoing relationship, including but not limited to romantic relationships. Baseline 
screening procedures and assessments will be conducted for both members of the dyad. 
Dyads in which both members meet all Inclusion and no Exclusion Criteria will be 
enrolled. 
 
Eligible and enrolled participants will undergo a 2-month course of psychotherapy as a 
dyad that includes CBCT for PTSD integrated with MDMA-assisted psychotherapy.  The 
CBCT sessions, as described in Monson and Fredman’s (2012) manual [1], will be 
integrated with elements of the Treatment Manual for MDMA-Assisted Psychotherapy 
[2] in order to modify CBCT to incorporate MDMA as a catalyst for the therapeutic 
process.  Sessions will be conducted by a co-therapy team and will include Preparatory 
Sessions, two Experimental Sessions of MDMA-plus psychotherapy and non-drug CBCT 
psychotherapy Integrative Sessions. The primary objective is to measure changes in 
PTSD symptoms via CAPS global severity scores in PTSD participants at Baseline and 
the Primary Endpoint, one month after the 15th CBCT session. 
 
The Experimental Sessions will last 6 to 8 hours and will be scheduled 3 weeks apart, 
with an intervening course of non-drug therapy. The non-drug psychotherapy includes 
two Preparatory Sessions prior to the first Experimental Session and five Integrative 
Sessions after each Experimental Session. Integrative Sessions will be conducted by 
telemedicine (video conferencing whenever possible, telephone if there are occasions 
when video conferencing is not technically possible) and will include both members of 
the dyad. The sessions will follow a combination of the MDMA-assisted psychotherapy 
manual and the CBCT manual, with each method modified as needed to combine the 
therapies. 
 
Safety: The safety objectives of the study are to monitor and assure safety of all 
participants during and after the Experimental Sessions by assessing physiological 
effects, psychological distress, SAEs, medical events, spontaneously reported reactions, 
and suicidal ideation and behavior.  All of the objectives below will be assessed in both 
participants: 
 
• Suicidal ideation and behavior will be assessed with the Columbia Suicide 
Severity Rating Scale (C-SSRS) according to the Table 3: Time and Events. 
• During Experimental Sessions, Subjective Units of Distress (SUD) and vital signs 
including blood pressure, heart rate, and temperature will be collected. 
• Serious Adverse Events (SAEs) will be collected in both groups through Study 
Termination. All Adverse Events (AEs) will be collected on the day of drug 
administration through the Primary Endpoint and will be followed to resolution. 


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• Any spontaneously reported reactions will be collected from the day of the 
Experimental Session through seven days after both Experimental Sessions.  
Reactions that have not resolved to Baseline level of severity after seven days will 
be collected on the Adverse Event Report page until resolution.  
• Assess General Wellbeing (clinician-rated) at all visits and phone calls for both 
participants. 
• AEs requiring medical attention will be collected through Study Termination. 
• 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. 
• Baseline medications and changes to psychiatric medications will be collected 
throughout the study. 
• Changes in pre-existing chronic pain and/or tinnitus symptoms will be collected 
throughout the study using a Visual Analog Scale in any members of the dyad 
reporting these symptoms. 
  
Statistical Analysis: This pilot RCT is the first study of its kind intended to establish 
preliminary effect size estimates of CBCT combined with MDMA-assisted 
psychotherapy for PTSD. In the absence of published effect sizes for this new treatment 
modality, effect sizes were estimated based on prior trials of these individual treatments. 
In a limited number of small pilot studies, CBCT for PTSD yielded paired-treatment 
effect sizes of g > 1.0 for improvements in PTSD on the primary outcome measure and 
co-morbid symptoms. The two completed controlled RCTs of MDMA-assisted 
psychotherapy for PTSD have yielded effect sizes of g > 1.0 for improvements in PTSD 
symptoms as well. Assuming that effect size of the combined treatment may be 
approximately 0.8, estimated power for a within-subject analysis with a significance level 
of .05 based on a 2-tailed test, is 62% for a sample size of 10 participants for the primary 
measure, suggesting the potential for an underpowered design, but with some possibility 
of detecting a within-subject effect due to treatment. Statistical power estimates were not 
available for secondary and exploratory measures, as they were previously not used in 
sponsor-supported studies.  
 
 


PROTOCOL MPVA-1 
IND 063384 
 
Original Protocol Version 1: July 13, 2015 
Protocol Version 2: September 2, 2015 
Protocol Amendment 1 Version 1:  December 2, 2015 
Protocol Amendment 2 Version 1:  March 2, 2016 
Protocol Amendment 3 Version 1: December 27, 2016 
Protocol Amendment 4 Version 1: May 8, 2017 
 
A Phase 1/2 Open-Label Treatment Development Study of MDMA-Assisted 
Cognitive-Behavioral Conjoint Therapy (CBCT) in Dyads in which 1 Member has 
Chronic Posttraumatic Stress Disorder (PTSD) 
 
 
 
SPONSOR 
Multidisciplinary Association for Psychedelic Studies  
(MAPS) 
1115 Mission Street 
Santa Cruz, CA 95060 
 
SPONSOR DESIGNEE  
Amy Emerson 
MAPS Public Benefit Corporation 
Phone number: 510-393-7224 
 
CLINICAL INVESTIGATOR 
Michael C. Mithoefer, M.D. 
208 Scott Street 
Mount Pleasant, SC 29464 
Phone number: 843-849-6899 
 
SUB-INVESTIGATOR 
Candice M. Monson, Ph.D. 
Department of Psychology 
Ryerson University 
350 Victoria Street 
Toronto, Ontario M5B 2K3 
 
MEDICAL MONITOR 
Julie Holland, M.D. 
200 East 33rd Street 
Suite 16H New York, NY 10016   
Phone number: 212-358-5808 
 
STUDY MONITOR 
Charlotte Harrison 
MAPS Public Benefit Corporation 
1115 Mission Street 
Santa Cruz, CA 95060 
Phone number: 774-257-3518 
 
Telephone number for trial related emergencies: 650-248-4647 


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Table of Contents 
Study Synopsis ................................................................................................................... 1 
Table of Contents .............................................................................................................. 8 
1.0 List of Abbreviations ................................................................................................ 10 
1.1 List of Tables .......................................................................................................... 12 
1.2 List of Figures ......................................................................................................... 12 
2.0 Introduction, Background, and Rationale .............................................................. 13 
2.1 Introduction ............................................................................................................. 13 
2.2 Background ............................................................................................................. 14 
2.2.1 PTSD ................................................................................................................ 14 
2.2.2 MDMA ............................................................................................................. 15 
2.2.3 Previous Clinical Experience with MDMA ..................................................... 16 
2.2.4 MDMA-assisted Psychotherapy and CBCT for PTSD .................................... 17 
2.3 Protocol Purpose ..................................................................................................... 20 
2.4 Rationale of Dose Selection .................................................................................... 20 
3.0 Protocol Objectives ................................................................................................... 21 
3.1 Primary Objective ................................................................................................... 21 
3.2 Secondary Objectives.............................................................................................. 21 
3.3 Process Objectives: ................................................................................................. 22 
3.4 Safety Objectives .................................................................................................... 23 
4.0 Protocol Design.......................................................................................................... 23 
4.1 Planned Duration of Study and Visit Windows ...................................................... 26 
4.2 Recruitment and Participant Population ................................................................. 26 
4.2.1 Inclusion Criteria ............................................................................................. 27 
4.2.2 Exclusion Criteria ............................................................................................ 30 
5.0 Methods ...................................................................................................................... 32 
5.1 Measures ................................................................................................................. 32 
5.1.1 Outcome Measures........................................................................................... 36 
5.1.2 Safety Measures ............................................................................................... 40 
5.1.3 Process Measures ............................................................................................. 41 
5.2 Study Procedures and Visit Descriptions ................................................................ 42 
5.2.1 Prescreening, Screening, and Baseline Evaluation (Pre-study) ....................... 42 
5.2.2 Preparatory Psychotherapy Session (Visit 1 - Telemedicine Visit) ................. 44 
5.2.3 Preparatory Psychotherapy Session (Visit 2 - Clinic Visit) ............................. 45 
5.2.4 Experimental Sessions (Visits 3 and 10 - Overnight Stay) .............................. 46 
5.2.5 Integrative Sessions Day after Experimental Session (Visits 4 and 11 - Clinic 
Visit) ......................................................................................................................... 49 
5.2.5 Daily Telephone Contact for Seven Days after an Experimental Session ....... 50 
5.2.6 Integrative Sessions Between Experimental Sessions (Visits 5, 6, 7, 8, 12, 13, 
14, and 15 - Telemedicine Visits) ............................................................................. 50 
5.2.7 Evaluation and Preparation Visit at Midpoint (Visit 9 - Clinic Visit) ............. 52 
5.2.8 Primary Assessment (Visit 16 – Telemedicine Visit) ...................................... 53 
5.2.9 Long-term Follow-up (Visits 17 and 18 – Telemedicine Visits) ..................... 54 
5.3 Participant Numbering ............................................................................................ 55 
5.4 Removal of Participants from the Study ................................................................. 55 
5.5 Premature Discontinuation of the Study ................................................................. 56 
6.0 Investigational Product ............................................................................................ 56 


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6.1 Description of Active Compounds.......................................................................... 56 
6.2 Preparation and Administration .............................................................................. 56 
6.2.1 Doses ................................................................................................................ 56 
6.2.2 Compounding ................................................................................................... 56 
6.2.3 Labeling ........................................................................................................... 57 
6.3 Drug Accountability................................................................................................ 58 
6.4 Drug Storage and Handling .................................................................................... 58 
6.5 MDMA Stability ..................................................................................................... 59 
7.0 Risks of Participation ............................................................................................... 59 
7.1 Risks and Discomforts Associated with Psychotherapy Sessions and Assessment of 
Measures ....................................................................................................................... 59 
7.2 Risks of Receiving MDMA .................................................................................... 60 
7.2.1 Safety Plan and Procedures for Participants Who Screen Positive for Suicidal 
ideation or Intent ....................................................................................................... 61 
7.2.2 Cardiovascular and Sympathomimetic Effects ................................................ 62 
7.2.3 Psychological Distress ..................................................................................... 63 
7.2.4 Body Temperature ........................................................................................... 65 
7.2.5 Reproductive and Developmental Risks .......................................................... 65 
7.2.6 Potential Neurotoxicity Associated with Ecstasy Use ..................................... 66 
7.2.7 Risk Mitigation ................................................................................................ 66 
7.3 Abuse Liability........................................................................................................ 66 
8.0 Adverse Events .......................................................................................................... 67 
8.1 Adverse Events ....................................................................................................... 67 
8.2 Spontaneously Reported Reactions......................................................................... 68 
8.3 Serious Adverse Events .......................................................................................... 68 
8.4 Medical Emergencies .............................................................................................. 69 
8.5 Adverse Event Collection ....................................................................................... 69 
9.0 Concomitant Medications and Tapering Instructions........................................... 70 
10.0 Clinical Laboratory Assessments .......................................................................... 72 
11.0 Study Monitoring, Auditing, and Documentation ............................................... 73 
12.0 Data Analysis ........................................................................................................... 74 
12.1 Statistical Power.................................................................................................... 75 
13.0 Ethics ........................................................................................................................ 75 
14.0 Informed Consent ................................................................................................... 75 
15.0 Confidentiality ......................................................................................................... 76 
16.0 Costs to Participants ............................................................................................... 77 
17.0 Treatment and Compensation for Study-Related Injury.................................... 77 
18.0 Record Retention .................................................................................................... 77 
19.0 Publication Policy.................................................................................................... 77 
20.0 References ................................................................................................................ 78 
 
 
 


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1.0 List of Abbreviations 
 
AE(s)  
Adverse Event(s) 
AED  
Automated External Defibrillator 
A:G 
 
Abumin : Globulin ratio 
ALT/SGPT 
Alanine aminotransferase 
AMI   
Acute Myocardial Infarction 
AST/SGOT 
Aspartate aminotransferase 
BDI-II  
Beck Depression Inventory II 
BP 
 
Blood Pressure 
BT 
 
Body Temperature 
BUN  
Blood Urea Nitrogen 
C 
 
Celsius 
CAPS  
Clinician Administered PTSD Scale for DSM-5 
CBCT  
Cognitive- Behavioral Conjoint Therapy 
CI 
 
Clinical Investigator (e.g. therapists, co-investigators) 
CPK 
 
Creatine Phosphokinase 
CRA  
Clinical Research Associate 
CRF(s) 
Case Report Form(s) 
CSI 
 
Couples Satisfaction Index 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTS-2  
Conflict Tactics and Aggression 
DBP 
 
Diastolic Blood Pressure 
DEA  
Drug Enforcement Administration 
DMF  
Drug Master File 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders - 5 
ECG/EKG 
Electrocardiogram 
ED 
 
Emergency Department 
EMDR  
Eye Movement Desensitization and Reprocessing 
EMS  
Emergency Medical Services 
ERQ  
Emotional Regulation Questionnaire 
F 
 
Fahrenheit 
FDA  
Food and Drug Administration  
GAF   
Global Assessment of Functioning 
GCP 
 
Good Clinical Practice 
HCl 
 
Hydrochloride 
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  
IPC 
 
Interpersonal Closeness Measure 
IPF 
 
Inventory of Psychosocial Functioning 
IR 
 
Independent Rater 
IRI 
 
Interpersonal Reactivity Index 
IRB 
 
Institutional Review Board 


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ISF 
 
Investigator Site File 
IV 
 
intra-venous 
LTFU  
Long-term Follow-up Questionnaire 
MAOI  
Monoamine oxidase inhibitor 
MAPS  
Multidisciplinary Association for Psychedelic Studies 
MCH  
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV   
Mean Corpuscular Volume  
MDI 
 
Multiscale Dissociation Inventory 
MDMA 
3,4-methylenedioxymethamphetamine 
MP-1  
MAPS’ first clinical trial of MDMA-assisted psychotherapy for PTSD 
MP-2  
MAPS’ second clinical trial of MDMA-assisted psychotherapy for PTSD 
MSIS  
Miller Social Intimacy Scale 
PCL 
 
Posttraumatic Symptom Checklist 
PI 
 
Principal Clinical Investigator 
PRN 
 
As needed 
PSQI  
Pittsburgh Sleep Quality Index 
PTCA   
Percutaneous Transluminal Coronary Angioplasty 
PTGI  
Posttraumatic Growth Inventory 
PTSD  
Posttraumatic Stress Disorder 
PTT 
 
Partial Thromboplastin Time 
QRI 
 
Quality of Relationships Inventory 
RBANS  
Repeatable Battery for the Assessment of Neuropsychological Status  
RBC  
Red Blood Cell Count 
RDW  
Red Cell Distribution Width 
RRPQ  
Reactions to Research Participation Questionnaire 
SAE(s) 
Serious Adverse Event(s) 
SBP 
 
Systolic Blood Pressure 
SCID-I-RV 
Structured Clinical Interview for Diagnoses Axis I Research Version 
SERT   
Serotonin Transporter 
SL 
 
Sublingual 
SNRI  
Selective Serotonin and Norepinephrine Uptake Inhibitor 
SOCQ  
States of Consciousness Questionnaire  
SOP(s)  
Standard Operating Procedure(s) 
SORTS 
Significant Others’ Responses to Trauma Scale 
SSRI  
Selective Serotonin Reuptake Inhibitor  
SUD   
Subjective Units of Distress 
TABS  
Trauma and Belief Attachment Scale 
TAS-20 
Toronto Alexithymia Scale 
TSH 
 
Thyroid Stimulating Hormones 
U.S. 
 
United States of America 
WBC   
White Blood Cell Count 
  
 
 


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1.1 List of Tables  
 
Table 1. Treatment Condition ........................................................................................... 20 
Table 2: Dose Selection .................................................................................................... 20 
Table 3: Time and Events ................................................................................................. 25 
Table 4: Study Measures ................................................................................................... 33 
Table 5. Schedule of Procedures for Experimental Sessions ............................................ 46 
Table 6. Treatment Condition ........................................................................................... 56 
Table 7. Medication Tapering Table ................................................................................. 71 
 
1.2 List of Figures  
 
Figure 1. Examples of Drug Labels .................................................................................. 57 
 
 
 
 


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2.0 Introduction, Background, and Rationale 
 
2.1 Introduction 
 
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit 
research and educational organization sponsoring clinical trials of MDMA-assisted 
psychotherapy in patients with chronic posttraumatic stress disorder (PTSD). This small 
pilot Phase 1/2 open-label experimental medicine study is the first study designed to 
explore the effectiveness of the combination of MDMA-assisted psychotherapy with an 
evidence-based PTSD psychotherapy treatment such as Cognitive- Behavioral Conjoint 
Therapy (CBCT) in treating individuals with chronic, treatment-resistant PTSD and a 
significant other experiencing associated psychological distress. This is exploratory and 
is not intended to lead to a registration study. 
 
MAPS has published results showing clinically and statistically significant improvements 
in PTSD severity from 20 participants treated in their first pilot study (MP-1) in the 
United States (U.S.) [23]. Findings from the long-term follow-up of MP-1 participants 
suggest that therapeutic benefits were sustained over an average of 41 months post-
treatment [24]. The sponsor’s second Phase 2 pilot study conducted in Switzerland (MP-
2) in 12 participants suggests clinically significant improvements in PTSD symptoms 
with a trend toward statistical significance and a similar effect size to the initial study 
[25]. Long-term follow-up data 12 months later suggest that therapeutic benefits 
continued to increase in this participant population. Ongoing Phase 2 studies, are laying 
the groundwork for an eventual End-of-Phase 2 meeting with FDA and possible Phase 3 
multi-site research studies with MDMA-assisted psychotherapy for chronic, treatment-
resistant PTSD.  
 
To date, there have been three case studies [26-28], three uncontrolled trials [29-31] and 
one randomized controlled trial [32] demonstrating the efficacy of CBCT for PTSD. 
Together, the results of these studies demonstrate that receiving CBCT for PTSD can 
result in significant and large effect size reductions in some individuals’ PTSD symptoms 
that are on par with, or better than, existing individual evidence-based PTSD treatments. 
  
In addition, the treatment has been shown to lead to improvements in intimate 
relationship functioning and significant improvements in intimate partners’ mental health 
[33, 34]. Research also suggests that CBCT for PTSD improves parenting satisfaction 
and efficacy among those with children [13], and that regardless of initial levels of 
intimate relationship functioning, individuals with PTSD profit from the treatment [35]. 
 
This is a Phase 1/2 open-label experimental medicine study in 10 dyads including a 
participant who has been diagnosed with PTSD for at least 6 months and a significant 
other participant (i.e., intimate or non-intimate person) who does not have a current 
diagnosis of PTSD and significant other experiencing associated psychological distress as 
assessed per the V-codes in the DSM-5. The dyad members will be referred to 
individually as the PTSD+ participant (diagnosed with PTSD) and the CSO Participant 
(concerned significant other). Eligible and enrolled participants will undergo a 2-month 
course of psychotherapy as a dyad that includes CBCT for PTSD integrated with 
MDMA-assisted psychotherapy. The CBCT sessions, as described in Monson and 


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Fredman’s (2012) manual [1] will be integrated with elements of the Treatment Manual 
for MDMA-assisted Psychotherapy in order to modify CBCT to incorporate MDMA as a 
catalyst for the therapeutic process [2]. The integration of these treatments will provide 
the researcher with a consistent psychotherapy approach and test an experimental form of 
drug-assisted psychotherapy. This study is designed to obtain estimates of effect size for 
safety and efficacy. This study is also intended to contribute to the development of a 
manualized psychotherapeutic approach to this potential treatment. Since this is the first 
time that CBCT is being combined with MDMA-assisted psychotherapy for PTSD, we 
are interested in gathering preliminary information about the blending of these two 
therapeutic approaches.  
 
2.2 Background 
 
2.2.1 PTSD 
 
PTSD is a debilitating psychiatric disorder arising after a traumatic life event. PTSD 
severely reduces quality of life and may directly or indirectly lead to or exacerbate other 
psychiatric and medical problems. A complex biopsychosocial condition that also has 
negative effects on families, PTSD is characterized by a combination of three types of 
symptoms: hyperarousal (e.g. hypervigilance, anxiety and sleep disturbance), intrusive 
re-experiencing of traumatic experiences (e.g. intrusive memories, nightmares or 
flashbacks), and avoidance symptoms, (e.g. emotional numbing and withdrawal) [36, 37]. 
The DSM-5 criteria for PTSD include:  
 
a. Exposure to death, threatened death, actual or threated serious injury, or actual or 
threatened sexual violence 
b. Persistent re-experiencing of the event or aspects of the experience 
c. Persistent effortful avoidance of trauma-related stimuli after the event 
d. Negative alterations in cognition and mood that began or worsened after the event 
e. Trauma-related alterations in arousal and reactivity that began or worsened after 
the traumatic event 
f. Persistence of symptoms for more than one month 
g. Significant symptom-related distress or functional impairment 
 
The lifetime prevalence of PTSD in the U.S. general population is between 6% and 10% 
[38-42], but it is common in other countries as well [39, 43-46]. According to some 
estimates, PTSD appears to be less prevalent in the general population of Europe at 1.9% 
[47]. In U.S. soldiers returning from combat in the Iraq war, the incidence of PTSD is as 
high as 18% [48], and it is estimated that the number of service members returning home 
with PTSD will ultimately be between 75,000 and 225,000 [49]. In countries with 
endemic armed conflict, the incidence of PTSD in civilians is often far greater [50-52].  
 
PTSD is clearly a serious public health problem and contributes substantially to 
healthcare costs [37, 40, 41]. PTSD is typically a chronic illness [38, 53] associated with 
high rates of psychiatric and medical comorbidity, disability, suffering, and suicide [39-
42, 54]. People suffering from PTSD face challenges in relationships and work 
productivity [55]. Despite the sheer number of individuals suffering from PTSD and its 
devastating effects, questions remain concerning the best possible treatments [56]. Two 


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selective serotonin reuptake inhibitors (SSRI), sertraline and paroxetine, which are 
known to affect the serotonergic components of PTSD, are currently marketed as PTSD 
medications in the U.S. [57, 58]. In addition, SSRIs must be used every day in order to be 
effective for PTSD symptoms [59], and are associated with a high rate of discontinuation 
due to lack of tolerability caused by treatment-emergent side effects that may be under-
reported [60, 61]. 
  
A wider array of effective treatments is needed for PTSD. At least a third of PTSD 
patients fail to respond to established PTSD psychotherapies or do not respond in a 
clinically significant manner [62-64]. In the U.S. National Comorbidity Study, the 
median time to remission for PTSD was 36 months with treatment and 64 months without 
treatment. In both subgroups, more than a third of the patients still had symptoms several 
times per week after 10 years [46]. Forty to 60% of PTSD patients were found to be 
resistant to treatment in this study. In a comparison of two types of psychotherapy for 
women with PTSD after sexual assault in 2002, 47% of each treatment group still 
satisfied diagnostic criteria for PTSD based on high Clinician Administered PTSD Scale 
(CAPS) scores, and this was considered highly efficacious [65]. At least one study of 
paroxetine indicated that men with PTSD did not respond to this drug [38], and another 
randomized, double-blind study found no difference between sertraline and placebo in the 
treatment of PTSD [57]. These findings suggest that there is still a substantial need for 
innovative treatments for PTSD. 
 
Another treatment approach is to develop drugs and/or psychotherapeutic treatments that 
may indirectly decrease or eliminate the neurochemical pathologies underlying the 
chronic hyperarousal associated with PTSD. Cognitive behavioral therapies, particularly 
prolonged exposure and cognitive processing therapy, are considered among the most 
effective psychotherapies. Other methods such as psychodynamic therapy and eye 
movement desensitization and reprocessing (EMDR) have also proven to be effective in 
treating some symptoms of PTSD [37, 66], although some patients may need more than 
one type of treatment to reduce or resolve those symptoms [67]. A recent meta-analysis 
concluded that all “bona fide” psychotherapies, including those listed above, are similarly 
effective for PTSD [68]. In recent years, there has been a growing amount of research 
into drugs and other methods that may augment the effectiveness of psychotherapy for 
PTSD (see [69] for a review). Examples of this are virtual reality-assisted exposure 
therapy [70, 71]  and D-cycloserine-assisted psychotherapy [72]. MDMA-assisted 
psychotherapy is another such approach. 
 
2.2.2 MDMA 
 
MDMA is a ring-substituted phenylisopropylamine derivative invented by the Merck 
pharmaceutical company in 1912 [73, 74]. MDMA is a monoamine releaser that has its 
greatest effects on serotonin, followed by norepinephrine and dopamine [75-81]. MDMA 
is capable of inducing unique psychopharmacological effects, including: 
 
• Decreased feelings of fear 
• Increased feelings of wellbeing 
• Increased sociability and extroversion 
• Increased interpersonal trust 


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• Alert state of consciousness 
 
Early observers noted increased acceptance of self and others, increased tolerance of 
emotionally upsetting materials and the ability to address these issues without extreme 
disorientation or ego loss [21, 22, 82, 83]. In the U.S., MDMA was used as an adjunct to 
psychotherapy by a considerable number of psychiatrists and other therapists in the 
treatment of neuroses, relationship problems, and PTSD [21, 82, 84, 85] before it was 
placed in Schedule I in 1985 as a result of extensive non-medical use [20, 22, 86]. 
Placement in Schedule I prohibited it for use except in a federally approved research 
setting.  
 
Oxytocin is a neurohormone associated with pair bonding and social affiliation in 
mammals [87]. Oxytocin administration is associated with increased interpersonal trust 
and attenuated reactivity to threatening faces[88, 89], and some researchers have 
suggested a role for oxytocin in treating PTSD [90]. MDMA has been shown to elevate 
serum oxytocin in humans [91, 92]. Brain imaging after MDMA indicates less reactivity 
to angry facial expressions and greater reward in happy faces [93]. The effects of MDMA 
on oxytocin may increase empathy or compassion for self and others and decrease 
defensiveness. Findings from a recent imaging study suggests that MDMA can make 
recall of negative memories more tolerable [94], and other studies report increased 
interpersonal or social focus reflected in language use and a greater readiness to see 
others as empathetic and caring [95-97]. These factors taken together can provide the 
opportunity for a corrective emotional experience [82].  
 
In contrast to daily administrations of SSRIs, MDMA-assisted psychotherapy consists of 
several drug-assisted sessions interspersed with a moderate course of non-drug 
psychotherapy. Thus the effects of MDMA are distinct from and go well beyond those of 
anti-anxiety drugs such as benzodiazepines. Furthermore, there is no evidence that 
MDMA creates a physical dependency, as benzodiazepines do. Previous studies of 
polydrug users found a small percentage of people exhibit problematic use of “Ecstasy” 
(material represented as containing MDMA) [98, 99]. Studies of regular or problematic 
users indicate that on average, regular use occurs no more often than once a week [100]. 
Hence, MDMA may have moderate abuse potential. See the Investigator’s Brochure (IB) 
for a more detailed explanation. 
 
2.2.3 Previous Clinical Experience with MDMA 
 
Classification as a Schedule I drug hampered research into the medical uses of MDMA. 
In recent years, clinical investigation of the safety and effectiveness of MDMA-assisted 
psychotherapy has become more feasible due to an open IND with the FDA [101-103]. 
The first double-blind, placebo controlled U.S. Phase 1 study sanctioned by the FDA was 
conducted in 1994, with findings that suggested MDMA caused a significant increase in 
body temperature and heart rate in some healthy volunteers [12]. However, these 
increases were found to be transient and generally tolerable in a controlled clinical setting 
[12]. Subsequent trials confirmed that MDMA produced significant increases in heart rate 
and blood pressure that were likely to be well tolerated by healthy individuals [10-13, 91, 
104, 105] [74, 87-92]. The noted elevation in body temperature was not clinically 
significant [23].   


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The potentially therapeutic effects of MDMA were initially investigated starting in 2000 
in a MAPS-sponsored dose response pilot study in Spain in women survivors of sexual 
assault with treatment-resistant PTSD [106, 107]. Unfortunately, the study in Spain was 
halted in 2002 due to political pressure from the Madrid Anti-Drug Authority. Prior to its 
suspension, six women were enrolled and treated in this study without any adverse events 
(AEs) or signs of deteriorating mental health, and with some mild signs of improvement, 
with single doses ranging from 50 mg to 75 mg [107] [94].  
 
MAPS went on to sponsor the first U.S. Phase 2 study of MDMA-assisted psychotherapy 
for the treatment of chronic, treatment resistant PTSD, designated as MP-1. This study 
employed the CAPS as a primary outcome measure, with PTSD symptoms measured by a 
blinded Independent Rater (IR) at Baseline, three to five days after each Experimental 
Session, and two months after the final Experimental Session. Data from this 
randomized, placebo-controlled pilot study suggests that MDMA is associated with 
significantly greater improvement in PTSD than placebo (N=20), with a large effect size  
[23]. Findings from the long-term follow-up evaluating these participants at an average of 
41 months post-treatment suggests that the therapeutic benefits have been sustained over 
time on average, although two participants experienced a relapse in PTSD symptoms 
[24]. The sponsor also supported a randomized, double-blind pilot study in 12 
participants with chronic, treatment-resistant PTSD in Switzerland with three 
Experimental Sessions. The study results suggested a trend toward significant 
improvement in participants receiving full dose MDMA, when compared to 25 mg active 
placebo MDMA at two-month follow-up, with an effect size similar to the first study. 
The improvement continued to increase during the 12-month follow-up [25]. In addition, 
the sponsor supported an initial pilot study with two Experimental Sessions comparing 
full dose to 25 mg active placebo MDMA in Israel that enrolled five participants, with no 
drug-related Serious Adverse Events (SAEs). Participants reported benefits that were not 
reflected in CAPS scores, leading to termination of the study for additional training of the 
Israeli therapists and research team. Most recently, in the U.S., MAPS has completed 
treatments in a follow-up to its initial U.S. trial with a PTSD relapse study, along with a 
second Phase 2 trial, specifically treating U.S. military veterans, firefighters, and police 
officers.  
 
As of December 2015, MDMA has been administered to more than 1185 research 
participants, in both Phase 1 and Phase 2 studies, without any published or reported 
occurrences of unexpected drug-related SAEs [11, 23, 25, 80, 93, 94, 96, 108-130].  
 
2.2.4 MDMA-assisted Psychotherapy and CBCT for PTSD 
 
In the context of psychotherapy, MDMA has been noted to reduce defenses and fear of 
emotional injury while enhancing communication and capacity for introspection [20]. 
MDMA-assisted psychotherapy is an innovative mode of treatment that combines 
psychotherapeutic techniques with the administration of MDMA, a pharmacological 
adjunct that may enhance or amplify certain aspects of psychotherapy. MDMA possesses 
unique pharmacological properties that may make it especially well suited to use as an 
adjunct to psychotherapy in PTSD patients [91, 93, 97, 108, 112, 131, 132].  
 


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Treatment goals of MDMA-assisted psychotherapy for PTSD include alleviating 
symptoms, interrupting and counteracting the stress-induced neurobiological 
abnormalities that may be associated with the condition. In fact, the biologic and 
psychotherapeutic approaches overlap and reinforce each other. Knowledge about the 
connections between the neurobiological and therapeutic effects of MDMA is far from 
complete, but it has been observed that MDMA acutely decreases activity in the left 
amygdala [132], and attenuates amygdalar response to angry faces [93]. 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 [133-135]. The reduction in stress-induced activation of the amygdala 
may be supported and enhanced by interacting with the therapists during and after the 
MDMA experience. 
 
CBCT for PTSD is a three-phase, 15-session, manualized treatment [1] described with 
the acronym “R.E.S.U.M.E. Living” to convey the sequential treatment phases and to 
signify the recovery-focused nature of the therapy. The “R” and “E” (Rationale for 
treatment and Education about PTSD and relationships) capture the overall goals of 
Phase 1, which are to provide a rationale for treatment and to educate the couple about 
PTSD and associated interpersonal problems. The “S” and “U” (Satisfaction 
enhancement and Undermining avoidance) stand for the overall goals of Phase 2, which 
are to enhance relationship satisfaction and undermine avoidance that maintains PTSD 
and relationship issues. The “M” and “E” (Making meaning of the trauma and End of 
therapy) represent the overall goals of Phase 3, which are to make meaning of the 
traumatic event(s) and the end of therapy (but not the end of using the skills). Content 
from sessions 6 and 7 of Phase 2, and sessions 8 and 9 of Phase 3 of CBCT for PTSD 
will be completed in four phone or video-teleconferencing sessions during the two weeks 
between the Experimental Sessions. All of the CBCT Sessions are 75 minutes each and 
include within-session practice and out-of-session assignments to facilitate the couple’s 
skill acquisition outside of session. Each therapy team will have one therapist trained and 
experienced in MDMA assisted psychotherapy and one therapist trained and experienced 
in CBCT. Whenever possible both therapists will have had training in both methods. It is 
believed that MDMA holds great promise to catalyze the effects of CBCT for PTSD. 
Given the properties of MDMA, specifically in inducing empathy and interpersonal 
openness, these psychopharmacological effects are especially relevant to the purported 
mechanisms of CBCT for PTSD. 
 
This study will combine methods described in the Treatment Manual for conducting 
MDMA-assisted psychotherapy with methods from the CBCT for PTSD manual. The 
integration of these manuals will provide the researcher with a consistent psychotherapy 
approach and test an investigational form of drug-assisted psychotherapy. The MDMA 
assisted-psychotherapy manual is not intended to define all interactions that occur in the 
therapy. It provides a structure within which the therapy is expected to occur and allows 
individual therapist teams to include therapeutic interventions based on their own 
training, experience, intuition, and clinical judgment, provided the interventions are 
compatible with the tenor of the method and appropriate to the participants’ unfolding 
experience. The therapists will carefully work with both participants to establish a sense 
of safety, trust, and openness to create an environment supportive of healing.   
 


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A combined treatment of MDMA-assisted psychotherapy and CBCT may be especially 
useful for treating PTSD because MDMA can attenuate the fear response of a perceived 
threat to one’s emotional integrity and decrease defensiveness without blocking access to 
memories or preventing a deep and genuine experience of emotion [21-23, 107]. 
Elimination of these conditioned fear responses can lead to more open and comfortable 
communication about past traumatic events and greater access to information about them 
[82]. Participants are able to experience and express fear, anger, and grief with less 
likelihood of feeling overwhelmed by these emotions. MDMA seems to engender internal 
awareness that even painful feelings that arise are an important part of the therapeutic 
process. In addition, feelings of empathy, love, and deep appreciation often emerge, 
along with a clearer perspective of the trauma as a past event, a more accurate perspective 
about its significance and a heightened awareness of the support and safety that exists in 
the present. As a result, MDMA-assisted psychotherapy with CBCT may enable the 
participants to restructure their intrapsychic realities and develop a wider behavioral and 
emotional repertoire with which to respond to anxiogenic stimuli.  
 
MDMA-assisted psychotherapy integrated with CBCT may be able to improve 
psychosocial circumstances of the CSO participant as a potential secondary benefit, either 
indirectly through treatment of the PTSD+ participant or directly by improving the CSO 
participant’s perception of their own psychosocial circumstances. There are several 
important reasons to include significant others in PTSD treatment, and to treat them as 
clients versus “support persons”, in addition to the data supporting the efficacy of CBCT 
for PTSD noted above. First, four studies have been published showing that pre-treatment 
interpersonal functioning affects individual treatment outcomes [3-6]. These studies 
consistently document that poorer pre-treatment intimate relationship functioning and 
social support are associated with worse individual treatment outcomes for those 
receiving front-line individual treatments for PTSD. Second, loved ones of those with 
PTSD consistently document their own psychological distress, caregiver burden, and 
relationship distress associated with being in relation to someone with PTSD [7]. Thus, 
one cannot assume a psychologically healthy significant other to be participating in 
therapy with someone who is diagnosed with PTSD. Third, loved ones may engage in 
well-meaning behaviors, but in fact may exacerbate or at least maintain individual 
psychopathology. This phenomenon has been termed “partner accommodation” [8, 9], 
and has been shown to be associated with poorer outcomes for CBCT for PTSD. Fourth, 
in addition to interventions aimed at intrapsychic mechanisms, the communication and 
connection between loved ones is a target of intervention. MDMA is expected to 
facilitate this communication and connection, given MDMA’s purported mechanisms of 
action. For these reasons, CBCT for PTSD was developed to be a true interpersonal 
treatment for PTSD, and explains the choice to administer MDMA to both members of 
the dyad. 
 
A comprehensive review of MDMA research is included in the IB supplied by the 
sponsor. This document should be reviewed prior to initiating the protocol. 
 


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2.3 Protocol Purpose 
 
This is a Phase 1/2 open-label study in 10 dyads including a participant who has been 
diagnosed with PTSD for at least 6 months (PTSD+ participant) and a concerned 
significant other participant (i.e., intimate or non-intimate person) who does not have a 
current diagnosis of PTSD (CSO participant). Eligible and enrolled participants will 
undergo a 2-month course of psychotherapy as a dyad that includes CBCT for PTSD 
integrated with MDMA-assisted psychotherapy. The CBCT sessions will be integrated 
with elements of the Treatment Manual for MDMA-Assisted Psychotherapy in order to 
modify CBCT to incorporate MDMA as a catalyst for the therapeutic process. Separately, 
each treatment appears to be effective. The goal of this study and the continuing research 
program will be to explore whether the methods in combination will prove to be effective 
for treatment of chronic, treatment-resistant PTSD. 
 
Table 1. Treatment Condition 
Treatment Group 
1st Experimental Session Dose 
2nd Experimental Session Dose 
Active MDMA-assisted 
Psychotherapy  
(N=10 dyads) 
75 mg MDMA 
+ optional 37.5 mg supplement  
100 mg MDMA 
+ optional 50 mg supplement  
or  
75 mg MDMA 
+ optional 37.5 mg supplement 
 
2.4 Rationale of Dose Selection 
 
This study will assess the effects of psychotherapy sessions assisted by two therapeutic 
doses. The first experimental dose will use 75 mg of MDMA followed 1.5 to 2 hours later 
by an optional dose of 37.5 mg. During the second Experimental Session an initial dose 
of either 100 mg or 75 mg will be administered followed by an optional supplemental 
half-dose 1.5 to 2 hours after the initial MDMA dose. The default dose for the second 
session will be 100 mg (followed by an optional supplemental half-dose), however if, 
after discussion with the Clinical Investigators, each participant may be permitted to stay 
at 75 mg (followed by an optional supplemental half-dose) for the second session.   
 
Table 2: Dose Selection 
Initial  
MDMA Dose  
Optional Supplemental  
MDMA Dose  
Cumulative (Initial + Optional)  
MDMA Dose  
75 mg 
37.5 mg 
112.5 mg 
100 mg 
50 mg 
150 mg 
 
MDMA appears to temporarily reduce fear and increase interpersonal trust, without 
clouding the sensorium or inhibiting access to emotions. MDMA may catalyze 
therapeutic exposure by enhancing the ability to tolerate negative or threatening 
emotional states and allowing patients to stay emotionally engaged without being 
overwhelmed by the intense emotions surrounding their condition. 
 
The active dose of MDMA to be used in this study is similar to the full dose of 125mg 
followed by 62.5mg supplemental dose used in previous studies in the U.S., Switzerland, 
and Israel. Previous researchers have also used doses within this range [10-19]. Prior to 
the scheduling of MDMA, similar doses and regimens were used in psychotherapy [20-


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22]. The MDMA doses to be used in this study have been used in previous studies 
sponsored by MAPS.  
 
The initial active doses are 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.  
 
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 conjunction with CBCT on PTSD 
symptoms in PTSD+ participants and relationship functioning in both participants. 
 
3.1 Primary Objective 
 
The primary objective of the study is to assess changes in PTSD symptoms from baseline 
as measured by CAPS in PTSD+ participants at the Primary Endpoint. 
 
3.2 Secondary Objectives 
 
Secondary and exploratory objectives are to assess changes in the dyad’s relationship 
functioning at the Midpoint and Primary Endpoints, assess changes in self- and CSO 
participant-reported PTSD symptoms in the PTSD+ participant, and assess problems that 
often co-occur with PTSD, such as depression, sleep disturbances, maladaptive beliefs 
about self and others, and emotion regulation difficulties. 
 
• Assess changes in PTSD symptoms from baseline as measured by the CAPS in 
participants with chronic PTSD at Long-term Follow-up at 3 months and 6 
months. 
• Assess changes in self-reported PTSD symptoms from baseline as measured with 
the Posttraumatic Stress Disorder Checklist for the DSM-5 (PCL-5) at Baseline, at 
each Integrative Session, at the Midpoint, Primary Endpoint and Long-term 
Follow-up at 3 months and 6 months for both the PTSD+ participant and CSO 
participant (based on the (PTSD+ participant).  
• Assess changes in depression symptoms from baseline with the Beck Depression 
Inventory-II (BDI-II) at Baseline, Midpoint, the Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months for both participants.  
• Assess changes in self-reported sleep quality from baseline with the Pittsburgh 
Sleep Quality Index (PSQI) at Baseline, Midpoint, the Primary Endpoint, and 
Long-term Follow-up at 3 months and 6 months for both participants. 
• Assess changes in self-reported posttraumatic growth from baseline with the 
Posttraumatic Growth Inventory (PTGI) by the PTSD+ participant and CSO 
participant (based on the PTSD+ participant) at the Midpoint, the Primary 
Endpoint, and Long-term Follow-up at 3 months and 6 months. 
• Assess changes in psychological and physical aggression from baseline with the 


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Revised Conflict Tactics Scale (CTS-2) at the Midpoint, Primary Endpoint, and 
Long-term Follow-up at 3 months and 6 months for both participants. 
• Assess changes in emotional regulation from baseline with the Emotion 
Regulation Questionnaire (ERQ) at the Midpoint, Primary Endpoint, and Long-
term Follow-up at 3 months and 6 months for both participants. 
• Assess changes in compassion, empathy, and social functioning from baseline 
with the Interpersonal Reactivity Index (IRI) on the day after each Experimental 
Session, at Midpoint, Primary Endpoint, and Long-term Follow-up at 3 months 
and 6 months for both participants. 
• Assess changes in emotion recognition and alexithymia from baseline with the 
Toronto Alexithymia Scale-20 (TAS-20) at the Midpoint, Primary Endpoint, and 
Long-term Follow-up at 3 months and 6 months for both participants. 
• Assess changes in relationship satisfaction from baseline with the Quality of 
Relationships Inventory (QRI) at the Midpoint, Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months for both participants. 
• Assess changes in partner accommodation from baseline with the Significant 
Others’ Responses to Trauma Scale (SORTS) at the Midpoint, Primary Endpoint, 
and Long-term Follow-up at 3 months and 6 months for the CSO participant.  
• Assess changes in social intimacy from baseline with the Miller Social Intimacy 
Scale (MSIS) at the Midpoint, Primary Endpoint, and Long-term Follow-up at 3 
months and 6 months for both participants. 
• Assess changes in psychosocial functioning from baseline with the Inventory of 
Psychosocial Functioning (IPF) at the Midpoint, Primary Endpoint, and Long-
term Follow-up at 3 months and 6 months for both participants. 
• Assess changes in trauma-related beliefs from baseline with the Trauma and 
Attachment Beliefs Scale (TABS) at the Midpoint, Primary Endpoint, and Long-
term Follow-up at 3 months and 6 months for both participants. 
• Assess changes in dissociative symptomology from baseline with the Multiscale 
Dissociation Inventory (MDI) at the Midpoint, Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months for both participants. 
• Assess changes in interpersonal closeness from baseline with the Interpersonal 
Closeness Measure (IPC) during Experimental Sessions, at the Midpoint, Primary 
Endpoint, Long-term Follow-up at 3 months and 6 months for both participants. 
• Assess changes in couples satisfaction from baseline with the Couples 
Satisfaction Index (CSI) at the Midpoint, Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months for both participants if romantically 
involved.  
 
 
3.3 Process Objectives:   
 
The process objectives of the study are to assess reactions to research participation. 
 
• Assess participants’ reaction to research with the RRPQ at the Endpoint for both 
participants. 


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• Assess the process of participating in this study through a Long-term Follow-up 
Questionnaire (LTFU) at the Long-term Follow-up at 3 months and 6 months for 
both participants. 
 
3.4 Safety Objectives 
 
The safety objectives of the study are to monitor and assure safety of all participants 
during and after the Experimental Sessions by assessing physiological effects, 
psychological distress, SAEs, medical events, spontaneously reported reactions, and 
suicidal ideation and behavior. All of the objectives below will be assessed in both 
participants. 
 
• Suicidal ideation and behavior will be assessed with the Columbia Suicide 
Severity Rating Scale (C-SSRS) according to the Table 3: Time and Events. 
• During Experimental Sessions, Subjective Units of Distress (SUD) and vital signs 
including blood pressure, heart rate, and temperature will be collected. 
• Serious Adverse Events (SAEs) will be collected in both groups through Study 
Termination. All Adverse Events (AEs) will be collected on the day of drug 
administration through the Primary Endpoint and will be followed to resolution. 
• Any spontaneously reported reactions will be collected from the day of the 
Experimental Session through seven days after both Experimental Sessions. 
Reactions that have not resolved to the participants’ Baseline level of severity 
after seven days will be collected on the Adverse Event Report page until 
resolution.  
• Assess General Wellbeing (clinician-rated) at all visits and phone calls for both 
the participants. 
• AEs requiring medical attention will be collected through Study Termination. 
• 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. 
• Baseline medications and changes to psychiatric medications will be collected 
throughout the study. 
• Changes in pre-existing chronic pain and/or tinnitus symptoms will be collected 
throughout the study using a Visual Analog Scale in any members of the dyad 
reporting these symptoms. 
 
4.0 Protocol Design 
 
This is a Phase 1/2 open-label study in 10 dyads including a participant who has been 
diagnosed with PTSD for at least 6 months (PTSD+ participant) and a CSO participant 
(i.e., intimate or non-intimate person who does not have a current diagnosis of PTSD). At 
screening, both members of the dyad will sign separate informed consents. Both must 
give written informed consent in order for the dyad to be enrolled. Dyads must consist of 


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people who are in a significant ongoing relationship, including but not limited to 
romantic relationships. Baseline screening procedures and assessments will be conducted 
for both members of the dyad. Dyads in which both members meet all Inclusion and no 
Exclusion Criteria will be enrolled. 
 
Eligible and enrolled participants will undergo a 2-month course of psychotherapy as a 
dyad that includes CBCT for PTSD integrated with MDMA-assisted psychotherapy. The 
CBCT sessions, as described in Monson and Fredman’s (2012) manual [1], will be 
integrated with elements of the Treatment Manual for MDMA-assisted Psychotherapy [2] 
in order to modify CBCT to incorporate MDMA as a catalyst for the therapeutic process. 
Sessions will be conducted by a co-therapy team and will include Preparatory Sessions, 
two Experimental Sessions of MDMA plus psychotherapy, and non-drug CBCT 
psychotherapy Integrative Sessions. The primary objective is to measure changes in 
PTSD symptoms via CAPS global severity scores in PTSD+ participants at Baseline and 
the Primary Endpoint, one month after the 15th CBCT session. Additional measures 
evaluate various qualities of the relationship between the participants. 
 
The Experimental Sessions will last 6 to 8 hours and will be scheduled 3 weeks apart, 
with an intervening course of non-drug therapy. The non-drug psychotherapy includes 
two Preparatory Sessions prior to the first Experimental Session and five Integrative 
Sessions after each Experimental Session. Integration visits will be conducted by 
telemedicine (video conferencing whenever possible, telephone if there are occasions 
when video conferencing is not technically possible) and will include both members of 
the dyad. The sessions will follow a combination of the MDMA-assisted psychotherapy 
manual and the CBCT manual, with each method modified as needed to combine the 
therapies. 
 
 


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Table 3: Time and Events 
 
Screen 
Preparatory 
Experimental Session 1, Integrative Sessions 
Midpoint 
Experimental Session 2, Integrative Sessions 
Primary 
Assess 
3 Mo 
LTFU 
6 Mo 
LTFU  
Visit # 
Pre-Study 
V 1 
V 2 
V3 
V 4 
V 5 
V6 
V 7 
V 8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
Type of Session 
Screening 
Prep 
Prep 
Exp 
Int 
Int 
Int 
Int 
Int 
Assess 
/Prep 
Exp 
Int 
Int 
Int 
Int 
Int 
Outcome 
Assess 
Assess 
Visit Format 
Telemed or Visit 
Telemed 
Visit 
Visit  
(overnight) 
Visit 
Telemed Telemed Telemed Telemed 
Visit 
Visit  
(overnight) 
Visit 
Telemed Telemed Telemed Telemed Telemed Telemed 
Telemed 
Visit Timing Window 
>1 day, month prior 
to Visit 1 
≤ 1 Mo 
before V2J 
Day 0 
Day 1 
Day2 
4 visits  
over 3 weeks between V3 and V10 
~3 weeks 
post V3; 
prior to 
V10 
~3 weeks 
post V3 
1 day 
post 
V10 
 4 visits  
over 4 weeks between V10 and V15 
 
1 Mo 
post V15 
3 Mo post 
V15 
6 Mo post 
V15 
CBCT Manual Session # 
 
 
1, 2, 3 
4, 5 – 
Condensed 
delivery just 
after MDMA 
administration 
Review 
6 
7 
8 
9 
10, 11 
 
 
 Review  
Review 
12 
13 
14 
15 
 
 
 
Initial Phone Screen  
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric History (Medical Record Review) 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Phys. Exam (BP, Pulse, Temp) 
✓A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief Neurological Exam 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-RV 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Lab Tests, w/ HIV, HCV test 
✓A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Medication Taper (if applicable) 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Enrollment after meeting I/E 
 
✓ 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record to Audio/Video 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Drug Screen 
✓A 
 
 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
Pregnancy Screen (if applicable) 
✓A 
 
 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
Administer IP Drug + Therapy/CBCT 
 
 
 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
Integrative Session 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
Issue Out of Session Assignments 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
7 days of Telephone Contact 
 
 
 
 
✓ G 
✓ G 
✓ G 
 
 
 
 
✓ G 
✓ G 
✓ G 
 
 
 
 
 
CAPSI 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
✓ 
✓ 
PCL individual and participant  
✓ 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
BDI-II 
✓ 
 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
✓ 
✓ 
✓ 
IRI 
✓ 
 
 
 
✓ 
 
 
 
 
✓ 
 
✓ 
 
 
 
 
✓ 
✓ 
✓ 
General Wellbeing 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
TAS-20, QRI, SORTS, CTS-2, IPF, MSIS, TABS, 
MDI, ERQ, PSQI, PTGI, CSI 
✓ 
 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
✓ 
✓ 
✓ 
LTFU Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
✓ 
IPC 
✓ 
 
 
✓C 
 
 
 
 
 
✓ 
✓C 
 
 
 
 
 
✓ 
✓ 
✓ 
RRPQ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
 
 
Vitals (Monitoring of BP, Pulse and Temp) 
 
 
 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
Changes in Tinnitus and/or Pain H 
✓ 
✓ D 
✓ D 
✓ D 
✓ D 
✓ D 
✓ D 
✓ D 
✓ D 
✓ 
✓ D 
✓ D 
✓ D 
✓ D 
✓ D 
✓ D 
✓ 
✓ 
✓ 
Subjective Units of Distress 
 
 
 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
C-SSRS 
✓ 
 
✓F 
✓B, C, D 
✓ 
 
 
 
 
✓ 
✓B, C, D 
✓ 
 
 
 
 
✓ 
✓ 
✓ 
SAEs, AEs of psychiatric status or withdrawal 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
AEs Requiring Medical Attention 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Spontaneously Reported Reactions  
 
 
 
✓ 
✓ 
✓ 
✓ 
 
 
 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
 
All AEs 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
A = Performed locally.  
B = At the beginning of the session.  
C = Approximately 6 hours after administration of MDMA.  
D = As needed.  
E = Approximately every 60 minutes.  
F = Given after medication washout.  
G = For 7 days after Experimental Session, contact will be made by phone or telemedicine and not both, C-SSRS D2 and D7 of calls only, General Wellbeing for all 7 days.  
H = Only in participants with pre-existing chronic pain or tinnitus.  
I = CAPS may be recorded to video.  
J = Additional time allowed if necessary for medication tapering. 


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4.1 Planned Duration of Study and Visit Windows 
 
The active part of the study will take about 2 months for the dyads to complete. There are 
additional remote follow-up visits, 3 months and 6 months after the primary assessment. 
Total study participation will last about 8 months.  
 
Screening may take place over a 1-month period; final confirmation of enrollment may 
be combined with the first Preparatory Session. Additional time between the first and 
second Preparatory Session will be allowed if necessary for medication tapering. For 
example, the maximum washout would be seven weeks for participants tapering off of 
fluoxetine plus one week for stabilization. Enrolled dyads will immediately enter the 
Active Group (N=10). Dyads will participate in two Preparatory Sessions, two day-long 
Experimental Sessions with MDMA-facilitated CBCT sessions, and Integrative Sessions 
following each Experimental Session in conjunction with CBCT.    
 
The Experimental Sessions will last 6 to 8 hours and will be scheduled 3 weeks apart, 
with an intervening course of non-drug therapy. The non-drug psychotherapy includes 
two Preparatory Sessions prior to the first Experimental Session and five Integrative 
Sessions after each Experimental Session. Integrative Sessions will be conducted by 
telemedicine (video conferencing whenever possible, telephone if there are occasions 
when video conferencing is not technically possible) and will include both members of 
the dyad. The sessions will follow a combination of the MDMA-assisted psychotherapy 
manual and the CBCT manual, with each method modified as needed to combine the 
therapies. Any delay between visits would result in a corresponding extension of study 
duration. 
 
4.2 Recruitment and Participant Population 
 
Participants may be persons aged 18 or older, including a PTSD+ participant who has 
been diagnosed with PTSD for at least 6 months and a CSO participant (i.e., intimate or 
non-intimate person) who does not have a current diagnosis of PTSD but is experiencing 
associated psychological distress as assessed by V-codes in the DSM-5. There is no upper 
age limit designated in this protocol as age alone does not put participants at increased 
risk and is a less specific exclusion criterion when compared with direct assessment of 
general health.  Participants with medical conditions that would have contraindications to 
receiving MDMA would be excluded according to the Inclusion and Exclusion Criteria. 
Participants with a history of suicide attempts will not be excluded unless risk of suicidal 
behavior is present at the time of the screening assessment.  All participants will be 
evaluated by the CI to determine if there is a current risk of suicidal behavior.  
Participants will be enrolled according to the Inclusion and Exclusion Criteria based on 
the clinical judgment of the CI.  
 
The dyad members will be referred to individually as the PTSD+ participant and the CSO 
participant. PTSD+ participants would not be excluded for having more than one 
traumatic event. PTSD+ participants must have a last month CAPS score indicating at 
least moderate PTSD symptoms and must meet all Inclusion Criteria and no Exclusion 
Criteria at Baseline. CSO participants must also meet Inclusion Criteria and no Exclusion 
Criteria. Both participants must be in good physical health and without major medical 


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disorders that might affect the safety or tolerability of MDMA. Dyads will be recruited 
through printed ads, Internet ads, referrals from other psychiatrists, psychotherapists, or 
physicians, and through word of mouth. Recruitment will continue until 10 dyads that 
meet all Inclusion Criteria without meeting any Exclusion Criteria are enrolled. Only 
IRB-approved recruitment materials and advertisements will be used for the study. 
 
4.2.1 Inclusion Criteria 
 
Inclusion Criteria for Participants with PTSD 
Individuals eligible to be enrolled into this protocol are participants who:  
 
1. Meet DSM-5 criteria for current PTSD with a duration of 6 months or longer  
2. Satisfies diagnostic criteria for PTSD using the CAPS  
3. Are at least 18 years old 
4. If in ongoing psychotherapy at the time participants 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 Clinical Investigators to 
communicate directly with their therapist. Participants may not change therapists, 
increase the frequency of therapy, or commence any new type of therapy until 
after the evaluation session, 3 months after the final Experimental Session. 
Participants who do not live within reasonable driving distance of the study site 
(equal to or less than an estimated 2-hour drive from the study site) must be 
registered with a therapist or health clinic in the area in which they live so they 
can call for support and evaluation if necessary 
5. Are willing to refrain from taking any psychiatric medications during the study 
period, with the exception of gabapentin when prescribed for pain control. 
Individuals using opiates for pain management will be asked to decrease the dose 
or avoid taking their pain medication the morning of experimental sessions if 
possible. If the participant 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-assisted 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 
6. Agree that, for one week preceding the MDMA-assisted 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) 
7. Agree to take nothing by mouth except alcohol-free liquids after 12:00 A.M. 
(midnight) the evening before the Experimental Session 
8. Refrain from the use of any psychoactive drug, with the exception of caffeine or 
nicotine, within 24 hours of each MDMA-assisted session 
9. Agree not to use caffeine or nicotine for 2 hours before and 6 hours after the dose 


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of MDMA 
10. Are willing to be driven home the morning after the Experimental Sessions, after 
the Integrative Session, either by a driver arranged by the participant or by the site 
personnel or taxi and agree not to drive after each Experimental Session until the 
therapists deem it safe to do so 
11. Are willing to commit to medication dosing, Experimental Sessions, follow-up 
sessions, to complete evaluation instruments and commit to be contacted for all 
necessary telephone contacts 
12. Are willing to remain overnight at the study site after each Experimental Session 
until after the Integrative Session occurring the next morning 
13. Must have a negative pregnancy test at study entry and prior to each Experimental 
Session if able to bear children, and must agree to use adequate birth control 
through 10 days after the last dose of MDMA. Adequate birth control methods 
include intrauterine device (IUD), injected or implanted hormonal methods, 
abstinence, oral hormones plus a barrier contraception or double barrier 
contraception. Two forms of contraception are required with any barrier method 
or oral hormones (i.e. condom + diaphragm, condom or diaphragm + spermicide, 
oral hormonal contraceptives + spermicide or condom). Not of childbearing 
potential is defined as permanent sterilization, postmenopausal, or lacking a 
uterus. 
14. Must provide a contact (relative, spouse, close friend or other caregiver other than 
the CSO participant) who is willing and able to be reached by the Clinical 
Investigators in the event of a participant becoming suicidal.  
15. Must agree to inform the Clinical Investigators within 48 hours of any medical 
conditions and procedures 
16. Are proficient in speaking and reading English 
17. Agree to have all clinic visit and Integrative Sessions recorded to audio and video 
18. Agree to not participate in any other interventional clinical trials during the 
duration of this study 
 
Inclusion Criteria for Dyad Participant 
Individuals eligible to be enrolled into this protocol are participants who:  
 
1. Are at least 18 years old 
2. Meet criteria for V62.89 Other Problem Related to Psychosocial Circumstances 
under DSM-5, as determined through clinical interview, for current psychosocial 
circumstances contributing to relationship distress with intimate or non-intimate 
partner 
3. If in ongoing psychotherapy at the time participants 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 Clinical Investigators to 
communicate directly with their therapist. Participants may not change therapists, 
increase the frequency of therapy, or commence any new type of therapy until 
after the evaluation session 3 months after the final Experimental Session. 
Participants who do not live within reasonable driving distance of the study site 
(equal to or less than an estimated 2-hour 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 


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4. Are willing to refrain from taking any psychiatric medications during the study 
period, with the exception of gabapentin when prescribed for pain control. 
Individuals using opiates for pain management will be asked to decrease the dose 
or avoid taking their pain medication the morning of Experimental Sessions if 
possible. If the participant 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-assisted 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 
5. Agree that, for one week preceding the MDMA-assisted 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) 
6. Agree to take nothing by mouth except alcohol-free liquids after 12:00 A.M. 
(midnight) the evening before the Experimental Session 
7. Refrain from the use of any psychoactive drug, with the exception of caffeine or 
nicotine, within 24 hours of each MDMA-assisted session 
8. Agree not to use caffeine or nicotine for 2 hours before and 6 hours after the dose 
of MDMA 
9. Are willing to be driven home the morning after the Experimental Sessions, after 
the Integrative Session, either by a driver arranged by the participant or by the site 
personnel or taxi and agree not to drive after each Experimental Session until the 
therapists deem it safe to do so 
10. Are willing to commit to medication dosing, Experimental Sessions, follow-up 
sessions, to complete evaluation instruments and commit to be contacted for all 
necessary telephone contacts 
11. Are willing to remain overnight at the study site after each Experimental Session 
until after the Integrative Session occurring the next morning 
12. Must have a negative pregnancy test at study entry and prior to each Experimental 
Session if able to bear children, and must agree to use adequate birth control 
through 10 days after the last dose of MDMA. Adequate birth control methods 
include intrauterine device (IUD), injected or implanted hormonal methods, 
abstinence, oral hormones plus a barrier contraception or double barrier 
contraception. Two forms of contraception are required with any barrier method 
or oral hormones (i.e. condom + diaphragm, condom or diaphragm + spermicide, 
oral hormonal contraceptives + spermicide or condom). Not of childbearing 
potential is defined as permanent sterilization, postmenopausal, or lacking a 
uterus. 
13. Must provide a contact (relative, spouse, close friend or other caregiver other than 
the participant with PTSD) who is willing and able to be reached by the Clinical 
Investigators in the event of a participant becoming suicidal.  
14. Must agree to inform the Clinical Investigators within 48 hours of any medical 


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conditions and procedures 
15. Are proficient in speaking and reading English 
16. Agree to have all clinic visit sessions recorded to audio and video 
17. Agree to not participate in any other interventional clinical trials during the 
duration of this study 
 
4.2.2 Exclusion Criteria 
 
Exclusion Criteria for Participants with PTSD 
Individuals not eligible to be enrolled into this protocol are those who: 
 
1. Are pregnant or nursing, or are persons of childbearing 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 significant (controlled or uncontrolled) 
hematological, endocrine, cerebrovascular, cardiovascular, coronary, pulmonary, 
renal, gastrointestinal, immunocompromising, or neurological disease, including 
seizure disorder, or any other medical disorder judged by the investigator to 
significantly increase the risk of MDMA administration (participants with 
hypothyroidism who are on adequate and stable thyroid replacement will not be 
excluded);  
If participants present with a history of glaucoma, enrollment would be allowed 
only with the approval of their ophthalmologist.  
 
4. Have hypertension using the standard criteria of the American Heart Association 
(values of 140/90 or higher assessed on three separate occasions  
5. Have liver disease with the exception of asymptomatic participants with Hepatitis 
C who have previously undergone evaluation and successful treatment 
6. Have history of hyponatremia or hyperthermia 
7. Weigh less than 48 kg   
8. Any participant presenting current serious suicide risk, as determined through 
psychiatric interview, responses to C-SSRS, and clinical judgment of the Clinical 
Investigator will be excluded, however past history of suicide attempts is not an 
exclusion. In addition, any participant who is likely to require hospitalization 
related to suicidal ideation and behavior, in the judgment of the Clinical 
Investigator, will not be enrolled 
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 10 
times within the last 10 years or at least once within 6 months of the MDMA-
assisted session 
11. Require ongoing concomitant therapy with a psychiatric drug, excluding 
gabapentin and opiates for pain management 
12. Meet DSM-5 criteria for active substance use disorder for any substance save 
caffeine or nicotine in the past 60 days 
13. Are not able to give adequate informed consent 


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14. Have any current problem or a history of substance abuse which, in the opinion of 
the Clinical Investigator or Medical Monitor, might interfere with participation in 
the protocol 
15. Have a current eating disorder with active purging 
16. Have current major depressive disorder with psychotic features 
17. Have current Personality Disorders Cluster A (paranoid, schizoid, schizotypical), 
Cluster B (antisocial, borderline, histrionic, narcissistic) or Cluster C (avoidant, 
dependent, obsessive-compulsive) 
 
 
Exclusion Criteria for Dyad Participant 
Individuals not eligible to be enrolled into this protocol are those who: 
 
1. Are pregnant or nursing, or are persons of childbearing 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 significant (controlled or uncontrolled) 
hematological, endocrine, cerebrovascular, cardiovascular, coronary, pulmonary, 
renal, gastrointestinal, immunocompromising, or neurological disease, including 
seizure disorder, or any other medical disorder judged by the investigator to 
significantly increase the risk of MDMA administration (Participants with 
hypothyroidism who are on adequate and stable thyroid replacement will not be 
excluded);  
If participants present with a history of glaucoma, enrollment would be allowed 
only with the approval of their ophthalmologist.  
 
4. Have hypertension using the standard criteria of the American Heart Association 
(values of 140/90 or higher assessed on three separate occasions  
5. Have liver disease with the exception of asymptomatic participants with Hepatitis 
C who have undergone additional evaluation (see “Methods”). Participants 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. Any participant presenting current serious suicide risk, as determined through 
psychiatric interview, responses to C-SSRS, and clinical judgment of the Clinical 
Investigator will be excluded, however past history of suicide attempts is not an 
exclusion. In addition, any participant who is likely to require hospitalization 
related to suicidal ideation and behavior, in the judgment of the Clinical 
Investigator, will not be enrolled 
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 10 
times within the last 10 years or at least once within 6 months of the MDMA-
assisted session 
11. Require ongoing concomitant therapy with a psychiatric drug, excluding 


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gabapentin and opiates for pain management 
12. Meet DSM-5 criteria for active substance use disorder 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 Clinical Investigator or Medical Monitor, might interfere with participation in 
the protocol 
15. Have diagnosis of current PTSD not in remission 
16. Have a current eating disorder with active purging 
17. Have current major depressive disorder with psychotic features 
18. Have current Personality Disorders Cluster A (paranoid, schizoid, schizotypical), 
Cluster B (antisocial, borderline, histrionic, narcissistic) or Cluster C (avoidant, 
dependent, obsessive-compulsive) 
 
5.0 Methods 
 
5.1 Measures 
 
The following outcome, safety, and process measures will be used in the study. This 
study will utilize methods described in the Treatment Manual for conducting MDMA-
assisted Psychotherapy combined with methods from the CBCT for PTSD manual. The 
integration of these manuals will provide the researcher with a consistent psychotherapy 
approach and test an investigational form of drug-assisted psychotherapy. The Treatment 
Manual is not intended to define all interactions that occur in the therapy. All 
psychotherapy sessions, including Experimental Sessions, may be recorded to audio and 
video, with all recordings preserved for research and training purposes.  


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Table 4: Study Measures 
Measure 
Purpose 
Administration 
Time/ 
# of 
items 
When                 
PTSD+ 
Participant 
CSO 
Participant 
Screening, Inclusion & Exclusion 
 
 
 
 
 
 
SCID for DSM-5- AXIS 1 only and then 
screening question for AXIS 2 modules (do 
modules if needed) 
Screening 
Interview 
60 
minutes 
Baseline 
Y 
Y 
Primary & Secondary Outcomes 
 
 
 
 
 
 
CAPS-5 
Clinician Administered PTSD Scale for DSM-5 
PTSD Severity  
Interview        
90 
minutes  
Baseline, Endpoint, 
LTFU 3, 6 
Y 
N 
PCL (last month) 
PTSD Checklist for DSM-5 
 
PTSD symptoms 
Self-report 
10-15 
minutes 
Baseline (with LEC), 
Endpoint, LTFU 3, 6 
Y 
Y  
(PCL-
Participant) 
PCL (since last visit) 
PTSD Checklist for DSM-5 
 
PTSD symptoms 
Self-report 
10-15 
minutes 
Integrative Sessions, 
Midpoint 
Y 
Y  
(PCL-
Participant) 
PCL (since last week) 
PTSD Checklist for DSM-5 
PTSD symptoms 
Self-report 
10-15 
minutes 
Visit 2 
Y 
Y  
(PCL-
Participant) 
BDI-II 
Beck Depression Inventory 
Depression 
Symptoms 
Self-report 
5-10 
minutes 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6 
Y 
Y 
ERQ 
Emotional Regulation Questionnaire 
Emotion 
regulation 
Self-report 
4-6 
minutes 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6 
Y 
Y 
IRI 
Interpersonal Reactivity Index 
Compassion 
empathy, social 
functioning 
Self-report 
10 
minutes 
Baseline, Day after 
Experimental Sessions, 
Midpoint, Endpoint, 
LTFU 3, 6 
Y 
Y 
PSQI 
Pittsburg Sleep Quality Index 
Sleep Quality 
Self-report 
5-10 
minutes 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6 
Y 
Y 
PTGI 
Post Traumatic Growth Inventory 
Growth after 
Trauma 
Self-report 
5-10 
minutes 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6 
Y 
Modified for 
participant. 
Participant will 
rate the PTSD 
participant. Y 
TAS-20 
Toronto Alexithymia Scale 
Emotion 
recognition, 
alexithymia 
Self-report 
5 
minutes 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6 
Y 
Y 
QRI 
Quality of Relationships Inventory 
Relationship 
Satisfaction  
Self-report      
32  
items 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6 
Y 
Y 


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Measure 
Purpose 
Administration 
Time/ 
# of 
items 
When                 
PTSD+ 
Participant 
CSO 
Participant 
SORTS 
Significant Others’ Responses to Trauma Scale 
Partner 
Accommodation 
Self-report 
40  
items 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6 
Y 
CTS-2 (edited) 
Severe Items of the psychological and physical 
aggression subscales 
 
Conflict Tactics 
and Aggression 
Self-report 
14 items 
severe, 
40 items 
for two 
subscales 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6  
Y 
Y 
IPF 
Inventory of Psychosocial Functioning 
Psychosocial 
Functioning 
Self-report 
80 items 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6 
Y 
Y 
MSIS 
Miller Social Intimacy Scale 
Social Intimacy 
Self-report 
17 items 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6 
Y 
Y 
TABS 
The Trauma and Attachment Beliefs Scale 
Trauma-related 
beliefs 
Self-report 
15 items 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6 
Y 
Y (modify for 
participant) 
MDI 
Multiscale Dissociation Inventory 
Dissociation 
Symptomology 
Self-report 
30  
items, 
10-15 
minutes 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6 
Y 
Y 
IPC 
Interpersonal Closeness Measure 
Interpersonal 
closeness 
Self-report 
2-4 
minutes 
Baseline, During 
Experimental Sessions, 
Midpoint, Endpoint, 
LTFU 3, 6  
Y 
Y 
CSI 
Couples Satisfaction Index 
(Romantic couples only) 
Couples 
satisfaction 
Self-report 
32 items 
5 
minutes 
Baseline, Midpoint, 
Endpoint, LTFU 3, 6 
Y 
Y 
Process Measures 
 
 
 
 
 
 
RRPQ 
Reactions to Research Participation 
Questionnaire 
Process 
Self-report 
10 
minutes 
Endpoint 
Y 
Y 
Long-term Follow-up Questionnaire 
Process, 
Outcome, Safety 
Self-Report 
10-20 
minutes 
LTFU 3, 6  
Y 
Y (modify for 
participant) 
Safety Measures 
 
 
 
 
 
 
Vitals (blood pressure, pulse, body temperature) 
Safety 
Medical 
Monitor 
--- 
During Experimental 
Sessions 
Y 
Y 
Somatic Symptoms 
Outcome, Safety 
Self-report 
1-2 
minutes 
Baseline, throughout 
study (as needed), 
LTFU 3, 6 
Y 
Y 
SUD 
Subjective Units of Distress 
Outcome, Safety 
Self-report 
1  
minute 
During Experimental 
Sessions 
Y 
Y 


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Measure 
Purpose 
Administration 
Time/ 
# of 
items 
When                 
PTSD+ 
Participant 
CSO 
Participant 
C-SSRS 
Columbia Suicide Severity Ratings Scale 
Suicidal ideation 
and behavior 
Clinician-
administered 
5-20 
minutes 
All in-person visits, on 
Day2 and Day7 phone 
contact days after 
Experimental Sessions, 
Endpoint, LTFU 3, 6 
Y 
Y 
General Wellbeing 
General 
Wellbeing 
Clinician-rated 
1-item  
All visits and phone 
calls 
Y 
Y 
Baseline = During 1-month screening period prior to enrollment day. 
Midpoint = 2 weeks after 1st Experimental Session. 
Primary Endpoint = 1 month post Visit 15. 
LTFU 3, 6 = 3 months and 6 months after Visit 15. 
 
 
 
 
 
 
 


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5.1.1 Outcome Measures 
 
The primary measure will be change in CAPS scores from Baseline to Primary Endpoint. 
A qualified, blinded IR will perform the CAPS at Baseline and outcome measurement 
time points. The IR will not be present during the participant’s Experimental Sessions nor 
have any information regarding the Experimental Sessions. CAPS-5 [136] is a semi-
structured clinical interview used to assess index history of DSM-5-defined traumatic 
event exposure [36], including the most distressing event, time since exposure, and total 
number of exposures, as well as frequency and severity of posttraumatic stress symptoms, 
as evidenced by CAPS total score. The CAPS provides diagnostic status (presence versus 
absence) of PTSD as well as PTSD symptom severity. Changes in the CAPS total score 
will be used as the primary PTSD outcome measure, and will be the primary determinant 
of effect size for this pilot study. All assessments, including those at Baseline, will use 
the CAPS assessment of symptoms over the last month. The IR will administer the CAPS 
at visits described in Table 3: Time and Events either in person or via telemedicine. 
Studies for validation of this measure are ongoing. 
 
The secondary measure of PTSD symptoms will be the PCL (reported for last month, 
since last visit, and since last week per Table 4), a self-report measure designed to follow 
DSM-5 criteria for assessing PTSD. The PTSD Checklist (PCL-5) [137] is a 20-item self-
report questionnaire in which respondents indicate the presence and severity of PTSD 
symptoms, derived from the DSM-5 symptoms of PTSD [36]. Participants indicate how 
much distress they have experienced due to symptoms such as “Repeated, disturbing 
memories, thoughts, or images of a stressful experience from the past,” “Trouble 
remembering important parts of a stressful experience from the past,” and “Feeling 
irritable or having angry outbursts” on a five-point Likert-type scale (1 = not at all, 5 = 
extremely). The total PCL-5 score (a sum of all 20 items) provides an index of overall 
PTSD symptom severity. Reports on reliability and validation of the PCL-5 are 
underway; preliminary comparison with the PCL for DSM IV suggests that the cut-off 
for PCL-5 is 11 to 14 points lower than for the PCL [137]. Participants will complete the 
PCL-5 questionnaire, as specified in Table 3: Time and Events. The PTSD+ participant 
will complete it based on their own symptoms and the CSO participant will complete it 
based on the PTSD+ participant.  
 
The BDI-II is a 1996 revision of the BDI, a 21-item self-report measure [138, 139] that 
will serve as a measure of depression according to DSM-IV criteria [140]. The BDI-II 
has been validated, has high internal consistency and good test/re-test reliability, and is 
not overly sensitive to daily variations in mood. It takes five to ten minutes to complete 
[140]. Score cutoffs indicate: 0-13 minimal depression, 14-19 mild depression, 20-28 
moderate depression, and 29-63 severe depression. Initial and subsequent studies report 
that the BDI-II total score has a reliability coefficient of 0.90 to 0.91 and that it is related 
to other measures of depression symptoms [140, 141]. Higher scores indicate more severe 
depressive symptoms. Both the participants will complete the BDI-II according to Table 
3: Time and Events.  
 
The ERQ is a brief measure of self-reported emotion-regulation. It consists of ten items 
that is intended to assess means of coping with emotions via changing them, as through 
reappraisal, or suppressing them [142]. Respondents rate indicate the extent of their 


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agreement or disagreement with each item by selecting a point on a 7-point Likert scale, 
where 1= strongly disagree and 7 = strongly agree. The ERQ should take four to six 
minutes to complete. Specific items are summed to produce two separate scales, 
Reappraisal and Suppression. The measure is reliable, with Reappraisal obtaining a 
Cronbach’s alpha of 0.79 and Suppression an alpha of 0.73, and test-retest reliability of 
0.69 [142], and scores on the ERQ are correlated with other measures of degree of 
emotional expressivity. The ERQ will be completed by both the PTSD+ participant and 
the CSO the participant according to Table 3: Time and Events. 
 
The IRI assesses four aspects of empathy: social functioning, self-esteem, emotionality, 
and sensitivity to others [143-145]. Empathy is not a discrete emotion. More accurately, 
empathy is a set of constructs. Therefore, the IRI accounts for the fact that each construct 
concerns an individual’s responses to the observed experiences of other people, yet each 
construct is distinctive from the others. The self-report questionnaire includes 28 items 
that are rated on a 5-point, Likert-type scale. The four 7-item subscales include two 
measures of cognitive empathy and two measures of affective empathy. The internal 
reliabilities for the four scales range from 0.71 to 0.77, and test-retest reliabilities range 
from 0.62 to 0.71 [143, 144]. The IRI will be completed by both the PTSD+ participant 
and the CSO participant, according to Table 3: Time and Events. 
 
The 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 [146]. 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 five indicative of good sleep. It takes five to 10 minutes to 
complete. Test-retest reliability ranges from 0.85 to 0.87, and it is internally consistent, 
with a Cronbach’s alpha of 0.83 [146, 147]. Global scores correlate with other measures 
of alertness and self-reported sleep quality [143]. The Pittsburgh Sleep Quality-PTSD 
Addendum [148] is a seven-item addendum for the PSQI that assesses disruptive 
nocturnal behavior specific to PTSD (e.g., hot flashes, nervousness, trauma nightmares). 
The PTSD+ participant will indicate the presence and severity of trauma-related sleep 
disturbances. Both the PTSD+ participant and the CSO participant will complete the 
PSQI according to Table 3: Time and Events. 
 
The 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 [149, 150]. 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. PTGI sub-scale scores are reliable, with reliability coefficients 
ranging from 0.83 to 0.90, and the scale scores were moderately related to each other 
[149, 151]. PTGI scores are corroborated by others’ assessments of posttraumatic growth, 
suggesting that the measure has convergent validity [152, 153]. Both the PTSD+ 
participant and the CSO participant will complete the PTGI according to Table 3: Time 
and Events. 


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The TAS-20 is a 20-item measure of self-reported difficulties with recognizing and 
verbalizing emotions [154, 155]. Responses are made on a 5-point Likert scale where 1 = 
strongly disagree and 5 = strongly agree. Estimated time of measurement is 5 to 10 
minutes. The scale is comprised of three subscales; Difficulty Describing Feelings, 
Difficulty Identifying Feelings and Externally-Oriented Thinking, with all scales summed 
to create a total score reflecting presence and degree of alexithymia. The TAS-20 can be 
used diagnostically with a score of 61 or higher indicative of alexithymia. The TAS-20 is 
reliable and has good test-retest reliability (Cronbach’s alpha = 0.81, test-retest of 0.77). 
It is an established measure of alexithymia. There is some suggestion of an overlap 
between this condition and Asperger’s syndrome, with samples of people with Asperger’s 
syndrome showing greater rates of alexithymia than age and gender-matched controls 
[156, 157]. The TAS-20 will be completed by both the PTSD+ participant and the CSO 
participant (modified) according to Table 3: Time and Events. 
 
The Quality of Relationships Inventory (QRI) is used to assess the supportive and 
conflictual aspects of close relationships [158]. The QRI presents an overview of 
approaches taken to study the social support construct. The QRI emphasizes the role of 
situational, intrapersonal, and interpersonal contexts in social support processes. The QRI 
possesses good to excellent reliability, ranging from 0.7 to 0.9 and moderate to good test-
retest stability (0.48 to 0.79) [159, 160]. Both the PTSD+ participant and the CSO 
participant will complete the QRI according to Table 3: Time and Events. 
 
The Significant Others' Responses to Trauma Scale (SORTS) [9] is a 14-item self-report 
measure of relationship problems and psychological distress faced by partners of people 
with PTSD. Each behavior or issue listed is rated on a five–point Likert scale (anchored 
at 0-4) for frequency of the behavior or issue and degree of distress the behavior or issue 
causes for the partner. The SORTS demonstrates strong internal consistency. It has 
Cronbach’s alpha for the total scale of 0.93 and alphas of 0.86 for frequency and 0.87 for 
intensity (degree of distress) scores, and associations with individual and relationship 
distress, including a positive correlation between SORTS score and PTSD symptom 
severity in the partner with PTSD, and between SORTS score and depressive symptoms 
in the partner without PTSD. The PTSD+ participant and the CSO participant will 
complete the SORTS about the PTSD+ participant according to Table 3: Time and 
Events. 
 
The Revised Conflict Tactics Scale [161] is a widely used measure of physical, 
psychological, and sexual aggression as well as injury and negotiation between partners. 
The scale consists of 39 conflict tactics, with respondents indicating the frequency with 
which they and their partner engage in each tactic, with each item presented as a “self” 
and “partner”. Responses are given on a seven-point Likert scale where 0 = “This has 
never happened” and 6 = “More than 20 times in the past month”, with 7 indicating 
occurrence in the past but not in the past year. The CTS2 contains four subscales; 
negotiation, psychological aggression, physical assault, and sexual coercion, and an 
injury score assessing impact of violence. CTS2 subscales are internally consistent, with 
alpha coefficients ranging from 0.79 to 0.95. Examining responses from relationship 
partners indicates high rates of agreement on responses. The CTS2 demonstrated 
construct validity, with scales demonstrating correlations with selected outcomes (for 


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instance, assault scale with injury). Research in a sample from a batterer-intervention 
program found moderate to good test-retest reliability (from 0.60 to 0.79) for all scales 
save sexual coercion [162]. Both the PTSD+ participant and the CSO participant will 
complete the CTS-2 according to Table 3: Time and Events.  
 
The Inventory of Psychosocial Functioning (IPF) is a self-report instrument designed to 
assess functional impairment across spectrum of domains. The IPF [163] is an 80-item 
measure that that was developed for use among individuals with PTSD. It assesses 
current psychosocial functioning across seven domains: romantic relationships, family, 
work, friendships, parenting, education, and self-care. Responses are made on a 7-point 
Likert scale, from “never” to “always.” Summation of scores across domains yields a 
total score for psychosocial functioning. The IPF has excellent psychometric properties 
[163, 164], with Cronbach’s alpha for the total scale computed at 0.93 and good internal 
consistency for subscales (ranging from 0.80 to 0.90) [164]. IPF subscale scores 
possessed positive correlations with similar scales or subscales on other measures. Both 
the PTSD+ participant and the CSO participant will complete the IPF according to Table 
3: Time and Events. 
 
The Miller Social Intimacy Scale (MSIS) is a 17-item measure of the maximum level of 
intimacy currently experienced. The MSIS contains six items assessing the frequency of 
intimate contact and 11 items addressing intensity of contact, with all responses given on 
an 10-point Likert scale, with the total score assessing a single factor [165]. The MSIS 
can be used to measure social intimacy for people referring to an opposite sex or a same 
sex person and intimacy in close friends or romantic partners [166]. The MSIS is reliable, 
with Cronbach’s alpha ranging from 0.84 to 0.95 [165, 166] and MSIS scores were 
positively related to scores on another measure of social intimacy [165]. Both the PTSD+ 
participant and the CSO participant will complete the MSIS according to Table 3: Time 
and Events. 
 
The Trauma and Attachment Beliefs Scale (TABS) was developed as a brief self-report 
measure of maladaptive beliefs about current life circumstances that may occur following 
trauma exposure [167]. The measure consists of 15 items, with responses made on a 
seven-point Likert scale with 1 = not at all true for you and 7 = completely true for you. 
This scale assesses maladaptive beliefs within three domains: (a) threat of harm, (b) self-
worth and judgment, and (c) reliability and trustworthiness of others. After following 
procedures for reverse-scored items, scores are summed to produce scale scores for each 
domain. The TABS has an overall reliability of alpha of 0.82, with scale reliability 
ranging from 0.71 to 0.76. TABS scores exhibit a positive association with CAPS global 
severity scores, particularly for the Threat of Harm scale, and the scale had a negative 
association with scores on the PTGI. Both the PTSD+ participant and the CSO 
participant will complete the TABS according to Table 3: Time and Events. The CSO 
participant will complete a modified version. 
 
The Multiscale Dissociation Inventory (MDI) is a 30-item self-report test of dissociative 
symptomatology in the last month, with responses made along a five-point Likert scale, 
with 1 = never and 5 = very often. It is fully standardized and normed, and measures six 
different type of dissociative response: disengagement, depersonalization, derealization, 
emotional constriction / numbing, memory disturbance, and identity dissociation. A total 


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dissociation score can also be calculated. Reliability for each subscale various from 0.74 
for memory disturbance to 0.91 for derealization. The MDI has been found to have good 
psychometric qualities in both the normative and validation samples [168-170]. Both the 
PTSD+ participant and the CSO participant will complete the MDI according to Table 3: 
Time and Events. 
 
The measure of state interpersonal closeness (IPC) is a 5-item non-verbal sponsor-
developed self-report measure. Participants are asked to draw on a sheet of paper “how 
close you feel right now” to the self as observed, the Clinical Investigators, a selected 
significant other and “the world.” Distance in mm between the self and each target will 
be considered an indirect measure of interpersonal closeness. The measure is expected to 
take between 2 and 4 minutes to complete. Both the PTSD+ participant and the CSO 
participant will complete the measures of interpersonal closeness according to Table 3: 
Time and Events.  
The Couples Satisfaction Index (CSI) is a self-report 32-item scale designed to measure 
one’s satisfaction in a relationship. The scale has a variety of items with different 
response scales and formats. The measure is expected to take approximately 5 minutes to 
complete. If the dyad is a romantic couple, both the PTSD+ participant and the CSO 
participant will complete the couples satisfaction index according to Table 3: Time and 
Events. 
The therapists will assess General Wellbeing during each Preparatory Session, on each 
Integrative Session and during telephone calls for seven days. Results of this scale are 
intended to assist therapists in maintaining participant safety throughout the study. Both 
the PTSD+ participant and the CSO participant will be assessed according to Table 3: 
Time and Events. 
 
5.1.2 Safety Measures 
 
Safety measures will be applied as described below to minimize risks associated with 
drug-assisted psychotherapy sessions. The therapists or study physician will be available 
via mobile phone or pager throughout the study to ensure participant safety. At least one 
member of each therapy team will maintain Basic Life Support (BLS) certification.  
 
Safety measures, including vital signs and a measurement of psychological distress, will 
be assessed during all Experimental Sessions. Participants will rate their current degree of 
subjective distress with the SUD scale, which is a single-item self-report scale. The SUD 
will be completed repeatedly during the Experimental Sessions, with the degree of 
distress marked along seven points. Results of the SUD are intended to assist therapists in 
maintaining participant safety during Experimental Sessions. Both the PTSD+ participant 
and the CSO participant will complete the SUD according to the Measures and Time and 
Events Table. 
 
The C-SSRS is a clinician-administered measure of suicidal behavior devised to detect 
potential suicidal thoughts or behaviors during a clinical trial [171]. It consists of a 
“Baseline” form that assesses lifetime suicidal ideation, ideation intensity, and behavior 
and a form for assessing current suicidal ideation and behavior. The C-SSRS consists of a 


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series of questions, and can be administered during a face-to-face interview or over the 
telephone. Suicidal ideation and behavior will be assessed at Baseline, during most face-
to-face visits, during the second and seventh days of telephone contact, and after each 
Experimental Session. Participants who are discontinuing medication to participate in the 
study will complete the C-SSRS before and after medication washout. The C-SSRS 
Intensity scale for Lifetime obtained a Cronbach’s alpha of 0.93 and 0.94 for the Since 
Last Visit form, and Last Visit C-SSRS severity scores were positively correlated with 
the BDI “suicide thoughts” item [172]. Both the PTSD+ participant and the CSO 
participant will complete the C-SSRS according to the Measures and Time and Events 
Table. 
 
Cardiovascular effects will be assessed via blood pressure and pulse measurement. Blood 
pressure, body temperature, and pulse will be measured at the outset of the Experimental 
Session, once prior to administration of the supplemental dose, and at the end of the 
Experimental Session, or until it returns to near baseline levels. The timing of these 
measurements will be adjusted so they do not interfere with the therapeutic process. 
Blood pressure will be measured more frequently if there are symptoms, such as chest 
pain, shortness of breath or neurological symptoms or any other signs or symptoms that 
may be indicative of a medical complication. 
 
A 100-millimeter visual analog scale will be used to assess changes in symptoms of pre-
existing tinnitus and/or chronic pain [173-175]. 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 [174, 176-178]. 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 [174, 177, 178]. 
Both the PTSD+ participant and the CSO participant will be evaluated for Somatic 
Symptoms. 
 
All AEs and spontaneously reported reactions will be collected, as described in Section 
8.5. AEs and spontaneously reported reactions may be collected during face-to-face visits 
or over the telephone. Common reactions that are spontaneously reported are collected 
for seven days after each Experimental Session on a separate CRF page and will be 
categorized as mild, moderate, or severe. The researchers will ask participants about 
thoughts about killing or harming themselves at these visits and during the second and 
seventh day of telephone contact with the study therapists.  
 
5.1.3 Process Measures 
 
All psychotherapy sessions, including Experimental Sessions, may be recorded to audio 
and video, with all recordings preserved for research and training purposes.  
 
The Reactions to Research Participation Questionnaire (RRPQ) [179] is an assessment of 
causes for taking part in research and responses to the experience of being a research 
participant. The RRPQ is intended to assess the participants’ experiences as research 
participants, perceived reasons for consenting to be a research participant and perceived 


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freedom to take part in the study. This will be completed by the PTSD+ participant and 
the CSO participant according to Table 3: Time and Events. 
 
The Long-term Follow-up Questionnaire has been developed internally by the sponsor to 
assess long-term benefits and harms of MDMA-assisted psychotherapy at the Long-term 
Follow-up Visits. Both the PTSD+ participant and the CSO participant will complete the 
Long-term Follow-up Questionnaire according to Table 3: Time and Events. The CSO 
participant will complete a modified version. 
 
5.2 Study Procedures and Visit Descriptions 
 
5.2.1 Prescreening, Screening, and Baseline Evaluation (Pre-study) 
 
Prospective dyads will be prescreened by telephone according to an IRB-approved script 
to learn if they meet basic eligibility criteria. Each dyad that is prescreened should be 
assigned a screening number, and recorded on the Screening Log where information on 
the selection of potential participants in the trial should be collected.  
 
Upon the PTSD+ participant and the CSO participant signing the IRB-approved informed 
consent form (ICF), either in person or over telemedicine, the potential dyad may 
commence study-related screening activities. The screening numbers should also be 
recorded on the signed ICF. If a dyad is enrolled, the study staff should record the 
enrollment date and assign dyad numbers. If a dyad is not enrolled, an explanation should 
be recorded on the Screening Log. If a CSO participant fails to qualify for the study, 
potential PTSD+ participants may nominate a different support participant. A CRF will 
not be completed for dyads that are not enrolled. These dyads will only be documented 
on the Screening Log and source records. It is the responsibility of the Clinical 
Investigator to file the Screening Log and the Dyad Identification Code List in the 
Investigator Site File (ISF) to be readily available for on-site monitoring and/or 
inspection by relevant authorities.  
 
Screening may take place over more than one day and should be complete by up to one 
month prior to enrollment. Screening visits may be conducted by telemedicine, phone, or 
in person. Screening may take up to one month, with the Baseline CAPS being conducted 
no more than 8 weeks before the first Experimental Session, leaving room for appropriate 
medication washout of at least five half-lives of pre-study psychiatric medications and 
active metabolites, plus one week for stabilization.  
 
If the CAPS is completed outside of this window for a participant, the PI should consult 
the CRA and Medical Monitor to determine if the Baseline CAPS should be repeated. 
The maximum window from the start of screening to the first Experimental Session is 8 
weeks. If, after reviewing all information, the PI concludes that the PTSD+ participant 
and CSO participant are eligible, they will enroll in the study. Visits will be scheduled 
consecutively as described in Table 3: Time and Events.  
 
a. Explain and obtain written informed consent from the PTSD+ participant and 
CSO participant. Written informed consent must be obtained prior to performing 
any tests or evaluations for the study 


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b. Assign the dyad a screening number. Complete the Screening Log 
c. Review the ability of participants of childbearing potential to become pregnant 
and their commitment to practice appropriate birth control as determined by the 
Clinical Investigator for the treatment period of the study 
d. Qualified study staff will obtain medical and psychological history by interview 
for both the PTSD+ participant and CSO participant 
e. Qualified study staff will administer the lifetime C-SSRS at baseline to assess 
suicide risk for both the PTSD+ participant and CSO participant 
f. General Wellbeing will be assessed for both the PTSD+ participant and CSO 
participant. 
g. Qualified study staff will collect information on pre-study and current 
medications for both the PTSD+ participant and CSO participant 
h. A physician will perform a general physical examination for both the PTSD+ 
participant and CSO participant. 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) 
• Electrocardiogram (ECG) 
• Serum electrolytes, metabolic profile, urinalysis and complete blood count 
• Thyroid stimulating hormone (TSH), free T3 and free T4 
• Human Immunodeficiency Virus (HIV) serology 
• Urine-dip pregnancy test on females with childbearing potential 
• Urinary drug test. 
 
Results of HIV serology will be kept confidential, and appropriate referral for counseling 
may be necessary in accordance with state law. The clinical laboratory values will be 
used to establish eligibility and will be kept with the participant’s source record. The 
clinical laboratory values will not be captured in the CRF, but will be used to establish 
eligibility and will be kept with the participant’s source record. Clinically significant 
abnormal values will be captured as medical history. If, upon examination, there are 
questions raised about possible medical problems, the study physician will request a 
review of participant medical records and request additional tests or assessments as 
indicated. 
 
A blinded IR who will not be present during any of the therapy sessions will administer:  
 
• Structured Clinical Interview for DSM-5 Diagnoses (Research Version) (SCID-
RV) to assess eligibility based on Axis I diagnoses, which includes a self-report 
questionnaire to focus on modules to use based on symptoms for both the PTSD+ 
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• SCID-II Axis 2 questionnaire to determine if specific modules of the SCID-II 
Interview will be conducted to confirm diagnoses of personality disorders 
• Last-month CAPS for the PTSD+ participant to assess PTSD symptoms and 
eligibility, which may be recorded to video in as many instances as necessary to 
establish inter-rater reliability 
 
The following self-report measures will be completed: 
 
• PTGI (in reference to time since the trauma) for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant 
• PCL-5 (last month) to assess PTSD symptoms for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant. 
• TABS to assess trauma related beliefs for the PTSD+ participant and modified for 
the CSO participant to rate the PTSD+ participant  
• MDI to assess dissociative symptomology for the PTSD+ participant and CSO 
participant 
• SORTS to assess partner accommodation for the CSO participant 
• BDI-II to assess depression symptoms for both the PTSD+ participant and CSO 
participant 
• PSQI to assess sleep quality for both the PTSD+ participant and CSO participant. 
PSQI-PTSD Addendum will be assessed for the PTSD+ participant only 
• ERQ to assess emotional regulation for both the PTSD+ participant and CSO 
participant  
• TAS-20 to assess emotion recognition, alexithymia for both the PTSD+ 
participant and CSO participant  
• QRI to assess relationship satisfaction for both the PTSD+ participant and CSO 
participant 
• CTS to assess conflict, tactics and aggression for both the PTSD+ participant and 
CSO participant 
• IPF to assess psychosocial functioning for both the PTSD+ participant and CSO 
participant  
• MSIS to assess social intimacy for both the PTSD+ participant and CSO 
participant 
• IRI to assess compassion, empathy and social functioning for both the PTSD+ 
participant and CSO participant  
• IPC for both the PTSD+ participant and CSO participant 
• CSI for both the PTSD+ participant and CSO participant, if in a romantic 
relationship 
 
5.2.2 Preparatory Psychotherapy Session (Visit 1 - Telemedicine Visit)  
 
(Less than 4 weeks prior to Visit 2) 
 
Participants who do not complete all screening activities will not be enrolled. Eligibility 
may be discussed by phone after screening is complete and at the time Visit 1 is 
scheduled but the final confirmation will occur at Visit 1. If all Inclusion Criteria and no 
Exclusion Criteria are met, eligibility will be confirmed with the participant. 


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a. Complete a final review of Inclusion and Exclusion Criteria 
b. Assess General Wellbeing 
c. Confirm eligibility and willingness to participate in study 
d. Enroll participant and issue dyad number 
e. Ensure medical history and medication history is complete. After enrollment new 
events will be collected as AEs and new medications, as described in Sections 8.0 
and 9.0. 
f. Discuss medication tapering, if applicable. Upon confirmation of eligibility, the 
PI or another designated study physician will consult the prescribing physician to 
initiate medication tapering for the PTSD+ participant and the CSO participant, if 
applicable, who must refrain from taking a psychiatric medication for the study. 
The prescribing physician’s opinion aboiut medication discontinuation will 
documented either in writing from the prescribing physician, or in writing by the 
study physician documenting phone contact with the prescribing physician. 
Tapering will follow a time course appropriate for the medication given its half-
life, with the first Experimental Session scheduled to occur after complete 
washout. Individuals using opiates for pain management will be asked to decrease 
the dose or avoid taking their pain medication for 24 hours prior to Experimental 
Sessions if possible, as these medications may reduce the efficacy of MDMA. 
Participants will be permitted to take their prescribed opiate medication during 
this period if necessitated by pain flare-ups. 
 
This first Preparatory Session will last 90 minutes and take place at Visit 1. During the 
Preparatory Sessions: 
 
a. This visit may be conducted by telemedicine or phone. 
b. Therapists may record all sessions to audio and video. The PTSD+ participant and 
the CSO participant will be given access to review audio or video recordings from 
the sessions upon request. 
c. The therapists will inquire about any possible changes in the PTSD+ participant’s 
or CSO participant’s health to ensure that eligibility criteria is met and if 
applicable, will confirm that the PTSD+ participant and CSO participant have 
appropriately tapered off of medications. 
d. The PTSD+ participant, CSO participant, and therapists will discuss goals for the 
Experimental Session and will complete preparatory psychotherapy. Preparatory 
sessions will promote a safe setting for confronting trauma-related memories, 
emotions, and thoughts. 
 
5.2.3 Preparatory Psychotherapy Session (Visit 2 - Clinic Visit)  
 
(Day 0) 
 
CBCT Manual Sessions 1, 2 and 3 
 
Sessions 1, 2 and 3 – Psychoeducation about PTSD, safety building for the relationship 
and beginning of communication skills. 
 


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This second Preparatory Session will last 90 minutes and take place at Visit 2. During the 
Preparatory Session: 
 
a. Therapists may record all sessions to audio and video. The PTSD+ participant and 
CSO participant will be given access to review audio or video recordings from the 
sessions upon request. 
b. Collect AEs and Medications, as described in Sections 8.0 and 9.0 
c. Confirm that the PTSD+ participant and CSO participant have appropriately 
tapered off of medications. 
d. Assess General Wellbeing 
e. Qualified study staff will administer the C-SSRS 
f. PCL-5 (last week) to assess PTSD symptoms for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant. 
g. The PTSD+ participant, CSO participant, and therapists will discuss goals for the 
Experimental Session and will complete preparatory psychotherapy. Preparatory 
sessions will promote a safe setting for confronting trauma-related memories, 
emotions, and thoughts. 
h. Give the Reminder of Study Rules to the dyad, which includes instructions and 
restrictions for conduct prior to receiving the drug. The PTSD+ participant and 
CSO participant must agree to: 
• Ingest only alcohol-free liquids after 24:00 (midnight) the evening before 
the Experimental Session 
• Refrain from the use of any psychoactive drug, with the exception of 
caffeine or nicotine, within 24 hours of each Experimental Session 
• Not use caffeine or nicotine for two hours before and six hours after 
ingesting the drug, or until therapists deem it safe to do so 
  
5.2.4 Experimental Sessions (Visits 3 and 10 - Overnight Stay) 
 
(Day 1 and approximately 3 weeks later) 
 
CBCT Manual Sessions 4 and 5 practice (Visit 3) and Review (Visit 10) 
 
Sessions 4 and 5 – Satisfaction enhancement and undermining avoidance. Specific 
content related to listening and approaching, and sharing of thoughts and feelings. 
  
Table 5. Schedule of Procedures for Experimental Sessions 
Approximate Time 
Procedure or Action 
9:00  
Urine drug screen and pregnancy test, participant acclimated to 
environment, C-SSRS 
 9:45  
Baseline BP, BT, Pulse, SUD 
10:00  
MDMA Administration, Begin video recording  
11:00  
SUD 
11:30  
BP, BT, SUD, Pulse, Administer optional supplemental dose  
12:30  
SUD 
14:00  
SUD 
As needed 
BP, BT, Pulse 
Every 60-90 minutes 
SUD 
Approximately six hours 
after drug administration 
C-SSRS, General Wellbeing, BP, BT, Pulse 


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The PTSD+ participant and CSO participant will receive two Experimental Sessions of 
open-label MDMA-assisted psychotherapy in conjunction with CBCT scheduled three 
weeks apart. Procedures for MDMA-assisted psychotherapy in conjunction with CBCT 
will remain the same across all sessions, and all procedures will be the same.  
 
Pre-drug: 
 
a. On the day of the Experimental Session, the PTSD+ participant and CSO 
participant will arrive approximately 60 to 90 minutes prior to drug 
administration. 
b. Confirm continuing eligibility by reviewing Inclusion and Exclusion Criteria 
including medications and adverse events. 
c. Perform a urine drug screen. A positive drug screen will be reviewed by the 
Clinical 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. 
d. If a participant is of childbearing potential, perform a urine pregnancy test. A 
positive pregnancy screen is cause for withdrawal from the protocol. 
e. If the dyad continues to meet criteria and the dyad reports that they followed 
appropriate rules and restrictions, the session will proceed. 
f. Review procedures for the Experimental Session with the dyad. 
g. Record the entire session to video and audio. Dyads will be given access to 
review audio or video recordings of their Experimental Sessions upon request. 
h. The session will last for approximately eight hours or longer, followed by an 
overnight stay at the study site. 
i. The therapists will administer the C-SSRS to the dyad prior to drug 
administration. 
j. Before drug administration, discuss and review the dyad’s goals, intentions and 
concerns and some of the commonly experienced effects of MDMA. 
k. Instruct the dyad not to use caffeine or nicotine two hours before or six hours after 
the dose of drug. 
l. PTSD+ participant and CSO participant body temperatures will be measured at 
Baseline and according to Table 4. The therapists may make more frequent 
measurements if body temperature exceeds more than 1C above Baseline. 
m. The PTSD+ participant and CSO participant will complete the SUD at Baseline 
prior to initial dose administration. The PTSD+ participant will complete the SUD 
every 60 to 90 minutes, until the session is over, allowing a window of up to 30 
minutes to fit into the psychotherapy process where a natural break occurs. If 
necessary, the therapists can make a greater number of measurements as their 
clinical judgment dictates. 
n. Measure blood pressure and pulse at Baseline prior to the Experimental Session, 
and according to Table 4 thereafter. More frequent measures will be taken if 
clinical signs and symptoms of hypertension are observed. 
 
 
 
 


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During: 
 
o. At approximately 10:00 in the morning, participants will receive the initial dose 
of drug along with a glass of water. 
p. The PTSD+ participant and CSO participant will sit or recline on comfortable 
furnishings. Eyeshades and a program of music will be provided if the PTSD+ 
participant or CSO participant wishes to use them. The PTSD+ participant and 
CSO participant may speak to the therapists whenever they wish, who will 
provide guidance and support as needed. CBCT therapy will be administered 
during the session according to the CBCT Manual. 
q. After the first hour, if the PTSD+ participant or CSO participant has not spoken 
spontaneously, check in with that participant about the nature of the experience. 
For the rest of the experience, as appropriate, the therapists will support and 
encourage the PTSD+ participant in emotional processing and resolution of 
whatever psychological material is emerging as described in the treatment 
manual. 
r. Record any spontaneously reported reactions during the session. 
s. Provide water and electrolyte containing fluids throughout the session but not to 
exceed 3L overall. 
t. An optional supplemental dose of MDMA half the amount of the initial dose may 
be administered approximately 1.5 to 2 hours after the initial dose unless 
contraindicated. 
u. Administer the self-report IPC for both the PTSD+ participant and the CSO 
participant. 
v. Provide food during the latter part of the session. 
w. If it is appropriate to do so, initiate the first question of the C-SSRS at any point in 
the session if the PTSD+ participant or CSO participant is experiencing 
significant psychological distress that does not respond readily to processing with 
the therapists according to the methods described in the treatment manual. The C-
SSRS is required at least once during the session; it is preferable to administer it 
towards the end of the session at about six hours after the initial dose. 
x. Assess General Wellbeing for both the PTSD+ participant and the CSO 
participant. 
y. End the session if all medical and psychiatric parameters are acceptable and the 
PTSD+ participant and the CSO participant are alert, ambulatory, and emotionally 
stable. 
 
Post-drug: 
 
a. The therapists will depart the site when they have concluded that the participants 
are emotionally and medically stable. Therapists and the study physician shall 
remain available to participants during the Experimental Session and for one 
week after via 24-hour cellular phone for integration as needed. 
b. Spontaneously reported reactions, AEs, and Medications will be collected, as 
described in Sections 8.0 and 9.0. 
  
The PTSD+ participant and the CSO participant will remain overnight in an appropriately 
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during the overnight stay. The attendant will monitor the PTSD+ participant’s and the 
CSO participant’s condition and will help the dyad relax during the overnight stay. The 
attendant will be an individual with some previous training in managing psychological 
distress, and will be thoroughly briefed by study staff about their role as an attendant who 
is available and supportive but not intrusive. If there is an emergency or the PTSD+ 
participant or the CSO participant needs additional support, the attendant can contact the 
therapists. The dyad will receive information that will allow them to contact the therapists 
during the overnight stay in the case of an emergency or request for additional support. 
The dyad 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. 
 
5.2.5 Integrative Sessions Day after Experimental Session (Visits 4 and 11 - Clinic 
Visit) 
 
(Day after each Experimental Session)  
 
CBCT Manual Sessions Review 
 
On the morning after each Experimental Session, both of the therapists from the dyad’s 
team will meet with the dyad during a 60 to 90-minute Integrative Session.  
 
Generally, these sessions include discussing material that emerged during Experimental 
Sessions and helping dyad integrate their experiences both internally and into daily life. 
Therapists will validate the choices of the participant about how much they wish to 
communicate their thoughts, feelings and experiences at this time, but will elicit enough 
information to be able to assess the participants’ level of emotional stability and state of 
emotional and physical wellbeing. Therapists will emphasize their commitment to 
support the participants during the integration period and will be available via phone for 
additional meetings if needed. The dyad will be encouraged to relax and rest as much as 
possible for several days after the Experimental Session. 
 
During Integrative Sessions: 
 
a. The Integrative Session will be recorded to audio and video when possible. 
Participants will be given access to review audio and video of the session upon 
request. 
b. The therapists will administer the C-SSRS during each Integrative Session. 
c. Discuss and review events that occurred with the dyad during the Experimental 
Session, including thoughts, feelings, and memories. If necessary, the therapists 
will help the participants to reduce any residual psychological distress they are 
experiencing. The therapists will also encourage reconnection with any feelings of 
acceptance, intimacy, and reduced fear experienced in Experimental Sessions, and 
reflection about integrating those experiences into their relationships and 
everyday lives. The therapists will be supportive, validating the experience and 
facilitating understanding and emotional clearing. 
d. The therapists will remain accessible any time the participants need support 
outside the scheduled Integrative Sessions. 
e. Assess the PTSD+ participant’s mental health and the presence of any remaining 


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reactions during the Integrative Session immediately after each Experimental 
Session. 
f. Integrative Sessions can also serve as an opportunity for the therapists to gather 
information about the effects of the drug on the PTSD+ participant in an 
unstructured manner. 
g. Assess General Wellbeing for both the PTSD+ participant and CSO participant. 
h. Administer the self-report PCL-5 (since last visit) to assess PTSD symptoms for 
the PTSD+ participant and modified for the CSO participant to rate the PTSD+ 
participant. 
i. Administer the self-report IRI to assess compassion, empathy, and social 
functioning for both the PTSD+ participant and CSO participant. 
j. After the Integrative Sessions, a person previously selected by the dyad will 
provide a ride home. If the dyad are unable to locate an individual willing or able 
to take them home, or if the designated person is unable to assist due to 
unforeseen events, the therapists will aid the dyad in finding an alternative means 
of returning home. 
k. Spontaneously reported reactions, AEs and Medications will be collected, as 
described in Sections 8.0 and 9.0. 
l. Give the dyad the Out of Session Assignments to be completed after the end of 
the Integrative Session and returned to the study staff by the next visit. 
m. Remind the participants that they will have daily contact by phone or during 
telemedicine visits for the next seven days. 
 
5.2.5 Daily Telephone Contact for Seven Days after an Experimental Session 
 
During daily phone contact:  
 
a. Starting on the day of the Integrative Session following each Experimental 
Session, one of the therapists will contact the PTSD+ participant and CSO 
participant via telephone, telemedicine, or in person every day for one week. The 
goal of daily contact is assessment of changes in General Wellbeing, safety, and 
offering support. 
b. The telephone contact will be for a brief check-in lasting five to 15 minutes, or as 
long as necessary to address any participant’s concerns and to assess participants’ 
wellbeing. Additional telephone contact can be initiated at the request of the 
therapists or participant. 
c. On the second and seventh day of contact after the Experimental Session, the 
therapists will administer the C-SSRS. 
d. General Wellbeing will be assessed at each phone call. 
e. Spontaneously reported reactions, AEs and Medications will be collected, as 
described in Sections 8.0 and 9.0. 
 
5.2.6 Integrative Sessions Between Experimental Sessions (Visits 5, 6, 7, 8, 12, 13, 14, 
and 15 - Telemedicine Visits) 
 
Visits 5, 6, 7, and 8 will occur over 3 weeks between Experimental Sessions 1 and 2 
(Visits 3 and 10); Visits 12, 13, 14, 15 will occur over 4 weeks following Visit 10. 
 


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CBCT Manual Sessions Review, 6, 7, 8, 9, 12, 13, 14, and 15 
 
Sessions 6 (visit 5) and 7  (visit 6)– Getting UNSTUCK (learning the process of dyadic 
cognitive restructuring) and problem solving. 
 
Sessions 8 (visit  7) and 9 (visit 8) – Making meaning of the trauma, specifically 
regarding acceptance and blame. 
 
Sessions 12 (visit 12) , 13 (visit 13) , 14 (visit 14), and 15 (visit 15) – Making meaning of 
the trauma. Discussion specifically of themes of emotional closeness, physical closeness, 
posttraumatic growth, and review and reinforcement of treatment gains. 
 
After each Experimental Session, in addition to the session the following morning, the 
PTSD+ participant and CSO participant will have four additional Integrative Sessions 
with the therapists lasting 75-90 minutes each. The therapists may conduct more sessions 
if they and the PTSD+ participant deem it necessary.  
 
Generally, these sessions include integration of material that emerged as a part of 
Experimental Sessions and afterward into daily life. Therapists will emphasize their 
commitment to support the PTSD+ participant during the integration period and will be 
available via phone or pager. Dyads will be encouraged to relax and rest as much as 
possible for several days after the Experimental Session. 
 
During Integrative Sessions: 
 
a. These visits may be conducted by telemedicine or phone. 
b. Record each Integrative Session to audio and video. Dyads will be given access to 
review one or more Integrative Sessions upon request. 
c. The C-SSRS will be administered just prior to beginning each Integrative Session.  
d. General Wellbeing will be assessed at each Integrative Session. 
e. The PTSD+ participant and therapists will continue to work on supporting the 
PTSD+ participant as they consider their experiences during Experimental 
Sessions. 
f. Assess General Wellbeing for both the PTSD+ participant and CSO participant. 
g. Administer the self-report PCL-5 (since last visit) to assess PTSD symptoms for 
the PTSD+ participant and modified for the CSO participant to rate the PTSD+ 
participant. 
h. Give the dyad the Out of Session Assignments to be completed after the end of 
the Integrative Session and returned by the next visit. (Except Visit 15). 
i. The therapists will use clinical judgment to assess the PTSD+ participant’s 
psychological wellbeing. during this period of time. If there are any indications of 
continuing anxiety or distress, the therapists may arrange to work on reducing the 
distress at a specially scheduled Integrative Session, through continuing contact, 
or at the next regularly scheduled Integrative Session. The PTSD+ participant or 
CSO participant may also initiate contact with the therapists at any time 
throughout the study. 
j. Collect AEs and medications, as described in Sections 8.0 and 9.0. 


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5.2.7 Evaluation and Preparation Visit at Midpoint (Visit 9 - Clinic Visit) 
 
(Approximately 3 weeks after V3; prior to V10) 
 
CBCT Manual Sessions 10 and 11 
 
Sessions 10 and 11 – Making meaning of the trauma. Discussion of the themes of trust 
and control. 
 
The midpoint evaluation will occur approximately 20 days after the first Experimental 
Session. Dyads who have withdrawn from treatment but have continued for follow-up 
will also complete this time point. This session will be recorded to audio/video. 
 
a. The therapists will assess suicidal ideation and behavior with the C-SSRS 
b. General Wellbeing will be assessed 
c. Collect AEs and medications, as described in Sections 8.0 and 9.0 
 
The following self-report measures will be completed at the midpoint: 
 
• PTGI (in reference to time since the trauma) for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant 
• PCL (since last visit) to assess PTSD symptoms for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant 
• TABS to assess trauma related beliefs for the PTSD+ participant and modified for 
the CSO participant to rate the PTSD+ participant  
• MDI to assess dissociative symptomology for the PTSD+ participant and CSO 
participant 
• SORTS to assess partner accommodation for the CSO participant  
• BDI-II to assess depression symptoms for both the PTSD+ participant and CSO 
participant  
• PSQI to assess sleep quality for both the PTSD+ participant and CSO participant. 
PSQI PTSD addendum will be completed by PTSD+ participant only 
• ERQ to assess emotional regulation for both the PTSD+ participant and CSO 
participant 
• TAS-20 to assess emotion recognition, alexithymia for both the PTSD+ 
participant and CSO participant  
• QRI to assess relationship satisfaction for both the PTSD+ participant and CSO 
participant 
• CTS to assess conflict, tactics and aggression for both the PTSD+ participant and 
CSO participant 
• IPF to assess psychosocial functioning for both the PTSD+ participant and CSO 
participant 
• MSIS to assess social intimacy for both the PTSD+ participant and CSO 
participant 
• IRI to assess compassion, empathy and social functioning for both the PTSD+ 
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• IPC for both the PTSD+ participant and CSO participant 
• CSI for both the PTSD+ participant and CSO participant, if in a romantic 
relationship 
 
5.2.8 Primary Assessment (Visit 16 – Telemedicine Visit) 
 
(30 days post Visit 15; window of -2/+7 days) 
 
The PTSD+ participant and CSO participant will repeat all outcome measures with the IR 
and meet with the therapists again 30 days after Visit 15. This visit may consist of two 
meetings that may be completed on separate days, one with the IR and the other with the 
therapists. Session may be recorded to audio/video. 
 
a. The therapists will assess suicidal ideation and behavior with the C-SSRS 
b. General Wellbeing will be assessed 
c. Last-month CAPS for the PTSD+ participant only will be performed to assess 
PTSD symptoms, which may be recorded to video in as many instances as 
necessary to establish inter-rater reliability 
d. Collect AEs and medications, as described in Sections 8.0 and 9.0 
 
The following self-report measures will be completed at the outcome assessment: 
 
• PTGI (in reference to time since the trauma) for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant  
• PCL (last month) to assess PTSD symptoms for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant 
• TABS to assess trauma related beliefs for the PTSD+ participant and modified for 
the CSO participant to rate the PTSD+ participant  
• MDI to assess dissociative symptomology for the PTSD+ participant and CSO 
participant 
• SORTS to assess partner accommodation for the PTSD+ participant and CSO 
participant 
• BDI-II to assess depression symptoms for both the PTSD+ participant and CSO 
participant 
• PSQI to assess sleep quality for both the PTSD+ participant and CSO participant 
PSQI PTSD addendum will be completed by PTSD+ participant only 
• ERQ to assess emotional regulation for both the PTSD+ participant and CSO 
participant 
• TAS-20 to assess emotion recognition, alexithymia for both the PTSD+ 
participant and CSO participant 
• QRI to assess relationship satisfaction for both the PTSD+ participant and CSO 
participant 
• CTS to assess conflict, tactics and aggression for both the PTSD+ participant and 
CSO participant 
• IPF to assess psychosocial functioning for both the PTSD+ participant and CSO 
participant 


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• MSIS to assess social intimacy for both the PTSD+ participant and CSO 
participant 
• IRI to assess compassion, empathy and social functioning for both the PTSD+ 
participant and CSO participant  
• IPC for both the PTSD+ participant and CSO participant 
• RRPQ to assess the process for both the PTSD+ participant and CSO participant 
• CSI for both the PTSD+ participant and CSO participant, if in a romantic 
relationship 
 
5.2.9 Long-term Follow-up (Visits 17 and 18 – Telemedicine Visits) 
 
(3 months and 6 months post Visit 15, window of -2/+7 days) 
 
The PTSD+ participant and CSO participant will be evaluated for long-term effects 3 
months and 6 months after their last MDMA-assisted psychotherapy with CBCT session. 
This visit will consist of two meetings, one with the IR and the other with the therapists 
via telemedicine. PTSD+ participants and CSO participants who have withdrawn from 
treatment but have continued for follow-up will also complete these time points. At the 
Long-term Follow-up Visits:  
 
a. The therapists will assess suicidal ideation and behavior with the C-SSRS. 
b. General Wellbeing will be assessed. 
c. Last-month CAPS for the PTSD+ participant will be performed to assess PTSD 
symptoms, which may be recorded to video in as many instances as necessary to 
establish inter-rater reliability. 
d. Collect AEs and medications, as described in Sections 8.0 and 9.0. 
 
The following self-report measures will be completed at the outcome: 
 
• PTGI (in reference to time since the trauma) for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant  
• PCL-5 (last month) to assess PTSD symptoms for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant 
• TABS to assess trauma related beliefs for the PTSD+ participant and modified for 
the CSO participant to rate the PTSD+ participant  
• MDI to assess dissociative symptomology for the PTSD+ participant and CSO 
participant 
• SORTS to assess partner accommodation for the CSO participant 
• BDI-II to assess depression symptoms for both the PTSD+ participant and CSO 
participant 
• PSQI to assess sleep quality for both the PTSD+ participant and CSO participant. 
PSQI PTSD addendum will be completed by PTSD+ participant only 
• ERQ to assess emotional regulation for both the PTSD+ participant and CSO 
participant 
• TAS-20 to assess emotion recognition, alexithymia for both the PTSD+ 
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• QRI to assess relationship satisfaction for both the PTSD+ participant and CSO 
participant 
• CTS to assess conflict, tactics and aggression for both the PTSD+ participant and 
CSO participant 
• IPF to assess psychosocial functioning for both the PTSD+ participant and CSO 
participant 
• MSIS to assess social intimacy for both the PTSD+ participant and CSO 
participant 
• IRI to assess compassion, empathy, and social functioning for both the PTSD+ 
participant and CSO participant  
• IPC for both the PTSD+ participant and CSO participant 
• CSI for both the PTSD+ participant and CSO participant, if in a romantic 
relationship 
• Long-term Follow-up Questionnaire to assess the process, outcome and safety for 
the PTSD+ participant and modified foe the CSO participant  
 
5.3 Participant Numbering 
 
Prior to enrollment, the dyad will be tracked with two sets of initials and a screening 
number assigned sequentially starting at “S001”. Dyads who meet all Inclusion and no 
Exclusion Criteria will be enrolled into the study and will be assigned a five-digit 
participant number. The first two digits will be “ 01” or “02” and will identify the PTSD+ 
participant versus the CSO participant. The next three digits identify the dyad within the 
site and will be assigned sequentially, with 001 corresponding to the first dyad enrolled, 
e.g. the first enrolled dyad will be 01001 and 02001 and the second dyad will be 01002 
and 02002, etc.  
 
5.4 Removal of Participants from the Study 
 
Participants can withdraw consent at any time without prejudice. The therapists can 
withdraw a participant if, in their clinical judgment, it is in the best interest of the dyad or 
if the participant cannot comply with elements of the protocol that are critical for safety 
or for the scientific integrity of the study. If the therapists withdraw a dyad from the 
study, the therapists will explain the reason for withdrawing the dyad. The reason for 
early termination will be recorded in both the PTSD+ participant’s and the CSO 
participant’s source records and CRF. If one person in the dyad wishes to withdraw, both 
participants will be dropped from treatment. 
 
Participants will be clinically monitored after withdrawal, the cause of which will be re-
corded in their source records and CRF. Whenever possible, the tests and evaluations 
listed for the termination and outcome visits will be carried out. Efforts will be made to 
obtain information about AE outcomes, if deemed necessary by the PI and/or sponsor. 
 
If a participant develops any Exclusion Criteria that in the opinion of the Medical 
Monitor, affects the safety of either member of the dyad, including psychiatric diagnosis, 
pregnancy or excluded medications, the PTSD+ participant will discontinue treatment but 
remain in the study for follow-up purposes. Whenever possible, the tests and evaluations 


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listed for the Midpoint, Outcome, and 3-month and 6-month follow-up will be carried 
out. Efforts will be made to obtain information about AE outcomes, if deemed necessary 
by the Clinical Investigators, Medical Monitor, and/or sponsor. Dyads who discontinue 
treatment will not be replaced.  
 
5.5 Premature Discontinuation of the Study 
 
The sponsor or the lead Clinical Investigator (following consultation with the sponsor) 
has the right to discontinue this study at any time. If the trial is prematurely terminated, 
the Clinical Investigator is to promptly inform the study participants and will assure 
appropriate therapy and follow-up. If the trial or study is prematurely discontinued, all 
procedures and requirements pertaining to retention and storage of documents will be 
observed. All other study materials will be returned to the sponsor and will be treated in 
accordance with federal and state regulations. 
 
6.0 Investigational Product 
 
6.1 Description of Active Compounds 
 
The investigational product 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 [180-182]. Its direct actions on serotonergic, 
adrenergic and other receptors are considerably lower. See Section 2.2.3 Previous 
Clinical Experience with MDMA and the IB for more information on the investigational 
product. 
 
6.2 Preparation and Administration 
 
In this study, 10 dyads will receive MDMA in an open-label fashion. 
 
6.2.1 Doses 
 
Table 6. Treatment Condition 
Treatment Group 
1st Experimental Session Dose 
2nd Experimental Session Dose 
Active MDMA-assisted 
Psychotherapy  
(N=10 dyads) 
75 mg MDMA 
+ optional 37.5 mg supplement  
100 mg MDMA 
+ optional 50 mg supplement  
or  
75 mg MDMA 
+ optional 37.5 mg supplement 
 
6.2.2 Compounding 
 
MDMA in bulk will be sent from a Schedule 1 licensed storage facility to the Drug 
Enforcement Agency (DEA) Schedule I license holder for the study. The Schedule I 
license holder will oversee compounding by a pharmacist. The pharmacist will provide 
bulk lactose for compounding MDMA capsules. The pharmacist will weigh the MDMA 
into doses of 75 mg, 100 mg, 50 mg, and 37.5 mg (calculated as the weight of the 
hydrochloride salt) and place it in gelatin capsules with lactose. Capsules for the initial 


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dose will be clearly differentiated from capsules used for the supplemental dose. The 
encapsulation will be performed by a pharmacist who has the appropriate skills.  
 
6.2.3 Labeling 
 
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, 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 PTSD+ participant and CSO participant per Experimental Session. The 
sponsor monitor will oversee the process of drug packaging conducted by the pharmacist.  
 
Figure 1. Examples of Drug Labels  
 
Holding Box Labels: 
 
 
Holding Box Label 
 
MAPS Study: MPVA-1 
Investigational Product: MDMA  
Dose: X mg 
Lot #: XXX 
Administer as per protocol 
Caution: Limited by Law to Investigational Use Only 
 
 
Primary Container Outer Labels: 
 
 
Container Label 
 
MAPS Study: MPVA-1 
Open Label 
100 mg + 50 mg MDMA  
Lot #: XXX 
Container #: XXX  
 
Dyad #: ____________  
Experimental Session #: ____________ 
Administer as per protocol - Investigational Use Only 
 
 


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Container Label 
 
MAPS Study: MPVA-1 
Open Label 
75 mg + 37.5 mg MDMA  
Lot #: XXX 
Container #: XXX  
 
Dyad #: ____________  
Experimental Session #: ____________ 
Administer as per protocol - Investigational Use Only 
 
 
Primary Container Inner Labels: 
 
Open Label 
INITIAL DOSE 75 mg 
Dyad #: _________Experimental Session #: ___  
 
Open Label  
SUPPLEMENTAL DOSE 37.5 mg 
Dyad #: _________Experimental Session #: ___  
 
 
 
Open Label 
INITIAL DOSE 100 mg 
Dyad #: _________Experimental Session #: ___  
 
Open Label  
SUPPLEMENTAL DOSE 50 mg 
Dyad #: _________Experimental Session #: ___  
 
Initial doses will be distinguished from supplemental doses through labeling them to 
ensure that the correct dose is administered at the scheduled time. Each dose of MDMA 
will be administered along with a glass of water or electrolyte-containing fluid. MDMA 
will be administered in the same manner during each Experimental Session.  
 
6.3 Drug Accountability 
 
Forms will be provided to track drug accountability and administration throughout the 
study. 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.  
 
6.4 Drug Storage and Handling  
 
MDMA is a Schedule I compound and will be stored and handled in compliance with all 
relevant federal and state regulations. In accordance with these requirements, the 
Schedule I license holder will be responsible for storing, dispensing, and administering 
the MDMA. It will be stored in a secure safe in accordance with federal and state 
regulations.   
 
IP will only be removed for a single Experimental Session at a time and will be 
administered orally at the treatment site. All doses administered will be recorded on the 
appropriate accountability and administration logs. Only the initial dose is required to be 
given at each Experimental Session. Supplemental doses are provided for each 


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Experimental Session but are optional to use. In addition, the clinical titration doses with 
corresponding supplemental dose are provided for the second Experimental Session. The 
dose to be used at the second session is at the discretion of the CI. 
 
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.  
 
Records pertaining to the use of scheduled, regulated compounds will be maintained in 
accordance with relevant federal and state regulations.   
 
6.5 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., at the Department of 
Medicinal Chemistry and Pharmacology at 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 is currently in use in an ongoing investigation of MDMA-
assisted psychotherapy in the U.S., was also used in MP-1 with drug administration 
ending in 2008, and it was also used in a non-sponsor supported study in 2006 [183]. 
 
7.0 Risks of Participation 
 
7.1 Risks and Discomforts Associated with Psychotherapy Sessions and Assessment 
of Measures 
 
In preparation for drug-assisted psychotherapy sessions, blood draws and a full medical 
examination are required to establish eligibility for the study. Temporary discomfort, 
inflammation, or infection could arise as a result of sampling blood at the punctured vein. 
Submitting to a full medical examination may also cause discomfort or psychological 
distress. Since medical examinations and blood draws are required to establish eligibility 
for the study, they cannot be omitted from the protocol. 
 
During screening, non-drug and drug-assisted psychotherapy sessions and assessment of 
study measures, 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, experimental, and open-label sessions. Psychotherapy is conducted 


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as part of the research study, including the experimental intervention, and people 
undergoing psychotherapy are expected to confront unpleasant thoughts, feelings, and 
memories in the process of therapy. Because psychotherapy is an integral part of the 
research study design, the potential distress arising from psychotherapy is unavoidable.   
 
All psychotherapy sessions may be recorded to audio and video for research and training 
purposes. Participants may feel uncomfortable with having their sessions recorded. 
Participants will have access to recordings if they request them. The recordings are 
necessary for developing the experimental treatment manual. 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 researchers or regulatory agencies. 
 
7.2 Risks of Receiving MDMA 
 
Spontaneously reported reactions and common adverse effects of MDMA are modest and 
have generally not been associated with serious discomfort by healthy volunteers in 
previous studies. Common reactions include lack of appetite, insomnia, dizziness, tight 
jaw or bruxism (tooth-grinding), difficulty concentrating, impaired gait or balance, dry 
mouth, ruminations, and thirst. Other slightly less common reactions include restlessness, 
parasthesias (odd somatic feelings, such as tingling, feeling hot or cold), impaired 
judgment, perspiration, drowsiness, and nystagmus (eye-wiggling). While anxiety, 
headache, fatigue, insomnia and lack of appetite were spontaneously reported by 40% to 
80% of participants in both conditions in MAPS study MP-1 (N=23), tight jaw, nausea, 
impaired gait/balance, and sensitivity to cold were more often reported by participants in 
the MDMA than the placebo condition, and irritability was slightly more likely to be 
reported in the placebo condition. Additionally, participants in the MDMA condition 
were more likely to report muscle tension in various body parts and diarrhea.  
 
These effects are transient and diminish as drug effects wane. Sub-acute effects that may 
either continue for the next 24 hours or appear later include insomnia, fatigue, needing 
more sleep, weakness, heavy legs, dry mouth, low mood or irritability. Sub-acute effects 
are reported less often than acute effects. More information on spontaneously reported 
reactions is described in the IB.  
 
MDMA may produce mild alterations in sensory perception and altered perception of 
time [10, 109, 184]. Women may be more sensitive to these effects [15]. MDMA acutely 
affects attention, information processing, and memory. MDMA acutely impairs verbal 
memory and recall for object location without affecting recall of complex scene changes 
[185]. For this reason, participants will stay at the site overnight and will not be permitted 
to drive after Experimental Sessions.  
 
MDMA may produce modest changes in immune functioning, lasting up to 48 hours. 
Because of their limited duration, these changes are not likely to have clinical 
significance beyond several days of possible increased risk of viral upper respiratory 
infection or similar illness.  
 


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Further information on the risks associated with MDMA, including information drawn 
from case reports and studies of users, can be found in the sponsor’s Investigator 
Brochure.  
 
7.2.1 Safety Plan and Procedures for Participants Who Screen Positive for Suicidal 
ideation or Intent 
 
The CI will minimize risks by carefully evaluating all participants to determine if there is 
a current risk of suicidal behavior.  Participants with a history of suicide attempts will not 
be excluded unless risk of suicidal behavior is present at the time of the screening 
assessment. Participants will be enrolled according to the Inclusion and Exclusion 
Criteria based on the clinical judgment of the CI.  
 
After enrollment, data on General Wellbeing will be collected at each visit on the 
participant’s current demeanor and state of mind and risk of deterioration. Participants 
will be telephoned on a daily basis for the first week after each experimental session to 
assess General Wellbeing, safety, and offer support.  
 
The CI or qualified designee will administer the C-SSRS according to the Time and 
Events table, and as needed depending on clinical presentation of the participants, to 
monitor for development and intensity of suicidal ideation and/or behavior. The therapist 
will implement the following plan to assess elevated or imminent suicide risk. 
 
If the Since Last Visit C-SSRS reveals current serious Suicidal Ideation (Scores of 4 or 
greater), indicating risk at the time of the assessment, or positive Suicidal Behavior 
(Scores of 1 or greater) then the participant will be referred for further 
management as described below. 
 
1. 
If the participant has current suicidal ideation, but no specific plan to 
commit suicide (Suicidal Ideation Score = 4), the therapist administering the 
C-SSRS will ensure: 
a. 
Participants are evaluated by the investigators to determine appropriate 
course of action and will discuss the findings with the participant and their 
personal therapist, if applicable. 
b. 
Regular check-ins via phone or in person will be continued until the 
participant has stabilized or a new course of action is taken based on 
changes in C-SSRS score and/or ongoing clinical assessment. 
c. 
If this finding is treatment-emergent and clinically significant, the event 
will be collected as an Adverse Event.  
d. 
Treatment would be continued when deemed appropriate by the CI and 
Medical Monitor, unless it is determined that treatment should be 
discontinued, in which case the participant will enter follow-up. 
 
2.  
If the participant has suicidal ideation, and a plan to commit suicide (Suicidal 
Ideation Score = 5) or positive Suicidal Behavior (Score greater than or equal to 
1), the therapist administering the C-SSRS will assess whether the risk is 
imminent. A Suicidal Ideation score of 5 does not necessarily indicate an 
immediate risk if the thoughts are fleeting, fairly easily controlled, and deterrents 


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are strong. If there is no imminent risk, the therapist will follow the procedure 
described in number 1. If there is imminent risk of suicidal behavior, the therapist 
will ensure: 
a. 
Participants are evaluated to determine appropriate course of action, and 
the study therapist will contact their personal therapist or come to the 
study site for a visit, depending on their location. 
b. 
If it is determined that the participant is at imminent risk of suicide, the 
CI or qualified staff member will do one of the following:  
1) 
Escort the participant to the Emergency Department;  
2) 
Escort the participant to an appropriate mental health services 
facility (e.g.hospital psychiatric unit); or  
3)  
call 911 and ensure that the participant is transferred to the 
responding medical personnel. 
c. 
If the participant will not comply and wishes to leave without 
consultation, call 911. Explain that the participant is in immediate 
danger of committing suicide. Provide a complete description of the 
participant and give any other needed details to ensure the participant’s 
safety. 
d. 
Notify appropriate members of the study team and Sponsor 
representatives. 
e. 
If this finding is treatment-emergent and clinically significant, the event 
will be collected as an Adverse Event and the seriousness will be 
evaluated. SAEs will be reported per FDA guidance. 
f. 
Treatment would be continued when deemed appropriate by the CI and 
Medical Monitor, unless it is determined that treatment should be 
discontinued, in which case the participant will enter follow-up. 
 
7.2.2 Cardiovascular and Sympathomimetic Effects 
 
The highest dose to be employed in this study, the active dose of 100 mg, followed by a 
supplemental dose of 50 mg after 1.5 to 2.0 hours, is expected to produce significant but 
transient, self-limited increases in blood pressure and heart rate. These changes should 
last no more than six hours. In less than 5% of volunteers in Phase 1 studies, peak blood 
pressure values were higher than 140/90 mmHg. Clinical intervention was not required in 
any of these cases. Nonetheless, careful monitoring of participants and predefined 
contingency plans will allow the researchers to rapidly identify and manage any related 
toxicity. For more information, see the sponsor’s Investigator Brochure. 
 
Risks posed by elevated blood pressure will be addressed by excluding people with pre-
existing hypertension and monitoring blood pressure and pulse, as described in Section 
5.1.2. During Experimental Sessions the co-therapists will continually evaluate the 
patient for signs or symptoms of a developing hypertensive or other cardiovascular 
emergency. Participants reporting chest pain, shortness of breath or neurological 
symptoms or other potential indicators of hypertensive emergency or any other serious 
medical problem will have more frequent measurements and assessment by the study 
physician. Any participant who experiences medical complications during an 
Experimental Session will not be given another Experimental Session unless it is 
approved by the Clinical Investigator, study physician and the Medical Monitor.   


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In case of need, participants will be transferred to the emergency room at the closest 
hospital, as described in Section 8.4. Reasons for moving a patient to an Emergency 
Department (ED) would include, but not be limited to, severe headache in the setting of 
hypertension, angina, or neurological deficits regardless of blood pressure. The Clinical 
Investigators and study physician may, at any time, make a clinical judgment to transfer 
the patient to the ED for closer monitoring and additional treatment.  
 
The study physician will be prepared to respond to rare complications of cardiovascular 
effects, such as stroke or acute myocardial infarction (AMI). The therapists will attend to 
any signs or symptoms of neurological deficit or confusion that is more extensive than 
might be expected from MDMA or from psychological distress, and will notify the study 
physician if this occurs for on-site evaluation or a decision to initiate transfer to the ED. 
If any participant has neurological deficits, as assessed by the study physician, whether or 
not they are associated with hypertensive crisis, they will receive oxygen and vital signs 
and general condition will be closely monitored pending transfer to the hospital. If 
necessary, they will be transported to the emergency department at the closest hospital for 
further management. If evaluation at the hospital reveals a nonhemorrhagic stroke, there 
will be time to administer recombinant tissue plasminogen within the three-hour time 
frame recommended in the American Academy of Neurology/American Heart 
Association guidelines [186, 187]. 
 
The therapists will observe the participants and note any complaints of chest pain. If a 
participant experiences ischemic type chest pain, whether or not it is associated with 
hypertensive crisis, they will receive heart rhythm monitoring, oxygen and will be 
monitored as described above. If necessary, they will be transported to the ED or a 
location in the hospital where appropriate care can be given. They will be given 
nitroglycerin 0.4 mg SL q 5 minutes PRN chest pain pending transport to the hospital. If 
further evaluation at the hospital reveals that the participant has had an AMI, they will be 
well within the time frame required for definitive therapy. The American College of 
Cardiology/ American Heart Association guidelines for the treatment of AMI recommend 
percutaneous transluminal coronary angioplasty (PTCA) as the treatment of choice when 
it can be performed within 90 minutes of arrival at the hospital in patients who present 
within 12 hours of an episode of chest pain lasting more than 30 minutes and who have 
ECG evidence of AMI [188]. 
 
7.2.3 Psychological Distress 
 
Mild anxiety and depressed mood are occasionally reported one to three days after 
MDMA administration [13, 15, and see the IB]. Psychological distress from MDMA 
could arise at any time from the first indications of drug effects until the last effects have 
dissipated (approximately three to five hours after drug administration), or even later. 
Any anxiety or distress occurring during the session may last for as little as five minutes 
or for as long as five hours or more. In addition, psychological distress could arise 
following an MDMA-assisted 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 therapists, with occasional use of benzodiazepines for anxiety. In 


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this study, participants will have the intention of confronting and working through 
traumatic experiences. Hence signs of psychological distress, panic or other unpleasant 
psychological reactions are to be expected and may be considered an element of the 
psychotherapeutic process.  
 
Proper preparation and follow-up support will reduce the difficulties participants might 
have with acute or sub-acute reactions. The potential for destabilizing psychological 
distress will be minimized by: 
 
• Excluding people who might be more vulnerable to it (such as people diagnosed 
with bipolar affective disorder-1 or with psychotic disorders) 
• Preparatory non-drug psychotherapy sessions before the Experimental Session. 
• Creating an atmosphere of trust during the Experimental Session 
• Close monitoring 
• Daily contact with participants for the period of a week after the Experimental 
Session 
• Providing non-drug psychotherapy Integrative Sessions 
• Participants will remain at the study site for the night of each Experimental 
Session to further reduce psychological distress. Qualified personnel will be 
available during the overnight stay to respond to the needs of the participants. 
Attendants will be instructed to contact the therapists upon request or at the 
appearance of signs of a potential serious adverse event.  
 
During the Preparatory Sessions, 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 Experimental 
Session, including empathic listening on the part of the therapists and performance of 
diaphragmatic breathing or other stress inoculation techniques by participants.  
 
At the end of the Experimental Session, which lasts six to eight hours, if the PTSD+ 
participant or CSO participant is still severely agitated or experiencing any other severe 
psychological distress, the following measures will be taken:  
 
• If the PTSD+ participant or CSO participant is anxious, agitated, in danger of any 
self-harm or is suicidal at the end of the Experimental Session, the therapists will 
remain with them for at least two more hours. During this time, the therapists will 
employ affect management techniques, will talk with the participant to help them 
gain cognitive perspective of their experiences, and will help them implement the 
self-soothing and stress inoculation techniques presented during the Preparatory 
Session. If this situation should occur during an Integrative Session, at least one 
of the therapists will be available to stay with the person for at least two 
additional hours. 
• If a PTSD+ participant or CSO 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 
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1. A psychiatric nurse, therapeutic assistant, physician, or therapist will stay 
with the PTSD+ participant or CSO participant until the time of their 
appointment with the therapists the next day. The therapists will then meet 
with the participant daily until the period of destabilization has passed.  
2. If a PTSD+ participant or CSO participant experiences severe, persisting 
emotional distress, such as panic attacks, severe generalized anxiety, or 
insomnia following an MDMA-assisted session, the study physician may 
prescribe a rescue medication such as a benzodiazepine, zolpidem, or 
other anxiolytic or sedative according to the physician's clinical judgment. 
This medication will be captured on the concomitant medications CRF 
page. The physician should not prescribe an SSRI, SNRI or MAOI in this 
context unless it has been determined that the participant will be 
withdrawn from the study. Residual symptoms will be addressed during 
the frequent follow-up psychotherapy visits with the therapists. 
3. Hospitalization for stabilization. If a PTSD+ participant or CSO 
participant should become psychotic arrangements will be made to 
stabilize them and transfer them to the ED if necessary. 
 
PTSD+ participants or CSO participants hospitalized after a severe panic reaction will be 
suspended from the protocol until after recovery or stabilization, at which time the 
Clinical Investigators will carefully evaluate their emotional status.   
 
For those PTSD+ participants or CSO participants engaged in an ongoing therapeutic 
relationship with a psychotherapist or psychiatrist, the outside therapists will be involved 
in the management of any psychiatric complications. For those PTSD+ participant or 
CSO participants engaged in an ongoing psychotherapeutic relationship with the Clinical 
Investigators, the management of any psychiatric complications will be undertaken by 
them in their capacity as therapists.   
 
7.2.4 Body Temperature 
 
MDMA administered in a controlled setting produces only a slight increase in body 
temperature [15] and ambient temperature does not enhance or attenuate this slight 
elevation in humans.   
 
If temperature rises more than 1°C, attempts will be made to lower it by removing 
blankets and layers of clothing, decreasing the ambient temperature and, if necessary, 
directing a fan toward the participant. If at any time the temperature rises more than 
1.5°C above Baseline despite these efforts, the study physician will be consulted for 
further evaluation and treatment.   
 
7.2.5 Reproductive and Developmental Risks 
 
Risks posed by MDMA to pregnant persons 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 [189, 190], 
and a third reported some developmental delays in mothers reporting use of and other 
drugs during pregnancy [191] as discussed in the IB.   


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Pregnant and lactating persons will be excluded from participation in the study, and 
participants who are able to become pregnant must have a negative pregnancy screen 
before undergoing each Experimental Session and must agree to use birth control for the 
treatment portion of the study. 
 
7.2.6 Potential Neurotoxicity Associated with Ecstasy Use 
 
Some researchers believe that MDMA is neurotoxic in humans even at doses used in 
clinical trials [192]. However, they are basing their case on studies that employed 
inappropriately high doses of MDMA utilized in animal studies, and on human studies 
comparing the effects of repeated use of MDMA, often along with other drugs. 
Meanwhile, another recently published meta-analysis has taken careful steps to overcome 
methodological limitations in previous work, and found only modest evidence of 
neurotoxicity [193]. We have carefully considered the risks of such neurotoxicity and 
conclude that they are minimal in the proposed study. This conclusion is supported by 
empirical and toxicokinetic evidence and is consistent with the lack of toxicity reported 
in previous clinical MDMA studies. More information on the potential neurotoxicity of 
MDMA can be found in the IB.  
 
7.2.7 Risk Mitigation 
 
Careful review of medical screening data will be utilized to exclude potential participants 
with pre-existing exclusionary medical conditions from the study. Study procedures have 
been developed to mitigate the risks of receiving MDMA described in detail in the IB. 
Ambient temperature will be kept at a comfortable level during Experimental Sessions. 
Participants will not be allowed to drink more than 3L of fluids over the course of the 
Experimental Session, and fluid intake will be spread out appropriately during the 
session. Fluids administered will include electrolytes. If a participant exhibits any signs 
of toxicity or clinically significant dilutional hyponatremia despite these precautions after 
an Experimental Session, they will not be given another Experimental Session unless it is 
approved by the Clinical Investigator, study physician, and the Medical Monitor.   
 
7.3 Abuse Liability 
 
Findings in humans and animals suggests that MDMA possesses moderate abuse 
potential that is higher than that reported for “classic hallucinogens” like psilocybin, but 
lower than that reported for psychostimulants such as cocaine or methamphetamine. 
More information on abuse liability is provided in the IB. 
 
Whether MDMA-assisted psychotherapy will cause some PTSD patients to develop an 
MDMA use disorder is an open question that the sponsor is addressing on an ongoing 
basis. Based on Long-term Follow-up data from two sponsor-supported studies (N=32), 
only one participant took Ecstasy after completing the study and failed to reproduce the 
experience from the study, and a number of participants volunteered that they would 
never seek out Ecstasy outside a legal, controlled, therapeutic setting. In addition, 
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MP-2 (N=12) supports that none of these participants took Ecstasy outside of the study 
during the Long-term Follow-up period.   
 
Diversion is not an issue in this protocol because MDMA will only be administered a few 
times under the supervision of the 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. 
 
8.0 Adverse Events 
 
8.1 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 
participant’s involvement in the research, whether or not considered related to 
participation in the research. This definition includes concurrent illnesses or injuries and 
exacerbation of pre-existing conditions.  
 
An unexpected adverse event is one that is not listed in the current IB or an event that is 
by nature more specific or more severe than a listed event. 
 
All AEs will be monitored by the therapists 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 Clinical 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 
study physician as: 
 
• Mild: no limitation in normal daily activity 
• Moderate: some limitation in normal daily activity 
• Severe: unable to perform normal daily activity 
 
The relationship of the study treatment to an AE will be determined by the study 
physician 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 participant’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 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. 


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8.2 Spontaneously Reported Reactions  
 
Commonly expected spontaneously reported reactions are collected on a separate CRF 
page and will be categorized as mild, moderate, or severe. Common, expected reactions 
are defined as those most frequently reported in the literature and include:  Anxiety, 
Diarrhea, Difficulty Concentrating, Dizziness, Drowsiness, Dry Mouth, Fatigue, 
Headache, Heavy Legs, Impaired Gait/Balance, Impaired Judgment, Increased 
Irritability, Insomnia, Jaw Clenching or Tight Jaw, Lack of Appetite, Low Mood, Muscle 
Tension, Nausea, Need More Sleep, Nystagmus, Parasthesias, Perspiration, Restlessness, 
Rumination (increased private worries), Sensitivity to Cold, Thirst, and Weakness. 
Spontaneously reported reactions will be collected during the Experimental Session and 
the seven days of telephone contact following the Integrative Session that occurs on the 
day after each Experimental Session. Each reported reaction will be actively followed 
during follow-up phone calls or visits until resolution. Any reported event that is not 
listed as a Spontaneously Reported Reaction will be collected as an Adverse Event 
following the plan in Section 8.5 Adverse Event Collection. Any common reaction 
lasting longer than seven days will be tracked as an adverse event in order to obtain a 
resolution date. 
 
8.3 Serious Adverse Events 
 
An SAE is defined as any untoward medical occurrence that at any dose: 
 
• Results in death 
• Is life-threatening (i.e., the participant was, in the opinion of the Clinical 
Investigator, at immediate risk of death from the event as it occurred); it does not 
refer to an event which hypothetically might have caused death if it were more 
severe 
• Requires or prolongs inpatient hospitalization 
• Results in persistent or significant disability/incapacity (i.e., the event causes 
substantial disruption of a person’s ability to conduct normal life functions) 
• Results in a congenital anomaly/birth defect 
• Requires intervention to prevent permanent impairment or damage 
• Is an important and significant medical event that may not be immediately life-
threatening or resulting in death or hospitalization, but based upon appropriate 
medical judgment, may jeopardize the patient/participant or may require 
intervention to prevent one of the other outcomes listed above 
 
AEs that 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 study 
physician, hospitalization was prolonged as a result of participation in the clinical trial or 


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was necessary due to a worsening of the pre-existing condition. This is because the onset 
of the event (the reason for the procedure) occurred before the participant was entered in 
the trial. Hospitalization for cosmetics, non-emergency prophylaxis, or abortion does not 
result in an SAE report unless, in the view of the study physician, hospitalization for 
these procedures was prolonged as a result of participation in the clinical trial. 
 
8.4 Medical Emergencies 
 
The sessions will be conducted in a private practice setting, 3.3 miles away from the East 
Cooper Medical Center where emergency equipment is immediately available. The study 
physician will be available in the case of medical emergencies and will be within three 
miles away from the study site during Experimental Sessions. The therapists or study 
physician will be available via mobile phone or pager throughout the study if any 
problem occurs when a PTSD+ participant or CSO participant is not at the site, and they 
will continue to see their outside therapist as needed throughout the study. For a recently 
completed Phase 2 trial, the sponsor has established contingency plans for responding to 
those AEs that appear most likely, based on a comprehensive review of literature 
described in the current IB. Similar contingency plans will be used in this protocol. The 
site will provide an Automated External Defibrillator (AED). The at least one therapist on 
each team will maintain BLS certification.  
 
With these personnel and equipment, the therapists or study physician will be able to 
perform basic cardiac life support if necessary and call Emergency Medical Services 
(EMS) to transport the participant to the ED at the closest hospital. In the event of a 
medical emergency or any other medical problem, the study physician will be 
immediately available by phone, and based on his assessment of the situation, he will 
make the decision to either evaluate the participant himself at the site or have the 
therapists call EMS to transport the participant to the ED. 
 
8.5 Adverse Event Collection 
 
The study physician will be responsible for reviewing and confirming all AEs and SAEs 
collected during the study. The therapists will collect AEs during study/telemedicine 
visits after enrollment.  
 
All SAEs will be collected for the duration of the protocol. All SAEs which occur during 
the course of the trial, whether considered to be associated with the study drug or not, 
have to be reported within 24 hours of the Clinical Investigator’s awareness of their 
occurrence. All SAE reports should be faxed to the sponsor. A fax number will be 
provided to the site in separate site-specific instruction for SAE reporting. In addition to 
the fax, the study physician, Clinical Investigator, or designee should call the CRA during 
normal working hours and verbally inform the CRA of the SAE. During off business 
hours or if medical advice is needed immediately please call the sponsor Medical 
Monitor. An SAE reporting instruction with all contact numbers will be provided to the 
site prior to study start.   
 
Medical Monitor:  
 


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Julie Holland, M.D.  
200 East 33rd Street 
Suite 16H New York, NY 10016   
Phone number: 212-358-5808 
 
Study Monitor contact information will be provided in a separate contact list. 
 
Adverse events that will be collected for the duration of the protocol are: 
 
• All SAEs will be collected through participant termination 
• All AEs and spontaneously reported reactions will be collected on the day of drug 
administration and for seven days after each Experimental Session 
• Any spontaneously reported reactions that have not resolved to the PTSD+ 
participant’s or CSO participant’s Baseline level of severity after seven days will 
be collected on the Adverse Event Report page until resolution 
• Events requiring medical attention will be collected from enrollment through the 
PTSD+ participant’s or CSO participant’s last follow-up 
• Events related to planned treatments or physician visits for Baseline conditions 
collected in the Medical History will not be collected unless there is an 
exacerbation of the condition 
• Any Adverse Event leading to withdrawal from the protocol will be collected 
throughout the study 
• All AEs related to changes in psychiatric status will be collected throughout the 
study 
 
A memory aid card will be provided to the participants on the last visit prior to the 3-
month Follow-up to record information on medications taken to treat SAEs, AEs leading 
to withdrawal and psychiatric AEs during the follow-up period. The memory aid card 
will not be collected, but information from the card will be used to aid the participants in 
providing information to the Clinical Investigator. This information may be collected by 
phone. 
 
9.0 Concomitant Medications and Tapering Instructions 
 
If the PTSD+ participant or CSO participant is being treated with psychiatric drugs at the 
time they are recruited into the study, the prospective PTSD+ participant and CSO 
participant will be encouraged to discuss medication tapering with their outside treating 
physician, if needed, and will be required to give the PI permission to do so as well. The 
drugs will then be tapered in an appropriate fashion to avoid withdrawal effects. They 
will be discontinued long enough before the first Experimental Session to avoid the 
possibility of any drug-drug interaction (the interval will be at least five times the 
particular drug and active metabolites’ half-life, plus one week for stabilization).  
 
The therapists will request information about any changes in medication just prior to each 
Experimental Session. The study physician will be responsible for reviewing and 
confirming all medications collected during the study.  
 


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All medications, over the counter (OTC) and prescription will be collected from 
screening through seven days after the last MDMA-assisted session. From seven days 
after the last MDMA-assisted session through Study Termination only prescription or 
OTC medications taken to treat AEs will be collected. Throughout the protocol all 
medications used to treat AEs will be collected, as described in Section 8.5, and all 
changes including discontinuations or additions to psychiatric medications will be 
collected. Medications will be recorded on the concomitant medications CRF.   
 
In general, any MAOi will require a washout of at least 14 days or five half-lives of the 
medication or active metabolite (whichever is greater) plus one week for symptom 
stabilization. The Medication Tapering Table now includes phenelzine, an example 
MAOi, (half life of 11.6 hours) with a minimum of 14-day washout as requested. 
However, this table is not exhaustive. The washout time for any drug not listed on the 
table will be at least 5 times the half life of the drug or active metabolite as published in 
the package insert, plus 1 week for symptom stabilization. 
 
PTSD+ participants and CSO participants must be willing to refrain from taking any 
psychiatric medications during the active portion of the study with the exception of 
gabapentin when prescribed for pain control. If a participant is on stimulants for ADHD 
at Baseline, they can continue to use them at the same dose and frequency as long as they 
discontinue five half-lives before each Experimental Session and do not restart for ten 
days after each Experimental Session. Individuals using opiates for pain management will 
be asked to decrease the dose or avoid taking their pain medication for 24 hours prior to 
Experimental Sessions if possible, as these medications may reduce the efficacy of 
MDMA. Participants will be permitted to take their prescribed opiate medication during 
this period if necessitated by pain flare-ups.  
  
Table 7. 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 
phenelzine 
Nardil 
11.6 
14 
prazosin 
Minipress 
2-3 
1 
quetiapine 
Seroquel 
6 
2 
risperidone 
Risperdal 
3-20 
4 
sertraline 
Zoloft 
26 
6 


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temazepam 
Restoril 
8-12 
3 
trazodone 
Desyrel 
9 
2 
venlafaxine 
Effexor 
12 
3 
ziprazidone 
Geodon 
7 
2 
zolpidem 
Ambien 
2.5 
<1 
 
The PI 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.  
 
PTSD+ participants and CSO participants must agree that, for one week preceding the 
MDMA-assisted session: 
 
a. They will refrain from taking any herbal supplement (except with prior approval 
of the research team) 
b. They will refrain from taking any prescription or nonprescription medications 
(with the exception of non-steroidal anti-inflammatory drugs, acetaminophen, 
birth control pills, thyroid hormones, or other medications approved by the 
research team) 
 
PTSD+ participants and CSO participants will receive a memory aid card to record 
information at the 3-month and 6-month follow-up, as described in Section 8.5. PTSD+ 
participants will use this card to record changes in psychiatric medications that they will 
be asked about at the Study Termination Visit. Memory aids will not be collected. 
PTSD+ participants may return to taking psychiatric medications and discontinue birth 
control after the Primary Endpoint if necessary. 
 
10.0 Clinical Laboratory Assessments 
 
The PI will examine laboratory assessments gathered in screening for assessing 
participant eligibility. The study physician will use a list of normal ranges to conclude 
whether participants are eligible for the protocol, and will indicate justification for 
admitting participants with abnormal values, after consultation with the Medical Monitor. 
 
The following laboratory assessments will be performed as a part of screening:  
 
• Serum electrolytes and metabolic profile 
o ALT/SGPT 
o Albumin:globulin (A:G) ratio 
o Albumin, serum 
o Alkaline phosphatase, serum 
o AST/SGOT 
o Bilirubin, total 
o BUN:creatinine ratio 
o Calcium, serum 


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o Carbon dioxide 
o Chloride, serum 
o Creatinine, serum 
o Globulin, total 
o Glucose, serum 
o Potassium, serum 
o Protein, total, serum 
o Sodium, serum 
• CBC 
o Hematocrit 
o Hemoglobin 
o MCV 
o MCH 
o MCHC 
o RDW 
o Percentage and absolute differential counts 
o RBC 
o Red blood cell count 
o White blood cell count 
• Urinalysis 
o Color 
o Appearance 
o Specific gravity 
o pH 
o Protein 
o Glucose 
o Ketones 
o Occult blood 
o Leukocyte esterase 
o Nitrite 
o Bilirubin 
o Urobilinogen 
• Thyroid function 
o TSH high sensitivity 
o Free T4 
o Free T3 
• HIV serology 
• Urine-dip pregnancy test for participants of childbearing potential 
• Urinary drug test will be performed 
 
Any national LabCorp laboratory may perform assessments other than the urine drug 
screen and pregnancy test. 
 
11.0 Study Monitoring, Auditing, and Documentation 
 
The Clinical Investigator, therapists, and their study staff will be trained prior to the start 
of the study. The study site will be monitored by site visits and telephone calls to the 


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Clinical 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. During each monitoring visit, source data verification 
will be performed to ensure compliance, including accurate and complete recording of 
data on CRFs, source documents, and drug accountability records. Electronic CRFs 
supplied by the sponsor will be completed for each participant enrolled. Monitoring and 
auditing procedures will be supplied in a separate document.  
 
During or after the study, the regulatory authorities, the IRB, and/or representatives of the 
sponsor may request access to all source documents, CRFs and other protocol 
documentation for on-site audit or inspection. 
 
12.0 Data Analysis  
 
Key Personnel, MAPS, and the biostatistician will agree on a Statistical Analysis Plan at 
the beginning of the study. The biostatistician will perform an Intent to Treat (ITT) 
analysis using repeated measures Analysis of Covariance (ANCOVA) to compare 
demographics and all available data from any participant receiving at least one 
Experimental Session and completing follow-up assessments from all participants, even 
if they withdraw from the allocated treatment prior to the Primary Endpoint.  
 
This pilot study will test the impact of MDMA-assisted psychotherapy with CBCT for 
reducing PTSD and other psychological symptomology (e.g., depression) among a 
sample (N=10) of participants with PTSD. The primary measure will be a paired T-test of 
CAPS scores from Baseline to Primary Endpoint. In addition, to determine the strength of 
the treatment effect, pre to post (paired) mean differences effect size estimates will be 
calculated. Durability of effects will be examined by comparing changes from Baseline to 
the assessments at three and six months after the final Experimental Session using mixed-
effects regression methods, which accounts for both missing data and the nesting of 
correlated longitudinal data within participants.  
 
Effect sizes will be estimated for all outcome measures using Cohen’s (1988) procedures 
(Cohen’s d and small sample bias corrected Hedges’ g) [194]. Effects on depression 
symptoms, psychological functioning, trauma-related beliefs, interpersonal closeness, and 
sleep quality will also be assessed for exploratory purposes. The biostatistician will 
conduct secondary analyses of self-report assessments using repeated measures 
ANCOVA. As a secondary outcome measure, weekly PCL-5 assessments will be 
conducted 15 times, starting at the second prep visit, weekly during treatment, and three 
follow-up assessments. To examine changes in PCL-5 over the 15 time points, the 
sponsor statistician will use linear mixed-effects regression with restricted maximum 
likelihood estimation, using weeks as a continuous variable. Measures of relationship 
satisfaction will be analyzed separately for participants with and without PTSD. 
Statistical significance will be determined based on α < .05 for all tests other than the 
PCL-5, which will be a secondary measure for self-reported PTSD symptoms intended to 
support the CAPS.  
 
Qualitative safety analyses will examine adverse events, concomitant medications, and 
spontaneously reported reactions by summary tables listing maximum severity and 


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duration, as well as frequencies and percentages, tabulated overall and by PTSD+ 
participants and CSO participants. Quantitative safety analyses will examine vital signs, 
changes in Tinnitus and/or Pain, SUD, and C-SSRS, with comparisons made between by 
PTSD+ participants and CSO participants for effect of PTSD on safety measures.   
 
12.1 Statistical Power 
 
This pilot RCT is the first study of its kind intended to establish preliminary effect size 
estimates of CBCT combined with MDMA-assisted psychotherapy for PTSD. In the 
absence of published effect sizes for this new treatment modality, effect sizes were 
estimated based on prior trials of these individual treatments. In a limited number of 
small pilot studies, CBCT for PTSD yielded paired-treatment effect sizes of g > 1.0 for 
improvements in PTSD on the primary outcome measure and co-morbid symptoms. The 
two completed controlled RCTs of MDMA-assisted psychotherapy for PTSD have 
yielded effect sizes of g > 1.0 for improvements in PTSD symptoms as well. Assuming 
that effect size of the combined treatment may be approximately 0.8, estimated power for 
a within-subject analysis with a significance level of .05 based on a 2-tailed test, is 62% 
for a sample size of 10 participants for the primary measure, suggesting the potential for 
an underpowered design, but with some possibility of detecting a within-subject effect 
due to treatment. Statistical power estimates were not available for secondary and 
exploratory measures, as they were previously not used in sponsor-supported studies. 
 
13.0 Ethics 
 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.  
 
The protocol and the ICF must be reviewed and approved by a properly constituted IRB 
and FDA before study start. Signed and dated documentation of IRB and FDA approvals 
must be provided to the sponsor. Prior to study start, the Clinical Investigator is required 
to sign a protocol signature page confirming their agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to the sponsor. 
 
14.0 Informed Consent 
 
The main licensed therapists are responsible for obtaining informed consent in adherence 
to GCP and according to applicable regulations prior to entering the participant into the 
trial. Information about the study must be given orally and in an understandable form. 
Written information about the trial will also be provided. The informed consent 
discussion must be conducted by a person who is qualified according to FDA regulations. 
The PTSD+ participants and CSO participants should have the opportunity to inquire 
about details of the MDMA-assisted session and to consider participation.  
 
For all PTSD+ participants and CSO participants the dose of MDMA will be disclosed. 
This is not a blinded study. 


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In addition to the explanation of study visits, the information should include that access 
to original medical records and processing of coded personal information must be 
authorized. Written consent to take part in the study includes giving the Clinical 
Investigators permission to view the PTSD+ participant’s and CSO 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. 
 
Eligible PTSD+ participants and CSO participants may only be included in the study 
after signing the IRB approved ICF. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol, including screening activities). The process of obtaining informed consent 
should be documented in the PTSD+ participant and CSO participant source documents. 
The therapists will provide a copy of the signed ICF to the dyad and will maintain the 
original in the ISF. The ICF process may be performed via telemedicine. 
 
The written ICF and any other written information to be provided to PTSD+ participants 
and CSO participants should be revised whenever important new information becomes 
available that may be relevant to the dyad’s consent. Any revised ICF and written 
information should receive approval from an IRB before use. The PTSD+ participant and 
CSO participant should be informed in a timely manner if new information becomes 
available that might affect the decision to take part in the MDMA-assisted session. The 
communication of this information should be documented.  
 
PTSD+ participants and CSO participants can withdraw consent at any time without 
prejudice. If a PTSD+ participant or CSO participant withdraws consent but does not 
revoke the Health Insurance Portability and Accountability Act (HIPAA) authorization, 
the Clinical Investigators will have full access to the PTSD+ participant’s or CSO 
participant’s medical records, including Study Termination Visit information. If only the 
HIPAA authorization is revoked, the Clinical Investigators will have full access to all of 
the medical records prior to the date and time of revocation. 
 
15.0 Confidentiality 
 
Every effort will be made to strictly safeguard the confidentiality of PTSD+ participants 
and CSO 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. Except for the screening log, the ICF, and a participant 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 five-digit 
participant 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 PTSD+ participant’s and CSO participant’s participant number. Any 
materials mailed to PTSD+ participants and CSO participants will be sent along with 
stamped return envelopes using the office address of the Clinical Investigator both as 


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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 Clinical 
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.  
 
16.0 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 PTSD+ 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 
PTSD+ participant or to the participant directly. 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.  
 
17.0 Treatment and Compensation for 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 Clinical Investigators, as described in 
Section 8.4. If the study physician cannot treat a study-related emergency, then there are 
contingency plans for the transport of participants to the nearest hospital.   
 
18.0 Record Retention 
 
Clinical Investigators must retain all study records required by the sponsor and applicable 
ICH-GCP and FDA regulations in a secure and safe facility. The Clinical Investigator 
must consult a representative of the sponsor before disposal of any study records. 
“Essential documents” are defined as documents that individually and collectively permit 
evaluation of the conduct of a trial and the quality of the data produced. These documents 
will be filed according to ICH-GCP regulations in the ISF. It is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need 
to be retained.  
  
19.0 Publication Policy 
 


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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 
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. 
  
20.0 References 
 
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Bedi, G., et al., Effects of MDMA on sociability and neural response to social 
threat and social reward. Psychopharmacology (Berl), 2009. 207(1): p. 73-83. 


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94. 
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subjective and BOLD-fMRI responses to favourite and worst autobiographical 
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SAP_001.pdf: 
                                                                                     MPVA-1 Statistical Analysis Plan  
                                                                                                                                            Version 1: 7 November 2018 
                                            
                                                                                            
 
 
 
 
 
MPVA-1 Statistical Analysis Plan 
 
Version 1: 7 November 2018 
 
 
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 Phase 1/2 Open-Label Treatment Development Study 
of MDMA-Assisted Cognitive-Behavioral Conjoint 
Therapy (CBCT) in Dyads in which 1 Member has 
Chronic Posttraumatic Stress Disorder (PTSD) 
 
 
LATEST PROTOCOL  
Amendment 4 Version 1, May 8, 2017 
 
CLINICAL INVESTIGATOR 
 
SUB-INVESETIGATOR 
Michael C. Mithoefer, M.D. 
 
Candice M. Monson, Ph.D. 
 
MEDICAL MONITOR 
 
 
Julie Holland, M.D. 
 


                                                                                     MPVA-1 Statistical Analysis Plan  
                                                                                                                                            Version 1: 7 November 2018 
                                            
                                                                                            
 
STUDY MONITOR 
Charlotte Harrison 
 
STATISTICIANS 
 
Scott Hamilton, Ph.D. 
 
PLAN PREPARED BY 
 
Scott Hamilton, Ph.D. 
Allison Feduccia, Ph.D. 
Julie Wang, Ph.D. 
 
 
 
 


                                                                                     MPVA-1 Statistical Analysis Plan  
                                                                                                                                            Version 1: 7 November 2018 
                                            
                                                                                            
 
Table of Contents 
List of Abbreviations .................................................................................................................... 4 
1.0 
Introduction ....................................................................................................................... 6 
2.0 
Background ....................................................................................................................... 6 
3.0 
Study Objectives................................................................................................................ 7 
Primary Objective ................................................................................................................................... 7 
3.2 
Exploratory Objectives .............................................................................................................. 7 
3.3 
Process Objectives ...................................................................................................................... 9 
3.4 
Safety Objectives ........................................................................................................................ 9 
4.0 
Protocol Design................................................................................................................ 10 
5.0 
Measures .......................................................................................................................... 13 
5.1 
Outcome Measures ................................................................................................................... 13 
5.2 
Process Measures...................................................................................................................... 13 
6.0 
Analyses ........................................................................................................................... 14 
Analysis Populations ............................................................................................................................. 14 
Handling of Dropouts, Missing Data ................................................................................................... 15 
Protocol Deviations................................................................................................................................ 16 
Pooling of Investigator Centers ............................................................................................................ 16 
Baseline Values ...................................................................................................................................... 16 
Subject Disposition and Dosing Summary .......................................................................................... 16 
Demographics and Baseline Characteristics ....................................................................................... 17 
Prior and Concomitant Medications ................................................................................................... 17 
Efficacy Analyses ................................................................................................................................... 17 
1. 
Primary Efficacy Analyses ......................................................................................................... 18 
2. 
Secondary and Exploratory Efficacy Analyses .......................................................................... 18 
4. 
Additional Exploratory Analysis ................................................................................................ 19 
6. 
Safety Analyses .......................................................................................................................... 19 
Timing of Analyses ................................................................................................................................ 21 
Statistical Software ..................................................................................................................... 21 
References .................................................................................................................................... 21 
 
 
 
 
 
 
 
 
 
 


                                                                                     MPVA-1 Statistical Analysis Plan  
                                                                                                                                            Version 1: 7 November 2018 
                                            
                                                                                            
 
List of Abbreviations 
AE(s)  
Adverse Event(s) 
AED  
Automated External Defibrillator 
A:G 
 
Abumin : Globulin ratio 
ALT/SGPT 
Alanine aminotransferase 
AMI   
Acute Myocardial Infarction 
AST/SGOT 
Aspartate aminotransferase 
BDI-II  
Beck Depression Inventory II 
BP 
 
Blood Pressure 
BT 
 
Body Temperature 
BUN  
Blood Urea Nitrogen 
C 
 
Celsius 
CAPS  
Clinician Administered PTSD Scale for DSM-5 
CBCT  
Cognitive- Behavioral Conjoint Therapy 
CI 
 
Clinical Investigator (e.g. therapists, co-investigators) 
CPK 
 
Creatine Phosphokinase 
CRA  
Clinical Research Associate 
CRF(s) 
Case Report Form(s) 
CSI 
 
Couples Satisfaction Index 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTS-2  
Conflict Tactics and Aggression 
DBP 
 
Diastolic Blood Pressure 
DEA  
Drug Enforcement Administration 
DMF  
Drug Master File 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders - 5 
ECG/EKG 
Electrocardiogram 
ED 
 
Emergency Department 
EMDR  
Eye Movement Desensitization and Reprocessing 
EMS  
Emergency Medical Services 
ERQ  
Emotional Regulation Questionnaire 
F 
 
Fahrenheit 
FDA  
Food and Drug Administration  
GAF   
Global Assessment of Functioning 
GCP 
 
Good Clinical Practice 
HCl 
 
Hydrochloride 
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  
IPC 
 
Interpersonal Closeness Measure 
IPF 
 
Inventory of Psychosocial Functioning 
IR 
 
Independent Rater 
IRI 
 
Interpersonal Reactivity Index 


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IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
IV 
 
intra-venous 
LTFU  
Long-term Follow-up Questionnaire 
MAOI  
Monoamine oxidase inhibitor 
MAPS  
Multidisciplinary Association for Psychedelic Studies 
MCH  
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV   
Mean Corpuscular Volume  
MDI 
 
Multiscale Dissociation Inventory 
MDMA 
3,4-methylenedioxymethamphetamine 
MMRM           Mixed Effect Model Repeat Measures 
MP-1  
MAPS’ first clinical trial of MDMA-assisted psychotherapy for PTSD 
MP-2  
MAPS’ second clinical trial of MDMA-assisted psychotherapy for PTSD 
MSIS  
Miller Social Intimacy Scale 
PCL 
 
Posttraumatic Symptom Checklist 
PI 
 
Principal Clinical Investigator 
PRN 
 
As needed 
PSQI  
Pittsburgh Sleep Quality Index 
PTCA   
Percutaneous Transluminal Coronary Angioplasty 
PTGI  
Posttraumatic Growth Inventory 
PTSD  
Posttraumatic Stress Disorder 
PTT 
 
Partial Thromboplastin Time 
QRI 
 
Quality of Relationships Inventory 
RBANS  
Repeatable Battery for the Assessment of Neuropsychological Status  
RBC  
Red Blood Cell Count 
RDW  
Red Cell Distribution Width 
RRPQ  
Reactions to Research Participation Questionnaire 
SAE(s) 
Serious Adverse Event(s) 
SAP                 Statistical Analysis Plan 
SBP 
 
Systolic Blood Pressure 
SCID-I-RV 
Structured Clinical Interview for Diagnoses Axis I Research Version 
SERT   
Serotonin Transporter 
SL 
 
Sublingual 
SNRI  
Selective Serotonin and Norepinephrine Uptake Inhibitor 
SOCQ  
States of Consciousness Questionnaire  
SOP(s)  
Standard Operating Procedure(s) 
SORTS 
Significant Others’ Responses to Trauma Scale 
SSRI  
Selective Serotonin Reuptake Inhibitor  
SUD   
Subjective Units of Distress 
TABS  
Trauma and Belief Attachment Scale 
TAS-20 
Toronto Alexithymia Scale 
TEAE  
Treatment Emergent Adverse Events 
TSH 
 
Thyroid Stimulating Hormones 
U.S. 
 
United States of America 
WBC   
White Blood Cell Count 


                                                                                     MPVA-1 Statistical Analysis Plan  
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1.0 Introduction 
 
This document presents a Statistical Analysis Plan (SAP) for MAPS study protocol MPVA-1, a 
Phase 1/2 open-label feasibility study exploring the safety and efficacy of combined MDMA-
assisted pyschotherapy with Cognitive-Behavioral Conjoint Therapy (CBCT) for treating 
individulas with chronic treatment-resistent Posttraumatic Stress Disorder (PTSD) and a 
significant other with associated pyschological distress. This study is not intended to lead to a 
registration study.   
 
The statistical plan described hereafter is an a priori plan based on the statistical analysis plans 
included in the study protocol. This SAP will be finalized prior to any inferential or descriptive 
analyses of data pertaining to the MAPS-sponsored MPVA-1 study. SAS programming may 
occur as study data accumulate in order to have analysis programs ready at the time data are 
locked and available for analysis. For the reasons stated here, the conduct of the study in the field 
is considered to be independent of any study outcomes that might materialize upon enactment of 
the currently proposed statistical plan. 
2.0 Background 
 
This is a feasibility and method development study to examine combining CBCT and MDMA-
assisted psychotherapy in subjects with chronic PTSD (PTSD+ participant) and a Concerned 
Significant Other participant (CSO participant) without a current PTSD diagnosis but with 
related psychological distress. Eligible and enrolled participants will undergo a 2-month 
treatment course in dyads that includes CBCT, as described in Monson and Fredman’s (2012) 
manual [1], integrated with elements of the Treatment Manual for MDMA-assisted 
psychotherapy to guide the incorporation of CBCT and MDMA [2]. This study will serve as a 
guide for reseasrchers to test the feasibility of two therapeutic doses of MDMA: (a) 75 mg + 
optional 37.5 mg supplement in Experimental Session 1 and (b) 100 mg  + optional 50 mg 
(default dose) or 75 mg + optional 37.5 mg supplement in Experiemntal Session 2, plus 
psychotherapy sessions and non-drug CBCT sessions for PTSD (Tables 1& 2). The initial active 
doses are expected to produce all the commonly reported effects of MDMA, including changes 
in affect, mood, cognition, feelings of interpersonal closeness, and trust. The supplemental dose 
will prolong subjective drug effects without producing physiological effects any greater than 
peak effects expected after the initial dose. Each therapy team will have one therapist 
professionally trained and experienced in MDMA-assisted psychotherapy and the other therapist 
in CBCT. Whenever possible both therapists will have had training in both methods.    
 
Table 1. Treatment Condition 
Treatment Group 
1st Experimental Session Dose 
2nd Experimental Session Dose 
Active MDMA-assisted 
Psychotherapy  
(N=10 dyads) 
75 mg MDMA 
+ optional 37.5 mg supplement  
100 mg MDMA 
+ optional 50 mg supplement  
or  
75 mg MDMA 
+ optional 37.5 mg supplement 


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Table 2: Dose Selection 
Initial  
MDMA Dose  
Optional Supplemental  
MDMA Dose  
Cumulative (Initial + Optional)  
MDMA Dose  
75 mg 
37.5 mg 
112.5 mg 
100 mg 
50 mg 
150 mg 
 
The purpose of this study is to test the feasibility of combining MDMA-assisted psychotherapy 
with CBCT in participants diagnosed with PTSD and their partners. Results from this study will 
serve as preliminary data to design a larger study to examine the safety and efficacy of this new 
treatment.  
3.0 Study Objectives 
Primary Objective  
 
The primary objective of the study is to assess changes in PTSD symptoms as measured by 
CAPS-5 in PTSD+ participants from Baseline to the Primary Endpoint. 
 
3.2 Exploratory Objectives  
 
Secondary and other exploratory objectives are to assess changes in the dyad’s relationship 
functioning at the Midpoint and Primary Endpoints, assess changes in self- and CSO participant-
reported PTSD symptoms in the PTSD+ participant, and assess problems that often co-occur 
with PTSD, such as depression, sleep disturbances, maladaptive beliefs about self and others, 
and emotion regulation difficulties. 
 
PTSD+ Participants Only 
 
• Assess changes in PTSD symptoms from baseline as measured by the CAPS-5 in 
participants with chronic PTSD at Long-term Follow-up at 3 months and 6 months. 
 
CSO Participants Only 
 
• Assess changes in partner accommodation from baseline with the Significant Others’ 
Responses to Trauma Scale (SORTS) at the Midpoint, Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months for the CSO participant.  
 
PTSD+ Participants and CSO Participants 
 
• Assess changes in self-reported PTSD symptoms from baseline as measured with the 
Posttraumatic Stress Disorder Checklist for the DSM-5 (PCL-5) at Baseline, at each 
Integrative Session, at the Midpoint, Primary Endpoint and Long-term Follow-up at 3 
months and 6 months for both the PTSD+ participant and CSO participant (based on the 


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(PTSD+ participant). 
• Assess changes in depression symptoms from baseline with the Beck Depression 
Inventory-II (BDI-II) at Baseline, Midpoint, the Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months for both participants.  
• Assess changes in emotional regulation from baseline with the Emotion Regulation 
Questionnaire (ERQ) at the Midpoint, Primary Endpoint, and Long-term Follow-up at 3 
months and 6 months for both participants. 
• Assess changes in self-reported sleep quality from baseline with the Pittsburgh Sleep 
Quality Index (PSQI) at Baseline, Midpoint, the Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months for both participants. 
• Assess changes in self-reported posttraumatic growth from baseline with the 
Posttraumatic Growth Inventory (PTGI) by the PTSD+ participant and CSO participant 
(based on the PTSD+ participant) at the Midpoint, the Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months. 
• Assess changes in emotion recognition and alexithymia from baseline with the Toronto 
Alexithymia Scale-20 (TAS-20) at the Midpoint, Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months for both participants. 
• Assess changes in psychosocial functioning from baseline with the Inventory of 
Psychosocial Functioning (IPF) at the Midpoint, Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months for both participants. 
• Assess changes in psychological and physical aggression from baseline with the Revised 
Conflict Tactics Scale (CTS-2) at the Midpoint, Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months for both participants. 
• Assess changes in trauma-related beliefs from baseline with the Trauma and Attachment 
Beliefs Scale (TABS) at the Midpoint, Primary Endpoint, and Long-term Follow-up at 3 
months and 6 months for both participants. 
• Assess changes in dissociative symptomology from baseline with the Multiscale 
Dissociation Inventory (MDI) at the Midpoint, Primary Endpoint, and Long-term Follow-
up at 3 months and 6 months for both participants. 
 
 
Relationship Outcomes 
 
• Assess changes in compassion, empathy, and social functioning from baseline with the 
Interpersonal Reactivity Index (IRI) on the day after each Experimental Session, at 
Midpoint, Primary Endpoint, and Long-term Follow-up at 3 months and 6 months for 
both participants. 
• Assess changes in relationship satisfaction from baseline with the Quality of 
Relationships Inventory (QRI) at the Midpoint, Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months for both participants. 
• Assess changes in social intimacy from baseline with the Miller Social Intimacy Scale 
(MSIS) at the Midpoint, Primary Endpoint, and Long-term Follow-up at 3 months and 6 
months for both participants. 
• Assess changes in interpersonal closeness from baseline with the Interpersonal Closeness 
Measure (IPC) during Experimental Sessions, at the Midpoint, Primary Endpoint, Long-


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term Follow-up at 3 months and 6 months for both participants. 
• Assess changes in couples satisfaction from baseline with the Couples Satisfaction Index 
(CSI) at the Midpoint, Primary Endpoint, and Long-term Follow-up at 3 months and 6 
months for both participants if romantically involved.  
 
3.3 Process Objectives  
 
The process objectives of the study are to assess reactions to research participation. 
 
• Assess participants’ reaction to research with the RRPQ at the Endpoint for both 
participants. 
• Assess the process of participating in this study through a Long-term Follow-up 
Questionnaire (LTFU) at the Long-term Follow-up at 3 months and 6 months for both 
participants. 
 
3.4 Safety Objectives  
 
The safety objectives of the study are to monitor and assure safety of all participants during and 
after the Experimental Sessions by assessing physiological effects, psychological distress, AEs, 
SAEs, medical events, spontaneously reported reactions, and suicidal ideation and behavior. All 
of the objectives below will be assessed in both participants. 
 
• Suicidal ideation and behavior will be assessed with the Columbia Suicide Severity 
Rating Scale (C-SSRS) according to the Table 3: Time and Events. 
• During Experimental Sessions, Subjective Units of Distress (SUD) and vital signs 
including blood pressure, heart rate, and temperature will be collected. 
• Serious Adverse Events (SAEs) will be collected in both groups through Study 
Termination. All Adverse Events (AEs) will be collected on the day of drug 
administration through the Primary Endpoint and will be followed to resolution. 
• Any spontaneously reported reactions will be collected from the day of the Experimental 
Session through seven days after both Experimental Sessions. Reactions that have not 
resolved to the participants’ Baseline level of severity after seven days will be collected 
on the Adverse Event Report page until resolution.  
• Assess General Wellbeing (clinician-rated) at all visits and phone calls for both the 
participants. 
• AEs requiring medical attention will be collected through Study Termination. 
• 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. 
• Baseline medications and changes to psychiatric medications will be collected throughout 
the study. 
• Changes in pre-existing chronic pain and/or tinnitus symptoms will be collected 


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throughout the study using a Visual Analog Scale in any members of the dyad reporting 
these symptoms. 
4.0 Protocol Design 
 
As background for the statistical methods presented below, this section provides an overview of 
the study design. This overview is a summary only. The protocol is the definitive reference for 
all matters discussed in what follows. 
 
This is a Phase 1/2 open-label study to examine the feasibility of combined MDMA-assisted 
psychotherapy with CBCT in 10 dyads that include one participant who has been diagnosed with 
PTSD for at least 6 months (PTSD+ participant) and a CSO participant (i.e., intimate or non-
intimate partner who does not have a current diagnosis of PTSD). Dyads must consist of people 
who are in a significant ongoing relationship, including but not limited to romantic relationships. 
Baseline screening procedures and assessments will be conducted for both members of the dyad. 
Dyads in which both members meet all Inclusion and no Exclusion Criteria will be enrolled.  
 
Eligible and enrolled participants will undergo a 2-month course of psychotherapy as a dyad that 
includes CBCT for PTSD integrated with MDMA-assisted psychotherapy. The CBCT sessions, 
as described in Monson and Fredman’s (2012) manual, will be integrated with elements of the 
Treatment Manual for MDMA-assisted Psychotherapy in order to modify CBCT to incorporate 
MDMA as a catalyst for the therapeutic process. Sessions will be conducted by a co-therapy 
team and will include Preparatory Sessions, two Experimental Sessions of MDMA plus 
psychotherapy, and non-drug CBCT psychotherapy Integrative Sessions. The primary objective 
is to measure changes in PTSD symptoms via CAPS global severity scores in PTSD+ 
participants at Baseline and the Primary Endpoint, one month after the 15th CBCT session. 
Additional measures evaluate various qualities of the relationship between the participants. (See 
Time and Events Table). 
 
The Experimental Sessions will last 6 to 8 hours and will be scheduled 3 weeks apart, with an 
intervening course of non-drug therapy. The non-drug psychotherapy includes two Preparatory 
Sessions prior to the first Experimental Session and five Integrative Sessions after each 
Experimental Session. Integration visits will be conducted by telemedicine (video conferencing 
whenever possible, telephone if there are occasions when video conferencing is not technically 
possible) and will include both members of the dyad. The sessions will follow a combination of 
the MDMA-assisted psychotherapy manual and the CBCT manual, with each method modified 
as needed to combine the therapies (See Time and Events Table).  


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                                                                                                               Page 11 of 21 
Table 3: Time and Events 
 
Screen 
Preparatory 
Experimental Session 1, Integrative Sessions 
Midpoint 
Experimental Session 2, Integrative Sessions 
Primary 
Assess 
3 Mo 
LTFU 
6 Mo 
LTFU  
Visit # 
Pre-Study 
V 1 
V 2 
V3 
V 4 
V 5 
V6 
V 7 
V 8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
Type of Session 
Screening 
Prep 
Prep 
Exp 
Int 
Int 
Int 
Int 
Int 
Assess 
/Prep 
Exp 
Int 
Int 
Int 
Int 
Int 
Outcome 
Assess 
Assess 
Visit Format 
Telemed or Visit 
Telemed 
Visit 
Visit  
(overnight) 
Visit 
Telemed Telemed Telemed Telemed 
Visit 
Visit  
(overnight) 
Visit 
Telemed Telemed Telemed Telemed Telemed Telemed 
Telemed 
Visit Timing Window 
>1 day, month prior 
to Visit 1 
≤ 1 Mo 
before V2J 
Day 0 
Day 1 
Day2 
4 visits  
over 3 weeks between V3 and V10 
~3 weeks 
post V3; 
prior to 
V10 
~3 weeks 
post V3 
1 day 
post 
V10 
 4 visits  
over 4 weeks between V10 and V15 
 
1 Mo 
post V15 
3 Mo post 
V15 
6 Mo post 
V15 
CBCT Manual Session # 
 
 
1, 2, 3 
4, 5 – 
Condensed 
delivery just 
after MDMA 
administration 
Review 
6 
7 
8 
9 
10, 11 
 
 
 Review  
Review 
12 
13 
14 
15 
 
 
 
Initial Phone Screen  
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric History (Medical Record Review) 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Phys. Exam (BP, Pulse, Temp) 
✓A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief Neurological Exam 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-RV 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Lab Tests, w/ HIV, HCV test 
✓A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Medication Taper (if applicable) 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Enrollment after meeting I/E 
 
✓ 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record to Audio/Video 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Drug Screen 
✓A 
 
 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
Pregnancy Screen (if applicable) 
✓A 
 
 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
Administer IP Drug + Therapy/CBCT 
 
 
 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
Integrative Session 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
Issue Out of Session Assignments 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
7 days of Telephone Contact 
 
 
 
 
✓ G 
✓ G 
✓ G 
 
 
 
 
✓ G 
✓ G 
✓ G 
 
 
 
 
 
CAPSI 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
✓ 
✓ 
PCL individual and participant  
✓ 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
BDI-II 
✓ 
 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
✓ 
✓ 
✓ 
IRI 
✓ 
 
 
 
✓ 
 
 
 
 
✓ 
 
✓ 
 
 
 
 
✓ 
✓ 
✓ 
General Wellbeing 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
TAS-20, QRI, SORTS, CTS-2, IPF, MSIS, TABS, 
MDI, ERQ, PSQI, PTGI, CSI 
✓ 
 
 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
✓ 
✓ 
✓ 
LTFU Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
✓ 
IPC 
✓ 
 
 
✓C 
 
 
 
 
 
✓ 
✓C 
 
 
 
 
 
✓ 
✓ 
✓ 
RRPQ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
 
 
Vitals (Monitoring of BP, Pulse and Temp) 
 
 
 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
Changes in Tinnitus and/or Pain H 
✓ 
✓ D 
✓ D 
✓ D 
✓ D 
✓ D 
✓ D 
✓ D 
✓ D 
✓ 
✓ D 
✓ D 
✓ D 
✓ D 
✓ D 
✓ D 
✓ 
✓ 
✓ 
Subjective Units of Distress 
 
 
 
✓ 
 
 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
C-SSRS 
✓ 
 
✓F 
✓B, C, D 
✓ 
 
 
 
 
✓ 
✓B, C, D 
✓ 
 
 
 
 
✓ 
✓ 
✓ 
SAEs, AEs of psychiatric status or withdrawal 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
AEs Requiring Medical Attention 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Spontaneously Reported Reactions  
 
 
 
✓ 
✓ 
✓ 
✓ 
 
 
 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
 
All AEs 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
A = Performed locally.  
B = At the beginning of the session.  
C = Approximately 6 hours after administration of MDMA.  


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                                                                                                               Page 12 of 21 
D = As needed.  
E = Approximately every 60 minutes.  
F = Given after medication washout.  
G = For 7 days after Experimental Session, contact will be made by phone or telemedicine and not both, C-SSRS D2 and D7 of calls only, General Wellbeing for all 7 days.  
H = Only in participants with pre-existing chronic pain or tinnitus.  
I = CAPS may be recorded to video.  
J = Additional time allowed if necessary for medication tapering.


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                                                                                                               Page 13 of 21 
5.0 Measures 
 
5.1 Outcome Measures 
 
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) 
 
PTSD Checklist for DSM-5 (PCL): last month, since last visit, since last week 
 
Beck Depression Inventory-II (BDI-II) 
 
Emotional Regulations Questionnaire (ERQ) 
 
Interpersonal Reactivity Index (IRI) 
 
Pittsburgh Sleep Quality Index (PSQI) 
 
Post Traumatic Growth Inventory (PTGI) 
 
Toronto Alexithymia Scale (TAS-20),  
 
Quality of Relationships Inventory (QRI) 
 
Significant Others’ Responses to Trauma Scale (SORTS) 
 
Revised Conflicts Tactics Scale (CTS2) 
 
Inventory of Psychosocial Functioning (IPF) 
 
Miller Social Intimacy Scale (MSIS) 
 
The Trauma and Attachment Beliefs Scale (TABS) 
 
Multiscale Dissociation Inventory (MDI) 
 
Interpersonal Closeness Measure (IPC) 
 
Couples Satisfaction Index (Romantic couples only) (CSI) 
 
 
5.2 Process Measures 
 
Reactions to Research Participation Questionnaire (RRPQ) 
 


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                                                                                                               Page 14 of 21 
Long-term Follow-up Questionnaire (LTFUQ) 
 
 
5.3 Safety Measures 
 
Vitals (blood pressure, pulse, body temperature) 
 
Somatic Symptoms 
 
Subjective Units of Distress (SUD) 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
General Well-being (GWB) 
 
Spontaneously Reported Reactions (SRR) 
 
Adverse Events (AEs) 
6.0 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. P-value less than 0.0001 will be 
shown in tables as <0.0001. For any analysis that is called out as parametric, e.g. t-test, the 
parametric assumptions will be examined.  If necessary, nonparametric analyses will be utilized, 
e.g. Wilcoxon rank-sum test. 
 
Clinical data will be presented in tabular format. Data not subject to analysis according to this 
plan will not appear in any tables or graphs but will be included in the data listings. Analyses 
will be carried out with SAS Version 9.4 (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. 
 
Analysis Populations 
 
Modified Intent-to-treat (mITT): all dyads that received at least one experimental session and 
completed at least one outcome assessment 
 


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                                                                                                               Page 15 of 21 
Per protocol (PP): all dyads that completed two experimental sessions and primary outcome 
assessment, and did not experience a major protocol deviation 
 
Safety: all subjects who received any study treatment 
 
Handling of Dropouts, Missing Data 
 
Dyads who discontinue treatment prior to completing the second experimental session and the 
primary endpoint will be replaced. These dropout subjects will be asked to complete an outcome 
assessment prior to continuing to the long-term follow-up.  
Early termination visit data for mITT and Safety variables will be analyzed at the closest 
scheduled visit after the last experimental session completed. If the closest visit has valid data, 
the early termination data will be assigned to the next available visit. If a dyad discontinues and 
does not participate in an early termination visit, data from the last available visit will be used to 
replace the missing early termination visit data.  
Partial or Missing Dates:  
The following conventions will be used to impute missing portions of dates for adverse events 
and concomitant medications. Note that the imputed values outlined here may not always 
provide the most conservative date. In those circumstances, the imputed value may be replaced 
by a date that will lead to a more conservative analysis. 
A. 
Start Dates 
1) 
If the year is unknown, then the date will not be imputed and will be assigned a 
missing value.  
2) 
If the month is unknown, then: 
i) If the year matches the first dose date year, then impute the month and day of 
the first dose date. 
ii) Otherwise, assign ‘January.’  
3) 
 If the day is unknown, then: 
i) If the month and year match the first dose date month and year, then impute the 
day of the first dose date. 
ii) Otherwise, assign the first day of the month. 
 
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.’ 


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                                                                                                               Page 16 of 21 
3) 
If the day is unknown, then assign the last day of the month. 
 
Protocol Deviations  
All protocol deviations will be included as a categorized listing. Safety and mITT analyses will 
include all enrolled dyads with all available data. Dyads with major deviations will be excluded 
from the per protocol analyses. Possible protocol deviations include the following seven 
categories: 
• 
Subject entered study but did not meet criteria 
• 
Subject developed withdrawal criteria but was not withdrawn 
• 
Subject received excluded concomitant treatment 
• 
Protocol procedure not performed per protocol 
• 
Subject received incorrect treatment or incorrect dose 
• 
Protocol procedure performed out of range 
• 
Miscellaneous 
The number of dyads in each protocol deviation category listed below will be summarized by 
MDMA group, and individual subjects will be listed in the appendix. 
Pooling of Investigator Centers 
 
All subjects in this study come from one investigational center.  
 
Baseline Values 
 
Baseline values are from screening/baseline visit for all measures, except CAPS-5 and C-SSRS. 
Baseline CAPS-5 will be assessed, during screening (pre-study), no more than 8 weeks before 
the first experimental session. This allows adequate washout of at least five half-lives of pre-
study psychiatric medications and active metabolites, plus one week for stabilization. If CAPS-5 
is completed outside of this window for a participant, the PI will consult the CRA and Medical 
Monitor to determine if the Baseline CAPS should be repeated. For C-SSRS, pre-enrollment 
scores will be used as a measure of ‘lifetime’ suicidal ideation and behavior, and preparatory 
session 2 (visit 2) prior to drug administration will used as ‘baseline.’ If a subject was not 
administered the C-SSRS at preparatory session 2 (visit 2), then ‘baseline’ scores will be visit 3 
pre-drug C-SSRS observation. 
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 will be displayed for all subjects in the Safety population, in the mITT population, and 


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in the PP population. The number and percent of subjects who completed or discontinued the 
study will be reported along with reasons for early termination. Percents will be defined as the 
number of participants who completed, or number discontinued, over the total number of 
subjects in the total study sample, and separately, for PTSD+ participants and CSO participants. 
The timepoint of doses and total MDMA (mg) administered will be summarized for the Safety, 
mITT and PP populations for the total sample and by PTSD+ participants and CSO participants. 
 
Demographics and Baseline Characteristics 
 
Subject demographic data and baseline characteristics will be summarized descriptively overall 
and by PTST+ participants and CSO participants. The demographic data and baseline 
characteristics will be summarized for the mITT.  
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 the total sample and by PTSD+ participants and 
CSO participants. Concomitant medications will be summarized similarly. Prior and concomitant 
medications will be summarized for the Safety Population. Psychiatric medications will be coded 
to common drug classes and terms. 
 
Efficacy Analyses 
For all primary, secondary, and exploratory endpoints descriptive statistics (n, mean, standard 
deviation, median, range, effect size (for measures of interest), or frequencies and percentages 
where appropriate) will be provided for the total sample and by PTSD+ participants and CSO 
participants.  
Effect size (Hedges’ g) will be determined by calculating the mean difference pre- and post- 
treatment divided by the pooled weighted standard deviations for means at baseline and follow-
up [3]. 
 
Hedges’ g = (M1 – M2) / SD*pooled  
Where:  
• 
M1 – M2 = difference in means 
• SD*pooled = pooled and weighted standard deviations 


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1. Primary Efficacy Analyses 
 
The primary efficacy evaluation is a paired t-test of CAPS-5 Total Severity scores at baseline 
and the primary endpoint (visit 16) at an alpha level of 0.05. If the parametric assumptions for t-
test analyses are not met, the analogous nonparametric methods will be used (Wilcoxon Rank-
Sum). 
2. Secondary and Exploratory Efficacy Analyses 
 
Efficacy of secondary and other exploratory outcome measures will be assessed at baseline, 
midpoint (visit 9), and primary endpoint (visit 16) to examine change in scores over time in the 
total sample, and separately, by PTSD+ participants and CSO participants.  
 
For each model, a one-way repeated-measures ANOVA with post-hoc contrast comparisons will 
be conducted to test the effects of the treatment on: PTSD CAPS-5; Significant Others’ 
Responses to Trauma Scale (SORTS); Posttraumatic Stress Disorder Checklist for the DSM-5 
(PCL-5); Beck Depression Inventory-II (BDI-II); Emotion Regulation Questionnaire (ERQ); 
Pittsburgh Sleep Quality Index (PSQI); Posttraumatic Growth Inventory (PTGI); Toronto 
Alexithymia Scale-20 (TAS-20); Inventory of Psychosocial Functioning (IPF); Revised Conflict 
Tactics Scale (CTS-2); Trauma and Attachment Beliefs Scale (TABS); and Multiscale 
Dissociation Inventory (MDI). Relationship distress outcome measures include: Interpersonal 
Reactivity Index (IRI); Quality of Relationships Inventory (QRI); Miller Social Intimacy Scale 
(MSIS); Interpersonal Closeness Measure (IPC); and Couples Satisfaction Index (CSI). 
 
3. Secondary Efficacy Analyses at Secondary Endpoints (Long-Term Follow-up) 
 
Efficacy of outcome measures for long-term follow-up will be assessed at baseline, midpoint 
(visit 9), primary endpoint (visit 16), 3-month follow-up (visit 17), and 6-month follow-up (Visit 
18) to examine changes over time in the total sample, and separately, by PTSD+ participants and 
CSO participants.  
 
For each model, a one-way repeated-measures ANCOVA with baseline scores as covariates and 
post-hoc contrast comparisons will be conducted to test the effects of the treatment on: PTSD 
CAPS-5; Significant Others’ Responses to Trauma Scale (SORTS); Posttraumatic Stress 
Disorder Checklist for the DSM-5 (PCL-5); Beck Depression Inventory-II (BDI-II); Emotion 
Regulation Questionnaire (ERQ); Pittsburgh Sleep Quality Index (PSQI); Posttraumatic Growth 
Inventory (PTGI); Toronto Alexithymia Scale-20 (TAS-20); Inventory of Psychosocial 
Functioning (IPF); Revised Conflict Tactics Scale (CTS-2); Trauma and Attachment Beliefs 
Scale (TABS); and Multiscale Dissociation Inventory (MDI). Relationship distress outcome 
measures include: Interpersonal Reactivity Index (IRI); Quality of Relationships Inventory 
(QRI); Miller Social Intimacy Scale (MSIS); Interpersonal Closeness Measure (IPC); and 
Couples Satisfaction Index (CSI). 
 
If data is missing from participant dropouts a mixed effect model repeat measures (MMRM) will 
be used instead of an ANCOVA.  
 


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4. Additional Exploratory Analysis 
 
Pearson Correlations will be computed between PTSD+ participants’ CAPS-5 scores and CSO 
participants’ outcomes (all) [4]. This analysis will be conducted for baseline, midpoint (visit 9), 
primary endpoint (visit 16), 3-month follow-up (visit 17), and primary endpoint (visit 18). 
Correlations (r) and p values will be reported to assess the direction and magnitude of these 
relationships. This analysis is intended to explore the potential impact of CSO participants’ 
responses to the given treatment on PTSD+ participants’ CAPS-5 scores over time.  
 
5. Process Measures  
 
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. Results will be reported for the total sample and by 
PTSD+ participants and CSO participants.  
 
Reactions to Research Participation Questionnaire (RRPQ) 
Frequency of responses will be tabulated for ‘reasons for participation’ for the total sample and 
by PTSD+ participants and CSO participants. Descriptive statistics will be computed for total 
scores for subscales and reported for the total sample and by PTSD+ participants and CSO 
participants.  
 
6. Safety Analyses 
 
The primary measure of safety will be reports of adverse events. Adverse events are Treatment 
Emergent Adverse Events (TEAE) defined as those AE’s that occurred after dosing and existing 
medical history diagnoses that worsened during the study. Verbatim terms on case report forms 
will be mapped to preferred terms and system organ classes using the MedDRA dictionary. For 
incidence reporting if a subject has more than one AE mapped to the same preferred term, that 
AE will be reported only once using the highest severity and closest relationship to study drug.  
Subject incidence of AEs will be displayed by group and by system organ class. AEs will also be 
summarized by severity. Subject incidence of SAEs will also be displayed. In addition to the 
listing of all AEs, a listing of SAEs and a listing of AEs leading to discontinuation of study drug 
will be included.  
 
Summary tables of frequency listings of commonly reported AEs (Spontaneously Reported 
Reactions) mapped to preferred terms will be displayed during and after each experimental 
session by PTSD+ participants and CSO participants. Additional safety measures will be 
analyzed as follows: 
 


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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 [5][5]. A positive 
response for suicidal ideation is counted when subjects respond “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 subjects answer “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 overall and by PTSD+ participants and CSO participants for each 
time period. Lifetime serious suicidal ideation and positive behavior frequencies will be 
compared to cumulative frequencies at all timepoints throughout the study. 
 
Subjective Units of Distress (SUD) and Vital Signs 
 
SUD scores will be calculated including frequencies and percentages in the total sample and by 
PTSD+ participants and CSO participants at experimental treatment 1 (visit 3) and experimental 
treatment 2 (visit 10). Vital signs include heart rate, body temperature, systolic and diastolic 
blood pressure, and will be summarized using descriptive statistics at baseline and at each post-
baseline time point. Systolic and diastolic blood pressure, heart rate, and body temperature 
readings above the pre-determined cutoff will be reported using numbers and percentages by 
timepoint.  
 
General Well-being 
Therapists will assess PTSD+ participants’ and CSO participants’ general well-being using the 
General Well-being scale at each timepoint and on a daily basis for seven consecutive days after 
each experimental session. Frequencies, percentages, and mean (SD) total scores will be reported 
for the total sample and by PTSD+ participants’ and CSO participants. 
 
Adverse Events Requiring Medical Attention  
All adverse events requiring medical attention will be collected from enrollment through the last 
follow-up. Each occurrence will be reported for the total sample and separately for PTSD+ 
participants and CSO participants. 
 
Events Related to Medical History 
Occurrences will be reported for the total sample and separately for PTSD+ participants and 
CSO participants. 
 
• 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. 
• Baseline medications and changes to psychiatric medications will be collected throughout 
the study. 
• Changes in pre-existing chronic pain and/or tinnitus symptoms will be collected 
throughout the study using a Visual Analog Scale in any members of the dyad reporting 
these symptoms. 


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Timing of Analyses 
 
The primary efficacy analysis will be conducted after all subjects complete the study. 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.  
Statistical Software 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher) for 
Windows. If the use of other software is warranted, the final clinical study report will detail what 
software was used and for what purposes. 
 
 
 
References 
 
1. 
Monson, C.M. and S.J. Fredman, Cognitive-Behavioral Conjoint Therapy for PTSD: 
Harnessing the Healing Power of Relationships. 1 edition ed. 2012, New York: The 
Guilford Press. 239. 
2. 
Mithoefer, M., A Manual for MDMA-Assisted Psychotherapy in the Treatment of 
Posttraumatic Stress Disorder; Version 6: http://www.maps.org/research/mdma/MDMA-
Assisted_Psychotherapy_Treatment_Manual_Version_6_FINAL.pdf. Multidisciplinary 
Association for Psychedelic Studies, 2013. 
3. 
Hedges, L.V., Distribution theory for Glass's estimator of effect size and related 
estimators. J Educ Statistics 1981. 6(2): p. 107-128. 
4. 
Pearson, K., Note on regression and inheritance in the case of two parents. Proceedings 
of the Royal Society of London, 1895. 58: p. 240-242. 
5. 
Nilsson, M.E., et al., Columbia Suicide Severity Rating Scale Scoring and Data Analysis 
Guide, in CSSRS Scoring Version 2.0. 2013: 
http://www.cssrs.columbia.edu/documents/ScoringandDataAnalysisGuide_Feb2013.pdf. 
p. 1-13.