Clinical trial NCT02427568
Conditions: Anxiety
Keywords: Anxiety MDMA Life-threatening illness Therapy midomafetamine
Sponsor: Lykos Therapeutics
Start date: 2015-05-14; Completion date: 2018-05-17
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical trial is to learn if MDMA-assisted therapy is safe and effective in people with anxiety associated with a life-threatening illness. The main question it aims to answer is: Does anxiety decrease in people receiving two sessions of MDMA-assisted therapy?

Researchers will compare people receiving placebo with therapy to people receiving MDMA-assisted therapy.

* Participants will undergo three non-drug preparatory therapy sessions before their first blinded session of MDMA or placebo with therapy.
* Each medication session will be followed by three non-drug integrative therapy sessions.
* After the second blinded medication session, participants receiving MDMA will complete a third open-label medication session.
* Participants who received placebo will be given the option to crossover and receive three sessions of assisted therapy.

Detailed description:
This Phase 2 pilot study is a randomized, double-blind, placebo-controlled study in 18 participants comparing the effects of MDMA-assisted therapy vs. placebo with therapy. Thirteen participants were randomized to the active dose condition of 125 mg of MDMA HCl (plus an optional supplemental dose of 62.5 mg MDMA HCl) with therapy and five participants were randomized to the placebo with therapy condition. The study consisted of two blinded experimental sessions of MDMA-assisted therapy or placebo with therapy, each session lasting six to eight hours and scheduled two to four weeks apart. Each participant was unblinded one month after their second experimental session in Stage 1. After unblinding, participants receiving MDMA were to complete a third open-label experimental session of MDMA-assisted therapy and participants who originally received placebo had the opportunity to cross over to open-label Stage 2 and receive active MDMA-assisted therapy in 3 sessions.

The primary objective of the study is to assess changes in trait anxiety in subjects receiving active dose MDMA compared to those receiving placebo as measured by State-Trait Anxiety Index (STAI) Trait scores from Baseline to the Primary Endpoint (one month after the second experimental session).

Arms: arm 1: Inactive placebo administered on 2 blinded experimental sessions scheduled 2 to 4 weeks apart. Initial dose possibly followed 1.5 to 2.5 hours later by (optional) inactive placebo supplemental dose. arm 2: 125 mg midomafetamine HCl administered on 2 blinded experimental sessions scheduled 2 to 4 weeks apart. Initial dose possibly followed 1.5 to 2.5 hours later by a (optional) supplemental dose of 62.5 mg.
Interventions: intervention 1: Midomafetamine HCl intervention 2: Placebo intervention 3: Therapy
Intervention descriptions: intervention 1: Two sessions of MDMA-assisted therapy lasting six to eight hours, scheduled two to four weeks apart. intervention 2: Two sessions of placebo with therapy lasting six to eight hours, scheduled two to four weeks apart. intervention 3: Manualized therapy

Protocol documents:
ICF_002.pdf: 




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Why am I invited to take part in this research study? 
You are being asked to participate in this research study because you have been 
diagnosed with a life-threatening cancer or neurological illness and because you are 
experiencing significant anxiety as a result of that illness.  
 
What should I know about a research study? 
• Someone will explain this research study to you. 
• Research studies only include people who choose to take part. 
• Whether or not you take part is up to you. 
• You can choose not to take part in the research study. 
• You can agree to take part now and later change your mind. 
• Whatever you decide will not be held against you. 
• Feel free to ask all the questions you want before you decide. 
 
Please take your time to make your decision about taking part. You may discuss your 
decision with your friends and family. You can also discuss it with your health care team. 
If you have questions, you can ask your study doctor to explain the study more. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
any time.  
 
Why is this study being done? 
This small study is designed to provide information on whether MDMA-assisted 
psychotherapy is safe and helpful for subjects with anxiety related to a life-threatening 
cancer or neurological illness.  We plan to use the results of this study to design future 
studies of MDMA-assisted psychotherapy. 
 
The study is sponsored by a U.S.-based non-profit organization, the Multidisciplinary 
Association for Psychedelic Studies (MAPS, www.maps.org). MAPS has completed two 
previous studies of MDMA-assisted psychotherapy for a different condition – post-
traumatic stress disorder (PTSD) – and is currently conducting several more studies for 
this condition. MAPS is also conducting studies of MDMA-assisted psychotherapy for 
social anxiety in people with autism. 
 
MDMA is a chemical that is structurally similar to some stimulant chemicals, like 
methamphetamine, which is both a major drug of abuse and an FDA-approved treatment 
for Attention Deficit Disorder, and to some psychedelic (hallucinogenic) chemicals, like 
mescaline, which is found in peyote cactus.  MDMA causes the release of serotonin, 
dopamine, and norepinephrine in the brain, and the hormones oxytocin and prolactin. The 
effects most people experience from MDMA are mostly due to serotonin release, and 
somewhat due to norepinephrine and dopamine release. The release of these chemicals 
in the brain can change people’s emotions and feelings. It has some stimulant-like effects 
such as raising your heart rate or body temperature or making you feel more energetic. It 
also has some perceptual effects, like changing how you see yourself or how you see the 
world. MDMA’s effects last between 4-6 hours in most healthy adults. 


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MDMA is experimental, which means it has not been approved by the FDA for medical 
use, except within research studies like this one. MDMA is illegal to use outside of 
research and is sometimes known as "Ecstasy" (which is supposed to contain MDMA, 
but can often contain other drugs instead of or in addition to MDMA).  
 
MDMA operates differently from currently approved anti-anxiety drugs, in that it is not 
sedating and does not need to be taken daily. Before it became illegal, some 
psychotherapists combined MDMA with psychotherapy (“talk therapy”) to help people 
with psychological problems, sometimes including anxiety related to life-threatening 
illness and there are narrative reports of people being helped in this way. No studies 
have yet been conducted to evaluate whether MDMA-assisted psychotherapy can help 
people with this kind of anxiety. We know that MDMA increases positive mood and also 
changes the way we see and think about the world around us.  This may make it easier 
to recall upsetting experiences and think about them differently.  It may also enable 
people to handle fears about their future and to re-evaluate these with less anxiety.  
 
Some people report that MDMA helps them to feel more caring, connected, and 
forgiving toward themselves and others after MDMA. MDMA can sometimes decrease 
fear, avoidance, and negativity and increase trust and connection between a patient and 
their therapist.  When this occurs, MDMA may make the therapy more likely to work. It 
is possible that these MDMA-related positive effects, in combination with 
psychotherapy, will help some people with their anxiety about the recurrence or 
presence of a life-threatening illness.  
 
Two scientific studies of MDMA-assisted psychotherapy reported reduction in symptoms 
from a different type of anxiety disorder, Posttraumatic Stress Disorder (PTSD). In 
addition, published scientific research has shown that psychedelic (hallucinogenic) 
drugs such as psilocybin and LSD, combined with a similar type of psychotherapy, 
reduced anxiety in people with a life-threatening illness 
 
Are there potential conflicts of interest? 
The study doctor inviting you to take part in this research study may also be your 
treating doctor. In such cases, your study/treating doctor has an interest in both your 
care and promoting the successful conduct of this research. Sometimes these two 
interests may cause conflict. You can choose not to take part in the study and still 
receive treatment from your doctor. If you do wish to consider taking part in the study,, 
you will need to speak about the study to an independent doctor who is not your 
personal doctor and is not a member of the treatment team a This independent doctor 
will answer your questions and conduct the informed consent process. 
 
The study doctor conducting this research does not have any financial interest in the 
sponsor of this study, which is a non-profit organization, or in the study; this means that 
the study doctor will not be financially affected whether the results of the study are 
positive or not. However, the study doctor and his staff will be paid by the sponsor for 
the work that he and the study staff have to do as part of this study and for the use of 
the site’s facilities. The study doctor is contracted by the sponsor to conduct the study, 
and is not an employee of the sponsor. 


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MAPS, the non-profit company sponsoring the study, is seeking to develop MDMA into 
an FDA-approved prescription medication that it can market under highly regulated 
conditions, with the potential to generate income to further MAPS’ mission.  
 
How many people will take part in the study? 
A total of 18 people will take part in this study. At this time, this site is the only site that 
is conducting this study.  
 
Who can be in the study? 
We are looking for men and women who are over 18 years old, and who have a life-
threatening illness that is either cancer or a neurological illness that does not affect your 
ability to think clearly. You must also have significant anxiety because of your illness. 
You must not be currently receiving primary treatment for your illness in order to be in 
the study. This means you cannot be receiving treatments like chemotherapy or 
radiation at the same time that you are in the study. If you are receiving maintenance 
treatments for your illness, the study doctor will need to talk to your regular doctor to 
see if you can be in the study. There are also other requirements you must meet in 
order to be in the study. The study doctor will discuss these requirements with you. 
 
What will happen if I take part in this research study?   
 
You must be aware of the following: 
• We may video-record all office visits and therapy sessions for research purposes, 
which include developing a treatment manual, and to possibly train future 
therapists in this type of therapy. You can ask to view these recordings at any 
time while you are taking part in this study. These videos are part of the study 
data and are kept in the same secure way as all information collected about your 
participation in the study. Only specific researchers can view these videos.  If you 
ask to view them, you will be given a personal hard drive with your video data 
uploaded onto it. When we video record you, we will include your face. We will 
not label the video with your name, address, or any other identifying information. 
You will be given the option to not have these videos used for training or 
research presentations. We will discuss this with you before you enter the follow-
up period if you complete the treatment period, or at the time you stop 
participating in the study if you do not complete the treatment period. 
 
If the Principal Investigator 
 is not one of the therapists on your 
therapy team, he will still monitor your study sessions by video. 
 
• You will have to avoid taking any medicines for psychological problems from the 
time of enrollment in the study up until you complete the one-month follow-up 
after your final experimental session, unless the study doctor makes a specific 
exception, such as giving you medicine for sleep or anxiety temporarily and if 
needed. Decisions about which medications you can keep taking and which you 
will have to stop will be made by the investigator after talking to your doctor. If 
you are taking opiate medications for pain management, you can remain on 


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these medications, although we may ask you to reduce the dose or avoid 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. 
You will need to give the study doctor or a member of his study team permission 
to talk with your own doctor. They may discuss ways to help you safely stop or 
decrease your medication if necessary. We will help you do this. You may return 
to taking your medications during the follow-up period.  
 
• You must let us know about any medical conditions or procedures, like surgery, 
within 48 hours of their occurrence. 
 
• You will need to name a relative, spouse or close friend as your support partner 
during the study. This person will complete questionnaires about you, and may 
come to some study visits if you and your therapists agree that they can be there.  
 
• We will ask you to name two other people who know you very well and see you 
regularly to answer questionnaires about you during the study. They do not need 
to come with you to any study visits. 
 
• We will not allow you to drive after each experimental session in which you 
receive the study drug (MDMA or placebo). We will arrange for your 
transportation after experimental sessions.  
 
• You will need to give us the name and contact information (telephone number, 
cell phone number, or email) of a relative, spouse, or close friend to contact in 
case of medical emergency. 
 
• If you are currently seeing a psychotherapist, you may not begin any new 
psychotherapy or change the type, frequency, or length of visits with your 
psychotherapist until after your final session/visit. This is so any change in your 
anxiety symptoms are more likely to be from the experimental treatment rather 
than from any new psychotherapy treatments. 
 
• For your safety, it is very important to tell us about all medicines you are taking, 
including herbal or “natural” remedies or supplements, and to check with us 
before you begin taking a new medicine while in this study.   
 
• You will also need to tell us if you become pregnant anytime during the study. If 
you are a woman that can have children, you must not get pregnant while you 
are taking part in this research study. You must agree to practice two effective 
and acceptable forms of birth control (described later in this form). 
 
• If you have an increase in symptoms for which you previously took medicine, if 
you need to contact your outside therapist other than for the usual appointments, 
and/or if you start or stop taking prescribed medicine, you should let us know as 
soon as possible.  


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• You should not be a part of any other clinical trial (research study) or take MDMA 
or Ecstasy outside of the study during the whole time you are in this study. 
 
• If you must go the hospital or are in a life-threatening situation at any time during 
the study even if it doesn’t have anything to do with the study, you will need to 
call us as soon as you can to let us know the details.  
 
• We will ask you to allow us to obtain copies and review your medical records 
from your treating doctors.  We will require a signed release form from you in 
order to do this.  
 
How long will I be in the study? 
This study may take up to 15 months or 18 visits if you receive MDMA in Stage 1 of this 
study. This time period includes active participation for up to 3.5 months and long-term 
follow-up visits 6 and 12 months after the last experimental session. 
 
This study can take up to 18 months or 29 visits to complete both Stage 1 and 2 plus 
the long-term follow-up visit if you receive the placebo dose in Stage 1.  If you are in this 
placebo group, you will have 12 visits in Stage 1 and you can choose to have an 
additional 15 visits in Stage 2, where you will receive the active dose of MDMA over an 
additional 3.5 months. This total time period includes 6 months of active participation 
plus long-term follow-up visits at 6 and 12 months after the last experimental session. 
 
The timeline after enrollment for starting treatment can move fast or slow depending on 
availability of open appointments. You may start therapy as soon as one week after 
enrollment or be delayed by as long as two months. Depending on your group, you will 
visit the therapist’s office approximately once a week for 3.5 (active dose groups) or 6 
months (placebo group) during the active period. Experimental sessions last all day and 
require an overnight stay; they are approximately every two to four weeks for 3 or 6 
months depending on the group you are assigned to. After these overnight stays, you 
will also have a brief daily phone call with the therapists for 7 days and you will have 3 
psychotherapy sessions a week apart. You will have testing visits, which require 
interviews, 5-6 times during the study. After active participation is complete, you will 
have a follow up visit one month after your final experimental session and six months 
and one year later.  
 
Types of visits and duration:  
 
Psychotherapy sessions (90-minutes each): 3 introductory sessions at the start of 
participation and 3 sessions after each experimental session. These are approximately 
once a week.  
 
Experimental sessions (8-hours long plus an overnight stay): 3 sessions for each 
person in the active dose arm and 2 sessions plus 3 optional sessions for each person 
in the placebo arm. These are every 2-4 weeks. 
 




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• A urine pregnancy test if you are a woman and are able to get pregnant.  Your 
urine pregnancy test must be negative for you to take part in the study.  
 
If you have decided that you want to be in the study and if we find that you are eligible, 
then you can be in the study and you will schedule your first preparatory psychotherapy 
session with one of the study therapist teams. You will see the same therapy team for 
the whole study. If you were taking psychiatric medicines when the therapists first 
checked to see if you could be in the study and it took time to taper off of them, you may 
have your anxiety and other symptoms measured again after you have stopped taking 
your medications.  Your first experimental session will be between 3 and 8 weeks after 
your baseline anxiety symptoms are measured. The time will depend on scheduling and 
on the time it takes for any medication to clear from your body. 
 
Preparatory Sessions and Baseline Measures: 
Once screening is complete and you are enrolled in the study, you will meet with the 
study therapists three separate times before the first experimental session.  These visits 
will last about 90 minutes. During each preparatory session, you will talk about the 
emotions and issues that you are dealing with as a result of your illness, the ways these 
issues are affecting your life, and what you would like to achieve during these sessions. 
You will also learn more about what to expect during experimental sessions.  You will 
be asked questions about thoughts or feelings you might or might not have about 
suicide during one of these preparatory sessions. You will be asked about this at 
multiple visits, although you may not experience these thoughts or feelings at all.  
 
You will also answer some more questionnaires about your symptoms during the 
preparatory sessions: 
 
• During the first preparatory session, you will answer questionnaires about the 
quality of your sleep, personal growth since your diagnosis, and your attitudes or 
beliefs about death. 
• During the second preparatory session, you will answer questionnaires about 
ways you pay attention to or are mindful of your experience, and how you treat 
yourself during difficult or painful experiences. 
• During the third preparatory session, you will answer questionnaires about your 
anxiety and overall quality of life. 
 
You may also be asked about any pain you may be experiencing in your body. 
 
We will give you a card that says you are taking part in a research study involving the 
use of MDMA. This card will also include the telephone numbers to reach us (the 
researchers) and the Copernicus Group Independent Review Board.  You can keep this 
card in your wallet to make it easier for you or anyone treating you in an emergency to 
contact us if you or they need to do so. 
 
 
 


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Stage 1 Experimental Sessions: 
This study is double-blind, meaning that neither you nor the study researchers will know 
what drug you will receive. The drug you get will be decided at random, as if by tossing 
a coin.  However, this information is available if needed in an emergency.  Thirteen 
people will receive the full dose and five people will receive placebo.  You will have a 
72% chance of receiving full dose MDMA and a 28% chance of receiving the placebo.  
You will find out what you received about 1 month after your second experimental 
session is complete.  
 
After you have completed three preparatory therapy sessions, you will have the first of 
two day-long experimental sessions combined with psychotherapy. During these 
sessions, you will receive either full dose MDMA or placebo. These sessions will 
happen two to four weeks apart. After each experimental session, there will be an 
integrative session and over the next two weeks, two additional integrative sessions. 
These integrative sessions are designed to help you express, understand, bring 
together, and connect any thoughts or feelings you may be having about your 
symptoms and their causes, and to think and talk about your experience during the 
experimental sessions. Each experimental session will last about eight hours, though 
one or both study therapists will remain with you for a longer time if needed. Afterwards, 
you will stay overnight in a comfortable setting at the study site.  
 
Experimental sessions will take place in 
 home psychotherapy office, 
which is located 3.3 miles from the Marin General Hospital. The treatment room will be 
comfortably furnished, with a bed in which you will sit or lie on during the MDMA 
experience along with chairs for both co-therapists. The treatment room has a restroom 
nearby. The treatment room will be equipped with video cameras to record the sessions 
and stereo and speakers for music during the sessions. The treatment room has 
windows from which only trees, bushes and landscaping is visible and is in a quiet 
location. A nearby overnight room will also be used following experimental sessions, 
and there will be space for both the co-therapy team and a night attendant to remain on- 
site overnight if necessary. 
 will also remain on-site overnight.  
 
The next morning, after each session, you will have an “Integrative Session” at which 
we will check to see how you are doing and discuss any concerns of yours that may 
have arisen. The details of these sessions are described below. 
 
One week before each of the experimental sessions, you will need to avoid 
taking: 
 
• Any herbal supplement (except with prior permission);  
• Any non-prescription medications, unless you have permission (with the 
exception of non-steroidal anti-inflammatory drugs or acetaminophen [Tylenol]); 
• Any prescription medications, unless you have permission (with the exception of 
birth control pills, thyroid hormones or other medications).  You will need to talk 
to the study doctor about which medications are okay to keep taking. 
 


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You must not eat after midnight on the night before each session, but you can drink 
non-alcoholic liquids during this time, such as water or juice. You cannot use nicotine or 
caffeine for 2 hours before and 6 hours after receiving the capsule. If you are taking 
opiate medications for pain management, you may be asked to reduce the dose or 
avoid taking them for 24 hours prior to each session, although if your pain becomes too 
severe, you will be permitted to take these medications. We will give you a paper with 
these instructions before your first experimental session. 
 
Before you receive the MDMA or placebo during each experimental session 
(about 9:00 am): 
• We will collect a sample of your urine for a drug screen. If the drug screen is 
positive, the result may be reason for delaying or rescheduling the session, or for 
withdrawal from the study. 
• If you are a woman who can have children, we will use your urine sample for a 
pregnancy test. You cannot take part in this study if you are pregnant. 
 
After you receive either MDMA or placebo during each experimental session: 
• Your therapy team will measure and record your blood pressure, temperature, 
and pulse every 60-90 minutes and as needed (at least 7 times). 
• Your therapy team will ask you to rate the amount of distress you feel on a scale 
of 1 to 7 every 60-90 minutes and as needed (at least 7 times). 
• Your therapy team will remain with you for six to eight hours after you take the 
study drug (MDMA or placebo). 
• During each experimental session, you may sit or lie down in a comfortable 
position.  You can ask for an eyeshade or headphones. Music will be a part of 
your sessions.  Lying or sitting in a comfortable position and listening to music 
are meant to bring out thoughts and feelings, including thoughts and feelings 
relating to your illness or diagnosis. You will be able to move about and use the 
toilet, as needed for your comfort. 
• Your therapy team will ask to talk to you at least every hour, but you can talk to 
us or remain silent whenever you wish. 
• About one and a half to two and a half hours after receiving MDMA or placebo, 
you and the study therapists will talk about taking a second capsule. The second 
dose will be half the amount of the first dose. If you and the study therapists 
agree, then you will take the second dose. If you or the study therapists notice 
problems after the first capsule, then you will not get the second capsule. 
• Your therapy team will give you food and drinks during each session at your 
request. 
• If you request it and your therapy team agrees to it, your support partner may 
stay with you during some of the experimental session, starting at an agreed-
upon time. When your support partner arrives, they will stay in the waiting room 
until there is a good time for them to come into the experimental session. 
 
If you are still confused or very upset eight or more hours after the start of the 
experimental session, your therapy team will stay with you until you have recovered 
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else, they will either stay with you all night or have you stay in a nearby hospital until 
they are certain you are not at risk. If the study therapists decide that the effects of the 
drug have worn off and you are in a good frame of mind, they will leave the study site 
with the attendant in charge.  
 
You will spend the night in a comfortably furnished room at the study site. If you request 
and the study doctor agrees, you may also have a companion stay with you at the study 
site during or after an experimental session. This can be the person who is completing 
questionnaires as part of the study or it can be another person. An attendant will stay in 
another room at the same location from the time after you are done with the 
experimental session until the integrative session the next morning. The attendant will 
offer dinner and breakfast, help you with any physical needs if requested, and contact 
the study therapists to speak with them or to have them return to the study site at your 
request, or if the attendant thinks it is needed.  
 
If you find you need to talk with the study doctor or a member of his study team or you 
are having other problems and need to contact them, your support partner may contact 
them for help.  
 
You will complete some questionnaires about feelings you might have experienced 
during or after the experimental session. You can complete these questionnaires at any 
time between the end of the experimental session and the start of the integrative 
session on the next day. During the time between the end of the experimental session 
and the start of the integrative session the next day, we ask that you use the time as a 
period of rest and reflection in our quiet setting. 
 
Integrative Session – Therapy after Experimental Sessions 
On the next morning, you will have a non-drug (integrative) therapy session to help you 
express, understand, bring together, and connect any thoughts or feelings you may be 
having about your symptoms and their causes, and to think and talk about your 
experience during the experimental sessions. Each integrative session will last about 60 
to 90 minutes. You and the study therapists may discuss whether you would like your 
support partner present inside or outside these sessions. 
 
Before starting integrative therapy on the day after each experimental session, we will 
ask you to guess whether you got MDMA or placebo. However, we will not tell you if 
your guess is correct.  
 
Time between Each Experimental Session (2-5 weeks) 
After the integrative sessions, your therapy team will telephone you every day for a 
week to see how you are feeling and whether you should return to see the study doctor 
or a member of his study team before your next scheduled psychotherapy session. 
These telephone calls will take about 5 to 15 minutes, although they can be longer if 
needed. 
 


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You may schedule additional meetings with the study doctor or a member of his study 
team besides those that are scheduled as part of the study.  You can contact them at 
any time. You will be able to reach one of them by telephone 24 hours a day throughout 
this entire research study. 
 
You will meet with your therapy team during two additional integrative sessions after 
each experimental session. During these sessions with the study therapists, you will 
have regular psychotherapy to help you express, understand, and integrate (bring 
together and connect to your life) any thoughts or feelings you may be having about 
your anxiety symptoms and their causes and about your experiences during 
experimental sessions. These sessions will last 60 to 90 minutes. You and the study 
therapists will also discuss ways to use what you learned to help you manage your 
anxiety, and to solve difficulties that may have arisen during the experimental sessions.  
This will enable you to gain maximum benefit and understanding from the experimental 
sessions.  
 
If there are delays in following the usual study schedule, your therapy team will 
telephone you at least once a week to talk about how you're doing. These telephone 
calls will take approximately 5 to 15 minutes. You are requested to call the study 
therapists if any of the following things happens: you have an increase in symptoms for 
which you previously took medication, you need to contact your outside therapist other 
than for the usual appointments, you start or stop taking prescribed medication, and/or 
you go to the hospital for any reason. 
 
Measuring Anxiety, Depression and Other Tests After Experimental Sessions 
Approximately two to three months after the start of the study (one month after the 
second experimental session), a study researcher will ask you about your anxiety and 
other symptoms. This visit may last about two and a half hours. These tests are so that 
the study therapists can tell if your symptoms have changed or stayed the same over 
time. As before, some of the tests will be given by another researcher who is not one of 
the study therapists.  
 
We will also ask the people you chose at the beginning of the study to fill out the same 
questionnaires about your mood and personal growth. These questionnaires can be 
done away from the study site and returned in the mail. 
 
After you complete these tests, you will meet with the other study therapists. You and 
the study therapists will learn whether you received the placebo dose or the full dose of 
MDMA. The study researcher that measured your depression symptoms will not find 
out. The tests will help the study therapists tell if your symptoms have changed or 
stayed the same over time. 
 
If you learn, after your second experimental session, that you received the placebo 
dose, then you will be given the option to go on to the next part of the study without 
finishing Stage 1, described below (Stage 2). 
 


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Open-label MDMA Session for People who received Full Dose 
If you are one of the thirteen participants in the full dose group, you will have a third 
day-long experimental session with the same dose of MDMA that you had in your first 
two sessions. After learning that you were in the full dose condition, you will schedule 
and complete your last experimental session, which will be “open label,” meaning you 
will receive MDMA, but this time you will know. You will have the same regular 
psychotherapy visits after this last experimental session. 
 
Approximately five months after the start of the study (one month after the third 
experimental session), you will meet with the study researcher again. The researcher 
will ask about your symptoms and you will fill out the same questionnaires you filled out 
at the last assessment session. You will also be asked to participate in an interview with 
one of the study therapists, where they will ask you questions about your experiences 
while participating in the study. This visit may last about 3.5 hours, and can take place 
over more than one day. 
 
We will also ask the people you chose at the beginning of the study to fill out the same 
questionnaires about your mood and personal growth. These questionnaires can be 
done away from the study site and returned in the mail. 
 
At this time, approximately one month after your third experimental session, you will 
receive a memory aid card to help you keep track of your health in between your last 
visit and follow-up visits 6 and 12 months after the final experimental session. The card 
will help you to remember to tell the researchers about any new problems or medical 
conditions or changes in medication that happened during this time. 
 
Stage 2 Experimental Sessions – Open-label MDMA  
If you are one of the five subjects who received a placebo, you may take part in three 
open-label MDMA-assisted sessions scheduled two to four weeks apart as part of Stage 
2.  In this part of the study, you will receive an active dose of MDMA during each 
session. Signing this consent form means you agree to take part in the second part of 
the study. The 13 people who receive a full dose of MDMA during Stage 1 cannot 
take part in Stage 2. 
 
If you decide to take part in Stage 2, you will have 12 more visits with your therapy team 
and three experimental sessions. These sessions will be conducted similarly to the 
experimental sessions you had during the first part of the study, except that you will 
know you are getting full dose MDMA with an optional supplemental dose that is half the 
initial dose. You will only have one preparatory session rather than three sessions 
before your first experimental session in Stage 2. The study timing and procedures will 
be similar to Stage 1.  
 
You will be given the same tests for anxiety and other symptoms, well-being and 
attitudes about yourself and about death, about one month after the second and one 
month after the third open-label experimental session, and you will have an interview 
with one of the therapists about your experiences in the study one month after the third 
open-label session.  
 


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We will also ask the people you chose at the beginning of the study to fill out the same 
questionnaires about your mood and personal growth at these visits. These 
questionnaires can be done away from the study site and returned in the mail. 
 
At the one-month follow-up after your third experimental session, you will receive a 
memory aid card to help you keep track of your health in between your last visit and 
follow up visits 6 and 12 months after the final experimental session. The card will help 
you to remember to tell the researchers about any new problems or medical conditions, 
or changes in medication that happened during this time. You may have your regular 
doctor fill out this card for you. 
 
Long-term Follow-up 6 and 12 Months after Last Experimental Session 
About 6 months and then 12 months after your last experimental session, you will 
complete measurements of your anxiety and other symptoms either over the phone or 
in person. If you only participated in Stage 1, then this will happen 6 and 12 months 
after your third experimental session, and if you were in Stage 2, then this will happen 6 
and 12 months after the third experimental session in Stage 2.  
 
The same study personnel who asked you about your anxiety and other symptoms will 
do so again, either in person or over the telephone. You will be asked about any 
thoughts you may have about the good and bad points of MDMA-assisted therapy, and 
your thoughts about taking MDMA. There are no right or wrong answers to these 
questions. 
 
The questionnaires may be mailed to you for you to fill out.  It will come with an 
envelope that is already stamped and has only the researcher’s address on it.  Do not 
put your name on the questionnaires. 
 
We will also ask the people you chose at the beginning of the study to fill out the same 
questionnaires about your mood and personal growth. These questionnaires can be 
done away from the study site and returned in the mail. 
 
A researcher who is part of the study may ask you about any changes in medication or 
your mental health, including any benefits or harms, during the follow-up period 
between your last visit and the 6-month and 12-month follow-up visit in person or over 
the phone. 
 
The researchers will use your answers to these questionnaires to see if there are any 
long-lasting effects of being in the study, such as changes in anxiety and other 
symptoms and the study’s impact on your and your support persons’ lives.  
 




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What are my responsibilities if I take part in this research? 
If you take part in this research study, you are responsible for coming to all study visits, 
following the study doctor’s and his study team’s instructions, informing the study team 
about any changes in your health, taking the study drug (MDMA or placebo) as agreed 
upon, and completing all therapy sessions, questionnaires, and interviews.  
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Please discuss your concerns with the study 
doctor if you are thinking about stopping or have decided to stop. If you decide to stop 
participation in the study, the study doctor will assist you with follow-up care and 
restarting your medications, if necessary. 
 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
the MDMA can be evaluated by your doctor.  Another reason to tell your doctor that you 
are thinking about stopping is to discuss what follow-up care and testing could be most 
helpful for you. 
 
Your doctor, the sponsor of the study (MAPS), the Copernicus Group IRB, or the FDA 
has the right to stop your participation in the study at any time, with or without your 
consent, for any of the following reasons:  
 
• if you have an adverse effect from the study drugs,  
• if you need a treatment not allowed in this study, such as restarting medication 
for psychological problems,  
• if you do not keep appointments,  
• if you have very high blood pressure,  
• if you get significantly ill, or if your already-existing illness gets significantly 
worse,  
• if you have an important and strong lasting reaction (unwanted effect or health 
problem) during or after an experimental session,  
• if you do not take the study drug as instructed,  
• if you become pregnant, or  
• if the study is canceled by the FDA or the sponsor company. 
 
If any of these things happen, you or the study doctor may decide that you should not 
take part in the next experimental session.  You may make this decision to stop taking 
part in the study for any reason. If the study doctor decides to take you out of the study, 
he will let you know that he is doing this and tell you his reason for doing this.  If you are 
taken out of the study or decide you do not want to receive treatment in the study, the 
study doctor will ask you to complete some final questionnaires about your mental 
status. If you decide you do not want to continue in the study during an experimental 
session, we will ask you to stay in the office until the study doctor thinks that you are 
well enough to leave and that all the effects of the drug have worn off.  If this happens, 
we will also ask you to allow us to interview you about your thoughts on being in the 
study and for you to complete the same questionnaires you completed at the beginning 
of the study during the follow-up visit in 6 and then 12 months. 


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We will tell you about new information or changes in the study that may affect your 
health or your willingness to continue in the study. 
 
If you stop being in the study, already collected data (information collected from and 
about you while you are in the study) may not be removed from the study database. We 
will ask whether we can collect data from your routine medical care. If you agree, we will 
handle this data the same as research data. 
 
What treatments and/or procedures are experimental? 
We are carrying out all of the procedures and/or treatments described above for 
research or experimental purposes. MDMA is an experimental drug, and has not been 
approved for use by the U.S. Food and Drug Administration (FDA) for medical use 
except in research studies.  
 
What side effects or risks can I expect from being in the study?  
You may have side effects while on the study.  We will watch everyone taking part in the 
study carefully for any side effects.  As of December 2015, more than 1185 people have 
received MDMA in clinical research settings without any serious unexpected problems 
happening.  However, doctors don’t know all the side effects that may happen.  Side 
effects may be anything from mild to very serious. Your study doctor or his/her staff may 
give you medicines to help lessen side effects. Many side effects go away soon after 
you stop taking the MDMA. In some cases, side effects can be serious, long lasting, or 
may never go away.  
 
You should talk to your study doctor about any side effects that you have while taking 
part in the study even if you think they may not be caused by the medicines.    
 
Side effects that are most frequently reported by 25% or more of participants during the 
MDMA experience (100 to 125mg) are:  
 
• Muscle tightness (jaw) (55%) 
• Decreased appetite (42%)  
• Muscle tightness (27%) 
• Nausea (27%) 
• Feeling Cold (27%) 
• Sweating (25%) 
• Restlessness (25%)  
 
In these studies, participants (mostly with Posttraumatic Stress Disorder) also 
experienced anxiety, headache, and fatigue at a similar rate during MDMA or placebo. 
Less than 25% of participants receiving MDMA reported  dizziness, insomnia, thirst, 
problems walking or with balance, dry mouth, difficulty concentrating, depressed mood, 
and nystagmus (eye wiggles), from most to least common. When these side effects 
occur, they usually last less than four hours. However, some effects have been reported 
to last for more than 24 hours and (rarely) for as long as four days. 


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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: 
 
Physical Risks: 
 
Serious problems: There have been some serious problems, and even deaths, 
associated with the use of Ecstasy outside of controlled settings (outside of research 
studies). In research studies (clinical trials), none of these serious problems have 
happened. Outside of medical settings, these problems have included high fever, brain 
swelling associated with drinking too much liquid, convulsions (seizures), and liver 
damage. Since you will be receiving moderate amounts of uncontaminated MDMA in a 
controlled setting with trained and experienced researchers who will be closely 
monitoring your physical and psychological reactions, these problems are not expected 
to occur either during or after the experimental sessions.  While this does not guarantee 
that they will not occur, it does mean that if they do occur, the researchers are prepared 
to respond in a safe and professional manner. 
 
Changes in vision, hearing or other senses:  In previous studies in which MDMA was 
given to volunteers (including a total of about 365 participants without emotional 
disorders and 21 with PTSD) most participants 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 12-33 out of every 100 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 28 mmHg (measurement unit 
for blood pressure) and average diastolic blood pressure increase is 13 mmHg. Heart 
rate may increase by approximately 30 beats per minute (BPM) on average. 
 
In previous studies, blood pressure rose well above normal levels in a few people (a 
little less than 1 out of every 20) after receiving MDMA, but they did not report any 
discomfort and did not require any treatment. Although these increases in blood 
pressure are similar to what happens after heavy exercise, they could cause serious 
problems in individuals with pre-existing heart or vessel conditions. These serious 
problems could include heart attack or stroke.  We will ask you about and check you for 
heart problems during the screening for this study. While this doesn't guarantee that no 
heart problems will occur, it does reduce the risk of this happening. 
 
Immune System: You may have a less active immune system for 2 or 3 days after 
receiving MDMA. This may make you more likely to become sick with a cold or other 
infection during this time. The study describing this finding did not report how many 
people in the study showed these changes. 
 


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Addiction:  There is a small chance that you may become dependent on (addicted to) 
MDMA. One study found that up to 6% (a little more than 1 out of every 20) of people 
using Ecstasy for recreational purposes were dependent on it.  However, three studies 
of people who had received MDMA in a research study found that they did not want to 
try MDMA again outside of the study. People who have recently (in the last 2 months) 
had problems with drug abuse should not take part in this study. 
 
Mental Risks: 
 
Anxious or jittery feeling: Some participants in past studies with an anxiety disorder 
who received MDMA (48%, or about half) or placebo (58%, or about 6 out of 10 people) 
reported feeling over-stimulated or anxious at a similar rate. 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 your support person or attendant to call the 
study doctors immediately if you have any thoughts about hurting or killing yourself so 
they can help you resolve them safely. If necessary, they may prescribe anti-anxiety 
medication or medication for sleep. 
 
The way MDMA affects the brain has the potential to cause mania in some people, 
although mania has not been reported in individuals receiving MDMA or ecstasy. 
 
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. MDMA is not known 
to increase the risk of suicide. 
 
Mood:  Some after-effects of MDMA may be noticeable up to 2 or 3 days after receiving 
MDMA. While some people felt that their mood is better, 11%, or about 1 in 10; felt that 
it was worse after receiving MDMA in other research studies. Your mood may or may 
not change in the days following your treatment sessions. 
 
Possible risks to brain function: One study conducted by the sponsor in 20 people 
with PTSD found that two doses of 125mg MDMA spaced a month apart did not lead to 
differences in how well their brain functioned from a placebo control. The dose you will 
receive in this study will be similar to this amount. 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, which may or may not contain MDMA, in a recreational setting 
with people who did not take them found less improvement in memory in the people 
who took Ecstasy, and no other changes in thinking or planning. It is believed that the 
amount of MDMA you will receive will not produce any lasting changes in memory or 
planning, though this cannot be guaranteed. 
 


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Only one study has looked at brain scans of people before they got MDMA and then 
again after they have received one or two moderate doses of MDMA. This study did not 
show any changes in the brain following MDMA, though it is possible that there were 
changes that were too small to notice. Other studies looked at people before and after 
they decided to take a few tablets of Ecstasy in a recreational setting, and found one 
small change in the amount of blood flow in a specific part of the brain, but did not show 
signs of brain injury. The decrease in blood volume might be from temporary lowering of 
a type of brain receptor, or it might be a sign of reduced function in this area. Findings 
from these studies suggest that the amount of MDMA you will receive in this study will 
not produce any lasting changes in your brain, though this is not guaranteed. 
 
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. They also 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. 
 
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 those studies were far higher than those typically taken by humans in 
either recreational or laboratory settings. 
 
Worsening of symptoms: You may experience a worsening of your anxiety symptoms 
while taking part in this study. This may occur when you are stopping your current 
medications and if you receive placebo (no active medicine). This may also occur if you 
receive MDMA during this study.  
 
Other Risks: 
You should not drive or use machinery immediately after each experimental 
session (up to 24 hours afterwards).  This is because the study drug (MDMA) may 
cause drowsiness, lack of co-ordination, or slower reaction time. If needed, the study 
doctor may prescribe medication for sleep. 
 


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If you complete a urine drug screen within three days of each experimental session, you 
may test positive. The researchers will provide you with an information card explaining 
this. If you are tested for drugs while you are taking part in this study, you can have the 
person(s) testing you call us to verify that you are taking part 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. 
 
In order to be eligible for this study, you must complete a blood test. 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. If you are not 
comfortable with giving blood for screening, please let us know because it is required to 
take part in this study. 
 
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. If this happens, 
you should talk with your outside therapist and the study doctor. If you have to start 
taking medicine again, then the study doctor will have to take you out of the study. 
 
Reproductive Risks - Females: Effects of MDMA on the growth and development of 
an unborn baby are not known; therefore you will not be allowed to enter the study if 
you are pregnant.  If you become pregnant after you have had at least one experimental 
session, the study doctor and the sponsor (MAPS) will ask you about and keep track of 
the pregnancy. If this happens, you will need to stop being in the study and they will 
need to know about the outcome of your pregnancy. 
 
Women who are able to become pregnant must use one of the allowed birth control 
methods, such as birth control pills or shots, IUDs (intrauterine devices), and barrier 
method used along with spermicide for at least one month afterward your final study 
visit/session. We will explain these methods to you and will help you decide which might 
be best for you, and they can suggest to you where you can get more information and 
advice. 
 
If you are a woman that can become pregnant, we will give you a pregnancy test 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 notify us immediately.  If you should 
become pregnant during the study, we will help you get proper advice and help you and 
your unborn baby get proper care while you are pregnant. However, you are 
responsible for the costs of the care for your pregnancy.  
 
For more information about risks and side effects, ask your study doctor. 
 
 
 


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Are there benefits to taking part in the study? 
Your mental health may improve while taking part in this study, but 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 of 
anxiety and other symptoms in individuals with life-threatening illnesses in the future. 
 
What other choices do I have if I do not take part in this study? 
One alternative to being in this study is to decide not to take part in it. You may decide 
to try other treatments for anxiety. There are other medicines, such as anti-anxiety 
medications like Valium (diazepam) or 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 researchers can discuss the alternatives and their potential risks and benefits with 
you.  Talk to your doctor about your choices before you decide if you will take part in 
this study. 
 
Will my personal and medical information be kept confidential?  
To ensure confidentiality, your information will be stored in secure electronic systems or 
in a locked office. Absolute confidentiality and security cannot be guaranteed, but every 
effort will be made to maintain your confidentiality. 
 
People outside of your treatment team will need access to your information to monitor 
the study and conduct further research and training. Any paperwork copied will have 
any information that could be used to identify you removed first, except for videos, 
which will still show your face. If records are copied, only your participant number and 
initials will identify you to the study sponsor unless you give specific permission, for 
example at a time when you sign a media release.  
 
Medical records, including video, which identify you, and the consent form signed by 
you will be looked at and/or copied for research or regulatory purposes.  These records 
may be looked at by: 
 
• The sponsor, MAPS and the people they hire. 
• Researchers who cooperate with MAPS to conduct further research, and people 
who conduct therapist trainings on behalf of MAPS. 
• The FDA and similar agencies in other countries. 
• Governmental agencies in other countries. 
• The Copernicus Group Independent Review Board (CGIRB). 
 
All records in California are subject 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. Video of your sessions may be 
used in training sessions for research therapists or other researchers only in controlled 
settings as described below. 


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Video recordings: The study therapists will video record each visit. The purposes for 
this recording that you are agreeing to by signing this informed consent are: 
 
• So that you will have access to review your own therapy sessions. 
• So the study therapists will have accurate records of the session. 
• 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, or for further development of the Treatment Manual.  
• For further research on the therapy and how it is performed.  
• For training other therapists and scientists to develop and work on additional 
research.  
 
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.  
 
Information contained in recordings that could be used to identify you may include: 
 
• Your physical appearance 
• Your voice 
• Your name (if it is spoken on the recording) 
• Situations from your life that might be discussed 
 
You may 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 access to your own recordings. Your name or other 
identifying information will not be used to label these recordings. Sometimes audio or 
transcripts from these video files will be processed separately and used for additional 
research. 
 
With your permission, the investigators and/or sponsor may use portions of your videos 
to 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. You are not required to agree to 
use of your video in these settings in order to participate in the study. Signing this 
consent form does not mean you have given permission for your videos to be used in 
this way. You will have the opportunity to sign an additional release for these situations 
if they arise and if you choose to allow this use. At the end of the treatment period 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 hard drives stored in a locked and secure location 
when not in use. No personally identifying information will be used to label the video 
recordings. A copy will be transferred to the sponsor for electronic storage on the web to 
allow for viewing purposes described above. Electronic systems used will include 
measures to protect confidentiality of your identity and video data. Total security cannot 
be guaranteed, but the sponsor is consistently working to maintain and improve the 






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SUBJECT’S STATEMENT OF CONSENT 
 
“A Randomized, Double-Blind, Placebo-Controlled Phase 2 Pilot Study of MDMA-
Assisted Psychotherapy for Anxiety Associated with a Life-Threatening Illness” 
 
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 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 subject 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 and the Experimental Subject’s 
Bill of Rights.  
 
 
 ___________________________________________________________________  
Signature of Subject 
Date 
 
 
 __________________________________  
Printed Name of Subject 
 
I certify that the information provided was given in language that was understandable to 
the subject. 
 
 
 ___________________________________________________________________  
Signature of Person Obtaining Consent 
Date 
 
 
 __________________________________  
Printed Name of Person Obtaining Consent 
 
 
 
 


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Witness signature lines and attestation 
The information in the consent form was accurately explained to, and appeared to be 
understood by the subject. Informed consent was freely given. 
 
 
 
 
Signature of Witness  
 
 
 
 
Date 
 






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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.   
 
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. 
 
 
 
 
Printed Name of Subject 
 
 
 
 
 
 
Signature of Subject 
 
Date 
 
 
 
 
Printed Name of Person Obtaining Authorization 
 
 
 
 
 
 
Signature of Person Obtaining Authorization  
Date 
 
 

Prot_000.pdf: 
MAPS Study MDA-1                                                                                            Protocol Amendment 1  
U.S.                                                                                                                                   29 April, 2015 
 
PROTOCOL MDA-1 
IND #63,384 
 
Original Protocol Version 1: August 5, 2014 
Original Protocol Version 2: August 19, 2014 
Original Protocol Version 3: September 23, 2014 
Original Protocol Version 4: November 30, 2014 
Protocol Amendment 1: April 29, 2015 
 
 
A Randomized, Double-Blind, Placebo-Controlled Phase 2 Pilot Study of MDMA-
Assisted Psychotherapy for Anxiety Associated with a Life-Threatening Illness  
 
 
SPONSOR!
Multidisciplinary Association for Psychedelic Studies 
(MAPS) 
1115 Mission Street 
Santa Cruz, CA 95060 
!
SPONSOR DESIGNEE!
Rick Doblin, Ph.D. 
Phone number: 617-484-8711 
!
PRINCIPAL  
INVESTIGATOR!
Philip Wolfson, MD 
6 Crest Avenue 
San Anselmo, CA 94960 
Phone number: 415-550-1700 
!
MEDICAL MONITOR!
Michael C. Mithoefer, M.D. 
208 Scott Street 
Mount Pleasant, SC 29464 
Phone number: 843-849-6899 
!
STUDY MONITOR!
Benjamin Shechet 
1215 Mission Street 
Santa Cruz, CA 95060 
Phone number: 831-429-6362 x104 
!
 
 
Phone number for trial related emergencies: 859-221-0343  
 
 


MAPS Study MDA-1                                                                                            Protocol Amendment 1  
U.S.                                                                                                                                   29 April, 2015 
 
Table of Contents 
 
1.0 LIST OF ABBREVIATIONS ................................................................................................................. 4!
2.0 INTRODUCTION, BACKGROUND, AND RATIONALE ................................................................ 6!
2.1 INTRODUCTION ...................................................................................................................................... 6!
2.2 BACKGROUND ........................................................................................................................................ 6!
2.3 PROTOCOL PURPOSE ............................................................................................................................ 10!
2.4 RATIONALE OF DOSE SELECTION ......................................................................................................... 11!
3.0 PROTOCOL OBJECTIVES ................................................................................................................ 11!
3.1 PRIMARY OBJECTIVE ........................................................................................................................... 12!
3.2 SECONDARY OBJECTIVES .................................................................................................................... 12!
3.3 SAFETY OBJECTIVES ............................................................................................................................ 13!
4.0 PROTOCOL DESIGN .......................................................................................................................... 13!
4.1 PLANNED DURATION OF STUDY .......................................................................................................... 18!
4.2 RECRUITMENT AND SUBJECT POPULATION .......................................................................................... 18!
5.0 METHODS ............................................................................................................................................. 21!
5.1 MEASURES ........................................................................................................................................... 21!
5.2 STUDY PROCEDURES, VISIT DESCRIPTIONS, AND ADHERENCE ............................................................ 27!
5.3 RANDOMIZATION AND SUBJECT NUMBERING ...................................................................................... 38!
5.4 REMOVAL OF SUBJECTS FROM THE STUDY .......................................................................................... 39!
5.5 PREMATURE DISCONTINUATION OF THE STUDY .................................................................................. 39!
6.0 INVESTIGATIONAL PRODUCT ...................................................................................................... 40!
6.1 DESCRIPTION OF ACTIVE COMPOUNDS ................................................................................................ 40!
6.2 PREPARATION AND ADMINISTRATION ................................................................................................. 40!
6.3 DRUG ACCOUNTABILITY ..................................................................................................................... 43!
6.4 DRUG STORAGE AND HANDLING ......................................................................................................... 43!
6.5 MDMA STABILITY .............................................................................................................................. 43!
7.0 RISKS OF PARTICIPATION ............................................................................................................. 44!
7.1 RISKS AND DISCOMFORTS ASSOCIATED WITH NON-DRUG AND EXPERIMENTAL SESSIONS AND 
ASSESSMENT OF MEASURES ...................................................................................................................... 44!
7.2 RISKS OF RECEIVING MDMA .............................................................................................................. 44!
7.3 ABUSE LIABILITY ................................................................................................................................. 50!
8.0 ADVERSE EVENTS ............................................................................................................................. 50!
8.1 ADVERSE EVENTS ................................................................................................................................ 50!
8.2 SPONTANEOUSLY REPORTED REACTIONS ............................................................................................ 51!
8.3 SERIOUS ADVERSE EVENTS ................................................................................................................. 51!
8.4 MEDICAL EMERGENCIES ...................................................................................................................... 52!
8.5 ADVERSE EVENT COLLECTION ............................................................................................................ 53!
8.6 MEDICAL MONITOR ............................................................................................................................. 54!
9.0 CONCOMITANT MEDICATIONS AND TAPERING INSTRUCTIONS ..................................... 54!
10.0 CLINICAL LABORATORY ASSESSMENTS ................................................................................ 57!
11.0 STUDY MONITORING, AUDITING, AND DOCUMENTATION .............................................. 58!
12.0 DATA ANALYSIS ............................................................................................................................... 59!
12.1 STATISTICAL POWER .......................................................................................................................... 61!


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13.0 ETHICS ................................................................................................................................................ 62!
14.0 INFORMED CONSENT ..................................................................................................................... 62!
15.0 CONFIDENTIALITY ......................................................................................................................... 63!
16.0 COSTS TO SUBJECTS ...................................................................................................................... 64!
17.0 TREATMENT AND COMPENSATION FOR STUDY RELATED INJURY ............................. 64!
18.0 RECORD RETENTION ..................................................................................................................... 64!
19.0 PUBLICATION POLICY ................................................................................................................... 64!
20.0 REFERENCES .................................................................................................................................... 66!
 


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1.0 List of Abbreviations 
 
 
AE(s)  
Adverse Event(s) 
ALT/SGPT 
Alanine aminotransferase 
AMI   
Acute Myocardial Infarction 
AST/SGOT 
Aspartate aminotransferase 
BDI-II  
Beck Depression Inventory II 
BPI-S  
Brief Pain Inventory—Short Form 
C 
 
Celsius 
CI 
 
Clinical Investigator(s) (e.g. therapists, co-investigators) 
CPK 
 
Creatine phosphokinase 
CRA  
Clinical Research Associate 
CRF(s) 
Case Report Form(s) 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DAP  
Death Attitudes Profile 
DEA  
Drug Enforcement Administration 
DBP 
 
Diastolic Blood Pressure 
DMF  
Drug Master File 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders - IV 
ECG  
Electrocardiogram 
ED 
 
Emergency Department 
EMDR  
Eye Movement Desensitization and Reprocessing 
EMS  
 
Emergency Medical Services 
F 
 
Fahrenheit 
FACIT  
Functional Assessment of Chronic Illness Therapy Scale 
FDA  
Food and Drug Administration  
FFMQ  
Five-Facet Mindfulness Questionnaire 
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 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
IND 
 
Investigational New Drug  
IR 
 
IR 
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
IV 
 
Intra-venous 
LSD 
 
d-Lysergic acid diethylamide 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MAOI  
Monoamine oxidase Inhibitor 
MAPS  
Multidisciplinary Association for Psychedelic Studies 
MCH  
Mean Corpuscular Hemoglobin 


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MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV   
Mean Corpuscular Volume  
MDMA 
3,4-Methylenedioxymethamphetamine 
MP-1  
MAPS’ first clinical trial of MDMA-assisted psychotherapy for PTSD 
OASIS  
Overall Anxiety Severity and Impairment Scale 
ORF 
 
Observer Rating Form 
PRN 
 
As Needed 
PSQI  
Pittsburgh Sleep Quality Index 
PTCA   
Percutaneous Transluminal Coronary Angioplasty 
PTGI  
Posttraumatic Growth Inventory 
PTGI-C 
Posttraumatic Growth Inventory—Caregiver Form 
PTSD  
Posttraumatic Stress Disorder 
PTT 
 
Partial Thromboplastin Time 
RBC  
Red Blood Cell Count 
RDW  
Red Cell Distribution Width 
SAE(s) 
Serious Adverse Event(s) 
SBP 
 
Systolic Blood Pressure 
SCID-RV 
Structured Clinical Interview for DSM-IV Research Version 
SCS 
 
Self-Compassion Scale 
SERT   
Serotonin Transporter 
SL 
 
Sublingual 
SNRI  
Selective Serotonin and Norepinephrine Uptake Inhibitor 
SOCQ  
States of Consciousness Questionnaire  
PPQ 
 
Psychological Process Questionnaire 
SOP(s)  
Standard Operating Procedure(s) 
SSRI  
Selective Serotonin Reuptake Inhibitor  
STAI  
State-Trait Anxiety Inventory 
SUD   
Subjective Units of Distress 
TSH 
 
Thyroid Stimulating Hormones 
U.S. 
 
United States of America 
WBC   
White Blood Cell Count 


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2.0 Introduction, Background, and Rationale 
 
2.1 Introduction 
 
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit 
research and educational organization working to obtain approval as a clinical trial 
sponsor for the prescription use of 3,4-methylenedioxymethamphetamine (MDMA) to 
assist psychotherapy. Currently MAPS is conducting a global series of Phase 2 clinical 
trials designed to evaluate the safety and efficacy of MDMA-assisted psychotherapy in 
treating Posttraumatic Stress Disorder (PTSD). This study will explore the use of MDMA 
in an additional indication for anxiety and stress disorders, related to end of life. This 
study is a randomized, double-blind, placebo-controlled exploratory pilot study of 
MDMA-assisted psychotherapy for anxiety in people with a life-threatening illness that is 
ongoing or with the possibility of recurrence.   
 
The ongoing studies using MDMA-assisted psychotherapy in the treatment of PTSD will 
be used to inform the safety and dosing aspects of this new investigation of a potential 
therapy that could benefit the quality of life of adults with end-of-life anxiety. MAPS has 
published results showing clinically and statistically significant improvements in PTSD 
severity from twenty subjects treated in their first pilot study (MP-1) in the United States 
(U.S.) [1]. Findings from the long-term follow-up of MP-1 subjects suggest that 
therapeutic benefits were sustained over an average of 41 months post-treatment [2]. The 
sponsor’s second Phase 2 pilot study conducted in Switzerland (MP-2) in twelve subjects 
suggests clinically significant improvements in PTSD symptoms with a trend toward 
statistical significance [3]. Long-term follow-up data, twelve months later, suggest that 
therapeutic benefits continued to increase in this subject population.  
This exploratory placebo-controlled study is designed to investigate the safety and 
feasibility of MDMA-assisted therapy in 18 adults who have a prognosis for at least nine 
months life expectancy and currently have anxiety related to a life-threatening illness that 
is ongoing or is in remission with the possibility of recurrence.  This partial cross over 
study will assess safety and obtain estimates of effect size in response to two 
experimental sessions of MDMA-assisted therapy in comparison to an inactive placebo 
control. Outcomes will include treatment-related changes in anxiety, depression, sleep 
quality, quality of life, self-reported and observer-reported changes in attitudes, attitudes 
toward death and the prospect of death, and changes in self-compassion and self-reported 
mindfulness. Results from this study, if promising, will inform the dose, end points and 
treatment regimen for subsequent studies. This study is also intended to develop a 
manualized psychotherapeutic approach to this potential treatment. 
 
2.2 Background 
 
2.2.1 Anxiety Related to Life-Threatening Illness 
 
Individuals facing, or who have faced, a life-threatening illness contend with more than 
just the physical symptoms of their condition. Anxiety, depression, anger, and despair 
often exacerbate the distress already caused by the illness itself, and can significantly 


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increase caregiver distress as well [4]. End-of-life problems, including pain management, 
are increasingly recognized by caregivers and the public as significant public health 
concerns [5-7]. Research suggests that diagnosis of, and living with a life-threatening 
illness can result in symptoms similar to those seen in Posttraumatic Stress Disorder 
(PTSD), and that these symptoms may persist even if the individual recovers, or their 
illness goes into remission [8, 9]. These symptoms may include emotional avoidance and 
numbing, difficulty relating to or connecting with friends or loved ones, difficulty 
sleeping, a sense of foreshortened future, and intrusive thoughts or memories related to 
the illness. 
 
While efforts to enhance palliative care for the terminally ill have improved greatly over 
the last several decades, and significant strides have been made in reducing individuals’ 
physical pain and discomfort, less progress has been made in helping individuals reduce 
or come to terms with the psychological and existential issues raised by their condition. 
Fears of loss of autonomy, helplessness, and death itself are also often accompanied by 
challenging internal family dynamics that surface around the end of life. In a 2003 report, 
McClain et al. [10] support developing additional palliative care interventions to improve 
the well-being of people with terminal illness by “…keeping the psychological distress of 
patients who are facing death to a minimum. What is less clear, however, is whether 
interventions exist that can help raise a terminally ill individual’s sense of spiritual well-
being.” 
 
Given that in this situation, spiritual, familial, psychological, and existential concerns all 
take a position of primary and imminent importance for many people, the development of 
new treatment modalities to meet these needs is a clear imperative. Enabling individuals 
to face life-threatening illness and all of its concomitant difficulties with dignity, 
creativity, love, support, and kindness is the primary impetus for this research study.  
 
2.2.2 MDMA 
 
MDMA is a ring-substituted phenylisopropylamine derivative invented by the Merck 
pharmaceutical company in 1912 [11, 12]. MDMA is a monoamine releaser that has its 
greatest effects on serotonin, followed by norepinephrine and dopamine [13-18]. MDMA 
is capable of inducing unique psychopharmacological effects, including: 
 
• Decreased feelings of fear 
• Increased feelings of wellbeing 
• Increased sociability and extroversion 
• Increased interpersonal trust 
• Alert state of consciousness 
 
Early observers noted increased acceptance of self and others, increased tolerance of 
emotionally upsetting materials, and the ability to address these issues without extreme 
disorientation or ego loss [19-22]. In the U.S., MDMA was used as an adjunct to 
psychotherapy by a considerable number of psychiatrists, including this study’s Principal 
Investigator (PI) and other therapists in the treatment of neuroses, relationship problems, 


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and PTSD [19, 20, 23, 24] before it was placed in Schedule 1 in 1985, as a result of the 
DEA’s concern for extensive non-medical use [22, 25, 26]. Placement in Schedule 1 
prohibited it for use, except in a federally-approved research setting.  
 
In contrast to daily administrations of SSRIs, MDMA-assisted psychotherapy consists of 
several drug-assisted sessions interspersed with a moderate course of non-drug 
psychotherapy. Thus the effects of MDMA are distinct from and go well beyond those of 
anti-anxiety drugs such as benzodiazepines. Furthermore, there is no evidence that 
MDMA creates a physical dependency, as benzodiazepines do. Previous studies of 
polydrug users have found a small percentage of people exhibit problematic use of 
ecstasy (material represented as containing MDMA) [27, 28]. Studies of regular or 
problematic ecstasy users indicate that on average, regular use occurs no more often than 
once a week [29]. 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 1 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[30-32]. 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 [33]. However, these 
increases were found to be transient and generally tolerable in a controlled clinical setting 
[33]. Subsequent trials confirmed that MDMA produced significant increases in heart rate 
and blood pressure that were likely to be well tolerated by healthy individuals [33-39]. 
The elevation in body temperature noted in healthy volunteers was not clinically 
significant in the sponsor’s proof-of-principle MP-1 study comparing MDMA to placebo 
in subjects with PTSD [1].   
 
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 [40, 41]. 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 who were enrolled and treated in this study with single doses 
ranging from 50 mg to 75 mg demonstrated mild signs of improvement without any 
adverse events (AEs) or signs of deteriorating mental health [41].  
 
MAPS went on to sponsor the first randomized, placebo-controlled Phase 2 pilot study of 
MDMA-assisted psychotherapy for the treatment of chronic, treatment resistant PTSD, 
which demonstrated promising results in a sample of 20 subjects [1]. Findings from the 
long-term follow-up of this study indicate that the therapeutic benefits have been 
sustained over time on average, although two subjects experienced a relapse in PTSD 
symptoms [2]. The sponsor also supported a randomized, double-blind pilot study in 12 
subjects with chronic, treatment-resistant PTSD in Switzerland, which found a trend 
toward significant improvement in subjects receiving 125 mg MDMA at two-month 


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follow-up, when compared to a 25 mg active placebo MDMA. The improvement 
continued to increase during the twelve-month follow-up [3]. These studies have shown 
promise for MDMA-assisted psychotherapy to help people overcome PTSD, an anxiety-
related disorder, that suggest this treatment could also be useful in treating anxiety 
associated with end-of-life issues. 
 
As of July 2014, MDMA has been administered to more than 1080 research subjects, in 
both Phase 1 and Phase 2 studies, with only a single occurrence of a drug-related SAE, 
and no unexpected related SAEs [1, 3, 13, 16, 25, 33, 34, 36, 37, 39, 40, 42-85].  
 
2.2.4 MDMA-Assisted Psychotherapy for Anxiety Associated with a Life-
Threatening Illness  
 
A small body of research, mainly conducted in the 1950s and 1960s prior to the 
placement of most psychedelic drugs into Schedule 1, suggests that therapeutic 
interventions involving psychedelics such as LSD, psilocybin, and MDMA may help to 
address the personal, interpersonal, and existential issues that present during the course of 
a life-threatening illness [86-91]. MDMA shares with the ‘classical’ psychedelics LSD 
and psilocybin the ability to produce perceptions of new meanings for thoughts and 
objects [92], and increases tolerance for confronting negative memories [93]. Narrative 
reports support its use as a psychotherapeutic adjunct [94-97]. 
 
Prior to placement into Schedule I, MDMA was used in combination with psychotherapy  
in the treatment of neuroses, relationship problems, and PTSD [20, 22, 24]. It was also 
used in the treatment of some individuals with chronic pain [19, 98], and in individuals 
with advanced cancer [19, 94-96, 98]. Case reports and narrative accounts of MDMA-
assisted therapy indicate that the treatment was often successful [19, 20, 22, 23, 99, 100]. 
A discussion of MDMA-assisted psychotherapy and a discussion of several case studies 
appeared in a peer-reviewed journal [19].  
 
MDMA-assisted psychotherapy is an innovative mode of treatment that combines 
psychotherapeutic techniques with the administration of MDMA as 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 and anxiety patients [37, 63, 66, 67, 85, 93, 101-103].  
 
In a psychotherapeutic context, MDMA was reported to produce a lowering of defenses  
and greater ability to think about and reflect on distressing thoughts and feelings [19, 21, 
22, 76].  When spending time with loved ones, individuals who took MDMA in 
therapeutic contexts often spent time discussing painful or emotionally sensitive topics, 
such as the impending death of a loved one in the advanced stages of cancer [94-97]. 
Reduction in pain was often reported [19, 94-97, 104].  
 
 
Treatment goals of MDMA-assisted psychotherapy for anxiety associated with life-
threatening illness include alleviating symptoms, as well as helping individuals find a 
perspective and orientation toward death and remaining life that supports well-being, 


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creativity, love, compassion, and dignity. The biologic and psychotherapeutic approaches 
are intended to 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 [101] 
and attenuates amygdalar response to angry faces [67]. This action is compatible with its 
reported reduction in fear or defensiveness and is in contrast to the stimulation of the 
amygdala which is observed in animal models of conditioned fear, a state similar to 
PTSD [105-107]. 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. 
 
Oxytocin is a neurohormone associated with pair bonding and social affiliation in 
mammals [108]. Oxytocin administration is associated with increased interpersonal trust 
and attenuated reactivity to threatening faces [108-110]. Some researchers have 
suggested a role for oxytocin in treating PTSD [111]. MDMA has been shown to elevate 
serum oxytocin in humans [37, 112]. Brain imaging after MDMA indicates less reactivity 
to angry facial expressions and greater reward in happy faces [67]. The effects of MDMA 
on oxytocin may influence empathy or compassion for self and others, decrease 
defensiveness, and strengthen therapeutic alliance. These factors taken together can 
provide the opportunity for a corrective emotional experience [19].  
 
A combined treatment of MDMA and psychotherapy may be especially useful for 
treating anxiety disorders 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 [1, 20, 22, 41]. This 
reduction in defensiveness may permit a deeper engagement with material that would 
otherwise be too distressing to face. Subjects are able to experience and express fear, 
anger, and grief with less likelihood of feeling overwhelmed by these emotions. MDMA 
seems to engender internal awareness that even painful feelings that arise are an 
important part of the therapeutic process. In addition, feelings of empathy, love, and deep 
appreciation often emerge, along with a clearer perspective of present difficulties, a more 
accurate perspective about their significance, and a heightened awareness of the support 
and safety that exists in the present. As a result, MDMA-assisted psychotherapy may 
enable the subjects to restructure their intra-psychic realities and develop a wider 
behavioral and emotional repertoire with which to respond to anxiogenic stimuli.  
 
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. 
 
2.3 Protocol Purpose 
 
This Phase 2 pilot study is a randomized, double-blind placebo-controlled study in 18 
subjects comparing the effects of placebo and active dose MDMA as an adjunct to 
psychotherapy. Thirteen subjects will be randomized to the active dose condition of 125 
mg of MDMA and five subjects will be randomized to the placebo condition. The study 
will consist of two blinded experimental sessions of MDMA-assisted psychotherapy or 


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placebo, each lasting six to eight hours and scheduled two to four weeks apart, within a 
moderate course of non-drug psychotherapy. Each study subject will be unblinded one 
month after their second experimental session in Stage 1 after completion of outcome 
measures, which constitutes the Primary Endpoint assessment for that subject.  
 
After unblinding, subjects receiving placebo will have the opportunity to cross over to 
open-label Stage 2 and only subjects receiving active dose MDMA will complete the 
third open-label experimental session. The primary outcome measure will be completed 
via subject self-report at Baseline, at the Primary Endpoint one month after the second 
experimental session, and at the End of Stage 1 visit, one month after the third open-label 
experimental session, and at equivalent points in Stage 2. Some secondary outcome 
measures will be administered by a blinded Independent Rater, while others will be 
completed by subjects’ self-report. This study will provide an estimate of effect size 
based on response of anxiety symptoms to MDMA-assisted psychotherapy.  
 
The PI and a co-therapist, along with supervised intern therapists will conduct 
psychotherapy visits in male/female therapy teams. 
 
2.4 Rationale of Dose Selection 
 
This study will compare the effects of psychotherapy sessions assisted by placebo or 
active dose MDMA. Placebo will consist of lactose.  The active dose will be 125 mg 
MDMA, followed one and half to two and a half hours later by an optional supplemental 
dose of 62.5 mg. 
 
Table 1. MDMA Dose Regimen 
 
Initial Dose 
Optional 
Supplemental Dose 
Cumulative Dose (Initial + 
Supplement) per Session 
Placebo 
0 mg 
0 mg 
0 mg 
Active 
Dose 
125 mg 
62.5 mg 
187.5 mg 
 
The active dose of MDMA to be used in this study is identical to those used in previous 
studies in the U.S., Switzerland, and Israel [1]. Previous researchers have also used doses 
within this range [33, 34, 36, 38, 54, 113-117]. Prior to the scheduling of MDMA, similar 
doses and regimens were used in psychotherapy [20, 22, 25]. The initial active dose is 
expected to produce all the commonly reported effects of MDMA. The supplemental 
dose will prolong subjective drug effects without producing physiological effects any 
greater than peak effects occurring after the initial dose. 
 
3.0 Protocol Objectives 
 
The overall objective of this study is to examine whether an active dose of MDMA 
versus a placebo used in conjunction with psychotherapy will reduce or attenuate anxiety 


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and depression symptoms, and improve quality of life as evaluated by standard clinical 
measures and to collect safety data. 
 
3.1 Primary Objective 
 
The primary objective of the study is to assess changes in trait anxiety in subjects 
receiving active dose MDMA compared to those receiving placebo as measured by 
STAI-Trait scores at Baseline and the Primary Endpoint, one month after the second 
experimental session. 
 
3.2 Secondary Objectives 
 
The additional objectives of the study involve comparing subjects receiving active dose 
MDMA to those receiving placebo for the following exploratory objectives: 
 
• Assess changes in self-reported State Anxiety symptoms as measured with the 
State-Trait Anxiety Inventory—State subscale (STAI-State) from Baseline to the 
Primary Endpoint. 
• Assess changes in self-reported depression symptoms with the Beck Depression 
Inventory- II (BDI-II) from Baseline to the Primary Endpoint. 
• Assess changes in clinician ratings of depression symptoms with the 
Montgomery-Asberg Depression Rating Scale (MADRS) from Baseline to the 
Primary Endpoint. 
• Assess changes in quality of life with Functional Assessment of Chronic Illness 
Therapy Scale (FACIT-Sp) from Baseline to the Primary Endpoint. 
• Assess changes in global functioning with the Global Assessment of Functionality 
(GAF) from Baseline and the Primary Endpoint. 
• Assess changes in self-reported sleep quality with the Pittsburgh Sleep Quality 
Index (PSQI) from Baseline to the Primary Endpoint.  
• Assess changes in subjects’ attitudes toward death with the Death Attitudes 
Profile (DAP) from Baseline to the Primary Endpoint. 
• Assess personal growth with the Post-Traumatic Growth Inventory (PTGI) from 
Baseline to the Primary Endpoint. 
• Assess caregiver perceptions of subjects’ personal growth with the Post-
Traumatic Growth Inventory—Caregiver Form (PTGI-C) from Baseline to the 
Primary Endpoint. 
• Assess changes in self-oriented compassion with the Self-Compassion Scale 
(SCS) from Baseline to the Primary Endpoint. 
• Assess changes in self-reported mindfulness with the Five-Facet Mindfulness 
Questionnaire (FFMQ) from Baseline to the Primary Endpoint. 
 
The following objectives will include exploratory analyses intended to inform protocol 
design: 
 
• Explore the effects of each experimental session with active dose MDMA or 
placebo upon self-reported changes in consciousness, as those associated with a 


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transformational or mystical experience via the States of Consciousness 
Questionnaire (SOCQ). 
• Explore the effects of each experimental session upon self-reported cognitive and 
emotional processing via the Psychological Process Questionnaire (PPQ). 
• Assess the effect of the third experimental session using a within-subject 
comparison of the Primary/Secondary Endpoint to 1-month follow-up assessment 
in active dose subjects using STAI-Trait, STAI-State, MADRS, BDI-II, DAP, 
GAF, FFMQ, PTGI, PSQI, PTGI-C, SCS, and FACIT.  
• Conduct a within-subject analysis comparing Stage 1 and Stage 2 in placebo 
subjects using STAI-Trait, STAI-State, MADRS, BDI-II, DAP, GAF, FFMQ, 
PTGI, PTGI-C, PSQI, SCS, and FACIT at the Primary and Secondary Endpoints. 
• Assess durability of changes in outcome measures using STAI-Trait, STAI-State, 
MADRS, BDI-II, DAP, GAF, FFMQ, PTGI, PTGI-C, PSQI, SCS, and FACIT at 
the 6-month and 12-month follow-up visits. 
• Assess qualitative reports of subjects’ experiences in the study via a semi-
structured interview at the 1-month follow-up assessment. 
• Assess observations of the subject’s overall state of being from up to three 
observers using the Observer Rating Form (ORF) at Baseline, the Primary 
Endpoint, and the 6- and 12-month follow-up visits. 
• Assess the ability of the Clinical Investigator(s) (CI) and subjects to accurately 
guess condition assignment in Stage 1. 
 
3.3 Safety Objectives 
 
The safety objectives of the study are to monitor and assure safety of subjects during and 
after the experimental sessions by assessing physiological effects, psychological distress, 
adverse events, spontaneously reported reactions, and suicidality.   
 
• 
Suicidality will be assessed with the Columbia Suicide Severity Rating Scale (C-
SSRS) during visits prior to experimental sessions, twice during experimental 
sessions, and several times after each experimental session, with comparisons 
made between subjects in each condition. 
• 
Subjective Units of Distress (SUD) and vital signs including blood pressure, heart 
rate, and temperature will be measured during each experimental session.  Vital 
signs will be compared between subjects in each condition. 
• Changes to pre-existing chronic pain symptoms, when applicable, will be 
collected using the Brief Pain Inventory—Short Form (BPI-S) at Baseline and 
throughout the study, with comparisons made for Primary Endpoint, end of Stage 
1 or Stage 2 and 6- and 12-month follow up.  
• 
Serious adverse events (SAEs), adverse events, and spontaneously reported 
reactions will be collected during the study according to Section 8.5. 
 
4.0 Protocol Design 
 
This is a randomized, double-blind, placebo-controlled pilot study that will examine the 
safety and efficacy of MDMA-assisted psychotherapy in subjects diagnosed with anxiety 


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associated with a life-threatening cancer or non-dementing neurological illness, which 
may be ongoing or in remission but with the possibility of recurrence. Stage 1 will 
include two blinded and one open-label MDMA-assisted psychotherapy sessions 
scheduled two to four weeks apart with a male/female co-therapist team. Therapy teams 
will consist of varying combinations of the Principal Investigator, experienced co-
therapists, and intern co-therapists. Subjects will be treated by the same therapy team 
throughout their participation in the study. There will also be a moderate course of 
preparatory sessions and integrative sessions, as described in the Time and Events Table. 
 
Upon enrollment, subjects will be randomly assigned to receive either placebo (five 
subjects) or active dose (thirteen subjects) MDMA. In Stage 1, subjects will meet with 
their therapist team for three preparatory sessions and two blinded experimental sessions 
of MDMA-assisted psychotherapy. After each experimental session, subjects will stay 
overnight at the site and complete an integrative session the next day, followed by daily 
telephone calls for the next seven days and two additional integrative sessions. One 
month after the second experimental session, the Primary Endpoint assessment will take 
place, after which the blind will be broken. All subjects who received the active dose will 
then receive a third open-label experimental session with active dose MDMA. Subjects 
who receive the placebo will be offered the option to continue to the open-label Stage 2, 
unless they meet any exclusion criteria for study participation. In Stage 2, subjects will 
receive active dose MDMA in three experimental sessions that will otherwise follow the 
same sequence of events after a single preparatory session. (See Time and Events Table).  
 
A blinded Independent Rater will administer the MADRS and the GAF; all other 
outcome measures will be collected via subjects’ self-report or via report provided by a 
caregiver or observer. 
 
Anxiety symptoms will be assessed in all subjects throughout Stage 1, and anxiety 
symptoms will be assessed throughout Stage 2 for subjects continuing on to Stage 2. All 
subjects will complete a follow-up occurring one month after their third experimental 
session in Stage 1 for active dose subjects, and one month after their third experimental 
session in Stage 2 for subjects who received placebo in Stage 1. In addition all subjects 
will complete visits six months and then 12 months after their final experimental session 
where outcome measures and a questionnaire on any lasting benefits or harms of the 
treatment will be administered. (See Time and Events Table) 
 
The sponsor will conduct an ongoing review of video data of psychotherapy sessions, 
entry criteria, vital signs, and reaction data for completed sessions and any AEs. The 
sponsor will provide ongoing feedback to the co-therapist teams to ensure proper 
therapist training, subject safety, and to support the sponsor’s effort to manualize 
MDMA-assisted psychotherapy for this indication.  
 


        MAPS Study MDA-1                                                                                                                                                                                  Protocol Amendment 1 
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A =First Integrative session is 1 day after exp session B = At least 24 hrs prior to 1st exp. session C =Approximately 6 hours post MDMA    D =At the beginning of the session E =As needed  
F=Approximately every 90 minutes G =Given on 1st preparatory session (V2) H= Given on 2nd preparatory session (V1) I= Given on 3rd preparatory session (V3) J =For 7 days post Exp. Session, C-
SSRS D2 and D7 of calls only, General well being for all 7 days. K= On the day of the 1st integrative session following the Exp. Session L=On the third integrative session after the first experimental 
session only. M= Given at all three integrative sessions  
 
Table 2.Stage 1 Time&Events  
Preparatory 
Experimental Session 
1 
Experimental Session 2 
Experimental Session 
3 
Follow-Up 
Visit # 
Pre-Study 
V 1,2,3 
V4 
V 5,6,7 
V8 
V 9,10,11 
V12 
V13 
V 14,15,16 
V17 
Type of Visit 
Screening may take place 
over more than one day 
Preparatory 
Sessions 
Experimental 
Session 1 
Integrative 
Sessions 
Experimental 
Session 2 
Integrative 
Sessions 
Primary 
Endpoint 
Experimental 
Session 3  
Integrative 
Sessions 
End of Stage 1 & 
Outcome 
Visit Timing or Study day or Window 
Up to 2 months prior to  
Visit 1 
Prior to V4  
Up to 5 weeks 
post V1 
Before V8 A 2-4 weeks post 
V4 
Before 
V12A 
1 month 
+/- 1 week 
post V8 
3-4 weeks post 
V8 N 
Before V17 
A, N 
May happen over > 
1 day. 1 mo. +/- 1 
week post V13 N 
Initial Phone Screen 
! 
 
 
 
 
 
 
 
 
 
Informed Consent 
! 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric History  
! 
 
 
 
 
 
 
 
 
 
General Phys. Exam (BP, Pulse, Temp) 
! 
 
 
 
 
 
 
 
 
 
Brief Neurological Exam 
! 
 
 
 
 
 
 
 
 
 
ECG 
! 
 
 
 
 
 
 
 
 
 
SCID-RV 
! 
 
 
 
 
 
 
 
 
 
Clinical Lab Tests, w/ HIV, HCV test 
! 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
! 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Medication Taper (if applicable) 
! 
 
 
 
 
 
 
 
 
 
Study Enrollment after meeting I/E 
 
!
G 
 
 
 
 
 
 
 
 
Record to Audio/Video 
 
! 
! 
! 
! 
! 
!  
! 
! 
! 
General Well-Being 
 
! 
! 
! 
! 
! 
 
! 
! 
 
Drug Screen 
! 
 
! 
 
! 
 
 
! 
 
 
Pregnancy Screen (if applicable) 
! 
 
! 
 
! 
 
 
! 
 
 
Complete Randomization Procedure 
 
 
!
 B 
 
 
 
 
 
 
 
STAI-Trait 
!
  
 
 
 
 
 
! 
 
 
! 
STAI-State 
! 
!I 
 
 
 
 
! 
 
 
! 
BDI-II 
! 
 
 
!L 
 
 
! 
 
 
! 
BPI-Short 
 
!I 
 
!K 
 
!K 
! 
 
!K 
! 
GAF, MADRS 
 
! 
 
 
 
 
! 
 
 
! 
DAP, PTGI, PTGI-C PSQI 
 
!G 
 
 
 
 
! 
 
 
! 
FFMQ, SCS 
 
!H 
 
 
 
 
! 
 
 
! 
FACIT 
 
!I 
 
 
 
 
! 
 
 
! 
ORF 
! 
 
 
 
 
 
! 
 
 
 
C-SSRS 
! 
! 
!C, D, E 
!J, M 
!C, D, E  
!J,M 
! 
! C, D, E  
!J,M 
! 
Administer IP Drug + Therapy, SOCQ, 
PPQ 
 
 
! 
 
! 
 
 
! 
 
 
Monitoring of BP, Pulse and Temp.  
 
 
! 
 
! 
 
 
! 
 
 
SUD 
 
 
! F, E 
 
! F, E 
 
 
! F, E 
 
 
Beliefs of Condition Assignment 
 
 
 
!K 
 
!K 
 
 
!K 
 
Overnight Stay 
 
 
! 
 
! 
 
 
! 
 
 
Integrative Therapy Session 
 
 
 
! 
 
! 
 
 
! 
 
7 days Integrative Telephone Contact 
 
 
 
!
 J 
 
!
 J 
 
 
!
 J 
 
AEs Requiring Medical Attention 
 
 
! 
! 
! 
! 
! 
! 
!  
! 
Spont. Reported Reactions and all AEs 
 
 
! 
! 
! 
! 
 
! 
! 
 
AEs of psychiatric status or withdrawal  
 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Serious Adverse Events 
 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Issue Memory Aid Card  
 
 
 
 
 
 
 
 
 
! 
Semi-Structured Interview 
 
 
 
 
 
 
 
 
 
! 
Unblinding
 J 
 
 
 
 
 
 
! 
 
 
 


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* If Visit 18 is more than 30 days after Visit 12, then subjects will need to repeat measures prior to starting Stage 2. 
 
A = First session is one day after experimental session; B = Approximately six hours post MDMA; C = At the beginning of the session; D = As needed; E = Approximately every 90 minutes; F = Reactions 
collected for seven days post experimental session; G = Day 2 and Day 7 phone calls only; H = 2 weeks after the second experimental session but before the third experimental session; I = On the day of the first 
integrative session following the Exp. Session; J=At the third integrative session following the first experimental session only; K=At all three integrative sessions; L=At the 12-month follow-up visit only.
Table 3. Time & Events Stage 2 
 
Preparatory 
Session 
Experimental 
Session 1 
Experimental 
Session 2 
Secondary 
Endpoint 
Experimental 
Session 3 
End of 
Stage 2 
 
Long-term 
Follow-up  
Visit # 
V18* 
V19 
V20,21,22 
V23 
V24,25,26 
V27 
V28 
V29, 30, 31 
V32 
 
LTFU 
Type of Visit 
Preparatory  Experimental Integrative 
Experimental 
Integrative 
Outcome 
Experimental 
Integrative 
Outcome 
Follow-up 
Visit Timing 
Within 1 
month post 
V12* 
1 week 
post V18 
Between 
V19 and 
V23  
2-4 weeks 
post V19 
Between 
V23 and V27  
1 month +/- 1 
week 
post V23 
3-4 weeks  
post V23 
Between 
V28 and V32  
1 month +/- 1
week 
post V28 
6 months 
AND 1 year 
post V13 or 
V28 
Confirm Informed Consent 
! 
 
 
 
 
 
 
 
 
 
Confirm Inclusion/Exclusion 
! 
 
 
 
 
 
 
 
 
 
Enrollment in Stage 2 
! 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
! 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Record to Audio/Video 
! 
! 
! 
! 
! 
 
! 
! 
 
 
General Well-Being 
! 
! 
! 
! 
! 
! 
! 
! 
 
 
Drug Screen 
 
! 
 
! 
 
 
! 
 
 
 
Pregnancy Screen (if applicable) 
 
! 
 
! 
 
 
! 
 
 
 
STAI-Trait, MADRS 
Use V12* 
 
 
 
 
!H 
 
 
! 
! 
STAI-State, GAF, DAP, PTGI, PTGI-C 
PSQI, FFMQ, SCS, FACIT 
Use V12* 
 
 
 
 
! 
 
 
! 
! 
BDI-II 
Use V12* 
 
!J 
 
 
! 
 
 
! 
! 
BPI-Short 
Use V12* 
 
!I 
 
!I 
! 
 
!I 
! 
 
ORF 
 
 
 
 
 
! 
 
 
 
! 
C-SSRS 
! 
!B,C,D 
!G,K 
!B,C,D 
!G,K 
! 
!B,C,D 
!G,K 
! 
! 
Administer Drug + Therapy 
 
! 
 
! 
 
 
! 
 
 
 
Monitoring of BP, Pulse, and Temp.  
 
! 
 
! 
 
 
! 
 
 
 
SUD 
 
!D,E 
 
!D,E 
 
 
!D,E 
 
 
 
Overnight Stay, SOCQ, PPQ 
 
! 
 
! 
 
 
! 
 
 
 
Integrative Therapy Session 
 
 
!A 
 
!A 
 
 
!A 
 
 
Seven Days Telephone Contact 
 
 
! 
 
! 
 
 
! 
 
 
AEs Requiring Medical Attention 
! 
! 
! 
! 
! 
! 
! 
! 
! 
 
Spont. Reported Reactions and all AEs 
 
! 
!F 
! 
!F 
 
! 
!F 
 
 
AEs of psychiatric status or withdrawal  
! 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Serious Adverse Events 
! 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Complete Stage 2 go to follow-up 
 
 
 
 
 
 
 
 
! 
 
Issue Memory Aid Card 
 
 
 
 
 
 
 
 
! 
 
Semi-Structured Interview 
 
 
 
 
 
 
 
 
! 
 
Follow-up Questionnaire 
 
 
 
 
 
 
 
 
 
!L 
Termination Visit 
 
 
 
 
 
 
 
 
 
!L 


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4.1 Planned Duration of Study 
 
Subjects enrolled in this study will fall into two categories that will determine the 
duration of the study.  
 
1. 
Subjects receiving active dose MDMA completing Stage 1 only: 15 months or 18 
visits, including active participation for 3.5 months plus long-term follow-up 
visits at six and 12 months after the last experimental session. 
2. 
Subjects receiving placebo who continue and complete Stage 2: 18 months or 29 
visits, including active participation for six months plus long-term follow-up 
visits at six and 12 months after the last experimental session. 
 
Screening may take up to two months. The time period between the End of Stage 1 and 
the start of Stage 2 should be one month and is not to exceed five months for any subject. 
Any delay between visits would result in a corresponding extension of study duration. 
  
4.2 Recruitment and Subject Population 
 
Subjects may be men or women aged 18 or older with significant anxiety related to a 
diagnosis of a life-threatening illness. The illness can be current or have the possibility of 
recurring. Subjects should be diagnosed with cancer or a life-threatening, non-dementing 
neurological illness, and have a prognosis of at least nine months’ life expectancy in 
order to enter the study. Subjects will be recruited through printed ads, internet ads, 
referrals from other psychiatrists, psychotherapists or physicians, and through word of 
mouth. Eighteen subjects who meet all inclusion criteria without meeting any exclusion 
criteria will be admitted to the study. Only IRB-approved recruitment materials and 
advertisements will be used for the study. 
 
4.2.1 Inclusion Criteria 
  
 
Individuals eligible to be enrolled into this protocol: 
 
1. Have received a diagnosis of a life-threatening cancer or non-dementing 
neurological illness, which may be ongoing or in remission but with the 
possibility of recurrence; 
2. Have a prognosis of at least nine months’ life expectancy from the time of 
screening; 
3. Have a score of 45 or higher on the STAI-Trait, indicating moderate to severe 
anxiety; 
4. If the individual has a documented history of anxiety disorder, the patient and 
investigator are in agreement that the individual’s present anxiety is primarily 
resultant from or exacerbated by their illness; 
5. May have a concurrent affective disorder, excepting bipolar affective disorder 1; 
6. Are at least 18 years old; 


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7. If in ongoing psychotherapy at the time of recruitment, are able to continue to see 
their outside therapist during the course of the study. Subjects must sign a release 
permitting the CI to communicate directly with their therapist;  
8. If currently prescribed medications or medical interventions by a physician related 
to treatment of their illness, subjects must agree to permit the CI to communicate 
directly with their prescribing physician; 
9. Are willing to refrain from changing therapists, increasing the frequency of 
therapy, or commencing any new type of therapy until after the evaluation session 
at the End of Stage 1 or 2, as applicable; 
10. Are willing to refrain from taking any psychiatric medications during the study 
period (defined as the period commencing with enrollment in the study through 
the follow-up visit one month after the final experimental session), 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 for 24 hours prior to experimental sessions if possible, as 
these medications may reduce the efficacy of MDMA. Subjects will be permitted 
to take their prescribed opiate medication during this period if necessitated by 
pain flare-ups. If the subject is on stimulants for ADHD at Baseline, they can 
continue to use them at the same dose and frequency as long as they discontinue 
five half-lives and one week for symptom stabilization before each experimental 
session and do not restart for ten days after each experimental session. Any 
psychiatric drugs will be tapered in an appropriate fashion to avoid withdrawal 
effects.  Medications will only be discontinued after consultation with the 
prescribing physician;   
11. Agree to refrain from taking, for one week preceding each experimental session: 
a. Any herbal supplement (except with prior approval of the research 
team).  
b. Any nonprescription medications (with the exception of non-steroidal 
anti-inflammatory drugs or acetaminophen, unless with prior approval of 
the research team). 
c. Any prescription medications (with the exception of birth control pills, 
thyroid hormones, or other medications approved by the research team); 
NOTE: Must have physician’s approval 
 
Exceptions will be made for medications necessary for the ongoing treatment of
 
life-threatening illnesses, as per the PI in consultation with treating physicians; 
12. Agree to take nothing by mouth except alcohol-free liquids after midnight the 
evening before the experimental session;  
13. Agree to refrain from the use of any psychoactive drug, with the exception of 
caffeine or nicotine, within twenty-four hours of each experimental session;  
14. Agree not to use caffeine or nicotine for two hours before and six hours after 
ingesting the drug or until the therapists deem it safe to do so;  
15. Are willing to commit to medication dosing, experimental sessions, follow-up 
sessions, and to complete evaluation instruments; 
16. Are willing to remain overnight at the study site after each experimental session 
until after the integrative session occurring the next morning;  


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17. Are willing to be driven home the morning after the experimental sessions, after 
the integrative session either by a driver arranged by the subject or by the site 
personnel or taxi;  
18. Are willing to be contacted via telephone on a daily basis by one of the therapists 
for a week after each experimental session;  
19. Are willing to provide a contact (relative, spouse, close friend, or other caregiver) 
who is willing and able to be reached by CI in the event of a subject becoming 
suicidal; 
20. Are willing to select up to three observers who will complete observer measures 
of subject attitudes and behavior; 
21. Agree to inform the CI within 48 hours of any planned medical interventions; 
22. Are willing to refrain from participating in any other interventional clinical trial 
for the duration of this clinical trial, including the follow-up period;  
23. If female subjects of childbearing potential, must have negative pregnancy test 
results, be willing to have pregnancy tests, and must agree to use an effective 
form of birth control during the treatment period; 
24. Are proficient in speaking and reading English; 
25. Agree to have all psychotherapy sessions recorded to audio/video. 
 
4.2.2 Exclusion Criteria 
 
Individuals not eligible to be enrolled into this protocol are those who: 
 
1. Are pregnant or nursing, or of child bearing potential and not practicing an 
effective means of birth control; 
2. Have a history of, or current primary psychotic disorder or bipolar affective 
disorder type 1 or a personality disorder that, in the opinion of the investigator, 
would interfere with the patient’s participation in the study; 
3. Are diagnosed with dissociative identity disorder or an eating disorder with active 
purging;   
4. Have evidence or history of significant (controlled or uncontrolled) 
cerebrovascular or cardiovascular disease, primary or metastatic tumors in the 
brain, renal disease, or any other medical disorder judged by the CI to 
significantly increase the risk of MDMA administration (Subjects with 
hypothyroidism who are on adequate and stable thyroid replacement will not be 
excluded); 
5. Are diagnosed with a dementing neurological illness; 
6. Are experiencing cognitive and/or affective deficits as a result of chemotherapy 
that, in the opinion of the investigator, would interfere with the subject’s ability to 
participate in the study; 
7. Subjects who are receiving primary treatment for their illness such as initial 
chemotherapy or radiation, or who are recovering from surgery will be excluded. 
Subjects in ongoing maintenance treatment will be considered on a case by case 
basis and will be excluded if the CI, in consultation with the prescribing 
physician, judges that the maintenance drug is likely to lead to adverse drug 
interactions; 


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8. Have hypertension using the standard criteria of the American Heart Association 
(values of 140/90 or higher assessed on three separate occasions); 
9. Have evidence or history of liver disease that would affect metabolism of 
MDMA; 
10. Have diabetes type I or II; 
11. Have history of hyponatremia or hyperthermia; 
12. Weigh less than 48 kg; 
13. Would present a serious suicide risk, as determined through psychiatric interview, 
responses to CSSRS and through clinical judgment of the CI, or who are likely to 
require hospitalization during the course of the study; 
14. Have used “Ecstasy” (material represented as containing MDMA) at least once 
within twelve months of enrollment; 
15. Require uninterrupted concomitant therapy with a psychiatric drug, including but 
not limited to SSRIs, SNRIs, or MAOIs; 
16. Meet DSM-IV criteria for substance abuse or dependence for any substance in the 
past sixty days except caffeine or nicotine; 
17. Have glaucoma, significant atherosclerosis, or hyperthyroidism; 
18. Have any current problem, which in the opinion of the CI or Medical Monitor, 
might interfere with participation in the study; 
19. Are participating in an interventional clinical trial concurrent with the study; 
20. Are not able to give adequate informed consent. 
 
5.0 Methods 
 
5.1 Measures 
 
The following outcome, safety, and process measures will be used in the study. All 
psychotherapy sessions, including experimental sessions, will be recorded to video, with 
all recordings preserved for research and training purposes.  
 
5.1.1 Outcome Measures 
 
The primary outcome measure will be the trait subscale of the State-Trait Anxiety 
Inventory (STAI), a 20-item self-report measure of intensity of anxiety [118]. The STAI 
is considered the definitive instrument for assessing anxiety in adults, and has been 
administered to advanced-stage cancer patients. Each item consists of a 4-point Likert 
rating scale ranging from 1 (‘Not at all’) to 4 (‘Very Much So’). The STAI differentiates 
between state anxiety, defined as anxiety experienced in reaction to a specific 
environmental circumstance, and trait anxiety, defined as long-standing nervous affect or 
anxiety disorder. The Trait score has good to strong test-retest reliability in adults and is a 
well-established measure of anxiety. The use of the trait subscale as the primary outcome 
measure is intended to target those anxiety symptoms that are chronic and pervasive. The 
STAI-Trait will be administered at baseline, the primary and secondary endpoints, and at 
the one, six, and 12-month follow-up visits. 
 


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The secondary measure of anxiety symptoms will be the state subscale of the STAI 
(STAI-S), a 20-item self-report scale which will assess subjects’ levels of transient, 
situationally oriented anxiety [118]. Like the trait subscale, participants respond to each 
item on the state subscale by selecting a response from a 4-point Likert scale. The 
comparison of the two subscales will provide information about the specific anxiolytic 
effects of MDMA, as well as the types of anxiety most often experienced in individuals 
with a life-threatening illness. The STAI-State will be administered at baseline, the third 
preparatory session, the primary and secondary endpoints, and at the one, six, and 12-
month follow-up visits. 
 
The Beck Depression Inventory-II (BDI-II) is a 1996 revision of the BDI, a 21-item self-
report measure [119, 120], that will serve as a measure of depression according to DSM-
IV criteria [121]. 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 [121]. Score cutoffs indicate: 0-13 minimal depression, 14-19 
mild depression, 20-28 moderate depression, and 29-63 severe depression. Higher scores 
indicate more severe depressive symptoms. The BDI-II will be administered at baseline, 
the third integrative session after the first experimental session, the primary and 
secondary endpoints, and at the one, six, and 12-month follow-up visits. 
 
The Global Assessment of Function (GAF) is a measure of global functioning made 
through clinical observation. The GAF consists of a single score, with scores ranging 
from 0 to 100, with 100 reflecting superior function and zero reflecting serious risk of 
causing harm to the self or others. The GAF is a reliable, validated measure of social 
functioning [122]. The GAF will be administered by the blinded Independent Rater at the 
first preparatory session, the primary and secondary endpoints, and at the one, six, and 
12-month follow-up visits. 
 
The Pittsburgh Sleep Quality Index (PSQI) is a measure of self-reported sleep quality 
over a one month period. The PSQI was designed to be a reliable, standardized measure 
able to distinguish between good and poor sleepers. It consists of 19 items, with possible 
responses ranging from zero to four on a five-point scale [123]. The PSQI consists of 
seven sub-scales; sleep quality, sleep latency, sleep duration, habitual sleep efficiency, 
sleep disturbance, use of sleeping medications, and daytime dysfunction. These are all 
summed to produce a single global scale. Global scores can range from 0 to 21, with 
higher scores reflecting poorer sleep quality, and a score below 5 indicative of good 
sleep. It takes five to ten minutes to complete. Test-retest reliability ranges from 0.85 to 
0.87, and it is internally consistent, with a Cronbach’s alpha of 0.83[123, 124]. Global 
scores correlate with other measures of alertness and self-reported sleep quality [125]. 
The PSQI will be administered at the first preparatory session, the primary and secondary 
endpoints, and at the one, six, and 12-month follow-up visits. 
 
The Montgomery-Asberg Depression Rating Scale (MADRS) is a10-item, clinician-
administered questionnaire used to diagnose the severity of depressive episodes. The 
MADRS was designed as a measure of depression that would be more sensitive to the 
changes produced by treatment than previously existing scales [126]. Score cutoffs 


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indicate: 0-6 normal/symptom absent, 7-19 mild depression, 20-34 moderate depression, 
>34 severe depression. The MADRS will be administered by a blinded independent rater 
at the first preparatory session, the primary and secondary endpoint visits, and at the one, 
six, and 12-month follow-up visits. MADRS scores are strongly correlated with scores on 
the Hamilton Depression Rating scale [126].  
 
The Posttraumatic Growth Inventory (PTGI) is a 21-item self-report measure of 
perceived growth or benefits occurring after a traumatic event [127]. It contains five 
subscales; relationship to others, new possibilities, personal strength, spiritual change, 
and appreciation of life [127, 128]. In this study, subjects will complete the PTGI in 
reference to the time since their diagnosis at baseline, but will respond in reference to the 
beginning of their participation in the study on all subsequent occasions. Subjects will 
complete the PTGI according to the Time and Events table. The PTGI will be 
administered at the first preparatory session, the primary and secondary endpoints, and at 
the one, six, and 12-month follow-up visits. The PTGI has been used in samples of 
people with life-threatening illnesses, such as diagnosis with breast cancer [129, 130].  
 
The Posttraumatic Growth Inventory—Caregiver Form (PTGI-C) is a version of the 
original 21-item PTGI questionnaire containing the same items but with modified 
instructions for a caregiver to provide perceptions of subjects [131]. Where the subject 
version of the PTGI prompts the subject to answer based on their own experience, the 
PTGI-C prompts the caregiver or study partner to rate the study subject along the same 
metrics. This adaptation of the PTGI has not been validated, but has been used in other 
research, including studies of people with cancer or cancer survivors and significant 
others [130-132]. The PTGI-C will be administered at the first preparatory session, the 
primary and secondary endpoints, and at the one, six, and 12-month follow-up visits.  
 
The Observer Rating Form is a 15-item questionnaire that prompts individuals close to 
the study subject to rate changes to the subject’s mood, demeanor, and behavior over the 
course of their participation in the study. The ORF is typically administered to 
individuals who are in regular contact with the study subject. The ORF is not a peer-
reviewed or validated scale, but it has been used in a currently ongoing study of 
psilocybin for anxiety associated with a life-threatening illness at Johns Hopkins 
University. The ORF will be administered to up to three individuals selected by the 
participant at baseline, the primary endpoint, and at the six- and 12-month follow-up 
visits. There are no current reports on validity or reliability of the ORF, but researchers 
investigating the effects of psilocybin have employed this measure [133]. 
 
The Functional Assessment of Chronic Illness Therapy Scale (FACIT-Sp) is a 27-item 
self-report measure of quality of life issues specifically relevant to individuals with a 
chronic or life-threatening illness or condition [134, 135]. The core questionnaire consists 
of four subscales: Physical Well-being, Social/Family Well-being, Emotional Well-being, 
and Functional Well-being. The version of the FACIT selected for this study also 
includes a 12-item spirituality subscale. The FACIT is a well-validated instrument with 
direct applicability to individuals with chronic health concerns. The FACIT will be 


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administered at the third preparatory session, the primary and secondary endpoints, and at 
the one, six, and 12-month follow-up visits. 
 
The Death Attitudes Profile (DAP) is a 32-item self-report questionnaire that assesses 
individual attitudes and beliefs about death and dying. Each item on the scale is rated 
along a 7-point Likert scale ranging from ‘strongly agree’ to ‘strongly disagree.’ [136-
138]. The DAP divides items along 5 dimensions: fear of death, death avoidance, neutral 
acceptance, approach acceptance, and escape acceptance. The DAP will be administered 
at the first preparatory session, the primary and secondary endpoints, and at the one, six, 
and 12-month follow-up visits.  
 
The Five-Facet Mindfulness Questionnaire (FFMQ) is a 39-item self-report questionnaire 
that assesses how often and to what degree respondents experience or utilize mindfulness 
in their everyday life [139, 140]. Subjects respond to the FFMQ using a five-point Likert-
type scale ranging from 1=never or very rarely true to 5=very often or always true. The 
questionnaire divides mindfulness into five component skills: observing, describing, 
acting with awareness, nonjudging of inner experience, and nonreactivity to inner 
experience. The FFMQ has been found to have good construct validity in discerning 
regular practitioners of mindfulness meditation from nonpractitioners [140-142]. Its use 
in this study is intended to explore the effects of MDMA-assisted psychotherapy on 
experiences of mindfulness, regardless of past meditation or mindfulness experience. The 
FFMQ will be administered at the second preparatory session, the primary and secondary 
endpoints, and at the one, six, and 12-month follow-up visits. 
 
The Self-Compassion Scale (SCS) is a 26-item self-report questionnaire that assesses 
how respondents relate to themselves and treat themselves during difficult or painful 
experiences [143]. Items are scored along a 5-point Likert-type scale ranging from 
1=almost never to 5=almost always. The SCS has six component scores: self-kindness, 
self-judgment, common humanity, isolation, mindfulness, and over-identification. These 
subscores can also be used to generate an overall composite score. Higher scores have 
been found to correlate with positive mental health outcomes, as well as decreased 
depression and anxiety . The SCS will be administered at the second preparatory session, 
the primary and secondary endpoints, and at the one, six, and 12-month follow-up visits. 
The SCS is reliable, with strong test-retest reliability and validation in comparison with 
measures selected for similarity or distinctness from the construct [143]  
 
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 six and 12-
month follow-up visits.  The measure has been used to assess the durability and nature of 
effects of MDMA-assisted psychotherapy in people with PTSD [2]. 
 
5.1.2 Safety Measures 
 
Safety measures will be applied, as described below, to minimize risks associated with 
drug-assisted psychotherapy sessions. The therapists will be available via mobile phone 


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Page 25 of 76 
or pager throughout the study to ensure subject safety. The therapists 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. Subjects will rate their current degree of 
subjective distress with the SUD scale, which is a single-item self-report scale. The SUD 
will be completed repeatedly during the experimental sessions, with the degree of distress 
described as a single number along a seven-point scale. Results of the SUD are intended 
to assist therapists in maintaining subject safety during Experimental sessions. 
 
The therapists will assess general wellbeing during each preparatory session, on each 
integrative session and during integrative telephone calls for seven days. Results of this 
scale are intended to assist therapists in maintaining subject safety throughout the study. 
 
The C-SSRS is a clinician-administered measure of suicidal behavior devised to detect 
potential suicidal thoughts or behaviors during a clinical trial [144]. 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 
series of questions, and can be administered during a face-to-face interview or over the 
telephone. Suicidality will be assessed at Baseline, once during any face-to-face visit, 
during the second and seventh days of integrative telephone contact, and twice during 
each experimental session. Subjects who are discontinuing medication to participate in 
the study will complete the C-SSRS before and after medication washout. The C-SSRS 
data will be collected on Case Report Forms (CRFs) for all administrations except for the 
second integrative session, unless the therapists observe an increase in suicidality. C-
SSRS data from the second integrative session after each experimental session will be 
kept with the subject’s Source Record. 
 
The Brief Pain Inventory—Short Form (BPI-S) is a self-report measure of physical pain 
symptoms that is intended to provide an overall picture of subjects’ chronic pain over the 
course of the study [145]. The BPI-S includes a visual component, where subjects are 
asked to indicate where on their body they experience pain, scales for rating pain 
severity, efficacy of pharmacotherapy in relieving pain, and the degree to which pain 
impinges upon subjects’ ability to function. This measure or translations of it are used in 
studies assessing cancer pain and pain arising from other illnesses, such as osteoarthritis 
[7, 146, 147] The BPI-S will be administered during the preparatory period, as well as at 
the first integrative session following each experimental session, and at the primary and 
secondary endpoints.  
 
Cardiovascular effects will be assessed via blood pressure and pulse measurement.  
Blood pressure and heart rate will be assessed periodically during each experimental 
session by an automatic blood pressure (BP) and pulse monitor. Blood pressure and pulse 
will be measured at the outset of the experimental session, once approximately every 30 
minutes for the first four hours of the experimental session, and then once every hour, or 
as needed, thereafter. More frequent measures will be taken if the established thresholds 
of 180 systolic, 120 diastolic, or pulse of 120 are exceeded.  Blood pressure will also be 


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measured more frequently if there are symptoms, such as chest pain, shortness of breath, 
or neurological symptoms that may be indicative of hypertension. The therapists will 
measure subject body temperature approximately every 60 to 90 minutes. Cardiovascular 
effects will be assessed via blood pressure measurement. The timing of these 
measurements will be adjusted so that they do not interfere with the therapeutic process.  
 
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. 
 
5.1.3 Process Measures 
 
All psychotherapy sessions, including experimental sessions, will be recorded to audio 
and video, with all recordings preserved for research and training purposes.  
 
Belief of condition assignment and certainty will be collected from each therapist 
responsible for treating the subject and the subject at the integrative session on the day 
after each blinded experimental session in Stage 1. These beliefs are collected as a part of 
the sponsor’s ongoing initiative to optimize the double-blind as a part of dose response 
studies.  
 
The States of Consciousness Questionnaire (SOCQ) is a 100-item questionnaire based on 
the “Peak Experience Profile” designed by Pahnke and colleagues [133, 148]. Subjects 
respond to the SOCQ using a six-point Likert-type scale anchored at 0=none at all and 
5=extreme (more than ever before in my life). It has seven subscale scores; internal unity, 
external unity, transcendence of time and space, ineffability and paradoxicality (claim of 
difficulty in describing the experience in words), sense of sacredness, noetic quality, and 
deeply felt positive mood. The measure is a self-report instrument and takes 
approximately twenty to thirty minutes to complete. Subjects will complete the SOCQ 
after each experimental session, at any time between the end of an experimental session 
and prior to leaving the treatment facility the next day. 
 
The Psychological Process Questionnaire (PPQ) is a 35-item companion questionnaire to 
the SOCQ designed by investigators working with the SOCQ, in which subjects rate each 
item along the same six-point Likert-type scale. It is intended to capture a broader array 
of experiences and benefits than those captured in the SOCQ, particularly in respect to 
perceived insights or benefits from alterations in consciousness [149]. The PPQ focuses 
primarily upon changes in cognitive and/or emotional processing that may be 
experienced in the course of an MDMA-assisted psychotherapy session, and is intended 
to provide a fuller picture of the changes in perception that may occur during treatment 
sessions. Subjects will complete the PPQ after each experimental session, at any time 
between the end of an experimental session and prior to leaving the treatment facility the 
next day. 
 


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5.2 Study Procedures and Visit Descriptions 
 
 
5.2.1 Prescreening, Screening, and Baseline Evaluation - Pre-study 
 
 
Prospective subjects will be prescreened by telephone according to an IRB-approved 
script to learn if they meet basic eligibility criteria. This script will include the STAI-
Trait and the Overall Anxiety Severity and Impairment Scale (OASIS) [150] instruments 
as a means of estimating eligibility for the study. Data from these assessments will not be 
used in any study analyses, and the STAI-Trait assessment will be repeated in full at each 
subjects’ baseline visit. All individuals who are prescreened should be assigned a 
screening number and recorded on the Subject Screening Log where information on the 
selection of potential subjects in the trial should be collected.  
 
Upon signing the IRB-approved informed consent form (ICF), the potential subject may 
commence study-related screening activities. The screening number should also be 
recorded on the signed ICF. If a subject is enrolled, the study staff should record the 
enrollment date and assign a subject number. If a subject is not enrolled, an explanation 
should be recorded on the Screening Log. A CRF will not be completed for subjects who 
are not enrolled. These subjects will only be documented on the Screening Log and 
Source Records.  It is the responsibility of the CI to file the Screening Log in the 
investigator site file (ISF) to be readily available for on-site monitoring and/or inspection 
by relevant authorities. Screening may take place over more than one day and should be 
complete by up to two months prior to enrollment. If, after reviewing all information, the 
CI concludes that a subject is eligible, they will enroll the subject in the study. Visits will 
be scheduled consecutively, as described in the Time and Events Table.  
 
a. Explain and obtain written informed consent from the subject. Written informed 
consent must be obtained prior to performing any tests or evaluations for the study. 
Any potential subjects who are private patients of the CI must have their records and 
eligibility reviewed by an independent physician, who will also conduct the informed 
consent process with the subject. 
b. Assign the subject a screening number. Complete the Screening Log.  
c. Review the ability of females of childbearing potential to become pregnant and their 
commitment to practice appropriate birth control, as determined by the CI for the 
treatment period of the study. 
d. The PI will obtain medical and psychological history by interview. 
e. The PI will collect information on pre-study and current medications. 
f. The PI will perform a general physical examination. The examination will involve the 
following procedures:  
 
• Blood pressure 
• Pulse 
• Height 


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• 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 
• C-SSRS to assess suicide risk  
 
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 subject’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 subject’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 PI will request a review of subject 
medical records and request additional tests or assessments, as indicated. 
 
The PI, or another qualified investigator will administer: 
• Structured Clinical Interview for DSM-IV Research Version (SCID-RV) to 
assess eligibility based on DSM-IV diagnoses, which includes a self-report 
questionnaire to focus on modules to use based on symptoms. 
 
The subject will complete the following self-report measures: 
• STAI to assess anxiety symptoms, and to determine eligibility 
• BDI-II to assess depression symptoms 
 
5.2.2 Preparatory Psychotherapy Sessions - Visits 1, 2, 3 (Stage 1), 18 (Stage 2) 
 
Subjects who do not complete all screening activities will not be enrolled. Eligibility may 
be discussed by phone after screening is complete and at the time Visit 1 is scheduled but 
the final confirmation will occur at Visit 1. If all inclusion criteria and no exclusion 
criteria are met, eligibility will be confirmed with the subject. 
 
a. Complete a final review of inclusion/exclusion criteria. 
b. Assess general wellbeing. 
c. Confirm eligibility and willingness to participate in study. 
d. Enroll subject and issue subject 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 Section 8.5 
and Section 9.0. 


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f. Discuss medication tapering, if applicable. Upon confirmation of eligibility, the 
PI will consult the prescribing physician to initiate medication tapering for 
subjects who must refrain from taking a psychiatric medication during the study 
period, beginning with enrollment through the one-month follow-up visit 
following the subject’s final experimental session. 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.  
 
The subjects will undergo three preparatory sessions lasting approximately ninety 
minutes with their therapist team, prior to their first experimental session. The first 
preparatory session will take place at Visit 1 after enrollment confirmation.  
In Stage 2 (for placebo crossover subjects) only one preparatory session will take place 
prior to their first active dose open-label experimental session, as described in the Time 
and Events Table.  
 
 
During the preparatory sessions: 
 
a. Therapists will record all sessions to audio and video.  Subjects may receive 
copies of audio or video recordings from these sessions upon request.  
b. Collect AEs and Medications, as described in Section 8.5 and Section 9.0. 
c. The therapists will inquire about any possible changes in the subject’s health to 
ensure that subject continues to meet eligibility criteria and, if applicable, will 
confirm that the subject has appropriately tapered off of medications.  
d. The subject and therapists will discuss goals for the experimental session and will 
review what will happen during the experimental session.  
e. If a subject would like a companion present during or after the experimental session, 
a meeting between the therapists and that individual will be scheduled prior to the 
first experimental session. There must be mutual agreement between the subject and 
therapists concerning the presence of the companion. The companion can be but is 
not required to be the caregiver, transportation partner, or one of the observers. 
f. The blinded Independent Rater will administer the GAF and MADRS at the first 
preparatory session. 
g. The subject will complete the DAP, PTGI, and PSQI at the first preparatory session. 
h. The subject’s caregiver will complete the PTGI-C at the first preparatory session. 
i. Up to three individuals in close contact with the subject will complete the ORF during 
the preparatory period, prior to the first experimental session. One of them may be the 
caregiver, transportation partner, and/or experimental session companion 
j. The subject will complete the FFMQ and SCS at the second preparatory session. 
k. The subject will complete the FACIT, STAI-State, and BPI-S at the third preparatory 
session. 
l. The therapists will administer the C-SSRS just prior to beginning the second 
preparatory session, unless a subject is still undergoing medication washout.  Subjects 
still undergoing medication washout will complete the C-SSRS during the second 
preparatory session or at a point after washout is complete prior to the first 
experimental session.  


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m. Assess general wellbeing at each preparatory session. 
n. During the third and last preparatory session, give the Reminder of Study Rules to the 
subject, which includes instructions and restrictions for conduct prior to receiving the 
drug. Subjects must agree to: 
 
• Ingest only alcohol-free liquids after 24:00 (midnight) the evening before the 
experimental session.  
• Refrain from the use of any psychoactive drug, with the exception of caffeine or 
nicotine, within 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. 
  
5.2.3 Experimental sessions - Visits 4, 8 (Stage 1), 13, (Active dose Group Stage 1), 
19, 23, 28 (Stage 2) 
 
Subjects in Stage 1 will receive two experimental sessions of MDMA-assisted 
psychotherapy, blinded with respect to dose, scheduled approximately two to four weeks 
apart. Subjects in the open-label third experimental session in Stage 1 and open-label 
Stage 2 will receive experimental sessions with the active dose of MDMA. Procedures 
for MDMA-assisted psychotherapy will remain the same across all sessions and all 
procedures except the dose of the drug received will be the same.  
 
Generally, therapists will create and communicate a setting of safety and support the 
subject during periods of inner focus. Therapists will use a largely nondirective approach, 
following the lead of the subject’s inner healing intelligence. Therapists will provide 
encouragement for staying present with difficult experiences. Therapists may 
occasionally offer gentle guidance or redirection as a choice to encourage collaborative 
exploration if the subject repeatedly avoids relevant material. Therapists will inquire 
about somatic symptoms and if necessary encourage release of tension through 
movement, in whatever way feels appropriate to the subject. Therapists will use music to 
support the experience without being intrusive.  
 
The Principal Investigator will monitor all experimental sessions for medical issues in his 
capacity as a licensed physician. If the PI is the treating therapist for a subject, he will 
conduct this monitoring concomitant to the session therapy. If the subject is being treated 
by another therapist team, the PI will be available to supervise the session via closed-
circuit camera system from an adjacent room. 
 
Table 4. Schedule of Procedures for Experimental Sessions 
Approximate Time 
Procedure or Action 
9:00  
Urine drug screen and pregnancy test. Subject acclimated to 
environment, C-SSRS 
9:45  
Baseline Blood Pressure (BP), Pulse, Subjective Units of Distress 
Rating (SUD) 
9:55  
2nd Baseline BP, Pulse, Body Temperature (BT), SUD 
10:00  
MDMA Administration, begin recording to audio and video 


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Pre-drug: 
 
a. At least 24 hours prior to the first experimental session the subject will be randomized 
to one of the two conditions. The PI will obtain the container assignment using a web-
based randomization program prior to the blinded sessions.  
b. On the day of the experimental session, the subject will arrive approximately one to 
one and a half hours prior to drug administration.  
c. Confirm continuing eligibility by reviewing inclusion/exclusion criteria. 
d. Perform a urine drug screen.  A positive drug screen will be reviewed by the CI and 
may be cause for delaying drug administration to a later time, rescheduling the 
session to a later date, or withdrawing the subject from the study. 
e. If a woman is of childbearing potential, perform a urine pregnancy test. A positive 
pregnancy screen is cause for withdrawal from the protocol. 
f. If the subject continues to meet criteria and the subject reports that they followed 
appropriate rules and restrictions, the session will proceed. 
g. Review procedures for the experimental session with the subject. 
h. Record the entire session to video and audio. Subjects may review video recordings 
of their experimental sessions upon request. 
i. The session will last for approximately eight hours or longer, followed by an 
overnight stay at the study site. 
j. The therapists will administer the C-SSRS prior to drug administration. 
k. Before drug administration, discuss and review the subject’s goals, intentions, and 
concerns and some of the commonly experienced effects of MDMA. 
l. Instruct the subject not to use caffeine or nicotine two hours before or six hours after 
the dose of drug. 
m. Subject body temperature will be measured at baseline prior to administration of the 
initial dose and approximately every hour after that. The therapists may make more 
frequent measurements if body temperature exceeds more than 1oC above baseline. 
n. Subjects will complete the SUD at baseline prior to administration of the initial dose.  
Subjects will complete the SUD every 60 to 90 minutes, until the session is over, 
10:30  
BP, Pulse 
11:00  
BP, Pulse, SUD, BT 
11:30  
BP, Pulse; Administer optional Supplemental Dose  
12:00  
BP, Pulse, BT 
12:30  
BP, Pulse, SUD 
13:00  
BP, Pulse 
13:30  
BP, Pulse, BT 
14:00  
BP, Pulse, SUD 
Every hour 
and as needed 
BP, Pulse 
Every sixty to 
ninety minutes 
SUD, BT 
Approximately six 
hours after drug 
administration 
C-SSRS, General Wellbeing 


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allowing a window of up to 30 minutes to fit into the psychotherapy process where a 
natural break occurs. If necessary, the therapists can make a greater number of 
measurements, as their clinical judgment dictates. 
o. Measure blood pressure and pulse at baseline prior to the experimental session and 
once every half-hour for the first four hours of the experimental session, and once 
every hour thereafter if the established thresholds for normal blood pressure and pulse 
have not been exceeded for the duration of the experimental session. More frequent 
measures will be taken if the established thresholds of 180 systolic, 120 diastolic, or 
pulse 120 are exceeded. Measurements should be taken more frequently until the 
values fall below these levels or until they have been decreasing for 15 minutes or 
have stabilized at a level judged by the CI to be safe. The therapists may also make 
more frequent measurements if a subject exhibits symptoms indicative of 
hypertension. 
 
During: 
 
p. At approximately 10:00 in the morning, subjects will receive the initial dose of drug 
along with a glass of water.  
q. The subject will sit or recline on comfortable furnishings. Eyeshades and a program 
of music will be provided if the subject wishes to use them. Subjects may speak to the 
therapists whenever they wish, who will provide guidance and support, as needed.  
r. After the first hour, if the subject has not spoken spontaneously, check in with 
him/her about the nature of the experience. For the rest of the experience, as 
appropriate, the therapists will support and encourage the subject in emotional 
processing and resolution of whatever psychological material is emerging.  
s. Record any spontaneously reported reactions during the session. 
t. Provide water and electrolyte containing fluids throughout the session but not to 
exceed 3 L overall. 
u. A supplemental dose half the size of the initial dose will be administered 
approximately one and a half to two and a half hours after the initial dose, unless 
contraindicated. 
v. Provide food during the latter part of the session.  
w. If there is a companion who has previously been asked and has agreed to be present 
during part or all of the MDMA session, that person may arrive during the session at 
whatever time has been agreed upon, but will wait in the waiting room until brought 
back to the session room by one of the therapists. Alternatively, the support person 
may arrive after the session has ended. 
x. If it is appropriate to do so, initiate the first question of the C-SSRS at any point in the 
session if the subject is experiencing significant psychological distress that does not 
respond readily to processing with the therapists. The C-SSRS is required at least 
once during the session.  It is preferable to administer it towards the end of the 
session, about six hours after the initial dose.  
y. End the session if all medical and psychiatric parameters are acceptable and the 
subject is alert, ambulatory, and emotionally stable. 
 
Post-drug: 


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z. Give the subject the SOCQ and PPQ to be completed after the end of the 
experimental session and prior to leaving the treatment facility the next day. 
aa. The therapists will depart the site when they have concluded that the subject is 
emotionally and medically stable. Therapists or the PI shall remain available to 
subjects during the experimental session and for one week after via 24 hour cellular 
phone for integration, as needed. 
bb. Spontaneously reported reactions, AEs, and concomitant medications will be 
collected, as described in Section 8.5 and Section 9.0.  
  
Subjects will remain overnight in an appropriately furnished room at the study site.  With 
the approval of the therapists, a companion may accompany the subject during the 
overnight stay. An attendant will check in periodically on the subject during the overnight 
stay, even if a companion is present. The attendant will monitor subject condition and 
will help subjects relax during the overnight stay.  The attendant will be an individual 
with some previous training in managing psychological distress.  If there is an emergency 
or the subject needs additional support, the attendant can contact the therapists. The 
subject and a companion (if applicable) will receive information that will allow them to 
contact the therapists during the overnight stay in the case of an emergency or request for 
additional support. Subjects will be encouraged to use much of the time during their 
overnight stay for rest and for a period of reflection and integration in a quiet atmosphere. 
 
5.2.4 Integrative Sessions 24 Hours after Experimental Session - Visits 5, 9 (Stage 1), 
14 (Active dose Group Stage 1), 20, 24, 29 (Stage 2) 
 
 
On the morning after each experimental session, both of the therapists from the subject’s 
team will meet with the subject during a 60 to 90 minute integrative psychotherapy 
session.  
 
Generally, these sessions include discussing material that emerged during experimental 
sessions and helping subjects integrate their experiences both internally and into daily 
life. Therapists will validate the choices of the subject about how much they wish to 
communicate their thoughts, feelings, and experiences at this time, but will elicit enough 
information to be able to assess the subject’s level of emotional stability and state of 
emotional and physical wellbeing. Therapists will emphasize their commitment to 
support the subject during the integration period and will be available via phone for 
additional meetings if needed. Subjects will be encouraged to relax and rest as much as 
possible for several days after the experimental session. 
 
During integrative sessions: 
 
a. The integrative session will be recorded to audio and video. Subjects may receive 
copies of this session upon request. 
b. The therapists will administer the C-SSRS during each integrative session.  
c. If applicable, subjects will complete the BPI-S at the first integrative session 


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immediately following each experimental session. 
d. Prior to the integrative session, the subject and both therapists will indicate their 
beliefs concerning subject condition assignment.  
e. Discuss and review events that occurred with the subject during the experimental 
session, including thoughts, feelings, and memories. If necessary, the therapists 
will help the subject to reduce any residual psychological distress he or she is 
experiencing. The therapists will also encourage the transfer of states of 
acceptance, feelings of intimacy, closeness, and reduced fear experienced in 
experimental sessions to emotionally threatening everyday situations. The 
therapists will be supportive, validating the experience, and facilitating 
understanding and emotional clearing.  
f. The therapists will remain accessible any time the subject needs support outside 
the scheduled integration sessions.  
g. Assess the subject’s mental health and the presence of any remaining reactions 
during the integrative session.  
h. Integrative sessions can also serve as an opportunity for the therapists to gather 
information about the effects of the drug on the subject in an unstructured manner.  
i. After the integrative session, a person previously selected by the subject will 
provide a ride home to the subject. If the subject is unable to locate an individual 
willing or able to take him or her home, or if the designated person is unable to 
assist the subject due to unforeseen events, the therapists will assist the subject in 
finding an alternative means of returning home. 
j. Spontaneously reported reactions, AEs, and concomitant medications will be 
collected, as described in Section 8.5 and Section 9.0.  
k. Remind the subjects that they will have daily phone contact 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 subject via telephone or in person on a daily 
basis for one week. The goal of daily contact is assessment of changes in general 
wellbeing, safety of the subjects, and offering support for subjects.  
b. The integrative phone contact will be for a brief check-in lasting five to fifteen 
minutes or as long as necessary to address any subject’s concerns and to assess 
subject’s wellbeing. Additional telephone contact can be initiated at the request of 
the therapists or subject. 
c. On the second and seventh day of contact after the experimental session, one of 
the therapists will administer the C-SSRS. 
d. General wellbeing will be assessed at each phone call. 
e. Spontaneously reported reactions, AEs, and concomitant medications will be 
collected, as described in Section 8.5 and Section 9.0. 
 


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5.2.6 Integrative Sessions between Experimental sessions - Visits 6, 7, 10, 11  (Stage 
1), 15, 16 (Active dose Group Stage 1), 21, 22, 25, 26, 30, 31 (Stage 2) 
 
 
In addition to the integrative session the morning after each experimental session, the 
subject will have two additional integrative sessions with the therapists lasting 60 to 90 
minutes with the therapists between each experimental session and in the month 
following the last experimental session. The therapists may conduct more integrative 
sessions if they and the subject 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 subject during the integration period and will be available via 
phone or pager. Subjects will be encouraged to relax and rest as much as possible for 
several days after the experimental session. 
 
During integrative sessions: 
 
a. Record each integrative session to audio and video. Subjects may review video of 
one or more integrative sessions upon request. 
b. The C-SSRS will be administered just prior to beginning each integrative session.  
c. General wellbeing will be assessed at each integrative session. 
d. The subject will complete the BDI-II at the third integrative session following the 
first experimental session only, according to the Time and Events Table. 
e. The subject and therapists will continue to work on supporting the subject as she 
or he considers his or her experiences during experimental sessions.  
f. The therapists will use clinical judgment to assess the subject’s psychological 
wellbeing during this period of time. If there are any indications of continuing 
anxiety or distress, the therapists may arrange to work on reducing the distress at 
a specially scheduled integrative session, through continuing contact, or at the 
next regularly scheduled integrative session. The subject may also initiate contact 
with the therapists at any time throughout the study.  
g. Spontaneously reported reactions, AEs, and concomitant medications will be 
collected, as described in Section 8.5 and Section 9.0. 
h. NOTE: If an integrative session falls within the period of telephone contact and 
additional phone call is not required that day, all data normally collected during 
the telephone call will be completed in person. 
 
5.2.7 Evaluation at Primary Endpoint and Unblinding - Visit 12 (Stage 1) 
 
The Primary Endpoint evaluation in Stage 1 will occur one month (within a window of 
+/- one week) after the second blinded experimental session. This visit will consist of two 
meetings that may be completed on separate days, one with the IR and the other with the 
therapists. Subjects who have withdrawn from treatment but have continued for follow-
up will also complete this time point one month after their last experimental session. 
 


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At the Primary Endpoint: 
 
a. The blinded IR will administer:  
 
• MADRS to assess depression symptoms 
• GAF to assess general psychological function 
 
b. The subject’s support partner will complete the PTGI-C 
c. The individuals who completed the ORF at baseline will repeat the assessment. 
d. The subject will complete the following self-report measures: 
• 
STAI to assess anxiety symptoms 
• 
BDI-II to assess depression symptoms 
• 
DAP to assess changes in attitudes toward death 
• 
PTGI to assess posttraumatic growth 
• 
PSQI to assess sleep quality 
• 
FFMQ to assess mindfulness 
• 
SCS to assess self-compassion 
• 
FACIT to assess quality of life/care 
e. After completing all assessments and measures with the IR, the subject will meet 
with the therapists for approximately 30 minutes. 
f. The therapists will assess suicidality with the C-SSRS. 
g. General wellbeing will be assessed. 
h. The blind will be broken for the subject’s condition assignment. Only the IR will 
remain blind to condition assignment at this time.  
i. If the subject was assigned to receive placebo, the therapists will discuss 
enrollment in Stage 2 (See Section 5.2.9). Subjects receiving placebo will not 
complete the third experimental session and associated integrative sessions in 
Stage 1. 
j. If the subject was assigned to receive active dose MDMA, the subject will 
complete a third open-label experimental session, with associated daily phone 
calls and integrative sessions in Stage 1 (See Section 5.2.3, Section 5.2.4, Section 
5.2.5, and Section 5.2.6).  
 
5.2.8 End of Stage 1 - Visit 17 (Active dose Group Stage 1) 
 
 
Subjects receiving active dose MDMA will repeat all outcome measures with the IR and 
meet with the therapists again one month (within a window of +/- one week) after their 
final open-label experimental session, which will be their final visit in Stage 1 (See 
Section 5.2.7). This visit will consist of two meetings that may be completed on separate 
days, one with the IR and the other with the therapists. A qualitative, semi-structured 
interview will be conducted by one of the therapists, which will provide narrative data 
about subjects’ experiences in the study. 
 
At the End of Stage 1: 
 


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a. Subjects receiving active dose MDMA who complete Stage 1 and subjects 
receiving placebo dose MDMA who elect not to participate in Stage 2 will 
continue on to the long-term follow-up visit.  
b. Subjects who will continue on to the long-term follow-up may return to taking 
psychiatric medications after the End of Stage 1 if necessary.  
c. Subjects who will continue on to the long-term follow-up will receive a memory 
aid card for use between their End of Stage 1 visit and the twelve-month follow-
up.  Subjects will use this card to record AEs, medications, and changes in 
psychiatric status that they will be asked about at the termination visit.  Memory 
Aids will not be collected.  
d. Spontaneously reported reactions, AEs, and concomitant medications will be 
collected, as described in Section 8.5 and Section 9.0. 
 
5.2.9 Open-Label Stage 2 (Placebo Group from Stage 1) 
 
During Stage 2: 
 
a. Subjects will be reminded that participation in Stage 2 is voluntary and optional. 
b. Subjects who elect to cross over to Stage 2 will undergo the same course of 
therapy and evaluation as in Stage 1, but with active dose MDMA during three 
experimental sessions. 
c. Assessment of PTSD symptoms at the Primary Endpoint will serve as baseline 
assessments in Stage 2.  
d. If the start of Stage 2 is delayed for more than thirty days from the Primary 
Endpoint (Visit 12) to the first preparatory session in Stage 2 (Visit 18), the IR 
will re-administer the MADRS and GAF, and the subject will complete the 
STAI,, DAP, PTGI, PTGI-C, PSQI, BDI-II, FFMQ, SCS, and FACIT, and these 
scores will be used as the baseline for comparison to assessment at the Secondary 
Endpoint and the End of Stage 2. 
e. Subjects entering Stage 2 will meet with both therapists for a single preparatory 
psychotherapy session.  
f. Subjects will have the same sequence of Experimental sessions and integrative 
sessions as subjects receiving active dose MDMA in Stage 1 in an open-label 
context (e.g. without unblinding). Visits will be scheduled consecutively 
according to the Time and Events Table.  
g. The same outcome measures completed by subjects receiving active dose MDMA 
in Stage 1 will be administered during Stage 2. 
h. The same safety measures as those in Stage 1 will be administered during Stage 2. 
i. The End of Stage 2 will be completed in the same manner as the End of Stage 1 
(See Section 5.2.8). 
 
5.2.10 Long-term Follow-up 
 
 
All subjects will be evaluated for long-term effects six and twelve months (within a visit 
window of +/- 1 month) after their last MDMA-assisted psychotherapy session. These 


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visits will consist of two meetings, one with the IR and the other with the therapists. 
Subjects who have withdrawn from treatment but have continued for follow-up will also 
complete this time point whenever possible. 
 
At the long-term follow-up visit:  
 
a. The IR will administer the MADRS and GAF. 
b. Subjects will complete the STAI, DAP, PTGI, PTGI-C, PSQI, BDI-II, FFMQ, 
SCS, and FACIT. 
c. The subject’s support partner will complete the PTGI-C. 
d. The individuals who completed the ORF at baseline and the primary endpoint will 
repeat the assessment. 
e. Subjects will have a final meeting with at least one of the therapists to review 
specified AEs and medications since the last visit. Subjects should bring the 
Memory Aid Cards to this visit, to be used as aids in recollection.  These cards 
will not be collected. AEs and concomitant medications will be collected, as 
described in Section 8.5 and Section 9.0. 
f. One of the therapists will assess suicidality with the C-SSRS.  
g. General wellbeing will be assessed. 
h. Subjects will complete a questionnaire assessing positive and negative long-term 
effects of the study.   
i. Subjects will complete the termination visit at this time. 
 
5.3 Randomization and Subject Numbering 
 
Prior to enrollment, subjects will be tracked with their initials and a screening number 
assigned sequentially starting at “S001”. Subjects who meet all inclusion criteria and no 
exclusion criteria will be enrolled into the study and will be assigned a five-digit 
alphanumeric subject identification number.  The first two digits will be “51” and will 
identify the protocol. The next three digits identify the subject within the site and will be 
assigned sequentially, with 001 corresponding to the first subject enrolled, e.g. the first 
enrolled subject will be 51001, the second will be 51002, etc. 
 
 
In total, 18 subjects will be enrolled into the study. The randomized portion of the study 
will be blinded and there will be a 13:5 ratio between subjects in the active dose and 
placebo conditions. An unblinded Randomization Monitor will generate the 
randomization list. Subjects will be assigned subject numbers consecutively, and subjects 
will be randomized in a blinded fashion. Upon enrolling a subject, the CI will be 
provided with an enrollment code for that subject. Randomization numbers will be pre-
printed on the container labels corresponding to doses for individual sessions. 
Randomization will be performed at least 24 hours before the experimental session for 
each subject. The therapists will utilize a web-based randomization program to obtain the 
container assignment for each experimental session. Blinded personnel will conduct all 
study evaluations in the randomized portion of the study until the blind is broken for each 


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subject at the Primary Endpoint per protocol via the web-based randomization program. 
Detailed instructions will be provided to the site in a separate document. 
 
If there is an emergency requiring knowledge of subject's condition assignment, the blind 
may be broken for an individual subject. The CI will be provided with sealed emergency 
unblinding envelopes corresponding to each enrollment code.  These sealed envelopes 
will be stored in a secure limited access area and should remain sealed if there are no 
emergency unblinding events during the study.  
 
5.4 Removal of Subjects from the Study 
 
Subjects can withdraw consent at any time without prejudice.  The therapists can 
withdraw a subject if, in their clinical judgment, it is in the best interest of the subject or 
if the subject cannot comply with elements of the protocol that are critical for safety or 
for the scientific integrity of the study.  If the therapists withdraw a subject from the 
study, the therapists will explain the reason for withdrawing the subject. The reason for 
early termination will be recorded in the subject’s Source Records and CRF. 
 
Subjects will be clinically monitored after withdrawal, the cause of which will be re-
corded in the subject’s source records and CRF. Whenever possible, the tests and 
evaluations listed for the termination and outcome visits will be carried out. Efforts will 
be made to obtain information about AE outcomes, if deemed necessary by the PI and/or 
sponsor. 
 
If a subject develops any exclusion criteria that in the opinion of the Medical Monitor, 
affects the safety of the subject, including psychiatric diagnosis, pregnancy, or requiring 
use of excluded medications, the subject will discontinue treatment but remain in the 
study for follow-up purposes. Whenever possible, the tests and evaluations listed for the 
Primary Endpoint and twelve-month follow-up will be carried out. Efforts will be made 
to obtain information about AE outcomes, if deemed necessary by the PI, Medical 
Monitor, and/or sponsor. 
 
Subjects who discontinue treatment prior to the second experimental session will be 
replaced. Individuals who replace these subjects will be assigned the next available 
subject number. Subjects who discontinue treatment after the second experimental 
session will not be replaced. If Stage 1 subjects discontinue treatment before the second 
experimental session, the site should contact the Randomization Monitor for replacement 
instructions. Detailed instructions will be provided to the site in a separate document.  
 
5.5 Premature Discontinuation of the Study 
 
The sponsor or the PI (following consultation with the sponsor) has the right to 
discontinue this study at any time.  If the trial is prematurely terminated, the CI is to 
promptly inform the study subjects and will assure appropriate therapy and follow-up. If 
the trial or study is prematurely discontinued, all procedures and requirements pertaining 
to retention and storage of documents will be observed. All other study materials will be 


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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 
phenethylamine has a complex pharmacology, but it acts most prominently as a 
monoamine releaser and uptake inhibitor [151-153]. Its direct actions on serotonergic, 
adrenergic and other receptors are considerably lower. See Section 2.2.3 and the IB for 
more information on the investigational product. 
 
6.2 Preparation and Administration 
 
In this study, 18 subjects will be randomized to the two conditions, as described in Table 
5 (below). The blind will be broken for each subject after the Primary Endpoint is 
completed. The subjects who received MDMA will be offered one additional open-label 
experimental session with active dose MDMA. The subjects who received the placebo 
will be offered the opportunity to enroll in an open-label Stage 2 where they will receive 
active dose MDMA-assisted psychotherapy. Stage 2 visits will be conducted in a manner 
similar to Stage 1. 
 
6.2.1 Doses 
 
Table 5. Doses of MDMA 
Number of 
Subjects 
Condition 
(first 2 exp. 
Sessions) 
Blind? 
Initial 
Dose 
Supplemental 
Dose 
Cumulative 
Dose 
5 
Placebo 
Blinded 
0 mg 
0 mg 
0 mg 
13 
Active dose 
Blinded 
125 mg 
62.5 mg 
187.5 mg 
5 
Active dose 
Stage 2 
Open Label 
125 mg 
62.5 mg 
187.5 mg 
 
 
6.2.2 Compounding and Encapsulation 
 


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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 and unblinded randomization monitor will oversee compounding by a 
pharmacist in a manner that will maintain the blind for the Schedule I license holder. The 
pharmacist will provide bulk lactose for compounding MDMA capsules. The pharmacist 
will compound the MDMA with lactose into doses of 125 mg and 62.5 mg (calculated as 
the weight of the hydrochloride salt) and placed in gelatin capsules. Capsules for the 
initial dose will be clearly differentiated from capsules used for the supplemental dose by 
individually labeled packages. All capsules will be compounded so that they weigh the 
same amount, but contain varying amounts of MDMA and lactose.  
 
The encapsulation will be performed by a pharmacist who has the appropriate skills. The 
MDMA will be weighed out (calculated as the weight of the hydrochloride salt) into 
gelatin capsules in combination with lactose used to ensure that all capsules have similar 
appearance and weight. Capsules for all experimental, double-blind sessions will be 
prepared in such a way as to prevent Clinical Investigators and subjects from 
distinguishing contents of active dose and comparator dose capsules. Dosage for open-
label sessions will be clearly indicated in the packaging. 
 
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, stage, and a statement that the drug is restricted to clinical 
trial use only. All drug labels will comply with federal and state regulations and will be 
provided in English. The initial and supplemental dose will be packaged in separate 
labeled “inner envelopes” within the primary container. There will be one primary 
container per subject per experimental session. The sponsor randomization monitor will 
oversee the process of blinded drug packaging conducted by the pharmacist according to 
the randomization list. This list will not be shared with any blinded site or sponsor staff. 
The pharmacist and randomization monitor will be the only staff who are unblinded.  
 
Figure 2. Holding Box Label 
 
 
 
 
 
 
 
 
Box Label 
MAPS Study: MDA-1 
Investigational Product: MDMA OR PLACEBO 
Dose: 0mg OR 125 mg OR 62.5 mgLot #: XXXXX 
 
Administer as per Protocol 
Caution: Limited by Law to Investigational Use Only 


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Figure 3. Container Labels 
Stage 1 Primary Container Labels 
Blinded Sessions 
 
 
Open-Label Session 3 
Container Label MAPS Study: MDA-1 
Stage 1  
Lot #: XXXXX 
Container #: XXX  
 
 
Subject #: ____________ 
Exp. Session #: ________ 
 
Administer as per Protocol 
Investigational Use Only 
Container Label MAPS Study: MDA-1 
Stage 1 – Open Label 
Lot #: XXXXX 
Container #: XXX  
125 mg & 62.5 mg MDMA 
 
Subject #: ____________  
Exp. Session #: 3 
 
Administer as per Protocol 
Investigational Use Only 
 
Stage 1 Inner Envelope Labels 
                Blinded 
 
 
 
 
Blinded 
Stage 1                    Container # XXX 
INITIAL DOSE 
Subject #_________Ex. Ses # ______ 
 
Stage 1                    Container # XXX 
SUPPLEMENTAL DOSE 
Subject #_________Ex. Ses # ______ 
 
Open Label Session 3 
 
Open Label Session 3 
Stage 1                    Container #XXX 
INITIAL DOSE   125mg 
Subject #_________Ex. Ses # ___ 
 
Stage 1                  Container #XXX  
SUPPLEMENTAL DOSE  62.5mg 
Subject #_________Ex. Ses # ___ 
 
Stage 2 Primary Container Labels 
 
Container Label – MAPS Study # MP-12 
Stage 2 
125mg & 62.5mg MDMA 
Lot # XXX 
Container # XXX  
 
Subject #____________  
Exp. Session #___________ 
Administer as per protocol Investigational Use Only 
 
Stage 2 Inner Envelope Labels 
  
 
 
   
 
Stage 2                    Container#XXX 
INITIAL DOSE         125mg 
Subject #_________Exp. Ses # ____ 
 
Stage 2                   Container#XXX 
SUPPLEMENTAL DOSE 62.5mg 
Subject #_________Exp. Ses #_____ 
 
Each dose will consist of the specified amount of racemic MDMA mixed with an inactive 
substance, such as lactose, to prevent the therapists from distinguishing doses through 
weight or appearance of the capsules. 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.  
 


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6.3 Drug Accountability 
 
Forms will be provided to track drug accountability and administration throughout the 
study. Blinded drug accountability and administration logs will be reviewed during 
routine monitoring visits. MDMA will be handled in accordance with all state and federal 
regulations and forms pertaining to the use of controlled substances, and forms will be 
maintained by the Schedule 1 License Holder.  
 
Each primary container label will contain a unique container number for the drug 
assigned to a single experimental session. The container numbers will be used to track 
drug administration in the Source Record and the drug administration log. The web-based 
randomization system will enable tracking of blinded primary containers for drug 
accountability purposes. 
 
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 office of the PI. All doses administered will be recorded on the 
appropriate accountability and administration logs. Only the initial dose is required to be 
given at each experimental session. Supplemental doses are provided for each 
experimental session but are optional to use.  
 
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 Dept. of 
Medicinal Chemistry and Pharmacology, Purdue University.  The identity and purity of 
this MDMA was confirmed using High Performance Liquid Chromatography (HPLC) in 
1997, as described in DMF # 6293, and was found to be 99.87% pure. On August 12, 
2002, Chemic Laboratories reanalyzed the MDMA at the request of the sponsor prior to 


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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 in 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.  It was also used in MP-1, with drug 
administration ending in 2008, and in a non-sponsor supported study in 2006 [154]. 
 
7.0 Risks of Participation 
 
7.1 Risks and Discomforts Associated with Non-drug and Experimental Sessions 
and Assessment of Measures 
 
 
In preparation for drug-assisted psychotherapy sessions, blood draws and a full medical 
examination are required to establish eligibility for the study. Temporary discomfort, 
inflammation, or infection could arise as a result of sampling blood at the punctured vein. 
Submitting to a full medical examination may also cause discomfort or psychological 
distress. Since medical examinations and blood draws are required to establish eligibility 
for the study, they cannot be omitted from the protocol. 
 
During screening, non-drug and drug-assisted psychotherapy sessions and assessment of 
study measures, subjects will be asked to think about and discuss their thoughts and 
emotions relating to their illness.  They may experience intense emotional responses to 
recalling and speaking about this material.  Even in a therapeutic context, thinking about 
and discussing the process or prospect of illness, death, and dying can produce distress 
during and immediately after non-drug psychotherapy, experimental, and open-label 
sessions.  Psychotherapy is conducted as part of this study, and people undergoing 
psychotherapy are expected to confront unpleasant thoughts, feelings and memories in 
the process of therapy. Because psychotherapy is an integral part of the research study 
design, the potential distress arising from psychotherapy is unavoidable.   
 
All psychotherapy sessions will be recorded to audio and video for research and training 
purposes. Subjects may feel uncomfortable with having their sessions recorded. Subjects 
may have access to recordings if they request them. The recordings are necessary for 
developing the experimental treatment and will be used to create a Treatment Manual. 
Subjects will receive information on who will have access to any of their recordings and 
will have control over any presentation of this material beyond viewing by researchers or 
regulatory agencies. 
 
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 


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mouth, ruminations, and thirst. Other slightly less common reactions include restlessness, 
parasthesias (odd somatic feelings, such as tingling or feeling hot or cold), impaired 
judgment, perspiration, drowsiness, and nystagmus (eye-wiggling).  While anxiety, 
headache, fatigue, insomnia, and lack of appetite were spontaneously reported by 40% to 
80% of subjects in both conditions in MAPS study MP-1 (N=23), tight jaw, nausea, 
impaired gait/balance, and sensitivity to cold were more often reported by subjects in the 
MDMA than the placebo condition, and irritability was slightly more likely to be reported 
in the placebo condition. Additionally, subjects in the MDMA condition were more likely 
to report muscle tension in various body parts and diarrhea.  
 
These effects are transient and diminish as drug effects wane. Sub-acute effects that may 
either continue for the next 24 hours or appear later include insomnia, fatigue, needing 
more sleep, weakness, heavy legs, dry mouth, low mood, or irritability. Sub-acute effects 
are reported less often than acute effects. More information on spontaneously reported 
reactions is described in the IB.  
 
MDMA may produce mild alterations in sensory perception and altered perception of 
time [36, 92, 155].  Women may be more sensitive to these effects [114].  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 [156]. Preclinical data in animals suggests that the profile of neurotransmitter 
release observed after MDMA administration may increase the risk of mania in some 
individuals [157], although mania has not yet been a reported side effect of MDMA or 
ecstasy.!
 
For this reason, subjects will stay at the site overnight and will not be permitted to drive 
after experimental sessions.  
 
MDMA may produce modest changes in immune functioning, lasting up to 48 hours 
[158, 159]. 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. For this reason, potential subjects with lowered white blood 
cell counts or other signs of impaired immunity will be excluded from the study. 
 
Further information on the risks associated with MDMA, including information drawn 
from case reports and studies of ecstasy users, can be found in the IB.  
 
7.2.1 Cardiovascular and Sympathomimetic Effects 
 
The active dose of 125 mg, followed by a supplemental dose of 62.5 mg after one and a 
half to two and a half hours, is expected to produce significant but transient, self-limited 
increases in blood pressure and heart rate. These changes should last no more than six 
hours. In less than 5% of volunteers in Phase 1 studies, peak blood pressure values were 
higher than 140/90 mmHg. Clinical intervention was not required in any of these cases. 
Nonetheless, careful monitoring of subjects and predefined contingency plans will allow 


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the researchers to rapidly identify and manage any related toxicity. For more information, 
see the IB. 
 
Risks posed by elevated blood pressure will be addressed by excluding people with pre-
existing hypertension and serious cardiovascular or cerebrovascular illness and 
monitoring blood pressure and pulse, as described in Section 5.1.2. During experimental 
sessions, the co-therapists will evaluate the patient for increasing blood pressure and 
signs or symptoms of a developing hypertensive or other cardiovascular emergency. 
Subjects reporting chest pain, shortness of breath, neurological symptoms, or other 
potential indicators of medical complications will have more frequent measurements and 
assessment by the PI. Any subject who experiences medical complications during an 
experimental session will not be given another experimental session, unless it is approved 
by the CI, PI, and the Medical Monitor.   
 
In case of need, subjects 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 CI and PI may, at any 
time, make a clinical judgment to transfer the patient to the ED for closer monitoring and 
additional treatment.  
 
The PI will be prepared to respond to rare complications of cardiovascular effects, such 
as stroke or acute myocardial infarction (AMI). The PI will attend to any signs or 
symptoms of neurological deficit or confusion that is more pronounced than might be 
expected from MDMA or from psychological distress and will make an on-site 
evaluation or a decision on whether to initiate transfer to the ED. If any subject has 
neurological deficits, as assessed by the PI, whether or not they are associated with 
hypertensive crisis, they will be monitored, as described above. If necessary, the subject 
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 
sufficient time to administer recombinant tissue plasminogen within the three-hour time 
frame recommended in the American Academy of Neurology/American Heart 
Association guidelines [160, 161]. 
 
The therapists will observe the subject and note any complaints of chest pain. If a subject 
experiences ischemic type chest pain, whether or not it is associated with hypertensive 
crisis, he or she will be transported to the ED or a location in the hospital where 
appropriate care can be given. The subject will be given 81mg of aspirin to chew if there 
are no contraindications, and nitroglycerin 0.4 mg SL q 5 minutes PRN chest pain 
pending transport to the hospital. If further evaluation at the hospital reveals that the 
subject has had an AMI, they will be well within the time frame required for definitive 
therapy. The American College of Cardiology/American Heart Association guidelines for 
the treatment of AMI recommend percutaneous transluminal coronary angioplasty 
(PTCA) as the treatment of choice when it can be performed within 90 minutes of arrival 
at the hospital in patients who present within 12 hours of an episode of chest pain lasting 
more than 30 minutes and who have ECG evidence of AMI [162]. 


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7.2.2 Psychological Distress 
 
Mild anxiety and depressed mood are occasionally reported one to three days after 
MDMA administration [34, 114, and see the IB]. Psychological distress from MDMA 
could arise from the first indications of drug effects until the last effects have dissipated 
(approximately three to five hours after drug administration) or even later. Anxiety or 
distress during the session may last for as little as five minutes or for as long as five hours 
or more.  In addition, psychological distress could arise following an MDMA session as a 
result of subjects having difficulty integrating their experience after the MDMA effect 
has subsided. In previous Phase 1 and Phase 2 studies, these symptoms have been self-
limiting and have responded well to reassurance from the therapists, with occasional use 
of benzodiazepines for anxiety. In this study, subjects will have the intention of 
confronting and working through intense emotions related to their experiences of illness 
and mortality, or other distressing thoughts and feelings. Accordingly, signs of 
psychological distress, panic, or other unpleasant psychological reactions are to be 
expected and may be considered an element of the psychotherapeutic process.  
 
Proper preparation and follow-up support will reduce the difficulties subjects might have 
with acute or sub-acute reactions. The potential for destabilizing psychological distress 
will be minimized by: 
 
• Excluding people who might be more vulnerable to it (such as people diagnosed 
with bipolar affective disorder - 1 or with psychotic disorders) 
• Preparatory non-drug psychotherapy sessions before the experimental session 
• Creating an atmosphere of trust during the experimental session 
• Close monitoring 
• Daily contact with subjects for the period of a week after the experimental session 
• Providing non-drug psychotherapy sessions 
• Subjects will remain at the study site for the night of each experimental session to 
further reduce psychological distress. Qualified personnel will be available during 
the overnight stay to respond to the needs of the subject. Attendants will be 
instructed to contact the therapists upon request or at the appearance of signs of a 
potential serious adverse event.  
 
During the preparatory sessions, subjects will be made aware of the fact that difficult 
emotions, including grief, rage, fear or panic, may arise during experimental sessions.  
Every effort will be made to help subjects resolve difficult symptoms and to arrive at a 
more comfortable and relaxed state by the conclusion of the experimental session, 
including empathic listening on the part of the therapists and performance of 
diaphragmatic breathing and meditation by subjects.  
 
At the end of the six to eight hour experimental session, if the subject is still severely 
agitated or experiencing any other severe psychological distress, the following measures 
will be taken:  
 


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


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MDMA administered in a controlled setting produces only a slight increase in body 
temperature [114]. Ambient temperature does not enhance or attenuate this slight 
elevation in humans.   
 
If temperature rises more than 1° C, attempts will be made to lower it by removing 
blankets and layers of clothing, decreasing the ambient temperature, and, if necessary, 
directing a fan toward the subject.  If at any time the temperature rises more than 1.5° C 
above baseline despite these efforts, the PI will be consulted for further evaluation and 
treatment.   
 
 
7.2.4 Reproductive and Developmental Risks 
 
Risks posed by MDMA to pregnant women are not known.  One of two studies of 
Ecstasy users suggests that use of Ecstasy and other drugs during pregnancy may be 
associated with some abnormalities at birth while the other failed to find this association 
[163, 164], and a third reported some developmental delays in mothers reporting use of 
ecstasy and other drugs during pregnancy [165].   
 
Pregnant and lactating women will be excluded from participation in the study. Women 
who are able to become pregnant must have a negative pregnancy screen before 
undergoing each experimental session and must agree to use birth control for the 
treatment portion of the study. 
 
7.2.5 Potential Neurotoxicity Associated with Ecstasy Use 
 
Some researchers believe that MDMA is neurotoxic in humans even at doses used in 
clinical trials [166].  However, they are basing their case on studies that employed 
inappropriately high doses of MDMA utilized in animal studies and on human studies 
comparing the effects of repeated use of ecstasy, often along with other drugs. 
Meanwhile, another recently published meta-analysis has taken careful steps to overcome 
methodological limitations in previous work and found only modest evidence of 
neurotoxicity [167]. We have carefully considered the risks of such neurotoxicity and 
conclude that they are minimal in this 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.  
 
7.2.6 Risk Mitigation 
 
Careful review of medical screening data will be utilized to exclude potential subjects 
with pre-existing exclusionary medical conditions from the study. Study procedures have 
been developed to mitigate the risks of receiving MDMA described in detail in the IB. 
Ambient temperature will be kept at a comfortable level during Experimental sessions. 
Subjects will not be allowed to drink more than 3L of fluids over the course of the 
experimental session and fluid intake will be spread out appropriately during the session. 


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Fluids administered will include electrolytes. If a subject exhibits any signs of toxicity or 
clinically significant dilutional hyponatremia despite these precautions after an 
experimental session, they will not be given another experimental session unless it is 
approved by the CI, PI 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. 
 
To ensure MDMA-assisted psychotherapy does not cause patients to develop symptoms 
of drug abuse after the treatment period of the study, drug use is monitored during the 
long-term follow-up. Based on long-term follow-up data from two sponsor-supported 
studies (N=32), only one subject took Ecstasy after completing the study and failed to 
reproduce the experience from the study and a number of subjects volunteered that they 
would never seek out Ecstasy outside a legal, controlled, therapeutic setting. In addition, 
negative results from MDMA-specific drug testing data obtained from the Swiss study 
MP-2 (N=12) supports that none of these subjects took Ecstasy outside of the study 
during the long-term follow-up period.   
 
Diversion is not an issue in this protocol because MDMA will only be administered in a 
controlled environment under the supervision of the CI 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 subject, including any abnormal sign (e.g. abnormal physical 
exam or laboratory finding), symptom, or disease, temporally associated with the 
subject’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 can be identified.  If an AE is unresolved at the conclusion of the 
protocol, a clinical assessment will be made by the CI and/or Medical Monitor as to 
whether continued follow-up of the AE is warranted. 


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The severity of events reported on the “Adverse Events” CRF will be determined by the 
PI 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 PI based on 
the following definitions: 
 
1. “Not Related”: The AE is not related if exposure to the investigational product has not 
occurred, or the occurrence of the AE is not reasonably related in time, or the AE is 
considered unlikely to be related to use of the investigational product, i.e. there are no 
facts (evidence) or arguments to suggest a causal relationship, or the AE is more likely 
related to the subject’s pre-existing condition. 
 
2. “Possibly Related”: The administration of the investigational product and AE are 
considered reasonably related in time and the AE could be explained by causes other than 
exposure to the 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. 
 
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. Reactions lasting longer than 
seven days above baseline levels of intensity will be classified as Adverse Events and 
recorded in the AE log. Any reported event that is not listed on the commonly reported 
reactions list will be collected as an adverse event following the plan in section 8.6. 
 
8.3 Serious Adverse Events 
 
An SAE is defined as any untoward medical occurrence that at any dose: 


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• Results in death 
• Is life-threatening (i.e. the subject was, in the opinion of the CI, 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 subject or may require intervention to 
prevent one of the other outcomes listed above. 
 
AEs which do not fall into these categories are defined as non-serious.  It should be noted 
that a severe adverse event need not be serious in nature and that a SAE need not, by  
definition, be severe. 
 
In addition, 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 PI, 
hospitalization was prolonged as a result of participation in the clinical trial or was 
necessary due to a worsening of the pre-existing condition.  This is because the onset of 
the event (the reason for the procedure) occurred before the subject was entered in the 
trial.  Hospitalization for cosmetics, non-emergency prophylaxis, or abortion does not  
result in an SAE report, unless, in the view of the PI, hospitalization for these procedures 
was prolonged as a result of participation in the clinical trial. 
 
8.4 Medical Emergencies 
 
Experimental sessions will take place in the PI’s home therapy office, located 3.3 miles 
from Marin General hospital in a residential area. The Study Coordinator will have an 
office on-site. The treatment room will be comfortably furnished, with an adjacent 
restroom. An overnight room will also be used following experimental sessions, and there 
will be space for both the co-therapy team and a night attendant to remain on-site 
overnight if necessary. The PI will also remain on-site overnight. The study includes 
access to an emergency medicine specialist if needed. The therapists or PI will be 
available via mobile phone or pager throughout the study if any problem occurs when a 
subject is not at the site. Subjects will continue to see their outside therapist 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. The same contingency plans and 
equipment will be used in this protocol. The site will provide an Automated External 
Defibrillator (AED). The therapists will maintain BLS certification.  


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With these personnel and equipment, the therapists or PI will be able to perform basic 
cardiac life support if necessary and call Emergency Medical Services (EMS) to transport 
the subject to the ED at the closes hospital. In the event of a medical emergency or any 
other medical problem, the PI will be on site during the course of the experimental 
sessions, or immediately available by phone if the experimental session has concluded, 
and based on his assessment of the situation, he will make the decision to either evaluate 
the subject himself at the site, have the therapists call EMS to transport the subject to the 
ED, or instruct the therapists to take the subject to the ED where he will meet them. 
 
8.5 Adverse Event Collection 
 
The PI will be responsible for reviewing and confirming all AEs and SAEs collected 
during the study. The therapists will collect AEs during study visits after enrollment.  
 
Adverse events that will be collected for the duration of the protocol are: 
 
• All SAEs will be collected through subject termination. 
• All spontaneously reported reactions will be collected on the day of drug 
administration and for seven days after each experimental session or until they 
resolve. All reported reactions will be actively followed until they resolve.  
• Any reported reactions still above the subject’s baseline level of severity after 
seven days will be classified as Adverse Events and tracked in the AE log.  
• All AEs (defined as any adverse event that is not enumerated in the list of 
commonly reported reactions) will be collected from enrollment through the 
subject’s last one-month follow-up. All adverse events will be actively followed 
until they resolve. 
• Events related to planned treatments or physician visits for baseline conditions 
collected in the medical history will not be collected, unless there is an 
exacerbation of the condition, in which case they will be actively followed until 
resolution. 
• 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 and will be actively followed until resolution. 
 
A Memory Aid Card will be provided to the subject on the last visit prior to the twelve-
month follow-up to record information on medications taken to treat SAEs, AEs leading 
to withdrawal and psychiatric AEs during the follow-up period between the End of Stage 
1/Stage 2 and the twelve-month follow-up evaluation. The Memory Aid Card will not be 
collected, but information from the card will be used to aid the subjects in providing 
information to the CI. This information may be collected by phone. 
 
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 CI’s awareness of their occurrence.  All SAE 
reports should be faxed to the sponsor.  A fax number will be provided to the site in 


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separate site-specific instruction for SAE reporting. In addition to the fax, the PI, CI, 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.   
 
8.6 Medical Monitor  
 
Michael C Mithoefer  
Email: mmithoefer@mac.com  
Telephone: (843)-849-6899 
Fax:  (843)-278-9188 
 
Study Monitor contact information will be provided in a separate contact list.  
 
9.0 Concomitant Medications and Tapering Instructions 
 
The PI will record concomitant medications during screening. If the subject is being 
treated with psychiatric drugs at the time he or she is recruited into the study, the 
prospective subject will be encouraged to discuss medication tapering with his or her 
outside treating physician, if any, and will be required to give the 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 MDMA session to avoid 
the possibility of any drug-drug interaction (the interval will be at least five times the 
particular drug’s half-life, plus one week for stabilization). If applicable, the PI will 
consult with the prescribing physician concerning drug tapering.  If the participant is 
taking opiates for pain management, then possible reduction in dose prior to experimental 
sessions will be discussed.   
 
The therapists will request information about any changes in medication just prior to each 
experimental session. The PI will be responsible for reviewing and confirming all 
medications collected during the study.  
 
All medications, over the counter (OTC) and prescription, will be collected from 
screening through seven days after the last MDMA session.  From seven days after the 
last MDMA session through study termination, only prescription or OTC medications 
taken to treat AEs will be collected.  Throughout the protocol all medications used to 
treat AEs will be collected as specified 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.   
 
Subjects must be willing to refrain from taking any psychiatric medications during Stage 
1 and Stage 2, with the exception of gabapentin when prescribed for pain control. If the 
subject is on stimulants for ADHD at baseline, they can continue to use them at the same 
dose and frequency, as long as they discontinue five half-lives before each experimental 
session and do not restart for ten days after each experimental session. If the subject is on 


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opiate medications for pain management, they can continue to use them at the same dose 
and frequency although they may be asked to decrease the dose or temporarily 
discontinue use 24 hours before each experimental session if they are able to do so 
without undue distress. In the event of a pain flare-up during this period, subjects will be 
permitted to use their prescribed medication as necessary.   
 
 


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Table 6. Medication Tapering Table  
Generic Name  Brand Name  Half-life (hours) 
Including Active Metabolites  Days for Washout  
alprazolam  
Xanax  
11  
3  
aripiprazole  
Abilify  
75  
16  
atomoxetine  
Strattera  
5-24  
5  
bupropion  
Wellbutrin  
21  
5  
citalopram  
Celexa  
35  
8  
clonazepam  
Klonopin  
30-40  
8  
diazepam  
Valium  
20-70  
15  
duloxetine  
Cymbalta  
12  
3  
escitalopram  
Lexapro  
32  
7  
fluoxetine  
Prozac  
7-9 (days)  
45  
imiprimine  
Tofranil  
6-18  
4  
lamotrigine  
Lamictal  
25  
6  
lorazepam  
Ativan  
12  
3  
mirtazapine  
Remeron  
20-40  
8  
olanzapine  
Zyprexa  
21-54  
11  
paroxetine  
Paxil  
21  
5  
prazosin  
Minipress  
2-3  
1  
quetiapine  
Seroquel  
6  
2  
risperidone  
Risperdal  
3-20  
4  
sertraline  
Zoloft  
26  
6  
temazepam  
Restoril  
8-12  
3  
trazodone  
Desyrel  
9  
2  
venlafaxine  
Effexor  
12  
3  
ziprazidone  
Geodon  
7  
2  
zolpidem  
Ambien  
2.5  
<1  
 
The 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). Rescue medications may include medications 
such as benzodiazepines or sedative/hypnotics, (eg. lorazepam or zolpidem), or the 
subject’s previously-prescribed opiate medications for pain management. SSRIs, SNRIs, 
and MAOIs should not be used as rescue medications. 
 
Subjects must agree that, for one week preceding the MDMA session: 
a. They will refrain from taking any herbal supplement (except with prior approval 
of the research team).  
b. They will refrain from taking any prescription or nonprescription medications 
(with the exception of non-steroidal anti-inflammatory drugs, acetaminophen, 


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birth control pills, thyroid hormones, or other medications approved by the 
research team).  
 
Subjects will receive a Memory Aid Card for use between the End of Stage1/Stage 2 visit 
and the twelve-month follow-up, as described in Section 8.5.  Subjects will use this card 
to record changes in psychiatric medications that they will be asked about at the 
termination visit.  Memory Aids will not be collected. Subjects may return to taking 
psychiatric medications and discontinue birth control after the final one-month 
assessment if necessary. 
 
10.0 Clinical Laboratory Assessments 
 
The PI will examine laboratory assessments gathered in screening for assessing subject 
eligibility.  The PI will use a list of normal ranges to conclude whether subjects are 
eligible for the protocol, and will indicate justification for admitting subjects with 
abnormal values, after consultation with the Medical Monitor. 
 
The following laboratory assessments will be performed as a part of screening:  
 
Serum electrolytes and metabolic profile, which includes: 
 
• ALT/SGPT 
• Albumin:globulin (A:G) ratio 
• Albumin, serum 
• Alkaline phosphatase, serum 
• AST/SGOT 
• Bilirubin, total 
• BUN:creatinine ratio 
• Calcium, serum 
• Carbon dioxide 
• Chloride, serum 
• Creatinine, serum 
• Globulin, total 
• Glucose, serum 
• Potassium, serum 
• Protein, total, serum 
• Sodium, serum 
 
CBC, which includes:  
 
• Hematocrit 
• Hemoglobin 
• MCV 
• MCH 
• MCHC 


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• RDW 
• Percentage and absolute differential counts 
• RBC 
• WBC 
 
Urinalysis, which includes:  
 
• Color 
• Appearance 
• Specific gravity 
• pH 
• Protein 
• Glucose 
• Ketones 
• Occult blood 
• Leukocyte esterase 
• Nitrite 
• Bilirubin 
• Urobilinogen 
 
Thyroid function, which includes:  
 
• TSH high sensitivity 
• Free T4 
• Free T3 
 
HIV serology will be performed.   
 
A urine-dip pregnancy test for females of childbearing potential will be performed. The 
urinary pregnancy tests and drug tests will be performed at the study site.  
 
The laboratory that will perform assessments, other than the urine drug screen, and 
pregnancy test is: 
LabCorp 
2000 Van Ness Avenue 
San Francisco, CA 94109 
Phone: (415) 409-2563 
 
11.0 Study Monitoring, Auditing, and Documentation 
 
The CI, 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 CI by representatives 
of the sponsor.  The site will be monitored as appropriate for the rate of enrollment in 
order to comply with GCP guidelines and to ensure validity of the study data. From the 
start of the study, videos from selected sessions will be reviewed for development of a 


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Treatment Manual, therapeutic alliance and inter-rater reliability. Adherence to the 
protocol will be checked by monitoring and by review of selected video 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. A CRF collation supplied by the sponsor will be completed for 
each subject 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  
 
The sponsor will judge the clinical and statistical significance of the study based on a 
comparison of data collected at Baseline and the Primary Endpoint using the STAI-Trait 
as the primary outcome measure. Descriptive statistics will be computed overall and 
within the two conditions for all available data from outcome measures, including 
minimum, maximum, average, and standard deviation. Distributional characteristics will 
be examined for outliers and extreme values and, if either is evident, nonparametric 
statistics will be utilized in the analysis. The sponsor will utilize the results of this pilot 
study to assess variability of the estimates to determine effect size for the impact of two 
sessions of MDMA-assisted psychotherapy on standardized clinical outcome measures of 
anxiety, depression, and quality of life. Effect size of the active treatment will be 
estimated using Cohen's techniques for all outcome measures for Stage 1, Stage 2, and 
long-term follow-up. 
 
The sponsor will examine placebo and MDMA groups for homogeneity at baseline 
through comparing demographic characteristics. There is no expectation that conditions 
will differ in composition by gender, race or ethnicity, duration of anxiety, or presence 
versus absence of other permitted psychiatric disorders, such as depression. However, 
owing to small sample size, such variations may arise by chance. 
 
The sponsor will examine STAI-Trait scores at Baseline and the Primary Endpoint in 
placebo and MDMA conditions using difference scores, and independent sample t-tests 
will be used to test for significance between groups, with p value set at 0.05. This is the 
main analysis for this study.  
 
This study is exploratory. As a result, the sponsor will perform tests on all formal 
statistical comparisons without correcting for multiple comparisons in order to better 
detect any indications of change. 
 
Independent T-tests that will compare Baseline to Primary Endpoint difference scores for 
MDMA and placebo will also be performed on STAI-State scores, MADRS scores, BDI-
II scores, FACIT-Sp scores will be tested for significance to detect any changes after two 
experimental sessions.  


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Changes in symptoms of anxiety, depression, global function, attitudes toward death, 
sleep quality, posttraumatic growth, quality of life, self-compassion and mindfulness 
from the Primary or Secondary Endpoint to one month after the third Stage 1 
Experimental Session will be used for an exploratory within-subject analysis with p value 
set at 0.05 to see whether a third active-dose MDMA session produces further 
improvements. 
 
Descriptive statistics will be computed for all outcome measures administered during 
Stage 2. Formal statistical comparisons between Stage 1 and Stage 2 scores may only 
occur if, at minimum, three subjects complete Stage 2. Data from the open-label third 
Experimental Session in Stage 1 will be tested for equivalence with Stage 2 data and will 
be combined with Stage 2 data if found to be equivalent. The sponsor will perform an 
analysis comparing STAI-Trait and STAI-State scores if STAI-Trait changes 
significantly, after additional open-label experimental sessions.  
 
The sponsor will examine STAI-Trait scores six and twelve months after the final 
MDMA-assisted psychotherapy session. If there is enough data available for formal 
comparisons, the sponsor will examine trends in individual data and will use repeated 
measures ANOVAs with p value set at 0.05 to compare the one month follow-up STAI-
Trait scores, six-month follow-up and 12-month follow-up scores. If there are a greater 
number of responses from either the six-month or 12-month follow-up, then the follow up 
with fewer responses may be removed from the repeated-measures analysis for all 
subjects. Two separate analyses may be performed for each follow up if this occurs. Data 
from secondary outcome measures will be informally analyzed, comparing results at 
Baseline, one-month, six-month and 12-month follow-up.   
 
Subjects who discontinue treatment prior to the Primary Endpoint will be asked to 
complete an outcome assessment prior to continuing to the long-term follow-up. All 
available data from these subjects will be presented as an exploratory last observation 
carried forward analysis to examine results without bias towards subjects more likely to 
complete the study per protocol.  
 
The therapists will record average Baseline and peak and post-drug blood pressure, heart 
rate, and body temperature for subjects during experimental sessions. The therapists will 
also record spontaneously reported reactions and AEs, as described in Section 8.5. 
Descriptive statistics will be computed for vital signs and subjective distress during each 
experimental or open-label session. The sponsor will compare peak blood pressure, heart 
rate, and body temperature for subjects after sessions with placebo or active dose MDMA 
whenever possible. Descriptive statistics will be computed for CSSRS scores prior 
experimental sessions and participant mean and maximum CSSRS ideation and 
behavioral scores. If applicable, the sponsor may examine vital signs in relation to 
medical diagnoses to further determine the safety of MDMA within this population.  
Frequency tables will be produced on prevalence of spontaneously reported reactions and 
AEs.  
 


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Responses to the SOCQ and PPQ will be collected. The sponsor will compute descriptive 
statistics for SOCQ and PPQ scores after each MDMA-assisted psychotherapy session, 
and average scores for each measure for blinded experimental sessions will be compared 
between conditions. The data will be explored for effects of condition on domain scores 
in the SOCQ. If MDMA significantly reduces trait anxiety when compared with placebo, 
the sponsor will correlate STAI-Trait with scores on the PPQ and SOCQ to determine 
whether experiencing a non-ordinary state of consciousness or any facet of this state is 
associated with a change in anxiety symptoms.  
 
An interim analysis may be completed when all subjects have completed Stage 1 and 
Stage 2, but not all subjects have completed the twelve-month follow-up evaluation. 
Additionally, an interim analysis may be performed after all subjects have completed 
Stage 1, but not necessarily before all eligible subjects complete Stage 2. This analysis 
will address safety, efficacy, and process measures. Results of the interim analysis will 
have no effect on study conduct. 
 
The sponsor will collect Observer Form and PTGI-Caregiver measures completed by the 
participant’s selected support partner(s) at baseline, primary endpoint and each 
subsequent endpoint up through 12 month follow up. If more than one support partner 
completes community ratings, the scores will be averaged for a given time point. The 
sponsor will compute descriptive statistics for the PTGI-Caregiver and any quantitative 
responses on the Observer Form. Participant and support partner responses at the same 
administration time will be compared with a correlational analysis or, if applicable, a 
non-parametric analysis of equivalence, such as the chi square. The sponsor will compare 
PTGI-Caregiver and quantitative Observer Form scores from the placebo and active dose 
MDMA conditions following the same procedures used for participant PTGI responses. If 
the main analysis of anxiety symptoms detects a significant between-group difference in 
reduction in anxiety symptoms and if participant and caregiver PTGI responses, then the 
sponsor will correlate PTGI-Caregiver scores with STAI-Trait and STAI-State to see if 
significant other observations are also related to changes in anxiety symptoms. 
 
The sponsor will compute descriptive statistics concerning participant and investigator 
beliefs concerning condition assignment to determine strength of the study blind.  
 
12.1 Statistical Power 
 
 
The sponsor will utilize the results of this pilot study to collect estimates of effect size for 
the impact of two sessions of MDMA-assisted psychotherapy on standardized clinical 
outcome measures of anxiety, depression, and quality of life. The study is likely to be 
underpowered for detection of differences of a small or moderate effect size and it may 
detect differences if the effect size is large. When completed, it will be the first study to 
investigate the effects of MDMA-assisted psychotherapy in people with anxiety arising 
from confronting a life-threatening illness. There are no previous studies on which to 
estimate effect size for these findings.  
 


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Analyses of MAPS’ completed U.S. study of MDMA-assisted psychotherapy in twenty 
people with PTSD found an effect size of 1.24 for treatment efficacy, as represented by 
changes in CAPS score [168]. The degree to which symptoms of anxiety and depression 
will respond in a similar fashion is currently not known. Narrative reports suggest 
symptomatic reduction and improvement in quality of life but do not provide information 
for computing effect size.  
 
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 PI is required to sign a protocol 
signature page confirming her/his agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to 
give access to all relevant data and records to the sponsor. 
 
14.0 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 subject 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 document will be 
provided to the subject in advance of the informed consent discussion, with enough time 
provided for the subject to review the document in an environment of their own choosing. 
The informed consent discussion must be conducted by a person who is qualified 
according to FDA regulations. The subject should have the opportunity to inquire about 
details of the MDMA session and to consider participation. A witness must be present for 
the informed consent process, and must sign the informed consent document as well. 
Individuals who are being treated in the CI’s private therapy practice may participate in 
the study. In these cases, another physician will conduct an independent review of these 
participants’ eligibility and administer informed consent procedures. 
 
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 CIs permission to 
view the subject's recent medical records to assess protocol eligibility, if needed.  
Information necessary for protocol participation includes past medical history, psychiatric 
interview, physical examination, and clinical laboratory tests. 
 
Eligible subjects may only be included in the study after signing the IRB approved ICF. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. 


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all of the procedures described in the protocol, including screening activities). The 
process of obtaining informed consent should be documented in the subject Source 
Records. The therapists will provide a copy of the signed ICF to the subject and will 
maintain the original in the ISF. Support partners and individuals close to the subject who 
will be completing measures will also be required to sign a brief Informed Consent 
document. 
 
The written ICF and any other written information to be provided to subjects should be 
revised whenever important new information becomes available that may be relevant to 
the subject’s consent.  Any revised ICF and written information should receive approval 
from an IRB before use. The subject should be informed in a timely manner if new 
information becomes available that may affect the decision to take part in the MDMA-
assisted session. The communication of this information should be documented. Subjects 
can withdraw consent at any time without prejudice.  If a subject withdraws consent but 
does not revoke the Health Insurance Portability and Accountability Act (HIPAA) 
authorization, the CIs will have full access to the subject’s medical records, including 
termination visit information.  If a subject revokes only the HIPAA authorization, the CIs 
will have full access to all of the subject’s medical records prior to the date and time of 
revocation. 
 
15.0 Confidentiality 
 
Every effort will be made to strictly safeguard the confidentiality of subjects in their role 
as research subjects. Removing identifying information from data and restricting access 
to researchers directly involved in assessing the subjects should prevent the dissemination 
of confidential data, with or without identifying information. Except for the screening 
log, the informed consent and a subject contact information sheet that will be stored 
separately from other documents, all data will be identified only by the subject's initials 
on the source document and five-digit subject number.  If past medical records are 
needed, subjects will sign forms for the release of information upon consent to permit 
screening for protocol enrollment. Copies of audio and video recordings intended for 
sharing with subjects will only be marked with the subject’s subject number.  Any 
materials mailed to subjects will be sent along with stamped return envelopes using the 
office address of the PI both as main and return address.  All assessment records will be 
kept in a locked file drawer or cabinet in a locked office, and access to measures will be 
limited to regulatory agencies, researchers, and individuals analyzing data.  Researchers, 
other than the CIs who are directly involved in the protocol, with access to data will not 
be provided with any information that would identify subjects by name or by other 
means, such as social security number.  
 
All psychotherapy sessions will 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. Full names and addresses will not appear in 
these recordings. They will be maintained on a secure, HIPAA-compliant server. 
 


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16.0 Costs to Subjects 
 
There will be no costs to the study subjects.  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 subject’s condition 
that are unrelated to the research study or any of its procedures will continue to be billed 
to the health insurance provider of the subject or to the subject him or herself.  It is 
anticipated that there will not be any charges for treatment that is unrelated to the study 
except in the case of subjects who previously received therapy from the CIs 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 subject’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 subject’s health insurance. Some 
study-related emergencies can be treated by the PI, as described under Section 8.4.  If the 
PI cannot treat a study-related emergency, then there are contingency plans for the 
transport of subjects to the nearest hospital.   
 
18.0 Record Retention 
 
The PI must retain all study records required by the sponsor and applicable ICH-GCP and 
FDA regulations in a secure and safe facility. The PI 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 PI or 
institution as to when these documents no longer need to be retained.  
 
19.0 Publication Policy 
 
The sponsor recognizes the importance of communicating medical study data and 
therefore encourages publications in reputable scientific journals and presentations at 
seminars or conferences.  It is understood by the CIs that the information generated in 
this study will be used by the sponsor in connection with the development of the 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 CI is obliged to 
provide the sponsor with complete test results, all study data, and access to all study 
records. 
 
Any results of medical investigations with the sponsor products and/or 
publication/lecture/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 


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maintaining submissions to health authorities, and coordinating with other ongoing 
studies in the same field. 
 
The full details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this trial will be described in the Clinical Study 
Agreement. 


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20.0 References 
 
 
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2. 
Mithoefer, M.C., et al., Durability of improvement in post-traumatic stress 
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3. 
Oehen, P., et al., A randomized, controlled pilot study of MDMA (+/- 3,4-
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4. 
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5. 
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Randall-David, E., et al., Barriers to cancer pain management: home-health and 
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Shvartzman, P., et al., Pain control in ambulatory cancer patients--can we do 
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McClain, C.S., B. Rosenfeld, and W. Breitbart, Effect of spiritual well-being on 
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11. 
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Farre, M., et al., Pharmacological interaction between 3,4-
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Liechti, M.E. and F.X. Vollenweider, The serotonin uptake inhibitor citalopram 
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15. 
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Tancer, M. and C.E. Johanson, The effects of fluoxetine on the subjective and 
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Hysek, C.M., et al., The Norepinephrine Transporter Inhibitor Reboxetine 
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Lieb, R., et al., Mental disorders in ecstasy users: a prospective-longitudinal 
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von Sydow, K., et al., Use, abuse and dependence of ecstasy and related drugs in 
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32. 
Doblin, R., A clinical plan for MDMA (Ecstasy) in the treatment of posttraumatic 
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34(2): p. 185-94. 


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33. 
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in humans: methodological considerations and preliminary observations. Behav 
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34. 
Harris, D.S., et al., Subjective and hormonal effects of 3,4-
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39. 
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40. 
Bouso, J.C., MDMA/PTSD research in Spain: An update. MAPS Bulletin, 2003. 
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41. 
Bouso, J.C., et al., MDMA-assisted psychotherapy using low doses in a small 
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42. 
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de la Torre, R., et al., MDMA (ecstasy) pharmacokinetics in a CYP2D6 poor 
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44. 
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48. 
Kirkpatrick, M.G., et al., A direct comparison of the behavioral and physiological 
effects of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) 
in humans. Psychopharmacology (Berl), 2012. 219(1): p. 109-22. 


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49. 
Pacifici, R., et al., Cell-mediated immune response in MDMA users after repeated 
dose administration: studies in controlled versus noncontrolled settings. Ann N Y 
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Veldstra, J.L., et al., Effects of alcohol (BAC 0.5 per thousand) and ecstasy 
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Tancer, M. and C.E. Johanson, Reinforcing, subjective, and physiological effects 
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Chang, L., et al., Effect of ecstasy [3,4-methylenedioxymethamphetamine 
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Ramaekers, J.G., et al., Involvement of inferior parietal lobules in prospective 
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positive emotions and impairs "mind reading" of negative emotions. 
Psychopharmacology (Berl), 2012. 222(2): p. 293-302. 


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64. 
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81. 
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94. 
Stevens, S., Speaking the silence; MDMA in a couple dealing with cancer. MAPS 
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Stevens, S., MDMA and a couple struggling with cancer: Sue's final letter. . 
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100. 
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Inventory. Ann Acad Med Singapore, 1994. 23(2): p. 129-38. 
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induces fenfluramine-like proliferative actions on human cardiac valvular 
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Verrico, C.D., G.M. Miller, and B.K. Madras, MDMA (Ecstasy) and human 
dopamine, norepinephrine, and serotonin transporters: implications for MDMA-


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Neuropsychopharmacology, 2001. 24(3): p. 333-6. 


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controlled pilot study. J Psychopharmacol, 2010. 
 
 

SAP_001.pdf: 
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MAPS Public Benefit Corporation                                                                               MDA1 Statistical Analysis Plan  
US                                                                                                                                           Version 1: 7 August 2017  
  
 
Internal Approval Page  
  
Protocol Number: MDA-1   
Document Under review: Statistical Analysis Plan Version 1 August 7, 2017  
  
  
This document was subject to review. The information it contains is consistent with:  
• 
The current version of the Investigator’s Brochure  
• 
The moral, ethical and scientific principles governing clinical research as set out in the 
Good Clinical Practice guidelines  
The investigator will be supplied with details of any significant or new findings, including adverse 
events.  
  
MPBC  
Author   
Alli Feduccia  
  
  
8/8/2017 
………………………………………………………..                   ……………………………..  
[Author Approval]    
  
  
  
  
           [Date]  
  
MPBC  
Internal Reviewer  
Ilsa Jerome   
  
 8/8/2017 
………………………………………………………..                   ……………………………..  
[Internal Reviewer Approval]  
  
  
  
  
[Date]  
  
  
MPBC  
Statistician  
Scott Hamilton    
  
  
 8/8/2017 
………………………………………………………..                   ……………………………..  
[Statistician Approval]  
                                                      [Date]  
  
  


DocuSign Envelope ID: 7A9FAADF-5682-41A9-BBB6-C0545344307C 
MAPS Public Benefit Corporation                                                                               MDA1 Statistical Analysis Plan  
US                                                                                                                                           Version 1: 7 August 2017  
  
 
  
 
  
MDA-1 Statistical Analysis Plan  
  
Version 1: 7 August 2017  
  
CORPORATION  
 
 
 
MAPS Public Benefit Corporation (MPBC)  
1115 Mission Street  
Santa Cruz, CA 95060  
 
CORPORATION DESIGNEE  
 
Amy Emerson  
Executive Director and Director of Clinical Research  
USE  
In conjunction with relevant FDA guidance  
STUDY TITLE  
 
 
A Randomized, Double-Blind, Placebo-Controlled 
Phase 2 Pilot Study of MDMA-Assisted Psychotherapy 
for Anxiety Associated with a Life-Threatening Illness  
LATEST PROTOCOL   
Amendment 5 Version 1, August 14, 2013  
 
INVESTIGATORS  
Michael C. Mithoefer, M.D.  
 
MEDICAL MONITORS  
 
Julie Holland M.D.  
 
STATISTICIAN  
 
Scott Hamilton, Ph.D.  
 
PLAN PREPARED BY  
 
Scott Hamilton, Ph.D.  
Allison Feduccia Ph.D.  
Berra Yazar-Klosinski, Ph.D.  
  
  
  


DocuSign Envelope ID: 7A9FAADF-5682-41A9-BBB6-C0545344307C 
MAPS Public Benefit Corporation                                                                               MDA1 Statistical Analysis Plan  
US                                                                                                                                           Version 1: 7 August 2017  
  
 
Table of Contents  
1.0  Definitions of Terms ............................................................................................................... 5 
2.0  Introduction ............................................................................................................................. 6 
3.0 Study Objectives ...................................................................................................................... 6 
3.1 Primary Objective ................................................................................................................................ 6 
3.2 Secondary Objectives ........................................................................................................................... 6 
3.3  Safety Objectives .................................................................................................................................. 8 
4.0  Study Design ............................................................................................................................ 8 
5.0  Randomization and Blinding ............................................................................................... 14 
6.0  Sample Size and Power Considerations .............................................................................. 14 
7.0 Measures ................................................................................................................................. 14 
7.1 Outcome Measures ............................................................................................................................. 14 
7.2  Safety Measures ................................................................................................................................. 15 
7.3  Process Measures ............................................................................................................................... 15 
8.0 Analyses .................................................................................................................................. 15 
8.1 Analysis Populations ........................................................................................................................... 16 
8.2  Handling of Dropouts, Missing Data ................................................................................................ 16 
8.2.1  Partial or Missing Dates ........................................................................................................... 16 
8.3  Protocol Deviations ............................................................................................................................ 17 
8.4  Pooling of Investigator Centers ........................................................................................................ 18 
8.5  Baseline Values ................................................................................................................................... 18 
8.6 Subject Disposition and Dosing Summary ....................................................................................... 18 
8.7 Demographics and Baseline Characteristics .................................................................................... 18 
8.8 Prior and Concomitant Medications ................................................................................................. 18 
8.9  Efficacy Analyses ............................................................................................................................... 19 
8.9.1  Primary Efficacy Analyses ....................................................................................................... 19 
8.9.2  Secondary Efficacy Analyses ................................................................................................... 19 
8.9.3  Exploratory Analyses ............................................................................................................... 21 
8.9.4  Safety Analyses ........................................................................................................................ 22 
8.10  Timing of Analyses........................................................................................................................... 23 
9.0  References .............................................................................................................................. 23 
 
List of Abbreviations  
 
AE   
Adverse Event  
BDI-II BPI-
S  
Beck Depression Inventory-II  
Brief Pain Inventory-Short Form  
BT   
Body Temperature  
C-SSRS  
DAP  
Columbia Suicide Severity Rating Scale  
Death Attitudes Profile  
DBP   
Diastolic Blood Pressure  


DocuSign Envelope ID: 7A9FAADF-5682-41A9-BBB6-C0545344307C 
MAPS Public Benefit Corporation                                                                               MDA1 Statistical Analysis Plan  
US                                                                                                                                           Version 1: 7 August 2017  
  
 
ES   
FACIT  
FFMQ  
Effect Size  
Functional Assessment of Chronic Illness Therapy Scale  
Five-Facet Mindfulness Questionnaire  
GAF  
Global Assessment of Functioning  
GWB  
General Well-being  
HR   
Heart Rate  
ITT   
MADRS  
Intent To Treat   
Montgomery-Asberg Depression Rating Scale  
MAPS  
Multidisciplinary Association for Psychedelic Studies  
PP  PPQ  
Per Protocol  
Psychological Process Questionnaire  
PSQI   
Pittsburgh Sleep Quality Index  
PTGI PTGI-
C  
Post Traumatic Growth Inventory  
Posttraumatic Growth Inventory—Caregiver Form  
SBP  SCS  
Systolic Blood Pressure Self-Compassion 
Scale  
SOCQ  
STAI  
States of Consciousness Questionnaire State-
Trait Anxiety Inventory  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
  
  


DocuSign Envelope ID: 7A9FAADF-5682-41A9-BBB6-C0545344307C 
MAPS Public Benefit Corporation                                                                               MDA1 Statistical Analysis Plan  
US                                                                                                                                           Version 1: 7 August 2017  
  
 
1.0   Definitions of Terms  
  
Categorical data: refers to discrete (indivisible) variables, such as gender or ethnicity; data will 
be presented as total numbers of each category as needed to describe the sample  
Descriptive data: includes mean, median, standard deviation, minimum and maximum of 
numerical data used as needed to describe the sample  
Difference scores: consist of scores computed by subtracting one value from another, as 
subtracting baseline from End of Stage 1 score, used to test for differences between and within 
groups to determine change as a function of experimental treatment over time  
Efficacy: type of analysis used to assess therapeutic effects or benefits  
Exploratory analyses: inferential or descriptive analysis of the data to determine trends that 
might lead to hypotheses for further study  
Frequency listing: tabular listing of numbers and/or percentages of events used as needed to 
describe the sample or data characteristics  
Outcome measures: primary and secondary study measures that are used to test the study 
hypotheses  
Process measures: study measures or qualitative observations collected during the study that 
may increase depth of understanding and that are not necessarily related to safety or efficacy  
Protocol deviation: event that represents significant divergence from the intended study design 
as described in the protocol  
Safety: assessment of the condition of study subjects that examines potential risks, adverse 
events, and reactions  
Safety measures: study measures that assess safety, such as heart rate monitoring, that are used to 
assess safety of the study drug  
Spontaneously reported reactions, reactions: specific expected reactions gathered from the 
literature on MDMA  
Study design: all elements of a research project that define the study question, experimental 
methods, study procedures including blinding and randomization, measurement techniques, flow 
sheet of data, and statistical analysis  
Tabular listing: list of each variable or item for each individual subject either in total or by 
condition in a table format  
  
  
    


DocuSign Envelope ID: 7A9FAADF-5682-41A9-BBB6-C0545344307C 
MAPS Public Benefit Corporation                                                                               MDA1 Statistical Analysis Plan  
US                                                                                                                                           Version 1: 7 August 2017  
  
 
2.0   Introduction  
  
This document contains a Statistical Analysis Plan for the study, “A Randomized, Double-Blind,  
Placebo-Controlled Phase 2 Pilot Study of MDMA-Assisted Psychotherapy for Anxiety 
Associated with a Life-Threatening Illness”  
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit research and 
educational organization working to obtain approval for the prescription use of 
3,4methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in persons with anxiety 
associated with a life-threatening illness.  
  
This is an initial pilot study to assess the efficacy of MDMA for this indication, following 
promising results from MAPS-sponsored studies of MDMA-assisted psychotherapy for 
posttraumatic stress disorder (PTSD).   
  
This study, MDA-1, will examine the safety and efficacy of MDMA-assisted psychotherapy in 
18 individuals with anxiety associated with a life-threatening illness, which may be either current 
or in remission with the possibility of recurrence, and will seek to enroll roughly equal numbers 
of men and women. This study will include those with moderate to severe anxiety, as measured 
by the Trait subscale of the Spielberger State-Trait Anxiety Inventory. Full dose and placebo 
MDMA will be assessed in Stage 1, as well as the benefit of three vs. two full dose sessions. 
Subjects who received the placebo during Stage 1 will have the opportunity to cross over and 
take part in a second study segment, referred to as Stage 2, with three open-label experimental 
sessions.   
  
This pilot study is an early investigation in this indication. As a result, the sponsor will perform 
tests on all statistical comparisons as exploratory and hypothesis generating without correcting 
for multiple comparisons.  
3.0   Study Objectives  
  
3.1   Primary Objective   
  
The primary objective is to assess changes in anxiety symptoms via the Trait subscale of the 
State-Trait Anxiety Inventory (STAI) in subjects randomized to study arms (MDMA and 
placebo) at baseline and the primary endpoint, one month after the second experimental session.   
3.2   Secondary Objectives  
  
The following objectives will compare full dose and placebo subjects in the blinded portion of 
Stage 1:  
  


DocuSign Envelope ID: 7A9FAADF-5682-41A9-BBB6-C0545344307C 
MAPS Public Benefit Corporation                                                                               MDA1 Statistical Analysis Plan  
US                                                                                                                                           Version 1: 7 August 2017  
  
 
• 
Assess changes in self-reported State Anxiety symptoms as measured with the State-Trait 
Anxiety Inventory—State subscale (STAI-State) from Baseline to the Primary Endpoint. 
 
• 
Assess changes in self-reported depression symptoms with the Beck Depression 
Inventory- II (BDI-II) from Baseline to the Primary Endpoint.  
• 
Assess changes in clinician ratings of depression symptoms with the MontgomeryAsberg 
Depression Rating Scale (MADRS) from Baseline to the Primary Endpoint.  
• 
Assess changes in quality of life with Functional Assessment of Chronic Illness Therapy 
Scale (FACIT-Sp) from Baseline to the Primary Endpoint.  
• 
Assess changes in global functioning with the Global Assessment of Functionality (GAF) 
from Baseline and the Primary Endpoint.  
• 
Assess changes in self-reported sleep quality with the Pittsburgh Sleep Quality Index  
(PSQI) from Baseline to the Primary Endpoint.  
• 
Assess changes in subjects’ attitudes toward death with the Death Attitudes Profile  
(DAP) from Baseline to the Primary Endpoint.  
• 
Assess personal growth with the Post-Traumatic Growth Inventory (PTGI) from Baseline 
to the Primary Endpoint.  
• 
Assess caregiver perceptions of subjects’ personal growth with the Post- Traumatic 
Growth Inventory—Caregiver Form (PTGI-C) from Baseline to the Primary Endpoint.  
• 
Assess changes in self-oriented compassion with the Self-Compassion Scale (SCS) from 
Baseline to the Primary Endpoint.  
• 
Assess changes in self-reported mindfulness with the Five-Facet Mindfulness 
Questionnaire (FFMQ) from Baseline to the Primary Endpoint.   
• 
Explore the effects of each experimental session with active dose MDMA or placebo 
upon self-reported changes in consciousness, as those associated with a transformational 
or mystical experience via the States of Consciousness Questionnaire (SOCQ).  
• 
Explore the effects of each experimental session upon self-reported cognitive and 
emotional processing via the Psychological Process Questionnaire (PPQ).   
• 
Assess the effect of the third experimental session using a within-subject comparison of 
the Primary/Secondary Endpoint to 1-month follow-up assessment in active dose subjects 
using STAI-Trait, STAI-State, MADRS, BDI-II, DAP, GAF, FFMQ, PTGI, PSQI, PTGI-
C, SCS, and FACIT.   
• 
Conduct a within-subject analysis comparing Stage 1 and Stage 2 in placebo subjects 
using STAI-Trait, STAI-State, MADRS, BDI-II, DAP, GAF, FFMQ, PTGI, PTGI-C, 
PSQI, SCS, and FACIT at the Primary and Secondary Endpoints.   
• 
Assess durability of changes in outcome measures using STAI-Trait, STAI-State, 
MADRS, BDI-II, DAP, GAF, FFMQ, PTGI, PTGI-C, PSQI, SCS, and FACIT at the 
6month and 12-month follow-up visits.   
• 
Assess qualitative reports of subjects’ experiences in the study via a semi- structured 
interview at the 1-month follow-up assessment.   
• 
Assess observations of the subject’s overall state of being from up to three observers 
using the Observer Rating Form (ORF) at Baseline, the Primary Endpoint, and the 6- and 
12-month follow-up visits.   


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• 
Assess the ability of the Clinical Investigator(s) (CI) and subjects to accurately guess 
condition assignment in Stage 1.  
  
3.3   Safety Objectives  
  
• 
Suicidality will be assessed with the Columbia Suicide Severity Rating Scale (C-SSRS) 
during visits prior to experimental sessions, twice during experimental sessions, and 
several times after each experimental session, with comparisons made between subjects 
in each condition.   
• 
Subjective Units of Distress (SUD) and vital signs including blood pressure, heart rate, 
and temperature will be measured during each experimental session. Vital signs will be 
compared between subjects in each condition.   
• 
Changes to pre-existing chronic pain symptoms, when applicable, will be collected 
using the Brief Pain Inventory—Short Form (BPI-S) at Baseline and throughout the 
study, with comparisons made for Primary Endpoint, end of Stage 1 or Stage 2 and 6- 
and 12-month follow up.   
• 
Serious adverse events (SAEs), adverse events, and spontaneously reported reactions 
will be collected during the study according to Section 8.5 of the protocol.  
4.0   Study Design  
  
This is a randomized, double-blind, placebo-controlled pilot study that will examine the safety 
and efficacy of MDMA-assisted psychotherapy in subjects diagnosed with anxiety associated 
with a life-threatening cancer or non-dementing neurological illness, which may be ongoing or in 
remission but with the possibility of recurrence. Stage 1 will include two blinded and one 
openlabel MDMA-assisted psychotherapy sessions scheduled two to four weeks apart with a 
male/female co-therapist team. Therapy teams will consist of varying combinations of the 
Principal Investigator, experienced co- therapists, and intern co-therapists. Subjects will be 
treated by the same therapy team throughout their participation in the study. There will also be a 
moderate course of preparatory sessions and integrative sessions, as described in the Time and 
Events Table.  
Upon enrollment, subjects will be randomly assigned to receive either placebo (n=5) or active 
dose (n=13) MDMA. In Stage 1, subjects will meet with their therapist team for three 
preparatory sessions and two blinded experimental sessions of MDMA-assisted psychotherapy. 
After each experimental session, subjects will stay overnight at the site and complete an 
integrative session the next day, followed by daily telephone calls for the next seven days and 
two additional integrative sessions. One month after the second experimental session, the 
Primary Endpoint assessment will take place, after which the blind will be broken. All subjects 
who received the active dose will then receive a third open-label experimental session with 
active dose MDMA. Subjects who receive the placebo will be offered the option to continue to 
the open-label Stage 2, unless they meet any exclusion criteria for study participation. In Stage 2, 
subjects will receive active dose MDMA in three experimental sessions that will otherwise 


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follow the same sequence of events after a single preparatory session. (See Time and Events 
Table).  
A blinded Independent Rater will administer the MADRS and the GAF; all other outcome 
measures will be collected via subjects’ self-report or via report provided by a caregiver or 
observer.  
Anxiety symptoms will be assessed in all subjects throughout Stage 1, and anxiety symptoms 
will be assessed throughout Stage 2 for subjects continuing on to Stage 2. All subjects will 
complete a follow-up occurring one month after their third experimental session in Stage 1 for 
active dose subjects, and one month after their third experimental session in Stage 2 for subjects 
who received placebo in Stage 1. In addition all subjects will complete visits six months and then 
12 months after their final experimental session where outcome measures and a questionnaire on 
any lasting benefits or harms of the treatment will be administered (See Time and Events Table).  
Sub-studies in a select group of subjects in this study may be conducted for exploratory purposes. 
Subjects will complete a separate consent process if they chose to participate in these studies.  
  
Table 1: Stage 1 Blinded Drug Doses   
Group  
Number of 
Subjects  
Initial Dose  
Supplemental 
Dose   
Min-Max  
Cumulative Dose  
Placebo  
5  
0 mg  
0 mg  
0 mg  
Full Dose  
13  
125 mg  
62.5 mg  
125-187.5 mg  
  
Table 2: Stage 2 Drug Doses   
Experiment 
al Session  
Dose  
Initial 
Dose  
Optional  
Supplement 
al Dose  
Min-Max  
Cumulative 
Dose  
1, 2, & 3  
Full Dose  
125 mg  
62.5 mg  
125-187.5 
mg  
  
For further details please refer to the protocol Section 5.0 Protocol. 


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Table 3.Stage 1 Time&Events  
Preparatory  
Experimental Session  
1  
Experimental Session 2  
Experimental Session  
3  
Follow-Up  
Visit #  
Pre-Study  
V 1,2,3  
V4  
V 5,6,7  
V8  
V 9,10,11  
V12  
V13  
V 14,15,16  
V17  
Type of Visit  
Screening may take place 
over more than one day  
Preparatory 
Sessions  
Experimental 
Session 1  
Integrative 
Sessions  
Experimental 
Session 2  
Integrative 
Sessions  
Primary 
Endpoint  
Experimental 
Session 3   
Integrative 
Sessions  
End of Stage 1 & 
Outcome  
Visit Timing or Study day or Window  
Up to 2 months prior to  
Visit 1  
Prior to V4   Up to 5 weeks 
post V1  
Before V8 A  2-4 weeks post 
V4  
 
Before  
V12A  
1 month  
+/- 1 week 
post V8  
3-4 weeks post 
V8 N  
Before V17  
A, N  
May happen over >  
1 day. 1 mo. +/- 1  
week post V13 N  
Initial Phone Screen  
✓  
  
  
  
  
  
  
  
  
  
Informed Consent  
✓  
  
  
  
  
  
  
  
  
  
Medical/Psychiatric History   
✓  
  
  
  
  
  
  
  
  
  
General Phys. Exam (BP, Pulse, Temp)  
✓  
  
  
  
  
  
  
  
  
  
Brief Neurological Exam  
✓  
  
  
  
  
  
  
  
  
  
ECG  
✓  
  
  
  
  
  
  
  
  
  
SCID-RV  
✓  
  
  
  
  
  
  
  
  
  
Clinical Lab Tests, w/ HIV, HCV test  
✓  
  
  
  
  
  
  
  
  
  
Collect Concomitant Medication  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
Medication Taper (if applicable)  
✓  
  
  
  
  
  
  
  
  
  
Study Enrollment after meeting I/E  
  
✓G  
  
  
  
  
  
  
  
  
Record to Audio/Video  
  
✓  
✓  
✓  
✓  
✓  
✓   
✓  
✓  
✓  
General Well-Being  
  
✓  
✓  
✓  
✓  
✓  
  
✓  
✓  
  
Drug Screen  
✓  
  
✓  
  
✓  
  
  
✓  
  
  
Pregnancy Screen (if applicable)  
✓  
  
✓  
  
✓  
  
  
✓  
  
  
Complete Randomization Procedure  
  
  
✓ B  
  
  
  
  
  
  
  
STAI-Trait  
✓   
  
  
  
  
  
✓  
  
  
✓  
STAI-State  
✓  
✓I  
  
  
  
  
✓  
  
  
✓  
BDI-II  
✓  
  
  
✓L  
  
  
✓  
  
  
✓  
BPI-Short  
  
✓I  
  
✓K  
  
✓K  
✓  
  
✓K  
✓  
GAF, MADRS  
  
✓  
  
  
  
  
✓  
  
  
✓  
DAP, PTGI, PTGI-C PSQI  
  
✓G  
  
  
  
  
✓  
  
  
✓  
FFMQ, SCS  
  
✓H  
  
  
  
  
✓  
  
  
✓  


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FACIT  
  
✓I  
  
  
  
  
✓  
  
  
✓  
ORF  
✓  
  
  
  
  
  
✓  
  
  
  
C-SSRS  
✓  
✓  
✓C, D, E  
✓J, M  
✓C, D, E   
✓J,M  
✓  
✓ C, D, E   
✓J,M  
✓  
Administer IP Drug + Therapy, SOCQ, 
PPQ  
 
  
  
✓  
  
✓  
  
  
✓  
  
  
Monitoring of BP, Pulse and Temp.   
  
  
✓  
  
✓  
  
  
✓  
  
  
SUD  
  
  
✓ F, E  
  
✓ F, E  
  
  
✓ F, E  
  
  
Beliefs of Condition Assignment  
  
  
  
✓K  
  
✓K  
  
  
✓K  
  
Overnight Stay  
  
  
✓  
  
✓  
  
  
✓  
  
  
Integrative Therapy Session  
  
  
  
✓  
  
✓  
  
  
✓  
  
7 days Integrative Telephone Contact  
  
  
  
✓ J  
  
✓ J  
  
  
✓ J  
  
AEs Requiring Medical Attention  
  
  
✓  
✓  
✓  
✓  
✓  
✓  
✓   
✓  
Spont. Reported Reactions and all AEs  
  
  
✓  
✓  
✓  
✓  
  
✓  
✓  
  
AEs of psychiatric status or withdrawal   
  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
Serious Adverse Events  
  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
Issue Memory Aid Card   
  
  
  
  
  
  
  
  
  
✓  
Semi-Structured Interview  
  
  
  
  
  
  
  
  
  
✓  
  
Unblinding J  
  
  
  
  
  
  
✓  
  
  
  
A =First Integrative session is 1 day after exp session B = At least 24 hrs prior to 1st exp. session C =Approximately 6 hours post MDMA    D =At the beginning of the session E =As needed   
F=Approximately every 90 minutes G =Given on 1st preparatory session (V2) H= Given on 2nd preparatory session (V1) I= Given on 3rd preparatory session (V3) J =For 7 days post Exp. Session, CSSRS 
D2 and D7 of calls only, General well being for all 7 days. K= On the day of the 1st integrative session following the Exp. Session L=On the third integrative session after the first experimental session 
only. M= Given at all three integrative sessions 
        MAPS Study MDA-1                                                                                                                                                                                  MDA1 Statistical Analysis Plan  
        U.S.  
  
       29 April, 2015  
  
  
Table 4. Time & Events Stage 2  
  
Preparatory 
Session  
 
Experimental  
Session 1  
Experimental 
Session 2  
Secondary 
Endpoint  
Experimental 
Session 3  
End of 
Stage 2  
 
Long-term 
Follow-up   
Visit #  
V18*  
V19  
V20,21,22  
V23  
V24,25,26  
V27  
V28  
V29, 30, 31  
V32  
  
LTFU  
Type of Visit  
Preparatory  Experimental Integrative 
Experimental  
Integrative  
Outcome  
Experimental 
Integrative  
Outcome  
Follow-up  
Visit Timing  
Within 1 
month post  
V12*  
1 week 
post V18  
Between  
V19 and 
V23   
2-4 
weeks
post V19  
Between 
V23 and V27  
1 month +/- 
1 week post 
V23  
3-4 weeks  
post V23  
Between 
V28 and V32 
1 month +/- 
1 week post 
V28  
6 months 
AND 1 year 
post V13 or  
V28  
Confirm Informed Consent  
✓  
  
  
  
  
  
  
  
  
  
Confirm Inclusion/Exclusion  
✓  
  
  
  
  
  
  
  
  
  
Enrollment in Stage 2  
✓  
  
  
  
  
  
  
  
  
  
  


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Collect Concomitant Medication  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
Record to Audio/Video  
✓  
✓  
✓  
✓  
✓  
  
✓  
✓  
  
  
General Well-Being  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
  
  
Drug Screen  
  
✓  
  
✓  
  
  
✓  
  
  
  
Pregnancy Screen (if applicable)  
  
✓  
  
✓  
  
  
✓  
  
  
  
STAI-Trait, MADRS  
Use V12*  
  
  
  
  
✓H  
  
  
✓  
✓  
STAI-State, GAF, DAP, PTGI, PTGI-C 
PSQI, FFMQ, SCS, FACIT  
Use V12*  
  
  
  
  
✓  
  
  
✓  
✓  
BDI-II  
Use V12*  
  
✓J  
  
  
✓  
  
  
✓  
✓  
BPI-Short  
Use V12*  
  
✓I  
  
✓I  
✓  
  
✓I  
✓  
  
ORF  
  
  
  
  
  
✓  
  
  
  
✓  
C-SSRS  
✓  
✓B,C,D  
✓G,K  
✓B,C,D  
✓G,K  
✓  
✓B,C,D  
✓G,K  
✓  
✓  
Administer Drug + Therapy  
  
✓  
  
✓  
  
  
✓  
  
  
  
Monitoring of BP, Pulse, and Temp.   
  
✓  
  
✓  
  
  
✓  
  
  
  
SUD  
  
✓D,E  
  
✓D,E  
  
  
✓D,E  
  
  
  
Overnight Stay, SOCQ, PPQ  
  
✓  
  
✓  
  
  
✓  
  
  
  
Integrative Therapy Session  
  
  
✓A  
  
✓A  
  
  
✓A  
  
  
Seven Days Telephone Contact  
  
  
✓  
  
✓  
  
  
✓  
  
  
AEs Requiring Medical Attention  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
  
Spont. Reported Reactions and all AEs  
  
✓  
✓F  
✓  
✓F  
  
✓  
✓F  
  
  
AEs of psychiatric status or withdrawal   
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
Serious Adverse Events  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
✓  
Complete Stage 2 go to follow-up  
  
  
  
  
  
  
  
  
✓  
  
Issue Memory Aid Card  
  
  
  
  
  
  
  
  
✓  
  
Semi-Structured Interview  
  
  
  
  
  
  
  
  
✓  
  
Follow-up Questionnaire  
  
  
  
  
  
  
  
  
  
✓L  
Termination Visit  
  
  
  
  
  
  
  
  
  
✓L  
* If Visit 18 is more than 30 days after Visit 12, then subjects will need to repeat measures prior to starting Stage 2.  
  
A = First session is one day after experimental session; B = Approximately six hours post MDMA; C = At the beginning of the session; D = As needed; E = Approximately every 90 minutes; F = Reactions collected 
for seven days post experimental session; G = Day 2 and Day 7 phone calls only; H = 2 weeks after the second experimental session but before the third experimental session; I = On the day of the first integrative 
session following the Exp. Session; J=At the third integrative session following the first experimental session only; K=At all three integrative sessions; L=At the 12-month follow-up visit only. 


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5.0   Randomization and Blinding  
  
Each subject will be assigned to one of the two dose conditions: placebo or 125 mg (full 
dose). Thirteen evaluable subjects will be assigned to the full dose condition, and five to 
the placebo condition. The study will employ a blinded list-based randomization 
procedure that will maintain the 13:5 ratio while maintaining the blind and ensuring that 
each subsequent condition assignment is not predicated on the previous assignment.   
6.0   Sample Size and Power Considerations  
  
This study is a pilot investigation intended to gather preliminary data on the safety and 
efficacy of MDMA in 18 evaluable individuals with anxiety related to a life-threatening 
illness. Because of their exploratory nature, pilot studies are often not powered for 
detecting the desired effect. Because it is a pilot study in a small sample, results will used 
to collect effect size estimates for statistical power calculations for adequately powered 
subsequent studies.  
7.0   Measures  
  
7.1   Outcome Measures  
  
• 
State-Trait Anxiety Inventory (STAI), Trait Subscale  
  
• 
State-Trait Anxiety Inventory (STAI), State Subscale  
  
• 
Global Assessment of Functioning (GAF), total score  
  
• 
Beck Depression Inventory-II (BDI-II), total score  
  
• 
Post Traumatic Growth Inventory (PTGI), total   
  
• 
Post Traumatic Growth Inventory—Caregiver Form (PTGI-C), total score  
  
• 
Montgomery-Asberg Depression Rating Scale (MADRS), total score  
  
• 
Pittsburgh Sleep Quality Index (PSQI), total score  
  
• 
Observer Rating Form (ORF)  


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• 
Functional Assessment of Chronic Illness Therapy Scale (FACIT-Sp), total and 
composite scores  
  
• 
Death Attitudes Profile (DAP), composite scores  
  
• 
Five-Facet Mindfulness Questionnaire (FFMQ), composite scores  
  
• 
Self-compassion Scale (SCS)  
  
• 
Long-term Follow-up Questionnaire (LTFU Questionnaire)  
  
7.2   Safety Measures  
  
• 
Columbia Suicide Severity Rating Scale (C-SSRS)  
  
• 
Subjective Units of Distress (SUD)  
  
• 
General Well-being (GWB)  
  
• 
Brief Pain Inventory—Short Form (BPI-S)  
  
• 
Vital signs (systolic blood pressure (SBP), diastolic blood pressure (DBP), heart 
rate (HR), body temperature (BT))   
  
• 
Adverse Events (AE), including Spontaneously Reported Reactions (SRR)  
  
7.3   Process Measures  
  
• 
Belief of Treatment Group Assignment  
  
• 
States of Consciousness Questionnaire (SOCQ), total and composite scores  
  
• 
Psychological Process Questionnaire (PPQ), total and composite scores  
8.0   Analyses  
  
In general, nominal variables will be described in terms of frequencies and percentages 
and analyzed using chi square analysis. Ordinal and non-normal continuous variables will 
be described using sample median and range, and analyzed by non-parametric statistical 
tests, and approximately normal variables will be described using sample mean and 


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standard deviations and analyzed by parametric statistical tests. All statistical tests will be 
two-sided. All p-values will be rounded to and displayed in four decimals. If a p-value 
less than 0.0001 occurs it will be shown in tables as <0.0001.  
  
Clinical data will be presented in tabular format. Data not subject to analysis according to 
this plan will not appear in any tables or graphs, but will be included in the data listings. 
Analyses will be carried out with SAS Version 9.3 or higher. Selected results may be 
presented graphically using standard graphical software.  
  
Post-hoc exploratory analyses not identified in this SAP may be performed to further 
examine the study data. These analyses will be clearly identified as such in the final 
clinical study report.  
  
8.1   Analysis Populations  
  
Intent-to-treat (ITT): all subjects who were randomized  
  
Per protocol (PP): all subjects who completed Stage 1, underwent assessment of anxiety 
symptoms, and did not experience a major protocol deviation  
  
Crossover: all subjects who completed Stage 2 in addition to completing Stage 1  
  
Safety: all subjects who receive any study treatment  
  
8.2   Handling of Dropouts, Missing Data  
  
Early termination visit data for ITT and Safety variables will be analyzed at the closest 
scheduled visit. If the closest visit has valid data, the early termination data will be 
assigned to the next available visit. Subjects who discontinue treatment prior to 
completing the second experimental session prior to the primary endpoint will be 
replaced. These subjects will be asked to complete an outcome assessment prior to 
continuing to the long-term follow-up. These subjects will be included in the ITT 
population. If subjects repeat a measure because the next visit is out of the allotted time 
window, data from the most recent visit will be included in analyses.   
8.2.1   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.  


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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.’  
3) 
If the day is unknown, then assign the last day of the month.  
  
8.3   Protocol Deviations  
All protocol deviations will be included as a categorized listing. Safety and Intent to Treat 
analyses will include all enrolled subjects with all available data. Subjects with major 
deviations will be excluded from the per protocol analyses. Major deviations will be 
defined as anyone complete through the primary endpoint and anyone who was enrolled 
but found to not meet inclusion/exclusion criteria during the course of the study. The 
number of subjects in each protocol deviation category listed below will be summarized 
by MDMA group, and individual subjects will be listed in the appendix.  
Possible protocol deviations include the following five categories:  
• 
Subject entered study but did not meet criteria  
• 
Subject developed withdrawal criteria but was not withdrawn  
• 
Subject received excluded concomitant treatment  
• 
Protocol procedure not performed per protocol  
• 
Subject received incorrect treatment or incorrect dose  
• 
Protocol procedure performed out of range  
• 
Miscellaneous  


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8.4   Pooling of Investigator Centers  
  
All subjects in this study come from one investigational center.   
 
8.5   Baseline Values  
  
Baseline values are from screening/baseline visit for all measures, except C-SSRS. For 
CSSRS, pre-enrollment scores will be used as a measure of ‘lifetime’ suicidal ideation 
and behavior, and preparatory sessions and pre-drug experimental session 1 C-SSRS will 
be used as ‘baseline.’   
8.6   Subject Disposition and Dosing Summary  
All subjects enrolled in the study (i.e., who sign informed consent and complete 
inclusion/exclusion criteria) will be included in the summary of subject disposition and 
accountability. No inferential statistical tests will be performed. The tabulation of number 
of subjects in each treatment group and overall will be displayed for all subjects who are 
randomized and had any treatment exposure, in the Safety Population, in the ITT 
Population, and in the PP Population. The number and percent of subjects who completed 
or discontinued the study will be displayed for each treatment group and overall together 
with reasons for early termination, where the percent is with respect to the total number 
of randomized subjects in that treatment group. The timepoint of doses and total MDMA 
(mg) administered will be summarized by treatment group for the Safety, ITT and PP 
Populations.   
  
8.7   Demographics and Baseline Characteristics  
  
Subject demographic data and baseline characteristics will be summarized descriptively 
by treatment group and overall. The demographic data and baseline characteristics will be 
summarized for the ITT and Crossover Populations.   
8.8   Prior and Concomitant Medications   
The number and percent of subjects who took medications prior to and after signing 
informed consent will be summarized descriptively for each treatment group. 
Concomitant medications will be summarized similarly. Prior and concomitant 
medications will be summarized for the Safety Population.  


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8.9   Efficacy Analyses  
For all primary, secondary and exploratory endpoints descriptive statistics (n, mean, 
standard deviation, median, range, or counts and percentages where appropriate) will be 
provided by treatment group.   
8.9.1   Primary Efficacy Analyses  
  
State-Trait Anxiety Inventory, Trait Subscale  
  
The primary efficacy evaluation is the change from baseline to the primary outcome 
timepoint (visit 13) in the STAI-Trait subscale (difference score). The primary efficacy 
comparison on difference scores will be made with an independent sample t-test at an 
alpha level of 0.05. If the parametric assumptions for the independent samples t-test 
analyses are not met, the analogous nonparametric methods will be used (Wilcoxon 
Rank-Sum test).   
  
8.9.2   Secondary Efficacy Analyses  
  
8.9.2.1 Secondary Efficacy Analyses at Primary Endpoint  
  
The secondary efficacy analyses will be made with independent samples t-tests at an 
alpha level of 0.05 comparing change from baseline (visit 1) to the primary outcome 
timepoint (visit 13) for the following secondary measures. If the parametric assumptions 
for the independent samples t-test analyses are not met, the analogous nonparametric 
methods will be used (Wilcoxon Rank-Sum test).   
  
State-Trait Anxiety Inventory (STAI) Trait subscale sores will also be analyzed for effect 
size with the Cohen’s d analysis.  
  
State-Trait Anxiety Inventory (STAI) State subscale scores will be analyzed in the same 
manner as the STAI-Trait scale primary analysis.  
  
Montgomery-Asberg Depression Rating Scale (MADRS) total will be analyzed in the 
same manner as the STAI-Trait scale primary analysis.  
  
Beck Depression Inventory-II (BDI-II) total score will be analyzed in the same manner as 
the STAI-Trait scale primary analysis.  
  
Functional Assessment of Chronic Illness Therapy Scale (FACIT-Sp) factor scores will 
be analyzed in the same manner as the STAI-Trait scale primary analysis.  
  


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Global Assessment of Functioning (GAF) total score will be analyzed in the same manner 
as the STAI-Trait scale primary analysis.  
  
  
Post Traumatic Growth Inventory (PTGI) total will be analyzed in the same manner as 
the STAI-Trait scale primary analysis.  
  
Pittsburgh Sleep Quality Index (PSQI) global scores will be analyzed in the same manner 
the STAI-Trait scale primary analysis.  
  
Death Attitudes Profile (DAP) factor scores will be analyzed in the same manner as the 
STAI-Trait scale primary analysis.  
  
Five-Facet Mindfulness Questionnaire (FFMQ) factor scores will be analyzed in the same 
manner as the STAI-Trait scale primary analysis.  
  
Posttraumatic Growth Inventory—Caregiver Form (PTGI-C) total will be analyzed in the 
same manner as the STAI-Trait scale primary analysis.  
  
Self-Compassion Scale (SCS) total will be analyzed in the same manner as the STAITrait 
scale primary analysis.  
  
Observer Rating Form (ORF) subscale and total scores will be analyzed in the same 
manner as the STAI-Trait scale primary analysis.  
   
8.9.2.2 Secondary Efficacy Analyses at Secondary Endpoints  
  
Assess 3 vs. 2 experimental MDMA Sessions  
For the STAI-Trait, STAI-State, PTGI, PTGI-C, BDI-II, GAF, PSQI, FACIT-Sp, 
MADRS, FFMQ, DAP, and SCS, the absolute changes in the measures from the primary 
endpoint to end of Stage 1 for the 125 mg group will be compared with t-tests. In the 
crossover subjects (placebo group) the absolute changes in the measures from the 
secondary endpoint to end of Stage 2 will be compared with t-tests.   
  
Crossover Subject Analyses   
Data from subjects assigned to the placebo group, i.e. ‘crossover population,’ will be 
analyzed by within-subject t-tests comparing difference scores from primary endpoint in 
Stage 1 to secondary endpoint in Stage 2. The following measures total scores will be 
analyzed in this fashion: STAI-Trait, STAI-State, PTGI, PTGI-C, BDI-II, GAF, PSQI, 
FACIT-Sp, MADRS, FFMQ, DAP, and SCS.  
  


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Six- and Twelve-month Follow-up  
For the STAI-Trait, STAI-State, PTGI, PTGI-C, BDI-II, GAF, PSQI, FACIT-Sp, 
MADRS, FFMQ, DAP, and SCS, the absolute changes in the measures from baseline to 
the 6- and 12-month follow-up visit will be compared with t-tests. The absolute changes 
in the measures from follow-up visits to End of Stage 1 (visit 18, 125 mg) or follow-up 
visits compared to End of Stage 2 (visit 33, placebo) will be compared with withinsubject 
t-tests.    
  
8.9.3   Exploratory Analyses  
  
Post-hoc exploratory analyses not identified in this SAP may be performed to further 
examine the study data. These analyses will be clearly identified as such in the final 
clinical study report.  
8.9.3.1 Process Measures   
  
States of Consciousness Questionnaire (SOCQ)   
Descriptive statistics will be computed for SOCQ scores completed after each 
MDMAassisted psychotherapy session, and average SOCQ scores for blinded 
experimental sessions will be compared between treatment groups using independent 
samples t-tests at an alpha level of 0.05. The data will be explored for effects on domain 
scores in the SOCQ. If MDMA significantly reduces trait anxiety when compared with 
placebo, the sponsor will run a two-tailed Pearson’s correlation on STAI-Trait and SOCQ 
total scores to determine whether experiencing a non-ordinary state of consciousness or 
any facet of this state is associated with a change in anxiety symptoms.   
  
Psychological Process Questionnaire (PPQ)  
Descriptive statistics will be computed for PPQ scores completed after each 
MDMAassisted psychotherapy session, and average PPQ scores for blinded experimental 
sessions will be compared between treatment groups using independent samples t-tests at 
an alpha level of 0.05. If MDMA significantly reduces trait anxiety when compared with 
placebo, the sponsor will run a Pearson’s correlation on STAI-Trait and PPQ total scores 
to determine whether experiencing a non-ordinary state of consciousness or any facet of 
this state is associated with a change in anxiety symptoms.   
  
Long-term Follow-up Questionnaire (LTFU Questionnaire)  
The LTFU Questionnaire nominal variables will be described in terms of frequencies and 
percentages, while ordinal and non-normal continuous variables will be described using 
sample mean, standard deviations, and range.   
  
Belief of Treatment Group Assignment  
In order to compare the therapists’, independent raters’, and subjects’ belief of treatment 
assignment to actual MDMA dose received in each blinded session, the frequency of 


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correct guesses will be calculated and depicted by dose condition and study role (subject, 
therapist, or independent rater).  
  
Qualitative Interviews  
Qualitative interviews conducted by a researcher who is part of the study team during the 
follow-up visit one month after the final experimental session will be transcribed to text. 
A computer-assisted qualitative data analysis software package will be utilized to assist in 
thematic content analysis of the interview transcripts. A member of the research team will 
code the interviews for content, to identify emerging themes and organize data into 
thematic constructs utilizing a grounded theory approach. Descriptive statistics will be 
calculated for emerging themes.  
  
8.9.4   Safety Analyses  
  
The primary measure of safety will be the reporting of adverse events. The Adverse 
events considered are Treatment Emergent Adverse Events (TEAE) defined as those  
AE’s that occurred after dosing and those existing AEs that worsened during the study.  
Verbatim terms on case report forms will be mapped to preferred terms and system organ 
classes using the MedDRA dictionary. For incidence reporting if a subject has more than 
one adverse event mapped to the same preferred term, that adverse event will be reported 
only once using the highest severity and closest relationship to study drug. In separate 
columns, the overall frequency of AE's will be reported.  Subject incidence of adverse 
events will be displayed by treatment group and by system organ class. Adverse events 
will also be summarized by severity and relationship to study drug. Subject incidence of 
serious adverse events by treatment group will also be displayed. In addition to the listing 
of all adverse events, a listing of serious adverse events and a listing of adverse events 
leading to discontinuation of study drug will be included.   
  
Summary tables of frequency listings of expected adverse events (Spontaneously 
Reported Reactions) mapped to preferred terms will be displayed during and after each 
experimental session by condition.  
  
Columbia Suicide Severity Rating Scale (C-SSRS)  
Suicidal ideation and behavior will be summarized according to suggestions made in the 
Columbia-Suicide Severity Rating Scale Scoring and Data Analysis Guide [3]. A positive 
response for suicidal ideation is counted when a subject answers “yes” to any one of the 
five suicidal ideation questions (Categories 1-5) on the C-SSRS, i.e. a score > 0 for 
suicidal ideation score. Serious suicidal ideation is a suicidal ideation score of 4 or 5. A 
positive response for suicidal behavior occurs when a subject answers “yes” to any one of 
the five suicidal behavior questions (Categories 6-10) on the C-SSRS, i.e. a score > 0 for 
suicidal behavior score. The number and percent of positive responses of Positive 
Ideation, Serious Ideation, and Positive Behavior will be tabulated by treatment group 
and time period. P-values will be calculated using the chi-squared test for overall 


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treatment group differences and Fisher’s exact test will be used for pairwise testing. 
Compare lifetime serious suicidal ideation and positive behavior frequencies to 
cumulative frequencies anytime during the study until end of stage 1 and stage 2 using 
chi-squared test for overall treatment group differences and Fisher’s exact test for 
pairwise testing.  
  
Subjective Units of Distress (SUD)  
Descriptive statistics for SUD scores will be calculated by treatment group and time 
period with counts and percentages.   
  
Vital signs   
Vital signs (heart rate, body temperature, systolic and diastolic blood pressure) will be 
summarized using descriptive statistics at baseline and at each post-baseline time point. 
For experimental sessions, mean peak heart rate, blood pressure, and body temperature 
will be analyzed by condition with t-tests. Occurrences of systolic and diastolic blood 
pressure, heart rate, and body temperature readings above the pre-determined cutoff will 
be displayed with numbers and percentages by timepoint. A within-subjects t-tests for 
pre- and post-drug endpoints will be conducted for each session for heart rate, blood 
pressure, and body temperature.  
  
Brief Pain Inventory-Short Form (BPI-S)  
Descriptive statistics for BPI responses will be calculated by treatment group and time 
period with counts and percentages. Within-subjects t-tests will compare scores at 
baseline to scores at Primary Endpoint, End of Stage 1 or 2, 6-month follow-up, and 
12month follow-up.  
  
8.10   Timing of Analyses  
  
The primary efficacy analysis will be conducted after all subjects complete Stage 2, but 
before all long-term follow-up data has been collected. Subsequent analyses on this data 
set will not be conducted after initial analyses are performed, unless for further 
exploratory post-hoc analyses. Changes to protocol will not occur after primary analysis. 
The final analysis of secondary endpoints will include only data not analyzed in the 
primary efficacy analysis, i.e. data will not be analyzed twice.   
9.0   References  
  
1. 
Mithoefer, M.C., et al., The safety and efficacy of {+/-
}3,4methylenedioxymethamphetamine-assisted psychotherapy in subjects with 
chronic, treatment-resistant posttraumatic stress disorder: the first randomized 
controlled pilot study. J Psychopharmacol, 2011. 25(4): p. 439-52.  


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2. 
Mithoefer, M.C., et al., Durability of improvement in post-traumatic stress 
disorder symptoms and absence of harmful effects or drug dependency after 
3,4methylenedioxymethamphetamine-assisted psychotherapy: a prospective 
longterm follow-up study. J Psychopharmacol, 2013. 27(1): p. 28-39.  
3. 
Nilsson, M.E., et al., Columbia Suicide Severity Rating Scale Scoring and Data 
Analysis Guide, in CSSRS Scoring Version 2.0. 2013:  
http://www.cssrs.columbia.edu/documents/ScoringandDataAnalysisGuide_Feb20 
13.pdf. p. 1-13.