A Randomized, Double-Blind, Placebo-Controlled Phase 2 Pilot Study of MDMA-Assisted Psychotherapy for Anxiety Associated With a Life-Threatening Illness
Phase: PHASE2
Conditions: Anxiety
Sponsor: Lykos Therapeutics

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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  
 
 

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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 

MAPS Study MDA-1                                                                                            Protocol Amendment 1  
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Page 14 of 76 
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 
        U.S. 
 
29 April, 2015 

        MAPS Study MDA-1                                                                                                                                                                                  Protocol Amendment 1 
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Page 16 of 76 
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 
 
 
 
 
 
 
! 
 
 
 

        MAPS Study MDA-1                                                                                                                                                                                  Protocol Amendment 1 
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29 April, 2015 
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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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Page 23 of 76 
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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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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15. 
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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. Psychopharmacology (Berl), 2012. 219(1): p. 109-22. 

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49. 
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