A Randomized, Double-Blind, Active Placebo-Controlled Phase 2 Pilot Study of MDMA-assisted Psychotherapy in People With Chronic, Treatment-Resistant Posttraumatic Stress Disorder (PTSD)
Phase: PHASE2
Conditions: Posttraumatic Stress Disorder (PTSD)
Sponsor: Lykos Therapeutics

PROTOCOL MP-9 
 
IND #63-384 
 
Original Protocol:  January 10, 2011 
Amendment 1 Version 1: February 14, 2011 
Amendment 2 Version 1: June 7, 2011 
Amendment 3 Version 1: March 30, 2015 
 
A Randomized, Double-Blind, Active Placebo-Controlled Phase 2 Pilot Study of 
MDMA-assisted Psychotherapy in People with Chronic, Treatment-Resistant 
Posttraumatic Stress Disorder (PTSD) 
 
SPONSOR 
Multidisciplinary Association for Psychedelic 
Studies (MAPS) 
1115 Mission Street 
Santa Cruz, CA 95060 
SPONSOR DESIGNEE 
Amy Emerson 
Phone number: 510-393-7224 
 
CLINICAL INVESTIGATOR 
Prof. Moshe Kotler 
PO Box 1, Beer Yaakov 
70350, Israel 
08-9258241 
MEDICAL MONITOR 
Michael C. Mithoefer, M.D.  
208 Scott Street 
Mount Pleasant, SC 29464 
Phone number:  843-849-6899 
 
 

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Table of Contents 
 
1.0 LIST OF ABBREVIATIONS ................................................................................................................. 6 
2.0 INTRODUCTION, BACKGROUND AND RATIONALE ................................................................. 8 
2.3 PROTOCOL PURPOSE ............................................................................................................................ 12 
2.4 RATIONALE OF DOSE SELECTION ......................................................................................................... 12 
3.0 PROTOCOL OBJECTIVES ................................................................................................................ 13 
3.1 PRIMARY OBJECTIVE............................................................................................................................ 13 
3.2 SECONDARY OBJECTIVES ..................................................................................................................... 13 
3.3 SAFETY OBJECTIVES ............................................................................................................................ 14 
4.0 PROTOCOL DESIGN .......................................................................................................................... 14 
4.1 PLANNED DURATION OF STUDY ........................................................................................................... 15 
4.2 RECRUITMENT AND SUBJECT POPULATION .......................................................................................... 19 
5.0 METHODS ............................................................................................................................................. 21 
5.1 MEASURES ........................................................................................................................................... 21 
5.2 STUDY PROCEDURES AND VISIT DESCRIPTIONS ................................................................................... 24 
5.3 RANDOMIZATION AND SUBJECT NUMBERING ...................................................................................... 33 
5.4 REMOVAL OR WITHDRAWAL OF SUBJECTS FROM THE STUDY ............................................................. 34 
5.5 PREMATURE DISCONTINUATION OF THE STUDY................................................................................... 35 
6.0 INVESTIGATIONAL PRODUCT ....................................................................................................... 35 
6.1 DESCRIPTION OF ACTIVE COMPOUNDS ................................................................................................ 35 
6.2 PREPARATION AND ADMINISTRATION .................................................................................................. 35 
6.3 DRUG ACCOUNTABILITY ...................................................................................................................... 37 
6.4 DRUG STORAGE AND HANDLING ......................................................................................................... 37 
6.5 MDMA STABILITY .............................................................................................................................. 37 
7.0 RISKS OF PARTICIPATION .............................................................................................................. 38 
7.1 RISKS AND DISCOMFORTS ASSOCIATED WITH NON-DRUG AND EXPERIMENTAL PSYCHOTHERAPY 
SESSIONS AND ASSESSMENT OF MEASURES ............................................................................................... 38 
7.2 RISKS OF RECEIVING MDMA .............................................................................................................. 38 
7.3 ABUSE LIABILITY ................................................................................................................................. 44 
8.0 ADVERSE EVENTS.............................................................................................................................. 44 
8.1 ADVERSE EVENTS ................................................................................................................................ 44 
8.2 SPONTANEOUSLY REPORTED REACTIONS ............................................................................................ 45 
8.3 SERIOUS ADVERSE EVENTS.................................................................................................................. 45 
8.4 MEDICAL EMERGENCIES ...................................................................................................................... 46 
8.5 ADVERSE EVENT COLLECTION............................................................................................................. 47 
9.0 CONCOMITANT MEDICATIONS AND TAPERING INSTRUCTIONS ..................................... 48 
10.0 CLINICAL LABORATORY ASSESSMENTS ................................................................................ 49 
11.0 STUDY MONITORING, AUDITING AND DOCUMENTATION................................................ 50 
12.0 DATA ANALYSIS ............................................................................................................................... 51 
12.1 STATISTICAL POWER .......................................................................................................................... 52 
13.0 ETHICS................................................................................................................................................. 52 
14.0 INFORMED CONSENT ..................................................................................................................... 53 

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15.0 CONFIDENTIALITY ......................................................................................................................... 53 
16.0 COSTS TO PARTICIPANTS ............................................................................................................. 54 
17.0 TREATMENT AND COMPENSATION FOR STUDY RELATED INJURY .............................. 54 
18.0 RECORD RETENTION ..................................................................................................................... 54 
19.0 REFERENCES ..................................................................................................................................... 55 
 
 
 

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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 
C 
 
Celsius 
CAPS  
Clinician Administered PTSD Scale 
CI 
 
Clinical Investigator (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 
DEA  
Drug Enforcement Administration 
DBP 
 
Diastolic Blood Pressure 
DMF  
Drug Master File 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders - IV 
ECG/EKG 
Electrocardiogram 
EMDR  
Eye Movement Desensitization and Reprocessing 
F 
 
     Fahrenheit 
FDA  
Food and Drug Administration  
GAF   
Global Assessment of Functioning 
GCP 
 
Good Clinical Practice 
HCl 
 
Hydrochloride 
HIPAA  
Health Insurance Portability and Accountability Act 
HIV 
 
Human Immunodeficiency Virus  
HPLC  
High Performance Liquid Chromatography 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
IND 
 
Investigational New Drug  
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
IV 
 
intra-venous 
LSD 
 
d-lysergic acid diethylamide 
MAOI  
Monoamine oxidase inhibitor 
MAPS  
Multidisciplinary Association for Psychedelic Studies 
MCH  
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV   
Mean Corpuscular Volume  
MDMA 
3,4-methylenedioxymethamine 
MP-1  
MAPS’ first clinical trial of MDMA-assisted psychotherapy for PTSD 
PDS 
 
Posttraumatic Diagnostic Scale 
PSQI  
Pittsburgh Sleep Quality Index 
PTSD  
Posttraumatic Stress Disorder 
PRN 
 
As needed 

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PTCA   
Percutaneous Transluminal Coronary Angioplasty 
PTSD  
Posttraumatic Stress Disorder 
PTT 
 
Partial Thromboplastin Time 
RBC  
Red Blood Cell Count 
RDW  
Red Cell Distribution Width 
RRPQ  
Reactions to Research Participation Questionnaire 
SAE(s) 
Serious Adverse Event(s) 
SBP 
 
Systolic Blood Pressure 
SCID  
Structured Clinical Interview for Diagnoses 
SERT   
Serotonin Transporter 
SL 
 
Sublingual 
SNRI  
Selective Serotonin and Norepinephrine Uptake Inhibitor 
SOP(s)  
Standard Operating Procedure(s) 
SSRI  
Selective Serotonin Reuptake Inhibitor  
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 
 
This study is sponsored by the Multidisciplinary Association for Psychedelic Studies 
(MAPS), a U.S.-based IRS-approved non-profit research and educational organization 
that sponsors research into the therapeutic potential of MDMA, other psychedelic 
compounds, and marijuana. MAPS’ top priority project is working to obtain approval for 
the prescription use of 3,4-methylenedioxymethamine (MDMA)-assisted psychotherapy 
in patients with posttraumatic stress disorder (PTSD). This study is a part of an 
international, multi-site series of Phase 2 studies designed to evaluate safety and efficacy 
of MDMA-assisted psychotherapy in treating chronic, treatment-resistant PTSD for 
possible use as an approved prescription medication in the U.S., Europe and Israel [1].  
 
MAPS’ initial US MDMA/PTSD study has been completed, with promising results 
published in the Journal of Psychopharmacology [2].  Findings from the long-term 
follow-up study, evaluating the US subjects at an average of 40 months post-treatment, 
has shown that the therapeutic benefits have been sustained over time. MAPS’ Swiss 
pilot study was completed in early 2011, with the data currently being prepared for 
publication. MDMA was administered without evidence of harm and generated 
promising data about efficacy. MAPS’ initial Israeli MDMA/PTSD study enrolled five 
subjects, with the data summarized in our abbreviated report.  Additional pilot studies are 
underway in the US (in veterans with war-related PTSD) and are in the approval process 
in Canada and Jordan. 
 
This Phase 2 research study will investigate the safety and efficacy of MDMA-assisted 
psychotherapy in 10 people with chronic, treatment-resistant posttraumatic stress disorder 
(PTSD). The study will include an open-label lead-in in two subjects followed by a 
randomized, double-blind arm comparing 125 vs. 25 mg MDMA in eight participants, 
and an open-label arm for participants who received active placebo. This study is also 
intended to continue the development of a manualized psychotherapeutic approach to this 
potential treatment, to be used in the planning of possible Phase 3 studies. 
 
2.2 Background 
 
2.2.1 Post Traumatic Stress Disorder (PTSD)    
 
PTSD is a debilitating psychiatric disorder arising after a traumatic life event. PTSD 
severely reduces quality of life and may directly or indirectly lead to or exacerbate other 
psychiatric and medical problems. The DSM-IV (APA 1994) criteria for PTSD include:  
 
A. Exposure to a significant traumatic event accompanied by an intense acute 
emotional response.   
B. Persistent re-experiencing of the event or aspects of the experience.   
C. Persistent avoidance of stimuli associated with the event, and/or withdrawal from 
some aspects of life.   

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D. Persistent symptoms of increased arousal.   
E. The above symptoms must last for more than one month for Acute PTSD and 
more than three months for Chronic PTSD.  
 
PTSD is a worldwide public health problem for which a wider array of effective 
treatments is needed. The lifetime prevalence of PTSD in the U.S. general population is 
between 6 and 10% % [3-7], but it is common in other countries as well [4, 8-11]. 
According to some estimates, PTSD appears to be less prevalent in the general population 
of Europe at 1.9% [12]. In U.S. soldiers returning from combat in the Iraq war, the 
incidence of PTSD is as high as 18% [13], and it is estimated that the number of service 
members returning home with PTSD will ultimately be between 75,000 and 225,000 [14]. 
In countries with endemic armed conflict, the incidence of PTSD in civilians is often far 
greater  [15-17].  
 
The search for novel and more effective treatments is of major public health and 
economic significance. PTSD is typically a chronic illness [3, 18] associated with high 
rates of psychiatric and medical comorbidity, disability, suffering, and suicide [4-7]. 
People with PTSD face challenges in relationships and work productivity [19]. In the 
U.S. National Comorbidity Study, the median time to remission for PTSD was 36 months 
with treatment and 64 months without treatment. In both subgroups, more than a third of 
the patients still had symptoms several times per week after 10 years [3].  Forty to sixty 
percent of PTSD patients were found to be resistant to treatment in this study. In a 
comparison of two types of psychotherapy for women with PTSD after sexual assault in 
2002, 47% of each treatment group was diagnosed with PTSD based on high Clinician 
Administered PTSD Scale (CAPS) scores [20].  
 
Despite the sheer number of individuals suffering from PTSD and its devastating effects, 
questions remain concerning the best possible treatments [21]. PTSD treatment goals 
include alleviating symptoms and correcting stress-induced neurochemical abnormalities 
associated with the condition. Two selective serotonin reuptake inhibitors (SSRI), 
sertraline and paroxetine, are currently marketed as PTSD medications in the U.S. These 
drugs are known to affect the serotonergic components of PTSD, but it is not known 
whether they can arrest and reverse the hippocampal atrophy found in individuals with 
PTSD [34]. In addition, SSRIs affect PTSD symptoms in a dosage dependent manner and 
they must be used every day in order to be effective [22]. 
 
Another treatment approach is to develop drugs and/or psychotherapeutic treatments that 
may indirectly decrease or eliminate the neurochemical pathologies underlying the 
chronic hyperarousal associated with PTSD. Cognitive behavioral therapies, particularly 
prolonged exposure and cognitive processing therapy, are considered among the most 
effective psychotherapies. Other methods such as psychodynamic therapy and eye 
movement desensitization and reprocessing (EMDR) have also proven to be effective in 
treating some symptoms of PTSD [28], although some patients may need more than one 
treatment to reduce or resolve those symptoms [20]. A recent meta-analysis concluded 
that all “bona fide” psychotherapies, including those listed above, are similarly effective 
with PTSD [29].  

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At least a third of PTSD patients fail to respond to established PTSD psychotherapies or 
respond in a way that falls outside of clinical significance [23-25]. At least one study of 
paroxetine indicated that men with PTSD did not respond to this drug [26], and another 
randomized, double-blind study found no difference between sertraline and placebo in the 
treatment of PTSD [27]. These findings suggest that there is still a substantial need for 
innovative treatments for PTSD. In recent years, there has been a growing amount of 
research into drugs and other methods that may augment the effectiveness of 
psychotherapy for PTSD (see [28] for a review).  Examples of this are virtual reality-
assisted exposure therapy [29, 30] and D-cycloserine-assisted psychotherapy [31]. 
MDMA-assisted psychotherapy is another example of such emergent treatments. 
 
2.2.2 MDMA 
 
MDMA is a ring-substituted phenylisopropylamine derivative invented by the Merck 
pharmaceutical company in 1912 that bears structural and pharmacological similarities to 
both the stimulant amphetamine and the psychedelic drug mescaline. It was initially 
patented by Merck as an intermediary product and then rediscovered by chemist 
Alexander Shulgin in the 1970s [32, 33]. In the United States, MDMA was used as an 
adjunct to psychotherapy by a considerable number of psychiatrists and other therapists 
before it was placed in Schedule 1 in 1985 as a result of extensive non-medical use [34-
36]. Placement in Schedule 1 prohibited it for use except in a federally approved research 
setting.  
 
Prior to scheduling, MDMA in combination with psychotherapy was used in the 
treatment of neuroses, relationship problems and PTSD [37-40]. Case reports and 
narrative accounts of MDMA-assisted therapy suggest that the treatment was often 
successful.  Based on these experiences, assertions have been made that MDMA, used in 
the proper therapeutic setting, can act in several beneficial ways. Specifically, MDMA 
can “reduce or somehow eliminate fear of a perceived threat to one’s emotional integrity” 
[38]. Elimination of these “conditioned fear responses” can lead to more open and 
comfortable communication about past traumatic events, greater access to information 
about them, and a more accurate perspective about their significance in the present. Some 
clinicians and researchers have asserted that MDMA causes increased empathy or 
compassion for self and others, decreased defensiveness and strengthening of the 
therapeutic alliance, and that the above factors taken together can provide the opportunity 
for a corrective emotional experience [38].  Some investigators suggest that MDMA be 
categorized as part of a new class of psychotropic agents referred to as entactogens [41]. 
The term refers to MDMA and similar substances that produce increased sensitivity to 
emotions, increased insights about the self, especially in the context of interpersonal 
relationships, and increased feelings of closeness to others.    
 
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 efficacy of MDMA-assisted 

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psychotherapy has become more feasible [1, 42, 43]. 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 [44]. However, these increases were found to be 
transient and generally tolerable in a controlled clinical setting [44]. Subsequent trials 
confirmed that MDMA produced significant increases in heart rate and blood pressure 
that were likely to be well tolerated by healthy individuals [45].  
 
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 [46, 47]. Unfortunately, the study in Spain was 
halted in 2002 due to political pressure from the Madrid Anti-Drug Authority.  Prior to its 
suspension, six women were enrolled and treated in this study without any adverse events 
or signs of deteriorating mental health, and with some mild signs of improvement, with 
single doses ranging from 50 to 75 mg [47].  
 
As of 2010, MDMA has been administered to approximately 494 research participants, in 
both Phase 1 and Phase 2 studies, without any occurrences of drug-related Serious  
Adverse Events (SAEs) [48-62]. In the context of psychotherapy, MDMA has been noted 
to reduce defenses and fear of emotional injury while enhancing communication and 
capacity for introspection [34]. 
 
MAPS recently completed its first U.S. study of MDMA-assisted psychotherapy for the 
treatment of PTSD, known as MP-1. This study employed the CAPS as a primary 
outcome measure, with PTSD symptoms measured by a blinded independent rater at 
baseline, 3 to 5 days after each experimental (MDMA or placebo) session, and two 
months after the final experimental session. All participants in this study tolerated 
MDMA, and MP-1 data suggests that MDMA is associated with significantly greater 
improvement in PTSD than placebo [2]. Findings from the long-term follow-up 
evaluating the US subjects at an average of 40 months post-treatment, suggests that the 
therapeutic benefits have been sustained over time [63]. The sponsor has also supported a 
randomized, double-blind study of MDMA-assisted psychotherapy in twelve subjects 
with PTSD in Switzerland (data analysis in process), and in five subjects in our initial 
Israeli MDMA/PTSD pilot study (data summarized in our abbreviated report). 
 
2.2.4 MDMA-assisted Psychotherapy for PTSD 
 
MDMA-assisted psychotherapy is an innovative mode of treatment that combines 
psychotherapeutic techniques with the administration of MDMA, a pharmacological 
adjunct that may enhance or amplify certain aspects of psychotherapy. MDMA possesses 
unique pharmacological properties that may make it especially well suited to use as an 
adjunct to psychotherapy in PTSD patients [30-33]. In contrast to daily administrations of 
SSRIs, this treatment consists of several sessions of MDMA-assisted psychotherapy 
within the context of a moderate course of non-drug psychotherapy.  
 

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Treatment goals of MDMA-assisted psychotherapy for PTSD include alleviating 
symptoms and interrupting the stress-induced neurochemical abnormalities produced by 
the condition. Reports of past experience with MDMA-assisted psychotherapy suggest 
that it may also counteract the effects of PTSD. In fact, the biologic and 
psychotherapeutic approaches overlap and reinforce each other. Knowledge about the 
connections between the neurobiological and the therapeutic effects of MDMA is far 
from complete, but it has been observed that MDMA acutely decreases activity in the left 
amygdala [64]. This action is compatible with its reported reduction in fear or 
defensiveness, and is in contrast to the stimulation of the amygdala observed in animal 
models of conditioned fear, a state similar to PTSD [65, 66].  
 
A comprehensive review of MDMA research is included in the Investigator’s Brochure 
supplied by the Sponsor. This document should be reviewed prior to initiating the 
protocol. 
 
2.3 Protocol Purpose 
 
This Phase 2 study is a randomized, double-blind study in 10 subjects comparing the 
effects of low and full dose MDMA as an adjunct to manualized psychotherapy. The first 
two subjects will be enrolled in the open label full dose lead-in.  The remaining eight 
subjects will enroll in Stage 1 of the protocol and receive either an active placebo dose 
(low dose) or a fully active dose of MDMA during two experimental psychotherapy 
sessions, each lasting six to eight hours and scheduled three to five weeks apart.  Five 
subjects will be randomized to the full dose and 3 subjects will be randomized to the 
active placebo dose of MDMA. The extent of PTSD symptoms will be assessed at 
baseline, and two months after the second experimental session by a clinician and 
throughout using a self-report measure. Subjects enrolled in Stage 1 who receive the 
active placebo will have the opportunity to enroll in Stage 2 of the protocol and complete 
open-label experimental sessions with the fully active dose of MDMA on the same 
schedule as Stage 1. Participants assigned to receive the full dose of MDMA will be 
assessed at 12 months after the second experimental session of Stage 1, and participants 
assigned to active placebo who enroll in Stage 2 will be assessed 12 months after the 
second Stage 2 experimental session. This study will allow comparison between the 
impact of active placebo and full dose MDMA on PTSD symptoms, and on symptoms of 
depression and sleep quality. This study will also permit the refinement of the treatment 
manual. 
 
2.4 Rationale of Dose Selection 
 
This study will compare the effects of psychotherapy sessions assisted by full or active 
placebo dose MDMA. Active placebo will be 25 mg MDMA followed one and a half to 
two and a half hours later by 12.5 mg, and the fully active dose will be 125 mg followed 
one and a half to two and a half hours by 62.5 mg. 
 

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Table 1. Dose Regimen 
Initial  
Dose 
Supplemental 
Dose 
Cumulative Dose 
Active Placebo 
Dose 
25 mg 
12.5 mg 
37.5 mg 
Full Dose 
125 mg 
62.5 mg 
187.5 mg 
 
The full MDMA dose to be used in this study is identical to those used in previous studies 
in the U.S., Switzerland and Israel. Previous researchers have also used doses within this 
range [44, 45, 49, 56, 67, 68] [49, 67, 69-72]. Prior to the scheduling of MDMA, similar 
doses and regimens were used in psychotherapy [34, 36, 39]. The initial full dose is 
expected to produce all the commonly reported effects of MDMA. The supplemental 
dose will prolong subjective drug effects without producing physiological effects any 
greater than peak effects occurring after the initial dose. 
 
The active placebo dose of MDMA was chosen on the basis of its demonstrated ability to 
produce detectable subjective effects in the absence of full therapeutic effects, thus 
serving as an active placebo [45, 70, 73]. These doses are expected to produce increases 
in positive mood and tension, but without the range of effects seen at higher doses. This 
dose was also used in the previous Swiss and Israeli studies conducted by the Sponsor.  
3.0 Protocol Objectives 
The objective of this study is to examine whether a full dose of MDMA versus an active 
placebo dose of MDMA used in conjunction with psychotherapy will reduce or attenuate 
PTSD symptoms and to collect safety data. 
 
3.1 Primary Objective 
 
1. Assess changes in PTSD symptoms in participants receiving the full dose of 
MDMA and the active placebo dose as measured via CAPS score at baseline and 
the end of Stage 1.  
 
3.2 Secondary Objectives 
 
x Assess changes in self-reported PTSD symptoms in participants receiving the full 
dose of MDMA and the active placebo dose as measured via PDS score at 
baseline, during the third integrative session after each experimental session and 
at the end of Stage 1. 
x Assess depression symptoms via the Beck Depression Inventory- II (BDI-II) at 
baseline and the end of Stage 1. 
x Assess quality of life via the Global Assessment of Functionality (GAF) at 
baseline and the end of Stage 1. 

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x Assess self-reported sleep quality via the Pittsburgh Sleep Quality Index (PSQI) at 
baseline and the end of Stage 1. 
x Assess PTSD symptoms via CAPS, depression symptoms via BDI-II, quality of 
life via GAF and sleep quality with PSQI at the end of Stage 2 in all participants 
enrolled in Stage 2. 
x Assess long-term effects symptoms of PTSD, depression and global function via  
CAPS, BDI-II and GAF one year after the final MDMA-assisted psychotherapy 
session for each participant.  
x Assess changes in PTSD symptoms via PDS during the third integrative session 
after each Stage 2 experimental session and at the end of Stage 2. 
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.   
 
x 
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. 
x 
Subjective Units of Distress (SUD) scores and vital signs including blood 
pressure, heart rate and temperature will be measured during each experimental 
session, and results will be compared between groups. 
x 
Serious adverse events, adverse events and spontaneously reported adverse events 
(“reactions”) will be collected during the study according to Section 8.5. 
 
4.0 Protocol Design 
This randomized, double-blind, active placebo controlled study will examine the safety 
and efficacy of MDMA-assisted psychotherapy in subjects diagnosed with chronic, 
treatment-resistant PTSD of at least six months duration. The open-label lead-in, Stage 1 
and Stage 2 will follow the same basic sequence of events and methods. The schedule 
will include two MDMA-assisted psychotherapy sessions scheduled approximately one 
month apart with a male/female co-therapist team. There will be three sets of male/female 
co-therapist teams.  Subjects will remain with only one team for the entirety of the study.  
The first two teams will complete treatment of one of the two lead-in subjects for training 
purposes. Upon enrollment, subjects will meet with their therapist team for 3 preparatory 
sessions. Each MDMA-assisted psychotherapy session will be followed by an overnight 
stay at the clinic, an integrative psychotherapy session the next day, and daily telephone 
calls for the next seven days. Experimental sessions will be followed by two additional 
integrative sessions. PTSD symptoms will be assessed throughout Stage 1. For subjects 
continuing on to Stage 2, PTSD symptoms will be assessed throughout Stage 2. All 
subjects will be evaluated for long-term effects 12 months after their last experimental 
session. (See Table 3 Time and Events). 
 

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The open-label lead-in will follow the same sequence of events as Stage 1 and will enroll 
the first two subjects. The Sponsor will conduct an ongoing review of videotapes of at 
least two of four experimental sessions, entry criteria, vital signs and reaction data for 
completed sessions and any adverse events (AEs). Stage 1 will proceed after the data has 
been reviewed by the Sponsor and feedback provided to the co-therapist teams to ensure 
proper therapist training and subject safety. After review, the Sponsor will notify the site 
when Stage 1 may proceed. The goal of the lead-in will be to ensure standardization of 
therapy techniques in the Sponsor’s ongoing effort to manualize MDMA-assisted 
psychotherapy.  
 
In Stage 1, subjects will be randomly assigned to receive two experimental psychotherapy 
sessions assisted by either active placebo MDMA (3 subjects) or full dose MDMA (5 
subjects). Subjects who receive the active placebo dose of MDMA will be offered the 
option to enroll in the open-label Stage 2 unless they meet any exclusion criteria for study 
participation. In Stage 2, subjects will receive full dose MDMA and the experimental 
sessions will otherwise follow the same sequence of events after a single preparatory 
session. (See Table 3 Time and Events) 
 
All outcome measures will be assessed by a blinded independent rater. The independent 
rater will assess PTSD symptoms with the CAPS and PDS, quality of life with the GAF, 
symptoms of depression with the BDI-II, and sleep quality with the PSQI. The subjects 
will complete the PDS, a self-report measure of their PTSD symptoms, to provide 
correlations with measures administered by the independent rater. The PDS will be 
completed at baseline, during every third integrative session after an experimental 
session, and at the end of each Stage. Baseline assessments will be compared with 
assessments made in Stage 1.  
 
All subjects will complete a follow-up occurring 2 months after their last experimental 
session in Stage 1 and Stage 2, if applicable. The blind will be broken for all subjects in 
Stage 1 after completing this assessment. In addition all subjects will complete a visit 12 
months after their final experimental session where outcome measures and a 
questionnaire on any lasting benefits or harms of the treatment will be administered.  
 
At each visit with the therapists, the subject’s general wellbeing and suicidality will be 
assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Adverse Events and 
Concomitant Medications will be collected as described in Section 8.5 and 9.0 of the 
protocol. 
4.1 Planned Duration of Study 
Subjects enrolled in this study will fall into two categories that will determine the 
duration of the study. These include screening and the follow-up portion of the study. 
x Open-label lead-in and Stage 1 only subjects: 14 months  
x Stage 1 subjects who continue to Stage 2: 18 months 

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Table 2. Time & Events MP9 Stage 1  
Screen/Baseline 
Preparatory 
Experimental Session 1 
Experimental Session 2 
End of Stage 1 
Visit # 
Prior to  Enrollment 
V1, 2, 3 
V4 
V5, 6, 7 
V8 
V9, 10, 11 
V12 
Type of Visit 
Baseline Screening may take 
place over more than one day up 
to one month prior to Visit 1 
Preparatory 
Sessions 
Experimental 
Session 1 
Integrative 
Sessions 
Experimental 
Session 2 
Integrative 
Sessions 
Follow-Up & Outcome 
Visit Timing or Study day or Window 
Approx. 1 
week apart 
3-5 weeks post 
V1 
Approx. 1 week 
apart A 
3-5 weeks post 
V4 
Approx. 1 
week apart A 
May happen over more then 1 day.  
2 months post V8 
Informed Consent 
X 
 
 
 
 
 
 
Medical/Psychiatric History  
X 
 
 
 
 
 
 
General Physical Exam, ECG 
X 
 
 
 
 
 
 
Brief Neurological Exam 
X 
 
 
 
 
 
 
SCID 
X 
 
 
 
 
 
 
Clinical Lab Tests, w/ HIV test 
X 
 
 
 
 
 
 
Collect Concomitant Medication 
 
X 
X 
X 
X 
X 
X 
Medication Taper (if applicable) 
 
X 
 
 
 
 
 
Drug Screen 
X 
 
X 
 
X 
 
 
Pregnancy Screen (if applicable) 
X 
 
X 
 
X 
 
 
CAPS, GAF, BDI –II,  PSQI (with Ind. Rater) 
X  
 
 
 
 
 
X 
Study Enrollment after meeting I/E 
 
X B 
 
 
 
 
 
Record to Audio/Video 
 
X 
X 
X 
X 
X 
 
General Well-Being 
 
X 
X D 
X 
X D 
X 
X 
Obtain Container Assignment from  
Randomization Program 
 
 
X C 
 
X C 
 
 
C-SSRS 
X 
XH 
X D, E, F 
X J 
X D, E, F 
X J 
X 
Administer IP Drug + Therapy 
 
 
X 
 
X 
 
 
Monitoring of BP, Pulse and Temp.  
 
 
X 
 
X 
 
 
SUD 
 
 
X E, G 
 
X E, G 
 
 
Beliefs of Condition Assignment 
 
 
 
X I 
 
X I 
 
Overnight Stay 
 
 
X 
 
X 
 
 
PDS 
X 
 
 
XN 
 
XN 
X 
Integrative Therapy Session 
 
 
 
X 
 
X 
 
7 days Integrative Telephone Contact 
 
 
 
X J 
 
X J 
 
AEs Requiring Medical Attention 
 
 
X 
X 
X 
X 
X 
Spont. Reactions and all AEs  
 
 
XK 
XK 
XK 
XK 
 
AEs related to changes in psychiatric status or 
withdrawal 
 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
 
X 
X 
X 
X 
X 
X 
Unblinding 
 
 
 
 
 
 
X L 
RRPQ  
 
 
 
 
 
 
XM 
Issue Memory Aid Card  
 
 
 
 
 
 
XM 
A =First Integrative session is 1 day after Exp. session B =Only on Visit 1 C = At least 24 hrs prior to exp. session D =Approximately 6 hours post MDMA    E =At the beginning of the session F =As needed G 
=Approximately every 60 minutes H =Given on 2nd preparatory session only (V2) I= At 1st integrative visit after each Exp. Session for subjects & therapists and at V12 for the independent rater J = For 7 days post 
Exp. Session, CSSRS D2 and D7 of calls only, General well being for all 7 days K= Spontaneously reported reactions will be collected on the day of MDMA administration and for seven days after each Exp. 
Session. L= Determine after completion: Go on to Long-term follow up or Stage 2 M= Only for subjects not going to Stage 2 N= Subjects will complete PDS on third integrative session only 

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Table 3.  Time & Events MP9 Stage 2 
Preparatory Experimental Session 1 
Experimental Session 2 
End of Stage 2 
Long Term Follow up after Stage 1 or Stage 2 
Long Term 
Follow-Up  
 Visit # 
V13* 
V14 
V 15, 16, 17 
V18 
V 19, 20, 21 
V22 
1 Year Follow-up 
Type of Visit 
Preparatory 
Session 
Experimental 
Session 1 
Integrative 
Sessions 
Experimental 
Session 2 
Integrative 
Sessions 
Follow-Up & 
Outcome 
Follow-Up & 
Outcome 
Visit Timing or Study day or Window 
Within 1 
month of 
V12* 
 
1 week post 
V13 
Approx. 1 
week apart A 
3-5 weeks 
post V14 
Approx. 1 week 
apart A 
May happen over 
more then 1 day.  
2 months post 
V17 
May happen over 
more then 1 day. 
One Year After V8 
or V17 
Confirm Informed Consent 
X 
 
 
 
 
 
 
Confirm Inclusion/Exclusion 
X 
 
 
 
 
 
 
Entry into Stage 2 
X 
 
 
 
 
 
 
Collect Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
Record to Audio/Video 
X 
X 
X 
X 
X 
 
 
General Well-Being 
X 
X B 
X 
X B 
X 
X 
X 
Drug Screen 
 
X 
 
X 
 
 
 
Pregnancy Screen (if applicable) 
 
X 
 
X 
 
 
 
CAPS, GAF, PSQI, BDI-II (with Ind. Rater) 
Use V12* 
 
 
 
 
X 
X 
C-SSRS 
X 
X B, C, D 
X 
X B, C, D 
X 
X 
X 
Administer IP Drug + Therapy 
 
X 
 
X 
 
 
 
Monitoring of BP, Pulse and Temp.  
 
X 
 
X 
 
 
 
SUD 
 
X C, E 
 
X C, E 
 
 
 
Overnight Stay 
 
X 
 
X 
 
 
 
PDS 
Use V12* 
 
XH 
 
XH 
X 
X 
Integrative Therapy Session 
 
 
X 
 
X 
 
 
7 days Integrative Telephone Contact 
 
 
X F 
 
X F 
 
 
AEs Requiring Medical Attention 
X 
X 
X 
X 
X 
X 
 
Spont. Reactions and all AEs  
 
XG 
XG 
XG 
XG 
 
 
AEs related to changes in psychiatric status or 
withdrawal 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
X 
X 
X 
RRPQ 
 
 
 
 
 
X 
 
Issue Memory Aid Card 
 
 
 
 
 
X 
 
Follow up Questionnaire 
 
 
 
 
 
 
X 
Termination Visit 
 
 
 
 
 
 
X 
* Re-baseline if Visit 13 is more than 1 month from V12, then the measures from V12 will need to be repeated prior to starting Stage 2. 
A = First Integrative session is 1 day after Exp. session B =Approximately 6 hours post MDMA C =At the beginning of the session D =As needed E=Approximately every 60 minutes F = For 7 days post 
Exp. Session, CSSRS D2 and D7 of calls only, General well being for all 7 days G= Spontaneously reported reactions will be collected on the day of MDMA administration and for seven days after each 
Exp. Session. H = Subjects will complete PDS on third integrative session only 

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4.2 Recruitment and Subject Population 
 
Participants may be men or women aged 18 or older with a confirmed diagnosis of 
chronic PTSD who have undergone at least one treatment for PTSD without achieving 
remission. Prior treatment can include psychotherapeutic or pharmacological treatments, 
and people who have undergone one or more prior treatments are eligible for study 
participation. Subjects would not be excluded for having more than one traumatic event. 
Subjects must have a CAPS score equal to or greater than 50 and must meet all inclusion 
criteria and no exclusion criteria at baseline. Participants must be in good physical health 
and without major medical disorders that might affect the safety or tolerability of 
MDMA. Participants will be recruited through printed ads, internet ads, referrals from 
other psychiatrists, psychotherapists or physicians, through the Israeli Defense Forces 
(IDF) and through word of mouth. The first ten participants who meet all inclusion 
criteria without meeting any exclusion criteria will be admitted to the study. All 
recruitment materials and advertisements will be approved by the institution’s IRB/EC. 
 
4.2.1 Inclusion Criteria 
 
Individuals eligible to be enrolled into this protocol are subjects who: 
 
1. Meet DSM IV criteria for chronic PTSD with a duration of at least six months. 
Participants may have experienced one or more traumatic event; 
2. Have a CAPS score of 50 or higher, indicating moderate to severe PTSD 
symptoms;  
3. Have had at least one unsuccessful attempt at treatment for PTSD:  
a. Treatment with a selective serotonin uptake inhibitor (SSRI), mirtazapine, 
a Serotonin Norepinephrine Reuptake Inhibitor (SNRI) or a monoamine 
oxidase inhibitor (MAOI)   
b. Any form of psychotherapy for the treatment of PTSD;  
4. May have a concurrent affective disorder, excepting bipolar affective disorder 1; 
5. Are at least 18 years old; 
6. 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 investigators to communicate directly with their therapist.  
7. May not change therapists, increase the frequency of therapy or commence any 
new type of therapy until after the evaluation session at the end of Stage 1 or 2, as 
applicable; 
8. Are willing to refrain from taking any psychiatric medications during the study 
period, with the exception of gabapentin when prescribed for pain control.  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.   
9. Agree to, for one week preceding each experimental session: 
a. 
Refrain from taking any herbal supplement (except with prior approval of 
the research team)  

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b. 
Refrain from taking any nonprescription medications (with the exception 
of non-steroidal anti-inflammatory drugs or acetaminophen unless with 
prior approval of the research team) 
c. 
Not take 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;  
10.  Agree to take nothing by mouth except alcohol-free liquids after 24:00 
(midnight) the evening before the experimental session;  
11. Agree to refrain from the use of any psychoactive drug, with the exception of 
caffeine or nicotine, within 24 hours of each experimental session;  
12. Agree not to use caffeine or nicotine for 1 hour before and 3 hours after ingesting 
the drug, or until the therapists deem it safe to do so;  
13. Are willing to commit to medication dosing, experimental sessions, follow-up 
sessions and to complete evaluation instruments; 
14.  Are willing to remain overnight at the study site after each experimental session 
until after the integrative session occurring the next morning;  
15. Are willing to be driven home the morning after the experimental sessions, after 
the integrative therapy session either by a driver arranged by the subject or by the 
site personnel or taxi;  
16. Are willing to be contacted via telephone on a daily basis by one of the therapists 
for a week after each experimental session;  
17. Are willing to refrain from participating in any other clinical trial for the duration 
of this clinical trial, including the follow up period;  
18. 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; 
19. Are proficient in speaking and reading Hebrew; 
20. 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 borderline personality disorder; 
3. Are diagnosed with dissociative identity disorder or an eating disorder with active 
purging;   
4. Have evidence or history of significant (controlled or uncontrolled) 
hematological, endocrine, cerebrovascular, cardiovascular, coronary, pulmonary, 
renal, gastrointestinal, immunocompromising, or neurological disease, including 
seizure disorder, or any other medical disorder judged by the investigator to 
significantly increase the risk of MDMA administration (Subjects with 
hypothyroidism who are on adequate and stable thyroid replacement will not be 
excluded); 

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5. Have hypertension using the standard criteria of the American Heart Association 
(values of 140/90 or higher assessed on three separate occasions [74]); 
6. Have liver disease;  
7. Have history of Diabetes Type I or II; 
8. Have history of hyponatremia or hyperthermia; 
9. Weigh less than 48 kg; 
10. Would present a serious suicide risk or who are likely to require hospitalization 
during the course of the study; 
11. Have used “Ecstasy” (material represented as containing MDMA) more than five 
times or at least once within 6 months of the MDMA session; 
12. Require ongoing concomitant therapy with a psychiatric drug, including SSRIs, 
SNRIs, or MAOIs; 
13. Meet DSM-IV criteria for substance abuse or dependence for any substance save 
caffeine or nicotine in the past 60 days; 
14. Have glaucoma, significant atherosclerosis or hyperthyroidism; 
15. Have any current problem, which in the opinion of the investigator or medical 
monitor, might interfere with participation in the study; 
16. Are not able to give adequate informed consent. 
5.0 Methods 
5.1 Measures 
 
The following outcome and safety measures will be used in Stage 1 and Stage 2: 
 
5.1.1 Outcome Measures 
 
The primary outcome measure will be the CAPS, a clinician-scored measure for PTSD 
diagnosis and measure of symptom intensity and severity. A qualified, blinded 
independent rater will perform the CAPS. The independent rater will not be present 
during the subject’s experimental sessions nor have any information regarding the 
experimental sessions. Subjects will be instructed not to tell the independent rater any 
beliefs they or others have concerning their condition assignment during the evaluation 
session. The CAPS provides a standardized method to evaluate the frequency and 
intensity dimensions of each symptom, impact of symptoms on the subject's social and 
occupational functioning, overall severity of the symptom complex and global 
improvement since baseline and the validity of the ratings obtained. The CAPS interview 
takes approximately one hour to complete. The CAPS has been determined to have good 
internal consistency, concurrent validity, and test/retest reliability [75, 76]. An 
independent rater will assess all subjects at baseline and the end of Stage 1. The 
independent rater will also assess applicable subjects at the end of Stage 2 and 12 months 
after the subject’s final experimental session.   
 
The secondary measure of PTSD symptoms will be the PDS, a self-report measure 
designed to follow DSM IV criteria for assessing PTSD. The measure is derived from the 
Posttraumatic Symptom Scale – Self Report (PSS-SR), a measure also intended to tap 
into diagnostic criteria for PTSD. The PDS contains 49 items, with responses made on a 

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four-point scale, ranging from 0 (“not at all”) to 3 (“five or more times a week”). The 
PDS consists of a list of 12 potential traumatic events, 12 items addressing elements of 
the traumatic event, of 17 symptom items, and nine items assessing impact on areas of 
life function [77]. Items addressing elements of the traumatic event and life function are 
answered as either present or not present (Yes or No). The seventeen items are summed 
to create a symptom severity scale. Cronbach’s alpha for the symptom severity scale is 
0.92. The PDS has test-retest reliability of 0.74 after a two-week and one-month interval, 
and subscales are inter-correlated, with correlations ranging from 0.73 to 0.82, and PDS 
scores had a moderate to good correlation with SCID diagnosis, with kappa = 0.65 [77]. 
The Hebrew translation of the 17-item symptom scale of the PDS will be used for this 
study [78, 79]. A study of the reliability and validity of the Hebrew translation has been 
conducted [80], with at least one report giving internal consistency of 0.94 [81].    
 
The Beck Depression Inventory-II (BDI-II) is a 1996 revision of the BDI, a 21-item self-
report measure [82, 83], that will serve as a measure of depression according to DSM-IV 
criteria[84]. 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 [84]. 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 has been translated and validated 
in Hebrew [85]. Subjects will complete the BDI-II at the same times as the CAPS.  
 
The Global Assessment of Function (GAF) is a measure of quality of life and general 
function made through observations. The GAF consists of a single score, with scores 
ranging from 0 to 100, with 100 reflecting superior function and zero reflecting serious 
risk of causing harm to the self or others. The GAF is a reliable, validated measure of 
social functioning [86]. Subjects will complete the GAF at the same time as the CAPS. 
 
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 4 on a five-point scale [87]. 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[87, 88]. Global scores correlate 
with other measures of alertness and self-reported sleep quality [89]. The Hebrew 
translation will be used [90]. Analysis of the Hebrew translation found that it has a 
Cronbach’s alpha of 0.70 in sleep clinic patients and 0.52 for non-clinic patients, with the 
lower alpha possibly the result of sleep clinic patients referred for snoring rather than 
insomnia. 
 
The Reactions to Research Participation Questionnaire (RRPQ) [91] is an assessment of 
causes for taking part in research and responses to the experience of being a research 

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subject. Subjects will complete this measure during their final study visit, with exact time 
of completion varying in accordance with subject enrollment in the open label study 
segment or in the third open label MDMA-assisted psychotherapy session in Stage 2. The 
RRPQ is intended to assess the subject’s experience as a research subject, perceived 
reasons for consenting to be a research subject and perceived freedom to take part in the 
study, and is not an outcome measure. 
 
The long-term follow up questionnaire has been developed internally by the Sponsor to 
assess long-term benefits and harms of MDMA-assisted psychotherapy at the 12 month 
follow up visit. It will be translated into Hebrew.  
 
All psychotherapy sessions, including experimental sessions, will be recorded to audio 
and video, with all recordings preserved for research purposes. Safety measures will be 
applied as described below to minimize risks associated with drug-assisted psychotherapy 
sessions. 
 
5.1.2 Safety Measures 
 
Safety measures, 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 a single-item, self-report scale, the SUD scale, repeatedly during the 
experimental sessions, with the degree of distress marked along seven points. 
 
The C-SSRS (Hebrew translation) is a clinician-administered measure of suicidal 
behavior devised to detect potential suicidal thoughts or behaviors during a clinical trial 
[92]. 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 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 an increase in suicidality is observed by 
the therapists. C-SSRS data from the second integrative session after each experimental 
session will be kept with the subject’s source record. 
 
The therapists will assess general wellbeing during each preparatory session, on each 
integrative session and integrative telephone calls for seven days.  
 
Blood pressure and heart rate will be assessed periodically during each experimental 
session. Blood pressure and pulse will be measured at the outset of the experimental 
session, and once approximately every 30 minutes during the experimental session. More 
frequent measures will be taken if the established thresholds of 160 systolic, 110 diastolic 
or pulse of 110 are exceeded.  Blood pressure will also be measured more frequently if 
there are symptoms, such as chest pain, shortness of breath or neurological symptoms, 

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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 they do not interfere with the therapeutic process.  
 
All AEs and spontaneously reported reactions will be collected as described in section 
8.5. Adverse events and spontaneously reported reactions may be collected during face to 
face visits or over the telephone. Commonly reported 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. 
 
5.2 Study Procedures and Visit Descriptions 
 
5.2.1 Prescreening, Screening and Baseline Evaluation (Pre-study) 
 
All individuals who enter screening, as defined in this section, should be assigned a 
screening number and recorded on the “subject screening log” where information on the 
selection of potential subjects in the trial should be collected. The subject screening 
number should also be recorded on the subject’s informed consent form. If a subject is 
enrolled, the study staff should record the enrollment date and assign a subject number. If 
a subject is not enrolled, an explanation should be recorded on the screening log. A CRF 
will not be completed for subjects who are not enrolled. These subjects will only be 
documented on the screening log and source records.  It is the responsibility of the 
investigator 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 up to one month prior to Visit 1. If, after 
reviewing all information, the investigator concludes that a subject is eligible, he 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.  
b. Assign the subject a screening number. Complete the screening log.  
c. Subjects will provide a medical and psychological history. 
d. Review the ability of females of childbearing potential to become pregnant and their 
commitment to practice appropriate birth control as determined by the investigator for 
the total duration of the study. 
e. A physician will perform a general physical examination. The examination will 
involve the following procedures:  
x blood pressure 
x pulse 
x height 
x weight 
x body temperature 

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x examination of head, eyes, ears, nose, throat, skin, heart, lungs, abdomen 
and extremities 
x brief neurological exam (cranial nerves 2-12, sensory, motor, reflexes and 
cerebellar function) 
x electrocardiogram (ECG)  
x serum electrolytes, metabolic profile, urinalysis and complete blood count 
x Human Immunodeficiency Virus (HIV) serology 
x Urine-dip pregnancy test on females with childbearing potential  
x C-SSRS to assess suicide risk  
 
Results of HIV serology will be kept confidential, and appropriate referral for counseling 
will be made if necessary. 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 vales will be captured as 
medical history. If, upon examination, there are questions raised about possible medical 
problems, the therapists will request a review of subject medical records and request 
additional tests or assessments as indicated. 
 
An independent rater who will not be present during any of the therapy sessions will 
administer:  
x SCID to assess eligibility  
x CAPS to assess PTSD symptoms 
x PDS to assess self-reported PTSD symptoms 
x BDI-II to assess depression symptoms 
x GAF to assess general psychological function 
x PSQI to assess sleep quality 
 
5.2.2 Preparatory Psychotherapy Sessions (Visits 1, 2 and 3) 
 
Subjects who do not complete all screening activities will not be enrolled. If all inclusion 
criteria and no exclusion criteria are met, eligibility will be confirmed with the subject 
during Visit 1. After eligibility is confirmed, the subject will be enrolled during Visit 1 
and issued a subject number. The first preparatory session will take place after enrollment 
during Visit 1. Remaining preparatory sessions will be scheduled as described in the 
Time and Events table.  
 
Upon enrollment, subjects who must refrain from taking a psychiatric medication will 
begin tapering off that medication following a time course appropriate for the medication 
given its half-life, with the first experimental session scheduled to occur after complete 
washout. The therapists will perform the C-SSRS once after medication washout but 
prior to the first experimental session. This may occur during a scheduled administration 
of the C-SSRS during the second preparatory session, or at an additional time appropriate 
to the medication washout. 
 
a. Record preparatory sessions to audio and video.  Subjects may receive 

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copies of audio or video recordings from these preparatory sessions upon request.  
b. AEs and Medications will be recorded as described in Section 8.5 and 9.0 of the 
protocol from the time the subject is enrolled at Visit 1. 
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 will undergo three preparatory sessions lasting at least an hour with the 
therapists, who will be a male and a female co-therapist team. The therapists will 
work with the subject to prepare him or her for MDMA-assisted psychotherapy. The 
therapists and subject will seek to form a strong working relationship with each other, 
and they will help the subject prepare for upcoming experimental sessions. 
Preparatory sessions will promote a safe space for confronting trauma-related 
memories, emotions and thoughts.  Subjects will remain with the therapist team they 
begin with throughout the study. 
e. The subject and therapists will discuss goals for the experimental session and will 
review what will happen during the experimental session, following standard 
procedures and techniques discussed in the Sponsor’s treatment manual.  
f. During one of the preparatory sessions the therapists will introduce the subject to the 
attendant that will remain with the subject during each overnight stay after each 
MDMA-assisted psychotherapy session. The attendant will be an individual with 
previous training in managing psychological distress.  
g. If a subject would like another individual 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 support individual. 
h. Subjects will complete 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. 
i. General wellbeing will be assessed at each preparatory session. 
j. AEs and medications will be collected as described in Sections 8.5 and 9.0 of the 
protocol. 
k. During the third and last preparatory session, the therapists will give the Subject 
Information Sheet to the subject, which includes instructions and restrictions for 
conduct 24 hours prior to receiving the drug, including restrictions on food and 
alcohol consumption. Subjects must agree to take: 
x Nothing by mouth except alcohol-free liquids after 24:00 (midnight) the evening 
before the experimental session.  
x Subjects must also refrain from the use of any psychoactive drug, with the 
exception of caffeine or nicotine, within 24 hours of each experimental session. 
x Subjects must not use caffeine or nicotine for 1 hour before and 3 hours after 
ingesting the drug, or until therapists deem it safe to do so. 
x Subjects must refrain from smoking marijuana for at least 3 days prior to the 
experimental session.  They may smoke marijuana on the 8th day after the 
experimental session if needed. This will be collected with the Concomitant 
Medications. 

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5.2.3 Experimental Sessions (Visit 4 and 8) 
 
Subjects in Stage 1 will receive two double-blind experimental sessions of MDMA-assisted 
psychotherapy scheduled approximately 3-5 weeks apart, and subjects in the open label lead-
in and open label Stage 2 will receive two experimental sessions with the full dose of 
MDMA. Procedures for MDMA-assisted psychotherapy will remain the same across all 
sessions, and all procedures except the drug received will be the same.  
 
a. At least 24 hours prior to the first experimental session the subject will be 
randomized. The therapist team conducting the session will obtain the container 
assignment using a web-based randomization program prior to the session.  
b. On the day of the experimental session, the subject will arrive approximately 1-1.5 
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 
investigator and may be cause for delaying drug administration to a later time, 
rescheduling the session to a later date, or withdrawing the subject from the study. 
e. If a woman is of childbearing potential, perform a urine pregnancy test. A positive 
pregnancy screen is cause for withdrawal from the protocol. 
f. If the subject continues to meet criteria and the subject reports that he/she 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 receive a copy of audio or 
video recordings of their experimental sessions upon request. 
i. The session will last for approximately eight hours or longer, followed by an 
overnight stay at the study site. 
j. The subject will complete the C-SSRS approximately one hour to a half hour prior to 
drug administration. 
 
Table 4. Schedule of procedures and measures 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 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 
10:30  
BP, Pulse 
11:00  
BP, Pulse, SUD, BT 
11:30  
BP, Pulse; Can 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 

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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 1 hour before or 3 hours after the 
dose of drug. 
m. Subject body temperature will be measured 15 and 5 minutes prior to initial dose 
administration 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 15 and 5 minutes prior to initial dose administration.  
Subjects will complete the SUD every 60 to 90 minutes, until the session is over, 
allowing a window of up to 30 minutes to fit into the psychotherapy process where a 
natural break occurs. If necessary, the therapists can make a greater number of 
measurements as their clinical judgment dictates. 
o. Measure blood pressure and pulse 15 and 5 minutes prior the experimental session, 
and once every half-hour throughout the experimental session if the established 
thresholds for normal blood pressure and pulse have not been exceeded for the 
duration of the experimental session. More frequent measures will be taken if the 
established thresholds of 160 systolic, 110 diastolic or pulse 110 are exceeded. 
Measurements should be taken every 5 minutes until the values fall below these 
levels or until they have been decreasing for 15 minutes or have stabilized at a level 
judged by the investigator to be safe. The therapists may also make more frequent 
measurements if a subject exhibits symptoms indicative of hypertension. 
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 will listen to a 
program of music designed to support their experience by initially aiding relaxation 
and later evoking and supporting deep emotions and the emergence of unconscious 
material [77-79]. 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. 
Every hour, and as 
needed 
BP, Pulse 
Every 60-90 minutes SUD, BT 
Approximately 6 
hours after drug 
administration 
C-SSRS, General Wellbeing 

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u. A supplemental dose half the size of the initial dose may be administered 
approximately 1.5 to 2.5 hours after the initial dose upon mutual agreement between 
the therapists and subject.  
v. Provide food during the latter part of the session.  
w. If there is a support-individual who has previously been asked and has agreed to be 
present during part or all of the MDMA session, that person may arrive during the 
session at whatever time has been agreed upon, but will wait in the waiting room until 
brought back to the session room by one of the therapists. The 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 according to the methods described 
in the MDMA-assisted psychotherapy treatment manual. 
y. End the session if all medical and psychiatric parameters are acceptable and the 
subject is alert, ambulatory and emotionally stable. 
z. The therapists will depart the site when they have concluded that the subject is 
emotionally and medically stable. Therapists shall remain available to subjects during 
the experimental session and for one week after via 24-hour cellular phone. 
aa. Spontaneously reported reactions, AEs and Medications will be collected as described 
in Sections 8.5 and 9.0 of the protocol.  
 
Subjects will remain overnight in an appropriately furnished room at the study site.  With 
the approval of the therapists, a companion may accompany the subject during the 
overnight stay. An attendant will check in periodically on the subject during the overnight 
stay, even if a companion is present. The attendant will monitor subject health 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 and 9) 
a. On the morning after each experimental session, both of the therapists from the 
subject’s team will meet with the subject during a 90-minute integrative therapy 
session.  
b. The entire integrative psychotherapy session will be recorded to audio and video. 
Subjects may receive copies of this session upon request. 
c. Subjects will complete the C-SSRS just prior to beginning each integrative 
session.  
d. Prior to integrative psychotherapy, 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 integrative 
session, including thoughts, feelings and memories. If necessary, the therapists 
will help the subject to reduce any residual psychological distress he or she is 

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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 integrative psychotherapy immediately after each experimental session.  
h. Integrative psychotherapy sessions can also serve as an opportunity for the 
therapists to gather information about the effects of the drug on the subject in an 
unstructured manner.  
i. After the integrative psychotherapy sessions, 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, Adverse Events and Medications will be 
collected as described in Sections 8.5 and 9.0 of the protocol.  
k. Remind the subjects that they will have daily contact for the next 7 days. 
 
 
5.2.5 Daily Telephone Contact for Seven days after an Experimental Session 
 
a. Starting on the day of the integrative psychotherapy session following each 
experimental session, one of the therapists will contact the subject via telephone 
or in person on a daily basis for one week.  
b. The integrative contact will be for a brief check-in lasting 5 to 15 minutes, or as 
long as necessary to address any subject’s concerns and to assess subject’s well-
being. 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, the 
subject will complete the C-SSRS. 
d. General wellbeing will be assessed at each phone call. 
e. Spontaneously reported reactions, AEs and Medications will be collected as 
described in Sections 8.5 and 9.0 of the protocol. 
 
5.2.6 Integrative Psychotherapy Between Experimental Sessions (Visits 6, 7, 10 and 
11) 
 
a. The subject will have two additional integrative psychotherapy sessions lasting at 
least an hour with at least one of the therapists from the subject’s therapist team 
between each experimental session. The therapists may conduct more sessions if 
they and the subject deem it necessary.  
b. Record each integrative session to audio and video. Subjects may receive a copy 
of one or more integrative sessions upon request. 

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c. The C-SSRS will be administered just prior to beginning each integrative session.  
d. General wellbeing will be assessed at each integrative session. 
e. The subject will complete the PDS questionnaire on the third integrative session. 
f. The subject and therapists will continue to work on supporting the subject as she 
or he considers his or her experiences during experimental sessions.  
g. The therapists will use clinical judgment to assess the subject’s psychological 
wellbeing during this period of time. If there are any indications of continuing 
anxiety or distress, the therapists may arrange to work on reducing the distress at 
a specially scheduled integrative therapy session, through continuing contact, or at 
the next regularly scheduled integrative therapy session. The subject may also 
initiate contact with the therapists at any time throughout the study.  
h. AEs and medications will be collected as described in Sections 8.5 and 9.0 of the 
protocol. 
i. If an integrative session falls within the period of telephone contact and additional 
phone call is not required that day, all things normally collected during the 
telephone call will be completed in person. 
 
5.2.7 Evaluation at End of Stage 1 and Unblinding (Visit 12) 
 
The final evaluation in Stage 1 will occur two months after the second experimental 
session. This visit will consist of two meetings that may be completed on separate days, 
one with the independent rater and the other with the therapists. 
 
a. Subjects will meet the independent rater for at least an hour and a half. 
b. The blinded independent rater will administer:  
x CAPS to assess PTSD symptoms 
x PDS to assess self-reported PTSD symptoms 
x BDI-II to assess depression symptoms 
x GAF to assess general psychological function 
x PSQI to assess sleep quality 
c. The blinded independent rater will provide their belief of the subject’s condition. 
d. After completing all assessments and measures with the independent rater, the 
subject will meet with the therapists for approximately 30 minutes. 
e. The therapists will assess suicidality with the C-SSRS. 
f. General wellbeing will be assessed. 
g.  The blind will be broken for the subject’s condition assignment. The independent 
rater will remain blind to condition assignment at this time.  
h. If the subject has received active placebo dose MDMA in Stage 1, the therapists 
will discuss enrollment in Stage 2. (See section 5.2.8) 
i. If the subject has received full dose MDMA in Stage 1 or the open label lead-in, 
or they elect not to participate in Stage 2, they will complete the Responses to 
Research Participation Questionnaire (RRPQ) and continue on to the 12-month 
Follow Up visit and study termination. 
j. Subjects who are not enrolled in Stage 2 may return to taking psychiatric 
medications if necessary.  
k. Subjects not enrolled in Stage 2 will receive a memory aid card for use between 

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this visit and the 12-month follow up.  Subjects will use this card to record AEs, 
medications, and changes in psychiatric status that they will be asked about at the 
termination visit.  Memory Aids will not be collected.  
l. AEs and medications will be collected as described in Sections 8.5 and 9.0 of the 
protocol. 
 
5.2.8 Open Label Stage 2 for Active Placebo Subjects 
 
a. Subjects will be reminded that participation in Stage 2 is voluntary and optional. 
b. Subjects who elect to enroll in Stage 2 will undergo the same course of therapy 
and evaluation as in Stage 1, but with full dose MDMA during two experimental 
sessions. 
c. Assessment of PTSD symptoms at the end of Stage 1 will serve as baseline 
assessments in Stage 2.  
d. If the start of Stage 2 is delayed for more than 30 days from the time of the last 
CAPS in Stage 1 to the first preparatory session in Stage 2 (Visit 13), the 
independent rater will re-administer the CAPS, PDS, BDI-II, GAF and PSQI, and 
these scores will be used as the baseline for comparison to assessment at the end 
of Stage 2. 
e. Subjects entering Stage 2 will meet with both therapists for a single review and 
preparatory psychotherapy session (Visit 13).  
f. Subjects will receive two open-label MDMA-assisted therapy sessions (V14, 18).  
g. Subjects will have the same sequence of sessions and integrative therapy as in 
Stage 1. Visits will be scheduled consecutively according to the Time and Events 
Table 3.  
h. Subjects will complete the PDS on the third integrative session. 
i. The same safety measures will be administered during Stage 2, including C-SSRS 
before, during and after each open-label session, vital signs and SUD during each 
open-label session. 
j. Spontaneously reported reactions, AEs and Medications will be collected and 
reported as described in Section 8.5 and 9.0 of the protocol. 
 
5.2.9 Evaluation at the End of Stage 2 
 
Treatment effects will be assessed at the end of Stage 2. This visit will consist of two 
meetings that may be completed on separate days, one with the independent rater and the 
other with the therapists. 
 
a. Subjects will meet the independent rater for at least an hour and a half. 
b. The blinded independent rater will administer:  
x CAPS to assess PTSD symptoms 
x PDS to assess self-reported PTSD symptoms 
x BDI-II to assess depression symptoms 
x GAF to assess general psychological function 
x PSQI to assess sleep quality 

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c. After completing all assessments and measures with the independent rater, the 
subject will meet with the therapists for approximately 30 minutes. 
d. The therapists will assess suicidality with the C-SSRS. 
e. General wellbeing will be assessed. 
f. The subject will complete the Responses to Research Participation Questionnaire 
(RRPQ). 
g. Subjects may return to taking psychiatric medications if necessary.  
h. Subjects will receive a memory aid card for use between this visit and the 12-
month follow up.  Subjects will use this card to record AEs, medications, and 
changes in psychiatric status that they will be asked about at the termination visit.  
Memory Aids will not be collected.  
i. AEs and medications will be collected as described in Sections 8.5 and 9.0 of the 
protocol. 
 
5.2.10 Long-Term Follow-up 
 
All subjects who completed the lead-in, Stage 1 and Stage 2 will be evaluated for long-
term effects 12 months after their last MDMA-assisted psychotherapy session. This visit 
will consist of two meetings, one with the independent rater and the other with the 
therapists.  
a. The independent rater will administer the CAPS, PDS, BDI-II, GAF and the 
PSQI. 
b. Subjects will have a final meeting with at least one of the therapists to review 
specified AEs and medications since the last visit. Subjects should bring the 
Memory Aid Cards to this visit, to be used as aids in recollection.  These cards 
will not be collected. AEs and Medications will be collected as described in 
Sections 8.5 and 9.0 of the protocol. 
c. The therapists will assess suicidality with the C-SSRS.  
d. General wellbeing will be assessed. 
e. Subjects will complete a questionnaire assessing positive and negative long-term 
effects of the study.   
f. 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 "001". Subjects who meet all inclusion and no exclusion 
criteria will be enrolled into the study and will be assigned a five-digit subject number.  
The first two digits will be “09” and will identify the protocol number. 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 09001, 
second 09002, etc. 
 
In total, ten subjects will be enrolled into the study.  The first two subjects will be 
enrolled in the open-label lead-in and assigned to the full dose condition. The subsequent 

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eight subjects will be enrolled in the randomized Stage 1. The randomized portion of the 
study will be blinded and there will be a 5/3 ratio between subjects in the Full Dose and 
Active 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 investigator 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 
subject at the end of Stage 1. Detailed instructions will be provided to the site in a 
separate document. 
 
5.4 Removal or Withdrawal of Subjects from the Study 
 
Subjects can withdraw consent at any time without prejudice.  The therapists can 
withdraw a subject if, in his or her clinical judgment, it is in the best interest of the 
subject or if the subject cannot comply with elements of experimental sessions and 
related visits that are critical for safety.  If the therapists withdraw a subject from the 
session, the therapists will explain the reason for withdrawing the subject.  
If a subject develops any exclusion criteria that in the opinion of the Medical Monitor, 
affects the safety of the subject, including psychiatric diagnosis, pregnancy or excluded 
medications, the subject may be removed from the study.  
 
Subjects will be clinically monitored after withdrawal by at least one of the therapists, the 
cause of which will be recorded in the subject’s source records and CRF.  Whenever 
possible, the tests and evaluations listed for the termination and evaluation visits will be 
carried out.  Efforts will be made to obtain information about AE outcomes, if deemed 
necessary by the therapist and/or Sponsor. 
 
Individuals who replace subjects who withdraw from the open label lead-in and Stage 1 
will be assigned the next available subject number. Lead-in subjects will be replaced if 
they withdraw between the first and second experimental sessions. Lead-in subjects who 
withdraw after the second experimental session will not be replaced. If Stage 1 subjects 
withdraw from the study before the blind is broken, the site should contact the 
randomization monitor for replacement instructions. If there is an emergency requiring 
knowledge of subject's condition assignment, the blind may be broken for an individual 
subject. The investigator will be provided with sealed emergency unblinding envelopes 
corresponding to each Enrollment Code.  These sealed envelopes will be stored in a 
secure limited access area and should remain sealed if there are no emergency unblinding 
events during the study. The therapists, independent rater, and subject will remain blind 
to condition assignment until unblinding at the end of Stage 1, at which point the subject 
and therapists, but not the independent rater, will learn an individual’s condition 
assignment. Unblinding at the end of Stage 1 will be done using the web-based 

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randomization program. Detailed instructions will be provided to the site in a separate 
document.  
 
5.5 Premature Discontinuation of the Study 
 
The Sponsor or the principal investigator (following consultation with the Sponsor) has 
the right to discontinue this study at any time.  If the trial is prematurely terminated, the 
investigator is to promptly inform the study subjects and will assure appropriate therapy 
and follow-up. If the trial or study is prematurely discontinued, all procedures and 
requirements pertaining to retention and storage of documents will be observed. All other 
study materials will be returned to the Sponsor and will be treated in accordance with 
federal and local regulations. 
6.0 Investigational Product 
6.1 Description of Active Compounds 
 
The experimental active compound to be used in this protocol is MDMA. This ring-
substituted phenylisopropylamine has a complex pharmacology, but it acts most 
prominently as a monoamine releaser and uptake inhibitor (Battaglia 1988, Setola 2003, 
Verrico 2007).  Its direct actions on serotonergic, adrenergic and other receptors are 
considerably lower.  
 
6.2 Preparation and Administration 
 
The study will consist of an open-label lead-in, where two subjects will receive  a full 
dose of 125 mg possibly followed by a dose of 62.5 mg. The remaining eight subjects 
will enroll in the double-blind Stage 1 where subjects will be randomized to the two 
conditions described in Table 5 below. The blind will be broken for each subject when 
they reach the end of Stage 1. The subjects who received the active placebo dose of 
MDMA during the randomized study will be offered the opportunity to enroll in an open-
label Stage 2 where they will receive full dose MDMA-assisted psychotherapy. Stage 2 
visits will be conducted in a manner similar to Stage 1. 
 
6.2.1 Doses 
 

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Table 5. Doses of MDMA 
Number of 
Subjects 
Condition 
Blind? 
Initial  
Dose 
Supplemental 
Dose 
Cumulative Dose 
2 
Lead-jn 
Open Label 
125 mg 
62.5 mg 
187.5 mg 
3 
Active Placebo 
Dose 
Blinded 
25 mg 
12.5 mg 
37.5 mg 
5 
Full Dose 
Blinded 
125 mg 
62.5 mg 
187.5 mg 
3 or less 
Stage 2 
Open Label 
125 mg 
62.5 mg 
187.5 mg 
 
6.2.2 Compounding 
 
MDMA in bulk has been provided by Lipomed AG, Switzerland to the Beer Yaakov 
Pharmacy and compounded by the appropriate pharmacist with the inactive compounds. 
MDMA is weighed into capsules of 125, 62.5, 25 and 12.5 mg (calculated as the weight 
of the hydrochloride salt), with capsules for initial dose different in color from capsules 
for supplemental dose. Additional inactive material (lactose) is used to ensure that active 
dose capsules are of equal weight to full-dose capsules. Capsules for the initial dose are a 
different color from capsules used for the supplemental dose, or should be otherwise 
clearly labeled as such.   
 
6.2.3 Labeling 
 
The primary and supplemental doses of MDMA for a single subject to complete one 
experimental session will be stored in a single box labeled with the protocol number, drug 
name, lot number, unique box number, Sponsor name and a statement that the drug is for 
clinical trial use only (see box label). Each dose of MDMA for each experimental session 
will be labeled and stored individually within the box (see container labels for each 
session and dose).  Labels will be provided by the Sponsor and applied by the pharmacist.   
The box and container labels will be hidden from the investigator and therapists to assure 
blinding.  All drug labels will comply with local regulations. 
 
 
 
 
 
 
 
 
Container label 
MAPS Study #   XXX 
Container # XXX  
 
Subject #____________  
Stage 1 MDMA 
Administer as per protocol 
Investigational Use Only   
 
Container label 
MAPS Study #   XXX 
 
Subject #____________  
Stage 2  
125mg & 62.5mg MDMA 
Administer as per protocol 
Investigational Use Only   
Box Label 
MAPS Study# XXXX 
Investigational Product: MDMA  
Dose: Blinded (25 mg, 12.5 mg OR 125 mg, 62.5 mg) 
Randomization # XXX 
Subject Number _____________ 
Lot #: XXXXX 
Administer as per protocol 
Caution-Limited by Law to Investigational Use Only 

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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 of the two experimental sessions in Stage 1. Doses for use in Stage 2 will all 
consist of capsules containing 125 mg MDMA for the initial and 62.5 mg MDMA for the 
supplementary dose. 
 
6.3 Drug Accountability 
 
Forms will be provided to track drug accountability and administration throughout the 
study. Drug accountability will be reviewed during routine monitoring visits. 
 
6.4 Drug Storage and Handling  
 
MDMA is a Schedule 1 compound and will be stored and handled in compliance with all 
relevant local and international regulations. In accordance with these requirements, the 
license-holder or licensed pharmacist will be responsible for storing and dispensing the 
MDMA.  It will be stored in a secure safe within the hospital pharmacy used to store 
methadone and other strictly regulated compounds, in accordance with or approved by 
national drug authorities.   
 
Investigational product will only be removed from the safe for one subject at a time at the 
time of the session and the MDMA will not leave the premises.  All doses administered 
will be recorded on the appropriate accountability logs. 
 
Records pertaining to the use of scheduled, regulated compounds will be maintained in 
accordance with relevant national regulations.   
 
6.5 MDMA Stability 
 
The MDMA to be used in this study was synthesized by Lipomed AG, Switzerland, in 
December 1998 (batch Nr. 94.1B5.51) with a purity of 99.66% (see Analysis Data Sheet 
Lipomed 11.05.99). MDMA from this lot has been used previously in human studies 
conducted by Dr. Franz Vollenweider from the Psychiatric University Hospital Zurich, 
Switzerland. The same batch of MDMA has been used in sponsor-supported studies of 
MDMA-assisted psychotherapy in Switzerland and Israel and will be used in a similar 
study in Canada.The most recent quality control analysis was performed by Prof. Dr. R. 
Brenneisen, DCR, University of Bern, Switzerland on February 2, 2010.  This analysis 

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reconfirmed identity, purity and content of MDMA HCI Lipomed Batch no.94. 1 B5.5 
with no decomposition products detectable and an HPLC purity 99.9%.  
7.0 Risks of Participation 
7.1 Risks and Discomforts Associated with Non-drug and Experimental 
Psychotherapy Sessions and Assessment of Measures 
 
In preparation for drug-assisted psychotherapy sessions, blood draws and a full medical 
examination are required to establish eligibility for the study. Temporary discomfort, 
inflammation or infection could arise as a result of sampling blood at the punctured vein. 
Submitting to a full medical examination may also cause discomfort or psychological 
distress. Since medical examinations and blood draws are required to establish eligibility 
for the study, they cannot be omitted from the protocol. 
 
During screening, non-drug and drug-assisted psychotherapy sessions and assessment of 
study measures, subjects will be asked to think about and discuss their thoughts and 
emotions relating to the traumatic event or events.  They may experience intense 
emotional responses to recalling and speaking about this material.  Even in a therapeutic 
context, thinking about and discussing the trauma, symptoms related to the trauma or the 
effects of PTSD on life function can produce distress during and immediately after non-
drug psychotherapy, experimental and open label sessions.  Psychotherapy is conducted 
as part of the research study, including the experimental intervention, and people 
undergoing psychotherapy are expected to confront unpleasant thoughts, feelings and 
memories in the process of therapy. Because psychotherapy is an integral part of the 
research study design, the potential distress arising from psychotherapy is unavoidable.   
 
All psychotherapy sessions will be recorded to audio and video. 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. 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, dizziness, tight jaw or 
bruxism (tooth-grinding), difficulty concentrating, impaired gait or balance, dry mouth, 
ruminations, and thirst. Other slightly less common reactions include restlessness, 
parasthesias (odd somatic feelings, such as tingling, feeling hot or cold), impaired 
judgment, perspiration, drowsiness, and nystagmus (eye-wiggling).  While anxiety, 
headache, fatigue, insomnia and lack of appetite were spontaneously reported by 40% to 
80% of participants in both conditions in MAPS study MP-1 (N=23), tight jaw, nausea, 
impaired gait/balance, and sensitivity to cold were more often reported by participants in 

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the MDMA than the placebo condition, and irritability was slightly more likely to be 
reported in the placebo condition. Additionally, participants in the MDMA condition 
were more likely to report muscle tension in various body parts and diarrhea.  
These effects are transient and diminish as drug effects wane. Sub-acute effects that may 
either continue for the next 24 hours or appear later include insomnia, fatigue, needing 
more sleep, weakness, heavy legs, dry mouth, low mood or irritability. Sub-acute effects 
are reported less often than acute effects. More information on spontaneously reported 
reactions is described in the Investigator's Brochure.  
 
MDMA may produce mild alterations in sensory perception and altered perception of 
time [48, 67, 93].  Women may be more sensitive to these effects [68].  MDMA acutely 
affects attention, information processing and memory. MDMA acutely impairs verbal 
memory and recall for object location without affecting recall of scene change while 
driving [54]. For this reason, subjects will stay at the site overnight and will not be 
permitted to drive after experimental sessions.  
 
MDMA may produce modest changes in immune functioning, lasting up to 48 hours. 
Because of their limited duration, these changes are not likely to have clinical 
significance beyond several days of possible increased risk of viral upper respiratory 
infection or similar illness.  
 
Further information on the risks associated with MDMA, including information drawn 
from case reports and studies of ecstasy users, can be found in the Investigator’s 
Brochure.  
 
7.2.1 Cardiovascular and Sympathomimetic Effects 
 
The full dose of 125 mg, followed by a supplemental dose of 62.5 mg after 1.5 to 2.5 
hours, is expected to produce significant but transient, self-limited increases in blood 
pressure and heart rate. These changes should last no more than six hours. In less than 5% 
of volunteers in Phase 1 studies, increases in blood pressure were higher than 140/90 
mmHg. Clinical intervention was not required in any of these cases. Nonetheless, careful 
monitoring of participants and predefined contingency plans will allow the researchers to 
rapidly identify and manage any related toxicity. For more information, see the 
Investigator’s Brochure. 
 
Risks posed by elevated blood pressure will be addressed by excluding people with 
hypertension and monitoring blood pressure and pulse as described in Safety Measures 
section 5.1.2. During experimental sessions the co-therapists will continually evaluate the 
patient for increasing blood pressure and signs or symptoms of a developing hypertensive 
or other cardiovascular emergency. Subjects reporting chest pain, shortness of breath or 
neurologicfal symptoms or other potential indicators of hypertension will have more 
frequent measurements. Any participant who experiences sustained blood pressure of  > 
220 systolic or > 120 diastolic or heart rate > 75% predicted maximum during the first 
experimental session will not be given a second experimental session.  
 

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In case of need, subjects will be transferred to the emergency room at Assaf Harofeh 
Hospital. Subjects who are transferred will be accompanied by a physician or paramedic 
from the ICU of Maguen David Adom. Reasons for moving a patient to an ICU would 
include, but not be limited to, severe headache in the setting of hypertension, angina or 
neurological deficits regardless of blood pressure.  In the case of an emergency, 
intravenous anti-hypertensive agents will be available in addition to the usual 
resuscitation drugs and equipment. The investigator and co-therapists may, at any time, 
make a clinical judgment to transfer the patient to the ICU for closer monitoring and 
additional treatment.  
 
The co-therapists will be prepared to respond to rare complications of cardiovascular 
effects, such as stroke or myocardial infarction. The co-therapists will attend to any signs 
or symptoms of neurological deficit or confusion that is more extensive than might be 
expected from MDMA or from psychological distress. If any participant has neurological 
deficits, whether or not they are associated with hypertensive crisis, he or she will receive 
oxygen and an IV and will be monitored as described above. He or she will be 
transported to the emergency department at Beer Yaakov Hospital for further 
management. If evaluation at the hospital reveals a nonhemorrhagic stroke, there will be 
time to administer recombinant tissue plasminogen within the 3 hour time frame 
recommended in the American Academy of Neurology/American Heart Association 
guidelines [94, 95]. 
 
The co-therapists will observe the participant and note any complaints of chest pain. If a 
participant experiences ischemic type chest pain, whether or not it is associated with 
hypertensive crisis, he or she will undergo a stat ECG, receive oxygen and an IV and will 
be monitored as described above. If necessary, he or she will be transported to ICU or a 
location in the hospital where appropriate care can be given. He or she will be given 
nitroglycerin 0.4 mg SL q 5 minutes PRN chest pain pending transport to the hospital. If 
further evaluation at the hospital reveals that the participant has had an acute myocardial 
infarction (AMI), he or she 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 [96]. 
 
7.2.2 Psychological Distress 
 
Mild anxiety and depressed mood are occasionally reported 1–3 days after MDMA  
administration [45, 68, and see the IB]. Psychological distress from MDMA could arise 
from the first indications of drug effects until the last effects have dissipated 
(approximately 3 to 5 hours after drug administration). Anxiety or distress during the 
session may last for as little as 15 minutes or for as long as 5 hours.  In addition, 
psychological distress could arise following an MDMA session as a result of subjects 
having difficulty integrating their experience after the MDMA effect has subsided.  In 
previous Phase 1 and Phase 2 studies, these symptoms have been modest and self-

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limiting, and have responded well to reassurance from the therapists, with occasional use 
of benzodiazepines for anxiety. In this study, subjects will have the intention of 
confronting and working through traumatic experiences. Hence signs of psychological 
distress, panic or other unpleasant psychological reactions are to be expected and may be 
considered an element of the psychotherapeutic process.  
 
Proper preparation and follow-up support will reduce the difficulties subjects might have 
with acute or sub-acute reactions. The potential for destabilizing psychological distress 
will be minimized by: 
x excluding people who might be more vulnerable to it (such as people diagnosed 
with bipolar affective disorder - 1 or with psychotic disorders) 
x preparatory non-drug psychotherapy sessions before the experimental session 
x creating an atmosphere of trust during the experimental session 
x close monitoring 
x daily contact with subjects for the period of a week after the experimental session 
x providing non-drug integrative psychotherapy sessions   
x Subjects will remain at the study site for the night of each experimental session to 
further reduce psychological distress. Qualified personnel will be available during 
the overnight stay to respond to the needs of the subject. Attendants will be 
instructed to contact the therapists upon request or at the appearance of signs of a 
potential serious adverse event.  
 
During the preparatory sessions, subjects will be made aware of the fact that difficult 
emotions, including grief, rage and fear or panic, may arise during experimental sessions.  
Every effort will be made to help subjects resolve difficult symptoms and to arrive at a 
more comfortable and relaxed state by the conclusion of the experimental session, 
including empathic listening on the part of the therapists and performance of 
diaphragmatic breathing by subjects.  
 
At the end of the 6–8 hour experimental session, if the subject is still severely agitated or 
experiencing any other severe psychological distress, the following measures will be 
taken:  
x 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 of their experiences, and will help them implement the self- 
soothing and stress inoculation techniques presented during the preparatory 
session. If this situation should occur during an integrative therapy session, at 
least one of the therapists will be available to stay with the subject for at least two 
additional hours. 
 
x If a subject remains severely anxious, agitated or in danger of self-harm or 
suicide, or is otherwise psychologically unstable at the end of this two-hour  
stabilization period, the clinical investigator will decide between the following  
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1. A psychiatric nurse, therapeutic assistant or therapist will stay with the 
subject until the time of his or her appointment with 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 benzodiazepine or 
zolpidem as a “rescue medication.”  This medication will be captured 
on the concomitant medications CRF page. Therapists should not 
prescribe an SSRI, SNRI or MAOI in this context. 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 
ICU if necessary. 
 
Subjects hospitalized after a severe panic reaction will be suspended from the protocol 
until after recovery or stabilization, at which time the investigator 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.   
 
7.2.3 Body Temperature 
 
MDMA administered in a controlled setting produces only a slight increase in body 
temperature [68], and ambient temperature does not enhance or attenuate this slight 
elevation in humans.   
 
If temperature rises more than 1° C, attempts will be made to lower it by removing 
blankets and layers of clothing, decreasing the ambient temperature and, if necessary, 
directing a fan toward the participant.  If at any time the temperature rises more than 1.5° 
C above baseline despite these efforts, ice packs will be used, blood will be drawn for stat 
CBC, electrolytes, BUN/creatinine, glucose, CPK, PT, PTT, platelets and liver enzymes, 
and urine will be collected for urinalysis.   
 
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 
[97, 98], as discussed in the Investigator’s Brochure.   
 

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Pregnant and lactating women will be excluded from participation in the study, and 
women who are able to become pregnant must have a negative pregnancy screen before 
undergoing each experimental session and must agree to use birth control for the duration 
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 [99]. 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. We have 
carefully considered the risks of such neurotoxicity and conclude that they are minimal in 
the proposed study. This conclusion is supported by empirical and toxicokinetic evidence 
and is consistent with the lack of toxicity reported in previous clinical MDMA studies. 
More information on the potential neurotoxicity of MDMA can be found in the 
Investigator’s Brochure.  
 
7.2.6 Risk Mitigation 
 
Careful review of medical screening data will be utilized to exclude potential participants 
with preexisting exclusionary medical conditions from the study. Study procedures have 
been developed to mitigate the risks of receiving MDMA described in detail in the 
Investigator’s Brochure. Ambient temperature will be kept at a comfortable level during 
experimental sessions. Subjects will not be allowed to drink more than 3L of fluids over 
the course of the experimental session, and fluid intake will be spread out appropriately 
during the session. Fluids administered will include electrolytes. If a participant exhibits 
any signs of toxicity or clinically significant dilutional hyponatremia despite these 
precautions after the first experimental session, then he or she will not receive a second 
experimental session.  
 

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7.3 Abuse Liability 
Findings in humans and nonhuman animals suggests that MDMA possesses moderate 
abuse potential that is higher than that reported for “classic hallucinogens” like 
psilocybin, but lower than that reported for psychostimulants such as cocaine or 
methamphetamine. More information on abuse liability is provided in the Investigator’s 
Brochure 
 
Whether or not MDMA's abuse potential will negatively affect people with PTSD 
exposed to MDMA when given along with psychotherapy is an open question for which 
there is of yet no direct data. Mithoefer and colleagues are in the process of analyzing 
data from a long-term follow-up of participants in their study of MDMA-assisted 
psychotherapy. Only one of 20 participants took Ecstasy after completing the study and 
failed to reproduce the experience with the therapists, and a number of participants 
volunteered that they would never seek out Ecstasy outside a legal, controlled therapeutic 
setting.  
 
Diversion is not an issue in this protocol because MDMA will only be administered a few 
times under the supervision of the clinical investigator and no take-home doses will be 
permitted.  MDMA will be handled following all regulations pertaining to the handling 
and dispensing of controlled substances within research studies. 
 
8.0 Adverse Events 
8.1 Adverse Events 
An adverse event (AE) is defined as any untoward or unfavorable medical occurrence in 
a clinical research study participant, including any abnormal sign (e.g. abnormal physical 
exam or laboratory finding), symptom, or disease, temporally associated with the 
participants' involvement in the research, whether or not considered related to 
participation in the research. This definition includes concurrent illnesses or injuries and 
exacerbation of pre-existing conditions.  
 
An unexpected adverse event is one that is not listed in the current Investigator’s 
Brochure or an event that is by nature more specific or more severe than a listed event. 
 
All AEs will be monitored by the therapists until resolution or, if the AE becomes 
chronic, a cause identified.  If an AE is unresolved at the conclusion of the protocol, a 
clinical assessment will be made by the investigator and/or Medical Monitor as to 
whether continued follow-up of the AE is warranted. 
 
The severity of events reported on the “Adverse Events” CRF will be determined by the 
investigator as: 
 
· 
Mild: No limitation in normal daily activity 
· 
Moderate: Some limitation in normal daily activity 
· 
Severe: Unable to perform normal daily activity 
 

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The relationship of the study treatment to an AE will be determined by the investigator 
based on the following definitions: 
 
1. Not Related 
 
The AE is not related if exposure to the investigational product has not occurred, or the 
occurrence of the AE is not reasonably related in time, or the AE is considered unlikely 
to be related to use of the investigational product, i.e. there are no facts (evidence) or 
arguments to suggest a causal relationship, or the AE is more likely related to the 
subject’s pre-existing condition. 
 
2. Possibly Related 
 
The administration of the investigational product and AE are considered reasonably  
related in time and the AE could be explained by causes other than exposure to the  
investigational product. 
 
3. Probably Related 
 
Exposure to the investigational product and AE are reasonably related in time and the  
investigational product is more likely than other causes to be responsible for the AE, or is 
the most likely cause of the AE. 
 
The relationship of the study treatment to an AE will be determined by the investigator. 
 
8.2 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. 
 
8.3 Serious Adverse Events 
 
An SAE is defined as any untoward medical occurrence that at any dose: 
 

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x Results in death 
x Is life-threatening (i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event 
which hypothetically might have caused death if it were more severe 
x Requires or prolongs inpatient hospitalization 
x Results in persistent or significant disability/incapacity (i.e., the event causes 
substantial disruption of a person’s ability to conduct normal life functions) 
x Results in a congenital anomaly/birth defect 
x Requires intervention to prevent permanent impairment or damage 
x Is an important and significant medical event that may not be immediately life-
threatening or resulting in death or hospitalization, but based upon appropriate 
medical judgment, may jeopardize the patient/subject or may require intervention 
to prevent one of the other outcomes listed above. 
 
AEs which do not fall into these categories are defined as non-serious.  It should be noted 
that a severe adverse event need not be serious in nature and that a SAE need not, by  
definition, be severe. 
 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the medical history.  The hospitalization would not result in the event or  
condition being reported as a study-related SAE unless, in the view of the investigator,  
hospitalization was prolonged as a result of participation in the clinical trial or was  
necessary due to a worsening of the pre-existing condition.  This is because the onset of 
the event (the reason for the procedure) occurred before the subject was entered in the 
trial.  Hospitalization for cosmetics, non-emergency prophylaxis or abortion does not  
result in an SAE report unless, in the view of the investigator, hospitalization for these 
procedures was prolonged as a result of participation in the clinical trial. 
 
8.4 Medical Emergencies 
 
The sessions will be conducted in a general medical setting where emergency equipment 
will be immediately available, medical staff and experienced nurses will be on hand and 
there will be ready access to specialty medical back up and intensive care beds if 
necessary. Participants will have a means of contacting the clinical investigator if any 
problem occurs. 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 Investigator’s Brochure.  The 
same contingency plans and equipment will be used in this protocol.  In the event of a 
medical emergency, with these personnel and equipment, the therapists will be able to 
stabilize study subjects and then transport them to the emergency department or ICU at 
Beer Yaakov Hospital. In case of need, subjects will be transferred to the emergency 
room at Assaf Harofeh Hospital. Subjects who are transferred will be accompanied by a 
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8.5 Adverse Event Collection 
 
All SAEs will be collected for the duration of the protocol.  All SAEs which occur during 
the course of the trial, whether considered to be associated with the study drug or not, 
have to be reported within 24 hours of the investigator’s awareness of their occurrence.  
All SAE reports should be faxed to the Sponsor.  A fax number will be provided to the 
site in separate site-specific instruction for SAE reporting. In addition to the fax, the 
Clinical Investigator (CI) or designee should call the CRA during normal working hours 
and verbally inform the CRA of the SAE.  During off hours or if medical advice is 
needed immediately please call the Sponsor Medical Monitor.  An SAE reporting 
instruction with all contact numbers will be provided to the site prior to study start.   
 
Medical Monitor  
 
Michael C Mithoefer  
Email: mmithoefer@mac.com  
Telephone:  00-1-843-849-6899 
Fax:  00-1-843-278-9188 
 
Study Monitor contact information will be provided in a separate contact list. 
 
Adverse events that will be collected for the duration of the protocol are: 
 
x All SAEs will be collected through termination. 
x All Adverse Events and spontaneously reported reactions will be collected on the 
day of drug administration and for seven days after each experimental session. 
x Events requiring medical attention will be collected from the first experimental 
session through the subject’s last 2-month follow up. 
x 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. 
x Any Adverse Event leading to withdrawal from the protocol will be collected 
throughout the study. 
x All AEs related to changes in psychiatric status will be collected throughout the 
study. 
 
A Memory aid card will be provided to the subject on the last visit prior to the 12 month 
follow up to record information on medications taken to treat SAEs, AEs leading to 
withdrawal and psychiatric AEs during the period between the end of Stage 1 or end of 
Stage 2 and the 12 month follow-up evaluation. The memory aid card will not be 
collected, but information from the card will be used to aid the subjects in providing 
information to the investigator. This information may be collected by phone. 
 

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9.0 Concomitant Medications and Tapering Instructions 
Concomitant medications will be recorded 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 therapists 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 5 
times the particular drug's half-life).  
 
If a subject is using marijuana at least two months prior to administration of the baseline 
CAPS, the prospective subject will be encouraged to abstain from using marijuana during 
the study, and required to abstain during the period beginning 3 days prior to each 
experimental session as assessed by self-report. Subjects may resume marijuana use on 
the 8th day after each experimental session.. The same period of cessation of use will be 
required from Stage 2 participants. Participants who choose to use marijuana during the 
study will be given a document, “Reminder of Study Rules for Subjects Using 
Marijuana,” as a reminder for when they must refrain from using marijuana and what 
information about their marijuana use will be asked by the clinical study staff. Frequent 
marijuana users may test positive in a urine drug test up to one month after cessation. 
Subjects will be asked to report on their marijuana use (frequency, dose, route, and 
reason for use) at baseline and during the course of the study. Baseline measurements and 
experimental sessions will be conducted despite a positive urine drug test for marijuana.  
 
The therapists will request information about any changes in medication just prior to each 
experimental session. All medications, over the counter (OTC), marijuana, and 
prescription will be collected from screening through 7 days after the last MDMA 
session.  From 7 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.  
 
Subjects may receive a designated rescue medication that may be administered in the 
event of symptoms that require it during or after the experimental session (e.g. insomnia 
or severe anxiety that does not respond to other management outlined in the treatment 
manual). Rescue medications may be benzodiazepines, as lorazapam or zopiclone. 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).  

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b. They will refrain from taking any prescription or nonprescription medications 
(with the exception of non-steroidal anti-inflammatory drugs, acetaminophen, 
birth control pills, thyroid hormones, or other medications approved by the 
research team).  
 
Subjects will receive a memory aid card for use between the 2-month assessment visit 
and the 12-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 after the 2-month assessment if necessary. 
10.0 Clinical Laboratory Assessments 
The clinical investigator or study staff will examine laboratory assessments gathered in 
screening for assessing participant eligibility.  The investigator will use a list of normal 
ranges to conclude whether participants are eligible for the protocol, and will indicate 
justification for admitting participants with abnormal values. 
 
The following laboratory assessments will be performed as a part of screening  
 
Serum electrolytes and the metabolic profile, which includes: 
ALT/SGPT;  
albumin:globulin (A:G) ratio;  
albumin, serum;  
alkaline phosphatase, serum;  
AST/SGOT;  
bilirubin, total;   
BUN:creatinine ratio;  
calcium, serum;  
carbon dioxide;  
chloride, serum;  
creatinine, serum;  
globulin, total;  
glucose, serum;  
potassium, serum;  
protein, total, serum;  
sodium, serum;  
 
CBC, which includes:  
Hematocrit;  
hemoglobin;  
MCV;  
MCH;  
MCHC;  
RDW;  
percentage and absolute differential counts;  

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RBC;  
red cell count;  
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. 
 
In addition, HIV serology will be performed.   
 
A urine-dip pregnancy test for females of childbearing potential will be performed as 
well.  
 
The identity of the laboratory that will perform assessments other than the urine drug 
screen and pregnancy test will be provided on a separate document. 
 
 
The urinary pregnancy tests and drug tests will be performed at the study site.  
 
11.0 Study Monitoring, Auditing and Documentation 
The Clinical Investigator, therapists and their study staff will be trained prior to the start 
of the study.  The study site will be monitored by site visits and telephone calls to the 
investigator by representatives of the Sponsor.  The site will be monitored as appropriate 
for the rate of enrollment in order to comply with GCP guidelines and to ensure validity 
of the study data.  During each monitoring visit, source data verification will be 
performed to ensure compliance, including accurate and complete recording of data on 
CRFs, source documents, and drug accountability records.  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. For detailed monitoring information, 
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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 examine CAPS, PDS, BDI-II, GAF and PSQI scores at baseline and 
two months after the second experimental session at the end of Stage 1 in Active Placebo 
and Full Dose conditions with independent sample t-tests for baseline scores. When 
MDMA and Active Placebo scores are not significantly different at baseline, a second 
independent sample t-test will examine the scores at the end of Stage 1, with p. set at 
0.05. Subsequent independent sample t-tests will be applied to scores where there are 
significant differences in baseline values, with p. set at 0.05.  
 
A repeated measures analysis of variance (ANOVA) will be performed upon PDS scores 
at baseline, after the third integrative session (Visit 7), the sixth integrative session (Visit 
11) and at the end of stage 1, with p. set at 0.05. Condition (active placebo or full dose 
MDMA) will serve as a between-subjects factor. PDS and CAPS scores will be correlated 
at baseline and at the end of Stage 1 to examine the degree to which the two measures 
arrive at similar symptom severity scores.   
 
Formal statistical comparisons between Stage 1 and Stage 2 scores may only occur if all 
three eligible participants enroll in Stage 2. Lead-in subjects will be compared 
statistically to Stage 2 subjects, and data from lead-in subjects will only be utilized if they 
are equivalent to Stage 2 subjects. The sponsor will perform an analysis comparing CAPS 
and BDI-II scores after experimental and open-label sessions for participants in the full 
dose condition and another analysis for participants enrolled in Stage 2. Descriptive 
statistics will be computed for PDS scores for the end of Stage 1, the third and sixth 
integrative sessions of Stage 2 (Visits 17 and 21( and the end of 21. The sponsor will 
examine CAPS, PDS, GAF, BDI-II and PSQI scores 12 months after the final MDMA-
assisted psychotherapy session. If there is enough data available for formal comparisons, 
the Sponsor will use a repeated measures ANOVA with baseline, end of Stage 1 and end 
of Stage 2 scores as repeated measure at p. set at 0.05. 
 
Descriptive statistics will be calculated for all measurements overall and within the two 
dose conditions. Distributional characteristics will be examined for outliers and extreme 
values and, if either is evident, nonparametric statistics will be utilized in the analysis. 
Effect size of Active Placebo and Full Dose MDMA for all outcome measures for Stage 
1, Stage 2, and 12 months after the final experimental session will be estimated using 
Cohen's techniques. 
 
There is no expectation that conditions will differ in composition by gender, race or 
ethnicity, duration of PTSD diagnosis or presence versus absence of other permitted 
psychiatric disorders, as depression. However, owing to small sample size, such 
variations may arise by chance. 
 

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The therapists will record average baseline and post-drug peak blood pressure, heart rate 
and body temperature for participants 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 informally or formally compare 
peak blood pressure, heart rate and body temperature for participants after sessions with 
Active Placebo or Full Dose MDMA. Frequency tables will be produced on prevalence of 
spontaneously reported reactions and AEs. 
 
An interim analysis may be completed when all participants have completed the main 
study, including stage 1 and Stage 2, but not all participants have completed the 12-
month follow-up evaluation. Additionally, an interim analysis may be performed after all 
participants have completed Stage 1 but not necessarily before all eligible participants 
complete Stage 2. This analysis will address both safety and efficacy of the treatment. 
 
12.1 Statistical Power 
 
This is a pilot study, and as such, power analysis was not conducted for the study. The 
study is underpowered for detection of differences of a small or moderate effect size, and 
it may detect differences if the effect size is large.  
 
Analyses of MAPS’ completed US study of MDMA-assisted psychotherapy in 20 people 
with PTSD found an effect size of 1.24 for treatment efficacy, as represented by changes 
in CAPS score [2]. The estimated effect size for this study may be lower as a result of 
comparing the full dose of MDMA with a low dose of MDMA instead of with inactive 
placebo, small sample size and unequal distribution of conditions. The sponsor intends to 
pool data across studies or perform meta-analyses of CAPS scores across all pilot studies.  
 
The sponsor used Java applications created by Lenth and posted on the website listed 
below to calculate estimated statistical power for this study, assuming an effect size of 
0.8 for the impact of two sessions of MDMA-assisted psychotherapy on symptoms of 
PTSD and depression [100], reducing the effect size to account for the hypothesized 
effects of using an active placebo. The software calculated an estimated power of 0.15, 
indicating an underpowered study. Had we used the higher effect size of 1.1, power 
analysis still indicates that this study is underpowered, with an estimated effect size of 
0.25. Without previous data concerning the effects of MDMA-assisted psychotherapy 
upon sleep quality, no power estimates have been made for differences in sleep quality 
between full dose and active placebo participants. 
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.  
 

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The protocol and the proposed informed consent form must be reviewed and approved by 
local regulatory agencies and a properly constituted ethics board before study start. 
Signed and dated documentation that the protocol and informed consent have been 
approved by the ethics board and local agency must be provided to the sponsor. Prior to 
study start, the Clinical Investigator is required to sign a protocol signature page 
confirming his/her 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 therapists are responsible for obtaining informed consent in adherence to GCP and 
according to applicable regulations prior to entering the subject into the trial. Eligible 
subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), ethics board approved informed consent. Informed 
consent must be obtained before conducting any study-specific procedures (i.e. all of the 
procedures described in the protocol). The informed consent should include access to 
original medical records and processing of coded personal information. The informed 
consent discussion must be conducted by a person who is qualified according to 
applicable local regulations. The subject should have the opportunity to inquire about 
details of the MDMA session and to consider participation. 
 
The process of obtaining informed consent should be documented in the subject source 
documents. 
The therapists will provide a copy of the signed ICF to the subject, and will maintain the 
original in the investigator site file (ISF). 
The written ICF and any other written information to be provided to subjects should be 
revised whenever important new information becomes available that may be relevant to 
the subject's consent.  Any revised written informed consent form, and written 
information should receive approval from an ethics board 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 session. The communication of 
this information should be documented.  
 
15.0 Confidentiality 
Every effort will be made to strictly safeguard the confidentiality of subjects in their role 
as research subjects.  Despite this, absolute privacy cannot be guaranteed. Data collected 
from each subject will be identified only by the subject's initials and by a subject number 
on the source documents. All study measures, records, audio and video recordings will be 
kept in a locked file drawer in a locked office. Access to study measures will be limited 
to regulatory agencies, researchers assessing the subject for changes in symptoms, 
Sponsor representatives, and individuals analyzing data. Researchers with access to data 

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will not be provided with any information that would identify subjects by name or by 
other means.  
 
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. Maintaining data in a secure environment will 
prevent the accidental or deliberate examination or removal of data.  
 
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 therapy. They are intended to record the events occurring during therapy, and 
will not serve as outcome measures. Confidentiality of subject names and addresses will 
be maintained in these recordings. Full names and addresses will not appear in these 
recordings. 
16.0 Costs to Participants 
The Sponsor of this study will cover the costs that are directly related to this study. This 
includes the costs for all psychotherapy sessions, for the psychological and laboratory 
testing, for medical examinations, for the study drug and for any rescue medications used 
during the study. The subject, their private medical insurance (if any), and the public 
health insurance plan will not be charged for any procedures done solely for the purpose 
of the study. 
 
The subject or their private insurance remains responsible for ongoing treatment 
unrelated to the study. The Sponsor will not cover medical expenses related to injuries 
which occur during the study period that are not directly related to study procedures. 
17.0 Treatment and Compensation for Study Related Injury 
In the event of a study-related injury, the Sponsor will cover any costs that arise from 
treating the injury. The Sponsor has an insurance policy to cover the subjects' from any 
disabilities resulting from the study procedures.  The subject will be compensated 
according to the level of disability arising from medication or procedures used in the 
study. This insurance coverage protects the Sponsor, the institution and the investigators 
from any legal actions pursued against them.  
 
18.0 Record Retention 
Investigators must retain all study records required by the Sponsor and applicable ICH-
GCP and local regulations in a secure and safe facility. The investigator must consult a  
representative of the Sponsor before disposal of any study records.  “Essential 
documents” are defined as documents that individually and collectively permit evaluation 
of the conduct of a trial and the quality of the data produced. These documents will be 
filed according to ICH-GCP regulations in the ISF. It is the responsibility of the Sponsor 
to inform the investigator/institution as to when these documents no longer need to be 
retained.  
 

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