A Randomized, Double-Blind, Dose Response Phase 2 Pilot Study of Manualized MDMA-Assisted Psychotherapy in Subjects With Chronic, Treatment-Resistant Posttraumatic Stress Disorder (PTSD)
Phase: PHASE2
Conditions: Posttraumatic Stress Disorder
Sponsor: Lykos Therapeutics

 
 
Note to File 
 
Study: MP12 - A Randomized, Double-Blind, Dose Response Phase 2 Pilot Study of Manualized 
MDMA-Assisted Psychotherapy in Subjects with Chronic, Treatment-Resistant Posttraumatic 
Stress Disorder (PTSD) 
 
Site: Study Level 
 
Re: Typographical error on header date of Protocol Amendment 5 Version 1: August 15, 2014 
 
 
The title page of Protocol Amendment 5 Version 1: is dated August 15, 2014, however, the 
header is dated August 19, 2014. The correct date of the Protocol Amendment 5 Version 1: is 
August 15, 2014 
 
 
 
 
 
_____________________________________ 
 
______________________ 
Rebecca Matthews 
 
 
 
 
Date Signed 
Director and Head of Clinical Operations 
  
 

MAPS Study MP-12 
 
Protocol Amendment 5 Version 1 
U.S. 
 
August 19, 2014 
 
 
PROTOCOL MP-12 
IND #63,384 
 
Original Protocol Version 1: February 21, 2012 
Protocol Amendment 1 Version 1: March 26, 2013 
Protocol Amendment 2 Version 1: July 11, 2013 
Protocol Amendment 3 Version 1: October 17, 2013 
Protocol Amendment 4 Version 1: April 27, 2014 
Protocol Amendment 5 Version 1: August 15, 2014 
 
 
A Randomized, Double-Blind, Dose Response Phase 2 Pilot Study of Manualized 
MDMA-Assisted Psychotherapy in Subjects with Chronic, Treatment-Resistant 
Posttraumatic Stress Disorder (PTSD) 
 
 
 
SPONSOR 
Multidisciplinary Association for Psychedelic 
Studies (MAPS) 
1215 Mission Street 
Santa Cruz, CA 95060 
 
SPONSOR DESIGNEE 
Amy Emerson 
Phone number: 510-393-7224 
 
CLINICAL INVESTIGATOR 
Marcela Ot’alora G., M.A., L.P.C. 
1844 Pearl Street 
Boulder, CO 80302 
Phone number: 303-818-1419 
 
MEDICAL MONITOR 
Michael C. Mithoefer, M.D. 
208 Scott Street 
Mount Pleasant, SC 29464 
Phone number: 843-849-6899 
  
STUDY MONITOR 
Ben Shechet 
MAPS 1215 Mission Street 
Santa Cruz, CA 95060 
Phone number: 831-429-6362 ext. 104 
Fax number: 831-429-6370 
 
 
Telephone number for trial related emergencies: 650-248-4647 
 

MAPS Study MP-12 
 
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August 19, 2014 
 
 
 
Table of Contents 
 
1.0 List of Abbreviations ............................................................................................................................... 3 
2.0 Introduction, Background, and Rationale ............................................................................................. 5 
2.1 Introduction ........................................................................................................................................... 5 
2.2 Background ........................................................................................................................................... 6 
2.3 Protocol Purpose ................................................................................................................................. 10 
2.4 Rationale of Dose Selection ................................................................................................................ 11 
3.0 Protocol Objectives ................................................................................................................................ 13 
3.1 Primary Objective ............................................................................................................................... 13 
3.2 Secondary Objectives .......................................................................................................................... 13 
3.3 Safety Objectives................................................................................................................................. 14 
4.0 Protocol Design ....................................................................................................................................... 15 
4.1 Planned Duration of Study and Visit Windows .................................................................................. 20 
4.2 Recruitment and Subject Population ................................................................................................... 20 
5.0 Methods ................................................................................................................................................... 23 
5.1 Measures.............................................................................................................................................. 23 
5.2 Study Procedures, Visit Descriptions, and Adherence ........................................................................ 28 
5.3 Randomization and Subject Numbering ............................................................................................. 42 
5.4 Removal of Subjects from the Study................................................................................................... 42 
5.5 Premature Discontinuation of the Study ............................................................................................. 43 
6.0 Investigational Product.......................................................................................................................... 43 
6.1 Description of Active Compounds ...................................................................................................... 43 
6.2 Preparation and Administration .......................................................................................................... 43 
6.3 Drug Accountability ............................................................................................................................ 46 
6.4 Drug Storage and Handling ................................................................................................................. 47 
6.5 MDMA Stability ................................................................................................................................. 48 
7.0 Risks of Participation............................................................................................................................. 48 
7.1 Risks and Discomforts Associated with Psychotherapy Sessions and Assessment of Measures ....... 48 
7.2 Risks of Receiving MDMA................................................................................................................. 49 
7.3 Abuse Liability .................................................................................................................................... 54 
8.0 Adverse Events ....................................................................................................................................... 54 
8.1 Adverse Events .................................................................................................................................... 54 
8.2 Spontaneously Reported Reactions ..................................................................................................... 56 
8.3 Serious Adverse Events ....................................................................................................................... 56 
8.4 Medical Emergencies .......................................................................................................................... 57 
8.5 Adverse Event Collection.................................................................................................................... 57 
9.0 Concomitant Medications and Tapering Instructions ........................................................................ 58 
10.0 Clinical Laboratory Assessments ....................................................................................................... 61 
11.0 Study Monitoring, Auditing, and Documentation ............................................................................ 62 
12.0 Data Analysis ........................................................................................................................................ 63 
12.1 Statistical Power ................................................................................................................................ 66 
13.0 Ethics ..................................................................................................................................................... 66 
14.0 Informed Consent ................................................................................................................................ 67 
15.0 Confidentiality ...................................................................................................................................... 68 
16.0 Costs to Subjects................................................................................................................................... 69 
17.0 Treatment and Compensation for Study Related Injury ................................................................. 69 
18.0 Record Retention.................................................................................................................................. 69 
19.0 Publication Policy ................................................................................................................................. 69 
20.0 References ............................................................................................................................................. 71 
 
 
 

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1.0 List of Abbreviations 
 
AE(s)  
Adverse Event(s) 
AED  
Automated External Defibrillator 
A:G 
 
Abumin : Globulin ratio 
ALT/SGPT 
Alanine aminotransferase 
AMI   
Acute Myocardial Infarction 
AST/SGOT 
Aspartate aminotransferase 
BDI-II  
Beck Depression Inventory II 
BP 
 
Blood Pressure 
BT 
 
Body Temperature 
BUN  
Blood Urea Nitrogen 
C 
 
Celsius 
CAPS  
Clinician Administered PTSD Scale 
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 
DBP 
 
Diastolic Blood Pressure 
DEA  
Drug Enforcement Administration 
DES-II  
Dissociative Experiences Scale II 
DMF  
Drug Master File 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders - IV 
ECG/EKG 
Electrocardiogram 
ED 
 
Emergency Department 
EMDR  
Eye Movement Desensitization and Reprocessing 
EMS  
 
Emergency Medical Services 
F 
 
     Fahrenheit 
FDA  
Food and Drug Administration  
GAF   
Global Assessment of Functioning 
GCP 
 
Good Clinical Practice 
HCl 
 
Hydrochloride 
HIPAA  
Health Insurance Portability and Accountability Act 
HIV 
 
Human Immunodeficiency Virus  
HPLC  
High Performance Liquid Chromatography 
IB 
 
Investigator’s Brochure 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
IND 
 
Investigational New Drug  
IR 
 
IR 
IRB 
 
Institutional Review Board 
ISF 
 
Investigator Site File 
IV 
 
intra-venous 
MAOI  
Monoamine oxidase inhibitor 
MAPS  
Multidisciplinary Association for Psychedelic Studies 

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MCH  
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV   
Mean Corpuscular Volume  
MDMA 
3,4-methylenedioxymethamphetamine 
MP-1  
MAPS’ first clinical trial of MDMA-assisted psychotherapy for PTSD 
MP-2  
MAPS’ second clinical trial of MDMA-assisted psychotherapy for PTSD 
PASAT  
Paced Auditory Serial Addition Test 
PDS 
 
Posttraumatic Diagnostic Scale 
PI 
 
Principal Clinical Investigator 
PRN 
 
As needed 
PSQI  
Pittsburgh Sleep Quality Index 
PTCA   
Percutaneous Transluminal Coronary Angioplasty 
PTGI  
Posttraumatic Growth Inventory 
PTSD  
Posttraumatic Stress Disorder 
PTT 
 
Partial Thromboplastin Time 
RBANS  
Repeatable Battery for the Assessment of Neuropsychological Status  
RBC  
Red Blood Cell Count 
RDW  
Red Cell Distribution Width 
RRPQ  
Reactions to Research Participation Questionnaire 
SAE(s) 
Serious Adverse Event(s) 
SBP 
 
Systolic Blood Pressure 
SCID-I-RV 
Structured Clinical Interview for Diagnoses Axis I Research Version 
SERT   
Serotonin Transporter 
SL 
 
Sublingual 
SNRI  
Selective Serotonin and Norepinephrine Uptake Inhibitor 
SOCQ  
States of Consciousness Questionnaire  
SOP(s)  
Standard Operating Procedure(s) 
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 
 
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit 
research and educational organization working to obtain approval as a clinical trial 
sponsor for the prescription use of 3,4-methylenedioxymethamphetamine (MDMA)-
assisted psychotherapy in patients with chronic posttraumatic stress disorder (PTSD). 
This study is a part of a global series of Phase 2 pilot clinical trials designed to evaluate 
the safety and efficacy of MDMA-assisted psychotherapy in treating chronic, treatment-
resistant PTSD, as preparation for Phase 3 studies and possible use as an approved 
prescription medication.  
 
MAPS has published results showing clinically and statistically significant improvements 
in PTSD severity from 20 subjects treated in their first pilot study (MP-1) in the United 
States (U.S.) [1]. Findings from the long-term follow-up of MP-1 subjects suggest that 
therapeutic benefits were sustained over an average of 41 months post-treatment [2]. The 
sponsor’s second Phase 2 pilot study conducted in Switzerland (MP-2) in 12 subjects 
suggests clinically significant improvements in PTSD symptoms with a trend toward 
statistical significance [3]. Long-term follow-up data 12 months later suggest that 
therapeutic benefits continued to increase in this subject population. Ongoing and 
planned Phase 2 studies, along with the study described in this protocol, are laying the 
groundwork for an eventual End-of-Phase 2 meeting with FDA and possible Phase 3 
multi-site MDMA/PTSD research studies.  
 
This Phase 2 pilot study will examine the safety and efficacy of manualized MDMA-
assisted psychotherapy in 23 subjects with chronic, treatment-resistant PTSD of at least 
six months duration who were unable to achieve remission despite having received prior 
treatment with either pharmacotherapy or psychotherapy of adequate dose/duration or 
who discontinued treatment due to lack of tolerability.  Two active doses of MDMA and a 
comparator dose will be assessed in Stage 1, as will the benefit of three versus two active 
dose sessions. Subjects who received the comparator dose during Stage 1 will have the 
opportunity to cross over and take part in a second study segment, referred to as Stage 2, 
with three open-label experimental sessions. Stage 2 will be used to explore the optimal 
therapeutic dose of MDMA using a clinical titration dosing strategy. Two types of co-
therapist teams will conduct the study. Each team will have an experienced therapist with 
a background consistent with that required in the treatment manual paired with either 
another experienced therapist or an “intern” co-therapist that is either pre-licensure, is 
licensed but with less experience, has a different therapy background than indicated in the 
manual, or practices a different healing profession (physician, nurse, social worker). 
 
This study is designed to obtain estimates of effect size for safety and efficacy. The data 
will be combined with ongoing Phase 2 dose response studies in a meta-analysis. 
Cognitive function will also be assessed at baseline, one month after the second 
experimental session and two months after the third experimental session with active 

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dose MDMA. This study is also intended to continue the development of a manualized 
psychotherapeutic approach to this potential treatment. 
 
2.2 Background 
 
2.2.1 PTSD 
 
PTSD is a debilitating psychiatric disorder arising after a traumatic life event. PTSD 
severely reduces quality of life and may directly or indirectly lead to or exacerbate other 
psychiatric and medical problems. A complex biopsychosocial condition, PTSD is 
characterized by a combination of three types of symptoms: hyperarousal symptoms such 
as hypervigilance, anxiety and sleep disturbance, intrusive re-experiencing of traumatic 
experiences, such as intrusive memories, nightmares or flashbacks, and avoidance 
symptoms, including emotional numbing and withdrawal [4, 5]. The DSM-IV 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.   
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.  
 
The lifetime prevalence of PTSD in the U.S. general population is between 6% and 10% 
[6-10], but it is common in other countries as well [7, 11-14]. According to some 
estimates, PTSD appears to be less prevalent in the general population of Europe at 1.9% 
[15]. In U.S. soldiers returning from combat in the Iraq war, the incidence of PTSD is as 
high as 18% [16], and it is estimated that the number of service members returning home 
with PTSD will ultimately be between 75,000 and 225,000 [17]. In countries with 
endemic armed conflict, the incidence of PTSD in civilians is often far greater [18-20].  
 
PTSD is clearly a serious public health problem and contributes substantially to 
healthcare costs [5, 8, 9]. PTSD is typically a chronic illness [6, 21] associated with high 
rates of psychiatric and medical comorbidity, disability, suffering, and suicide [7-10, 22]. 
People suffering from PTSD face challenges in relationships and work productivity [23]. 
Despite the sheer number of individuals suffering from PTSD and its devastating effects, 
questions remain concerning the best possible treatments [24]. Two selective serotonin 
reuptake inhibitors (SSRI), sertraline and paroxetine, which are known to affect the 
serotonergic components of PTSD, are currently marketed as PTSD medications in the 
U.S. [25, 26]. In addition, SSRIs must be used every day in order to be effective for 
PTSD symptoms [27], and are associated with a high rate of discontinuation due to lack 
of tolerability caused by treatment-emergent side effects that may be under-reported [28, 
29]. 
  

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A wider array of effective treatments are needed for PTSD. At least a third of PTSD 
patients fail to respond to established PTSD psychotherapies or do not respond in a 
clinically significant manner [30-32]. 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 [33].  Forty to 60% of PTSD patients were found to be 
resistant to treatment in this study. In a comparison of two types of psychotherapy for 
women with PTSD after sexual assault in 2002, 47% of each treatment group still 
satisfied diagnostic criteria for PTSD based on high Clinician Administered PTSD Scale 
(CAPS) scores, and this was considered highly efficacious [34]. At least one study of 
paroxetine indicated that men with PTSD did not respond to this drug [25], and another 
randomized, double-blind study found no difference between sertraline and placebo in the 
treatment of PTSD [35]. These findings suggest that there is still a substantial need for 
innovative treatments for PTSD. 
 
Another treatment approach is to develop drugs and/or psychotherapeutic treatments that 
may indirectly decrease or eliminate the neurochemical pathologies underlying the 
chronic hyperarousal associated with PTSD. Cognitive behavioral therapies, particularly 
prolonged exposure and cognitive processing therapy, are considered among the most 
effective psychotherapies. Other methods such as psychodynamic therapy and eye 
movement desensitization and reprocessing (EMDR) have also proven to be effective in 
treating some symptoms of PTSD [28], although some patients may need more than one 
type of 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]. 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 [36] for a review).  Examples of this are virtual reality-assisted exposure 
therapy [37, 38] and D-cycloserine-assisted psychotherapy [39]. MDMA-assisted 
psychotherapy is another such approach. 
 
2.2.2 MDMA 
 
MDMA is a ring-substituted phenylisopropylamine derivative invented by the Merck 
pharmaceutical company in 1912 [40, 41]. MDMA is a monoamine releaser that has its 
greatest effects on serotonin, followed by norepinephrine and dopamine [42-48]. MDMA 
is capable of inducing unique psychopharmacological effects, including: 
 
• Decreased feelings of fear. 
• Increased feelings of wellbeing. 
• Increased sociability and extroversion. 
• Increased interpersonal trust. 
• Alert state of consciousness. 
 
Early observers noted increased acceptance of self and others, increased tolerance of 
emotionally upsetting materials and the ability to address these issues without extreme 
disorientation or ego loss [49-52]. In the U.S., MDMA was used as an adjunct to 

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psychotherapy by a considerable number of psychiatrists and other therapists in the 
treatment of neuroses, relationship problems, and PTSD [49, 50, 53, 54] before it was 
placed in Schedule I in 1985 as a result of extensive non-medical use [52, 55, 56]. 
Placement in Schedule I prohibited it for use except in a federally approved research 
setting.  
 
In contrast to daily administrations of SSRIs, MDMA-assisted psychotherapy consists of 
several drug-assisted sessions interspersed with a moderate course of non-drug 
psychotherapy. Thus the effects of MDMA are distinct from and go well beyond those of 
anti-anxiety drugs such as benzodiazepines. Furthermore, there is no evidence that 
MDMA creates a physical dependency, as benzodiazepines do. Previous studies of 
polydrug users found a small percentage of people exhibit problematic use of ecstasy, 
(material represented as containing MDMA) [57, 58]. Studies of regular or problematic 
ecstasy users indicate that on average, regular use occurs no more often than once a week 
[59]. Hence, MDMA may have moderate abuse potential. See the Investigator’s Brochure 
(IB) for a more detailed explanation. 
 
2.2.3 Previous Clinical Experience with MDMA 
 
Classification as a Schedule I drug hampered research into the medical uses of MDMA. 
In recent years, clinical investigation of the safety and effectiveness of MDMA-assisted 
psychotherapy has become more feasible due to an open IND with the FDA [60-62]. 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 [63]. However, these 
increases were found to be transient and generally tolerable in a controlled clinical setting 
[63]. Subsequent trials confirmed that MDMA produced significant increases in heart rate 
and blood pressure that were likely to be well tolerated by healthy individuals [63-69]. 
The noted elevation in body temperature was not clinically significant [1].   
 
The potentially therapeutic effects of MDMA were initially investigated starting in 2000 
in a MAPS-sponsored dose response pilot study in Spain in women survivors of sexual 
assault with treatment-resistant PTSD [70, 71]. Unfortunately, the study in Spain was 
halted in 2002 due to political pressure from the Madrid Anti-Drug Authority. Prior to its 
suspension, six women were enrolled and treated in this study without any adverse events 
(AEs) or signs of deteriorating mental health, and with some mild signs of improvement, 
with single doses ranging from 50 mg to 75 mg [71].  
 
MAPS went on to sponsor the first U.S. Phase 2 study of MDMA-assisted psychotherapy 
for the treatment of chronic, treatment resistant PTSD, designated as MP-1. This study 
employed the CAPS as a primary outcome measure, with PTSD symptoms measured by a 
blinded Independent Rater (IR) at baseline, three to five days after each experimental 
session, and two months after the final experimental session. Data from this randomized, 
placebo-controlled pilot study suggests that MDMA is associated with significantly 
greater improvement in PTSD than placebo (N=20)[1]. Findings from the long-term 
follow-up evaluating these subjects at an average of 41 months post-treatment suggests 

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that the therapeutic benefits have been sustained over time on average, although two 
subjects experienced a relapse in PTSD symptoms [2]. The sponsor also supported a 
randomized, double-blind pilot study in 12 subjects with chronic, treatment-resistant 
PTSD in Switzerland with three experimental sessions. The study results suggested a 
trend toward significant improvement in subjects receiving full dose MDMA, when 
compared to 25 mg active placebo MDMA at two-month follow-up. The improvement 
continued to increase during the 12-month follow-up [3]. In addition, the sponsor 
supported an initial pilot study with two experimental sessions comparing full dose to 25 
mg active placebo MDMA in Israel that enrolled five subjects, with no drug-related 
Serious Adverse Events (SAEs). Subjects reported benefits that were not reflected in 
CAPS scores, leading to termination of the study for additional training of the Israeli 
therapists and research team. Most recently, in the U.S., MAPS has commenced a follow-
up to its initial U.S. trial with a PTSD relapse study, along with a second Phase 2 trial, 
specifically treating U.S. military veterans.  
 
As of March 2014, MDMA has been administered to more than 960 research subjects, in 
both Phase 1 and Phase 2 studies, without any occurrences of unexpected drug-related 
SAEs [1, 3, 47, 68, 72-95].  
 
2.2.4 MDMA-assisted Psychotherapy for PTSD 
 
In the context of psychotherapy, MDMA has been noted to reduce defenses and fear of 
emotional injury while enhancing communication and capacity for introspection [55]. 
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 [67, 72-74, 79, 96, 97].  
 
Treatment goals of MDMA-assisted psychotherapy for PTSD include alleviating 
symptoms, interrupting and counteracting the stress-induced neurobiological 
abnormalities that may be associated with the condition. In fact, the biologic and 
psychotherapeutic approaches overlap and reinforce each other. Knowledge about the 
connections between the neurobiological and therapeutic effects of MDMA is far from 
complete, but it has been observed that MDMA acutely decreases activity in the left 
amygdala [96], and attenuates amygdalar response to angry faces [73]. 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 [98-100]. The reduction in stress-induced activation of the amygdala 
may be supported and enhanced by interacting with the therapists during and after the 
MDMA experience. 
 
Oxytocin is a neurohormone associated with pair bonding and social affiliation in 
mammals [101]. Oxytocin administration is associated with increased interpersonal trust 
and attenuated reactivity to threatening faces [102, 103], and some researchers have 
suggested a role for oxytocin in treating PTSD [104]. MDMA has been shown to elevate 

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serum oxytocin in humans [67, 105]. Brain imaging after MDMA indicates less reactivity 
to angry facial expressions and greater reward in happy faces [73]. The effects of MDMA 
on oxytocin may increase empathy or compassion for self and others and decrease 
defensiveness. Findings from a recent imaging study suggests that MDMA can make 
recall of negative memories more tolerable [74] , and other studies report increased 
interpersonal or social focus reflected in language use and a greater readiness to see 
others as empathetic and caring [97, 106, 107] . These factors taken together can provide 
the opportunity for a corrective emotional experience [49].  
 
A combined treatment of MDMA and psychotherapy may be especially useful for 
treating PTSD because MDMA can attenuate the fear response of a perceived threat to 
one’s emotional integrity and decrease defensiveness without blocking access to 
memories or preventing a deep and genuine experience of emotion [1, 50, 52, 71]. 
Elimination of these conditioned fear responses can lead to more open and comfortable 
communication about past traumatic events and greater access to information about them 
[49]. Subjects are able to experience and express fear, anger, and grief with less 
likelihood of feeling overwhelmed by these emotions. MDMA seems to engender internal 
awareness that even painful feelings that arise are an important part of the therapeutic 
process. In addition, feelings of empathy, love, and deep appreciation often emerge, along 
with a clearer perspective of the trauma as a past event, a more accurate perspective about 
its significance and a heightened awareness of the support and safety that exists in the 
present. As a result MDMA-assisted psychotherapy may enable the subjects to restructure 
their intrapsychic realities and develop a wider behavioral and emotional repertoire with 
which to respond to anxiogenic stimuli.  
 
A comprehensive review of MDMA research is included in the IB supplied by the 
Sponsor. This document should be reviewed prior to initiating the protocol. 
 
2.3 Protocol Purpose 
 
This Phase 2 pilot study is a randomized, double-blind, dose response study in 23 
subjects comparing the effects of two active doses and a comparator dose of MDMA as 
an adjunct to manualized psychotherapy. In Stage 1 the study will assess two different 
active doses (100 mg and 125 mg) and one comparator dose (40 mg) of MDMA, an 
optional supplemental dose that is half of the assigned dose may be offered to all subjects 
1.5 to 2.5 hours after the initial dose.  Nine subjects will be randomized to active dose 
group 1, nine subjects to active dose group 2, and five subjects will be randomized to 
receive the comparator dose. Stage 1 of the study will consist of two blinded 
experimental sessions and one open-label experimental session of manualized MDMA-
assisted psychotherapy, each lasting six to eight hours and scheduled three to five weeks 
apart, within a moderate course of non-drug psychotherapy.  
 
The study will be unblinded one month after the second experimental session in Stage 1, 
after completion of outcome measures, which constitutes the primary endpoint 
assessment. After unblinding, subjects who received active dose 1 (125 mg MDMA with 
optional supplemental half dose) during the first two sessions will receive the same active 

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dose during the open-label third experimental session. Subjects who received active dose 
2 (100 mg MDMA with optional supplemental half dose) during the first two sessions 
will be able to choose, in consultation with the therapist, to either continue to receive 
active dose 2 during the third session or to increase their dose to active dose 1. The 
benefit of three versus two active dose sessions will be assessed.  
 
Subjects who received the comparator dose during Stage 1 will have the opportunity to 
cross over to Stage 2 with three open-label experimental sessions at equivalent time 
points to Stage 1. Stage 2 will be used to explore the optimal therapeutic dose of MDMA 
using a clinical titration dosing strategy.  The active dose 2 will be administered during 
the first experimental session and the therapists will choose one of the two active doses of 
MDMA for the second and third experimental sessions, with an optional supplemental 
half-dose.  
 
A blinded IR will assess the severity of PTSD symptoms at baseline, at the primary 
endpoint one month after the second experimental session, two months after the third 
open-label experimental session and at equivalent points in Stage 2. Cognitive function 
will be assessed at baseline, one month after the second experimental session and at two-
month follow-up. All subjects will complete a long-term follow-up visit 12 months after 
their final experimental session in either Stage 1 or Stage 2. This study will provide an 
estimate of effect size based on dose response of PTSD symptoms to MDMA-assisted 
psychotherapy.  
 
Two types of therapy teams will conduct psychotherapy visits according to the treatment 
manual [108]. Subjects will either be treated by teams consisting of two experienced co-
therapists or teams consisting of an intern therapist paired with an experienced co-
therapist. Information will be collected regarding consistency and response between the 
teams by reviewing adherence criteria in blinded videos of therapy sessions. This study 
will also continue the refinement of the treatment manual. 
 
2.4 Rationale of Dose Selection 
 
This study will compare the effects of psychotherapy sessions assisted by either one of 
two active doses of MDMA or a comparator dose.  The active dose 1 will be 125 mg 
MDMA followed 1.5 to 2.5 hours later by an optional supplemental dose of 62.5 mg 
MDMA.  The active dose 2 will be 100 mg MDMA followed 1.5 to 2.5 hours later by an 
optional supplemental dose of 50 mg MDMA. The comparator dose will be 40 mg 
MDMA followed 1.5 to 2.5 hours later by an optional supplemental dose of 20 mg 
MDMA. Eighteen of 23 subjects, or 78%, will be assigned to one of the active dose 
conditions, and five of 23, or 22%, will be assigned to the comparator dose condition.  
The active dose 1 is equal to the full dose in other MAPS-supported MDMA/PTSD 
studies. 
 
Subjects in the comparator dose condition during Stage 1 will have the opportunity to 
cross over to Stage 2. Stage 2 will be used to explore the optimal therapeutic dose using a 
clinical titration dosing strategy in the second and third Stage 2 sessions allowing for a 

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choice between two different active doses of MDMA. In Stage 2 subjects will receive an 
initial dose of 100 mg followed 1.5 to 2.5 hours later by an optional supplemental dose of 
50 mg MDMA during the first experimental session. In the second and third session they 
will receive an initial dose of 100 mg or 125 mg MDMA followed 1.5 to 2.5 hours later 
by an optional supplemental dose of 50 mg or 62.5 mg, respectively. The decision to 
titrate the dose in the second and third session will be based on the experience of the first 
session. If 100 mg MDMA does not seem to be the optimal therapeutic dose based on the 
first experimental session in Stage 2, the dosage may be increased by an increment of 25 
mg in order to achieve the optimal therapeutic dose. The supplemental doses for each 
experimental session will be half of the initial dose, respectively. The same choice will be 
provided to Active Dose 2 subjects continuing on to receive a third experimental session 
in Stage 1 in an open label context. 
 
Table 1. Dose Regimen 
 
Dose 
Initial 
Dose 
Optional 
Supplemental 
Dose 
Min-Max 
Cumulative 
Dose 
Min-Max 
Cumulative Dose 
with Titration 
Active Dose 1  
125 mg 
62.5 mg 
125-187.5 mg 
N/A 
Active Dose 2  
100 mg 
50 mg 
100-150 mg 
N/A 
Active Dose 2 
100 mg 
50 mg 
100-150 mg 
N/A 
+ Optional 
Titration Dose 
25 mg 
12.5 mg 
N/A 
125-187.5 mg 
Comparator Dose 
40 mg 
20 mg 
40-60 mg 
N/A 
 
The active dose 1 of MDMA to be used in this study is identical to the full dose used in 
previous studies in the U.S., Switzerland, and Israel. Previous researchers have also used 
doses within this range [63, 64, 66, 68, 109-114]. Prior to the scheduling of MDMA, 
similar doses and regimens were used in psychotherapy [50, 52, 55]. The initial active 
doses are expected to produce all the commonly reported effects of MDMA, including 
changes in affect, mood, and cognition and changes in feelings of interpersonal closeness 
and trust. The supplemental dose will prolong subjective drug effects without producing 
physiological effects any greater than peak effects occurring after the initial dose.  
 
The doses to be compared in this study have been chosen on the basis of the Sponsor’s 
ongoing initiative to develop a dose response curve of MDMA-assisted psychotherapy in 
the treatment of PTSD. They are very similar to doses used in Phase 1 studies [64, 69]. 
This dose is expected to produce increases in positive mood and tension, in combination 
with a lower degree of therapeutic effects than the active doses.  
 
The 100 mg MDMA initial dose will be administered in the first experimental session in 
Stage 2. Prior to both the second and third experimental sessions in Stage 2 the co-
therapists, in consultation with the subject, will decide whether the same dose or an initial 
dose of 125 mg (each with the corresponding optional supplemental dose) would be more 
likely to constitute the optimal therapeutic dose for each of these experimental sessions. 

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During the third experimental session in Stage 1, subjects who receive the 100 mg 
MDMA initial dose will also have this consultation.  
 
3.0 Protocol Objectives 
 
The overall objective of this study is to compare effects of each of the active doses and 
the comparator dose of MDMA, used in conjunction with manualized psychotherapy, on 
reduction or attenuation of PTSD symptoms as evaluated by standard clinical measures 
and to collect safety data. 
 
3.1 Primary Objective 
 
• Assess changes in PTSD symptoms in each active dose group and the comparator 
dose group, as measured by last-month Global CAPS scores at baseline and the 
primary endpoint, one month after the second experimental session. 
 
3.2 Secondary Objectives 
 
The following objectives will compare each active dose group and the comparator dose 
group in Stage 1: 
 
• Assess changes in self-reported PTSD symptoms as measured with the PTSD 
Diagnostic Scale (PDS) at baseline, after each experimental session and/or the 
primary endpoint. 
• Assess depression symptoms with the Beck Depression Inventory-II (BDI-II) at 
baseline and the primary endpoint. 
• Assess global functioning with the Global Assessment of Functionality (GAF) at 
baseline and the primary endpoint. 
• Assess self-reported sleep quality with the Pittsburgh Sleep Quality Index (PSQI) 
at baseline and the primary endpoint. 
• Assess self-reported dissociation symptoms with the Dissociative Experiences 
Scale II (DES-II) at baseline and the primary endpoint. 
• Assess self-reported posttraumatic growth with the Posttraumatic Growth 
Inventory (PTGI) at baseline and the primary endpoint. 
 
The following objectives will compare effects in specified subjects: 
 
• Assess PTSD symptoms via CAPS and PDS, depression symptoms via BDI-II, 
global functioning via GAF, sleep quality via PSQI, posttraumatic growth via 
PTGI, and dissociation symptoms via the DES-II, throughout Stage 2 in 
comparison to Stage 1 in crossover subjects. 
• Assess long-term effects of MDMA-assisted psychotherapy on symptoms of 
PTSD, depression, and global function, sleep quality, dissociation symptoms via 
CAPS and PDS, BDI-II, GAF, PSQI, PTGI (in reference to start of the study), and 
DES-II one year after the final experimental session for each subject. 
 

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The following objectives will include exploratory analyses intended to inform protocol 
design: 
 
• Explore the effects of each experimental session upon self-reported changes in 
consciousness, as those associated with a transformational or mystical experience 
via the States of Consciousness Questionnaire (SOCQ). 
• Assess the effect of the third experimental session for active dose subjects in 
Stage 1 and Stage 2 using CAPS, PDS, BDI-II, GAF, PSQI, PTGI (in reference to 
start of the study), and DES-II.  
• Assess the ability of the investigators and subjects to accurately guess condition 
assignment in Stage 1. 
• Correlate adherence to the treatment manual with Global CAPS scores using 
adherence criteria ratings to assess videos of psychotherapy sessions. 
 
3.3 Safety Objectives 
 
The safety objectives of the study are to monitor and assure safety of subjects during and 
after the experimental sessions by assessing physiological effects, psychological distress, 
adverse events, spontaneously reported reactions and suicidality.   
 
• Suicidality will be assessed with the Columbia Suicide Severity Rating Scale (C-
SSRS) during some visits prior to experimental sessions, twice during 
experimental sessions, and several times after each experimental session, with 
comparisons made between subjects in each condition. 
• Assess cognitive function with the Paced Auditory Serial Addition Test (PASAT) 
and the Repeatable Battery for the Assessment of Neuropsychological Status 
(RBANS) at baseline and the primary endpoint by condition, and end of Stage 
1/end of Stage 2 for maximal exposure. 
• Subjective Units of Distress (SUD) and vital signs including blood pressure, heart 
rate, and temperature will be measured during each experimental session, and 
vital signs will be compared between subjects in each condition. 
• Collect changes to pre-existing tinnitus and/or chronic pain symptoms using a 
visual analog scale, specifically in subjects with a medical history of tinnitus 
and/or chronic pain.  
• Serious adverse events, adverse events, and spontaneously reported reactions will 
be collected during the study, as described in Section 8.5. 
 

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4.0 Protocol Design 
 
This randomized, double-blind, dose response pilot study that will examine the safety and 
efficacy of MDMA-assisted psychotherapy in subjects diagnosed with chronic, treatment-
resistant PTSD of at least six months duration. Stage 1 will include two blinded and one 
open-label MDMA-assisted psychotherapy session scheduled approximately one month 
apart with a male/female co-therapist team. There will also be a moderate course of 
preparatory and integrative psychotherapy sessions as described in the Time and Events 
Table. 
 
There will be two types of male/female co-therapy teams treating subjects, one type will 
have two experienced psychotherapists and the other type will have one of the 
experienced psychotherapist paired with an intern therapist. An “intern” co-therapist is 
defined as a therapist who is either pre-licensure, licensed but with less experience, has a 
different therapy background than indicated in the manual, or practices a different healing 
profession (physician, nurse, social worker). Each subject will be treated by the same co-
therapist team in psychotherapy sessions throughout the study. 
 
Upon enrollment, subjects will be randomly assigned to receive either active dose 1 (nine 
subjects), active dose 2 of MDMA (nine subjects), or comparator dose (five subjects). In 
Stage 1, subjects will meet with their therapist team for three preparatory sessions and 
two blinded experimental psychotherapy sessions of MDMA-assisted psychotherapy. 
After each experimental session, subjects will stay overnight at the site and complete an 
integrative psychotherapy session the next day, followed by daily telephone calls for the 
next seven days and two additional integrative sessions. One month after the second 
experimental session, the primary endpoint assessment will take place, after which the 
blind will be broken. Subjects who receive one of the active doses will receive a third 
open-label experimental session with similar procedures. Subjects who receive the active 
dose 2 during the first two experimental sessions will be given the option to increase their 
dose in the third experimental session to match the active dose 1 condition. Subjects who 
receive the comparator dose will be offered the option to continue to the open-label Stage 
2 unless they meet any exclusion criteria for study participation. Stage 2 will be used to 
explore the optimal therapeutic dose of MDMA using a clinical titration dosing strategy. 
After a single preparatory session, active dose 2 will be administered at the first session 
and the therapists will choose one of the two active doses of MDMA for the second and 
third experimental sessions, with an optional supplemental half dose at each of three 
experimental sessions at time points equivalent to those in Stage 1 (See Time and Events 
Table). 
 
A blinded IR will administer outcome measures. The IR will assess PTSD symptoms 
with the CAPS, quality of life with the GAF, symptoms of depression with the BDI-II, 
sleep quality with the PSQI, posttraumatic growth with the PTGI (in reference to the start 
of the study), and dissociation with the DES-II. The subjects will complete the PDS, a 
self-report measure of their PTSD symptoms, to provide correlations with measures 
administered by the IR. A blinded IR will also assess cognitive function with the Paced 
Auditory Serial Addition Test (PASAT) and the Repeatable Battery for the Assessment 

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of Neuropsychological Status (RBANS) at baseline and the primary endpoint by 
condition, and end of Stage 1/end of Stage 2 for maximal exposure. 
 
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 complete a 
follow-up occurring two months after their last experimental session in Stage 1 and Stage 
2, if applicable. 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 (see Time and Events Table). 
 
The Sponsor will conduct an ongoing review of videotapes of psychotherapy sessions, 
entry criteria, vital signs, and reaction data for completed sessions and any AEs. The 
sponsor will provide ongoing feedback to the co-therapist teams to ensure proper 
therapist training, subject safety, and to ensure standardization of therapy techniques in 
the Sponsor’s ongoing effort to manualize MDMA-assisted psychotherapy. 
 

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A = First Integrative session is one day after experimental session; B = At least 24 hours prior to experimental session; C = Approximately six hours post MDMA; D = At the beginning of the session; E = As needed; F  = 
Approximately every 60 minutes; G = Given on 2nd preparatory session after washout; H = Only for subjects starting long-term follow-up; I = All visits and Day 2 and Day 7 phone calls only; J = Reactions collected for 
seven days post experimental session; K = On the day of the first integrative session following the experimental session; L = One month after the second experimental session but before the third experimental session; M = 
On the day of the third integrative session; N = Active dose subjects only; O = Only on Visit 1; P = Only in subjects with pre-existing tinnitus and/or chronic pain. 
Table 2. Time & Events Stage 1 
Screen/ 
Baseline 
Preparatory 
Sessions 
Experimental 
Session 1 
Experimental 
Session 2 
Primary 
Endpoint 
Experimental 
Session 3 
End of 
Stage 1 
Visit # 
Prior to 
enrollment 
V1,2,3 
V4 
V5,6,7 
V8 
V9,10,11 
V12 
V13 N 
V14,15,16 N 
V17N 
Type of Visit 
Screening 
Preparatory Experimental 
Integrative 
Experimental 
Integrative 
Outcome  
Experimental 
Integrative 
Outcome 
Visit Timing 
Over 2 mo. 
prior to V1 
Appr.1 week 
apart 
3-5 weeks 
post baseline 
Between 
V4 and V8  
3-5 weeks 
post V4 
Between 
V8 and V12  
1 month 
post V8 
After V12 
Between 
V13 and V17 
2 months 
post V13 
Initial Phone Screen 
✓ 
 
 
 
 
 
 
 
 
 
Informed Consent 
✓ 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric History  
✓ 
 
 
 
 
 
 
 
 
 
General Physical Exam, ECG 
✓ 
 
 
 
 
 
 
 
 
 
Brief Neurological Exam 
✓ 
 
 
 
 
 
 
 
 
 
SCID  
✓ 
 
 
 
 
 
 
 
 
 
Clinical Lab Tests, w/ HIV test 
✓ 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Medication Taper (if applicable) 
 
✓ 
 
 
 
 
 
 
 
 
Study Enrollment if eligible 
 
✓O 
 
 
 
 
 
 
 
 
Record to Audio/Video 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
 
General Well-Being 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Drug Screen 
✓ 
 
✓ 
 
✓ 
 
 
✓ 
 
 
Pregnancy Screen (if applicable) 
✓ 
 
✓ 
 
✓ 
 
 
✓ 
 
 
Obtain container assignment 
 
 
✓B 
 
✓B 
 
 
 
 
 
CAPS, GAF, BDI-II, PSQI, PTGI, DES-II 
✓ 
 
 
 
 
 
✓L 
 
 
✓ 
RBANS/PASAT 
✓ 
 
 
 
 
 
✓ 
 
 
✓ 
PDS  
✓ 
 
 
✓M 
 
 
✓ 
 
✓M 
✓ 
C-SSRS 
✓ 
✓G 
✓C,D,E 
✓I 
✓C,D,E 
✓I 
✓ 
✓C,D,E 
✓I 
✓ 
Administer Drug + Therapy 
 
 
✓ 
 
✓ 
 
 
✓ 
 
 
Monitoring of BP, Pulse, and Temp.  
 
 
✓ 
 
✓ 
 
 
✓ 
 
 
SUD 
 
 
✓E,F 
 
✓E,F 
 
 
✓E,F 
 
 
Belief of Condition Assignment 
 
 
 
✓K 
 
✓K 
 
 
 
 
Overnight Stay, SOCQ 
 
 
✓ 
 
✓ 
 
 
✓ 
 
 
Integrative Therapy Session 
 
 
 
✓A 
 
✓A 
 
 
✓A 
 
Seven Days Telephone Contact 
 
 
 
✓ 
 
✓ 
 
 
✓ 
 
AEs Requiring Medical Attention 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Spont. Reported Reactions & all AEs 
 
 
✓J 
✓ 
✓J 
✓ 
✓ 
✓J 
✓ 
 
Changes in Tinnitus and/or Pain 
✓P 
 
✓E,P 
✓E,P 
✓E,P 
✓E,P 
✓P 
✓E,P 
✓E,P 
✓P 
AEs of psychiatric status or withdrawal  
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Serious Adverse Events 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Issue Memory Aid Card  
 
 
 
 
 
 
 
 
 
✓H 
Unblinding  
 
 
 
 
 
 
✓ 
 
 
 
Perception of Experimental Sessions 
 
 
 
 
 
 
✓N 
 
 
✓N 
RRPQ 
 
 
 
 
 
 
 
 
 
✓H 

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* If Visit 18 is more than 8 weeks after Visit 12, then subjects will need to repeat measures prior to starting Stage 2.  
 
A = First session is one day after experimental session; B = Approximately six hours post MDMA; C = At the beginning of the session; D = As needed; E = Approximately every 60 minutes; F = Reactions collected for 
seven days post experimental session; G =All visits and Day 2 and Day 7 phone calls only; H = One month after the second experimental session but before the third experimental session; I = On the day of the third 
integrative session; J = Only in subjects with pre-existing tinnitus and/or chronic pain. 
Table 3. Time & Events Stage 2 
 
Preparatory 
Session 
Experimental 
Session 1 
Experimental 
Session 2 
Secondary 
Endpoint 
Experimental 
Session 3 
End of 
Stage 2 
 
Long-term 
Follow-up  
Visit # 
V18* 
V19 
V20,21,22 
V23 
V24,25,26 
V27 
V28 
V29, 30, 31 
V32 
 
LTFU 
Type of Visit 
Preparatory  
Experimental 
Integrative 
Experimental 
Integrative 
Outcome 
Experimental 
Integrative 
Outcome 
Follow-up 
Visit Timing 
Within 1 
month post 
V12* 
1 week 
post V18 
Between 
V19 and V23  
3-5 weeks 
post V19 
Between 
V23 and V27  
1 month 
post V23 
1 month 
post V23 
Between 
V28 and V32  
2 months 
post V28 
1 year post 
V13 or V28 
Confirm Informed Consent 
✓ 
 
 
 
 
 
 
 
 
 
Confirm Inclusion/Exclusion 
✓ 
 
 
 
 
 
 
 
 
 
Enrollment in Stage 2 
✓ 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Record to Audio/Video 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
 
 
General Well-Being 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
Drug Screen 
 
✓ 
 
✓ 
 
 
✓ 
 
 
 
Pregnancy Screen (if applicable) 
 
✓ 
 
✓ 
 
 
✓ 
 
 
 
CAPS, GAF, BDI-II, PSQ, PTGI, DES-
II 
Use V12* 
 
 
 
 
✓H 
 
 
✓ 
✓ 
RBANS/PASAT 
 
 
 
 
 
 
 
 
✓ 
 
PDS 
Use V12* 
 
✓I 
 
 
✓ 
 
✓I 
✓ 
✓ 
C-SSRS 
✓ 
✓B,C,D 
✓G 
✓B,C,D 
✓G 
✓ 
✓B,C,D 
✓G 
✓ 
✓ 
Administer Drug + Therapy 
 
✓ 
 
✓ 
 
 
✓ 
 
 
 
Monitoring of BP, Pulse, and Temp.  
 
✓ 
 
✓ 
 
 
✓ 
 
 
 
SUD 
 
✓D,E 
 
✓D,E 
 
 
✓D,E 
 
 
 
Overnight Stay, SOCQ 
 
✓ 
 
✓ 
 
 
✓ 
 
 
 
Integrative Therapy Session 
 
 
✓A 
 
✓A 
 
 
✓A 
 
 
Seven Days Telephone Contact 
 
 
✓ 
 
✓ 
 
 
✓ 
 
 
AEs Requiring Medical Attention 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Spont. Reported Reactions and all AEs 
 
✓ 
✓F 
✓ 
✓F 
 
✓ 
✓F 
 
 
Changes in Tinnitus and/or Pain 
 
✓J,D 
✓J,D 
✓J,D 
✓J,D 
✓J 
✓J,D 
✓J,D 
✓J 
✓J 
AEs of psychiatric status or withdrawal  
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Serious Adverse Events 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Perception of Experimental Sessions 
 
 
 
 
 
✓ 
 
 
✓ 
 
Complete Stage 2 go to follow-up 
 
 
 
 
 
 
 
 
✓ 
 
RRPQ 
 
 
 
 
 
 
 
 
✓ 
 
Issue Memory Aid Card 
 
 
 
 
 
 
 
 
✓ 
 
Follow-up Questionnaire 
 
 
 
 
 
 
 
 
 
✓ 
Termination Visit 
 
 
 
 
 
 
 
 
 
✓ 

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4.1 Planned Duration of Study and Visit Windows 
 
Subjects enrolled in this study will fall into two categories that will determine the 
duration of the study. These include the follow-up portion of the study, which 
encompasses 12 months after the final experimental session. 
 
• Active dose subjects completing Stage 1 only: 15 months.  
• Comparator dose subjects who continue and complete Stage 2: 18 months. 
 
Screening may take up to two months, with the baseline CAPS being conducted no more 
than 8 weeks before the first experimental session, leaving room for appropriate 
medication washout of at least five half-lives of pre-study psychiatric medications and 
active metabolites, and one additional week for stabilization. For example, the maximum 
washout would be seven weeks for subjects tapering off of fluoxetine plus one week for 
stabilization. Preparatory sessions should be scheduled approximately one week apart, 
with the first experimental session taking place three to five weeks after enrollment, and 
at most 8 weeks after the baseline CAPS. The maximum window from the start of 
screening to the first experimental session is 13 weeks. The optimal timing for Stage 2 is 
one month after the primary endpoint visit in Stage 1, with a maximum allowable 
window of five months. Any delay between visits would result in a corresponding 
extension of study duration. 
 
4.2 Recruitment and Subject Population 
 
Subjects may be men or women aged 18 or older with a confirmed diagnosis of chronic, 
treatment-resistant PTSD who have undergone psychotherapeutic or 
psychopharmacological treatment for PTSD of adequate dose/duration without achieving 
remission. Subjects who discontinued PTSD treatment due to inability to tolerate 
psychotherapy (e.g. due to persistent “over-engagement”) or psychopharmacology due to 
treatment-emergent side effects would not be excluded. Subjects would also not be 
excluded for having more than one traumatic event. Subjects must have a last month 
CAPS score equal to or greater than 50 and must meet all inclusion criteria and no 
exclusion criteria at baseline. They must be in good physical health and without major 
medical disorders that might affect the safety or tolerability of MDMA. Subjects will be 
recruited through printed ads, internet ads, referrals from other psychiatrists, 
psychotherapists, or physicians, and through word of mouth. Recruitment will continue 
until twenty-three subjects who meet all inclusion criteria without meeting any exclusion 
criteria complete the primary end point. Only IRB-approved recruitment materials and 
advertisements will be used for the study. 
 

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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. 
Subjects may have experienced one or more traumatic event; 
2. Have a last month CAPS score of 50 or higher, indicating moderate to severe 
PTSD symptoms; 
3. Have treatment-resistant PTSD, who were unable to achieve remission despite 
receiving adequate dose/duration of psychotherapy or psychopharmacology or 
who discontinued treatment due to either:  
a. Inability to tolerate psychotherapy for PTSD (e.g. persistent “over-
engagement” when attempting Prolonged Exposure Therapy); 
b. Inability to tolerate psychopharmacology for PTSD due to treatment-
emergent side effects; 
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 
Stage 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. 
Individuals using opiates for pain management will be asked to decrease the dose 
or avoid taking their pain medication for 24 hours prior to experimental sessions 
if possible. If the subject is on stimulants for ADHD at baseline, they can continue 
to use them at the same dose and frequency as long as they discontinue five half-
lives before each experimental session and do not restart for 10 days after each 
experimental session. 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 refrain from taking, for one week preceding each experimental session: 
a. Any herbal supplement (except with prior approval of the research 
team);  
b. Any nonprescription medications (with the exception of non-steroidal 
anti-inflammatory drugs or acetaminophen unless with prior approval of 
the research team); 
c. Any prescription medications (with the exception of birth control pills, 
thyroid hormones or other medications approved by the research team). 
Note: Must have physician’s approval; 
10. Agree to take nothing by mouth except alcohol-free liquids after 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; 

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12. Agree not to use caffeine or nicotine for two hours before and six hours after 
ingesting the drug, or until the therapists deem it safe to do so; 
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 provide a contact (relative, spouse, close friend or other caregiver) 
who is willing and able to be reached by investigators in the event of a subject 
becoming suicidal; 
18. Agree to inform the investigators within 48 hours of any planned medical 
interventions; 
19. Are willing to refrain from participating in any other interventional clinical trial 
for the duration of this clinical trial, including the follow-up period; 
20. If female subjects of childbearing potential, must have negative pregnancy test 
results, be willing to have pregnancy tests and must agree to use an effective form 
of birth control during the treatment period; 
21. Are proficient in speaking and reading English; 
22. 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 Personality Disorders Cluster A (paranoid, schizoid, 
schizotypical), Cluster B (Antisocial, borderline, histrionic, narcissistic) or Cluster 
C (avoidant, dependant, obsessive-compulsive); 
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); 
5. Have hypertension using the standard criteria of the American Heart Association 
(values of 140/90 or higher assessed on three separate occasions); 
6. Have evidence or history of liver disease; 

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7. Have 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, as determined through psychiatric interview, 
responses to CSSRS and through clinical judgment of the investigator, 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 in the last ten years or at least once within six months of the MDMA 
session; 
12. Require ongoing concomitant therapy with a psychiatric drug, including but not 
limited to SSRIs, SNRIs, or MAOIs; 
13. Meet DSM-IV criteria for substance abuse or dependence for any substance in the 
past 60 days save caffeine or nicotine; 
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, safety, and process measures will be used in the study. 
Investigators will follow the most recent version of the treatment manual in all matters 
relating to the psychotherapy sessions and follow-up. All psychotherapy sessions, 
including experimental sessions, may be recorded to audio and video, with all recordings 
preserved for research and training purposes.  
 
5.1.1 Outcome Measures 
 
The primary outcome measure will be the CAPS, a clinician-administered measure for 
PTSD diagnosis and assessment of symptom intensity and frequency. A qualified, 
blinded IR will perform the CAPS at baseline and outcome measurement timepoints. The 
IR will not be present during the subject’s experimental sessions nor have any 
information regarding the experimental sessions. Subjects will be instructed not to inform 
the IR of 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. All assessments, including those at baseline, 
will use the CAPS assessment of symptoms over the last month. The CAPS has been 
determined to have good internal consistency, concurrent validity, and test/retest 
reliability [115, 116].  
 

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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 
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 [117]. Items addressing elements of the traumatic event and life function are 
answered as either present or not present (Yes or No). The 17 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 have a moderate to good correlation with SCID diagnosis, with kappa = 0.65 
[117]. Subjects will complete the PDS questionnaire at baseline, after each experimental 
session, and the end of Stage 1 or Stage 2, as specified in the Time and Events Table.  
 
The BDI-II is a 1996 revision of the BDI, a 21-item self-report measure [118, 119], that 
will serve as a measure of depression according to DSM-IV criteria [120]. 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 
[120]. 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. Subjects will complete the BDI-II at the same times as the CAPS.  
 
The 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 0 reflecting serious risk of causing harm to the self or 
others. The GAF is a reliable, validated measure of social functioning [121]. Subjects will 
complete the GAF at the same time as the CAPS. 
 
The PSQI is a measure of self-reported sleep quality over a one-month period. The PSQI 
was designed to be a reliable, standardized measure able to distinguish between good and 
poor sleepers. It consists of 19 items, with possible responses ranging from 0 to 4 on a 
five-point scale [122]. 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 10 minutes to 
complete. Test-retest reliability ranges from 0.85 to 0.87, and it is internally consistent, 
with a Cronbach’s alpha of 0.83 [122, 123]. Global scores correlate with other measures 
of alertness and self-reported sleep quality [124]. Subjects will complete the PSQI at the 
same time as the CAPS. 
 
The PTGI is a 21-item self-report measure of perceived growth or benefits occurring after 
a traumatic event. It contains five subscales; relationship to others, new possibilities, 
personal strength, spiritual change, and appreciation of life [125, 126]. In this study, 

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subjects will complete the PTGI in reference to the time since the trauma at baseline, but 
will respond in reference to the beginning of their participation in the study on all 
subsequent occasions. Subjects will complete the PTGI according to the Time and Events 
table.  
 
The DES-II is a 28-item self-report measure of dissociation, defined as a lack of normal 
integration of an individual’s thoughts, feelings, or experiences into the stream of 
consciousness or memory [127, 128]. It is an established measure of dissociative 
symptoms. The scale consists of statements describing facets of dissociation. 
Respondents indicate how often the specific experience happens to them, from “never” to 
“always.” Responses on the original scale were made via visual analog scales. The DES-
II uses the same items but with responses made on a ten-point scale from “0%” to 
“100%” of the time. The scale is scored by treating percentages as single digits to 
produce a total score. The DES-II can also be used to produce scores for three factors, 
amnesia, depersonalization, and derealization. The scale differentiated between 
respondents without psychiatric disorders or with psychiatric disorders with few 
dissociative symptoms and respondents with psychiatric disorders associated with 
dissociative symptoms [127]. Reliability of the DES-II is high (ranging from 0.79 to 0.96 
in an early review), and a reported Cronbach’s alpha of 0.95 [128, 129]. There may be a 
relationship between experiencing dissociation and occurrence of chronic PTSD [128, 
130]. 
 
The long-term follow-up questionnaire has been developed internally by the Sponsor to 
assess long-term benefits and harms of MDMA-assisted psychotherapy at the long-term 
follow-up visit.   
 
5.1.2 Safety Measures 
 
Safety measures will be applied as described below to minimize risks associated with 
drug-assisted psychotherapy sessions. The therapists or study physician will be available 
via mobile phone or pager throughout the study to ensure subject safety. The therapists 
will maintain Basic Life Support (BLS) certification. 
 
Safety measures, including vital signs and a measurement of psychological distress, will 
be assessed during all experimental sessions. Subjects will rate their current degree of 
subjective distress with the SUD scale, which is a single-item self-report scale. The SUD 
will be completed repeatedly during the experimental sessions, with the degree of distress 
marked along seven points. Results of the SUD are intended to assist therapists in 
maintaining subject safety during experimental sessions. 
 
The therapists will assess general wellbeing during each preparatory session, on each 
integrative session and during telephone calls for seven days. Results of this scale are 
intended to assist therapists in maintaining subject safety throughout the study. 
 
The C-SSRS is a clinician-administered measure of suicidal behavior devised to detect 
potential suicidal thoughts or behaviors during a clinical trial [131]. It consists of a 

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“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, during most face-to-face visits, 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 the therapists observe an increase in suicidality. C-SSRS data 
from the second integrative session after each experimental session will be kept with the 
subject’s source record. 
 
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
[132] is a relatively brief battery of assessments for cognitive function. It consists of 12 
subtests that cover verbal and visual memory and attention and takes approximately 30 
minutes to administer. Tasks include recall of lists, figures and stories, picture naming, 
semantic fluency, copying a figure, digit span and coding, and line orientation. Scores on 
the RBANS subtests can be used to obtain a total score and five index scores; attention, 
immediate memory, delayed memory, language and visuospatial/constructional scores. 
Factor analyses of the RBANS and samples of veterans and people with schizophrenia 
suggest that the RBANS possesses two factors rather than five [133, 134]. The RBANS 
has alternate forms, allowing repeated administration. Test performance by healthy 
controls were distinguishable from performance by people with probable Alzheimer’s 
disease or the neurodegenerative condition Huntington’s disease [135], and the test has 
high split-half reliability, with coefficients ranging from 0.80 to 0.88 [132]. Test-retest 
reliability is good for total RBANS scores in healthy controls and psychiatric patients 
[136]. The RBANS has been used in community-based and psychiatric samples [133, 
137] and in a prospective investigation of the effects of chemotherapy upon cognitive 
function [138]. Each administration of the RBANS will use one of parallel forms of 
RBANS, and each participant will not complete the same form twice. This measure was 
employed as a means of assessing safety after two sessions of MDMA-assisted 
psychotherapy for PTSD [1]. See Time and Events Table for a detailed schedule. 
 
The Paced Auditory Serial Addition Test (PASAT) is a measure of psychomotor speed, 
auditory information processing and computation ability [139]. The PASAT was 
originally designed to assess recovery after traumatic brain injury, and has been used 
subsequently to assess cognitive function in other populations [139-141]. It takes 
approximately ten to 15 minutes to administer. The measure involves the addition of a 
series of digits presented at a three or two second interval, with responses made by 
adding each number to the prior digit. The PASAT consists of two alternate forms, 
permitting repeated administration. PASAT scoring includes collecting number of correct 
and incorrect responses, time to response (latency of response) and any failure to 
respond. There was a positive correlation between responses on the PASAT and a non-
numerical paced measure. The measure is internally consistent (Cronbach’s alpha of 
0.90), and it has high test-retest reliability, with reliability ranging from 0.90 to 0.97 
[140-142]. The first administration of the PASAT will use one of the two alternate forms, 

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and the second administration will use the other. This measure was employed as a means 
of assessing safety after two sessions of MDMA-assisted psychotherapy for PTSD  [1]. 
See Time and Events Table for a detailed schedule. 
 
Cardiovascular effects will be assessed via blood pressure and pulse measurement.  
Blood pressure and heart rate will be assessed periodically during each experimental 
session by an automatic blood pressure (BP) and pulse monitor. Blood pressure and pulse 
will be measured at the outset of the experimental session, and once approximately every 
30 minutes for the first four hours of the experimental session, and once every hour, or as 
needed, thereafter. 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 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.  
 
A 100-millimeter visual analog scale will be used to assess changes in symptoms of pre-
existing tinnitus and/or chronic pain [143-145]. The Changes in Tinnitus and/or Pain 
visual analog scale will allow rating of symptom severity from “None” to “Worst Case 
Imaginable”. This exploratory measure will enable quantification of subjective somatic 
symptoms that are known to be associated with PTSD [144, 146-148]. Presence of 
chronic pain is associated with PTSD, possibly as a result of psychological response to 
traumatic stress as reflected in brain activity, such as increased amygdalar activity in 
response to pain and transmitter systems involved in the stress response [144, 147, 148]. 
 
All AEs and spontaneously reported reactions will be collected, as described in Section 
8.5. AEs and spontaneously reported reactions may be collected during face-to-face visits 
or over the telephone. Common reactions that are spontaneously reported are collected 
for seven days after each experimental session on a separate CRF page and will be 
categorized as mild, moderate, or severe. 
 
5.1.3 Process Measures 
 
All psychotherapy sessions, including experimental sessions, may be recorded to audio 
and video, with all recordings preserved for research and training purposes.  
 
Adherence criteria and competence ratings will be conducted by qualified, trained 
blinded adherence raters who will analyze video data from selected preparatory, 
experimental and integrative sessions. The elements included in adherence criteria are 
specific to each type of session. These ratings will be collected, at minimum, for each 
therapist team in the study. The goal of these ratings will be to correlate therapist 
adherence to the treatment manual with outcome as a part of the sponsor’s ongoing 
efforts to standardize treatment methods of MDMA-assisted psychotherapy for PTSD.  
 

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The SOCQ is a 100-item questionnaire based on the “Peak Experience Profile” designed 
by Pahnke and colleagues [149, 150]. Subjects respond to the SOCQ using a six-point 
Likert-type scale anchored at 0=none at all and 5=extreme (more than ever before in my 
life). It has seven subscale scores; internal unity, external unity, transcendence of time 
and space, ineffability and paradoxicality (claim of difficulty in describing the experience 
in words), sense of sacredness, noetic quality, and deeply felt positive mood. The 
measure is a self-report instrument and takes approximately 20 to 30 minutes to 
complete. Subjects will complete the SOCQ after each experimental session, at any time 
between the end of an experimental session and prior to leaving the treatment facility the 
next day. 
 
Questions regarding the belief of condition assignment and certainty of the belief will be 
asked of the therapists and subjects at the integrative session on the day after each 
blinded experimental session in Stage 1. Each therapist responsible for treating the 
subject will indicate their belief of condition assignment and certainty based on the active 
doses (125 mg or 100 mg) and comparator dose groups. In line with informed consent 
obfuscation, where the comparator dose is not revealed, subjects will initially be asked if 
they believe they received MDMA or not during this assessment. If they believe they 
received MDMA, they will be asked about what dose they think they received. These 
beliefs are collected as a part of the sponsor’s ongoing initiative to optimize the double-
blind as a part of dose response studies.  
 
Subject perceptions about experimental sessions will be collected from each active dose 
subject at the Primary Endpoint after unblinding and the two-month follow-up in Stage 1. 
Stage 2 subjects will complete the same measure at the Secondary Endpoint and the two-
month follow-up in Stage 2. These perceptions are collected as a part of the sponsor’s 
ongoing initiative to assess the therapeutic value of the third experimental session and to 
gather information on the optimal therapeutic dose for MDMA. 
 
The Reactions to Research Participation Questionnaire (RRPQ) [151] is an assessment of 
causes for taking part in research and responses to the experience of being a research 
subject. Subjects will complete this measure during their two-month follow-up, with 
exact time of completion varying in accordance with participation in the third open-label 
experimental session in Stage 1 or in Stage 2. The RRPQ is intended to assess the 
subject’s experience as a research subject, perceived reasons for consenting to be a 
research subject and perceived freedom to take part in the study. 
 
5.2 Study Procedures, Visit Descriptions, and Adherence 
 
To ensure consistency of the manualized therapy, each type of visit described below must 
follow the treatment manual. Adherence to the manualized therapy will be reviewed by 
monitoring of data and/or rating videos of these visits as part of the data review process. 
All criteria for a visit type should be completed as a part of the visit series, which may 
take place over more than one day.  
 

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5.2.1 Prescreening, Screening, and Baseline Evaluation (Pre-study) 
 
Prospective subjects will be prescreened by telephone according to an IRB-approved 
script to learn if they meet basic eligibility criteria. All individuals who are prescreened 
should be assigned a screening number and recorded on the Subject Screening Log where 
information on the selection of potential subjects in the trial should be collected.  
 
Upon signing the IRB-approved informed consent form (ICF), the potential subject may 
commence study-related screening activities. The screening number should also be 
recorded on the signed ICF. If a subject is enrolled, the study staff should record the 
enrollment date and assign a subject number. If a subject is not enrolled, an explanation 
should be recorded on the Screening Log. A CRF will not be completed for subjects who 
are not enrolled. These subjects will only be documented on the Screening Log and 
source records. It is the responsibility of the 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 should be complete by up to two 
months prior to enrollment. Screening may take up to two months, with the baseline 
CAPS being conducted no more than 8 weeks before the first experimental session, 
leaving room for appropriate medication washout of at least five half-lives of pre-study 
psychiatric medications and active metabolites, plus one week for stabilization.  
If the CAPS is completed outside of this window for a subject, the PI should consult the 
Sponsor CRA and Medical Monitor to determine if the baseline CAPS should be 
repeated. The maximum window from the start of screening to the first experimental 
session is 13 weeks. If, after reviewing all information, the PI concludes that a subject is 
eligible, they will enroll the subject in the study. Visits will be scheduled consecutively as 
described in the Time and Events Table.  
 
a. Explain and obtain written informed consent from the subject. Written informed 
consent must be obtained prior to performing any tests or evaluations for the 
study.  
b. Assign the subject a screening number. Complete the Screening Log.  
c. Review the ability of females of childbearing potential to become pregnant and 
their commitment to practice appropriate birth control as determined by the 
investigator for the treatment period of the study. 
d. The study physician will obtain medical and psychological history by interview. 
e. Tinnitus and chronic pain symptom severity will be collected using a visual 
analog scale in subjects with a medical history of these conditions. 
f. The C-SSRS will be administered to assess suicide risk. 
g. The study physician will collect information on pre-study and current 
medications. 
h. The study physician will perform a general physical examination. The 
examination will involve the following procedures:  
• Blood pressure. 
• Pulse. 

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• Height. 
• Weight. 
• Body temperature. 
• Examination of head, eyes, ears, nose, throat, skin, heart, lungs, abdomen, 
and extremities. 
• Brief neurological exam (cranial nerves 2-12, sensory, motor, reflexes and 
cerebellar function). 
• Electrocardiogram (ECG). 
• Serum electrolytes, metabolic profile, urinalysis and complete blood count. 
• Thyroid stimulating hormone (TSH), free T3 and free T4. 
• Human Immunodeficiency Virus (HIV) serology. 
• Urine-dip pregnancy test on females with childbearing potential. 
• Urinary drug test. 
 
Results of HIV serology will be kept confidential, and appropriate referral for counseling 
may be necessary in accordance with state law. The clinical laboratory values will be 
used to establish eligibility and will be kept with the subject’s source record. The clinical 
laboratory values will not be captured in the CRF, but will be used to establish eligibility 
and will be kept with the subject’s source record. Clinically significant abnormal values 
will be captured as medical history. If, upon examination, there are questions raised about 
possible medical problems, the study physician will request a review of subject medical 
records and request additional tests or assessments as indicated. 
 
A blinded IR who will not be present during any of the therapy sessions will administer:  
 
• Structured Clinical Interview for Diagnoses I Research Version (SCID-I-RV) to 
assess eligibility based on Axis I diagnoses, which includes a self-report 
questionnaire to focus on modules to use based on symptoms. 
• SCID-II Axis 2 questionnaire to determine if any modules of the SCID-II 
Interview are required to exclude possible personality disorders in Cluster A, B or 
C. If required, specific modules of the SCID-II Interview will be conducted to 
confirm diagnoses of personality disorders. 
• Last-month CAPS to assess PTSD symptoms and eligibility, which may be 
recorded to video in as many instances as necessary to establish inter-rater 
reliability. 
• GAF to assess general psychological function. 
• PASAT to assess cognitive function. 
• RBANS to assess cognitive function. 
 
The subject will complete the following self-report measures: 
 
• PTGI (in reference to time since the trauma) 
• PDS to assess self-reported PTSD symptoms 
• BDI-II to assess depression symptoms 
• PSQI to assess sleep quality 

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• DES-II to assess dissociation symptoms 
 
5.2.2 Preparatory Psychotherapy Sessions - Visits 1, 2, 3 (Stage 1), 18 (Stage 2) 
 
Subjects who do not complete all screening activities will not be enrolled. Eligibility may 
be discussed by phone after screening is complete and at the time Visit 1 is scheduled but 
the final confirmation will occur at Visit 1. If all inclusion criteria and no exclusion 
criteria are met, eligibility will be confirmed with the subject. 
 
a. Complete a final review of Inclusion/exclusion criteria. 
b. Assess general wellbeing. 
c. Confirm eligibility and willingness to participate in study. 
d. Enroll subject and issue subject number. 
e. Ensure medical history and medication history is complete. After enrollment new 
events will be collected as AEs and new medications, as described in Sections 8.5 
and 9.0. 
f. Discuss medication tapering, if applicable. Upon confirmation of eligibility, the 
study physician will consult the prescribing physician to initiate medication 
tapering for subjects who must refrain from taking a psychiatric medication for 
the study. Tapering will follow a time course appropriate for the medication given 
its half-life, with the first experimental session scheduled to occur after complete 
washout. Individuals using opiates for pain management will be asked to decrease 
the dose or avoid taking their pain medication for 24 hours prior to experimental 
sessions if possible, as these medications may reduce the efficacy of MDMA. 
Subjects will be permitted to take their prescribed opiate medication during this 
period if necessitated by pain flare-ups. 
 
The subjects will undergo three preparatory sessions lasting 90 minutes with their 
therapist team, prior to their first experimental session. The first preparatory session will 
take place at Visit 1 after enrollment confirmation. Preparatory sessions should be 
scheduled approximately one week apart, with the first experimental session taking place 
three to five weeks after enrollment, and no more than eight weeks ± one week after the 
baseline CAPS. In Stage 2 (for comparator dose crossover subjects) only one preparatory 
session will take place prior to their first open-label experimental session, as described in 
the Time and Events Table.  
 
Adherence criteria for preparatory sessions should be completed as a part of one of the 
three sessions. These elements do not have to be accomplished in any specific order or in 
every preparatory session. Generally, adherence criteria for these sessions include that the 
therapists will work with the subject to prepare for MDMA-assisted psychotherapy. The 
therapists and subject will seek to form a strong working relationship with each other, 
and they will help the subject prepare for upcoming experimental sessions. Preparatory 
sessions will promote a safe set and setting for confronting trauma-related memories, 
emotions, and thoughts.  
 

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During the preparatory sessions: 
 
a. Therapists may record all sessions to audio and video. Subjects will be given 
access to review audio or video recordings from these sessions upon request.  
b. Collect AEs and Medications, as described in Sections 8.5 and 9.0. 
c. The therapists will inquire about any possible changes in the subject’s health to 
ensure that subject continues to meet eligibility criteria and if applicable, will 
confirm that the subject has appropriately tapered off of medications. 
d. If subjects who have pre-existing tinnitus or chronic pain mention any changes, 
use the visual analog scale to collect the changes in symptoms. 
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 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 a companion present during or after the experimental 
session, a meeting between the therapists and that individual will be scheduled 
prior to the first experimental session. There must be mutual agreement between 
the subject and therapists concerning the presence of the companion. 
h. The therapists will administer the C-SSRS just prior to beginning the second 
preparatory session, unless a subject is still undergoing medication washout. 
Subjects still undergoing medication washout will complete the C-SSRS during 
the second preparatory session or at a point after washout is complete prior to the 
first experimental session.  
i. Assess general wellbeing at each preparatory session. 
j. During the third and last preparatory session, give the Reminder of Study Rules to 
the subject, which includes instructions and restrictions for conduct prior to 
receiving the drug. Subjects must agree to: 
• Ingest only alcohol-free liquids after 24:00 (midnight) the evening before the 
experimental session.  
• Refrain from the use of any psychoactive drug, with the exception of caffeine 
or nicotine, within 24 hours of each experimental session. 
• Not use caffeine or nicotine for two hour before and six hours after ingesting 
the drug, or until therapists deem it safe to do so. 
  
5.2.3 Experimental Sessions - Visits 4, 8 (Stage 1), 13, (Active Dose Groups Stage 1), 
19, 23, 28 (Stage 2) 
 
Subjects in Stage 1 will receive two experimental sessions of MDMA-assisted 
psychotherapy blinded with respect to dose, scheduled approximately three to five weeks 
apart. Procedures for MDMA-assisted psychotherapy will remain the same across all 
sessions, and all procedures except the dose of the drug received will be the same.  
 

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Adherence criteria for experimental sessions should be completed as a part of each 
experimental session. These elements do not have to be accomplished in any specific 
order. Generally, adherence criteria for these sessions include that the therapists will 
create and communicate a setting of safety and support the subject during periods of inner 
focus. Therapists will use a largely nondirective approach, following the lead of the 
subject’s inner healing intelligence. Therapists will provide encouragement for staying 
present with difficult experiences. Therapists may occasionally offer gentle guidance or 
redirection as a choice to encourage collaborative exploration if the subject repeatedly 
avoids trauma related material. Therapists will inquire about somatic symptoms and if 
necessary encourage release of tension through movement, in whatever way feels 
appropriate to the subject. Therapists will use music to support the experience without 
being intrusive.  
 
Table 4. Schedule of Procedures for Experimental Sessions 
 
Pre-drug: 
 
a. At least 24 hours prior to the first experimental session the subject will be 
randomized. The study physician will obtain the container assignment using a 
web-based randomization program prior to the blinded sessions.  
b. On the day of the experimental session, the subject will arrive approximately 60 
to 90 minutes 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. 
Approximate Time 
Procedure or Action 
9:00  
Urine drug screen and pregnancy test, subject acclimated 
to environment, C-SSRS 
 9:45  
Baseline BP, SUD 
 9:55  
2nd Baseline BP, Pulse, Body Temperature (BT), SUD 
10:00  
MDMA Administration, begin video recording  
10:30  
BP, Pulse 
11:00  
BP, Pulse, SUD, BT 
11:30  
BP, Pulse; Administer optional supplemental dose  
12:00  
BP, Pulse, BT 
12:30  
BP, Pulse, SUD 
13:00  
BP, Pulse 
13:30  
BP, Pulse, BT 
14:00  
BP, Pulse, SUD 
Every hour and as needed 
BP, Pulse 
Every 60-90 minutes 
SUD, BT 
Approximately six hours 
after drug administration 
C-SSRS, General Wellbeing 

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f. If the subject continues to meet criteria and the subject reports that they followed 
appropriate rules and restrictions, the session will proceed. 
g. Review procedures for the experimental session with the subject. 
h. Record the entire session to video and audio. Subjects will be given access to 
review 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 therapists will administer the C-SSRS prior to drug administration. 
k. Before drug administration, discuss and review the subject’s goals, intentions and 
concerns and some of the commonly experienced effects of MDMA. 
l. Instruct the subject not to use caffeine or nicotine two hours before or six hours 
after the dose of drug. 
m. Subject body temperature will be measured at baseline prior to 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 at baseline 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 at baseline prior to 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 more frequently until the values fall below these 
levels or until they have been decreasing for 15 minutes or have stabilized at a 
level judged by the investigator to be safe. The therapists may also make more 
frequent measurements if a subject exhibits symptoms indicative of hypertension. 
 
During: 
 
p. At approximately 10:00 in the morning, subjects will receive the initial dose of 
drug along with a glass of water.  
q. The subject will sit or recline on comfortable furnishings. Eyeshades and a 
program of music will be provided if the subject wishes to use them. Subjects 
may speak to the therapists whenever they wish, who will provide guidance and 
support as needed.  
r. After the first hour, if the subject has not spoken spontaneously, check in with 
him/her about the nature of the experience. For the rest of the experience, as 
appropriate, the therapists will support and encourage the subject in emotional 
processing and resolution of whatever psychological material is emerging as 
described in the treatment manual. 
s. Record any spontaneously reported reactions during the session. 
t. If subjects who have pre-existing tinnitus or chronic pain mention any changes, 

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use the visual analog scale to collect the changes in symptoms. 
u. Provide water and electrolyte containing fluids throughout the session but not to 
exceed 3L overall. 
v. A supplemental dose half the size of the initial dose may be administered 
approximately 1.5 to 2.5 hours after the initial dose unless contraindicated. 
w. Provide food during the latter part of the session.  
x. If there is a companion who has previously been asked and has agreed to be 
present during part or all of the MDMA session, that person may arrive during the 
session at whatever time has been agreed upon, but will wait in the waiting room 
until brought back to the session room by one of the therapists. Alternatively, the 
support person may arrive after the session has ended. 
y. 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 treatment manual. The C-SSRS is required at least once 
during the session; it is preferable to administer it towards the end of the session 
at about six hours after the initial dose.  
z. End the session if all medical and psychiatric parameters are acceptable and the 
subject is alert, ambulatory, and emotionally stable. 
 
Post-drug: 
 
aa. Give the subject the SOCQ to be completed after the end of the experimental 
session and prior to leaving the treatment facility the next day. 
bb. The therapists will depart the site when they have concluded that the subject is 
emotionally and medically stable. Therapists or the study physician shall remain 
available to subjects during the experimental session and for one week after via 
24-hour cellular phone for integration as needed. 
cc. Spontaneously reported reactions, AEs, and Medications will be collected, as 
described in Sections 8.5 and 9.0.  
  
Subjects will remain overnight in an appropriately furnished room at the study site. With 
the approval of the therapists, a companion may accompany the subject during the 
overnight stay. An attendant will check in periodically on the subject during the overnight 
stay, even if a companion is present. The attendant will monitor subject condition and 
will help subjects relax during the overnight stay. The attendant will be an individual 
with some previous training in managing psychological distress. If there is an emergency 
or the subject needs additional support, the attendant can contact the therapists. The 
subject and a companion (if applicable) will receive information that will allow them to 
contact the therapists during the overnight stay in the case of an emergency or request for 
additional support. Subjects will be encouraged to use much of the time during their 
overnight stay for rest and for a period of reflection and integration in a quiet atmosphere. 
 

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5.2.4 Integrative Sessions 24 Hours after Experimental Session - Visits 5, 9 (Stage 1), 
14 (Active Dose Groups Stage 1), 20, 24, 29 (Stage 2) 
 
On the morning after each experimental session, both of the therapists from the subject’s 
team will meet with the subject during a 60 to 90-minute integrative therapy session.  
 
Adherence criteria for integrative sessions should be completed as a part of one of the 
three sessions following each experimental session. These elements do not have to be 
accomplished in any specific order or all in each and every integrative session. Generally, 
adherence criteria for these sessions include discussing material that emerged during 
experimental sessions and helping subjects integrate their experiences both internally and 
into daily life. Therapists will validate the choices of the subject about how much they 
wish to communicate their thoughts, feelings and experiences at this time, but will elicit 
enough information to be able to assess the subject’s level of emotional stability and state 
of emotional and physical wellbeing. Therapists will emphasize their commitment to 
support the subject during the integration period and will be available via phone for 
additional meetings if needed. Subjects will be encouraged to relax and rest as much as 
possible for several days after the experimental session. 
 
During integrative psychotherapy sessions: 
 
a. The integrative psychotherapy session may be recorded to audio and video. 
Subjects will be given access to review audio and video of the session upon 
request. 
b. The therapists will administer the C-SSRS during each integrative session.  
c. Prior to integrative psychotherapy, the subject and both therapists will indicate 
their beliefs concerning subject condition assignment.  
d. Discuss and review events that occurred with the subject during the experimental 
session, including thoughts, feelings, and memories. If necessary, the therapists 
will help the subject to reduce any residual psychological distress he or she is 
experiencing. The therapists will also encourage the transfer of states of 
acceptance, feelings of intimacy, closeness, and reduced fear experienced in 
experimental sessions to emotionally threatening everyday situations. The 
therapists will be supportive, validating the experience and facilitating 
understanding and emotional clearing.  
e. The therapists will remain accessible any time the subject needs support outside 
the scheduled integration sessions.  
f. Assess the subject’s mental health and the presence of any remaining reactions 
during integrative psychotherapy immediately after each experimental session.  
g. 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.  
h. If subjects who have pre-existing tinnitus or chronic pain mention any changes, 
use the visual analog scale to collect the changes in symptoms. 
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 

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individual willing or able to take him or her home, or if the designated person is 
unable to assist the subject due to unforeseen events, the therapists will assist the 
subject in finding an alternative means of returning home. 
j. Spontaneously reported reactions, AEs and Medications will be collected, as 
described in Sections 8.5 and 9.0.  
k. Remind the subjects that they will have daily phone contact for the next seven 
days. 
 
5.2.5 Daily Telephone Contact for Seven Days after an Experimental Session 
 
During daily phone contact:  
 
a. Investigators will follow the most recent version of the treatment manual in all 
matters relating to follow-up subsequent to the experimental psychotherapy 
sessions. 
b. 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. The goal of daily contact is assessment 
of changes in general wellbeing, safety of the subjects, and offering support for 
subjects.  
c. The telephone contact will be for a brief check-in lasting five 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. 
d. On the second and seventh day of contact after the experimental session, the 
therapists will administer the C-SSRS. 
e. General wellbeing will be assessed at each phone call. 
f. Spontaneously reported reactions, AEs and Medications will be collected, as 
described in Sections 8.5 and 9.0. 
 
5.2.6 Integrative Psychotherapy Between Experimental Sessions - Visits 6, 7, 10, 11,  
(Stage 1), 15, 16, (Active Dose Groups Stage 1), 21, 22, 25, 26, 30, 31 (Stage 2) 
 
In addition to the session the morning after each experimental session, the subject will 
have two additional integrative psychotherapy sessions with the therapists lasting 90 
minutes with the therapists between each experimental session and in the month 
following the last experimental session. The therapists may conduct more sessions if they 
and the subject deem it necessary.  
 
Adherence criteria for integrative sessions should be completed as a part of one of the 
three sessions following each experimental session. These elements do not have to be 
accomplished in any specific order or in each integrative session. Generally, adherence 
criteria for these sessions include integration of material that emerged as a part of 
experimental sessions and afterward into daily life. Therapists will emphasize their 
commitment to support the subject during the integration period and will be available via 
phone or pager. Subjects will be encouraged to relax and rest as much as possible for 

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several days after the experimental session. 
 
During integrative psychotherapy sessions: 
 
a. Record each integrative session to audio and video. Subjects will be given access 
to review one or more integrative sessions upon request. 
b. The C-SSRS will be administered just prior to beginning each integrative session.  
c. General wellbeing will be assessed at each integrative session. 
d. If subjects who have pre-existing tinnitus or chronic pain mention any changes, 
use the visual analog scale to collect the changes in symptoms. 
e. The subject will complete the PDS questionnaire after each experimental session 
on the third integrative session or primary endpoint (after the second experimental 
session only), according to the Time and Events Table. 
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. Collect AEs and medications, as described in Sections 8.5 and 9.0. 
i. NOTE: If an integrative session falls within the period of telephone contact and 
additional phone call is not required that day, all data normally collected during 
the telephone call will be completed in person. 
 
5.2.7 Evaluation at Primary Endpoint and Unblinding - Visit 12 (Stage 1) 
 
The primary endpoint evaluation in Stage 1 will occur one month (within a window of 
plus or minus two weeks) after the second blinded experimental session. This visit will 
consist of two meetings that may be completed on separate days, one with the IR and the 
other with the therapists. Subjects who have withdrawn from treatment but have 
continued for follow-up will also complete this time point one month after their last 
experimental session. 
 
At the primary endpoint: 
 
a. Subjects will meet the IR for at least an hour and a half. 
b. The blinded IR will administer:  
• Last month CAPS to assess PTSD symptoms, which may be recorded to video 
in as many instances as necessary to establish inter-rater reliability. 
• GAF to assess general psychological function. 
• PASAT to assess cognitive function. 
• RBANS to assess cognitive function. 
c. The subject will complete the following self-report measures: 
• PTGI to assess post-traumatic growth (in reference to start of the study) 

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• PDS to assess PTSD symptoms. 
• BDI-II to assess depression symptoms. 
• PSQI to assess changes in sleep quality. 
• DES-II to assess dissociation symptoms. 
d. After completing all assessments and measures with the IR, 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 visual analog scale will be used to collect changes in pre-existing tinnitus and 
chronic pain symptoms.  
h. The blind will be broken for the subject’s condition assignment. Only the IR will 
remain blind to condition assignment at this time.  
i. If the subject was assigned to receive comparator dose MDMA, the therapists will 
discuss enrollment in Stage 2 (see Section 5.2.9). Comparator dose subjects will not 
complete the third experimental session and associated integrative sessions in Stage 1. 
j. Collect perceptions of experimental sessions from active dose subjects after 
unblinding. 
k. If the subject was assigned to receive active dose MDMA, the subject will complete a 
third open-label experimental session, with associated daily phone calls and 
integrative sessions in Stage 1 (see Sections 5.2.3-6).  
 
5.2.8 End of Stage 1 - Visit 17 (Active Dose Groups Stage 1) 
 
Active dose subjects will repeat all outcome measures with the IR and meet with the 
therapists again two months (within a window of plus or minus two weeks) after their 
final open-label experimental session, which will be the final visit in Stage 1 (see Section 
5.2.7). This visit will consist of two meetings that may be completed on separate days, 
one with the IR and the other with the therapists. 
 
At the end of Stage 1: 
 
a. The Independent Rater will administer the last month CAPS, GAF, RBANS and 
PASAT. 
b. Subjects will complete the PDS, BDI-II, DES-II, PSQI, and PTGI (in reference to 
start of the study). 
c. Active dose subjects who complete Stage 1 and comparator dose subjects who elect 
not to participate in Stage 2 will complete the RRPQ and continue on to the long-term 
follow-up visit.  
d. The visual analog scale will be used to collect changes in pre-existing tinnitus and 
chronic pain symptoms.  
e. The therapists will assess suicidality with the C-SSRS. 
f. Collect perceptions of experimental sessions. 

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g. Subjects who will continue on to the long-term follow-up may return to taking 
psychiatric medications after the end of Stage 1 if necessary.  
h. Subjects who will continue on the long-term follow-up will receive a memory aid 
card for use between their end of Stage 1 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. Collect AEs and medications, as described in Sections 8.5 and 9.0. 
 
5.2.9 Open-label Stage 2 (Comparator Dose Subjects from Stage 1) 
 
During Stage 2: 
 
a. Subjects will be reminded that participation in Stage 2 is voluntary and optional. 
b. Subjects who elect to cross over to Stage 2 will undergo the same course of 
therapy and evaluation as in Stage 1, with the exception that the subject will 
complete a single preparatory psychotherapy session instead of three (see Section 
5.2.2), and varied active doses of MDMA will be administered in an open-label 
context to explore the optimal therapeutic dose (e.g. without unblinding). Visits 
will be scheduled consecutively according to the Time and Events Table. 
c. Assessment of PTSD symptoms at the primary endpoint will serve as baseline 
assessments in Stage 2.  
d. If the start of Stage 2 is delayed for more than eight weeks from the primary 
endpoint (Visit 12) to the first preparatory session in Stage 2 (Visit 18), the IR 
will re-administer the CAPS and GAF. The subjects will complete the PDS, BDI-
II, PSQI, PTGI (in reference to start of the study), and the DES-II. These scores 
will be used as the baseline for comparison to assessment at the secondary 
endpoint and the end of Stage 2. 
e. Experimental sessions will be conducted according to procedures described in 
Section 5.2.3.  
1. During the first experimental session, subjects will receive a 100 mg initial 
dose of MDMA and may receive a 50 mg optional supplemental dose of 
MDMA. 
2. At the beginning of each of the second and third experimental sessions, the 
co-therapists, in consultation with the subject, will decide whether to 
administer an initial dose of 100 mg or 125 mg initial dose of MDMA. If a 
100 mg initial dose of MDMA is selected, an optional supplemental dose of 
50 mg MDMA may be administered. If a 125 mg initial dose of MDMA is 
selected, an optional supplemental dose of 62.5 mg MDMA may be 
administered. 
3. If the PI decides not to administer the optional supplemental dose and/or the 
optional clinical titration dose in a given experimental session, the unused 
capsules will be kept in their respective inner envelopes inside of the primary 
container in the safe. 
f.    Integrative sessions will be conducted according to procedures described in 
Sections 5.2.4 and 5.2.6. 
g.   Phone calls will be conducted according to procedures described in Section 5.2.5. 

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h. At the secondary endpoint based on procedures described in Section 5.2.7, the 
Independent Rater will administer the CAPS and GAF. Subjects will complete the 
PDS, BDI-II, PSQI, PTGI (in reference to the start of the study), and DES-II as 
described in the Time and Events Table. 
i.   At the end of Stage 2 based on procedures described in Section 9.4.8, the 
Independent Rater will administer the CAPS, GAF, RBANS and PASAT. 
Subjects will complete the PDS, BDI-II, DES-II, PSQI, and PTGI (in reference to 
the start of the study), as described in the Time and Events Table. 
j.  The end of Stage 2 will be completed in the same manner as the end of Stage 1 
(see Section 5.2.8). 
k. Investigators will follow the most recent treatment manual in all matters relating to 
the Open-Label Stage 2 experimental psychotherapy sessions.  
 
5.2.10 Long-term Follow-up 
 
All subjects will be evaluated for long-term effects 12 months (within a visit window of 
plus or minus one month) after their last MDMA-assisted psychotherapy session. This 
visit will consist of two meetings, one with the IR and the other with the therapists. 
Subjects who have withdrawn from treatment but have continued for follow-up will also 
complete this time point. 
 
At the long-term follow-up visit:  
 
a. The IR will administer the last month CAPS, PDS, BDI-II, GAF, PSQI, PTGI (in 
reference to start of the study), and DES-II. 
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. 
c. Subjects will complete a questionnaire and answer questions assessing positive 
and negative long-term effects of the study.  This session may be video recorded. 
d. The therapists will assess suicidality with the C-SSRS.  
e. General wellbeing will be assessed. 
f. A researcher who is a part of the study team may ask the subject questions about 
positive or negative effects about the study in person or on the phone. 
g. The visual analog scale will be used to collect changes in pre-existing tinnitus and 
chronic pain symptoms.  
h. Subjects will complete the termination visit at this time. 

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5.3 Randomization and Subject Numbering 
 
Prior to enrollment, subjects will be tracked with their initials and a screening number 
assigned sequentially starting at “S001”. Subjects who meet all inclusion 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 “12” 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 12001, 
second 12002, etc. 
 
In total, 23 subjects will be enrolled into the study. The randomized portion of the study 
will be blinded and there will be a 9:9:5 ratio between subjects in the active dose 1, active 
dose 2, and comparator dose conditions. An unblinded randomization monitor will 
generate the randomization list. Subjects will be assigned subject numbers, 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 primary endpoint per protocol via the web-based randomization program. 
Detailed instructions will be provided to the site in a separate document. 
 
If there is an emergency requiring knowledge of subject’s condition assignment, the blind 
may be broken for an individual subject. The investigator may be provided with the 
condition assignment in case of emergency through the web-based randomization system.  
 
5.4 Removal of Subjects from the Study 
 
Subjects can withdraw consent at any time without prejudice. The therapists can 
withdraw a subject if, in their clinical judgment, it is in the best interest of the subject or 
if the subject cannot comply with elements of the protocol that are critical for safety or 
for the scientific integrity of the study. If the therapists withdraw a subject from the 
study, the therapists will explain the reason for withdrawing the subject. The reason for 
early termination will be recorded in the subject’s source records and CRF. 
 
Subjects will be clinically monitored after withdrawal, the cause of which will be re-
corded in the subject’s source records and CRF. Whenever possible, the tests and 
evaluations listed for the termination and outcome visits will be carried out. Efforts will 
be made to obtain information about AE outcomes, if deemed necessary by the PI and/or 
sponsor. 
 
If a subject develops any exclusion criteria that in the opinion of the Medical Monitor, 
affects the safety of the subject, including psychiatric diagnosis, pregnancy or excluded 

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medications, the subject will discontinue treatment but remain in the study for follow-up 
purposes. Whenever possible, the tests and evaluations listed for the primary endpoint 
and 12-month follow-up will be carried out. Efforts will be made to obtain information 
about AE outcomes, if deemed necessary by the investigators, Medical Monitor and/or 
Sponsor. 
 
Subjects who discontinue treatment prior to the primary endpoint will be replaced. 
Individuals who replace these subjects will be assigned the next available subject 
number. Subjects who discontinue treatment after the primary endpoint in Stage 1 will 
not be replaced. If Stage 1 subjects discontinue treatment before the primary endpoint, 
the site should contact the randomization monitor for replacement instructions. Detailed 
instructions will be provided to the site in a separate document.  
 
5.5 Premature Discontinuation of the Study 
 
The Sponsor or the lead Clinical Investigator (following consultation with the Sponsor) 
has the right to discontinue this study at any time. If the trial is prematurely terminated, 
the 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 state regulations. 
 
6.0 Investigational Product 
 
6.1 Description of Active Compounds 
 
The investigational product to be used in this protocol is MDMA. This ring-substituted 
phenylisopropylamine has a complex pharmacology, but it acts most prominently as a 
monoamine releaser and uptake inhibitor [152-154]. Its direct actions on serotonergic, 
adrenergic and other receptors are considerably lower. See Section 2.2.3 and the IB for 
more information on the investigational product. 
 
6.2 Preparation and Administration 
 
In this study, 23 subjects will be randomized to the three conditions described in Table 5 
(below). The blind will be broken for each subject after the primary endpoint is 
completed. The subjects who received comparator dose MDMA will be offered the 
opportunity to enroll in an open-label Stage 2 where they will receive one of two active 
doses of MDMA-assisted psychotherapy. Stage 2 visits will be conducted in a manner 
similar to Stage 1. 
 

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6.2.1 Doses 
 
Table 5. Dose Regimen 
 
Stage 1 Drug Doses  
Experimental 
Session 
Dose 
Initial 
Dose 
Optional 
Supplemental 
Dose 
Min-Max 
Cumulative 
Dose 
Min-Max 
Cumulative 
Dose with 
Titration 
1, 2, and 3 
Active Dose 1  
125 mg 
62.5 mg 
125-187.5 
mg 
 
1 and 2  
Active Dose 2  
100 mg 
50 mg 
100-150 mg 
 
3  
Active Dose 2 
100 mg 
50 mg 
100-150 mg 
 
+ Optional  
Titration Dose 
25 mg 
12.5 mg 
 
125-187.5 mg 
1 and 2  
Comparator 
Dose 
40 mg 
20 mg 
40-60 mg 
 
 
 
Stage 2 Drug Doses 
Experimental 
Session 
Dose 
Initial 
Dose 
Optional 
Supplemental 
Dose 
Min-Max 
Cumulative 
Dose 
Min-Max 
Cumulative 
Dose with 
Titration 
1 
Active Dose 2 
100 mg 
50 mg 
100-150 mg 
 
2 and 3 
Active Dose 2 
100 mg 
50 mg 
100-150 mg 
 
+ Optional 
Titration Dose 
25 mg 
12.5 mg 
 
125-187.5 mg 
 
6.2.2 Compounding 
 
MDMA in bulk will be sent from a Schedule 1 licensed storage facility to the Drug 
Enforcement Agency (DEA) Schedule I license holder for the study. The Schedule I 
license holder and unblinded randomization monitor will oversee compounding by a 
pharmacist in a manner that will maintain the blind for the Schedule I license holder. The 
pharmacist will provide bulk lactose for compounding MDMA capsules. The pharmacist 
will weigh the MDMA into doses of 125 mg, 100 mg, 62.5 mg, 50 mg, 40 mg, 20 mg, 
and 12.5 mg (calculated as the weight of the hydrochloride salt) and placed in gelatin 
capsules with lactose. Capsules for the initial dose will be clearly differentiated from 
capsules used for the supplemental dose. All capsules will be compounded so that they 
weigh the same amount, but contain varying amounts of MDMA and lactose.  
 
The encapsulation will be performed by a pharmacist who has the appropriate skills. The 
MDMA will be weighed out (calculated as the weight of the hydrochloride salt) into 
gelatin capsules in combination with lactose used to ensure that all capsules have similar 
appearance and weight. Capsules for all experimental, double-blind sessions will be 

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prepared in such a way as to prevent Clinical Investigators and subjects from 
distinguishing contents of active dose and comparator dose capsules. Dosage for open-
label sessions will be clearly indicated in the packaging. 
 
6.2.3 Labeling 
 
The IP for each experimental session will be packaged in one primary container, labeled 
with a unique container number, protocol number, drug name, lot number, sponsor name, 
experimental session number, stage, and a statement that the drug is restricted to clinical 
trial use only. All drug labels will comply with federal and state regulations and will be 
provided in English. The initial and supplemental dose will be packaged in separate 
labeled “inner envelopes” within the primary container. There will be one primary 
container per subject per experimental session. The sponsor randomization monitor will 
oversee the process of blinded drug packaging conducted by the pharmacist according to 
the randomization list. This list will not be shared with any blinded site or sponsor staff. 
The pharmacist and randomization monitor will be the only staff who are unblinded.  
 
Figure 1. Examples of Drug Labels  
 
 
 
 
 
 
 
 
Stage 1 Primary Container Labels 
       Blinded 
 
 
 
 
 
Open Label Session 3 
 
Container Label – MAPS Study # MP-12 
Lot # XXX 
Container # XXX  
Stage 1  
 
Subject #____________  
 
Experimental Session #___  
Administer as per protocol Investigational Use 
Only 
 
Container Label – MAPS Study # MP-12 
Stage 1 Open Label 
100mg + 25mg & 50mg +12.5mg MDMA  
Lot # XXX 
Container # XXX  
 
Subject #____________  
Experimental Session #3 
Administer as per protocol Investigational Use Only 
 
 
Container Label – MAPS Study # MP-12 
Stage 1 Open Label 
125mg & 62.5mg MDMA 
Lot # XXX 
Container # XXX  
 
Subject #____________  
Experimental Session #1 
Administer as per protocol Investigational Use Only 
 
 
 
Holding Box Labels 
 
Holding Box Label 
MAPS Study# MP-12 
Investigational Product: MDMA  
Dose: XXmg 
Lot #: XXX 
Administer as per protocol 
Caution-Limited by Law to Investigational Use Only 

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Stage 1 Inner Envelope Labels 
                Blinded 
 
 
 
 
Blinded 
Stage 1                    Container # XXX 
INITIAL DOSE 
Subject #_________Ex. Ses # ______ 
 
Stage 1                    Container # XXX 
SUPPLEMENTAL DOSE 
Subject #_________Ex. Ses # ______ 
 
Open Label Session 3 
 
Open Label Session 3 
Stage 1                    Open Label 
INITIAL DOSE 100mg 
Subject #_________Ex. Ses # ___ 
 
Stage 1                  Open Label  
SUPPLEMENTAL DOSE 50mg 
Subject #_________Ex. Ses # ___ 
Stage 1                    Open Label 
INITIAL DOSE 25mg 
Subject #_________Ex. Ses # ___ 
 
Stage 1                  Open Label  
SUPPLEMENTAL DOSE 12.5mg 
Subject #_________Ex. Ses # ____ 
 
Stage 2 Primary Container Labels 
       Open Label Session 1 
 
 
         Open Label Session 2 or 3 
 
         
Container Label – MAPS Study # MP-12 
Stage 2 
100mg & 50mg MDMA 
Lot # XXX 
Container # XXX  
 
Subject #____________  
Experimental Session #1 
Administer as per protocol Investigational Use Only 
 
Container Label – MAPS Study # MP-12 
Stage 2 
100+25mg & 50+12.5mg MDMA 
Lot # XXX 
Container # XXX  
 
Subject #____________  
Experimental Session #___  
Administer as per protocol Investigational Use Only 
 
Stage 2 Inner Envelope Labels 
 Open Label Session 1 
 
        Open Label Session 1 
 
Stage 2                    Open Label 100mg 
INITIAL DOSE 
Subject #_________Ex. Ses # 1 
 
Stage 2                   Open Label 50mg 
SUPPLEMENTAL DOSE 
Subject #_________Ex. Ses # 1 
 
 
Open Label Session 2 or 3 
 
 
 
Open Label Session 2 or 3 
Stage 2                    Open Label 100mg 
INITIAL DOSE 
Subject #_________Ex. Ses # ___ 
 
Stage 2                   Open Label 50mg 
SUPPLEMENTAL DOSE 
Subject #_________Ex. Ses # ___ 
Stage 2                    Open Label 25mg 
INITIAL DOSE 
Subject #_________Ex. Ses # ___ 
 
Stage 2                   Open Label 12.5mg 
SUPPLEMENTAL DOSE 
Subject #_________Ex. Ses # ____ 
 
Each dose will consist of the specified amount of racemic MDMA mixed with an inactive 
substance, such as lactose, to prevent the therapists from distinguishing doses through 
weight or appearance of the capsules. Initial doses will be distinguished from 
supplemental doses through labeling them to ensure that the correct dose is administered 
at the scheduled time. Each dose of MDMA will be administered along with a glass of 
water or electrolyte-containing fluid. MDMA will be administered in the same manner 
during each experimental session.  
 
6.3 Drug Accountability 
 
Forms will be provided to track drug accountability and administration throughout the 
study. Blinded drug accountability and administration logs will be reviewed during 

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routine monitoring visits. MDMA will be handled in accordance with all state and federal 
regulations and forms pertaining to the use of controlled substances, and forms will be 
maintained by the Schedule 1 License Holder.  
 
Each primary container label will contain a unique container number for the drug 
assigned to a single experimental session. The container numbers will be used to track 
drug administration in the Source Record and the drug administration log. The web-based 
randomization system will enable tracking of blinded primary containers for drug 
accountability purposes. 
 
6.4 Drug Storage and Handling  
 
MDMA is a Schedule I compound and will be stored and handled in compliance with all 
relevant federal and state regulations. In accordance with these requirements, the 
Schedule I license holder will be responsible for storing, dispensing, and administering 
the MDMA. It will be stored in a secure safe in accordance with federal and state 
regulations.   
 
IP will only be removed for a single experimental session at a time and will be 
administered orally at the office of the Principal Clinical Investigator (PI). All doses 
administered will be recorded on the appropriate accountability and administration logs. 
Only the initial dose is required to be given at each experimental session. Supplemental 
doses are provided for each experimental session but are optional to use. In addition, the 
clinical titration doses with corresponding supplemental dose are provided in Stage 2 
second and third experimental sessions and are optional to use. 
 
The Schedule 1 License Holder will dispense the appropriate container number for each 
experimental session.  If an optional dose is not administered, the unused capsules will be 
kept in their respective inner envelopes inside of the primary container in the safe for 
drug accountability.  
 
Records pertaining to the use of scheduled, regulated compounds will be maintained in 
accordance with relevant federal and state regulations.   
 

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6.5 MDMA Stability 
 
Complete details on the chemistry, manufacturing, and control of the MDMA to be used 
are described in Drug Master file (DMF) # 6293. As described in that file, MDMA was 
prepared for human consumption in 1985 by David Nichols, Ph.D., at the Dept. of 
Medicinal Chemistry and Pharmacology, Purdue University.  The identity and purity of 
this MDMA was confirmed using High Performance Liquid Chromatography (HPLC) in 
1997 as described in DMF # 6293 and was found to be 99.87% pure. On August 12, 
2002, Chemic Laboratories reanalyzed the MDMA at the request of the sponsor prior to 
starting MAPS’ first U.S. pilot study of MDMA-assisted psychotherapy in people with 
PTSD. The analysis found the MDMA to be more than 99.7% pure. A more recent 
analysis performed by Nichols at the request of researcher Dr. Carl Hart on February, 
2006, continued to find a high degree of purity. This analysis found the MDMA in 
question to be 99.9% pure. This MDMA is currently in use in an ongoing investigation of 
MDMA-assisted psychotherapy in the U.S., was also used in MP-1 with drug 
administration ending in 2008, and it was also used in a non-sponsor supported study in 
2006 [155]. 
 
7.0 Risks of Participation 
 
7.1 Risks and Discomforts Associated with Psychotherapy Sessions and Assessment 
of Measures 
 
In preparation for drug-assisted psychotherapy sessions, blood draws and a full medical 
examination are required to establish eligibility for the study. Temporary discomfort, 
inflammation, or infection could arise as a result of sampling blood at the punctured vein. 
Submitting to a full medical examination may also cause discomfort or psychological 
distress. Since medical examinations and blood draws are required to establish eligibility 
for the study, they cannot be omitted from the protocol. 
 
During screening, non-drug and drug-assisted psychotherapy sessions and assessment of 
study measures, 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 may be recorded to audio and video for research and training 
purposes. Subjects may feel uncomfortable with having their sessions recorded. Subjects 
will have access to recordings if they request them. The recordings are necessary for 
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Subjects will receive information on who will have access to any of their recordings and 
will have control over any presentation of this material beyond viewing by researchers or 
regulatory agencies. 
 
7.2 Risks of Receiving MDMA 
 
Spontaneously reported reactions and common adverse effects of MDMA are modest and 
have generally not been associated with serious discomfort by healthy volunteers in 
previous studies. Common reactions include lack of appetite, insomnia, dizziness, tight 
jaw or bruxism (tooth-grinding), difficulty concentrating, impaired gait or balance, dry 
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 subjects in both conditions in MAPS study MP-1 (N=23), tight jaw, nausea, 
impaired gait/balance, and sensitivity to cold were more often reported by subjects in the 
MDMA than the placebo condition, and irritability was slightly more likely to be reported 
in the placebo condition. Additionally, subjects in the MDMA condition were more likely 
to report muscle tension in various body parts and diarrhea.  
 
These effects are transient and diminish as drug effects wane. Sub-acute effects that may 
either continue for the next 24 hours or appear later include insomnia, fatigue, needing 
more sleep, weakness, heavy legs, dry mouth, low mood or irritability. Sub-acute effects 
are reported less often than acute effects. More information on spontaneously reported 
reactions is described in the IB.  
 
MDMA may produce mild alterations in sensory perception and altered perception of 
time [66, 75, 156]. Women may be more sensitive to these effects [110].  MDMA acutely 
affects attention, information processing, and memory. MDMA acutely impairs verbal 
memory and recall for object location without affecting recall of complex scene changes 
[157]. 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 sponsor’s Investigator 
Brochure.  
 

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7.2.1 Cardiovascular and Sympathomimetic Effects 
 
The highest dose to be employed in this study, active dose 1 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, peak 
blood pressure values were higher than 140/90 mmHg. Clinical intervention was not 
required in any of these cases. Nonetheless, careful monitoring of subjects and predefined 
contingency plans will allow the researchers to rapidly identify and manage any related 
toxicity. For more information, see the sponsor’s Investigator Brochure. 
 
Risks posed by elevated blood pressure will be addressed by excluding people with pre-
existing hypertension and monitoring blood pressure and pulse, as described in Section 
5.1.2. During experimental sessions the co-therapists will continually evaluate the patient 
for increasing blood pressure and signs or symptoms of a developing hypertensive or 
other cardiovascular emergency. Subjects reporting chest pain, shortness of breath or 
neurological symptoms or other potential indicators of hypertension will have more 
frequent measurements and assessment by the study physician. Any subject who 
experiences medical complications during an experimental session will not be given 
another experimental session unless it is approved by the Clinical Investigator, study 
physician and the Medical Monitor.   
 
In case of need, subjects will be transferred to the emergency room at the closest hospital, 
as described in Section 8.4. Reasons for moving a patient to an Emergency Department 
(ED) would include, but not be limited to, severe headache in the setting of hypertension, 
angina, or neurological deficits regardless of blood pressure. The investigators and study 
physician may, at any time, make a clinical judgment to transfer the patient to the ED for 
closer monitoring and additional treatment.  
 
The study physician will be prepared to respond to rare complications of cardiovascular 
effects, such as stroke or acute myocardial infarction (AMI). The therapists will attend to 
any signs or symptoms of neurological deficit or confusion that is more extensive than 
might be expected from MDMA or from psychological distress, and will notify the study 
physician if this occurs for on-site evaluation or a decision to initiate transfer to the ED. 
If any subject has neurological deficits, as assessed by the study physician, whether or not 
they are associated with hypertensive crisis, they will receive oxygen and will be 
monitored as described above. If necessary, they will be transported to the emergency 
department at the closest Hospital for further management. If evaluation at the hospital 
reveals a nonhemorrhagic stroke, there will be time to administer recombinant tissue 
plasminogen within the three-hour time frame recommended in the American Academy 
of Neurology/American Heart Association guidelines [158, 159]. 
 
The therapists will observe the subject and note any complaints of chest pain. If a subject 
experiences ischemic type chest pain, whether or not it is associated with hypertensive 
crisis, he or she will receive heart rhythm monitoring, oxygen and will be monitored as 
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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 subject has had an AMI, they will be well within the time 
frame required for definitive therapy. The American College of Cardiology/ American 
Heart Association guidelines for the treatment of AMI recommend percutaneous 
transluminal coronary angioplasty (PTCA) as the treatment of choice when it can be 
performed within 90 minutes of arrival at the hospital in patients who present within 12 
hours of an episode of chest pain lasting more than 30 minutes and who have ECG 
evidence of AMI [160]. 
 
7.2.2 Psychological Distress 
 
Mild anxiety and depressed mood are occasionally reported one to three days after 
MDMA administration [64, 110, and see the IB]. Psychological distress from MDMA 
could arise from the first indications of drug effects until the last effects have dissipated 
(approximately three to five hours after drug administration), or even later. Anxiety or 
distress during the session may last for as little as five minutes or for as long as five hours 
or more. In addition, psychological distress could arise following an MDMA session as a 
result of subjects having difficulty integrating their experience after the MDMA effect 
has subsided. In previous Phase 1 and Phase 2 studies, these symptoms have been self-
limiting, and have responded well to reassurance from the therapists, with occasional use 
of benzodiazepines for anxiety. In this study, subjects will have the intention of 
confronting and working through 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: 
 
• Excluding people who might be more vulnerable to it (such as people diagnosed 
with bipolar affective disorder-1 or with psychotic disorders). 
• Preparatory non-drug psychotherapy sessions before the experimental session. 
• Creating an atmosphere of trust during the experimental session. 
• Close monitoring. 
• Daily contact with subjects for the period of a week after the experimental session 
• Providing non-drug integrative psychotherapy sessions. 
• Subjects will remain at the study site for the night of each experimental session to 
further reduce psychological distress. Qualified personnel will be available during 
the overnight stay to respond to the needs of the subject. Attendants will be 
instructed to contact the therapists upon request or at the appearance of signs of a 
potential serious adverse event.  
 
During the preparatory sessions, subjects will be made aware of the fact that difficult 
emotions, including grief, rage and fear or panic, may arise during experimental sessions. 
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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 six to eight hour experimental session, if the subject is still severely 
agitated or experiencing any other severe psychological distress, the following measures 
will be taken:  
 
• 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. 
• 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 
options: 
1. A psychiatric nurse, therapeutic assistant, physician, or therapist will stay with 
the subject until the time of his or her appointment with the therapists the next 
day. The therapists will then meet with the subject daily until the period of 
destabilization has passed.  
2. If a subject experiences severe, persisting emotional distress, such as panic 
attacks, severe generalized anxiety, or insomnia following an MDMA session, 
the study physician may prescribe a rescue medication such as a 
benzodiazepine, zolpidem or other anxiolytic or sedative according to the 
physician's clinical judgment. This medication will be captured on the 
concomitant medications CRF page. The physician should not prescribe an 
SSRI, SNRI or MAOI in this context unless it has been determined that the 
subject will be withdrawn from the study. Residual symptoms will be 
addressed during the frequent follow-up psychotherapy visits with the 
therapists. 
3. Hospitalization for stabilization. If a subject should become psychotic 
arrangements will be made to stabilize them and transfer them to the ED if 
necessary. 
 
Subjects hospitalized after a severe panic reaction will be suspended from the protocol 
until after recovery or stabilization, at which time the investigators will carefully evaluate 
the subject’s emotional status.   
 
For those subjects engaged in an ongoing therapeutic relationship with a psychotherapist 
or psychiatrist, the subject’s outside therapists will be involved in the management of any 
psychiatric complications. For those subjects engaged in an ongoing psychotherapeutic 

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relationship with the investigator(s), the management of any psychiatric complications 
will be undertaken by them in their capacity as therapists.   
 
7.2.3 Body Temperature 
 
MDMA administered in a controlled setting produces only a slight increase in body 
temperature [110] 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 subject. If at any time the temperature rises more than 1.5°C 
above baseline despite these efforts, the study physician will be consulted for further 
evaluation and treatment.   
 
7.2.4 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 [161, 162], 
and a third reported some developmental delays in mothers reporting use of ecstasy and 
other drugs during pregnancy [163]as discussed in the IB.   
 
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 
treatment portion of the study. 
 
7.2.5 Potential Neurotoxicity Associated with Ecstasy Use 
 
Some researchers believe that MDMA is neurotoxic in humans even at doses used in 
clinical trials [164].  However, they are basing their case on studies that employed 
inappropriately high doses of MDMA utilized in animal studies, and on human studies 
comparing the effects of repeated use of ecstasy, often along with other drugs. 
Meanwhile, another recently published meta-analysis has taken careful steps to overcome 
methodological limitations in previous work, and found only modest evidence of 
neurotoxicity [165]. We have carefully considered the risks of such neurotoxicity and 
conclude that they are minimal in the proposed study. This conclusion is supported by 
empirical and toxicokinetic evidence and is consistent with the lack of toxicity reported 
in previous clinical MDMA studies. More information on the potential neurotoxicity of 
MDMA can be found in the IB.  
 

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7.2.6 Risk Mitigation 
 
Careful review of medical screening data will be utilized to exclude potential subjects 
with pre-existing exclusionary medical conditions from the study. Study procedures have 
been developed to mitigate the risks of receiving MDMA described in detail in the IB. 
Ambient temperature will be kept at a comfortable level during experimental sessions. 
Subjects will not be allowed to drink more than 3L of fluids over the course of the 
experimental session, and fluid intake will be spread out appropriately during the session. 
Fluids administered will include electrolytes. If a subject exhibits any signs of toxicity or 
clinically significant dilutional hyponatremia despite these precautions after an 
experimental session, they will not be given another experimental session unless it is 
approved by the Clinical Investigator, study physician and the Medical Monitor.   
 
7.3 Abuse Liability 
 
Findings in humans and animals suggests that MDMA possesses moderate abuse 
potential that is higher than that reported for “classic hallucinogens” like psilocybin, but 
lower than that reported for psychostimulants such as cocaine or methamphetamine. 
More information on abuse liability is provided in the IB. 
 
Whether MDMA-assisted psychotherapy will cause PTSD patients to develop symptoms 
of abuse is an open question that the sponsor is addressing on an ongoing basis. Based on 
long-term follow-up data from two sponsor-supported studies (N=32), only one subject 
took Ecstasy after completing the study and failed to reproduce the experience from the 
study, and a number of subjects volunteered that they would never seek out Ecstasy 
outside a legal, controlled, therapeutic setting. In addition, negative results from MDMA-
specific drug testing data obtained from the Swiss study MP-2 (N=12) supports that none 
of these subjects took Ecstasy outside of the study during the long-term follow-up period.   
 
Diversion is not an issue in this protocol because MDMA will only be administered 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 subject, including any abnormal sign (e.g. abnormal physical 
exam or laboratory finding), symptom, or disease, temporally associated with the 
subjects’ 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.  
 

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An unexpected adverse event is one that is not listed in the current IB or an event that is 
by nature more specific or more severe than a listed event. 
 
All AEs will be monitored by the therapists until resolution or, if the AE becomes 
chronic, a cause identified.  If an AE is unresolved at the conclusion of the protocol, a 
clinical assessment will be made by the investigator and/or Medical Monitor as to 
whether continued follow-up of the AE is warranted. 
 
The severity of events reported on the “Adverse Events” CRF will be determined by the 
study physician as: 
 
• Mild: No limitation in normal daily activity. 
• Moderate: Some limitation in normal daily activity. 
• Severe: Unable to perform normal daily activity. 
 
The relationship of the study treatment to an AE will be determined by the study 
physician based on the following definitions: 
 
1. Not Related 
 
The AE is not related if exposure to the investigational product has not occurred, or the 
occurrence of the AE is not reasonably related in time, or the AE is considered unlikely 
to be related to use of the investigational product, i.e. there are no facts (evidence) or 
arguments to suggest a causal relationship, or the AE is more likely related to the 
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. 
 

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8.2 Spontaneously Reported Reactions  
 
Commonly expected spontaneously reported reactions are collected on a separate CRF 
page and will be categorized as mild, moderate, or severe. Common, expected reactions 
are defined as those most frequently reported in the literature and include:  Anxiety, 
Diarrhea, Difficulty Concentrating, Dizziness, Drowsiness, Dry Mouth, Fatigue, 
Headache, Heavy Legs, Impaired Gait/Balance, Impaired Judgment, Increased 
Irritability, Insomnia, Jaw Clenching or Tight Jaw, Lack of Appetite, Low Mood, Muscle 
Tension, Nausea, Need More Sleep, Nystagmus, Parasthesias, Perspiration, Restlessness, 
Rumination (increased private worries), Sensitivity to Cold, Thirst, and Weakness. 
Spontaneously reported reactions will be collected during the experimental session and 
the seven days of telephone contact following the integrative session that occurs on the 
day after each experimental session. Each reported reaction will be actively followed 
during follow-up phone calls or visits until resolution. Any reported event that is not 
listed as a Spontaneously Reported Reaction will be collected as an Adverse Event 
following the plan in Section 8.5. Any common reaction lasting longer than seven days 
will be tracked as an adverse event in order to obtain a resolution date. 
 
8.3 Serious Adverse Events 
 
An SAE is defined as any untoward medical occurrence that at any dose: 
 
• Results in death. 
• Is life-threatening (i.e., the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
• Requires or prolongs inpatient hospitalization. 
• Results in persistent or significant disability/incapacity (i.e., the event causes 
substantial disruption of a person’s ability to conduct normal life functions). 
• Results in a congenital anomaly/birth defect. 
• Requires intervention to prevent permanent impairment or damage. 
• Is an important and significant medical event that may not be immediately life-
threatening or resulting in death or hospitalization, but based upon appropriate 
medical judgment, may jeopardize the patient/subject or may require intervention 
to prevent one of the other outcomes listed above. 
 
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 study 
physician, 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 
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trial.  Hospitalization for cosmetics, non-emergency prophylaxis or abortion does not  
result in an SAE report unless, in the view of the study physician, hospitalization for 
these procedures was prolonged as a result of participation in the clinical trial. 
 
8.4 Medical Emergencies 
 
The sessions will be conducted in a private practice setting, 1.2 miles away from the 
Boulder Community Hospital, where emergency equipment is immediately available. 
The study physician will be available in the case of medical emergencies and will be 
three miles away from the study site during experimental sessions. The therapists or study 
physician will be available via mobile phone or pager throughout the study if any 
problem occurs when a subject is not at the site, and they will continue to see their 
outside therapist throughout the study. For a recently completed Phase 2 trial, the 
Sponsor has established contingency plans for responding to those AEs that appear most 
likely, based on a comprehensive review of literature described in the current IB. Similar 
contingency plans will be used in this protocol. The site will provide an Automated 
External Defibrillator (AED). The therapists will maintain BLS certification.  
 
With these personnel and equipment, the therapists or study physician will be able to 
perform basic cardiac life support if necessary and call Emergency Medical Services 
(EMS) to transport the subject to the ED at the closest hospital. In the event of a medical 
emergency or any other medical problem, the study physician will be immediately 
available by phone, and based on his assessment of the situation, he will make the 
decision to either evaluate the subject himself at the site, have the therapists call EMS to 
transport the subject to the ED, or instruct the therapists to take the subject to the ED 
where he will meet them. 
 
8.5 Adverse Event Collection 
 
The study physician will be responsible for reviewing and confirming all AEs and SAEs 
collected during the study. The therapists will collect AEs during study visits after 
enrollment.  
 
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 
study physician, Clinical Investigator (CI), or designee should call the CRA during 
normal working hours and verbally inform the CRA of the SAE. During off business 
hours or if medical advice is needed immediately please call the Sponsor Medical 
Monitor. An SAE reporting instruction with all contact numbers will be provided to the 
site prior to study start.   
 

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Medical Monitor:  
 
Michael C. Mithoefer  
Email: mmithoefer@mac.com  
Telephone number: 843-849-6899 
Fax number: 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: 
 
• All SAEs will be collected through subject termination. 
• All AEs and spontaneously reported reactions will be collected on the day of drug 
administration and for seven days after each experimental session. 
• Any spontaneously reported reactions that have not resolved to the subject’s 
baseline level of severity after seven days will be collected on the Adverse Event 
Report page until resolution. 
• Events requiring medical attention will be collected from enrollment through the 
subject’s last two-month follow-up. 
• Events related to planned treatments or physician visits for baseline conditions 
collected in the Medical History will not be collected unless there is an 
exacerbation of the condition. 
• Any Adverse Event leading to withdrawal from the protocol will be collected 
throughout the study. 
• All AEs related to changes in psychiatric status will be collected throughout the 
study. 
 
A Memory aid card will be provided to the 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 follow-up period between the end of Stage 
1/Stage 2 and the 12-month follow-up evaluation. The memory aid card will not be 
collected, but information from the card will be used to aid the subjects in providing 
information to the investigator. This information may be collected by phone. 
 
9.0 Concomitant Medications and Tapering Instructions 
 
The study physician will record concomitant medications during screening. If the subject 
is being treated with psychiatric drugs at the time he or she is recruited into the study, the 
prospective subject will be encouraged to discuss medication tapering with his or her 
outside treating physician, if any, and will be required to give the study physician and PI 
permission to do so as well. The drugs will then be tapered in an appropriate fashion to 
avoid withdrawal effects. They will be discontinued long enough before the first 
experimental session to avoid the possibility of any drug-drug interaction (the interval 
will be at least five times the particular drug and active metabolites’ half-life, plus one 
week for stabilization).  
 

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The therapists will request information about any changes in medication just prior to each 
experimental session. The study physician will be responsible for reviewing and 
confirming all medications collected during the study.  
 
All medications, over the counter (OTC) and prescription will be collected from 
screening through seven days after the last MDMA session. From seven days after the 
last MDMA session through study termination only prescription or OTC medications 
taken to treat AEs will be collected. Throughout the protocol all medications used to treat 
AEs will be collected, as described in Section 8.5, and all changes including 
discontinuations or additions to psychiatric medications will be collected. Medications 
will be recorded on the concomitant medications CRF.   
 
Subjects must be willing to refrain from taking any psychiatric medications during Stage 
1 and Stage 2, with the exception of gabapentin when prescribed for pain control. If the 
subject is on stimulants for ADHD at baseline, they can continue to use them at the same 
dose and frequency as long as they discontinue five half-lives before each experimental 
session and do not restart for ten days after each experimental session. Individuals using 
opiates for pain management will be asked to decrease the dose or avoid taking their pain 
medication for 24 hours prior to experimental sessions if possible, as these medications 
may reduce the efficacy of MDMA. Subjects will be permitted to take their prescribed 
opiate medication during this period if necessitated by pain flare-ups.  
 

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Table 6. Medication Tapering Table 
Generic Name Brand Name 
Half-life (hours) 
Including Active Metabolites 
Days for Washout 
alprazolam 
Xanax 
11 
3 
aripiprazole 
Abilify 
75 
16 
atomoxetine 
Strattera 
5-24 
5 
bupropion 
Wellbutrin 
21 
5 
citalopram 
Celexa 
35 
8 
clonazepam 
Klonopin 
30-40 
8 
diazepam 
Valium 
20-70 
15 
duloxetine 
Cymbalta 
12 
3 
escitalopram 
Lexapro 
32 
7 
fluoxetine 
Prozac 
7-9 (days) 
45 
imiprimine 
Tofranil 
6-18 
4 
lamotrigine 
Lamictal 
25 
6 
lorazepam 
Ativan 
12 
3 
mirtazapine 
Remeron 
20-40 
8 
olanzapine 
Zyprexa 
21-54 
11 
paroxetine 
Paxil 
21 
5 
prazosin 
Minipress 
2-3 
1 
quetiapine 
Seroquel 
6 
2 
risperidone 
Risperdal 
3-20 
4 
sertraline 
Zoloft 
26 
6 
temazepam 
Restoril 
8-12 
3 
trazodone 
Desyrel 
9 
2 
venlafaxine 
Effexor 
12 
3 
ziprazidone 
Geodon 
7 
2 
zolpidem 
Ambien 
2.5 
<1 
 
The study physician may prescribe a designated rescue medication in the event of 
symptoms that require it during or after the experimental session (e.g. insomnia or severe 
anxiety that does not respond to other management outlined in the treatment manual). 
Rescue medications may be a benzodiazepine, zolpidem or other anxiolytic or sedative 
according to the physician's clinical judgment. SSRIs, SNRIs, and MAOIs should not be 
used as rescue medications.  
 
Subjects must agree that, for one week preceding the MDMA session: 
 
a. They will refrain from taking any herbal supplement (except with prior approval 
of the research team).  
b. They will refrain from taking any prescription or nonprescription medications 
(with the exception of non-steroidal anti-inflammatory drugs, acetaminophen, 
birth control pills, thyroid hormones, or other medications approved by the 
research team).  

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Subjects will receive a memory aid card for use between the end of Stage1/Stage 2 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 and discontinue birth control after the final two-month assessment if 
necessary. 
 
10.0 Clinical Laboratory Assessments 
 
The study physician will examine laboratory assessments gathered in screening for 
assessing subject eligibility. The study physician will use a list of normal ranges to 
conclude whether subjects are eligible for the protocol, and will indicate justification for 
admitting subjects with abnormal values, after consultation with the medical monitor. 
 
The following laboratory assessments will be performed as a part of screening:  
 
• Serum electrolytes and metabolic profile. 
o ALT/SGPT 
o Albumin:globulin (A:G) ratio 
o Albumin, serum 
o Alkaline phosphatase, serum 
o AST/SGOT 
o Bilirubin, total 
o BUN:creatinine ratio 
o Calcium, serum 
o Carbon dioxide 
o Chloride, serum 
o Creatinine, serum 
o Globulin, total 
o Glucose, serum 
o Potassium, serum 
o Protein, total, serum 
o Sodium, serum 
• CBC. 
o Hematocrit 
o Hemoglobin 
o MCV 
o MCH 
o MCHC 
o RDW 
o Percentage and absolute differential counts 
o RBC 
o Red blood cell count 
o White blood cell count 
• Urinalysis. 

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o Color 
o Appearance 
o Specific gravity 
o pH 
o Protein 
o Glucose 
o Ketones 
o Occult blood 
o Leukocyte esterase 
o Nitrite 
o Bilirubin 
o Urobilinogen 
• Thyroid function. 
o TSH high sensitivity 
o Free T4 
o Free T3 
• HIV serology. 
• Urine-dip pregnancy test for females of childbearing potential. 
• Urinary drug test will be performed.  
 
The laboratory that will perform assessments other than the urine drug screen and 
pregnancy test is: 
 
LabCorp 
5377 Manhattan Circle 100 
Boulder, CO 80303 
Telephone number: 303-499-1138 
 
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. From the start of the study, videos from selected sessions will be 
reviewed for adherence to the treatment manual, and inter-rater reliability. Adherence 
will be checked by monitoring and by review of selected video data. During each 
monitoring visit, source data verification will be performed to ensure compliance, 
including accurate and complete recording of data on CRFs, source documents, and drug 
accountability records. Electronic CRFs supplied by the Sponsor will be completed for 
each subject enrolled. Monitoring and auditing procedures will be supplied in a separate 
document.  
 
During or after the study, the regulatory authorities, the IRB, and/or representatives of the 
Sponsor may request access to all source documents, CRFs and other protocol 
documentation for on-site audit or inspection. 

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12.0 Data Analysis  
 
The Sponsor will judge the clinical and statistical significance of the study based on a 
comparison of observer-blind data collected at baseline and the primary endpoint using 
the primary outcome measure, which is the CAPS. Descriptive statistics will be computed 
overall and within the three dose conditions for all available data from outcome 
measures, including minimum, maximum, average, and standard deviation. Distributional 
characteristics will be examined for outliers and extreme values and, if either is evident, 
nonparametric statistics will be utilized in the analysis. Effect size of the three doses for 
all outcome measures for Stage 1, Stage 2, and 12 months after the final experimental 
session will be estimated using Cohen’s techniques. 
 
The Sponsor will examine each active dose group and the comparator dose group for 
homogeneity through comparing demographic characteristics. 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. 
 
The Sponsor will examine CAPS scores for the primary outcome analysis at baseline and 
the primary endpoint in each active dose and comparator dose conditions. Active dose 1 
and active dose 2 CAPS data at the primary endpoint will be tested for equivalence using 
confidence intervals. If the two groups are found to be equivalent, then outcomes for the 
active dose groups will be combined and will be tested for significant differences from 
the comparator group using difference scores in independent sample t-tests, with p value 
set at 0.05. If CAPS scores for active dose 1 are not equivalent to active dose 2, then 
analysis of variance (ANOVA) will be used to compare outcomes from all three groups. 
Additional exploratory analyses comparing the effect of a third experimental session with 
either active dose 1 or active dose 2 may be conducted if sufficient group sizes are 
attained, and analyses comparing outcomes at third session may be conducted with and 
without active dose 2 participants who elected to take active dose 1 during the third 
experimental session. 
 
For exploratory purposes, the sponsor will examine individual PDS, BDI-II, GAF, PSQI, 
PTGI, and DES-II scores at baseline and the primary endpoint in each active dose and 
comparator dose conditions. Analysis of variance, or nonparametric analysis if 
assumptions are not met, will be used to compare the dose conditions for change in BDI-
II, PTGI, PSQI, GAF, and DES-II scores separately. If scores cannot be examined 
sufficiently in this model, then analyses will compare available data through the use of 
difference scores.  
 
Changes in CAPS from the primary/secondary endpoint to the two-month follow-up in 
Stage 1/Stage 2 will be compared for a within-subject analysis with p value set at 0.05 to 
see whether a third session with an active dose produces further decline in symptoms. 
Stage 2 data will only be combined with open label Stage 1 data for this analysis, if data 
is equivalent between stages based on confidence intervals. Subjects who receive active 

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dose 1 in the third experimental session may be compared to subjects who receive active 
dose 2 for exploratory purposes if at least three subjects are in either group. If less than 
three subjects from the 100mg group select active dose 2, then analyses will be conducted 
with and without these subjects to determine the effect of a third session with active dose 
1. The sponsor will perform an exploratory within-subject analysis of crossover 
participants in Stage 2. 
 
A repeated measures analysis of variance (ANOVA) will be performed upon PDS scores 
at baseline, after each experimental session, and at the end of Stage 1, with p value set at 
0.05. Condition will serve as a between-subjects factor. Results of ANOVA analysis will 
be used to examine the effects of each experimental session on self-reported PTSD 
symptom severity. PDS and CAPS scores will be correlated via Pearson’s product 
moment correlation at baseline and the primary endpoint to provide a comparison of a 
self-report measure with a clinician-administered measure of PTSD symptoms.   
 
The sponsor will compute descriptive statistics for SOCQ scores from after each MDMA-
assisted psychotherapy session, and average SOCQ scores for blinded experimental 
sessions will be compared between conditions. The data will be explored for effects of 
condition on domain scores in the SOCQ. 
 
The sponsor will collect Changes in Tinnitus and/or Pain visual analog scale scores from 
any subject reporting tinnitus or chronic pain during each point of administration, 
including baseline, experimental and integrative sessions, the primary endpoint, and two-
month follow-up. The sponsor will plot out and examine all changes in tinnitus and/or 
pain visual analog scale scores across both groups and in each active dose group and the 
comparator dose group for trends. Formal analysis of changes in tinnitus and/or pain 
visual analog scale scores will only occur if three or more subjects complete changes in 
tinnitus and/or pain visual analog scale at baseline and primary endpoint. Likewise, 
formal between-groups analyses will not be performed if all primary endpoint scores are 
from subjects assigned to the same condition. The sponsor will perform an independent t-
test on the difference between baseline and primary endpoint Changes in Tinnitus and/or 
Pain visual analog scale scores between each active dose and comparator dose conditions, 
with p. set at 0.05. If the only scores available are for subjects in a single condition, then 
a paired t-test will be performed comparing baseline and primary endpoint Changes in 
Tinnitus and/or Pain visual analog scale scores, with p. set at 0.05.    
 
Perception of the experimental sessions will be examined during Stage 1 and Stage 2, 
before and after subjects have undergone a third experimental session. The results of this 
exploratory analysis will inform the sponsor of expectancies and the value of the third 
session for future protocol development. These data may be correlated with 
primary/secondary endpoint CAPS data compared to end of Stage 1/Stage 2 CAPS data 
to assess the potential contribution of expectation and self-reported response to changes 
in PTSD symptoms.  
 

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The sponsor will compare CAPS, PDS, PTGI, GAF, BDI-II, PSQI, and DES-II, scores at 
the final two-month follow-up assessment to the 12-month follow-up using difference 
scores in an independent t-test for a within-subject analysis with p value set at 0.05. 
 
The sponsor will compare baseline and primary endpoint RBANS and PASAT scores in 
each active dose group and comparator dose groups. Active dose 1 and active dose 2 
RBANS and PASAT data will be tested for equivalence using confidence intervals. If the 
two groups are found to be equivalent, then outcomes for the active dose groups will be 
combined and will be tested for significant differences from the comparator group using 
difference scores in independent sample t-tests, with p value set at 0.05. If scores for 
active dose 1 are not equivalent to active dose 2, then analysis of variance (ANOVA) will 
be used to compare outcomes from all three groups.  The sponsor will examine the effects 
of maximal exposure to MDMA on neurocognitive function using the RBANS and 
PASAT by performing a within-subject repeated measures ANOVA with time of 
administration as a within-subjects factor.  
 
The sponsor will collect ratings of adherence to the treatment manual from specifically 
selected types of sessions. Descriptive statistics will be computed for each adherence 
scale within a given session. The sponsor will explore the factors and structure of the 
measures of adherence to assist in further development of adherence and competence 
measures. If sufficient data is available, the sponsor will correlate the mean adherence 
ratings for adherence scale and session type with Global CAPS scores to investigate the 
effects of adherence to the treatment manual on reduction in PTSD symptoms. If it is 
found that there are specific factors within the adherence scales, then the factor will be 
correlated with Global CAPS score. 
 
Subjects who discontinue treatment prior to the primary endpoint will be asked to 
complete an outcome assessment prior to continuing to the long-term follow-up. The data 
from these subjects will be tested for equivalence to data from subjects completing the 
study per protocol. If found to be equivalent, data from these subjects will be presented as 
an exploratory Intent-to-treat analysis to examine results without bias towards subjects 
more likely to complete the study per protocol, with last observation carried forward. 
 
The therapists will record average baseline and peak and post-drug blood pressure, heart 
rate and body temperature for subjects during experimental sessions. The therapists will 
also record spontaneously reported reactions and AEs, as described in Section 8.5. 
Descriptive statistics will be computed for vital signs and subjective distress during each 
experimental or open-label session. Whenever possible, the sponsor will compare peak 
blood pressure, heart rate and body temperature after active dose 1, active dose 2 and 
comparator dose. Frequency tables will be produced on prevalence of spontaneously 
reported reactions and AEs. 
 
An interim analysis may be completed when all subjects have completed Stage 1 and 
Stage 2, but possibly before all subjects have completed the 12-month follow-up 
evaluation. Additionally, an interim analysis may be performed after all subjects have 
completed Stage 1 but not necessarily before all eligible subjects complete Stage 2. This 

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analysis will address safety, efficacy and process measures. Results of the interim 
analysis will have no effect on study conduct. 
 
12.1 Statistical Power 
 
This is a pilot study intended to collect and compare estimates of effect size for each 
active dose and the comparator dose. 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 U.S. 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 [166]. The estimated effect size for this study may be lower as a 
result of comparing each active dose with the comparator dose instead of with an 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 to calculate estimated statistical 
power for the primary outcome measure of this study. The calculation assumed that 
active dose 1 and active dose 2 would be equivalent and could be combined, assuming an 
effect size of 0.8 for the impact of two sessions of MDMA-assisted psychotherapy on 
symptoms of PTSD [167], reducing the effect size to account for the hypothesized effects 
of using a comparator dose of 40 mg that is higher than the 25 mg dose employed as an 
active placebo in a sponsor-supported study. The software calculated an estimated power 
of 0.33 for a comparison of 18 versus 5, 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 0.55, but higher than previously calculated prior to the 
addition of these subjects. Statistical power estimates were not available for secondary 
and exploratory measures, as they were previously not used in sponsor-supported studies. 
 
13.0 Ethics 
 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.  
 
The protocol and the ICF must be reviewed and approved by a properly constituted IRB 
and FDA before study start. Signed and dated documentation of IRB and FDA approvals 
must be provided to the sponsor. Prior to study start, the Clinical Investigator is required 
to sign a protocol signature page confirming 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. 
 

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14.0 Informed Consent 
 
The main licensed therapists are responsible for obtaining informed consent in adherence 
to GCP and according to applicable regulations prior to entering the subject into the trial. 
Information about the study must be given orally and in an understandable form. Written 
information about the trial will also be provided. The informed consent discussion must 
be conducted by a person who is qualified according to FDA regulations. The subject 
should have the opportunity to inquire about details of the MDMA-assisted session and to 
consider participation.  
 
The ICF will state the probability of random assignment to one of the active dose groups 
or the comparator dose group, however there will be a level of obfuscation, which makes 
it unclear that there is only one comparator dose of 40 mg and two active doses of 
MDMA. The ICF will indicate the comparator dose may or may not contain MDMA. If 
subjects ask about the composition of investigational product in the comparator dose 
group, the exact contents of the comparator dose will be said to include lactose and may 
or may not include MDMA, however everyone assigned to the comparator dose group 
will have the opportunity to receive active doses of clinically titrated doses of MDMA 
during Stage 2. For all subjects, the dose will be disclosed after the primary endpoint visit 
when unblinding occurs. Unblinding and debriefing at the primary endpoint will take 
place with the co-therapist team and the subject. During the debriefing, subjects will be 
informed of the contents of the investigational product they received during the blinded 
experimental sessions in Stage 1 and the contents of investigational product will be fully 
disclosed. 
 
In addition to the explanation of study visits, the information should include that access 
to original medical records and processing of coded personal information must be 
authorized. Written consent to take part in the study includes giving the investigators 
permission to view the subject’s recent medical records to assess protocol eligibility, if 
needed. Information necessary for protocol participation includes past medical history, 
psychiatric interview, physical examination, and clinical laboratory tests. 
 
Eligible subjects may only be included in the study after signing the IRB approved ICF. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. 
all of the procedures described in the protocol, including screening activities). 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 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 ICF and written information should receive approval 
from an IRB before use. The subject should be informed in a timely manner if new 
information becomes available that might affect the decision to take part in the MDMA-
assisted session. The communication of this information should be documented.  
 

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Subjects can withdraw consent at any time without prejudice. If a subject withdraws 
consent but does not revoke the Health Insurance Portability and Accountability Act 
(HIPAA) authorization, the investigators will have full access to the subject’s medical 
records, including termination visit information. If a subject revokes only the HIPAA 
authorization, the investigators will have full access to all of the subject’s medical records 
prior to the date and time of revocation. 
 
15.0 Confidentiality 
 
Every effort will be made to strictly safeguard the confidentiality of subjects in their role 
as research subjects. Removing identifying information from data and restricting access 
to researchers directly involved in assessing the subjects should prevent the dissemination 
of confidential data, with or without identifying information. Except for the screening 
log, the ICF, and a subject contact information sheet that will be stored separately from 
other documents, all data will be identified only by the subject’s initials on the source 
document and five-digit subject number.  If past medical records are needed, subjects will 
sign forms for the release of information upon consent to permit screening for protocol 
enrollment. Copies of audio and video recordings intended for sharing with subjects will 
only be marked with the subject’s subject number. Any materials mailed to subjects will 
be sent along with stamped return envelopes using the office address of the Clinical 
Investigator both as main and return address. All assessment records will be kept in a 
locked file drawer or cabinet in a locked office, and access to measures will be limited to 
regulatory agencies, researchers, and individuals analyzing data. Researchers, other than 
the investigators directly involved in the protocol, with access to data will not be 
provided with any information that would identify subjects by name or by other means, 
such as social security number.  
 
All psychotherapy sessions may be recorded to video and audio. These recordings will be 
used for manual development and potentially for training therapists to perform MDMA-
assisted psychotherapy. They are intended to record the events occurring during therapy, 
and will not serve as outcome measures. CAPS assessments may also be recorded to 
video to establish inter-rater reliability. Full names and addresses will not appear in these 
recordings.  
 

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16.0 Costs to Subjects 
 
There will be no costs to the study subjects for any study-related procedures. The sponsor 
will cover all costs of study participation, including any assessments or tests performed 
solely for the purpose of establishing eligibility for participation. Charges for treatment of 
the subject’s condition that are unrelated to the research study or any of its procedures 
will continue to be billed to the health insurance provider of the subject or to the subject 
him or herself. It is anticipated that there will not be any charges for treatment that is 
unrelated to the study except in the case of subjects who previously received therapy 
from the Clinical Investigator and who will continue to receive ongoing treatment that is 
not related to participating in the study.  The sponsor will not reimburse subjects for 
travel, food and lodging. Subjects will not be paid for participation in the study. 
 
17.0 Treatment and Compensation for Study Related Injury 
 
Treatment of a study-related emergency would first be billed to a subject’s health 
insurance provider. The sponsor will cover any direct costs relating to the treatment of a 
study-related emergency that are not covered by a subject’s health insurance. Some 
study-related emergencies can be treated by the investigators, as described in Section 8.4.  
If the study physician cannot treat a study-related emergency, then there are contingency 
plans for the transport of subjects to the nearest hospital.   
 
18.0 Record Retention 
 
Investigators must retain all study records required by the Sponsor and applicable ICH-
GCP and FDA 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.  
 
19.0 Publication Policy 
 
The sponsor recognizes the importance of communicating medical study data and 
therefore encourages publications in reputable scientific journals and presentations at 
seminars or conferences. It is understood by the PI that the information generated in this 
study will be used by the sponsor in connection with the development of the 
investigational product and therefore may be disclosed to government agencies in various 
countries. To allow for the use of information derived from the study, it is understood 
that the PI is obliged to provide the sponsor with complete test results, all study data, and 
access to all study records. It is mandatory that all data analysis is done on the official 
monitored sponsor database and that the analysis plan is agreed upon with the sponsor 
statistician. 
 

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Any results of medical investigations with the sponsor products and/or publications/ 
lectures/manuscripts based thereon, shall be exchanged and discussed by the PI and the 
sponsor clinical research representative(s) prior to submission for publication or 
presentation. Due regard shall be given to the sponsor's legitimate interests, e.g. 
manuscript authorship, obtaining optimal patient protection, coordinating and 
maintaining submissions to health authorities, and coordinating with other studies in the 
same field. 
 
The full details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this trial will be described in the Clinical Trial 
Agreement. 

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20.0 References 
 
1. 
Mithoefer, M.C., et al., The safety and efficacy of {+/-}3,4-
methylenedioxymethamphetamine-assisted psychotherapy in subjects with 
chronic, treatment-resistant posttraumatic stress disorder: the first randomized 
controlled pilot study. J Psychopharmacol, 2011. 25(4): p. 439-52. 
2. 
Mithoefer, M.C., et al., Durability of improvement in post-traumatic stress 
disorder symptoms and absence of harmful effects or drug dependency after 3,4-
methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-
term follow-up study. J Psychopharmacol, 2013. 27(1): p. 28-39. 
3. 
Oehen, P., et al., A randomized, controlled pilot study of MDMA (+/- 3,4-
Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of 
resistant, chronic Post-Traumatic Stress Disorder (PTSD). J Psychopharmacol, 
2013. 27(1): p. 40-52. 
4. 
American Psychiatric Association, Diagnostic and Statistical manual of Mental 
Disorders: 4th Edition. 4th ed. 2000, Arlington, VA.: American Psychiatric 
Association. 
5. 
Foa, E.B., et al., Effective Treatments for PTSD, Practice Guidelines from the 
International Society for Traumatic Stress Studies. Second ed. 2009, New York, 
NY: Guilford Press. 
6. 
Kessler, R.C., et al., Lifetime prevalence and age-of-onset distributions of DSM-
IV disorders in the National Comorbidity Survey Replication. Arch Gen 
Psychiatry, 2005. 62(6): p. 593-602. 
7. 
Perkonigg, A., et al., Traumatic events and post-traumatic stress disorder in the 
community: prevalence, risk factors and comorbidity. Acta Psychiatr Scand, 
2000. 101(1): p. 46-59. 
8. 
Kessler, R.C., et al., Prevalence, severity, and comorbidity of 12-month DSM-IV 
disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry, 
2005. 62(6): p. 617-27. 
9. 
Breslau, N., The epidemiology of posttraumatic stress disorder: what is the extent 
of the problem? J Clin Psychiatry, 2001. 62 Suppl 17: p. 16-22. 
10. 
Frayne, S.M., et al., Burden of medical illness in women with depression and 
posttraumatic stress disorder. Arch Intern Med, 2004. 164(12): p. 1306-12. 
11. 
Brunello, N., et al., Posttraumatic stress disorder: diagnosis and epidemiology, 
comorbidity and social consequences, biology and treatment. 
Neuropsychobiology, 2001. 43(3): p. 150-62. 
12. 
Norris, F.H., et al., Epidemiology of trauma and posttraumatic stress disorder in 
Mexico. J Abnorm Psychol, 2003. 112(4): p. 646-56. 
13. 
Sareen, J., et al., Disability and poor quality of life associated with comorbid 
anxiety disorders and physical conditions. Arch Intern Med, 2006. 166(19): p. 
2109-16. 
14. 
Zlotnick, C., et al., Epidemiology of trauma, post-traumatic stress disorder 
(PTSD) and co-morbid disorders in Chile. Psychol Med, 2006. 36(11): p. 1523-
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15. 
Alonso, J., et al., Prevalence of mental disorders in Europe: results from the 
European Study of the Epidemiology of Mental Disorders (ESEMeD) project. 
Acta Psychiatr Scand Suppl, 2004(420): p. 21-7. 
16. 
Hoge, C.W., et al., Combat duty in Iraq and Afghanistan, mental health problems, 
and barriers to care. N Engl J Med, 2004. 351(1): p. 13-22. 
17. 
Tanielian, T.L., L. Jaycox, and Rand Corporation., Invisible wounds of war : 
psychological and cognitive injuries, their consequences, and services to assist 
recovery. 2008, Santa Monica, CA: RAND. xliii, 453 p. 
18. 
de Jong, J.T., I.H. Komproe, and M. Van Ommeren, Common mental disorders in 
postconflict settings. Lancet, 2003. 361(9375): p. 2128-30. 
19. 
Thabet, A.A. and P. Vostanis, Post-traumatic stress reactions in children of war. 
J Child Psychol Psychiatry, 1999. 40(3): p. 385-91. 
20. 
Weine, S.M., et al., Psychiatric consequences of "ethnic cleansing": clinical 
assessments and trauma testimonies of newly resettled Bosnian refugees. Am J 
Psychiatry, 1995. 152(4): p. 536-42. 
21. 
Breslau, N. and G.C. Davis, Posttraumatic stress disorder in an urban population 
of young adults: risk factors for chronicity. Am J Psychiatry, 1992. 149(5): p. 
671-5. 
22. 
Seal, K.H., et al., VA mental health services utilization in Iraq and Afghanistan 
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