A Phase 1/2 Open-Label Treatment Development Study of Methylenedioxymethamphetamine (MDMA)-Assisted Cognitive-Behavioral Conjoint Therapy (CBCT) in Dyads in Which 1 Member Has Chronic Posttraumatic Stress Disorder (PTSD)
Phase: PHASE1
Conditions: Posttraumatic Stress Disorder
Sponsor: Lykos Therapeutics

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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22]. The MDMA doses to be used in this study have been used in previous studies 
sponsored by MAPS.  
 
The initial active doses are expected to produce all the commonly reported effects of 
MDMA, including changes in affect, mood, and cognition and changes in feelings of 
interpersonal closeness and trust. The supplemental dose will prolong subjective drug 
effects without producing physiological effects any greater than peak effects occurring 
after the initial dose.  
 
3.0 Protocol Objectives 
 
The overall objective of this study is to explore the safety and estimate the effect size of 
efficacy for MDMA-assisted psychotherapy in conjunction with CBCT on PTSD 
symptoms in PTSD+ participants and relationship functioning in both participants. 
 
3.1 Primary Objective 
 
The primary objective of the study is to assess changes in PTSD symptoms from baseline 
as measured by CAPS in PTSD+ participants at the Primary Endpoint. 
 
3.2 Secondary Objectives 
 
Secondary and exploratory objectives are to assess changes in the dyad’s relationship 
functioning at the Midpoint and Primary Endpoints, assess changes in self- and CSO 
participant-reported PTSD symptoms in the PTSD+ participant, and assess problems that 
often co-occur with PTSD, such as depression, sleep disturbances, maladaptive beliefs 
about self and others, and emotion regulation difficulties. 
 
• Assess changes in PTSD symptoms from baseline as measured by the CAPS in 
participants with chronic PTSD at Long-term Follow-up at 3 months and 6 
months. 
• Assess changes in self-reported PTSD symptoms from baseline as measured with 
the Posttraumatic Stress Disorder Checklist for the DSM-5 (PCL-5) at Baseline, at 
each Integrative Session, at the Midpoint, Primary Endpoint and Long-term 
Follow-up at 3 months and 6 months for both the PTSD+ participant and CSO 
participant (based on the (PTSD+ participant).  
• Assess changes in depression symptoms from baseline with the Beck Depression 
Inventory-II (BDI-II) at Baseline, Midpoint, the Primary Endpoint, and Long-term 
Follow-up at 3 months and 6 months for both participants.  
• Assess changes in self-reported sleep quality from baseline with the Pittsburgh 
Sleep Quality Index (PSQI) at Baseline, Midpoint, the Primary Endpoint, and 
Long-term Follow-up at 3 months and 6 months for both participants. 
• Assess changes in self-reported posttraumatic growth from baseline with the 
Posttraumatic Growth Inventory (PTGI) by the PTSD+ participant and CSO 
participant (based on the PTSD+ participant) at the Midpoint, the Primary 
Endpoint, and Long-term Follow-up at 3 months and 6 months. 
• Assess changes in psychological and physical aggression from baseline with the 

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

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

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Page 24 of 89 
people who are in a significant ongoing relationship, including but not limited to 
romantic relationships. Baseline screening procedures and assessments will be conducted 
for both members of the dyad. Dyads in which both members meet all Inclusion and no 
Exclusion Criteria will be enrolled. 
 
Eligible and enrolled participants will undergo a 2-month course of psychotherapy as a 
dyad that includes CBCT for PTSD integrated with MDMA-assisted psychotherapy. The 
CBCT sessions, as described in Monson and Fredman’s (2012) manual [1], will be 
integrated with elements of the Treatment Manual for MDMA-assisted Psychotherapy [2] 
in order to modify CBCT to incorporate MDMA as a catalyst for the therapeutic process. 
Sessions will be conducted by a co-therapy team and will include Preparatory Sessions, 
two Experimental Sessions of MDMA plus psychotherapy, and non-drug CBCT 
psychotherapy Integrative Sessions. The primary objective is to measure changes in 
PTSD symptoms via CAPS global severity scores in PTSD+ participants at Baseline and 
the Primary Endpoint, one month after the 15th CBCT session. Additional measures 
evaluate various qualities of the relationship between the participants. 
 
The Experimental Sessions will last 6 to 8 hours and will be scheduled 3 weeks apart, 
with an intervening course of non-drug therapy. The non-drug psychotherapy includes 
two Preparatory Sessions prior to the first Experimental Session and five Integrative 
Sessions after each Experimental Session. Integration visits will be conducted by 
telemedicine (video conferencing whenever possible, telephone if there are occasions 
when video conferencing is not technically possible) and will include both members of 
the dyad. The sessions will follow a combination of the MDMA-assisted psychotherapy 
manual and the CBCT manual, with each method modified as needed to combine the 
therapies. 
 
 

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

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

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disorders that might affect the safety or tolerability of MDMA. Dyads will be recruited 
through printed ads, Internet ads, referrals from other psychiatrists, psychotherapists, or 
physicians, and through word of mouth. Recruitment will continue until 10 dyads that 
meet all Inclusion Criteria without meeting any Exclusion Criteria are enrolled. Only 
IRB-approved recruitment materials and advertisements will be used for the study. 
 
4.2.1 Inclusion Criteria 
 
Inclusion Criteria for Participants with PTSD 
Individuals eligible to be enrolled into this protocol are participants who:  
 
1. Meet DSM-5 criteria for current PTSD with a duration of 6 months or longer  
2. Satisfies diagnostic criteria for PTSD using the CAPS  
3. Are at least 18 years old 
4. If in ongoing psychotherapy at the time participants are recruited into the study, 
participants may continue to see their outside therapist during the course of the 
study. Participants must sign a release for the Clinical Investigators to 
communicate directly with their therapist. Participants may not change therapists, 
increase the frequency of therapy, or commence any new type of therapy until 
after the evaluation session, 3 months after the final Experimental Session. 
Participants who do not live within reasonable driving distance of the study site 
(equal to or less than an estimated 2-hour drive from the study site) must be 
registered with a therapist or health clinic in the area in which they live so they 
can call for support and evaluation if necessary 
5. Are willing to refrain from taking any psychiatric medications during the study 
period, with the exception of gabapentin when prescribed for pain control. 
Individuals using opiates for pain management will be asked to decrease the dose 
or avoid taking their pain medication the morning of experimental sessions if 
possible. If the participant is on stimulants for ADHD at Baseline, they can 
continue to use them at the same dose and frequency as long as they discontinue 5 
half-lives before each MDMA-assisted session and do not restart for 10 days after 
each MDMA administration. Any psychoactive drugs, including stimulants, will 
be tapered in an appropriate fashion to avoid withdrawal effects. Medications will 
only be discontinued after consultation with the prescribing physician 
6. Agree that, for one week preceding the MDMA-assisted session will refrain from: 
a. Taking any herbal supplement (except with prior approval of the research 
team) 
b. Taking any nonprescription medications (with the exception of non-
steroidal anti-inflammatory drugs or acetaminophen unless with prior 
approval of the research team) 
c. Taking any prescription medications (with the exception of birth control 
pills, thyroid hormones or other medications approved by the research 
team) 
7. Agree to take nothing by mouth except alcohol-free liquids after 12:00 A.M. 
(midnight) the evening before the Experimental Session 
8. Refrain from the use of any psychoactive drug, with the exception of caffeine or 
nicotine, within 24 hours of each MDMA-assisted session 
9. Agree not to use caffeine or nicotine for 2 hours before and 6 hours after the dose 

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

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

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

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14. Have any current problem or a history of substance abuse which, in the opinion of 
the Clinical Investigator or Medical Monitor, might interfere with participation in 
the protocol 
15. Have a current eating disorder with active purging 
16. Have current major depressive disorder with psychotic features 
17. Have current Personality Disorders Cluster A (paranoid, schizoid, schizotypical), 
Cluster B (antisocial, borderline, histrionic, narcissistic) or Cluster C (avoidant, 
dependent, obsessive-compulsive) 
 
 
Exclusion Criteria for Dyad Participant 
Individuals not eligible to be enrolled into this protocol are those who: 
 
1. Are pregnant or nursing, or are persons of childbearing potential who are not 
practicing an effective means of birth control 
2. Have a history of, or a current primary psychotic disorder, bipolar affective 
disorder type 1 or dissociative identity disorder 
3. Have evidence or history of significant (controlled or uncontrolled) 
hematological, endocrine, cerebrovascular, cardiovascular, coronary, pulmonary, 
renal, gastrointestinal, immunocompromising, or neurological disease, including 
seizure disorder, or any other medical disorder judged by the investigator to 
significantly increase the risk of MDMA administration (Participants with 
hypothyroidism who are on adequate and stable thyroid replacement will not be 
excluded);  
If participants present with a history of glaucoma, enrollment would be allowed 
only with the approval of their ophthalmologist.  
 
4. Have hypertension using the standard criteria of the American Heart Association 
(values of 140/90 or higher assessed on three separate occasions  
5. Have liver disease with the exception of asymptomatic participants with Hepatitis 
C who have undergone additional evaluation (see “Methods”). Participants with 
Hepatitis C may be enrolled if they have received appropriate screening (see 
“Methods”) 
6. Have history of hyponatremia or hyperthermia 
7. Weigh less than 48 kg 
8. Any participant presenting current serious suicide risk, as determined through 
psychiatric interview, responses to C-SSRS, and clinical judgment of the Clinical 
Investigator will be excluded, however past history of suicide attempts is not an 
exclusion. In addition, any participant who is likely to require hospitalization 
related to suicidal ideation and behavior, in the judgment of the Clinical 
Investigator, will not be enrolled 
9. Would present a serious risk to others as established through clinical interview 
and contact with treating psychiatrist 
10. Have used “Ecstasy” (material represented as containing MDMA) more than 10 
times within the last 10 years or at least once within 6 months of the MDMA-
assisted session 
11. Require ongoing concomitant therapy with a psychiatric drug, excluding 

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gabapentin and opiates for pain management 
12. Meet DSM-5 criteria for active substance use disorder for any substance save 
caffeine or nicotine in the past 60 days 
13. Are not able to give adequate informed consent 
14. Have any current problem or a history of substance abuse which, in the opinion of 
the Clinical Investigator or Medical Monitor, might interfere with participation in 
the protocol 
15. Have diagnosis of current PTSD not in remission 
16. Have a current eating disorder with active purging 
17. Have current major depressive disorder with psychotic features 
18. Have current Personality Disorders Cluster A (paranoid, schizoid, schizotypical), 
Cluster B (antisocial, borderline, histrionic, narcissistic) or Cluster C (avoidant, 
dependent, obsessive-compulsive) 
 
5.0 Methods 
 
5.1 Measures 
 
The following outcome, safety, and process measures will be used in the study. This 
study will utilize methods described in the Treatment Manual for conducting MDMA-
assisted Psychotherapy combined with methods from the CBCT for PTSD manual. The 
integration of these manuals will provide the researcher with a consistent psychotherapy 
approach and test an investigational form of drug-assisted psychotherapy. The Treatment 
Manual is not intended to define all interactions that occur in the therapy. All 
psychotherapy sessions, including Experimental Sessions, may be recorded to audio and 
video, with all recordings preserved for research and training purposes.  

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

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

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

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

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agreement or disagreement with each item by selecting a point on a 7-point Likert scale, 
where 1= strongly disagree and 7 = strongly agree. The ERQ should take four to six 
minutes to complete. Specific items are summed to produce two separate scales, 
Reappraisal and Suppression. The measure is reliable, with Reappraisal obtaining a 
Cronbach’s alpha of 0.79 and Suppression an alpha of 0.73, and test-retest reliability of 
0.69 [142], and scores on the ERQ are correlated with other measures of degree of 
emotional expressivity. The ERQ will be completed by both the PTSD+ participant and 
the CSO the participant according to Table 3: Time and Events. 
 
The IRI assesses four aspects of empathy: social functioning, self-esteem, emotionality, 
and sensitivity to others [143-145]. Empathy is not a discrete emotion. More accurately, 
empathy is a set of constructs. Therefore, the IRI accounts for the fact that each construct 
concerns an individual’s responses to the observed experiences of other people, yet each 
construct is distinctive from the others. The self-report questionnaire includes 28 items 
that are rated on a 5-point, Likert-type scale. The four 7-item subscales include two 
measures of cognitive empathy and two measures of affective empathy. The internal 
reliabilities for the four scales range from 0.71 to 0.77, and test-retest reliabilities range 
from 0.62 to 0.71 [143, 144]. The IRI will be completed by both the PTSD+ participant 
and the CSO participant, according to Table 3: Time and Events. 
 
The PSQI is a measure of self-reported sleep quality over a one-month period. The PSQI 
was designed to be a reliable, standardized measure able to distinguish between good and 
poor sleepers. It consists of 19 items, with possible responses ranging from 0 to 4 on a 
five-point scale [146]. The PSQI consists of seven sub-scales; sleep quality, sleep 
latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleeping 
medications, and daytime dysfunction. These are all summed to produce a single global 
scale. Global scores can range from 0 to 21, with higher scores reflecting poorer sleep 
quality, and a score below five indicative of good sleep. It takes five to 10 minutes to 
complete. Test-retest reliability ranges from 0.85 to 0.87, and it is internally consistent, 
with a Cronbach’s alpha of 0.83 [146, 147]. Global scores correlate with other measures 
of alertness and self-reported sleep quality [143]. The Pittsburgh Sleep Quality-PTSD 
Addendum [148] is a seven-item addendum for the PSQI that assesses disruptive 
nocturnal behavior specific to PTSD (e.g., hot flashes, nervousness, trauma nightmares). 
The PTSD+ participant will indicate the presence and severity of trauma-related sleep 
disturbances. Both the PTSD+ participant and the CSO participant will complete the 
PSQI according to Table 3: Time and Events. 
 
The PTGI is a 21-item self-report measure of perceived growth or benefits occurring after 
a traumatic event. It contains five subscales: relationship to others, new possibilities, 
personal strength, spiritual change, and appreciation of life [149, 150]. In this study, 
participants will complete the PTGI in reference to the time since the trauma at Baseline, 
but will respond in reference to the beginning of their participation in the study on all 
subsequent occasions. PTGI sub-scale scores are reliable, with reliability coefficients 
ranging from 0.83 to 0.90, and the scale scores were moderately related to each other 
[149, 151]. PTGI scores are corroborated by others’ assessments of posttraumatic growth, 
suggesting that the measure has convergent validity [152, 153]. Both the PTSD+ 
participant and the CSO participant will complete the PTGI according to Table 3: Time 
and Events. 

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

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

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

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series of questions, and can be administered during a face-to-face interview or over the 
telephone. Suicidal ideation and behavior will be assessed at Baseline, during most face-
to-face visits, during the second and seventh days of telephone contact, and after each 
Experimental Session. Participants who are discontinuing medication to participate in the 
study will complete the C-SSRS before and after medication washout. The C-SSRS 
Intensity scale for Lifetime obtained a Cronbach’s alpha of 0.93 and 0.94 for the Since 
Last Visit form, and Last Visit C-SSRS severity scores were positively correlated with 
the BDI “suicide thoughts” item [172]. Both the PTSD+ participant and the CSO 
participant will complete the C-SSRS according to the Measures and Time and Events 
Table. 
 
Cardiovascular effects will be assessed via blood pressure and pulse measurement. Blood 
pressure, body temperature, and pulse will be measured at the outset of the Experimental 
Session, once prior to administration of the supplemental dose, and at the end of the 
Experimental Session, or until it returns to near baseline levels. The timing of these 
measurements will be adjusted so they do not interfere with the therapeutic process. 
Blood pressure will be measured more frequently if there are symptoms, such as chest 
pain, shortness of breath or neurological symptoms or any other signs or symptoms that 
may be indicative of a medical complication. 
 
A 100-millimeter visual analog scale will be used to assess changes in symptoms of pre-
existing tinnitus and/or chronic pain [173-175]. The Changes in Tinnitus and/or Pain 
visual analog scale will allow rating of symptom severity from “None” to “Worst Case 
Imaginable”. This exploratory measure will enable quantification of subjective somatic 
symptoms that are known to be associated with PTSD [174, 176-178]. Presence of 
chronic pain is associated with PTSD, possibly as a result of psychological response to 
traumatic stress as reflected in brain activity, such as increased amygdalar activity in 
response to pain and transmitter systems involved in the stress response [174, 177, 178]. 
Both the PTSD+ participant and the CSO participant will be evaluated for Somatic 
Symptoms. 
 
All AEs and spontaneously reported reactions will be collected, as described in Section 
8.5. AEs and spontaneously reported reactions may be collected during face-to-face visits 
or over the telephone. Common reactions that are spontaneously reported are collected 
for seven days after each Experimental Session on a separate CRF page and will be 
categorized as mild, moderate, or severe. The researchers will ask participants about 
thoughts about killing or harming themselves at these visits and during the second and 
seventh day of telephone contact with the study therapists.  
 
5.1.3 Process Measures 
 
All psychotherapy sessions, including Experimental Sessions, may be recorded to audio 
and video, with all recordings preserved for research and training purposes.  
 
The Reactions to Research Participation Questionnaire (RRPQ) [179] is an assessment of 
causes for taking part in research and responses to the experience of being a research 
participant. The RRPQ is intended to assess the participants’ experiences as research 
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freedom to take part in the study. This will be completed by the PTSD+ participant and 
the CSO participant according to Table 3: Time and Events. 
 
The Long-term Follow-up Questionnaire has been developed internally by the sponsor to 
assess long-term benefits and harms of MDMA-assisted psychotherapy at the Long-term 
Follow-up Visits. Both the PTSD+ participant and the CSO participant will complete the 
Long-term Follow-up Questionnaire according to Table 3: Time and Events. The CSO 
participant will complete a modified version. 
 
5.2 Study Procedures and Visit Descriptions 
 
5.2.1 Prescreening, Screening, and Baseline Evaluation (Pre-study) 
 
Prospective dyads will be prescreened by telephone according to an IRB-approved script 
to learn if they meet basic eligibility criteria. Each dyad that is prescreened should be 
assigned a screening number, and recorded on the Screening Log where information on 
the selection of potential participants in the trial should be collected.  
 
Upon the PTSD+ participant and the CSO participant signing the IRB-approved informed 
consent form (ICF), either in person or over telemedicine, the potential dyad may 
commence study-related screening activities. The screening numbers should also be 
recorded on the signed ICF. If a dyad is enrolled, the study staff should record the 
enrollment date and assign dyad numbers. If a dyad is not enrolled, an explanation should 
be recorded on the Screening Log. If a CSO participant fails to qualify for the study, 
potential PTSD+ participants may nominate a different support participant. A CRF will 
not be completed for dyads that are not enrolled. These dyads will only be documented 
on the Screening Log and source records. It is the responsibility of the Clinical 
Investigator to file the Screening Log and the Dyad Identification Code List in the 
Investigator Site File (ISF) to be readily available for on-site monitoring and/or 
inspection by relevant authorities.  
 
Screening may take place over more than one day and should be complete by up to one 
month prior to enrollment. Screening visits may be conducted by telemedicine, phone, or 
in person. Screening may take up to one month, with the Baseline CAPS being conducted 
no more than 8 weeks before the first Experimental Session, leaving room for appropriate 
medication washout of at least five half-lives of pre-study psychiatric medications and 
active metabolites, plus one week for stabilization.  
 
If the CAPS is completed outside of this window for a participant, the PI should consult 
the CRA and Medical Monitor to determine if the Baseline CAPS should be repeated. 
The maximum window from the start of screening to the first Experimental Session is 8 
weeks. If, after reviewing all information, the PI concludes that the PTSD+ participant 
and CSO participant are eligible, they will enroll in the study. Visits will be scheduled 
consecutively as described in Table 3: Time and Events.  
 
a. Explain and obtain written informed consent from the PTSD+ participant and 
CSO participant. Written informed consent must be obtained prior to performing 
any tests or evaluations for the study 

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b. Assign the dyad a screening number. Complete the Screening Log 
c. Review the ability of participants of childbearing potential to become pregnant 
and their commitment to practice appropriate birth control as determined by the 
Clinical Investigator for the treatment period of the study 
d. Qualified study staff will obtain medical and psychological history by interview 
for both the PTSD+ participant and CSO participant 
e. Qualified study staff will administer the lifetime C-SSRS at baseline to assess 
suicide risk for both the PTSD+ participant and CSO participant 
f. General Wellbeing will be assessed for both the PTSD+ participant and CSO 
participant. 
g. Qualified study staff will collect information on pre-study and current 
medications for both the PTSD+ participant and CSO participant 
h. A physician will perform a general physical examination for both the PTSD+ 
participant and CSO participant. The examination will involve the following 
procedures:  
• Blood pressure 
• Pulse 
• Height 
• Weight 
• Body temperature 
• Examination of head, eyes, ears, nose, throat, skin, heart, lungs, abdomen, 
and extremities 
• Brief neurological exam (cranial nerves 2-12, sensory, motor, reflexes and 
cerebellar function) 
• Electrocardiogram (ECG) 
• Serum electrolytes, metabolic profile, urinalysis and complete blood count 
• Thyroid stimulating hormone (TSH), free T3 and free T4 
• Human Immunodeficiency Virus (HIV) serology 
• Urine-dip pregnancy test on females with childbearing potential 
• Urinary drug test. 
 
Results of HIV serology will be kept confidential, and appropriate referral for counseling 
may be necessary in accordance with state law. The clinical laboratory values will be 
used to establish eligibility and will be kept with the participant’s source record. The 
clinical laboratory values will not be captured in the CRF, but will be used to establish 
eligibility and will be kept with the participant’s source record. Clinically significant 
abnormal values will be captured as medical history. If, upon examination, there are 
questions raised about possible medical problems, the study physician will request a 
review of participant medical records and request additional tests or assessments as 
indicated. 
 
A blinded IR who will not be present during any of the therapy sessions will administer:  
 
• Structured Clinical Interview for DSM-5 Diagnoses (Research Version) (SCID-
RV) to assess eligibility based on Axis I diagnoses, which includes a self-report 
questionnaire to focus on modules to use based on symptoms for both the PTSD+ 
participant and CSO participant  

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• SCID-II Axis 2 questionnaire to determine if specific modules of the SCID-II 
Interview will be conducted to confirm diagnoses of personality disorders 
• Last-month CAPS for the PTSD+ participant to assess PTSD symptoms and 
eligibility, which may be recorded to video in as many instances as necessary to 
establish inter-rater reliability 
 
The following self-report measures will be completed: 
 
• PTGI (in reference to time since the trauma) for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant 
• PCL-5 (last month) to assess PTSD symptoms for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant. 
• TABS to assess trauma related beliefs for the PTSD+ participant and modified for 
the CSO participant to rate the PTSD+ participant  
• MDI to assess dissociative symptomology for the PTSD+ participant and CSO 
participant 
• SORTS to assess partner accommodation for the CSO participant 
• BDI-II to assess depression symptoms for both the PTSD+ participant and CSO 
participant 
• PSQI to assess sleep quality for both the PTSD+ participant and CSO participant. 
PSQI-PTSD Addendum will be assessed for the PTSD+ participant only 
• ERQ to assess emotional regulation for both the PTSD+ participant and CSO 
participant  
• TAS-20 to assess emotion recognition, alexithymia for both the PTSD+ 
participant and CSO participant  
• QRI to assess relationship satisfaction for both the PTSD+ participant and CSO 
participant 
• CTS to assess conflict, tactics and aggression for both the PTSD+ participant and 
CSO participant 
• IPF to assess psychosocial functioning for both the PTSD+ participant and CSO 
participant  
• MSIS to assess social intimacy for both the PTSD+ participant and CSO 
participant 
• IRI to assess compassion, empathy and social functioning for both the PTSD+ 
participant and CSO participant  
• IPC for both the PTSD+ participant and CSO participant 
• CSI for both the PTSD+ participant and CSO participant, if in a romantic 
relationship 
 
5.2.2 Preparatory Psychotherapy Session (Visit 1 - Telemedicine Visit)  
 
(Less than 4 weeks prior to Visit 2) 
 
Participants who do not complete all screening activities will not be enrolled. Eligibility 
may be discussed by phone after screening is complete and at the time Visit 1 is 
scheduled but the final confirmation will occur at Visit 1. If all Inclusion Criteria and no 
Exclusion Criteria are met, eligibility will be confirmed with the participant. 

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

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

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

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During: 
 
o. At approximately 10:00 in the morning, participants will receive the initial dose 
of drug along with a glass of water. 
p. The PTSD+ participant and CSO participant will sit or recline on comfortable 
furnishings. Eyeshades and a program of music will be provided if the PTSD+ 
participant or CSO participant wishes to use them. The PTSD+ participant and 
CSO participant may speak to the therapists whenever they wish, who will 
provide guidance and support as needed. CBCT therapy will be administered 
during the session according to the CBCT Manual. 
q. After the first hour, if the PTSD+ participant or CSO participant has not spoken 
spontaneously, check in with that participant about the nature of the experience. 
For the rest of the experience, as appropriate, the therapists will support and 
encourage the PTSD+ participant in emotional processing and resolution of 
whatever psychological material is emerging as described in the treatment 
manual. 
r. Record any spontaneously reported reactions during the session. 
s. Provide water and electrolyte containing fluids throughout the session but not to 
exceed 3L overall. 
t. An optional supplemental dose of MDMA half the amount of the initial dose may 
be administered approximately 1.5 to 2 hours after the initial dose unless 
contraindicated. 
u. Administer the self-report IPC for both the PTSD+ participant and the CSO 
participant. 
v. Provide food during the latter part of the session. 
w. If it is appropriate to do so, initiate the first question of the C-SSRS at any point in 
the session if the PTSD+ participant or CSO participant is experiencing 
significant psychological distress that does not respond readily to processing with 
the therapists according to the methods described in the treatment manual. The C-
SSRS is required at least once during the session; it is preferable to administer it 
towards the end of the session at about six hours after the initial dose. 
x. Assess General Wellbeing for both the PTSD+ participant and the CSO 
participant. 
y. End the session if all medical and psychiatric parameters are acceptable and the 
PTSD+ participant and the CSO participant are alert, ambulatory, and emotionally 
stable. 
 
Post-drug: 
 
a. The therapists will depart the site when they have concluded that the participants 
are emotionally and medically stable. Therapists and the study physician shall 
remain available to participants during the Experimental Session and for one 
week after via 24-hour cellular phone for integration as needed. 
b. Spontaneously reported reactions, AEs, and Medications will be collected, as 
described in Sections 8.0 and 9.0. 
  
The PTSD+ participant and the CSO participant will remain overnight in an appropriately 
furnished room at the study site. An attendant will check in periodically on the dyad 

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during the overnight stay. The attendant will monitor the PTSD+ participant’s and the 
CSO participant’s condition and will help the dyad relax during the overnight stay. The 
attendant will be an individual with some previous training in managing psychological 
distress, and will be thoroughly briefed by study staff about their role as an attendant who 
is available and supportive but not intrusive. If there is an emergency or the PTSD+ 
participant or the CSO participant needs additional support, the attendant can contact the 
therapists. The dyad will receive information that will allow them to contact the therapists 
during the overnight stay in the case of an emergency or request for additional support. 
The dyad will be encouraged to use much of the time during their overnight stay for rest 
and for a period of reflection and integration in a quiet atmosphere. 
 
5.2.5 Integrative Sessions Day after Experimental Session (Visits 4 and 11 - Clinic 
Visit) 
 
(Day after each Experimental Session)  
 
CBCT Manual Sessions Review 
 
On the morning after each Experimental Session, both of the therapists from the dyad’s 
team will meet with the dyad during a 60 to 90-minute Integrative Session.  
 
Generally, these sessions include discussing material that emerged during Experimental 
Sessions and helping dyad integrate their experiences both internally and into daily life. 
Therapists will validate the choices of the participant about how much they wish to 
communicate their thoughts, feelings and experiences at this time, but will elicit enough 
information to be able to assess the participants’ level of emotional stability and state of 
emotional and physical wellbeing. Therapists will emphasize their commitment to 
support the participants during the integration period and will be available via phone for 
additional meetings if needed. The dyad will be encouraged to relax and rest as much as 
possible for several days after the Experimental Session. 
 
During Integrative Sessions: 
 
a. The Integrative Session will be recorded to audio and video when possible. 
Participants will be given access to review audio and video of the session upon 
request. 
b. The therapists will administer the C-SSRS during each Integrative Session. 
c. Discuss and review events that occurred with the dyad during the Experimental 
Session, including thoughts, feelings, and memories. If necessary, the therapists 
will help the participants to reduce any residual psychological distress they are 
experiencing. The therapists will also encourage reconnection with any feelings of 
acceptance, intimacy, and reduced fear experienced in Experimental Sessions, and 
reflection about integrating those experiences into their relationships and 
everyday lives. The therapists will be supportive, validating the experience and 
facilitating understanding and emotional clearing. 
d. The therapists will remain accessible any time the participants need support 
outside the scheduled Integrative Sessions. 
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reactions during the Integrative Session immediately after each Experimental 
Session. 
f. Integrative Sessions can also serve as an opportunity for the therapists to gather 
information about the effects of the drug on the PTSD+ participant in an 
unstructured manner. 
g. Assess General Wellbeing for both the PTSD+ participant and CSO participant. 
h. Administer the self-report PCL-5 (since last visit) to assess PTSD symptoms for 
the PTSD+ participant and modified for the CSO participant to rate the PTSD+ 
participant. 
i. Administer the self-report IRI to assess compassion, empathy, and social 
functioning for both the PTSD+ participant and CSO participant. 
j. After the Integrative Sessions, a person previously selected by the dyad will 
provide a ride home. If the dyad are unable to locate an individual willing or able 
to take them home, or if the designated person is unable to assist due to 
unforeseen events, the therapists will aid the dyad in finding an alternative means 
of returning home. 
k. Spontaneously reported reactions, AEs and Medications will be collected, as 
described in Sections 8.0 and 9.0. 
l. Give the dyad the Out of Session Assignments to be completed after the end of 
the Integrative Session and returned to the study staff by the next visit. 
m. Remind the participants that they will have daily contact by phone or during 
telemedicine visits for the next seven days. 
 
5.2.5 Daily Telephone Contact for Seven Days after an Experimental Session 
 
During daily phone contact:  
 
a. Starting on the day of the Integrative Session following each Experimental 
Session, one of the therapists will contact the PTSD+ participant and CSO 
participant via telephone, telemedicine, or in person every day for one week. The 
goal of daily contact is assessment of changes in General Wellbeing, safety, and 
offering support. 
b. The telephone contact will be for a brief check-in lasting five to 15 minutes, or as 
long as necessary to address any participant’s concerns and to assess participants’ 
wellbeing. Additional telephone contact can be initiated at the request of the 
therapists or participant. 
c. On the second and seventh day of contact after the Experimental Session, the 
therapists will administer the C-SSRS. 
d. General Wellbeing will be assessed at each phone call. 
e. Spontaneously reported reactions, AEs and Medications will be collected, as 
described in Sections 8.0 and 9.0. 
 
5.2.6 Integrative Sessions Between Experimental Sessions (Visits 5, 6, 7, 8, 12, 13, 14, 
and 15 - Telemedicine Visits) 
 
Visits 5, 6, 7, and 8 will occur over 3 weeks between Experimental Sessions 1 and 2 
(Visits 3 and 10); Visits 12, 13, 14, 15 will occur over 4 weeks following Visit 10. 
 

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

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5.2.7 Evaluation and Preparation Visit at Midpoint (Visit 9 - Clinic Visit) 
 
(Approximately 3 weeks after V3; prior to V10) 
 
CBCT Manual Sessions 10 and 11 
 
Sessions 10 and 11 – Making meaning of the trauma. Discussion of the themes of trust 
and control. 
 
The midpoint evaluation will occur approximately 20 days after the first Experimental 
Session. Dyads who have withdrawn from treatment but have continued for follow-up 
will also complete this time point. This session will be recorded to audio/video. 
 
a. The therapists will assess suicidal ideation and behavior with the C-SSRS 
b. General Wellbeing will be assessed 
c. Collect AEs and medications, as described in Sections 8.0 and 9.0 
 
The following self-report measures will be completed at the midpoint: 
 
• PTGI (in reference to time since the trauma) for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant 
• PCL (since last visit) to assess PTSD symptoms for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant 
• TABS to assess trauma related beliefs for the PTSD+ participant and modified for 
the CSO participant to rate the PTSD+ participant  
• MDI to assess dissociative symptomology for the PTSD+ participant and CSO 
participant 
• SORTS to assess partner accommodation for the CSO participant  
• BDI-II to assess depression symptoms for both the PTSD+ participant and CSO 
participant  
• PSQI to assess sleep quality for both the PTSD+ participant and CSO participant. 
PSQI PTSD addendum will be completed by PTSD+ participant only 
• ERQ to assess emotional regulation for both the PTSD+ participant and CSO 
participant 
• TAS-20 to assess emotion recognition, alexithymia for both the PTSD+ 
participant and CSO participant  
• QRI to assess relationship satisfaction for both the PTSD+ participant and CSO 
participant 
• CTS to assess conflict, tactics and aggression for both the PTSD+ participant and 
CSO participant 
• IPF to assess psychosocial functioning for both the PTSD+ participant and CSO 
participant 
• MSIS to assess social intimacy for both the PTSD+ participant and CSO 
participant 
• IRI to assess compassion, empathy and social functioning for both the PTSD+ 
participant and CSO participant  

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• IPC for both the PTSD+ participant and CSO participant 
• CSI for both the PTSD+ participant and CSO participant, if in a romantic 
relationship 
 
5.2.8 Primary Assessment (Visit 16 – Telemedicine Visit) 
 
(30 days post Visit 15; window of -2/+7 days) 
 
The PTSD+ participant and CSO participant will repeat all outcome measures with the IR 
and meet with the therapists again 30 days after Visit 15. This visit may consist of two 
meetings that may be completed on separate days, one with the IR and the other with the 
therapists. Session may be recorded to audio/video. 
 
a. The therapists will assess suicidal ideation and behavior with the C-SSRS 
b. General Wellbeing will be assessed 
c. Last-month CAPS for the PTSD+ participant only will be performed to assess 
PTSD symptoms, which may be recorded to video in as many instances as 
necessary to establish inter-rater reliability 
d. Collect AEs and medications, as described in Sections 8.0 and 9.0 
 
The following self-report measures will be completed at the outcome assessment: 
 
• PTGI (in reference to time since the trauma) for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant  
• PCL (last month) to assess PTSD symptoms for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant 
• TABS to assess trauma related beliefs for the PTSD+ participant and modified for 
the CSO participant to rate the PTSD+ participant  
• MDI to assess dissociative symptomology for the PTSD+ participant and CSO 
participant 
• SORTS to assess partner accommodation for the PTSD+ participant and CSO 
participant 
• BDI-II to assess depression symptoms for both the PTSD+ participant and CSO 
participant 
• PSQI to assess sleep quality for both the PTSD+ participant and CSO participant 
PSQI PTSD addendum will be completed by PTSD+ participant only 
• ERQ to assess emotional regulation for both the PTSD+ participant and CSO 
participant 
• TAS-20 to assess emotion recognition, alexithymia for both the PTSD+ 
participant and CSO participant 
• QRI to assess relationship satisfaction for both the PTSD+ participant and CSO 
participant 
• CTS to assess conflict, tactics and aggression for both the PTSD+ participant and 
CSO participant 
• IPF to assess psychosocial functioning for both the PTSD+ participant and CSO 
participant 

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• MSIS to assess social intimacy for both the PTSD+ participant and CSO 
participant 
• IRI to assess compassion, empathy and social functioning for both the PTSD+ 
participant and CSO participant  
• IPC for both the PTSD+ participant and CSO participant 
• RRPQ to assess the process for both the PTSD+ participant and CSO participant 
• CSI for both the PTSD+ participant and CSO participant, if in a romantic 
relationship 
 
5.2.9 Long-term Follow-up (Visits 17 and 18 – Telemedicine Visits) 
 
(3 months and 6 months post Visit 15, window of -2/+7 days) 
 
The PTSD+ participant and CSO participant will be evaluated for long-term effects 3 
months and 6 months after their last MDMA-assisted psychotherapy with CBCT session. 
This visit will consist of two meetings, one with the IR and the other with the therapists 
via telemedicine. PTSD+ participants and CSO participants who have withdrawn from 
treatment but have continued for follow-up will also complete these time points. At the 
Long-term Follow-up Visits:  
 
a. The therapists will assess suicidal ideation and behavior with the C-SSRS. 
b. General Wellbeing will be assessed. 
c. Last-month CAPS for the PTSD+ participant will be performed to assess PTSD 
symptoms, which may be recorded to video in as many instances as necessary to 
establish inter-rater reliability. 
d. Collect AEs and medications, as described in Sections 8.0 and 9.0. 
 
The following self-report measures will be completed at the outcome: 
 
• PTGI (in reference to time since the trauma) for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant  
• PCL-5 (last month) to assess PTSD symptoms for the PTSD+ participant and 
modified for the CSO participant to rate the PTSD+ participant 
• TABS to assess trauma related beliefs for the PTSD+ participant and modified for 
the CSO participant to rate the PTSD+ participant  
• MDI to assess dissociative symptomology for the PTSD+ participant and CSO 
participant 
• SORTS to assess partner accommodation for the CSO participant 
• BDI-II to assess depression symptoms for both the PTSD+ participant and CSO 
participant 
• PSQI to assess sleep quality for both the PTSD+ participant and CSO participant. 
PSQI PTSD addendum will be completed by PTSD+ participant only 
• ERQ to assess emotional regulation for both the PTSD+ participant and CSO 
participant 
• TAS-20 to assess emotion recognition, alexithymia for both the PTSD+ 
participant and CSO participant  

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• QRI to assess relationship satisfaction for both the PTSD+ participant and CSO 
participant 
• CTS to assess conflict, tactics and aggression for both the PTSD+ participant and 
CSO participant 
• IPF to assess psychosocial functioning for both the PTSD+ participant and CSO 
participant 
• MSIS to assess social intimacy for both the PTSD+ participant and CSO 
participant 
• IRI to assess compassion, empathy, and social functioning for both the PTSD+ 
participant and CSO participant  
• IPC for both the PTSD+ participant and CSO participant 
• CSI for both the PTSD+ participant and CSO participant, if in a romantic 
relationship 
• Long-term Follow-up Questionnaire to assess the process, outcome and safety for 
the PTSD+ participant and modified foe the CSO participant  
 
5.3 Participant Numbering 
 
Prior to enrollment, the dyad will be tracked with two sets of initials and a screening 
number assigned sequentially starting at “S001”. Dyads who meet all Inclusion and no 
Exclusion Criteria will be enrolled into the study and will be assigned a five-digit 
participant number. The first two digits will be “ 01” or “02” and will identify the PTSD+ 
participant versus the CSO participant. The next three digits identify the dyad within the 
site and will be assigned sequentially, with 001 corresponding to the first dyad enrolled, 
e.g. the first enrolled dyad will be 01001 and 02001 and the second dyad will be 01002 
and 02002, etc.  
 
5.4 Removal of Participants from the Study 
 
Participants can withdraw consent at any time without prejudice. The therapists can 
withdraw a participant if, in their clinical judgment, it is in the best interest of the dyad or 
if the participant cannot comply with elements of the protocol that are critical for safety 
or for the scientific integrity of the study. If the therapists withdraw a dyad from the 
study, the therapists will explain the reason for withdrawing the dyad. The reason for 
early termination will be recorded in both the PTSD+ participant’s and the CSO 
participant’s source records and CRF. If one person in the dyad wishes to withdraw, both 
participants will be dropped from treatment. 
 
Participants will be clinically monitored after withdrawal, the cause of which will be re-
corded in their source records and CRF. Whenever possible, the tests and evaluations 
listed for the termination and outcome visits will be carried out. Efforts will be made to 
obtain information about AE outcomes, if deemed necessary by the PI and/or sponsor. 
 
If a participant develops any Exclusion Criteria that in the opinion of the Medical 
Monitor, affects the safety of either member of the dyad, including psychiatric diagnosis, 
pregnancy or excluded medications, the PTSD+ participant will discontinue treatment but 
remain in the study for follow-up purposes. Whenever possible, the tests and evaluations 

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

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dose will be clearly differentiated from capsules used for the supplemental dose. The 
encapsulation will be performed by a pharmacist who has the appropriate skills.  
 
6.2.3 Labeling 
 
The IP for each Experimental Session will be packaged in one primary container, labeled 
with a unique container number, protocol number, drug name, lot number, sponsor name, 
Experimental Session number, and a statement that the drug is restricted to clinical trial 
use only. All drug labels will comply with federal and state regulations and will be 
provided in English. The initial and supplemental dose will be packaged in separate 
labeled “inner envelopes” within the primary container. There will be one primary 
container per PTSD+ participant and CSO participant per Experimental Session. The 
sponsor monitor will oversee the process of drug packaging conducted by the pharmacist.  
 
Figure 1. Examples of Drug Labels  
 
Holding Box Labels: 
 
 
Holding Box Label 
 
MAPS Study: MPVA-1 
Investigational Product: MDMA  
Dose: X mg 
Lot #: XXX 
Administer as per protocol 
Caution: Limited by Law to Investigational Use Only 
 
 
Primary Container Outer Labels: 
 
 
Container Label 
 
MAPS Study: MPVA-1 
Open Label 
100 mg + 50 mg MDMA  
Lot #: XXX 
Container #: XXX  
 
Dyad #: ____________  
Experimental Session #: ____________ 
Administer as per protocol - Investigational Use Only 
 
 

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

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Experimental Session but are optional to use. In addition, the clinical titration doses with 
corresponding supplemental dose are provided for the second Experimental Session. The 
dose to be used at the second session is at the discretion of the CI. 
 
The Schedule 1 License Holder will dispense the appropriate container number for each 
Experimental Session. If an optional dose is not administered, the unused capsules will be 
kept in their respective inner envelopes inside of the primary container in the safe for 
drug accountability.  
 
Records pertaining to the use of scheduled, regulated compounds will be maintained in 
accordance with relevant federal and state regulations.   
 
6.5 MDMA Stability 
 
Complete details on the chemistry, manufacturing, and control of the MDMA to be used 
are described in Drug Master file (DMF) #6293. As described in that file, MDMA was 
prepared for human consumption in 1985 by David Nichols, Ph.D., at the Department of 
Medicinal Chemistry and Pharmacology at Purdue University. The identity and purity of 
this MDMA was confirmed using High Performance Liquid Chromatography (HPLC) in 
1997 as described in DMF #6293 and was found to be 99.87% pure. On August 12, 2002, 
Chemic Laboratories reanalyzed the MDMA at the request of the sponsor prior to starting 
MAPS’ first U.S. pilot study of MDMA-assisted psychotherapy in people with PTSD. 
The analysis found the MDMA to be more than 99.7% pure. A more recent analysis 
performed by Nichols at the request of researcher Dr. Carl Hart on February 2006, 
continued to find a high degree of purity. This analysis found the MDMA in question to 
be 99.9% pure. This MDMA is currently in use in an ongoing investigation of MDMA-
assisted psychotherapy in the U.S., was also used in MP-1 with drug administration 
ending in 2008, and it was also used in a non-sponsor supported study in 2006 [183]. 
 
7.0 Risks of Participation 
 
7.1 Risks and Discomforts Associated with Psychotherapy Sessions and Assessment 
of Measures 
 
In preparation for drug-assisted psychotherapy sessions, blood draws and a full medical 
examination are required to establish eligibility for the study. Temporary discomfort, 
inflammation, or infection could arise as a result of sampling blood at the punctured vein. 
Submitting to a full medical examination may also cause discomfort or psychological 
distress. Since medical examinations and blood draws are required to establish eligibility 
for the study, they cannot be omitted from the protocol. 
 
During screening, non-drug and drug-assisted psychotherapy sessions and assessment of 
study measures, participants will be asked to think about and discuss their thoughts and 
emotions relating to the traumatic event or events. They may experience intense 
emotional responses to recalling and speaking about this material. Even in a therapeutic 
context, thinking about and discussing the trauma, symptoms related to the trauma or the 
effects of PTSD on life function can produce distress during and immediately after non-
drug psychotherapy, experimental, and open-label sessions. Psychotherapy is conducted 

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

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Further information on the risks associated with MDMA, including information drawn 
from case reports and studies of users, can be found in the sponsor’s Investigator 
Brochure.  
 
7.2.1 Safety Plan and Procedures for Participants Who Screen Positive for Suicidal 
ideation or Intent 
 
The CI will minimize risks by carefully evaluating all participants to determine if there is 
a current risk of suicidal behavior.  Participants with a history of suicide attempts will not 
be excluded unless risk of suicidal behavior is present at the time of the screening 
assessment. Participants will be enrolled according to the Inclusion and Exclusion 
Criteria based on the clinical judgment of the CI.  
 
After enrollment, data on General Wellbeing will be collected at each visit on the 
participant’s current demeanor and state of mind and risk of deterioration. Participants 
will be telephoned on a daily basis for the first week after each experimental session to 
assess General Wellbeing, safety, and offer support.  
 
The CI or qualified designee will administer the C-SSRS according to the Time and 
Events table, and as needed depending on clinical presentation of the participants, to 
monitor for development and intensity of suicidal ideation and/or behavior. The therapist 
will implement the following plan to assess elevated or imminent suicide risk. 
 
If the Since Last Visit C-SSRS reveals current serious Suicidal Ideation (Scores of 4 or 
greater), indicating risk at the time of the assessment, or positive Suicidal Behavior 
(Scores of 1 or greater) then the participant will be referred for further 
management as described below. 
 
1. 
If the participant has current suicidal ideation, but no specific plan to 
commit suicide (Suicidal Ideation Score = 4), the therapist administering the 
C-SSRS will ensure: 
a. 
Participants are evaluated by the investigators to determine appropriate 
course of action and will discuss the findings with the participant and their 
personal therapist, if applicable. 
b. 
Regular check-ins via phone or in person will be continued until the 
participant has stabilized or a new course of action is taken based on 
changes in C-SSRS score and/or ongoing clinical assessment. 
c. 
If this finding is treatment-emergent and clinically significant, the event 
will be collected as an Adverse Event.  
d. 
Treatment would be continued when deemed appropriate by the CI and 
Medical Monitor, unless it is determined that treatment should be 
discontinued, in which case the participant will enter follow-up. 
 
2.  
If the participant has suicidal ideation, and a plan to commit suicide (Suicidal 
Ideation Score = 5) or positive Suicidal Behavior (Score greater than or equal to 
1), the therapist administering the C-SSRS will assess whether the risk is 
imminent. A Suicidal Ideation score of 5 does not necessarily indicate an 
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are strong. If there is no imminent risk, the therapist will follow the procedure 
described in number 1. If there is imminent risk of suicidal behavior, the therapist 
will ensure: 
a. 
Participants are evaluated to determine appropriate course of action, and 
the study therapist will contact their personal therapist or come to the 
study site for a visit, depending on their location. 
b. 
If it is determined that the participant is at imminent risk of suicide, the 
CI or qualified staff member will do one of the following:  
1) 
Escort the participant to the Emergency Department;  
2) 
Escort the participant to an appropriate mental health services 
facility (e.g.hospital psychiatric unit); or  
3)  
call 911 and ensure that the participant is transferred to the 
responding medical personnel. 
c. 
If the participant will not comply and wishes to leave without 
consultation, call 911. Explain that the participant is in immediate 
danger of committing suicide. Provide a complete description of the 
participant and give any other needed details to ensure the participant’s 
safety. 
d. 
Notify appropriate members of the study team and Sponsor 
representatives. 
e. 
If this finding is treatment-emergent and clinically significant, the event 
will be collected as an Adverse Event and the seriousness will be 
evaluated. SAEs will be reported per FDA guidance. 
f. 
Treatment would be continued when deemed appropriate by the CI and 
Medical Monitor, unless it is determined that treatment should be 
discontinued, in which case the participant will enter follow-up. 
 
7.2.2 Cardiovascular and Sympathomimetic Effects 
 
The highest dose to be employed in this study, the active dose of 100 mg, followed by a 
supplemental dose of 50 mg after 1.5 to 2.0 hours, is expected to produce significant but 
transient, self-limited increases in blood pressure and heart rate. These changes should 
last no more than six hours. In less than 5% of volunteers in Phase 1 studies, peak blood 
pressure values were higher than 140/90 mmHg. Clinical intervention was not required in 
any of these cases. Nonetheless, careful monitoring of participants and predefined 
contingency plans will allow the researchers to rapidly identify and manage any related 
toxicity. For more information, see the sponsor’s Investigator Brochure. 
 
Risks posed by elevated blood pressure will be addressed by excluding people with pre-
existing hypertension and monitoring blood pressure and pulse, as described in Section 
5.1.2. During Experimental Sessions the co-therapists will continually evaluate the 
patient for signs or symptoms of a developing hypertensive or other cardiovascular 
emergency. Participants reporting chest pain, shortness of breath or neurological 
symptoms or other potential indicators of hypertensive emergency or any other serious 
medical problem will have more frequent measurements and assessment by the study 
physician. Any participant who experiences medical complications during an 
Experimental Session will not be given another Experimental Session unless it is 
approved by the Clinical Investigator, study physician and the Medical Monitor.   

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In case of need, participants will be transferred to the emergency room at the closest 
hospital, as described in Section 8.4. Reasons for moving a patient to an Emergency 
Department (ED) would include, but not be limited to, severe headache in the setting of 
hypertension, angina, or neurological deficits regardless of blood pressure. The Clinical 
Investigators and study physician may, at any time, make a clinical judgment to transfer 
the patient to the ED for closer monitoring and additional treatment.  
 
The study physician will be prepared to respond to rare complications of cardiovascular 
effects, such as stroke or acute myocardial infarction (AMI). The therapists will attend to 
any signs or symptoms of neurological deficit or confusion that is more extensive than 
might be expected from MDMA or from psychological distress, and will notify the study 
physician if this occurs for on-site evaluation or a decision to initiate transfer to the ED. 
If any participant has neurological deficits, as assessed by the study physician, whether or 
not they are associated with hypertensive crisis, they will receive oxygen and vital signs 
and general condition will be closely monitored pending transfer to the hospital. If 
necessary, they will be transported to the emergency department at the closest hospital for 
further management. If evaluation at the hospital reveals a nonhemorrhagic stroke, there 
will be time to administer recombinant tissue plasminogen within the three-hour time 
frame recommended in the American Academy of Neurology/American Heart 
Association guidelines [186, 187]. 
 
The therapists will observe the participants and note any complaints of chest pain. If a 
participant experiences ischemic type chest pain, whether or not it is associated with 
hypertensive crisis, they will receive heart rhythm monitoring, oxygen and will be 
monitored as described above. If necessary, they will be transported to the ED or a 
location in the hospital where appropriate care can be given. They will be given 
nitroglycerin 0.4 mg SL q 5 minutes PRN chest pain pending transport to the hospital. If 
further evaluation at the hospital reveals that the participant has had an AMI, they will be 
well within the time frame required for definitive therapy. The American College of 
Cardiology/ American Heart Association guidelines for the treatment of AMI recommend 
percutaneous transluminal coronary angioplasty (PTCA) as the treatment of choice when 
it can be performed within 90 minutes of arrival at the hospital in patients who present 
within 12 hours of an episode of chest pain lasting more than 30 minutes and who have 
ECG evidence of AMI [188]. 
 
7.2.3 Psychological Distress 
 
Mild anxiety and depressed mood are occasionally reported one to three days after 
MDMA administration [13, 15, and see the IB]. Psychological distress from MDMA 
could arise at any time from the first indications of drug effects until the last effects have 
dissipated (approximately three to five hours after drug administration), or even later. 
Any anxiety or distress occurring during the session may last for as little as five minutes 
or for as long as five hours or more. In addition, psychological distress could arise 
following an MDMA-assisted session as a result of participants having difficulty 
integrating their experience after the MDMA effect has subsided. In previous Phase 1 and 
Phase 2 studies, these symptoms have been self-limiting, and have responded well to 
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this study, participants will have the intention of confronting and working through 
traumatic experiences. Hence signs of psychological distress, panic or other unpleasant 
psychological reactions are to be expected and may be considered an element of the 
psychotherapeutic process.  
 
Proper preparation and follow-up support will reduce the difficulties participants might 
have with acute or sub-acute reactions. The potential for destabilizing psychological 
distress will be minimized by: 
 
• Excluding people who might be more vulnerable to it (such as people diagnosed 
with bipolar affective disorder-1 or with psychotic disorders) 
• Preparatory non-drug psychotherapy sessions before the Experimental Session. 
• Creating an atmosphere of trust during the Experimental Session 
• Close monitoring 
• Daily contact with participants for the period of a week after the Experimental 
Session 
• Providing non-drug psychotherapy Integrative Sessions 
• Participants will remain at the study site for the night of each Experimental 
Session to further reduce psychological distress. Qualified personnel will be 
available during the overnight stay to respond to the needs of the participants. 
Attendants will be instructed to contact the therapists upon request or at the 
appearance of signs of a potential serious adverse event.  
 
During the Preparatory Sessions, participants will be made aware of the fact that difficult 
emotions, including grief, rage and fear or panic, may arise during Experimental 
Sessions. Every effort will be made to help participants resolve difficult symptoms and to 
arrive at a more comfortable and relaxed state by the conclusion of the Experimental 
Session, including empathic listening on the part of the therapists and performance of 
diaphragmatic breathing or other stress inoculation techniques by participants.  
 
At the end of the Experimental Session, which lasts six to eight hours, if the PTSD+ 
participant or CSO participant is still severely agitated or experiencing any other severe 
psychological distress, the following measures will be taken:  
 
• If the PTSD+ participant or CSO participant is anxious, agitated, in danger of any 
self-harm or is suicidal at the end of the Experimental Session, the therapists will 
remain with them for at least two more hours. During this time, the therapists will 
employ affect management techniques, will talk with the participant to help them 
gain cognitive perspective of their experiences, and will help them implement the 
self-soothing and stress inoculation techniques presented during the Preparatory 
Session. If this situation should occur during an Integrative Session, at least one 
of the therapists will be available to stay with the person for at least two 
additional hours. 
• If a PTSD+ participant or CSO participant remains severely anxious, agitated or 
in danger of self-harm or suicide, or is otherwise psychologically unstable at the 
end of this two-hour stabilization period, the Clinical Investigator will decide 
between the following options: 

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1. A psychiatric nurse, therapeutic assistant, physician, or therapist will stay 
with the PTSD+ participant or CSO participant until the time of their 
appointment with the therapists the next day. The therapists will then meet 
with the participant daily until the period of destabilization has passed.  
2. If a PTSD+ participant or CSO participant experiences severe, persisting 
emotional distress, such as panic attacks, severe generalized anxiety, or 
insomnia following an MDMA-assisted session, the study physician may 
prescribe a rescue medication such as a benzodiazepine, zolpidem, or 
other anxiolytic or sedative according to the physician's clinical judgment. 
This medication will be captured on the concomitant medications CRF 
page. The physician should not prescribe an SSRI, SNRI or MAOI in this 
context unless it has been determined that the participant will be 
withdrawn from the study. Residual symptoms will be addressed during 
the frequent follow-up psychotherapy visits with the therapists. 
3. Hospitalization for stabilization. If a PTSD+ participant or CSO 
participant should become psychotic arrangements will be made to 
stabilize them and transfer them to the ED if necessary. 
 
PTSD+ participants or CSO participants hospitalized after a severe panic reaction will be 
suspended from the protocol until after recovery or stabilization, at which time the 
Clinical Investigators will carefully evaluate their emotional status.   
 
For those PTSD+ participants or CSO participants engaged in an ongoing therapeutic 
relationship with a psychotherapist or psychiatrist, the outside therapists will be involved 
in the management of any psychiatric complications. For those PTSD+ participant or 
CSO participants engaged in an ongoing psychotherapeutic relationship with the Clinical 
Investigators, the management of any psychiatric complications will be undertaken by 
them in their capacity as therapists.   
 
7.2.4 Body Temperature 
 
MDMA administered in a controlled setting produces only a slight increase in body 
temperature [15] and ambient temperature does not enhance or attenuate this slight 
elevation in humans.   
 
If temperature rises more than 1°C, attempts will be made to lower it by removing 
blankets and layers of clothing, decreasing the ambient temperature and, if necessary, 
directing a fan toward the participant. If at any time the temperature rises more than 
1.5°C above Baseline despite these efforts, the study physician will be consulted for 
further evaluation and treatment.   
 
7.2.5 Reproductive and Developmental Risks 
 
Risks posed by MDMA to pregnant persons are not known. One of two studies of Ecstasy 
users suggests that use of Ecstasy and other drugs during pregnancy may be associated 
with some abnormalities at birth while the other failed to find this association [189, 190], 
and a third reported some developmental delays in mothers reporting use of and other 
drugs during pregnancy [191] as discussed in the IB.   

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

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

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

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

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All medications, over the counter (OTC) and prescription will be collected from 
screening through seven days after the last MDMA-assisted session. From seven days 
after the last MDMA-assisted session through Study Termination only prescription or 
OTC medications taken to treat AEs will be collected. Throughout the protocol all 
medications used to treat AEs will be collected, as described in Section 8.5, and all 
changes including discontinuations or additions to psychiatric medications will be 
collected. Medications will be recorded on the concomitant medications CRF.   
 
In general, any MAOi will require a washout of at least 14 days or five half-lives of the 
medication or active metabolite (whichever is greater) plus one week for symptom 
stabilization. The Medication Tapering Table now includes phenelzine, an example 
MAOi, (half life of 11.6 hours) with a minimum of 14-day washout as requested. 
However, this table is not exhaustive. The washout time for any drug not listed on the 
table will be at least 5 times the half life of the drug or active metabolite as published in 
the package insert, plus 1 week for symptom stabilization. 
 
PTSD+ participants and CSO participants must be willing to refrain from taking any 
psychiatric medications during the active portion of the study with the exception of 
gabapentin when prescribed for pain control. If a participant is on stimulants for ADHD 
at Baseline, they can continue to use them at the same dose and frequency as long as they 
discontinue five half-lives before each Experimental Session and do not restart for ten 
days after each Experimental Session. Individuals using opiates for pain management will 
be asked to decrease the dose or avoid taking their pain medication for 24 hours prior to 
Experimental Sessions if possible, as these medications may reduce the efficacy of 
MDMA. Participants will be permitted to take their prescribed opiate medication during 
this period if necessitated by pain flare-ups.  
  
Table 7. Medication Tapering Table 
Generic Name 
Brand Name 
Half-life (hours) 
Including Active Metabolites 
Days for Washout 
alprazolam 
Xanax 
11 
3 
aripiprazole 
Abilify 
75 
16 
atomoxetine 
Strattera 
5-24 
5 
bupropion 
Wellbutrin 
21 
5 
citalopram 
Celexa 
35 
8 
clonazepam 
Klonopin 
30-40 
8 
diazepam 
Valium 
20-70 
15 
duloxetine 
Cymbalta 
12 
3 
escitalopram 
Lexapro 
32 
7 
fluoxetine 
Prozac 
7-9 (days) 
45 
imiprimine 
Tofranil 
6-18 
4 
lamotrigine 
Lamictal 
25 
6 
lorazepam 
Ativan 
12 
3 
mirtazapine 
Remeron 
20-40 
8 
olanzapine 
Zyprexa 
21-54 
11 
paroxetine 
Paxil 
21 
5 
phenelzine 
Nardil 
11.6 
14 
prazosin 
Minipress 
2-3 
1 
quetiapine 
Seroquel 
6 
2 
risperidone 
Risperdal 
3-20 
4 
sertraline 
Zoloft 
26 
6 

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

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

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Clinical Investigator by representatives of the sponsor. The site will be monitored as 
appropriate for the rate of enrollment in order to comply with GCP guidelines and to 
ensure validity of the study data. During each monitoring visit, source data verification 
will be performed to ensure compliance, including accurate and complete recording of 
data on CRFs, source documents, and drug accountability records. Electronic CRFs 
supplied by the sponsor will be completed for each participant enrolled. Monitoring and 
auditing procedures will be supplied in a separate document.  
 
During or after the study, the regulatory authorities, the IRB, and/or representatives of the 
sponsor may request access to all source documents, CRFs and other protocol 
documentation for on-site audit or inspection. 
 
12.0 Data Analysis  
 
Key Personnel, MAPS, and the biostatistician will agree on a Statistical Analysis Plan at 
the beginning of the study. The biostatistician will perform an Intent to Treat (ITT) 
analysis using repeated measures Analysis of Covariance (ANCOVA) to compare 
demographics and all available data from any participant receiving at least one 
Experimental Session and completing follow-up assessments from all participants, even 
if they withdraw from the allocated treatment prior to the Primary Endpoint.  
 
This pilot study will test the impact of MDMA-assisted psychotherapy with CBCT for 
reducing PTSD and other psychological symptomology (e.g., depression) among a 
sample (N=10) of participants with PTSD. The primary measure will be a paired T-test of 
CAPS scores from Baseline to Primary Endpoint. In addition, to determine the strength of 
the treatment effect, pre to post (paired) mean differences effect size estimates will be 
calculated. Durability of effects will be examined by comparing changes from Baseline to 
the assessments at three and six months after the final Experimental Session using mixed-
effects regression methods, which accounts for both missing data and the nesting of 
correlated longitudinal data within participants.  
 
Effect sizes will be estimated for all outcome measures using Cohen’s (1988) procedures 
(Cohen’s d and small sample bias corrected Hedges’ g) [194]. Effects on depression 
symptoms, psychological functioning, trauma-related beliefs, interpersonal closeness, and 
sleep quality will also be assessed for exploratory purposes. The biostatistician will 
conduct secondary analyses of self-report assessments using repeated measures 
ANCOVA. As a secondary outcome measure, weekly PCL-5 assessments will be 
conducted 15 times, starting at the second prep visit, weekly during treatment, and three 
follow-up assessments. To examine changes in PCL-5 over the 15 time points, the 
sponsor statistician will use linear mixed-effects regression with restricted maximum 
likelihood estimation, using weeks as a continuous variable. Measures of relationship 
satisfaction will be analyzed separately for participants with and without PTSD. 
Statistical significance will be determined based on α < .05 for all tests other than the 
PCL-5, which will be a secondary measure for self-reported PTSD symptoms intended to 
support the CAPS.  
 
Qualitative safety analyses will examine adverse events, concomitant medications, and 
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duration, as well as frequencies and percentages, tabulated overall and by PTSD+ 
participants and CSO participants. Quantitative safety analyses will examine vital signs, 
changes in Tinnitus and/or Pain, SUD, and C-SSRS, with comparisons made between by 
PTSD+ participants and CSO participants for effect of PTSD on safety measures.   
 
12.1 Statistical Power 
 
This pilot RCT is the first study of its kind intended to establish preliminary effect size 
estimates of CBCT combined with MDMA-assisted psychotherapy for PTSD. In the 
absence of published effect sizes for this new treatment modality, effect sizes were 
estimated based on prior trials of these individual treatments. In a limited number of 
small pilot studies, CBCT for PTSD yielded paired-treatment effect sizes of g > 1.0 for 
improvements in PTSD on the primary outcome measure and co-morbid symptoms. The 
two completed controlled RCTs of MDMA-assisted psychotherapy for PTSD have 
yielded effect sizes of g > 1.0 for improvements in PTSD symptoms as well. Assuming 
that effect size of the combined treatment may be approximately 0.8, estimated power for 
a within-subject analysis with a significance level of .05 based on a 2-tailed test, is 62% 
for a sample size of 10 participants for the primary measure, suggesting the potential for 
an underpowered design, but with some possibility of detecting a within-subject effect 
due to treatment. Statistical power estimates were not available for secondary and 
exploratory measures, as they were previously not used in sponsor-supported studies. 
 
13.0 Ethics 
 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.  
 
The protocol and the ICF must be reviewed and approved by a properly constituted IRB 
and FDA before study start. Signed and dated documentation of IRB and FDA approvals 
must be provided to the sponsor. Prior to study start, the Clinical Investigator is required 
to sign a protocol signature page confirming their agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to the sponsor. 
 
14.0 Informed Consent 
 
The main licensed therapists are responsible for obtaining informed consent in adherence 
to GCP and according to applicable regulations prior to entering the participant into the 
trial. Information about the study must be given orally and in an understandable form. 
Written information about the trial will also be provided. The informed consent 
discussion must be conducted by a person who is qualified according to FDA regulations. 
The PTSD+ participants and CSO participants should have the opportunity to inquire 
about details of the MDMA-assisted session and to consider participation.  
 
For all PTSD+ participants and CSO participants the dose of MDMA will be disclosed. 
This is not a blinded study. 

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In addition to the explanation of study visits, the information should include that access 
to original medical records and processing of coded personal information must be 
authorized. Written consent to take part in the study includes giving the Clinical 
Investigators permission to view the PTSD+ participant’s and CSO participant’s recent 
medical records to assess protocol eligibility, if needed. Information necessary for 
protocol participation includes past medical history, psychiatric interview, physical 
examination, and clinical laboratory tests. 
 
Eligible PTSD+ participants and CSO participants may only be included in the study 
after signing the IRB approved ICF. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol, including screening activities). The process of obtaining informed consent 
should be documented in the PTSD+ participant and CSO participant source documents. 
The therapists will provide a copy of the signed ICF to the dyad and will maintain the 
original in the ISF. The ICF process may be performed via telemedicine. 
 
The written ICF and any other written information to be provided to PTSD+ participants 
and CSO participants should be revised whenever important new information becomes 
available that may be relevant to the dyad’s consent. Any revised ICF and written 
information should receive approval from an IRB before use. The PTSD+ participant and 
CSO participant should be informed in a timely manner if new information becomes 
available that might affect the decision to take part in the MDMA-assisted session. The 
communication of this information should be documented.  
 
PTSD+ participants and CSO participants can withdraw consent at any time without 
prejudice. If a PTSD+ participant or CSO participant withdraws consent but does not 
revoke the Health Insurance Portability and Accountability Act (HIPAA) authorization, 
the Clinical Investigators will have full access to the PTSD+ participant’s or CSO 
participant’s medical records, including Study Termination Visit information. If only the 
HIPAA authorization is revoked, the Clinical Investigators will have full access to all of 
the medical records prior to the date and time of revocation. 
 
15.0 Confidentiality 
 
Every effort will be made to strictly safeguard the confidentiality of PTSD+ participants 
and CSO participants in their role as research participants. Removing identifying 
information from data and restricting access to researchers directly involved in assessing 
the participants should prevent the dissemination of confidential data, with or without 
identifying information. Except for the screening log, the ICF, and a participant contact 
information sheet that will be stored separately from other documents, all data will be 
identified only by the participant’s initials on the source document and five-digit 
participant number. If past medical records are needed, participants will sign forms for 
the release of information upon consent to permit screening for protocol enrollment. 
Copies of audio and video recordings intended for sharing with participants will only be 
marked with the PTSD+ participant’s and CSO participant’s participant number. Any 
materials mailed to PTSD+ participants and CSO participants will be sent along with 
stamped return envelopes using the office address of the Clinical Investigator both as 

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main and return address. All assessment records will be kept in a locked file drawer or 
cabinet in a locked office, and access to measures will be limited to regulatory agencies, 
researchers, and individuals analyzing data. Researchers, other than the Clinical 
Investigators directly involved in the protocol, with access to data will not be provided 
with any information that would identify participants by name or by other means, such as 
social security number.  
 
All psychotherapy sessions may be recorded to video and audio. These recordings will be 
used for manual development and potentially for training therapists to perform MDMA-
assisted psychotherapy. They are intended to record the events occurring during therapy, 
and will not serve as outcome measures. CAPS assessments may also be recorded to 
video to establish inter-rater reliability. Full names and addresses will not appear in these 
recordings.  
 
16.0 Costs to Participants 
 
There will be no costs to the study participants for any study-related procedures. The 
sponsor will cover all costs of study participation, including any assessments or tests 
performed solely for the purpose of establishing eligibility for participation. Charges for 
treatment of the PTSD+ participant’s condition that are unrelated to the research study or 
any of its procedures will continue to be billed to the health insurance provider of the 
PTSD+ participant or to the participant directly. It is anticipated that there will not be any 
charges for treatment that is unrelated to the study except in the case of participants who 
previously received therapy from the Clinical Investigator and who will continue to 
receive ongoing treatment that is not related to participating in the study.  
 
17.0 Treatment and Compensation for Study-Related Injury 
 
Treatment of a study-related emergency would first be billed to a participant’s health 
insurance provider. The sponsor will cover any direct costs relating to the treatment of a 
study-related emergency that are not covered by a participant’s health insurance. Some 
study-related emergencies can be treated by the Clinical Investigators, as described in 
Section 8.4. If the study physician cannot treat a study-related emergency, then there are 
contingency plans for the transport of participants to the nearest hospital.   
 
18.0 Record Retention 
 
Clinical Investigators must retain all study records required by the sponsor and applicable 
ICH-GCP and FDA regulations in a secure and safe facility. The Clinical Investigator 
must consult a representative of the sponsor before disposal of any study records. 
“Essential documents” are defined as documents that individually and collectively permit 
evaluation of the conduct of a trial and the quality of the data produced. These documents 
will be filed according to ICH-GCP regulations in the ISF. It is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need 
to be retained.  
  
19.0 Publication Policy 
 

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The sponsor recognizes the importance of communicating medical study data and 
therefore encourages publications in reputable scientific journals and presentations at 
seminars or conferences. It is understood by the PI that the information generated in this 
study will be used by the sponsor in connection with the development of the 
investigational product and therefore may be disclosed to government agencies in various 
countries. To allow for the use of information derived from the study, it is understood 
that the PI is obliged to provide the sponsor with complete test results, all study data, and 
access to all study records. It is mandatory that all data analysis is done on the official 
monitored sponsor database and that the analysis plan is agreed upon with the sponsor 
statistician. 
 
Any results of medical investigations with the sponsor products and/or publications/ 
lectures/manuscripts based thereon, shall be exchanged and discussed by the PI and the 
sponsor clinical research representative(s) prior to submission for publication or 
presentation. Due regard shall be given to the sponsor's legitimate interests, e.g. 
manuscript authorship, obtaining optimal patient protection, coordinating and 
maintaining submissions to health authorities, and coordinating with other studies in the 
same field. 
 
The full details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this trial will be described in the Clinical Trial 
Agreement. 
  
20.0 References 
 
References 
 
1. 
Monson, C.M. and S.J. Fredman, Cognitive-Behavioral Conjoint Therapy for 
PTSD: Harnessing the Healing Power of Relationships. 1 edition ed. 2012, New 
York: The Guilford Press. 239. 
2. 
Mithoefer, M., A Manual for MDMA-Assisted Psychotherapy in the Treatment of 
Posttraumatic Stress Disorder; Version 6: 
http://www.maps.org/research/mdma/MDMA-
Assisted_Psychotherapy_Treatment_Manual_Version_6_FINAL.pdf. 
Multidisciplinary Association for Psychedelic Studies, 2013. 
3. 
Monson, C.M., B.F. Rodriguez, and R. Warner, Cognitive-behavioral therapy for 
PTSD in the real world: do interpersonal relationships make a real difference? J 
Clin Psychol, 2005. 61(6): p. 751-61. 
4. 
Price, M., et al., The Role of Social Support in Exposure Therapy for Operation 
Iraqi Freedom/Operation Enduring Freedom Veterans: A Preliminary 
Investigation. Psychol Trauma, 2013. 5(1): p. 93-100. 
5. 
Tarrier, N., C. Sommerfield, and H. Pilgrim, Relatives' expressed emotion (EE) 
and PTSD treatment outcome. Psychol Med, 1999. 29(4): p. 801-11. 
6. 
Thrasher, S., et al., Social support moderates outcome in a randomized controlled 
trial of exposure therapy and (or) cognitive restructuring for chronic 
posttraumatic stress disorder. Can J Psychiatry, 2010. 55(3): p. 187-90. 

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7. 
Lambert, J.E., et al., Impact of posttraumatic stress disorder on the relationship 
quality and psychological distress of intimate partners: a meta-analytic review. J 
Fam Psychol, 2012. 26(5): p. 729-37. 
8. 
Fredman, S.J., et al., Partner accommodation moderates treatment outcomes for 
couple therapy for posttraumatic stress disorder. J Consult Clin Psychol, in press. 
9. 
Fredman, S.J., et al., Partner accommodation in posttraumatic stress disorder: 
initial testing of the Significant Others' Responses to Trauma Scale (SORTS). J 
Anxiety Disord, 2014. 28(4): p. 372-81. 
10. 
Cami, J., et al., Human pharmacology of 3,4-methylenedioxymethamphetamine 
("ecstasy"): psychomotor performance and subjective effects. J Clin 
Psychopharmacol, 2000. 20(4): p. 455-66. 
11. 
Freedman, R.R., C.E. Johanson, and M.E. Tancer, Thermoregulatory effects of 
3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology 
(Berl), 2005. 183(2): p. 248-56. 
12. 
Grob, C.S., et al., Psychobiologic effects of 3,4-methylenedioxymethamphetamine 
in humans: methodological considerations and preliminary observations. Behav 
Brain Res, 1996. 73(1-2): p. 103-7. 
13. 
Harris, D.S., et al., Subjective and hormonal effects of 3,4-
methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology 
(Berl), 2002. 162(4): p. 396-405. 
14. 
Kuypers, K.P., N. Samyn, and J.G. Ramaekers, MDMA and alcohol effects, 
combined and alone, on objective and subjective measures of actual driving 
performance and psychomotor function. Psychopharmacology (Berl), 2006. 
187(4): p. 467-75. 
15. 
Liechti, M.E., A. Gamma, and F.X. Vollenweider, Gender differences in the 
subjective effects of MDMA. Psychopharmacology (Berl), 2001. 154(2): p. 161-8. 
16. 
de la Torre, R., et al., Non-linear pharmacokinetics of MDMA ('ecstasy') in 
humans. Br J Clin Pharmacol, 2000. 49(2): p. 104-9. 
17. 
Grob, C., Unpublished data on human study of psychological and physiological 
effects of MDMA. 2001. 
18. 
Mas, M., et al., Cardiovascular and neuroendocrine effects and pharmacokinetics 
of 3, 4-methylenedioxymethamphetamine in humans. J Pharmacol Exp Ther, 1999. 
290(1): p. 136-45. 
19. 
Tancer, M. and C.E. Johanson, Reinforcing, subjective, and physiological effects 
of MDMA in humans: a comparison with d-amphetamine and mCPP. Drug 
Alcohol Depend, 2003. 72(1): p. 33-44. 
20. 
Greer, G. and R. Tolbert, Subjective reports of the effects of MDMA in a clinical 
setting. J Psychoactive Drugs, 1986. 18(4): p. 319-27. 
21. 
Metzner, R. and S. Adamson, Using MDMA in healing, psychotherapy and 
spiritual practice, in Ecstasy, A Complete Guide: A Comprehensive Look at the 
Risks and Benefits of MDMA., J. Holland, Editor. 2001, Inner Traditions: 
Rochester VT. p. 182-207. 
22. 
Stolaroff, M., The Secret Chief Revealed: Conversations with a pioneer of the 
underground therapy movement. 2004, Sarasota FL: Multidisciplinary 
Association for Psychedelic Studies. 
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