A Randomized, Double-Blind, Controlled Phase 2 Pilot Study of Manualized 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy in 12 Subjects With Treatment-Resistant Posttraumatic Stress Disorder (PTSD) - Canada
Phase: PHASE2
Conditions: Posttraumatic Stress Disorder
Sponsor: Lykos Therapeutics



MAPS Study MP-4 
 
Protocol Synopsis Amendment 2 Version 3 
Canada 
 
June 20, 2014 
 
Page 1 of 7 
A Randomized, Double-Blind, Controlled Phase 2 Pilot Study of Manualized 
3,4-methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy in 12 Subjects 
with Treatment-Resistant Posttraumatic Stress Disorder (PTSD) – Canada 
 
Amendment 2 Version 3: June 20, 2014 
 
Study Code:  
MP-4 
 
Sponsor:  
Multidisciplinary Association for Psychedelic Studies (MAPS) 
1215 Mission St. 
Santa Cruz, CA 95060, USA 
Qualified  
Investigator:  
Ingrid Pacey MBBS FRCP[C]  
Research Affiliate, CARBC 
University of Victoria 
Tel:  604-732-9309 
 
Sub-Investigator:   Donna Dryer, MD, FRCP[C]  
Clinical Assistant Professor, Department of Psychiatry,  
University of British Columbia 
Medical Director, Orenda Institute 
Psychiatrist, Connect Health Centre for Integrative Medicine 
Cell: 778-938-6926 
Voice/FAX: 250-935-0037 
 
Site: 
3369 West 4th Avenue  
Vancouver BC Canada 
V6R 1N6 
Tel:  604-336-4822 
 
Medical Monitor:  Michael C. Mithoefer M.D. 
Assistant Clinical Professor of Psychiatry 
Medical University of South Carolina 
208 Scott Street 
Mount Pleasant, SC 29464-4345 
Tel:  843-849-6899 
 
Study Description: This is a Phase 2 randomized, double-blind, placebo controlled study to 
assess safety and efficacy of manualized MDMA-assisted psychotherapy in treating chronic, 
treatment-resistant PTSD. Seven subjects will be randomized to receive full dose MDMA (full 
dose condition) and five subjects will receive a comparator dose (comparator condition), with an 
optional supplemental half-dose available 1.5 to 2.5 hours after the initial dose.  
 
A team consisting of a male and female therapist will conduct psychotherapy according the 
treatment manual provided. There are two teams involved with this study. One team will consist 
of the Qualified Investigator and a co-therapist, and the second team will consist of a co-therapist 
and a Sub-investigator who have been delegated the authority to conduct therapy by the 

MAPS Study MP-4 
 
Protocol Synopsis Amendment 2 Version 3 
Canada 
 
June 20, 2014 
 
Page 2 of 7 
Qualified Investigator. Information will be collected regarding consistency and response of these 
teams by reviewing adherence criteria in selected blinded videos of therapy sessions. All study 
procedures, including administration of the Investigational Product, will be done by the 
Investigator or designated qualified study personnel. 
 
In Stage 1, all subjects will have two blinded experimental sessions of manualized MDMA-
assisted psychotherapy scheduled at a three to five week interval, within a moderate course of 
non-drug psychotherapy (preparatory and integrative sessions), after which they will complete 
the primary endpoint assessment. Integrative sessions may be completed via telemedicine, 
telephone or in person. After the primary endpoint assessment, the subject and the therapists will 
be unblinded. Subjects assigned to receive full dose MDMA will receive a third open-label 
experimental session and complete Stage 1. Subjects assigned to receive comparator dose will 
have the option to cross over, without completing Stage 1, to an open-label study segment 
following similar procedures, referred to as Stage 2. Stage 2 will be used to explore the optimal 
therapeutic dose of MDMA using a clinical titration dosing strategy. Stage 2 follows similar 
procedures and visit schedule as Stage 1 using varied active doses of MDMA, in which each 
initial dose may be followed by a supplemental dose that will be half of the initial dose. In Stage 
2, subjects will receive an initial dose of 100 mg MDMA during the first experimental session. 
The co-therapists, in consultation with the subject, will decide whether to administer an initial 
dose of 100 mg or 125 mg MDMA in the second and third experimental sessions.  
 
A blinded Independent Rater (IR) will assess PTSD symptoms, general function, and 
psychological symptoms. These symptoms will be assessed at baseline, the primary endpoint, 
and two months after the third experimental session in Stage 1 and equivalent timepoints in 
Stage 2. Outcome measures after baseline may be completed via telemedicine or in person. 
Neurocognitive measures must be done in person. Symptoms and long-term benefits and harms 
will be assessed again twelve months after the final experimental session. This study will provide 
an estimate of effect size based on dose comparison of PTSD symptoms to MDMA-assisted 
psychotherapy. This study will also permit the refinement of the treatment manual through 
blinded review of adherence criteria assessed by rating videos of psychotherapy sessions. 

MAPS Study MP-4 
 
Protocol Synopsis Amendment 2 Version 3 
Canada 
 
June 20, 2014 
 
Page 3 of 7 
Dose Selection: This study will compare the effects of psychotherapy sessions assisted by 
comparator dose or full dose MDMA. The comparator dose will be 0 mg MDMA followed 1.5 to 
2.5 hours later by 0 mg MDMA. The full dose will be 125 mg MDMA followed 1.5 to 2.5  hours 
later by 62.5 mg MDMA. 
 
Table 1. Stage 1 Drug Doses  
Experimental 
Session 
Dose 
Initial 
Dose 
Optional 
Supplemental 
Dose 
Min-Max 
Cumulative 
Dose 
1 and 2 
Comparator Dose 
0 mg 
0 mg 
0 mg 
1, 2, and 3 
Full Dose 
125 mg 
62.5 mg 
125-187.5 mg 
 
Table 2. Stage 2 Drug Doses  
Experimental 
Session 
Dose 
Initial 
Dose 
Optional 
Supplemental 
Dose 
Min-Max 
Cumulative 
Dose 
Min-Max 
Cumulative 
Dose with 
Titration 
1 
Active Dose 
100 mg 
50 mg 
100-150 mg 
 
Active Dose 
100 mg 
50 mg 
100-150 mg 
 
2 and 3 
+ Optional 
Titration Dose 
25 mg 
12.5 mg 
 
125-187.5 mg 
 
The MDMA doses to be used in this study have been used in previous studies sponsored by 
MAPS. The initial full dose is expected to produce all the commonly reported effects of MDMA. 
The supplemental dose will prolong subjective drug effects without producing physiological 
effects any greater than peak effects occurring after the initial dose.  The comparator dose is not 
expected to produce effects associated with MDMA.   
 
Protocol Objectives: The overall objective of this study is to examine whether the full dose of 
MDMA versus the comparator used in conjunction with manualized psychotherapy will reduce 
or attenuate PTSD symptoms as evaluated by standard clinical measures and to collect safety 
data.  
 
 
Primary Objective: Assess changes in PTSD symptoms in subjects receiving the full dose of 
MDMA compared to the comparator dose as measured by Global CAPS scores at baseline and 
the primary endpoint, one month after the second experimental session. 
 
Primary Outcome Measure: Clinician-Administered PTSD scale (CAPS) administered by a 
blinded Independent Rater. With the exception of the Screening/Baseline visit this measure can 
be administered via telemedicine or in person. 
 
Secondary Outcome Measures: Posttraumatic Diagnostic Scale (PDS), Global Assessment of 
Function (GAF), Beck Depression Inventory-II (BDI-II), Neuroticism Extroversion Openness 
Personality Inventory (NEO-PI), Pittsburgh Sleep Quality Index (PSQI), Posttraumatic Growth 
Inventory (PTGI), and Dissociation Scale II (DES-II) 

MAPS Study MP-4 
 
Protocol Synopsis Amendment 2 Version 3 
Canada 
 
June 20, 2014 
 
Page 4 of 7 
 
Safety Measures: Columbia Suicide Severity Rating Scale (C-SSRS), Repeatable Battery for 
Assessment of Neuropsychological Status (RBANS), Paced Auditory Serial Addition Task 
(PASAT), Vital signs, Subjective Units of Distress (SUD), Adverse Events and Spontaneously 
Reported Reactions, Concomitant Medications, Visual analog scales assessing pain and tinnitus, 
in participants with medical history of chronic pain and/or tinnitus  
 
Process Measures: Belief of condition assignment, States of Consciousness Questionnaire 
(SOCQ), Perceptions of Experimental Sessions, Reactions to Research Participation 
Questionnaire (RRPQ), Adherence to Treatment Manual 
 
Recruitment and Subject Population:  Subjects may be male or female, aged 21 or older, with a 
confirmed diagnosis of chronic PTSD, who have undergone at least one treatment of adequate 
dose/duration for PTSD without achieving remission. Prior treatment can include 
psychotherapeutic or pharmacological treatments, and people who have undergone one or more 
prior treatments are eligible for study participation. Subjects would not be excluded for having 
more than one traumatic event. Subjects must have a CAPS score equal to or greater than 60 and 
must meet all protocol inclusion criteria and no exclusion criteria at baseline. Subjects must be in 
good physical health and without major medical disorders that might affect the safety or 
tolerability of MDMA. Subjects will be recruited through printed ads, internet ads, referrals from 
other psychiatrists, psychotherapists or physicians, and through word of mouth. 
 
Study Procedures: After giving written informed consent, prospective subjects will be screened 
for eligibility, and twelve subjects meeting study criteria will be enrolled. In consultation with 
their prescribing physician, any individuals taking psychiatric medications will taper off these 
medications, allowing for a washout period of at least five times the medication half-life plus one 
week for stabilization before the first experimental session. Subjects taking psychostimulants for 
ADHD or gabapentin for pain management may continue to take these medications so long as 
they discontinue use for five half lives prior to each experimental session and resume use of 
psychostimulants ten days after an experimental session. During the study, benzodiazepines or 
zolpidem or other anxiolytic or sedative may be used as rescue medications if needed as 
approved by the qualified investigator responsible for the study. Any subjects who are in 
psychotherapy with an outside therapist at the time of enrollment may continue that therapy 
during the study without increasing the number or type of sessions or changing psychotherapists 
or type of psychotherapy.  
 
Symptoms of PTSD, perceived positive changes or growth after trauma, general psychological 
function, depression, sleep quality and dissociative experiences will be assessed at baseline in all 
subjects. The RBANS and PASAT will be administered to all subjects at baseline. The CAPS 
interviews may be recorded to audio and video to assess reliability of CAPS ratings. The first 
experimental session will be preceded by three preparatory sessions and followed by three 
integrative psychotherapy sessions. During preparatory sessions, subjects will learn what to 
expect during experimental sessions, and during integrative sessions they will receive support in 
integrating their experiences and insights from the experimental sessions. Preparatory, 
experimental and integrative sessions will be audio and video recorded for research purposes. 
Video data will be evaluated for adherence to the therapy manual using adherence criteria 
ratings. 

MAPS Study MP-4 
 
Protocol Synopsis Amendment 2 Version 3 
Canada 
 
June 20, 2014 
 
Page 5 of 7 
 
Seven subjects will be randomized to receive a full dose of MDMA and five will be randomized 
to receive comparator dose during two experimental psychotherapy sessions scheduled three to 
five weeks apart. After each experimental session, subjects will spend the night at the treatment 
facility with an attendant on duty. Subjects will complete the SOCQ in the time between an 
experimental session and the integrative session on the day after. Subjects and therapists will 
report their beliefs on their condition assignment at the integrative session on the day after each 
experimental session. There will be daily phone contact with one of the therapists for seven days 
after each experimental session. Throughout the study, changes in symptom severity of tinnitus 
and/or chronic pain will be collected as needed when subjects who have a medical history of 
these conditions report a change in symptoms using a simple visual analog scale. The PDS will 
be completed on the third integrative session after the first and third experimental sessions and 
during IR visits. Symptoms of PTSD, depression, sleep quality, dissociation, and perceived 
growth, general psychological function and cognitive function will be repeated for each subject 
at the primary endpoint, after which the blind will be broken. Subjects who learn they were 
assigned to full dose will have a third and final open-label experimental session with full dose 
MDMA, two months after which their psychological symptoms will be assessed again. Subjects 
who learn they were assigned to receive comparator dose will have the opportunity to enroll in 
Stage 2. Stage 2 consists of a similar series of procedures and visits except that subjects receive 
one preparatory visit and three open-label experimental sessions. Subjects will receive 100 mg 
MDMA possibly followed by 50 mg during the first open-label session. The decision to titrate 
the dose in the second and third experimental sessions in Stage 2 will be based on the experience 
of the first session. If 100mg MDMA does not seem to be the optimal therapeutic dose based on 
the first experimental session in Stage 2, the dosage may be increased by an increment of 25mg 
in order to achieve the optimal therapeutic dose. The supplemental doses for each experimental 
session will be half of the initial dose, respectively. Cognitive function will be assessed via 
RBANS and PASAT again at the primary endpoint and two months after the third Stage 1/Stage 
2 experimental sessions. 
 
There will be a long-term follow-up with repeated outcome measures for symptoms of PTSD, 
depression, dissociation, posttraumatic growth, sleep quality, pain and/or tinnitus, if applicable, 
twelve months after the subjects’ final experimental session.  The study therapists will maintain 
communication with the referring physician or therapist and any other healthcare providers 
requested by the subject.  
 
Subjects discontinuing treatment prior to the primary endpoint will be replaced until complete 
data has been collected from twelve subjects.  
 
Safety: The safety of subjects will be assured during and after the experimental sessions by 
assessing physiological effects, psychological distress, adverse events (AEs), spontaneously 
reported reactions, and suicidality.   
 
• 
Suicidality will be assessed with the Columbia Suicide Severity Rating Scale (C-SSRS) 
during visits prior to experimental sessions, twice during experimental sessions, and 
several times after each experimental session. 
• 
Subjective Units of Distress (SUD) scores and vital signs including blood pressure, heart 
rate and temperature will be measured during each experimental session. 

MAPS Study MP-4 
 
Protocol Synopsis Amendment 2 Version 3 
Canada 
 
June 20, 2014 
 
Page 6 of 7 
• Serious Adverse Events (SAEs) will be collected through termination.  
• All AEs and spontaneously reported reactions will be collected on the day of drug 
administration and for seven days after each experimental session. 
• AEs requiring medical attention will be collected from the first experimental session 
through the subject’s last two-month follow-up. 
• AEs 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. 
• Changes in pre-existing tinnitus and/or chronic pain symptoms will be collected using a 
visual analog scale, specifically in subjects with a medical history of tinnitus and/or 
chronic pain. 
• Changes in memory, attention, speed of information processing and problem solving will 
be measured with RBANS and PASAT at the primary endpoint and two months after the 
final Stage 1 or Stage 2 experimental session. 
 
Statistical Analysis: This is a pilot study intended to collect estimates of effect size of full dose 
MDMA (125 mg) versus placebo comparator dose. The study is underpowered for detection of 
differences of a small or moderate effect size, but it may detect differences if the effect size is 
large. The Sponsor will judge the clinical and statistical significance of the study based on a 
comparison of observer-blind data collected at baseline and the primary endpoint using the 
primary outcome measure, which is the CAPS. Descriptive statistics will be computed overall 
and within the two conditions for all available data from outcome measures. Effect sizes will be 
estimated for all outcome measures using Cohen’s techniques. RBANS and PASAT scores at 
baseline and primary endpoint will be compared across conditions using difference scores and 
independent-sample t-tests, with p value set at 0.05. Descriptive statistics will be computed for 
each adherence scale within a specific given session. The sponsor will explore the factors and 
structure of the measures of adherence to assist in further development of adherence and 
competence measures. If sufficient data is available, the sponsor will correlate the mean 
adherence ratings for adherence scale and session type with Global CAPS scores to investigate 
the effects of adherence to the treatment manual on reduction in PTSD symptoms.  
 

MAPS Study MP-4 
 
Study Synopsis 
Canada 
 
June 20, 2014 
 
Page 7 of 7 
Figure 1. Study Structure Overview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outcome Measure 
Unblinding 
Stage 2 for 
comparator 
dose subjects 
Screening 
Measures 
Integrative 
Sessions 
Open Label 
Experimental 
Session for full 
dose subjects 
Experimental 
Session 
Experimental 
Session  
Integrative 
Sessions 
Integrative 
Sessions 
Outcome Measure 
 
Outcome Measure 
Long-term Follow-up 
Preparatory  
Sessions 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 1 of 83 
PROTOCOL MP-4 
IND #63,384 
Original Protocol: March 17, 2009 
Amendment 1 Version 1: October 27, 2010 
Amendment 1 Version 2: June 20, 2013 
Amendment 2 Version 1: February 4, 2014 
Amendment 2 Version 2: June 02, 2014 
Amendment 2 Version 3: June 20, 2014 
 
A Randomized, Double-Blind, Controlled Phase 2 Pilot Study of Manualized 
3,4-methylenedioxymethamphetamine (MDMA)-assisted Psychotherapy in 12 
Subjects with Treatment-Resistant Posttraumatic Stress Disorder (PTSD) - Canada 
 
SPONSOR 
Multidisciplinary Association for Psychedelic 
Studies (MAPS)  
1215 Mission St. 
Santa Cruz, CA 95060 
SPONSOR DESIGNEE 
Amy Emerson 
Phone number: 510-393-7224 
 
QUALIFIED 
INVESTIGATOR 
 
 
 
Ingrid Pacey, M.B.B.S., F.R.C.P.[C]  
Research Affiliate, CARBC 
University of Victoria 
Tel: 604-732-9309 
SUB-INVESTIGATOR 
 
 
 
 
 
 
 
SITE 
Donna Dryer, M.D., F.R.C.P.[C]  
Clinical Assistant Professor,  
Department of Psychiatry, UBC 
Medical Director, Orenda Institute 
Cell: 778-938-6926 
Voice/FAX: 250-935-0037 
 
3369 West 4th Avenue  
Vancouver, BC Canada 
V6R 1N6 
Tel:  604-336-4822 
 
MEDICAL MONITOR 
Michael C. Mithoefer, M.D. 
Assistant Clinical Professor of Psychiatry 
Medical University of South Carolina 
208 Scott Street  
Mount Pleasant SC, 29464-4345 
Tel: 843-849-6899 
 
For trial related emergencies, call: 650-248-4647

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 2 of 83 
Table of Contents 
 
1.0 List of Abbreviations ............................................................................................................................. 4!
2.0 Introduction............................................................................................................................................ 6!
3.0 Background............................................................................................................................................. 7!
3.1 Posttraumatic Stress Disorder......................................................................................................7!
3.2 MDMA ........................................................................................................................................9!
3.3 Previous Clinical Experience with MDMA.................................................................................9!
3.4 MDMA-assisted Psychotherapy for PTSD................................................................................11!
3.5 Purpose ......................................................................................................................................13!
4.0 Ethics..................................................................................................................................................... 13!
5.0 Informed Consent ................................................................................................................................ 14!
6.0 Study Objectives................................................................................................................................... 15!
6.1 Primary Objective......................................................................................................................15!
6.2 Secondary Objectives ................................................................................................................15!
6.3 Safety Objectives.......................................................................................................................16!
7.0 General Investigational Plan............................................................................................................... 17!
7.1 Recruitment and Subject Population .........................................................................................17!
7.2 Enrollment Criteria ....................................................................................................................18!
7.2.1 Inclusion Criteria ..............................................................................................18!
7.2.2 Exclusion Criteria .............................................................................................19!
7.3 Planned Duration of Study and Visit Windows.........................................................................20!
8.0 Drug Description and Dosage ............................................................................................................. 20!
8.1 Drug Compounding, Doses, and Labeling ................................................................................22!
8.2 MDMA Accountability..............................................................................................................24!
8.3 MDMA Storage and Handling...................................................................................................25!
9.0 Method .................................................................................................................................................. 25!
9.1 Randomization...........................................................................................................................26!
9.2 Subject Numbering ....................................................................................................................26!
9.3 Assessments and Measures........................................................................................................30!
9.3.1 Outcome Measures............................................................................................30!
9.3.2 Safety Measures................................................................................................32!
9.3.3 Process Measures..............................................................................................34!
9.4 Visit Descriptions ......................................................................................................................35!
9.4.1 Prescreening, Screening, and Baseline Evaluation (Pre-study)........................35!
9.4.2 Preparatory Psychotherapy Sessions - Visits 1, 2, 3 (Stage 1), 18 (Stage 2)....38!
9.4.3 Experimental Sessions - Visits 4, 8 (Stage 1), 13, (Full Dose Group Stage 1), 
19 23, 28 (Stage 2).....................................................................................................39!
9.4.4 Integrative Sessions 24 Hours after Experimental Session - Visits 5, 9 (Stage 
1), 14 (Full Dose Group Stage 1), 20, 24, 29 (Stage 2) .............................................43!
9.4.5 A Week of Daily Contact..................................................................................44!
9.4.6 Integrative Psychotherapy Between Experimental Sessions - Visits 6, 7, 10, 
11,  (Stage 1), 15, 16, (Full Dose Group Stage 1), 21, 22, 25, 26, 30, 31 (Stage 2)..44!
9.4.7 Evaluation at Primary Endpoint and Unblinding - Visit 12 (Stage 1)..............45!
9.4.8 End of Stage 1 - Visit 17 (Full Dose Group Stage 1) .......................................46!
9.4.9 Open-label Stage 2 (Comparator Dose Subjects from Stage 1)........................47!
9.4.9 Long-term Follow-up........................................................................................48!
10.0 Removal of Subjects from Therapy or Assessment ........................................................................ 49!
11.0 Premature Discontinuation of the Study ......................................................................................... 50!
12.0 Data Analysis...................................................................................................................................... 50!
12.1 Statistical Power ......................................................................................................................52!

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 3 of 83 
13.0 Risk Mitigation................................................................................................................................... 53!
13.1 Medical Emergencies...............................................................................................................53!
14.0 Adverse Events ................................................................................................................................... 54!
14.1 Serious Adverse Events ...........................................................................................................55!
14.2 Adverse Event Collection........................................................................................................56!
14.3 Spontaneously Reported Reactions .........................................................................................57!
14.4 Collection of Concomitant Medications and Tapering Instructions........................................57!
14.5 Clinical Laboratory Assessments ............................................................................................60!
15.0 Study Monitoring, Auditing, and Documentation .......................................................................... 61!
16.0 Risks of Participation......................................................................................................................... 62!
16.1 Risks and Discomforts Associated with Psychotherapy Sessions and Assessment of 
Measures..........................................................................................................................................62!
16.2 Risks of Receiving MDMA.....................................................................................................62!
16.2.1 Cardiovascular and Sympathomimetic Effects...............................................63!
16.2.2 Psychological Distress ....................................................................................64!
16.2.3 Body Temperature ..........................................................................................67!
16.2.4 Reproductive and Developmental Risks.........................................................67!
16.2.5 Potential Neurotoxicity Associated with Ecstasy Use....................................67!
16.3 Abuse Liability ........................................................................................................................67!
16.4 Risks and Discomforts of Receiving the Comparator Dose of Study Drug ............................68!
17.0 Alternative Treatments and Procedures.......................................................................................... 68!
18.0 Confidentiality.................................................................................................................................... 69!
19.0 Costs to Subjects................................................................................................................................. 70!
20.0 Record Retention................................................................................................................................ 70!
21.0 Publication Policy............................................................................................................................... 70!
22.0 References........................................................................................................................................... 72!
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 4 of 83 
1.0 List of Abbreviations 
 
AE(s)  
Adverse Event(s) 
AED  
Automated External Defibrillator 
A:G 
 
Abumin : Globulin ratio 
ALT/SGPT 
Alanine Aminotransferase 
AMI   
Acute Myocardial Infarction 
AST/SGOT 
Aspartate Aminotransferase 
BDI-II  
Beck Depression Inventory II 
BP 
 
Blood Pressure 
BT 
 
Body Temperature 
BUN  
Blood Urea Nitrogen 
C 
 
Celsius 
CAPS  
Clinician Administered PTSD Scale 
CI 
 
Clinical Investigator(s) (e.g. therapists, Sub-Investigator(s)) 
CPK 
 
Creatine phosphokinase 
CPT 
 
Cognitive Processing Therapy 
CRA  
Clinical Research Associate 
CRF(s) 
Case Report Form(s) 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DBP 
 
Diastolic Blood Pressure 
DEA  
Drug Enforcement Administration 
DES-II  
Dissociation Experiences Scale II 
DMF  
Drug Master File 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders IV 
ECG/EKG 
Electrocardiogram 
ED 
 
Emergency Department 
EMDR  
Eye Movement Desensitization and Reprocessing 
EMS  
 
Emergency Medical Services 
F 
 
Fahrenheit 
FDA  
Food and Drug Administration  
GAF   
Global Assessment of Functioning 
GCP 
 
Good Clinical Practice 
HCl 
 
Hydrochloride 
HIPA   
Health Information Protection Act 
HIV 
 
Human Immunodeficiency Virus  
HPLC  
High Performance Liquid Chromatography 
IB 
 
Investigator’s Brochure 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
IND 
 
Investigational New Drug  
IR 
 
Independent Rater 
IRB 
 
Institutional Review Board 
ISF 
 
Clinical Investigator Site File 
IV 
 
Intra-venous 
LSD 
 
d-Lysergic acid diethylamide 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 5 of 83 
MAOI  
Monoamine oxidase Inhibitor 
MAPS  
Multidisciplinary Association for Psychedelic Studies 
MCH  
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV   
Mean Corpuscular Volume  
MDMA 
3,4-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 
NEO-PI 
Neuroticism Extroversion Openness Personality Inventory  
OT 
 
Oxytocin 
PASAT  
Paced Auditory Serial Addition Test 
PDS 
 
PTSD Diagnostic Scale 
PI 
 
Principal Investigator 
PRN 
 
As Needed 
PSQI  
Pittsburgh Sleep Quality Index 
PTSD  
Posttraumatic Stress Disorder 
PTCA   
Percutaneous Transluminal Coronary Angioplasty 
PTGI  
Posttraumatic Growth Inventory 
PTSD  
Posttraumatic Stress Disorder 
PTT 
 
Partial Thromboplastin Time 
RBANS  
Repeatable Battery for the Assessment of Neuropsychological Status  
RBC  
Red Blood Cell Count 
RDW  
Red Cell Distribution Width 
RRPQ  
Reactions to Research Participation Questionnaire 
SAE(s) 
Serious Adverse Event(s) 
SBP 
 
Systolic Blood Pressure 
SCID-RV 
Structured Clinical Interview for Diagnoses Research Version 
SERT   
Serotonin Transporter 
SL 
 
Sublingual 
SNRI  
Serotonin Norepinephrine Reuptake Inhibitor 
SOP(s)  
Standard Operating Procedure(s) 
SSRI  
Selective Serotonin Reuptake Inhibitor  
SUD   
Subjective Units of Distress 
T3 
 
Triiodothyronine 
T4 
 
Thyroxine 
TSH 
 
Thyroid Stimulating Hormones 
U.S. 
 
United States of America 
WBC   
White Blood Cell Count 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 6 of 83 
2.0 Introduction 
 
The Multidisciplinary Association for Psychedelic Studies (MAPS) is a non-profit 
research and educational organization working to obtain approval for the prescription 
use of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in 
patients with chronic treatment-resistant posttraumatic stress disorder (PTSD). This 
study, seeking to test MDMA-assisted psychotherapy in Canadian residents with chronic 
treatment-resistant PTSD, is part of an international series of Phase 2 clinical trials. 
Ongoing and planned Phase 2 studies are laying the groundwork for a possible End-of-
Phase 2 meeting with FDA and Phase 3 multi-site studies. 
 
MAPS has published results indicating sustained improvements in PTSD severity after 
MDMA-assisted psychotherapy [1-3].  MAPS is currently conducting a U.S.-based 
Phase 2 trial treating U.S. military veterans, firefighters, and police officers with service-
related, chronic, treatment-resistant PTSD, a U.S. Phase 2 pilot study in 12 subjects in 
Boulder, Colorado, and an Israeli Phase 2 pilot study in 10 subjects. Taken together, 
these pilot studies will help to gather preliminary data about the safety and efficacy of 
MDMA-assisted psychotherapy that will inform the design of possible Phase 3 multi-site 
studies. 
 
This Canadian pilot study is a randomized, double-blind, placebo-controlled evaluation 
of MDMA-assisted psychotherapy in 12 patients with chronic, treatment-resistant PTSD. 
PTSD must be of at least 6 months duration without remission from prior treatment with 
either pharmacotherapy or psychotherapy of adequate dose/duration or where treatment 
was discontinued due to lack of tolerability.  This study is designed to obtain estimates 
of effect size for safety and efficacy. The data will be combined with ongoing Phase 2 
dose response studies in a meta-analysis. 
 
This pilot study will be the first study of the therapeutic potential of MDMA to be 
conducted in Canada. In this study, seven of 12 people will receive a dose of MDMA 
expected to be fully therapeutic (full dose) and five of 12 will receive a comparator dose 
of 0 mg (inactive placebo) during the blinded part of the study, referred to as Stage 1.  
PTSD and associated symptoms will be assessed at baseline and one month after the 
second double-blind MDMA-assisted (experimental) psychotherapy session. Cognitive 
function will also be assessed at baseline and again one month after the second 
experimental session. Study subjects will receive psychotherapy before and after each 
experimental session.  
 
Unblinding will take place after the primary endpoint assessments. Full dose subjects 
will continue in Stage 1 and receive a third MDMA-assisted (experimental) 
psychotherapy session. The benefit of three vs. two full dose sessions will be assessed. 
Subjects who received the comparator dose during Stage 1 will have the opportunity to 
cross over and take part in a second study segment, referred to as Stage 2, with three 
experimental sessions. Stage 2 will be used to explore the optimal therapeutic dose of 
MDMA using a clinical titration dosing strategy. Stage 2 follows similar procedures and 
visit schedule as Stage 1 using varied active doses of MDMA, in which each initial dose 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 7 of 83 
may be followed by a supplemental dose that will be half of the initial dose. In Stage 2, 
subjects will receive an initial dose of 100 mg MDMA during the first experimental 
session. The co-therapists, in consultation with the subject, will decide whether to 
administer an initial dose of 100 mg or 125 mg MDMA in the second and third 
experimental sessions.  
 
3.0 Background 
 
3.1 Posttraumatic Stress Disorder 
 
PTSD is a debilitating psychiatric disorder arising after a traumatic life event. PTSD 
severely reduces quality of life and may directly or indirectly lead to or exacerbate other 
psychiatric and medical problems. A complex biopsychosocial condition, PTSD is 
characterized by a combination of three types of symptoms: 
 
1. Hyperarousal symptoms such as hypervigilance, anxiety, and sleep disturbance. 
2. Intrusive re-experiencing of traumatic experiences, such as intrusive memories, 
nightmares, or flashbacks. 
3. Avoidance symptoms, including emotional numbing and withdrawal [4, 5].  
 
The DSM-IV criteria for PTSD include:  
 
• Exposure to a significant traumatic event accompanied by an intense, acute 
emotional response.   
• Persistent re-experiencing of the event or aspects of the experience.   
• Persistent avoidance of stimuli associated with the event and/or withdrawal from 
some aspects of life.   
• Persistent symptoms of increased arousal.   
• The above symptoms must last for more than one month for Acute PTSD and 
more than three months for Chronic PTSD.  
 
The lifetime prevalence of PTSD in the U.S. general population is between 6% and 10% 
[6-10], but it is common in other countries as well [11-14]. According to some estimates, 
PTSD appears to be less prevalent in the general population of Europe at 1.9% [13]. In 
U.S. military personnel returning from combat in the Iraq war, the incidence of PTSD is 
as high as 18% [15]. It is estimated that the number of service members returning home 
with PTSD will ultimately be between 75,000 and 225,000 [16]. In countries with 
endemic armed conflict, the incidence of PTSD in civilians is often far greater [14, 17, 
18].  
 
Although presently we are not aware of any national surveys of lifetime PTSD 
prevalence in Canada, it is likely that the percentage of Canadians experiencing PTSD is 
similar to the 8% to 11% listed in samples from the United States and Europe. Likewise, 
a large prospective, longitudinal epidemiological study of adolescents and young adults 
in Germany showed a lifetime prevalence of PTSD, including sub-threshold cases, at 
baseline of 5.6%; by the end of the follow-up period (35-50 months) this had increased 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 8 of 83 
to 10.3% [19]. A survey of 3062 women in Ontario reported a 10.7% lifetime prevalence 
rate [20]. A study of Canadian peacekeepers reported higher rates of prevalence, with 
peacekeepers with single deployment diagnosed with PTSD at a rate of 10.9% and a 
14.8% rate in peacekeepers that were deployed more than once [21]. These findings 
suggest that Canadians have PTSD at rates comparable to the US and Europe and that as 
expected, certain populations will experience higher rates of PTSD. 
 
PTSD is clearly a serious public health problem and contributes substantially to 
healthcare costs [5, 8, 9]. PTSD is typically a chronic illness [6, 22] associated with high 
rates of psychiatric and medical comorbidity, disability, suffering, and suicide [7-10, 
23]. People suffering from PTSD face challenges in relationships and work productivity 
[24]. Despite the sheer number of individuals suffering from PTSD and its devastating 
effects, questions remain concerning the best possible treatments [25]. Two selective 
serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, which are known to 
affect the serotonergic components of PTSD, are currently marketed as PTSD 
medications in the U.S. [26, 27]. SSRIs must be used every day in order to be effective 
for PTSD symptoms [28]. However, SSRIs are associated with a high rate of 
discontinuation due to lack of tolerability caused by treatment-emergent side effects that 
may be under-reported [29, 30]. 
  
A wider array of effective treatments are needed for PTSD. At least a third of PTSD 
patients fail to respond to established PTSD psychotherapies or do not respond in a 
clinically significant manner [31-33]. 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 [34].  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 Clinician 
Administered PTSD Scale (CAPS) scores, an outcome which was considered highly 
efficacious [35]. At least one study of paroxetine indicated that men with PTSD did not 
respond to this drug [26] and another randomized, double-blind study found no 
difference between sertraline and placebo in the treatment of PTSD [36]. 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 [37-39]. 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 [40, 41], although some patients may need 
more than one type of treatment to reduce or resolve those symptoms [28]. A recent 
meta-analysis concluded that all “bona fide” psychotherapies, including those listed 
above, are similarly effective with PTSD [42]. In recent years, there has been a growing 
amount of research into drugs and other methods that may augment the effectiveness of 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 9 of 83 
psychotherapy for PTSD (see [43] for a review).  Examples of this are virtual reality-
assisted exposure therapy [44-47] and D-cycloserine-assisted psychotherapy [48]. 
MDMA-assisted psychotherapy is another such approach. 
 
3.2 MDMA 
 
MDMA is a ring-substituted phenylisopropylamine derivative. Chemists at the Merck 
pharmaceutical company first synthesized it in 1912 [49, 50], though its clinical effects 
were not subject to formal investigation until the 1980s. MDMA is a potent monoamine 
releaser that has its greatest effects on serotonin, followed by norepinephrine and 
dopamine [51-56].  
 
MDMA acutely decreases activity in the left amygdala [57], a brain region involved in 
interpretation of negative cues, and attenuates amygdalar response to angry faces [58]. 
This action of MDMA is compatible with its reported reduction in fear of emotional 
injury or defensiveness [59]. Brain imaging after MDMA indicates less reactivity to 
angry facial expressions and greater reward in happy faces [58]. A recent study in 
healthy volunteers found correlations between oxytocin (OT) levels, amygdalar volume, 
and extraverted personality [60].  
 
OT is a neuropeptide associated with pair bonding and social affiliation in mammals that 
also attenuates amygdalar response to anxiogenic stimuli [61, 62]. OT administration is 
associated with increased interpersonal trust and changes in social perception, including 
attenuated reactivity to threatening faces [63-66]. MDMA elevates OT in peripheral 
blood [67-69], which is an imperfect but somewhat reliable indicator of elevated OT in 
the brain [62]. Findings of an association between elevated OT and detectable MDMA 
in peripheral blood were first reported in a naturalistic study of London nightclub 
attendees with and without detectable serum MDMA levels [67]. Dumont and 
colleagues reproduced these results in humans and found that MDMA significantly 
elevated peripheral plasma OT levels in a placebo-controlled study in healthy volunteers 
[68], in addition to a positive association between elevated levels of OT and prosocial 
feelings. Hysek and colleagues replicated these results and reported that administering a 
serotonin reuptake inhibitor, but not a norepinephrine uptake inhibitor nor several 
adrenergic antagonists, attenuated the effects of MDMA on OT levels, suggesting a 
serotonergic mechanism in producing elevated OT [69]. The effects of MDMA on OT 
may influence empathy or compassion for self and others, decrease defensiveness, and 
strengthen therapeutic alliance. The multi-level effects of MDMA on monoaminergic 
signaling and OT, combined with a therapeutic setting, are more likely to provide the 
opportunity for a corrective emotional experience than OT alone, and could be useful in 
the treatment of PTSD. 
 
3.3 Previous Clinical Experience with MDMA 
 
Classification as a Schedule I drug in the United States has hampered research into the 
medical uses of MDMA. In recent years, clinical investigation of the safety and efficacy 
of MDMA-assisted psychotherapy has become more feasible due to an open IND with 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 10 of 83 
the FDA [70]. The first double-blind, placebo-controlled U.S. Phase 1 study sanctioned 
by the FDA was conducted at Harbor-UCLA Medical Center in 1994, with findings that 
suggested MDMA may cause a statistically significant increase in body temperature, 
heart rate, and blood pressure in some healthy volunteers [71]. However, these increases 
were found to be transient and generally tolerable in a controlled clinical setting. 
Subsequent trials confirmed that MDMA produced significant increases in heart rate and 
blood pressure that were likely to be well tolerated by healthy individuals [68, 71-76]. 
The elevation in body temperature noted in healthy volunteers was not clinically 
significant in sponsor-supported studies at normal ambient temperatures [1, 77]. As of 
May 2013, MDMA has been administered to more than 845 research subjects, in both 
Phase 1 and Phase 2 studies, and the sponsor has not been informed of or seen published 
reports of any unexpected MDMA-related Serious Adverse Events (SAEs) in research 
studies [1, 51, 54, 58, 59, 68, 69, 71, 72, 74, 76-108]. 
 
The potentially therapeutic effects of MDMA were initially investigated in a dose 
response pilot study funded by MAPS in Spain, in six female survivors of sexual assault 
with treatment-resistant PTSD [78, 109]. In this study, doses ranging from 50 mg to 75 
mg demonstrated mild signs of improvement without any adverse events (AEs) or signs 
of deteriorating mental health [109].  
 
MAPS sponsored the first U.S. Phase 2 randomized, placebo-controlled study of 
MDMA-assisted psychotherapy for the treatment of chronic, treatment resistant PTSD, 
designated as MP-1. MP-1 demonstrated promising results in a sample of 20 subjects 
[77]. 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 at two-month follow-up. Data from this 
randomized, placebo-controlled pilot study suggests that MDMA is associated with 
significantly greater improvement in PTSD than placebo (N=20) [77]. Two months after 
treatment with MDMA-assisted psychotherapy, 83.3% (8 of 12) of the subjects no 
longer had a PTSD diagnosis and exhibited a 68% drop in CAPS global severity scores. 
Twenty five percent (two of eight) of the subjects in the placebo and psychotherapy 
group no longer had a PTSD diagnosis and exhibited a 26% drop in CAPS global 
severity scores. Seven of the eight subjects receiving placebo went through the treatment 
program again to receive full dose MDMA. The crossover subjects experienced a 48% 
drop in CAPS scores and none of these subjects qualified for a PTSD diagnosis at the 
end of the study, establishing that subjects receiving placebo were not more resistant to 
treatment. Evaluation of subjects on an average of 45.4 months after receiving MDMA-
assisted psychotherapy indicates that the therapeutic benefits have been sustained over 
time on average, although two subjects experienced a relapse in PTSD symptoms [3]. 
PTSD symptom severity in subjects who completed the CAPS at long-term follow-up 
(mean CAPS scores 23.7±22.8, N=16) were statistically equivalent on average to the end 
of the treatment program (mean CAPS scores 24.6±18.6, N=16) [3].  
 
The sponsor also supported a randomized, double-blind pilot study in 12 subjects with 
chronic, treatment-resistant PTSD in Switzerland with three experimental sessions, 
designated as MP-2. The study results suggested a trend toward significant improvement 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 11 of 83 
in subjects receiving full dose MDMA, when compared to a 25 mg active placebo 
MDMA at two-month follow-up [1]. The improvement continued to increase during the 
12-month follow-up [1]. 
 
In addition, the sponsor supported an initial pilot study with two experimental sessions 
comparing full dose to 25 mg active placebo MDMA in Israel that enrolled five subjects, 
with no drug-related Serious Adverse Events (SAEs).  
 
Overall, the results of these studies suggest that MDMA-assisted psychotherapy may be 
safe and effective in these subjects regardless of trauma etiology.  
 
3.4 MDMA-assisted Psychotherapy for PTSD 
 
MDMA-assisted psychotherapy is an innovative mode of treatment that combines 
therapeutic techniques with the administration of MDMA, a pharmacological adjunct 
that may enhance or amplify certain aspects of therapy. MDMA possesses unique 
pharmacological properties that may make it especially well suited to use as an adjunct 
to therapy. MDMA is capable of inducing unique psychopharmacological effects, 
including: 
 
• Decreased feelings of fear. 
• Increased feelings of wellbeing. 
• Increased sociability and extroversion. 
• Increased interpersonal trust. 
• Alert state of consciousness. 
 
Early observers noted increased acceptance of self and others, increased tolerance of 
emotionally upsetting materials, and the ability to address these issues without extreme 
disorientation or ego loss [110-113]. 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 [110, 111, 114, 115] before it 
was placed in Schedule I in 1985, as a result of extensive non-medical use [59, 113, 
116]. Placement in Schedule I prohibited it for use, except in a federally approved 
research setting in the U.S.  
 
In contrast to daily administrations of SSRIs, MDMA-assisted psychotherapy consists of 
several drug-assisted sessions interspersed with a moderate course of non-drug 
psychotherapy. Thus the effects of MDMA are distinct from and go well beyond those 
of anti-anxiety drugs such as benzodiazepines. Furthermore, there is no evidence that 
MDMA creates a physical dependency, as benzodiazepines do. Previous studies of 
polydrug users have found a small percentage of people exhibit problematic use of 
Ecstasy (material represented as containing MDMA) [117, 118]. Studies of regular or 
problematic Ecstasy users indicate that on average, regular use occurs no more often 
than once a week [119]. Hence, MDMA may have moderate abuse potential. See the 
Investigator’s Brochure (IB) for a more detailed explanation. 
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 12 of 83 
Many psychotherapies for PTSD involve the induction and extinction of abnormal 
autonomic responses through revisiting traumatic experiences in psychotherapy with an 
appropriate level of emotional engagement [5].  To be effective, exposure must be 
accompanied by a degree of emotional engagement or “fear activation” while avoiding 
dissociation or overwhelming emotion [120].  This has been referred to as working 
within the “optimal arousal zone” or “window of tolerance” [121-123]. When given in 
an appropriate setting, MDMA produces increased positive mood, facilitates recall and 
imagination, changes in emotion perception, and social affiliation [58, 68, 69, 103, 124]. 
These effects are thought to permit revisiting of trauma-associated memories, thoughts, 
and feelings while maintaining the window of tolerance.  
 
In the context of psychotherapy, MDMA has been noted to reduce defenses and fear of 
emotional injury while enhancing communication and capacity for introspection [59]. 
MDMA-assisted psychotherapy is an innovative mode of treatment that combines 
psychotherapeutic techniques with the administration of MDMA as a pharmacological 
adjunct. MDMA possesses unique pharmacological properties that may make it 
especially well suited to use as an adjunct to psychotherapy in PTSD patients, as it 
appears to stimulate spontaneous engagement in elements of conventional therapies, 
such as exposure therapy, psychodynamic therapy, and internal family systems therapy 
in the therapeutic context. 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. The biologic 
and therapeutic approaches are intended to overlap and reinforce each other.  
 
A combined treatment of MDMA and psychotherapy may be especially useful for 
treating PTSD because MDMA can attenuate the fear response of a perceived threat to 
one’s emotional integrity and decrease defensiveness without blocking access to 
memories or preventing a deep and genuine experience of emotion [77, 109, 111, 113]. 
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 
[110]. Subjects are able to experience and express fear, anger, and grief with less 
likelihood of feeling overwhelmed by these emotions. MDMA seems to engender 
internal awareness that even painful feelings that arise are an important part of the 
therapeutic process. In addition, feelings of empathy, love, and deep appreciation often 
emerge, along with a clearer perspective of the trauma as a past event, a more accurate 
perspective about its significance, and a heightened awareness of the support and safety 
that exists in the present. As a result, MDMA-assisted psychotherapy may enable the 
subjects to restructure their perspective and develop a wider behavioral and emotional 
repertoire with which to respond to anxiogenic stimuli.  
 
Based on these data and on an extensive review of the MDMA literature, we conclude 
that MDMA-assisted psychotherapy may have the potential to serve as an innovative 
treatment for PTSD, particularly in people who fail to respond to currently available 
therapies, and that the modest risks of administering MDMA within a therapeutic 
context are outweighed by the possibility that this treatment may offer significant 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 13 of 83 
benefits. 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. 
 
3.5 Purpose 
 
This Phase 2 pilot study is a randomized, double-blind, placebo controlled study in 12 
subjects that will estimate the effect sizes of full dose and comparator dose MDMA as 
an adjunct to manualized psychotherapy. Seven subjects will be randomized to the full 
dose condition and five subjects will be randomized to the comparator dose condition. 
Stage 1 will consist of two blinded experimental sessions and one open-label 
experimental session of manualized MDMA-assisted psychotherapy, each lasting six to 
eight hours and scheduled three to five weeks apart, within a moderate course of non-
drug psychotherapy. The study will be unblinded one month after the second 
experimental session in Stage 1, after completion of outcome measures, which 
constitutes the primary endpoint assessment.  
 
After unblinding, full dose subjects will continue in Stage 1 and receive a third MDMA-
assisted psychotherapy session. The benefit of three vs. two full dose sessions will be 
assessed. Subjects who received the comparator dose during Stage 1 will have the 
opportunity to cross over to Stage 2 with three experimental sessions. Stage 2 will be 
used to explore the optimal therapeutic dose of MDMA using a clinical titration dosing 
strategy. 
 
A blinded IR will assess the severity of PTSD symptoms at baseline, at the primary 
endpoint one month after the second experimental session, two months after the third 
open-label experimental session and at equivalent time points in Stage 2. All subjects 
will complete a long-term follow-up visit 12 months after their final experimental 
session in either Stage 1 or Stage 2.  
 
Two therapy teams will conduct psychotherapy visits according the treatment manual 
provided. One team will consist of the Qualified Investigator and a co-therapist, and the 
second team will consist of a co-therapist and a Sub-investigator who have been 
delegated the authority to conduct therapy by the Qualified Investigator. All study 
procedures, including administration of the Investigational Product, will be done by the 
Investigator or designated qualified study personnel according to the Site Responsibility 
Log. 
 
4.0 Ethics 
 
The trial will not be initiated until appropriate Health Canada and Institutional Review 
Board (IRB) approval of the protocol and the informed consent document has been 
obtained. All documents will be submitted to other authorities in compliance with local 
jurisdictions. The IRB and, if applicable, other authorities must be informed of protocol 
amendments in accordance with local legal requirements. The protocol will also be 
submitted to FDA under U.S. IND #63,384. 
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 14 of 83 
This trial will be conducted in accordance with the most recently acceptable version of 
the Declaration of Helsinki, Good Clinical Practice (GCP) according to International 
Conference on Harmonization (ICH) guidelines, and applicable Standard Operating 
Procedures (SOPs). The trial will be conducted under a protocol reviewed and approved 
by an IRB.  The trial will be conducted by scientifically and medically qualified persons.  
The benefits of the study will be considered in proportion to the risks.  The rights and 
welfare of the subjects will be respected.  The physicians conducting the trial do not find 
the hazards to outweigh the potential benefits.  Each subject will give his or her written 
informed consent before any protocol-driven tests or evaluations are performed. 
 
5.0 Informed Consent 
 
The Investigator is responsible for overseeing informed consent is obtained in adherence 
to GCP and according to applicable regulations prior to entering the subject into the trial. 
The informed consent discussion must be conducted by a person who is qualified 
according to regulations. Written information about the trial will be provided in an 
understandable Informed Consent Form (ICF).  Written consent must be given by the 
subject.  The ICF document must be explained and the subjects’ questions must be 
answered. The subject should have the opportunity to inquire about details of the 
MDMA-assisted session and to consider participation.  
 
The ICF will state the probability of random assignment to the full dose group or the 
comparator dose group, however there will be a level of obfuscation, which makes it 
unclear that there is only one comparator dose, and that it is an inactive placebo. The 
ICF will indicate the comparator dose may or may not contain MDMA. If subjects ask 
about the composition of investigational product in the comparator dose group, the exact 
contents of the comparator dose will be said to include lactose and may or may not 
include MDMA, however everyone assigned to the comparator dose group will have the 
opportunity to receive active dose MDMA during Stage 2. For all subjects in the 
comparator dose group, the content of the comparator dose will be disclosed after the 
primary endpoint visit when unblinding occurs. Unblinding and debriefing at the 
primary endpoint will take place with the co-therapist team and the subject. During the 
debriefing, subjects will be informed of the contents of the investigational product they 
received during the blinded experimental sessions in Stage 1. 
 
In addition to the explanation of study visits, the ICF 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 Investigator 
permission to view the subject’s recent medical records to assess protocol eligibility, if 
needed. Information necessary for protocol participation includes past medical history, 
psychiatric interview, physical examination, and clinical laboratory tests. 
 
Eligible subjects may only be included in the study after signing the IRB approved ICF. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. 
all of the procedures described in the protocol, including screening activities). The 
process of obtaining informed consent should be documented in the subject source 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 15 of 83 
records. The therapists will provide a copy of the signed ICF to the subject and will 
maintain the original in the ISF. 
 
The written ICF and any other written information to be provided to subjects should be 
revised whenever important new information becomes available that may be relevant to 
the subject’s consent. Any revised ICF and written information should receive approval 
from an IRB before use. The subject should be informed in a timely manner if new 
information becomes available that might affect the decision to take part in the MDMA-
assisted session. The communication of this information should be documented.  
 
Subjects can withdraw consent at any time without prejudice. If a subject withdraws 
consent but does not revoke Health Information Protection Act (HIPA), the Investigator 
will have access to the subject’s study related medical records and data will be used. If a 
subject revokes consent and HIPA, the Investigator will have access to the subject’s 
medical records prior to the date and time of revocation but the data will not be used.  
 
6.0 Study Objectives 
 
The overall objective of this study is to examine whether the full dose of MDMA versus 
the comparator dose used in conjunction with manualized psychotherapy will reduce or 
attenuate PTSD symptoms as evaluated by standard clinical measures and to collect 
safety data. 
 
6.1 Primary Objective 
 
• Assess changes in PTSD symptoms in subjects receiving the full dose of MDMA 
compared to the comparator dose as measured by Global CAPS scores at 
baseline and the primary endpoint, one month after the second experimental 
session. 
 
6.2 Secondary Objectives 
 
The following objectives will compare full dose subjects to comparator dose subjects in 
Stage 1: 
 
• Assess changes in self-reported PTSD symptoms as measured with the PTSD 
Diagnostic Scale (PDS) at baseline, after each experimental session and/or the 
primary endpoint. 
• Assess depression symptoms with the Beck Depression Inventory (BDI-II) at 
baseline and the primary endpoint. 
• Assess global functioning with the Global Assessment of Functioning (GAF) at 
baseline and the primary endpoint. 
• Assess changes in personality with the Neuroticism Extroversion Openness 
Personality Inventory (NEO-PI) at baseline and the primary endpoint. 
• Assess self-reported sleep quality with the Pittsburgh Sleep Quality Index (PSQI) 
at baseline and the primary endpoint. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 16 of 83 
• Assess self-reported dissociation symptoms with the Dissociation Experiences 
Scale II (DES-II) at baseline and the primary endpoint. 
• Assess self-reported posttraumatic growth with the Posttraumatic Growth 
Inventory (PTGI) at baseline and the primary endpoint. 
 
The following objectives will compare effects in specified subjects: 
 
• Assess PTSD symptoms via CAPS and PDS, depression symptoms via BDI-II, 
global functioning via GAF, sleep quality via PSQI, posttraumatic growth via 
PTGI, changes in personality via NEO-PI and dissociation symptoms via the 
DES-II, throughout Stage 2 in comparison to Stage 1 in crossover subjects. 
• Assess long-term effects of MDMA-assisted psychotherapy on symptoms of 
PTSD, depression, global function, sleep quality, posttraumatic growth, and 
dissociation symptoms via CAPS, PDS, BDI-II, GAF, PTGI, PSQI, PTGI (in 
reference to start of the study), DES-II, and changes in personality via NEO-PI 
one year after the final experimental session for each subject. 
 
The following objectives will include exploratory analyses intended to inform protocol 
design: 
 
• Explore the effects of each experimental session upon self-reported changes in 
consciousness, as those associated with a transformational or mystical experience 
via the States of Consciousness Questionnaire (SOCQ). 
• Assess the effect of the third experimental session for full dose subjects in Stage 
1 and Stage 2 using CAPS, PDS, BDI-II, GAF, PSQI, PTGI, NEO-PI, and DES-
II.  
• Assess the ability of the therapists and subjects to accurately guess condition 
assignment in Stage 1. 
• Correlate adherence to the treatment manual with Global CAPS scores using 
adherence criteria ratings to assess videos of psychotherapy sessions. 
 
6.3 Safety Objectives 
 
The study will monitor and ensure safety in subjects enrolled in the study by assessing 
physiological effects, psychological distress, spontaneously reported reactions, and 
suicidality. 
 
• Vital signs (blood pressure, heart rate, and temperature) and Subjective Units of 
Distress (SUD) will be measured during each experimental session. Comparisons 
will be made for SUD scores and vital signs between each condition.  
• SAEs, AEs, and spontaneously reported reactions will be collected during the 
study according to protocol Section 14.0.  
• Suicidality will be assessed with the Columbia Suicide Severity Rating Scale (C-
SSRS) during visits prior to and after experimental sessions, twice during 
experimental sessions, and several times after each experimental session. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 17 of 83 
Comparisons will be made for C-SSRS scores for subjects in each condition. The 
same schedule of assessment will be followed during Stage 2. 
• Assess cognitive function with the Paced Auditory Serial Addition Test 
(PASAT) and the Repeatable Battery for the Assessment of Neuropsychological 
Status (RBANS) at baseline and the primary endpoint by condition, and end of 
Stage 1/end of Stage 2 for maximal exposure. 
• Collect changes to pre-existing tinnitus and/or chronic pain symptoms using a 
visual analog scale, specifically in subjects with a medical history of tinnitus 
and/or chronic pain.  
 
7.0 General Investigational Plan 
 
7.1 Recruitment and Subject Population 
 
Subjects may be men or women aged 21 or older with a confirmed diagnosis of chronic, 
treatment-resistant PTSD who have undergone psychotherapeutic or 
psychopharmacological treatment for PTSD of adequate dose/duration without 
achieving remission. Subjects who discontinued PTSD treatment due to inability to 
tolerate psychotherapy (e.g. due to persistent “over-engagement”) or 
psychopharmacology due to treatment-emergent side effects would not be excluded. 
Subjects will also not be excluded for having more than one traumatic event. Subjects 
must have a CAPS score equal to or greater than 60 and meet all inclusion criteria and 
no exclusion criteria at baseline. They must be in good physical health and without 
major medical disorders that might affect the safety or tolerability of MDMA Seven of 
12 subjects will be randomly assigned to receive the full dose and five subjects will be 
randomly assigned to receive the comparator dose.  
 
Study subjects will be Canadian residents recruited by letters of referral sent to 
psychiatrists and psychotherapists, written advertisements, announcements placed on 
appropriate Internet sites and the sponsor site, and through word of mouth. Site staff will 
interview prospective subjects by telephone to learn if they meet basic eligibility criteria. 
If the prospective subject is interested in taking part in the study, the Study Coordinator 
will provide the prospective subject with consent materials for review and consideration.  
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 18 of 83 
7.2 Enrollment Criteria 
 
7.2.1 Inclusion Criteria 
 
Individuals eligible to be enrolled into this protocol are subjects who: 
 
1. Meet DSM-IV criteria for current PTSD, with a CAPS score of 60 or higher, 
indicating moderate to severe PTSD symptoms; 
2. Have chronic PTSD, defined as PTSD persisting for longer than 6 months; 
subjects may have experienced one or more traumatic event; 
3. Have treatment-resistant PTSD, who were unable to achieve remission despite 
receiving adequate dose/duration of psychotherapy or psychopharmacology with 
an SSRI, mirtazapine, or MAOI, or who discontinued treatment due to either:  
a. Inability to tolerate psychotherapy for PTSD (e.g. persistent “over-
engagement” when attempting Prolonged Exposure Therapy). 
b. Inability to tolerate psychopharmacology for PTSD due to treatment-
emergent side effects; 
4. Are at least 21 years old; 
5. Are willing to commit to medication dosing, experimental sessions, follow-up 
session and completion of evaluation instruments; 
6. Are willing to refrain from taking any psychiatric medications during the study 
period, with the exception of gabapentin when prescribed for pain control. If the 
subject is on stimulants for ADHD at baseline, they can continue to use them at 
the same dose and frequency as long as they discontinue five half-lives before 
each experimental session and do not restart for ten days after each experimental 
session. Any psychiatric drugs will be tapered in an appropriate fashion to avoid 
withdrawal effects. Medications will only be discontinued after consultation with 
the prescribing physician; 
7. If in ongoing psychotherapy at the time of recruitment, are able to continue to see 
their outside therapist during the course of the study. Subjects must sign a release 
permitting the Investigator or Sub-Investigator to communicate directly with 
their therapist. Subjects may not change therapists, increase the frequency of 
therapy, or commence any new type of therapy until after the evaluation session 
at the end of Stage 1 or Stage 2, as applicable; 
8. Agree to refrain from taking, for one week preceding each experimental session: 
a. Any herbal supplement (except with prior approval of the research 
team).  
b. Any nonprescription medications (with the exception of non-steroidal 
anti-inflammatory drugs or acetaminophen unless with prior approval of 
the research team). 
c. Any prescription medications (with the exception of birth control pills, 
thyroid hormones or other medications approved by the research team). 
Note: Must have physician’s approval; 
9. Agree to take nothing by mouth except alcohol-free liquids after midnight the 
evening before the experimental session. Subjects must also refrain from the use 
of any psychoactive drug, with the exception of caffeine or nicotine, within 24 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 19 of 83 
hours of each experimental session. They must agree not to use caffeine or 
nicotine for 2 hours before and 6 hours after each experimental session; 
10. Are willing to remain overnight at the clinic after each experimental session until 
the integrative session occurring the next morning. An attendant with previous 
training in managing psychological distress will be present to assist with personal 
needs if requested and offer dinner and breakfast; 
11. Are willing to locate an individual to drive them home the morning after the 
experimental sessions, after the integrative session. If a subject is unable to 
locate someone to transport them home, the therapists will assist the subject in 
obtaining transport from the clinic to the subject’s home or any other location 
where he or she is staying temporarily; 
12. Are willing to be contacted via telephone on a daily basis by one of the therapists 
for a week after each experimental session; 
13. Are willing to provide a contact (relative, spouse, close friend, or other 
caregiver) who is willing and able to be reached by the therapists in the event of 
a subject becoming suicidal; 
14. Agree to inform the therapists within 48 hours of any planned medical 
interventions; 
15. Have a negative pregnancy test and must agree to use an effective form of birth 
control, if the participant is a female of childbearing potential; 
16. Are literate and proficient in reading documents written in English and speaking 
English; 
17. Agree to have all clinic visit sessions recorded to audio and video; 
18. Agree not to participate in any other interventional clinical trial for the duration 
of this clinical trial, including the follow-up period. 
 
7.2.2 Exclusion Criteria 
 
Individuals not eligible to be enrolled into this protocol are those who: 
 
1. Are pregnant or nursing, or of child bearing potential and not practicing an 
effective means of birth control; 
2. Have a history of, or current primary psychotic disorder or bipolar affective 
disorder type 1 or borderline personality disorder; 
3. Have dissociative identity disorder or an eating disorder with active purging; 
4. Have evidence or history of significant hematological, endocrine, 
cerebrovascular, cardiovascular, cardiac, coronary, pulmonary, renal, 
gastrointestinal, immunocompromising, or neurological disease, including 
seizure disorder, or any other medical disorder judged by the Investigator or Sub-
Investigator to significantly increase the risk of MDMA administration (Subjects 
with hypothyroidism who are on adequate and stable thyroid replacement will 
not be excluded); 
5. Have hypertension using the standard criteria of the American Heart Association  
of values of 140/90 or higher assessed on three separate occasions, peripheral 
vascular disease, hepatic disease (with or without abnormal liver enzymes), or 
history of hyponatremia or hyperthermia; 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 20 of 83 
6. Weigh less than 48 kg; 
7. Have used “Ecstasy” (illicit drug preparations purported to contain MDMA) 
more than five times in the last 10 years or at least once within six months of 
enrollment;  
8. Would present a serious suicide risk, or who are likely to require hospitalization 
during the course of the study, as determined through psychiatric interview, 
responses to C-SSRS and through clinical judgment of the Investigator or Sub-
Investigator; 
9. Require ongoing concomitant therapy with a psychiatric drug, including but not 
limited to SSRIs, SNRIs, or MAOIs; 
10. Meet DSM-IV criteria for active substance abuse or dependence for any 
substance other than caffeine or nicotine in the past 6 months; 
11. Are not able to give adequate informed consent; 
12. Have any current problem, which in the opinion of the Investigator, Sub-
Investigator, or Medical Monitor, might interfere with participation in the study. 
 
7.3 Planned Duration of Study and Visit Windows 
 
Subjects enrolled in this study will fall into two categories that will determine the 
duration of the study. These include the follow-up portion of the study, which 
encompasses 12 months after the final experimental session. 
 
• Full dose subjects completing Stage 1 only: 15 months  
• Comparator dose subjects who complete Stage 2: 18 months 
 
Screening may take up to two months, with the baseline CAPS being conducted 4 to 8 
weeks before the first experimental session, in order to allow for appropriate medication 
washout of at least 5 half-lives of pre-study psychiatric medications and active 
metabolites, and one additional week for stabilization. For example, the maximum 
washout would be 7 weeks for subjects tapering off of fluoxetine plus one week for 
stabilization. Tapering off high doses of benzodiazepines may take a comparable period 
of time. Scheduling of preparatory sessions must be between screening and the first 
experimental session at intervals that suite the scheduling needs of participants and the 
research team, with the first experimental session taking place 3-5 weeks after 
enrollment, and at most 5 weeks after the baseline CAPS. The maximum window from 
the start of screening to the first experimental session is 13 weeks. The optimal timing 
for Stage 2 is within one month after the primary endpoint visit in Stage 1, with a 
maximum allowable window of five months. Any delay between visits would result in a 
corresponding extension of study duration. 
 
8.0 Drug Description and Dosage 
 
Subjects assigned to the full dose condition will receive three experimental sessions with 
an initial dose of 125 mg possibly followed 1.5 to 2.5 hours later by an optional 
supplemental dose of 62.5 mg MDMA. Subjects in the comparator dose condition will 
be assigned to receive two experimental sessions with an initial dose of 0 mg MDMA 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 21 of 83 
possibly followed 1.5 to 2.5 hours later by an optional supplemental dose of 0 mg 
MDMA. Seven of 12 subjects, or 58%, will be assigned to the full dose condition, and 
five of 12, or 42%, will be assigned to the comparator dose condition.  
 
Subjects in the comparator dose condition during Stage 1 will have the opportunity to 
cross over to Stage 2. Stage 2 will be used to explore the optimal therapeutic dose using 
a clinical titration dosing strategy using varied active doses of MDMA. In Stage 2 
subjects will receive an initial dose of 100 mg followed 1.5 to 2.5 hours later by an 
optional supplemental dose of 50 mg MDMA during the first experimental session. In 
the second and third session they will receive an initial dose of 100 mg or 125 mg 
MDMA followed 1.5 to 2.5 hours later by an optional supplemental dose of 50 mg or 
62.5mg as appropriate to the initial dose of MDMA. The decision to titrate the dose in 
the second and third session will be based on the experience of the first session, if 
100mg MDMA does not seem to be the optimal therapeutic dose based on the first 
experimental session in Stage 2, the dosage may be increased by an increment of 25mg 
in order to achieve the optimal therapeutic dose. The supplemental doses for each 
experimental session will be half of the initial dose, respectively. 
 
The initial and supplemental doses of 125 mg MDMA and 62.5 mg used in the full dose 
condition are identical to those in use in other sponsor-supported studies of MDMA-
assisted psychotherapy. Previous researchers have also used doses within this range [71, 
72, 74, 75, 124, 125]. Doses equal to or exceeding 125 mg have been employed in 
previous uncontrolled and controlled studies of MDMA [74, 75, 91, 126-128]. Prior to 
the time MDMA was placed in Schedule I in the U.S., identical or similar doses and 
regimens were used in psychotherapy [59, 111, 113]. The initial full dose is expected to 
produce all the common 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. In this study, the 100mg 
MDMA initial dose will be administered in the first experimental session in Stage 2. The 
co-therapists, in consultation with the subject, will have the option to explore whether 
this dose or the clinical titration of an additional 25mg initial dose, with corresponding 
supplemental doses, would constitute the optimal therapeutic dose for the second and/or 
third experimental sessions.   
 
The doses to be compared in this study have been chosen on the basis of the Sponsor’s 
ongoing initiative to develop MDMA-assisted psychotherapy as a treatment for PTSD 
and in Stage 2 to develop a dose-response curve for the treatment. The Stage 1 
comparator dose of 0 mg MDMA is not expected to produce the therapeutic or 
physiological effects of MDMA. The goal of this study is to estimate the effect size of 
comparator and full dose MDMA for safety and efficacy. The placebo dose will provide 
clear adverse event, neurocognitive and efficacy data. 
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 22 of 83 
Table 1. Stage 1 Drug Doses  
 
Experimental 
Session 
Dose 
Initial 
Dose 
Optional 
Supplemental 
Dose 
Min-Max 
Cumulative 
Dose 
1 and 2 
Comparator Dose 
0 mg 
0 mg 
0 mg 
1, 2, and 3 
Full Dose 
125 mg 
62.5 mg 
125-187.5 mg 
 
Table 2. Stage 2 Drug Doses  
 
Experimental 
Session 
Dose 
Initial 
Dose 
Optional 
Supplemental 
Dose 
Min-Max 
Cumulative 
Dose 
Min-Max 
Cumulative 
Dose with 
Titration 
1 
Active Dose 
100 mg 
50 mg 
100-150 mg 
 
Active Dose 
100 mg 
50 mg 
100-150 mg 
 
2 and 3 
+ Optional 
Titration Dose 
25 mg 
12.5 mg 
 
125-187.5 mg 
 
8.1 Drug Compounding, Doses, and Labeling 
 
The investigational product (IP) for the study is MDMA. Bulk IP will be received at the 
pharmacy via a secure delivery system in accordance with all local regulations. A receipt 
will be kept on file at the pharmacy and at the site. Seven strengths of IP will be created: 
125 mg, 100 mg, 62.5 mg, 50 mg, 25 mg, 12.5 mg and 0 mg (placebo only).  Each of 
these batches will be created with the bulk MDMA and varied amounts of lactose during 
the compounding process. A “packing stat” will be created by filling 10 capsules with 
lactose to calibrate the amount of compounded IP per capsule. Once encapsulated, the 
total number of capsules will be recorded on the drug accountability log.  
 
The encapsulation will be performed by a pharmacist who has the appropriate skills. The 
MDMA will be weighed out (calculated as the weight of the hydrochloride salt) into 
gelatin capsules in combination with lactose used to ensure that all capsules have similar 
weights. The placebo capsule will consist of lactose only. Capsules for all experimental, 
double-blind sessions will be prepared in such a way as to prevent therapists and 
subjects from distinguishing contents of full dose and comparator dose capsules. Dosage 
for open-label sessions will be clearly indicated in the packaging. 
 
The IP for each experimental session will be packaged in one primary container, labeled 
with a unique container number, protocol number, drug name, lot number, sponsor 
name, experimental session number, stage, and a statement that the drug is restricted to 
clinical trial use only. All drug labels will comply with local regulations and will be 
provided in English. The initial and supplemental dose will be packaged in separate 
labeled “inner envelopes” within the primary container. There will be one primary 
container per subject per experimental session. The sponsor randomization monitor will 
oversee the process of blinded drug packaging conducted by the pharmacist according to 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 23 of 83 
the randomization list. This list will not be shared with any blinded site or sponsor staff. 
The pharmacist and randomization monitor will be the only staff who are unblinded.  
  
Figure 1. Examples of Drug Labels  
 
 
 
 
 
 
 
Stage 1 Primary Container Labels 
       Blinded 
 
 
Open Label Session 3 
Primary Container 
MAPS 1215 Mission St, Santa 
Cruz, CA USA 95060 
Study # MP-4 
Stage 1 Blinded 
Experimental Session #___  
Container # XXX  
Lot # XXX 
Expiry date: XXX 
Store at 22
oC 
 
Subject #____________  
Restricted drug for clinical trial 
use by Qualified investigator only 
 
Primary Container 
MAPS 1215 Mission St, Santa Cruz, 
CA USA 95060 
Study # MP-4 
Stage 1 Open Label 
Experimental Session #3  
Container # XXX 
125mg & 62.5mg MDMA 
Lot # XXX 
Expiry date: XXX 
Store at 22
oC 
Subject #____________  
Restricted drug for clinical trial use 
by Qualified investigator only 
 
Stage 1 Inner Envelope Labels 
                Blinded 
 
 
 
 
Blinded 
Inner Envelope 
MAPS Study # MP-4 
Stage 1 
Container # XXX 
Initial Dose  
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
Inner Envelope 
MAPS Study # MP-4 
Stage 1 
Container # XXX 
Supplemental Dose  
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
Open Label Session 3 
 
 
Open Label Session 3 
Inner Envelope 
MAPS Study # MP-4 
Stage 1 Open Label 
Container # XXX 
Initial Dose 125mg MDMA 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
Inner Envelope 
MAPS Study # MP-4 
Stage 1 Open Label 
Container # XXX 
Supplemental Dose 62.5mg MDMA 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
 
 
 
 
Holding Box Labels 
 
Holding Box Label 
MAPS Study# MP-4 
Investigational Product: MDMA  
Dose: XXmg 
Lot #: XXX 
Restricted drug for clinical trial use by Qualified investigator only 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 24 of 83 
Stage 2 Primary Container Labels 
       Open Label 
 
 
  Open Label  
               Open Label 
Primary Container 
MAPS 1215 Mission St, Santa 
Cruz, CA USA 95060 
Study # MP-4 
Stage 2 
Experimental Session # 1  
Container # XXX 
100mg & 50mg MDMA 
Lot #: XXX 
Expiry date: XXX 
Store at 22
oC 
Subject #____________  
Restricted drug for clinical trial 
use by Qualified investigator only 
 
Primary Container 
MAPS 1215 Mission St, Santa 
Cruz, CA USA 95060 
Study # MP-4 
Stage 2 
Experimental Session # 2  
Container # XXX 
100+25mg & 50+12.5mg MDMA 
Lot #: XXX 
Expiry date: XXX 
Store at 22
oC 
Subject #____________  
Restricted drug for clinical trial 
use by Qualified investigator only 
 
Primary Container 
MAPS 1215 Mission St, Santa Cruz, 
CA USA 95060 
Study # MP-4 
Stage 2 
Experimental Session # 3  
Container # XXX 
100+25mg & 50+12.5mg MDMA 
Lot #: XXX 
Expiry date: XXX 
Store at 22
oC 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
Stage 2 Inner Envelope Labels 
 
Unblinded Session 1  
 
Unblinded Session 1 
Inner Envelope 
MAPS Study # MP-4 
Stage 2 Open Label 
Experimental Session # 1  
Container # XXX 
Initial Dose 100mg MDMA 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
Inner Envelope 
MAPS Study # MP-4 
Stage 2 Open Label 
Experimental Session # 1 
Container # XXX 
Supplemental Dose  
50mg MDMA 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
Unblinded Session 2 or 3 
 
 
Unblinded Session 2 or 3 
 
Inner Envelope 
MAPS Study # MP-4 
Stage 2 Open Label 
Experimental Session #___ 
Container # XXX 
Initial Dose 100mg MDMA 
Open Label 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
Inner Envelope 
MAPS Study # MP-4 
Stage 2 Open Label 
Experimental Session #__  
Container # XXX 
Initial Dose increment 
25mg MDMA 
Subject #____________  
Restricted drug for clinical trial use by 
Qualified investigator only 
 
8.2 MDMA Accountability 
 
Forms will be provided to track drug accountability and administration throughout the 
study. Blinded drug accountability and administration logs will be reviewed during 
routine monitoring visits. MDMA will be handled in accordance with all provincial and 
national regulations and forms pertaining to the use of controlled substances in Canada, 
and forms will be maintained by the pharmacist.  
 
Each primary container label will contain a unique container number for the drug 
assigned to a single experimental session. The container numbers will be used to track 
drug administration in the Source Record and the drug administration log. The web-
based randomization system will enable tracking of blinded primary containers for drug 
accountability purposes. 
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 25 of 83 
8.3 MDMA Storage and Handling 
 
MDMA is a Schedule III compound in Canada and the pharmacist will store and handle 
it in compliance with relevant Federal and Province regulations. The pharmacist will be 
responsible for storing and dispensing the MDMA in accordance with all regulatory 
requirements. The IP will be stored at room temperature in a locked safe at the pharmacy 
and only the pharmacist will have access to it.  
 
IP will only be removed for a single experimental session at a time and will be 
administered orally at the site by the Investigator or Sub-Investigator. All doses 
administered will be recorded on the appropriate accountability and administration logs. 
Only the initial dose is required to be given at each experimental session. Supplemental 
doses are provided for each experimental session but are optional to use. In addition, the 
clinical titration doses with corresponding supplemental dose are provided in Stage 2 
session 2 and 3 and are optional to use. 
 
The pharmacist will dispense one primary container with the appropriate container 
number to the Investigator or Sub-Investigator before each experimental session. If the 
Investigator or Sub-Investigator decides not to administer the optional supplemental 
dose and/or the optional clinical titration dose in a given experimental session, the 
unused capsules will be kept in their respective inner envelopes inside of the primary 
container until the end of the experimental session. Within 24 hours of the end of the 
experimental session (as soon as possible within the working hours of the pharmacy), 
the Investigator or Sub-Investigator will return the container and any remaining unused 
capsules to the Pharmacist for return to the pharmacy safe. At the end of the study, the 
Sponsor will be consulted to determine the course of action if there is any unused IP 
remaining. 
 
9.0 Method 
 
This Phase 2 pilot study is a randomized, double-blind, controlled study in 12 subjects 
comparing the effect size of comparator dose to full dose MDMA as an adjunct to 
manualized MDMA-assisted psychotherapy. Two therapy teams will conduct 
psychotherapy visits according to the treatment manual provided. The teams will consist 
of two therapists who will work together, with a physician on each team. Seven subjects 
will be randomized to the full dose condition and five subjects will be randomized to the 
comparator dose condition. Stage 1 of the study will consist of two blinded experimental 
sessions for all subjects and one open-label experimental session for full dose subjects, 
each lasting six to eight hours and scheduled three to five weeks apart, within a 
moderate course of non-drug psychotherapy. Each subject will be unblinded after 
completion of outcome measures at the primary endpoint, one month after the second 
experimental session in Stage 1. A blinded IR will assess the severity of PTSD 
symptoms at baseline, at the primary endpoint one month after the second experimental 
session, two months after the third open-label experimental session as well as the 
equivalent time points in Stage 2. After unblinding, full dose subjects will have one 
more full dose session in Stage 1 and comparator dose subjects will have the opportunity 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 
Page 26 of 83 
to cross over to open-label Stage 2, which will be used to explore the optimal therapeutic 
dose for cross over subjects. All subjects will complete a long-term follow-up visit 12 
months after their final experimental session in either Stage 1 or Stage 2.  This study will 
provide an estimate of effect size based on a dose comparison of PTSD symptoms to 
MDMA-assisted psychotherapy.  
 
9.1 Randomization 
 
In total, 12 subjects will be enrolled in the study. The randomized portion of the study 
will be blinded and there will be a 7:5 ratio between subjects in the full dose and 
comparator dose conditions. An unblinded randomization monitor will generate the 
randomization list prior to enrollment of subjects. Subjects will be assigned sequential 
subject numbers upon enrollment for randomization assignment in a blinded fashion. 
Upon enrollment, the randomization monitor will provide the Investigator or Sub-
Investigator or designated study personnel with the randomization enrollment code 
corresponding to that subject’s sequential subject number. A unique container number 
will be pre-printed on the container labels corresponding to doses for each experimental 
session. The Investigator or Sub-Investigator or designated study personnel will enter 
the randomized enrollment code into the web-based randomization program to obtain the 
container number based on the condition assignment for each blinded experimental 
session. Blinded personnel will conduct all study evaluations in the randomized portion 
of the study until the blind is broken for each subject at the primary endpoint per 
protocol via the web-based randomization program. Detailed instructions will be 
provided to the site in a separate document. 
 
The therapists, the IR, and all site personnel except the pharmacist will remain blind to 
condition assignment. If there is an adverse event or other emergency requiring 
knowledge of the subject’s condition assignment, the blind may be broken for an 
individual subject by contacting the Sponsor’s Randomization Monitor. In most cases it 
should be sufficient to inform the treating physician for the emergency that the subject 
had received a minimum of 0 mg MDMA and a maximum of 125mg MDMA with a 
supplemental dose of 62.5mg MDMA. 
 
9.2 Subject Numbering 
 
Prior to enrollment, subjects will be tracked with a secondary identifier number and a 
screening number assigned sequentially starting at “001”. Subjects who meet the 
enrollment criteria will be enrolled in the study and assigned a 5-digit subject number. 
The first two digits identify the study site. The next three digits identify the subject 
within the site and will be assigned sequentially, with 01 corresponding to the first 
subject enrolled, e.g. the first enrolled subject will be 04001, second 04002, etc. 

MAPS Study MP-4 
 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
 

MAPS Study MP-4 
 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
Table 3. Time & Events Stage 1 
 
Study Phase 
Screen/ 
Baseline 
Preparatory 
Sessions 
Experimental 
Session 1 
Experimental 
Session 2 
Primary 
Endpoint 
Experimental 
Session 3 
End of 
Stage 1 
Visit # 
Prior to enrollment
V1,2,3 
V4 
V5,6,7 
V8 
V9,10,11 
V12 
V13 N 
V14,15,16N 
V17N 
Type of Visit 
Screening/Baseline
Preparatory 
Experimental 
Integrative 
Experimental 
Integrative 
Outcome 
Experimental 
Integrative 
Outcome 
Visit Timing – see Section 7.3 for visit 
windows 
Up to 2 months 
prior to V1 
Between 
baseline and V4 
within 13 weeks 
post  CAPS 
Between 
V4 and V8 
2-5 weeks 
post V4 
Between 
V8 and V12 
3-5 weeks 
post V8 
3-5 weeks 
post V8 
Between 
V13 and V17 
7-10 weeks 
post V13 
Initial Phone Screen 
! 
 
 
 
 
 
 
 
 
 
Informed Consent 
! 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric History  
! 
 
 
 
 
 
 
 
 
 
General Physical Exam, ECG 
! 
 
 
 
 
 
 
 
 
 
Brief Neurological Exam 
! 
 
 
 
 
 
 
 
 
 
SCID-RV (IR) 
! 
 
 
 
 
 
 
 
 
 
Clinical Lab Tests with HIV test 
! 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
! 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Medication Taper (if applicable) 
 
! 
 
 
 
 
 
 
 
 
Study Enrollment (if eligible) 
 
!O 
 
 
 
 
 
 
 
 
Record to Audio/Video 
 
! 
! 
! 
! 
! 
 
! 
! 
 
General Wellbeing 
 
! 
! 
! 
! 
! 
! 
! 
! 
 
Drug Screen 
! 
 
! 
 
! 
 
 
! 
 
 
Pregnancy Screen (if applicable) 
! 
 
! 
 
! 
 
 
! 
 
 
Obtain Container Assignment  
 
 
!B 
 
!B 
 
 
 
 
 
CAPS, GAF, BDI-II, NEO-PI, PSQI, 
PTGI, DES-II 
! 
 
 
 
 
 
!L 
 
 
! Q 
RBANS/PASAT 
! 
 
 
 
 
 
! 
 
 
! 
PDS  
! 
 
 
!M 
 
 
! 
 
!M 
! 
C-SSRS 
! 
!G 
!C, D, E 
!I 
!C, D, E 
!I 
! 
!C, D, E 
!I 
! 
Administer Drug + Therapy 
 
 
! 
!
! 
!
!
! 
 
 
Monitoring of BP, Pulse, and Temp.  
 
 
! 
!
! 
!
!
! 
 
 
SUD 
 
 
!F, E 
!
!F, E 
!
!
!F, E 
 
 
Belief of Condition Assignment 
 
 
 
!K 
 
!K 
 
 
 
 
Overnight Stay, SOCQ 
 
 
! 
 
! 
 
 
! 
 
 
Integrative Therapy Session 
 
 
 
!A 
 
!A 
 
 
!A 
 
7 Days Integrative Telephone Contact 
 
 
 
! 
 
! 
 
 
! 
 
AEs Requiring Medical Attention 
 
 
! 
! 
! 
! 
! 
! 
! 
! 
Spont. Reported Reactions & All AEs 
 
 
!J 
! 
!J 
! 
! 
!J 
! 
 
Changes in Tinnitus and/or Pain 
!P 
 
!E,P 
!E,P 
!E,P 
!E,P 
!P 
!E,P 
!E,P 
!P 
AEs of Psychiatric Status or Withdrawal 
 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Serious Adverse Events 
 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Issue Memory Aid Card  
 
 
 
 
 
 
 
 
 
!H 
Unblinding
  
 
 
 
 
 
 
! 
 
 
!
Perception of Experimental Sessions 
 
 
 
 
 
 
!N 
 
 
!N 
RRPQ 
 
 
 
 
 
 
 
 
 
!H 
A = First Integrative session is one day after experimental session; B = At least 24 hours prior to experimental session; C = Approximately six hours post MDMA; D = At the beginning of the session; E = As needed;  
F  = Approximately every 60 minutes; G = Given on 2nd preparatory session after washout; H = Only for subjects starting LTFU; I = Every face to face visit and Day 2 and Day 7 phone calls only; J = Reactions collected for 
seven days post experimental session; K = On the day of the first integrative session following the experimental session; L = One month after the second experimental session but before the third experimental session; M = 
On the day of the third integrative session; N = After unblinding for full dose subjects only; O = Only on Visit 1; P = Only in subjects with pre-existing tinnitus and/or chronic pain; Q = All measures listed except for the 
NEO-CI. 

MAPS Study MP-4 
 
 
Amendment 2 Version 3 
Canada 
 
June 20, 2014 
  
 
Table 4. Time & Events Stage 2 
 
Study Phase 
Preparatory 
Sessions 
Experimental 
Session 1 
Experimental 
Session 2 
Secondary 
Endpoint 
Experimental 
Session 3 
End of 
Stage 2 
 
Long-term 
Follow-up 
Visit # 
V18* 
V19 
V20,21,22 
V23 
V24,25,26 
V27 
V28 
V29,30,31 
V32 
LTFU 
Type of Visit 
Preparatory 
Experimental 
Integrative 
Experimental 
Integrative 
Outcome 
Experimental  
Integrative 
Outcome 
Follow-up 
Visit Timing – See Section 7.3 for visit 
windows 
Within 1 month 
post V12* 
+/_1 week 
post V18 
Between 
V19 and V23 
2-5 weeks 
post V19 
Between 
V23 and V27 
3-5 weeks 
post V23 
3-5 weeks 
post V23 
Between 
V28 and V32 
7-10 Weeks 
post V28 
1 year 
post V13 or V28 
Confirm Informed Consent 
! 
 
 
 
 
 
 
 
 
 
Confirm Inclusion/Exclusion 
! 
 
 
 
 
 
 
 
 
 
Enrollment in Stage 2 
! 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
! 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Record to Audio/Video 
! 
! 
! 
! 
! 
 
! 
! 
 
 
General Wellbeing 
! 
! 
! 
! 
! 
! 
! 
! 
 
 
Drug Screen 
 
! 
 
! 
 
 
! 
 
 
 
Pregnancy Screen (if applicable) 
 
! 
 
! 
 
 
! 
 
 
 
CAPS, GAF, BDI-II, NEO-PI, PSQI, 
PTGI, DES-II 
Use V12* 
 
 
 
 
!H 
 
 
! 
! 
RBANS/PASAT 
 
 
 
 
 
 
 
 
! 
 
PDS 
Use V12* 
 
!I 
 
 
! 
 
!I 
! 
! 
C-SSRS 
! 
!B, C, D 
!
G 
!B, C, D 
!
G 
! 
!B, C, D 
!
G 
! 
! 
Administer Drug + Therapy 
 
! 
!
! 
!
!
! 
 
 
 
Monitoring of BP, Pulse, and Temp.  
 
! 
!
! 
!
!
! 
 
 
 
SUD 
 
!D, E 
!
!D, E 
!
!
!D, E 
 
 
 
Overnight Stay, SOCQ 
 
! 
 
! 
 
 
! 
 
 
 
Integrative Therapy Session 
 
 
! A 
 
!A 
 
 
!A 
 
 
7 Days Integrative Telephone Contact 
 
 
! 
 
! 
 
 
! 
 
 
AEs Requiring Medical Attention 
! 
! 
! 
! 
! 
! 
! 
! 
! 
 
Spont. Reported Reactions and All AEs 
 
! 
!
F 
! 
!
F 
 
! 
!
F 
 
 
Changes in Tinnitus and/or Pain 
 
!J,D 
!J,D 
!J,D 
!J,D 
!J,D 
!J,D 
!J,D 
!J, D 
!J 
AEs of Psychiatric Status or Withdrawal 
! 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Serious Adverse Events 
! 
! 
! 
! 
! 
! 
! 
! 
! 
! 
Perception of Experimental Sessions 
 
 
 
 
 
! 
 
 
! 
!
Complete Stage 2, Go to Follow-up 
 
 
 
 
 
 
 
 
! 
!
RRPQ 
 
 
 
 
 
 
 
 
! 
!
Issue Memory Aid Card 
 
 
 
 
 
 
 
 
! 
!
Follow-up Questionnaire 
 
 
 
 
 
 
 
 
!
! 
Termination Visit 
 
 
 
 
 
 
 
 
!
 
! 
* If Visit 18 is more than 8 weeks after Visit 12, then subjects will need to repeat measures prior to starting Stage 2 with the exception of NEO-PI.  
 
A = First session is one day after experimental session; B = Approximately six hours post MDMA; C = At the beginning of the session; D = As needed; E = Approximately every 60 minutes; F = Reactions collected for seven 
days post experimental session; G = Every face to face visit and Day 2 and Day 7 phone calls only; H = One month after the second experimental session but before the third experimental session; I = On the day of the third 
integrative session; J = Only in subjects with pre-existing tinnitus and/or chronic pain; K = All measures listed except for the NEO-PI 
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 30 of 83 
 
 
9.3 Assessments and Measures 
 
Screening and outcome measures were chosen to be well recognized in the literature and 
because of prior use in other sponsor-supported studies of MDMA-assisted 
psychotherapy in people with PTSD.  
 
Eligibility for the study will be determined based on psychiatric diagnoses confirmed 
during screening through medical history, the Structured Clinical Interview for Diagnoses 
(SCID-RV) and the CAPS. 
 
9.3.1 Outcome Measures 
 
The primary outcome measure will be the CAPS, a clinician-administered measure for 
PTSD diagnosis and assessment of symptom intensity and frequency. A qualified, 
blinded IR will perform the CAPS at baseline and outcome measurement time points 
according to the Time and Events Table. The baseline CAPS will be administered by the 
IR during a face-to-face visit, with administration of the CAPS being conducted via 
telemedicine or in person at subsequent visits.  The IR will not be present during the 
subject’s experimental sessions nor have any information regarding the experimental 
sessions. Subjects will be instructed not to inform the IR of any beliefs they or others 
have concerning their condition assignment during the evaluation session. The CAPS 
provides a standardized method to evaluate the frequency and intensity dimensions of 
each symptom, impact of symptoms on the subject’s social and occupational functioning, 
overall severity of the symptom complex and global improvement since baseline and the 
validity of the ratings obtained. The CAPS interview takes approximately one hour to 
complete. All assessments, including those at baseline, will use the CAPS assessment of 
symptoms over the last month. The CAPS interviews have been determined to have good 
internal consistency, concurrent validity, and test/retest reliability [129, 130].   
 
The secondary measure of PTSD symptoms will be the PDS, a self-report measure 
designed to follow DSM-IV criteria for assessing PTSD. The measure is derived from the 
Posttraumatic Symptom Scale – Self Report (PSS-SR), a measure also intended to tap 
into diagnostic criteria for PTSD. The PDS contains 49 items, with responses made on a 
four-point scale, ranging from 0 (“not at all”) to 3 (“five or more times a week”). The 
PDS consists of a list of 12 potential traumatic events, 12 items addressing elements of 
the traumatic event, of 17 symptom items, and nine items assessing impact on areas of 
life function [131]. Items addressing elements of the traumatic event and life function are 
answered as either present or not present (Yes or No). The 17 items are summed to create 
a symptom severity scale. Cronbach’s alpha for the symptom severity scale is 0.92. The 
PDS has test-retest reliability of 0.74 after a two-week and one-month interval, and 
subscales are inter-correlated, with correlations ranging from 0.73 to 0.82, and PDS 
scores have a moderate to good correlation with SCID-RV diagnosis, with kappa = 0.65 
[131]. Subjects will complete the PDS questionnaire at baseline, after the first and third 
experimental sessions, at the primary endpoint, at the end of Stage 1, and equivalent time 
points in Stage 2 and at the Long Term Follow-up, as specified in the Time and Events 
Table. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 31 of 83 
 
 
 
The Global Assessment of Function (GAF) is a measure of general function made 
through clinical observation. The GAF consists of a single score, ranging from 0 to 100, 
with 100 reflecting superior function and 0 reflecting serious risk of causing harm to the 
self or others. The IR administering the CAPS will perform the GAF assessment with the 
baseline GAF being administered during a face-to-face visit. Administration of the GAF 
at subsequent visits will be conducted in person or via telemedicine. The GAF will serve 
as a measure of global functioning and will be performed at the same times the CAPS is 
administered.   
 
The Post Traumatic Growth Inventory (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 [132, 133]. In this study, subjects will complete the PTGI in reference 
to the time since the trauma at baseline, but will respond in reference to the beginning of 
their participation in the study on all subsequent occasions. Subjects will complete the 
PTGI according to the Time and Events table.  
 
The BDI-II is a 1996 revision of the BDI, a 21-item self-report measure [134, 135], that 
will serve as a measure of depression according to DSM-IV criteria [136]. 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 10 minutes to complete 
[136]. Score cutoffs indicate: 0-13 minimal depression, 14-19 mild depression, 20-28 
moderate depression, and 29-63 severe depression. Higher scores indicate more severe 
depressive symptoms. Subjects will complete the BDI-II according to the Time and 
Events table. 
 
The NEO-PI will serve as a measurement of personality [137, 138]. The NEO-PI is a 
240-item self-report assessment that takes between 30 and 40 minutes to complete. It is a 
well-established measure of five personality traits with sound properties of reliability and 
validity that operationally define personality structure according to a five-factor model. 
Subjects will complete the NEO-PI according to the Time and Events table. 
 
The Pittsburgh Sleep Quality Index (PSQI) is a 19-item 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. Possible responses range 
from 0 to 4 on a five-point scale [139]. The PSQI consists of seven sub-scales; sleep 
quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of 
sleeping medications, and daytime dysfunction. These are all summed to produce a single 
global scale. Global scores can range from 0 to 21, with higher scores reflecting poorer 
sleep quality, and a score below 5 indicative of good sleep. It takes five to 10 minutes to 
complete. Test-retest reliability ranges from 0.85 to 0.87, and it is internally consistent, 
with a Cronbach’s alpha of 0.83[139, 140]. Global scores correlate with other measures 
of alertness and self-reported sleep quality [141]. Subjects will complete the PSQI 
according to the Time and Events table. 
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 32 of 83 
 
 
The DES-II is a 28-item self-report measure of dissociation, defined as a lack of normal 
integration of an individual’s thoughts, feelings, or experiences into the stream of 
consciousness or memory [142, 143].  It is an established measure of dissociative 
symptoms. The scale consists of statements describing facets of dissociation. 
Respondents indicate how often the specific experience happens to them, from “never” to 
“always.” Responses on the original scale were made via visual analog scales. The DES-
II uses the same items but with responses made on a 10-point scale from “0%” to “100%” 
of the time. The scale is scored by treating percentages as single digits to produce a total 
score. The DES-II can also be used to produce scores for three factors, amnesia, 
depersonalization, and derealization. The scale differentiated between respondents 
without psychiatric disorders or with psychiatric disorders with few dissociative 
symptoms and respondents with psychiatric disorders associated with dissociative 
symptoms [142]. Reliability of the DES-II is high (ranging from 0.79 to 0.96 in an early 
review), and a reported Cronbach’s alpha of 0.95 [143, 144]. There may be a relationship 
between experiencing dissociation and occurrence of chronic PTSD [143, 145]. Subjects 
will complete the DES-II according to the Time and Events table. 
 
9.3.2 Safety Measures 
 
Safety measures will be applied as described below to minimize risks associated with 
drug-assisted psychotherapy sessions. The therapists will be available via mobile phone 
or pager throughout the study to ensure subject safety.  
 
Safety measures, including vital signs and a measurement of psychological distress, will 
be assessed during all experimental sessions. Subjects will rate their current degree of 
subjective distress with the SUD scale, which is a single-item self-report scale. The SUD 
will be completed repeatedly during the experimental sessions, with the degree of distress 
marked along seven points. Results of the SUD are intended to assist therapists in 
maintaining subject safety during experimental sessions. 
 
The therapists will assess general wellbeing during each preparatory session, on each 
integrative session and during telephone calls for seven days. Results of this scale are 
intended to assist therapists in maintaining subject safety throughout the study. 
 
During the course of each MDMA-assisted psychotherapy session, the Subjective Units 
of Distress (SUD) scale will be used to assess degree of psychological distress 
experienced at various points during the session. Subject and therapists’ beliefs 
concerning subject condition assignment (either full dose or comparator) will be assessed 
during the non-drug psychotherapy session occurring on the day after each experimental 
session. Neither the SUD scale nor condition assignment beliefs measures are outcome 
measures.  
 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a clinician-administered 
measure of suicidal behavior devised to detect potential suicidal thoughts or behaviors 
during a clinical trial [146]. It assesses lifetime suicidal ideation, ideation intensity and 
behavior, and a form for assessing current suicidal ideation and behavior. The C-SSRS 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 33 of 83 
 
 
consists of a series of questions, and can be administered during face-to-face interview or 
over the telephone. C-SSRS scores are sensitive to changes in suicidal ideation or 
behavior over time, and the measure demonstrates good convergent validity with other 
measures of suicidality [147]. The C-SSRS will be performed by the therapists or 
designated qualified study personnel at baseline, and repeated throughout the protocol to 
assess suicidality. See the Time and Events Table for a detailed schedule. 
 
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
[148] is a relatively brief battery of assessments for cognitive function. It consists of 12 
subtests that cover verbal and visual memory and attention and takes approximately 30 
minutes to administer. Tasks include recall of lists, figures and stories, picture naming, 
semantic fluency, copying a figure, digit span and coding, and line orientation. Scores on 
the RBANS subtests can be used to obtain a total score and five index scores; attention, 
immediate memory, delayed memory, language and visuospatial/constructional scores. 
Factor analyses of the RBANS and samples of veterans and people with schizophrenia 
suggest that the RBANS possesses two factors rather than five [149, 150]. The RBANS 
has alternate forms, allowing repeated administration. Test performance by healthy 
controls were distinguishable from performance by people with probable Alzheimer’s 
disease or the neurodegenerative condition Huntington’s disease [151], and the test has 
high split-half reliability, with coefficients ranging from 0.80 to 0.88 [148]. Test-retest 
reliability is good for total RBANS scores in healthy controls and psychiatric patients 
[152]. The RBANS has been used in community-based and psychiatric samples [149, 
153] and in a prospective investigation of the effects of chemotherapy upon cognitive 
function [154]. Each administration of the RBANS will use one of parallel forms of 
RBANS, and each participant will not complete the same form twice. This measure was 
employed as a means of assessing safety after two sessions of MDMA-assisted 
psychotherapy for PTSD [77]. See Time and Events Table for a detailed schedule. 
 
The Paced Auditory Serial Addition Test (PASAT) is a measure of psychomotor speed, 
auditory information processing and computation ability [155]. The PASAT was 
originally designed to assess recovery after traumatic brain injury, and has been used 
subsequently to assess cognitive function in other populations [155, 156]. It takes 
approximately ten to 15 minutes to administer. The measure involves the addition of a 
series of digits presented at a three or two second interval, with responses made by 
adding each number to the prior digit. The PASAT consists of two alternate forms, 
permitting repeated administration. PASAT scoring includes collecting number of correct 
and incorrect responses, time to response (latency of response) and any failure to 
respond. There was a positive correlation between responses on the PASAT and a non-
numerical paced measure. The measure is internally consistent (Cronbach’s alpha of 
0.90), and it has high test-retest reliability, with reliability ranging from 0.90 to 0.97 
[156-158]. The first administration of the PASAT will use one of the two alternate forms, 
and the second administration will use the other. This measure was employed as a means 
of assessing safety after two sessions of MDMA-assisted psychotherapy for PTSD [77]. 
See Time and Events Table for a detailed schedule. 
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 34 of 83 
 
 
Cardiovascular effects will be assessed via blood pressure and pulse measurement.  
Blood pressure and heart rate will be assessed periodically during each experimental 
session by an automatic blood pressure (BP) and pulse monitor. Blood pressure and pulse 
will be measured at the outset of the experimental session, and once approximately every 
30 minutes for the first four hours of the experimental session, and once every hour, or as 
needed, thereafter. More frequent measures will be taken if the established thresholds of 
160 systolic, 110 diastolic, or pulse of 110 are exceeded. Blood pressure will also be 
measured more frequently if there are symptoms, such as chest pain, shortness of breath 
or neurological symptoms that may be indicative of hypertension. The therapists will 
measure subject body temperature approximately every 60 to 90 minutes. Cardiovascular 
effects will be assessed via BP measurement. The timing of these measurements will be 
adjusted so they do not interfere with the therapeutic process.  
 
A 100-millimeter visual analog scale will be used to assess changes in symptoms of pre-
existing tinnitus and/or chronic pain [159-161].  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 [160, 162-164]. 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 [160, 163, 164]. 
 
All AEs and spontaneously reported reactions will be collected, as described in Section 
14.0. 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. 
 
9.3.3 Process Measures 
 
All sessions after enrollment may be recorded to audio and video, including introductory, 
integrative and experimental sessions for research and training purposes. These 
recordings will be used for further development of the manual of standard procedures for 
performing MDMA-assisted psychotherapy in people with PTSD. 
 
Adherence criteria and competence ratings will be conducted by qualified, trained 
blinded adherence raters who will analyze video data from selected preparatory, 
experimental and integrative sessions. The elements included in adherence criteria are 
specific to each type of session. These ratings will be collected, at minimum, for each 
therapist team in the study. The goal of these ratings will be to correlate therapist 
adherence to the treatment manual with outcome as a part of the sponsor’s ongoing 
efforts to standardize treatment methods of MDMA-assisted psychotherapy for PTSD.  
 
The SOCQ is a 100-item questionnaire based on the “Peak Experience Profile” designed 
by Pahnke and colleagues [165, 166].  Subjects respond to the SOCQ using a six-point 
Likert-type scale anchored at 0=none at all and 5=extreme (more than ever before in my 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 35 of 83 
 
 
life). It has seven subscale scores; internal unity, external unity, transcendence of time 
and space, ineffability and paradoxicality (claim of difficulty in describing the experience 
in words), sense of sacredness, noetic quality, and deeply felt positive mood. The 
measure is a self-report instrument and takes approximately 20 to 30 minutes to 
complete. Subjects will complete the SOCQ after each experimental session, at any time 
between the end of an experimental session and prior to leaving the treatment facility the 
next day. 
 
Response to study participation and perceived degree of choice in taking part in the study 
will be assessed with the Reactions to Research Participation Questionnaire (RRPQ) 
[167]. Subjects will complete this measure during their final study visit, roughly six 
weeks after the last experimental session. The RRPQ is intended to assess the subject’s 
experience as a research subject, perceived reasons for consenting to be a research subject 
and perceived freedom to take part in the study, and is a process measure.  
 
Questions regarding the belief of condition assignment and certainty of the belief will be 
asked of the therapists and subjects at the integrative session on the day after each 
blinded experimental session in Stage 1. Each therapist responsible for treating the 
subject will indicate their belief of condition assignment and certainty based on the full 
dose (125mg) and comparator dose (0 mg) groups. In line with informed consent 
obfuscation, where the comparator dose is not revealed, subjects will initially be asked if 
they believe they received MDMA or not during this assessment. If they believe they 
received MDMA, they will be asked about what dose they think they received. These 
beliefs are collected as a part of the sponsor’s ongoing initiative to optimize the double-
blind as a part of dose response studies.  
 
Perceptions of the experimental sessions will be collected from each full dose subject 
during the primary endpoint visit after unblinding and from Stage 2 subjects during the 
secondary endpoint visit in Stage 2 before the third experimental session in Stage 1/Stage 
2. Perceptions will be collected again at the end of Stage 1/Stage 2 according to the Time 
and Events Table. These perceptions are collected as a part of the sponsor’s ongoing 
initiative to assess the therapeutic value of the third experimental session and information 
on the optimal therapeutic dose of MDMA. 
 
The long-term follow-up questionnaire has been developed internally by the Sponsor to 
assess long-term benefits and harms of MDMA-assisted psychotherapy at the long-term 
follow-up visit.   
  
9.4 Visit Descriptions 
 
9.4.1 Prescreening, Screening, and Baseline Evaluation (Pre-study) 
 
Prospective subjects will be prescreened by telephone according to an IRB-approved 
script to learn if they meet basic eligibility criteria. All individuals who are prescreened 
should be assigned a screening number and recorded on the Subject Screening Log where 
information on the selection of potential subjects in the trial should be collected.  

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 36 of 83 
 
 
 
Upon signing the IRB-approved informed consent form (ICF), the potential subject may 
commence study-related screening activities. The screening number should also be 
recorded on the signed ICF. If a subject is enrolled, the study staff should record the 
enrollment date and assign a subject number. If a subject is not enrolled, an explanation 
should be recorded on the Screening Log. A CRF will not be completed for subjects who 
are not enrolled. These subjects will only be documented on the Screening Log and 
source records. It is the responsibility of the Investigator and study coordinator to file the 
Screening Log in the Investigator Site File (ISF) to be readily available for on-site 
monitoring and/or inspection by relevant authorities.  
 
Screening may take place over more than one day and should be complete by up to two 
months prior to enrollment. Screening may take up to two months, with the baseline 
CAPS being conducted no more than 5 – 8 weeks before the first experimental session, 
leaving room for appropriate medication washout of at least 5 half-lives of pre-study 
psychiatric medications and active metabolites, plus one week for stabilization.  A 
window of up to 8 weeks is allowed if needed for medication tapering. If the CAPS is 
completed outside of this window for a subject, the Investigator  or Sub-Investigator 
should consult the Sponsor CRA and Medical Monitor to determine if the baseline CAPS 
should be repeated. The maximum window from the start of screening to the first 
experimental session is 13 weeks. If, after reviewing all information, the Investigator or 
Sub-Investigator concludes that a subject is eligible, they will enroll the subject in the 
study. Visits will be scheduled consecutively as described in the Time and Events Table. 
During the screening visit: 
 
a. Explain and obtain written informed consent from the subject. Written informed 
consent must be obtained prior to performing any tests or evaluations for the study. 
The Investigator or Sub-Investigator and qualified designated staff may all participate 
in conducting the informed consent. 
b. Assign the subject a screening number. Complete the Screening Log.  
c. Review the ability of females of childbearing potential to become pregnant and their 
commitment to practice appropriate birth control as determined by the CI for the 
treatment period of the study. 
d. Obtain medical and psychological history by interview. 
e. Collect information on pre-study and current medications. 
f. Tinnitus and chronic pain symptom severity will be collected using a visual analog 
scale in subjects with a medical history of these conditions. 
g. Administer the C-SSRS to assess past and current suicide risk.  
h. A physician will perform a general physical examination. 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 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 37 of 83 
 
 
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 local law. The clinical laboratory values will not be 
captured in the CRF, but will be used to establish eligibility and will be kept with the 
subject’s source record. Clinically significant abnormal values will be captured as 
medical history in the CRF. If, upon examination, there are questions raised about 
possible medical problems, the Investigator or Sub-Investigator will request a review of 
subject medical records and request additional tests or assessments as indicated. 
 
• A blinded IR who will not be present during any of the therapy sessions will 
administer the following during a face-to -face interview: 
• Structured Clinical Interview for Diagnoses Research Version (SCID-RV) to 
assess eligibility based on diagnoses, which includes a self-report questionnaire to 
focus on modules to use based on symptoms. 
• Last month’s CAPS to assess PTSD symptoms and eligibility, which may be 
recorded to video in as many instances as necessary to establish inter-rater 
reliability. 
• GAF to assess general psychological function. 
• PASAT to assess cognitive function. 
• RBANS to assess cognitive function. 
 
The subject will complete the following self-report measures: 
• PTGI (in reference to time since the trauma) 
• PDS to assess self-reported PTSD symptoms 
• BDI-II to assess depression symptoms 
• NEO-PI to assess changes in personality 
• PSQI to assess changes in sleep quality 
• DES-II to assess dissociation symptoms 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 38 of 83 
 
 
9.4.2 Preparatory Psychotherapy Sessions - Visits 1, 2, 3 (Stage 1), 18 (Stage 2) 
 
Subjects who do not complete all screening activities will not be enrolled. Eligibility may 
be discussed by phone after screening is complete and at the time Visit 1 is scheduled but 
the final confirmation will occur at Visit 1. If all inclusion criteria and no exclusion 
criteria are met, the subject will be enrolled and issued a subject number.  
 
During Visit 1: 
a. Complete a final review of Inclusion/exclusion criteria. 
b. Assess general wellbeing. 
c. Confirm eligibility and willingness to participate in study. 
d. Assess general wellbeing. 
e. Ensure medical history and medication history is complete. After enrollment new 
events will be collected as AEs and new medications will be collected as 
described in Section 14.0 of the protocol. 
f. Discuss medication tapering, if applicable. Upon confirmation of eligibility, the 
Investigator or Sub-Investigator will consult the prescribing physician to initiate 
medication tapering for subjects who must refrain from taking a psychiatric 
medication for the study. Tapering will follow a time course appropriate for the 
medication as specified in the Medication Tapering Table in Section 14.4 of the 
protocol, with the first experimental session scheduled to occur one week after 
complete washout. 
 
The subjects will undergo three preparatory sessions lasting 90 minutes with their 
therapist team, prior to their first experimental session. The first preparatory session will 
take place at Visit 1 after enrollment confirmation. Three preparatory sessions should be 
scheduled prior to the first experimental session  The preparatory sessions should be 
completed in time to ensure the experimental session occurs within 5 -8 weeks (plus any 
additional time needed for longer drug tapering) after the baseline CAPS. In Stage 2 (for 
comparator dose crossover subjects), only one preparatory session will take place prior to 
their first full dose open-label experimental session, as described in the Time and Events 
Table.  
 
Adherence criteria for preparatory sessions should be completed as a part of one of the 
three sessions. These elements do not have to be accomplished in any specific order or in 
every preparatory session. Generally, adherence criteria for these sessions include that the 
therapists will work with the subject to prepare for MDMA-assisted psychotherapy. The 
therapists and subject will seek to form a strong working relationship with each other, 
and they will help the subject prepare for upcoming experimental sessions. Preparatory 
sessions will promote a safe set and setting for confronting trauma-related memories, 
emotions, and thoughts, which is intended to develop therapeutic alliance.  
 
During the preparatory sessions: 
 
a. Therapists may record all sessions to audio and video. Subjects may review 
recordings from these sessions upon request.  

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 39 of 83 
 
 
b. Collect AEs and Medications as described in Section 14.0 of the protocol. 
c. The therapists will inquire about any possible changes in the subject’s health to 
ensure that subject continues to meet eligibility criteria and if applicable, will confirm 
that the subject has appropriately tapered off of medications.  
d. If subjects who have pre-existing tinnitus or chronic pain mention any changes, use 
the visual analog scale to collect the changes in symptoms. 
e. The subject and therapists will discuss goals for the experimental session and will 
review what will happen during the experimental session, following standard 
procedures and techniques discussed in the treatment manual.  
f. Prior to the experimental session, the therapists will introduce the subject to the 
attendant that will remain with the subject during each overnight stay after each 
MDMA-assisted psychotherapy session. The attendant will be an individual with 
previous training in managing psychological distress.  
g. If a subject would like a companion present during or after the experimental session, 
a meeting between the therapists and that individual will be scheduled prior to the 
first experimental session. There must be mutual agreement between the subject and 
therapists concerning the presence of the companion. 
h. The therapists or qualified study personnel will administer the C-SSRS just prior to 
beginning the second preparatory session, unless a subject is still undergoing 
medication washout. Subjects still undergoing medication washout will complete the 
C-SSRS during the second preparatory session or at a point after washout is complete 
prior to the first experimental session.  
i. Assess general wellbeing at each preparatory session. 
j. During the third and last preparatory session, give the Reminder of Study Rules to the 
subject, which includes instructions and restrictions for conduct prior to receiving the 
drug. Subjects must agree to: 
 
• Ingest only alcohol-free liquids after 24:00 (midnight) the evening before the 
experimental session.  
• Refrain from the use of any psychoactive drug, with the exception of caffeine or 
nicotine, within twenty-four 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. 
 
9.4.3 Experimental Sessions - Visits 4, 8 (Stage 1), 13, (Full Dose Group Stage 1), 19 
23, 28 (Stage 2) 
 
Experimental sessions of MDMA-assisted psychotherapy should be scheduled 
approximately 4 weeks apart (2-5 weeks) . Procedures for MDMA-assisted 
psychotherapy will remain the same across all sessions. The dose of the drug and 
blinding procedures will vary based on the stage of the study.  
 
Adherence criteria for experimental sessions should be completed as a part of each 
experimental session. These elements do not have to be accomplished in any specific 
order. Generally, adherence criteria for these sessions include that the therapists will 
create and communicate a setting of safety and support the subject during periods of inner 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 40 of 83 
 
 
focus. Therapists will use a largely nondirective approach, following the lead of the 
subject’s inner healing intelligence. Therapists will provide encouragement for staying 
present with difficult experiences. Therapists may occasionally offer gentle guidance or 
redirection as a choice to encourage collaborative exploration if the subject repeatedly 
avoids trauma related material. Therapists will inquire about somatic symptoms and if 
necessary encourage release of tension through movement, in whatever way feels 
appropriate to the subject. Therapists will use music to support the experience without 
being intrusive.  
 
Pre-drug: 
 
a. At least 24 hours prior to the first experimental session the subject will be 
randomized. The Investigator or Sub-Investigator or designated study personnel will 
obtain the container assignment using a web-based randomization program prior to 
the blinded sessions.  
b. On the day of the experimental session, the subject will arrive approximately 60 to 90 
minutes prior to drug administration.  
c. Confirm continuing eligibility by reviewing inclusion/exclusion criteria. 
d. Perform a urine drug screen. A positive drug screen will be reviewed by the 
Investigator or Sub-Investigator and may be cause for delaying drug administration to 
a later time, rescheduling the session to a later date, or withdrawing the subject from 
the study. 
e. If a woman is of childbearing potential, perform a urine pregnancy test. A positive 
pregnancy screen is cause for withdrawal from the protocol. 
f. If the subject continues to meet criteria and the subject reports that they followed 
appropriate rules and restrictions, the session will proceed. 
g. Review procedures for the experimental session with the subject. 
h. Record the entire session to video and audio if possible. Subjects may review audio or 
video recordings of their experimental sessions upon request. 
i. The session will last for approximately eight hours or longer, followed by an 
overnight stay at the study site. 
j. The therapists or qualified study personnel will administer the C-SSRS prior to drug 
administration. 
k. Before drug administration, discuss and review the subject’s goals, intentions and 
concerns and some of the commonly experienced effects of MDMA. 
l. Instruct the subject not to use caffeine or nicotine two hours before or six hours after 
the dose of drug. 
m. Subject body temperature will be measured at baseline prior to initial dose 
administration and approximately every hour after that. Measurements can be done 
more frequently if body temperature exceeds more than 1oC above baseline. 
n. Subjects will complete the SUD at baseline prior to initial dose administration. 
Subjects will complete the SUD every 60 to 90 minutes, until the session is over, 
allowing a window of up to 30 minutes to fit into the psychotherapy process where a 
natural break occurs. If necessary, the therapists can make a greater number of 
measurements as their clinical judgment dictates. 
o. Measure blood pressure and pulse at baseline prior to the experimental session, and 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 41 of 83 
 
 
once every half-hour throughout the experimental session if the established thresholds 
for normal blood pressure and pulse have not been exceeded for the duration of the 
experimental session. More frequent measures will be taken if the established 
thresholds of 160 systolic, 110 diastolic, or pulse 110 are exceeded. Measurements 
should be taken more frequently until the values fall below these levels or until they 
have been decreasing for 15 minutes or have stabilized at a level judged by the 
Investigator or Sub-Investigator to be safe. The therapists may also make more 
frequent measurements if a subject exhibits symptoms indicative of hypertension. 
 
During: 
 
p. At approximately 10:00 in the morning, subjects will receive the initial dose of drug 
along with a glass of water. This will be administered by the Investigator or Sub-
Investigator. 
q. The subject will sit or recline on comfortable furnishings. Eyeshades and a program 
of music will be provided if the subject wishes to use them. Subjects may speak to the 
therapists whenever they wish, who will provide guidance and support as needed.  
r. After the first hour, if the subject has not spoken spontaneously, check in with 
him/her about the nature of the experience. For the rest of the experience, as 
appropriate, the therapists will support and encourage the subject in emotional 
processing and resolution of whatever psychological material is emerging as 
described in the treatment manual. 
s. Record any spontaneously reported reactions during the session. 
t. If subjects who have pre-existing tinnitus or chronic pain mention any changes, use 
the visual analog scale to collect the changes in symptoms. 
u. Provide water and electrolyte containing fluids throughout the session but not to 
exceed 3L overall. 
v. An optional supplemental dose half the size of the initial dose may be administered 
approximately 1.5 to 2.5 hours after the initial dose unless contraindicated. 
w. Provide food during the latter part of the session.  
x. If there is a companion who has previously been asked and has agreed to be present 
during part or all of the MDMA-assisted session, that person may arrive during the 
session at whatever time has been agreed upon, but will wait in the waiting room until 
brought back to the session room by one of the therapists.  Alternatively, the support 
person may arrive after the session has ended. 
y. If it is appropriate to do so, initiate the first question of the C-SSRS at any point in the 
session if the subject is experiencing significant psychological distress that does not 
respond readily to processing with the therapists according to the methods described 
in the treatment manual. The C-SSRS is required at least once during the session. It is 
preferable to administer it towards the end of the session at about six hours after the 
initial dose.  
z. End the session if all medical and psychiatric parameters are acceptable and the 
subject is alert, ambulatory, and emotionally stable. 
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 42 of 83 
 
 
Table 5. Example Schedule of Procedures and Measures for Experimental Sessions  
Approximate Time 
Procedure or Action 
9:00  
Urine drug screen, pregnancy test, C-SSRS 
 9:45  
Baseline BP, pulse, SUD 
 9:55  
2nd Baseline BP, pulse, BT, SUD 
10:00  
Drug Administration, begin recording to audio and video 
10:30  
BP, pulse 
11:00  
BP, pulse, SUD, BT 
11:30  
BP, pulse, May administer supplemental dose  
12:00  
BP, pulse, BT 
12:30  
BP, pulse, SUD 
13:00  
BP, pulse 
13:30  
BP, pulse, BT 
14:00  
BP, pulse, SUD 
Every hour, and as needed 
BP, pulse 
Every 60 to 90 minutes 
SUD, temperature 
Approximately six hours 
after administration 
C-SSRS, General Wellbeing 
 
 
Post-drug: 
 
aa. Give the subject the SOCQ to be completed after the end of the experimental session 
and prior to leaving the treatment facility the next day. 
bb. The therapists will depart the site when they have concluded that the subject is 
emotionally and medically stable. Therapists shall remain available to subjects during 
the experimental session and for one week after via twenty-four-hour cellular phone 
for integration as needed. 
cc. If the Investigator or Sub-Investigator decides not to administer any optional 
supplemental or clinical titration doses, as described in Section 8.3, in a given 
experimental session, the unused capsules will be kept in their respective inner 
envelopes inside of the primary container until the end of the experimental session. At 
the end of the experimental session, the Investigator or Sub-Investigator will return 
the container and any remaining unused capsules to the pharmacy safe. 
dd. Spontaneously reported reactions, AEs, and Medications will be collected as 
described in Section 14.0 of the protocol.  
  
Subjects will remain overnight in an appropriately furnished room at the study site. With 
the approval of the therapists, a companion may accompany the subject during the 
overnight stay. An attendant will check in periodically on the subject during the overnight 
stay, even if a companion is present. The attendant will monitor subject condition and 
will help subjects relax during the overnight stay. The attendant will be an individual 
with some previous training in managing psychological distress. If there is an emergency 
or the subject needs additional support, the attendant can contact the therapists. The 
subject and a companion (if applicable) will receive information that will allow them to 
contact the therapists during the overnight stay in the case of an emergency or request for 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 43 of 83 
 
 
additional support. Subjects will be encouraged to use much of the time during their 
overnight stay for rest and for a period of reflection and integration in a quiet atmosphere. 
 
9.4.4 Integrative Sessions 24 Hours after Experimental Session - Visits 5, 9 (Stage 1), 
14 (Full Dose Group Stage 1), 20, 24, 29 (Stage 2) 
 
On the morning after each experimental session, both of the therapists from the subject’s 
team will meet with the subject during a 60 to 90-minute integrative therapy session.  
 
Adherence criteria for integrative sessions should be completed as a part of one of the 
three sessions following each experimental session. These elements do not have to be 
accomplished in any specific order or all in each and every integrative session. Generally, 
adherence criteria for these sessions include discussing material that emerged during 
experimental sessions and helping subjects integrate their experiences both internally and 
into daily life. Therapists will validate the choices of the subject about how much they 
wish to communicate their thoughts, feelings and experiences at this time, but will elicit 
enough information to be able to assess the subject’s level of emotional stability and state 
of emotional and physical wellbeing. Therapists will emphasize their commitment to 
support the subject during the integration period and will be available via phone for 
additional meetings if needed. Subjects will be encouraged to relax and rest as much as 
possible for several days after the experimental session. 
 
During integrative psychotherapy sessions: 
 
a. The integrative psychotherapy session may be recorded to audio and video. Subjects 
may review these data upon request. 
b. The therapists will administer the C-SSRS during each integrative session.  
c. Prior to integrative psychotherapy, the subject and both therapists will indicate their 
beliefs concerning subject condition assignment.  
d. Discuss and review events that occurred with the subject during the experimental 
session, including thoughts, feelings, and memories. If necessary, the therapists will 
help the subject to reduce any residual psychological distress he or she is 
experiencing. The therapists will also encourage the transfer of states of acceptance, 
feelings of intimacy, closeness, and reduced fear experienced in experimental 
sessions to emotionally threatening everyday situations. The therapists will be 
supportive, validating the experience and facilitating understanding and emotional 
clearing.  
e. The therapists will remain accessible any time the subject needs support outside the 
scheduled integration sessions.  
f. Assess the subject’s mental health, general wellbeing and the presence of any 
remaining reactions during integrative psychotherapy immediately after each 
experimental session.  
g. Integrative psychotherapy sessions can also serve as an opportunity for the therapists 
to gather information about the effects of the drug on the subject in an unstructured 
manner.  
h. If subjects who have pre-existing tinnitus or chronic pain mention any changes, use 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 44 of 83 
 
 
the visual analog scale to collect the changes in symptoms. 
i. After the integrative psychotherapy session following the experimental session, a 
person previously selected by the subject will provide a ride home to the subject. If 
the subject is unable to locate an individual willing or able to take him or her home, 
or if the designated person is unable to assist the subject due to unforeseen events, the 
therapists will assist the subject in finding an alternative means of returning home. 
j. Spontaneously reported reactions, AEs, and Medications will be collected as 
described in 14.0 of the protocol.  
k. Remind the subjects that they will have daily phone contact for the next seven days. 
 
9.4.5 A Week of Daily Contact 
 
During daily phone contact:  
 
a. Therapists will follow the most recent version of the treatment manual in all matters 
relating to follow-up subsequent to the experimental psychotherapy sessions. 
b. Starting on the day of the integrative psychotherapy session following each 
experimental session, one of the therapists will contact the subject via telephone or in 
person on a daily basis for one week. The goal of daily contact is assessment of 
changes in general wellbeing, safety of the subjects, and offering support for subjects.  
c. The integrative phone contact will be for a brief check-in lasting five to 15 minutes, 
or as long as necessary to address any subject’s concerns and to assess subject’s 
wellbeing. Additional telephone contact can be initiated at the request of the 
therapists or subject. 
d. On the second and seventh day of phone contact after the experimental session, the 
therapists will administer the C-SSRS. 
e. General wellbeing will be assessed at each phone call. 
f. Spontaneously reported reactions, AEs, and Medications will be collected as 
described in Section 14.0 of the protocol. 
 
9.4.6 Integrative Psychotherapy Between Experimental Sessions - Visits 6, 7, 10, 11,  
(Stage 1), 15, 16, (Full Dose Group Stage 1), 21, 22, 25, 26, 30, 31 (Stage 2) 
 
In addition to the session the morning after each experimental session, the subject will 
have two additional integrative psychotherapy sessions with the therapists lasting 90 
minutes with the therapists between each experimental session and in the month 
following the last experimental session. The therapists may conduct more sessions if they 
and the subject deem it necessary. Some of these sessions may be done via telemedicine 
or phone calls. 
 
Adherence criteria for integrative sessions should be completed as a part of one of the 
three sessions following each experimental session. These elements do not have to be 
accomplished in any specific order or in each integrative session. Generally, adherence 
criteria for these sessions include integration of material that emerged as a part of 
experimental sessions and afterward into daily life. Therapists will emphasize their 
commitment to support the subject during the integration period and will be available via 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 45 of 83 
 
 
phone or pager. Subjects will be encouraged to relax and rest as much as possible for 
several days after the experimental session. 
 
During integrative psychotherapy sessions: 
 
a. Record each integrative session to audio and video if possible. Subjects may 
review these recordings upon request. 
b. The C-SSRS will be administered just prior to beginning each integrative session.  
c. General wellbeing will be assessed at each integrative session. 
d. If subjects who have pre-existing tinnitus or chronic pain mention any changes, 
use the visual analog scale to collect the changes in symptoms. 
e. The subject will complete the PDS questionnaire on the third integrative session 
after the first and third experimental sessions, according to the Time and Events 
Table. 
f. The subject and therapists will continue to work on supporting the subject as she 
or he considers his or her experiences during experimental sessions.  
g. The therapists will use clinical judgment to assess the subject’s psychological 
wellbeing during this period of time. If there are any indications of continuing 
anxiety or distress, the therapists may arrange to work on reducing the distress at 
a specially scheduled integrative therapy session, through continuing contact, or at 
the next regularly scheduled integrative therapy session. The subject may also 
initiate contact with the therapists at any time throughout the study.  
h. Collect AEs and medications as described in Section 14.0 of the protocol. 
i. NOTE: If an integrative session falls within the period of telephone contact and 
additional phone call is not required that day, all data normally collected during 
the telephone call will be completed in person. 
 
9.4.7 Evaluation at Primary Endpoint and Unblinding - Visit 12 (Stage 1) 
 
The primary endpoint evaluation in Stage 1 will occur one month (within a window of 3-
5 weeks) after the second blinded experimental session. This visit will consist of two 
meetings that may be completed on separate days, one with the IR and the other with the 
therapists. Subjects who have withdrawn from treatment but have continued for follow-
up will also complete this time point one month after their last experimental session. 
 
At the primary endpoint: 
 
a. Subjects will complete the following assessments in person:  
• PASAT to assess cognitive function. 
• RBANS to assess cognitive function. 
b. The GAF to assess general psychological function, and CAPS to assess PTSD will be 
administered by the blinded IR in person or via telemedicine. CAPS interviews may 
be recorded to video in as many instances as necessary to establish inter-rater 
reliability. 
 
c. The subject will complete the following self-report measures: 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 46 of 83 
 
 
• PTGI to assess post-traumatic growth (in reference to start of the study) 
• PDS to assess PTSD symptoms. 
• BDI-II to assess depression symptoms. 
• NEO-PI to assess changes in personality. 
• PSQI to assess changes in sleep quality. 
• DES-II to assess dissociation symptoms. 
d. After completing all assessments and measures, the subject will meet with the 
therapists for approximately 30 minutes. 
e. The therapists or qualified study personnel will assess suicidality with the C-SSRS. 
f. General wellbeing will be assessed. 
g. The visual analog scale will be used to collect changes in pre-existing tinnitus and 
chronic pain symptoms.  
h. The blind will be broken for the subject’s condition assignment. Only the IR will 
remain blind to condition assignment at this time.  
i. If the subject was assigned to receive the comparator dose, the therapists will discuss 
continuation to Stage 2. Comparator dose subjects will not complete the third 
experimental session and associated integrative sessions in Stage 1. 
j. Collect perceptions of experimental sessions from full dose subjects after unblinding. 
k. Collect AEs and medications as described in Section 14.0 of the protocol. 
l. If the subject was assigned to receive full dose MDMA, the subject will complete a 
third open-label experimental session, with associated daily phone calls and 
integrative sessions in Stage 1.  
9.4.8 End of Stage 1 - Visit 17 (Full Dose Group Stage 1) 
 
Full dose subjects will repeat outcome measures and meet with the therapists again two 
months (within a window of plus or minus two weeks) after their final open-label 
experimental session, which will be their final visit in Stage 1. This visit will consist of 
two meetings that may be completed on separate days, one with the IR and the other with 
the therapists. 
 
At the end of Stage 1: 
 
a. The IR will administer the CAPS in person or via telemedicine, the RBANS and 
PASAT will be administered in a face-to-face visit. 
b. Subjects will complete the PDS, BDI-II, DES-II and PSQI, PTGI (in reference to start 
of the study). 
c. Full dose subjects who complete Stage 1 and comparator dose subjects who elect not 
to participate in Stage 2 will complete the RRPQ and continue on to the Long-term 
Follow-up.  
d. The visual analog scale will be used to collect changes in pre-existing tinnitus and 
chronic pain symptoms.  
e. The therapists or qualified study personnel will assess suicidality with the C-SSRS. 
f. Collect perceptions of experimental sessions. 
g. Subjects who will continue on to the Long-term Follow-up may return to taking 
psychiatric medications after the End of Stage 1 if necessary.  

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 47 of 83 
 
 
h. Subjects who will continue on the Long-term Follow-up will receive a memory aid 
card for use between their End of Stage 1 visit and the 12-month follow-up. Subjects 
will use this card to record AEs, medications, and changes in psychiatric status that 
they will be asked about at the termination visit. Memory Aids will not be collected.  
i. Collect AEs and medications as described in Section 14.0 of the protocol. 
 
9.4.9 Open-label Stage 2 (Comparator Dose Subjects from Stage 1) 
 
During Stage 2: 
 
a. Subjects will be reminded that participation in Stage 2 is voluntary and optional. 
b. Subjects who elect to cross over to Stage 2 will undergo the same course of therapy 
and evaluation as in Stage 1, with the exception that the subject will complete a single 
preparatory psychotherapy session instead of three (see Section 9.4.2), and varied 
active doses of MDMA will be administered in an open-label context to explore the 
optimal therapeutic dose (e.g. without unblinding). Visits will be scheduled 
consecutively according to the Time and Events Table. 
c. Assessment of PTSD symptoms at the primary endpoint will serve as baseline 
assessments in Stage 2. If the start of Stage 2 is delayed for more than 8 weeks from 
the primary endpoint (Visit 12) to the first preparatory session in Stage 2 (Visit 18), 
the IR will re-administer the CAPS and GAF. The subjects will complete the PDS, 
BDI-II, PSQI, PTGI (in reference to start of the study), and the DES-II. These scores 
will be used as the baseline for comparison to assessment at the secondary endpoint 
and end of Stage 2.   
d. Experimental sessions will be conducted according to procedures described in Section 
9.4.3.  
1. During the first experimental session, subjects will receive a 100mg initial 
dose of MDMA and may receive a 50mg optional supplemental dose of 
MDMA. 
2. At the beginning of the second and third experimental sessions, the therapists, 
in consultation with the subject, will decide whether to administer an initial 
dose of 100 mg or 125 mg initial dose of MDMA. If a 100mg initial dose of 
MDMA is selected, an optional supplemental dose of 50 mg MDMA may be 
administered. If a 125mg initial dose of MDMA is selected, an optional 
supplemental dose of 62.5mg MDMA may be administered 
3. If the Investigator or Sub-Investigator decides not to administer the optional 
supplemental dose and/or the optional clinical titration dose in a given 
experimental session, the unused capsules will be kept in their respective inner 
envelopes inside of the primary container until the end of the experimental 
session. The Investigator or Sub-Investigator will return the container and any 
remaining unused capsules to the pharmacy for storage in the safe. 
e. Integrative sessions will be conducted according to procedures described in Sections 
9.4.4 and 9.4.6. 
f. Phone calls will be conducted according to procedures described in Section 9.4.5. 
g. At the secondary endpoint based on procedures described in Section 9.4.7, the IR will 
administer the CAPS and GAF. Subjects will complete the PDS, BDI-II, PSQI, PTGI 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 48 of 83 
 
 
(in reference to start of the study), and DES-II as described in the Time and Events 
Table.  
h. At the end of Stage 2 based on procedures described in Section 9.4.8, the IR will 
administer the CAPS, GAF, RBANS and PASAT. Subjects will complete the PDS, 
BDI-II, DES-II, PSQI, PTGI (in reference to start of the study), and NEO-PI as 
described in the Time and Events Table. 
i. The End of Stage 2 will be completed in the same manner as the End of Stage 1 as 
described in Section 9.4.8.  
j. Therapists will follow the most recent treatment manual in all matters relating to the 
psychotherapy sessions. 
 
9.4.9 Long-term Follow-up  
 
All subjects will be evaluated for long-term effects 12 months (within a visit window of 
plus or minus one month) after their last MDMA-assisted psychotherapy session.  This 
visit will consist of two meetings, one with the IR and the other with the therapists. 
Subjects who have withdrawn from treatment but have continued for follow-up will also 
complete this time point.  This visit may be audio and video recorded. 
 
At the Long-term Follow-up visit:  
 
a. The IR will administer the CAPS and GAF via telemedicine or in person.  
b. Subjects will complete the PDS, BDI-II, NEO-PI, PSQI, PTGI (in reference to start of 
the study), and DES-II. 
c. Subjects will have a final meeting with at least one of the therapists to review 
specified AEs and medications since the last visit. Subjects should bring the Memory 
Aid Cards to this visit, to be used as aids in recollection. These cards will not be 
collected. AEs and Medications will be collected as described in Section 14.0 of the 
protocol. 
d. The therapists or qualified study personnel will assess suicidality with the C-SSRS.  
e. Subjects will complete a questionnaire assessing positive and negative long-term 
effects of the study.   
f. A researcher who is a part of the study team may ask the subject questions about 
positive or negative effects about the study in person or on the phone. 
g. The visual analog scale will be used to collect changes in pre-existing tinnitus and 
chronic pain symptoms. 
h. Subjects will complete the termination visit at this time. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 49 of 83 
 
 
 
10.0 Removal of Subjects from Therapy or Assessment 
 
Subjects can withdraw consent at any time without prejudice. The Investigator or Sub-
Investigator can withdraw a subject if, in his or her clinical judgment, it is in the best 
interest of the subject or if the subject cannot comply with elements of the protocol that 
are critical for safety and/or for the scientific integrity of the study. If the Investigator or 
Sub-Investigator withdraws a subject from the study, the Investigator or Sub-Investigator 
will explain the reason for withdrawing the subject. The reason for early termination will 
be recorded in the subject’s source records and CRF. 
 
Subjects will be clinically monitored after withdrawal, the cause of which will be re-
corded in the subject’s source records and CRF. Whenever possible, the tests and 
evaluations listed for the termination and outcome visits will be carried out. Efforts will 
be made to obtain information about AE outcomes, if deemed necessary by the 
Investigator or Sub-Investigator and/or sponsor. 
 
If the subject develops any exclusion criteria, which in the opinion of the Medical 
Monitor, affects the safety of the subjects (including psychiatric diagnosis, pregnancy or 
excluded medications), the subject will discontinue treatment but remain in the study for 
follow-up purposes. Whenever possible, the tests and evaluations listed for the primary 
endpoint and 12-month follow-up will be carried out. Efforts will be made to obtain 
information about AE outcomes, if deemed necessary by the Investigator or Sub-
Investigator, Medical Monitor and/or Sponsor. 
 
Subjects who discontinue treatment prior to the primary endpoint will be replaced. 
Individuals who replace these subjects will be assigned the next available subject 
number. Subjects who discontinue treatment after the primary endpoint in Stage 1 or after 
continuation to Stage 2 will not be replaced. If Stage 1 subjects discontinue treatment 
before the primary endpoint, the site should contact the randomization monitor for 
replacement instructions. Detailed instructions will be provided to the site in a separate 
document.  
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 50 of 83 
 
 
11.0 Premature Discontinuation of the Study 
 
The sponsor or the Investigator (following consultation with the sponsor) has the right to 
discontinue this study at any time. If the trial is prematurely terminated, the Investigator  
or Sub-Investigator are to promptly inform the study subjects and will assure appropriate 
therapy and follow-up. If the trial or study is prematurely discontinued, all procedures 
and requirements pertaining to the archiving of the documents will be observed. All other 
study materials will be returned to the sponsor and will be treated in accordance with 
national and provincial regulations. 
 
12.0 Data Analysis  
 
The sponsor will judge the clinical and statistical significance of the study based on a 
comparison of observer-blind data collected at baseline and the primary endpoint using 
the primary outcome measure, which is the CAPS. Descriptive statistics will be computed 
overall and within the two dose conditions for all available data from outcome measures, 
including minimum, maximum, average, and standard deviation. Distributional 
characteristics will be examined for outliers and extreme values and, if either is evident, 
nonparametric statistics will be utilized in the analysis. Cohen’s techniques will be used 
to estimate effect sizes between conditions for all outcome measures for Stage 1, Stage 2, 
and 12-month follow-up.  
 
The sponsor will examine full dose and comparator dose groups for homogeneity through 
comparing demographic characteristics. There is no expectation that conditions will 
differ in composition by gender, race or ethnicity, duration of PTSD diagnosis or 
presence versus absence of other permitted psychiatric disorders, as depression. 
However, owing to small sample size, such variations may arise by chance. 
 
The sponsor will examine CAPS scores for the primary outcome analysis at baseline and 
the primary endpoint in full dose and comparator dose conditions using difference scores, 
and independent sample t-tests will be used to test for significance between groups, with 
p value set at 0.05.  
 
For exploratory purposes, the sponsor will examine PDS, BDI-II, GAF, PSQI, PTGI, 
NEO-PI, and DES-II scores at baseline and the primary endpoint in full dose and 
comparator dose conditions using difference scores, and independent sample t-tests will 
be used to test for significance between groups, with p value set at 0.05. Changes in 
outcome measures from the primary/secondary endpoint to the 2-month follow-up in 
Stage 1/Stage 2 will be compared for a within-subject analysis with p value set at 0.05 to 
see whether a third session produces further decline in symptoms.  
 
An exploratory repeated measures analysis of variance (ANOVA) will be performed 
upon PDS scores at baseline, after each experimental session, at the primary endpoint, 
and at the end of Stage 1 with p value set at 0.05. Condition will serve as a between-
subjects factor. Results of ANOVA analysis will be used to examine the effects of each 
experimental session on self-reported PTSD symptom severity. PDS and CAPS scores 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 51 of 83 
 
 
may be correlated via Pearson’s product moment correlation at baseline and the primary 
endpoint to provide a comparison of a self-report measure with a clinician-administered 
measure of PTSD symptoms.   
 
Formal statistical comparisons between Stage 1 and Stage 2 scores may only occur if, at 
minimum, three subjects complete Stage 2. Data from the open-label third experimental 
session in Stage 1 will be compared statistically to Stage 2 data, and data from this 
session will only be utilized if they are equivalent to Stage 2 data.  
 
The sponsor will compare CAPS, PDS, GAF, BDI-II, PSQI, PTGI, and DES-II, scores at 
the final assessment prior to the 12 month follow-up to the 12-month follow-up using 
difference scores in an independent t-test for a within-subject analysis with p value set at 
0.05. 
 
The sponsor will compare baseline and primary endpoint RBANS and PASAT scores in 
full dose and comparator dose conditions using difference scores in an independent 
sample t-test to test for significance between groups, with p value set at 0.05. The sponsor 
will examine the effects of maximal exposure to MDMA on neurocognitive function 
using the RBANS and PASAT by performing a within-subject repeated measures 
ANOVA with time of administration as a within-subjects factor and with p. set at 0.05.  
 
The sponsor will collect Changes in Tinnitus and/or Pain visual analog scale scores from 
any subject reporting tinnitus or chronic pain during each point of administration, 
including baseline, experimental and integrative sessions, the primary endpoint, and two-
month follow-up. The sponsor will plot out and examine all Changes in Tinnitus and/or 
Pain visual analog scale scores across both groups and in the full dose and comparator 
dose groups for trends. Formal analysis of Changes in Tinnitus and/or Pain visual analog 
scale scores will only occur if three or more subjects complete Changes in Tinnitus 
and/or Pain visual analog scale at baseline and primary endpoint. Likewise, formal 
between-groups analyses will not be performed if all primary endpoint scores are from 
subjects assigned to the same condition. The sponsor will perform an independent t-test 
on the difference between baseline and primary endpoint Changes in Tinnitus and/or Pain 
visual analog scale scores in the full dose and comparator dose conditions, with p. set at 
0.05. If the only scores available are for subjects in a single condition, then a paired t-test 
will be performed comparing baseline and primary endpoint Changes in Tinnitus and/or 
Pain visual analog scale scores, with p. set at 0.05.    
 
Descriptive statistics will be computed for vital signs and subjective distress during each 
experimental or open-label session. The sponsor will compare peak blood pressure, heart 
rate, and body temperature for subjects after sessions with full dose MDMA or 
comparator dose MDMA whenever possible. Frequency tables will be produced on 
prevalence of spontaneously reported reactions and AEs. 
 
The sponsor will collect ratings of adherence to the treatment manual from specifically 
selected types of sessions. Descriptive statistics will be computed for each adherence 
scale within a specific type session. The sponsor will explore the factors and structure of 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 52 of 83 
 
 
the measures of adherence to assist in further development of adherence and competence 
measures. If sufficient data is available, the sponsor will correlate the mean adherence 
ratings for adherence scale and session type with Global CAPS scores to investigate the 
effects of adherence to the treatment manual on reduction in PTSD symptoms. If it is 
found that there are specific factors within the adherence scales, then the factor will be 
correlated with global CAPS score. 
 
The sponsor will compute descriptive statistics for SOCQ scores from after each MDMA-
assisted psychotherapy session, and average SOCQ scores for blinded experimental 
sessions will be compared between conditions. The data will be explored for effects of 
condition on domain scores in the SOCQ. 
 
Perception of experimental sessions will be examined during Stage 1 and Stage 2, before 
and after subjects have undergone a third experimental session. The results of this 
analysis will inform the sponsor of expectancies and the value of the third session for 
future protocol development. These data may be correlated with difference scores 
calculated from the primary/secondary endpoint CAPS data compared to end of Stage 
1/Stage 2 CAPS data to assess the potential contribution of expectation and self-reported 
response to changes in PTSD symptoms.  
 
Subjects who discontinue treatment prior to the primary endpoint will be asked to 
complete an outcome assessment prior to continuing to the long-term follow-up. The data 
from these subjects will be tested for equivalence to data from subjects completing the 
study per protocol. If found to be equivalent, data from these subjects will be presented as 
an exploratory intent-to-treat analysis to examine results without bias towards subjects 
more likely to complete the study per protocol.  
 
An interim analysis may be completed when all subjects have completed Stage 1 and 
Stage 2, but not all subjects have completed the 12-month follow-up evaluation. 
Additionally, an interim analysis may be performed after all subjects have completed 
Stage 1 but not necessarily before all eligible subjects complete Stage 2. This analysis 
will address safety, efficacy and process measures. Results of the interim analysis will 
have no effect on study conduct. 
 
12.1 Statistical Power 
 
This study is a pilot investigation intended to estimate effect sizes of the safety and 
efficacy of MDMA-assisted psychotherapy in people with PTSD. Because of their 
exploratory nature, pilot studies are often underpowered for detecting the desired effect. 
Because it is a pilot study in a small sample, statistical power is difficult to assess but it is 
likely to be low. Analyses of MAPS’ completed US study of MDMA-assisted 
psychotherapy in 20 people with PTSD found an effect size of 1.24 for treatment 
efficacy, as represented by changes in CAPS score [77]. The estimated effect size for this 
study may be lower as a result of employing a smaller sample size. The sponsor intends 
to combine effect size estimates to develop a dose response curve as a meta-analyses of 
CAPS scores across MAPS-sponsored pilot studies.  

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 53 of 83 
 
 
 
The sponsor used Java applications created by Lenth and posted on the website listed 
below to calculate estimated statistical power for this study, assuming an effect size of 
1for the impact of two sessions of MDMA-assisted psychotherapy on symptoms [168], 
reducing the effect size to account for the hypothesized effects of using a comparator 
dose. The software calculated an estimated power of 0.34, indicating an underpowered 
study. Had we used the higher effect size of 1.1, power analysis still indicates that this 
study is underpowered, with an estimated effect size of 0.37. Statistical power estimates 
were not available for secondary and exploratory measures, as they were previously not 
used in sponsor-supported studies. 
 
13.0 Risk Mitigation 
 
Careful review of medical screening data will be utilized to exclude potential subjects 
with pre-existing exclusionary medical conditions from the study. Study procedures have 
been developed to mitigate the risks of receiving MDMA described in detail in the IB. 
Ambient temperature will be kept at a comfortable level during experimental sessions. 
Subjects will not be allowed to drink more than 3L of fluids over the course of the 
experimental session, and fluid intake will be spread out appropriately during the session. 
Fluids administered will include electrolytes. If a subject exhibits any signs of toxicity or 
clinically significant dilutional hyponatremia despite these precautions after an 
experimental session, the subject will not receive another experimental session unless it is 
approved by the Investigator and the Medical Monitor.   
 
13.1 Medical Emergencies 
 
Psychotherapy sessions will take place in the offices of the Investigator. Subjects may sit 
or lie on a couch or bed. The offices are furnished with beds that allow for two people to 
remain overnight. They can be heated or cooled with fans. One therapist can reach the 
offices within five to 10 minutes of contact if necessary. The study site will contain 
equipment for assessing blood pressure, pulse, and body temperature and there will be an 
automatic external defibrillator (AED) on site. The therapists will maintain basic life 
support (BLS) certification or its equivalent in Canada in cardiopulmonary resuscitation 
(CPR) including training in using an AED. The site is five minutes from the University of 
British Columbia emergency department and eight to 15 minutes away from St. Paul’s 
Hospital emergency department. In the event of a medical emergency paramedics will be 
summoned and study subjects will be transported to either hospital as appropriate.   This 
is an adequate level of emergency backup based on experience with previous Phase 2 
studies in the U.S. and Switzerland during which there have been no adverse events 
during experimental sessions requiring emergency treatment.   
 
The first U.S. Phase 2 trial with MDMA was conducted in an outpatient setting with a 
“crash cart” of emergency equipment on hand and an emergency physician and nurse in 
the building. The estimated transport time from this site to the nearest hospital emergency 
department was approximately 10 minutes with an estimated response time for an 
emergency medical services ambulance of approximately eight minutes. In this study, 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 54 of 83 
 
 
MDMA was administered on 51 different occasions at a dose of either 125 mg by mouth 
or 125 mg followed in 2 to 2.5 hours by an additional 62.5 mg. Blood pressure, pulse, and 
temperature were closely monitored but never reached levels that required intervention 
nor were there any other medical problems requiring treatment during the MDMA-
assisted sessions. Subsequently, a similar study was completed in Switzerland and was 
conducted in an outpatient psychiatry office, approximately five minutes from the nearest 
hospital without a crash cart or emergency personnel on site.  The Swiss therapists have 
administered 125 mg followed by 62.5 mg MDMA on 39 occasions and administered 150 
mg MDMA on four occasions without medical incident. 
 
14.0 Adverse Events 
 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product at any dose that does 
not necessarily have to have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational product. 
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 
until resolution or, if the AE becomes chronic, a cause identified. If an AE is unresolved 
at the conclusion of the study, a clinical assessment will be made by the Investigator or 
Sub-Investigator and Medical Monitor as to whether continued follow-up of the AE is 
warranted. 
 
The severity of events reported on the “Adverse Events” CRF will be determined by the 
Investigator or Sub-Investigator 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 Investigator or 
Sub-Investigator based on the following definitions: 
 
• “Not Related”: The AE is not related if exposure to the investigational product 
has not occurred, or the occurrence of the AE is not reasonably related in time or 
the AE is considered unlikely to be related to use of the investigational product, 
i.e. there are no facts (evidence) or arguments to suggest a causal relationship, or 
the AE is more likely related to the subject’s pre-existing condition. 
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 55 of 83 
 
 
• “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. 
 
• “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. 
 
14.1 Serious Adverse Events 
 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any 
dose: 
 
• Results in death. 
• Is life threatening (i.e., the subject was, in the opinion of the Investigator or Sub-
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 a 
substantial disruption of a person’s ability to conduct normal life functions). 
• Results in a congenital anomaly/birth defect. 
• Requires intervention to prevent permanent impairment or damage. 
• Is an important and significant medical event that may not be immediately life 
threatening or resulting in death or hospitalization but based upon appropriate 
medical judgment, may jeopardize the patient/subject or may require intervention 
to prevent one of the other outcomes listed above. 
 
Adverse events which do not fall into these categories are defined as non-serious. It 
should be noted that a severe adverse event need not be serious in nature and that a 
serious adverse event 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 an on study SAE unless, in the view of the Investigator or 
Sub-Investigator, hospitalization was prolonged as a result of participation in the clinical 
trial or was necessary due to a worsening of the pre-existing condition. This is because 
the onset of the event (the reason for the procedure) occurred before the subject was 
entered in the trial. Hospitalization for cosmetics, non-emergency prophylaxis, or 
abortion does not result in an SAE report unless, in the view of the Investigator or Sub-
Investigator, hospitalization for these procedures was prolonged as a result of 
participation in the clinical trial. 
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 56 of 83 
 
 
14.2 Adverse Event Collection 
 
The Investigator or Sub-Investigator will be responsible for reviewing and confirming all 
AEs and SAEs collected during the study. The Investigator or Sub-Investigator and/or 
qualified study personnel will collect AEs during study visits after enrollment.  
 
All SAEs will be collected for the duration of the protocol. All SAEs which occur during 
the course of the trial, whether considered to be associated with the study drug or not, 
have to be reported within 24 hours of the Investigator’s awareness of their occurrence.  
All SAE reports should be faxed to the Sponsor. A fax number will be provided to the 
site in separate site-specific instruction for SAE reporting. In addition to the fax, the 
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.   
 
SAE Reporting: 
MAPS Office 
 
Telephone: 831-429-6362, ext. 104 
Fax: 831-429-6370     
 
Medical Monitor: 
Michael C. Mithoefer, M.D. 
Email: mmithoefer@mac.com  
Telephone: 843-849-6899 (office) 843-566-4252 (cell) 
Fax number: 843-278-9188 
 
Study Monitor contact information will be provided in a separate contact list. 
 
Adverse events that will be collected for the duration of the protocol are: 
 
• All SAEs will be collected through subject termination. 
• All AEs and spontaneously reported reactions will be collected on the day of drug 
administration and for seven days after each experimental session. 
• Events requiring medical attention will be collected from enrollment through the 
subject’s last two-month follow-up. 
• Events related to planned treatments or physician visits for baseline conditions 
collected in the Medical History will not be collected unless there is an 
exacerbation of the condition. 
• Any Adverse Event leading to withdrawal from the protocol will be collected 
throughout the study. 
• All AEs related to changes in psychiatric status will be collected throughout the 
study. 
 
A Memory aid card will be provided to the subject on the last visit prior to the 12-month 
follow-up to record information on medications taken to treat SAEs, AEs leading to 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 57 of 83 
 
 
withdrawal and psychiatric AEs during the follow-up period between the end of Stage 
1/Stage 2 and the 12-month follow-up evaluation. The memory aid card will not be 
collected, but information from the card will be used to aid the subjects in providing 
information to the Investigator or Sub-Investigator. This information may be collected by 
phone. 
 
14.3 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 followed during 
follow-up phone calls or visits until resolution. 
 
14.4 Collection of Concomitant Medications and Tapering Instructions 
 
The Investigator, Sub-Investigator, or designated study personnel will record concomitant 
medications during screening. If the subject is being treated with psychiatric drugs at the 
time he or she is recruited into the study, the prospective subject will be encouraged to 
discuss medication tapering with his or her outside treating physician, if any, and will be 
required to give the Investigator, Sub-Investigator or qualified study personnel 
permission to do so as well. The drugs will then be tapered in an appropriate fashion to 
avoid withdrawal effects. They will be discontinued long enough before the first MDMA 
session to avoid the possibility of any drug-drug interaction (the interval will be at least 
five times the particular drug’s and active metabolites half-life).  
 
If a subject is taking opiates for pain control they may continue them if necessary in the 
opinion of the Investigator or Sub-Investigator and Medical Monitor, but will be asked to 
taper to the lowest dose possible by the day of the experimental sessions. The dose and 
method of tapering should be agreed upon by the subject, the investigator or Sub-
Investigator and the prescribing physician.  If the subject is using opiates as needed 
(PRN) but not every day they should be asked to refrain from taking them the morning of 
the experimental session.   
 
The therapists or designated study personnel will request information about any changes 
in medication just prior to each experimental session. The Investigator or Sub-
Investigator will be responsible for reviewing and confirming all medications collected 
during the study.  
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 58 of 83 
 
 
All medications, over the counter (OTC) and prescription will be collected from 
screening through seven days after the last MDMA session. From seven days after the 
last MDMA session through study termination only prescription or OTC medications 
taken to treat AEs will be collected. Throughout the protocol all medications used to treat 
AEs will be collected, as described in Section 14.0, and all changes including 
discontinuations or additions to psychiatric medications will be collected. Medications 
will be recorded on the concomitant medications CRF.   
 
Subjects must be willing to refrain from taking any psychiatric medications during Stage 
1 and Stage 2, with the exception of gabapentin when prescribed for pain control. If the 
subject is on stimulants for ADHD at baseline, they can continue to use them at the same 
dose and frequency as long as they discontinue five half-lives before each experimental 
session and do not restart for 10 days after each experimental session. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 59 of 83 
 
 
Table 6. Medication Tapering Table 
Generic Name Brand Name 
Half-life (hours) 
including active metabolites 
Days for Washout 
alprazolam 
Xanax 
11 
3 
aripiprazole 
Abilify 
75 
16 
atomoxetine 
Strattera 
5-24 
5 
bupropion 
Wellbutrin 
21 
5 
citalopram 
Celexa 
35 
8 
clonazepam 
Klonopin 
30-40 
8 
diazepam 
Valium 
20-70 
15 
duloxetine 
Cymbalta 
12 
3 
escitalopram 
Lexapro 
32 
7 
fluoxetine 
Prozac 
7-9 (days) 
45 
imiprimine 
Tofranil 
6-18 
4 
lamotrigine 
Lamictal 
25 
6 
lorazepam 
Ativan 
12 
3 
mirtazapine 
Remeron 
20-40 
8 
olanzapine 
Zyprexa 
21-54 
11 
paroxetine 
Paxil 
21 
5 
prazosin 
Minipress 
2-3 
1 
quetiapine 
Seroquel 
6 
2 
risperidone 
Risperdal 
3-20 
4 
sertraline 
Zoloft 
26 
6 
temazepam 
Restoril 
8-12 
3 
trazodone 
Desyrel 
9 
2 
venlafaxine 
Effexor 
12 
3 
ziprazidone 
Geodon 
7 
2 
zolpidem 
Ambien 
2.5 
<1 
 
The Investigator or Sub-Investigator may prescribe a designated rescue medication in the 
event of symptoms that require it during or after the experimental session (e.g. insomnia 
or severe anxiety that does not respond to other management outlined in the treatment 
manual). Rescue medications may be a benzodiazepine, zolpidem or other anxiolytic or 
sedative according to the physician's clinical judgment. SSRIs, SNRIs, and MAOIs 
should not be used as rescue medications.  
 
Subjects must agree that, for one week preceding the MDMA session: 
 
a. They will refrain from taking any herbal supplement (except with prior approval 
of the research team).  
b. They will refrain from taking any prescription or nonprescription medications 
(with the exception of non-steroidal anti-inflammatory drugs, acetaminophen, 
birth control pills, thyroid hormones, or other medications approved by the 
research team).  
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 60 of 83 
 
 
Subjects will receive a memory aid card for use between the end of Stage1/Stage 2 visit 
and the 12-month follow-up. Subjects will use this card to record changes in psychiatric 
medications that they will be asked about at the termination visit. Memory aids will not 
be collected. Subjects may return to taking psychiatric medications and discontinue birth 
control after the final two-month assessment if necessary. 
 
14.5 Clinical Laboratory Assessments 
 
The Investigator or Sub-Investigator will examine laboratory assessments gathered in 
screening for assessing subject eligibility. The Investigator or Sub-Investigator will use a 
list of normal ranges to conclude whether subjects are eligible for the protocol, and will 
indicate justification for admitting subjects with abnormal values, after consultation with 
the medical monitor.  
 
The following laboratory assessments will be performed as a part of screening: 
 
• Serum electrolytes and metabolic profile 
o ALT/SGPT 
o Albumin:globulin (A:G) ratio 
o Albumin, serum 
o Alkaline phosphatase, serum 
o AST/SGOT 
o Bilirubin, total 
o BUN:creatinine ratio 
o Calcium, serum 
o Carbon dioxide 
o Chloride, serum 
o Creatinine, serum 
o 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 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 61 of 83 
 
 
o Specific gravity 
o pH 
o Protein 
o Glucose 
o Ketones 
o Blood in urine 
o Leukocyte esterase 
o Nitrite 
• Thyroid function. 
o TSH high sensitivity 
o Free T4 
o Free T3 
• HIV serology. 
• Urine-dip pregnancy test for females of childbearing potential. 
• Urinary drug test will be performed.  
 
The clinical lab assessments and ECG will be performed by: 
  
LifeLabs Medical Laboratory Services 
 
 
 
15.0 Study Monitoring, Auditing, and Documentation 
 
The Investigator, Sub-Investigator, therapists, and their study staff will be trained prior to 
the start of the study.  The clinical study site will be monitored by site visits and regular 
contact with the Investigator and qualified study personnel by representatives of the 
sponsor. The site will be monitored as appropriate for the rate of enrollment. During each 
monitoring visit, source data verification will be performed by a Clinical Research 
Associate to ensure compliance, including accurate and complete recording of data in 
CRFs, source documents, and drug accountability records, while maintaining the blind 
during Stage 1. CRFs will be supplied by the sponsor will be completed for each subject 
enrolled. Monitoring and auditing procedures of the sponsor will be followed in order to 
comply with GCP guidelines and to ensure validity of the study data. Monitoring and 
auditing procedures will be supplied in a separate document. 
 
The sponsor will review the study documentation used for planning, conduct, and 
monitoring of the study in order to ensure compliance with GCP and local regulations. 
This documentation includes as a minimum: the IB, the Protocol, the CRFs, and the 
Subject Information and Consent Form. 
 
During or after the clinical 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. 
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 62 of 83 
 
 
16.0 Risks of Participation 
 
16.1 Risks and Discomforts Associated with Psychotherapy Sessions and Assessment 
of Measures 
 
In preparation for drug-assisted psychotherapy sessions, blood draws and a full medical 
examination are required to establish eligibility for the study. Temporary discomfort, 
inflammation, or infection could arise as a result of sampling blood at the punctured vein. 
Submitting to a full medical examination may also cause discomfort or psychological 
distress. Since medical examinations and blood draws are required to establish eligibility 
for the study, they cannot be omitted from the protocol. 
 
During screening, non-drug and drug-assisted psychotherapy sessions and assessment of 
study measures, subjects will be asked to think about and discuss their thoughts and 
emotions relating to the traumatic event or events. They may experience intense 
emotional responses to recalling and speaking about this material. Even in a therapeutic 
context, thinking about and discussing the trauma, symptoms related to the trauma or the 
effects of PTSD on life function can produce distress during and immediately after non-
drug psychotherapy, experimental, and open-label sessions. Psychotherapy is conducted 
as part of the research study, including the experimental intervention, and people 
undergoing psychotherapy are expected to confront unpleasant thoughts, feelings, and 
memories in the process of therapy. Because psychotherapy is an integral part of the 
research study design, the potential distress arising from psychotherapy is unavoidable.   
 
All psychotherapy sessions may be recorded to audio and video for research and training 
purposes. Subjects may feel uncomfortable with having their sessions recorded. Subjects 
may have access to recordings if they request them. The recordings are necessary for 
developing the experimental treatment and assessing adherence to the treatment manual. 
Subjects will receive information on who will have access to any of their recordings and 
will have control over any presentation of this material beyond viewing by researchers or 
regulatory agencies.  
 
As with any medical procedure, there are potential risks associated with the use of 
telemedicine. In rare cases, information transmitted may not be sufficient (e.g. poor 
resolution or choppy video connection) to allow for appropriate medical decision making 
by your therapy team or the researchers. Delays in medical evaluation and treatment 
could occur due to deficiencies or failures of the equipment or internet service. In very 
rare instances, security protocols could fail, causing a breach of privacy of personal 
medical information. 
 
16.2 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 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 63 of 83 
 
 
mouth, ruminations, and thirst. Other slightly less common reactions include restlessness, 
parasthesias (odd somatic feelings, such as tingling, feeling hot or cold), impaired 
judgment, perspiration, drowsiness, and nystagmus (eye-wiggling). While anxiety, 
headache, fatigue, insomnia and lack of appetite were spontaneously reported by 40% to 
80% of subjects in both conditions in MAPS study MP-1 (N=23), tight jaw, nausea, 
impaired gait/balance, and sensitivity to cold were more often reported by subjects in the 
MDMA than the placebo condition, and irritability was slightly more likely to be reported 
in the placebo condition. Additionally, subjects in the MDMA condition were more likely 
to report muscle tension in various body parts and diarrhea.  
 
These effects are transient and diminish as drug effects wane. Sub-acute effects that may 
either continue for the next 24 hours or appear later include insomnia, fatigue, needing 
more sleep, weakness, heavy legs, dry mouth, low mood or irritability. Sub-acute effects 
are reported less often than acute effects. More information on spontaneously reported 
reactions is described in the IB.  
 
MDMA may produce mild alterations in sensory perception and altered perception of 
time [74, 169, 170]. Women may be more sensitive to these effects [124].  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 [171]. For this reason, subjects will stay at the site overnight and will not be 
permitted to drive after experimental sessions.  
 
MDMA may produce modest changes in immune functioning, lasting up to 48 hours. 
Because of their limited duration, these changes are not likely to have clinical 
significance beyond several days of possible increased risk of viral upper respiratory 
infection or similar illness.  
 
Further information on the risks associated with MDMA, including information drawn 
from case reports and studies of ecstasy users, can be found in the sponsor’s IB.  
 
16.2.1 Cardiovascular and Sympathomimetic Effects 
 
The full dose of 125 mg, followed by a supplemental dose of 62.5 mg after 1.5 to 2.5 
hours, is expected to produce significant but transient, self-limited increases in blood 
pressure and heart rate. These changes should last no more than six hours. In less than 5% 
of volunteers in Phase 1 studies, peak blood pressure values were higher than 140/90 
mmHg. Clinical intervention was not required in any of these cases. Nonetheless, careful 
monitoring of subjects and predefined contingency plans will allow the researchers to 
rapidly identify and manage any related toxicity. For more information, see the sponsor’s 
IB. 
 
Risks posed by elevated blood pressure will be addressed by excluding people with pre-
existing hypertension and monitoring blood pressure and pulse, as described in Section 
5.1.2. During experimental sessions the co-therapists will continually evaluate the patient 
for increasing blood pressure and signs or symptoms of a developing hypertensive or 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 64 of 83 
 
 
other cardiovascular emergency. Subjects reporting chest pain, shortness of breath or 
neurological symptoms or other potential indicators of hypertension will have more 
frequent measurements and assessment by the Investigator or Sub-Investigator. Any 
subject who experiences medical complications during an experimental session will not 
be given another experimental session unless it is approved by the Investigator or Sub-
Investigator and the Medical Monitor.   
In case of need, subjects will be transferred to the emergency room at the closest hospital, 
as described in Section 13.1. 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 Investigator or Sub-
Investigator may, at any time, make a clinical judgment to transfer the patient to the ED 
for closer monitoring and additional treatment.  
 
The Investigator or Sub-Investigator 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 Investigator or Sub-Investigator if this occurs for on-site evaluation or a 
decision to initiate transfer to the ED. If any subject has neurological deficits, as assessed 
by the Investigator or Sub-Investigator, whether or not they are associated with 
hypertensive crisis, paramedics will be summoned to initiate the applicable protocols for 
further evaluation and stabilization and 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 [172, 173]. 
 
The Investigator or Sub-Investigator will observe the subject and note any complaints of 
chest pain. If a subject experiences ischemic type chest pain, whether or not it is 
associated with hypertensive crisis, paramedics will be summoned to initiate the 
applicable protocols for further evaluation and stabilization and, if necessary, he or she 
will be transported to the ED or a location in the hospital where appropriate care can be 
given. He or she will be given nitroglycerin 0.4 mg SL q 5 minutes PRN chest pain 
pending transport to the hospital. If further evaluation at the hospital reveals that the 
subject has had an AMI, they will be well within the time frame required for definitive 
therapy. The American College of Cardiology/ American Heart Association guidelines 
for the treatment of AMI recommend percutaneous transluminal coronary angioplasty 
(PTCA) as the treatment of choice when it can be performed within 90 minutes of arrival 
at the hospital in patients who present within 12 hours of an episode of chest pain lasting 
more than 30 minutes and who have ECG evidence of AMI [174]. 
 
16.2.2 Psychological Distress 
 
Mild anxiety and depressed mood are occasionally reported one to three days after 
MDMA administration [72, 124, and see the IB]. Psychological distress from MDMA 
could arise from the first indications of drug effects until the last effects have dissipated 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 65 of 83 
 
 
(approximately three to five hours after drug administration), or even later. Anxiety or 
distress during the session may last for as little as five minutes or for as long as five hours 
or more. In addition, psychological distress could arise following an MDMA session as a 
result of subjects having difficulty integrating their experience after the MDMA effect 
has subsided. In previous Phase 1 and Phase 2 studies, these symptoms have been self-
limiting, and have responded well to reassurance from the therapists, with occasional use 
of benzodiazepines for anxiety. In this study, subjects will have the intention of 
confronting and working through traumatic experiences. Hence signs of psychological 
distress, panic or other unpleasant psychological reactions are to be expected and may be 
considered an element of the psychotherapeutic process.  
 
Proper preparation and follow-up support will reduce the difficulties subjects might have 
with acute or sub-acute reactions. The potential for destabilizing psychological distress 
will be minimized by: 
 
• Excluding people who might be more vulnerable to it (such as people diagnosed 
with bipolar affective disorder-1 or with psychotic disorders). 
• Preparatory non-drug psychotherapy sessions before the experimental session. 
• Creating an atmosphere of trust during the experimental session. 
• Close monitoring. 
• Daily contact with subjects for the period of a week after the experimental session 
• Providing non-drug integrative psychotherapy sessions. 
• Subjects will remain at the study site for the night of each experimental session to 
further reduce psychological distress. Qualified personnel will be available during 
the overnight stay to respond to the needs of the subject. Attendants will be 
instructed to contact the therapists upon request or at the appearance of signs of a 
potential serious adverse event.  
 
During the preparatory sessions, subjects will be made aware of the fact that difficult 
emotions, including grief, rage and fear or panic, may arise during experimental sessions. 
Every effort will be made to help subjects resolve difficult symptoms and to arrive at a 
more comfortable and relaxed state by the conclusion of the experimental session, 
including empathic listening on the part of the therapists and performance of 
diaphragmatic breathing by subjects.  
 
At the end of the six to eight hour experimental session, if the subject is still severely 
agitated or experiencing any other severe psychological distress, the following measures 
will be taken:  
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 66 of 83 
 
 
• If the subject is anxious, agitated, in danger of any self-harm or is suicidal at the 
end of the experimental session, one or both of the therapists will remain with the 
subject for at least two more hours. During this time, the therapists will employ 
affect management techniques, will talk with the subject to help him or her gain 
cognitive perspective of their experiences, and will help them implement the self- 
soothing and stress inoculation techniques presented during the preparatory 
session. If this situation should occur during an integrative therapy session, at 
least one of the therapists will be available to stay (in person or on the phone if 
the visit is a phone visit) with the subject for at least two additional hours. 
• If a subject remains severely anxious, agitated or in danger of self-harm or 
suicide, or is otherwise psychologically unstable at the end of this two-hour 
stabilization period, the Investigator or Sub-Investigator will decide between the 
following options: 
1. A psychiatric nurse, therapeutic assistant, physician, or therapist will stay with 
the subject until the time of his or her appointment with the therapists the next 
day. The therapists will then meet with the subject daily until the period of 
destabilization has passed.  
2. If a subject experiences severe, persisting emotional distress, such as panic 
attacks, severe generalized anxiety, or insomnia following an MDMA session, 
the Investigator or Sub-Investigator may prescribe a rescue medication such as 
a benzodiazepine, zolpidem or other anxiolytic or sedative according to the 
physician's clinical judgment. This medication will be captured on the 
concomitant medications CRF page. The physician should not prescribe an 
SSRI, SNRI or MAOI in this context unless it has been determined that the 
subject will be withdrawn from the study. Residual symptoms will be 
addressed during the frequent follow-up psychotherapy visits with the 
therapists. 
3. Hospitalization for stabilization. If a subject should become psychotic 
arrangements will be made to stabilize them and transfer them to the ED if 
necessary. 
 
Subjects hospitalized after a severe panic reaction will be suspended from the protocol 
until after recovery or stabilization, at which time the Investigator or Sub-Investigator 
will carefully evaluate the subject’s emotional status.   
 
For those subjects engaged in an ongoing therapeutic relationship with a psychotherapist 
or psychiatrist, the subject’s outside therapists will be involved in the management of any 
psychiatric complications. For those subjects engaged in an ongoing psychotherapeutic 
relationship with the Investigator or Sub-Investigator, the management of any psychiatric 
complications will be undertaken by them in their capacity as therapists.   
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 67 of 83 
 
 
16.2.3 Body Temperature 
 
MDMA administered in a controlled setting produces only a slight increase in body 
temperature [124] and ambient temperature does not enhance or attenuate this slight 
elevation in humans [75].   
 
If temperature rises more than 1°C, attempts will be made to lower it by removing 
blankets and layers of clothing, decreasing the ambient temperature and, if necessary, 
directing a fan toward the subject. If at any time the temperature rises more than 1.5°C 
above baseline despite these efforts, the Investigator or Sub-Investigator will be consulted 
for further evaluation and treatment.   
 
16.2.4 Reproductive and Developmental Risks 
 
Risks posed by MDMA to pregnant women are not known. One of two studies of Ecstasy 
users suggests that use of Ecstasy and other drugs during pregnancy may be associated 
with some abnormalities at birth while the other failed to find this association [175, 176],  
and a third reported some developmental delays in mothers reporting use of ecstasy and 
other drugs during pregnancy [177].   
 
Pregnant and lactating women will be excluded from participation in the study, and 
women who are able to become pregnant must have a negative pregnancy screen before 
undergoing each experimental session and must agree to use birth control for the 
treatment portion of the study. 
 
16.2.5 Potential Neurotoxicity Associated with Ecstasy Use 
 
Some researchers believe that MDMA is neurotoxic in humans even at doses used in 
clinical trials [178].  However, they are basing their case on studies that employed 
inappropriately high doses of MDMA utilized in animal studies, and on human studies 
comparing the effects of repeated use of ecstasy, often along with other drugs. 
Meanwhile, another recently published meta-analysis has taken careful steps to overcome 
methodological limitations in previous work, and found only modest evidence of 
neurotoxicity [179]. 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.  
 
16.3 Abuse Liability 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 68 of 83 
 
 
 
Findings in humans and animals suggests that MDMA possesses moderate abuse 
potential that is higher than that reported for “classic hallucinogens” like psilocybin, but 
lower than that reported for psychostimulants such as cocaine or methamphetamine. 
More information on abuse liability is provided in the IB. 
 
Whether MDMA-assisted psychotherapy will cause PTSD patients to develop symptoms 
of abuse is an open question that the sponsor is addressing on an ongoing basis. Based on 
long-term follow-up data from two sponsor-supported studies (N=32), only one subject 
took Ecstasy after completing the study and failed to reproduce the experience from the 
study, and a number of subjects volunteered that they would never seek out Ecstasy 
outside a legal, controlled, therapeutic setting. In addition, negative results from MDMA-
specific drug testing data obtained from the Swiss study MP-2 (N=12) supports that none 
of these subjects took Ecstasy outside of the study during the long-term follow-up period.   
 
Diversion is not an issue in this protocol because MDMA will only be administered a few 
times under the supervision of the Investigator or Sub-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. 
 
16.4 Risks and Discomforts of Receiving the Comparator Dose of Study Drug 
 
Receiving the comparator dose of 0mg MDMA may be associated with less reduction in 
anxiety and a smaller drop in PTSD symptoms than after full dose MDMA. The 
comparator is not expected to produce the therapeutic effects of MDMA. However, it is 
notable participants receiving placebo in the first sponsor-supported study exhibited some 
reduction in PTSD symptoms after undergoing two experimental sessions [77, 180].  The 
comparator dose of MDMA is not expected to produce most or all of the potentially 
therapeutic effects of the drug, such as increased positive mood, facilitated recall, 
changed perception of meaning, and increased feelings of closeness to others. All 
participants receiving the comparator may enroll in Stage 2 and receive active doses of 
MDMA. 
 
17.0 Alternative Treatments and Procedures 
 
The alternative to participating in the research study is to decide not to take part in the 
study. The decision not to participate in this research study will not in any way alter or 
compromise the care offered to individuals receiving therapy from the Investigator or 
Sub-Investigator or any physician involved in this research study.   
  
The Investigator or Sub-Investigator will discuss alternatives to study participation, 
including other available treatments, with all potential subjects. There are a number of 
recognized treatments for PTSD. Treatment often includes both psychotherapy and 
medication. Most commonly recommended psychotherapeutic treatments for PTSD 
include anxiety management (stress inoculation training), cognitive therapy, exposure 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 69 of 83 
 
 
therapy, and psychoeducation. Psychodynamic psychotherapy and Eye Movement 
Desensitization and Reprocessing are also used to treat PTSD. 
 
Drugs available in Canada for treating PTSD include paroxetine, and in the US, sertraline 
and paroxetine are approved for use in treatment of PTSD. Sertraline has been shown to 
decrease the hyperarousal and avoidance symptoms, but not the re-experiencing 
symptoms, of PTSD. Paroxetine has been shown to have an effect on all three categories 
of symptoms in approximately 62% of patients. Other medications commonly used are 
other SSRIs, nefazedone, venlafaxine, tricyclic antidepressants, benzodiazepines, 
buspirone, zolpidem, and mood stabilizers. 
 
18.0 Confidentiality 
 
Every effort will be made to strictly safeguard the confidentiality of subjects in their role 
as research subjects. Removing identifying information from data and restricting access 
to researchers directly involved in assessing the subjects should prevent the dissemination 
of confidential data, with or without identifying information. Except for the screening 
log, the ICF, and a subject contact information sheet that will be stored separately from 
other documents, all data will be identified only by the subject’s secondary identifier 
number on the source document and five-digit subject number.  If past medical records 
are needed, subjects will sign forms for the release of information upon consent to permit 
screening for protocol enrollment.  
 
All psychotherapy sessions and the 12-month follow-up may be recorded to video and 
audio. In addition the CAPS assessment may also be recorded to audio and video to 
establish inter-rater reliability. These recordings will be used for manual development 
and potentially for training therapists to perform MDMA-assisted psychotherapy. They 
are intended to record the events occurring during therapy, and will not serve as outcome 
measures. Full names and addresses will not appear in these recordings. Audio and video 
recordings will only be marked with the subject’s subject number. Video data will be 
stored on a HIPA-compliant remote server with encryption and authentication in place to 
ensure confidentiality. Study subjects will only be able to view their own video data by 
logging in to a secure HIPA-compliant server. Only HIPA-certified researchers who have 
signed a Data Confidentiality Agreement, completed Good Clinical Practice training, and 
received approval from the Investigator  will be permitted to access video data for 
research and training purposes.  
 
Any materials mailed to subjects will be sent along with stamped return envelopes using 
the office address of the Investigator  both as main and return address. All assessment 
records will be kept in a locked file drawer or cabinet in a locked office, and access to 
measures will be limited to regulatory agencies, researchers, and individuals analyzing 
data. Researchers, other than the Investigator or Sub-Investigator directly involved in the 
protocol, with access to data will not be provided with any information that would 
identify subjects by name or by other means, such as social security number.  
 
 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 70 of 83 
 
 
19.0 Costs to Subjects 
 
There will be no costs to subjects for any study-related procedures. Only Canadian 
residents with Canadian health insurance will be enrolled in the study. The sponsor 
(MAPS) will pay for all assessments, laboratory work, or physical examinations needed 
to determine study eligibility. The sponsor will also cover costs of the study drug and 
remaining at the study site on the night after each experimental session. The sponsor will 
pay for all study drugs and study procedures. The sponsor will not reimburse subjects for 
travel, food, and lodging.  Subjects will not be paid for their participation in this study. 
 
Charges for treatment of the subject’s condition that are unrelated to the research study or 
any of its procedures will continue to be billed to the health insurance provider of the 
subject or to the subject him or herself. It is anticipated that there will not be any charges 
for treatment that is unrelated to the study except in the case of subjects who previously 
received therapy from the Investigator or Sub-Investigator and who will continue to 
receive ongoing treatment that is not related to participating in the study.   
 
20.0 Record Retention 
 
The Investigator must retain all study records required by MAPS and by the applicable 
regulations in a secure and safe facility for 25 years in accordance with Health Canada 
regulations. The Investigator must consult a MAPS representative 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. It is the responsibility of the sponsor to inform the Investigator as to when 
these documents no longer need to be retained. 
 
21.0 Publication Policy 
 
The sponsor recognizes the importance of communicating medical study data and 
therefore encourages publications in reputable scientific journals and presentations at 
seminars or conferences. It is understood by the Investigator 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 Investigator and Sub-Investigator are 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 Investigator 
or Sub-Investigator 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 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 71 of 83 
 
 
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. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 72 of 83 
 
 
22.0 References 
 
1. 
Oehen, P., et al., A randomized, controlled pilot study of MDMA (+/- 3,4-
Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of 
resistant, chronic Post-Traumatic Stress Disorder (PTSD). J Psychopharmacol, 
2013. 27(1): p. 40-52. 
2. 
Mithoefer, M.T., et al., MDMA-Assisted Psychotherapy for the Treatment of 
Posttraumatic Stress Disorder: A Revised Teaching Manual Draft. . 2011, MAPS. 
3. 
Mithoefer, M.C., et al., Durability of improvement in post-traumatic stress 
disorder symptoms and absence of harmful effects or drug dependency after 3,4-
methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-
term follow-up study. J Psychopharmacol, 2013. 27(1): p. 28-39. 
4. 
American Psychiatric Association, Diagnostic and Statistical manual of Mental 
Disorders: 4th Edition. 4th ed. 2000, Arlington, VA.: American Psychiatric 
Association. 
5. 
Foa, E.B., et al., Effective Treatments for PTSD, Practice Guidelines from the 
International Society for Traumatic Stress Studies. Second ed. 2009, New York, 
NY: Guilford Press. 
6. 
Kessler, R.C., et al., Lifetime prevalence and age-of-onset distributions of DSM-
IV disorders in the National Comorbidity Survey Replication. Arch Gen 
Psychiatry, 2005. 62(6): p. 593-602. 
7. 
Perkonigg, A., et al., Traumatic events and post-traumatic stress disorder in the 
community: prevalence, risk factors and comorbidity. Acta Psychiatr Scand, 
2000. 101(1): p. 46-59. 
8. 
Kessler, R.C., et al., Prevalence, severity, and comorbidity of 12-month DSM-IV 
disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry, 
2005. 62(6): p. 617-27. 
9. 
Breslau, N., The epidemiology of posttraumatic stress disorder: what is the extent 
of the problem? J Clin Psychiatry, 2001. 62 Suppl 17: p. 16-22. 
10. 
Frayne, S.M., et al., Burden of medical illness in women with depression and 
posttraumatic stress disorder. Arch Intern Med, 2004. 164(12): p. 1306-12. 
11. 
Norris, F.H., et al., Epidemiology of trauma and posttraumatic stress disorder in 
Mexico. J Abnorm Psychol, 2003. 112(4): p. 646-56. 
12. 
Zlotnick, C., et al., Epidemiology of trauma, post-traumatic stress disorder 
(PTSD) and co-morbid disorders in Chile. Psychol Med, 2006. 36(11): p. 1523-
33. 
13. 
Alonso, J., et al., Prevalence of mental disorders in Europe: results from the 
European Study of the Epidemiology of Mental Disorders (ESEMeD) project. 
Acta Psychiatr Scand Suppl, 2004(420): p. 21-7. 
14. 
Weine, S.M., et al., Psychiatric consequences of "ethnic cleansing": clinical 
assessments and trauma testimonies of newly resettled Bosnian refugees. Am J 
Psychiatry, 1995. 152(4): p. 536-42. 
15. 
Hoge, C.W., et al., Combat duty in Iraq and Afghanistan, mental health problems, 
and barriers to care. N Engl J Med, 2004. 351(1): p. 13-22. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 73 of 83 
 
 
16. 
Tanielian, T.L., L. Jaycox, and Rand Corporation., Invisible wounds of war : 
psychological and cognitive injuries, their consequences, and services to assist 
recovery. 2008, Santa Monica, CA: RAND. xliii, 453 p. 
17. 
de Jong, J.T., I.H. Komproe, and M. Van Ommeren, Common mental disorders in 
postconflict settings. Lancet, 2003. 361(9375): p. 2128-30. 
18. 
Thabet, A.A. and P. Vostanis, Post-traumatic stress reactions in children of war. 
J Child Psychol Psychiatry, 1999. 40(3): p. 385-91. 
19. 
Perkonigg, A., et al., Longitudinal course of posttraumatic stress disorder and 
posttraumatic stress disorder symptoms in a community sample of adolescents 
and young adults. Am J Psychiatry, 2005. 162(7): p. 1320-7. 
20. 
Frise, S., et al., Psychiatric disorders and use of mental health services by Ontario 
women. Can J Psychiatry, 2002. 47(9): p. 849-56. 
21. 
Richardson, J.D., J.A. Naifeh, and J.D. Elhai, Posttraumatic stress disorder and 
associated risk factors in Canadian peacekeeping veterans with health-related 
disabilities. Can J Psychiatry, 2007. 52(8): p. 510-8. 
22. 
Breslau, N. and G.C. Davis, Posttraumatic stress disorder in an urban population 
of young adults: risk factors for chronicity. Am J Psychiatry, 1992. 149(5): p. 
671-5. 
23. 
Seal, K.H., et al., VA mental health services utilization in Iraq and Afghanistan 
veterans in the first year of receiving new mental health diagnoses. J Trauma 
Stress, 2010. 23(1): p. 5-16. 
24. 
Brady, K.T., T.S. Charney, and J.R.T. Davidson, Current Issues in the 
Management of Posttraumatic Stress Disorder. 2000, Littleton, CO.: Medical 
Education Resources. 
25. 
Montgomery, S. and P. Bech, ECNP consensus meeting, March 5-6, 1999, Nice. 
Post traumatic stress disorder: guidelines for investigating efficacy of 
pharmacological intervention. ECNP and ECST. Eur Neuropsychopharmacol, 
2000. 10(4): p. 297-303. 
26. 
Brady, K., et al., Efficacy and safety of sertraline treatment of posttraumatic 
stress disorder: a randomized controlled trial. JAMA, 2000. 283(14): p. 1837-44. 
27. 
Marshall, R.D., et al., Efficacy and safety of paroxetine treatment for chronic 
PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry, 2001. 158(12): p. 
1982-8. 
28. 
Hamner, M.B., S. Robert, and B.C. Frueh, Treatment-resistant posttraumatic 
stress disorder: strategies for intervention. CNS Spectr, 2004. 9(10): p. 740-52. 
29. 
Ferguson, J.M., SSRI Antidepressant Medications: Adverse Effects and 
Tolerability. Prim Care Companion J Clin Psychiatry, 2001. 3(1): p. 22-27. 
30. 
Cassano, P. and M. Fava, Tolerability issues during long-term treatment with 
antidepressants. Ann Clin Psychiatry, 2004. 16(1): p. 15-25. 
31. 
Bradley, R., et al., A multidimensional meta-analysis of psychotherapy for PTSD. 
Am J Psychiatry, 2005. 162(2): p. 214-27. 
32. 
Foa, E.B., et al., A comparison of exposure therapy, stress inoculation training, 
and their combination for reducing posttraumatic stress disorder in female 
assault victims. J Consult Clin Psychol, 1999. 67(2): p. 194-200. 
33. 
Resick, P.A. and M.K. Schnicke, Cognitive processing therapy for sexual assault 
victims. J Consult Clin Psychol, 1992. 60(5): p. 748-56. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 74 of 83 
 
 
34. 
Kessler, R.C., et al., Posttraumatic stress disorder in the National Comorbidity 
Survey. Arch Gen Psychiatry, 1995. 52(12): p. 1048-60. 
35. 
Resick, P.A., et al., A comparison of cognitive-processing therapy with prolonged 
exposure and a waiting condition for the treatment of chronic posttraumatic 
stress disorder in female rape victims. J Consult Clin Psychol, 2002. 70(4): p. 
867-79. 
36. 
Friedman, M.J., et al., Randomized, double-blind comparison of sertraline and 
placebo for posttraumatic stress disorder in a Department of Veterans Affairs 
setting. J Clin Psychiatry, 2007. 68(5): p. 711-20. 
37. 
Foa, E.B., Psychosocial therapy for posttraumatic stress disorder. J Clin 
Psychiatry, 2006. 67 Suppl 2: p. 40-5. 
38. 
Schnurr, P.P., et al., Cognitive behavioral therapy for posttraumatic stress 
disorder in women: a randomized controlled trial. Jama, 2007. 297(8): p. 820-30. 
39. 
Rauch, S.A., et al., Changes in reported physical health symptoms and social 
function with prolonged exposure therapy for chronic posttraumatic stress 
disorder. Depress Anxiety, 2009. 26(8): p. 732-8. 
40. 
Hogberg, G., et al., Treatment of post-traumatic stress disorder with eye 
movement desensitization and reprocessing: outcome is stable in 35-month 
follow-up. Psychiatry Res, 2008. 159(1-2): p. 101-8. 
41. 
Ursano, R.J., et al., Practice guideline for the treatment of patients with acute 
stress disorder and posttraumatic stress disorder. Am J Psychiatry, 2004. 161(11 
Suppl): p. 3-31. 
42. 
Benish, S.G., Z.E. Imel, and B.E. Wampold, The relative efficacy of bona fide 
psychotherapies for treating post-traumatic stress disorder: a meta-analysis of 
direct comparisons. Clin Psychol Rev, 2008. 28(5): p. 746-58. 
43. 
Cukor, J., et al., Emerging treatments for PTSD. Clin Psychol Rev, 2009. 29(8): p. 
715-26. 
44. 
Basoglu, M., E. Salcioglu, and M. Livanou, A randomized controlled study of 
single-session behavioural treatment of earthquake-related post-traumatic stress 
disorder using an earthquake simulator. Psychol Med, 2007. 37(2): p. 203-13. 
45. 
Gerardi, M., et al., Virtual reality exposure therapy using a virtual Iraq: case 
report. J Trauma Stress, 2008. 21(2): p. 209-13. 
46. 
McLay, R.N., et al., A randomized, controlled trial of virtual reality-graded 
exposure therapy for post-traumatic stress disorder in active duty service 
members with combat-related post-traumatic stress disorder. Cyberpsychol 
Behav Soc Netw, 2011. 14(4): p. 223-9. 
47. 
Rothbaum, B.O., A.S. Rizzo, and J. Difede, Virtual reality exposure therapy for 
combat-related posttraumatic stress disorder. Ann N Y Acad Sci, 2010. 1208: p. 
126-32. 
48. 
Heresco-Levy, U., et al., Pilot-controlled trial of D-cycloserine for the treatment 
of post-traumatic stress disorder. Int J Neuropsychopharmacol, 2002. 5(4): p. 
301-7. 
49. 
Freudenmann, R.W., F. Oxler, and S. Bernschneider-Reif, The origin of MDMA 
(ecstasy) revisited: the true story reconstructed from the original documents. 
Addiction, 2006. 101(9): p. 1241-5. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 75 of 83 
 
 
50. 
Shulgin, A.T., The background and chemistry of MDMA. J Psychoactive Drugs, 
1986. 18(4): p. 291-304. 
51. 
Farre, M., et al., Pharmacological interaction between 3,4-
methylenedioxymethamphetamine (ecstasy) and paroxetine: pharmacological 
effects and pharmacokinetics. J Pharmacol Exp Ther, 2007. 323(3): p. 954-62. 
52. 
Liechti, M.E. and F.X. Vollenweider, The serotonin uptake inhibitor citalopram 
reduces acute cardiovascular and vegetative effects of 3,4-
methylenedioxymethamphetamine ('Ecstasy') in healthy volunteers. J 
Psychopharmacol, 2000. 14(3): p. 269-74. 
53. 
Liechti, M.E. and F.X. Vollenweider, Which neuroreceptors mediate the 
subjective effects of MDMA in humans? A summary of mechanistic studies. Hum 
Psychopharmacol, 2001. 16(8): p. 589-598. 
54. 
Tancer, M. and C.E. Johanson, The effects of fluoxetine on the subjective and 
physiological effects of 3,4-methylenedioxymethamphetamine (MDMA) in 
humans. Psychopharmacology (Berl), 2007. 189(4): p. 565-73. 
55. 
Hysek, C.M., et al., The norepinephrine transporter inhibitor reboxetine reduces 
stimulant effects of MDMA ("ecstasy") in humans. Clin Pharmacol Ther, 2011. 
90(2): p. 246-55. 
56. 
Liechti, M.E. and F.X. Vollenweider, Acute psychological and physiological 
effects of MDMA ("Ecstasy") after haloperidol pretreatment in healthy humans. 
Eur Neuropsychopharmacol, 2000. 10(4): p. 289-95. 
57. 
Gamma, A., et al., 3,4-Methylenedioxymethamphetamine (MDMA) modulates 
cortical and limbic brain activity as measured by [H(2)(15)O]-PET in healthy 
humans. Neuropsychopharmacology, 2000. 23(4): p. 388-95. 
58. 
Bedi, G., et al., Effects of MDMA on sociability and neural response to social 
threat and social reward. Psychopharmacology (Berl), 2009. 207(1): p. 73-83. 
59. 
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. 
60. 
Andari, E., et al., Oxytocin's Fingerprint in Personality Traits and Regional Brain 
Volume. Cereb Cortex, 2012. 
61. 
Adolphs, R., D. Tranel, and T.W. Buchanan, Amygdala damage impairs 
emotional memory for gist but not details of complex stimuli. Nat Neurosci, 2005. 
8(4): p. 512-8. 
62. 
Bartz, J.A. and E. Hollander, The neuroscience of affiliation: forging links 
between basic and clinical research on neuropeptides and social behavior. Horm 
Behav, 2006. 50(4): p. 518-28. 
63. 
da Costa, J.L. and A.A. da Matta Chasin, Determination of MDMA, MDEA and 
MDA in urine by high performance liquid chromatography with fluorescence 
detection. J Chromatogr B Analyt Technol Biomed Life Sci, 2004. 811(1): p. 41-
5. 
64. 
Domes, G., et al., Oxytocin Attenuates Amygdala Responses to Emotional Faces 
Regardless of Valence. Biol Psychiatry, 2007. 
65. 
Domes, G., et al., Oxytocin improves "mind-reading" in humans. Biol Psychiatry, 
2007. 61(6): p. 731-3. 
66. 
Kosfeld, M., et al., Oxytocin increases trust in humans. Nature, 2005. 435(7042): 
p. 673-6. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 76 of 83 
 
 
67. 
Wolff, K., et al., Vasopressin and oxytocin secretion in response to the 
consumption of ecstasy in a clubbing population. J Psychopharmacol, 2006. 
20(3): p. 400-10. 
68. 
Dumont, G.J., et al., Increased oxytocin concentrations and prosocial feelings in 
humans after ecstasy (3,4-methylenedioxymethamphetamine) administration. Soc 
Neurosci, 2009. 4(4): p. 359-66. 
69. 
Hysek, C.M., G. Domes, and M.E. Liechti, MDMA enhances "mind reading" of 
positive emotions and impairs "mind reading" of negative emotions. 
Psychopharmacology (Berl), 2012. 222(2): p. 293-302. 
70. 
Doblin, R., A clinical plan for MDMA (Ecstasy) in the treatment of posttraumatic 
stress disorder (PTSD): partnering with the FDA. J Psychoactive Drugs, 2002. 
34(2): p. 185-94. 
71. 
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. 
72. 
Harris, D.S., et al., Subjective and hormonal effects of 3,4-
methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology 
(Berl), 2002. 162(4): p. 396-405. 
73. 
Bedi, G., N.T. Van Dam, and J. Redman, Ecstasy (MDMA) and high prevalence 
psychiatric symptomatology: somatic anxiety symptoms are associated with 
polydrug, not ecstasy, use. J Psychopharmacol, 2010. 24(2): p. 233-40. 
74. 
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. 
75. 
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. 
76. 
Bosker, W.M., et al., Dose-related effects of MDMA on psychomotor function and 
mood before, during, and after a night of sleep loss. Psychopharmacology (Berl), 
2010. 209(1): p. 69-76. 
77. 
Mithoefer, M.C., et al., The safety and efficacy of {+/-}3,4-
methylenedioxymethamphetamine-assisted psychotherapy in subjects with 
chronic, treatment-resistant posttraumatic stress disorder: the first randomized 
controlled pilot study. J Psychopharmacol, 2011. 25(4): p. 439-52. 
78. 
Bouso, J.C., MDMA/PTSD research in Spain: An update. MAPS Bulletin, 2003. 
13(1): p. 7-8. 
79. 
de la Torre, R., et al., Pharmacology of MDMA in humans. Ann N Y Acad Sci, 
2000. 914: p. 225-37. 
80. 
de la Torre, R., et al., MDMA (ecstasy) pharmacokinetics in a CYP2D6 poor 
metaboliser and in nine CYP2D6 extensive metabolisers. Eur J Clin Pharmacol, 
2005. 61(7): p. 551-4. 
81. 
Downing, J., The psychological and physiological effects of MDMA on normal 
volunteers. J Psychoactive Drugs, 1986. 18(4): p. 335-40. 
82. 
Dumont, G.J., et al., Ethanol co-administration moderates 3,4-
methylenedioxymethamphetamine effects on human physiology. J 
Psychopharmacol, 2010. 24(2): p. 165-74. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 77 of 83 
 
 
83. 
Farre, M., et al., Repeated doses administration of MDMA in humans: 
pharmacological effects and pharmacokinetics. Psychopharmacology (Berl), 
2004. 173(3-4): p. 364-75. 
84. 
Studerus, E., A. Gamma, and F.X. Vollenweider, Psychometric evaluation of the 
altered states of consciousness rating scale (OAV). PLoS One, 2010. 5(8): p. 
e12412. 
85. 
Kirkpatrick, M.G., et al., A direct comparison of the behavioral and physiological 
effects of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) 
in humans. Psychopharmacology (Berl), 2012. 219(1): p. 109-22. 
86. 
Pacifici, R., et al., Cell-mediated immune response in MDMA users after repeated 
dose administration: studies in controlled versus noncontrolled settings. Ann N Y 
Acad Sci, 2002. 965: p. 421-33. 
87. 
Parrott, A.C., et al., MDMA and methamphetamine: some paradoxical negative 
and positive mood changes in an acute dose laboratory study. 
Psychopharmacology (Berl), 2011. 215(3): p. 527-36. 
88. 
Baggott, M.J., et al., 3,4-Methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) 
and Prazosin Interactions in Humans., in 70th Annual Meeting of the College on 
Problems of Drug Dependence. 2008: San Juan, Puerto Rico. 
89. 
van Wel, J.H., et al., Blockade of 5-HT(2) Receptor Selectively Prevents MDMA-
Induced Verbal Memory Impairment. Neuropsychopharmacology, 2011. 36(9): p. 
1932-9. 
90. 
Veldstra, J.L., et al., Effects of alcohol (BAC 0.5 per thousand) and ecstasy 
(MDMA 100 mg) on simulated driving performance and traffic safety. 
Psychopharmacology (Berl), 2012. 222(3): p. 377-90. 
91. 
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. 
92. 
Tancer, M.E. and C.E. Johanson, The subjective effects of MDMA and mCPP in 
moderate MDMA users. Drug Alcohol Depend, 2001. 65(1): p. 97-101. 
93. 
Chang, L., et al., Effect of ecstasy [3,4-methylenedioxymethamphetamine 
(MDMA)] on cerebral blood flow: a co-registered SPECT and MRI study. 
Psychiatry Res, 2000. 98(1): p. 15-28. 
94. 
Ramaekers, J.G., et al., Involvement of inferior parietal lobules in prospective 
memory impairment during acute MDMA (ecstasy) intoxication: an event-related 
fMRI study. Neuropsychopharmacology, 2009. 34(7): p. 1641-8. 
95. 
Randall, S., et al., Effects of acute 3,4-methylenedioxymethamphetamine on sleep 
and daytime sleepiness in MDMA users: a preliminary study. Sleep, 2009. 32(11): 
p. 1513-9. 
96. 
Ramaekers, J.G., K.P. Kuypers, and N. Samyn, Stimulant effects of 3,4-
methylenedioxymethamphetamine (MDMA) 75 mg and methylphenidate 20 mg on 
actual driving during intoxication and withdrawal. Addiction, 2006. 101(11): p. 
1614-21. 
97. 
Ramaekers, J.G. and K.P. Kuypers, Acute effects of 3,4-
methylenedioxymethamphetamine (MDMA) on behavioral measures of 
impulsivity: alone and in combination with alcohol. Neuropsychopharmacology, 
2006. 31(5): p. 1048-55. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 78 of 83 
 
 
98. 
Yubero-Lahoz, S., et al., Changes in CYP1A2 activity in humans after 3,4-
methylenedioxymethamphetamine (MDMA, Ecstasy) administration using caffeine 
as probe drug. Drug Metab Pharmacokinet, 2012. 
99. 
O'Mathuna, B., et al., The consequences of 3,4-methylenedioxymethamphetamine 
induced CYP2D6 inhibition in humans. J Clin Psychopharmacol, 2008. 28(5): p. 
523-9. 
100. 
Kuypers, K.P., et al., MDMA intoxication and verbal memory performance: a 
placebo-controlled pharmaco-MRI study. J Psychopharmacol, 2011. 25(8): p. 
1053-61. 
101. 
Kuypers, K.P., et al., Inhibition of MDMA-induced increase in cortisol does not 
prevent acute impairment of verbal memory. Br J Pharmacol, 2013. 168(3): p. 
607-17. 
102. 
Hernandez-Lopez, C., et al., 3,4-Methylenedioxymethamphetamine (ecstasy) and 
alcohol interactions in humans: psychomotor performance, subjective effects, and 
pharmacokinetics. J Pharmacol Exp Ther, 2002. 300(1): p. 236-44. 
103. 
Bedi, G., D. Hyman, and H. de Wit, Is ecstasy an "empathogen"? Effects of +/-
3,4-methylenedioxymethamphetamine on prosocial feelings and identification of 
emotional states in others. Biol Psychiatry, 2010. 68(12): p. 1134-40. 
104. 
Lawton, G., A real fMRI high: My ecstasy brain scan, in New Scientist. 2012. p. 
11. 
105. 
Peiro, A.M., et al., Human pharmacology of 3,4-
methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 2 
h apart. Psychopharmacology (Berl), 2013. 225(4): p. 883-93. 
106. 
Hysek, C., et al., Carvedilol inhibits the cardiostimulant and thermogenic effects 
of MDMA in humans. Br J Pharmacol, 2012. 166(8): p. 2277-88. 
107. 
Wardle, M.C., C.G. Frye, and H. De Wit, MDMA buffers against cues of social 
rejection, in 51st Annual Meeting of the American College of 
Neuropsychopharmacology. 2012: Hollywood, FL. 
108. 
Pardo-Lozano, R., et al., Clinical Pharmacology of 3,4-
Methylenedioxymethamphetamine (MDMA, "Ecstasy"): The Influence of Gender 
and Genetics (CYP2D6, COMT, 5-HTT). PLoS One, 2012. 7(10): p. e47599. 
109. 
Bouso, J.C., et al., MDMA-assisted psychotherapy using low doses in a small 
sample of women with chronic posttraumatic stress disorder. J Psychoactive 
Drugs, 2008. 40(3): p. 225-36. 
110. 
Greer, G.R. and R. Tolbert, A method of conducting therapeutic sessions with 
MDMA. J Psychoactive Drugs, 1998. 30(4): p. 371-379. 
111. 
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. 
112. 
Naranjo, C., Experience with the interpersonal psychedelics., in Ecstasy, a 
Complete Guide: A Comprehensive Look at the Risks and Benefits of MDMA., J. 
Holland, Editor. 2001, Inner Traditions: Rochester, VT. p. 208-221. 
113. 
Stolaroff, M., The Secret Chief Revealed: Conversations with a pioneer of the 
underground therapy movement. 2004, Sarasota FL: Multidisciplinary 
Association for Psychedelic Studies. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 79 of 83 
 
 
114. 
Adamson, S., Through the gateway of the heart: Accounts of experiences  With 
MDMA and other empathogenic substances. 1985, San Francisco CA: Four Trees 
Publications. 
115. 
d'Otalora, M. MDMA and LSD Therapy in the Treatment of Post Traumatic Stress 
Disorder in a Case of Sexual Abuse. .  2004  [cited 2004; Available from: 
http://www.maps.org/research/mdma/moaccount.html. 
116. 
Saunders, N., E for Ecstasy. 1993, London: Neal's Yard. 
117. 
Huizink, A.C., et al., Symptoms of anxiety and depression in childhood and use of 
MDMA: prospective, population based study. Bmj, 2006. 332(7545): p. 825-8. 
118. 
Lieb, R., et al., Mental disorders in ecstasy users: a prospective-longitudinal 
investigation. Drug Alcohol Depend, 2002. 68(2): p. 195-207. 
119. 
von Sydow, K., et al., Use, abuse and dependence of ecstasy and related drugs in 
adolescents and young adults-a transient phenomenon? Results from a 
longitudinal community study. Drug Alcohol Depend, 2002. 66(2): p. 147-59. 
120. 
Foa, E.B., Prolonged exposure therapy for PTSD: emotional processing of 
traumatic experiences: therapist guide. 2007, New York: Oxford University 
Press. 
121. 
Wilbarger, P. and J. Wilbarger, Sensory defensiveness and related 
social/emotional and neurological problems. 1997, Van Nuys, CA.: Avanti 
Education Program. 
122. 
Siegel, D.J., The Developing Mind. 1999, New York: Guilford Press. 
123. 
Ogden, P., K. Minton, and C. Pain, Trauma and the body: A sensorimotor 
approach to Psychotherapy. New York. 2006, W. W. Norton and Company. 
124. 
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. 
125. 
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. 
126. 
de la Torre, R., et al., Non-linear pharmacokinetics of MDMA ('ecstasy') in 
humans. Br J Clin Pharmacol, 2000. 49(2): p. 104-9. 
127. 
Grob, C., Unpublished data on human study of psychological and physiological 
effects of MDMA. 2001. 
128. 
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. 
129. 
Blake, D.D., et al., A clinician rating scale for assessing current and lifetime 
PTSD: the CAPS-1. . Behav Ther, 1990. 13: p. 187-188. 
130. 
Nagy, L.M., et al., Open prospective trial of fluoxetine for posttraumatic stress 
disorder. J Clin Psychopharmacol, 1993. 13(2): p. 107-13. 
131. 
Foa, E.B., et al., The validation of a self-report measure of posttraumatic stress 
disorder: The Posttraumatic Diagnostic Scale. Psychological Assessment., 1997. 
9: p. 445–451. 
132. 
Tedeschi, R.G. and L.G. Calhoun, The Posttraumatic Growth Inventory: 
measuring the positive legacy of trauma. J Trauma Stress, 1996. 9(3): p. 455-71. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 80 of 83 
 
 
133. 
Tedeschi, R.G. and L.G. Calhoun, Expert comparisons; Posttraumatic growth in 
clinical practice, in Handbook of posttraumatic growth: Research and practice, 
L.G. Calhoun and R.G. Tedeschi, Editors. 2006, Erlbaum: Mahwah, NJ. p. 291-
310. 
134. 
Beck, A.T. and C.H. Ward, Dreams of depressed patients. Characteristic themes 
in manifest content. Arch Gen Psychiatry, 1961. 5: p. 462-7. 
135. 
Beck, A.T. and R.A. Steer, Internal consistencies of the original and revised Beck 
Depression Inventory. J Clin Psychol, 1984. 40(6): p. 1365-7. 
136. 
Beck, A.T., et al., Comparison of Beck Depression Inventories -IA and -II in 
psychiatric outpatients. J Pers Assess, 1996. 67(3): p. 588-97. 
137. 
Costa, P.T. and R.R. Macrae, The NEO personality inventory manual. 1985, 
Odessa, FL: Psychological Assessment Resources. 
138. 
Costa, P.T. and R.R. Macrae, NEO PI-R professional manual. 1992, Odessa, FL: 
Psychological Assessment Resources. 
139. 
Buysse, D.J., et al., The Pittsburgh Sleep Quality Index: a new instrument for 
psychiatric practice and research. Psychiatry Res, 1989. 28(2): p. 193-213. 
140. 
Backhaus, J., et al., Test-retest reliability and validity of the Pittsburgh Sleep 
Quality Index in primary insomnia. J Psychosom Res, 2002. 53(3): p. 737-40. 
141. 
Carpenter, J.S. and M.A. Andrykowski, Psychometric evaluation of the 
Pittsburgh Sleep Quality Index. J Psychosom Res, 1998. 45(1 Spec No): p. 5-13. 
142. 
Bernstein, E.M. and F.W. Putnam, Development, reliability, and validity of a 
dissociation scale. J Nerv Ment Dis, 1986. 174(12): p. 727-35. 
143. 
Carlson, E.B. and F.w. Putnam, An Update on the Dissociative Experiences Scale. 
Dissociation, 1993. 6(1): p. 16-27. 
144. 
Frischholz, E.J., et al., The Dissociative Experiences Scale: Further replication 
and validation. Dissociation, 1990. 3(3): p. 151-153. 
145. 
Karatzias, T., et al., Posttraumatic symptomatology and dissociation in 
outpatients with chronic posttraumatic stress disorder. J Trauma Dissociation, 
2010. 11(1): p. 83-92. 
146. 
Posner, K., et al., Columbia Classification Algorithm of Suicide Assessment (C-
CASA): classification of suicidal events in the FDA's pediatric suicidal risk 
analysis of antidepressants. Am J Psychiatry, 2007. 164(7): p. 1035-43. 
147. 
Posner, K., et al., The Columbia-Suicide Severity Rating Scale: initial validity and 
internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry, 2011. 168(12): p. 1266-77. 
148. 
Randolph, C., Repeatable Battery for the Assessment of Neuropsychological 
Status manual. 1998, San Antonio, TX: The Psychological Corporation. 
149. 
Carlozzi, N.E., et al., Factor analysis of the Repeatable Battery for the 
Assessment of Neuropsychological Status. Appl Neuropsychol, 2008. 15(4): p. 
274-9. 
150. 
King, L.C., et al., Is the repeatable battery for the assessment of 
neuropsychological status factor structure appropriate for inpatient psychiatry? 
An exploratory and higher-order analysis. Arch Clin Neuropsychol, 2012. 27(7): 
p. 756-65. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 81 of 83 
 
 
151. 
Randolph, C., et al., The Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp 
Neuropsychol, 1998. 20(3): p. 310-9. 
152. 
Wilk, C.M., et al., Test-retest stability of the Repeatable Battery for the 
Assessment of Neuropsychological Status in schizophrenia. Am J Psychiatry, 
2002. 159(5): p. 838-44. 
153. 
Duff, K., et al., Test-retest stability and practice effects of the RBANS in a 
community dwelling elderly sample. J Clin Exp Neuropsychol, 2005. 27(5): p. 
565-75. 
154. 
Jansen, C.E., et al., A prospective longitudinal study of chemotherapy-induced 
cognitive changes in breast cancer patients. Support Care Cancer, 2011. 19(10): 
p. 1647-56. 
155. 
Gronwall, D.M., Paced auditory serial-addition task: a measure of recovery from 
concussion. Percept Mot Skills, 1977. 44(2): p. 367-73. 
156. 
Tombaugh, T.N., A comprehensive review of the Paced Auditory Serial Addition 
Test (PASAT). Arch Clin Neuropsychol, 2006. 21(1): p. 53-76. 
157. 
McCaffrey, R.J., H.J. Westervelt, and R.F. Haase, Serial neuropsychological 
assessment with the National Institute of Mental Health (NIMH) AIDS 
Abbreviated Neuropsychological Battery. Arch Clin Neuropsychol, 2001. 16(1): 
p. 9-18. 
158. 
Crawford, J.R., M.C. Obonsawin, and K.M. Allan, PASAT and components 
ofWAIS-R performance: Convergent and discriminant validity. 
Neuropsychological Rehabilitation, 1998. 8: p. 255-272. 
159. 
Adamchic, I., et al., Psychometric evaluation of visual analog scale for the 
assessment of chronic tinnitus. Am J Audiol, 2012. 21(2): p. 215-25. 
160. 
De Ridder, D., et al., Phantom percepts: tinnitus and pain as persisting aversive 
memory networks. Proc Natl Acad Sci U S A, 2011. 108(20): p. 8075-80. 
161. 
Myles, P.S., et al., The pain visual analog scale: is it linear or nonlinear? Anesth 
Analg, 1999. 89(6): p. 1517-20. 
162. 
Fagelson, M.A., The association between tinnitus and posttraumatic stress 
disorder. Am J Audiol, 2007. 16(2): p. 107-17. 
163. 
Moeller-Bertram, T., J. Keltner, and I.A. Strigo, Pain and post traumatic stress 
disorder - review of clinical and experimental evidence. Neuropharmacology, 
2012. 62(2): p. 586-97. 
164. 
McLean, S.A., et al., The development of persistent pain and psychological 
morbidity after motor vehicle collision: integrating the potential role of stress 
response systems into a biopsychosocial model. Psychosom Med, 2005. 67(5): p. 
783-90. 
165. 
Griffiths, R.R., et al., Psilocybin can occasion mystical-type experiences having 
substantial and sustained personal meaning and spiritual significance. 
Psychopharmacology (Berl), 2006. 187(3): p. 268-83; discussion 284-92. 
166. 
Pahnke, W.N., Psychedelic drugs and mystical experience. Int Psychiatry Clin, 
1969. 5(4): p. 149-62. 
167. 
Newman, E., et al., Empirically supported ethical research practice: the costs and 
benefits of research from the participants' view. Account Res, 2001. 8(4): p. 309-
29. 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 82 of 83 
 
 
168. 
Lenth, R.V. Java Applets for Power and Sample Size (Computer software).  2006  
[cited 2012 June]; Software allowing computation of power under various 
circumstances; uses online Java programs on site. 
http://www.stat.uiowa.edu/~rlenth/Power]. Available from: 
http://www.stat.uiowa.edu/~rlenth/Power. 
169. 
Dumont, G.J. and R.J. Verkes, A review of acute effects of 3,4-
methylenedioxymethamphetamine in healthy volunteers. J Psychopharmacol, 
2006. 20(2): p. 176-87. 
170. 
Vollenweider, F.X., et al., Psychological and cardiovascular effects and short-
term sequelae of MDMA ("ecstasy") in MDMA-naive healthy volunteers. 
Neuropsychopharmacology, 1998. 19(4): p. 241-51. 
171. 
Kuypers, K.P. and J.G. Ramaekers, Transient memory impairment after acute 
dose of 75mg 3.4-Methylene-dioxymethamphetamine. J Psychopharmacol, 2005. 
19(6): p. 633-9. 
172. 
Practice advisory: thrombolytic therapy for acute ischemic stroke--summary 
statement. Report of the Quality Standards Subcommittee of the American 
Academy of Neurology. Neurology, 1996. 47(3): p. 835-9. 
173. 
Adams, H.P., Jr., et al., Guidelines for the early management of adults with 
ischemic stroke: a guideline from the American Heart Association/American 
Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular 
Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular 
Disease and Quality of Care Outcomes in Research Interdisciplinary Working 
Groups: the American Academy of Neurology affirms the value of this guideline 
as an educational tool for neurologists. Stroke, 2007. 38(5): p. 1655-711. 
174. 
Ryan, T.J., et al., 1999 update: ACC/AHA guidelines for the management of 
patients with acute myocardial infarction. A report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines 
(Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol, 
1999. 34(3): p. 890-911. 
175. 
McElhatton, P.R., et al., Congenital anomalies after prenatal ecstasy exposure 
[letter]. Lancet, 1999. 354(9188): p. 1441-2. 
176. 
Bateman, D.N., et al., A case control study to examine the pharmacological 
factors underlying ventricular septal defects in the North of England. Eur J Clin 
Pharmacol, 2004. 60(9): p. 635-41. 
177. 
Singer, L.T., et al., Neurobehavioral outcomes of infants exposed to MDMA 
(Ecstasy) and other recreational drugs during pregnancy. Neurotoxicol Teratol, 
2012. 34(3): p. 303-10. 
178. 
McCann, U.D. and G.A. Ricaurte, Caveat emptor: editors beware. 
Neuropsychopharmacology, 2001. 24(3): p. 333-6. 
179. 
Rogers, G., et al., The harmful health effects of recreational ecstasy: a systematic 
review of observational evidence. Health Technol Assess, 2009. 13(6): p. iii-iv, 
ix-xii, 1-315. 
180. 
Mithoefer, M.C., et al., Safety, Efficacy and Durability of MDMA-Assisted 
Psychotherapy in Subjects with Chronic, Treatment-Resistant Posttraumatic 
Stress Disorder: Completed and Ongoing Randomized, Controlled, Triple-blind 

MAPS Study MP-4 
 
Amendment 2 Version 3 
Canada 
 
   June 20, 2014   
 
 
 
Page 83 of 83 
 
 
Phase 2 Pilot Studies, in Military medical research across the continuum of care. 
2012: Fort Lauderdale, FL.