Conditions: Social Anxiety in Autistic Adults
Keywords: MDMA autism social anxiety
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 12
Healthy volunteers: no

Brief summary:
The goal of this clinical trial is to learn if MDMA-assisted therapy is safe and effective at reducing social anxiety in adults with autism.

The main questions it aims to answer are:

* Do two sessions of MDMA-assisted therapy reduce social anxiety?
* What dose of MDMA is most effective at reducing social anxiety?

Researchers will compare two blinded sessions of MDMA-assisted therapy to two blinded sessions of placebo with therapy.

Participants will undergo three non-drug preparatory therapy sessions before the first blinded medication session. After each medication session, participants will undergo three non-drug integrative therapy sessions.

In Stage 2, participants who received placebo with therapy in the first two blinded sessions will be able to undergo two sessions with MDMA-assisted therapy.

Detailed description:
The main objective of this study was to collect safety data to examine whether MDMA-assisted therapy was tolerated and to estimate symptom reduction in social anxiety and other psychiatric symptoms that are common in the adult autistic population as evaluated by standard clinical measures. The primary outcome measure was change in social anxiety symptoms as measured by the Liebowitz Social Anxiety Scale (LSAS) \[Heimberg et al., 1999\].

Each of the 12 subjects participated in two blinded experimental sessions, with either MDMA or placebo, which lasted seven hours. Before experimental sessions, participants underwent three separate hour-long preparatory sessions to learn what to expect and complete pre-treatment assignments. After each experimental session, participants underwent three separate hour-long integrative sessions to help integrate their experiences and insights from the experimental sessions.

This study was designed as a dose escalation study to assist with the exploration of safety and finding the most effective dose in this population. Upon enrollment, participants (Group 1) were randomized to receive one dose of either placebo or 75 mg of midomafetamine HCl. In the second experimental session one month later, Group 1 subjects randomized to MDMA escalated to 100 mg of midomafetamine HCl, unless contraindicated. The second group of subjects enrolled (Group 2) were randomized to receive one dose of either placebo or 100 mg of midomafetamine HCl. In the second experimental session one month later, Group 2 subjects randomized to MDMA escalated to 125 mg of midomafetamine HCl, unless contraindicated.

The blind was maintained through the six-month follow-up. In Stage 2 after the blind was broken, subjects who received placebo in Stage 1 were offered an open-label extension with two experimental sessions of MDMA-assisted therapy scheduled one month apart. Subjects received 75 mg of midomafetamine HCl in the first session and escalated to 125 mg of midomafetamine HCl in the second session, unless contraindicated.

Arms:
arm 1: Participants will receive inactive placebo during two psychotherapy sessions lasting approximately 7 hours. arm 2: Participants will receive 75 mg and 100 mg midomafetamine HCl during two sessions of MDMA-assisted therapy, respectively, lasting approximately 7 hours. arm 3: Participants will receive 100 mg and 125 mg midomafetamine HCl during two sessions of MDMA-assisted therapy, respectively, lasting approximately 7 hours.

Interventions: intervention 1: Placebo intervention 2: Midomafetamine HCl intervention 3: Therapy
Intervention descriptions: intervention 1: Subjects will receive capsules of lactose of identical appearance to MDMA capsules during each of two experimental sessions. Capsules will be administered along with therapy. intervention 2: Participants in Group 1 receive 75 or 100 mg during the two experimental sessions and participants in Group 2 receive 100 or 125 mg during two experimental sessions. intervention 3: Therapy conducted throughout experimental sessions. Therapists will use a largely nondirective approach. There will be periods of structured and unstructured interactions. The structured interactions will be selected based on elements of therapeutic interventions that are currently in use in this population for the treatment of social anxiety.

Protocol document:
Prot_002.pdf: 
PROTOCOL MAA-1 
IND #63,384 
 
Original Protocol Version 1: February 22, 2013 
Original Protocol Version 2: May 21, 2013 
A Placebo-controlled, Randomized, Blinded, Dose Finding Phase 2 Pilot Safety Study of MDMA-
assisted Therapy for Social Anxiety in Autistic Adults 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone number for trial related emergencies: 650-248-4647 
SPONSOR  
Multidisciplinary Association for Psychedelic Studies (MAPS) 
1215 Mission Street 
Santa Cruz, CA 95060 
Phone: 831-429-6362 
SPONSOR DESIGNEE 
Amy Emerson 
MAPS Director of Clinical Research 
Phone number: 510-393-7224 
PRINCIPAL 
INVESTIGATOR 
 
 
 
 
Charles S. Grob, M.D. 
Harbor-UCLA Medical Center 
 
Phone number: 310-222-3112 
CO-INVESTIGATOR 
Alicia Danforth, Ph.D. Candidate 
Harbor-UCLA Medical Center 
CO-INVESTIGATOR 
Karen J. Parker, Ph.D. 
Stanford University School of Medicine 
Department of Psychiatry and Behavioral Sciences 
CO-INVESTIGATOR 
Dean S. Carson, Ph.D. 
Stanford University School of Medicine 
Department of Psychiatry and Behavioral Sciences 
MEDICAL MONITOR 
Michael C. Mithoefer, M.D. 
Phone number: 843-849-6899 
DATA SAFETY 
MONITOR 
Ira M. Lesser, M.D. 
Harbor-UCLA Medical Center 
Phone number: 310-222-3137 
STUDY MONITOR 
Berra Yazar-Klosinski, Ph.D. 
Lead Clinical Research Associate 
Phone number: 831-429-6362 ext. 104 
Fax number: 831-429-6370 


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Table of Contents 
 
1.0 LIST OF ABBREVIATIONS ................................................................................................................ 4 
2.0 INTRODUCTION, BACKGROUND, AND RATIONALE ............................................................... 6 
2.1 INTRODUCTION ..................................................................................................................................... 6 
2.2 BACKGROUND ...................................................................................................................................... 6 
2.3 PROTOCOL PURPOSE ............................................................................................................................12 
2.4 RATIONALE OF DOSE SELECTION .........................................................................................................13 
3.0 PROTOCOL OBJECTIVES ................................................................................................................14 
3.1 PRIMARY OBJECTIVE: ..........................................................................................................................14 
3.2 SECONDARY OBJECTIVES: ...................................................................................................................14 
3.3 SAFETY OBJECTIVES: ...........................................................................................................................15 
4.0 PROTOCOL DESIGN ..........................................................................................................................16 
4.1 PLANNED DURATION OF STUDY ..........................................................................................................18 
4.2 RECRUITMENT AND SUBJECT POPULATION ..........................................................................................21 
5.0 METHODS .............................................................................................................................................23 
5.1 MEASURES ...........................................................................................................................................23 
5.2 STUDY PROCEDURES AND VISIT DESCRIPTIONS ..................................................................................28 
5.3 RANDOMIZATION AND SUBJECT NUMBERING ......................................................................................39 
5.4 REMOVAL OF SUBJECTS FROM THE STUDY ..........................................................................................39 
5.5 PREMATURE DISCONTINUATION OF THE STUDY ..................................................................................40 
6.0 INVESTIGATIONAL PRODUCT ......................................................................................................40 
6.1 DESCRIPTION OF ACTIVE COMPOUNDS ................................................................................................40 
6.2 PREPARATION AND ADMINISTRATION .................................................................................................40 
6.3 DRUG ACCOUNTABILITY .....................................................................................................................42 
6.4 DRUG STORAGE AND HANDLING .........................................................................................................42 
6.5 STABILITY ...........................................................................................................................................42 
7.0 RISKS OF PARTICIPATION .............................................................................................................43 
7.1 RISKS AND DISCOMFORTS ASSOCIATED WITH NON-DRUG AND EXPERIMENTAL SESSIONS AND 
ASSESSMENT OF MEASURES ......................................................................................................................43 
7.2 RISKS OF RECEIVING MDMA ..............................................................................................................43 
7.3 ABUSE LIABILITY ................................................................................................................................49 
8.0 ADVERSE EVENTS .............................................................................................................................49 
8.1 ADVERSE EVENTS ................................................................................................................................49 
8.2 SPONTANEOUSLY REPORTED REACTIONS ............................................................................................50 
8.3 SERIOUS ADVERSE EVENTS .................................................................................................................50 
8.4 MEDICAL EMERGENCIES ......................................................................................................................51 
8.5 ADVERSE EVENT COLLECTION ............................................................................................................51 
8.6 MEDICAL MONITOR .............................................................................................................................52 
9.0 CONCOMITANT MEDICATIONS AND TAPERING INSTRUCTIONS .....................................53 
10.0 CLINICAL LABORATORY ASSESSMENTS ................................................................................54 
10.1 SCREENING ASSESSMENTS .................................................................................................................54 
10.2 BIOMARKER ANALYSIS ......................................................................................................................56 
11.0 STUDY MONITORING, AUDITING, AND DOCUMENTATION ...............................................56 
12.0 DATA ANALYSIS ...............................................................................................................................57 


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12.1 STATISTICAL POWER .........................................................................................................................59 
13.0 ETHICS ................................................................................................................................................60 
14.0 INFORMED CONSENT .....................................................................................................................60 
15.0 CONFIDENTIALITY .........................................................................................................................61 
16.0 COSTS TO SUBJECTS ......................................................................................................................61 
17.0 TREATMENT AND COMPENSATION FOR STUDY RELATED INJURY ..............................62 
18.0 RECORD RETENTION .....................................................................................................................62 
19.0 PUBLICATION POLICY ..................................................................................................................62 
20.0 REFERENCES ....................................................................................................................................62 
 


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1.0 List of Abbreviations 
 
ADOS-2 
Autism Diagnostic Observation Schedule, Second Edition (Module 4) 
AE(s)  
Adverse Event(s) 
A:G 
 
Albumin : Globulin ratio 
ALT/SGPT 
Alanine aminotransferase 
AMI   
Acute Myocardial Infarction 
AS 
 
Asperger’s Syndrome or Disorder 
ASD  
Autism Spectrum Disorder 
AST/SGOT 
Aspartate Aminotransferase 
AVP  
Arginine Vasopressin 
BDI-II  
Beck Depression Inventory II 
BUN  
Blood Urea Nitrogen 
C 
 
Celsius 
CI 
 
Clinical Investigator  
CORT  
Cortisol 
CRA  
Clinical Research Associate 
CRF(s) 
Case Report Form(s) 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DEA  
Drug Enforcement Administration 
DMF  
Drug Master File 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders - IV 
ECG/EKG 
Electrocardiogram 
ED 
 
Emergency Department 
ERQ  
Emotion Regulation Questionnaire 
FDA  
Food and Drug Administration  
GCP  
Good Clinical Practice 
HIPAA  
Health Insurance Portability and Accountability Act 
HIV 
 
Human Immunodeficiency Virus  
HPLC  
High Performance Liquid Chromatography 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
IND 
 
Investigational New Drug  
IR 
 
Independent Rater 
IRB 
 
Institutional Review Board 
IRI 
 
Interpersonal Reactivity Index 
ISF 
 
Investigator Site File 
LSAS  
Liebowitz Social Anxiety Scale 
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 
OT 
 
Oxytocin 


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PDD-NOS 
Pervasive Developmental Disorder – Not Otherwise Specified 
PI 
 
Principal Investigator 
PRN  
As Needed 
PSS 
 
Perceived Stress Scale 
PTCA   
Percutaneous Transluminal Coronary Angioplasty 
PTSD  
Posttraumatic Stress Disorder 
RBC  
Red Blood Cell Count 
RDW  
Red Cell Distribution Width 
RSES  
Rosenberg Self Esteem Scale 
SAE(s) 
Serious Adverse Event(s) 
SCID  
Structured Clinical Interview for Diagnoses Axis I Research Version 
SL 
 
Sublingual 
SNRI  
Selective Serotonin and Norepinephrine Uptake Inhibitor 
SSRI  
Selective Serotonin Reuptake Inhibitor  
STAI  
State-Trait Anxiety Index 
SUD   
Subjective Units of Distress 
TAS-20 
Toronto Alexithymia Scale – 20  
TASIT  
(The) Awareness of Social Inference Test 
TD 
 
Typically Developing 
T3 
 
Triiodothyronine 
T4 
 
Thyroxine 
TSH 
 
Thyroid Stimulating Hormones 
U.S. 
 
United States of America 
WBC   
White Blood Cell Count 


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2.0 Introduction, Background, and Rationale 
 
2.1 Introduction 
The Multidisciplinary Association for Psychedelic Studies (MAPS), a non-profit research 
and educational organization, is proposing a double-blind, randomized, placebo-
controlled exploratory pilot study with dose escalation to assess safety and feasibility of 
3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for social anxiety in 12 
MDMA-naïve adults on the autism spectrum. This study will also obtain estimates of 
effect size based on response to two experimental sessions of MDMA-assisted therapy in 
comparison to an inactive placebo control group in order to properly power subsequent 
investigations. The study will be conducted in association with researchers at Los 
Angeles Biomedical Research Institute (Harbor-UCLA Medical Center, main site) and 
Stanford University Medical Center (collaborating site). The sponsor has ongoing studies 
using MDMA-assisted psychotherapy in the treatment of posttraumatic stress disorder 
(PTSD) that will be used to inform the safety and dosing aspects of this new investigation 
as a potential therapy for social anxiety that could benefit the quality of life of adults on 
the autism spectrum. 
 
Based on the known effects of MDMA, as well as individual reports, the sponsor intends 
to conduct this exploratory study which will focus on enhancing functional skills and 
quality of life in this underserved population, who tend to experience greater anxiety, 
depression and victimization than typically developing (TD) adults. The exploratory 
elements of this study are: group sequential dosing, refinement of the treatment method, 
study endpoints, assessment of clinical response, appropriateness of the chosen measures, 
and biomarker analysis of response to treatment. This study is designed to explore 
treatment-related changes in social anxiety, social perception, and neuromodulators such 
as oxytocin (OT), arginine vasopression (AVP) and cortisol (CORT), that are critically 
involved in anxiety and social behavior. Outcomes from this study, if promising, will 
inform the dose, endpoints and treatment regimen for subsequent studies.  
 
2.2 Background 
 
2.2.1 Autism  
The term autism refers to a spectrum of congenital pervasive developmental disabilities. 
A complex developmental and biopsychosocial condition, autism is characterized by a 
combination of six or more types of behaviors under the following symptom domains in 
the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) [1]: 
 
(A) Qualitative impairment in social interaction;  
(B) Qualitative impairments in communication; 
(C) Restricted repetitive and stereotyped patterns of behavior, interests and activities. 
 
At present, the DSM-IV criteria for Autistic Disorder also apply to varying degrees to 
Asperger’s Disorder (AS) and Pervasive Developmental Disorder – Not Otherwise 
Specified (PDD-NOS). However, individuals with AS do not present with marked 
language or cognitive development delays, motor skills problems (i.e., clumsiness, 


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awkward gait) are more prevalent than with other autistic conditions, and, in the majority 
of cases, intelligence quotient (IQ) scores range from average to superior. However, they 
tend to lack requisite skills for social adaptability among the TD population, such as 
interpreting facial expressions, body language, and subtle nuances of social 
communication such as figures of speech and sarcasm. A major revision of autism 
diagnostic criteria is anticipated in the upcoming 5th edition of the DSM (DSM-V), which 
would eliminate the distinctions between autism categories and combine them under 
Autism Spectrum Disorders (ASD). Therefore, the AS and PDD-NOS diagnostic 
categories may become obsolete prior to completion of this study; thus, in this protocol 
we have chosen to utilize autism or ASD as the diagnostic term in anticipation of the new 
version of the DSM. 
 
AS was first defined in English-language medical literature in 1981[2]. The condition is 
often misdiagnosed or not identified until adolescence or early adulthood, after the period 
when developmentally appropriate social skills would need to be developed. PDD was 
the more common diagnosis utilized for milder forms of autism throughout the 1980s and 
early 1990s, whereas AS was not employed until later. As recently as the 1980s, ASDs 
were considered rare [3]. However, in 2008, the prevalence of ASDs in 8-year-old 
children at 14 Autism and Developmental Disabilities Monitoring Network sites across 
the United States was estimated at one in 88, an increase of 78 percent since 2002 [4]. 
The increase in diagnoses may be due to increased awareness of the diagnostic criteria 
among clinicians, increased public awareness and education, as well as improved 
accuracy in recognizing spectrum disorders in females and minority populations. These 
factors were found to contribute to increases in prevalence estimates, but a true rise in 
cases could not be ruled out. As a result, the Centers for Disease Control and Prevention 
consider escalating prevalence rates of autism in the general population as an urgent 
public health concern. This dramatic rise in prevalence has led some to propose that 
autism is more accurately conceptualized as variations of cognitive differences that have 
always presented in humans as opposed to an epidemic or spectrum of disorders [5]. 
 
Autistic adults often present for treatment of common co-occurring conditions such as 
anxiety, trauma, depression, and social adaptability challenges. However, responses to 
conventional prescription medications developed in TD individuals are often ineffective 
in autistics [6], and difficulties with establishing therapeutic rapport with therapists can 
interfere with conventional psychotherapy [7]. The search for new supportive treatments 
for autistic adults is relevant in the absence of established or effective treatment options.  
 
2.2.2 Social Anxiety and Autism 
 
Social anxiety, also known as social phobia, is characterized by fear of scrutiny and 
avoidance of social interactions. Social anxiety is prevalent [8], begins early [9, 10], and 
follows a chronic course [11]. Impairment is substantial in TD individuals [12] and it 
interferes with ability to work and attend school, as well as developing relationships, 
leading to low quality of life [13, 14]. Social anxiety is differentiated from anxiety 
proneness[15], and is described in the DSM-IV as: 
 


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(A) Marked and persistent fear of one or more social or performance situations in 
which the person is exposed to unfamiliar people or to possible scrutiny by others. 
The individual fears that he or she will act in a way (or show anxiety symptoms) 
that will be humiliating or embarrassing. Note: In children, there must be evidence 
of the capacity for age-appropriate social relationships with familiar people and the 
anxiety must occur in peer settings, not just in interactions with adults. 
(B) Exposure to the feared social situation almost invariably provokes anxiety, 
which may take the form of a situationally bound or situationally predisposed panic 
attack. Note: In children, the anxiety may be expressed by crying, tantrums, 
freezing, or shrinking from social situations with unfamiliar people. 
(C) The person recognizes that the fear is excessive or unreasonable. Note: In 
children, this feature may be absent. 
(D) The feared social or performance situations are avoided or else are endured 
with intense anxiety or distress. 
(E) The avoidance, anxious anticipation, or distress in the feared social or 
performance situation(s) interferes significantly with the person’s normal routine, 
occupational (academic) functioning, or social activities or relationships, or there is 
marked distress about having the phobia. 
(F) In individuals under the age of 18, the duration is at least 6 months.  
(G) The fear or avoidance is not due to the direct physiological effects of a 
substance (e.g., drug abuse, a medication) or a general medical condition and is not 
better accounted for by another mental disorder (e.g., panic disorder with or without 
agoraphobia, separation anxiety disorder, body dysmorphic disorder, a pervasive 
developmental disorder, or schizoid personality disorder). 
(H) If a general medical condition or another mental disorder is present, the fear in 
Criterion A is unrelated to it, e.g., the fear is not of stuttering, trembling in 
Parkinson’s disease, or exhibiting abnormal eating behavior in anorexia nervosa or 
bulimia nervosa. 
Specify if: Generalized: if the fears include most social situations (also consider the 
additional diagnosis of avoidant personality disorder) 
 
Autistic adults who are verbal and whose autism might not be immediately recognizable 
to others often initially present in a clinical setting with symptoms of anxiety or 
depression [16]. Autistic adults are at an increased risk for developing co-morbid anxiety 
and depression as they are faced with increasing amounts of exposure to social situations 
compared to children [2, 17]. Long-term multi-cohort studies following autistic children 
into early adulthood have found that co-morbid behavior and emotional problems remain 
high in adulthood [18]. Comparative studies suggest that autistic adults, especially those 
who are verbal and whose autism might not be immediately recognizable to others and 
who are faced with strong pressure to conform to non-autistic social norms, are at greater 
risk for lifetime and current co-morbid psychological disorders, especially social anxiety 
[19-21]. Social anxiety frequently compounds the considerable social challenges 
experienced by autistic adults [22].  


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There are currently no pharmacologic treatments approved for autistic adults, although 
off-label prescription of selective serotonin reuptake inhibitors (SSRIs) are on the rise in 
this population [23]. The antipsychotics risperidone and aripiprazole are the only 
pharmacologic treatments approved by the FDA for irritability associated with autism in 
children and adolescents. Conventional anti-anxiety medications, including SSRIs, 
monoamine oxidase inhibitors (MAOIs), and benzodiazepines, lack clinical effectiveness 
in autistic adults, potentially due to physiological differences between autistic and TD 
individuals. There is some evidence for a lower number of benzodiazepine binding sites 
in the brains of autistic adults [24]. Although serotonergic dysfunction has been proposed 
as a potential neurobiological basis for autism, efficacy data on SSRIs in the treatment of 
symptoms associated with autism are of varied nature, with some trials finding efficacy 
for global severity and repetitive behaviors [23] and a large multi-site trial finding no 
efficacy for repetitive behaviors [25]. Given the paucity of confirmed efficacy in clinical 
trials and clinical practice, the search for supportive treatments for social anxiety in 
autistic adults is relevant in the absence of established or effective treatment options.  
 
2.2.3 MDMA 
MDMA is a ring-substituted phenylisopropylamine derivative. Chemists at the Merck 
pharmaceutical company first synthesized it in 1912 [26, 27], 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 [28-33].  
In TD healthy volunteers, MDMA administration acutely decreases activity in the left 
amygdala [34], a brain region involved in interpretation of negative cues, and attenuates 
amygdalar response to angry faces [35]. This action of MDMA is compatible with its 
reported reduction in fear of emotional injury or defensiveness [36]. Thus, brain imaging 
after MDMA indicates less reactivity to angry facial expressions and greater reward in 
happy faces [35]. Based on functional brain imaging studies with anxiogenic stimuli in 
autistic individuals, the amygdala may be differentially activated [37] or it may signal in 
an altered manner to the fusiform gyrus, a key brain region for facial recognition, 
resulting in differences in social perception [38]. A recent study in TD healthy volunteers 
found correlations between plasma OT levels, amygdalar volume, and extraverted 
personality [39].  
OT is a neuropeptide associated with pair bonding and social affiliation in mammals that 
also attenuates amygdalar response to anxiogenic stimuli [40, 41]. OT administration is 
associated with increased interpersonal trust and changes in social perception, including 
attenuated reactivity to threatening faces [42-44]. OT administration also improves 
empathic accuracy in some individuals who are shy or lack adequate social skills 
[45]. Alterations in OT signaling have also been proposed as a potential mechanism for 
the underlying neurological basis for the core social differences in autism and has been 
implicated as a possible novel therapy [41]. These claims are now supported by several 
clinical trials of intranasal OT treatment for the core social impairments in autism [46-
49].  
 
MDMA elevates OT in peripheral blood [50-52], which is an imperfect but somewhat 


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reliable indicator of elevated OT in the brain [41]. 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 plasma 
MDMA levels [50]. 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 [51], in addition to a positive association between 
elevated levels of OT and prosocial feelings. Hysek and colleagues replicated these 
results and further 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 
[52]. The effects of MDMA on OT could be partially responsible for changes in 
personality [53] and empathy [54]. However, the multi-level effects of MDMA on 
monoaminergic signaling and OT, combined with a therapeutic setting focused on 
enhancing functional skills, are more likely to provide the opportunity for a corrective 
emotional experience greater than OT alone, and could be useful in the treatment of 
social anxiety in autistic adults. 
In addition to increased OT release, MDMA also results in increased secretion of the 
highly related neuropeptide AVP [50]. AVP neurobiology has been linked to social 
behavior in animal models and has been shown to increase social cognition when 
administered to healthy adult volunteers [46, 55, 56].  
 
Also of interest is the stress-related hormone CORT, the major output of the 
hypothalamic-pituitary-adrenal (HPA) axis. MDMA has also been shown to increase 
CORT levels and it has been proposed that these changes are related to the stimulating 
effects of the drug [57]. In addition to the extensive prosocial behavioral effects of OT 
and AVP, their release has been shown to modulate other neuroendocrine systems, 
particularly the stress responsive activity of the HPA axis, that is dysregulated in 
individuals with social anxiety [58, 59].  
2.2.4 MDMA-Assisted Therapy 
MDMA-assisted therapy 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. The therapeutic method that is most 
appropriate for this population will be adapted from therapy techniques that have been 
empirically developed in adults with an AS diagnosis [7]. The main features of the 
therapy will focus on developing a therapeutic relationship with the subjects that will 
provide a permissive setting to learn and practice social skills.  
 
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 
psychological effects, including: 
 
 Decreased feelings of fear 
 Increased feelings of wellbeing 
 Increased sociability  
 Increased interpersonal trust 


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 Alert state of consciousness 
 Increased awareness of some domains of empathy[36, 60, 61] 
 
Early observers in clinical settings noted increased acceptance of self and others in the 
TD population, increased tolerance of emotionally upsetting materials, and the ability to 
address these issues without extreme disorientation or ego loss [36, 60-64]. 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 [61, 62, 65, 66] before it was placed in Schedule 1 in 1985, as a result of extensive 
non-medical use [36, 64, 67]. Placement in Schedule 1 prohibited it for use, except within 
federally-approved research settings.  
 
As part of her dissertation at the Institute of Transpersonal Psychology, co-investigator 
Alicia Danforth, Ph.D. Candidate, gathered 100 surveys, 90 anecdotal reports, and 
conducted interviews with 24 individuals on the autism spectrum who have taken 
Ecstasy, a street drug purported to contain MDMA, in non-medical settings. A majority 
of these individuals reported the experience to be helpful in their learning to cope more 
effectively in social situations [68]. From a list of commonly reported MDMA effects, 
72% of survey respondents (N=100) reported experiencing “more comfort in social 
settings,” with 12% indicating that the change lasted over two years. 78% of respondents 
reported “feeling at ease in my own body,” with 15% experiencing this effect for over 
two years. 77% reported “easier than usual to talk to others,” with 18% reporting that the 
effect lasted up to a year or longer. These anecdotal reports suggest that MDMA 
may be a suitable pharmacologic agent for the treatment of social anxiety in autistic 
adults and warrants further investigation in a randomized controlled clinical trial. 
 
In contrast to daily administrations of SSRIs, MDMA-assisted therapy consists of only a 
few drug-assisted sessions interspersed within a brief course of non-drug therapy. Thus 
the effects of MDMA are distinct from and go well beyond those of anti-anxiety drugs 
such as SSRIs and benzodiazepines. Furthermore, there is no evidence that MDMA 
creates a physical dependency, as benzodiazepines do. Previous studies of polydrug users 
have found that a small percentage of non-medical, recreational users exhibit problematic 
use of Ecstasy (material represented as containing MDMA, though often the object of 
drug substitution of compounds other than MDMA, including methamphetamine and 
other addictive psychostimulants) [69, 70]. Studies of regular or problematic Ecstasy 
users indicate that on average, regular use occurs no more often than once a week [71]. 
Hence, MDMA may have moderate abuse potential in a subset of individuals. A 
comprehensive review of MDMA research is included in the IB supplied by the sponsor. 
This document should be reviewed prior to initiating the protocol. 
 
2.2.5 Previous Clinical Experience with MDMA 
Classification as a Schedule 1 drug has hampered research into the medical uses of 
MDMA. In recent years, clinical investigation of the safety and effectiveness of MDMA-
assisted therapy has become more feasible due to an open IND with the FDA [72-74]. 
The first double-blind, placebo controlled U.S. Phase 1 study sanctioned by the FDA was 
conducted by the Principal Investigator (PI) of this study at Harbor-UCLA Medical 


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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 
[75]. 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 [51, 75-80]. The elevation in body temperature noted in healthy volunteers 
was not clinically significant in sponsor-supported studies at normal ambient 
temperatures [81, 82]. 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 [28, 31, 35, 36, 52, 54, 75, 76, 79-122].  
 
The potentially therapeutic effects of MDMA were initially investigated in a placebo-
controlled, blinded dose response pilot study funded by MAPS in Spain, in six female 
survivors of sexual assault with treatment-resistant PTSD [101]. 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 [101]. MAPS went on to 
sponsor the first randomized, placebo-controlled Phase 2 pilot study of MDMA-assisted 
psychotherapy for the treatment of chronic, treatment resistant PTSD, which 
demonstrated promising results in a sample of 20 subjects [82]. Findings from the long-
term follow-up of this study indicate that the therapeutic benefits have been sustained 
over time on average, although two subjects experienced a relapse in PTSD symptoms 
[123]. The sponsor also supported a randomized, double-blind pilot study in 12 subjects 
with chronic, treatment-resistant PTSD in Switzerland, which found a trend toward 
significant improvement in subjects receiving full dose MDMA, when compared to a 25 
mg active placebo MDMA, at two-month follow-up. The improvement continued to 
increase during the twelve-month follow-up [81]. These studies have shown promise for 
MDMA-assisted psychotherapy to help people overcome PTSD, an anxiety-related 
disorder, that suggest this treatment could also be useful in treating social anxiety in 
autistic adults. 
 
2.3 Protocol Purpose 
This is a double-blind, randomized, placebo-controlled, dose-finding Phase 2 pilot study 
designed to explore the safety and the therapeutic potential of MDMA-assisted therapy 
for treating social anxiety in 12 MDMA-naïve adults on the autism spectrum. This study 
will provide an estimate of effect size based on response to two experimental sessions of 
MDMA-assisted therapy in autistic adults on measures of safety, social anxiety, social 
perception, and psychiatric symptoms in comparison to a placebo control group. The 
primary outcome measure for the study will be the clinician-administered Liebowitz 
Social Anxiety Scale (LSAS) administered by a blinded Independent Rater (IR). Self-
report measures will correspond to indications that often co-present with autism, 
including anxiety, stress, depression, emotion regulation, alexithymia, differences in 
some empathy domains, and other psychosocial challenges. Subjects will receive ongoing 
social support during the study in the form of non-drug therapy and active involvement of 
a support partner. 
 


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This study will employ biomarker analyses in combination with clinical outcome 
measures to provide useful insights into the underlying mechanism of MDMA's 
psychosocial and anxiolytic effects, and to examine any biological differences to 
treatment responses. The time course of biomarker concentrations will be used to 
determine if MDMA-assisted therapy causes lasting changes in biomarker levels in 
comparison to baseline.  
Each of the 12 subjects will participate in two blinded experimental sessions, assisted by 
either MDMA or placebo, of seven hours in duration within a brief course of non-drug 
therapy, including three hour-long preparatory sessions at the start of the study and three 
hour-long integrative sessions during the month after each experimental session at two 
week intervals. This study is designed as a dose escalation study to assist with the 
exploration of safety and finding the most effective dose in this population. Based on 
anecdotal reports, subjects in this population may be more sensitive to the standard dose 
of 125mg MDMA that has indications of efficacy for PTSD [68]. Subjects assigned to the 
MDMA group will receive two of three different doses, either 75mg, 100mg, or 125mg 
MDMA. Overall, eight subjects (66.7%) will be randomized to the MDMA group and 
four subjects (33.3%) will be randomized to the placebo group. During the study, there 
will be a maximum of 24 experimental sessions with MDMA, with eight sessions in each 
dose group, and eight experimental sessions with placebo. Observations before, during, 
and after experimental sessions will be compared between these groups of equal size to 
explore the effects of MDMA-assisted therapy in the first double-blind, randomized, 
placebo-controlled trial of this treatment for social anxiety in a sample of autistic adults. 
 
2.4 Rationale of Dose Selection 
The MDMA doses of 75mg and 125mg to be used in this study have been used in 
previous and ongoing MAPS-sponsored studies in the U.S., Switzerland, and Israel [81, 
82]. Previous researchers have also used doses within this range up to 225mg [75, 76, 78, 
79, 91, 99, 116, 124-126]. Prior to the scheduling of MDMA, similar doses and regimens 
were used in psychotherapy [36, 62, 64]. Each MDMA dose is expected to produce the 
commonly reported effects of MDMA.  
 
Anecdotal reports suggest a potential for increased sensitivity to the effects of MDMA in 
autistic individuals who experience sensory hyperarousal [68]. Therefore, subjects will 
only receive a single administration of MDMA during experimental sessions, and the 
lower 75 mg and 100 mg doses will be administered to assess for enhanced sensitivity 
during the first experimental session to subjects randomized to MDMA. MDMA subjects 
will only escalate to a 25mg higher dose in the second experimental session that they 
receive one month later. If any subjects within each dose group experience a drug-related 
SAE, the dose escalation procedure will not continue for remaining subjects in the same 
dose group in the interest of subject safety. If this occurs, the institutional Data Safety 
Monitor and Sponsor Medical Monitor will be consulted to determine the course of 
action. Any subject who experiences a drug-related SAE will be excluded from any 
additional experimental sessions, but will continue with non-drug therapy and follow-up 
assessments whenever possible. 


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Table 1. Dose Regimen 
 
3.0 Protocol Objectives 
The main objective of this study is to collect safety data to examine whether MDMA-
assisted therapy will be tolerated and to estimate effect size of symptom reduction in 
social anxiety that is common in the adult autistic population as evaluated by standard 
clinical measures.  
 
3.1 Primary Objective:  
To estimate effect sizes of social anxiety symptom reduction between MDMA and 
placebo, as measured by the clinician-administered LSAS administered by a blinded IR, 
at baseline, one day, two weeks, and one month after each experimental session, and at 6-
month follow-up. 
 
3.2 Secondary Objectives: 
The following objectives will compare MDMA subjects to placebo subjects in Stage 1: 
 To assess effects on levels of OT, AVP, and CORT in peripheral blood at 
baseline, once during each experimental session between hours 2 – 3, one month 
after the second experimental session, and at 6-month follow-up. 
 To assess effects on social perception using The Awareness of Social Inference 
Test (TASIT) at baseline, once during each experimental session between hours 2 
– 3, one month after the second experimental session, and at 6-month follow-up.  
 To assess effects on emotion labeling using the Toronto Alexithymia Scale-20 
(TAS-20) at baseline, one month after each experimental session, and 6-month 
follow-up. 
 To assess effects on emotion regulation using the Emotion Regulation 
Questionnaire (ERQ) at baseline, one month after each experimental session, and 
6-month follow-up. 
 To assess effects on depression symptoms as measured by the Beck Depression 
Inventory-II (BDI-II) at baseline, one day, two weeks, one month after each 
Group # 
/Randomization
/Sample 
Stage 1 
Stage 2 Open-Label Extension 
Session 1 
Month 1 
Session 2 
Month 2 
Session 1 
Month 6 
Session 2 
Month 7 
Group 1 active 
N=4 
75 mg  
100 mg  
N/A 
N/A 
Group 1 placebo 
N=2 
Placebo 
Placebo 
75 mg 
125 mg 
Group2 active 
N=4 
100 mg  
125 mg  
N/A 
N/A 
Group 2 placebo 
N=2 
Placebo 
Placebo 
75 mg 
125 mg 


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experimental session, monthly by mail during the 5 months leading up to the 6-
month follow-up assessment. 
 To assess effects on perceptions of stress as measured by the Perceived Stress 
Scale (PSS) at baseline, within 24 hours after each experimental session, one 
month after each experimental session and monthly by mail leading up to the 6-
month follow-up assessment.  
 To assess effects on four aspects of empathy, as measured by the Interpersonal 
Reactivity Index (IRI) at baseline, within 24 hours after each experimental 
session, one month after each experimental session, and at the 6-month follow-up 
assessment. 
 To assess effects on self-esteem as measured by the Rosenberg Self-Esteem Scale 
(RSES) at baseline, within 24 hours after each experimental session, one month 
after each experimental session, and at the 6-month follow-up assessment.  
 To assess effects on state and trait anxiety as measured by the State-Trait Anxiety 
Index (STAI Form Y) at baseline, one day, two weeks, and one month after each 
experimental session, and monthly by mail leading up to the the 6-month follow-
up assessment.  
 
The following objectives will compare effects in specified subjects: 
 To conduct a within-subject comparison of Stage 1 LSAS outcomes to Stage 2 
open-label LSAS outcomes. 
 To conduct a hierarchical regression analysis using condition assignment in Stage 
1 and TAS-20 scores and OT, AVP, and CORT at baseline as predictors and 
LSAS outcomes as dependent variables. 
 
The following objectives will include exploratory analyses intended to inform protocol 
design: 
 To assess the ability of the investigators and subjects to accurately guess 
condition assignment in Stage 1. 
 To assess perceptions about dose and study procedures at baseline and 6-month 
follow-up using a qualitative interview and feedback questionnaire. 
 To determine feasibility of recruiting, testing and treating subjects on the autism 
spectrum with MDMA-assisted therapy as measured by enrollment rates, dropout 
rates, and completion of assessments and other study-related procedures.  
 
3.3 Safety Objectives: 
 
The safety of subjects will be assured during and after the experimental sessions by 
assessing physiological effects, psychological distress, AEs, spontaneously reported 
reactions and suicidality.  
 Vital signs (BP, HR, temp.) will be measured at baseline and every hour during 
experimental sessions until they return to baseline.   
 Participant distress will be measured by the Subjective Units of Distress (SUD) 
scale at baseline and every hour during experimental sessions until return to 
baseline. 


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 Risk of suicide will be measured by the Columbia Suicide Severity Rating Scale 
(CSSRS) during all in person visits, as well as twice during each experimental 
session at two hours after drug administration and the end of the experimental 
session, and on Day 2 and Day 7 after each experimental session. 
 SAEs and AEs will be assessed throughout the study and spontaneously reported 
reactions, defined as expected AEs, will be assessed during each experimental 
session and for seven days after each experimental session, or until resolution.  
 In addition to spontaneously reported reactions, symptoms specific to the study 
population will be collected at baseline and tracked throughout the study.  
 
4.0 Protocol Design 
Twelve subjects meeting eligibility criteria will be enrolled. Throughout the study, the 
study therapists will maintain communication with the referring physician or therapist 
and any other health care providers requested by the subject. In consultation with their 
prescribing physician, any individuals taking psychiatric medications will taper off these 
medications, allowing for a washout period of at least 5 times the medication and active 
metabolite half-lives plus one week for stabilization before the experimental session. 
During the study, benzodiazepines or atypical antipsychotics may be used to alleviate 
severe distress or panic responses if other interventions are ineffective. Subjects who are 
in psychotherapy with an outside therapist at the time of enrollment may continue that 
therapy during the treatment period without increasing the number or type of sessions or 
changing type of psychotherapy until after the outcome assessment, one month after the 
second experimental session in Stage 1. After the treatment period, subjects may resume 
psychotropic medications and may change therapists or psychotherapy type. 
 
Each of the 12 subjects will participate in two experimental MDMA-assisted therapy 
sessions of seven hours in duration within a brief course of non-drug therapy, including 
three preparatory sessions at the start of the study and three integrative sessions during 
the month after each experimental session. During preparatory sessions, subjects will 
learn what to expect during experimental sessions and complete pre-treatment 
assessments. The second preparatory session will include a comprehensive tour of the 
treatment location and introductions to all available research and support personnel who 
subjects are likely to see during experimental sessions. In-person visits will occur in a 
private room in an outpatient research facility. All in-person sessions after enrollment 
may be video recorded for the purposes of evaluating structural elements of therapy for 
effectiveness and feasibility. Video recordings will be used for research and training 
purposes during and after the study. 
 
Upon enrollment, the first six subjects (Group 1) will be randomized to receive one dose 
of either placebo (N=2) or 75 mg MDMA (N=4). In the second experimental session one 
month later, Group 1 subjects randomized to MDMA will escalate to 100 mg MDMA, 
unless contraindicated by safety and tolerability concerns. The second six subjects 
(Group 2) will be randomized to receive one dose of either placebo (N=2) or 100 mg 
MDMA (N=4). In the second experimental session one month later, Group 2 subjects 
randomized to MDMA will escalate to 125 mg MDMA, unless contraindicated by safety 
and tolerability concerns. Subjects randomized to placebo in Group 1 and Group 2 will 


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receive placebo in both experimental sessions also scheduled one month apart. The blind 
will be maintained through the six-month follow-up for each individual subject, after 
which the blind will be broken. Placebo subjects will be offered an open-label extension 
(Stage 2) with two experimental sessions scheduled one month apart, in addition to three 
hour-long integrative sessions during the month after each experimental session. Stage 2 
subjects will receive 75 mg MDMA in the first experimental session and will escalate to 
125mg MDMA in the second experimental session, unless contraindicated by safety and 
tolerability concerns from other subjects in Stage 1. 
 
During experimental sessions, there will be periods of structured and unstructured 
interactions. The structured interactions will be selected based on elements of therapeutic 
interventions that are currently in use in this population for the treatment of social anxiety 
and to enhance functional skills [7]. The unstructured interactions will include an array of 
therapeutic activities and approaches that would be appropriate for subjects to engage in 
during experimental sessions. All subjects will follow the same schedule of structured 
alternating with unstructured periods but will be able to choose from a selection of 
activities during each unstructured period. Examples include, but are not limited to, 
working with art supplies, listening to preselected music, writing in journals, silent 
introspection, and engaging in rapport-building interactions with researchers.  
 
An overnight stay at a hotel located close to the site will be offered to subjects, 
accompanied by their support partners, if they live further than 30 miles from the site. 
Subjects will attend a 1-hour follow-up integrative therapy session on the day after the 
experimental session. Two additional integrative sessions will be conducted within the 
month following each experimental session, prior to outcome assessments being 
conducted one month after each experimental session. During integrative therapy 
sessions subjects will receive support in integrating their experiences and insights from 
the experimental session. The second experimental session will be scheduled 
approximately one month after the first experimental session, after outcome assessments 
have been completed.  
 
All subjects, even those who have a prior diagnosis, will be clinically evaluated by the PI 
to determine autistic status. In addition, autistic status will be confirmed with the gold-
standard diagnostic measure of autism and diagnosis of co-morbid psychological 
disorders will be conducted according to DSM-IV criteria at screening. Outcome 
measures will be assessed prior to treatment, during the treatment period, one month after 
each experimental session, and during the 6-month follow-up according to the Time and 
Events table. The sponsor will conduct an ongoing review of videos of therapy sessions, 
entry criteria, vital signs, and reaction data for completed sessions and any AEs. The 
sponsor will provide ongoing feedback to the co-therapist teams to ensure subject safety.  
For all subjects blood samples will be obtained for biomarker analysis at baseline and 
during the study according to the Time and Events Table. Biomarker analyses including 
plasma OT, AVP, and CORT will be explored as surrogate endpoints at baseline, two 
hours after drug administration during the second experimental session, one month after 
the second experimental session, and at 6-month follow-up. Blood will be collected 
during the open-label extension Stage 2 two hours after drug administration during both 


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experimental sessions and one month after both experimental sessions. Biomarkers will 
be evaluated for predictive and prognostic power.  
4.1 Planned Duration of Study 
 
 Subjects in Stage 1 and follow-up: 8 months  
 Subjects in Stage 1, follow-up, and Stage 2: 10 months 
 
These lengths of time do not include screening, which may take up to two months. The 
total duration of the study will depend on enrollment rates, but is expected to last at least 
22 months. Any delay between visits would result in a corresponding extension of study 
duration. 
 
 
 


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Table 2. Time & Events Stage 1 
Study Phase 
Baseline Baseline 
Preparatory Sessions 
Experimental 
Session 
Integrative 
Sessions 
Experimental 
Session 
Integrative 
Sessions 
Follow-up 6-Month 
Follow-up 
Visit # 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
(remote) 
V14 
Visit Timing 
 
 
Week 1 Week 2 Week 3 
 
1 day 
later 
2 Wks 
later 
2 Wks 
later 
Appr.1 Month 
after V6  
1 day 
later 
2 Wks 
later 
2 Wks 
later 
Monthly By 
Mail 
6 Months 
after V10 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Psychiatric History & Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Physical Exam (includes neurological) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Clinical Lab Tests, EKG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADOS-2 
 
 H 
 
 
 
 
 
 
 
 
 
 
 
 
 
LSAS 
 
 G, H 
 
 
 
 
 G 
 G 
 G 
 
 G 
 G 
 G 
 
 G 
C-SSRS 
 
 
 
 
 
 A, C, D  
 E 
 
 
 A, C, D 
 E 
 
 
 
 
Feedback Questionnaire, Qualitative Interview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Enrollment if Eligible 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Start Medication Taper (if applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 I 
Collect Serology Samples (OT, AVP, CORT) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record to Video 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Wellbeing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Screen (if applicable), Drug Screen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI-II, STAI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRI, RSES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TASIT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ERQ, TAS-20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QoL-Q  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Drug + Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monitoring of BP, Pulse, and Temperature, SUD 
 
 
 
 
 
 A, B, C 
 
 
 
 A, B, C 
 
 
 
 
 
Belief of Condition Assignment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Integrative Therapy Session 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Start 7 Days Phone Contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spont. Reported Reactions & All Adverse Events 
 
 
 
 
 
 
 F 
 
 
 
 F 
 
 
 
 
Symptoms at Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events Requiring Doctor’s Visit  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events Causing Withdrawal, SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unblinding & Termination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 J 
Approximate Hours for Study Visit 
3 
1.8 
1.5 
1.5 
1.8 
8.0 
1.9 
1.7 
2.1 
8.0 
1.9 
1.7 
2.6 
0 
2.2 
A = At the beginning of the session; B = Approximately every sixty minutes; C = As needed; D = Approximately six hours post drug; E =Day 2 and Day 7 phone calls only; F = Reactions  
collected for seven days post experimental session; G = Independent Rater administered; H = May be recorded to video; I = Stage 2 subjects only; J = Only MDMA subjects will terminate. 


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Table 3. Time & Events Stage 2 
Study Phase 
Experimental 
Session 
Integrative 
Sessions 
Experimental 
Session 
Integrative 
Sessions 
Visit # 
V15 
V16 V17 V18 
V19 
V20 V21 V22 
Visit Timing 
 
1 day 
later 
2 
Wks 
later 
2 
Wks 
later 
Appr.1 Month 
after V15 
1 day 
later 
2 
Wks 
later 
2 
Wks 
later 
LSAS 
 
 G  G  G 
 
 G  G  G 
C-SSRS 
 A, C, D  
 E 
 
 
 A, C, D 
 E 
 
 
Feedback Questionnaire, Qualitative Interview 
 
 
 
 
 
 
 
 
Collect Concomitant Medication 
 
 
 
 
 
 
 
 
End Medication Taper (if applicable) 
 I 
 
 
 
 
 
 
 
Collect Serology Samples (OT, AVP, CORT) 
 
 
 
 
 
 
 
 
Record to Video 
 
 
 
 
 
 
 
 
General Wellbeing 
 
 
 
 
 
 
 
 
Drug Screen 
 
 
 
 
 
 
 
 
Pregnancy Screen (if applicable) 
 
 
 
 
 
 
 
 
BDI-II, STAI 
 
 
 
 
 
 
 
 
PSS 
 
 
 
 
 
 
 
 
IRI, RSES 
 
 
 
 
 
 
 
 
TASIT 
 
 
 
 
 
 
 
 
ERQ, TAS-20 
 
 
 
 
 
 
 
 
Administer Drug + Therapy 
 
 
 
 
 
 
 
 
Monitoring of BP, Pulse, and Temperature, SUD 
 A, B, C 
 
 
 
 A, B, C 
 
 
 
Integrative Therapy Session 
 
 
 
 
 
 
 
 
Start 7 Days Integrative Phone Contact 
 
 
 
 
 
 
 
 
Spont. Reported Reactions & All Adverse Events 
 
 F 
 
 
 
 F 
 
 
Symptoms at Baseline 
 
 
 
 
 
 
 
 
Adverse Events Requiring Doctor’s Visit  
 
 
 
 
 
 
 
 
Adverse Events Causing Withdrawal 
 
 
 
 
 
 
 
 
SAEs 
 
 
 
 
 
 
 
 
Termination 
 
 
 
 
 
 
 
 
Approximate Hours for Study Visit 
8.0 
1.9 1.7 2.1 
8.0 
1.9 1.7 2.7 
A = At the beginning of the session; B = Approximately every sixty minutes; C = As needed; D = Approximately six hours post MDMA; E =Day 2 and Day 7 phone calls only; F = Reactions 
collected for seven days post experimental session; G = Independent Rater administered; H = May be recorded to video; I = At least 5 half-lives and 1 week before the experimental session.


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4.2 Recruitment and Subject Population 
 
Subjects may be male or female, aged 21 or older, with a confirmed diagnosis of autism 
and two years of college-level education or comparable vocational training. Verbal and 
written proficiency in English will be required. Subjects communicating with text-to-
speech technology will also be permitted. Therefore, the researchers anticipate that all 
subjects will have an AS diagnosis or a diagnosis of Autistic Disorder, as defined in the 
DSM-IV, coupled with strong verbal proficiency. Subjects 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 must be MDMA-naïve. Subjects will be asked to confirm that they will 
not take MDMA outside of the context of study participation during the study. Subjects 
will be recruited through printed advertisements, internet advertisements and discussion 
forums, referrals from other psychiatrists, psychotherapists or physicians, and through 
word-of-mouth. 
 
4.2.1 Inclusion Criteria 
 
Individuals eligible to be enrolled into this protocol are subjects who: 
 
1. Be diagnosed with Autism Spectrum Disorder;  
2. Have at least moderate to severe Anxiety;  
3. Have had at least one unsuccessful attempt at treatment for PTSD either with talk 
therapy or with drugs, or discontinuing treatment because of inability to tolerate 
psychotherapy or drug therapy.  
4. Are at least 21 years old;  
5. Have completed two years of college-level education or comparable vocational 
training;  
6. Must be generally healthy;  
7. Must sign a medical release for the investigators to communicate directly with their 
therapist and doctors;  
8. Are willing to refrain from taking any psychiatric medications during the study period;  
9. Willing to follow restrictions and guidelines concerning consumption of food, 
beverages, and nicotine the night before and just prior to each  
experimental session;  


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10. Willing to remain overnight at the study site;  
11. Agree to have transportation other than driving themselves home or to where they are 
staying after the integrative session on the day after the MDMA session;  
12. Are willing to be contacted via telephone for all necessary telephone contacts;  
13. Willing to give blood samples;  
14. Must have a negative pregnancy test if able to bear children, and agree to use an 
effective form of birth control;  
15. Must provide a contact in the event of a participant becoming suicidal;  
16. Are proficient in speaking and reading English;  
17. Agree to have all clinic visit sessions recorded to audio and video  
18. Agree not to participate in any other interventional clinical trials during the duration 
of this study.  
 
4.2.2 Exclusion Criteria 
 
Individuals not eligible to be enrolled into this protocol are those who: 
 
1. Are pregnant or nursing, or if a woman who can have children, those who are not 
practicing an effective means of birth control;  
2. Weigh less than 48 kg;  
3. Are abusing illegal drugs;  
4. Are unable to give adequate informed consent;  
5. Upon review of past and current drugs/medication must not be on or have taken a 
medication that is exclusionary.  
6. Upon review of medical or psychiatric history must not have any current or past 
diagnosis that would be considered a risk to participation in the study.  
 
5.0 Methods 
 


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5.1 Measures 
 
The following diagnostic, outcome, safety, and process measures will be used in the 
study. All therapy sessions, including experimental sessions, may be recorded to audio 
and video, with all recordings preserved for research and training purposes.  
 
5.1.1 Diagnostic Measures 
 
The Autism Diagnostic Observation Schedule, Second Edition (ADOS-2, Module 4) is a 
semi-structured social interaction to assess autism and autism-spectrum disorders in 
adults [127]. It takes 40 to 60 minutes to administer ADOS-2 Module 4. The assessment 
includes a construction task, semi-structured conversation with the assessor, emotional 
and creative responses to cartoons and pictures, describing an unusual event and telling a 
story. The assessment is scored by an algorithm and assessment is made on observation 
of participant nonverbal and verbal behavior, restricted or stereotyped behavior and 
degree of empathy. Most factors of the original Module 4 were reliable, with kappa 
greater than 0.60 and inter-rater reliability was high, from 0.83 for “repetitive /restrictive” 
to 0.93 for “social” [127]. Subsequent specific examination of the measure found that 
Module 4 could reliably detect ASD in adults, and that it could differentiate between 
autism spectrum disorders, psychopathy and typical development [128]. The activities 
used in the ADOS-2 are identical to those used in the original version of the ADOS, but 
instructions have been revised. A certified assessor will administer the ADOS-2 at 
screening to confirm autistic status. 
 
The Structured Clinical Interview for Diagnoses Axis 1 Research Version (SCID-I-RV) 
is a structured interview used to assess and diagnose psychiatric conditions listed in the 
DSM–IV [129]. The interview is designed for use in adults and is suitable for use with 
psychiatric and non-psychiatric populations. The SCID consists of ten modules. Modules 
are based upon the symptoms listed for diagnoses as set out in the DSM-IV. The SCID 
can take from 30 to 90 minutes to perform. The SCID will be used to assess for 
psychological disorders. The PI will administer the SCID once at screening.  
 
5.1.2 Outcome Measures 
 
The primary outcome measure for the study will be the clinician-administered LSAS 
[130]. The LSAS is a 24-item, semi-structured interview on the severity of Social 
Anxiety Disorder, which has been widely used in clinical studies, including research on 
social anxiety in autistic adults [16]. The LSAS separately assesses fear (0 to 3 = none, 
mild, moderate, severe) and avoidance (0 to 3 = never, occasionally, often, usually) of 24 
social situations, providing an overall social anxiety severity rating and subscale scores 
for performance fear, performance avoidance, social fear, and social avoidance.  The 
overall scores are interpreted as: 55-65 moderate, 65-80 marked, 80-95 severe, and 
greater than 95 very severe social anxiety. The LSAS has been shown to have good 
internal consistency (score inter-correlations ranging from 0.81 to 0.96), reliability, 
convergent validity with other measures of anxiety, and sensitivity to treatment response. 
The LSAS was also demonstrated to be sensitive to the effects of pharmacological 


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treatments of social phobia in comparison to placebo and to have convergent validity 
[15]. A qualified blinded IR, who will not be present during experimental sessions, will 
complete the LSAS assessment. Subjects will be instructed not to inform the IR of any 
beliefs they or others have concerning their condition assignment during the assessment.  
 
The BDI-II is a 1996 revision of the BDI, a 21-item self-report measure [131, 132], that 
will serve as a measure of depression according to DSM-IV criteria [133]. The BDI-II 
has been validated, has high internal consistency and good test/re-test reliability, and is 
not overly sensitive to daily variations in mood. It takes five to ten minutes to complete 
[133]. Score cutoffs indicate: 0-13 minimal depression, 14-19 mild depression, 20-28 
moderate depression, and 29-63 severe depression. Higher scores indicate more severe 
depressive symptoms. The BDI-II will be completed according to the Time and Events 
table. 
 
The PSS is a 10-item self-report measure that is widely used in research to assess stress in 
persisting conditions and takes about 1 – 2 minutes to complete. The PSS includes six 
negative items that are intended to assess lack of control and negative affective reactions 
and four positive items that measure the degree of ability to cope with existing stressors. 
Individuals indicate how often they felt or thought a certain way during the last month (0 
= never , 4 = very often). The PSS was correlated with depressive symptomatology and 
social anxiety in TD populations [134]. The PSS will be completed according to the Time 
and Events table. 
 
The IRI assesses four aspects of empathy: social functioning, self-esteem, emotionality, 
and sensitivity to others [135-137]. Empathy is not a discrete emotion. More accurately, 
empathy is a set of constructs. Therefore, the IRI accounts for the fact that each construct 
concerns an individual’s responses to the observed experiences of other people, yet each 
construct is distinctive from the others. The self-report questionnaire includes 28 items 
that are rated on a 5-point, Likert-type scale. The four 7-item subscales include two 
measures of cognitive empathy and two measures of affective empathy. The internal 
reliabilities for the four scales range from .71 to .77, and test-retest reliabilities range 
from .62 to .71 [135]. One study [138] administered the IRI to 21 adults with Asperger’s 
Syndrome and to 21 matched controls. As anticipated, the Asperger’s group scored lower 
on the measures of cognitive empathy, but they scored similarly to controls on the 
Empathic Concern scale, and scored higher than controls on the Personal Distress scale. 
In the absence of an abundance of robust validity testing of empathy assessments with 
adult autistic populations, the IRI provides a good option for a multidimensional 
assessment of empathy factors. The IRI will be completed according to the Time and 
Events table. 
 
The RSES is widely used in clinical research to assess two facets of self-esteem: self-
competence (instrumental value) and self liking (intrinsic value) [139]. The RSES is a 
simple, 10-item scale with five questions for each facet, and it can be completed in 1 – 2 
minutes. In anecdotal accounts, autistic adults have reported increased self-esteem and 
self-competence following MDMA use, attributes that influence anxiety, affective states, 
and interpersonal style. The RSES satisfies tests of item convergent and discriminant 


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validity, internal consistency and reliability, and floor and ceiling effects [140]. 
Cronbach’s α has been shown to be substantial M = 0.81) across cultural contexts [140]. 
The RSES will be completed according to the Time and Events table. 
 
The STAI Form Y is a widely used self-report instrument for assessing anxiety in adults 
that includes separate measures of state and trait anxiety [141, 142]. The STAI evaluates 
the essential qualities of feelings of apprehension, tension, nervousness, and worry. The 
STAI differentiates between the temporary condition of "state anxiety" and the more 
general and long-standing quality of "trait anxiety." The STAI state scale asks for 
feelings at the moment of filling out the questionnaire, and the STAI trait scale asks 
subjects to indicate how they generally view themselves. The proposed study will use the 
20-item trait scale with questions about how respondents generally feel. Response options 
are based on a 4-point Likert-type scale (1=almost never, 2=sometimes, 3=often, 
4=almost always). The STAI will be completed according to the Time and Events table. 
 
The TASIT is an audio-visual test of social perception and emotional expression 
comprehension presented in video vignettes of interpersonal interactions [143]. 
Standardized response probes assess understanding of emotional expression. The 3-part 
test includes The Emotion Evaluation Test, the Social Inference-Minimal, and the Social 
Inference-Enriched test. Each part takes approximately 10 – 15 minutes to complete. The 
TASIT has demonstrated adequate test-retest reliability (range = 0.74 for “Emotional 
Evaluation” to 0.88 for “Social Inference - Minimal”) and high internal consistency α = 
0.71 [144, 145]. The TASIT will be completed according to the Time and Events table. 
 
The ERQ is a brief measure of self-reported emotion-regulation. It consists of ten items 
that is intended to assess means of coping with emotions via changing them, as through 
reappraisal, or suppressing them [146]. Respondents rate indicate the extent of their 
agreement or disagreement with each item by selecting a point on a 7-point Likert scale, 
where 1= strongly disagree and 7 = strongly agree. The ERQ should take four to six 
minutes to complete. Specific items are summed to produce two separate scales, 
Reappraisal and Suppression. The measure is reliable, with Reappraisal obtaining a 
Cronbach’s alpha of 0.79 and Suppression an alpha of 0.73, and test-retest reliability of 
0.69 [146], and scores on the ERQ are correlated with other measures of degree of 
emotional expressivity. Studies in people with Asperger’s or ASD suggest difficulties 
with emotion regulation that include less use of reappraisal and greater numbers of 
negative versus positive emotions [147]. The ERQ will be completed according to the 
Time and Events table. 
 
The TAS-20 is a 20-item measure of self-reported difficulties with recognizing and 
verbalizing emotions[148, 149]. Responses are made on a 5-point Likert scale where 1 = 
strongly disagree and 5 = strongly agree. Estimated time of measurement is 5 to 10 
minutes. The scale is comprised of three subscales; Difficulty Describing Feelings, 
Difficulty Identifying Feelings and Externally-Oriented Thinking, with all scales summed 
to create a total score reflecting presence and degree of alexithymia. The TAS-20 can be 
used diagnostically with a score of 61 or higher indicative of alexithymia. The TAS-20 is 
reliable and has good test-retest reliability (Cronbach’s alpha = 0.81, test-retest of 0.77). 


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It is an established measure of alexithymia. There is some suggestion of an overlap 
between this condition and Asperger’s syndrome, with samples of people with Asperger’s 
syndrome showing greater rates of alexithymia than age and gender-matched controls 
[147, 150]. The TAS-20 will be completed according to the Time and Events table. 
 
The QoL-Q is a 40-item measure of quality of life. It is administered as an interview and 
assesses eight domains [151]. The QoL-Q assesses the following domains; self-
determination, (autonomy and decision-making), social inclusion (acceptance by others 
within the community, supports), material well-being (financial security and 
socioeconomic status), personal development (education, skills and competence), 
emotional well-being (spirituality, happiness, sense of safety) interpersonal relations 
(intimacy, affection, friendship), rights (voting, privacy, legal rights and protections) and 
physical well-being (health, nutrition, mobility).  It is estimated to take between a half 
hour to an hour to complete the QoL-Q. It can be used in diverse populations, including 
autistics and other developmentally disabled people [152, 153]. The measure has 
excellent internal reliability (alpha = 0.90) and strong test-retest reliability (alpha = 0.87). 
The QoL-Q will be completed according to the Time and Events table. 
 
 
5.1.3 Safety Measures 
 
Safety measures will be applied, as described below, to minimize risks associated with 
drug-assisted therapy sessions. The co-therapist or PI 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 integrative telephone calls for seven days. Results of this 
scale are intended to assist therapists in maintaining subject safety throughout the 
treatment period of the study. 
 
The C-SSRS is a clinician-administered measure of suicidal behavior devised to detect 
potential suicidal thoughts or behaviors during a clinical trial [154]. It consists of a 
Baseline form that assesses lifetime suicidal ideation, ideation intensity and behavior, and 
a form for assessing current suicidal ideation and behavior. The C-SSRS consists of a 
series of questions, and can be administered during a face-to-face interview or over the 
telephone. Suicidality will be assessed at Baseline, once during any face-to-face visit, 
during the second and seventh days of integrative telephone contact, and twice during 
each experimental session. Subjects who are discontinuing medication to participate in 
the study will complete the C-SSRS before and after medication washout. The C-SSRS 


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data will be collected on Case Report Forms (CRFs) for all administrations except for the 
second integrative session, unless the therapists observe an increase in suicidality. C-
SSRS data from the second integrative session after each experimental session will be 
kept with the subject’s Source Record. 
 
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 and pulse monitor. Blood pressure and pulse will be 
measured at the outset of the experimental session, once approximately every hour, or as 
needed. More frequent measures will be taken 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. The timing of these measurements will be adjusted so that they do not interfere 
with the therapeutic process.  
 
All AEs and spontaneously reported reactions will be collected, as described in Section 
8.5. AEs and spontaneously reported reactions may be collected during face-to-face visits 
or over the telephone. Common reactions that are spontaneously reported are collected 
for seven days after each experimental session on a separate CRF page and will be 
categorized as mild, moderate, or severe. 
 
As an additional safety and support measure, all subjects will be required to designate a 
family member, close friend, or significant other who knows them well to provide 
ongoing support for the duration of their active participation in the study. Precedence for 
the importance of post-session support has been established in earlier similar studies 
[155]. Responsibilities of the designated support person include: 
 
 Providing reliable transportation, as required, to and from pre- and post-session 
appointments and participating in study visits, as appropriate.  
 Driving the subject home or to another secure location following sessions. No 
participant will be allowed to drive themselves home after experimental sessions.  
 Remaining available to attend to basic comfort needs and to talk with subject in 
person, by phone, or online for 24 hours post-session.  
 
5.1.4 Process Measures 
 
All therapy sessions, including experimental sessions, may be recorded to audio and 
video, with all recordings preserved for research and training purposes.  
 
Belief of condition assignment and certainty will be collected from each therapist 
responsible for treating the subject and the subject at the integrative session on the day 
after each blinded experimental session in Stage 1. These beliefs are collected as a part of 
the sponsor’s ongoing initiative to optimize the blinding of MDMA-assisted therapy.  
 
The Feedback Questionnaire has been developed internally by the sponsor to assess 
perceived benefits and harms of MDMA-assisted therapy, feedback on therapeutic 


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methods, and prior treatments received. The questionnaire will be completed as a self-
report measure and then reviewed with the subject in order to ask follow-on questions 
during a semi-structured qualitative interview, which may be video recorded. This 
questionnaire will be completed at baseline and at the 6-month follow-up visit. 
 
5.2 Study Procedures and Visit Descriptions  
 
5.2.1 Prescreening and Screening 
 
The therapist team for this study will consist of the PI, Charles Grob, M.D., and co-
investigator Alicia Danforth, Ph.D. Candidate, and all study visits will be completed at 
Harbor-UCLA Medical Center. Prospective subjects will be prescreened by telephone or 
email according to an IRB-approved script to learn if they meet basic eligibility criteria. 
All individuals who are prescreened should be assigned a screening number and recorded 
on the Subject Screening Log where information on the selection of potential subjects in 
the trial should be collected.  
 
Upon signing the IRB-approved informed consent form (ICF), the potential subject may 
commence study-related screening activities. The screening number should also be 
recorded on the signed ICF. If a subject is enrolled, the study staff should record the 
enrollment date and assign a subject number. If a subject is not enrolled, an explanation 
should be recorded on the Screening Log. A CRF will not be completed for subjects who 
are not enrolled. These subjects will only be documented on the Screening Log and 
Source Records. It is the responsibility of the PI to file the Screening Log in the 
investigator site file (ISF) to be readily available for on-site monitoring and/or inspection 
by relevant authorities. Screening may take place over more than one day and should be 
complete by up to two months prior to enrollment. If, after reviewing all information, the 
PI concludes that a subject is eligible, they will enroll the subject in the study. Visits will 
be scheduled consecutively, as described in the Time and Events Table.  
 
a. Explain and obtain written informed consent from the subject and Support Partner. 
Written informed consent must be obtained from the subject prior to performing any 
tests or evaluations for the study.  
b. Assign the subject a screening number. Complete the Screening Log.  
c. Review the ability of females of childbearing potential to become pregnant and their 
commitment to practice appropriate birth control, as determined by the PI for the 
treatment period of the study. 
d. Collect perceptions about the study using the Feedback Questionnaire. 
e. Administer C-SSRS to assess suicide risk. 
f. Administer the SCID-I-RV to assess co-morbid psychological disorders. 
g. Administer ADOS-2, Module 4 to confirm autistic status. 
h. A blinded IR will administer the LSAS. 
i. Obtain medical and psychological history by interview. 
j. Collect symptoms at baseline specific to the study population. 
k. Collect information on pre-study and current medications. 


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l. 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 extremities 
 Brief neurological exam (cranial nerves 2-12, sensory, motor, reflexes, and 
cerebellar function) 
 Urine-dip pregnancy test on females with childbearing potential  
 Urinary drug test 
k. Conduct Electrocardiogram (ECG/EKG) 
l. Collect information on phase of menstrual cycle for female subjects. 
m. Collect samples for clinical lab assessments, including: 
 Blood for screening clinical lab assessments (see Section 10.1) 
 Blood for baseline OT,AVP, and CORT analysis  (see Section 10.2) 
 
 
Results of HIV serology will be kept confidential and appropriate referral for counseling 
may be necessary in accordance with state law. The clinical laboratory values will be 
used to establish eligibility and will be kept with the subject’s Source Record. The 
clinical laboratory values will not be captured in the CRF, but will be used to establish 
eligibility and will be kept with the subject’s Source Record. Clinically significant 
abnormal values will be captured as medical history. If, upon examination, there are 
questions raised about possible medical problems, the PI will request a review of subject 
medical records and request additional tests or assessments, as indicated. 
 
5.2.2 Preparatory Sessions and Baseline Measures 
 
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 3 is scheduled but 
the final confirmation will occur at Visit 3. If all inclusion criteria and no exclusion 
criteria are met, eligibility will be confirmed with the subject. 
 Complete a final review of inclusion/exclusion criteria. 
 Assess general wellbeing. 
 Confirm eligibility and willingness to participate in study. 
 Enroll subject and issue subject number. 
 Ensure medical history and medication history is complete. After enrollment new 
events will be collected as AEs and new medications, as described in Section 8.5 
and Section 9.0. 
 Assess status of symptoms at baseline specific to the study population. 
 Discuss medication tapering, if applicable. Upon confirmation of eligibility, the 
PI will consult the prescribing physician to initiate medication tapering for 


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subjects who must refrain from taking a psychiatric medication for the study. 
Tapering will follow a time course appropriate for the medication given its half-
life, with the first experimental session scheduled to occur after complete 
washout.  
 
The subjects will undergo three preparatory sessions lasting approximately sixty minutes 
each with their therapist team, prior to their first experimental session. The first 
preparatory session will take place at Visit 1 after enrollment confirmation. Baseline 
measures will be spread out among preparatory sessions in order to reduce participant 
fatigue from completion of measures. 
 
The therapists will work with the subject to prepare for MDMA-assisted therapy. The 
therapists and subject will seek to form a strong working relationship with each other as 
the therapists help the subject prepare for upcoming experimental sessions. Preparatory 
sessions will promote a safe set and setting for confronting emotions and are intended to 
develop therapeutic alliance.  
 
During preparatory sessions: 
a. Therapists may record all sessions to audio and video. Subjects may access video 
recordings from these sessions upon request via a secure and password protected 
website.  
b. Collect AEs and medications, as described in Section 8.5 and Section 9.0. 
c. Assess status of symptoms at baseline specific to the study population. 
d. 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.  
e. The subject and therapists will discuss goals for the experimental session and will 
review what will happen during the experimental session. 
f. During one of the preparatory sessions, the therapists will introduce the subject to the 
staff at the outpatient research center who they will be most likely to encounter 
before, during, or after treatment sessions.  
g. The Support Partner will meet with the therapists prior to the first experimental 
session to review and confirm their role and responsibilities and sign an ICF 
addendum. There must be mutual agreement between the subject and therapists 
concerning the presence of the Support Partner. 
h. The therapists will administer the C-SSRS just prior to beginning the second 
preparatory session, unless a subject is still undergoing medication washout. Subjects 
still undergoing medication washout will complete the C-SSRS during the second 
preparatory session or at a point after washout is complete prior to the first 
experimental session.  
i. Assess general wellbeing at each preparatory session. 
j. At the end of the first preparatory session, subjects will complete: 
a. BDI-II 
b. STAI  
c. PSS 
d. IRI 


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e. RSES 
k. At the end of the second preparatory session, subjects will complete the TASIT. 
l. The second preparatory session will include a comprehensive tour of the treatment 
location and introductions to all available research and support personnel who 
subjects are likely to see during experimental sessions. 
m. At the end of the third preparatory session, subjects will complete: 
a. ERQ 
b. TAS-20 
c. QoL-Q 
n. During the third and last preparatory session, give the Reminder of Study Rules to the 
subject, which includes instructions and restrictions for conduct prior to receiving the 
drug. Subjects must agree to: 
 Refrain from eating after 24:00 (midnight) the evening before the experimental 
session. 
 Ingest only alcohol-free liquids after 24:00 (midnight) the evening before the 
experimental session.  
 Refrain from the use of any psychoactive drug, with the exception of caffeine or 
nicotine, within 24 hours of each experimental session. 
 Not use caffeine or nicotine for two hours before and six hours after ingesting the 
drug, or until therapists deem it safe to do so. 
5.2.3 Experimental sessions  
Subjects will receive two blinded experimental sessions of therapy assisted by MDMA or 
placebo, scheduled one month apart after integrative sessions are complete. Procedures 
for drug-assisted therapy will remain the same across all sessions. During experimental 
sessions, there will be periods of structured and unstructured interactions. The structured 
interactions will be selected based on elements of therapeutic interventions that are 
currently in use in this population for the treatment of social anxiety. Structured 
interactions during experimental sessions are intended to develop the therapeutic 
relationship between subjects and therapists and to enhance skills of social perception 
through administration of the TASIT. The unstructured interactions will include an array 
of therapeutic activities and approaches that would be appropriate for subjects to engage 
in during experimental sessions. All subjects will follow the same schedule of structured 
alternating with unstructured periods but will be able to choose from a selection of 
activities during each unstructured period. Examples include, but are not limited to, 
working with art supplies, listening to preselected music, writing in journals, silent 
introspection, and engaging in rapport-building interactions with therapists. The 
therapists will create and communicate a setting of safety and support the subject during 
periods of inner focus. Therapists will use a largely nondirective approach. 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 interpersonal contact. Therapists 
will use music to support the experience without being intrusive.  
Table 4. Schedule of Procedures for Experimental Sessions 
Approximate Time 
Procedure or Action 


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Pre-drug: 
a. At least 24 hours prior to the first experimental session the subject will be 
randomized. The PI will obtain the container assignment using a web-based 
randomization program prior to the blinded sessions.  
b. On the day of the experimental session, the subject will arrive approximately one to 
one and a half hours prior to drug administration.  
c. Confirm continuing eligibility by reviewing inclusion/exclusion criteria. 
d. Collect information on phase of menstrual cycle for female subjects. 
e. Perform a urine drug screen. A positive drug screen will be reviewed by the PI 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. 
f. If a woman is of childbearing potential, perform a urine pregnancy test. A positive 
pregnancy screen is cause for withdrawal from the protocol. 
g. If the subject continues to meet criteria and the subject reports that they followed 
appropriate rules and restrictions, the session will proceed. 
h. Review procedures for the experimental session with the subject. 
i. Record the entire session to video and audio. Subjects may review video recordings 
of their experimental sessions upon request. 
j. The session will last for approximately seven hours or longer. 
k. The therapists will administer the C-SSRS prior to drug administration. 
l. Before drug administration, discuss and review the subject’s goals, intentions, and 
concerns and some of the commonly experienced effects of MDMA. 
m. Instruct the subject not to use caffeine or nicotine two hours before or six hours after 
the dose of drug. 
n. Subject body temperature will be measured at baseline prior to administration of the 
9:00  
Urine drug screen and pregnancy test. Subject acclimated to 
environment, C-SSRS 
9:45  
Baseline Blood Pressure (BP), Pulse, SUD 
10:00  
MDMA Administration, begin recording to audio and video 
11:00  
BP, Pulse, SUD, BT 
12:00  
BP, Pulse, BT, SUD, During 2nd exp. session only: Blood draw  
12:15 
Start TASIT (EET, SM-I, SM-E) 
13:00  
BP, Pulse, BT, SUD 
14:00  
BP, Pulse, BT, SUD 
15:00 
BP, Pulse, BT, SUD 
16:00 
BP, Pulse, BT, SUD, C-SSRS, General Wellbeing 
17:00 
BP, Pulse, BT, SUD, End of session  


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initial dose and approximately every hour after that. The therapists may make more 
frequent measurements if body temperature exceeds more than 1oC above baseline. 
o. Subjects will complete the SUD at baseline prior to administration of the initial dose. 
Subjects will complete the SUD every 60 to 90 minutes, until the session is over, 
allowing a window of up to 30 minutes to fit into the therapy process where a natural 
break occurs. If necessary, the therapists can make a greater number of 
measurements, as their clinical judgment dictates. 
p. Measure BP, pulse, and BT at baseline prior to drug administration.  
 
During: 
q. At approximately 10:00 in the morning, subjects will receive the initial dose of drug 
along with a glass of water.  
r. 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. 
s. Measure BP, pulse, and BT once every hour throughout the experimental session. 
More frequent measures will be taken if clinical signs and symptoms of hypertension 
are observed. If BP values are sustained at 180 systolic and/or 110 diastolic, the PI 
will make a decision about whether to conduct additional measurements or to provide 
treatment. Measurements may be repeated until they have been decreasing for 15 
minutes or have stabilized at a level judged by the PI to be safe.   
t. 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. 
u. Approximately two hours after drug administration during the second experimental 
session, prepare the subject for the blood draw for biomarker analysis. Bring in the 
phlebotomy technician when the subject is emotionally ready for the blood draw. 
v. Initiate the TASIT. The TASIT administration may be spread out between hours two 
and three to fit around the therapeutic process.  
w. Record any spontaneously reported reactions during the session. 
x. Provide water and electrolyte containing fluids throughout the session but not to 
exceed 3 L overall. 
y. Provide food during the latter part of the session.  
z. If it is appropriate to do so, initiate the first question of the C-SSRS at any point in the 
session if the subject is experiencing significant psychological distress that does not 
respond readily to processing with the therapists. The C-SSRS is required at least 
once during the session. It is preferable to administer it towards the end of the 
session, about six hours after the initial dose.  
aa. End the session if all medical and psychiatric parameters are acceptable and the 
subject is alert, ambulatory, and emotionally stable. 
 
Post-drug: 
bb. The therapists will depart from the site when they have concluded that the subject is 
emotionally and medically stable. Therapists shall remain available to subjects during 
the experimental session and for one week after via 24 hour cellular phone for 


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integration, as needed. 
cc. Spontaneously reported reactions, AEs, and concomitant medications will be 
collected, as described in Section 8.5 and Section 9.0. 
dd. Assess status of symptoms at baseline specific to the study population. 
ee. After the experimental sessions, an overnight stay at a hotel located close to the site 
will be offered to subjects, accompanied by their support partners, if they live further 
than 30 miles from the site. 
ff. During the night of the experimental session, subjects will be given the following 
measures to complete prior to the integrative session on the next day: 
a. RSES 
b. IRI 
c. PSS 
 
5.2.4 Integrative Sessions 24 Hours after Experimental Session  
 
The subject and support partner (if applicable) will receive pagers (or similar device) that 
will allow them to contact the therapists during the period after the first in-person office 
visit following treatment sessions in the case of an emergency or request for additional 
support. Subjects will be encouraged to use much of the time during the 24-hours post-
session for rest and for a period of reflection and integration in a quiet atmosphere. On 
the morning after each experimental session, the therapists will meet with the subject for 
a 60-minute integrative therapy session.  
 
Activities during these sessions include discussing material that emerged during 
experimental sessions and helping subjects integrate their experiences both internally and 
into daily life. Therapists will validate the choices of the subject about how much they 
wish to communicate their thoughts, feelings, and experiences at this time, but will elicit 
enough information to be able to assess the subject’s level of emotional stability and state 
of emotional and physical wellbeing. Therapists will emphasize their commitment to 
support the subject during the integration period and will be available via phone for 
additional meetings if needed. Subjects will be encouraged to relax and rest as much as 
possible for several days after the experimental session. 
 
During integrative sessions: 
 
a. The integrative session may be recorded to audio and video. Subjects may receive 
access to copies of the recordings on a secure, password-protected website upon 
request. 
b. The therapists will administer the C-SSRS during each integrative session. 
c. 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 
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experimental sessions to emotionally threatening everyday situations. The 
therapists will be supportive, validating the experience, and facilitating 
understanding and emotional clearing.  
e. The therapists will remain accessible any time the subject needs support outside 
the scheduled integration sessions.  
f. Assess the subject’s mental health and the presence of any remaining reactions 
during the integrative session.  
g. Integrative sessions can also serve as an opportunity for the therapists to gather 
information about the effects of the drug on the subject in an unstructured manner.  
h. At the end of the session, subjects will complete: 
a. BDI-II 
b. STAI 
i. The IR will administer the LSAS. 
j. Spontaneously reported reactions, AEs, and concomitant medications will be 
collected, as described in Section 8.5 and Section 9.0. 
k. Assess status of symptoms at baseline specific to the study population.  
l. After the integrative session, a person previously selected by the subject will 
provide a ride home to the subject. If the subject is unable to locate an individual 
willing or able to take him or her home, or if the designated person is unable to 
assist the subject due to unforeseen events, the therapists will assist the subject in 
finding an alternative means of returning home. 
m. Remind the subjects that they will have daily phone contact for the next seven 
days. 
5.2.5 Daily Contact for Seven Days after an Experimental Session 
 
During daily contact:  
 
a. Starting on the day of the integrative session following each experimental session, 
one of the therapists will contact the subject via telephone or email on a daily 
basis for seven days. The goal of daily contact is assessment of changes in general 
wellbeing, safety of the subjects, and offering support for subjects.  
b. The integrative phone contact will be for a brief check-in lasting five to fifteen 
minutes or as long as necessary to address any concerns a subject has and to 
assess subject’s wellbeing. Additional telephone contact can be initiated at the 
request of the therapists or subject. 
c. On the second and seventh day of contact after the experimental session, one of 
the therapists will administer the C-SSRS. 
d. General wellbeing will be assessed at each phone call. 
e. Assess status of symptoms at baseline specific to the study population. 
f. Spontaneously reported reactions, AEs, and concomitant medications will be 
collected, as described in Section 8.5 and Section 9.0. 
 
5.2.6 Biweekly Integrative Sessions  
 
In addition to the integrative session the morning after each experimental session, the 
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with the therapists between each experimental session scheduled at two-week intervals 
following the last integrative session. The therapists may conduct more or longer 
integrative sessions if they and the subject deem it necessary.  
 
Activities for these sessions include integration of material that emerged as a part of 
experimental sessions and afterward into daily life. Therapists will emphasize their 
commitment to support the subject during the integration period and will be available via 
phone or pager.  
 
During integrative sessions: 
 
a. Record each integrative session to audio and video. Subjects may receive access 
to copies of the recordings on a secure, password-protected website upon request. 
b. The C-SSRS will be administered just prior to beginning each integrative session.  
c. General wellbeing will be assessed at each integrative session. 
d. The subject and therapists will continue to work on supporting the subject as she 
or he considers his or her experiences during experimental sessions.  
e. The therapists will use clinical judgment to assess the subject’s psychological 
wellbeing during this period of time. If there are any indications of continuing 
anxiety or distress, the therapists may arrange to work on reducing the distress at 
a specially scheduled integrative session, through continuing contact, or at the 
next regularly scheduled integrative session. The subject may also initiate contact 
with the therapists at any time throughout the study. 
f. At the second integrative session after the second experimental session, blood will 
be drawn for biomarker analysis. 
g. At the second integrative session after the second experimental session, collect 
information on phase of menstrual cycle for female subjects. 
h. At the beginning or end of each integrative session, subjects will complete: 
a. BDI-II 
b. STAI 
i. At the beginning or end of each integrative session, the IR will administer the 
LSAS.  
j. At the beginning or end of the third integrative session, subjects will also 
complete: 
a. ERQ 
b. TAS-20 
c. TASIT 
k. Spontaneously reported reactions, AEs, and concomitant medications will be 
collected, as described in Section 8.5 and Section 9.0. 
l. Assess status of symptoms at baseline specific to the study population. 
m. Remind the subject that the last integrative session in Stage 1 that this will be the 
last in-person visit prior to the 6-month Follow-up visit, and that some measures 
will be collected monthly by mail. 
n. Review how to use the Memory Aid Card with the subject. Subjects will use this 
card to record AEs, medications, and changes in psychiatric status that they will 
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5.2.7 6-Month Follow-up   
Subjects who have withdrawn from treatment but have continued for follow-up will also 
complete these assessments whenever possible. During the follow-up period: 
a. Subjects may return to taking psychiatric medications or change frequency or 
method of psychotherapy received from outside therapists if necessary.  
b. The following self-report measures will be completed by subjects and collected 
monthly at two, three, four, and five months after the second experimental session 
by mail: 
a. BDI-II 
b. STAI 
c. PSS 
c. At the 6-month follow-up, an in-person visit will be conducted. 
d. The IR will administer the LSAS. 
e. Collect information on phase of menstrual cycle for female subjects. 
f. Blood will be drawn for biomarker analysis. 
g. Subjects will complete self-report outcome assessments, including: 
a. ERQ 
b. TAS-20 
c. TASIT 
d. QoL-Q 
e. RSES 
f. IRI 
g. BDI-II 
h. STAI 
i. PSS 
j. Feedback Questionnaire 
h. Review specified AEs and medications as described in Section 8.5 and Section 
9.0. Subjects should bring the Memory Aid Cards to this visit, to be used as aids 
in recollection. These cards will not be collected.  
i. Assess status of symptoms at baseline specific to the study population. 
j. One of the therapists will assess suicidality with the C-SSRS.  
k. General wellbeing will be assessed. 
l. The therapists will review the responses to the Feedback Questionnaire assessing 
effects of the study with the subject. During the qualitative interview, additional 
follow-on questions may be asked to elucidate self-reported responses on the 
questionnaire.  
m. After all assessments are complete, the therapists will break the blind for the 
individual subject. 
n. Subjects who were randomized to the MDMA group will complete the 
termination visit at this time. 
o. Subjects who were randomized to the placebo group will be offered participation 
in Stage 2 with open-label MDMA. 
 


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5.2.8 Open-Label Stage 2  
During Stage 2: 
 
a. Subjects will be reminded that participation in Stage 2 is voluntary and optional. 
b. Subjects who elect to cross over to Stage 2 will undergo the same course of 
therapy and evaluation as in Stage 1, but with 75 mg MDMA during the first 
experimental session and will escalate to 125mg MDMA during the second 
experimental session, unless contraindicated. 
c. Subjects will have the same sequence of experimental sessions and integrative 
sessions as subjects receiving MDMA in Stage 1 in an open-label context. Visits 
will be scheduled consecutively according to the Time and Events Table.  
d. The same outcome measures completed by subjects receiving full dose MDMA in 
Stage 1 will be administered during Stage 2. 
e. The same safety measures as those in Stage 1 will be administered during Stage 2. 
f. Biomarker samples will be collected 2 hours after drug administration during both 
experimental sessions and one month after both experimental sessions during 
Stage 2. 
g. Stage 2 subjects will not complete an additional 6-month follow-up. 
h. Stage 2 subjects will complete the termination visit at the end of the final 
integrative session. 
 
5.3 Randomization and Subject Numbering 
 
Prior to enrollment, subjects will be tracked with their initials and a screening number 
assigned sequentially starting at “S001”. Subjects who meet all inclusion criteria and no 
exclusion criteria will be enrolled into the study and will be assigned a four-digit subject 
number. The first two digits will be “A1” and will identify the protocol number. The next 
two 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 A101, the 
second will be A102, etc. 
 
In total, 12 subjects will be enrolled in the study. Stage 1 will be blinded and randomized 
and there will be an 8:4 ratio between subjects in the MDMA and placebo conditions. An 
unblinded Randomization Monitor will generate the randomization list. Subjects will be 
assigned subject numbers and this number will be used to ensure that confidentiality and 
HIPAA compliance is maintained throughout the study. Upon enrolling a subject, the PI 
will be provided with an enrollment code for that subject. Container numbers will be pre-
printed on the container labels corresponding to doses for individual experimental 
sessions. Randomization will be performed at least 24 hours before the experimental 
session for each subject. The therapists will utilize a web-based randomization program 
to obtain the container assignment for each experimental session. Blinded personnel will 
conduct all study evaluations in the randomized portion of the study until the blind is 
broken for each subject per protocol via the web-based randomization program. Detailed 
instructions will be provided to the site in a separate document. 
 


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If there is an emergency requiring knowledge of subject's condition assignment, the blind 
may be broken for an individual subject. The PI will be provided with sealed emergency 
unblinding envelopes corresponding to each enrollment code. These sealed envelopes 
will be stored in a secure limited access area and should remain sealed if there are no 
emergency unblinding events during the study.  
 
5.4 Removal of Subjects from the Study 
 
Subjects can withdraw consent at any time without prejudice. The therapists can 
withdraw a subject if, in their clinical judgment, it is in the best interest of the subject or 
if the subject cannot comply with elements of the protocol that are critical for safety or 
for the scientific integrity of the study. If the therapists withdraw a subject from the 
study, the therapists will explain the reason for withdrawing the subject. The reason for 
early termination will be recorded in the subject’s Source Records and CRF. 
 
If a subject develops any exclusion criteria that in the opinion of the Medical Monitor, 
affects the safety of the subject, including psychiatric diagnosis, pregnancy, or requiring 
use of excluded medications, the subject will discontinue treatment but remain in the 
study for follow-up purposes. Whenever possible, the tests and evaluations listed for the 
follow-up will be carried out. Efforts will be made to obtain information about AE 
outcomes, if deemed necessary by the PI, Data Safety Monitor, Medical Monitor, and/or 
sponsor. 
 
Subjects discontinuing treatment before the first experimental session will be replaced 
until blinded data has been collected from 12 subjects. Subjects who discontinue 
participation after the first experimental session will not be replaced, and an intent-to-
treat analysis will be conducted with all available data. Subjects discontinuing treatment 
prior to the second experimental session will be asked to complete integrative therapy 
sessions, outcome assessments prior to discontinuation and complete the six-month 
follow-up assessment if possible. The blind will not be broken for these subjects until 
after the six-month follow-up assessments have been completed.  
 
5.5 Premature Discontinuation of the Study 
 
The sponsor or the PI (following consultation with the sponsor) has the right to 
discontinue this study at any time. If the trial is prematurely terminated, the PI is to 
promptly inform the study subjects and will assure appropriate therapy and follow-up. If 
the trial or study is prematurely discontinued, all procedures and requirements pertaining 
to retention and storage of documents will be observed. All other study materials will be 
returned to the sponsor and will be treated in accordance with federal and state 
regulations. 
 
6.0 Investigational Product 
 
6.1 Description of Active Compounds 
 


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The investigational product to be used in this protocol is MDMA. This ring-substituted 
phenethylamine has a complex pharmacology, but it acts most prominently as a 
monoamine releaser and uptake inhibitor [156-158]. MDMA primarily releases serotonin 
but also releases adrenaline and dopamine. It is also an indirect serotonin receptor 
agonist. See Section 2.2.3 and the IB for more information and references on the 
investigational product. 
 
6.2 Preparation and Administration 
 
6.2.1 Doses 
 
Doses of MDMA to be used in this study will be 75 mg, 100 mg or 125 mg MDMA.  
Upon enrollment, the first six subjects (Group 1) will be randomized to receive one dose 
of either placebo (N=2) or 75 mg MDMA (N=4). In the second experimental session one 
month later, Group 1 subjects randomized to MDMA will escalate to 100 mg MDMA, 
unless contraindicated by safety and tolerability concerns. The second six subjects 
(Group 2) will be randomized to receive one dose of either placebo (N=2) or 100 mg 
MDMA (N=4). In the second experimental session one month later, Group 2 subjects 
randomized to MDMA will escalate to 125 mg MDMA, unless contraindicated by safety 
and tolerability concerns. Subjects randomized to placebo in Group 1 and Group 2 will 
receive placebo in both experimental sessions also scheduled one month apart. The blind 
will be maintained through the six-month follow-up for each individual subject, after 
which the blind will be broken. Placebo subjects will be offered an open-label extension 
(Stage 2) with two experimental sessions scheduled one month apart, in addition to three 
hour-long integrative sessions during the month after each experimental session. Stage 2 
subjects will receive 75 mg MDMA in the first experimental session and will escalate to 
125mg MDMA in the second experimental session, unless contraindicated by safety and 
tolerability concerns from other subjects in Stage 1. 
 
6.2.2 Compounding and Encapsulation 
 
All drug shipments will be conducted in compliance with national and international 
controlled substance laws. Schedule 1 licenses will be obtained from the U.S. Drug 
Enforcement Agency (DEA) whenever applicable. MDMA in bulk will be sent from the 
Schedule 1 storage facility to the Schedule 1 license holder for the study. The Schedule 1 
license holder and unblinded Randomization Monitor will oversee compounding by a 
pharmacist in a manner that will maintain the blind for the Schedule 1 license holder. The 
pharmacist will provide bulk lactose for compounding MDMA capsules. The pharmacist 
will compound the MDMA in bulk and then weigh the MDMA into doses of 75 mg, 100 
mg, and 125mg (calculated as the weight of the hydrochloride salt) and place it in gelatin 
capsules with lactose. Placebo capsules will contain only lactose. All capsules will be 
compounded so that they weigh the same amount, but contain varying amounts of 
MDMA and lactose. 
 
6.2.3 Labeling 
 


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During compounding, bulk MDMA will be stored in a holding box prior to encapsulation. 
Each holding box will be labeled with the protocol code, drug name, lot number, sponsor 
name, and a statement that the drug is for clinical trial use only (see box label). 
 
The doses of MDMA for a single subject to complete one experimental session will be 
stored in a single container labeled with the protocol code, drug name, lot number, unique 
container number, sponsor name, and a statement that the drug is for clinical trial use 
only (see container label). Each dose of MDMA for each experimental session will be 
labeled and stored individually within the container (see container labels for each session 
and dose). Labels will be provided by the sponsor and applied by the pharmacist. During 
packaging and labeling, the randomization list will be hidden from the PI and therapists 
to assure blinding. All drug labels will comply with federal and state regulations. 
 
Figure 1. Holding Box Label 
 
 
 
 
 
 
 
 
Figure 2. Container Labels 
Container Label 
MAPS Study #: MAA-1 
Container #: XXX  
 
Subject #: ____________  
Stage 1: Blinded 
Administer as per Protocol  
Caution: Limited by Law to 
Investigational Use Only 
Container Label 
MAPS Study #: MAA-1 
Container #: XXX  
 
Subject #: ____________  
Stage 2: 75mg OR 125mg 
Administer as per Protocol  
Caution: Limited by Law to 
Investigational Use Only 
 
Each dose will consist of the specified amount of racemic MDMA mixed with lactose, to 
prevent the therapists from distinguishing doses through weight or appearance of the 
capsules. Each dose of investigational product will be administered along with a glass of 
water or electrolyte-containing fluid. Investigational product will be administered in the 
same manner during each experimental session.  
 
6.3 Drug Accountability 
 
Forms will be provided to track drug accountability and administration throughout the 
study. Drug accountability will be reviewed during routine monitoring visits. 
 
6.4 Drug Storage and Handling  
 
Box Label 
MAPS Study #: MAA-1 
Investigational Product: MDMA  
Dose: 75 mg, 100 mg OR 125 mg 
Lot #: XXXXX 
Administer as per Protocol 
Caution: Limited by Law to Investigational Use Only 


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MDMA is a Schedule 1 compound and will be stored and handled in compliance with all 
relevant federal and state regulations. In accordance with these requirements, the 
Schedule 1 license holder will be responsible for storing, dispensing, and administering 
the investigational product. It will be stored in a secure safe, in accordance with 
international, federal and state regulations.  
 
Investigational product will only be removed from the safe for one experimental session 
at a time prior to the session and the investigational product will not leave the control of 
the Schedule 1 license holder until consumed by the designated subject. All doses 
administered will be recorded on the appropriate accountability logs. 
 
Records pertaining to the use of scheduled, regulated compounds will be maintained in 
accordance with all relevant regulations.  
 
6.5 Stability 
 
Complete details on the chemistry, manufacturing, and control of the MDMA to be used 
are described in Drug Master file (DMF) # 6293. As described in that file, MDMA was 
prepared for human consumption in 1985 by David Nichols, Ph.D., at the Dept. of 
Medicinal Chemistry and Pharmacology, Purdue University. The identity and purity of 
this MDMA was confirmed using High Performance Liquid Chromatography (HPLC) in 
1997, as described in DMF # 6293, and was found to be 99.87% pure. On August 12, 
2002, Chemic Laboratories reanalyzed the MDMA at the request of the sponsor prior to 
starting MAPS’ first U.S. pilot study of MDMA-assisted psychotherapy in people with 
PTSD. The analysis found the MDMA to be more than 99.7% pure. A more recent 
analysis performed by Nichols at the request of researcher Dr. Carl Hart on February, 
2006, continued to find a high degree of purity. This analysis found the MDMA in 
question to be 99.9% pure. This MDMA is currently in use in an ongoing investigation of 
MDMA-assisted psychotherapy in the U.S. The MDMA is currently stored at Organix, 
Inc. and will be shipped from that facility for the study. 
 
7.0 Risks of Participation 
7.1 Risks and Discomforts Associated with Non-drug and Experimental Sessions and 
Assessment of Measures 
In preparation for drug-assisted therapy sessions, blood draws and a full medical 
examination are required to establish eligibility for the study and for biomarker analyses. 
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 therapy sessions and assessment of study 
measures, subjects will be asked to think about and discuss their thoughts and emotions 
relating to social anxiety symptoms. They may experience intense emotional responses to 
recalling and speaking about this material. In a therapeutic context, thinking about and 


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discussing the effects of social anxiety on life function can produce distress during and 
immediately after non-drug therapy, experimental, and open-label sessions. Therapy is 
conducted as part of this study, and people undergoing therapy are expected to confront 
unpleasant thoughts, feelings and memories in the process of therapy. Because therapy is 
an integral part of the research study design, the potential distress arising from therapy is 
unavoidable.  
 
All in-person sessions after enrollment may be recorded to 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. Subjects will receive information on who will 
have access to any of their recordings outside of a research and training setting and will 
have control over any presentation of this material beyond viewing by researchers or 
regulatory agencies. 
 
7.2 Risks of Receiving MDMA 
Spontaneously reported reactions and common adverse effects of MDMA are modest and 
have generally not been associated with serious discomfort by healthy volunteers and 
PTSD subjects in previous studies. Common reactions include lack of appetite, insomnia, 
dizziness, tight jaw or bruxism (tooth-grinding), difficulty concentrating, impaired gait or 
balance, dry mouth, ruminations, and thirst. Other slightly less common reactions include 
restlessness, parasthesias (odd somatic feelings, such as tingling or feeling hot or cold), 
impaired judgment, perspiration, drowsiness, and nystagmus (eye-wiggling). While 
anxiety, headache, fatigue, insomnia, and lack of appetite were spontaneously reported by 
40% to 80% of subjects in both conditions in MAPS study MP-1 (N=23), tight jaw, 
nausea, impaired gait/balance, and sensitivity to cold were more often reported by 
subjects in the MDMA than the placebo condition, and irritability was slightly more 
likely to be reported in the placebo condition. Additionally, subjects in the MDMA 
condition were more likely to report muscle tension in various body parts and diarrhea.  
 
These effects are transient and diminish as drug effects wane. Sub-acute effects that may 
either continue for the next 24 hours or appear later include insomnia, fatigue, needing 
more sleep, weakness, heavy legs, dry mouth, low mood, or irritability. Sub-acute effects 
are reported less often than acute effects. More information on spontaneously reported 
reactions is described in the IB.  
 
MDMA may produce mild alterations in sensory perception and altered perception of 
time [78, 109, 159]. 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 [114]. For this reason, subjects will stay close to 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 


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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 IB.  
 
7.2.1 Cardiovascular and Sympathomimetic Effects 
The MDMA dose of 125 mg 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 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 PI will be present throughout and will 
continually evaluate the patient for increasing blood pressure and signs or symptoms of a 
developing hypertensive or other cardiovascular emergency. Subjects reporting chest 
pain, shortness of breath, neurological symptoms, or other potential indicators of 
hypertension will have more frequent measurements and assessment by the PI. Any 
subject who experiences medical complications during an experimental session will not 
be given another experimental session, unless it is approved by the PI, the Data Safety 
Monitor and the Medical Monitor. Subjects who are excluded from receiving another 
experimental session would continue in integrative therapy sessions and follow-up 
assessments whenever possible.  
 
If a subject has a sustained blood pressure of 180 systolic and/or 110 diastolic without 
evidence of end organ damage (such as chest pain, shortness of breath, signs of 
encephalopathy), then the responsible physician should make a judgment about possible 
treatment. In most cases, the most appropriate course would be to monitor the subject 
clinically and wait for the hypertensive effect of the MDMA to wear off. If the blood 
pressure remains elevated above 180 systolic and/or 110 diastolic and is not decreasing 
three to four hours after MDMA administration, or if for some other reason the PI deems 
gradual treatment appropriate, then oral carvedilol would be a good choice because of its 
mixed alpha and beta blocking effects [160].  If the blood pressure is in the range of 180 
systolic and/or 110 diastolic or higher with accompanying evidence of end organ damage, 
then a hypertensive emergency would be indicated and the subject should be transported 
to the medical Emergency Department at the site for definitive evaluation and treatment 
with intravenous drugs for more rapid management of the blood pressure and any 
complications. Reasons for moving a patient to the medical Emergency Department 
would include, but not be limited to, severe headache in the setting of hypertension, 
angina, or neurological deficits regardless of blood pressure. The PI may, at any time, 


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make a clinical judgment to transfer the patient to the medical Emergency Department for 
closer monitoring and additional treatment.  
 
The PI will be prepared to respond to rare complications of cardiovascular effects, such 
as stroke or acute myocardial infarction (AMI). If any subject has neurological deficits, 
as assessed by the PI, whether or not they are associated with hypertensive crisis, they 
will receive oxygen and will be monitored, as described below. If evaluation at the 
medical Emergency Department reveals a nonhemorrhagic stroke, there will be sufficient 
time to administer recombinant tissue plasminogen within the three-hour time frame 
recommended in the American Academy of Neurology/American Heart Association 
guidelines [161, 162]. 
 
The PI will observe the subject and note any complaints of chest pain. If a subject 
experiences ischemic type chest pain, whether or not it is associated with hypertensive 
crisis, he or she will receive heart rhythm monitoring, oxygen, and will be monitored as 
described above. If necessary, he or she will be transported to the Harbor-UCLA Medical 
Center medical Emergency Department or a location in the hospital where appropriate 
care can be given. The subject will be given nitroglycerin 0.4 mg SL q 5 minutes as 
needed (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 acute myocardial infarction (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 [163]. 
 
7.2.2 Psychological Distress 
Mild anxiety and depressed mood are occasionally reported one to three days after 
MDMA administration [76, 124, and see the IB]. Psychological distress from MDMA 
could arise from the first indications of drug effects until the last effects have dissipated 
(approximately three to five hours after drug administration) or even later. Anxiety or 
distress during the session may last for as little as five minutes or for as long as five hours 
or more. In addition, psychological distress could arise following an experimental 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 
PRN use of benzodiazepines for anxiety. In this study, subjects spontaneously might 
confront and work through unpleasant experiences. Accordingly, signs of psychological 
distress, panic, or other unpleasant psychological reactions are to be expected and may be 
considered an element of the therapeutic 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: 


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 Excluding people who might be more vulnerable to it (such as people diagnosed 
with bipolar affective disorder – 1, psychotic disorders) 
 Preparatory non-drug therapy 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 therapy sessions 
 
During the preparatory sessions, subjects will be made aware of the fact that difficult 
emotions, including grief, rage, anxiety, 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 seven hour experimental session, if the subject is still severely agitated 
or experiencing any other severe psychological distress, the following measures will be 
taken:  
 
 If the subject is anxious, agitated, in danger of any self-harm, or is suicidal at the 
end of the experimental session, the therapists will remain with the subject for at 
least two more hours. During this time, the therapists will employ affect 
management techniques, will talk with the subject to help him or her gain 
cognitive perspective of their experiences, and will help the subject implement the 
self-soothing and stress inoculation techniques presented during the preparatory 
sessions. If this situation should occur during an integrative session, at least one 
of the therapists will be available to stay with the subject for at least two 
additional hours. 
 If a subject remains severely anxious, agitated, in danger of self-harm or suicide, 
or is otherwise psychologically unstable at the end of this two-hour  
stabilization period, the PI will decide between the following options: 
 
1. The Harbor-UCLA psychiatric Emergency Department will admit the 
subject for direct monitoring until the time of his or her appointment 
with the therapists the next day. The therapists will then meet with the 
subject daily if necessary 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 PI may prescribe a benzodiazepine, atypical 
antipsychotic, or zolpidem as a “rescue medication.” Any atypical 
antipsychotic medications used during the experimental session or the 
week after should not be primarily metabolized by CYP2D6, such as 
quetiapine instead of risperidone. This medication will be captured on 
the concomitant medications CRF page. The physician should not 


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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 therapy 
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 
psychiatric Emergency Department at Harbor-UCLA Medical Center 
if necessary. 
 
Subjects hospitalized after a severe panic or anxiety reaction will be suspended from the 
protocol until after recovery or stabilization, at which time the PI will carefully evaluate 
the subject’s emotional status. Subjects will continue with non-drug integrative therapy 
visits and follow-up assessments whenever possible. 
 
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 PI, the management of any psychiatric complications will be 
undertaken by them in their capacity as the subject’s therapist.  
 
7.2.3 Body Temperature 
MDMA administered in a controlled setting produces only a slight increase in body 
temperature [124]. Ambient temperature does not enhance or attenuate this slight 
elevation in humans.  
 
If temperature rises more than 1° C, attempts will be made to lower it by removing 
blankets and layers of clothing, decreasing the ambient temperature, and, if necessary, 
directing a fan toward the subject. If at any time the temperature rises more than 1.5° C 
above baseline despite these efforts, the PI will be present at all times and will determine 
the need for further evaluation and treatment.  
 
7.2.4 Reproductive and Developmental Risks 
Risks posed by MDMA to pregnant women are not known. One of two studies of Ecstasy 
users suggests that use of Ecstasy and other drugs during pregnancy may be associated 
with some abnormalities at birth while the other failed to find this association [164, 165], 
and a third reported some developmental delays in mothers reporting use of ecstasy and 
other drugs during pregnancy [166]. These studies are discussed in the IB. 
 
Pregnant and lactating women will be excluded from participation in the study. Women 
who are able to become pregnant must have a negative pregnancy screen before 
undergoing each experimental session and must agree to use birth control for the 
treatment portion of the study. 
 
7.2.5 Potential Neurotoxicity Associated with Ecstasy Use 
 


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Some researchers believe that MDMA is neurotoxic in humans even at doses used in 
clinical trials [167]. 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 [168]. We have carefully considered the risks of such neurotoxicity and 
conclude that they are minimal in the proposed study. This conclusion is supported by 
empirical and toxicokinetic evidence and is consistent with the lack of toxicity reported 
in previous clinical MDMA studies. More information on the potential neurotoxicity of 
MDMA can be found in the IB.  
 
7.2.6 Risk Mitigation 
 
Careful review of medical screening data will be utilized to exclude potential subjects 
with pre-existing exclusionary medical conditions from the study. Study procedures have 
been developed to mitigate the risks of receiving MDMA described in detail in the IB. 
Ambient temperature will be kept at a comfortable level during Experimental sessions. 
Subjects will not be allowed to drink more than 3L of fluids over the course of the 
experimental session and fluid intake will be spread out appropriately during the session. 
Fluids administered will include electrolytes. If a subject exhibits any signs of toxicity or 
clinically significant dilutional hyponatremia despite these precautions after an 
experimental session, subjects will be excluded from receiving future experimental 
sessions, unless approved by the PI, Data Safety Monitor, and the Medical Monitor.  
 
7.3 Abuse Liability 
 
Findings in humans and animals suggests that MDMA possesses moderate abuse 
potential that is higher than that reported for “classic hallucinogens,” like psilocybin, but 
lower than that reported for psychostimulants, such as cocaine or methamphetamine. 
More information on abuse liability is provided in the IB. 
 
To ensure MDMA-assisted therapy does not cause  autistic adults to develop symptoms 
of drug abuse after the treatment period of the study, drug use is monitored during the 
follow-up period. 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 a 12-month follow-up period.  
 
Diversion is not an issue in this protocol because MDMA will only be administered in a 
controlled environment under the supervision of the PI 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. 


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8.0 Adverse Events 
 
8.1 Adverse Events 
 
An adverse event (AE) is defined as any untoward or unfavorable medical occurrence in 
a clinical research study subject, including any abnormal sign (e.g. abnormal physical 
exam or laboratory finding), symptom, or disease, temporally associated with the 
subject’s involvement in the research, whether or not considered related to participation 
in the research. This definition includes concurrent illnesses or injuries and exacerbation 
of pre-existing conditions.  
 
An unexpected adverse event is one that is not listed in the current IB or an event that is 
by nature more specific or more severe than a listed event. 
 
All AEs will be monitored by the therapists until resolution or, if the AE becomes 
chronic, a cause can be identified. If an AE is unresolved at the conclusion of the 
protocol, a clinical assessment will be made by the CI and/or Medical Monitor as to 
whether continued follow-up of the AE is warranted. 
 
The severity of events reported on the “Adverse Events” CRF will be determined by the 
PI as: 
 
 Mild: No limitation in normal daily activity 
 Moderate: Some limitation in normal daily activity 
 Severe: Unable to perform normal daily activity 
 
The relationship of the study treatment to an AE will be determined by the PI based on 
the following definitions: 
 
1. “Not Related”: The AE is not related if exposure to the investigational product has not 
occurred, or the occurrence of the AE is not reasonably related in time, or the AE is 
considered unlikely to be related to use of the investigational product, i.e. there are no 
facts (evidence) or arguments to suggest a causal relationship, or the AE is more likely 
related to the subject’s pre-existing condition. 
 
2. “Possibly Related”: The administration of the investigational product and AE are 
considered reasonably related in time and the AE could be explained by causes other than 
exposure to the investigational product. 
 
3. “Probably Related”: Exposure to the investigational product and AE are reasonably 
related in time and the investigational product is more likely than other causes to be 
responsible for the AE, or is the most likely cause of the AE. 
 
8.2 Spontaneously Reported Reactions  
 


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Commonly expected spontaneously reported reactions to MDMA 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. Reactions that persist beyond the seven 
days after each experimental session will be recorded as AEs on the AE CRF page. 
 
8.3 Serious Adverse Events 
 
An SAE is defined as any untoward medical occurrence that at any dose: 
 
 Results in death 
 Is life-threatening (i.e. the subject was, in the opinion of the CI, at immediate risk 
of death from the event as it occurred); it does not refer to an event which 
hypothetically might have caused death if it were more severe 
 Requires or prolongs inpatient hospitalization 
 Results in persistent or significant disability/incapacity (i.e. the event causes 
substantial disruption of a person’s ability to conduct normal life functions) 
 Results in a congenital anomaly/birth defect 
 Requires intervention to prevent permanent impairment or damage 
 Is an important and significant medical event that may not be immediately life-
threatening or resulting in death or hospitalization, but based upon appropriate 
medical judgment, may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above. 
 
AEs which do not fall into these categories are defined as non-serious. It should be noted 
that a severe adverse event need not be serious in nature and that a SAE need not, by  
definition, be severe. 
 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded on the medical history. The hospitalization would not result in the event or  
condition being reported as a study-related SAE, unless, in the view of the PI, 
hospitalization was prolonged as a result of participation in the clinical trial or was 
necessary due to a worsening of the pre-existing condition. This is because the onset of 
the event (the reason for the procedure) occurred before the subject was entered in the 
trial. Hospitalization for cosmetics, non-emergency prophylaxis, or abortion does not  


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result in an SAE report, unless, in the view of the PI, hospitalization for these procedures 
was prolonged as a result of participation in the clinical trial. 
 
8.4 Medical Emergencies 
 
The sessions will be conducted in an outpatient research building on the campus of the 
Harbor-UCLA Medical Center, which is a 10 minute walk from the Emergency 
Department. The PI will conduct all experimental sessions accompanied by co-
investigator Alicia Danforth. The co-therapist or PI will be available via mobile phone or 
pager throughout the study if any problem occurs when a subject is not at the site. 
Subjects will continue to see their outside therapist throughout the study. For a recently 
completed Phase 2 trial, the sponsor has established contingency plans for responding to 
those AEs that appear most likely, based on a comprehensive review of literature 
described in the current IB. The same contingency plans and equipment will be used in 
this protocol.  
 
8.5 Adverse Event Collection 
 
The PI will be responsible for reviewing and confirming all AEs and SAEs collected 
during the study. The co-therapist or PI 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 CI’s awareness of their occurrence. All SAE 
reports should be faxed to the sponsor. A fax number will be provided to the site in 
separate site-specific instruction for SAE reporting. In addition to the fax, the PI, or 
designee should call the Clinical Research Associate (CRA) during normal working 
hours and verbally inform the CRA of the SAE. During off business hours or if medical 
advice is needed immediately, the sponsor Medical Monitor will be called. SAE reporting 
instructions with all contact numbers will be provided to the site prior to study start.  
 
The following symptoms will be assessed at baseline and exacerbations during the study 
will be tracked and categorized as mild, moderate, or severe on a separate Symptoms 
CRF log page: Persistent feelings of alienation, Rigidity, Tremor, Dystonic Symptoms, 
Akathisia, Increased Motor Activity, Decreased Motor Activity, Sensory Hyperarousal, 
Excitement/Agitation.  
 
AEs to be collected during the study are: 
 
 Serious Adverse Events (SAEs) will be collected from enrollment through 
termination.  
 All AEs and spontaneously reported reactions will be collected on the day of and 
seven days after each experimental session or until they resolve.  


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 AEs requiring medical attention, including a doctor visit or treatment with 
prescription medication, will be collected from the first experimental session 
through the final integrative session after the second experimental session. 
 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 will be collected throughout the study. 
 All AEs related to changes in psychiatric status will be collected throughout the 
study. 
 Any exacerbations of Symptoms recorded at Medical History will be collected 
throughout the study. 
 
A Memory Aid Card will be provided to the subject on the last visit prior to the 6-month 
follow-up to record information on medications taken to treat SAEs, AEs leading to 
withdrawal and psychiatric AEs during the follow-up period during the follow-up period. 
The Memory Aid Card will not be collected, but information from the card will be used 
to aid the subjects in providing information to the CI.  
 
8.6 Medical Monitor  
Michael C Mithoefer  
Email: mmithoefer@mac.com  
Telephone: (843)-849-6899 
Fax:  (843)-278-9188 
 
9.0 Concomitant Medications and Tapering Instructions 
 
The PI will record concomitant medications during screening. If the subject is being 
treated with psychiatric drugs at the time he or she is recruited into the study, the 
prospective subject will be encouraged to discuss medication tapering with his or her 
outside treating physician, if any, and will be required to give the PI permission to do so 
as well. The drugs will then be tapered in an appropriate fashion to avoid withdrawal 
effects. They will be discontinued long enough before the first experimental session to 
avoid the possibility of any drug interactions (the interval will be at least five times the 
particular drug’s half-life).  
 
Table 5: Medication Washout Table for MDMA studies 
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 


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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 therapists will request information about any changes in medication just prior to each 
experimental session. The PI will be responsible for reviewing and confirming all 
medications collected during the study.  
 
All medications, over the counter (OTC) and prescription, will be collected from 
screening through seven days after the last experimental session. From the end of the 
seven days after the last experimental session through the 6-month follow-up visit, only 
prescription or OTC medications taken to treat AEs will be collected. Throughout the 
protocol all medications used to treat AEs will be collected as specified in Section 8.5 
and all changes to psychiatric medications will be collected, including discontinuations or 
additions. Medications will be recorded on the concomitant medications CRF.  
 
Subjects must be willing to refrain from taking any psychiatric medications during 
treatments received in Stage 1 and Stage 2. 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 
utilize a washout period of at least five half-lives of the drug and active metabolites plus 
one week for stabilization before each experimental session and do not restart for ten 
days after each experimental session.  
 
The PI may prescribe a designated rescue medication in the event of symptoms that 
require it during or after the experimental session (e.g. insomnia or severe anxiety that 
does not respond to other management). Rescue medications may be benzodiazepines 
such as lorazepam, or sedative hypnotics such as zolpidem, or atypical antipsychotics. 
Any atypical antipsychotic medications used during the experimental session or the week 
after should not be primarily metabolized by CYP2D6, such as quetiapine instead of 
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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).  
 
Subjects may return to taking psychiatric medications and discontinue birth control 
during the follow-up period if necessary. Subjects will receive a Memory Aid Card to 
record these medications between the final integrative visit in Stage 1 and the 6-month 
follow-up, as described in Section 8.5. Subjects will use this card to record changes in 
psychiatric medications that they will be asked about at the 6-month follow-up visit. 
Memory Aids will not be collected.  
 
10.0 Clinical Laboratory Assessments 
 
10.1 Screening Assessments 
 
A central laboratory will perform clinical laboratory tests conducted at screening to 
establish medical eligibility. Effective clinical lab normal ranges will be provided by the 
clinical laboratory and kept on file in the ISF. Abnormal clinically significant clinical 
laboratory results will be reported as a part of Medical History and must be recorded on 
the Medical History CRF page. The PI will examine laboratory assessments gathered 
during screening to assess subject eligibility using the appropriate list of normal ranges to 
conclude whether subjects are eligible for the protocol, and will indicate justification for 
admitting subjects with abnormal values, after consultation with the Medical Monitor. 
 
The following laboratory assessments will be performed as a part of screening:  
 
Serum electrolytes and metabolic profile, which includes: 
 ALT/SGPT 
 Albumin:globulin (A:G) ratio 
 Albumin, serum 
 Alkaline phosphatase, serum 
 AST/SGOT 
 Bilirubin, total 
 BUN:creatinine ratio 
 Calcium, serum 
 Carbon dioxide 
 Chloride, serum 
 Creatinine, serum 
 Globulin, total 
 Glucose, serum 


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 Potassium, serum 
 Protein, total, serum 
 Sodium, serum 
 
CBC, which includes:  
 Hematocrit 
 Hemoglobin 
 MCV 
 MCH 
 MCHC 
 RDW 
 Percentage and absolute differential counts 
 Red blood cell  (RBC) count 
 White blood cell (WBC) count 
 
Urinalysis, which includes:  
 Color 
 Appearance 
 Specific gravity 
 pH 
 Protein 
 Glucose 
 Ketones 
 Occult blood 
 Leukocyte esterase 
 Nitrite 
 Bilirubin 
 Urobilinogen 
 
Thyroid function, which includes:  
 TSH high sensitivity 
 Free T4 
 Free T3 
 
HIV serology will be performed.  
 
A urine-dip pregnancy test for females of childbearing potential will be performed. The 
urinary pregnancy tests and drug tests will be performed at the study site.  
 
The central laboratory that will perform screening assessments, other than the urine drug 
screen and pregnancy tests, is: 
LabCorp 
21501 Avalon Blvd Suite 150 
Carson, CA 


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Phone: (310) 513-0701 
Fax: (310) 513-0702 
 
10.2 Biomarker Analysis 
 
Biomarker laboratory analyses will be performed using plasma for OT, AVP, and CORT 
collected from all subjects at the Harbor-UCLA Medical Center according to the Time 
and Events Table. For blood samples, a butterfly needle will be used to draw 30mL of 
blood into chilled EDTA vacutainer tubes. Samples will be immediately placed on wet 
ice. Plasma will be extracted by centrifugation in a refrigerated (4oC) centrifuge at 1,300g 
for 10 minutes, aliquotted into individual tubes, and stored at -80oC at Harbor-UCLA 
Medical Center prior to shipment to the collaborating site at Stanford University Medical 
Center. Biomarker analyses will be performed by Dr. Dean Carson and Dr. Karen Parker 
in Dr. Parker’s laboratory at the Stanford University Medical Center in Stanford, 
California (collaborating site). Concentrations of OT and AVP will be quantified using 
commercially available enzyme immunoassay kits (Enzo Life Sciences, Farmingdale, 
New York) and concentrations of CORT will be quantified using radio immunoassay kits 
(Siemens, Deerfield, Illinois) that have been validated for use in humans. These kits are 
highly specific and exclusively recognize OT, AVP and CORT respectively, and not 
related peptides. Plasma samples are extracted using Strata-X columns and then assayed 
in duplicate and measured using a tunable microplate reader for 96-well format according 
to manufacturer’s instructions. 
 
11.0 Study Monitoring, Auditing, and Documentation 
 
Prior to trial initiation, the CI must provide to MAPS a fully executed and signed FDA 
Form 1572 and a Financial Disclosure Form.  Financial Disclosure Forms also must be 
completed for all sub-investigators listed on the Form 1572 who will be directly involved 
in the treatment or evaluation of research subjects in this trial. 
The CI, therapists, and study staff will be trained prior to the start of the study. The trial 
will be administered and monitored by employees or representatives of the sponsor. The 
site and collaborating sites will be monitored as appropriate for the rate of enrollment in 
order to comply with GCP guidelines and to ensure validity of the study data.  During 
each monitoring visit, source data verification will be performed to ensure compliance, 
including accurate and complete recording of data on CRFs, source documents, and drug 
accountability records. A CRF collation supplied by the sponsor will be completed for 
each subject enrolled. Study monitor contact information, monitoring and auditing 
procedures will be supplied in a separate document.  
 
During or after the study, the regulatory authorities, the IRB, and/or representatives of the 
sponsor may request access to all source documents, CRFs and other protocol 
documentation for on-site audit or inspection. 
 
12.0 Data Analysis  
 


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This study is primarily a safety study that will also obtain estimates of effect size  
comparing MDMA vs. placebo using observer-blind data from the LSAS as the primary 
outcome measure. MDMA doses are not expected to differ greatly in treatment outcomes 
and will be combined for effect size estimates. Descriptive statistics will be computed 
overall for MDMA and placebo, and within the MDMA dose groups for all available data 
from outcome measures, including minimum, maximum, average, and standard deviation. 
Distributional characteristics will be examined for outliers and extreme values and, if 
either is evident, nonparametric statistics will be utilized in the analysis. Effect size for all 
outcome measures will be estimated using Cohen's techniques. 
 
The sponsor will examine MDMA and placebo groups for homogeneity through 
comparing demographic characteristics. There is no expectation that conditions will 
differ in composition by gender, race or ethnicity, duration of autism diagnosis, or 
presence versus absence of other permitted psychiatric disorders, such as depression. 
However, owing to small sample size, such variations may arise by chance. If MDMA 
and placebo subjects differ upon a demographic variable, then the effects of this variable 
will be taken into account when looking at safety analyses. No systematic differences are 
expected.  
 
Primary and secondary outcome measure scores will be plotted across each time of 
administrations for trend analyses. The number of intervals will vary in accordance with 
times listed for each measure, but will include in most cases baseline, one or more times 
after the first experimental session, one or more times after the second experimental 
session and at six month follow up. Plots will be made for MDMA and placebo subjects, 
and if trends occur for MDMA subjects, separate exploratory plots will be made for 
outcome measures after 0, 75, 100 and 125 mg MDMA.  
 
The main estimates of effect size from blinded data will be conducted after the outcome 
measure assessments at the six-month follow-up are complete for all subjects. Data from 
all doses of MDMA during Stage 1 (n=16), to be compared with all data from placebo 
sessions (n=8), with each experimental session treated as an independent observation. 
The MDMA condition will encompass both Group 1 and Group 2 MDMA doses.  
Estimates of effect size will be obtained from BDI-II, STAI, PSS, IRI, RSES, ERQ, TAS-
20, and QoL-Q scores collected pre-treatment, during and after each experimental 
session, and the follow-up period, with p value set at 0.05. Effect size will be used to 
determine the appropriate sample size for future studies.  
 
Scores for BDI-II, STAI, PSS, IRI and RSES completed after each of the experimental 
session will be averaged to produce mean scores for these periods, including a post-
experimental session 1 and post-experimental session 2 average score. BDI-II, STAI and 
PSS scores gathered via postal mail at monthly intervals from two to five months after 
the second experimental session will be averaged to produce mean scores for the follow-
up period. Missing responses will be replaced with the sample average. These averages 
will be used for estimates of effect size.  
 


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TASIT scores will be compared assessing baseline, after experimental session 1, after 
experimental session 2, at integrative session six and at 6-month follow up. Correlations 
between TASIT scores and LSAS scores at the time point following each TASIT score 
will be made to see whether increased awareness of social cues is associated with reduced 
social anxiety. MDMA dose will be used as a covariate in order to examine the potential 
relationship between dose and changes in one or more variable, with dose (75, 100 or 125 
mg) serving as the covariate.  
 
Biomarkers will be evaluated for predictive and prognostic power. Separate estimates of 
effect size will be performed for OT, AVP and CORT. Changes in biomarker 
concentrations from pre-treatment levels will be used to analyze effects of acute dosing 
and to determine the time-course of elevated OT and AVP levels post-drug. Pre-treatment 
biomarker concentrations will be evaluated for predictive power using an exploratory 
hierarchical regression analysis with condition assignment in Stage 1 and biomarker 
concentrations at baseline as predictors and treatment outcomes as dependent variables. 
One regression will be performed with biomarker values taken at the second experimental 
session. A second regression will be performed on biomarker values taken two weeks 
after the second experimental session. 
 
TAS-20 scores will be evaluated for predictive power using an exploratory hierarchical 
regression analysis with condition assignment in Stage 1 and TAS-20 scores at baseline 
as predictors and with LSAS scores as dependent measures. One regression will examine 
the predictive power of condition and baseline TAS-20 scores upon LSAS scores one 
month after the first experimental session and the other will investigate whether condition 
and baseline TAS-20 and will predict LSAS score at one month after the second 
experimental session. 
 
Subjects who discontinue treatment prior to the second experimental session will be 
asked to complete the final outcome assessment prior to continuing to the 6-month 
follow-up whenever possible. 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 combined for an exploratory intent-to-treat effect size 
estimate to examine results without bias towards subjects more likely to complete the 
study per protocol.  
 
Stage 1 and Stage 2 outcomes in extension subjects will be compared after the outcome 
measure assessments are complete for all extension subjects. 
 
Descriptive statistics will be computed for vital signs and subjective distress during each 
experimental or open-label session. The sponsor will compare pre-drug and post-drug 
peak blood pressure, heart rate, and body temperature during and after all experimental 
sessions by condition and MDMA dose. Analyses will compare peak vital signs between 
MDMA and placebo subjects, and a separate analysis will consider the effects of dose (0, 
75, 100 or 125 mg MDMA) upon vital signs.  
 


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Frequency tables will be produced on prevalence of spontaneously reported reactions and 
AEs. Number and severity of spontaneously reported reactions will be compared in 
MDMA and placebo subjects using a one-way analysis of variance (ANOVA). The 
effects of MDMA dose upon number and severity of spontaneously reported reactions 
will also be assessed. Presence and degree of exacerbated symptoms across MDMA and 
placebo participant will also be examined. 
 
Perceptions of study participation will be examined at baseline, 6-month follow-up, and 
end of Stage 2 using the Feedback Questionnaire and a qualitative interview. The results 
of this qualitative analysis will inform the sponsor of expectancies and perceptions about 
study procedures for future protocol development. Similarly, belief of condition 
assignments collected during Stage 1 will be used to assess the effectiveness of the 
double-blind in preparation for future studies. Results from the Feedback Questionnaire 
and safety data will be utilized to find the appropriate active MDMA dose for future 
studies. 
 
To facilitate the planning of future studies, a preliminary estimate of effect size may be 
performed after all the subjects have completed the outcome assessments, one month 
after the second experimental session, but not all subjects have completed the six-month 
follow-up evaluation. This preliminary estimate will consist of safety and outcome 
measures. Results of the preliminary estimate will have no effect on study conduct.  
 
12.1 Statistical Power 
This is a pilot study intended to collect estimates of effect size of MDMA compared to 
placebo. The study is likely to be underpowered for detection of differences of a small or 
moderate effect size and it may detect differences if the effect size is large. Statistical 
power estimates were not available for this study, as this is the first prospective clinical 
trial of MDMA-assisted therapy for social anxiety in this population.  
 
13.0 Ethics 
This clinical study was designed and shall be implemented and reported in accordance 
with the ICH Harmonized Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21) and with the ethical principles laid down in the Declaration of Helsinki.  
 
The protocol, ICF and accompanying documents given to subjects must be reviewed and 
approved by a properly constituted IRB and FDA before study start. Signed and dated 
documentation of IRB and FDA approvals must be provided to the sponsor. Prior to 
study start, the PI is required to sign an Investigator Agreement page confirming her/his 
agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data 
and records to the sponsor. 
 


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14.0 Informed Consent 
A properly executed, written ICF, in compliance with the Declaration of Helsinki, ICH-
GCP Guidelines, US Code of Federal Regulations for Protection of Human Subjects (21 
CFR 50.25[a, b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance 
Portability and Accountability Act (HIPAA), and applicable state regulations, will be 
obtained by a study therapist from each subject and support partner prior to entering the 
trial. In addition to the explanation of study visits, the ICF should include a HIPAA 
release giving the PI permission to access original medical records and processing of 
coded personal information. A copy of the ICF will be submitted by the PI to the IRB for 
review and approval prior to the start of the study. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. 
all of the procedures described in the protocol, including screening activities). 
Information about the study must be given orally and in an understandable form. Written 
information about the trial will also be provided. The subject and support partner should 
have the opportunity to inquire about details of the study and adequate time to consider 
participation. Subjects will be informed in the ICF that they may receive either MDMA 
or placebo during the study. The ICF and the HIPAA authorization must be signed and 
dated by the subject and support partner and must be countersigned by the qualified 
therapist who conducted the informed consent discussion (according to local, national, 
and international agreements and laws). The therapist will provide a copy of the signed 
ICF to each of the subjects and support partners, and will maintain the original in the 
subject’s source records.   
 
The subject and Support Partner are to be informed in a timely manner if new 
information becomes available that may be relevant to the subject's willingness to 
continue participation in the clinical study. The communication of this information is to 
be documented. The written ICF and any other written information to be provided to 
subjects and support partners 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. 
Subjects can withdraw consent at any time without prejudice. If a subject withdraws 
consent but does not revoke the HIPAA authorization, the PI will have full access to the 
subject’s medical records, including termination visit information. If a subject revokes 
only the HIPAA authorization, the PI will have full access to all of the subject’s medical 
records prior to the date and time of revocation. 
 
15.0 Confidentiality 
Every effort will be made to strictly safeguard the confidentiality of subjects in their role 
as research subjects. Removing identifying information from data and restricting access 
only to approved researchers should prevent the dissemination of confidential data, with 
or without identifying information. Except for the screening log, the informed consent 
and a subject contact information sheet that will be stored separately from other 
documents, all data will be identified only by the subject's initials on the source document 


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and four-digit subject number. If past medical records are needed, subjects will sign 
forms for the release of information upon consent to permit screening. Any materials 
mailed to subjects will be sent along with stamped return envelopes using the office 
address of the PI both as main and return address. All assessment records will be kept in a 
locked file drawer or cabinet in a locked office, and access to measures will be limited to 
regulatory agencies, researchers, and individuals analyzing data. Researchers, other than 
the PI who are directly involved in conducting the protocol, with access to data will not 
be provided with any information that would identify subjects by name or by other 
means. 
 
All in-person visits after enrollment may be recorded to video. Diagnostic assessments 
may also be video recorded to establish inter-rater reliability. These recordings will be 
used for treatment manual development and potentially for training therapists to perform 
MDMA-assisted therapy to reproduce results in subsequent studies. Recordings are 
intended to document the events occurring during in-person visits, and will not serve as 
outcome measures. Full names and addresses will not appear in these recordings. Copies 
of video recordings intended for sharing with subjects will only be marked with the 
subject’s subject number. 
 
16.0 Costs to Subjects 
There will be no costs to the study subjects. The sponsor will cover all costs of study 
participation, including any assessments or tests performed solely for the purpose of 
establishing eligibility for participation. Charges for treatment of the subject’s condition 
that are unrelated to the research study or any of its procedures will continue to be billed 
to the health insurance provider of the subject or to the subject him or herself. It is 
anticipated that there will not be any charges for treatment that is unrelated to the study 
except in the case of subjects who previously received therapy from the PI and who will 
continue to receive ongoing treatment that is not related to participating in the study.  
 
17.0 Treatment and Compensation for Study Related Injury 
Costs for treatment of a study-related emergency would first be billed to a subject’s 
health insurance provider. The sponsor will cover any direct costs relating to the 
treatment of a study-related emergency that are not covered by a subject’s health 
insurance. Some study-related emergencies can be treated by the PI, as described under 
Section 8.4. If the PI cannot treat a study-related emergency, then there are contingency 
plans for the transport of subjects to the appropriate Harbor-UCLA Medical Center 
Emergency Department.  
 
18.0 Record Retention 
The PI is responsible for retaining all study records required by the sponsor and 
applicable ICH-GCP and FDA regulations in a secure and safe facility. The PI must 
consult a representative of the sponsor before disposal of any study records. “Essential 
documents” are defined as documents that individually and collectively permit evaluation 
of the conduct of a trial and the quality of the data produced. These documents will be 


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filed according to ICH-GCP regulations in the ISF. It is the responsibility of the sponsor 
to inform the PI or institution as to when these documents no longer need to be retained.  
 
19.0 Publication Policy 
The sponsor recognizes the importance of communicating medical study data and 
therefore encourages publications in reputable scientific journals and presentations at 
seminars or conferences. It is understood by the PI that the information generated in this 
study will be used by the sponsor in connection with the development of the 
investigational product and therefore may be disclosed to government agencies in various 
countries. To allow for the use of information derived from the study, it is understood 
that the PI is obliged to provide the sponsor with complete test results, all study data, and 
access to all study records. It is mandatory that all data analysis is done on the official 
monitored sponsor database and that the analysis plan is agreed upon with the sponsor 
statistician. 
 
Any results of medical investigations with the sponsor products and/or publications/ 
lectures/manuscripts based thereon, shall be exchanged and discussed by the PI and the 
sponsor clinical research representative(s) prior to submission for publication or 
presentation. Due regard shall be given to the sponsor's legitimate interests, e.g. 
manuscript authorship, obtaining optimal patient protection, coordinating and 
maintaining submissions to health authorities, and coordinating with other studies in the 
same field. 
The full details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this trial will be described in the Clinical Trial 
Agreement. 
 
20.0 References 
 
 
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humans. Br J Clin Pharmacol, 2000. 49(2): p. 104-9. 


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unaffected. Psychopharmacology (Berl), 2007. 189(4): p. 557-63. 
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Marrone, G.F., et al., Amphetamine analogs methamphetamine and 3,4-
methylenedioxymethamphetamine (MDMA) differentially affect speech. 
Psychopharmacology (Berl), 2010. 208(2): p. 169-77. 


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Autism Dev Disord, 2007. 37(4): p. 709-15. 
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Rosenberg, M., Society and the adolescent self-image. 1965, Princeton: Princeton 
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Esteem Scale in 53 nations: exploring the universal and culture-specific features 
of global self-esteem. . J Pers Soc Psy, 2005. 89(4): p. 623-42. 
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ix-xii, 1-315. 
 
 

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Page 2 
 
 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This website will not include information that can identify you. At most, the website will include a summary of 
the results. You can search this website any time.  
 
Why is this study being done? 
 
This small (“pilot”) study is designed to provide information on whether therapy combined with the drug 3,4-
methylenedioxymethamphetamine (MDMA) is safe and helpful for autistic adults with social anxiety symptoms. 
The researchers plan to use the results of this study to design further studies. 
 
MDMA is an experimental drug, which means that it has not been approved by the U.S. Food and Drug 
Administration (FDA) for medical use except in research studies. MDMA is also a controlled drug (illegal to 
use outside of research) and is sometimes known as “Ecstasy” or “Molly” (which is supposed to contain 
MDMA but often contains other drugs instead of or in addition to MDMA). MDMA has already been used 
legally in research and illegally in uncontrolled environments, such as nightclubs. While much is known about 
MDMA and its risks, much remains unknown about this drug. 
 
This study is sponsored by a US-based non-profit organization, the Multidisciplinary Association for 
Psychedelic Studies (MAPS). Before it became illegal in 1985, some psychologists and psychiatrists combined 
MDMA with psychotherapy (therapy involving talking with others and counseling) to help people with 
psychological problems, including posttraumatic stress disorder (PTSD). Though we do not know why MDMA 
therapy may help people with anxiety disorders like PTSD, we know that MDMA increases positive mood and 
changes the way we see and think about the world around us, making it easier to think about and recall things 
that happened that are upsetting. People say they feel caring and forgiving toward themselves and others during 
the MDMA experience. It is possible that these drug effects, when combined with therapy, could help people 
work through thoughts, memories and emotions related to anxiety. 
 
This study will compare the effects of therapy combined with MDMA to just therapy alone. 
 
Are there potential conflicts of interest? 
 
The study doctor conducting this research does not have any financial interest in the sponsor or in the study; this 
means that the study doctor will not be financially affected by the results of the study (good or bad). However, 
the study doctor and his staff will be reimbursed by the sponsor for the work that he and the study staff have to 
do as part of this study and for the use of the site‟s facilities.  
 
The person inviting you to take part in this research study may also be your treating doctor. In such cases, the 
doctor has an interest in both your care and promoting the successful conduct of this research. Sometimes these 
two interests may cause conflict. You can choose not to take part in the study and still receive treatment from 
your doctor. If you wish, you may also request to speak to another doctor who is not a member of the study 
team about your options. 
 
How many people will take part in the study? 
 
A total of 12 people will take part in this study. At this time LA BioMed is the only site that is conducting this 
study.  
 
IRB NUMBER: 30026-01
IRB APPROVAL DATE: 07/29/2015
IRB EXPIRATION DATE: 07/28/2016


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What will happen if I take part in this research study?   
 
You must be aware of the following: 
 We may video record all office visits and therapy sessions for research purposes which include 
developing a treatment manual and to possibly train future therapists in this type of therapy. We will 
also use the video recordings to make sure all procedures are being done consistently. You can ask to 
view these recordings at any time while you are taking part in this study. We will post the video 
recordings on a secure (password is needed) website and only select researchers, but also including 
yourself if you ask, can view them. When we video record you, we will include your face. We will not 
label the video with your name, address or any other identifying information.  
 
We may also audio record (record only voices – no images) all office visits and therapy sessions. We 
will not label this recording with your name, address or any other identifying information. This 
recording will be used as a back-up for the video recordings for training and manual development. You 
may ask to hear these recordings as well. 
 
Video and audio recordings will be destroyed after 20 years from the end of the study. 
 
 You will have to avoid taking any medicines for psychological problems from the beginning of the study 
up until you complete the last integrative session unless the study doctor makes a specific exception, 
such as giving you medicine for sleep or anxiety temporarily and if needed. If you are taking this type of 
medicine, you will need to give the study doctor or a member of his study team permission to talk with 
your own doctor about how best to stop taking your medicine. We will help you do this. You may return 
to taking your medications during the follow-up period.  
 
 You must let us know about any medical conditions or procedures, like surgery, within 48 hours of their 
occurrence. 
 
 You will need to bring a relative, spouse or close friend with you to visits to be your support partner 
during the study. This person (called a Support Partner) will also take part in this study by providing you 
with transportation during the study. We will not allow you to drive after each experimental session in 
which you receive the study drug (MDMA or placebo). We will ask your support partner to also provide 
you with emotional support during the study. We may ask this person to take part in the study sessions 
and provide information about you.  
 
 If you are currently seeing a psychotherapist, you may not begin any new psychotherapy or change the 
type, frequency or length of visits with your psychotherapist until after your final session/visit. This is so 
any change in your social anxiety symptoms are more likely to be from the experimental treatment 
rather than from any new psychotherapy treatments. 
 
 For your safety, it is very important to tell us about all medicines you are taking, including herbal or 
“natural” remedies or supplements, and to check with us before you begin taking a new medicine while 
in this study.  
 
 You will also need to tell us if you become pregnant anytime during the study. If you are a woman that 
can have children you must not get pregnant while you are taking part in this research study. You must 
agree to practice two effective and acceptable forms of birth control (described later in this form). 
 
IRB NUMBER: 30026-01
IRB APPROVAL DATE: 07/29/2015
IRB EXPIRATION DATE: 07/28/2016


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 If you have an increase in symptoms for which you previously took medicine, if you need to contact 
your outside therapist other than for the usual appointments, and/or if you start or stop taking prescribed 
medicine, you should contact us before doing this.  
 
 You should not be a part of any other clinical trial (research study) or take MDMA or Ecstasy outside of 
the study during the whole time you are in this study. 
 
 If you must go the hospital or are in a life-threatening situation at any time during the study even if it 
doesn‟t have anything to do with the study, you will need to call us as soon as you can to let us know the 
details.  
 
Screening 
You will need to have the following exams, tests or procedures to find out if you can be in the study. This is 
called screening and this process can take up to 2 months. You may see the study doctor (
) or a 
member of his study team on two or more occasions during this time. We may ask your permission to contact 
your doctor or psychotherapist to get information about your medical and psychiatric history. We may need to 
do this so that we will know if you can be in the study or not. If you feel that these evaluations are too much to 
deal with during a given office visit, please tell us so we can schedule a different office visit for you to complete 
them.  
 
 
The screening tests and procedures include the following: 
 We will ask you questions about your medical history, including questions about your emotional and 
psychiatric history and medications you have taken in the past. This may include any previous medical 
or psychiatric problems or treatment and may include questions about difficult experiences you may 
have had during childhood or at other times during your life.  
 We will interview you and ask about your social anxiety symptoms and how you deal with them in 
your everyday life. We will use your score on this interview to decide if you can be in the study.  
 We will ask you questions about the features of autism you experience. 
 We will ask you questions about thoughts or feelings you might have about hurting or killing yourself. 
 You will undergo a physical and neurological examination that will include measuring your blood 
pressure, pulse, temperature, and body weight. The neurological examination will check your reflexes 
and senses. 
 You will have an ECG (electrocardiogram) taken. This is a recording of the electrical activity of your 
heart. For the ECG, you will have sticky patches placed on your chest, abdomen and sides. We will 
connect the wires (electrodes) from the ECG to these patches. Once the recording is complete, we will 
remove the sticky patches. This will take about 5-10 minutes.  
 We will take a sample of your blood (about 1.5 tablespoons) from a vein in your arm and collect a 
sample of your urine for routine laboratory testing, including tests to check your metabolism and liver 
function. Once it looks like you can enroll in the study, a second sample of your blood (about 2 
tablespoons) will be taken from a vein in your arm to measure the amount of hormones in your body. 
 We will also use the first blood sample for a test to see if you have the human immunodeficiency virus 
(HIV) which is the virus that causes AIDS. If you choose not to have this test, you will not be able to 
take part in this study. If the tests find out that you have HIV, then we will have to submit a confidential 
report to the California Department of Public Health within seven days telling them of your positive test 
result. This is required by State law. We will also refer you for counseling and treatment. 
 You will provide a sample of your urine to test for the presence of drugs of abuse. If this urine test is 
positive you will not be able to take part in the study, unless there is a medical reason for the positive 
test. 
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 If you are a woman who can become or may be pregnant, we will use your urine sample for a pregnancy 
test as well. If the pregnant test is positive you will not be able to take part in the study. 
 You will complete a questionnaire and we will interview about what you think about the study so far. 
 
If necessary, we may ask you to allow us to get copies and review your medical record from your treating 
doctors. We will require a signed release form from you in order to do this.  
 
If, based on the results of the screening tests and procedures, you qualify to take part in the study, we will 
schedule you for the next part of the study called “Preparatory Sessions and Baseline Measures”.  
 
Preparatory Sessions and Baseline Measures: 
We will meet with you on three separate occasions for preparatory sessions before we schedule your first 
experimental session. Each of these visits will last about  two hours and will be about 1 week apart. At each of 
these visits we will ask you about how you are doing and if there have been any changes in your health or the 
medications you are taking. We will ask you questions to check your symptoms. During each preparatory 
session, you will learn more about what to expect during the experimental sessions and we will video record 
these sessions as well. During these sessions, you will complete a number of different questionnaires about your 
mental health, emotions and quality of life. You will also complete a computer-based laboratory assessment 
(like a questionnaire) during one of the sessions.  
 
It is during these sessions that we will have you stop taking any medication that you are not allowed to take 
while you are taking part in this study. We will have you stop taking the medication based on your 
therapist/doctor and the study doctor decide how to best have you stop it. This means that it may be done by 
lowering the dose over time until you are no longer taking the medication.  
 
During the first session you will go on a tour of the study site to help prepare for the experimental sessions. 
 
We will give you a card that says you are taking part in a research study involving the use of MDMA. This card 
will also include the telephone numbers to reach us (the researchers) and the Institutional Review Board. You 
can keep this card in your wallet to make it easier for you or anyone treating you in an emergency to contact us 
if you or they need to do so. 
 
Stage 1 Experimental Sessions: 
You will take part in two experimental sessions, when you will receive MDMA or placebo together with 
psychotherapy, each happening about one month apart. The placebo looks like MDMA but contains no active 
medicine. The first experimental session will occur after you have finished the third preparatory session.  
 
We will "randomize" you into one of the study groups described below. Randomization means that you are put 
into a group by chance (like tossing a coin). A computer program will place you in one of the study groups. 
Neither you nor the study doctor can choose the group you will be in. You will have 2 out of 3 chances of 
receiving MDMA, and 1 chance out of 3 of receiving placebo. Neither your study doctor or his staff nor you 
will know which study group or drug (MDMA or placebo) you will be receiving. However should a medical 
emergency occur, this information will be made immediately available to your study doctor.  
 
If, at the end of this study, we find that you were in the group that did not receive MDMA, there will be a 
second part of the study („Stage 2‟) where you will be offered two additional experimental sessions with 
MDMA (no placebo is given). (Stage 2 is described below.) 
 
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Each Experimental Session will last about 8 hours. We will schedule them so that they start at 9:00 am and end 
by 5:00 pm. Unless there are unusual circumstances, the Experimental Sessions will take place on Saturdays. 
The day after each session you will need to return to the study site for an “Integrative Session” at which we will 
check to see how you are doing. The details of these sessions are described below. 
 
Before each Experimental Session you must: 
 Not eat anything after midnight the evening before each session; 
 Drink only beverages not containing alcohol after midnight the evening before each session; 
 Not take any psychoactive drugs, with the exception of caffeine or nicotine, within the 24 hours before 
each session; and 
 Not consume caffeine or use nicotine for 2 hours before and 6 hours after receiving the study drug 
(MDMA or placebo) or until therapists tells you it is safe to do so. 
 
Before (about 9:00 am) you are to receive with the MDMA or placebo during each experimental session: 
 We will collect a sample of your urine to test for drugs of abuse. You cannot take part in this study if your 
urine drug screen is positive for drugs of abuse. 
 If you are a woman who can have children, we will use your urine sample for a pregnancy test. You cannot 
take part in this study if you are pregnant. 
 
After you receive either MDMA or placebo (at 10:00 am) during each experimental session: 
 We will measure and record your blood pressure, temperature, and pulse every hour until 5:00 pm (7 times 
total). 
 We will ask you to rate the amount of distress you feel on a scale of 1 to 7 every hour until 5:00 pm (7 times 
total). 
 Just before you are to receive the study drug (MDMA or placebo) and about 6 hours after you receive it, as a 
standard safety precaution, we will ask you about thoughts you might have about hurting or killing yourself.  
 We will remain with you for seven hours after you take the study drug (MDMA or placebo). 
 During each 8 hour session, you may sit or lie down in a comfortable position. You can ask for an eyeshade 
or headphones. 
 We will ask to talk to you at least every hour, but you can talk to us or remain silent whenever you wish. 
 Two hours after you take the study drug (MDMA or placebo) during the Experimental Session 2, we will 
take a sample of your blood (about 2 tablespoons) from a vein in your arm to measure the amount of 
hormones in your body.  
 Two hours after you take the study drug (MDMA or placebo), you will complete the same computer-based 
laboratory assessment you completed during the Preparatory Sessions. 
 
We will give you food and drinks during each session at your request. 
 If you request it and we agree to it, your support partner may stay with you during some of the experimental 
session, starting at an agreed-upon time. When your support partner arrives, they will stay in the waiting 
room until there is a good time for them to come into the experimental session. 
 
You can go home after each experimental session is over (5:00 pm or so). However, you will have to make 
arrangements so that you do not drive yourself home. We ask that this arrangement be made because we do not 
know how MDMA will affect your ability to drive, and because some people report feeling tired, less alert or 
having trouble concentrating after having taken MDMA. 
 
If you live more than 30 miles away from the study site (LA BioMed), we will offer you and your support 
partner a hotel room at a location close to the study site. If you live less than 30 miles away from the study site, 
someone or your support partner will drive you home or to the hotel and back to the study site the next day for 
another study visit to see how you are doing. 
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If you find you need to talk with the study doctor or a member of his study team or you are having other 
problems and need to contact them, your support partner may contact us for help.  
 
You will complete some questionnaires about feelings you might have experienced during or after the 
experimental session. You can complete these questionnaires at any time between the end of the experimental 
session and the start of the integrative session on the next day. During the time between the end of the 
experimental session and the start of the integrative session the next day, we ask that you use the time as a 
period of rest and reflection in a quiet setting. 
 
Integrative Session - Therapy After Experimental Sessions 
On the next day, you will have a non-drug (integrative) therapy session to help you express, understand, bring 
together and connect any thoughts or feelings you may be having about your symptoms and their causes, and to 
think and talk about your experience during the experimental sessions. Each Integrative Session will last about 
60 to 90 minutes. Your support partner will need to wait outside the therapy room during this visit. 
 
Before starting integrative therapy on the day after each experimental session, we will ask you to guess whether 
you got MDMA or placebo. However, we will not tell you if your guess is correct. As an extra safety measure, 
we will ask you if you have had any thoughts of harming yourself.  
 
After the integrative therapy session, we will interview you about your social anxiety symptoms and you will 
complete questionnaires about your mental health. 
 
Time Between Each Experimental Session (about 1 month) 
After the integrative sessions, we will telephone you every day for a week to see how you are feeling and 
whether you should return to see the study doctor or a member of his study team before your next scheduled 
psychotherapy session. We will also ask you about any thoughts of harming yourself on Day 2 and Day 7 of 
these telephone check-ins. These telephone calls will take about 5 to 15 minutes, though they can be as long as 
you need them to be.  
 
You may schedule additional meetings with the study doctor or a member of his study team besides those that 
are scheduled as part of the study. You can contact them at any time. You can reach one of them by telephone 
24 hours a day throughout this entire research study. 
 
You will have integrative therapy with the researchers on two more visits every two weeks during the month 
after the experimental session. These integrative sessions will last 60 to 90 minutes. You and the researchers 
will also talk about ways to use what you learned to help work on treating your social anxiety, face and solve 
difficulties you may have faced during the experimental sessions and gain the most benefit and understanding 
from the experimental sessions. We will ask you about any thoughts of harming yourself. At each integrative 
session, we will interview you about your social anxiety symptoms and you will complete questionnaires about 
your mental health.  
 
At the very last integrative session (about 1 month after Experimental Session 2), we will take a sample of your 
blood (about 2 tablespoons) from a vein in your arm to measure the amount of hormones in your body. You will 
also complete additional questionnaires about your feelings and the computer-based laboratory assessment. 
 
Follow-up Period 
During the next five months, you won‟t have any office visits scheduled for the study. You may go back to 
taking any medications if you need them for psychological problems and you can change your outside therapist 
or any therapy you receive outside of the study.  
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To keep track of any medications, therapies or if you have to go the doctor, we will give you a memory aid 
card. This card is to help you to remember any new problems or medical conditions, or changes in medication 
during the months between your last integrative therapy visit and the 6-month follow-up visit.  
 
Just as you agreed to do during the rest of the study, you will need to avoid taking any MDMA or Ecstasy 
outside of the research study. 
 
Every month during the follow-up period, you will need to complete questionnaires about your mental health. 
We may mail these questionnaires to you for you to fill out. If so, they will come with an envelope that is 
already stamped and have only the researcher‟s address on it. Do not put your name on the questionnaire as it 
will have your study identification (ID) number. This will help us to maintain your confidentiality should these 
questionnaires get lost. Alternatively, you may complete the questionnaires online using a secure internet 
connection, to keep everything confidential. We will explain how to do this and will be available to answer your 
questions. 
 
6-Month Follow-Up Visit 
About 6 months after your last experimental session, you will return to the study site for a study visit. During 
this visit, we will ask you questions about any thoughts of harming yourself, any changes in medications or your 
psychiatric health, including any benefits or harms, since your last visit. We will interview you and ask you 
about your thoughts on being in this research study. You will complete a questionnaire on the effects of being in 
this research study, any thoughts you have about the good and bad points of MDMA-assisted therapy, and your 
thoughts about taking MDMA. You will also complete questionnaires about your mental health. We will take a 
final sample of your blood (about 2 tablespoons) from a vein in your arm to measure the amount of hormones in 
your body. 
 
After you complete these tests, you will find out if you received MDMA or placebo. If you learn that you had 
the placebo, you may choose to receive two additional experimental sessions of therapy with two different 
doses of MDMA, followed by three integrative therapy sessions after each one. If you received MDMA during 
Stage 1 you cannot take part in Stage 2.  
 
Stage 2 Experimental Sessions - Open-Label MDMA  
If you received placebo in Stage 1, you can take part in Stage 2. If you take part in Stage 2, you will have eight 
more visits. During the first experimental session in Stage 2, you will receive 75mg of MDMA. During the 
second experimental session (about 1 month after the first session), you will receive 125mg of MDMA. All the 
procedures during Stage 2 will be the same as those done in Stage 1, except you will know that you will receive 
MDMA during the experimental sessions. We will take samples of your blood (about 2 tablespoons each time) 
from a vein in your arm during both the experimental sessions and the third integrative session after each 
experimental session in Stage 2. There is no 6 month follow-up period after your last integrative session. 
 
Signing this consent form means you agree to take part in Stage 2 should you qualify; however, you can change 
your mind at any time and stop without taking part in Stage 2. There won‟t be another follow-up period after 
Stage 2. 
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Study Plan 
 
Another way to find out what will happen to you during the study is to read the chart below. Start reading at the 
top and read down the list, following the lines and arrows.  
 
 
                                                               
 
 
                                                                    
 
 
 
 
   
 
 
 
                                 
                        
 
 
 
 
           
 
 
 
 
 
 
 
 
 
What are my responsibilities if I take part in this research? 
 
If you take part in this research study, you are responsible for coming to all study visits, following the study 
doctor‟s and his study team‟s instructions, taking the study drug (MDMA or placebo) as told and completing all 
therapy sessions, questionnaires, and interviews.  
 
How long will I be in the study? 
 
This study can take up to eight months or 14 visits if you receive MDMA in Stage 1 of this study. It can last for 
an additional two months or 8 more visits if you receive the placebo in Stage 1 and agree to take part in Stage 2.  
Social Anxiety related to Autism 
Medicine used in this study 
MDMA taken during therapy 
2 sessions, spaced 3-5 weeks apart 
Stage 1: Randomize  
(You will be put in one of two Groups) 
Group 2 
Placebo in therapy 
2 experimental sessions plus 6 
integrative sessions plus 6 month 
follow-up period 
Start Here 
Group 1 
MDMA in therapy 
2 experimental sessions plus 6 
integrative sessions plus 6 month 
follow-up period 
Stage 2 (optional) 
MDMA in therapy 
2 experimental sessions plus 6 
integrative sessions 
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Can I stop being in the study? 
 
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping or decide to 
stop. He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the MDMA can be 
evaluated by your doctor. Another reason to tell your doctor that you are thinking about stopping is to discuss 
what follow-up care and testing could be most helpful for you. 
 
Your doctor, the sponsor of the study (MAPS), or the FDA has the right to stop your participation in the study 
at any time, with or without your consent, for any of the following reasons:  
 if you have an adverse effect from the study drugs,  
 if you need a treatment not allowed in this study, such as restarting medication for psychological 
problems,  
 if you do not keep appointments,  
 if you do not take the study drug as instructed,  
 if you become pregnant, or  
 if the study is canceled by the FDA or the sponsor company. 
 
If you have very high blood pressure, get sick, or have an important and strong lasting reaction (unwanted effect 
or health problem) during or after an experimental session, you or the study doctor may decide that you should 
not take part in the next experimental session. You may make this decision to stop taking part in the study for 
any reason. If the study doctor decides to take you out of the study, he will let you know that he is doing this 
and tell you his reason for doing this. If you are taken out of the study or decide you do not want to receive 
treatment in the study, the study doctor will ask you to complete some final questionnaires about your mental 
health. If you decide you do not want to continue in the study during an experimental session, we will ask you 
to stay in the office until the study doctor thinks that you are well enough to leave and that all the effects of the 
drug have worn off. If this happens, we will also ask you to allow us to interview you about your thoughts on 
being in the study and for you to complete the same questionnaires you completed at the beginning of the study 
during the follow-up visit in 6 months. 
 
We will tell you about new information or changes in the study that may affect your health or your willingness 
to continue in the study. 
 
If you stop being in the study, already collected data (information collected from and about you while you are in 
the study) may not be removed from the study database. We will ask whether we can collect data from your 
routine medical care. If you agree, we will handle this data the same as research data. 
 
What treatments and/or procedures are experimental? 
 
We are carrying out all of the procedures and/or treatments described above for research or experimental 
purposes. MDMA is an experimental drug, and has not been approved for use by the U.S. Food and Drug 
Administration (FDA) for medical use except in research studies.  
 
 
 
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What side effects or risks can I expect from being in the study?  
 
You may have side effects while on the study. We will watch everyone taking part in the study carefully for any 
side effects. However, doctors don‟t know all the side effects that may happen. Side effects may be anything 
from mild to very serious. Your study doctor or his/her staff may give you medicines to help lessen side effects. 
Many side effects go away soon after you stop taking the MDMA. In some cases, side effects can be serious, 
long lasting, or may never go away.  
 
You should talk to your study doctor about any side effects that you have while taking part in the study even if 
you think they may not be caused by the medicines.   
 
Risks and side effects related to MDMA include those which are: 
 
Likely 
 Fatigue 
 Anxiety 
 Lack of appetite 
 Increased blood pressure 
 Increased heart rate 
 Dry mouth 
 Tight jaw/teeth grinding 
 Decreased ability to concentrate 
 Slight changes in vision, hearing or other senses 
 Headache 
 Insomnia (trouble sleeping) 
 Thirst 
 Restlessness 
 
 Less Likely   
 Nausea 
 Feeling down  
 Feeling cold 
 Dizziness  
 Impaired balance/gait 
 Reduced immune system function (making you more susceptible to infections) 
 Perspiration (sweating) 
 Feeling weak 
 Need for more sleep (feeling sleepy) 
 
Rare but serious 
 Potential for addiction (becoming dependent on the drug) 
 Very high blood pressure  
 Fast heartbeat (tachycardia) 
 Irregular heartbeat   
 Overheating (feeling hot) 
 Liver disease 
 Water intoxication (drinking too much water)   
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MDMA has not been widely tested in humans, but as of May 2013 about 845 people have received MDMA in 
research settings, without any serious problems happening. 
 
There may be unknown side effects or risks from the use of MDMA. Other possible risks of MDMA may 
include the following: 
 
Physical Risks: 
 
Serious problems: There have been some serious problems, and even deaths, associated with the use of Ecstasy 
outside of controlled settings (outside of research studies). In research studies (clinical trials), none of these 
serious problems have happened. Outside of medical settings, these problems have included high fever, brain 
swelling associated with drinking too much liquid, convulsions (seizures), and liver damage.  Since you will be 
receiving moderate amounts of uncontaminated MDMA in a controlled setting with trained and experienced 
researchers who will be closely monitoring your physical and psychological reactions, these problems are not 
expected to occur either during or after the experimental sessions. While this does not guarantee that they will 
not occur, it does mean that if they do occur, the researchers are prepared to respond in a safe and professional 
manner. 
 
Changes in vision, hearing or other senses:  Most people that took part in previous MDMA studies reported 
experiencing temporary and minor changes in vision and hearing, such as sounds seeming closer or farther 
away than usual or objects seeming brighter than usual. These changes typically lasted 2 to 3 hours. Between 
12-33 out of every 100 people who took MDMA also reported unusual feelings in their bodies, such as tingling 
or numbness. 
 
Blood pressure and heart rate:  The effects of MDMA usually last 4 to 6 hours. At the doses used in this 
study, the increases in blood pressure and heart rate are likely to be moderate. Average increase in systolic 
blood pressure is 35 mmHg (measurement unit for blood pressure) and average diastolic blood pressure increase 
is 20 mmHg. Heart rate may increase by about 30 beats per minute (BPM). 
 
In previous studies, blood pressure rose well above normal levels in a few people (a little less than 1 out of every 
20, and usually in subjects receiving higher doses of MDMA than will be administered in this study) after 
receiving MDMA, but they did not report any discomfort and did not require any treatment. Although these 
increases in blood pressure are similar to what happens after heavy exercise, they could cause serious problems in 
individuals with pre-existing heart or vessel conditions. These serious problems could include heart attack or 
stroke. We will ask you about and check you for heart problems during the screening for this study. While this 
doesn't guarantee that no heart problems will occur, it does reduce the risk of this happening. 
 
Immune System: You may have a less active immune system for 2 or 3 days after receiving MDMA. This may 
make you more likely to become sick with a cold or other infection during this time. The study describing this 
finding did not report how many people in the study showed these changes. 
 
Addiction:  There is a small chance that you may become dependent on (addicted to) MDMA. One study found 
that up to 6% (a little more than 1 out of every 20) of people using Ecstasy for recreational purposes were 
dependent on it. However, three studies of people who had received MDMA in a research study found that they 
did not want to try MDMA again outside of the study. People who have recently (in the last 2 months) had 
problems with drug abuse should not take part in this study. 
 
 
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Mental Risks: 
 
Anxious or jittery feeling: Some people in previous studies (about 4 out of every 25) reported feeling over-
stimulated or anxious. These feelings usually lasted less than 30 minutes. Letting yourself accept and feel these 
emotions deeply can be part of the therapy. If you are not able to deal with these experiences in a way that helps 
you, the researchers will work with you to deal with these feelings. It is possible that if such periods of 
heightened emotion do not clear up or grow weaker during the session, you could be at increased risk for 
suicide or other self-harm afterwards. We will encourage you to ask your support partner to call  us immediately 
if you have any thoughts about hurting or killing yourself so we can help you resolve them safely. If necessary, 
we may prescribe anti-anxiety medication or medication for sleep. Some recreational users of Ecstasy have 
become severely anxious, depressed or paranoid (thinking that other people are out to get them).  
 
If you are in immediate danger of hurting or killing yourself or hurting someone else, then the researchers may 
require you to be admitted to a hospital. 
 
Mood:  Some after-effects of MDMA may be noticeable up to 2 or 3 days later. While some people felt that 
their mood is better, about 3 out of every 20 felt that it was worse after receiving MDMA in other research 
studies. 
 
Possible Risks to Brain Function: One study conducted by the sponsor in 20 people with PTSD found that two 
doses of 125mg MDMA spaced a month apart did not lead to differences in how well their brain functioned 
from a placebo control. The dose you will receive in this study will be similar to or less than this amount, and 
you will only receive it twice, just like in the previous study. Studies of people receiving one or two doses of 
MDMA in a laboratory setting have not found any lasting changes in memory or planning. Studies comparing 
people before and after they decided to take a few tablets of Ecstasy, which may or may not contain MDMA, in 
a recreational setting with people who did not take them found less improvement in memory in the people who 
took Ecstasy, and no other changes in thinking or planning. It is believed that the amount of MDMA you will 
receive will not produce any lasting changes in memory or planning, though this cannot be guaranteed. 
 
Only one study has looked at brain scans of people before they got MDMA and then again after they have 
received one or two moderate doses of MDMA. This study did not show any changes in the brain following 
MDMA, though it is possible that there were changes that were too small to notice. Other studies looked at 
people before and after they decided to take a few tablets of Ecstasy in a recreational setting, and found one 
small change in the amount of blood flow in a specific part of the brain, but did not show signs of brain injury. 
The decrease in blood volume might be from temporary lowering of a type of brain receptor, or it might be a 
sign of reduced function in this area. Findings from these studies suggest that the amount of MDMA you will 
receive in this study will not produce any lasting changes in your brain, though this is not guaranteed. 
 
Many studies found that people who had used Ecstasy many times in recreational contexts were not able to 
recall words, pictures or patterns as well as people who did not use Ecstasy. They also performed less well on 
tests of planning and impulse control. These differences are not great, but they have lasted for at least a year 
after people had stopped taking Ecstasy. Not all studies have found Ecstasy users to have difficulty recalling 
words or pictures or to have impulse control problems. When compared with people who do not use Ecstasy, 
studies found Ecstasy users were more likely to report feeling generally anxious or depressed. Many of these 
studies found that using alcohol or other drugs was also associated with feeling anxious or depressed. At least 
two studies found that people who are anxious, depressed or have psychological problems before taking any 
drugs are more likely to take Ecstasy than people without these problems, but there is no proof that MDMA 
might not cause these problems in some people. 
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Experiments in rats and monkeys show that high and repeated doses of MDMA can change certain brain cells 
that release a chemical called serotonin; in mice (though not in humans), the affected cells release dopamine. 
The changes include loss of the parts of the cell (called "axons") that connect different brain areas. Rodents 
given repeated, high doses of MDMA are less sensitive to a later dose of MDMA, are more likely to become 
overheated when placed in a warm room, and some studies find they perform worse in difficult memory tests. 
Recent studies in monkeys and rodents suggest that the doses used in those studies were far higher than those 
typically taken by humans in either recreational or laboratory settings. 
 
Worsening of Symptoms: You may experience a worsening of your social anxiety symptoms while taking part 
in this study. This may occur when you are stopping your current medications and if you receive placebo (no 
active medicine). This may also occur if you receive MDMA during this study.  
 
Other Risks: 
 
You should not drive or use machinery immediately after each experimental session (up to 24 hours 
afterwards). This is because the study drug (MDMA) may cause drowsiness, lack of co-ordination or slower 
reaction time. 
 
If you are tested for drugs of abuse within three days of each experimental session, you may test positive. The 
researchers will provide you with an information card in case you are tested for drugs of abuse. If you are tested 
for drugs of abuse while you are taking part in this study, you can have the person(s) testing you call us to 
verify that you are taking part in this study. 
 
The interviews you have during the study involve no specific risks or discomforts beyond those of a standard 
clinical interview situation. You may feel upset at the review of your emotional experiences, or you may feel 
boredom or fatigue. Answering questions about thoughts you might have of hurting or killing yourself may be 
upsetting. 
 
This study involves blood tests. The risks of blood drawing include temporary discomfort from the needle stick, 
bruising and, rarely, infection at the site of the needle stick. Fainting could also happen. If you are not 
comfortable with giving blood for tests, please let us know because it is an important part of taking part in this 
study. 
 
It is possible that after you stop taking psychiatric medicine (as for depression or anxiety) as part of the study, 
you may start to have symptoms again. If this happens, you should talk with your outside therapist and the study 
doctor. If you have to start taking medicine again, then the study doctor will have to take you out of the study. 
 
Reproductive Risks - Females: Effects of MDMA on the growth and development of an unborn baby are not 
known; therefore you will not be allowed to enter the study if you are pregnant. If you become pregnant after 
you have had at least one experimental session, the  study doctor and the sponsor (MAPS) will ask you about 
and keep track of the pregnancy. If this happens, you will need to stop being in the study and they will need to 
know about the outcome of your pregnancy. 
 
Women who are able to become pregnant must use one of the allowed birth control methods, such as birth-
control pills or shots, IUDs (intrauterine devices), and barrier method used along with spermicide for at least 
one month afterward your final study visit/session. We will explain these methods to you and will help you 
decide which might be best for you, and they can suggest to you where you can get more information and 
advice. 
IRB NUMBER: 30026-01
IRB APPROVAL DATE: 07/29/2015
IRB EXPIRATION DATE: 07/28/2016


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If you are a woman that can become pregnant, we will give you a pregnancy test at the start of the study and 
again before each experimental session to see if you are pregnant. If, at any time during the study, you think that 
you may be pregnant or are worried that you may become pregnant, you must notify us immediately. If you 
should become pregnant during the study, we will help you get proper advice and help you and your unborn 
baby get proper care while you are pregnant. However, you are responsible for the costs of the care for your 
pregnancy.  
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
 
Your mental health symptoms may improve while taking part in this study. There is no guarantee that you will 
benefit from taking part in this research study. However, information obtained from this study may help doctors 
and researchers to improve treatment of autistic adults with social anxiety in the future. 
 
What other choices do I have if I do not take part in this study? 
 
One alternative to being in this study is to decide not to take part in it. This study does not offer you a treatment 
for your social anxiety but is rather looking to see if MDMA can be studied further as a possible treatment. This 
study is looking to find the appropriate dose for a possible future study. 
 
You may decide to try other treatments for social anxiety. There are other medicines, Valium (diazepam), 
Xanax (alprazolam), or Prozac (fluoxetine) and other forms of psychotherapy that you could try. If you are 
currently having psychotherapy and/or taking medicine, you could continue with those for a longer period of 
time.  
 
The researchers can discuss the alternatives and their potential risks and benefits with you. Talk to your doctor 
about your choices before you decide if you will take part in this study. 
 
 
Will my personal and medical information be kept private?  
 
We will do our best to make sure that the personal information in your medical record is kept private. However, 
we cannot guarantee total privacy. We may have to give out your personal information if required by law. If 
information from this study is published or presented at scientific meetings, we will not use your name and 
other personal information. To ensure confidentiality, we will only provide the sponsor with your data 
(study information) containing your study ID (not your name). 
 
When not in use, we will keep your medical record (containing all information collected from you during and 
for the study) in a locked office. Absolute confidentiality cannot be guaranteed, but every effort will be 
made to maintain your confidentiality. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance, and data 
analysis include: 
 The sponsor, Multidisciplinary Association of Psychedelic Studies (MAPS); 
 The U.S. Food and Drug Administration and similar regulatory agencies in other countries; 
 The Department of Health and Human Services (DHHS) agencies; 
 The Research Advisory Panel of California or State regulatory agencies; and 
 The Institutional Review Board (IRB). 
IRB NUMBER: 30026-01
IRB APPROVAL DATE: 07/29/2015
IRB EXPIRATION DATE: 07/28/2016


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Video recordings: The researchers (study doctor and study team), the sponsor (MAPS) staff and other 
researchers that the study doctor has given permission to who are seeking to better understand the principles of 
MDMA-assisted therapy will listen to or watch these recordings. No identifying information (such as your 
name) will be written on or attached to the recordings. You may listen to or watch the recordings if you wish, 
but you do not have to. You will not automatically receive a copy of the recordings of your experimental 
session, but if you wish, you may ask to view the recording. You have the right to view your study records and 
ask for changes if the information is not correct.  
 
What are the costs of taking part in this study? 
 
The sponsor of this study, MAPS, will cover the costs that are directly related to this study. This includes the 
costs for all therapy sessions that are a part of this study (includes all experimental and integrative sessions), for 
the psychological and laboratory testing, for medical examinations, including any extra tests you might have 
solely to see if you can be in the study (if you are eligible) and for the study drug. You, your private medical 
insurance (if any), and the public health insurance plan will not be charged for any procedures done solely for 
the purpose of the study. You or your insurance company will remain responsible for on-going treatment 
unrelated to the study.  
 
If you live more than 30 miles from the study site, you will be reimbursed for one night (the night after each 
experimental session) in a hotel room at a hotel close to the study site that will be comfortable for you and your 
support partner. 
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, 
 if you feel that you have been injured 
because of taking part in this study. You can tell the doctor in person or call him/her at 
. If you 
cannot reach your study doctor, you may call the hospital emergency department (adult, 
) or the 
hospital Psychiatric Emergency Department at 
. 
 
You will get medical treatment if you are injured as a result of taking part in this study. If you are injured as a 
direct result of the study medicines or procedures required by this study, we will provide you with appropriate 
medical care including treatment and hospitalization if necessary. The sponsor of this study agrees to pay for 
such medical care including treatments and hospitalizations that are not covered by your health insurance or 
other third party provider. 
 
What are my rights if I take part in this study? 
 
Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If 
you decide to take part in this study, you may leave the study at any time (unless if it‟s during an experimental 
session, in which case you are agreeing to remain in the treatment room until the doctor agrees that it is safe for 
you to leave).  No matter what decision you make, there will be no penalty to you and you will not lose any of 
your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from 
.   
 
By signing below, you will be agreeing to allow the researchers to decide what to do with any surplus tissue 
(blood) removed from your body during the research described above.  
IRB NUMBER: 30026-01
IRB APPROVAL DATE: 07/29/2015
IRB EXPIRATION DATE: 07/28/2016


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We will tell you about new information or changes in the study that may affect your health or your willingness 
to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by 
signing this form.  
 
IRB NUMBER: 30026-01
IRB APPROVAL DATE: 07/29/2015
IRB EXPIRATION DATE: 07/28/2016


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Who can answer my questions about the study? 
 
If you have questions, concerns, or complaints, or think the research has hurt you, talk to the research team at 
 
 
This research has been reviewed and approved by a John F. Wolf, M.D. Human Subjects Committee, which is 
located at 1124 W. Carson St., Building N-14 in Torrance, CA. You may talk to them at (310) 222-3624 or 
email them at compliancehs@labiomed.org for any of the following: 
 Your questions, concerns, or complaints are not being answered by the research team. 
 You cannot reach the research team. 
 You want to talk to someone besides the research team. 
 You have questions about your rights as a research subject. 
 You want to get information or provide input about this research. 
 
Have you taken part in any research studies within the past three months? 
Circle “Yes” or “No” 
Yes 
No 
 
 
If “YES”, please describe:  
 
 
 
 
 
 
 
If you want more information about this study, ask your study doctor. 
 
IRB NUMBER: 30026-01
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IRB EXPIRATION DATE: 07/28/2016


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SUBJECT’S STATEMENT OF CONSENT 
 
I have been given a copy of this consent form in its entirety (all pages). I have read it or it has been read to 
me. I understand the information and have had my questions answered. You will receive a copy of this 
signed informed consent form as well as a copy of the Human Subject‟s Bill of Rights. I agree to voluntarily 
take part in this study.  
 
By signing this consent form, I have not waived any of the legal rights which I otherwise would have as a 
participant in a research study. 
 
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
 
Your signature documents your permission to take part in this research. 
 
 
 
Signature of subject 
 
Date 
 
 
Printed name of subject 
 
 
 
Support partner‟s signature 
 
Date 
 
 
 
Printed name of support partner 
 
 
 
 
 
Witness to Subject Signature 
 
Date 
 
 
 
Signature of person obtaining consent 
 
Date 
 
Printed name of person obtaining consent 
 
 
 
Video and Audio Recording of Sessions:  
I agree to have my sessions video and/or audio (voice only) recorded for the purposes described in this consent 
form.  
Circle your choice (Yes or No) and sign below. 
 
Yes 
No 
 
 
 
 
Signature of subject 
 
Date 
 
IRB NUMBER: 30026-01
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IRB EXPIRATION DATE: 07/28/2016


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SUPPORT PARTNER’S STATEMENT OF CONSENT 
 
“A Placebo-controlled, Randomized, Blinded, Dose Finding Phase 2 Pilot Safety Study of MDMA-assisted 
Therapy for Social Anxiety in Autistic Adults” 
 
My participation in this study as a Support Partner is voluntary. I may refuse to take part in or I may stop taking 
part in this study as a Support Partner at any time. I will call the researchers if I decide to do this. My decision 
will not affect my current or future regular medical care or any benefits to which I am entitled at this medical 
center. The researchers and/or the sponsor may stop my participation in this study at any time without my 
consent if they decide it is in my best interest or if I do not follow the researchers‟ instructions. 
 
I have been told that my role as a Support Partner includes: 
 Providing reliable transportation, as required, to and from office visits and taking part in study visits, as 
appropriate.  
 Driving the participant home or to another secure location following sessions. No participant will be 
allowed to drive themselves home after experimental sessions.  
 Remaining available to attend to basic comfort needs and to talk with the participant in person for 24 
hours after experimental sessions.  
 
I have been given a copy of this consent form in its entirety (all pages). I have read it or it has been read to 
me. I have been given sufficient opportunity to consider participating in this study as a Support Partner. All 
of my questions so far about the study and my participation in it have been answered. You will receive a 
copy of this signed informed consent form as well as a copy of the Human Subject‟s Bill of Rights. I agree 
to voluntarily take part in this study.  
 
By signing this consent form, I have not waived any of the legal rights which I otherwise would have as a 
participant in a research study. 
 
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
 
Your signature documents your permission to take part in this research. 
 
 
 
Signature of support partner 
 
Date 
 
 
Printed name of support partner 
 
 
 
Witness to support partner‟s signature 
 
Date 
 
 
 
Signature of person obtaining consent 
 
Date 
 
 
 
Printed name of person obtaining consent 
 
 
IRB NUMBER: 30026-01
IRB APPROVAL DATE: 07/29/2015
IRB EXPIRATION DATE: 07/28/2016


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For the Investigator: 
 
I certify that I am the principal investigator and am responsible for this study, for ensuring that the subject is 
fully informed in accordance with applicable regulations, and for advising the Human Subjects Committee of 
any adverse reactions that develop from the study. 
 
Principal Investigator: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date   
 
 
 
 
Principal Investigator: 
  
Telephone Number: 
IRB NUMBER: 30026-01
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IRB EXPIRATION DATE: 07/28/2016


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HUMAN SUBJECT'S BILL OF RIGHTS 
 
Anyone asked to take part as a subject in a medical research study or asked to agree on behalf of 
someone else, has the right to understand the following: 
 
1. 
What the study is about and why it is being done. 
 
2. 
What you will have to do if you take part in the research study and what treatments, drugs 
or medical devices, if any, will be used. 
 
3. 
Any pain or discomfort you may expect to feel and what risks you might run, if any, from 
taking part in the research study. 
 
4. 
What benefit to your health, if any, you might get from taking part in the research study. 
 
5. 
Other non-research treatments, drugs or medical devices that may be available to treat 
your illness and a comparison of the risks and benefits of these other treatments with the 
one you are being asked to agree to receive. 
 
6. 
What medical treatment, if any, will be available to you after the research study, if 
medical complications arise as a result of the study. 
 
7. 
You will be given a chance to ask questions about the research study, until you are 
satisfied that you understand what is involved. You should expect your questions to be 
answered clearly, fully and honestly. 
 
8. 
If you agree to take part in the research study, you can later change your mind at any time 
without being penalized. Leaving the study will not affect your usual medical care. 
 
9. 
You will not be pressured, forced, misled, given wrong facts, bribed or unfairly 
influenced to get you to agree to take part in the experiment. 
10. 
You will be given a copy of any consent form you sign for the research study.  
IRB NUMBER: 30026-01
IRB APPROVAL DATE: 07/29/2015
IRB EXPIRATION DATE: 07/28/2016

SAP_001.pdf: 
MAPS Public Benefit Corporation                                                                               MAA-1 Statistical Analysis Plan 
US                                                                                                                           
Version 1: 31 August, 2017
 
-  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: 18501159-F2AE-4BA7-B452-BCB222E2CDF4


MAPS Public Benefit Corporation                                                                               MAA-1 Statistical Analysis Plan 
US                                                                                                                           
Version 1: 31 August, 2017
 
MAA-1 Statistical Analysis Plan 
 
Version 1: 31 August, 2017 
 
 
CORPORATION
 
 
 
MAPS Public Benefit Corporation (MPBC) 
1115 Mission Street 
Santa Cruz, CA 95060 
 
CORPORATION DESIGNEE 
 
Amy Emerson 
Executive Director and Director of Clinical Research 
USE
 
STUDY TITLE 
 
A Placebo-Controlled, Randomized, Blinded, Dose 
Finding Phase 2 Pilot Safety Study of MDMA-Assisted 
Psychotherapy for Social Anxiety in Autistic Adults 
LATEST PROTOCOL  
Version 2, May 21, 2013 
 
INVESTIGATOR 
Charles S. Grob, M.D. 
 
MEDICAL MONITOR 
 
Michael C. Mithoefer, M.D. 
 
STATISTICIAN 
 
Scott Hamilton, Ph.D. 
 
PLAN PREPARED BY 
 
Scott Hamilton, Ph.D. 
Allison Feduccia, Ph.D. 
Berra Yazar-Klosinski, Ph.D. 
 
Table of Contents 
List of Abbreviations .................................................................................................................... 4
DocuSign Envelope ID: 18501159-F2AE-4BA7-B452-BCB222E2CDF4


MAPS Public Benefit Corporation                                                                               MAA-1 Statistical Analysis Plan 
US                                                                                                                           
Version 1: 31 August, 2017
1.0
Definitions of Terms ......................................................................................................... 5
2.0
Introduction ....................................................................................................................... 6
3.0
Analysis Plan Objectives .................................................................................................. 6
3.1
Primary Objective ..................................................................................................................... 6
3.2
Secondary Objectives ................................................................................................................ 6
3.3
Safety Objectives ....................................................................................................................... 7
4.0
Study Design ...................................................................................................................... 8
5.0
Randomization and Blinding ......................................................................................... 12
6.0
Sample Size and Power Considerations ........................................................................ 12
7.0
Measures .......................................................................................................................... 12
7.1
Outcome Measures .................................................................................................................. 12
7.2
Safety Measures ....................................................................................................................... 13
7.3
Process Measures ..................................................................................................................... 13
8.0
Analyses ........................................................................................................................... 13
8.1
Analysis Populations ............................................................................................................... 14
8.2
Handling of Dropouts, Missing Data ..................................................................................... 14
8.3
Partial or Missing Dates .......................................................................................................... 14
8.4
Protocol Deviations .................................................................................................................. 15
8.5
Pooling of Investigator Centers .............................................................................................. 15
8.6
Baseline Values ........................................................................................................................ 15
8.7
Subject Disposition and Dosing Summary ............................................................................ 15
8.8
Demographics and Baseline Characteristics ......................................................................... 16
8.9
Prior and Concomitant Medications ...................................................................................... 16
8.10
Efficacy Analyses ..................................................................................................................... 16
8.10.1
Primary Efficacy Analyses ............................................................................................... 16
8.10.2
Secondary Efficacy Analyses ........................................................................................... 17
8.10.3
Exploratory Analyses ........................................................................................................ 18
8.10.4
Safety Analyses ................................................................................................................. 19
8.11
Timing of Analyses .................................................................................................................. 19
9.0
Statistical Software ......................................................................................................... 20
10.0
References ........................................................................................................................ 20
 
 
 
 
 
 
 
 
 
 
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MAPS Public Benefit Corporation                                                                               MAA-1 Statistical Analysis Plan 
US                                                                                                                           
Version 1: 31 August, 2017
List of Abbreviations  
 
AE(s)  
Adverse Event(s) 
ANOVA   
Analysis of Variance 
AVP 
Arginine Vasopressin 
BDI-II 
Beck Depression Inventory-II 
BP 
Blood Pressure 
BT  
Body Temperature 
CORT 
Cortisol 
C-SSRS  
Columbia Suicide Severity Rating Scale  
DBP  
Diastolic Blood Pressure 
DES-II 
Dissociative Experiences Scale-II 
ERQ 
Emotion Regulation Questionnaire 
ES  
Effect Size 
GWB 
General Well Being 
HR  
Heart Rate 
IR 
Independent Rater 
IRI 
Interpersonal Reactivity Index 
ITT  
Intent To Treat  
LSAS 
Liebowitz Social Anxiety Scale 
MAPS 
Multidisciplinary Association for Psychedelic Studies 
MDMA 
3,4-methylenedioxymethamphetamine 
MPBC 
MAPS Public Benefit Corporation  
OT 
Oxytocin 
PI 
Principal Investigator 
PP  
Per Protocol 
PSS 
 
PTSD  
Posttraumatic Stress Disorder 
QoL-Q 
Quality of Life Questionnaire 
RCT  
Randomized Controlled Trial 
RSES 
Rosenberg Self Esteem Scale 
SAE(s) 
 
SBP  
Systolic Blood Pressure 
SRR 
Spontaneously Reported Reactions 
STAI 
State-Trait Anxiety Index 
SUD 
Subjective Units of Distress 
TAS-20 
Toronto Alexithymia Scale  20 
TASIT 
(The) Awareness of Social Inference Test 
 
  
 
 
 
 
DocuSign Envelope ID: 18501159-F2AE-4BA7-B452-BCB222E2CDF4


MAPS Public Benefit Corporation                                                                               MAA-1 Statistical Analysis Plan 
US                                                                                                                           
Version 1: 31 August, 2017
1.0  
Definitions of Terms
Categorical data: refers to discrete (indivisible) variables, such as gender or ethnicity; data will 
be presented as total numbers of each category as needed to describe the sample 
 
Descriptive data: includes mean, median, standard deviation, minimum, and maximum of 
numerical data used as needed to describe the sample 
 
Difference scores: consist of scores computed by subtracting one value from another, as 
subtracting Baseline from End of Stage 1 score, used to test for differences between and within 
groups to determine change as a function of experimental treatment over time 
 
Efficacy: type of analysis used to assess therapeutic effects or benefits 
 
Exploratory analyses: inferential or descriptive analysis of the data to determine trends that 
might lead to hypotheses for further study 
 
Frequency listing: tabular listing of numbers and/or percentages of events used as needed to 
describe the sample or data characteristics 
 
Outcome measures: primary and secondary study measures that are used to test the study 
hypotheses 
 
Process measures: study measures or qualitative observations collected during the study that 
may increase depth of understanding and that are not necessarily related to safety or efficacy 
 
Protocol deviation: event that represents significant divergence from the intended study design 
as described in the protocol 
 
Safety: assessment of the condition of study subjects that examines potential risks, adverse 
events, and reactions 
 
Safety measures: study measures that assess safety, such as heart rate monitoring, that are used to 
assess safety of the study drug 
 
Spontaneously reported reactions, reactions: specific expected reactions gathered from the 
literature on MDMA 
 
Study design: all elements of a research project that define the study question, experimental 
methods, study procedures including randomization and blinding, measurement techniques, data 
workflow, and statistical analysis 
 
Tabular listing: list of each variable or item for each individual subject either in total or by 
condition in a table format 
 
 
 
DocuSign Envelope ID: 18501159-F2AE-4BA7-B452-BCB222E2CDF4


MAPS Public Benefit Corporation                                                                               MAA-1 Statistical Analysis Plan 
US                                                                                                                           
Version 1: 31 August, 2017
2.0  Introduction
 
This document presents a Statistical Analysis Plan (SAP) for MAPS study protocol MAA-1, a 
Phase 2 pilot clinical trial designed to evaluate the safety, feasibility, and efficacy of MDMA-
assisted psychotherapy in treating social anxiety in adults on the autism spectrum. 
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 adults on the autism 
spectrum with social anxiety. This is an initial pilot study to assess the efficacy of MDMA for 
this indication, following promising results from MAPS-sponsored studies of MDMA-assisted 
psychotherapy for posttraumatic stress disorder (PTSD). 
The Phase 2 pilot study will examine the safety, feasibility, and efficacy of MDMA-assisted 
psychotherapy for social anxiety in 12 MDMA-naïve adults on the autism spectrum. This study 
is designed as a dose escalation study to assist with the exploration of safety and finding the most 
effective dose in this population. Subjects assigned to the MDMA group will receive two of three 
different doses, either 75 mg, 100 mg, or 125 mg MDMA. Overall, eight subjects (66.7%) will 
be randomized to the MDMA group and four subjects (33.3%) will be randomized to the placebo 
group. Subjects who received the placebo during Stage 1 will have the opportunity to cross over 
and take part in a second study segment, referred to as Stage 2, with two open-label experimental 
sessions, after completing the six-month follow-up visit at the end of Stage 1.  
 
This study is designed to obtain safety data, and secondarily estimates of effect size for efficacy. 
The data will be used to determine study design and dosing for future studies for this indication.  
MAA-1 is also intended to contribute to the development of a manualized psychotherapeutic 
approach to this potential treatment. This study is exploratory. As a result, the sponsor will 
perform tests on all statistical comparisons without correcting for multiple comparisons. 
3.0   Analysis Plan Objectives 
 
3.1   Primary Objective  
 
The primary objective is to assess changes in social anxiety symptoms between MDMA and 
placebo groups, as measured by the clinician-administered administered Liebowitz Social 
Anxiety Scale (LSAS) administered by a blinded Independent Rater (IR), at baseline, one 
day, two weeks, and one month after each experimental session, and at 6- month follow-up. 
 
3.2   Secondary Objectives 
The following objectives will compare MDMA and placebo groups in the blinded Stage 1: 
 
 To assess effects on levels of oxytocin (OT), arginine vasopressin (AVP), and cortisol 
(CORT) in peripheral blood at baseline, once during each experimental session between 
hours 2  3, one month after the second experimental session, and at 6-month follow-up. 
 To assess effects on social perception using The Awareness of Social Inference 
Test (TASIT) at baseline, once during each experimental session between hours 2-3, one 
month after the second experimental session, and at 6-month follow-up. 
DocuSign Envelope ID: 18501159-F2AE-4BA7-B452-BCB222E2CDF4


MAPS Public Benefit Corporation                                                                               MAA-1 Statistical Analysis Plan 
US                                                                                                                           
Version 1: 31 August, 2017
 To assess effects on emotion labeling using the Toronto Alexithymia Scale-20 
(TAS-20) at baseline, one month after each experimental session, and 6-month 
follow-up. 
 To assess effects on emotion regulation using the Emotion Regulation 
Questionnaire (ERQ) at baseline, one month after each experimental session, and 
6-month follow-up. 
 To assess effects on depression symptoms as measured by the Beck Depression 
Inventory-II (BDI-II) at baseline, one day, two weeks, one month after each experimental 
session, monthly by mail during the 5 months leading up to the 6- month follow-up 
assessment.  
 To assess effects on perceptions of stress as measured by the Perceived Stress Scale 
(PSS) at baseline, within 24 hours after each experimental session, one month after each 
experimental session and monthly by mail leading up to the 6- month follow-up 
assessment.  
 To assess effects on four aspects of empathy, as measured by the Interpersonal Reactivity 
Index (IRI) at baseline, within 24 hours after each experimental session, one month after 
each experimental session, and at the 6-month follow-up assessment.  
 To assess effects on self-esteem as measured by the Rosenberg Self-Esteem Scale 
(RSES) at baseline, within 24 hours after each experimental session, one month after 
each experimental session, and at the 6-month follow-up assessment.  
 To assess effects on state and trait anxiety as measured by the State-Trait Anxiety Index 
(STAI Form Y) at baseline, one day, two weeks, and one month after each experimental 
session, and monthly by mail leading up to the 6-month followup assessment.  
 
The following objectives will compare effects in specified subjects:  
 To determine if subjects who receive placebo in Stage 1 show a reduction in LSAS scores 
after two open-label sessions in the Stage 2 crossover 
 To explore whether TAS-20 scores and OT, AVP, and CORT levels at baseline predict 
LSAS scores at the primary endpoint 
 
 
The following objectives will include exploratory analyses intended to inform protocol 
design: 
 To assess the ability of the investigators and subjects to accurately guess 
condition assignment in Stage 1. 
 To assess perceptions about dose and study procedures at baseline and 6-month 
follow-up using a qualitative interview and feedback questionnaire. 
 To determine feasibility of recruiting, testing and treating subjects on the autism 
spectrum with MDMA-assisted therapy as measured by enrollment rates, dropout 
rates, and completion of assessments and other study-related procedures.  
 
3.3   Safety Objectives 
 
The safety objectives of the study are to monitor and assure safety of subjects during and after 
the experimental sessions by assessing physiological effects, psychological distress, adverse 
events, spontaneously reported reactions and suicidality.   
 
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MAPS Public Benefit Corporation                                                                               MAA-1 Statistical Analysis Plan 
US                                                                                                                           
Version 1: 31 August, 2017
 Vital signs (BP, HR, BT) will be measured at baseline and every hour during 
experimental sessions until they return to baseline.  
 Participant distress will be measured by the Subjective Units of Distress (SUD) scale at 
baseline and every hour during experimental sessions until return to baseline. 
 Risk of suicide will be measured by the Columbia Suicide Severity Rating Scale (C-
SSRS) during all in person visits, as well as twice during each experimental session at 
two hours after drug administration and the end of the experimental session, and on Day 
2 and Day 7 after each experimental session.  
 SAEs and AEs will be assessed throughout the study and spontaneously reported 
reactions, defined as expected AEs, will be assessed during each experimental session 
and for seven days after each experimental session, or until resolution. 
 In addition to spontaneously reported reactions, symptoms specific to the study 
population will be collected at baseline and tracked throughout the study 
4.0   Study Design 
 
This randomized, double-blind, placebo-controlled study will examine the safety, feasibility, 
efficacy of MDMA-assisted psychotherapy in twelve adults on the autism spectrum with social 
anxiety. Each of the 12 subjects will participate in two experimental drug-assisted (MDMA or 
placebo) therapy sessions of seven hours in duration within a brief course of non-drug therapy, 
including three preparatory sessions at the start of the study and three integrative sessions during 
the month after each experimental session.  
 
Upon enrollment, the first six subjects (Group 1) will be randomized to receive one dose of 
either placebo (N=2) or 75 mg MDMA (N=4). In the second experimental session one month 
later, Group 1 subjects randomized to MDMA will escalate to 100 mg MDMA, unless 
contraindicated by safety and tolerability concerns. The second six subjects (Group 2) will be 
randomized to receive one dose of either placebo (N=2) or 100 mg MDMA (N=4). In the second 
experimental session one month later, Group 2 subjects randomized to MDMA will escalate to 
125 mg MDMA, unless contraindicated by safety and tolerability concerns. Subjects randomized 
to placebo in Group 1 and Group 2 will receive placebo in both experimental sessions also 
scheduled one month apart. The blind will be maintained through the six-month follow-up for 
each individual subject, after which the blind will be broken. Placebo subjects will be offered an 
open-label extension (Stage 2) with two experimental sessions scheduled one month apart, in 
addition to three hour-long integrative sessions during the month after each experimental session. 
Stage 2 subjects will receive 75 mg MDMA in the first experimental session and will escalate to 
125mg MDMA in the second experimental session, unless contraindicated by safety and 
tolerability concerns from other subjects in Stage 1. Subjects will attend a 1-hour follow-up 
integrative therapy session on the day after the experimental session. Two additional integrative 
sessions will be conducted within the month following each experimental session, prior to 
outcome assessments being conducted one month after each experimental session.  
 
Outcome measures will be assessed prior to treatment, during the treatment period, one month 
after each experimental session, and during the 6-month follow-up according to the Time and 
Events table. The sponsor will conduct an ongoing review of videos of therapy sessions, entry 
criteria, vital signs, and reaction data for completed sessions and any AEs. The sponsor will 
provide ongoing feedback to the co-therapist teams to ensure subject safety. Blood samples will 
be obtained for biomarker analysis at baseline and during the study according to the Time and 
Events Table. Biomarker analyses including plasma OT, AVP, and CORT will be explored as 
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surrogate endpoints at baseline, two hours after drug administration during the second 
experimental session, one month after the second experimental session, and at 6-month follow-
up. Blood will be collected during the open-label extension Stage 2 two hours after drug 
administration during both experimental sessions and one month after both experimental 
sessions. Biomarkers will be evaluated for predictive and prognostic power. Subjects will 
complete a 6-month follow-up visit after completing Stage 1 or 2.  
 
 
Table 1: Dose Regimen 
Group # 
/Randomization 
/Sample 
Stage 1 
Stage 2 Open-Label 
 
Session 1 
Month 1 
Session 2 
Month 2 
Session 1 
Month 6 
Session 2 
Month 7 
Group 1 Active  
(n=4) 
75 mg 
100 mg 
N/A 
N/A 
Group 1 Placebo 
(n=2)  
Placebo 
Placebo 
75 mg 
125 mg 
Group 2 Active 
(n=4) 
100 mg 
125 mg 
N/A 
N/A 
Group 2 Placebo 
(n=2) 
Placebo 
Placebo 
75 mg 
125 mg 
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Table 2: Time & Events Stage 1 
 
 
 
 
 
 
 
 
 
 
-
 
-
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-  
 
 H 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H 
 
 
 
 
  
  
  
 
  
  
  
 
  
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 J 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A = At the beginning of the session; B = Approximately every sixty minutes; C = As needed; D = Approximately six hours post drug; E =Day 2 and Day 7 phone calls only; F = Reactions  
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collected for seven days post experimental session; G = Independent Rater administered; H = May be recorded to video; I = Stage 2 subjects only; J = Only MDMA subjects will terminate. 
Table 3: Time and Events Stage 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A = At the beginning of the session; B = Approximately every sixty minutes; C = As needed; D = Approximately six hours post MDMA; E =Day 2 and Day 7 phone calls only; F = Reactions 
collected for seven days post experimental session; G = Independent Rater administered; H = May be recorded to video; I = At least 5 half-lives and 1 week before the experimental sessio
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
  
  
  
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.0   Randomization and Blinding 
 
This is a randomized, double-blind, placebo-controlled study with an open-label cross-over 
segment. For Stage 1, a randomization list will be prepared at the beginning of the study. If 
needed, subsequent randomization lists will be created to replace subjects who withdraw from 
the study to ensure that replacement subjects are not added to the end of the initial list. Each 
subject will be assigned to one of the two dose conditions: 0 mg (placebo) or 125 mg (full dose). 
Eight evaluable subjects will be assigned to the full dose condition, and four to the placebo 
condition. The study will employ a blinded randomization procedure that will maintain the 8:4 
ratio while maintaining the blind and ensuring that each subsequent condition assignment is not 
predicated on the previous assignment.  
6.0   Sample Size and Power Considerations 
 
This study is a pilot investigation intended to gather preliminary data on the safety and efficacy 
of MDMA in 12 subjects on the autism spectrum with social anxiety. Because of their 
exploratory nature, pilot studies are often not powered for detecting the desired effect. Because it 
is a pilot study in a small sample, results will used to collect effect size estimates for statistical 
power calculations for adequately powered subsequent studies. 
7.0   Measures 
 
7.1   Outcome Measures 
 
 Liebowitz Social Anxiety Scale (LSAS), total score 
 
 Perceived Stress Scale (PSS), total score 
 
 Beck Depression Inventory-II (BDI-II), total score 
 
 Interpersonal Reactivity Index (IRI), composite scores 
 
 Rosenberg Self Esteem Scale (RSES), total score  
 
 State Trait Anxiety Index (STAI), composite scores 
 
 The Awareness of Social Inference Test (TASIT), composite and total scores 
 
 Toronto Alexithymia Scale 20 (TAS-20), total score 
 
 Emotional Regulation Questionnaire (ERQ), composite scores 
 
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 Quality of Life Questionnaire (QoL-Q), composite and total scores 
 
7.2   Safety Measures 
 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 
 Subjective Units of Distress (SUD) 
 
 General Well-being (GWB) 
 
 Symptoms Specific to Population  
 
 Vital signs (systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate 
(HR), body temperature (BT))  
 
 Adverse Events (AE), including Spontaneously Reported Reactions (SRR) 
 
7.3   Process Measures 
 
 Belief of Treatment Group Assignment 
 
 Subject perceptions of Experimental Sessions 
 
 Feedback Questionnaire 
8.0   Analyses 
 
In general, nominal variables will be described in terms of frequencies and percentages and 
analyzed using chi square analysis. Ordinal and non-normal continuous variables will be 
described using sample median and range, and analyzed by non-parametric statistical tests, and 
approximately normal variables will be described using sample mean and standard deviations 
and analyzed by parametric statistical tests. All statistical tests will be two-sided. All p-values 
will be rounded to and displayed in four decimals. If a p-value less than 0.0001 occurs it will be 
shown in tables as <0.0001.  For any analysis that is called out as parametric, e.g. t-test, the 
parametric assumptions will be examined.  If necessary, nonparametric analyses will be utilized, 
e.g. Wilcoxon rank-sum test. 
 
Clinical data will be presented in tabular format. Data not subject to analysis according to this 
plan will not appear in any tables or graphs, but will be included in the data listings. Analyses 
will be carried out with SAS Version 9.3 or higher. Selected results may be presented graphically 
using standard graphical software. 
 
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Post-hoc exploratory analyses not identified in this SAP may be performed to further examine 
the study data. These analyses will be clearly identified as such in the final clinical study report. 
 
8.1   Analysis Populations 
 
Intent-to-treat (ITT): all subjects who were randomized 
 
Per protocol (PP): all subjects who completed Stage 1, underwent assessment of anxiety 
symptoms, and did not experience a major protocol deviation 
 
Crossover: all subjects who completed Stage 2 in addition to completing Stage 1 
 
Safety: all subjects who receive any study treatment 
 
8.2   Handling of Dropouts, Missing Data 
 
Early termination visit data for ITT and Safety variables will be analyzed at the closest scheduled 
visit. If the closest visit has valid data, the early termination data will be assigned to the next 
available visit. 
8.3   Partial or Missing Dates 
 
The following conventions will be used to impute missing portions of dates for adverse events 
and concomitant medications. Note that the imputed values outlined here may not always 
provide the most conservative date. In those circumstances, the imputed value may be replaced 
by a date that will lead to a more conservative analysis. 
A. 
Start Dates 
1) 
If the year is unknown, then the date will not be imputed and will be assigned a 
missing value.  
2) 
If the month is unknown, then: 
i) If the year matches the first dose date year, then impute the month and day of 
the first dose date. 
ii) 
  
3) 
 If the day is unknown, then: 
i) If the month and year match the first dose date month and year, then impute the 
day of the first dose date. 
ii) Otherwise, assign the first day of the month. 
B. 
Stop Dates 
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1) 
If the year is unknown, then the date will not be imputed and will be assigned a 
missing value. 
2) 
 
3) 
If the day is unknown, then assign the last day of the month. 
 
8.4   Protocol Deviations 
All protocol deviations will be included as a categorized listing. Safety and Intent to Treat 
analyses will include all enrolled subjects with all available data. Subjects with major deviations 
will be excluded from the per protocol analyses. Major deviations will be defined as anyone who 
completes through the primary endpoint and anyone who was enrolled but found to not meet 
inclusion/exclusion criteria during the course of the study. The number of subjects in each 
protocol deviation category listed below will be summarized by MDMA group, and individual 
subjects will be listed in the appendix. 
Possible protocol deviations include the following seven categories: 
 
Subject entered study but did not meet criteria 
 
Subject developed withdrawal criteria but was not withdrawn 
 
Subject received excluded concomitant treatment 
 
Protocol procedure not performed per protocol 
 
Subject received incorrect treatment or incorrect dose 
 
Protocol procedure performed out of range 
 
Miscellaneous 
8.5   Pooling of Investigator Centers 
 
All subjects in this study come from one investigational center.  
8.6   Baseline Values 
 
Baseline values are from screening/baseline visit for all measures, except C-SSRS. For C-SSRS, 
baseline (visit 2) scores will be used as a measure of 
 
8.7   Subject Disposition and Dosing Summary 
All subjects enrolled in the study (i.e., who sign informed consent and complete 
inclusion/exclusion criteria) will be included in the summary of subject disposition and 
accountability. No inferential statistical tests will be performed. The tabulation of number of 
subjects in each treatment group and overall will be displayed for all subjects in the Safety 
Population, in the ITT Population, and in the PP Population. The number and percent of subjects 
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who completed or discontinued the study will be displayed for each treatment group and overall 
together with reasons for early termination, where the percent is with respect to the total number 
of randomized subjects in that treatment group. The timepoint of doses and total MDMA (mg) 
administered will be summarized by treatment group for the Safety, ITT and PP Populations.  
 
8.8   Demographics and Baseline Characteristics 
 
Subject demographic data and baseline characteristics will be summarized descriptively by 
treatment group and overall. The demographic data and baseline characteristics will be 
summarized for the ITT and Crossover Populations. 
8.9   Prior and Concomitant Medications  
The number and percent of subjects who took medications prior to and after signing informed 
consent will be summarized descriptively for each treatment group. Concomitant medications 
will be summarized similarly. Prior and concomitant medications will be summarized for the 
Safety Population. Psychiatric medications will be coded to common drug classes and terms. 
8.10   Efficacy Analyses 
For all primary, secondary and exploratory endpoints descriptive statistics (n, mean, standard 
deviation, median, range, or counts and percentages where appropriate) will be provided by 
treatment group.  
8.10.1  Primary Efficacy Analyses 
 
Liebowitz Social Anxiety Scale (LSAS) 
 
The primary efficacy evaluation is the change from baseline to the primary outcome timepoint 
(visit 13, one month post experimental session 2) in the LSAS score of Social Anxiety 
(difference score).  The primary efficacy comparison on difference scores will be made with 
independent sample t-tests at an alpha level of 0.05.  If the primary hypothesis rejects, pairwise 
comparisons among the treatment groups will be made with t-tests. If the parametric assumptions 
for the t-test analyses are not met, the analogous nonparametric methods will be used (Wilcoxon 
-subtracted effect size will be 
estimated on mean difference scores from baseline to Visit 13 with confidence intervals.  
 
 
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8.10.2  Secondary Efficacy Analyses 
 
The secondary efficacy analyses will be made with independent sample t-test comparing change 
from baseline (Baseline) to the primary outcome timepoint (visit 13, one month post 
experimental session 2) of all the secondary measures, following the same methodology used for 
the primary endpoint. If the parametric assumptions for the t-test analyses are not met, the 
analogous nonparametric methods will be used (Wilcoxon Rank Sum Test).  
 
Liebowitz Social Anxiety Scale (LSAS) composite scores will be analyzed in the same manner 
as the LSAS total scale primary analysis, and LSAS total score will also be analyzed for effect 
d analysis. 
 
Perceived Stress Scale (PSS) total score will be analyzed in the same manner as the LSAS total 
scale primary analysis. 
 
Beck Depression Inventory-II (BDI-II) total score will be analyzed in the same manner as the 
LSAS total score primary analysis. 
 
Interpersonal Reactivity Index (IRI) composite scores will be analyzed in the same manner as the 
LSAS total score primary analysis. 
 
Rosenberg Self Esteem Scale (RSES) total score will be analyzed in the same manner as the 
LSAS total score primary analysis. 
 
State Trait Anxiety Index (STAI) subscale scores will be analyzed in the same manner as the 
LSAS total score primary analysis. 
 
The Awareness of Social Inference Test (TASIT) composite and total scores will be analyzed in 
the same manner as the LSAS total score primary analysis. 
 
Toronto Alexithymia Scale 20 (TAS-20) total score will be analyzed in the same manner as the 
LSAS total score primary analysis. 
 
Emotional Regulation Questionnaire (ERQ) composite scores will be analyzed in the same 
manner as the LSAS total score primary analysis. 
 
Quality of Life Questionnaire (QoL-Q) composite and total scores will be analyzed in the same 
manner as the LSAS total score primary analysis. 
 
Biomarker (oxytocin, vasopressin, and cortisol) levels will be analyzed in the same manner as 
the LSAS total score primary analysis. 
 
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8.10.2.1 Secondary Efficacy Analyses at Secondary Endpoints 
 
Crossover Subject Analyses  
LSAS data from subjects assigned to the placebo 
analyzed by t-tests on difference scores from Stage 1 endpoint (Visit 13) to Stage 2 endpoint 
(Visit 22) only if there is sufficient data to examine.  
 
6-month Follow-up Analyses 
To determine durability of effects, LSAS data will be analyzed by t-tests on difference scores 
from Stage 1 endpoint (Visit 13) to 6-month follow-
scores will be analyzed in this same fashion: PSS, BDI-II, IRI, RSES, STAI, TASIT, TAS-20, 
ERQ, QoL-Q 
8.10.3  Exploratory Analyses 
 
Exploratory analyses of biomarkers will examine their ability to predict clinical outcome. 
Analyses will be performed for OT, AVP, CORT, and BDNF. Changes in biomarker 
concentrations from pre-treatment levels will be used to analyze effects of acute dosing and to 
determine the time-course of elevated biomarker levels post-drug. Pre-treatment biomarker 
concentrations will be evaluated in regression analysis with condition assignment in Stage 1 and 
biomarker concentrations at baseline as predictors and treatment outcomes as dependent 
variables. Additionally, the effect of biomarker levels taken at the second experimental session, 
and two weeks and six months after the second experimental session, will be examined for 
correlation with LSAS outcomes.  
 
Distributional characteristics will be examined for outliers and extreme values. If outliers are 
found in primary or secondary outcome measures, the sponsor will perform analyses with and 
without the outlying data. 
 
Post-hoc exploratory analyses not identified in this SAP may be performed to further examine 
the study data. These analyses will be clearly identified as such in the final clinical study report. 
 
8.10.3.1 Process Measures  
 
Belief of Treatment Group Assignment 
In order to compare the t
actual dose received in each blinded session, the number and frequency of correct guesses will be 
calculated and depicted by treatment group and study role (subject, therapist, or independent 
rater). 
 
Feedback Questionnaire 
The Feedback Questionnaire nominal variables will be described in terms of frequencies and 
percentages, while ordinal and non-normal continuous variables will be described using sample 
mean, standard deviations, and range.  
 
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8.10.4  Safety Analyses 
 
The primary measure of safety will be the reporting of adverse events. The Adverse events 
after dosing and those existing AEs that worsened during the study. Verbatim terms on case 
report forms will be mapped to preferred terms and system organ classes using the MedDRA 
dictionary. For incidence reporting if a subject has more than one adverse event mapped to the 
same preferred term, that adverse event will be reported only once using the highest severity and 
closest relationship to study drug.  Subject incidence of adverse events will be displayed by 
Stage I treatment group and by system organ class. Adverse events will also be summarized by 
severity and relationship to study drug. Subject incidence of serious adverse events by Stage I 
treatment group will also be displayed. In addition to the listing of all adverse events, a listing of 
serious adverse events and a listing of adverse events leading to discontinuation of study drug 
will be included.  
 
Summary tables of frequency listings of expected adverse events (Spontaneously Reported 
Reactions) mapped to preferred terms will be displayed during and after each experimental 
session by Stage I treatment group. 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Suicidal ideation and behavior will be summarized according to suggestions made in the 
Columbia-Suicide Severity Rating Scale Scoring and Data Analysis Guide [3]. A positive 
response for suicidal ideation is counted when a subject ans
suicidal ideation questions (Categories 1-5) on the C-SSRS, i.e. a score > 0 for suicidal ideation 
score. Serious suicidal ideation is a suicidal ideation score of 4 or 5. A positive response for 
suicidal behavior occurs when a subject 
questions (Categories 6-10) on the C-SSRS, i.e. a score > 0 for suicidal behavior score. The 
number and percent of positive responses of Positive Ideation, Serious Ideation, and Positive 
Behavior will be tabulated by Stage I treatment group and time period. Compare lifetime serious 
suicidal ideation and positive behavior frequencies to cumulative frequencies anytime during the 
study until end of stage 1 and stage2. 
 
Subjective Units of Distress (SUD) 
Descriptive statistics for SUD scores will be calculated by Stage I treatment group and time 
period with counts and percentages.  
 
Vital signs  
Vital signs (heart rate, body temperature, systolic and diastolic blood pressure) will be 
summarized using descriptive statistics at baseline and at each post-baseline time point. 
Occurrences of systolic and diastolic blood pressure, heart rate, and body temperature readings 
above the pre-determined cutoff will be displayed with numbers and percentages by timepoint.  
 
8.11   Timing of Analyses 
 
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The primary efficacy analysis will be conducted after all subjects complete Stage 2. Subsequent 
analyses on this data set will not be conducted after initial analyses are performed, unless for 
further exploratory post-hoc analyses. Changes to protocol will not occur after primary analysis.  
9.0   Statistical Software 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.3 or higher) for 
Windows. If the use of other software is warranted, the final clinical study report will detail what 
software was used and for what purposes. 
 
10.0   References 
 
1. 
Mithoefer, M.C., et al., The safety and efficacy of {+/-}3,4-
methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, 
treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot 
study. J Psychopharmacol, 2011. 25(4): p. 439-52. 
2. 
Mithoefer, M.C., et al., Durability of improvement in post-traumatic stress disorder 
symptoms and absence of harmful effects or drug dependency after 3,4-
methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term 
follow-up study. J Psychopharmacol, 2013. 27(1): p. 28-39. 
3. 
Nilsson, M.E., et al., Columbia Suicide Severity Rating Scale Scoring and Data Analysis 
Guide, in CSSRS Scoring Version 2.0. 2013: 
http://www.cssrs.columbia.edu/documents/ScoringandDataAnalysisGuide_Feb2013.pdf. 
p. 1-13. 
 
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