MDMA-assisted Therapy for Social Anxiety in Autistic Adults

Studies suggest that autistic adults are at greater risk for social anxiety. Social anxiety
is a condition characterized by fear of scrutiny and avoidance of social interactions. Social
anxiety frequently compounds the considerable social challenges experienced by autistic
adults. There are currently no FDA-approved pharmacologic treatments for autistic adults,
although off-label prescription of selective serotonin reuptake inhibitors (SSRIs) are on the
rise in this population.

Based on the known effects of MDMA, as well as individual reports from autistic adults, this
exploratory study will focus on enhancing functional skills in this underserved population,
who tend to experience greater anxiety, depression and victimization than typically
developing adults. 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 and other psychiatric symptoms that are common in the adult
autistic population as evaluated by standard clinical measures. The primary outcome measure
will be change in social anxiety levels as measured by the Lieberman Social Anxiety Scale
(LSAS). Secondary measures include those of social anxiety, anxiety, depression, stress,
self-esteem, emotion labeling and recognition, empathy, and quality of life, and blood levels
of the hormones oxytocin, arginine vasopressin and cortisol.

Each of the 12 subjects will participate in two blinded experimental sessions, assisted by
either MDMA or placebo lasting seven hours within a brief course of non-drug therapy. The
non-drug therapy includes 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. Subjects assigned to the MDMA group
will receive two of three different doses, either 75mg, 100mg, 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. 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

The Principal Investigator will evaluate all subjects to confirm autistic status. In
addition, autistic status will be confirmed with the gold-standard diagnostic measure of
autism in adults. Upon enrollment, subjects will meet with the study therapists for three
1-hour preparatory sessions scheduled within the month prior to the first experimental
session to discuss what to expect during experimental sessions. In-person visits will occur
in a private room at the research facility. All in-person sessions will be video recorded.
Video recordings will be used for research and training purposes after the study.

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. 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 on
the night following the experimental session.

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 two weeks apart
following each experimental session. During integrative 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.

Biomarker levels will be analyzed to determine if MDMA-assisted therapy causes changes in
these modulators of social behavior in this population as previously demonstrated in
typically developing adults. Biomarker levels will be analyzed for persisting effects at one
month and 6 months after treatment. Blood samples will be obtained from all subjects to
measure plasma OT, AVP and CORT, which will be used to explore as potential 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.

Social anxiety will be measured by interview with a blinded Independent Rater. Questionnaires
measuring anxiety, depression, self-esteem, emotion labeling, emotion recognition, stress,
and self-esteem will be given at baseline and throughout treatment. Quality of life will be
assessed by interview at baseline and 6-month follow.

Inclusion Criteria:

- Have a diagnosis of Autism Spectrum Disorder

- Have at least moderate social anxiety (LSAS score =>60)

- MDMA-naive (no past use of MDMA/ecstasy)

- Are at least 21 years old

- Have completed two years of college-level education or comparable vocational training

- Willing to refrain from psychiatric medication for at least 5 half-lives plus a week
prior to experimental session

- Agree to follow all study-related instructions and restrictions, including
restrictions on food, alcohol and caffeine consumption prior to experimental sessions

- Willing to commit to preparatory sessions, medication management, experimental
sessions, follow-up sessions and to complete evaluation instruments.

- Agree not to use MDMA/ecstasy outside of study sessions during the study, including
the follow up period

- Willing to be contacted on a daily basis for a week after each experimental session

- willing to provide a contact willing and able to be reached by investigators,
accompany the subject during some or all of the study visits, and complete study
measures

- Willing to give blood samples

- Are proficient in speaking and reading English. Subjects communicating with
text-to-speech technology will also be permitted to enroll.

Exclusion Criteria:

- 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.

- Are abusing illegal drugs;

- Are not able to give adequate informed consent.

- Are not able to attend face-to-face visits or those who plan to move out of the area
within the treatment period.

- Are pregnant or nursing, or if a woman who can have children, those who are not
practicing an effective means of birth control;