This is a randomized, open-label delayed treatment study to assess the safety and effect of MDMA-assisted therapy in treating 20 participants diagnosed with moderate-to-severe social anxiety disorder (SAD) of the generalized subtype. This study will obtain an estimate of effect size for two experimental sessions of MDMA-assisted therapy for the treatment of social anxiety disorder on measures of safety, social anxiety, functional outcomes, psychiatric symptoms, and putative mechanisms of action. The primary outcome for this study will be the Liebowitz Social Anxiety Scale (LSAS) administered by a blinded Independent Rater (IR). Other assessments, including physiological, self-report, and behavioral tasks will be used to assess other exploratory variables. An additional aim of the trial will be the development of a treatment manual for MDMA-AT for SAD for future research.

SAD is a prevalent and disabling disorder characterized by intense fear of being scrutinized or negatively evaluated by others in social situations. SAD is the fourth most commonly diagnosed psychological disorder in the United States with onset commonly occurring in adolescence and assuming a chronic course even when treated. Evidence-based treatments for SAD exist, including medications and therapy, but a significant proportion of patients fail to improve, indicating the need for novel effective treatments.

3,4-methylenedioxymethamphetamine (MDMA) is a monoamine releaser and re-uptake inhibitor with indirect effects on neurohormone release. The combined neurobiological effects appear to reduce defenses and fear of emotional injury, enhance communication and introspection, and can increase empathy and compassion. MDMA may also enhance fear extinction learning in humans. The subjective effects of MDMA appear to create a productive psychological state that enhances the therapeutic process. These subjective effects of MDMA create a productive psychological state that enhances the therapeutic process for the treatment of SAD and other anxiety disorders. A Phase 2 MDMA-assisted therapy (MDMA-AT) trial sponsored by MAPS has provided preliminary evidence that social anxiety among adults with autism is treatable with two MDMA-AT sessions and associated non-drug preparatory and integrative psychotherapy (Danforth et al., 2018).

In this open-label Phase 2 study intended to gather supportive data on the safety and effectiveness of MDMA-assisted therapy (MDMA-AT), each of the 20 subjects will participate in two experimental sessions, with half proceeding immediately into treatment once enrolled, and half receiving the experimental treatment after an initial 16 week wait. This study involves a dose of MDMA administered during the Treatment Period with manualized therapy in two monthly Experimental Sessions. This 8-week Treatment Period is preceded by three 90-minute non-drug Preparatory Sessions. Each experimental Session is followed by three 90-minute non-drug Integrative Sessions of non-drug psychotherapy. The Primary Outcome measure is assessed by a blinded Independent Rater at study enrollment, at the primary outcome assessment point (2-weeks after the final integration session), and follow up assessment 26 weeks later. Participants will also be offered the chance to sign up for a long-term follow up extension study at the follow up assessments (with long-term follow up conducted 24 months post-treatment).

Inclusion:

1. Are between the ages of 18 and 65 years old.
2. Live in the Portland, OR area.
3. Are fluent in speaking and reading English.
4. Are able to swallow pills.
5. Agree to have study visits recorded, including Experimental Sessions, assessments, and non-drug psychotherapy sessions.
6. Must provide a contact (relative, spouse, close friend or other support person) who is willing and able to be reached by the investigators in the event of a participant becoming suicidal or unreachable.
7. Must agree to inform the investigators within 48 hours of any medical conditions and procedures.
8. If able to become pregnant, must have a negative pregnancy test at study entry and prior to each Experimental Session, and must agree to use adequate birth control through 10 days after the last Experimental Session.
9. Agree to the necessary lifestyle modifications.
10. Able to identify support person who can stay with participant overnight after experimental sessions.
11. Suitable home environments to allow completion of all study procedures, including sufficient privacy and access to computer or mobile device with internet access.
12. At Screening, meet DSM-5 criteria for current SAD, generalized subtype.
13. At Screening, may have well-controlled hypertension that has been successfully treated with anti-hypertensive medicines, if they pass additional screening to rule out underlying cardiovascular disease.
14. At Screening, may have asymptomatic hepatitis C virus (HCV) that has previously undergone evaluation and treatment as needed.
15. At Enrollment confirmation for those in delayed treatment group, continue to meet criteria for SAD, generalized subtype.
16. Enrollment is allowed with glaucoma only with the approval of their ophthalmologist.

Exclusion:

1. Are not able to give adequate informed consent.
2. Are currently engaged in compensation litigation whereby financial gain would be achieved from prolonged symptoms of SAD or any other psychiatric disorder.
3. Are likely, in the investigator's opinion and via observation during the Preparatory Period, to lack social support or lack a stable living situation or supportive family/network.
4. Have any current problem which, in the opinion of the investigator or Study Physician, might interfere with participation.
5. Would present a serious risk to others as assessed by investigator, Study Physician, or study team.
6. Require certain excluded medications.
7. Have evidence or history of significant (controlled or uncontrolled) hematological, endocrine, cerebrovascular, cardiovascular, coronary, pulmonary, renal, gastrointestinal, immunocompromising, or neurological disease, including seizure disorder, or any other medical disorder judged by the investigator to significantly increase the risk of MDMA administration (participants with hypothyroidism who are on adequate and stable thyroid replacement will not be excluded).
8. Have uncontrolled hypertension using the standard criteria of the American Heart Association (values of 140/90 millimeters of Mercury [mmHg] or higher assessed on three separate occasions).
9. Have a marked baseline prolongation of QT/QTc interval.
10. Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
11. Require use of concomitant medications that prolong the QT/QTc interval during Experimental Sessions.
12. Have symptomatic liver disease.
13. Have history of hyponatremia or hyperthermia.
14. Weigh less than 48 kilograms (kg).
15. Are pregnant, nursing, or are able to become pregnant and are not practicing an effective means of birth control.

Some eligibility criteria have been omitted to protect the integrity of the recruitment process. Full exclusion/inclusion criteria will be reported with results when recruitment is complete. In the interim, please contact research team to inquire about full inclusion/exclusion criteria.

We plan to share anonymized data underlying publications as data sets accessible to other researchers. Requests for other data by outside researchers will be considered on a case-by-case basis.

At time of study publications

Contact the sponsor-investigator to access data that is not publicly shared. Some deidentified data sets with be publicly shared.

Primary outcome measures will be administered by blinded, independent raters.