This pilot study is the first to investigate MDMA-assisted psychotherapy to treat generalized social anxiety, which is prevalent and often disabling for autistic adults. At primary endpoint, the mean change from baseline in LSAS scores was significantly greater for the MDMA group compared to the placebo group. The placebo-subtracted effect size for the changes in LSAS from baseline to the primary endpoint and to 6-month follow-up was very large (d = 1.4 and 1.1, respectively). Enrollment required a total score of 60 or greater on the LSAS at baseline, in a range highly suggestive of generalized SAD. Scores in this range are typical of individuals entering treatment and indicate high levels of distress and difficulties with social functioning. In addition, high mean scores on both the social anxiety and social avoidance subscales were suggestive of generalized SAD as opposed to specific, focal problems such as public speaking anxiety.

Mean scores for the placebo group improved at primary endpoint, but not to the degree of the MDMA group. In comparison, mean scores for the MDMA group remained below the enrollment cutoff after treatment and continued to decrease during the 5-month period when participants were not receiving therapy. Of seven participants in the MDMA group completing treatment, all dropped two to four levels in severity category, whereas the four participants in the placebo group dropped zero to three levels in severity. In addition, six of seven participants in the MDMA group had a > 20-point drop in LSAS scores compared to two of four participants in the placebo group.

To help mitigate potential bias and to minimize inter-rater variability, the same qualified blinded IR conducted every LSAS administration for all participants, which contributed to a high level of consistency in interview methods and scoring. The IR was not present during experimental sessions and did not discuss clinical impressions with investigators who were present during treatment. Participants were instructed not to inform the IR of beliefs concerning their group assignment during the assessment period. The general impression, supported by spontaneous participant feedback, was that the LSAS was an effective instrument for autistic study participants, who typically prefer quantifying responses without the limitations of multiple choice or Likert scales, which can feel imprecise for respondents.

Participant self-report on subjective effects was congruent with the marked decrease in LSAS mean scores, with no participant reporting a clinically significant increase in social anxiety or avoidance behaviors post-treatment. Examples of changes that were self-reported during audio-recorded post-treatment semi-structured interviews, clinical sessions, and in unstructured correspondence with therapists, included reduced barriers to successful social interactions and increased confidence in school, at work, in friendships, and in romantic relationships. Several participants and SSPs provided accounts of improved interpersonal interactions with family members. Two participants reported being able to initiate dating for the first time, and two reported feeling more comfortable with exploring and expressing gender identity. Examples of participant quotes on subjective effects are included in the Supplemental eTable 7.

The investigators’ clinical impressions regarding the mechanisms of action that made MDMA an effective adjunct to psychotherapy were consistent with research on MDMA’s neurobiological effects. Serotonergic effects likely contributed to previously inaccessible states of calm and well-being most participants reported during MDMA experimental sessions. Several participants experienced increased comfort with prolonged eye-contact and enhanced ability to express emotions verbally. Increases in OT levels after MDMA, as reported in healthy individuals, might have enhanced a sense of connection and enriched therapeutic rapport (Dumont et al. 2009; Hysek et al. 2014; Kuypers et al. 2017). Most participants reported a history of moderate to severe trauma, which is common in the autistic community (Roberts et al. 2015). Studies of MDMA in healthy individuals have demonstrated a reliable reduction of amygdalar activity (Bedi et al. 2009; Carhart-Harris et al. 2014; Carhart-Harris et al. 2015; Gamma et al. 2000) and a perception of less fear (Bedi et al. 2009; Dolder et al. 2018; Hysek et al. 2014), which might have aided participants in our study to remember and process past traumas and engage in corrective emotional experiences that were cathartic during the MDMA experimental sessions. Additional research will be required to determine whether theories of psychophysiological mechanisms of action of MDMA in psychotherapy are generalizable to autistic adult populations.

Investigators did not provide psychoeducation or training on how to implement or improve social skills. However, in the majority of cases, they observed emergence of apparently intact latent social skills (e.g., ease of initiating and sustaining conversation) that manifested and became apparent to observers during experimental sessions with MDMA when participants relaxed. These improvements persisted to varying degrees through follow-up. Eleven of 12 participants reported marked reductions in anxiety responses to in vivo exposure to triggers previously distressing for them, such as making a presentation, speaking on the telephone, entering new social settings, or interacting with authority figures.

One participant who received MDMA (100 and 125 mg) did not show expected changes in BP, HR, or BT and reported no subjective acute effects over the course of treatment. Both investigators present during these two MDMA experimental sessions incorrectly recorded their belief of condition assignment as placebo with high certainty. An ad hoc laboratory analysis after unblinding confirmed the presence of MDMA in a plasma sample taken during an experimental session which ruled out pharmacy or randomization error. This participant stopped taking a prescription SSRI (escitalopram), per protocol, approximately 2 months prior to treatment. Research in clinical settings with diverse study populations on the potential attenuation of effects of MDMA due to genetic factors, prior and recent SSRI use influencing downregulation of serotonin transporters, and other factors specific to autism are indicated as areas of future study.

Psychological function, particularly in regard to expressions of SAD, improved over the 6 months. There were no serious adverse psychological or medically related health events. Although moderate elevations in blood pressure, heart rate, and temperature were observed during most experimental sessions, no participants encountered any acute cardiovascular or hyperthermia crises. Regarding vital signs, there were significant expected elevations in the MDMA group in peak SBP, heart rate, and temperature, but not DBP, and well within margins of safety. BT in the MDMA group remained well within normal range. Long-term follow-up failed to detect any deleterious outcomes. Such findings are consistent with other formally approved MDMA clinical research investigations in people with PTSD (Mithoefer et al. 2018; Mithoefer et al. 2013; Oehen et al. 2013) and healthy controls (Grob et al. 1996; Vizeli and Liechti 2017).

When examining short-term response to treatment (during the experimental sessions and 1 week following), more anxiety (75% of participants) was reported in the MDMA group as compared to the placebo group. Although the protocol did not specify collection of reaction onset time or duration during experimental sessions, we observed that most of the reports reflected transient anxiety within the first hour following MDMA administration, which is common and expected. Virtually all of the adverse effects reported, by both MDMA and placebo participants, were relatively mild and of brief duration. Considerable care was also given to monitoring for emergence of suicidal ideation. The C-SSRS was administered at baseline, during the experimental session, daily for 7 days following each treatment, and at two integrative psychotherapy sessions. While mild levels of suicidal ideation were reported by a few participants, they were evaluated as being of very low risk and were reported at equal frequency (25%) by the MDMA and placebo group. No participants expressed serious suicidal ideation. However, one participant with a history of past suicidal behaviors reported transient suicidal ideation during a personal crisis that quickly resolved.

Limitations

The small sample size and broad range of scores limits claims about potential impact and generalizability of the treatment, despite the very large effect size for the primary outcome measure. The findings justify the need for future research for treatment of SAD with MDMA-assisted psychotherapy. Furthermore, the sample was too small to compare dose-response effects between subgroups. Heterogeneity in baseline scores and lack of significant differences between groups for the exploratory measures precluded assessment of meaningful clinical response. For example, not all participants presented with clinically significant depression symptoms at baseline, so changes in BDI scores were insignificant even though mean scores dropped below the level of clinical significance after treatment for participants with high baseline BDI scores. This signal supports future studies of MDMA-assisted psychotherapy for depression in autistic adults.

AEs reported to cause mild to moderate limitation of daily function related to depression, anxiety, panic, and suicidal ideation were reported. However, codiagnosis of these psychiatric symptoms and comorbid psychiatric disorders is common in autistic populations, and the sample size was too small for meaningful analysis of trends.

Another limitation was potential for inclusion or exclusion error due to imprecision in available autism diagnosis methods. Standardized assessment by the designated qualified rater with the ADOS-2 (adult module) with scores indicating autism was required for inclusion. However, a more comprehensive assessment would be indicated to confirm a formal diagnosis for some participants with no prior evaluation history.

Effective blinding is a challenge for trials of psychoactive substances when drug effects may be observable to participants and investigators. Delegating all administrations of the LSAS to a blinded IR who never saw the participants during experimental sessions strengthened the blind. One participant and both investigators made incorrect guesses, so double-blinding with an inactive placebo was considered adequate for this study. Both groups in this study received the same type of psychotherapy with encouragement toward self-directed healing and meaning-making. The investigators acknowledge that the MDMA effects that are observable to participants might be a factor that contributes in some way to efficacy of MDMA-assisted therapies.

Investigators had no means to confirm prior abstinence from MDMA, so deception at intake was possible. Undisclosed prior MDMA use had the potential to break the blind for any participant familiar with its effects. In addition, drug screening was completed at baseline and prior to experimental sessions, but undisclosed illicit drug use as well as reported concomitant psychiatric medications during follow-up had the potential to influence 6-month outcomes.

Recruitment delays were a challenge. Autistic adults with SAD experience high levels of social isolation and can be difficult to contact through conventional recruitment methods. Recruitment relied primarily on Internet advertisements, so individuals without online access were less likely to receive information about recruitment. Increasing recruitment through advertisements on drug-interest forums might have increased the likelihood of self-selection bias and subject-expectancy effects. Investigators took steps to mitigate these effects in recruitment, by placing advertisements in online autism forums and engaging in community outreach.