Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study

This double-blind, placebo-controlled, randomized pilot study (n=12) found a significant reduction in social anxiety (d=1.4) after MDMA-assisted psychotherapy (75-125mg, 2 sessions). The effects persisted even 6-months later (d=1.1).

Abstract

“Rationale: Standard therapeutic approaches to reduce social anxiety in autistic adults have limited effectiveness. Since 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy shows promise as a treatment for other anxiety disorders, a blinded, placebo-controlled pilot study was conducted.

Objectives: To explore the feasibility and safety of MDMA-assisted psychotherapy for reduction of social fear and avoidance that are common in the autistic population.

Methods: Autistic adults with marked to very severe social anxiety were randomized to receive MDMA (75 to 125 mg, n = 8) or inactive placebo (0 mg, n = 4) during two 8-h psychotherapy sessions (experimental sessions) in a controlled clinical setting. Double-blinded experimental sessions were spaced approximately 1 month apart with 3 non-drug psychotherapy sessions following each. The primary outcome was change in Leibowitz Social Anxiety Scale (LSAS) Total scores from Baseline to one month after the second experimental session. Outcomes were measured again six months after the last experimental session.

Results: Improvement in LSAS scores from baseline to the primary endpoint was significantly greater for the MDMA group compared to the placebo group (P = 0.037), and placebo-subtracted Cohen’s d effect size was very large (d = 1.4, CI − 0.074, 2.874). Change in LSAS scores from baseline to 6-month follow-up showed similar positive results (P = 0.036), with a Cohen’s d effect size of 1.1 (CI − 0.307, 2.527). Social anxiety remained the same or continued to improve slightly for most participants in the MDMA group after completing the active treatment phase.

Conclusions: This pilot trial demonstrated rapid and durable improvement in social anxiety symptoms in autistic adults following MDMA-assisted psychotherapy. Initial safety and efficacy outcomes support the expansion of research into larger samples to further investigate this novel treatment for social anxiety.”

Authors: Alicia L. Danforth, Charles S. Grob, Christopher Struble, Allison A. Feduccia, Nick Walker, Lisa Jerome, Berra Yazar-Klosinski & Amy Emerson

Notes

This paper builds on the earlier review work by Danforth et al. (2016).

Summary

A pilot study of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy was conducted in autistic adults.

Introduction

MDMA is a potent releaser of serotonin, norepinephrine, and dopamine, and promotes release of the neurohormone oxytocin. OT is associated with social affiliation in mammals and attenuates amygdalar response to anxiogenic stimuli.

MDMA has shown promise as an adjunct to psychotherapy for treatment of posttraumatic stress disorder. We published a preliminary paper on study rationale and methods.

Autism refers to a spectrum of congenital and pervasive neurocognitive variants, and may be caused by a combination of factors including atypical GABAergic inhibitory signaling, and atypical serotonin and dopamine transporter binding.

Qualitative data suggested that MDMA/ecstasy use by autistic adults was associated with social anxiety disorder. This study is the first controlled study of MDMA-assisted psychotherapy in autistic adults.

Trial design

We conducted a phase 2 study with 12 participants using a randomized, placebo-controlled, double-blind methodology. The participants received two blinded experimental sessions with MDMA or placebo, spaced approximately 1 month apart, followed by three non-drug integrative psychotherapy sessions over 3 weeks.

A dose-finding study design was selected in response to anecdotal data suggesting that a lower yet therapeutically active MDMA dose range might be needed in individuals with autism.

An independent rater administered the Leibowitz Social Anxiety Scale, the Beck Depression Inventory, the Spielberger State-Trait Inventory, and the Perceived Stress Scale to participants at baseline, 1 day, 2 weeks, and 4 weeks after each experimental session.

Screening, eligibility, and participants

Participants were recruited through Internet advertisements, word of mouth, and clinician referrals. All signed an informed consent after review with investigators, and were 21 or older, MDMA naive by self-report, physically healthy, and psychologically stable.

Preparatory and integrative psychotherapy

Research findings support mindfulness-based therapies for autistic adults. Mindfulness-based preparatory psychotherapy helped participants with transitioning into MDMA-influenced cognitive and affective states, as well as with communicating with others during novel, often ineffable altered states of consciousness.

Experimental sessions

Participants arrived around 09:30 and were provided with a den-like ambiance, soft lighting, noise abatement, and suitable décor items to support common autistic preferences.

Participants were given a guided progressive muscle relaxation exercise and a study drug around 10:30. They were video-recorded and given a contact for urgent assistance from an investigator physician.

Post-session follow-up

The morning following each experimental session, participants returned to the center for integrative psychotherapy. Two sessions were scheduled at 2-week intervals for 1 month.

Assessments

The LSAS was used as the primary outcome measure, and change from baseline was assessed using several secondary measures, including the BDI-II, PSS, IRI, RSES, STAI, TASIT, and ERQ.

Safety monitoring

Investigators collected adverse events and concomitant medications at each visit, and assessed suicidal ideation and subjective units of distress hourly. A consented study support partner drove the participant to and from experimental sessions.

Statistical analysis

Data from the MDMA dose subgroups were combined into one MDMA group for analysis. Independent samples t tests were used to test for significant changes in LSAS total score from baseline to 1 month post-second experimental session, and from baseline to 6-month follow-up.

Demographics

Forty-nine participants were recruited from 2014 to 2016; 12 were enrolled and randomized. They were 31.3 years old on average, had a history of depression, generalized anxiety disorder, and SAD, and a mean baseline BMI of 25.0 kg/m2.

Clinical response

At 6-month follow-up, the decline in mean LSAS score was significantly greater for the MDMA group than for the placebo group.

Fig. 1 CONSORT diagram

The mean LSAS score changed minimally from primary endpoint to 6-month follow-up for both groups, with the MDMA group retaining improvements at 6-month follow-up compared to primary endpoint. The rate of clinical response was 75% with MDMA versus 50% with placebo.

Pharmacodynamic measurements

MDMA elevated blood pressure, pulse, and body temperature, but did not cause clinically significant AEs. Blood pressure returned to pre-drug levels in both groups at session end, with no clinical intervention.

Safety

No serious side effects were reported during this study. Most commonly reported reactions were anxiety and difficulty concentrating, with rare reports after the third day of contact.

All reported adverse events (AEs) were mild or moderate and were classified as falling within the overarching class psychiatric disorders. Suicidal ideation was the most commonly reported AE, but prevalence was similar across groups and was pre-existing in medical history.

Blinding

Participants, therapists, and IR were blind to drug assignment. One in eight participants guessed their treatment assignment incorrectly.

Discussion

This pilot study investigated the use of MDMA-assisted psychotherapy to treat generalized social anxiety in autistic adults. The results indicated that the treatment was effective in improving social anxiety and social functioning.

The MDMA group had a greater improvement at primary endpoint than the placebo group, and the MDMA group continued to improve during the 5-month period when participants were not receiving therapy.

To minimize inter-rater variability and potential bias, the same qualified blinded IR conducted every LSAS administration for all participants. This contributed to a high level of consistency in interview methods and scoring.

The subjective effects of LSAS treatment were congruent with the decreased mean scores, and participants reported improved interpersonal interactions with family members, increased confidence, and more comfortable exploring and expressing gender identity.

The investigators’ clinical impressions regarding the mechanisms of action of MDMA in psychotherapy were consistent with research on MDMA’s neurobiological effects. MDMA might have enhanced a sense of connection and enriched therapeutic rapport, and helped participants to remember and process past traumas.

Investigators did not provide psychoeducation or training on how to implement or improve social skills, but observed that latent social skills manifested and became apparent to observers during experimental sessions with MDMA.

One participant who received MDMA did not show expected changes in BP, HR, or BT, and reported no subjective acute effects over the course of treatment. Both investigators incorrectly recorded their belief of condition assignment as placebo with high certainty.

Psychological function improved over the 6 months, with no serious adverse psychological or medically related health events. Elevations in blood pressure, heart rate, and temperature were observed during most experimental sessions, but no acute cardiovascular or hyperthermia crises were encountered.

During the experimental sessions and 1 week following, more anxiety was reported in the MDMA group as compared to the placebo group. Most adverse effects were mild and of brief duration, and no participants expressed serious suicidal ideation.

Limitations

The sample size was small and the range of scores was broad, which limits the ability to generalize the findings. Furthermore, the sample was too small to compare dose-response effects between subgroups, and the study did not assess meaningful clinical response.

Autism diagnosis methods are imprecise and require standardized assessment. More comprehensive assessments are indicated for 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. In this study, double-blinding with an inactive placebo was considered adequate, and participants were encouraged toward self-directed healing and meaning-making.

Recruitment was difficult because autistic adults with SAD experience high levels of social isolation, and Internet advertisements might increase the likelihood of self-selection bias and subject-expectations effects.

Conclusions

This study established the feasibility and safety of MDMA-assisted psychotherapy for social anxiety disorder in autistic adults. The findings support more trials in larger samples of adults with SAD.