Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study, Alicia L. Danforth, Charles S. Grob et al., 2018

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

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

Psychopharmacology, 2018,



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 feasibility and safety ofMDMA-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 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 expansion of research into larger samples to further investigate this novel treatment for social anxiety.

Trial registration : identifier, NCT00302744

Keywords : Social anxiety . MDMA . 3,4-Methylenedioxymethamphetamine . MDMA-assisted psychotherapy . Autism . Asperger’s . Liebowitz Social Anxiety Scale . Psychedelics . Anxiety


In humans, 3,4-methylenedioxymethamphetamine (MDMA) generates feelings of social affiliation and increases social approach while diminishing negative responses to social rejection (Kamilar-Britt and Bedi 2015). BEcstasy^ or Bmolly^ refers to chemical entities represented as containing MDMA. MDMA is primarily a potent releaser of serotonin and norepinephrine, and to a lesser extent dopamine (de la Torre et al. 2004; Hysek and Liechti 2012). MDMA also promotes release of the neuro-hormone oxytocin (OT) (Dumont et al. 2009; Hysek et al. 2012; Kirkpatrick et al. 2014; Kuypers et al. 2017). OT is associated with social affiliation in mammals and attenuates amygdalar response to anxiogenic stimuli (Adolphs et al. 2005; Bartz and Hollander 2006), and OT receptor gene variations may also modulate
prosocial effects of MDMA in humans (Bershad et al. 2016; Vizeli and Liechti 2018).

Due to its unique pharmacology,MDMA has shown promise as an adjunct to psychotherapy for treatment of posttraumatic stress disorder (Mithoefer et al. 2018; Mithoefer et al. 2011; Mithoefer et al. 2013; Oehen et al. 2013). Anticipating concerns about using a schedule 1 substance in a clinical trial with an autistic adult population, we published a preliminary paper on study rationale and methods including information on history, pharmacology, effects in animals and humans, safety, and clinical advantages of MDMA (Danforth et al. 2016).

Autism refers to a spectrum of congenital and pervasive neurocognitive variants. Autism presents with myriad manifestations resulting in considerable heterogeneity among individuals with atypical development of social and communication skills. At present, there are no published research data in support of compounds that can influence the course of autism or be a causative agent (Danforth 2013). There may be underlying biological reasons autistic adults have atypical responses to psychiatric medications commonly prescribed for anxiety, including evidence for fewer benzodiazepine binding sites, atypical GABAergic inhibitory signaling, and atypical serotonin and dopamine transporter binding in autistic brains (Coghlan et al. 2012; King et al. 2009; Nakamura et al. 2010; Uzunova et al. 2016).
Qualitative data onMDMA/ecstasy use by autistic adults in epidemiological settings supported the selection of social anxiety disorder (SAD) as the primary indication for this study (Danforth 2013). SAD is characterized by fear of scrutiny and avoidance of social interactions (American Psychiatric Association 2013). Comparative studies suggest that autistic individuals are at greater risk (1:4) of current or lifetime SAD (Bejerot et al. 2014). The study presented here is the first controlled study of MDMA-assisted psychotherapy in autistic adults. The objective of this investigational treatment was not to cure or alter the course of autism but to explore the feasibility and safety of treating SAD with MDMA-assisted psychotherapy in this underserved population.