MDMA-Assisted Psychotherapy for Social Anxiety in Adults with Autistic Spectrum Disorder: A Randomized, Double-Blind, Placebo-Controlled Longitudinal Study

Abstract

Social anxiety is among the most disabling comorbidities in autistic adults, affecting approximately 50% of this population (Spain et al., 2018). Current first-line treatments — cognitive-behavioural therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) — demonstrate limited and inconsistent efficacy in autistic individuals, partly because they were developed within neurotypical frameworks and address behaviour rather than the relational and affective roots of distress. This pre-registered study proposes a 12-month, parallel-group, randomised, double-blind, placebo-controlled longitudinal trial (N = 40–44) evaluating the efficacy, durability, and psychological mechanisms of MDMA-assisted psychotherapy (MDMA-AP) for social anxiety in autistic adults. Participants are English-speaking adults aged 21–55 with clinically significant social anxiety (LSAS > 60), recruited across four English-speaking countries (UK, USA, Australia, Canada). The intervention consists of an 11-session integrative psychotherapy protocol: three preparatory sessions, two supervised dosing sessions (80–120 mg MDMA or matched placebo, spaced four weeks apart; optional 40 mg booster), and six integration sessions. The primary outcome is change in Liebowitz Social Anxiety Scale (LSAS) total score at 3-month (T1) and 6-month (T2) follow-up. Secondary outcomes include social functioning (SFS), quality of life (WHOQOL-BREF), and alexithymia (TAS-20). Pre-specified mediators are plasma oxytocin reactivity, self-compassion (SCS-SF), and therapeutic alliance (WAI-SR). Autistic masking (CAT-Q) is a pre-specified moderator. The primary analysis uses linear mixed-effects models under the intent-to-treat principle. Causal mediation analyses and reflexive thematic analysis of qualitative interview data will supplement quantitative findings. The study is grounded in a neurodiversity-affirming ethical framework: its goal is to reduce suffering and support self-acceptance, not to normalise autistic traits.

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