Ecstasy (MDMA) for social anxiety in autism: a specialized application of empathogen therapy

To the Editor, Autism spectrum disorder (ASD) is a neurodevelopmental state in which there are early emerging problems in social communication along with fixed behavior patterns. Social difficulties in ASD are characterized by difficulty in interpretation of interpersonal signals such as facial expressions, tone of voice, and body language. Individuals with ASD often present with social anxiety, reduced interest in social situations, and problems in understanding others’ emotions as well as face challenges in maintaining social relationships leading to social isolation. Numerous interventions such as speech therapy and cognitive behavioral therapy aim to improve the above social skill deficits1. In many cases, people suffering from autism continue to endure clinically important social anxiety despite behavioral interventions as social anxiety, being a fear-based problem is not the same as lack of social skill. Selective serotonin reuptake inhibitors have been used in the treatment of autism. However, reports of available clinical trials have not consistently demonstrated real benefits for improving aggression and the symptoms of ASD2. 3,4 Methylenedioxymethamphetamine (MDMA), a psychoactive substance represented as an empathogen, appears to enhance prosocial behaviors and enhance empathy3. In contrast to post-traumatic stress disorder, in which MDMA-assisted psychotherapy has been linked with reductions in trauma-related fear traumatic memories, its recommended implementation in autism aims on reducing social fear and modifying maladaptive social risk assessment. In a randomized, double-blind, placebo-controlled pilot trial in which autistic adults were given MDMA-assisted psychotherapy, they presented with significant reductions in social fear and anxiety4. Preclinical studies further demonstrate that MDMA enhances social reward and affiliative behaviors while reducing aggression, potentially through serotonin 1A receptor-mediated oxytocin release interacting with vasopressin receptor 1A. In humans, MDMA is linked with decreasing negative facial expressions, improves body language, and enhances social affiliation and social approach by enhancing neurohormone oxytocin3. MDMA produces acute sympathomimetic effects including increase in heart rate, core body temperature, pupillary dilation, and blood pressure. Neuroimaging studies suggest that MDMA reduces amygdala reactivity, which may contribute to diminished fear responses to social threats. In addition, MDMA-induced release of oxytocin contributes to oxytocinergic effects that enhance prosocial feelings such as trust, emotional closeness, and social reward increasing the therapeutic effect of psychotherapy by improving social cues in autistic adults5. The acute adverse events (AEs) associated with MDMA administration in patients with ASD most commonly include fatigue, reduced appetite, cold intolerance, increased thirst, jaw clenching, and sweating. Anxiety and impaired concentration are the predominant acute psychological AEs. Reported delayed psychological effects include transient anxiety, reduced concentration, and depressed mood; fatigue and headache are delayed physiological AEs6. Cardiovascular AEs associated with MDMA include transient systolic hypertension and tachycardia, reflecting the sympathomimetic and adrenergic properties of MDMA. Due to its adrenergic effects, it is not recommended for patients with cardiovascular issues7. Some studies in the systematic review were monitored to be limited by small sample sizes and lack of long-term follow-up control groups, which restrict the viability of conclusions8. Research has shown that equal doses of MDMA per kilogram of body weight have stronger effects in women than men, suggesting that lower doses should be used for female patients. In men, cardiovascular stimulation is dose-dependent, which may lead to cardiovascular complications for patients with pre-existing cardiovascular disease9. The use of MDMA for management of social anxiety in patients with ASD is well-tolerated under the controlled and monitored clinical settings5. In the future, clinicians should take the required precautions when selecting the dose, as patients with ASD may have hypersensitivity to the sensory stimuli and might require lower doses while maintaining clinically effective MDMA doses4. MDMA-based therapeutic intervention in autistic adults appears to produce manageable AEs in controlled settings. However, delayed mood disturbances and psychological vulnerability in a minority of participants underscore the need for a stringent and an organized integration framework, and further large-scale safety trials. Currently 3,4-methylenedioxymethamphetamine is classified in the United States Controlled Substances Act as a Schedule 1 controlled substance, reflecting its high potential for abuse and limiting its use in the medical field10 . In the context of ASD, studies related to MDMA-assisted therapy have been conducted for social anxiety in autistic adults within strict supervision and approval highlighting that MDMA research can be carried out safely and legally. Initial safety and efficacy outcomes support expansion of research into larger samples for further investigation of this novel treatment for social anxiety. While MDMA is not yet approved for clinical use, thorough research and high-quality trials are necessary before it can be considered for autism-related therapies4. If validated in larger trials, MDMA-assisted therapy may give us an innovative complementary therapy for ameliorating social anxiety in autistic adults, while supporting functional well-being, rather than altering autistic identity.