Balancing Therapeutic Efficacy and Safety of MDMA and Novel MDXX Analogues as Novel Treatments for Autism Spectrum Disorder.

Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental syndromes diagnostically characterized by deficits in social communication and social interaction and repetitive, inflexible patterns of behaviors, interests, and thoughts. ASD affects people worldwide, irrespective of race, ethnicity, or socio-economic status, with debilitating effects on employment and interpersonal relationships. Though the atypical antipsychotics aripiprazole and risperidone are approved to treat irritability associated with ASD, these drugs may elicit treatment-limiting adverse effects, such as suicidal ideation, sedation, diarrhea, loss of appetite, dizziness, and weight gain. However, there are no approved pharmacotherapeutics for global symptoms of ASD, and better treatments are needed. Drugs with pro-social effects, such as 3,4-methylenedioxymethamphetamine (MDMA) and its analogues, may be beneficial here, as social anxiety and social avoidance are major complications of ASD that adversely impact the quality of life for sufferers and caregivers. This review describes the complex pharmacology of methylenedioxy amphetamine analogues (hereafter referred to as MDXX drugs), focusing on MDMA and 3,4-methylenedioxy-N-methyl-α-ethylphenylethylamine (MBDB) and how they may help treat ASD. Specifically, we address the roles of various drug-binding sites, metabolic enzymes, and chemical structure-activity relationships that mediate these substances' pharmacological and toxicological effects. Throughout the review, we emphasize the distinct profiles of individual stereoisomers of the MDXX drugs and how combining these enantiomers as racemic mixtures may explain the complexity of drug effects on behavior and physiology. We propose that the MDXX drugs represent a fruitful chemical space for developing clinically effective and relatively safer molecules and formulations for treating ASD.