Psychedelics and autism spectrum disorder: Mechanistic insights, translational evidence and ethical challenges.

Abstract

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by persistent deficits in social communication and interaction, restricted and repetitive patterns of behavior, and sensory processing alterations, frequently accompanied by anxiety, emotional dysregulation, and other psychiatric comorbidities. Despite advances in behavioral and pharmacological interventions, effective treatments for core ASD symptoms remain limited. Psychedelic compounds have recently emerged as potential therapeutic agents in psychiatry because of their ability to modulate serotonergic and glutamatergic signaling, enhance neuroplasticity, reorganize large-scale brain networks, and influence neurobiological pathways implicated in ASD. In this narrative review, we examine the mechanistic rationale supporting psychedelic-based approaches in ASD, including 5-HT2A receptor activation, oxytocin-serotonin interactions, excitation-inhibition dynamics, functional connectivity, and glutamatergic modulation associated with ketamine and related compounds. We also summarize current clinical and preclinical evidence involving substances such as psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, and ketamine. Particular attention is given to the distinction between core ASD symptoms and associated symptom domains. Current evidence does not support the direct treatment of core social communication deficits or restricted and repetitive behaviors; however, psychedelics may hold greater potential for dimensions such as social anxiety, emotional dysregulation, cognitive rigidity, and co-occurring mood symptoms. Ethical, regulatory, and developmental safety considerations are also discussed, particularly regarding neurodivergent populations and the absence of robust pediatric evidence. Although direct clinical studies in ASD remain scarce, psychedelic-assisted interventions represent a promising translational avenue that warrants further rigorous investigation through carefully designed clinical trials.