Classic psychedelics and autism spectrum disorder: preclinical evidence, mechanistic insights and unresolved challenges.

Abstract

Classic psychedelics have re-emerged as compelling probes of neural plasticity, raising interest in their potential relevance for behavioral and circuit-level features associated with autism spectrum disorder (ASD). Although only a limited number of studies have examined these compounds in validated animal models of ASD, a growing body of preclinical work has investigated their effects on behavioral and neurobiological processes relevant to ASD. In this context, this review adopts a domain-based perspective, discussing studies that examine the effects of classic psychedelics on behavioral domains overlapping with ASD phenotypes, including social interaction, communication, repetitive behaviors, anxiety-like traits, and cognitive function. We critically evaluate the neurobiological mechanisms underlying these effects, focusing on serotonergic signaling, glutamatergic neurotransmission, neuroinflammatory processes, BDNF/TrkB pathways, oxytocinergic and dopaminergic modulation. Across these domains, we identify points of mechanistic convergence with neurobiological alterations implicated in ASD, and integrate emerging preclinical findings that may guide future hypothesis-driven research. At the same time, we highlight significant gaps that constrain interpretation. We conclude by outlining key conceptual and methodological limitations, including the scarcity of studies in established animal models of ASD, reliance on simplified behavioral assays, and uncertainty regarding how ASD-specific circuit alterations may influence responses to psychedelics. Addressing these issues will be essential to determine whether psychedelic-induced plasticity can provide meaningful insights into ASD pathophysiology or inform future translational efforts.

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