Serotonergic psychedelics for Autism spectrum disorder: Neurobiological mechanisms and translational prospects.

Autism Spectrum Disorder involves social-communication deficits, cognitive rigidity, and atypical sensory processing, with current drugs providing only limited relief. Dysregulated serotonin signaling, impaired neuroplasticity, and chronic neuroimmune activation are central features. Serotonergic psychedelics like psilocybin and LSD, which act as 5-HT2A receptor agonists, may relax overly rigid cortical priors, reopen critical periods for social learning, and recalibrate neural circuits. They enhance synaptic plasticity via BDNF and mTOR signaling, modulate cortical oscillations, and suppress neuroinflammation. Systems-level frameworks suggest these compounds induce less constrained brain states that counteract hyper-segregated connectivity in ASD. Preclinical and early human studies report improvements in sociability, sensory responsiveness, and behavioral flexibility, but rigorous clinical trials are needed to establish safety and efficacy.

Study at a glance

Abstract

Autism Spectrum Disorder (ASD) is characterized by persistent social-communication deficits, cognitive rigidity, and atypical sensory processing. Current pharmacological treatments, including risperidone and aripiprazole, provide only limited symptomatic relief and do not address the underlying neurobiological mechanisms. Converging evidence implicates dysregulated serotonergic signaling, impaired neuroplasticity, and chronic neuroimmune activation as central features of ASD pathophysiology. Serotonergic psychedelics, such as psilocybin and LSD, act as high-affinity 5-HT2A receptor agonists and have re-emerged as candidates for modulating these core pathways. In this Review, we synthesize molecular, cellular, and systems-level findings suggesting that psychedelics may transiently relax overly rigid cortical priors, reopen critical periods for social learning, and recalibrate dysfunctional neural circuits in ASD. These compounds enhance synaptic plasticity via BDNF and mTOR signaling, modulate cortical oscillations, and suppress neuroinflammation by shifting microglial phenotypes and suppressing pro-inflammatory cytokines. Systems-level frameworks, including the REBUS and anarchic brain hypotheses, contextualize how psychedelics induce globally integrated, less constrained brain states that may counteract the hyper-segregated connectivity commonly observed in ASD. While preclinical and early human studies report improvements in sociability, sensory responsiveness, and behavioural flexibility, rigorous clinical trials are urgently needed to establish safety, efficacy, and optimal developmental windows for intervention. We conclude by outlining a translational roadmap to guide future research, emphasizing the need for structured integration with behavioural therapies, attention to ASD heterogeneity, ethical considerations, and the potential to shift ASD treatment beyond symptomatic management toward disease-modifying intervention.