Prenatal stress, excitatory-inhibitory imbalance, and ADHD risk: a hypothesis-driven perspective on...

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition in which prenatal stress and long-lasting disruptions of excitatory-inhibitory (E/I) balance have been implicated as key vulnerability factors. Although established pharmacological and behavioral treatments are effective for many individuals, they are not universally successful and do not directly target upstream neurodevelopmental mechanisms. In this hypothesis-driven perspective, we examine whether psilocybin-induced neuroplasticity could theoretically modulate stress-related neurodevelopmental risk pathways relevant to ADHD. Rather than presenting psilocybin as an evidence-based intervention, we synthesize findings from related preclinical and clinical literatures to explore conceptual plausibility. Preclinical studies in non-ADHD models indicate that psilocybin can induce rapid and sustained synaptic plasticity, alter cortical E/I dynamics, and reverse stress-associated structural and functional alterations. Human clinical trials in adults-primarily in mood, trauma-related, and substance use disorders-demonstrate durable changes in emotional regulation, cognitive flexibility, and large-scale brain network organization, processes that overlap with neural systems implicated in ADHD. Research into the use of psilocybin for ADHD is in its early stages, with emerging, largely self-reported, and preliminary studies suggesting potential benefits for managing symptoms like inattention, impulsivity, and emotional dysregulation. We therefore frame psilocybin as a speculative (secondary/tertiary) approach that could, in principle, be explored to probe mechanisms of E/I rebalancing and neuroplasticity. Key mechanistic uncertainties-including the state-dependent effects of psilocybin on excitation and inhibition and the possibility of exacerbating existing imbalances-are explicitly discussed. Ethical and developmental considerations, particularly regarding vulnerable populations, are emphasized as critical constraints on translation. Finally, we propose a translational research roadmap encompassing preclinical prenatal-stress models, biomarker-driven pilot studies in ADHD, and multimodal outcome measures integrating neuroimaging, electrophysiology, and molecular indices. By clearly distinguishing established evidence from hypothesis, this perspective aims to stimulate rigorous and ethically grounded research rather than to advocate premature clinical application.