Psychedelic Modulation of Excitation/Inhibition Balance: A Dual-Phase Neurodevelopmental Model.

Abstract

Psychedelics are a diverse class of psychoactive compounds that profoundly alter perception, cognition, and emotional states. Recently, classical serotonergic agents, such as psilocybin and lysergic acid diethylamide (LSD), along with atypical agents such as methylenedioxymethamphetamine (MDMA, ecstasy) and ibogaine, have attracted renewed attention due to their rapid and sustained clinical effects in psychiatric disorders. Preclinical and clinical studies indicate that serotonergic psychedelics acutely modulate glutamatergic and GABAergic transmission, enhance neuroplasticity, and reorganize brain network connectivity. However, a unified mechanistic framework linking these effects to enduring clinical outcomes remains elusive. Here, we propose a neurodevelopmental hypothesis in which psychedelics restore excitation/inhibition (E/I) balance, a fundamental property of both neurodevelopment and adult brain function. Acutely, psychedelics shift E/I dynamics through serotonergic and nonserotonergic mechanisms, creating a transient state of heightened plasticity similar to developmental sensitive periods. This permissive window facilitates the long-term reorganization of excitatory and inhibitory circuits with GABAergic interneurons as key mediators. By integrating established pharmacological effects with developmental principles, our dual-phase model links initial network excitability with subsequent neuroplasticity and circuit stabilization, providing a coherent framework for the rapid onset and sustained efficacy of psychedelic interventions across psychiatric disorders.