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

Psychedelics such as psilocybin, LSD, MDMA, and ibogaine produce rapid and lasting clinical effects in psychiatric disorders by altering perception, cognition, and emotion. Preclinical and clinical work shows they modulate glutamate and GABA transmission, enhance neuroplasticity, and reorganize brain networks. A unified explanation for how these acute changes lead to enduring outcomes has been lacking. The authors propose a neurodevelopmental hypothesis: psychedelics restore excitation/inhibition balance, initially shifting E/I dynamics to create a transient state of heightened plasticity akin to developmental sensitive periods. This window allows long-term reorganization of excitatory and inhibitory circuits, with GABAergic interneurons as key mediators. The dual-phase model links initial network excitability to subsequent neuroplasticity and circuit stabilization, offering a coherent framework for psychedelics' rapid onset and sustained efficacy.

Study at a glance

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.