Psychedelic Modulation of Excitation/Inhibition Balance: A Dual-Phase Neurodevelopmental Model.
ACS Chem Neurosci January 7, 2026 Charalampos L. Kandilakis, Costas Papatheodoropoulos
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.