Psychedelic modulation of excitation–inhibition balance and the Affective Core Self: A multilevel mechanistic framework

Abstract Serotonergic psychedelics reliably alter affective tone, emotional regulation, and self-experience. Prevailing theories emphasize acute changes in neural entropy, default mode network integrity, and large-scale functional connectivity but do not offer a clear mechanism that explains how 5-HT2A receptor pharmacology relates to lasting changes in affect and self-related processing. This article addresses this gap by proposing a testable mechanistic framework in which serotonergic modulation of excitation–inhibition (E-I) balance functions across a hierarchical regulatory architecture of the Affective Core Self, linking molecular, circuit, and network processes to shifts in affective self-dynamics. This theoretical article integrates evidence from neuroimaging and psychopharmacological studies of serotonergic psychedelics to evaluate this proposed mechanism that connects affective neurobiology with changes in self-related processing. Evidence is organized within a hierarchical Affective Core Self framework that includes homeostatic–autonomic, limbic, salience-network, and cortical self-referential regulatory levels. In this model, 5-HT2A receptor activation is proposed to influence E-I dynamics that may propagate across neural circuits and large-scale networks through vertical coupling among Affective Core Self levels. These vertically coupled interactions provide mechanisms through which psychedelic neuromodulation may reorganize affective tone and self-experience within this four-level Affective Core Self regulatory system. Post-acute plasticity and inhibitory recalibration are proposed to stabilize some of these altered regulatory dynamics. This provides a novel model linking acute psychedelic perturbation to enduring changes in affective regulation and self-experience and illustrates how psychedelic neuromodulation can reorganize the affective core of self-processing. This proposal generates falsifiable predictions that can be evaluated through measures of cortical E-I balance, bottom-up effective connectivity dynamics, and autonomic and affective regulation to assess whether psychedelic perturbations propagate across the levels of the Affective Core Self and are correlated with therapeutic outcomes.