From network destabilisation to adaptive reconfiguration: A hippocampal longitudinal Axis model of psychedelic therapy.

Psychedelic-assisted therapy has emerged as a promising therapeutic approach across several psychiatric disorders, yet the mechanisms linking acute brain-state changes and subjective experience to sustained clinical improvement remain incompletely understood. Here, we extend a previously proposed excitation/inhibition (E/I)-centred dual-phase model of psychedelic action to the therapeutic context and develop the hippocampal longitudinal axis as a circuit-level framework for its spatially differentiated effects. In Phase I, psychedelics induce a transient destabilisation of E/I dynamics, increasing neural flexibility and altering network organisation while loosening maladaptive activity patterns that may contribute to the acute psychedelic experience. In Phase II, activity- and experience-dependent plasticity processes promote adaptive reorganisation and re-stabilisation of neural circuits. We further hypothesise that the anterior-posterior hippocampal axis provides a spatially organised substrate through which regionally differentiated E/I dynamics may contribute to transdiagnostic therapeutic effects across affective, cognitive, and behavioural symptom domains, and help explain differential symptom responses across patients. This framework links acute network destabilisation to sustained circuit reconfiguration, providing a spatially resolved account of psychedelic-assisted therapeutic change and generating experimentally testable predictions regarding candidate biomarkers (e.g., E/I-related neuroimaging measures and hippocampal connectivity profiles), treatment response, and risk.