From network destabilisation to adaptive reconfiguration: A hippocampal longitudinal axis model of psychedelic therapy.
Charalampos L. Kandilakis, Costas Papatheodoropoulos
Progress in neuro-psychopharmacology & biological psychiatry August 20, 2026 DOI: 10.1016/j.pnpbp.2026.111898 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Longitudinal Peer reviewed |
|---|---|
| Topics | Neuroplasticity Psychedelic-assisted therapy |
| Keywords | Critical-period plasticity Excitation/inhibition balance Hippocampal longitudinal axis Interneurons Network dynamics Psychedelics Psychiatric disorders Hippocampus |
| Key points | Proposes that psychedelic-assisted therapy works through a dual-phase process: acute E/I destabilization (Phase I) followed by experience-dependent plasticity and re-stabilization (Phase II), with the hippocampal longitudinal axis providing a spatially organized substrate for transdiagnostic therapeutic effects. |
Abstract
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.