A spatiotemporal gating hypothesis for psilocybin plasticity: reconciling the 5-HT₂A-TrkB mechanistic paradox.

Abstract

Psilocybin has emerged as a transformative, rapid-acting, and long-lasting therapeutic for treatment-resistant depression, with its efficacy rooted in the induction of sustained structural and functional remodeling of mood-regulating neural circuits 1 , 2 . However, the field faces a fundamental mechanistic paradox that defies linear signaling models: psilocin, the bioactive metabolite of psilocybin, directly binds to and allosterically potentiates TrkB receptors — the primary transducers of BDNF-mediated neurotrophic and plastic effects 3 — yet deletion or pharmacological blockade of 5-HT₂A receptors completely ablates psilocybin-induced dendritic spine formation, circuit rewiring, and long-term antidepressant behavior 1 , 4 . This strict dependency on 5-HT₂A, despite direct TrkB engagement, raises a critical question: what is the functional relationship between these two receptors in mediating psilocybin’s plastic effects?