A spatiotemporal gating hypothesis for psilocybin plasticity: reconciling the 5-HT₂A-TrkB mechanistic paradox.
Cell Discov May 29, 2026
The authors propose a spatiotemporal gating hypothesis to resolve a paradox in how psilocybin produces lasting neural plasticity. Psilocybin activates 5-HT₂A receptors, but the plasticity it induces requires TrkB signaling, even though psilocybin does not directly bind TrkB. The hypothesis suggests that 5-HT₂A activation creates a specific pattern of neural activity—a spatiotemporal gate—that indirectly engages TrkB signaling, reconciling the two mechanisms. This framework aims to explain how a brief psychedelic experience can lead to sustained changes in brain structure and function.