LSD activates the TrkB signaling pathway in human neural stem cells (NSCs) similarly to the growth factor BDNF, but unlike BDNF, LSD does not promote NSC proliferation. This suggests LSD may activate an alternative mechanism that counteracts BDNF-TrkB signaling in NSCs, revealing a previously unrecognized cell type-specificity of LSD. The finding may deepen understanding of how LSD produces fast and persistent effects on anxiety and depression.
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.