Psychedelics and the Extracellular Matrix: Rewiring Neuroplasticity and Metaplasticity for Next-Generation Psychiatric Therapies
Biological Psychiatry February 1, 2026 Jin Zhang, Cong Lin, Xinyou Lv et al. 1 citation
Classic psychedelics like psilocybin, LSD, and DMT modulate neuroplasticity and metaplasticity in the adult brain beyond their transient psychotropic effects. They activate serotonin 5-HT2A receptors and signaling cascades involving CaMKII, ERK, mTOR, and BDNF pathways, inducing synaptogenesis, dendritic spine remodeling, and immediate early gene transcription. The brain's extracellular matrix, particularly perineuronal nets (PNNs), regulates synaptic stability and is a key target of psychedelic action. Psychedelics transiently disrupt ECM integrity by loosening PNNs, reopening critical periods of plasticity and restoring circuit flexibility. These ECM-mediated metaplastic effects appear essential for sustained therapeutic outcomes in psychedelic-assisted therapy for depression, PTSD, addiction, and potentially neurodegenerative diseases.