Psychedelics and the Extracellular Matrix: Rewiring Neuroplasticity and Metaplasticity for Next-Generation Psychiatric Therapies.

Classic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), have emerged as potent modulators of neuroplasticity and metaplasticity in the adult brain, offering novel therapeutic strategies for neuropsychiatric disorders. Recent findings reveal that beyond their transient psychotropic effects, these compounds activate serotonin 5-HT2A receptors and downstream signaling cascades-including CaMKII (calcium/calmodulin-dependent protein kinase II), ERK (extracellular signal-regulated kinase), mTOR (mechanistic target of rapamycin), and BDNF (brain-derived neurotrophic factor) pathways-thereby inducing synaptogenesis, dendritic spine remodeling, and transcription of the immediate early genes. Critically, the brain's extracellular matrix (ECM), particularly perineuronal nets (PNNs), has been identified as a central regulator of synaptic stability and a key target of psychedelic action. Psychedelics transiently disrupt ECM integrity by loosening PNNs and reorganizing pericellular scaffolds, a process that reopens developmentally restricted critical periods of plasticity and restores circuit-level flexibility. These ECM-mediated metaplastic effects appear essential to the sustained therapeutic outcomes observed in the clinical studies of psychedelic-assisted therapy for depression, posttraumatic stress disorder, addiction, and potentially neurodegenerative diseases. This article synthesizes current cellular, molecular, and translational evidence highlighting the ECM as a dynamic and permissive substrate through which classic psychedelics exert long-lasting structural and functional brain changes, underscoring its potential as a target for precision interventions in neuropsychiatric care.