Psychedelics and the Extracellular Matrix: Rewiring Neuroplasticity and Metaplasticity for Next-Generation Psychiatric Therapies
Jin Zhang, Cong Lin, Xinyou Lv, Huiying Zhao, Xiaohui Wang
Biological Psychiatry February 1, 2026 DOI: 10.1016/j.biopsych.2026.02.011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Neuroplasticity Psychedelic-assisted therapy |
| Keywords | Perineuronal net Regulator Metaplasticity Long-term potentiation Extracellular Neurotrophic factors Transcription factor Neurotransmission |
| Citations | 1 |
| Key findings | Classic psychedelics transiently disrupt perineuronal nets and reorganize the extracellular matrix, reopening critical periods of plasticity and enabling sustained therapeutic effects in neuropsychiatric disorders. |
Abstract
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.
Comparable studies
Other narrative reviews on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists | 2012 | Review | |
| Towards an understanding of psychedelic-induced neuroplasticity. Review of preclinical and clinical studies | 2023 | Review | |
| Buddha's Brain: Neuroplasticity and Meditation [In the Spotlight] | 2008 | Review | |
| Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics | 2021 | Review | |
| Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms | 2020 | Review |
Citations in the library
Cites 50
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
and 45 more in the library