The Emerging Neurobiology of Psychedelics: Critical Periods, Metaplasticity, and Extracellular Matrix Remodeling

This review argues that the therapeutic effects of psychedelics are better explained by large-scale neurobiological reorganisation rather than simple receptor-level pharmacology.

This new review proposes that psychedelics act as systems-level neuroplasticity agents that reopen critical-period-like states, engage metaplastic mechanisms, and remodel the extracellular matrix, thereby enabling large-scale reorganisation of brain networks underlying their therapeutic effects. The authors reject a purely neurotransmitter-based explanation. Instead, psychedelics are framed within a learning and systems-reorganisation model of brain function

“Psychedelics are a broad category of compounds that induce altered states of consciousness. These drugs have shown remarkable promise for the treatment of debilitating disorders ranging from posttraumatic stress disorder to depression and addiction. Although early studies focused on linking binding targets of psychedelics to their therapeutic effects, these pharmacological and biochemical explanations fail to account for the diversity, durability, and context dependence of psychedelics’ clinical and acute subjective effects.

More recently, neurobiological explanations offer fresh insights and demonstrate that a unifying property of psychedelics is that these compounds reopen critical periods, induce metaplasticity, and reorganize the extracellular matrix. Here we review this evidence and argue that the neurobiological and therapeutic effects of psychedelics challenge the biochemical imbalance model that has dominated translational neuroscience since the 1950s and favor instead a learning model that better accounts for psychedelics’ unique therapeutic profile.”

Dölen G, Wilkinson ML. The Emerging Neurobiology of Psychedelics: Critical Periods, Metaplasticity, and Extracellular Matrix Remodeling. Annu Rev Neurosci. 2026 Apr 16. doi: 10.1146/annurev-neuro-112723-045129. Epub ahead of print. PMID: 41990390. Read Paper

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