Psychedelics and neuroregenerative medicine: Illuminating the potential of psychoplastogens for neurodevelopment and central nervous system repair

Abstract

Central nervous system (CNS) injuries remain challenging to treat due to limited neurogenesis, inhibitory extracellular environments, and maladaptive neuroimmune responses. Psychedelic compounds, including classical serotonergic psychedelics, dissociative anesthetics, and empathogens, have re-emerged as mechanistically distinctive “psychoplastogens” capable of rapidly and persistently enhancing neuroplasticity. These substances act through converging molecular pathways involving 5-HT 2A receptor (5-HT 2A R), BDNF-TrkB signaling, mTOR activation, Sigma-1 receptor engagement, and neuroimmune modulation, collectively fostering neuritogenesis, synaptogenesis, and neural survival. Notably, psychedelics can reopen critical periods of brain plasticity and remodel extracellular matrix (ECM) constraints, creating a permissive environment for repair in the adult CNS. Preclinical and organoid models of stroke, traumatic brain injury, and spinal cord damage demonstrate functional recovery linked to psychedelic-induced circuit remodeling, while early clinical data suggest improved rehabilitation outcomes. This review synthesizes molecular, cellular, and systems-level evidence on how psychedelics influence neurodevelopmental and regenerative processes, evaluates their therapeutic potential for CNS injuries, and outlines translational strategies and challenges. Overall, these findings support a framework in which psychoplastogens could act as catalysts for experience- and activity-dependent neural repair, while emphasizing that disease modification or “cures” remain long-term, testable hypotheses: the current evidentiary base is dominated by preclinical studies, and no completed controlled clinical trials have yet demonstrated slowed atrophy, durable structural repair, or sustained functional restoration in humans.