Abstract

PSYCHEDELICS AND NEUROPLASTICITY: FROM BENCH TO BEDSIDE

Ezenwaeze Malachy Nwaeze*, Anusiem Chikere A., Ghasi Samuel Ikenna

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Abstract

Background: Psychedelic compounds such as psilocybin, lysergic acid diethylamide (LSD), N, N-dimethyltryptamine (DMT), mescaline, and methylenedioxymethamphetamine (MDMA) are undergoing a scientific resurgence after decades of prohibition. These agents have demonstrated rapid and sustained therapeutic benefits in psychiatric disorders including major depressive disorder, posttraumatic stress disorder (PTSD), and substance use disorders. Unlike conventional monoaminergic antidepressants, psychedelics appear to act via neuroplastic mechanisms that restructure synaptic and circuit level function. Objective: This review synthesizes current evidence on how psychedelics promote neuroplasticity across molecular, cellular, circuit, and behavioral levels, and evaluates their translational potential as next generation neuropsychiatric therapeutics. Methods: A narrative review of preclinical and clinical studies was conducted, focusing on structural spinogenesis and synaptogenesis, signaling cascades (BDNF–TrkB–mTOR axis), receptor pharmacology (serotonin(5- HT₂A)) and, and neuroimaging data. Comparative analysis with rapid acting antidepressants such as ketamine was integrated to highlight convergent biological mechanisms. Results: Preclinical data consistently demonstrate that psychedelics enhance dendritic spine density, synaptogenesis, and excitatory transmission in cortical and hippocampal circuits. These effects are mediated by BDNF TrkB and mTOR signaling and are dependent, though not exclusively, on 5-HT₂A receptor activation. Clinical studies show that one or two administrations of psilocybin or MDMA, combined with psychological support, yield rapid and durable symptom improvements in depression and PTSD. Functional neuroimaging reveals large scale network remodeling, including increased prefrontal limbic connectivity and reduced default mode network rigidity. Conclusion: Psychedelics represent a novel class of psychoplastogens, capable of rapidly and sustainably remodeling brain structure and function. Their clinical efficacy appears to derive from durable neuroplastic changes rather than chronic receptor occupancy. However, major challenges remain, including disentangling hallucinogenic from therapeutic effects, developing reliable biomarkers of plasticity, and overcoming regulatory barriers. Future work on non-hallucinogenic analogues and precision biomarkers may pave the way for scalable, safe, and personalized psychedelic assisted therapies.

Keywords: Psychedelics; Psilocybin; LSD; MDMA; Neuroplasticity; Synaptogenesis.