Unraveling Cannabidiol's Dual Modulatory Role in Schizophrenia: Network Pharmacology and In Vivo Validation of...

Schizophrenia (SCZ), a chronic psychiatric disorder, is characterized by cognitive impairment, hallucinations, and delusions, with current antipsychotic treatments offering limited efficacy and considerable side effects. Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown promise in treating neurological and psychiatric conditions, though its precise mechanisms in schizophrenia remain unclear. Using network pharmacology, this study predicts CBD's targets and pathways in schizophrenia, highlighting LPS-induced neuroinflammation and implicating 5-HT1AR-MAPK signaling as one potential contributor. In vitro, CBD (10 mg/kg, i.p.) treatment significantly reduced pro-inflammatory cytokines (e.g., NO, IL-1β, IL-6, TNF-α) and modulated the 5HT1AR-MAPK pathway, including increased 5HT1AR expression and decreased MAPK/ERK1/2 phosphorylation (p < 0.05). In vivo, CBD alleviated SCZ-like symptoms in a ketamine-induced animal model, reducing anxiety in the open field (p < 0.01) and elevated plus maze tests (p < 0.01), improving spatial memory in the Y-maze (p < 0.01) and social behavior (p < 0.0001) after 5 consecutive days of treatment. Critically, we validated CBD's central anti-inflammatory effects by demonstrating reduced pro-inflammatory cytokine levels in both plasma and brain tissues (p < 0.05). Further correlation analysis established a direct link between brain cytokine suppression and behavioral improvements, integrating in vitro findings from BV2 microglial cells with in vivo neuroinflammatory and behavioral outcomes.These findings suggest the potential therapeutic benefits of CBD for SCZ, though further research, particularly clinical trials, is required to validate its efficacy and establish it as a novel therapeutic strategy.