Psychopharmacological Effects of Cannabidiol in Rodent Models of Autism Spectrum Disorder: A Systematic Review of Behavioral Outcomes, Neurobiological Mechanisms, and Methodological Quality

ABSTRACT Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and interaction, as well as restricted and repetitive patterns of behavior. Although increasing evidence suggests that cannabidiol (CBD) may represent a promising therapeutic strategy for ASD, the preclinical literature remains fragmented, with substantial variability in experimental models, treatment protocols, CBD formulations, and reported outcomes. This systematic review (PROSPERO registration: CRD420251177933) aimed to critically evaluate the psychopharmacological effects of CBD in rodent models of ASD, with an emphasis on behavioral outcomes, underlying neurobiological mechanisms, and methodological quality. A systematic search was conducted in PubMed, Embase, Web of Science, Scopus, and ProQuest Dissertations & Theses, with a final sample of 14 articles. Due to the substantial heterogeneity across studies, a qualitative synthesis of results was performed using the Synthesis Without Meta-analysis (SWiM) approach. Overall, CBD and CBD-based preparations produced beneficial effects across multiple ASD-relevant behavioral domains. Enhanced social interaction, reductions in repetitive behaviors, anxiety-like responses, and cognitive impairments were observed in specific models. Neurobiological analyses revealed modulation of the endocannabinoid system, restoration of excitation/inhibition balance, anti-inflammatory and antioxidant effects, and transcriptional regulation. Positive outcomes were observed across pharmacological, genetic, and maternal immune activation models, suggesting that CBD acts on convergent neurobiological pathways implicated in ASD pathophysiology. Despite these promising findings, important limitations were identified, including substantial heterogeneity in experimental protocols and methodological limitations, such as insufficient reporting of randomization, blinding, and allocation concealment procedures, as well as the underrepresentation of female animals. This review synthesizes behavioral, neurobiological, and methodological evidence on CBD and CBD-based preparations in rodent models of ASD, highlighting its therapeutic potential and the need for more rigorous, standardized preclinical investigations that directly compare isolated CBD with its formulations and combinations.