Behavioral pharmacology of isolated cannabidiol in animal models of autism spectrum disorder: a systematic review.

RATIONALE: Autism spectrum disorder (ASD) is characterized by differences and challenges in social communication and interaction, restricted and repetitive behaviors, and variable cognitive alterations. Cannabidiol (CBD), a non-psychoactive phytocannabinoid with a complex pharmacological profile, has been investigated in preclinical models of ASD, particularly regarding its behavioral and neurobiological effects. OBJECTIVES: To systematically evaluate the behavioral effects of isolated cannabidiol in animal models of ASD and examine associated neurobiological correlates relevant to central nervous system function. METHODS: A systematic search was conducted in eight electronic databases without date restriction. Preclinical studies assessing isolated CBD in animal models of ASD were included. Owing to methodological heterogeneity, data were synthesized according to the Synthesis Without Meta-analysis (SWiM) guideline, with behavioral outcomes defined as primary endpoints and neurobiological measures as secondary outcomes. The review protocol was registered in PROSPERO (CRD420251003869). RESULTS: Nine studies met the inclusion criteria, predominantly using rodent models, especially valproic acid-induced ASD, as well as zebrafish larvae and one behavioral ASD-like rat model. CBD produced dose-, model-, and treatment-regimen-dependent improvements in repetitive behavior, social interaction, recognition memory, and locomotor hyperactivity. Anxiolytic-like effects were inconsistently reported. Behavioral modulation was accompanied by changes in neurobiological markers, including CB1 receptor expression, parvalbumin-positive interneuron density, oxidative/nitrosative stress parameters, and qualitative neuroanatomical and cellular alterations in brain regions implicated in ASD-related behaviors. However, sex-specific effects could not be adequately assessed because most rodent studies used only males, zebrafish studies were conducted at larval stages, and mixed-sex data were not stratified. CONCLUSIONS: Evidence from animal models suggests that isolated CBD exerts promising but heterogeneous behavioral effects in ASD-relevant paradigms, supported by neurobiological changes that may help explain some behavioral outcomes. However, substantial methodological variability, limited sex-specific analyses, and incomplete reporting of bias-control procedures limit certainty, highlighting the need for more rigorous preclinical studies addressing dose-response relationships, mechanisms, sex as a biological variable, safety, long-term outcomes, and translational relevance.