Cannabidiol-Induced Recovery of Social Behaviour in Mouse Models of Syndromic Autism

Despite the growing prevalence of autism, no pharmacological interventions have been approved for core symptoms. The endocannabinoid system (ECS) has recently gained interest as a potential target for treating autism. Cannabidiol (CBD), a compound found in Cannabis sativa , is a potential treatment due to its tolerability and promising early results in fragile X syndrome patients. Here, we aimed to evaluate CBD’s efficacy in treating social deficits and restrictive/repetitive behaviours in Shank3 and Fmr1 knockout (KO) mice. Male and female mice were tested in the 3-chamber social apparatus or for self-grooming and in the open field (baseline), followed by five daily treatments with vehicle or CBD (s.c., 5 mg/kg for males, 50 mg/kg for females), and retested post-treatment. At baseline and following vehicle treatment, male and female Shank3 and Fmr1 KO mice exhibited deficits in social novelty, which were restored to control levels following CBD administration. Meanwhile, self-grooming (increased in Shank3 KO mice) and open-field exploration (decreased locomotion in Shank3 KO mice) were not affected by CBD. Females had hippocampal CBD levels ~ 11.6 times higher than males (consistent with dosing) and exhibited elevated anandamide (AEA) levels in CBD-treated groups. Transcriptomic analysis of the hippocampus revealed few sex- and strain-specific differentially expressed genes (DEGs) and only three mRNAs regulated by CBD ( Vwf and Lcn2 in females and Grm2 in Shank3 KO mice). These findings highlight the potential for CBD as a treatment for social deficits in syndromic autism and indicate that the therapeutic effect may be driven by dose-, sex-, or strain-specific mechanisms.