¹Carleton University, Neuroscience, Ottawa, Canada, ²University of Calgary, Department of Cell Biology and Anatomy & Psychiatry, Calgary, Canada, ³McGill University, Psychiatry, Montreal, Canada, ⁴McGill University, Biochemistry, Montreal, Canada

Background: 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.

Aims & Objectives: Here, we aimed to evaluate the efficacy of CBD in treating social deficits and restrictive/repetitive behaviours in Shank3 and Fmr1 knockout (KO) mice.

Method: 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.

Results: 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).

Discussion & Conclusions: 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.