Alterations of the endocannabinoid system in autism spectrum disorder: a systematic review and meta-analysis

Dysregulation of the endocannabinoid system (ECS) might be related to autism spectrum disorder (ASD). This study conducts a meta-analysis on the dysregulation of the ECS across ASD animal models and individuals with ASD and systematically reviews the impact of these alterations in ASD animal models. Out of 47 papers assessed for eligibility, 16 animal studies and five human studies were included for narrative synthesis and seven and three for quantitative analysis, respectively. The results revealed a significant decrease in hippocampus anandamide (AEA) levels (SMD = -1.06, 95% CI [-1.78, -0.33], p < 0.01) among ASD animal models and a decrease in blood AEA levels in individuals with ASD (SMD = -0.79, 95% CI [-1.28, -0.30], p = 0.002) compared to normal controls. In the prefrontal cortex, 2-arachidonoylglycerol (2-AG) levels were significantly decreased, despite high heterogeneity between studies (SMD = -1.00, 95% CI [-1.93, -0.06], p = 0.04). No significant changes compared to normal controls were observed in levels of AEA (SMD = -0.48, 95% CI [-1.20, 0.25], p = 0.20), 2-AG (SMD = -0.62, 95% CI [-1.27, 0.02], p = 0.06) in combined brain regions. The narrative synthesis revealed that elevated AEA and 2-AG levels could ameliorate core and associated autistic-like symptoms with region and sex-dependent variations in ASD animal models. Future research should focus on specific mechanisms of endocannabinoids regional effects while considering sex-related influences.