Reduced Endocannabinoid Signaling in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

ABSTRACT Background:The endocannabinoid system (ECS) regulates neurodevelopment, synaptic plasticity, stress responsivity, and social behavior. Human studies examining peripheral endocannabinoids in autism spectrum disorder (ASD) have produced inconsistent findings. A quantitative synthesis is needed to determine whether specific endocannabinoid alterations represent robust biological signatures of ASD. Methods:A systematic search identified human studies reporting peripheral concentrations of anandamide (AEA), 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA), or oleoylethanolamide (OEA) in ASD and control groups. Effect sizes (Hedges g) were computed for each study. Random-effects meta-analyses were performed for each biomarker. Heterogeneity (Q, τ², I²), leave-one-out analyses, and moderator tests were conducted. Publication bias was assessed using funnel plots and Egger’s test when k ≥ 10. Results:Four studies reported AEA, five reported PEA, three reported OEA, and one reported 2-AG. AEA was significantly reduced in ASD (g = −0.87, 95% CI [−1.06, −0.67], I² = 0%). OEA was likewise significantly decreased (g = −0.71, 95% CI [−0.98, −0.44], I² = 0%). PEA showed no significant overall effect (g = −0.36, 95% CI [−0.89, 0.17]) and exhibited high heterogeneity (I² = 82.7%). The single available 2-AG study reported a significant reduction (g = −0.76). Leave-one-out analyses confirmed the robustness of AEA and OEA findings. Funnel plots showed no visual asymmetry, although Egger’s test was not interpretable due to limited study numbers. Conclusion:The meta-analysis provides convergent evidence for reduced peripheral AEA and OEA concentrations in ASD, supporting a model of endocannabinoid hypofunction. These findings align with mechanistic data implicating ECS signaling in social behavior, sensory processing, and stress regulation. PEA heterogeneity suggests context-dependent variation rather than a uniform deficit. Larger, standardized studies are needed to evaluate diagnostic utility and mechanistic specificity.