Does Omega-3 Help After All in Autism Spectrum Disorder? An Update Systematic Review and Meta-Analysis of Randomized Trials

Abstract

Background/Objectives: Autism Spectrum Disorder (ASD) affects approximately 60 × 104 incident cases, 283.3 × 105 prevalent cases, and 43.1 × 105 DALYs globally and is frequently accompanied by irritability, hyperactivity, and social withdrawal linked to low-grade neuroinflammation. Omega-3 supplementation is among the most common complementary approaches used by families, but clinical evidence remains inconsistent, and prior meta-analyses have relied on a single outcome instrument. This study aimed to evaluate the efficacy of omega-3 supplementation on ASD-associated behavioral symptoms by harmonizing outcomes across multiple validated instruments. Methods: Twelve randomized controlled trials (number of studies per domain: k = 6–12) were identified through a systematic search of ten databases (CRD420261390092). Outcomes from eight instruments (ABC, CGI-I, BASC-2, SRS/SRS-2, GARS-2, CARS/SDQ, VABS/PLS-4/PDDBI, and CBCL) were mapped onto five behavioral domains: Irritability, Lethargy/Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate Speech/Communication. Random-effects models (REML, Knapp-Hartung adjustment) pooled Hedges’ g for each domain, with fixed-effects, subgroup, and PET-PEESE publication-bias sensitivity analyses. Results: Significant pooled effects favoring omega-3 supplementation were observed for Irritability (g = −0.287, 95% CI [−0.562, −0.013], p = 0.043) and Inappropriate Speech/Communication (g = −0.213, 95% CI [−0.363, −0.063], p = 0.010). Lethargy/Social Withdrawal, Stereotypy, and Hyperactivity showed trivial-to-small, non-significant effects. Heterogeneity was negligible (I2 ≤ 0.83%) in four domains; Hyperactivity showed moderate heterogeneity (I2 = 37.86%). Sensitivity analyses confirmed robustness, and no evidence of publication bias was detected. Conclusions: Expanding synthesis beyond a single outcome instrument revealed statistically significant, though clinically modest, benefits of omega-3 supplementation on irritability and communication symptoms in ASD, effects undetectable in prior smaller, single-instrument analyses. These findings support its consideration as a low-risk adjunctive option, while larger, adequately powered trials remain needed to confirm clinical relevance.