{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T19:17:32Z","timestamp":1787944652883,"version":"build-2784847793"},"reference-count":36,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Autism Spectrum Disorder (ASD) affects approximately 60 \u00d7 104 incident cases, 283.3 \u00d7 105 prevalent cases, and 43.1 \u00d7 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\u201312) 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\u2019 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 = \u22120.287, 95% CI [\u22120.562, \u22120.013], p = 0.043) and Inappropriate Speech\/Communication (g = \u22120.213, 95% CI [\u22120.363, \u22120.063], p = 0.010). Lethargy\/Social Withdrawal, Stereotypy, and Hyperactivity showed trivial-to-small, non-significant effects. Heterogeneity was negligible (I2 \u2264 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.<\/jats:p>","DOI":"10.3390\/nu18172821","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T18:33:52Z","timestamp":1787942032000},"page":"2821","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Does Omega-3 Help After All in Autism Spectrum Disorder? An Update Systematic Review and Meta-Analysis of Randomized Trials"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5800-0033","authenticated-orcid":false,"given":"Inmaculada","family":"S\u00e1nchez-Garc\u00eda","sequence":"first","affiliation":[{"name":"Department of Nursing, Faculty of Health Sciences, University of Ja\u00e9n, 23071 Ja\u00e9n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2997-8515","authenticated-orcid":false,"given":"Cristina","family":"S\u00e1nchez-Quesada","sequence":"additional","affiliation":[{"name":"Preventive Medicine and Public Health Division, Department of Health Sciences, Faculty of Health Sciences, University of Ja\u00e9n, 23071 Ja\u00e9n, Spain"},{"name":"University Institute of Research on Olive and Olive Oils (INUO), University of Ja\u00e9n, 23071 Ja\u00e9n, Spain"},{"name":"Agrifood Campus of International Excellence (ceiA3), 14071 C\u00f3rdoba, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e33","DOI":"10.1017\/S2045796022000178","article-title":"Global, regional and national burden of autism spectrum disorder from 1990 to 2019: Results from the Global Burden of Disease Study 2019","volume":"31","author":"Li","year":"2022","journal-title":"Epidemiol. Psychiatr. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.2147\/NDT.S147305","article-title":"Supplementation of Omega 3 Fatty Acids May Improve Hyperactivity, Lethargy, and Stereotypy in Children with Autism Spectrum Disorders: A Meta-Analysis of Randomized Controlled Trials","volume":"13","author":"Cheng","year":"2017","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_3","first-page":"CD007992","article-title":"Omega-3 Fatty Acids Supplementation for Autism Spectrum Disorders (ASD)","volume":"11","author":"James","year":"2011","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"102386","DOI":"10.1016\/j.rasd.2024.102386","article-title":"Omega-3 and Omega-6 Polyunsaturated Fatty Acid Intake and Aberrant Behaviors in Jordanian Children with Autism Spectrum Disorders (ASD): A Pilot Study","volume":"114","author":"Rababah","year":"2024","journal-title":"Res. Autism Spectr. Disord."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13229-015-0010-7","article-title":"A Randomized, Placebo Controlled Trial of Omega-3 Fatty Acids in the Treatment of Young Children with Autism","volume":"6","author":"Mankad","year":"2015","journal-title":"Mol. Autism"},{"key":"ref_6","first-page":"165","article-title":"Role of Omega-3 Fatty Acids and Autism Spectrum Disorder: A Systematic Review","volume":"3","author":"Khattak","year":"2024","journal-title":"Pak. J. Med. Cardiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Berni, M., Mutti, G., Tancredi, R., Muratori, F., and Calderoni, S. (2026). Vitamin D and Omega-3 Supplementation for Emotional and Behavioral Dysregulation in Autism Spectrum Disorders: A Systematic Review. J. Clin. Med., 15.","DOI":"10.3390\/jcm15020745"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1017\/S0954422424000325","article-title":"Impact of Omega-3 Fatty Acid Supplementation on Clinical Manifestations in Autism Spectrum Disorders: An Umbrella Review of Meta-Analyses","volume":"38","author":"Abbasi","year":"2025","journal-title":"Nutr. Res. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Yui, K., and Imataka, G. (2025). A Comparison of the Treatment Effects of a Risperidone Solution, an Equal Ratio of DHA\/ARA, and a Larger Ratio of Omega-6 PUFA Added to Omega-3 PUFA: An Open-Label Clinical Trial. Curr. Issues Mol. Biol., 47.","DOI":"10.3390\/cimb47030184"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Siniscalco, D., Schultz, S., Brigida, A.L., and Antonucci, N. (2018). Inflammation and Neuro-Immune Dysregulations in Autism Spectrum Disorders. Pharmaceuticals, 11.","DOI":"10.3390\/ph11020056"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_12","unstructured":"Higgins, J.P.T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M.J., and Welch, V.A. (2024). Chapter 6: Choosing effect measures and computing estimates of effect. Cochrane Handbook for Systematic Reviews of Interventions Version 6.5, Cochrane."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A Revised Tool for Assessing Risk of Bias in Randomised Trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hedges, L.V., and Olkin, I. (1985). CHAPTER 1\u2014Introduction. Statistical Methods for Meta-Analysis, Academic Press.","DOI":"10.1016\/B978-0-08-057065-5.50006-3"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/j.euroneuro.2017.08.426","article-title":"Randomized Trial of Omega-3 for Autism Spectrum Disorders: Effect on Cell Membrane Composition and Behavior","volume":"27","author":"Parellada","year":"2017","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1017\/S0007114522000393","article-title":"Fish Oil Supplementation May Improve Attention, Working Memory and Attention-Deficit\/Hyperactivity Disorder Symptoms in Adults with Autism Spectrum Disorder: A Randomised Crossover Trial","volume":"128","author":"Lundbergh","year":"2022","journal-title":"Br. J. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"261","DOI":"10.3102\/10769986030003261","article-title":"Bias and Efficiency of Meta-Analytic Variance Estimators in the Random-Effects Model","volume":"30","author":"Viechtbauer","year":"2005","journal-title":"J. Educ. Behav. Stat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.1002\/sim.1482","article-title":"Improved Tests for a Random Effects Meta-Regression with a Single Covariate","volume":"22","author":"Knapp","year":"2003","journal-title":"Stat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1002\/sim.2514","article-title":"Confidence Intervals for the Amount of Heterogeneity in Meta-Analysis","volume":"26","author":"Viechtbauer","year":"2007","journal-title":"Stat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.biopsych.2006.05.007","article-title":"Omega-3 Fatty Acids Supplementation in Children with Autism: A Double-Blind Randomized, Placebo-Controlled Pilot Study","volume":"61","author":"Amminger","year":"2007","journal-title":"Biol. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s10803-010-1078-8","article-title":"A Pilot Randomized Controlled Trial of Omega-3 Fatty Acids for Autism Spectrum Disorder","volume":"41","author":"Bent","year":"2011","journal-title":"J. Autism Dev. Disord."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.jaac.2014.01.018","article-title":"Internet-Based, Randomized, Controlled Trial of Omega-3 Fatty Acids for Hyperactivity in Autism","volume":"53","author":"Bent","year":"2014","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jsbmb.2018.10.017","article-title":"A Randomised Controlled Trial of Vitamin D and Omega-3 Long Chain Polyunsaturated Fatty Acids in the Treatment of Irritability and Hyperactivity among Children with Autism Spectrum Disorder","volume":"187","author":"Mazahery","year":"2019","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.jclinepi.2007.11.010","article-title":"Contour-Enhanced Meta-Analysis Funnel Plots Help Distinguish Publication Bias from Other Causes of Asymmetry","volume":"61","author":"Peters","year":"2008","journal-title":"J. Clin. Epidemiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1002\/jrsm.1095","article-title":"Meta-Regression Approximations to Reduce Publication Selection Bias","volume":"5","author":"Stanley","year":"2014","journal-title":"Res. Synth. Methods"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"d4002","DOI":"10.1136\/bmj.d4002","article-title":"Recommendations for Examining and Interpreting Funnel Plot Asymmetry in Meta-Analyses of Randomised Controlled Trials","volume":"343","author":"Sterne","year":"2011","journal-title":"BMJ"},{"key":"ref_27","unstructured":"Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences, Lawrence Erlbaum Associates. [2nd ed.]."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"de la Torre-Aguilar, M.J., Gomez-Fernandez, A., Flores-Rojas, K., Martin-Borreguero, P., Mesa, M.D., Perez-Navero, J.L., Olivares, M., Gil, A., and Gil-Campos, M. (2022). Docosahexaenoic and Eicosapentaenoic Intervention Modifies Plasma and Erythrocyte Omega-3 Fatty Acid Profiles But Not the Clinical Course of Children With Autism Spectrum Disorder: A Randomized Control Trial. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.790250"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10882-009-9152-x","article-title":"Polyunsaturated Fatty Acid Supplementation in Young Children with Autism","volume":"22","author":"Johnson","year":"2010","journal-title":"J. Dev. Phys. Disabil."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1097\/MPG.0000000000000260","article-title":"Dietary Docosahexaenoic Acid Supplementation in Children with Autism","volume":"58","author":"Voigt","year":"2014","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12","DOI":"10.5114\/pedm.2020.101806","article-title":"The Effect of Omega-3 Fatty Acids Supplementation on Social and Behavioral Disorders of Children with Autism: A Randomized Clinical Trial","volume":"27","author":"Doaei","year":"2021","journal-title":"Pediatr. Endocrinol. Diabetes Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring Inconsistency in Meta-Analyses","volume":"327","author":"Higgins","year":"2003","journal-title":"BMJ"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/npp.2017.160","article-title":"Omega-3 Polyunsaturated Fatty Acids in Youths with Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Clinical Trials and Biological Studies","volume":"43","author":"Chang","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1056\/NEJMoa013171","article-title":"Risperidone in Children with Autism and Serious Behavioral Problems","volume":"347","author":"McCracken","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_35","first-page":"CD005040","article-title":"Risperidone for Autism Spectrum Disorder","volume":"1","author":"Jesner","year":"2007","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1542\/peds.2008-3782","article-title":"Aripiprazole in the Treatment of Irritability in Children and Adolescents with Autistic Disorder","volume":"124","author":"Owen","year":"2009","journal-title":"Pediatrics"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/17\/2821\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T18:36:34Z","timestamp":1787942194000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/17\/2821"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":36,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["nu18172821"],"URL":"https:\/\/doi.org\/10.3390\/nu18172821","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]}}}