Abstract
This double-blind, randomized controlled trial, tested fatty acid (FA) supplementation in children (ages 2- < 6 years) recently diagnosed with Autism Spectrum Disorder (ASD). Participants received daily oral FA supplement containing omega-3 and omega-6 FA, or a placebo for 90 days based on participant weight. Erythrocyte FAs and the cytokines, IL-1β, IL-2, IFNγ, were measured in plasma obtained from serial blood collections. Treatment increased omega-3 and omega-6 FA levels (1.40 mol% for EPA and 1.62 mol% for DHA) and reduced IL-2 levels compared to placebo (− 0.17 pg/mL, 95% CI − 0.31, − 0.02, d = − 0.62). Omega 3–6 treatment was tolerable and adherence was greater than 70%. Future research will assess the effects of Omega 3–6 treatment on ASD symptoms. Registered on 06/08/2018 with ClinicalTrials.gov: NCT03550209.
This is a preview of subscription content, access via your institution.
References
Amminger, G. P., Berger, G. E., Schäfer, M. R., Klier, C., Friedrich, M. H., & Feucht, M. (2007). Omega-3 Fatty Acids Supplementation in Children with Autism: A Double-blind Randomized, Placebo-controlled Pilot Study. Biological Psychiatry, 61, 551–553. https://doi.org/10.1016/j.biopsych.2006.05.007
Anisman, H., Hayley, S., Turrin, N., & Merali, Z. (2002). Cytokines as a stressor: Implications for depressive illness. International Journal of Neuropsychopharmacology, 5(4), 357–373. https://doi.org/10.1017/S1461145702003097
Arnold, L., Young, A., Belury, M., Cole, R., Gracious, B., Seidenfeld, A., Wolfson, H., & Fristad, M. (2017). Omega-3 Fatty Acid Plasma Levels Before and After Supplementation: Correlations with Mood and Clinical Outcomes in the Omega 3 and Therapy Studies (OATS). Journal of Child and Adolescent Psychopharmacology, 27(3), 223–233. https://doi.org/10.1089/cap.2016.0123
Bazan, N. G. (2006). Cell survival matters: Docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends in Neurosciences, 29(5), 263–271. https://doi.org/10.1016/j.tins.2006.03.005
Bent, S., Bertoglio, K., Ashwood, P., Bostrom, A., & Hendren, R. L. (2011). A pilot randomized controlled trial of omega-3 fatty acids for autism spectrum disorder. Journal of Autism and Developmental Disorders, 41(5), 545–554. https://doi.org/10.1007/s10803-010-1078-8
Bent, S., Hendren, R. L., Zandi, T., Law, K., Choi, J. E., Widjaja, F., Kalb, L., Nestle, J., & Law, P. (2014). Internet-based, randomized, controlled trial of omega-3 fatty acids for hyperactivity in autism. Journal of the American Academy of Child and Adolescent Psychiatry, 53(6), 658–666. https://doi.org/10.1016/j.jaac.2014.01.018
Bloch, M. H., & Qawasmi, A. (2011). Omega-3 fatty acid supplementation for the treatment of children with attention-deficit/hyperactivity disorder symptomatology: Systematic review and meta-analysis. Journal of the American Academy of Child and Adolescent Psychiatry, 50(10), 991–1000. https://doi.org/10.1016/j.jaac.2011.06.008
Boone, K. M., Pattison, K., Pelak, G., Sheppard, K. W., Rausch, J., Yeates, K. O., Nelin, M. A., Klebanoff, M. A., Norris Turner, A., & Rogers, L. K. (2021). Docosahexaenoic and arachidonic acid supplementation at 1 year has mixed effects on development and behavior at age 2 for preterm children. Acta Paediatrica. https://doi.org/10.1111/apa.15858
Brigandi, S. A., Shao, H., Qian, S. Y., Shen, Y. P., Wu, B. L., & Kang, J. X. (2015). Autistic Children Exhibit Decreased Levels of Essential Fatty Acids in Red Blood Cells. International Journal of Molecular Sciences, 16(5), 10061–10076. https://doi.org/10.3390/ijms160510061
Briggs-Gowan, M. J., Carter, A. S., Irwin, J. R., Wachtel, K., & Cicchetti, D. V. (2004). The Brief Infant-Toddler Social and Emotional Assessment: Screening for social-emotional problems and delays in competence. Journal of Pediatric Psychology, 29(2), 143–155. https://doi.org/10.1093/jpepsy/jsh017
Chalon, S. (2006). Omega-3 fatty acids and monoamine neurotransmission. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 75(4–5), 259–269. https://doi.org/10.1016/j.plefa.2006.07.005
Christian, L. M., Young, A. S., Mitchell, A. M., Belury, M. A., Gracious, B. L., Arnold, L. E., & Fristad, M. A. (2017). Body weight affects ω-3 polyunsaturated fatty acid (PUFA) accumulation in youth following supplementation in post-hoc analyses of a randomized controlled trial. PLoS ONE, 12(4), e0173087. https://doi.org/10.1371/journal.pone.0173087
Coffman, C. J., Edelman, D., & Woolson, R. F. (2016). To condition or not condition? Analysing “change” in longitudinal randomised controlled trials. British Medical Journal Open, 6(12), e013096. https://doi.org/10.1136/bmjopen-2016-013096
Coti Bertrand, P., O’Kusky, J. R., & Innis, S. M. (2006). Maternal dietary (n-3) fatty acid deficiency alters neurogenesis in the embryonic rat brain. Journal of Nutrition, 136(6), 1570–1575. https://doi.org/10.1093/jn/136.6.1570
Dawson, G., Rogers, S., Munson, J., Smith, M., Winter, J., Greenson, J., Donaldson, A., & Varley, J. (2010). Randomized, controlled trial of an intervention for toddlers with autism: The Early Start Denver Model. Pediatrics, 125(1), e17-23. https://doi.org/10.1542/peds.2009-0958
de Vinck-Baroody, O., Shui, A., Macklin, E. A., Hyman, S. L., Leventhal, J. M., & Weitzman, C. (2015). Overweight and obesity in a sample of children with autism spectrum disorder. Academic Pediatrics, 15(4), 396–404. https://doi.org/10.1016/j.acap.2015.03.008
Eder, K. (1995). Gas chromatographic analysis of fatty acid methyl esters. Journal of Chromatography B: Biomedical Applications, 671(1–2), 113–131.
Granpeesheh, D., Dixon, D. R., Tarbox, J., Kaplan, A. M., & Wilke, A. E. (2009). The effects of age and treatment intensity on behavioral intervention outcomes for children with autism spectrum disorders. Research in Autism Spectrum Disorders, 3(4), 1014–1022. https://doi.org/10.1016/j.rasd.2009.06.007
Greenhill, L. L., Vitiello, B., Fisher, P., Levine, J., Davies, M., Abikoff, H., Chrisman, A. K., Chuang, S., Findling, R. L., March, J., Scahill, L., Walkup, J., & Riddle, M. A. (2004). Comparison of increasingly detailed elicitation methods for the assessment of adverse events in pediatric psychopharmacology. Journal of the American Academy of Child and Adolescent Psychiatry, 43(12), 1488–1496. https://doi.org/10.1097/01.chi.0000142668.29191.13
Grosse, S. D., Ji, X., Nichols, P., Zuvekas, S. H., Rice, C. E., & Yeargin-Allsopp, M. (2021). Spending on young children with autism spectrum disorder in employer-sponsored plans, 2011–2017. Psychiatric Services, 72(1), 16–22. https://doi.org/10.1176/appi.ps.202000099
Ibrahim, S. H., Voigt, R. G., Katusic, S. K., Weaver, A. L., & Barbaresi, W. J. (2009). Incidence of gastrointestinal symptoms in children with autism: A population-based study. Pediatrics, 124(2), 680–686. https://doi.org/10.1542/peds.2008-2933
Innis, S. M. (2008). Dietary omega 3 fatty acids and the developing brain. Brain Research, 1237, 35–43. https://doi.org/10.1016/j.brainres.2008.08.078
Johnson, C. R., Handen, B. L., Zimmer, M., & Sacco, K. (2010). Polyunsaturated fatty acid supplementation in young children with autism. Journal of Developmental and Physical Disabilities, 22(1), 1–10. https://doi.org/10.1007/s10882-009-9152-x
Keim, S. A., Gracious, B., Boone, K. M., Klebanoff, M. A., Rogers, L. K., Rausch, J., Coury, D. L., Sheppard, K. W., Husk, J., & Rhoda, D. A. (2018). ω-3 and ω-6 fatty acid supplementation may reduce autism symptoms based on parent report in preterm toddlers. The Journal of Nutrition, 148(2), 227–235. https://doi.org/10.1093/jn/nxx047
Kitajka, K., Puskas, L. G., Zvara, A., Hackler, L., Jr., Barcelo-Coblijn, G., Yeo, Y. K., & Farkas, T. (2002). The role of n-3 polyunsaturated fatty acids in brain: Modulation of rat brain gene expression by dietary n-3 fatty acids. Proceedings of the National Academy of Sciences of the United States of America, 99(5), 2619–2624. https://doi.org/10.1073/pnas.042698699
Kuratko, C. (2013). Food-frequency questionnaire for assessing long-chain ω-3 fatty-acid intake: Re: Assessing long-chain ω-3 polyunsaturated fatty acids: A tailored food-frequency questionnaire is better. Nutrition, 29(5), 807–808. https://doi.org/10.1016/j.nut.2012.10.013
Lai, K., & Kelley, K. (2012). Accuracy in parameter estimation for ANCOVA and ANOVA contrasts: Sample size planning via narrow confidence intervals. British Journal of Mathematical and Statistical Psychology, 65(2), 350–370. https://doi.org/10.1111/j.2044-8317.2011.02029.x
Lazear, H. M., Nice, T. J., & Diamond, M. S. (2015). Interferon-lambda: Immune functions at barrier surfaces and beyond. Immunity, 43(1), 15–28. https://doi.org/10.1016/j.immuni.2015.07.001
Lord, C., Rutter, M., Dilavore, P. C., Risi, S., Gotham, K., & Bishop, S. L. (2012). Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). WPS.
Maenner, M. J., Shaw, K. A., Baio, J., Washington, A., Patrick, M., DiRienzo, M., Christensen, D. L., Wiggins, L. D., Pettygrove, S., Andrews, J. G., Lopez, M., Hudson, A., Baroud, T., Schwenk, Y., White, T., Rosenberg, C. R., Lee, L. C., Harrington, R. A., Huston, M., … Dietz, P. M. (2020). Prevalence of autism spectrum disorder among children aged 8 years—Autism and developmental disabilities monitoring network, 11 sites, United States, 2016. MMWR: Surveillance Summaries, 69(4), 1–12. https://doi.org/10.15585/mmwr.ss6904a1
Mankad, D., Dupuis, A., Smile, S., Roberts, W., Brian, J., Lui, T., Genore, L., Zaghloul, D., Iaboni, A., Marcon, P. M., & Anagnostou, E. (2015). A randomized, placebo controlled trial of omega-3 fatty acids in the treatment of young children with autism. Molecular Autism, 6, 18. https://doi.org/10.1186/s13229-015-0010-7
Martinez, M. (1994). Polyunsaturated fatty acids in the developing human brain, red cells and plasma—Influence of nutrition and peroxisomal disease. Fatty Acids and Lipids: Biological Aspects, 75, 70–78. https://doi.org/10.1159/000423553
Masi, A., Glozier, N., Dale, R., & Guastella, A. J. (2017). The immune system, cytokines, and biomarkers in autism spectrum disorder. Neuroscience Bulletin, 33(2), 194–204. https://doi.org/10.1007/s12264-017-0103-8
Masi, A., Quintana, D. S., Glozier, N., Lloyd, A. R., Hickie, I. B., & Guastella, A. J. (2015). Cytokine aberrations in autism spectrum disorder: A systematic review and meta-analysis. Molecular Psychiatry, 20(4), 440–446. https://doi.org/10.1038/mp.2014.59
Mazahery, H., Conlon, C. A., Beck, K. L., Mugridge, O., Kruger, M. C., Stonehouse, W., Camargo, C. A., Meyer, B. J., Tsang, B., & von Hurst, P. R. (2020). Inflammation (IL-1β) modifies the effect of vitamin D and omega-3 long chain polyunsaturated fatty acids on core symptoms of autism spectrum disorder—An exploratory pilot study. Nutrients, 12(3), 661. https://doi.org/10.3390/nu12030661
McPheeters, M. L., Warren, Z., Sathe, N., Bruzek, J. L., Krishnaswami, S., Jerome, R. N., & Veenstra-Vanderweele, J. (2011). A systematic review of medical treatments for children with autism spectrum disorders. Pediatrics, 127(5), e1312-1321. https://doi.org/10.1542/peds.2011-0427
Mozaffarian, D., & Wu, J. H. (2012). (n-3) fatty acids and cardiovascular health: Are effects of EPA and DHA shared or complementary? Journal of Nutrition, 142(3), 614S-625S. https://doi.org/10.3945/jn.111.149633
Ooi, Y. P., Weng, S. J., Jang, L. Y., Low, L., Seah, J., Teo, S., Ang, R. P., Lim, C. G., Liew, A., Fung, D. S., & Sung, M. (2015). Omega-3 fatty acids in the management of autism spectrum disorders: Findings from an open-label pilot study in Singapore. European Journal of Clinical Nutrition, 69(8), 969–971. https://doi.org/10.1038/ejcn.2015.28
Petitto, J. M., Meola, D., & Huang, Z. (2012). Interleukin-2 and the brain: Dissecting central versus peripheral contributions using unique mouse models. Methods in Molecular Biology, 934, 301–311. https://doi.org/10.1007/978-1-62703-071-7_15
Puri, B. K., & Martins, J. G. (2014). Which polyunsaturated fatty acids are active in children with attention-deficit hyperactivity disorder receiving PUFA supplementation? A fatty acid validated meta-regression analysis of randomized controlled trials. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 90(5), 179–189. https://doi.org/10.1016/j.plefa.2014.01.004
Reichow, B., & Wolery, M. (2009). Comprehensive synthesis of early intensive behavioral interventions for young children with autism based on the UCLA young autism project model. Journal of Autism and Developmental Disorders, 39(1), 23–41. https://doi.org/10.1007/s10803-008-0596-0
Salem, N., Litman, B., Kim, H. Y., & Gawrisch, K. (2001). Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids, 36(9), 945–959. https://doi.org/10.1007/s11745-001-0805-6
Sergeant, S., Rahbar, E., & Chilton, F. H. (2016). Gamma-linolenic acid, dihommo-gamma linolenic, eicosanoids and inflammatory processes. European Journal of Pharmacology, 785, 77–86. https://doi.org/10.1016/j.ejphar.2016.04.020
Sheppard, K. W., Gracious, B. K., Klebanoff, M. A., Rogers, L. K., Rausch, J., Bartlett, C., Coury, D. L., & Keim, S. A. (2017). Effect of Omega-3 and -6 Supplementation on Language in Preterm Toddlers Exhibiting Autism Spectrum Disorder Symptoms. Journal of Autism and Developmental Disorders, 47(11), 3358–3369. https://doi.org/10.1007/s10803-017-3249-3
Simopoulos, A. P. (2002). Omega-3 fatty acids in inflammation and autoimmune diseases. Journal of the American College of Nutrition, 21(6), 495–505. https://doi.org/10.1080/07315724.2002.10719248
Sweeten, T. L., Posey, D. J., Shankar, S., & McDougle, C. J. (2004). High nitric oxide production in autistic disorder: A possible role for interferon-gamma. Biological Psychiatry, 55(4), 434–437. https://doi.org/10.1016/j.biopsych.2003.09.001
Theoharides, T. C., Tsilioni, I., Patel, A. B., & Doyle, R. (2016). Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Translational Psychiatry, 6(6), e844. https://doi.org/10.1038/tp.2016.77
Tostes, M. H., Teixeira, H. C., Gattaz, W. F., Brandao, M. A., & Raposo, N. R. (2012). Altered neurotrophin, neuropeptide, cytokines and nitric oxide levels in autism. Pharmacopsychiatry, 45(6), 241–243. https://doi.org/10.1055/s-0032-1301914
Vancassel, S., Durand, G., Barthelemy, C., Lejeune, B., Martineau, J., Guilloteau, D., Andres, C., & Chalon, S. (2001). Plasma fatty acid levels in autistic children. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 65(1), 1–7. https://doi.org/10.1054/plef.2001.0281
Vezzani, A., & Viviani, B. (2015). Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology, 96(Pt A), 70–82. https://doi.org/10.1016/j.neuropharm.2014.10.027
Wei, M. Y., & Jacobson, T. A. (2011). Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: A systematic review and meta-analysis. Current Atherosclerosis Reports, 13(6), 474–483. https://doi.org/10.1007/s11883-011-0210-3
Whitehouse, A. J. (2013). Complementary and alternative medicine for autism spectrum disorders: Rationale, safety and efficacy. Journal of Paediatrics and Child Health, 49(9), E438–E442. https://doi.org/10.1111/jpc.12242 quiz E442.
Winkens, B., van Breukelen, G. J., Schouten, H. J., & Berger, M. P. (2007). Randomized clinical trials with a pre- and a post-treatment measurement: Repeated measures versus ANCOVA models. Contemporary Clinical Trials, 28(6), 713–719. https://doi.org/10.1016/j.cct.2007.04.002
Xu, N., Li, X., & Zhong, Y. (2015). Inflammatory cytokines: Potential biomarkers of immunologic dysfunction in autism spectrum disorders. Mediators of Inflammation, 2015, 531518. https://doi.org/10.1155/2015/531518
Yui, K., Imataka, G., Kawasak, Y., & Yamada, H. (2016). Increased omega-3 polyunsaturated fatty acid/arachidonic acid ratios and upregulation of signaling mediator in individuals with autism spectrum disorders. Life Sciences, 145, 205–212. https://doi.org/10.1016/j.lfs.2015.12.039
Acknowledgments
We thank Investigational Drug Services staff of Nationwide Children’s Hospital, the Child Development Center of Nationwide Children’s Hospital, Beth Burkhart of Research Information Solutions and Innovation, and Yolanda Yang of Nationwide Children’s Hospital for data collection and administrative support, the Independent Monitoring Committee members Robert Voigt, Lisa Bodnar, and Kenneth Kelley, and National Center for Complementary and Integrative Health Program Officer Wendy Weber. This study was supported by grants from the National Center for Complementary and Integrative Health (R61AT009632) and the National Center for Advancing Translational Sciences (UL1TR001070) of the National Institutes of Health.
Author information
Authors and Affiliations
Contributions
SAK and LKR were co-Principal Investigators for this study. SAK, LKR, DLC, JR, and MN contributed to the study conception and design. Material preparation, data collection, and analysis were performed by KS, AJ, and AQK. Formal analysis was performed by SAK, AQK, JR, SU, and LKR. Eligibility and safety were monitored by SAK, DLC, LRB, ARN, and LKR. The first draft of the manuscript was written by SAK, LKR, and AJ. All authors reviewed and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
None of the authors have conflicts of interest relevant to the content of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Nordic Naturals provided the investigational product at no cost; and Welsh, Holme, & Clark Co., Inc. provided canola oil at no cost. Neither the study sponsors nor product providers had a role in the study design; the collection, analysis, and interpretation of data; writing of this report; or the decision to submit the manuscript for publication.
Ethical Approval
All procedures performed in this study were in accordance with Good Clinical Practice (GCP) and the 1964 Declaration of Helsinki. The study was approved by the Nationwide Children’s Hospital Institutional Review Board (IRB #17–00517) and the National Institutes of Health.
Consent to Participate
Informed consent was obtained from legal guardians.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Keim, S.A., Jude, A., Smith, K. et al. Randomized Controlled Trial of Omega-3 and -6 Fatty Acid Supplementation to Reduce Inflammatory Markers in Children with Autism Spectrum Disorder. J Autism Dev Disord 52, 5342–5355 (2022). https://doi.org/10.1007/s10803-021-05396-9
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10803-021-05396-9
Keywords
- Autism spectrum disorder
- IL-2
- Inflammation
- Omega-3 fatty acids
- Omega-6 fatty acids
- Young child