Omega-3 Supplementation Modulates Whole-Blood EPA and DHA Without Improving Patient-Reported Outcomes in Youth with Migraine: A Quasi-Randomized Pilot Trial

Background/Objectives: Omega-3 polyunsaturated fatty acids (PUFAs) influence lipid-mediated inflammatory pathways implicated in migraine, yet randomized trial data evaluating biologic effects of omega-3 supplementation in youth with migraine remain limited. This pilot quasi-randomized clinical trial aimed to determine whether 12 weeks of omega-3 PUFA supplementation produces measurable changes in whole-blood EPA and DHA levels in children and adolescents with migraine, and to characterize changes in patient-reported measures of pain, migraine-related disability, and psychological distress. Methods: We conducted a parallel-group, quasi-randomized, double-blind, placebo-controlled trial in children and adolescents (ages 10–17) with migraine diagnosed per International Classification of Headache Disorders, 3rd edition criteria, recruited from pediatric neurology clinics at two academic medical centers. Of 57 participants allocated 1:1 to daily omega-3 PUFA supplementation (340 mg EPA + 510 mg DHA) or coconut oil placebo for 12 weeks, 44 completed the study and were analyzed. The primary outcome was change in whole-blood omega-3 PUFA index. Secondary outcomes included patient-reported measures of pain intensity, pain interference, migraine-related disability, and psychological distress. Exploratory outcomes included changes in omega-6/omega-3 and arachidonic acid/eicosapentaenoic acid (AA/EPA) ratios. Between-group differences were evaluated using ANCOVA adjusting for baseline values. Results: Omega-3 supplementation significantly altered lipid biomarker profiles. Compared with placebo, the intervention group demonstrated greater increases in omega-3 PUFA index (adjusted mean difference 1.64; 95% CI 0.94–2.35; p < 0.001) and greater reductions in omega-6/omega-3 ratio (−2.57; 95% CI −4.25 to −0.90; p = 0.003) and AA/EPA ratio (−13.52; 95% CI −21.55 to −5.49; p = 0.002), consistent with the increase in whole-blood omega-3 levels. No significant between-group differences were observed in patient-reported outcomes. Conclusions: Omega-3 PUFA supplementation significantly altered lipid biomarker profiles in youth with migraine over 12 weeks, supporting a measurable whole-blood EPA + DHA response in this proof-of-concept trial. Future larger-scale trials with longer duration are needed to evaluate clinical effects.