Effect of Pure EPA on Erythrocyte Membrane Fatty Acids During Supplementation and Washout: A Randomized Controlled Trial.

Distinct findings from pure eicosapentaenoic acid (EPA) and combined EPA + docosahexaenoic acid (DHA) supplementation trials have raised interest in molecule-specific effects of EPA. However, erythrocyte membrane fatty acid dynamics after pure EPA exposure and withdrawal remain incompletely characterized in healthy adults. In this randomized, double-blind, placebo-controlled trial, 48 healthy adults were assigned 1:1 to pure EPA (3 g/day) or corn oil for 4 weeks, followed by a 4-week washout stage. Twenty erythrocyte membrane fatty acid species were measured at Week 0, Week 4, and Week 8; the Omega-3 Index and Omega-6/Omega-3 ratio were derived. Between-group net differences across 22 outcomes were estimated using a covariate-adjusted linear mixed-effects model, with Benjamini-Hochberg false discovery rate (FDR) correction. At Week 4, pure EPA significantly altered 5 of the 22 outcomes after FDR correction. Erythrocyte EPA, docosapentaenoic acid (DPA), and the Omega-3 Index increased; the Omega-6/Omega-3 ratio decreased; and the increase in dihomo-gamma-linolenic acid was attenuated relative to corn oil. DHA and arachidonic acid showed no significant between-group net differences. After washout, EPA and the Omega-3 Index showed partial recovery, whereas the Omega-6/Omega-3 ratio showed limited recovery. DPA remained elevated at Week 8. EPA changes were largely uncorrelated with changes in other fatty acids during supplementation, whereas Week 8 DPA changes were positively associated with Week 8 EPA changes. Pure EPA supplementation selectively altered erythrocyte membrane fatty acids, with partial recovery of EPA but persistent DPA elevation after withdrawal.