Omega-3 (EPA/DHA)

What it is

EPA (20:5 n-3) and DHA (22:6 n-3) are 20- and 22-carbon polyunsaturated fatty acids with their first double bond at the omega-3 position. Humans convert dietary alpha-linolenic acid (ALA, 18:3 n-3 from flax, chia, walnut) to EPA and DHA only weakly (typically <5% to EPA, <0.5% to DHA), so dietary or supplemental marine sources are the practical way to raise tissue levels. Fish oil, krill oil, and algal oil are the common supplement forms; algal oil is the vegan source and is the original biosynthetic origin (fish accumulate EPA/DHA by eating algae).

Mechanism

EPA and DHA displace arachidonic acid (AA, the omega-6) from membrane phospholipids, shifting eicosanoid synthesis toward less inflammatory 3-series prostaglandins and 5-series leukotrienes. They are substrates for the synthesis of specialized pro-resolving mediators (SPMs) including resolvins (E and D series), protectins, and maresins, which actively resolve inflammation rather than merely suppressing it. DHA is particularly concentrated in neuronal and retinal membranes (about 30-40% of retinal photoreceptor phospholipid fatty acids).

Evidence for benefits

Triglycerides: clear dose-dependent lowering, ~25-30% reduction at 3-4 g/day combined EPA+DHA. FDA-approved prescription icosapent ethyl (EPA only, 4 g/day, REDUCE-IT trial) reduced major adverse cardiovascular events by ~25% in high-risk patients on statins. General fish-oil supplement RCTs (VITAL, ASCEND) showed neutral primary endpoints but some signal for myocardial infarction and cardiac death reduction. AHA Science Advisory endorses ~1 g/day EPA+DHA for established coronary heart disease. Mental health: meta-analyses suggest a modest antidepressant effect with EPA-predominant formulations (>60% EPA), particularly as adjunct to antidepressants. Rheumatoid arthritis: reduces joint tenderness and NSAID use. Pregnancy: DHA supports fetal neural and retinal development; supplementation reduces risk of early preterm birth.

Optimal dose & form

General health: 500-1000 mg combined EPA+DHA/day. Triglyceride lowering: 2-4 g/day. Mental health: 1-2 g/day with EPA dominant. Take with a fat-containing meal. Re-esterified triglyceride (rTG) and free fatty acid forms show somewhat better absorption than ethyl ester. Quality matters: look for IFOS or USP certification, low oxidation (TOTOX <10), and adequate concentration so capsule burden stays low.

Risks & interactions

Generally well tolerated. Fishy reflux is the most common complaint; freezing or splitting doses helps. High doses (>3 g/day) modestly prolong bleeding time; relevant in patients on warfarin or with bleeding disorders, though clinically significant bleeding events are rare. A slightly increased risk of atrial fibrillation has been observed in some high-dose RCTs (especially with EPA monotherapy at 4 g/day). Mercury and persistent organic pollutants are a concern with low-quality fish-oil products.

Testing

Omega-3 Index (RBC EPA+DHA as % of total fatty acids) is the validated marker. Targets: <4% high risk, 4-8% intermediate, >8% cardioprotective. Plasma EPA/DHA is acutely responsive but less stable.