EPA (eicosapentaenoic acid, 20:5n-3) and DHA (docosahexaenoic acid, 22:6n-3) are long-chain omega-3 polyunsaturated fatty acids that cannot be efficiently synthesized in the human body from the plant precursor ALA (alpha-linolenic acid, found in flaxseed, chia, walnuts). The conversion of ALA to EPA is approximately 5–10%; ALA to DHA is less than 1%. This means dietary EPA and DHA from marine sources — oily fish, seafood, or algae — are the only practical routes to maintaining adequate tissue levels for most people. The American Heart Association recommends at least 2 servings of oily fish per week; this provides approximately 500mg–1g EPA+DHA/day. Those with cardiovascular disease or elevated triglycerides benefit from higher doses achievable only via supplementation.
EPA and DHA have distinct functions: EPA is preferentially incorporated into cell membrane phospholipids and is the primary precursor for anti-inflammatory eicosanoids (prostaglandin E3, thromboxane A3, leukotriene B5 — all less inflammatory than the omega-6-derived series); EPA also directly reduces triglyceride synthesis. DHA is the dominant fatty acid in brain gray matter and retinal photoreceptors, making it critical for neurodevelopment and visual function; it is also incorporated into cardiac cell membranes where it stabilizes electrical conduction. Both are needed — targeting EPA alone or DHA alone addresses only part of the clinical picture.
| Form | Source / Production | Absorption | Notes |
|---|---|---|---|
| Natural triglyceride (TG) | Direct from fish oil concentrate; EPA+DHA in native TG structure | Best — absorbed via the same pathway as dietary fat | Less concentrated (typically 30% EPA+DHA by weight vs 60–90% for concentrates); requires more capsules for therapeutic doses; found in cod liver oil and some premium brands |
| Re-esterified triglyceride (rTG) | EE form converted back to TG form; concentrated then re-esterified | Excellent — comparable to natural TG; better than EE fasted or fed | Most premium fish oil brands use rTG: Nordic Naturals Ultimate Omega, Carlson Super Omega-3, Thorne; allows high concentration (60–80% EPA+DHA) with good absorption; the best combination of potency and bioavailability |
| Ethyl ester (EE) | Molecular distillation of fish oil; EPA+DHA esterified to ethanol backbone | Poor without food; requires bile acid stimulation from fat co-ingestion | Most common cheap supplement form; Omacor/Lovaza (prescription) is EE form; if taking EE fish oil, always take with a fat-containing meal; the ethanol backbone is cleaved by gut esterases — this step limits absorption without lipase activity stimulated by dietary fat |
| Phospholipid (krill oil) | Antarctic krill (Euphausia superba); EPA+DHA in phospholipid form | Good — phospholipid form absorbed without requiring bile; possibly superior brain uptake | Contains astaxanthin (antioxidant, prevents oxidation); much lower total EPA+DHA per capsule (typically 100–200mg vs 500–1000mg in fish oil); more expensive per gram of omega-3; sustainable sourcing concerns; no major outcome trials comparing krill vs fish oil head-to-head; may be preferred for those with fish oil GI intolerance |
| Algae oil (DHA-dominant) | Marine microalgae (Schizochytrium, Nannochloropsis); where fish get their omega-3s | Good — TG form typically; comparable to fish oil | Vegan/vegetarian source; DHA-heavy (some provide EPA as well, but less than fish oil per dose); higher cost per gram of EPA+DHA; the ecological original source — fish accumulate omega-3s from eating algae; excellent choice for vegans or those avoiding fish |
REDUCE-IT (Bhatt 2019 NEJM, N=8,179): 4g/day purified EPA (icosapentaenoic acid, Vascepa) → 25% MACE reduction in high-risk CV patients on statins with elevated TG. STRENGTH (Nicholls 2020 JAMA, N=13,078): 4g/day EPA+DHA (carboxylic acid form, Epanova) → no significant MACE reduction vs corn oil placebo. ASCEND (Bowman 2018 NEJM, N=15,480): 1g/day EPA+DHA → modest 11% MACE reduction in diabetics (borderline significant). The discordance may reflect: (1) pure EPA vs EPA+DHA — DHA may raise LDL-C slightly, attenuating EPA's cardiovascular benefit; (2) the REDUCE-IT placebo (mineral oil) may have raised CV events in the control arm, inflating the apparent treatment effect; (3) dose: 4g/day EPA is a pharmaceutical intervention, not equivalent to 1g/day OTC fish oil. The practical summary: high-dose purified EPA (prescription) has the strongest evidence for CV event reduction in high-risk patients with hypertriglyceridemia; standard OTC fish oil at 1–2g/day has modest, consistent triglyceride-lowering and anti-inflammatory effects but uncertain MACE benefit in general populations.
General health maintenance: 1–2g combined EPA+DHA daily from rTG-form fish oil taken with the largest fat-containing meal of the day. Look for: rTG or TG form on the label; IFOS 5-star certified or third-party tested for oxidation (TOTOX value <10 ideally); dark glass or opaque bottle (light oxidizes fish oil); no "fishy" smell (rancid odor = oxidized product). Brands with consistent quality: Nordic Naturals Ultimate Omega (rTG), Carlson Super Omega-3 Gems (TG), Thorne Super EPA+DHA (rTG).
Cardiovascular/triglyceride target: 2–4g EPA+DHA daily with meals. At 4g/day, prescription omega-3s (Vascepa — pure EPA; Lovaza/Omacor — EPA+DHA EE) have the most clinical evidence but require physician authorization. Over-the-counter rTG fish oil at 4g/day is a reasonable alternative for those who cannot access prescriptions. Retest triglycerides and Omega-3 Index at 12 weeks.
Brain and cognitive focus: 1–2g DHA daily + EPA; algae oil or high-DHA fish oil. Algae oil (Thorne Omega-3 with Algae, Ovega-3, Naturo Sciences) provides DHA in TG form without fish exposure. Important for vegans, pregnant women (DHA is critical for fetal brain development — minimum 200mg DHA/day during pregnancy), and older adults concerned about cognitive aging.
Oxidation warning: Omega-3 fatty acids are highly susceptible to oxidation — oxidized fish oil may be pro-inflammatory rather than anti-inflammatory. Store fish oil in the refrigerator (or freezer for bulk); buy from reputable brands with TOTOX testing; discard if burps smell strongly fishy (indicates oxidation). Smaller bottles turned over quickly are safer than warehouse bulk containers.
Blood thinning: At doses ≥3g/day, omega-3s have mild antiplatelet effects. Patients on warfarin, aspirin, or other anticoagulants should consult their physician before supplementing at high doses. At 1–2g/day this effect is clinically insignificant for most people.
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