EPA

• Cardiovascular health
• Anti-inflammatory
• Metabolic regulation
• Immune modulation

• Mood regulation
• Joint health
• Skin health
• Cognitive support
• Lipid profile improvement
• Blood pressure regulation

Eicosapentaenoic acid (EPA) exerts its biological effects through multiple interconnected mechanisms. As an anti-inflammatory agent, EPA competes with arachidonic acid (AA) for incorporation into cell membrane phospholipids, reducing the substrate available for pro-inflammatory eicosanoid production. When metabolized, EPA serves as a precursor for series-3 prostaglandins and series-5 leukotrienes, which are less inflammatory than their AA-derived counterparts. EPA is also converted to specialized pro-resolving mediators (SPMs) called E-series resolvins, which actively resolve inflammation by reducing neutrophil infiltration, enhancing macrophage phagocytosis of cellular debris, and promoting tissue repair.

In cardiovascular health, EPA reduces triglyceride synthesis in the liver by inhibiting key enzymes like diacylglycerol acyltransferase and fatty acid synthase while activating peroxisome proliferator-activated receptors (PPARs) that enhance fatty acid oxidation. EPA improves endothelial function by increasing nitric oxide production, reducing oxidative stress, and decreasing the expression of adhesion molecules that facilitate atherosclerotic plaque formation. It exhibits antithrombotic effects by reducing platelet aggregation and thromboxane A2 production while modestly increasing bleeding time. EPA modulates membrane fluidity and the function of membrane-bound proteins, including ion channels and receptors, which affects cellular signaling.

It influences gene expression through interaction with transcription factors, particularly PPARs, sterol regulatory element-binding proteins (SREBPs), and nuclear factor-kappa B (NF-κB), regulating genes involved in lipid metabolism, inflammation, and cellular differentiation. In metabolic regulation, EPA enhances insulin sensitivity by reducing inflammatory signaling in adipose tissue and improving glucose uptake through enhanced GLUT4 translocation. It may also protect pancreatic β-cells from oxidative damage. For mental health, EPA influences neurotransmitter systems, particularly serotonergic and dopaminergic pathways, and modulates neuroinflammation, which may explain its benefits in mood disorders.

Unlike DHA, EPA is not significantly incorporated into brain structural components but appears to exert its neuropsychiatric effects primarily through anti-inflammatory and cell signaling mechanisms. EPA also modulates the gut microbiome composition, potentially enhancing beneficial bacterial populations and intestinal barrier integrity, which may contribute to its systemic anti-inflammatory effects through the gut-brain axis.

250-1000 mg of EPA per day for general health maintenance. Combined EPA+DHA intake of 1000-3000 mg per day is commonly recommended for overall health benefits.

EPA absorption varies by form, typically 45-90% depending on the chemical form, formulation, and individual factors. Phospholipid forms (as in krill oil) show higher bioavailability (70-90%) compared to triglyceride forms (60-80%) and ethyl ester forms (45-65%).

Taking with a fat-containing meal increases absorption by stimulating bile release, Emulsified forms increase surface area for enhanced digestion, Phospholipid-bound EPA (as in krill oil) may have superior bioavailability, Triglyceride form is better absorbed than ethyl ester form, Enteric-coated capsules protect from stomach acid degradation, Consuming with lipase-containing foods may enhance absorption, Micronized or nano-emulsified formulations increase surface area, Co-supplementation with vitamin E protects from oxidation, Consuming with lecithin or phosphatidylcholine may enhance absorption, Dividing larger doses throughout the day may improve absorption efficiency

EPA supplements are best taken with meals, particularly those containing fat, to stimulate bile production and enhance absorption. For the ethyl ester form (including prescription icosapent ethyl/Vascepa), taking with a high-fat meal can significantly increase bioavailability. Dividing larger doses throughout the day with different meals may improve tolerance and absorption. Evening dosing may reduce the perception of any fishy aftertaste.

For individuals with sensitive stomachs, taking with the largest meal of the day or dividing the dose between multiple meals can reduce gastrointestinal discomfort. Consistent daily intake is more important than specific timing for achieving and maintaining optimal tissue levels of EPA. For those taking blood-thinning medications, it’s advisable to maintain consistent timing and dosing of EPA supplements to avoid fluctuations in anticoagulant effects.

• Fishy aftertaste or burping (most common)
• Gastrointestinal discomfort (mild nausea, indigestion)
• Loose stools or diarrhea (at high doses)
• Potential for increased bleeding time (theoretical at very high doses)
• Allergic reactions (rare, more common in those with fish allergies)
• Vitamin A and D toxicity (specific to cod liver oil sources)
• Halitosis (bad breath)
• Heartburn or acid reflux (particularly with non-enteric coated forms)

• Fish or shellfish allergy (for marine-derived EPA)
• Planned surgery within 1-2 weeks (due to theoretical bleeding risk at high doses)
• Hemophilia or other bleeding disorders (use with caution)
• Severe liver disease (consult healthcare provider)
• Atrial fibrillation (conflicting evidence, consult healthcare provider)
• Implanted defibrillators (some evidence of potential risk)

• Anticoagulant medications (warfarin, heparin, etc.) – may enhance effects
• Antiplatelet drugs (aspirin, clopidogrel) – may enhance effects
• Blood pressure medications – may enhance hypotensive effects
• Contraceptive drugs – may reduce effectiveness at very high doses
• Vitamin E supplements – combined blood-thinning effects
• Glucocorticoids – may reduce anti-inflammatory benefits of EPA
• Orlistat and other lipase inhibitors – may reduce absorption
• Bile acid sequestrants – may reduce absorption

No official upper limit has been established, but doses up to 3000 mg of combined EPA+DHA per day are generally recognized as safe for most adults. The FDA considers up to 5000 mg/day of combined EPA+DHA from all sources to be generally safe. Higher doses should only be used under medical supervision. For EPA specifically, prescription icosapent ethyl (Vascepa) has been studied at doses of 4000 mg/day with acceptable safety profiles when used under medical supervision.

In the United States, EPA is available both as a dietary supplement and as a prescription medication. As a dietary supplement, EPA falls under the Dietary Supplement Health and Education Act (DSHEA) of 1994, which does not require pre-market approval. The FDA has approved qualified health claims for EPA and DHA regarding their potential to reduce the risk of coronary heart disease. Highly purified EPA ethyl ester (icosapent ethyl, brand name Vascepa) has received FDA approval for two indications: (1) as an adjunct to diet to reduce triglyceride levels in adults with severe hypertriglyceridemia (≥500 mg/dL), and (2) as an adjunct to maximally tolerated statin therapy to reduce the risk of cardiovascular events in adults with elevated triglyceride levels (≥150 mg/dL) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular disease.

The FDA recommends that pregnant and nursing women consume omega-3 fatty acids including EPA from food sources. The FDA advises limiting combined EPA and DHA intake from supplements to no more than 5 grams per day.

Eu: The European Food Safety Authority (EFSA) has approved health claims for EPA and DHA related to maintenance of normal blood pressure, normal blood triglyceride levels, and normal cardiac function. A daily intake of 250 mg of EPA+DHA is recommended for general health. The European Medicines Agency (EMA) has approved medicinal products containing EPA for hypertriglyceridemia. In 2021, the EMA’s Committee for Medicinal Products for Human Use (CHMP) recommended against expanding the indication for icosapent ethyl to include cardiovascular risk reduction, citing concerns about the applicability of the REDUCE-IT trial results to European populations.

Canada: Health Canada classifies EPA as a Natural Health Product (NHP) when sold as a supplement. Health Canada has approved claims for EPA supporting cardiovascular health. Icosapent ethyl (Vascepa) received Health Canada approval in 2019 for reducing triglycerides in adults with hypertriglyceridemia, and in 2023 for reducing the risk of cardiovascular events in high-risk patients.

Australia: The Therapeutic Goods Administration (TGA) regulates EPA supplements as complementary medicines. The National Health and Medical Research Council (NHMRC) recommends 160 mg/day of combined EPA+DHA for men and 90 mg/day for women. Pharmaceutical-grade EPA is available for treating hypertriglyceridemia.

Japan: The Japanese Ministry of Health, Labour and Welfare recognizes EPA as a Food for Specified Health Uses (FOSHU) when certain requirements are met. EPA is widely incorporated into functional foods in the Japanese market. Highly purified EPA ethyl ester has been approved as a prescription medication (Epadel) in Japan since 1990 for hyperlipidemia and since 1994 for peripheral artery disease. The recommended intake is approximately 1800 mg/day of EPA.

China: The China Food and Drug Administration (CFDA) regulates EPA as both a food ingredient and a health food product. Health claims are permitted for cardiovascular benefits under specific conditions. Pharmaceutical-grade EPA products are available for treating hyperlipidemia.

Medium to high, depending on source, formulation, and whether it’s a pharmaceutical or supplement product. Pharmaceutical-grade EPA (icosapent ethyl/Vascepa) is significantly more expensive than dietary supplement forms. Algal EPA (vegetarian source) typically costs more than fish oil-derived EPA.

Standard fish oil (18% EPA): $0.10-0.30 per 500mg EPA dose. Concentrated fish oil (30-50% EPA): $0.20-0.50 per 500mg EPA dose. Triglyceride form fish oil: $0.30-0.60 per 500mg EPA dose. Algal EPA: $0.50-1.00 per 500mg EPA dose. Krill oil (phospholipid form): $0.60-1.20 per 500mg EPA dose. Pharmaceutical-grade EPA ethyl ester (Vascepa): $3.00-8.00 per 1000mg dose (before insurance).

When evaluating the cost-effectiveness of EPA supplementation, several factors should be considered beyond the simple price per milligram. For general health maintenance and primary prevention, standard fish oil supplements providing 250-500mg of EPA daily offer reasonable value. For specific therapeutic applications like hypertriglyceridemia or as adjunctive treatment for depression, higher-potency products may be necessary despite their increased cost. The form of EPA significantly impacts bioavailability and therefore true biological value.

Triglyceride and phospholipid forms, though more expensive, offer superior absorption compared to ethyl ester forms in dietary supplements, potentially providing better value despite higher costs. For vegetarians and vegans, algal EPA represents the only viable option despite its premium price. The purity and testing standards of a product also factor into its value proposition; third-party tested products with verified low levels of contaminants justify higher prices through quality assurance. For individuals with established cardiovascular disease or multiple risk factors, the pharmaceutical-grade icosapent ethyl (Vascepa) has demonstrated significant risk reduction in clinical trials, potentially justifying its substantially higher cost through prevention of expensive cardiovascular events.

However, insurance coverage varies widely, affecting out-of-pocket costs. For general health maintenance, consuming fatty fish 2-3 times weekly may be more cost-effective than supplements, while also providing additional nutrients. When comparing enhanced bioavailability formulations, calculating the cost per absorbed milligram rather than simply the dose provides a more accurate value assessment. Finally, considering the potential long-term healthcare cost savings from preventive EPA supplementation (particularly for cardiovascular health) may justify higher upfront expenditure on quality supplements.

Unopened EPA supplements typically have a shelf life of 1-2 years when properly stored. Once opened, fish oil and algal EPA products should ideally be used within 3-6 months to minimize oxidation. Pharmaceutical-grade EPA ethyl ester products may have longer shelf lives due to higher purity and better stabilization.

Store in a cool, dark place away from direct sunlight and heat sources. Refrigeration after opening is recommended, particularly for liquid formulations. Keep containers tightly sealed to minimize exposure to oxygen. Some manufacturers use dark or opaque containers to protect from light exposure.

Avoid storing near appliances that generate heat. For liquid fish oil, refrigeration is essential after opening. Blister-packed capsules may offer better protection against oxidation than bottles, as each dose remains sealed until use.

Oxygen exposure (primary factor in oxidation/rancidity), Heat (accelerates oxidation reactions), Light exposure (particularly UV light), Transition metals (iron, copper) that catalyze oxidation, Humidity and moisture, Microbial contamination (after opening), Repeated temperature fluctuations, Extended storage after opening, Exposure to strong acids or bases, Lack of adequate antioxidants in the formulation

Synthesis Methods

Natural Sources

Quality Considerations

While EPA was not specifically identified as a distinct compound until the 20th century, foods rich in this omega-3 fatty acid have been valued throughout human history. Traditional coastal and Arctic cultures, including the Inuit, Pacific Islanders, Mediterranean peoples, and Japanese fishing communities, consumed diets naturally high in EPA from marine sources. These populations historically demonstrated lower rates of cardiovascular disease and certain inflammatory conditions, a phenomenon that later became known as the ‘Eskimo paradox’ or ‘Japanese paradox.’ Fish oil as a medicinal substance dates back to ancient civilizations, with cod liver oil being used in Northern European countries since at least the Viking era for general health and to treat rickets (though this benefit was later attributed to its vitamin D content rather than EPA). The scientific understanding of EPA began in the 1920s-1930s with the identification of essential fatty acids, but EPA’s specific importance wasn’t recognized until the 1970s when researchers studying Greenland Inuit populations noted correlations between their marine-based diet and cardiovascular health.

In 1982, a landmark paper by Dyerberg and Bang proposed that omega-3 fatty acids from fish, particularly EPA, were responsible for the cardioprotective effects observed in these populations. The 1980s and 1990s saw an explosion of research into EPA’s role in inflammation and cardiovascular health. The Japan EPA Lipid Intervention Study (JELIS), published in 2007, was the first large-scale clinical trial to demonstrate cardiovascular benefits of purified EPA supplementation. Commercial EPA supplements first appeared in the 1980s, initially as fish oil capsules containing both EPA and DHA.

Highly purified EPA ethyl ester (icosapent ethyl) was developed as a pharmaceutical product and received FDA approval for treating very high triglycerides in 2012 under the brand name Vascepa. The landmark REDUCE-IT trial, published in 2019, demonstrated significant cardiovascular risk reduction with high-dose icosapent ethyl in high-risk patients, leading to expanded FDA approval for cardiovascular risk reduction. Today, EPA is recognized as one of the most well-studied nutritional compounds, with thousands of clinical trials and research papers documenting its effects on human health across multiple systems, particularly cardiovascular, inflammatory, and neuropsychiatric conditions.

Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;7(7):CD003177., Liao Y, Xie B, Zhang H, et al. Efficacy of omega-3 PUFAs in depression: A meta-analysis. Transl Psychiatry. 2019;9(1):190., Casula M, Soranna D, Catapano AL, Corrao G. Long-term effect of high dose omega-3 fatty acid supplementation for secondary prevention of cardiovascular outcomes: A meta-analysis of randomized, double blind, placebo controlled trials. Atheroscler Suppl. 2013;14(2):243-251., Balk EM, Adam GP, Langberg V, et al. Omega-3 Fatty Acids and Cardiovascular Disease: An Updated Systematic Review. Evidence Report/Technology Assessment No. 223. AHRQ Publication No. 16-E002-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2016., Maki KC, Dicklin MR. Omega-3 Fatty Acid Supplementation and Cardiovascular Disease Risk: Glass Half Full or Time to Nail the Coffin Shut? Nutrients. 2018;10(7):864.

RESPECT-EPA: Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy – Statin and Eicosapentaenoic Acid, EVAPORATE: Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy, OMEMI: Omega-3 Fatty Acids in Elderly Patients With Myocardial Infarction, STRENGTH-ADHD: Supplementation with Omega-3 Fatty Acids in ADHD Treatment, OCEAN-MDD: Omega-3 Supplementation for Major Depression with Inflammation