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Efficacy of High-Dose EPA Omega-3: Prevention and Management of Chronic Disorders Including Cardiovascular Disease by Dr Bruce Holub, PhD

Increased intakes of long-chain polyunsaturated omega-3 fatty acids in the form of EPA eicosapentaenoic acid (20:5 n-3) having 20 carbons in chain length and 5 double bonds (unsaturation sites between adjacent carbon atoms in the molecule) and DHA (22:6 n-3) with 22 carbons and 6 double bonds are well known to provide robust human health benefits. These include the prevention and complementary management of wide-ranging chronic disorders. Numerous human studies and clinical trials as published in the peer-reviewed medical/nutrition literature exhibiting such health benefits have provided EPA and/or DHA via nutritional supplements at daily levels which are safe but well above typical North American dietary intakes. Dietary sources of EPA and DHA are found mainly in fish/seafood with the levels of DHA generally predominating over EPA. However, low consumption rates of fish in Canada and the United States (averaging 1 to 1.5 servings/person/week) with only the minority being high omega-3 fish is responsible for the very low daily intakes of long-chain omega-3 fatty acids (1).

Early publication from our laboratory at the University of Guelph found the average intake of EPA amongst pregnant women to be only 35 mg/person/day (2). Based on a daily energy intake of 2000 kcal/adult/day, a very recent US study (the National Health and Nutrition Examination Survey) reported EPA intakes in mixed-gender adults 20 to 55 years old to average only 36 mg/person/day (1). Such very low intakes are well below minimal target EPA intakes for general health of 220 mg EPA/adult/day as recommended and a combined intake of EPA+DHA of at least 650 mg/adult/day (3). Fish/seafood generally contain significantly more DHA than EPA.

Except for the emphasis on DHA in pregnant/nursing mothers/infants, traditional recommendations for long-chain omega-3 fatty acid intakes from national and international health and government organizations for the general adult population have mostly advised on combined EPA + DHA target intakes (4). For many years, long-chain omega-3 fatty acids have been recognized and recommended globally for wide-ranging chronic diseases including coronary heart disease, rheumatoid arthritis, dementia, depression, others.

With the availability of supplements for human clinical trials which are highly enriched in EPA, strong evidence has been forthcoming to indicate the independent health benefits of EPA omega-3 supplementation when daily intakes well above those that can be readily obtained from dietary sources are employed. Such information is the focus of the present newsletter.

Studies have indicated that supplementation with EPA concentrates providing intakes of up to 1000 – 2000 mg EPA/day (alone or in addition to medical treatment) can offer beneficial effects in the management of those with mild or moderate depression as recently reviewed (5). Although EPA is not concentrated in the brain in contrast to DHA, it crosses the blood-brain barrier and the suggested beneficial mechanisms of action for the anti-depressant impact includes anti-inflammatory and other effects. Higher levels of EPA in the circulating blood directly resulting from higher EPA intakes have been associated with a decreased severity for depressive symptomology and a decreased risk of dementia (6). Recent research at the Massachusetts General Hospital suggests that depressed individuals who are overweight and have elevated inflammatory activity may be particularly good candidates for EPA treatment.  While EPA supplementation has appeared to offer support in preventing or alleviating symptoms of menopause (incl. hot flashes) and the severity of various mood disorders or other psychiatric conditions (7), more clinical research trials are needed to establish the daily dosing amount needed and overall efficacy. Very recently, high-dose EPA supplementation (at 1,200 mg EPA/day) over a 12-week period in youth (6-18 years old) with ADHD was found to improve cognitive symptoms (attention and vigilance) in those with a low EPA status at entry but not in those with high initial EPA levels (8).

The newly-published clinical study in the New England Journal of Medicine (9) known as the ‘REDUCE-IT’ trial has highlighted the pronounced health benefit of daily supplementation with EPA against adverse events and death in those at risk for cardiovascular disease-related outcomes. Historically, the ‘JELIS’ trial conducted in Japan (10) was the first randomized clinical trial to demonstrate additional cardiovascular benefit when added to the regimen of subjects given statin medication for blood cholesterol-lowering. Among the subjects, 14,981 had no cardiovascular disease (CAD) at entry (primary prevention cohort) and 3664 had documented CAD (secondary prevention cohort). In the omega-3 grouping, EPA was given at an intake level of 1,800 mg/day over a period of 4.6 years. Relative to the control subjects not receiving EPA, the EPA-supplemented subjects exhibited a significant 19% reduction in major coronary events (sudden cardiac death, myocardial infarction, unstable angina, and the need for heart surgery). The EPA supplementation reduced the risk of major coronary events in the high-risk subgroup by 53%.  

One rather unique feature of the REDUCE-IT trial (9) was the daily ingestion of a relatively high daily dose of EPA at 4 gm (4000 mg). A total of 8179 subjects were enrolled/randomized in the trial with half receiving 2000 mg of EPA taken twice daily with food and half serving as controls by receiving placebo capsules. The mixed-gender subjects (average age of 64 years) had known cardiovascular disease or had diabetes with at least one additional risk factor.  The subjects had a fasting blood triglyceride level of at least 135 mg/100 ml and were receiving statin medication for blood cholesterol-lowering. The subjects were followed for a duration of 4.9 years.

The overall primary cardiovascular outcomes (cardiovascular death, non-fatal myocardial infarction, stroke, unstable angina, need for coronary surgery) were significantly reduced with a risk reduction of 25% in the EPA group relative to controls. Also, there was a 35% reduction in the need for urgent heart surgery, a 32% reduction in hospitalization for unstable angina, and a 38% reduction in fatal or non-fatal strokes.  The suggested mechanisms for the EPA benefits include the reduction in blood triglyceride levels (by 18% in the REDUCE-IT trial) along with its anti-thrombotic effect, the stabilization or regression of pre-existing atherosclerotic plaque, the anti-inflammatory effect of EPA-derived metabolites, others.

In conclusion, the present article indicates that a single omega-3 fatty acid given in the form of EPA supplementation can offer diverse health benefits as well as the reduction and complementary management of chronic disorders including cardiovascular disease.


  1. Thompson, M, Hein, N, Hanson, C, et al. Omega-3 Fatty Acid Intake by Age, Gender, and Pregnancy Status in the United States: National Health and Nutrition Examination Survey 2003-2014. Nutrients. 2019; 11; 177-190.
  2.  Denomme, J, Stark, KD, Holub, BJ. Directly Quantitated Dietary (n-3) Fatty Acid intakes of Pregnant Canadian Women are Lower than Current Dietary Recommendations. J. Nutr. 2005; 135: 206-211.
  3.  Simopoulos AP, Leaf, A, Salem, N, Jr. Workshop Statement on the Essentiality of and Recommended Dietary Intakes for Omega-6 and Omega-3 Fatty Acids. Prostagl. Leukot. Essent. Fatty Acids. 2000; 63:119-121.
  4.  Global Recommendations for EPA and DHA Intake: https://goedomega3.com/storage/app/media/GOED%20Intake%20Recommendations.pdf
  5.  Liao,Y, Xie, B, He, Q, et al. Efficacy of Omega-3 PUFAs in Depression: a Meta-Analysis. Transl. Psychiatry. 2019; 9: 190-198.
  6. Samieri, C, Feart, C, Letenneur, L, et al. Low Plasma Eicosapentaenoic Acid and Depressive Symptomology are Independent Predictors of Dementia Risk. Am. J. Clin. Nutr. 2008; 88: 714-721.
  7. Lucas, M, Asselin, G, Merette, C, et al. Effects of Ethyl-Eicosapentaenoic Acid Omega-3 Fatty Acid Supplementation on Hot Flashes and Quality of Life Among Middle-Aged Women : a Double-Blind, Placebo-Controlled, Randomized Clinical Trial. Menopause. 16: 357-366.   
  8. Chang, JP, Su, KS, Mondelli, V, et al. High-dose Eicosapentaenoic Acid (EPA) Improves Attention and Vigilance in Children and Adolescents with Attention Deficit Hyperactivity Disorder (ADHD) and Low Endogenous EPA Levels. Transl. Psychiatry. 2019; 9: 303-311.
  9.  Bhatt, DL, Steg, PG, Miller, M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. New Engl. J. Med. 2019; 380: 11-22.
  10. Yokoyama, M, Origasa, H, Matsuzaki, M, et al. Effects of Eicosapentaenoic Acid on Major Coronary Events in Hypercholesterolemic Patients (JELIS): a Randomized Open-label, Blinded Endpoint Analysis. The Lancet. 2007;369:1090-1098.

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