Omega-3 Fatty Acids

Greenland studies and early interest

A 1971 Lancet paper by Bang and Dyerberg reported the plasma lipid and lipoprotein pattern of Greenlandic West-coast people, then called Eskimos, a term now considered outdated. The National Institutes of Health Office of Dietary Supplements (ODS) states that interest in omega-3 fatty acids and cardiovascular disease was spurred by epidemiological research from the 1970s that found low rates of myocardial infarction among Greenland Inuit and other fish-eating populations, such as those in Japan. The 1971 paper is cited here only for its title and publication details, and these sources do not show that diet alone explains the observed rates.

From observation to supplement trials

The GISSI-Prevenzione trial, published in the Lancet in 1999, randomly assigned 11,324 people who had survived a recent myocardial infarction to supplements of n-3 polyunsaturated fatty acids, vitamin E, both, or neither for 3.5 years. The authors reported that n-3 treatment, but not vitamin E, lowered the risk of the combined endpoint of death, nonfatal myocardial infarction and stroke, with the benefit attributed mainly to fewer deaths. This result helped establish fish oil capsules as a studied intervention in people with existing heart disease.

The 2020 Cochrane review notes that guidelines had recommended increasing omega-3-rich foods and sometimes supplementation, but that recent trials have not confirmed the expected cardiovascular benefit. Later sections describe those trials.

EPA, DHA and ALA

Omega-3 fatty acids, also written n-3, are a class of polyunsaturated fats. The National Center for Complementary and Integrative Health (NCCIH) says most research focuses on eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and that common sources include fish oil, fish liver oil, krill oil, algal oil and flaxseed oil. ODS describes alpha-linolenic acid (ALA) as the plant form found in flaxseed, soybean and canola oils, chia seeds and walnuts. The Cochrane review uses the abbreviation LCn3 for long-chain omega-3 fats from oily fish and keeps ALA as a separate category.

Supplements, foods and prescription medicines

Supplements can contain omega-3s as natural triglycerides, free fatty acids, ethyl esters, re-esterified triglycerides or phospholipids, according to ODS. Prescription products are medicines and differ from supplements, as NCCIH points out. Icosapent ethyl is a highly purified EPA ethyl ester, and trials of it are discussed here only to separate its findings from those of over-the-counter oils. Fish liver oil also contains vitamins A and D, which NCCIH says can be harmful in excess.

Omega-3 Fatty Acids is a member of the Machipedia family page Dietary Supplements, which covers supplements as a group. This page does not repeat that overview, and it addresses only omega-3 products, whose forms, evidence and cautions differ from those of vitamins, minerals and herbal products.

Forms and sources

Most trials of supplements used capsules, although some used enriched foods or dietary advice, as the Cochrane review describes. ODS lists fish oil, krill oil, cod liver oil and vegetarian algal oil products as common formulations. Algal oil and plant sources such as flaxseed and chia are relevant to readers following a Vegan Diet or Plant-Based Diet, although ALA from plants is a different compound from the EPA and DHA found in fish and algae.

Place within diet and care

ODS states that a person's nutritional needs should be met primarily through the diet, and that supplements may be useful where food alone cannot meet a specific need. NCCIH recommends seafood during pregnancy and breastfeeding, with choices lower in methylmercury. Related Machipedia pages include Mediterranean Diet, Nutritional Therapy, Nutritional Psychiatry and Dietetics, the profession that provides individual dietary assessment.

Heart health and triglycerides

Omega-3 supplements are most often taken with the aim of supporting heart health and lowering blood triglycerides. NCCIH says some evidence suggests people with heart disease or high triglycerides may benefit. The Cochrane review found that long-chain omega-3 intake lowered triglycerides by about 15 percent in a dose-dependent way, rated as high-certainty evidence, mainly from supplement trials.

Mood, attention, eyes, joints, pregnancy and cognition

NCCIH lists depression, attention-deficit/hyperactivity disorder (ADHD), Alzheimer's disease and cognition, eye conditions, rheumatoid arthritis and pregnancy among the other areas studied. Mood-related use connects to the field of Nutritional Psychiatry. These are areas of research interest, not established benefits, and the evidence is summarized in the sections below.

Cardiovascular outcomes

The 2020 Cochrane review by Abdelhamid and colleagues included 86 randomized trials with 162,796 participants. It found little or no effect of increasing long-chain omega-3 on all-cause mortality (high-certainty evidence) or cardiovascular events (risk ratio 0.96, interval 0.92 to 1.01), a slight reduction in cardiovascular mortality (0.92, 0.86 to 0.99, moderate certainty), and possible slight reductions in coronary heart disease events (low certainty).

In VITAL, 25,871 older adults without prior events were followed for a median of 5.3 years, and major cardiovascular events did not differ significantly from placebo (hazard ratio 0.92, 0.80 to 1.06). In ASCEND, 15,480 people with diabetes and no known cardiovascular disease showed no significant difference in serious vascular events over 7.4 years. An American Heart Association science advisory reviewed large trials and gave recommendations by clinical group.

Prescription trials and the placebo debate

REDUCE-IT enrolled 8,179 statin-treated patients with elevated triglycerides and reported fewer primary cardiovascular events with icosapent ethyl than placebo (17.2 percent versus 22.0 percent, hazard ratio 0.75). STRENGTH compared an omega-3 carboxylic acid medicine with corn oil in 13,078 comparable patients and found no difference (12.0 versus 12.2 percent), ending early for low probability of benefit.

REDUCE-IT used mineral oil as placebo, and some suggested part of its result reflected harm from that oil. A review of 80 studies of mineral oil placebos by Olshansky and colleagues found inconsistent biomarker changes and concluded it does not meaningfully affect the trial's conclusions. Why the two trials differed remains debated, and these sources do not settle it.

Atrial fibrillation

A 2021 meta-analysis of seven trials with 81,210 patients found marine omega-3 supplementation associated with higher atrial fibrillation risk (hazard ratio 1.25, 1.07 to 1.46), with a larger association in trials of higher daily amounts than lower ones. In REDUCE-IT, hospitalization for atrial fibrillation or flutter was 3.1 percent with icosapent ethyl versus 2.1 percent with placebo. ODS describes a slight increase in people with or at high risk of cardiovascular disease.

Depression, ADHD and cognition

A 2021 Cochrane review of 35 studies in adults with major depressive disorder found a small to modest benefit of omega-3s over placebo, rated very low-certainty and unlikely to be clinically meaningful, with no clear difference in remission or response. The 2023 Cochrane review of 37 trials in children and adolescents with ADHD found high-certainty evidence of no effect on parent-rated total symptoms, inattention or hyperactivity.

The 2012 Cochrane review of three trials in cognitively healthy people aged 60 and over found no benefit on cognitive function, and none examined incident dementia. NCCIH describes results in Alzheimer's disease and cognition as mixed.

Dry eye, arthritis and pregnancy

The DREAM trial randomized 535 adults with moderate to severe dry eye disease and found no significant difference from olive oil placebo in symptom score at 12 months. A 2017 meta-analysis of 42 trials of marine oils in arthritis found a small pain benefit overall, significant in rheumatoid arthritis but not osteoarthritis, with evidence of low quality, or moderate in rheumatoid arthritis.

The 2018 Cochrane review of 70 trials with 19,927 pregnant women reported fewer preterm births before 37 weeks (risk ratio 0.89, high-quality evidence) and before 34 weeks (0.58), and probably more prolonged pregnancies beyond 42 weeks. NCCIH notes that reviews disagree on preterm birth.

Side effects and bleeding

NCCIH says side effects of omega-3 supplements are usually mild, including unpleasant taste, bad breath, headache, heartburn, nausea and diarrhea. In STRENGTH, gastrointestinal adverse events were more frequent with the carboxylic acid medicine than with corn oil. ODS notes that the Institute of Medicine suggested that high intakes might increase bleeding time, while a 2014 review concluded omega-3s do not affect the risk of clinically significant bleeding. VITAL reported no excess bleeding.

Interactions and who should ask a clinician

ODS states that fish oil might prolong clotting times when taken with warfarin, although most research reports no significant effect on anticoagulation status, and advises people on regular medications to discuss interactions with their health care providers. Reasons to ask a clinician before use therefore include blood-thinning medicines, existing heart disease or arrhythmia, and pregnancy. Supplements should not delay or replace necessary care. The sources reviewed do not address fish or shellfish allergy.

Quality, contamination and sustainability

ODS says methylmercury has not been found in omega-3 supplements because processing removes it. A 2013 analysis of 16 top-selling liquid fish oils found over half did not meet label claims and a quarter exceeded a peroxide value limit, a measure of oxidation, whereas a 2022 analysis of 20 French products found nearly all met label claims and oxidation limits. Both samples were small and cannot represent the market, and these sources do not assess sustainability.