Omega-3 Fatty Acids
1. Identity: Chemical Names, Natural Sources, and Preparations
Chemical and Structural Identity
Omega-3 polyunsaturated fatty acids (O3FAs) are naturally occurring lipids consisting of a variable-length carbon chain with a methyl group at one (the omega [ω]) end and a carboxylic acid group at the other (alpha) end. Omega-3 fatty acids have a carbon–carbon double bond located three carbons from the methyl end of the chain. Omega-3s, sometimes referred to as n-3s, are present in certain foods such as flaxseed and fish, as well as dietary supplements such as fish oil.
Several different omega-3s exist, but the majority of scientific research focuses on three: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA contains 18 carbon atoms, whereas EPA and DHA are considered long-chain (LC) omega-3s because EPA contains 20 carbons and DHA contains 22. PUFAs are frequently designated by their number of carbon atoms and double bonds. ALA, for example, is known as C18:3n-3 because it has 18 carbons and 3 double bonds and is an n-3, or omega-3, fatty acid. Similarly, EPA is known as C20:5n-3 and DHA as C22:6n-3.
EPA and DHA have physiological (structural and signalling) activity as integral components of the cell plasma membrane in humans, but ALA is believed to be inactive in these roles. DHA and EPA are commonly found in krill oils, fish oils, and fish, whereas ALA is found in plant oils, like soybean, flaxseed, and canola oils. Humans can convert ALA into EPA and then DHA, but the conversion is very limited.
Natural Food Sources
ALA is present in plant oils, such as flaxseed, soybean, and canola oils. DHA and EPA are present in fish, fish oils, and krill oils, but they are originally synthesized by microalgae at the base of the marine food chain, not by the fish. As microalgae move up the food chain, fish acquire the omega-3s and accumulate them in their tissues.
EPA and DHA are found in seafood, especially cold-water fish such as salmon, mackerel, and tuna, as well as shellfish and fish oil supplements. ALA is found in certain plant oils, such as flaxseed, soybean, and canola oils, and in some other plant foods, such as chia seeds and walnuts. Plant oils that contain ALA include flaxseed (linseed), soybean, and canola oils. Chia seeds and walnuts also contain ALA.
Omega-3s are important components of the membranes that surround each cell in the body. DHA levels are especially high in retina (eye), brain, and sperm cells. Omega-3s also provide calories to give the body energy and have many functions in the heart, blood vessels, lungs, immune system, and endocrine system.
Common Supplement Forms and Preparations
Dietary supplements can contain several different forms of omega-3s, including natural triglycerides, free fatty acids, ethyl esters, re-esterified triglycerides, and phospholipids. Natural triglycerides are the form that occur naturally in fish oil, whereas ethyl esters are synthesized from natural triglycerides by replacement of the glycerol molecule of the triglyceride with ethanol. Re-esterified triglycerides are formed by the conversion of ethyl esters back to triglycerides.
Omega-3s as re-esterified triglycerides, natural triglycerides, and free fatty acids have somewhat higher bioavailability than ethyl esters, but consumption of all forms significantly increases plasma EPA and DHA levels.
Long-chain omega-3s are present in several dietary supplement formulations, including fish oil, krill oil, cod liver oil, and vegetarian products that contain algal oil. A typical fish oil supplement provides about 1,000 mg fish oil, containing 180 mg EPA and 120 mg DHA, but doses vary widely. Cod liver oil supplements provide vitamin A and vitamin D in addition to LC omega-3s.
Krill oil contains omega-3s in the form of phospholipids. Algal oils are a vegetarian source of DHA; some also contain EPA. Flaxseed oil contains ALA.
2. Traditional and Historical Use
Ancient and Premodern Use of Fish-Derived Oils
The fish oil industry can be traced back to the 1770s when the first cod liver oils were marketed in the United Kingdom. Well before that, Nordic and coastal cultures had long consumed fish in large quantities as a dietary staple, obtaining omega-3s from marine sources as an inherent part of their diet rather than as an isolated supplement.
Spanish food scientists recreated Roman garum using ancient recipes. They analysed the oil and found it contained extremely high amounts of omega-3 fatty acids, making it the world's first-known fish oil supplement. This ancient Roman fermented fish sauce thus represents one of the earliest documented concentrated sources of marine omega-3s in a culinary/medicinal preparation.
Cod Liver Oil in the 18th–20th Centuries
Cod liver was first used in medicine in 1789 to treat rheumatism, followed by rickets in 1824. By the 1930s, it was frequently given to children to help prevent rickets and other conditions caused by vitamin D deficiency. Cod-liver oil was widely used in the 18th, 19th, and early 20th centuries to treat and prevent rickets, a disease caused by vitamin D deficiency.
Known in both the German and Dutch language as "the English Disease," rickets reached epidemic proportions in Britain during the Industrial Revolution. A condition suffered by babies and children, it led to weakened bones, bowed legs, and stunted growth. The cause was a deficiency of vitamin D caused by poor diet and lack of sunshine. The thick industrial smog that covered the inner cities blocked out so much sunlight that some 80 percent of London children were thought to have varying degrees of rickets. Once it was established that vitamin D was to blame, cod liver oil was widely touted as the solution, because the liver of the codfish stored vitamin D in high amounts.
In Norway, there is a long tradition of using cod liver oil as a dietary supplement, due mainly to the fact that it was regarded as a valuable vitamin supplement. In Norway, a supplement made from fresh arctic cod liver oil (CLO, "Tran") has traditionally been a popular omega-3 fatty acid supplement.
Scientific Discovery of EPA and DHA
In the 1970s, Danish physicians Jørn Dyerberg and Hans Olaf Bang provided the first evidence that the fatty acids in fish have beneficial effects on coronary heart disease. Their hypothesis-generating observations stimulated high-quality preclinical and clinical research resulting in significant scientific substantiation for the benefits of the long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This interest was spurred by epidemiological research dating back to the 1970s that found low rates of myocardial infarction and other coronary events among Greenland Inuit and other fish-eating populations, such as those in Japan.
In the early 1970s, researchers Bang and Dyerberg determined that fish and fish oil contained two omega-3 fatty acids called eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Since their discovery, EPA and DHA have become some of the best-studied nutrients in history, with over 30,000 scientific papers to their names.
3. Key Constituents and Mechanisms of Action
Principal Active Compounds
The three nutritionally and clinically relevant omega-3 fatty acids are alpha-linolenic acid (ALA, C18:3n-3), eicosapentaenoic acid (EPA, C20:5n-3), and docosahexaenoic acid (DHA, C22:6n-3). ALA is found in significant quantities in seed oils, plants, and vegetables, but it is a poor substrate for human elongase and desaturase enzymes, meaning that the dominant dietary source of EPA and DHA is restricted to cold-water oily fish such as salmon, mackerel, and herring. DHA can be metabolized to some extent from its dietary essential precursor ALA via a series of desaturation and elongation reactions, although ALA can be metabolically converted into EPA and further to DHA, but the conversion rate is fairly low in humans.
Anti-Inflammatory Mechanisms
Omega-3 fatty acids dampen inflammation through multiple pathways. On the one hand, omega-3 fatty acids inhibit the formation of omega-6 fatty acid-derived pro-inflammatory eicosanoids (e.g., PGE2 and LTB4), and on the other hand these fatty acids can form several potent anti-inflammatory lipid mediators (e.g., resolvins and protectins).
These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte–endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines, and T cell reactivity.
EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation-resolving mediators called resolvins, protectins, and maresins. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor κB (NF-κB) so reducing expression of inflammatory genes, and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor γ (PPARγ).
Omega-3 PUFAs help resolve inflammation through generation of anti-inflammatory eicosanoids and specialized pro-resolving mediators, including resolvins, protectins, and maresins. Through binding to the GPR120/FFAR4 receptor, their beneficial effects result from phospholipid membrane remodeling, impairment of inflammatory signaling molecules clustering, subsequent inhibition of NF-κB and inflammasome activation, and a reduction in oxidative stress.
Specialized Pro-Resolving Mediators (SPMs)
Omega-3 PUFAs can reduce depressive symptoms and exert anti-inflammatory action putatively by the production of distinct n-3 PUFA-derived metabolites, such as resolvins D (RvD) and E (RvE) series, maresins (MaR), and protectins (PD), which are collectively named specialized pro-resolving mediators (SPMs) and act as strong anti-inflammatory agents.
The altered profile of lipid mediators generated during inflammation includes the production of newly identified, DHA-derived inflammation-resolving mediator classes, in addition to the formation of less pro-inflammatory eicosanoids from EPA. Resolvin D1 and Protectin D1 are potent, endogenous, DHA-derived lipid mediators that attenuate neutrophil migration and tissue injury in peritonitis and ischemia-reperfusion injury.
At a sufficiently high dose, marine n-3 PUFAs exert a range of anti-inflammatory actions including decreased adhesion molecule expression and adhesive interactions between leucocytes and endothelial cells, a decreased chemotactic response of leucocytes, decreased production of eicosanoids from arachidonic acid, increased production of eicosanoids with lower biological potency from EPA, increased production of anti-inflammatory and inflammation-resolving resolvins from EPA and DHA (and protectins from DHA), decreased production of the classic inflammatory cytokines TNF, IL-1β, and IL-6, and decreased T-cell reactivity. Overall, these observations indicate a shift from a strongly pro-inflammatory environment to one of reduced inflammation, lowered cell responsiveness, and increased resolution of inflammation.
Membrane Structural Role
The majority of omega-3 fatty acids reside naturally in a triglyceride (TG) form in the phospholipid bilayer of all cells. Their incorporation into cell membranes alters membrane fluidity, receptor function, and the activity of membrane-bound enzymes and ion channels, with DHA being particularly enriched in neural and retinal tissues. ALA (18 carbons and 3 double bonds) is used to make EPA (20 carbons and 5 double bonds), which is then used to make DHA (22 carbons and 6 double bonds).
4. Scientific Evidence by Area of Use
4.1 Cardiovascular Disease and Risk Factors
Many studies have assessed the effects of omega-3s — primarily EPA and DHA — on CVD and CVD risk factors, such as high blood pressure and elevated plasma lipids. This interest was spurred by epidemiological research dating back to the 1970s that found low rates of myocardial infarction and other coronary events among Greenland Inuit and other fish-eating populations, such as those in Japan.
Triglycerides
Triglycerides are a type of fat found in people's bodies; excessive levels may raise the risk of heart disease. Lifestyle changes such as dietary modifications, weight control, and exercise are used to lower triglyceride levels. Some people also need to take medicine to lower their triglyceride levels. A 2020 review of 23 studies (43,998 participants) showed that EPA and DHA reduce triglycerides by about 15 percent but do not affect body fat or other lipids. The U.S. FDA has approved several prescription omega-3 products specifically for treating severe hypertriglyceridemia.
Major Cardiovascular Events: The REDUCE-IT, STRENGTH, and VITAL Trials
REDUCE-IT was a multicenter, randomized, double-blind, placebo-controlled trial of icosapent ethyl (IPE, 4 g/d) or placebo (mineral oil) in 8,179 patients with CVD or type 2 diabetes plus at least one cardiovascular risk factor on a background of elevated triglyceride levels despite statin therapy. The median follow-up was 4.9 years. The results showed that IPE significantly reduced the risk of the primary endpoint (the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) by 25% (17.2% vs. 22%, HR = 0.75, 95% CI: 0.68–0.83), and also reduced cardiovascular death, fatal or nonfatal myocardial infarction, and fatal or nonfatal stroke, but there was no reduction in all-cause mortality.
In the Vitamin D and Omega-3 Trial (VITAL), 840 mg/d of EPA and DHA resulted in a 28% reduced risk for heart attacks, 50% reduced risk for fatal heart attacks, and 17% reduced risk for total coronary heart disease events. In the ASCEND trial (A Study of Cardiovascular Events in Diabetes), cardiovascular disease death was significantly reduced by 19% with 840 mg/d of EPA and DHA. However, the primary composite endpoints were not significantly reduced in either study.
Both REDUCE-IT and STRENGTH aimed to evaluate the effects of prolonged administration of omega-3 fatty acids on major adverse cardiovascular events (MACEs) in high-risk patients undergoing statin therapy. REDUCE-IT used eicosapentaenoic acid (EPA) ethyl ester with mineral oil as a control, while STRENGTH utilized a carboxylic acid formulation of both EPA and DHA with corn oil as a control. Notably, REDUCE-IT demonstrated a reduction in MACE risk with EPA, whereas STRENGTH showed no such benefit with the combination of EPA and DHA. Despite extensive discussions following publication of these trials, the underlying reasons for this discrepancy remain elusive.
Results from clinical trials have been mixed, and a few recent studies even suggest some potential harm. That has led scientists to conclude that the supplement's usefulness in heart disease prevention is nuanced, at best. Ongoing research — on everything from the particular omega-3 fatty acids that drive effectiveness to who benefits most and why — continues.
Evidence strength: The evidence for triglyceride-lowering is robust and consistent across multiple trials. Cardiovascular event reduction is supported by large RCTs but the findings are heterogeneous depending on the omega-3 formulation used (EPA-only vs. EPA+DHA), dose, and patient population. High-dose, purified EPA (icosapent ethyl) has the strongest cardiovascular outcome data in hypertriglyceridemic patients already on statins.
4.2 Mental Health: Depression
Omega-3 polyunsaturated fatty acids have received considerable attention in the field of mental health, particularly regarding the treatment of depression. Existing evidence demonstrates that omega-3 fatty acids — in particular EPA and DHA — have antidepressant effects that can be attributed to their modulation of neuroinflammation, neurotransmitter function, and neuroplasticity.
Nevertheless, clinical trials of omega-3 supplementation have yielded inconsistent results. Some studies have demonstrated significant reductions in depressive symptoms following omega-3 treatment, whereas others have shown minimal to no beneficial impact.
A randomized controlled trial compared EPA (at a dose of 4.4 g/day) plus DHA (at a dose of 2.2 g/day) with placebo as augmentation to antidepressants in 22 patients with major depression over eight weeks. Participants treated with omega-3 fatty acids had a significantly lower score on the Hamilton Depression Rating Scale (HDRS).
Although some studies have had promising results, it is uncertain whether omega-3 fatty acid supplements are helpful for depression. A 2021 review of 35 studies (1,964 participants) reaffirmed the conclusion from a 2015 review that if there is an effect, it may be too small to be meaningful. Further, the authors judged the quality of the evidence on which this result is based to be low or very low. Other reviews have suggested that if omega-3s do have an effect, EPA may be more beneficial than DHA and that omega-3s may best be used in addition to antidepressant medication rather than in place of it.
It has been shown that when EPA or supplements containing substantially more EPA than DHA were supplemented to subjects, the beneficial effects in alleviating symptoms of major depression and bipolar disorder were more evident. Most clinical trials seem to suggest that dietary supplementation with omega-3 fatty acids (EPA and DHA) may reduce the risk of depression during pregnancy and lactation.
Evidence strength: Preliminary to moderate. Multiple meta-analyses and RCTs exist, but results are inconsistent. EPA-dominant formulations appear more effective than DHA for mood symptoms. Quality of evidence is frequently rated low. Omega-3s may be most useful as an adjunct to standard antidepressant therapy rather than as a standalone treatment.
4.3 Perinatal and Infant Health
Consuming DHA during pregnancy is important for brain and eye development of the baby. The physiological demands of pregnancy and lactation put childbearing women at particular risk of experiencing a loss of DHA from tissues including the brain, especially in individuals with inadequate dietary n-3 PUFA intake or suboptimal metabolic capabilities.
Pregnancy and lactation are associated with higher demands for n-3 fatty acids, particularly during the third trimester when existing maternal depots of n-3 are depleted for fetal development. Deficiencies in n-3 fatty acids may arise more easily during this critical period and may increase the susceptibility of depression or anxiety disorders.
A study on 36 pregnant women with major depressive disorder compared omega-3 HUFAs monotherapy (2.2 g/day of EPA plus 1.2 g/day of DHA) with placebo. Twenty-four patients who finished the trial showed significantly lower depressive symptom ratings on the HDRS, the Edinburgh Postnatal Depression Scale (EPDS), and the BDI. These findings are notable because omega-3s are preferentially transported to the growing fetus during pregnancy, which can deplete maternal fatty acid stores.
A summary of evidence for the association between n-3 fatty acid supplementation during pregnancy and postpartum depression concluded that the current evidence from randomized controlled trials is inconclusive and does not support the routine use of n-3 fatty acids during pregnancy to reduce the risk of postpartum depression.
Evidence strength: DHA's structural role in fetal brain and retinal development is well established. Evidence for omega-3 supplementation reducing postpartum depression is currently inconclusive per systematic reviews. The type (EPA vs. DHA) and timing (pregnancy vs. lactation) of supplementation appear to matter for pregnancy-related depression outcomes.
4.4 Rheumatoid Arthritis and Inflammatory Joint Disease
Human trials demonstrate benefit of oral n-3 fatty acids in rheumatoid arthritis and in stabilizing advanced atherosclerotic plaques.
A 2022 review of 30 studies (1,420 participants) found eating foods rich in polyunsaturated fatty acids (PUFAs), especially omega-3s, may improve symptoms such as pain and swollen and tender joints, and might be an appropriate addition to drug therapy for rheumatoid arthritis. A 2021 review of 12 studies (776 participants) found that diets rich in omega-3 fatty acids resulted in lower pain than ordinary diets. However, the authors noted that evidence was low.
Preclinical evidence suggests several biological pathways by which omega-3 fatty acids may exert analgesic effects. Experimental evidence indicates that EPA and DHA modulate inflammatory pathways by competing with arachidonic acid metabolism, thereby reducing the production of pro-inflammatory prostaglandin E₂ and leukotriene B₄.
Evidence strength: Moderate. Multiple systematic reviews suggest symptomatic benefit (reduced pain, tender/swollen joint counts) in rheumatoid arthritis, but effect sizes are modest and evidence quality is frequently rated low to moderate. Omega-3s are considered a potential adjunct, not a replacement, for disease-modifying antirheumatic drugs (DMARDs).
4.5 Cognitive Function and Neurological Health
In preclinical models, resolvin D and E series treatments improved depressive-like behaviors, whereas protectins and maresins ameliorated neurological function. Resolvins increased serotonin levels in models of depression and decreased gliosis in neurodegenerative disorders. Protectins prevented neurite and dendrite retraction and apoptosis in models of neurodegeneration, while maresins reduced cell death across all studies.
In healthy adults, ALA has not improved cognition in the best-powered trial: the two-year WAHA walnut intervention (approximately 3.9 g/day ALA) was null. In healthy older adults, the best trials show no cognitive benefit from EPA+DHA — even among participants with low omega-3 blood levels comparable to those seen in some vegans (as in VITAL-COG and MAPT).
Evidence strength: Weak to preliminary for cognitive benefit in healthy adults. Mechanistic studies support omega-3s' importance in brain structure and neuroinflammation. However, large well-powered RCTs in healthy or cognitively intact populations have not consistently demonstrated cognitive improvement from supplementation. Further research is needed in at-risk populations.
4.6 Age-Related Macular Degeneration (AMD) and Eye Health
Omega-3s are important components of the membranes that surround each cell in the body. DHA levels are especially high in retina (eye), brain, and sperm cells. Areas of health in which omega-3s might play a role include age-related macular degeneration and dry eye disease.
The NIH ODS notes that studies suggest people who get higher amounts of omega-3s from food may have a lower risk of AMD. However, the ODS also notes that clinical trial evidence specifically for supplements and AMD is less conclusive.
Evidence strength: Observational data supports an association between higher dietary omega-3 intake and lower AMD risk. RCT evidence for supplements in AMD prevention is limited and currently insufficient to make firm conclusions.
4.7 Cancer
Results from observational studies using dietary intake data suggest that higher intakes of fish and/or omega-3s reduce prostate cancer risk. Both fish and omega-3 consumption were associated with a lower risk of fatal prostate cancer in a cohort of 293,464 men participating in the NIH-AARP study. In the Health Professionals Follow-up Study, a prospective cohort of over 47,000 men aged 40–75 years, those who consumed fish more than three times per week had a lower risk of metastatic prostate cancer than those who consumed fish less than twice per month.
A number of systematic reviews and meta-analyses of prospective studies on the effects of fish intakes, omega-3 intakes, and omega-3 blood levels on prostate cancer risk have had inconsistent findings. For example, circulating levels of EPA — but not DHA — were positively associated with prostate cancer risk in one meta-analysis.
Evidence strength: Inconsistent and insufficient. Observational studies are mixed and cannot establish causality. RCT evidence for omega-3 supplementation in cancer prevention is lacking. The NIH ODS does not currently recommend omega-3 supplementation for cancer prevention based on available evidence.
5. Body Systems and Health Areas Associated with Omega-3 Fatty Acids
- Cardiovascular system: The primary reason people take fish oil is for its cardiovascular benefits. Effects include triglyceride reduction, modest blood pressure lowering, and — at high prescription doses of EPA — reduction of major cardiovascular events in high-risk populations.
- Immune and inflammatory system: Omega-3 fatty acid supplements attenuate inflammation by modulating cell membrane function, down-regulating pro-inflammatory cytokines (such as IL-6), reducing production of arachidonic acid derivatives, and reducing reactive oxygen species.
- Central nervous system: DHA is a structural component of brain cell membranes; omega-3s modulate neurotransmitter pathways and neuroinflammation, with relevance to mood disorders and neurodegenerative conditions.
- Ocular system: Fish oil, rich in EPA and DHA, is sought after for health benefits associated with the brain and eyes, as well as general inflammation and multiple inflammatory conditions.
- Musculoskeletal system: Omega-3s have documented effects on joint inflammation, with symptomatic benefit observed in rheumatoid arthritis trials.
- Reproductive and perinatal: DHA accumulates in fetal neural and retinal tissue during the third trimester and is important for infant brain and visual development.
- Metabolic system: Obesity, a chronic inflammatory disease that contributes to metabolic disorders, is alleviated by n-3 PUFAs.
6. Dosage Forms and Dosages Reported in Studies
Long-chain omega-3s are present in several dietary supplement formulations, including fish oil, krill oil, cod liver oil, and vegetarian products that contain algal oil. A typical fish oil supplement provides about 1,000 mg fish oil, containing 180 mg EPA and 120 mg DHA, but doses vary widely.
The following dosages have been reported in specific studies and guidelines:
- General dietary recommendation (EPA + DHA): The Dietary Guidelines for Americans 2015–2020 recommends 450–500 milligrams of omega-3 fatty acids per day. Those with coronary heart disease should consume 1 gram of omega-3 fatty acid per day, preferably from fatty fish.
- ALA Adequate Intake (AI): The AI for α-linolenic acid is 1.6 grams/day for men and 1.1 grams/day for women.
- REDUCE-IT trial (high-dose EPA): In REDUCE-IT, there was a 25% decrease in the primary endpoint of major cardiovascular events with 4 g/d EPA (icosapent ethyl) in patients with elevated triglycerides (135–499 mg/dL) who were also taking a statin drug.
- VITAL trial: In the Vitamin D and Omega-3 Trial (VITAL), 840 mg/d of EPA and DHA resulted in a 28% reduced risk for heart attacks, 50% reduced risk for fatal heart attacks, and 17% reduced risk for total coronary heart disease events.
- ASCEND trial: In the ASCEND trial, cardiovascular disease death was significantly reduced by 19% with 840 mg/d of EPA and DHA.
- Depression augmentation (EPA + DHA): A randomized controlled trial compared EPA (4.4 g/day) plus DHA (2.2 g/day) as augmentation to antidepressants in 22 patients with major depression over eight weeks.
- Depression in pregnancy (EPA + DHA): A study on 36 pregnant women with major depressive disorder compared omega-3 HUFAs monotherapy at 2.2 g/day of EPA plus 1.2 g/day of DHA with placebo.
- Schizophrenia (EPA): Meta-analytic results in schizophrenia exclusively pertained to 2 g/d EPA.
- Omega-3 Index improvement: The lowest doses shown to be effective in raising the Omega-3 Index to recommended levels were greater than 1,000 mg/d of combination DHA plus EPA for 12 weeks or longer.
- FDA upper intake guidance: The FDA recommends consuming no more than 3 g/day of EPA and DHA combined, including up to 2 g/day from dietary supplements. Higher doses are sometimes used to lower triglycerides, but at these doses could cause bleeding problems and possibly affect immune function.
7. Safety Considerations and Interactions
Common Adverse Effects
Commonly reported side effects of omega-3 supplements are usually mild. Any side effects from taking omega-3 supplements in smaller amounts are usually mild. They include an unpleasant taste in the mouth, bad breath, heartburn, nausea, and stomach discomfort. A notable safety profile — beyond occasional and mild discomfort — for any type or dose of omega-3 fatty acid supplementation was not observed in a U.S. Agency for Healthcare Research and Quality (AHRQ) evidence review of omega-3s in mental health contexts.
Atrial Fibrillation Risk
The association between omega-3 supplementation and atrial fibrillation (AF) has been extensively examined, with mixed results depending on dose and study type. Two large clinical trials found that taking 4 g/day of omega-3 supplements for several years slightly increased the risk of atrial fibrillation in people with CVD or at high risk of CVD.
In meta-analysis, the use of marine omega-3 fatty acid supplements was associated with an increased risk of AF (HR 1.25, 95%CI 1.07–1.46, P=0.013). In analyses stratified by dose, the hazard ratio was greater in trials testing greater than 1 g/d (HR 1.49, 95%CI 1.04–2.15) as compared with those testing ≤1 g/d (HR 1.12, 95%CI 1.03–1.22). In meta-regression, the HR for AF increased per 1 gram increase of omega-3 fatty acids dosage (HR 1.11, 95%CI 1.06–1.15, P=0.001).
Contrasting this, a large biomarker-based analysis added complexity: A major new analysis published in the Journal of the American Heart Association found that higher circulating blood levels of omega-3 fatty acids are associated with a significantly lower risk of developing atrial fibrillation. The comprehensive study analyzed data from hundreds of thousands of participants in the UK Biobank. Higher circulating omega-3 fatty acid levels were associated with significantly lower incident AF risk in multivariable models. This apparent discrepancy between supplement-dose trials and biomarker studies suggests that the relationship between omega-3 supplementation and AF is dose-dependent and may also be influenced by baseline status. Both the benefits and risks of marine omega-3 supplementation should be discussed with patients, especially when prescribing a higher dosage. The risk-benefit ratio may not only vary according to dose or formulation but also differ according to patient characteristics.
Anticoagulation and Bleeding
Fish oil can have antiplatelet effects at high doses, although it appears to be less potent than aspirin. Fish oil might prolong clotting times, as indicated by an elevated international normalized ratio (INR), when taken with warfarin, but most research indicates that doses of 3–6 g/day fish oil do not significantly affect the anticoagulant status of patients taking warfarin. The authors of a 2014 review concluded that omega-3s do not affect the risk of clinically significant bleeding, and the FDA-approved package inserts for omega-3 pharmaceuticals state that studies with omega-3s have not produced "clinically significant bleeding episodes."
Cod Liver Oil: Vitamin A and D Toxicity Risk
Both vitamin A and vitamin D toxicity can result from the consumption of large amounts of cod liver oil. Fish liver oil supplements, such as cod liver oil, contain EPA and DHA, and they also contain vitamins A and D in amounts that vary from product to product. Vitamins A and D can be harmful in excessive amounts.
Supplement vs. Prescription Formulations
Several products containing omega-3s have been approved as prescription drugs to be used in combination with diet to reduce triglyceride levels. The composition of these products is not the same as that of typical omega-3 supplements, and the testing and regulation of prescription drugs differ from those for dietary supplements. Therefore, the effects of these prescription products may not be the same as those of omega-3 dietary supplements.
Dietary Reference Intakes and Upper Limits
In the United States, the Institute of Medicine publishes Dietary Reference Intakes. When there is insufficient evidence to determine an RDA, the institute may publish an Adequate Intake (AI) instead. The AI for α-linolenic acid is 1.6 grams/day for men and 1.1 grams/day for women, while the AMDR is 0.6% to 1.2% of total energy. The IOM did not establish specific intake recommendations for EPA, DHA, or other LC omega-3s.
Supplement Quality and Oxidation
Fish oil is high in omega-3 fatty acids, a valuable aspect in nutrition but one that makes it subject to oxidation, rancidification, and destruction of vitamin A when it is exposed to air. Omega-3 supplements should be stored appropriately to minimize oxidative degradation, which can diminish their biological potency.
Prevalence of Use
According to the 2019 European Society of Cardiology guidelines for dyslipidemia, icosapent ethyl has been integrated as second-line treatment in addition to statins for high-risk patients with high triglyceride values. According to the 2012 National Health Interview Survey, fish oil supplements are the natural product most commonly taken by adults, with about 7.8% of patients reporting their use, corresponding to approximately 18.8 million people in the United States.
References
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