Fish Oil
Identity: Chemical Names, Natural Sources, and Common Forms
Fish oil is a lipid-rich extract derived from the tissues of oily fish.
It is oil derived from the tissues of oily fish and contains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), precursors of certain eicosanoids known to reduce inflammation in the body and improve hypertriglyceridemia.
The three main omega-3 fatty acids are 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.
These compounds are classified as polyunsaturated fatty acids (PUFAs). Omega-3s are a class of polyunsaturated fatty acids (PUFAs), including the long-chain fatty acids DHA and EPA, as well as the essential fatty acid ALA.
The fish used as sources do not actually produce omega-3 fatty acids themselves; instead, the fish accumulate these acids by consuming either microalgae or prey fish that have accumulated omega-3 fatty acids.
The most widely available dietary source of EPA and DHA is cold-water oily fish, such as salmon, herring, mackerel, anchovies, and sardines.
Oils from these fish have a profile of around seven times as much omega-3 oils as omega-6 oils.
ALA is an essential fatty acid, meaning the body cannot make it, so it must be obtained from foods and beverages. The body can convert some ALA into EPA and then to DHA, but only in very small amounts. Therefore, getting EPA and DHA from foods and dietary supplements is the only practical way to increase levels of these omega-3 fatty acids in the body.
Common Forms and Preparations
Fish oil supplements come in liquid, capsule, and pill form.
LC omega-3s are present in several dietary supplement formulations, including fish oil, krill oil, cod liver oil, and vegetarian products that contain algal 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.
Krill oil contains omega-3s in the form of phospholipids.
Algal oils are a vegetarian source of DHA; some also contain EPA.
A typical fish oil supplement provides about 1,000 mg fish oil, containing 180 mg EPA and 120 mg DHA, but doses vary widely.
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.
The United States Food and Drug Administration (FDA) has approved four fish oil-based prescription drugs for the management of hypertriglyceridemia, namely Lovaza, Omtryg (both omega-3-acid ethyl esters), Vascepa (ethyl eicosapentaenoic acid), and Epanova (omega-3-carboxylic acids). None of these drugs are actually fish oil; they are all derivatives of acids found in fish oil.
Traditional and Historical Use
The use of fish-derived oils and fish products as health remedies predates modern science by centuries.
Fish oil became one of the earliest dietary supplements during the 1870s, and by the end of the 19th century, was used as a treatment for many diseases, including such ailments as tuberculosis and hysteria.
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.
Cod liver oil's role in preventing rickets was well established before the fatty acid content was identified; its value was attributed primarily to its vitamins A and D.
In the early 1970s, researchers Bang and Dyerberg seemed to uncover a missing puzzle piece. They 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, and have been researched for everything from heart disease to rheumatoid arthritis.
The scientific investigation of fish oil in cardiovascular contexts gained major momentum with a landmark clinical intervention.
The Diet and Reinfarction Trial (DART) was one of the first randomized, controlled studies to demonstrate the beneficial effects of omega-3 fatty acids in secondary prevention of coronary heart disease (CHD) and reported a 29% reduction in all-cause mortality over a 2-year period in 2,033 male myocardial infarction (MI) survivors advised to increase their intake of oily fish (200 to 400 g of fatty fish per week, which provided 500 to 800 mg/day of omega-3 fatty acids).
Subsequently, on August 7, 1999, the GISSI-Prevenzione trial was published in The Lancet: the first well-powered endpoint study to use fish oil supplements (Omacor) — not a dietary change — to reduce risk for death, cardiovascular death, and sudden cardiac death, all without meaningful lowering of cholesterol or triglycerides.
Key Constituents and Active Compounds
The primary bioactive constituents of fish oil are the long-chain polyunsaturated omega-3 fatty acids EPA and DHA, though the oil matrix contains other fatty acids as well.
Today, fish oil is practically synonymous with the word "omega-3s." While it is true that fish oils are potent sources of omega-3 fatty acids, natural fish oil contains far more than EPA and DHA. Natural cod liver oil, for example, contains a good amount of lesser-known omega-3 fatty acids, like DPA (docosapentaenoic acid) omega-3.
Marine oils are considered vital for brain health because 20% of the brain's dry weight comprises polyunsaturated fatty acids as a major structural component of neuronal cell membrane phospholipids.
Mechanisms of Action
Anti-inflammatory Pathways
EPA and DHA are omega-3 (n-3) fatty acids found in oily fish and fish oil supplements. These fatty acids are able to partly inhibit a number of aspects of inflammation including leukocyte chemotaxis, adhesion molecule expression and leukocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines, and T-helper 1 lymphocyte reactivity.
In addition, 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.
As tissues return to normal, resolvins and protectins, together with further oxygenated metabolites such as lipoxins and maresins, promote resolution of inflammation through removal of leucocytes and cellular debris.
Mechanisms underlying the anti-inflammatory actions of marine n-3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B (NFκB) so reducing expression of inflammatory genes, activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor γ (PPARγ), and binding to the G protein-coupled receptor GPR120.
Increased membrane content of EPA and DHA (and decreased arachidonic acid content) results in a changed pattern of production of eicosanoids and resolvins. Changing the fatty acid composition of cells involved in the inflammatory response also affects production of peptide mediators of inflammation (adhesion molecules, cytokines, etc.). Thus, the fatty acid composition of cells involved in the inflammatory response influences their function; the contents of arachidonic acid, EPA, and DHA appear to be especially important.
Cardiovascular Mechanisms
Wide-ranging biological effects of omega-3 fatty acids include benefits on lipoprotein metabolism, blood pressure, endothelial function and vascular reactivity, inflammation, platelet and fibrinolytic function, cytokine production, coagulation, and oxidative stress.
In vivo and in vitro experiments showed that these unsaturated fatty acids may have effects of anti-inflammation, anti-oxidation, protecting vascular endothelial cells, thrombosis inhibition, modifying autonomic nerve function, improving left ventricular remodeling, and regulating blood lipid.
Neurological Mechanisms
Polyunsaturated fatty acids — especially DHA — play a vital role in brain and nervous system function by supporting membrane integrity and neuronal activity. DHA may exert neuroprotective effects through anti-inflammatory mechanisms, in part by competing with pro-inflammatory omega-6 fatty acids.
Scientific Evidence by Area of Use
Cardiovascular Disease
The cardiovascular evidence base for fish oil is large but contains considerable complexity and conflicting results depending on the populations studied, doses used, and composition of the supplement (EPA alone vs. EPA+DHA mixtures).
In a major meta-analysis by Hu and colleagues, the researchers performed an updated analysis that included three recently completed large-scale trials, increasing the total sample size by 64%. The total population analyzed included more than 120,000 adults in 13 randomized trials worldwide.
The findings showed that people who took daily omega-3 fish oil supplements, compared with those who took a placebo, lowered their risk for most CVD outcomes except stroke, including an 8% reduced risk for heart attack and coronary heart disease (CHD) death.
The VITamin D and OmegA-3 TriaL (VITAL) was a randomized controlled trial in 25,871 participants older than 50 years of age with no previous history of cancer or cardiovascular disease. The median follow-up was 5.3 years with fish oil given at 1 gram per day (460 mg EPA and 380 mg of DHA). There was no significant reduction in the primary endpoint (a composite of myocardial infarction, stroke, or death from cardiovascular causes). However, there were significant reductions in myocardial infarction (28%) and coronary heart disease death (17%). Thus, while many consider VITAL a negative trial, there were important reductions in key secondary endpoints.
Furthermore, in those consuming less than 1.5 fish meals per week, there was a highly significant reduction in the risk of major adverse cardiovascular events by 19%, and a 40% reduction in myocardial infarction.
The REDUCE-IT (Reduction of Cardiovascular Events with EPA–Intervention Trial) trial reported that treatment of high-risk patients with icosapent ethyl, a purified and stabilized ethyl ester of EPA, reduced the risk of the trial's primary cardiovascular endpoint by 25% (95% CI, 32%–17%; P < .001).
However, the REDUCE-IT trial used mineral oil as the placebo, which has itself been noted to have potential confounding effects. The use of mineral oil as placebo in the REDUCE-IT trial may have magnified its results; nonetheless, its unfavorable impact on lipid and inflammatory profile was modest and unlikely to fully explain the difference in clinical outcomes.
In contrast, the STRENGTH trial yielded negative results.
A 2020 clinical trial known as STRENGTH found no significant CVD benefits with Epanova, a high-dose prescription form of omega-3s containing EPA and DHA in a carboxylic acid form. STRENGTH included 13,078 participants from 22 countries (mean age 62.5 years) at high cardiovascular risk, including hypertriglyceridemia, low HDL cholesterol, diabetes, and established CVD. Participants received either 4 g/day omega-3 CA or a placebo of corn oil in addition to their usual therapies, including statins, for a projected trial duration of 4.5 years.
Positive outcomes were observed in the JELIS, REDUCE-IT, and EVAPORATE trials, in which all used EPA alone, whereas negative outcomes were observed in the STRENGTH, OMEMI, VITAL, and ASCEND trials, in which all used a mixture of EPA and DHA.
This divergence has prompted ongoing debate about whether EPA-only formulations are superior to EPA+DHA mixtures for cardiovascular outcomes.
A meta-analysis analyzing data from 13 high-quality RCTs, including the GISSI-Prevenzione, JELIS, GISSI-HF, Alpha Omega, Omega, ORIGIN, VITAL, ASCEND, and REDUCE-IT trials, showed that omega-3 PUFA supplementation lowered the risk of MI (RR 0.88, 95% CI = 0.83–0.94), CHD death (RR 0.92, 95% CI = 0.86–0.98), total CHD (RR 0.95, 95% CI = 0.91–0.99), and CVD death (RR 0.92, 95% CI = 0.88–0.97). These favorable results remained significant even after exclusion of the REDUCE-IT trial, and the risk reduction appeared to be linearly related to omega-3 PUFA dose.
There has been a great deal of controversy in the 21st century about the role of fish oil in cardiovascular disease, with recent meta-analyses reaching different conclusions about its potential impact.
Overall, the evidence is mixed: dietary fish consumption is consistently associated with cardiovascular benefit in observational data, while results from randomized controlled trials of fish oil supplements are variable depending on dose, composition, population, and background treatment.
Hypertriglyceridemia
The evidence for fish oil's triglyceride-lowering effect is among the strongest and most consistent in the literature.
There is strong evidence that omega-3 fatty acids can significantly reduce blood triglyceride levels. There also appears to be a slight improvement in high-density lipoprotein (HDL, or "good") cholesterol, although an increase in levels of low-density lipoprotein (LDL, or "bad") cholesterol was also observed.
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.
Many studies show that eating fatty fish and other types of seafood as part of a healthy eating pattern helps keep the heart healthy and helps protect against some heart problems. Getting more EPA and DHA from foods or dietary supplements lowers triglyceride levels, for example.
Blood Pressure
Multiple studies report modest reductions in blood pressure in people who take fish oil supplements. There is some evidence that the beneficial effects of fish oil might be greater for people with moderate to severe high blood pressure than for those with mild blood pressure elevation.
Taking fish oil supplements might slightly lower blood pressure, and taking them with blood pressure drugs might increase the effects on blood pressure.
Stroke
According to a 2016 report from the Agency for Healthcare Research and Quality (AHRQ), there is some evidence that omega-3s from marine sources (such as fish oil) may reduce the risk of one type of stroke (ischemic stroke — the type caused by narrowing or blockage of a blood vessel in the brain), but omega-3s have not been shown to reduce total strokes or death from stroke.
No protective effect against the development of stroke or all-cause mortality has been seen in populations studied for cardiovascular outcomes.
Mental Health: Depression and Mood
Research on fish oil and depression is an active and evolving area, with a body of evidence that is promising but methodologically heterogeneous.
A meta-analysis and meta-regression of 13 randomized clinical trials by Mocking et al. concluded that supplementation with omega-3 fatty acids has a beneficial effect in patients with major depressive disorder (MDD), especially for higher doses of EPA and in patients taking antidepressants.
However, the strength of this evidence is contested. A Cochrane review evaluated the overall quality of the evidence of studies on omega-3 fatty acids and depressive symptomatology (n=26) as very low, with the body of evidence composed of a limited number of predominantly small studies at high risk of selection, performance, or attrition bias.
The observed effect of omega-3 fatty-acid supplementation on depression appears to be largely driven by the most imprecise studies.
Omega-3 long-chain PUFAs, including EPA and DHA, are found in fish oil and are known for their health benefits in fetal development and healthy aging. At the same time, these marine oils are considered vital for brain health because 20% of the brain's dry weight comprises polyunsaturated fatty acids as a major structural component of neuronal cell membrane phospholipids.
Rheumatoid Arthritis and Joint Health
Studies suggest fish oil supplements might help reduce pain, improve morning stiffness, and relieve joint tenderness in people with rheumatoid arthritis. While relief is often modest, it might be enough to reduce the need for anti-inflammatory medications.
Animal experiments demonstrate benefit from marine n-3 fatty acids in models of rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and asthma.
The clinical human evidence for fish oil reducing the incidence of RA (rather than treating existing RA symptoms) is less established. Observational data is mixed; one meta-analysis incorporating 12 studies with a total of over 396,000 patients consuming omega-3 via fish intake found that the evidence does not clearly support reduction in RA occurrence from omega-3 intake alone.
Cognitive Function and Neurological Health
Prospective epidemiological studies have shown a reduced incidence of dementia associated with the consumption of foods rich in antioxidants, unsaturated fats, and especially fish and fish oil, which are high in omega-3 fatty acids, particularly DHA and EPA.
In a systematic review and dose-response meta-analysis of 58 RCTs, each 2,000 mg/day omega-3 supplementation showed a significant improvement in attention (SMD: 0.98; 95% CI: 0.41, 1.54; GRADE = low) and perceptual speed (SMD: 0.50; 95% CI: 0.05, 0.95; GRADE = moderate).
The GRADE ratings for attention outcomes were "low" and for perceptual speed "moderate," reflecting the still-uncertain quality of the underlying evidence. Overall, while there is a plausible biological rationale and supportive epidemiological data, high-quality RCT evidence for cognitive benefits of fish oil supplementation in healthy adults or those with mild cognitive impairment remains limited. Ongoing NIH-funded research is investigating fish oil's effects on Alzheimer's disease and dementia.
Inflammatory Bowel Disease
Animal models of colitis indicate that fish oil decreases colonic damage and inflammation. Fish oil supplements in subjects with IBD have shown to modulate levels of inflammatory mediators and may be beneficial for the induction and maintenance of remission in ulcerative colitis.
This evidence is primarily from smaller clinical trials and animal studies; evidence from large, well-controlled RCTs is limited.
Respiratory Conditions
EPA and DHA exhibit anti-inflammatory effects by promoting the production of specialized pro-resolving mediators (SPMs), such as resolvins and protectins. Fish oil has been studied for its potential to reduce bronchial inflammation, a key feature of respiratory conditions like asthma and COPD.
Evidence is primarily from in vitro and animal studies, with the clinical human evidence still preliminary.
Body Systems and Health Areas Associated with Fish Oil
- Cardiovascular system: Accumulated evidence shows that fish oil supplementation may reduce the risk of cardiovascular events, and it may have potential benefits in improving the prognosis of patients with hypertension, coronary heart disease, cardiac arrhythmias, or heart failure; however, some studies have yielded inconsistent results.
- Lipid metabolism: Reduction of serum triglycerides (well-established); modest HDL elevation; possible LDL elevation at high doses.
- Nervous system / brain: DHA is a structural component of neuronal membranes; research is ongoing in depression, cognitive decline, ADHD, and Alzheimer's disease.
- Musculoskeletal / immune system: Evidence for reduction of joint pain and stiffness in rheumatoid arthritis.
- Metabolic / endocrine: Omega-3s are under investigation for effects on insulin resistance and glycemic outcomes, particularly in diabetic kidney disease.
- Ocular: DHA levels are especially high in the retina (eye), brain, and sperm cells. The Age-Related Eye Disease Study 2 (AREDS2) also examined omega-3 supplementation in relation to macular degeneration.
- Reproductive / developmental: DHA is essential for fetal neural and retinal development; fish oil is investigated for pregnancy outcomes and infant neurodevelopment.
- Gastrointestinal: Under investigation for inflammatory bowel disease.
Dosage Forms and Dosages Reported in Studies
A typical fish oil supplement provides about 1,000 mg fish oil, containing 180 mg EPA and 120 mg DHA, but doses vary widely.
Many people consume between one and six 1 g capsules of fish oil per day, which provide approximately 300–1,800 mg of EPA and DHA combined.
Study-specific dosages reported in the literature include:
- The VITAL trial administered fish oil at 1 gram per day (460 mg EPA and 380 mg DHA) to 25,871 participants over a median follow-up of 5.3 years.
- The STRENGTH trial used 4 g/day omega-3 carboxylic acid (EPA + DHA) for a projected duration of 4.5 years.
- One NIH-registered clinical trial instructed participants to take supplements equivalent to approximately 3 g per day of omega-3 fatty acid in three divided doses (4 capsules, three times a day after meals).
- One randomized double-blind placebo-controlled trial administered 2.5 g/day of fish oil (marine-derived n-3 PUFA) for 4 consecutive months, with each capsule containing 60% n-3 PUFA (24% DHA and 36% EPA).
- The DART trial involved 200–400 g of fatty fish per week, providing approximately 500–800 mg/day of omega-3 fatty acids.
Recommended amounts of EPA and DHA from supplements have not been formally established by the U.S. government.
According to the European Food Safety Authority (EFSA), long-term consumption of EPA and DHA supplements at combined doses of up to about 5 g/day appears to be safe. EFSA noted that these doses have not been shown to cause bleeding problems or affect immune function, glucose homeostasis, or lipid peroxidation. Similarly, the FDA has concluded that dietary supplements providing no more than 5 g/day EPA and DHA are safe when used as recommended.
Safety Considerations and Drug Interactions
Common Adverse Effects
Commonly reported side effects of omega-3 supplements are usually mild. These include unpleasant taste, bad breath, heartburn, nausea, gastrointestinal discomfort, diarrhea, headache, and odoriferous sweat.
The most common side effects of fish oil specifically include taste perversion and eructation (belching).
Atrial Fibrillation
Two large clinical trials completed after EFSA and FDA safety assessments 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 people with cardiovascular disease and those at risk of cardiovascular disease, taking very high doses of fish oil supplements for several years may slightly increase the risk of atrial fibrillation (AFib).
Bleeding Risk
Doses of 2–15 g/day EPA and/or DHA might increase bleeding time by reducing platelet aggregation.
However, actual clinical bleeding consequences appear limited in most research.
Some studies reported consumption of omega-3 fatty acids is associated with a prolongation of bleeding time. However, the prolongation of bleeding time has not been shown to surpass normal limits and did not result in clinically significant bleeding episodes.
A 2018 clinical trial suggested that taking fish oil supplements did not increase bleeding during surgical procedures and decreased the number of blood transfusions. A 2024 meta-analysis of clinical trials also suggested that omega-3 fatty acids are not associated with increased bleeding risk; however, the authors noted that people taking high-dose purified EPA may have an increased bleeding risk in theory, but that the risk was not significant in practice.
Interactions with Anticoagulants and Antiplatelet Agents
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.
Drug interactions may exist between individuals receiving aspirin or clopidogrel (Plavix).
More recent studies call the warfarin interaction into question. Two studies from 2016 and 2018, respectively, found no significant impact on bleeding incidence when fish oil and warfarin were taken together.
Interactions with Blood Pressure Medications
Taking fish oil supplements might slightly lower blood pressure. Taking them with blood pressure drugs might increase the effects on blood pressure.
Interactions with Other Drugs
Some contraceptive drugs might interfere with the effect fish oil typically has on triglycerides.
Taking fish oil with the weight-loss drug orlistat (Xenical, Alli) might decrease absorption of fish oil fatty acids; taking the supplement and drug two hours apart may be considered.
Taking fish oil can reduce vitamin E levels.
Allergic Reactions
Individuals with an unknown allergy to fish or shellfish may experience an anaphylactic reaction. In rare cases, fish oil supplements can trigger allergic reactions. Symptoms may include difficulty breathing, swelling of the face, fever, or flu-like symptoms and a skin rash.
Cod Liver Oil and Vitamin Toxicity
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.
Users of cod liver oil must account for the cumulative vitamin A and D intake from all sources to avoid toxicity.
Contaminants
Reliance on fish oil as a source of omega-3 fatty acids is complicated by significant taste, odor, and stability problems associated with this type of oil. Furthermore, product quality derived from fish oil is generally dependent on the season and location, and it can be affected by ocean pollution.
Industrial processing of commercial fish oil includes steps to remove persistent organic pollutants and heavy metals, but quality varies across manufacturers.
Regulatory Status
In the United States, fish oil is sold both as an over-the-counter dietary supplement and, at high doses with specific compositions, as prescription medications. The FDA has approved four fish oil-based prescription drugs for the management of hypertriglyceridemia: Lovaza, Omtryg (both omega-3-acid ethyl esters), Vascepa (ethyl eicosapentaenoic acid), and Epanova (omega-3-carboxylic acids).
The Federal Government's Dietary Guidelines for Americans 2020–2025 recommends that adults eat 8 ounces or more of a variety of seafood (fish or shellfish) per week for all the nutrients seafood provides.
The American Heart Association (AHA) does not recommend omega-3 supplements for people who do not have a high risk of cardiovascular disease.
References
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