Eicosapentaenoic Acid (EPA)
1. Identity and Chemical Characterization
Eicosapentaenoic acid (EPA) is a long-chain omega-3 polyunsaturated fatty acid (PUFA) of marine origin. Its CAS Registry Number is 10417-94-4, and its IUPAC name is (5Z,8Z,11Z,14Z,17Z)-5,8,11,14,17-icosapentaenoic acid. It also carries the trivial name timnodonic acid. In physiological and nutritional literature, EPA is designated as 20:5(n−3).
In chemical structure, EPA is a carboxylic acid with a 20-carbon chain and five cis double bonds; the first double bond is located at the third carbon from the omega end. The five double bonds are located at positions 5, 8, 11, 14, and 17, which gives EPA its scientific name of 5,8,11,14,17-eicosapentaenoic acid. EPA has the chemical formula C₂₀H₃₀O₂ with a molecular weight of approximately 302 g/mol.
Due to the location of the double bond, usually in the Z (cis) position, the alkyl chain is "bent," so there is limited availability for other molecules and no aggregation, thereby helping to maintain cell membrane fluidity. EPA exists as a colorless liquid at room temperature and is insoluble in water but soluble in organic solvents. It oxidizes easily when exposed to air, which is why EPA supplements often contain antioxidants to prevent rancidity.
Natural Sources
EPA is obtained in the human diet by eating oily fish — for example, cod liver, herring, mackerel, salmon, menhaden, and sardine — as well as various types of edible algae, or by taking supplemental forms of fish oil or algae oil. It is also found in human breast milk.
Fish do not produce EPA themselves; instead, it originates from plankton and microalgae in their diet, becoming more concentrated in fish higher up the food chain. Fish, like most vertebrates, can synthesize very little EPA from dietary alpha-linolenic acid (ALA). Because of this extremely low conversion rate, fish primarily obtain it from the algae they consume. In humans, EPA can be synthesized from the essential fatty acid α-linolenic acid (ALA), 18:3 (ω-3), but conversion is minimal. Sea mammals, such as whales and seals, are also rich in EPA and DHA.
Commercial Forms and Preparations
EPA can be found in several supplement preparations: fish oils, cod liver oil, krill oil, some algal oils, and concentrated pharmaceutical-grade preparations of EPA and DHA, or EPA alone. Three omega-3 fatty acid prescription formulations are approved in the US for the treatment of adults with severe hypertriglyceridemia: (1) omega-3 fatty acid ethyl esters (OM3EE), a mixture primarily of EPA and DHA (Lovaza®, Omtryg™, and generics); (2) icosapent ethyl (IPE), EPA ethyl esters (Vascepa®); and (3) omega-3 carboxylic acids (OM3CA), a mixture of long-chain omega-3 fatty acids in free fatty acid form, primarily EPA, DHA, and docosapentaenoic acid (Epanova®).
The high bioavailability of omega-3 acids is due to their free molecular form rather than as ethyl ester derivatives. Intake of large doses (2.0 to 4.0 g/day) of long-chain omega-3 fatty acids as prescription drugs or dietary supplements are generally required to achieve significant (>15%) lowering of triglycerides, and at those doses the effects can be significant (from 20% to 35%, and even up to 45% in individuals with levels greater than 500 mg/dL).
2. Traditional and Historical Use
The formal scientific identification of EPA is a relatively modern achievement, but populations around the world have consumed EPA-rich foods for millennia without knowing the specific molecule responsible for health effects.
Interest in EPA and DHA 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 late 1970s, Danish investigators studied rates of coronary heart disease (CHD) in native populations of Greenland and discovered significantly lower death rates from acute myocardial infarction in Inuits compared with age- and sex-matched Danes, concluding that the high level of ω-3 fatty acids in the sea-based Inuit diet may have accounted for this finding. Through a series of now-classic investigations, the "Eskimo factor" that apparently protected them from the ravages of CHD was proposed to be the omega-3 fatty acids (EPA and DHA) provided by the whale, seal, and fish consumed as part of their traditional diet.
Following their research in Greenland, the Danish investigators published a landmark paper in The Lancet on July 15, 1978, entitled "Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis?" in which they presented data supporting the idea that EPA (from the seafoods consumed by Inuit people) could substitute for arachidonic acid in the cyclo-oxygenase pathway. The EPA levels in Greenland Eskimos were seven times higher, and their DHA levels were four times higher, than those of Eskimos living in Denmark and eating a Danish diet.
The initial evidence of the health benefits of omega-3 fatty acids, namely EPA and DHA, came from Greenland Eskimos, who consumed a diet heavy in fish and had low rates of multiple sclerosis, asthma, type I diabetes mellitus, and coronary heart disease. Similar trends were observed in other fish-eating populations, such as the Japanese. Cod liver oil, a traditional preparation used across Scandinavia and coastal Europe, served as an early popular source of omega-3 fatty acids, including EPA, long before the molecular constituents were identified.
A watershed moment for omega-3 research came on May 9, 1985, when the New England Journal of Medicine published landmark papers including "The Inverse Relation Between Fish Consumption and 20-year mortality from Coronary Heart Disease" by Kromhout et al. These publications collectively transformed dietary EPA from a traditional food constituent into a subject of rigorous scientific inquiry.
3. Key Constituents, Biochemistry, and Mechanisms of Action
EPA acts through several interconnected biological mechanisms. Its effects are largely mediated by its incorporation into cell membrane phospholipids and its role as a precursor to specific lipid-signaling molecules.
Membrane Incorporation and Arachidonic Acid Competition
Long-chain fatty acids influence inflammation through a variety of mechanisms; many of these are mediated by changes in the fatty acid composition of cell membranes. Changes in these compositions can modify membrane fluidity, cell signaling leading to altered gene expression, and the pattern of lipid mediator production. Cells involved in the inflammatory response are typically rich in the n-6 fatty acid arachidonic acid, but the contents of arachidonic acid and of the n-3 fatty acids EPA and DHA can be altered through oral administration of EPA and DHA.
EPA competitively inhibits the incorporation of arachidonic acid (AA) into membrane phospholipids, thereby reducing the amount of substrate available for synthesis of two-series prostanoids such as PGE2, effectively reducing their synthesis. EPA can also competitively reduce the amount of two-series eicosanoids synthesized by COX enzymes.
Eicosanoid Production
The primary precursor for inflammatory eicosanoids is arachidonic acid (20:4, n-6), which is enzymatically transformed into inflammatory prostaglandins or leukotrienes that contain two and four double bonds, respectively. Prostaglandins and leukotrienes synthesized from n-3 fatty acids contain three and five double bonds, respectively, and are less biologically active. EPA is metabolized by COX and LOX enzymes to form anti-inflammatory mediators (resolvins) as well as an anti-aggregatory and vasodilatory mediator (PGI3). Pro-aggregatory (TXA3) and pro-inflammatory mediators (PGE3 and LTB5) derived from EPA are generally weaker in their inflammatory activity than their arachidonic acid-derived counterparts.
Resolvins and Specialized Pro-Resolving Mediators (SPMs)
Resolvins are a family of lipid mediators derived from omega-3 polyunsaturated fatty acids, namely EPA and DHA, which are generated during the resolution phase of acute inflammation. Resolvin E1 (5S,12R,18R-trihydroxy-EPA; RvE1) is an anti-inflammatory mediator endogenously synthesized from EPA by a novel transcellular mechanism involving the sequential actions of aspirin-acetylated COX-2 and 5-lipoxygenase during the spontaneous resolution phase of acute localized inflammation.
EPA is a substrate for the enzymatic metabolism into the lipid mediator resolvin E1 (RvE1), which activates the receptor ChemR23 to transduce an active resolution of inflammation. Resolvin E1, a recently identified oxygenated product of EPA, was prepared by total synthesis and in nanomolar range proved to dramatically reduce dermal inflammation, peritonitis, splenic dendritic cell migration, and interleukin-12 production.
Cytokine Modulation
Dietary fish oil supplementation reduces synthesis of inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF). Changing the fatty acid composition of cells involved in the inflammatory response also affects production of peptide mediators of inflammation, including adhesion molecules and cytokines.
Triglyceride Metabolism
The mechanism of omega-3 carboxylic acids is to enhance clearance of triglycerides from circulating very low-density lipoprotein (VLDL) particles in the blood. They can also enhance the activity of lipoprotein lipase in blood, though the detailed mechanism remains incompletely understood.
4. Scientific Evidence by Area of Use
4.1 Cardiovascular Disease and Hypertriglyceridemia
Hypertriglyceridemia — Prescription-grade evidence (strong): The strongest regulatory-grade evidence for EPA concerns its role in lowering triglycerides. Icosapent ethyl is a high-purity prescription form of EPA ethyl ester approved at a dose of 4 g/day as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. In clinical studies, icosapent ethyl produced dose-dependent increases in the concentrations of EPA in plasma and red blood cells. In the MARINE and ANCHOR trials, these dose-dependent EPA increases correlated with the degree of TG level lowering (all P<0.01).
REDUCE-IT Trial (strong evidence, high-risk population): A multicenter, randomized, double-blind, placebo-controlled trial involved patients with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg per deciliter. Patients were randomly assigned to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. In REDUCE-IT, there was a 25% decrease in the primary end point of major cardiovascular events with 4 g/d EPA (icosapent ethyl) in patients with elevated triglycerides (135–499 mg/dL) who also were taking a statin drug.
The REDUCE-IT trial explored the use of icosapent ethyl, a high-dose, prescription form of EPA, testing 4 grams daily in 8,000 people taking statin medication who also had high blood triglycerides, a prior history of CVD, or diabetes and other CVD risk factors. Researchers found that daily use of the drug over the five-year study period significantly reduced the risk of major CVD events, including both heart attack and stroke, by 25% in this high-risk population. The trial led to FDA approval for icosapent ethyl for a select group of high-risk patients.
STRENGTH Trial (negative, EPA+DHA combination): The STRENGTH trial 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 at high cardiovascular risk. Participants received either 4 g/day omega-3 CA or a placebo of corn oil. The trial was stopped after participants were treated for a median of about 3.5 years when the probability of benefit from omega-3 CA appeared low and the supplemented group had a higher incidence of atrial fibrillation.
EPA monotherapy vs. EPA+DHA combination: EPA monotherapy appears more effective than combined EPA + DHA formulations, as evidenced by trials such as REDUCE-IT showing significant benefits from EPA-ethyl ester and STRENGTH being terminated early due to futility. REDUCE-IT used 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. 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, the underlying reasons for this discrepancy remain elusive.
FDA approval status: In the United States, icosapent ethyl is indicated as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adults with elevated triglyceride levels (≥150 mg/dL) and established cardiovascular disease or diabetes with two or more additional risk factors. It is also indicated as an adjunct to diet to reduce triglyceride levels in adults with severe (≥500 mg/dL) hypertriglyceridemia.
European guideline endorsement: The 2019 dyslipidemia guidelines from the European Society of Cardiology and European Atherosclerosis Society recommend the use of 4 g of icosapent ethyl in individuals with established CVD and triglyceride levels of 135 to 499 mg despite statin use.
Observational and epidemiological evidence: Results from observational studies have been consistent with these findings, with several systematic reviews and meta-analyses showing that higher consumption of fish and higher dietary or plasma levels of omega-3s are associated with a lower risk of heart failure, coronary disease, and fatal coronary heart disease.
Early intervention trial — DART: The Diet and Reinfarction Trial (DART) enrolled 2,033 men who had experienced a myocardial infarction. One group was advised to increase their ω-3 intake by eating oily fish twice weekly, and the other received usual care. The group that consumed fish had a 29% reduction in overall mortality (P<0.05). Approximately 25% of patients who did not want to eat fish were given fish oil capsules providing 900 mg/d of EPA and DHA.
4.2 Mental Health: Depression
The existing body of 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.
A meta-analysis analyzed 26 studies which included 2,160 participants. The meta-analysis showed an overall beneficial effect of omega-3 polyunsaturated fatty acids on depression symptoms (SMD = −0.28, P = 0.004).
Randomized trials of omega-3 PUFA treatment for depression have differed in outcome. Recent meta-analyses ascribe discrepancies to differential effects of EPA versus DHA and to diagnostic heterogeneity. A specific meta-analysis tested the hypothesis that EPA is the effective component in PUFA treatment of major depressive episodes. Supplements containing EPA ≥ 60% of total EPA + DHA, in a dose range of 200 to 2,200 mg/d of EPA in excess of DHA, were effective against primary depression.
Using a random effects model, overall standardized mean depression scores were reduced in response to omega-3 LC-PUFA supplementation compared with placebo (standardized mean difference = −0.291, 95% CI = −0.463 to −0.120, z = −3.327, p = 0.001). This meta-analysis provides evidence that EPA may be more efficacious than DHA in treating depression. However, owing to the identified limitations of the included studies, larger, well-designed, randomized controlled trials of sufficient duration are needed to confirm these findings.
A review of clinical investigations reported that a total of six out of seven clinical trials showed that EPA significantly improved depressive symptoms when compared with the placebo-treated populations. 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. Evidence overall is promising but not yet conclusive; the picture is complicated by heterogeneity in dose, EPA/DHA ratio, diagnosis, comorbidity, and concomitant antidepressant use across trials.
4.3 Psychiatric Conditions: Schizophrenia and Bipolar Disorder
Decreased n-3 fatty acid levels have been reported in patients with depression, schizophrenia, and Alzheimer's disease. EPA has been studied for use in treating several psychiatric and neurodegenerative diseases due to its anti-inflammatory and neuroprotective effects. Several investigations have reported that EPA could effectively treat schizophrenia, though evidence in this area is preliminary and heterogeneous.
Given the critical need for antidepression treatments that might not carry the risk of precipitating a manic episode in bipolar patients, at least one open-label add-on trial of EPA in bipolar depression treated twelve bipolar I outpatients with depressive symptoms with 1.5 to 2 g/day of EPA. Evidence in bipolar disorder is limited to small trials and warrants further controlled study.
4.4 Inflammation and Rheumatoid Arthritis
The anti-inflammatory effects of marine n-3 PUFAs suggest that they may be useful as therapeutic agents in disorders with an inflammatory component. These fatty acids can moderately inhibit some inflammatory processes such as leukocyte chemotaxis, leukocyte-endothelial adhesive interactions, adhesion molecule expression, release of eicosanoids such as prostaglandins and leukotrienes from the ω-6 fatty acid arachidonic acid, and inflammatory cytokines and T cell reactivity.
Rheumatoid arthritis (RA) represents one of the more studied inflammatory conditions in relation to EPA. Benefits attributed to omega-3s include the management of lupus, eczema, and rheumatoid arthritis. Mendelian randomization evidence also suggests a potential link between EPA levels and protection against psoriatic arthritis: a heightened genetic predisposition for elevated levels of EPA was linked to a decreased susceptibility to psoriatic arthritis (PsA). Genetically predicted higher levels of EPA remained significantly associated with a reduced risk of PsA even after adjusting for multiple testing. The evidence in this field, however, is mostly from observational studies, secondary analyses, and small trials; large confirmatory RCTs are lacking.
4.5 Neurological and Neurodegenerative Conditions
A case report and a clinical trial have shown that EPA was beneficial for the management of most symptoms of Huntington's disease, while a more extensive clinical investigation demonstrated that EPA could only improve motor functions. Further clinical studies are required to fully explore the effects of EPA on other neurodegenerative diseases. Evidence in this field remains preliminary.
4.6 Cancer
The relationship between EPA and cancer is unclear. EPA and its metabolites have been shown to suppress proliferation in colon, pancreatic, breast, esophageal, and other cancer cell lines in vitro, and EPA-derived resolvins appear to have an anti-tumor effect in preclinical models. However, clinical studies show mixed results. Small studies in patients undergoing chemotherapy report changes in inflammatory markers and immune function with EPA (often combined with DHA). However, findings are inconsistent, and there is currently insufficient evidence to support routine use in cancer care.
5. Body Systems and Health Areas of Association
- Cardiovascular system: Triglyceride lowering, reduction of VLDL, anti-platelet aggregation, anti-atherosclerotic effects, reduction of cardiovascular events (in high-risk, hypertriglyceridemic patients on statins).
- Immune and inflammatory system: Modulation of eicosanoid production, reduction of pro-inflammatory cytokines (IL-1, TNF), generation of pro-resolving resolvins (RvE1, RvE2, RvE3), displacement of arachidonic acid from membrane phospholipids.
- Central nervous system / mental health: Evidence of antidepressant activity (particularly in EPA-predominant formulations), preliminary evidence in schizophrenia and bipolar depression.
- Musculoskeletal/autoimmune: Investigated in rheumatoid arthritis and psoriatic arthritis, with anti-inflammatory mechanisms potentially reducing disease activity markers.
- Endocrine and metabolic: Effects on lipid metabolism, triglyceride and VLDL clearance; reduction of the inflammatory environment relevant to type 2 diabetes risk.
- Cell membranes generally: EPA's incorporation into cell membranes helps maintain cell membrane fluidity, influencing signal transduction and receptor function across many tissues.
6. Dosage Forms and Reported Dosages
Fish oil supplements come in liquid, capsule, and pill form. EPA can also be found in cod liver oil, krill oil, algal oils, and concentrated pharmaceutical-grade preparations of EPA and DHA, or EPA alone.
The following dosages appear in the clinical literature, reported here as found in the source material:
- Hypertriglyceridemia (prescription, FDA-approved): The daily dose of icosapent ethyl (Vascepa) is 4 g taken as 2 capsules twice daily with food.
- Cardiovascular risk reduction (REDUCE-IT): Patients were randomly assigned to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g).
- Depression meta-analysis: Supplements containing EPA ≥ 60% of total EPA + DHA, in a dose range of 200 to 2,200 mg/d of EPA in excess of DHA, were effective against primary depression.
- Bipolar depression (open-label trial): EPA was administered at 1.5 to 2 g/day for up to a defined study period.
- Safety study in schizophrenia patients: Eighty-four subjects with schizophrenia were treated with either EPA 2 g/day or placebo in addition to their antipsychotic medication for 12 weeks.
- DART (fish oil capsules for cardiac secondary prevention): Fish oil capsules provided 900 mg/d of EPA and DHA for patients who declined to eat oily fish.
- General dietary guidance: 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.
7. Safety Considerations and Notable Interactions
General Safety Profile
According to the European Food Safety Authority, long-term consumption of EPA and DHA supplements at combined doses of up to about 5 g/day appears to be safe. 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.
N-3 PUFAs are generally considered safe; the most reported adverse reactions include gastrointestinal symptoms, musculoskeletal pain, peripheral edema, gout, rash, bleeding, and atrial fibrillation.
Bleeding Risk
Doses of 2–15 g/day of EPA and/or DHA might increase bleeding time by reducing platelet aggregation. However, according to the European Food Safety Authority, long-term consumption of EPA and DHA supplements at combined doses of up to about 5 g/day appears to be safe. In high doses, both prescription omega-3s and fish oil supplements can increase the risk of atrial fibrillation and also lead to an increased risk of bleeding.
Atrial Fibrillation Risk
The association between high-dose omega-3 supplementation and atrial fibrillation (AF) has emerged as a clinically relevant safety concern. A meta-analysis of 34 trials including 114,326 individuals found that high-dose EPA/DHA (>1,500 mg/day) in patients at high cardiovascular risk showed a statistically significant increase in AF risk with a pooled odds ratio (OR) of 1.48 (95% CI, 1.21–1.81) and an absolute risk difference of 0.8% (0.40–1.1%). None of the other three groups (high-risk/low-dose, low-risk/low-dose, and low-risk/high-dose) showed statistically significant levels of AF risk. This meta-analysis suggests that treatment with EPA/DHA is most likely to increase risk for AF in patients at high cardiovascular risk who are treated with high doses.
The STRENGTH trial was stopped after participants were treated for a median of about 3.5 years partly because the supplemented group had a higher incidence of atrial fibrillation.
Drug Interactions
EPA and DHA can act as alternative substrates for CYP450 metabolism and are partially metabolized by the CYP450 metabolic pathway. However, significant inhibition of CYP450 enzymes by DHA or EPA has not been observed, and no drug-drug interactions have been established with medications that use the CYP450 metabolic pathway. EPA-exclusive supplements have shown to have no drug-drug interactions with other medications that may use the P450 metabolic pathway, such as omeprazole, warfarin, atorvastatin, and rosiglitazone.
Despite the absence of established CYP450-mediated interactions, the platelet-inhibitory and anti-aggregatory properties of EPA (via its thromboxane- and prostaglandin-modulating effects) mean that the combination of high-dose EPA with anticoagulant or antiplatelet drugs remains an area of clinical vigilance, consistent with the general bleeding risk data noted above.
LDL Cholesterol (EPA vs. EPA+DHA)
DHA-containing omega-3 formulations may also increase LDL cholesterol. However, this is not accompanied by increased non-HDL cholesterol, which is thought to provide a better indication of cardiovascular risk in this patient population. Pure EPA preparations such as icosapent ethyl do not carry the same LDL-raising concern, which is considered one potential advantage of EPA monotherapy over combined EPA+DHA products.
Oxidative Stability
EPA oxidizes easily when exposed to air, which is why EPA supplements often contain antioxidants to prevent rancidity. Oxidized fish oil preparations may generate lipid peroxidation products; product quality and storage conditions therefore bear on safety in practice.
References
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