Eicosapentaenoic Acid (EPA)
1. Identity
Chemical Names and Nomenclature
Eicosapentaenoic acid (EPA; also known as icosapentaenoic acid) is an omega-3 fatty acid designated in physiological literature as 20:5(n−3). It also carries the trivial name timnodonic acid. 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 biologically active natural form is (5Z,8Z,11Z,14Z,17Z)-5,8,11,14,17-eicosapentaenoic acid, with all double bonds in the cis configuration.
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. Similarly, EPA is known as C20:5n-3 and DHA as C22:6n-3.
EPA is a polyunsaturated fatty acid (PUFA) that acts as a precursor for prostaglandin-3 (which inhibits platelet aggregation), thromboxane-3, and leukotriene-5 eicosanoids.
Natural Sources
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. It is obtained in the human diet by eating oily fish or fish oil — cod liver, herring, mackerel, salmon, menhaden, and sardine — and is also found in human breast milk.
Since the supply of fish oil — the most abundant and widely used natural source for EPA and DHA — is significantly declining, alternative and sustainable biological sources are required to provide LC-PUFAs in high quantities and quality. One commercially significant alternative is microalgae: Almega®PL is a polar-rich oil (>15%) derived from the microalga Nannochloropsis that contains EPA (>25%) with no DHA.
Mammalian cells cannot synthesize long-chain PUFAs de novo, although EPA can be synthesized from the essential fatty acid α-linolenic acid (ALA), 18:3(ω-3), but conversion is minimal. The most effective way to enrich cells in EPA is by dietary intake of fish oils.
Common Forms and Preparations
EPA is available in several distinct chemical forms as a dietary supplement and as a prescription pharmaceutical:
- Free fatty acid (FFA): The natural, unmodified form of EPA as it occurs in whole fish and many food-grade fish oils.
- Triglyceride (TG) form: EPA esterified to a glycerol backbone, as found in re-esterified triglyceride (rTG) fish oil concentrates.
- Ethyl ester (EE) form: There is now a method for producing EPA from natural sources such as krill oil. During purification, EPA is converted to its ethyl ester form and then can be restored to its free acid form.
- Phospholipid (PL) form: One form found naturally in algae is the polar lipid form — a mixture of various non-TG/EE forms, including PC (phosphatidylcholine), LPC (lysophosphatidylcholine), and other phospholipids.
- Icosapent ethyl (prescription drug): Icosapent ethyl is made from the omega-3 fatty acid EPA. The US Food and Drug Administration (FDA) granted approval of icosapent ethyl in 2012 to Amarin Corporation, making it the second fish oil-based medication after omega-3-acid ethyl esters (brand named Lovaza, itself approved in 2004). In December 2019, the FDA also approved Vascepa as the first drug specifically "to reduce cardiovascular risk among people with elevated triglyceride levels."
Fish oil supplements come in liquid, capsule, and pill form. Omega-3-acid ethyl esters, omega-3-carboxylic acids, and omega-3-acid ethyl esters A contain both EPA and DHA, whereas icosapent ethyl contains ethyl esters of EPA only.
2. Traditional and Historical Use
Pre-Scientific Dietary Traditions
While EPA as an isolated chemical compound was not identified until the mid-twentieth century, populations consuming large quantities of fatty marine animals have long demonstrated patterns of health associated with high omega-3 intake. In the early 1970s the Inuit were still a hunter and fisherman society, living mostly on seal meat and fish. Heart disease accounted for 5.3 per cent of deaths amongst Greenland males aged 45 to 64, compared to their US counterparts eating a vastly different diet, where 40 per cent of deaths were due to coronary heart disease. The traditional Inuit diet thus constitutes one of the most historically significant dietary contexts for high EPA consumption, though its health effects were not attributable to EPA specifically until modern biochemical analysis.
Cod liver oil — a source rich in both EPA and DHA — has a recorded history of medicinal use in Northern Europe extending several centuries. Norwegian and Icelandic fishing communities have traditionally used it to prevent and treat musculoskeletal conditions and to maintain general health through the cold, fish-dependent winters, though these preparations were not chemically characterised and their EPA content was not known at the time.
Scientific Discovery and Emergence of EPA Research
Dr. Jörn Dyerberg is a pioneer in the omega-3 fatty acid world, having made the discovery of their important heart health benefits more than four decades ago while researching the native Greenland Inuit. Along with his colleague Dr. Hans Olaf Bang, the two embarked on research that started in the late 1960s and trickled well into the 1970s. It started with their curiosity about the Inuit's high-fat diet and their very low incidence of heart disease.
Their initial findings, published in The Lancet in June 1971, surprised them: the average Greenland Inuit had lower serum cholesterol and lipid levels than the average Dane. Their levels were also lower than Inuits who lived in Denmark, suggesting an environmental, and not genetic, explanation.
It was in a subsequent publication in 1975 in the American Journal of Clinical Nutrition that they detailed the specific omega-3s eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This led to several landmark publications during the following decades and a stream of interest in these newly discovered molecules.
Following their research in Greenland, the investigators published a landmark paper in The Lancet on July 15, 1978, entitled "Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis?" Here they presented data supporting the idea that EPA (from the seafoods consumed by these Inuit people) could substitute for arachidonic acid in the cyclooxygenase pathway in platelets and reduce platelet "stickiness."
The breakthrough came in the 1970s when Dyerberg and Bang reported that the low incidence of atherosclerotic coronary disease in Greenland Eskimos was due to the high marine lipid content of their diet. They subsequently found that EPA, which was increased in Eskimo plasma, inhibited platelet aggregation, and they concluded that the low incidence of coronary artery disease was due to the anti-thrombotic effect of EPA.
The average intake of EPA and DHA among the Inuit was found to be more than 13 g per day, while Americans had below 200 mg, and nearly 25% had no intake of omega-3 at all.
The first highly purified EPA preparation for human use was developed in Japan. This eventually led to the large-scale Japanese clinical trials and ultimately to global pharmaceutical development of purified EPA products.
3. Key Constituents and Mechanisms of Action
Biochemical Identity
Long-chain fatty acids influence inflammation through a variety of mechanisms; many of these are mediated by, or at least associated with, changes in 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.
Eicosanoid Modulation
EPA and DHA 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.
One of the traditional theories is that omega-3 polyunsaturated fatty acids compete with the canonical omega-6 substrate arachidonic acid to generate eicosanoids such as prostaglandins of the 3-series and leukotrienes of the 5-series that are thought to be more anti-inflammatory than their arachidonic acid-derived counterparts.
Specialized Pro-Resolving Mediators (SPMs)
Resolvins are a family of lipid mediators derived from omega-3 polyunsaturated fatty acids, including EPA, which are generated during the resolution phase of acute inflammation. The resolvin E series (resolvin E1, E2, and E3) is biosynthesized from a common intermediate, 18-hydroxy eicosapentaenoic acid (18-HEPE), generated by cyclooxygenase (COX)-2-mediated conversion of EPA, and has been shown to possess significant anti-inflammatory properties, thereby protecting organs from collateral damage. It has been hypothesized that these E series resolvins contribute to the beneficial actions that have been attributed to EPA in certain human diseases, particularly those in which inflammation is suspected as a key component in pathogenesis.
More recently, researchers discovered that both EPA and DHA could be enzymatically converted in vivo to novel bioactive lipid mediators — termed resolvins, protectins, and maresins (collectively termed specialized pro-resolving mediators) — that stimulate the resolution of inflammation and have proven to be log-orders more potent than their precursors.
Transcription Factor Modulation
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 so reducing expression of inflammatory genes, and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor γ (PPARγ).
Triglyceride-Lowering Mechanism
Strong evidence shows that reduction in triglyceride concentration is caused by mechanisms such as reduced hepatic VLDL–triglyceride synthesis and secretion and increased triglyceride clearance from chylomicrons and VLDL particles. On the cellular level, EPA inhibits the action of acyl CoA:1,2 diacylglycerol acyltransferase, increases hepatic mitochondrial and peroxisomal beta-oxidation, and thus results in a reduction in the hepatic synthesis of triglycerides, lowering their blood levels.
Plaque and Antithrombotic Actions
Increased EPA lipid composition from carotid plaque specimens and increased circulating EPA/arachidonic acid ratio have been observed following EPA treatment. EPA inhibits platelet aggregation under some ex vivo conditions. Mediation analyses from REDUCE-IT suggested that the triglyceride reduction accounted for a minority of the drug's benefit, with approximately two-thirds of the benefit caused by the large increase in serum EPA that occurred on treatment. This finding implies significant pleiotropic mechanisms beyond lipid lowering.
Neurological Mechanisms
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. Despite the different bioactivity between EPA and DHA, there is a robust biological basis supporting their anxiolytic and antidepressant potential, comprising modulation of neuronal membrane properties, receptor expression and neurotransmission, antioxidant, anti-inflammatory and pro-resolving activity, and promotion of neuroplasticity and neuroprotection.
4. Scientific Evidence by Area of Use
4.1 Cardiovascular Disease and Triglyceride Reduction
Evidence strength: Strong for triglyceride reduction; significant but contested for hard cardiovascular event reduction.
Omega-3 fatty acids such as EPA may reduce the risk of atherosclerotic cardiovascular disease (ASCVD) events through various mechanisms, including triglyceride (TG) lowering, membrane stabilization, and antithrombotic, anti-inflammatory, or antiarrhythmic properties.
JELIS Trial: The first large-scale, prospective, randomized trial of combined treatment with a statin and EPA has shown that the addition of EPA to statin therapy provides additional benefit in preventing major coronary events, apparently through lipid-independent mechanisms. The Japan EPA Lipid Intervention Study (JELIS) tested the effects of long-term use of EPA 1,800 mg/day in addition to a statin in Japanese patients with hypercholesterolemia. JELIS was designed as a prospective, randomized, open-label, blinded-endpoint trial, with a maximum follow-up of 5 years. In the JELIS trial, which involved more than 18,000 participants taking statins and either 1.8 g of purified EPA or a placebo daily for five years, participants who received the EPA supplement experienced a 19% reduction in cardiovascular events. However, those with higher triglyceride levels (>150 mg/dL) and lower HDL-C (<40 mg/dL) experienced a 53% reduction in cardiovascular events with EPA treatment.
REDUCE-IT Trial: The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) showed significant cardiovascular benefit of EPA when compared to placebo in 8,179 statin-treated patients with elevated triglycerides and cardiovascular disease or diabetes. In REDUCE-IT, 8,179 high-risk patients received 3.6 g/day of EPA as ethyl ester or mineral oil as placebo with a median follow-up of 4.9 years. The REDUCE-IT trial showed large relative and absolute risk reductions in ischemic events with icosapent ethyl (a highly purified, pharmaceutical-grade ethyl ester of EPA), including a significant reduction in cardiovascular death in secondary and high-risk primary prevention patients with mildly to moderately elevated triglycerides. Interestingly, the benefit extended across the full range of baseline triglyceride values in the trial, including in the subgroup of patients who entered the trial with normal triglyceride levels.
STRENGTH Trial and the REDUCE-IT Controversy: A subsequent trial — STRENGTH (Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) — showed no significant reduction in major adverse cardiovascular events with a combination of EPA and DHA among 13,078 statin-treated patients when compared with placebo. 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. 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 discussion following the publication of these trials, the underlying reasons for this discrepancy remain elusive.
The REDUCE-IT trial has been mired in controversy, with suggestions that the benefit seen might have been exaggerated because of the use of a harmful placebo.
Meta-Analytic Evidence: A meta-analysis of 38 randomized controlled trials found that omega-3 fatty acids improved cardiovascular outcomes, with a greater reduction in cardiovascular risk in studies of EPA alone rather than of combined EPA plus DHA supplements. A meta-analysis of EPA trials showed greater relative risk reductions in cardiovascular outcomes than those of EPA+DHA. Several clinical guideline recommendations endorsed purified ethyl ester of EPA after REDUCE-IT.
Triglyceride Lowering (Consistent Finding): EPA and DHA both lower triglyceride levels, with DHA most likely having a slightly greater effect. The FDA recommends not exceeding 3 g/day EPA and DHA combined, with up to 2 g/day from dietary supplements.
UK Biobank Observational Data: One large prospective analysis based on UK Biobank data followed more than 415,000 individuals aged 40–69 years over 12 years. It was found that among participants without existing CVD, regular use of fish oil supplements was associated with an increased risk of developing atrial fibrillation (HR: 1.13, 95% CI: 1.10–1.17) and a slightly elevated risk of stroke (HR: 1.05, 95% CI: 1.00–1.11). This observational finding contrasts with RCT evidence and underscores residual uncertainty in primary prevention settings.
4.2 Depression and Mood Disorders
Evidence strength: Moderate, particularly for EPA-dominant formulations as adjunctive therapy.
Omega-3 polyunsaturated fatty acids have received considerable attention in the field of mental health, in particular regarding the treatment of depression. A body of evidence examines the role of omega-3 fatty acids in the prevention and treatment of depressive disorders. 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.
Key RCT Evidence: Peet and Horrobin (2002) conducted a randomized, placebo-controlled, dose-finding study of ethyl-eicosapentaenoate (EPA) as monotherapy for 70 adults (ages 18–70) with persistent depression despite treatment with a standard antidepressant. Subjects receiving 1 g/day EPA showed significantly higher response rates than subjects receiving placebo (53% vs. 29%), with notable improvement of depressed mood, anxiety, sleep disturbance, lassitude, diminished libido, and suicidality. The 2 g/day group showed little evidence for a drug–placebo difference, and the 4 g/day group showed a non-significant trend toward improvement.
Meta-Analytic Evidence: A meta-analysis analyzed 26 studies including 2,160 participants and showed an overall beneficial effect of omega-3 polyunsaturated fatty acids on depression symptoms (SMD = −0.28, P = 0.004). Compared with placebo, EPA-pure (=100% EPA) and EPA-major formulations (≥60% EPA) demonstrated clinical benefits with an EPA dosage ≤1 g/d (SMD = −0.50, P = 0.003, and SMD = −1.03, P = 0.03, respectively), whereas DHA-pure and DHA-major formulations did not exhibit such benefits.
Results support the antidepressant effects of EPA at proportions ≥60% of total EPA + DHA in a primarily clinical population at doses ≥1 g/day and <2 g/day. However, EPA at doses of ≥2 g/day does not appear to be efficacious against depression severity.
Omega-3 supplementation significantly reduced depressive symptoms compared with placebo, with a pooled effect size of Hedge's g = −0.45 (p<0.01). The most pronounced effects were observed in individuals with moderate-to-severe depressive symptoms. Subgroup analysis revealed that EPA supplementation was more effective when combined with antidepressants.
Despite methodological limitations, recent systematic reviews and meta-analyses converge in supporting the clinical utility of EPA-rich formulations, especially in adjunctive therapy for treatment-resistant depression (TRD), bipolar depression (depressive phase), and perinatal mood disorders.
Limitations: Methodological heterogeneity — including variability in sample size, diagnostic criteria, treatment duration, and particularly the use of biologically active placebos such as olive or sunflower oil — complicates cross-trial comparisons and may attenuate true effect sizes.
4.3 Inflammation and Rheumatoid Arthritis
Evidence strength: Moderate. The most consistent clinical evidence in inflammatory disease is for rheumatoid arthritis.
As a result of their anti-inflammatory actions, marine n-3 PUFAs have therapeutic efficacy in rheumatoid arthritis, although benefits in other inflammatory diseases and conditions have not been unequivocally demonstrated.
EPA and DHA 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.
A growing body of evidence indicates that omega-3 fatty acids may prevent or ameliorate symptoms associated with chronic health conditions such as cardiovascular disease, neurodegenerative disease, and rheumatoid arthritis, and may be beneficial in combating aging-related diseases.
4.4 Hypertriglyceridemia (Prescription Use)
Evidence strength: Strong. FDA-approved indication.
VASCEPA is an ethyl ester of EPA 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 adult patients with elevated triglyceride (TG) levels (≥150 mg/dL) and established cardiovascular disease or diabetes mellitus and 2 or more additional risk factors for cardiovascular disease.
Icosapent ethyl and omega-3-acid ethyl esters are approved for adults with very high triglycerides (≥500 mg/dL) as an adjunct to diet to decrease triglyceride levels and reduce cardiovascular events.
4.5 Microalgae-Derived EPA: Cholesterol Effects
Highly purified EPA therapy has proven to be particularly effective in the treatment of cardiovascular disease, but less is known about the benefits of EPA-only supplementation for the general healthy population. A double-blind, randomized, placebo-controlled trial of EPA-rich microalgal extract (Nannochloropsis-derived) in 120 participants given 1 g/day of either the algal EPA extract or placebo for 12 weeks measured differences in the Omega-3 Index, cardiometabolic markers, and other general health indicators at baseline, six, and 12 weeks.
5. Body Systems and Health Areas
EPA has been researched in relation to the following major body systems and health areas:
- Cardiovascular System: EPA is well described in numerous studies addressing the prevention and treatment of cardiovascular diseases due to its blood pressure-lowering and anti-inflammatory properties. Evidence encompasses triglyceride reduction, anti-platelet effects, plaque stabilization, and reduction of major adverse cardiovascular events in high-risk populations on statins.
- Immune and Inflammatory System: The anti-inflammatory effects of marine n-3 PUFAs suggest that they may be useful as therapeutic agents in disorders with an inflammatory component. This includes rheumatoid arthritis, inflammatory bowel conditions, and systemic inflammation.
- Central Nervous System / Mental Health: Omega-3 fatty acids, particularly EPA and DHA, exhibit anti-inflammatory properties, optimize serotonergic transmission, and stabilize neuronal membranes. EPA-dominant formulations have the most consistent clinical evidence for depression.
- Lipid Metabolism / Hepatic System: EPA reduces hepatic VLDL synthesis, decreases circulating triglycerides, and modifies lipoprotein particle profiles. Its effects on LDL-cholesterol are less consistent and may differ from DHA.
- Platelet and Coagulation System: EPA inhibits platelet aggregation by competing with arachidonic acid in the cyclooxygenase pathway, producing thromboxane A3 (less pro-aggregatory) instead of thromboxane A2.
- Endocrine / Metabolic System: EPA has been studied in the context of obesity and diabetes due to anti-inflammatory and blood pressure-lowering properties.
- Ocular Health: EPA and DHA have been studied in dry eye disease with mixed results. One large, randomized, double-blind clinical trial conducted in the United States found that EPA and DHA from fish oil supplements are no better than placebo at relieving symptoms or signs of dry eye disease.
- Perinatal / Reproductive Health: EPA-rich formulations have been studied in perinatal mood disorders.
6. Dosage Forms and Dosages Reported in Studies
The following dosages reflect those used or reported in the cited clinical literature and regulatory documents. They do not constitute recommendations.
- Triglyceride reduction / cardiovascular risk (prescription, REDUCE-IT): 8,179 high-risk patients received 3.6 g/day of EPA as ethyl ester (icosapent ethyl) or mineral oil as placebo with a median follow-up of 4.9 years.
- Triglyceride reduction / cardiovascular risk (JELIS trial): The JELIS trial used EPA 1,800 mg/day in addition to a statin in Japanese patients with hypercholesterolemia.
- Depression (Peet & Horrobin 2002 RCT): A randomized, placebo-controlled, dose-finding study used ethyl-EPA doses of 1 g/day, 2 g/day, and 4 g/day in 70 adults with persistent depression. Subjects receiving 1 g/day EPA showed significantly higher response rates than placebo (53% vs. 29%). The 2 g/day group showed little evidence for a drug–placebo difference.
- Depression (meta-analytic dose finding): Results support the antidepressant effects of EPA at doses ≥1 g/day and <2 g/day in a primarily clinical population. EPA at doses of ≥2 g/day does not appear to be efficacious against depression severity.
- Microalgae-derived EPA (cholesterol/cardiovascular, RCT): Participants (n=120) were given 1 g/day of either Almega®PL (EPA-rich algal oil) or placebo for 12 weeks.
- Dry eye disease (NIH-referenced RCT): 349 participants received daily supplements of 3,000 mg omega-3s (2,000 mg EPA plus 1,000 mg DHA), and 186 received a placebo containing 5,000 mg olive oil.
- Prescription dosage form (Vascepa/Vazkepa): Icosapent ethyl (Vazkepa®/Vascepa®) is approved at a dose of 4 g per day. It is available as 1 g (998 mg) EPA-EE in soft gelatin capsules, with each capsule containing the equivalent of 914 mg EPA free fatty acid. Dosing is recommended with meals.
Regarding safe upper limits: 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. Doses of 2–15 g/day EPA and/or DHA might also increase bleeding time by reducing platelet aggregation. EFSA noted that these doses have not been shown to cause bleeding problems or affect immune function, glucose homeostasis, or lipid peroxidation. Similarly, FDA has concluded that dietary supplements providing no more than 5 g/day EPA and DHA are safe when used as recommended.
7. Safety Considerations and Interactions
General Safety Profile
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. Omega-3 dietary supplements, such as fish oil, have the potential to interact with medications.
Atrial Fibrillation
The most common side effects of icosapent ethyl (prescription EPA) are musculoskeletal pain, peripheral edema, atrial fibrillation, and arthralgia. In clinical trials, icosapent ethyl was associated with an increased risk of atrial fibrillation or atrial flutter. Among participants without existing CVD in the UK Biobank prospective analysis, regular use of fish oil supplements was associated with an increased risk of developing atrial fibrillation (HR: 1.13, 95% CI: 1.10–1.17). This signal has been observed across multiple trial and observational datasets and is considered a clinically relevant concern at higher doses.
Bleeding Risk
Omega-3 PUFAs were not associated with increased bleeding risk overall, including fatal and central nervous system events, when compared with control. However, patients receiving high-dose purified EPA may incur additional bleeding risk, although its clinical significance is very modest. Bleeding risk appeared to be more closely associated with the dose of EPA than the background use of antiplatelet therapy.
Doses of 2–15 g/day EPA and/or DHA might also increase bleeding time by reducing platelet aggregation.
Drug Interactions
Adverse effects of omega-3 fatty acid supplements may include atrial fibrillation of new onset and increased propensity for bleeding. Drug interactions may exist between individuals receiving aspirin or clopidogrel (Plavix).
Taking fish oil supplements might slightly lower blood pressure, which is relevant to individuals on antihypertensive medications.
Additional Safety Notes
Omega-3 may rarely cause clinical or subclinical bleeding, worsening of glycemic control in people with impaired glucose tolerance, rise in LDL cholesterol, and possibly hypotension when combined with antihypertensive treatment.
Individuals with an unknown allergy to fish or shellfish not disclosed at screening may experience an anaphylactic reaction. In rare cases, fish oil supplements can trigger allergic reactions.
Safety and efficacy findings of EPA in subjects older than 60 years did not appear to differ from those of subjects younger than 60 years. Females tended to have more uptake of EPA into serum phospholipids than males; however, the clinical significance of this is unknown.
Pharmacokinetics of EPA have not been studied in pediatric populations. EPA has not been studied in patients with renal or hepatic impairment.
It is not clear whether fish oil is safe for people who are allergic to seafood.
The FDA has affirmed menhaden fish oil as Generally Recognized As Safe (GRAS) under 21 CFR 184.1472, provided that the daily intake of EPA and DHA combined does not exceed 3 g per person per day.
References
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