Fatty Acid

EPA

Eicosapentaenoic acid (20:5 n-3)

Evidence TierAWADA NOT PROHIBITED

tuneTypical Dose

500-2,000

watchEffect Window

4-8 weeks for mood. 12 weeks for lipid panels.

check_circleCompliance

WADA NOT PROHIBITED

Overview

Clinical Summary

EPA is an omega-3 fatty acid with anti-inflammatory actions and triglyceride lowering effects. It is used for cardiometabolic risk marker improvement and, in some cases, mood symptom support.

EPA reliably lowers triglycerides and can reduce inflammation-related biomarkers. Some evidence suggests EPA-predominant formulations may improve depressive symptoms in certain groups, with mixed results across trials. Minority evidence supports cardiovascular event reduction with specific high-dose purified EPA in high-risk patients. Effects vary with dose, baseline risk, and EPA to DHA balance.

Competes with arachidonic acid for COX/LOX enzymes, shifting eicosanoid production toward anti-inflammatory mediators. Modulates membrane fluidity and reduces neuroinflammation.

Outcomes

What This Is Expected To Influence

Primary Outcomes

  • Reduce triglycerides
  • Reduce symptoms of depression

Secondary Outcomes

  • Reduce joint pain/stiffness in RA
  • Reduce cardiovascular event risk

Safety

Contraindications and Interactions

Contraindications

  • Fish/shellfish allergy
  • Bleeding disorders

Side effects

  • Fishy burps
  • GI upset
  • Fishy body odor

Interactions

  • Anticoagulants (warfarin, aspirin)
  • Antihypertensives (additive BP lowering)

Avoid if

  • Fish/shellfish allergy
  • Bleeding disorders
  • Scheduled surgery

Evidence

Study-level References

epa-SRC-001Meta-analysis of RCTs
Sourceopen_in_new

Sublette ME, et al. "Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression." J Clin Psychiatry. 2011.

Population: Adults with diagnosed depression

Dose protocol: Source-listed

Key findings: Supplements containing ≥ 60% EPA showed a significant clinical benefit in treating depression, whereas formulas with a lower proportion of EPA (or pure DHA) did not.

Paper content

Supplements containing ≥ 60% EPA showed a significant clinical benefit in treating depression, whereas formulas with a lower proportion of EPA (or pure DHA) did not.

epa-SRC-002Multicenter, randomized, double-blind, placebo-controlled trial (REDUCE-IT).
Sourceopen_in_new

Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi:10.1056/NEJMoa1812792. PMID:30415628.

Population: Adults with established cardiovascular disease or diabetes plus risk factors, on statin therapy, with fasting triglycerides 135-499 mg/dL.

Dose protocol: Icosapent ethyl (purified EPA) 4 g/day versus mineral oil placebo for median 4.9 years

Key findings: 25% relative risk reduction in MACE (HR 0.75, 95% CI 0.68-0.83, P<0.001). NNT approximately 21 over 4.9 years.

Notes: REDUCE-IT. Landmark trial in 8,179 statin-treated patients. Industry funded. Result not replicated with mixed EPA-DHA products.

Paper content

REDUCE-IT was a landmark multicenter RCT that randomized 8,179 statin-treated patients with elevated triglycerides to 4 g/day of icosapent ethyl (purified EPA) or mineral oil placebo over a median of 4.9 years. The primary composite endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina) occurred in 17.2% of the icosapent ethyl group versus 22.0% of the placebo group (HR 0.75, 95% CI 0.68-0.83, P<0.001). This represents a 25% relative risk reduction with a number needed to treat of approximately 21. The result has not been replicated with mixed EPA-DHA products. This trial is the single strongest piece of cardiovascular outcome evidence for any omega-3 formulation and established high-dose purified EPA as a cardioprotective intervention in a defined high-risk population.

epa-SRC-003Systematic review and meta-analysis
Sourceopen_in_new

Kong L, Zhang Q, Wang H, Xu Y, Xu C, Chen Y, Lu J, Hu S. Exploration of the optimized portrait of omega-3 polyunsaturated fatty acids in treating depression: A meta-analysis of randomized-controlled trials. J Affect Disord. 2025;379:489-501. doi:10.1016/j.jad.2025.03.006. PMID:40049535.

Population: Adults with depressive symptoms or diagnosed depression across randomized supplementation trials.

Dose protocol: Omega-3 PUFAs at varying dosages across 36 RCTs. Optimal profile 1000-1500 mg/day with EPA:DHA 1:1 to 2:1.

Key findings: Significant overall antidepressant effect (SMD -0.26). EPA-enriched formulations drive the signal. Response and remission rates not significantly different from placebo.

Notes: 2025 meta-analysis confirming EPA as active component for mood. Effect is modest symptom reduction, not transformative.

Paper content

Updated meta-analysis supported small antidepressant effects for omega-3 supplementation overall, with the strongest signal in EPA-enriched formulations and continued heterogeneity across trials.

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