Omega-3 Fatty Acids | Supplementopedia

Overview

Definition: Omega-3 fatty acids are a family of polyunsaturated fatty acids (PUFAs) containing a double bond three carbons away from the terminal methyl group.
Bioactive Forms: The most biologically active forms for humans are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Function: Incorporated into cell membranes, they serve as precursors for anti-inflammatory lipid mediators. Their primary purpose is to modulate membrane fluidity, gene expression, and signaling pathways influencing cardiovascular, neural, and metabolic health.

Cardiovascular Health: Large-scale meta-analyses demonstrate that EPA/DHA supplementation modestly lowers triglycerides (≈15–30% reduction) and may reduce the risk of fatal heart disease when combined with statins. Randomized trials show improved endothelial function and modest blood pressure reduction (2–4 mmHg).
Brain Health: DHA supports synaptic plasticity; meta-analyses of 20+ trials find modest improvements in memory and processing speed in older adults.
Mental Health: EPA-rich supplementation reduces depressive symptoms by ~20% in major depressive disorder (Cochrane 2022).
Metabolic Health: EPA/DHA attenuate systemic inflammation by decreasing eicosanoid production and improve insulin sensitivity in patients with metabolic syndrome (≈0.5% HbA1c reduction).
Vision and Fetal Development: DHA supports retinal health and is essential for fetal neurodevelopment; maternal supplementation yields higher infant DHA status and improved visual acuity at 6 months.

Membrane Incorporation: EPA and DHA are incorporated into phospholipid membranes, increasing fluidity and altering raft domains where receptors and enzymes reside.
Eicosanoid Production: They are substrates for cyclooxygenase (COX), lipoxygenase (LOX), and CYP450 enzymes, generating specialized pro-resolving mediators (SPMs) such as resolvins, protectins, and maresins.
Inflammation Modulation: These SPMs bind G-protein-coupled receptors (e.g., GPR120, FPR2) to suppress NF-κB signaling, lowering cytokine (IL-6, TNF-α) production. EPA competes with arachidonic acid for COX/LOX, reducing pro-inflammatory eicosanoids (e.g., PGE₂).
Neuroprotection: DHA is a precursor for neuroprotective docosanoids (e.g., neuroprotectin D1) that modulate neuronal survival and synaptic plasticity via activation of the PI3K/Akt and MAPK pathways.
Metabolic Regulation: EPA/DHA also activate peroxisome proliferator-activated receptors (PPAR-α/γ), enhancing lipid oxidation and improving insulin sensitivity.

Cardiovascular Risk Reduction: Clinical trials typically use 1–3 g/day combined EPA/DHA, with EPA-dominant formulas (e.g., 1.8 g EPA + 0.6 g DHA) showing the strongest triglyceride-lowering effect.
Mood Disorders: For mood disorders, 2–4 g EPA (≥60% of total EPA/DHA) taken with meals improves absorption and GI tolerance.
Pregnancy/Lactation: Pregnant or lactating women are advised to consume 200–300 mg DHA/day (often achieved via 1 g total omega-3).
Dosing Strategies: Split dosing (morning and evening) minimizes fishy aftertaste and maximizes plasma EPA peaks. A conservative 1 g/day is recommended for individuals on anticoagulants, with periodic INR monitoring. Loading doses (e.g., 4–6 g/day for 1–2 weeks) are sometimes used to quickly raise plasma EPA/DHA to therapeutic levels, then maintained at 1–2 g/day.
Pediatric Dosing: Pediatric dosing follows weight-adjusted recommendations (10–20 mg/kg EPA+DHA).

General Tolerance: Omega-3s are generally well-tolerated; the most common adverse effects are mild gastrointestinal symptoms (e.g., eructation, nausea) and a fishy aftertaste.
Bleeding Risk: High doses (>5 g/day) can increase bleeding time; patients on warfarin, DOACs, or antiplatelet agents should limit intake to ≤3 g/day and monitor coagulation parameters.
Lipid Panel Monitoring: Omega-3s may modestly raise LDL-C in some individuals; lipid panels should be checked after 3–6 months.
Contraindications: Contraindications include known fish or shellfish allergy and severe hypertriglyceridemia (>1000 mg/dL) where prescription-grade omega-3 ethyl ester (e.g., icosapent ethyl) is recommended.
Pregnancy Considerations: Pregnant women should avoid products contaminated with PCBs or dioxins; choose certified “pharmaceutical-grade” products.

EPA: Eicosapentaenoic acid (EPA) – C₂₀H₃₀O₂, IUPAC: (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid.
DHA: Docosahexaenoic acid (DHA) – C₂₂H₃₂O₂, IUPAC: (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid.
Structural Features: Both are long-chain polyunsaturated fatty acids with multiple cis-double bonds spaced every three carbons (the “omega-3” position). The high degree of unsaturation confers low oxidative stability, measured by peroxide value. EPA has five double bonds; DHA has six, giving DHA a higher melting point and greater membrane fluidity. The carboxylic acid terminus (pKa≈4.8) allows incorporation into phosphatidylcholines and triglycerides.
Solubility and Stability: EPA/DHA are lipophilic, soluble in organic solvents (e.g., chloroform, hexane) and are vulnerable to oxidation; thus, antioxidants (e.g., vitamin E) are added to commercial formulations to preserve integrity.

Marine Sources: Marine sources dominate: fatty fish (salmon, mackerel, sardines) contain natural EPA/DHA; algae (Schizochytrium, Nannochloropsis) provide vegan DHA/EPA via fermentation.
Fish Oil Extraction: Fish-oil supplements are extracted by cold-press or supercritical CO₂, then molecularly distilled to remove contaminants (PCBs, dioxins).
Algal Oil Production: Algal oils are produced by cultivating micro-algae, then harvesting and purifying the lipids; this route avoids marine-derived pollutants and is sustainable.
Quality Metrics: Quality metrics include EPA/DHA content per capsule, oxidation status (PV <5 meq O₂/kg), and absence of heavy metals (≤0.5 ppm mercury). Pharmaceutical-grade products meet USP/EP standards and are often “phytochemical-free” (i.e., free of added flavors). Sourcing from certified, third-party tested brands ensures potency, purity, and consistent EPA/DHA ratios.