Salmon Omega-3: Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA)

Table of Contents

1. Why Marine Omega-3s Are Different from Alpha-Linolenic Acid
2. The Alpha-Linolenic Acid-to-EPA-to-DHA Elongation Pathway (and Why It's Inefficient)
3. Eicosapentaenoic Acid, Resolvins, and the Resolution of Inflammation
4. Docosahexaenoic Acid in the Brain and Retina
5. Cardiovascular Trials: GISSI, JELIS, REDUCE-IT
6. Triglyceride Reduction and Lipid Profile
7. Dosing: American Heart Association Recommendation and Therapeutic Doses
8. Pregnancy, Lactation, and Infant Neurodevelopment
9. Mental Health Applications (Depression, Attention-Deficit/Hyperactivity Disorder)
10. Fish Oil Capsules vs Whole Fish
11. Cautions and Drug Interactions
12. Key Research Papers
13. Connections
14. Featured Videos

Why Marine Omega-3s Are Different from Alpha-Linolenic Acid

Public confusion persists because "omega-3" is a chemical-family label, not a single nutrient. The omega-3 family contains three nutritionally relevant fatty acids:

• Alpha-linolenic acid (ALA, 18:3n-3) — the 18-carbon plant-source omega-3 found in flaxseed, chia seed, walnuts, hemp seed, and some leafy greens. Essential (the human body cannot synthesize it). The starting material for eicosapentaenoic acid and docosahexaenoic acid, but conversion efficiency is poor.
• Eicosapentaenoic acid (EPA, 20:5n-3) — the 20-carbon long-chain omega-3 found primarily in fatty fish (salmon, sardines, herring, mackerel, anchovies, tuna) and in krill and algae. The substrate for the E-series resolvins and for several anti-inflammatory eicosanoids.
• Docosahexaenoic acid (DHA, 22:6n-3) — the 22-carbon long-chain omega-3 found in the same fatty fish, krill, and certain marine algae. The dominant structural omega-3 in neuronal membranes, retinal rod and cone cells, and sperm.

The clinical distinction is fundamental: the cardiovascular, neurodevelopmental, anti-inflammatory, and triglyceride-lowering effects documented in randomized trials are produced by eicosapentaenoic acid and docosahexaenoic acid. Trials of alpha-linolenic acid alone (without concurrent eicosapentaenoic acid + docosahexaenoic acid) have not consistently reproduced these effects. The reason is the elongation-pathway inefficiency discussed in the next section.

This matters because vegan and vegetarian dietary advice often substitutes flax or chia for fish, with the implicit assumption that "omega-3 is omega-3." For most adults this is incorrect — flaxseed oil provides alpha-linolenic acid but very little of it is converted to the long-chain eicosapentaenoic acid and docosahexaenoic acid that the body actually needs. The vegan exception is algae-derived docosahexaenoic acid and eicosapentaenoic acid supplements, which deliver the long-chain forms directly without requiring fish.

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The Alpha-Linolenic Acid-to-EPA-to-DHA Elongation Pathway (and Why It's Inefficient)

The human body can in principle convert dietary alpha-linolenic acid to eicosapentaenoic acid and then to docosahexaenoic acid through a series of enzymatic desaturations and elongations:

Alpha-linolenic acid (18:3) → Stearidonic Acid (18:4) → Eicosatetraenoic Acid (20:4) → eicosapentaenoic acid (20:5) → DPA (22:5) → Tetracosapentaenoic (24:5) → Tetracosahexaenoic (24:6) → docosahexaenoic acid (22:6)

The pathway requires the enzymes delta-6 desaturase (FADS2), elongase, delta-5 desaturase (FADS1), and beta-oxidation. The same enzymes also process the parallel omega-6 pathway (linoleic acid → arachidonic acid), which creates competitive inhibition.

Conversion efficiency in healthy adults:

• Alpha-linolenic acid → eicosapentaenoic acid: approximately 5-10% in young men, 10-21% in young women (estrogen upregulates the conversion enzymes)
• Alpha-linolenic acid → docosahexaenoic acid: approximately 0.5-9% in young women, <1% in young men
• FADS1/FADS2 polymorphisms further reduce conversion by 20-50% in approximately 25-30% of European-ancestry populations and an even higher fraction of indigenous populations from regions historically dependent on marine fish

The clinical implication is that a tablespoon of flaxseed oil (containing roughly 7,000 mg alpha-linolenic acid) supplies only approximately 100-700 mg of eicosapentaenoic acid-equivalent and as little as 30-200 mg of docosahexaenoic acid-equivalent through the conversion pathway. By contrast, a 3.5 oz serving of wild sockeye salmon supplies approximately 600 mg eicosapentaenoic acid and 600 mg docosahexaenoic acid directly. The whole-fish source bypasses the rate-limiting conversion entirely.

This is a major reason that pre-formed eicosapentaenoic acid and docosahexaenoic acid (from fatty fish, fish oil, or algae oil) are functionally non-substitutable with alpha-linolenic acid from plant sources for individuals with cardiovascular risk, depression, attention-deficit/hyperactivity disorder (ADHD), or pregnancy demand on docosahexaenoic acid stores. Plant sources contribute, but they are inefficient relative to direct marine intake.

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Eicosapentaenoic Acid, Resolvins, and the Resolution of Inflammation

The traditional model of inflammation focused on initiation (tumor necrosis factor-alpha, interleukin-6 (IL-6), prostaglandins driving the inflammatory cascade) and resolution as a passive process — inflammation ended when the initiating signal stopped. Charles Serhan's laboratory at Harvard upended this model in the 2000s by identifying a class of endogenous lipid mediators, the specialized pro-resolving mediators (SPMs), that actively terminate inflammation by signaling neutrophil apoptosis, macrophage efferocytosis, and tissue regeneration.

The SPM families and their substrates:

• E-series resolvins (RvE1, RvE2, RvE3) — biosynthesized from eicosapentaenoic acid via cyclooxygenase and lipoxygenase pathways. RvE1 in particular has been the most studied, with effects on neutrophil transmigration, T-cell activation, and bacterial clearance
• D-series resolvins (RvD1 through RvD6) — biosynthesized from docosahexaenoic acid
• Protectins (PD1, neuroprotectin D1) — biosynthesized from docosahexaenoic acid, with strong activity in the central nervous system and retina
• Maresins (MaR1, MaR2) — biosynthesized from docosahexaenoic acid by macrophages, hence the name

The SPMs explain why omega-3 supplementation produces broad anti-inflammatory effects that the simple "eicosapentaenoic acid competes with arachidonic acid for COX/LOX enzymes" model could not fully account for. Eicosapentaenoic acid and docosahexaenoic acid are not just precursors that reduce omega-6-derived inflammation; they are precursors for an entire parallel resolution-of-inflammation signaling system.

The clinical implications are still being mapped. SPM analogs are in clinical trials for diseases of failed inflammation resolution (chronic periodontitis, dry eye disease, persistent post-surgical pain). For the average adult, the takeaway is that consistent dietary eicosapentaenoic acid and docosahexaenoic acid intake provides the substrate for ongoing endogenous SPM biosynthesis, a baseline anti-inflammatory tone that the omega-3-deficient Western diet lacks.

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Docosahexaenoic Acid in the Brain and Retina

Docosahexaenoic acid is the most abundant omega-3 fatty acid in the brain, comprising approximately 30% of total gray-matter phospholipid by mass. It is concentrated particularly in synaptic membranes (the highly dynamic membranes where neurotransmission occurs) and in retinal rod outer-segment discs (where it can comprise 50% or more of phospholipid acyl chains).

Why docosahexaenoic acid in these locations? The molecule's 22-carbon chain with 6 cis double bonds creates an unusually fluid, conformationally dynamic structure that supports:

• The conformational change of rhodopsin in retinal rods that initiates the visual transduction cascade
• The rapid endocytosis-exocytosis cycles of synaptic vesicles at presynaptic terminals
• The lateral mobility of membrane proteins required for receptor clustering and signal transduction
• The membrane curvature required for membrane fission and fusion events

Docosahexaenoic acid deficiency during the critical brain growth period (third trimester of pregnancy through the first 2 years of life) is associated with reduced infant visual acuity scores, reduced cognitive scores in preschool age, and increased behavioral problems. The DOMINO trial and several other randomized trials of maternal docosahexaenoic acid supplementation have shown modest but consistent improvements in infant neurodevelopmental outcomes, with the largest effects in mothers who started supplementation with the lowest baseline docosahexaenoic acid status.

For adults, the brain-DHA story extends to depression (lower docosahexaenoic acid levels in depressed populations), age-related cognitive decline (Framingham and other cohorts show fish consumption associated with reduced dementia incidence), and macular degeneration (docosahexaenoic acid is one of the substrates the AREDS2 formulation indirectly supports). For more on the structural role of docosahexaenoic acid in the eye, see our Vitamin A Vision page.

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Cardiovascular Trials: GISSI, JELIS, REDUCE-IT

The cardiovascular evidence for marine omega-3 intake has progressed through three generations of landmark trials.

GISSI-Prevenzione (1999, The Lancet): 11,324 post-myocardial-infarction Italian patients randomized to 1 g/day omega-3 (eicosapentaenoic acid + docosahexaenoic acid, approximately 850 mg combined) or placebo. After 3.5 years, the omega-3 group had a 20% reduction in all-cause mortality, 30% reduction in cardiovascular mortality, and 45% reduction in sudden cardiac death. The benefit was driven primarily by reduction in arrhythmic death, plausibly through the stabilizing effect of eicosapentaenoic acid and docosahexaenoic acid on cardiomyocyte ion channels.

JELIS (2007, The Lancet): 18,645 Japanese hypercholesterolemic patients on statin therapy were randomized to add 1.8 g/day eicosapentaenoic acid (no docosahexaenoic acid) or placebo. The eicosapentaenoic acid arm had a 19% reduction in major coronary events. The trial was important because it was conducted in a Japanese population with already-high dietary fish intake at baseline, and yet additional eicosapentaenoic acid still produced benefit.

REDUCE-IT (2019, NEJM): 8,179 statin-treated patients with elevated triglycerides and either established cardiovascular disease or diabetes plus risk factors were randomized to 4 g/day icosapent ethyl (a purified eicosapentaenoic acid ethyl ester, brand name Vascepa) or mineral-oil placebo. The eicosapentaenoic acid arm had a 25% reduction in major adverse cardiovascular events, leading to U.S. Food and Drug Administration (FDA) approval of icosapent ethyl as adjunct therapy for elevated triglycerides with statin treatment.

Notably, the parallel trial of similar design using a mixed eicosapentaenoic acid/docosahexaenoic acid preparation (STRENGTH trial, 2020) did NOT show benefit. This has driven ongoing scientific debate about whether the cardiovascular benefit is specifically attributable to eicosapentaenoic acid or to a particular eicosapentaenoic acid:docosahexaenoic acid ratio. The clinical consensus remains that whole-food intake of fatty fish providing both eicosapentaenoic acid and docosahexaenoic acid is the recommended population intervention, while purified eicosapentaenoic acid at high dose has the strongest randomized-trial evidence for high-risk secondary prevention.

For the underlying cardiovascular biology, see our Cardiology page.

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Triglyceride Reduction and Lipid Profile

Marine omega-3 intake at therapeutic doses produces a consistent, dose-dependent reduction in serum triglycerides. The mechanism involves:

• Reduced hepatic very-low-density lipoprotein (VLDL) triglyceride synthesis (eicosapentaenoic acid and docosahexaenoic acid inhibit diacylglycerol acyltransferase, DGAT)
• Increased plasma triglyceride clearance via upregulated lipoprotein lipase activity
• Beta-oxidation upregulation through PPAR-alpha agonism

At pharmacologic doses (3-4 g/day combined eicosapentaenoic acid + docosahexaenoic acid), serum triglycerides typically fall by 20-50% from baseline, an effect that scales with baseline triglyceride level. This is meaningful for patients with hypertriglyceridemia (TG >500 mg/dL), where omega-3 prescription products (Lovaza, Vascepa, Omtryg) are U.S. Food and Drug Administration-approved for triglyceride reduction.

The effect on low-density lipoprotein (LDL) cholesterol is variable and less pronounced. Eicosapentaenoic acid-only preparations (icosapent ethyl) tend to be low-density lipoprotein-neutral. Mixed eicosapentaenoic acid + docosahexaenoic acid preparations sometimes produce a small low-density lipoprotein increase, particularly in patients with severely elevated baseline TG. HDL typically rises modestly (3-5%).

The whole-food salmon translation: 2-3 servings per week supplies approximately 3-4 g/week of combined eicosapentaenoic acid + docosahexaenoic acid, which is enough to produce meaningful improvements in inflammatory markers and modest improvements in triglycerides for moderately elevated baseline values. For patients with TG >500 mg/dL requiring substantial reduction, prescription omega-3 at 4 g/day is generally needed in addition to dietary fish.

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Dosing: American Heart Association Recommendation and Therapeutic Doses

The American Heart Association recommends:

• General adult population without cardiovascular disease: at least 2 servings (3.5 oz each) of oily fish per week, providing approximately 500 mg/day average eicosapentaenoic acid + docosahexaenoic acid
• Patients with documented coronary heart disease: approximately 1 g/day eicosapentaenoic acid + docosahexaenoic acid from a combination of oily fish and/or supplements, in consultation with their physician
• Patients with very high triglycerides (>500 mg/dL): 2-4 g/day eicosapentaenoic acid + docosahexaenoic acid under physician supervision, typically using a prescription preparation for purity and dose precision

European Food Safety Authority recommendations are slightly higher (250-500 mg/day eicosapentaenoic acid + docosahexaenoic acid for general adult intake), and several other professional societies recommend similar ranges.

Practical translation to salmon servings:

• One 3.5 oz serving of wild sockeye provides approximately 1,200 mg eicosapentaenoic acid + docosahexaenoic acid
• One 3.5 oz serving of wild king (chinook) provides approximately 1,700 mg eicosapentaenoic acid + docosahexaenoic acid (highest of Pacific species)
• One 3.5 oz serving of farmed Atlantic provides approximately 2,400 mg eicosapentaenoic acid + docosahexaenoic acid (highest absolute amount, but with the omega-6 ratio caveat discussed in Wild vs Farmed)
• 2-3 servings per week of any of the above easily exceeds the American Heart Association (AHA) general-population recommendation

For non-fish-eaters, the equivalent dose can be obtained from approximately 1-2 standard fish oil capsules (typically 300-500 mg combined eicosapentaenoic acid + docosahexaenoic acid each) or 1-2 algae oil capsules per day.

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Pregnancy, Lactation, and Infant Neurodevelopment

The third trimester of pregnancy is the period of fastest fetal brain growth, and docosahexaenoic acid accumulation in the fetal brain accelerates dramatically during this window. The fetal supply depends entirely on maternal docosahexaenoic acid status and transplacental transfer. After birth, infant docosahexaenoic acid continues to come from breast milk (or formula docosahexaenoic acid fortification) for the entire first year, supporting continued brain development.

The clinical evidence:

• Visual acuity — multiple randomized trials of maternal docosahexaenoic acid supplementation (200-600 mg/day) have shown modest improvements in infant visual acuity at 4 and 6 months
• Cognitive scores — the DOMInO trial and other maternal supplementation trials have shown improved cognitive scores in offspring at 18 months and beyond, with effects most pronounced in mothers with lowest baseline docosahexaenoic acid
• Preterm birth — meta-analyses suggest maternal omega-3 supplementation may reduce risk of early preterm birth (<34 weeks) by approximately 40%
• Postpartum depression — mixed evidence; some trials show benefit of docosahexaenoic acid continuation through postpartum period

Practical recommendations for pregnancy: 2-3 servings per week of low-mercury fatty fish (salmon is a top choice along with sardines, herring, and anchovies). Pregnant women should avoid the high-mercury apex predators (king mackerel, marlin, swordfish, shark, bigeye tuna, tilefish from the Gulf of Mexico). Salmon is on the U.S. Food and Drug Administration-EPA "Best Choices" list for pregnancy.

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Mental Health Applications (Depression, Attention-Deficit/Hyperactivity Disorder)

Lower serum and red-cell membrane eicosapentaenoic acid and docosahexaenoic acid levels have been observed in populations with major depressive disorder, postpartum depression, bipolar disorder, attention-deficit/hyperactivity disorder, and schizophrenia across multiple cross-sectional and case-control studies. The mechanism is plausible (docosahexaenoic acid in synaptic membranes affects neurotransmission; resolvins affect neuroinflammation now recognized as a depression contributor), but the randomized-trial evidence for therapeutic supplementation is mixed.

• Major depression — meta-analyses suggest modest benefit of eicosapentaenoic acid-predominant supplementation (typically >60% eicosapentaenoic acid of eicosapentaenoic acid+docosahexaenoic acid) at doses of 1-2 g eicosapentaenoic acid/day for 8-12 weeks. Effect size is smaller than first-line selective serotonin reuptake inhibitor (SSRI) antidepressants but real, and omega-3 has a much better safety profile
• Attention-deficit/hyperactivity disorder in children — meta-analyses suggest modest improvement in attention and behavioral measures with omega-3 supplementation, with effect size smaller than stimulant medication but useful as adjunct or for families preferring non-pharmacologic approaches
• Bipolar depression — suggestive evidence but not yet definitive
• Postpartum depression — mixed evidence, some support for eicosapentaenoic acid-predominant supplementation

For mental health applications, the dose tends to be higher than the general cardiovascular dose — typically 2-4 g/day of combined eicosapentaenoic acid + docosahexaenoic acid with eicosapentaenoic acid predominance, taken for at least 8-12 weeks. Whole-food salmon contributes meaningfully but most mental-health trial protocols use supplementation in addition to dietary intake.

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Fish Oil Capsules vs Whole Fish

For a given delivered dose of eicosapentaenoic acid and docosahexaenoic acid, are fish oil capsules equivalent to whole salmon? Several considerations matter:

• Lipid carrier matrix — whole fish delivers eicosapentaenoic acid and docosahexaenoic acid in their natural triglyceride or phospholipid form, embedded in the fish's own muscle and oil matrix. Most cheap fish oil capsules use ethyl ester form, which has somewhat lower bioavailability than the natural triglyceride form. Higher-quality re-esterified triglyceride (rTG) preparations restore the natural form
• Oxidation — fish oil is exquisitely sensitive to oxidation. Many commercial fish oil products have significant oxidation by the time they reach the consumer, with measurable rancidity even in unopened bottles. Whole fish is far less susceptible (the antioxidants in the fish flesh, including astaxanthin, protect the omega-3s)
• Co-nutrients — salmon delivers Vitamin D, complete protein, B12, selenium, iodine, and astaxanthin in addition to eicosapentaenoic acid and docosahexaenoic acid. Fish oil capsules deliver only the fatty acids (plus often small amounts of D and A in cod-liver-oil preparations)
• Burden and burp — some patients find fish oil capsules unpleasant (fishy taste, fishy burps). Whole fish meals do not produce this
• Cost — fish oil is generally cheaper per gram of eicosapentaenoic acid + docosahexaenoic acid than wild salmon at retail. Both are competitive with farmed salmon

The pragmatic recommendation: whole-food salmon (and other oily fish) for 2-3 meals per week is the gold standard. Fish oil supplementation is useful for individuals who cannot or do not eat fish, for therapeutic doses beyond what can be obtained from fish alone (e.g. 3-4 g/day for major depression or REDUCE-IT-style secondary prevention), and as a convenient option for travel and other dietary disruptions.

For pure vegan / vegetarian alternatives, algae-derived docosahexaenoic acid (and increasingly eicosapentaenoic acid) supplements are now widely available and provide the same long-chain omega-3s that fish would otherwise supply.

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Cautions and Drug Interactions

• Bleeding risk — omega-3s at high doses (>3 g/day) have antiplatelet effects and theoretically increase bleeding risk. The clinical evidence for this is weaker than commonly assumed; trials of perioperative omega-3 have not shown clinically meaningful bleeding increases. Most surgeons no longer require omega-3 discontinuation before elective surgery, though high-dose users should disclose intake
• Atrial fibrillation signal — the STRENGTH and REDUCE-IT trials both showed a small increase in new-onset atrial fibrillation in the high-dose omega-3 arms (~1.5% absolute increase). The mechanism is unclear; the benefit-risk balance still favors omega-3 in the cardiovascular populations studied, but patients with paroxysmal atrial fibrillation (AF) history should discuss with their cardiologist
• Mercury — salmon itself is low mercury, but high-dose fish oil from unspecified sources can vary; choose IFOS or similar third-party tested products
• Anticoagulants — theoretical additive antiplatelet effect with warfarin, dabigatran, apixaban, clopidogrel. Clinical evidence is reassuring but disclosure to prescribing physician is appropriate
• Fish allergy — salmon allergy is genuine; algae-derived alternatives are appropriate for fish-allergic individuals who still need eicosapentaenoic acid and docosahexaenoic acid
• Vitamin A toxicity from cod liver oil — cod liver oil is a traditional fish oil source that also contains significant Vitamin A. High-dose cod liver oil intake can produce Vitamin A toxicity, particularly in pregnancy. Modern refined fish oils do not have this issue, but traditional cod liver oil must be dosed conservatively

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Key Research Papers

1. GISSI-Prevenzione Investigators (1999). Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. The Lancet. — PubMed
2. Yokoyama M et al. (2007). Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS). The Lancet. — PubMed PMID: 17398308
3. Bhatt DL et al. (2019). Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia (REDUCE-IT). NEJM. — PubMed PMID: 30415628
4. Serhan CN, Chiang N, Van Dyke TE (2008). Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nature Reviews Immunology. — PubMed
5. Burdge GC, Calder PC (2005). Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults. Reproduction Nutrition Development. — PubMed PMID: 16188209
6. Calder PC (2017). Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochemical Society Transactions. — PubMed PMID: 28900017
7. SanGiovanni JP, Chew EY (2005). The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Progress in Retinal and Eye Research. — PubMed PMID: 15555528
8. Makrides M et al. (2010). Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children (DOMInO trial). JAMA. — PubMed PMID: 20959577
9. Mozaffarian D, Wu JH (2011). Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. JACC. — PubMed PMID: 22051327
10. Mocking RJ et al. (2016). Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Translational Psychiatry. — PubMed
11. Bloch MH, Qawasmi A (2011). Omega-3 fatty acid supplementation for the treatment of children with attention-deficit/hyperactivity disorder symptomatology. JAACAP. — PubMed
12. Nicholls SJ et al. (2020). Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk (STRENGTH). JAMA. — PubMed PMID: 33190147

PubMed Topic Searches

1. PubMed: EPA / DHA and cardiovascular mortality
2. PubMed: Resolvins and protectins
3. PubMed: DHA and brain development
4. PubMed: ALA / EPA / DHA conversion
5. PubMed: Omega-3 triglyceride reduction

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Connections

• All Food
• Omega-3 and Fish Oil for Rheumatoid Arthritis — eicosapentaenoic acid and docosahexaenoic acid at therapeutic doses
• Salmon Overview
• Salmon Benefits Hub
• Salmon Astaxanthin & Skin
• Salmon Vitamin D Content
• Wild vs Farmed Salmon
• Omega-3 Fatty Acids
• Sardines
• Herring
• Cod
• Tuna
• Cardiology
• Neurology
• Depression
• Vitamin D3
• Vitamin E
• History
• Nutrients

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