Omega-3 Fatty Acids

Omega-3 fatty acids are a family of polyunsaturated fatty acids (PUFAs) defined by a carbon-carbon double bond beginning at the third carbon from the methyl (omega) end of the chain. The nutritionally relevant omega-3s are alpha-linolenic acid (ALA, 18:3n-3), eicosapentaenoic acid (EPA, 20:5n-3), and docosahexaenoic acid (DHA, 22:6n-3).

Essentiality

Humans lack the delta-15 desaturase enzyme that can introduce a double bond at the omega-3 position of a fatty acid; ALA must therefore be obtained from the diet. Once ingested, ALA can be elongated and desaturated to EPA and DHA via delta-6 desaturase, elongase-5, delta-5 desaturase, and peroxisomal beta-oxidation steps — but this conversion is inefficient in humans: only approximately 5-10% of ALA is converted to EPA and less than 0.5% to DHA. For this reason, direct dietary EPA and DHA (from fatty fish, algae, or supplements) are often considered functionally important beyond ALA intake alone.

Intake recommendations

The 2005 NAM DRI report sets Adequate Intake for ALA at 1.1 g/day for adult women and 1.6 g/day for adult men. No DRI exists for EPA or DHA individually. The American Heart Association recommends approximately 250-500 mg combined EPA+DHA per day from two servings of fatty fish per week for cardiovascular health. Pregnancy and lactation guidelines typically specify at least 200 mg DHA daily for neurodevelopmental support.

Mechanisms

EPA and DHA exert effects through multiple pathways: (1) incorporation into membrane phospholipids, altering fluidity and receptor function; (2) substrate for resolvins, protectins, and maresins — specialized pro-resolving mediators that actively terminate inflammation (identified by Serhan and colleagues); (3) ligands for GPR120 and PPAR-alpha, influencing gene expression; (4) competitive substrate for COX and LOX enzymes, shifting eicosanoid production away from pro-inflammatory 2-series prostaglandins toward 3-series prostaglandins.

Cardiovascular outcomes

The evidence base for omega-3 cardiovascular effects is nuanced. Older epidemiological work (Dyerberg, Bang in Greenland Inuit) suggested strong cardioprotective effects. Recent large randomized trials have produced mixed results: VITAL (2019) found no significant effect of 840 mg EPA+DHA/day on composite CVD events; REDUCE-IT (2019) found a 25% relative risk reduction in high-triglyceride statin-treated patients taking 4 g/day prescription icosapent ethyl (pure EPA); STRENGTH (2020) found no benefit from a 4 g/day EPA+DHA carboxylic acid formulation. The pattern suggests high-dose pure EPA in specific populations may have greater benefit than mixed-formulation supplementation in general populations.

Dietary sources

ALA sources (USDA FoodData Central): flaxseed oil (53% ALA by weight), chia seeds (18%), walnuts (9%), hemp seeds (8%), canola oil (9%). EPA and DHA sources: salmon (1.0-1.8 g combined per 100 g), sardines (1.5-2.0 g), mackerel (1.8-2.5 g), anchovies (1.4 g), herring (1.7 g). Algal oil is a plant-source option for direct DHA and increasingly EPA.

Safety and upper limits

The FDA GRAS determination permits EPA+DHA intakes up to approximately 3 g/day from supplements without significant bleeding risk in most adults; prescription-level 4 g/day formulations have been studied with acceptable safety profiles in the cardiovascular trials. Patients on anticoagulation should consult their clinician.