Omega-3 Fatty Acids: EPA, DHA, And The Inflammation-Resolving Story

Omega-3 fatty acids are among the most studied supplements for cardiovascular, brain, and inflammatory health, but the headlines often oversimplify the evidence.

In this post, we will discuss the difference between EPA, DHA, and ALA, how omega-3s resolve inflammation, what the major trials actually showed, and how to choose a supplement that is not already oxidized.

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What Are Omega-3 Fatty Acids

Omega-3 fatty acids are polyunsaturated fats that play structural and signaling roles in cell membranes, the brain, and the cardiovascular system. R

The three main types are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). R

ALA is found in plants, while EPA and DHA are found primarily in fatty fish and algae. R

EPA Vs DHA Vs ALA

ALA

ALA is an essential omega-3 found in flax, chia, walnuts, and hemp. R

Humans must convert ALA into EPA and DHA to use it for most physiological functions. R

This conversion is inefficient: less than 15% to EPA and less than 5% to DHA. R

Relying on ALA alone usually does not raise tissue DHA levels significantly. R

EPA

EPA is a long-chain omega-3 with strong anti-inflammatory and mood-supporting properties. R

It is the precursor to E-series resolvins and is often emphasized for depression, cardiovascular risk, and inflammatory conditions. R

DHA

DHA is a major structural component of the brain, retina, and cell membranes. R

It is critical for fetal brain development, cognitive function, and visual health. R

DHA is also the precursor to D-series resolvins, protectins, and maresins. R

Resolvins, Protectins, And Maresins

Omega-3s are not just anti-inflammatory; they actively resolve inflammation through specialized pro-resolving mediators (SPMs). R

Resolvins. Derived from EPA (E-series) and DHA (D-series), these signal the immune system to stop the inflammatory response. R Protectins. Derived from DHA, these protect neural tissue and support resolution. R Maresins. Also derived from DHA, these are produced by macrophages and promote tissue repair. R

This resolution function is what distinguishes omega-3s from simple NSAID-style anti-inflammatories. R

Cardiovascular Evidence

The cardiovascular evidence for omega-3s is more nuanced than headlines suggest. R

REDUCE-IT

The REDUCE-IT trial showed that high-dose icosapent ethyl, a purified EPA formulation at 4 g per day, reduced major adverse cardiovascular events in patients with elevated triglycerides on statin therapy. R

However, the placebo was mineral oil, which may have had biological activity and could have inflated the apparent benefit. R

STRENGTH

The STRENGTH trial used a mixed EPA/DHA formulation and did not show the same cardiovascular benefit. R

This suggests the benefit may be specific to high-dose EPA or to the population studied. R

Overall

Omega-3s likely reduce triglycerides and may lower cardiovascular risk in specific populations, but they are not a universal heart-health panacea. R

Mental Health And Pregnancy

Depression

Meta-analyses show a small-to-moderate benefit of omega-3 supplementation for depression. R

EPA-dominant formulations appear more effective than DHA-dominant ones. R

ADHD

Evidence for ADHD is mixed, with some studies showing benefit and recent meta-analyses showing inconsistent effects on core symptoms. R

Pregnancy

EPA and DHA are critical for fetal brain and retinal development. R

Supplementation is associated with slightly longer gestation and higher birth weight. R

Forms, Dosing, And Oxidation

Forms

Triglyceride (TG) or re-esterified triglyceride (rTG). The natural form found in fish. Generally better absorbed and more stable. R Ethyl ester (EE). A processed form used to concentrate EPA/DHA. More prone to oxidation and requires dietary fat for optimal absorption. R Phospholipid. Found in krill oil. May cross cell membranes more easily, though evidence is mixed. R

Dosing

Typical supplemental doses range from 1-3 g per day of combined EPA and DHA. R

Higher doses, such as the 4 g per day used in REDUCE-IT, are prescription-level and should be medically supervised. R

Oxidation

Omega-3s are highly polyunsaturated and prone to oxidation. R

Signs of rancidity include a strong fishy smell or taste. R

Store supplements in a cool, dark place, ideally refrigerated, and use them within the recommended timeframe. R

Mechanisms Of Action

Simple:

EPA and DHA are incorporated into cell membranes and influence membrane fluidity and signaling. They are converted into specialized pro-resolving mediators that actively resolve inflammation. They reduce triglyceride production in the liver.

Advanced:

SPM biosynthesis. EPA and DHA are released from membrane phospholipids by phospholipase A2 and converted by lipoxygenases and cyclooxygenases into resolvins, protectins, and maresins. R Membrane incorporation. DHA is highly concentrated in neuronal membranes and synaptic vesicles, where it supports neurotransmission and neuroplasticity. R Triglyceride lowering. EPA and DHA reduce hepatic VLDL production and increase lipoprotein lipase activity, lowering circulating triglycerides. R Gene expression. Omega-3s modulate transcription factors including PPARs and SREBP-1c, influencing lipid metabolism and inflammation. R

Genetics

FADS1 / FADS2

FADS1 and FADS2 encode desaturase enzymes that convert ALA to EPA and DHA. R

Genetic variants can reduce conversion efficiency, making direct EPA/DHA intake more important for some people. R

APOE

APOE variants may influence how omega-3s affect cognitive and cardiovascular outcomes. R

Some evidence suggests APOE4 carriers may respond differently to DHA supplementation. R

More Research

Inflammatory conditions. Omega-3s have been studied in rheumatoid arthritis, inflammatory bowel disease, and psoriasis, with some positive signals in RA. R Cognitive aging. DHA supplementation has been explored for cognitive decline and Alzheimer's disease, with mixed results. R Exercise recovery. Omega-3s may reduce muscle soreness and support recovery after intense exercise. R

• Testing. For biomarker testing I use the Comprehensive Metabolic Panel and Inflammation Panel to assess lipid status and inflammatory markers.