IngredientsThe two major classes of polyunsaturated fatty acids (PUFAs) are the omega-3 and omega-6 fatty acids. Like all fatty acids, PUFAs consist of long chains of carbon atoms with a carboxyl group at one end of the chain and a methyl group at the other. PUFAs are distinguished from saturated and monounsaturated fatty acids by the presence of two or more double bonds between carbons within the fatty acid chain.
The position of the carbon-carbon double bonds in carboxylic acid chains in fats is designated by Greek letters. The carbon atom closest to the carboxyl group is the alpha carbon, the next carbon is the beta carbon, and so on. In fatty acids, the carbon atom of the methyl group at the end of the hydrocarbon chain is called the omega carbon because omega is the last letter of the Greek alphabet. Omega-3 fatty acids have a double bond three carbons away from the methyl carbon, whereas omega-6 fatty acids have a double bond six carbons away from the methyl carbon.
Polyunsaturated fats are easily oxidized, meaning they are prone to react chemically with oxygen. This reaction typically breaks the fatty acid apart and produces oxidants (free radicals).
Ξ±-Linolenic acid (ALA, 18:3 omega-3), eicosapentaenoic acid (EPA, 20:5 omega-3), and docosahexaenoic acid (DHA, 22:6 omega-3) are all omega-3 fatty acids, whilst linoleic acid (LA, 18:2 omega-6) and arachidonic acid (AA, 20:4 omega-6) belong to the omega-6 fatty acids.
Several different omega-3s exist, but the majority of scientific research focuses on three: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA contains 18 carbon atoms, whereas EPA and DHA are considered long-chain (LC) omega-3s because EPA contains 20 carbons and DHA contains 22.
Although all the essential fatty acids (EFAs) can be found in human food sources, only linoleic and alpha-linolenic acid are considered truly essential, since the body contains enzymes with which it can synthesize all the other EFAs from these two fatty acids.
Through elongation stages, ALA is metabolized to EPA and DHA by two specific enzymes, Ξ6 desaturase and Ξ5 desaturase, whilst LA is metabolized to AA. EPA and ALA both compete for the same enzyme system; therefore, high background n-6 PUFA intake reduces interconversion of n-3 PUFAs.
EPA and DHA are found in seafood, especially cold-water fish such as salmon, mackerel, and tuna, as well as shellfish and fish oil supplements. A different type of omega-3, ALA (alpha-linolenic acid), is found in certain plant oils, such as flaxseed, soybean, and canola oils, and in some other plant foods, such as chia seeds and walnuts.
Oils containing these fatty acids originate in plant sources and can be found in fish, fish products, seeds, nuts, green leafy vegetables, and beans.
PUFAs are mainly produced by marine phytoplankton and contained in fish and seafood. The original biosynthetic source of marine EPA and DHA is thus microalgal, with fish accumulating these fatty acids through the food chain.
Long-chain omega-3s are present in several dietary supplement formulations, including fish oil, krill oil, cod liver oil, and vegetarian products that contain algal oil.
Omega-3s as re-esterified triglycerides, natural triglycerides, and free fatty acids have somewhat higher bioavailability than ethyl esters, but consumption of all forms significantly increases circulating omega-3 levels. Krill oil contains omega-3s primarily as phospholipids, and limited research suggests that these have somewhat higher bioavailability than the omega-3s in fish oil.
Plant-based sources of omega-3s from algal oil usually provide around 100β300 mg DHA; some contain EPA as well. These supplements typically contain omega-3s in the triglyceride form. According to a small study, the bioavailability of DHA from algal oil is equivalent to that from cooked salmon.
The FDA has approved two prescription omega-3 fatty acid products: icosapent ethyl and omega-3-acid ethyl esters.
Fats and lipids have always had a primary role in the history of humankind, from ancient civilisations to the modern and contemporary time, going from domestic and cosmetic uses, to the first medical applications and later to the large-scale industrial uses for food, pharmaceutical, cosmetics, and biofuel production.
Plants, fish, and animal fats have represented the primary source of lipids and fats for centuries. These bioactive compounds are not randomly distributed but are present in foods humans have consumed together historically. From traditional diets like the Mediterranean, which pairs olive oil (PUFAs and polyphenols) with vegetables and legumes, to Asian cuisines combining sesame seeds with turmeric, cultural practices have long harnessed this natural synergy.
Dietary fat was recognized as a good source of energy and fat-soluble vitamins by the first part of the 20th century, but fatty acids were not considered essential nutrients because they could be synthesized from dietary carbohydrate. This well-established view was challenged in 1929 by George and Mildred Burr, who reported that dietary fatty acid was required to prevent a deficiency disease that occurred in rats fed a fat-free diet. They concluded that fatty acids were essential nutrients and showed that linoleic acid prevented the disease and is an essential fatty acid. The Burrs subsequently demonstrated that linolenic acid, the omega-3 fatty acid analog of linoleic acid, is also an essential fatty acid.
The Burrs coined the phrase "essential fatty acids." Their 1929 paper on the topic led to the discovery of omega-6 fatty acids that prevent scaly skin and are required for proper skin barrier function. The concept of a "vitamin F" required for the skin was key to establishing dietary requirements for omega-6 in humans by the 1960s. Yet back then, so clear were the manifestations of omega-6 deficiency, and so subtle the symptoms of omega-3 deficiency, that few in medicine recognized the scientific hallmarks of omega-3 as a required nutrient.
The breakthrough came in the 1970s when Dyerberg and Bang reported that the low incidence of atherosclerotic coronary disease in Greenland Eskimos was due to the high marine lipid content of their diet. They subsequently found that EPA, which was increased in Eskimo plasma, inhibited platelet aggregation, and they concluded that the low incidence of coronary artery disease was due to the anti-thrombotic effect of EPA.
This interest was spurred by epidemiological research dating back to the 1970s that found low rates of myocardial infarction and other coronary events among Greenland Inuit and other fish-eating populations, such as those in Japan.
Awareness of the health benefits of essential fatty acids dramatically increased since the 1980s. A year after the Burrs' original finding, researchers showed that the polyunsaturated fatty acids linoleic acid and later Ξ±-linolenic acid could alleviate the symptoms produced by a fat-free diet. Although controversial at the time, there were thus two distinct types of PUFAs which were both essentialβthe n-3 (omega-3) and the n-6 (omega-6) families.
Beyond providing a substantial supply of energy to the body (a role that saturated fats can also perform), these unsaturated fatty acids β and especially the essential ones β are involved in cell membrane structure, blood pressure regulation, and coagulation; participate in the proper functioning of the immune system and assimilation of fat-soluble vitamins; influence the synthesis of pro- and anti-inflammatory substances; and protect the cardiovascular system.
Researchers have shown a growing interest in unsaturated essential fatty acids as they form the framework for the organism's cell membranes, particularly the neurones in the brain, are involved in the energy-transformation process, and regulate the information flows between cells. Polyunsaturated fatty acids are also precursors of "hormonal" molecules β often with opposing effects β including prostaglandins, prostacyclins, thromboxanes, leukotrienes, lipoxins, resolvins, and protectins that regulate immunity, platelet aggregation, and inflammation.
PUFAs exhibit a range of biological effects, many of which are mediated through the formation and actions of bioactive metabolites such as prostaglandins (PGs), leukotrienes (LTs), lipoxins (LXs), resolvins (Rvs), and protectins. The lipid mediators are potent endogenous regulators of inflammation and related diseases.
These fatty acids are metabolized by COX, LOX, and cytochrome P450 enzymes (CYP450) into various classes of lipid mediators. COX metabolizes the omega-6 arachidonic acid (AA) into pro-inflammatory eicosanoids such as prostaglandins and thromboxanes.
Omega-3 PUFAs are widely held to act via several possible mechanisms, such as preventing conversion of arachidonic acid (AA) into pro-inflammatory eicosanoids such as leukotrienes and prostaglandins via substrate competition, or serving as an alternative substrate to produce less potent products. In addition, EPA and DHA are converted to bioactive metabolites such as resolvins and protectins with anti-inflammatory and pro-resolving properties.
Specialized pro-resolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins, actively terminate inflammation and restore tissue homeostasis.
Several families of structurally and functionally distinct SPMs have been identified, including the E-series resolvins (RvE) derived from EPA via P450 metabolism or aspirin-acetylated cyclooxygenase (COX-2), and the D-series resolvins, protectins, and maresins derived from DHA via lipoxygenase (LOX) or aspirin-acetylated COX-2.
Fatty acids influence inflammation through a variety of mechanisms; many of these are mediated by, or at least associated with, changes in fatty acid composition of cell membranes. The fatty acid composition of cells involved in the inflammatory response influences their function; the contents of arachidonic acid, EPA, and DHA appear to be especially important.
Changes in fatty acid composition can modify lipid raft formation, cell signaling leading to altered gene expression, and the pattern of lipid and peptide mediator production.
Time course studies suggest that the net incorporation of EPA and DHA into human inflammatory cells begins within days and reaches its peak within a few weeks, while studies that have used multiple doses of fish oil show that the incorporation of EPA and DHA (and the parallel decline in arachidonic acid) occurs in a doseβresponse manner.
Their therapeutic and health-promoting effects have already been established in various chronic inflammatory and autoimmune diseases through various mechanisms, including modifications in cell membrane lipid composition, gene expression, cellular metabolism, and signal transduction.
In addition to other nutraceuticals, the dietary Ο-3 polyunsaturated fatty acids (PUFAs) can act on adipose tissue inflammation, in contrast to omega-6 (Ο-6) PUFAs, which exhibit pro-inflammatory properties.
Both Ο-3 and Ο-6 PUFAs contribute to the production of lipid mediators such as endocannabinoids, which are notably involved in control of food intake, energy sensing, and food-related disorders; reproduction; inflammation; the stress response; and cancer, among other things.
Results from observational studies have been consistent, with several systematic reviews and meta-analyses showing that higher consumption of fish and higher dietary or plasma levels of omega-3s are associated with a lower risk of heart failure, coronary disease, and fatal coronary heart disease.
Clinical trial data from the 1989 Diet and Reinfarction Trial, the 1999 open-label GISSI-Prevenzione trial, and others supported the hypothesis that long-chain omega-3s offer protection from CVD by reducing the heart's susceptibility to arrhythmias, lowering triglyceride levels, lowering blood pressure, and decreasing platelet aggregation.
In the Nurses' and Health Professional Follow-Up Studies combined, high saturated and trans fat intake is associated with an 8β13% higher mortality, and replacement of saturated fat with PUFA is associated with lower mortality, with PUFA being more effective than MUFA (19% reduction versus 11%). With CVD mortality only, PUFA and fish oil replacement of saturated fat lowers risk, with a 28% reduction in CVD mortality per 5% of energy.
Epidemiological studies have shown a beneficial association between polyunsaturated fatty acid (PUFA) intake β specifically linoleic acid (C18:2, n-6) β and cardiovascular disease morbidity and mortality. Clinical studies have shown that n-6 PUFAs have the most potent cholesterol-lowering effects of the individual fatty acid classes. However, some studies suggest that high intakes of linoleic acid may have adverse effects on pro-inflammatory cytokines and adhesion molecules.
From mechanistic aspects, n-3 PUFA confers protection against a wide range of CVD states, including modulating cell membrane function, regulating cardiac rhythm, improving endothelial function, as well as inhibiting inflammatory, oxidative, and thrombotic pathways implicated in atherosclerosis. N-3 PUFA also favors modulating triglyceride-rich lipoprotein metabolism. However, from clinical aspects, there still exists a great deal of controversy on the protective role of n-3 PUFA.
The potential health benefits of Ο-3 PUFA stimulated considerable research interest, resulting in over 500 clinical trials. Over 250 clinical studies have examined the impact of Ο-3 PUFA on cardiovascular disease (CVD) or risk factors linked to CVD, such as metabolic syndrome, diabetes, obesity, inflammation, dyslipidemia, and hypertension.
Overall, the strength of evidence for PUFA supplementation in cardiovascular prevention is moderate to strong for triglyceride lowering and moderate but inconsistent for hard clinical outcomes such as myocardial infarction and all-cause mortality. The most extensive systematic review of RCTs conducted to date to assess effects of increasing PUFA on cardiovascular disease, mortality, lipids, or adiposity concluded that increasing PUFA intake probably slightly reduces risk of coronary heart disease.
A 2020 review of 23 studies (43,998 participants) showed that EPA and DHA reduce triglycerides by about 15 percent but do not affect body fat or other lipids. Several products containing omega-3s have been approved as prescription drugs to be used in combination with diet to reduce triglyceride levels.
According to the US Food and Drug Administration's Dietary Guidelines, 20β35 percent of the daily calories should come from dietary fats. A valid health claim for EPA- and DHA-containing conventional foods and dietary supplements was recognized by the FDA in 2004. According to this health claim, "consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease"; however, the evidence is supportive rather than convincing.
The evidence for triglyceride lowering is among the most robust in the PUFA literature and is reflected in FDA approval of prescription-grade omega-3 preparations for hypertriglyceridemia.
Several clinical trials have reported that Ο-3 PUFA were able to prevent sudden cardiac death (SCD), prevent ventricular arrhythmia in patients with implantable cardioverters, lower occurrences of premature ventricular contractions, reduce heart rate, and prevent atrial fibrillation.
N-3 PUFA have been shown to attenuate structural atrial remodeling, prolong atrial effective refractory period through the prevention of reentry, and suppress ectopic firing from pulmonary veins. Dietary fish intake has been found to have no effect on the incidence of AF in the majority of studies. Circulating DHA has been consistently reported to be inversely associated with AF risk, whereas EPA has no such effect.
Although n-3 PUFA have antiarrhythmogenic properties, their clinical efficacy in the prevention of AF is not consistently supported. Further well-designed studies are needed to overcome the limitations of the existing studies and provide robust conclusions.
Omega-3 polyunsaturated fatty acids might have antiarrhythmic properties, but data conflict on whether n3-PUFAs reduce rates of atrial fibrillation (AF) after coronary artery bypass graft surgery (CABG). One randomized, double-blind, placebo-controlled, multicenter trial tested this hypothesis, randomizing patients undergoing CABG to pharmaceutical-grade n3-PUFAs 2 g orally twice daily (minimum of 6 g) or a matched placebo β₯24 hours before surgery.
Evidence strength: Mixed. While mechanistic plausibility exists, the clinical trial record for AF prevention specifically is inconsistent.
The most convincing evidence for beneficial effects of omega-3 PUFA is to be found in mood disorders. A meta-analysis of trials involving patients with major depressive disorder and bipolar disorder provided evidence that omega-3 PUFA supplementation reduces symptoms of depression. Furthermore, meta-regression analysis suggests that supplementation with eicosapentaenoic acid may be more beneficial in mood disorders than with docosahexaenoic acid.
Meta-analysis of 11 and 8 trials conducted respectively on patients with a DSM-defined diagnosis of major depressive disorder (MDD) and patients with depressive symptomatology but no diagnosis of MDD demonstrated significant clinical benefit of omega-3 PUFA treatment compared to placebo (standardized difference in random-effects model 0.56 SD [95% CI: 0.20, 0.92] and 0.22 SD [95% CI: 0.01, 0.43], respectively; pooled analysis was 0.38 SD [95% CI: 0.18, 0.59]). Use of mainly EPA within the preparation, rather than DHA, influenced final clinical efficacy. Significant clinical efficacy was also seen with the use of omega-3 PUFA as adjuvant rather than monotherapy.
A Cochrane review summarized the findings of randomized controlled trials that had examined the effects of omega-3 PUFA intake on major depressive disorder in adults. Twenty-five trials (N=1,373) had compared the effects of omega-3 PUFAs and a placebo on depressive symptoms and found that the former had yielded small to modest benefits. However, the evidence was considered to be biased and of very poor quality, and the reported effect was judged to be clinically irrelevant.
Despite the different bioactivity between EPA and DHA, there is a robust biological basis supporting their anxiolytic and antidepressant potential, comprising modulation of neuronal membrane properties, receptor expression and neurotransmission, antioxidant, anti-inflammatory and pro-resolving activity, and promotion of neuroplasticity and neuroprotection.
Some studies reported no superior therapeutic efficacy of n-3 PUFAs over placebo in MDD. These inconsistent findings may be attributed to several factors, including variations in study duration, n-3 PUFAs dosages, and sample size.
Evidence strength: Moderate for MDD when using EPA-predominant preparations as adjuvant therapy; weak to mixed for other indications and for monotherapy.
A 2023 review of 36 studies compared supplements of polyunsaturated fatty acids (omega-3s, omega-6s, or both) to placebo for ADHD treatment in children and adolescents. The authors evaluated three groups of omega-3 supplement studies and did not find evidence that ADHD symptoms are likely to improve in children or adolescents with ADHD who receive polyunsaturated fatty acid supplements. The authors noted that while research on the effectiveness of omega-3 supplements for ADHD has increased, more high-quality studies are needed due to small sample sizes and variations in types and dosages of supplements.
In the case of attention deficit hyperactivity disorder and related disorders, most trials showed at most small benefits over placebo. A limited meta-analysis of these trials suggested that benefits of omega-3 PUFA supplementation may be greater in a classroom setting than at home.
Evidence strength: Weak to inconclusive. Current evidence does not firmly support PUFA supplementation as a treatment for ADHD in children and adolescents.
Since their discovery in the 1970s as key components of brain tissue, long-chain n-3 PUFA have been postulated to serve critical roles in brain development and function; a lack of these fatty acids has been implicated in a number of mental health conditions over the lifespan, from developmental disorders and mental retardation in childhood, to depression, bipolar disorder, schizophrenia, and borderline personality disorder in adulthood, and cognitive decline, dementia, and Alzheimer's disease in late adulthood.
Evidence from observational studies suggests that diets high in omega-3 long-chain polyunsaturated fatty acids (PUFA) may protect people from cognitive decline and dementia. The strength of this potential protective effect has been tested in randomized controlled trials.
O3LC-PUFAs have been linked to neurological development, maternal and child health, and the etiology of certain non-communicable diseases including age-related cognitive decline, cardiovascular disease, and diabetes.
In one crossover RCT in healthy subjects aged 51β72, intake of n-3 PUFA improved cognitive performance after five weeks compared with placebo. In addition, inverse relations were obtained between cardiometabolic risk factors and cognitive performance, indicating a potential of dietary prevention strategies to delay onset of metabolic disorders and associated cognitive decline.
Evidence strength: Observational evidence is supportive, but RCT evidence for dementia prevention remains limited and mixed. The Cochrane review found insufficient trial evidence to conclude that omega-3 supplementation prevents cognitive decline in cognitively healthy older adults.
Marine n-3 PUFAs can act in a number of ways to reduce inflammation: they decrease production of eicosanoid mediators from arachidonic acid, many of which have pro-inflammatory roles; increase production of weakly inflammatory or anti-inflammatory eicosanoids from EPA; increase production of anti-inflammatory and inflammation-resolving resolvins from EPA and DHA; and decrease adhesion molecule expression on leukocytes and endothelial cells.
Dietary supplementation of omega-3 PUFAs including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) displays beneficial impact in a wide range of human diseases in which unresolved inflammation is suspected as a key component of pathogenesis.
In addition to inflammatory diseases, Ο-3 PUFA and resolvins appear to modulate cancer progression. Ο-3 PUFA intake has been associated with reduced inflammation in colorectal cancer, and a favorable phenotype in breast cancer. However, the clinical evidence in cancer is largely observational and should be characterized as preliminary.
Therapeutic and health-promoting effects of Ο-3 and Ο-6 PUFAs have already been established in various chronic inflammatory and autoimmune diseases. The application of Ο-3 and Ο-6 PUFAs in most common skin diseases has been examined in numerous studies, but their results and conclusions were mostly opposing and inconclusive.
Dietary supplementation and topical application of certain omega-3 PUFAs attenuates UV-induced photodamage, extrinsic signs of skin aging, and inflammatory skin responses.
Evidence strength: Preliminary to moderate for skin inflammatory conditions; more robust for the established role of linoleic acid (LA) in skin barrier function.
Studies suggest that people who get higher amounts of omega-3s from the foods they eat may have a lower risk of developing AMD (age-related macular degeneration).
DHA levels are especially high in retina (eye), brain, and sperm cells.
Evidence strength: Largely observational. Intervention trials (e.g., AREDS2) did not demonstrate a benefit of omega-3 supplementation for AMD outcomes.
The FDA states that dietary supplement labels cannot suggest a daily dose of EPA and DHA greater than 2 g.
The NIH ODS notes that omega-3 intakes up to 2 g/day from dietary supplements are generally considered safe. Higher doses are sometimes used to lower triglycerides, but anyone taking omega-3s for this purpose should be under the care of a healthcare provider because these doses could cause bleeding problems and possibly affect immune function.
Recommendations during breastfeeding are for 1000 mg of DHA plus EPA per day.
In one RCT (the FISH Trial), patients undergoing CABG were randomized to pharmaceutical-grade n3-PUFAs 2 g orally twice daily (minimum of 6 g total) or a matched placebo, administered at least 24 hours before surgery.
In one 8-week study, adults with MDD were administered 1 g of n-3 PUFAs enriched with EPA and DHA as monotherapy, with no significant differences observed across the groups.
Plant-based sources of omega-3s from algal oil usually provide around 100β300 mg DHA per serving.
The Federal Government's Dietary Guidelines for Americans 2020β2025 recommends that adults eat 8 ounces or more of a variety of seafood (fish or shellfish) per week for all the nutrients seafood provides.
Various dietary supplements in different chemical forms are currently available over the counter but have not been FDA-approved; they are not required to show safety and efficacy before marketing the product.
Commonly reported side effects of omega-3 supplements are usually mild. These include unpleasant taste, bad breath, heartburn, nausea, gastrointestinal discomfort, diarrhea, headache, and odoriferous sweat.
Omega-3 PUFA were well tolerated by both children and adults, with mild gastrointestinal effects being the only consistently reported adverse event in clinical trial reviews.
Omega-3 supplements may raise the risk of bleeding if a person is taking antiplatelet drugs or anticoagulants.
The mechanisms of action of these fatty acids include potential adverse effects, particularly the risk of interactions with anticoagulant medications, which require cautious use.
Given these possible interactions, careful clinical monitoring is essential. Specific indicators should include INR (International Normalized Ratio) in patients receiving anticoagulants, blood pressure monitoring in those on antihypertensive therapy, and lipid profiles in dyslipidemic patients.
High doses of fish oil pills may raise the risk of atrial fibrillation. This risk is particularly relevant at pharmacological doses (β₯4 g/day) used for triglyceride lowering and has been noted in large trials with high-dose icosapent ethyl and omega-3-acid ethyl esters.
When discussing adverse effects of misuse of Ο-3 and Ο-6 PUFAs, concerns include overconsumption of fish or supplements from fish oils that can lead to consumption of high levels of methylmercury.
Physicians should inquire about patients' diets to ensure proper DHA and EPA levels and that fish high in methyl mercury are avoided.
Polyunsaturated fats are easily oxidized, meaning they are prone to react chemically with oxygen. This reaction typically breaks the fatty acid apart and produces oxidants (free radicals). Supplement quality, storage conditions, and freshness are therefore important practical considerations when using PUFA preparations.
Dosing in patients with hepatic impairment is undefined. Dosing in patients with renal impairment is also undefined.
Despite their popularity, nutritional supplements such as food-based Ο-3 and Ο-6 are subject to quality, safety, and efficacy requirements that differ significantly from those applied to medicines, being regulated by different entities.
Health conditions that Polyunsaturated fat may help support.
Body systems that Polyunsaturated fat may help support.
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