What is Omega 3 Fatty Acids ?

During the past few years, there has been an increase in both scientific and public interest in the role of omega-3 fatty acids found in fish and fish oils in the prevention and management of cardiovascular disease ¹. The omega-3 fatty acids that are of particular interest for cardiovascular care include EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), which are found predominantly in fish and fish oils ², ³, ⁴. The basis of this heightened interest in dietary intakes of EPA and DHA comes partly from epidemiological and population studies ⁵ indicating that increased consumption of fish as a source of omega-3 fatty acids is often associated with decreased mortality (as well as morbidity) from cardiovascular disease.

What are polyunsaturated fatty acids

Fats are essential for living organisms. Fatty acid molecules have a variable length carbon chain with a methyl terminus and a carboxylic acid head group ⁶. They can be categorized based on the degree of saturation of their carbon chains. Saturated fatty acids possess the maximal number of hydrogen atoms, while monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) have one, or two or more, double bonds, respectively.

Figure 1. Monounsaturated Fatty Acids Structure

Figure 2. Polyunsaturated Fatty Acids Structure

Polyunsaturated fatty acids (PUFAs) can be further subdivided on the basis of the location of the first double bond relative to the methyl terminus of the chain. For example, n-3 and n-6 fatty acids are two of the most biologically significant polyunsaturated fatty acid classes, and have their first double bond on either the third or sixth carbon from the chain terminus, respectively. The final carbon in the fatty acid chain is also known as the omega carbon, hence the common reference to these fatty acids as omega-3 or omega-6 PUFAs. The distinction between omega-6 and omega-3 fatty acids is based on the location of the first double bond, counting from the methyl end of the fatty acid molecule (see Figure 3). Omega-6 fatty acids are represented by Linoleic acid (LA) (18:2ω-6) and Arachidonic acid (AA) (20:4ω-6) and omega-3 fatty acids by Alpha-linolenic acid (ALA) (18:3ω-3), Eicosapentaenoic acid (EPA) (20:5ω-3) and Docosahexaenoic acid (DHA) (22:6ω-3).

Long-chain n-3 and n-6 PUFAs are synthesized from the essential fatty acids: alpha-linolenic acid (ALA) and linoleic acid, respectively. Basic structures of these two parent PUFAs are shown in Figure 3. An essential fatty acid cannot be made by the body and must be obtained through dietary sources. Animals and humans have the capacity to metabolize essential fatty acids to long-chain derivatives. Because the n-6 and n-3 pathways compete with one another for enzyme activity, the ratio of n-6 to n-3 PUFAs is very important to human health. An overabundance of fatty acids from one family will limit the metabolic production of the longer chain products of the other. The typical Western diet provides n-6 and n-3 PUFAs in a ratio ranging from 8:1 to 25:1 ⁶, values in severe contrast with the recommendations from national health agencies of approximately 4:1 ⁷. Lowering the n-6:n-3 ratio would reduce competition for the enzymes and facilitate the metabolism of more downstream products of ALA.

Mammalian cells cannot convert omega-6 to omega-3 fatty acids because they lack the converting enzyme, omega-3 desaturase. Omega-6 and omega-3 fatty acids are not interconvertible, are metabolically and functionally distinct, and often have important opposing physiological effects, therefore their balance in the diet is important ⁸.

This study showed a balanced omega-6/omega-3 ratio 1–2/1 is one of the most important dietary factors in the prevention of obesity, along with physical activity. A lower omega-6/omega-3 ratio should be considered in the management of obesity ⁸.

Because most diets are already very rich in n-6 PUFAs, greater focus needs to be placed on incorporating n-3 PUFAs into the diet. Dietary sources of n-3 PUFAs are readily available but in limited quantities. Many foods contain alpha-linolenic acid (ALA), including certain vegetable oils, dairy products, flaxseed, walnuts and vegetables ⁹. Fatty fish, such as mackerel, herring and salmon, provide an excellent source of the long-chain derivatives of ALA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ⁷.

What are omega-3 fatty acids ?

Omega-3 fatty acids are long-chain polyunsaturated fatty acids (18–22 carbon atoms in chain length) with the first of many double bonds beginning with the third carbon atom (when counting from the methyl end of the fatty acid molecule). The three principal omega-3 fatty acids are:

1. Alpha-linolenic acid (ALA) (18:3ω-3),
2. Eicosapentaenoic acid (EPA) (20:5ω-3),
3. Docosahexaenoic acid (DHA) (22:6ω-3).

Non-fish oil based Omega-3 Polyunsaturated Fatty Acids

The main sources of alpha-linolenic acid (ALA) in the U.S. diet are vegetable oils, particularly canola and soybean oils; flaxseed oil is richer in alpha-linolenic acid (ALA) than soybean and canola oils but is not commonly consumed. The typical North American diet provides approximately 1.4 g of ALA per day, and 0.1 g to 0.2 g of EPA and DHA ¹⁰. Alpha-linolenic acid (ALA) can be converted, usually in small amounts, into (Eicosapentaenoic acid) EPA and (Docosahexaenoic acid) DHA in the body. Omega-3 EPA and Omega-3 DHA are found in seafood, including fatty fish (e.g., salmon, tuna, and trout) and shellfish (e.g., crab, mussels, and oysters). Note the differences between the Omega-3 fatty acids found in flaxseed, soybean, vegetable oils (alpha-linolenic acid (ALA)) from those in fish and seafoods (Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA)).

For those who do not consume fish, the omega-3 fatty acid known as alpha-linolenic acid (ALA) can be a dietary source of some metabolically derived Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA). The desaturation plus elongation reactions in the liver and elsewhere in the body that provide for the conversion of dietary ALA to EPA and DHA are depicted in Figure 4. The conversion of ALA to EPA and DHA occurs to a low extent (about 10%–15% efficiency) in the adult human body ¹¹. Nonetheless, there is evidence that the benefits of the Mediterranean-type diet after myocardial infarction may be partly caused by the higher intake of ALA (commonly found in nonhydrogenated canola oil, ground flaxseed and other selected ALA-enriched foods) ¹². A prospective cohort study (Nurses Health Study) revealed an inverse relation between ALA intakes and the risk of fatal ischemic heart disease among women ¹³. However, the Zutphen Elderly Study did not observe a beneficial effect of dietary ALA on the 10-year risk of coronary artery disease ¹⁴. The metabolic conversion of ALA to the longer chain omega-3 fatty acids (EPA and DHA) is thought to mediate any possible cardioprotective effects of dietary ALA. In contrast to the well-recognized serum triglyceride-lowering effect of EPA and DHA, most human intervention studies with ALA (e.g., using flaxseed oil) have not exhibited any lipid-lowering effects. Whereas ALA (from flaxseed oil) at a relatively high dose has been found to improve arterial compliance ¹⁵, considerably lower supplementation levels of EPA and DHA improved arterial and endothelial functioning in subjects with hypercholesterolemia ¹⁶ and subjects with type 2 diabetes mellitus ¹⁷.

Fish Oil Omega-3 Polyunsaturated Fatty Acids

The fish-based and fish-oil–based omega-3 polyunsaturated fatty acids (also referred to as n-3 PUFA) consist of EPA (20 carbon atoms, 5 double bonds) and DHA (22 carbon atoms, 6 double bonds). The general structures for EPA and DHA are shown in Fig. 3. Commonly available dietary sources of EPA and DHA are listed in Table 1. Whereas plant foods and vegetable oils lack EPA and DHA, some do contain varying amounts of the n-3 PUFA alpha-linolenic acid (ALA), which has 18 carbon atoms and 3 double bonds (Fig. 3). Many vegetable oils are greatly enriched in omega-6 fatty acids (mainly as linoleic acid in corn, safflower, sunflower and soybean oils), but canola oil (nonhydrogenated), ground flaxseed and walnuts are rich sources of ALA.

The typical North American diet provides about 1–3 g of n-3 PUFA alpha-linolenic acid (ALA) per day but only 0.10–0.15 g of EPA (Eicosapentaenoic acid) plus DHA (Docosahexaenoic acid) per day ¹⁸, ¹⁹. The very high intake of n-6 PUFA, mostly as linoleic acid (LA) (Fig. 3) in our diet (12–15 g/day) from common vegetable oils (corn, safflower, soybean) and other sources, yields an overall n-6:n-3 dietary ratio (total omega-6 fatty acids in the diet: total omega-3 fatty acids in the diet) of about 8:1. Health Canada has recommended that this ratio be as low as 4:19 to reduce the competitive influence of high LA intakes on ALA metabolism to its longer chain products (such as EPA and DHA). Although high intakes of LA can provide some modest blood cholesterol lowering, experimental studies in animals have raised concerns regarding the enhancing effect of these high intakes on certain cancers ²⁰. This association has not been established in human studies ²¹.

Figure 3. Omega-3 fatty acids and Omega-6 fatty acids structure

Figure 4. Conversion of dietary ALA to EPA and DHA via Desaturation, elongation and retroconversion of polyunsaturated fatty acids.

[Source ¹]

Table 1. Omega-3 Fatty Acid Foods EPA (Eicosapentaenoic acid) and DHA (Docosahexaenoic acid) – Fish and Seafood Sources

[Source ¹]

Table 2. EPA (Eicosapentaenoic acid) and DHA (Docosahexaenoic acid) Content of Fish Species

Fish Species and Description	DHA per 100 g	EPA per 100 g	DHA+EPA per 100 g	DHA+EPA per 85 g (3 oz.)
Crustaceans, crab, Alaska king, cooked, moist heat	0.118	0.295	0.413	0.351
Crustaceans, crab, blue, cooked, moist heat	0.231	0.243	0.474	0.403
Crustaceans, crab, Dungeness, cooked, moist heat	0.113	0.281	0.394	0.335
Crustaceans, crab, queen, cooked, moist heat	0.145	0.332	0.477	0.405
Crustaceans, crayfish, mixed species, farmed, cooked, moist heat	0.038	0.124	0.162	0.138
Crustaceans, crayfish, mixed species, wild, cooked, moist heat	0.047	0.119	0.166	0.141
Crustaceans, lobster, northern, cooked, moist heat	0.031	0.053	0.084	0.071
Crustaceans, shrimp, mixed species, cooked, moist heat	0.144	0.171	0.315	0.268
Crustaceans, spiny lobster, mixed species, cooked, moist heat	0.139	0.341	0.480	0.408
Fish, anchovy, European, raw	0.911	0.538	1.449	1.232
Fish, anchovy, European, canned in oil, drained solids	1.292	0.763	2.055	1.747
Fish, bass, freshwater, mixed species, cooked, dry heat	0.458	0.305	0.763	0.649
Fish, bass, striped, cooked, dry heat	0.750	0.217	0.967	0.822
Fish, bluefish, cooked, dry heat	0.665	0.323	0.988	0.840
Fish, turbot, cooked, dry heat	0.123	0.09	0.213	0.181
Fish, carp, cooked, dry heat	0.146	0.305	0.451	0.383
Fish, catfish, channel, farmed, cooked, dry heat	0.128	0.049	0.177	0.150
Fish, catfish, channel, wild, cooked, dry heat	0.137	0.100	0.237	0.201
Fish, caviar, black and red, granular	3.800	2.741	6.541	5.560
Fish, cod, Atlantic, cooked, dry heat	0.154	0.004	0.158	0.134
Fish, cod, Pacific, cooked, dry heat	0.173	0.103	0.276	0.235
Fish, croaker, Atlantic, raw	0.097	0.123	0.22	0.187
Fish, dolphin fish, cooked, dry heat	0.113	0.026	0.139	0.118
Fish, drum, freshwater, cooked, dry heat	0.368	0.295	0.663	0.564
Fish, eel, mixed species, cooked, dry heat	0.081	0.108	0.189	0.161
Fish, fish portions and sticks, frozen, preheated	0.128	0.086	0.214	0.182
Fish, flatfish (flounder and sole species), cooked, dry heat	0.258	0.243	0.501	0.426
Fish, grouper, mixed species, cooked, dry heat	0.213	0.035	0.248	0.211
Fish, haddock, cooked, dry heat	0.162	0.076	0.238	0.202
Fish, halibut, Atlantic and Pacific, cooked, dry heat	0.374	0.091	0.465	0.395
Fish, halibut, Greenland, cooked, dry heat	0.504	0.674	1.178	1.001
Fish, herring, Atlantic, cooked, dry heat	1.105	0.909	2.014	1.712
Fish, herring, Atlantic, kippered	1.179	0.97	2.149	1.827
Fish, herring, Pacific, cooked, dry heat	0.883	1.242	2.125	1.806
Fish, lingcod, cooked, dry heat	0.130	0.133	0.263	0.224
Fish, mackerel, Atlantic, cooked, dry heat	0.699	0.504	1.203	1.023
Fish, mackerel, king, cooked, dry heat	0.227	0.174	0.401	0.341
Fish, mackerel, Pacific and jack, mixed species, cooked, dry heat	1.195	0.653	1.848	1.571
Fish, mackerel, Spanish, cooked, dry heat	0.952	0.294	1.246	1.059
Fish, mullet, striped, cooked, dry heat	0.148	0.18	0.328	0.279
Fish, ocean perch, Atlantic, cooked, dry heat	0.271	0.103	0.374	0.318
Fish, perch, mixed species, cooked, dry heat	0.223	0.101	0.324	0.275
Fish, pike, northern, cooked, dry heat	0.095	0.042	0.137	0.116
Fish, pike, walleye, cooked, dry heat	0.288	0.11	0.398	0.338
Fish, pollock, Atlantic, cooked, dry heat	0.451	0.091	0.542	0.461
Fish, pompano, Florida, cooked, dry heat	??	??	??	0.620 est
Fish, rockfish, Pacific, mixed species, cooked, dry heat	0.262	0.181	0.443	0.377
Fish, roe, mixed species, cooked, dry heat	1.747	1.26	3.007	2.556
Fish, roe, mixed species, raw	1.363	0.983	2.346	1.994
Fish, roughy, orange, raw	0	0.001	0.001	0.001
Fish, sablefish, cooked, dry heat	0.920	0.867	1.787	1.519
Fish, sablefish, smoked	0.945	0.891	1.836	1.561
Fish, salmon, Atlantic, farmed, cooked, dry heat	1.457	0.69	2.147	1.825
Fish, salmon, Atlantic, wild, cooked, dry heat	1.429	0.411	1.84	1.564
Fish, salmon, Chinook, cooked, dry heat	0.727	1.01	1.737	1.476
Fish, salmon, chum, cooked, dry heat	0.505	0.299	0.804	0.683
Fish, salmon, chum, drained solids with bone	0.702	0.473	1.175	0.999
Fish, salmon, coho, farmed, cooked, dry heat	0.871	0.408	1.279	1.087
Fish, salmon, coho, wild, cooked, dry heat	0.658	0.401	1.059	0.900
Fish, salmon, pink, cooked, dry heat	0.751	0.537	1.288	1.095
Fish, salmon, sockeye, cooked, dry heat	0.700	0.53	1.23	1.046
Fish, sardine, Atlantic, canned in oil, drained solids with bone	0.509	0.473	0.982	0.835
Fish, scup, raw (Porgy—assigned to low omega-3 group)	no data	no data	no data	no data
Fish, sea bass, mixed species, cooked, dry heat	0.556	0.206	0.762	0.648
Fish, sea trout, mixed species, cooked, dry heat	0.265	0.211	0.476	0.405
Fish, shad, American, raw	1.321	1.086	2.407	2.046
Fish, shark, mixed species, raw	0.527	0.316	0.843	0.717
Fish, sheepshead, cooked, dry heat	0.107	0.083	0.19	0.162
Fish, smelt, rainbow, cooked, dry heat	0.536	0.353	0.889	0.756
Fish, snapper, mixed species, cooked, dry heat	0.273	0.048	0.321	0.273
Fish, spot, cooked, dry heat	0.526	0.282	0.808	0.687
Fish, sturgeon, mixed species, cooked, dry heat	0.119	0.249	0.368	0.313
Fish, sucker, white, cooked, dry heat	0.371	0.244	0.615	0.523
Fish, sunfish, pumpkin seed, cooked, dry heat	0.092	0.047	0.139	0.118
Fish, swordfish, cooked, dry heat	0.681	0.138	0.819	0.696
Fish, tilefish, cooked, dry heat	0.733	0.172	0.905	0.769
Fish, trout, mixed species, cooked, dry heat	0.677	0.259	0.936	0.796
Fish, trout, rainbow, farmed, cooked, dry heat	0.820	0.334	1.154	0.981
Fish, trout, rainbow, wild, cooked, dry heat	0.520	0.468	0.988	0.840
Fish, tuna, fresh, bluefin, cooked, dry heat	1.141	0.363	1.504	1.278
Fish, tuna, light, canned in oil, drained solids	0.101	0.027	0.128	0.109
Fish, tuna, light, canned in water, drained solids	0.223	0.047	0.27	0.230
Fish, tuna, skipjack, fresh, cooked, dry heat	0.237	0.091	0.328	0.279
Fish, tuna, white, canned in water, drained solids	0.629	0.233	0.862	0.733
Fish, tuna, yellowfin, fresh, cooked, dry heat	0.232	0.047	0.279	0.237
Fish, whitefish, mixed species, cooked, dry heat	1.206	0.406	1.612	1.370
Fish, whiting, mixed species, cooked, dry heat	0.235	0.283	0.518	0.440
Fish, wolffish, Atlantic, cooked, dry heat	0.405	0.393	0.798	0.678
Frog legs, raw			0.034	0.020
Mollusks, abalone, mixed species, raw	0	0.049	0.049	0.042
Mollusks, clam, mixed species, cooked, moist heat	0.146	0.138	0.284	0.241
Mollusks, conch, baked or broiled	0.072	0.048	0.12	0.102
Mollusks, cuttlefish, mixed species, cooked, moist heat	0.132	0.078	0.21	0.179
Mollusks, mussel, blue, cooked, moist heat	0.506	0.276	0.782	0.665
Mollusks, octopus, common, cooked, moist heat	0.162	0.152	0.314	0.267
Mollusks, oyster, eastern, farmed, cooked, dry heat	0.211	0.229	0.44	0.374
Mollusks, oyster, eastern, wild, cooked, dry heat	0.291	0.26	0.551	0.468
Mollusks, oyster, Pacific, cooked, moist heat	0.500	0.876	1.376	1.170
Mollusks, scallop, mixed species, cooked, breaded and fried	0.103	0.086	0.18	0.161
Mollusks, whelk, unspecified, cooked, moist heat	0.012	0.008	0.02	0.017

[Source ²²]

Table 3. Other sources of Omega-3 Alpha-Linolenic Acid (ALA) – Non-Seafood Sources

[Source ²³]

Some types of omega-3s are found in foods such as fatty fish and shellfish. Another type is found in some vegetable oils. Omega-3s are also available as dietary supplements. Note the differences between the Omega-3 fatty acids found in flaxseed, soybean, vegetable oils (alpha-linolenic acid (ALA)) from those in fish and seafoods (Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA)).

Commonly used dietary supplements that contain omega-3s include fish oil (which provides EPA and DHA) and flaxseed oil (which provides ALA). Algae oils are a vegetarian source of DHA.

Omega-3 fatty acids are important for a number of bodily functions, including muscle activity, blood clotting, digestion, fertility, and cell division and growth. DHA is important for brain development and function. ALA is an “essential” fatty acid, meaning that people must obtain it from food or supplements because the human body cannot manufacture it.

Possible biochemical and physiological mechanisms of action for Eicosapentaenoic acid (EPA), and Docosahexaenoic acid (DHA)

The various mechanisms by which increased dietary consumption of omega-3 fatty acids from fish and fish oils is considered to favorably modify cardiovascular disease and associated disorders are outlined in Table 4. Increasing the intake of EPA and DHA results in a corresponding increase of these omega-3 fatty acids in tissue or cellular lipids and circulatory lipids ²⁴, ²⁵ along with a simultaneous reduction in the omega-6 fatty acids such as LA and arachidonic acid (AA) (Fig. 3). The fatty acid shifts are particularly pronounced in the cell membrane–bound phospholipid components. These changed profiles alter the physicochemical properties of cell membranes and their functioning and modify cell signalling, gene expression and biosynthetic processes, and eicosanoid formations (the eicosanoids formed via oxygenase enzymes acting on AA and EPA include prostaglandins, leukotrienes and thromboxanes.). The beneficial effects of omega-3 fatty acids on cardiovascular disease are mediated by both eicosanoid-dependent and eicosanoid-independent processes. For example, the reduced blood platelet reactivity (antithrombotic effect) observed with increased EPA and DHA intakes involves the reduced formation of the proaggregatory eicosanoid known as thromboxane A2 (TxA2). The replacement of AA (the omega-6 fatty acid and TxA2 precursor) in blood platelet membrane phospholipid by EPA and DHA yields less TxA2 upon platelet stimulation; furthermore, EPA has an inhibitory effect on the cyclo-oxygenase enzyme that connects AA to TxA2 thus leading to a lessened thrombogenic state ¹.

Table 4. Cardio-protective Effects of EPA and DHA

Fish Rich in Omega-3 Fatty Acids Diet Health Benefits

Multiple prospective cohort studies support the benefit of a fish rich in omega-3 fatty acid diet ²⁶, ²⁷, ²⁸.

It has long been recognized that disease patterns for the Greenland Inuit, when compared with those for the population of Denmark, exhibit a significantly lower rate of death from acute myocardial infarction despite only moderate differences in blood cholesterol levels ²⁹. The high-fat traditional Inuit diet (Greenland; Nunavik) provides up to several grams of omega-3 fatty acid (EPA and DHA) daily in the form of marine mammals (seal, whale), wildfowl (seabirds) and various fish ²⁹, ³⁰. Furthermore, the higher fish intakes of the Japanese population relative to that of North America have been associated with considerably lower rates of acute myocardial infarctions, other ischemic heart disease and atherosclerosis despite only moderately lower blood cholesterol levels in the Japanese population ³¹. Various studies have also indicated that long-term consumption of fish (up to 2–3 servings per week) appears to be associated with lower primary and secondary heart attack rates and death from cardiovascular disease ⁵, ³², ³³. Following dietary consumption, the levels of EPA and DHA rise considerably in mammalian cells and tissues via their esterification into the 2-position (that is, the middle carbon of the glycerol backbone in a phospholipid structure) of the membrane phospholipid components. Fatty acid analyses of serum and plasma phospholipid, a biomarker for EPA and DHA intake and physiological status, have indicated that omega-3 fatty acids in general and DHA levels in particular are inversely correlated with coronary heart disease in men ³⁴. Among the Inuit of Nunavik, progressive increases in levels of EPA and DHA in plasma phospholipid have been found both to reflect dietary intakes of these fatty acids and to be beneficially associated with key risk factors for cardiovascular disease ²⁵.

Intervention studies using fish oil concentrates that provide EPA and DHA at intakes of up to 2–4g/day over a few weeks have shown that these fatty acids can favourably attenuate various risk factors for cardiovascular disease (independent of any blood cholesterol-lowering effect) ²⁴, ³, ⁴. These effects include an antithrombotic effect, lipid (triglyceride) lowering, reduced blood and plasma viscosity, and improvements in endothelial dysfunction ²⁴, ³, ⁴, ¹⁶. Omega-3 fatty acids accumulate to a considerable extent in various sites including circulating blood platelets, the heart and serum phospholipid. The accumulation of EPA and DHA in platelets is associated with decreased platelet adhesiveness and aggregation and an overall reduction in thrombogenicity. Antiatherogenic effects of omega-3 fatty acids have also been shown in animal studies.

Human studies have revealed the potent ability of EPA and DHA to significantly reduce circulating levels of blood triglyceride ³⁵, which is of interest because only moderate elevations in triglyceride (approaching 1.33 mmol/L or 118 mg/dL, or above) have been associated with a progressively increased risk of ischemic heart disease ³⁶. Within 2–3 weeks of EPA and DHA supplementation, significantly reduced blood triglyceride levels with an approximate reduction of 6%–8% (or more) per gram of EPA and DHA consumed are routinely observed. In a placebo-controlled, double-blind trial, a 26% lowering in fasting triglyceride levels in postmenopausal women receiving 4 g omega-3 (EPA and DHA) daily over 28 days was recently demonstrated ³⁷. In cases where combined statin therapy plus certain triglyceride-lowering therapies (e.g., fibric acid derivatives) may be contraindicated, statin plus omega-3 (EPA and DHA) therapy may be an attractive alternative. Supplementation with omega-3 (EPA and DHA), as given in addition to statin therapy in patients with combined hyperlipidemia, was found to reduce levels of atherogenic lipoproteins while more effectively reducing the hemostatic risk profile ³⁸. The antiarrhythmic potential of EPA and DHA (upon accumulation in cardiac tissue) has been considered to be yet another important mechanism by which consumption of these fatty acids can reduce mortality related to cardiovascular disease (particularly sudden cardiac death) ³⁹. This last effect is considered to be exhibited at even lower intakes of omega-3 (EPA and DHA combined) of about 1 g/day ⁵.

The Lyon Diet Heart Study ⁴⁰ randomized 605 participants with a previous heart attack for 46 months and showed an inverse relationship between alpha-linolenic acid (ALA) intake and the risk of a second heart attack. The intervention group was advised to eat more fish, fruits, and vegetables and to use an ALA-rich margarine. The control group was advised to follow a prudent diet. There was a 68% decrease in primary end points (cardiac death and nonfatal heart attack). Secondary end points (periprocedural infarctions, unstable angina, heart failure, stroke, and pulmonary or peripheral embolisms) also decreased. Of note, at four-year follow-up, most experimental patients were still closely following the recommended diet.

The results of this study suggested that higher prenatal fish intake and exposure to elongated n−3 PUFAs were associated with lower adiposity in early childhood. In this cohort, as in other populations in North America and Western Europe, the prenatal intake of elongated n−3 fatty acids was well below recommended concentrations. A higher n−3 PUFA intake may be associated with lower rates of obesity as well as less atopy and improved neurocognitive development ⁴¹.

In summary, there is evidence for the beneficial effect of regular fish consumption (up to 2–3 times/week) both in healthy subjects and in those at considerable risk for coronary artery disease or with established coronary artery disease.

Moderate evidence has emerged about the health benefits of eating seafood. The health benefits of omega-3 dietary supplements are unclear.

Omega-3 fatty acids and Body Weight Management

Several studies have provided supporting evidence for a role of omega-3 PUFAs in body composition ⁴². In this twenty-seven women with type 2 diabetes without hypertriglyceridemia were randomly allocated in a double-blind parallel design to 2 months of 3 g/day of either fish oil (1.8 g n−3 (containing 1.8 g n−3 PUFAs: 1.08 g eicosapentaenoic acid and 0.72 g docosahexaenoic acid) or placebo (paraffin oil). The participants had fasting plasma glucose between 7.7 and 14.0 mmol/L, glycated hemoglobin (HbA1c) of 7–10.5%, age from 40 to 60 yrs, body mass index (BMI; in kg/m2) between 27 and 40, and plasma triacylglycerol <2.5 mmol/L. The results after 2 months of taking fish oil show body weight and energy intake measured by use of a food diary were unchanged, but their total fat mass and subcutaneous adipocyte diameter were lower in the fish oil group than in the placebo group. Insulin sensitivity was not significantly different between the 2 groups. By contrast, atherogenic risk factors, including plasma triacylglycerol, the ratio of triacylglycerol to HDL cholesterol (atherogenic index) and plasma plasminogen activator inhibitor-1, were lower in the fish oil group than in the placebo group. In addition, a subset of inflammation-related genes was reduced in subcutaneous adipose tissue after the fish oil, but not the placebo ⁴².

In this fish oil and weight reduction study ⁴³, a total of 324 men and women aged 20-40 years, BMI 27.5-32.5 kg/m2 from Iceland, Spain and Ireland, were given energy-restricted diet with varying amount in fish and fish oil content for 8 weeks. Subjects were randomized to one of four groups: (1) control (sunflower oil capsules, no seafood); (2) lean fish (3 x 150 g portions of cod/week); (3) fatty fish (3 x 150 g portions of salmon/week); (4) fish oil (DHA/EPA capsules, no seafood). The macronutrient composition of the diets was similar between the groups and the capsule groups, were single-blinded. The energy-restricted diet for an average man in the study (95 kg at baseline) was 1600 kcal/day. The men in that study lost weight, but not the women. In young, overweight men, the inclusion of either lean or fatty fish, or fish oil as part of an energy-restricted diet resulted in approximately 1 kg more weight loss after 4 weeks, than did a similar diet without seafood or supplement of marine origin. The addition of seafood to a nutritionally balanced energy-restricted diet may boost weight loss ⁴³.

In this study the addition of omega-3 fatty acids to a calorie-restricted diet to treat overweight or obesity in overweight and obese volunteer (31+/-5 years; BMI: 28.3 kg/m2) during the last 2 weeks of an 8-week energy-restricted balanced diet providing either a low (<260 mg/day ) or a high amount (>1300 mg/day; n=121) of omega-3 fatty acids. The results were the addition of omega-3 fatty acids cause less hunger and more fullness in the overweight or obese volunteers ⁴⁴.

These findings support a potential role for omega-3 in appetite regulation in humans. Some intervention studies showed that omega-3 fatty acid supplementation reduced body weight and obesity in lean ⁴⁵, overweight ⁴³, ⁴⁶ and obese ⁴⁷ individuals. Couet et al. ⁴⁵ noted a 22% increase in basal lipid oxidation with 6 grams of fish oil for 3 weeks. Omega-3 fatty acids are long term metabolic fuel partitioners with greater partitioning towards β-oxidation in men than in women.

Omega-3 fatty acids for those at increased Cardiovascular Disease

Many studies have assessed the effects of omega-3s—primarily EPA and DHA—on cardiovascular disease and cardiovascular disease risk factors, such as high blood pressure and elevated plasma lipids. 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 the Japanese ⁴⁸. Results from observational studies have been consistent with these findings, 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 ⁴⁹, coronary disease, and fatal coronary heart disease ⁵⁰.

Results from the Japan EPA Lipid Intervention Study supported the growing body of evidence that long chain omega-3s reduce the risk of heart disease ⁵¹. In this study, 18,645 patients with hypercholesterolemia (total cholesterol of at least 251 mg/dL) with or without coronary artery disease received either 1.8 g/day EPA plus a statin or a statin only. After a mean of 4.6 years, patients in the EPA group had 19% fewer major coronary events than those in the control group. The EPA group also experienced a significant reduction in rates of unstable angina and non-fatal coronary events but not in rates of coronary death compared to the control group. A separate analysis of data from this study found that the EPA supplementation did not affect total stroke incidence but did reduce the risk of recurrent stroke by 20% in patients who had previously experienced a stroke ⁵².

The 2004 Cochrane review ⁵³ shows that it is not clear whether dietary or supplemental omega 3 fats (found in oily fish and some vegetable oils) alter total deaths, cardiovascular events (such as heart attacks and strokes) or cancers in the general population, or in people at risk of, or with, cardiovascular disease. When the analysis was limited to fish-based or plant-based, dietary or supplemental omega 3 fats there was still no evidence of reduction in deaths or cardiovascular events in any group. There is no clear evidence that omega 3 fats differ in effectiveness according to fish or plant sources, dietary or supplemental sources, dose or presence of placebo.

Therefore, based on available human trials data, it is not clear that dietary or supplemental omega 3 fats alter total mortality, combined cardiovascular events or cancers in people with, or at high risk of, cardiovascular disease or in the general population.

More recent studies suggest a more complicated picture, especially with respect to omega-3s from supplements as opposed to food. Higher consumption of seafood, such as fatty fish, appears to provide protection from many adverse cardiovascular disease outcomes. However, many studies have shown that taking omega-3 dietary supplements, such as fish oil supplements, might not provide the same protection. For example, in the Risk and Prevention Study, a randomized clinical trial of over 12,500 participants in Italy with multiple cardiovascular disease risk factors or atherosclerotic vascular disease, supplementation with 1 g/day omega-3s (including at least 85% EPA/DHA) for a median of 5 years failed to reduce the risk of death from cardiovascular causes or hospitalization for any cardiovascular cause compared to placebo ⁵². Similarly, in the ORIGIN trial that included 12,536 patients who had diabetes or a risk of diabetes and who were at high risk of cardiovascular events, supplementation with 1 g/day omega-3s (containing 375 mg DHA and 465 mg EPA) for about 6 years significantly lowered triglyceride levels but had no effect on risk of myocardial infarction, stroke, or death from cardiovascular causes compared to placebo ⁵⁴. In the Alpha Omega Trial, low-dose EPA and DHA supplementation (150 mg DHA and 226 mg EPA daily, supplied as a margarine) for 40 months also failed to reduce the rate of major cardiovascular events compared to placebo among 4,837 older men and women who had previously experienced a myocardial infarction and were receiving antihypertensive, antithrombotic, and/or lipid-lowering medications ⁵⁵. Finally, a 2014 ancillary study of the Age-Related Eye Disease Study 2 (AREDS2) found that daily supplementation with 350 mg DHA plus 650 mg EPA (in addition to the AREDS vitamin/mineral formula) for about 5 years did not reduce the risk of cardiovascular disease compared to placebo in elderly participants with AMD ⁵⁶.

The results of a 2018 meta-analysis of 10 randomized clinical trials that included 77,917 patients with a history of coronary heart disease or stroke, or at high risk of cardiovascular disease were contrary to those of earlier analyses. This analysis found that omega-3 supplementation (376–2,550 mg EPA+DHA/day) for 1 year or longer does not reduce the risk of fatal coronary heart disease, nonfatal myocardial infarction, stroke, or other major vascular events ⁵⁷. A 2014 meta-analysis of 27 randomized controlled trials also found that long chain- omega-3 supplementation does not significantly lower the risk of coronary disease, including fatal or nonfatal myocardial infarction, coronary heart disease, coronary insufficiency, coronary death, angina, or angiographic coronary stenosis ⁵⁸. Similarly, the authors of two meta-analyses published in 2012 concluded that omega-3 supplementation does not reduce the risk of cardiovascular events in patients with a history of cardiovascular disease ⁵⁹, and is not effective for the primary or secondary prevention of cerebrovascular disease ⁶⁰.

Possible reasons for conflicting findings: Some researchers suggest that discrepancies between the findings from earlier and more recent clinical trials might be explained, in part, by a rise in background dietary intakes of omega-3s in study populations [17,54,61]. Public-health messages touting the benefits of fish consumption have likely led to higher dietary intakes of LC omega-3s among participants in more recent supplementation studies than in older studies. A threshold effect might exist, above which increased omega-3 intake offers little or no additional cardiovascular benefit. For example, the authors of a review prepared by the Tufts Medical Center Evidence-based Practice Center on the effects of EPA and DHA on mortality concluded that mean intakes of up to 200 mg/day are associated with a reduced risk of cardiac, cardiovascular, or sudden cardiac death, but higher intakes do not reduce risk any further [62].

Increased use of statins and other cardioprotective therapies in more recent trials is another potential reason for the conflicting findings because omega-3s might offer little additional benefit beyond state-of-the-art pharmacotherapy [17,54,55,63-66]. In the GISSI-Prevenzione study conducted in the mid-1990s, for example, only about 5% of participants were taking a cholesterol-lowering drug at baseline [48]. In contrast, in the more recent Risk and Prevention Study and the ORIGIN trial, about 40–50% of the participants were taking a statin [53,54]. A 2011 meta-analysis of 10 randomized controlled trials examining the effects of omega-3s for secondary prevention of cardiovascular disease found that omega-3s reduced the risk of death from cardiac causes and sudden cardiac death in patients receiving the standard of care prior to 2003, but not in patients who received more aggressive guidelines-adjusted therapy starting in 2007 [64].

Agency for Healthcare Research and Quality ⁶¹ report: In 2016, Agency for Healthcare Research and Quality ⁶¹ published an updated review on the effects of omega-3s on cardiovascular disease and on risk factors and intermediate markers of cardiovascular disease ⁶¹. This comprehensive report evaluated 61 randomized controlled trials (primarily in people with cardiovascular disease or at risk of cardiovascular disease) and 37 observational studies (primarily in healthy people). The authors concluded that higher intakes of long chain omega-3s (primarily EPA and DHA from foods such as fish and seafood as well as dietary supplements) lower triglyceride levels and raise high-density lipoprotein levels, but also raise low-density lipoprotein levels. However, long chain omega-3s do not affect major adverse cardiovascular events or rates of coronary revascularization, sudden cardiac death, or all-cause death.

The Agency for Healthcare Research and Quality ⁶¹ authors also determined that higher intakes of long chain omega-3s do not affect systolic or diastolic blood pressure, whereas the evidence suggests, with less certainty, that long chain omega-3s lower the risk of ischemic stroke but do not affect the risk of hemorrhagic stroke, atrial fibrillation (a type of arrhythmia), or myocardial infarction. Finally, the authors found that long chain omega-3s have inconsistent effects on the risk of cardiac death based on the results of five randomized controlled trials ⁶¹.

Some of the Agency for Healthcare Research and Quality ⁶¹ findings conflict with those from other recent systematic reviews and meta-analyses. For example, a 2014 meta-analysis of 70 studies ⁶² as well as a 2013 systematic review of 17 studies ⁶³ found a small but statistically significant reduction in systolic (2.56 mmHg) and diastolic (1.47 mmHg) blood pressure in participants with hypertension (but not those with normal blood pressure) taking fish oil supplements. In addition, most ⁶⁴, ⁶⁵, ⁶⁶, ⁶⁷ but not all ⁶⁸ systematic reviews and meta-analyses published between 2006 and 2014 indicate that omega-3s reduce the risk of cardiac death.

Recommendations from the Dietary Guidelines for Americans: The 2015–2020 Dietary Guidelines for Americans states that strong evidence from mostly prospective cohort studies but also randomized controlled trials has shown that eating patterns that include seafood are associated with reduced risk of cardiovascular disease ⁶⁹. In addition, consuming about 8 ounces per week of a variety of seafood that provides about 250 mg per day EPA and DHA is associated with fewer cardiac deaths in both healthy individuals and those with preexisting cardiovascular disease.

Conclusions about omega-3s and cardiovascular disease

Overall, research indicates that consuming fish and other types of seafood as part of a balanced diet promotes heart health. Fish oil and other long chain omega-3 supplements improve blood lipids and appear to reduce the risk of cardiac death. However, their effects on other cardiovascular endpoints are unclear and might vary based on dietary omega-3 intakes and the use of cardioprotective medications.

The FDA has approved a qualified health claim for conventional foods and dietary supplements that contain EPA and DHA ⁷⁰. It states, “Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease.” The FDA also specifies that the labels of dietary supplements should not recommend a daily intake of EPA and DHA higher than 2 g ⁷⁰. For patients who need to lower their triglycerides, the American Heart Association recommends 2–4 g/day of EPA plus DHA under the care of a physician ⁷¹. Several prescription omega-3 preparations are also available to treat hypertriglyceridemia ⁷².

Scientists hope to gain additional insight on the effects of omega-3s for the prevention of cardiovascular disease from the VITamin D and OmegA-3 TriaL (VITAL) trial. This clinical trial will examine the effects of EPA (465 mg/day) and DHA (375 mg/day) supplementation with or without 2,000 IU/day vitamin D for 5 years in 25,875 older adults on the primary prevention of cancer and cardiovascular disease ⁷³. Results from this clinical trial and others ⁷⁴, ⁷² will shed more light on possible associations between omega-3s and cardiovascular events as well as blood pressure and atrial fibrillation.

Cancer prevention

Researchers have hypothesized that higher intakes of omega-3s from either foods or supplements might reduce the risk of cancer due to their anti-inflammatory effects and potential to inhibit cell growth factors ⁷⁵. For example, some studies have shown associations between higher intakes and/or blood levels of omega-3s and a decreased risk of certain cancers, including breast and colorectal cancers ⁷⁶. Other studies have found no associations between omega-3s and cancer risk, and some have even found associations in the opposite direction, suggesting that omega-3s might increase the risk of certain cancers such as prostate cancer ⁷⁷, ⁷⁸. To date, no large-scale clinical trials have examined the effects of omega-3s on the primary prevention of cancer in the general population, although a large clinical trial that addresses this question, the VITAL trial, is currently underway ⁷³. The VITAL trial will examine the effects of EPA (465 mg/day) and DHA (375 mg/day) supplementation (with and without 2,000 IU/day vitamin D) for 5 years in 25,875 older adults on the primary prevention of cancer and cardiovascular disease ⁷³. Results from this clinical trial will shed more light on possible associations between these omega-3s and cancer.

Results from observational studies however, have been inconsistent and vary by cancer site and other factors, including gender and genetic risk. Overall, data from observational studies show no consistent relationship between omega-3s and overall cancer risk. Although there are some suggestions of reduced risk for breast and possibly colorectal cancers with higher long chain omega-3 intakes, randomized clinical trials are needed to confirm these findings.

Breast cancer

Evidence from several observational studies suggests that higher intakes of long chain omega-3s are associated with a lower risk of breast cancer, but clinical trials are needed to confirm this finding. In the prospective Singapore Chinese Health Study of 35,298 women aged 45–74 years, those in the top three quartiles of dietary long chain omega-3 intake had a 26% lower risk of breast cancer after an average of 5.3 years of follow-up than those in the lowest quartile ⁷⁹. Similarly, among 35,016 female participants aged 50–76 years in the Vitamins And Lifestyle cohort, those who reported current use of fish-oil supplements had a 32% lower risk of breast cancer after a mean of 6 years than those who did not take fish oil ⁸⁰.

According to a systematic review of three case-control studies and five prospective studies published in 2007–2011, evidence is increasing that higher intakes of dietary and supplemental LC omega-3s are associated with a lower risk of breast cancer ⁸¹. Similarly, the authors of a meta-analysis of data from 21 prospective cohort studies concluded that women with the highest dietary intakes and/or tissue levels of long chain omega-3s had a 14% lower risk of breast cancer than those with the lowest intakes and tissue levels ⁷⁶. These authors also found a dose-response relationship between higher intakes of combined long chain omega-3s and reduced breast cancer risk. Intakes of ALA and of fish, however, had no association with differences in breast cancer risk. This finding, which could be due to varying levels of omega-3s in different fish species, warrants further investigation.

Colorectal cancer

Limited evidence from observational studies suggests that greater consumption of fish and long chain omega-3s is associated with a reduced risk of colorectal cancer ⁸¹.

The authors of a meta-analysis of 19 prospective cohort studies found no significant association between fish intake and risk of colorectal cancer overall. However, a stratified analysis showed that for participants with the highest fish consumption (those who ate fish at least seven times more often per month than those with the lowest fish consumption), the risk of colorectal cancer was 22% lower than that for the lowest fish consumers ⁸². Results from a more recent systematic review and meta-analysis of 22 prospective cohort studies and 19 case-control studies indicate that fish consumption is inversely associated with colorectal cancer risk. In this analysis, 21 of the studies distinguished between colon cancer and rectal cancer. The risk of rectal cancer was 21% lower for participants with the highest fish intakes (as much as one serving/day) compared to those with the lowest fish intakes (as little as none), but fish consumption had no significant association with risk of colon cancer alone ⁸³.

Results from the Vitamins And Lifestyle cohort study suggest that associations between fish or LC omega-3 intakes and colorectal cancer risk might vary by such factors as gender and genetic risk. In this study, researchers evaluated associations between colorectal cancer risk and EPA/DHA intakes from fatty fish (salmon and fresh tuna) and fish oil supplements in 68,109 Washington residents aged 50–76 ⁸⁴. The amount of fatty fish consumed ranged from none to 0.8 servings per week or more. Overall, EPA and DHA intakes (from either diet or supplements) and fatty fish consumption were not associated with colorectal cancer risk, but associations varied by genetic characteristics (certain inherited genetic mutations are associated with an increased risk of colorectal cancer). For individuals in the lowest two tertiles of genetic risk, higher fatty fish consumption and higher total EPA and DHA intakes were inversely associated with colorectal cancer risk. For individuals in the highest tertile of genetic risk, higher total EPA and DHA intakes were positively associated with colorectal cancer risk. Risk also varied by gender. Among men, use of fish oil supplements reduced colorectal cancer risk by an average of 34% or more depending on the frequency and duration of use, but this effect did not occur among women. Additional research is needed to clarify possible associations between fish and omega-3 intakes and colorectal cancer risk.

Prostate cancer

Several prospective and case-control studies have investigated associations between either blood levels or intakes of omega-3s and risk of low-grade or high-grade prostate cancer. Results from these studies have been inconsistent.

A few case-control and case-cohort studies have found positive associations between blood levels of LC omega-3s and prostate cancer risk (particularly high-grade disease that is more advanced and more likely to spread than low-grade cancer), suggesting that omega-3s might increase prostate cancer risk. In a nested case-control analysis of men aged 55–84 years participating in the Prostate Cancer Prevention Trial, serum phospholipid levels of DHA were positively associated with risk of high-grade, but not low-grade, prostate cancer ⁸⁵. Serum EPA levels, however, were not associated with risk of either grade of the disease.

Similarly, results from a case-cohort study within the Selenium and Vitamin E Cancer Prevention (SELECT) trial showed that men in the highest quartile of plasma phospholipid LC omega-3s had a 44% higher risk of low-grade prostate cancer and a 71% higher risk of high-grade prostate cancer than those in the lowest quartile ⁷⁸. An analysis of data from the European Prospective Investigation into Cancer and Nutrition cohort also found a higher prostate cancer risk in men with higher plasma levels of LC omega-3s ⁸⁶. Among whites participating in the Multiethnic Cohort Study, higher levels of omega-3s in erythrocyte membranes and higher ratios of omega-3s to omega-6s were both associated with an increased risk of prostate cancer. However, the results showed no associations, even with advanced or high-grade disease, for other ethnic groups or for the population as a whole ⁸⁷.

Although the findings from the Prostate Cancer Prevention Trial and the SELECT trial suggest that higher LC omega-3 intakes might increase prostate cancer risk, some scientists have questioned the significance of these findings ⁸⁸. They have noted, for example, that in the SELECT trial ⁷⁸, the difference in the omega-3 levels in the men with and without prostate cancer was very small and of questionable physiological significance. Other scientists have pointed out that localized (even high-grade) prostate cancers usually progress slowly and are common on autopsy in men who have died from other causes, suggesting that prostate cancer mortality is a more critical endpoint than prostate cancer incidence ⁸⁹. Finally, desaturation enzymes that convert ALA into EPA and DHA can be upregulated in some cancer cells, suggesting the possibility that it was the disease that raised the omega-3 levels, not the omega-3 levels that raised the disease risk ⁹⁰.

Results from other observational studies using dietary intake data suggest that higher intakes of fish and/or omega-3s reduce prostate cancer risk. Both fish and omega-3 consumption were associated with a lower risk of fatal prostate cancer in a cohort of 293,464 men participating in the NIH-AARP study ⁹¹. In the Health Professionals Follow-up Study, a prospective cohort of over 47,000 men aged 40–75 years, those who consumed fish more than three times per week had a lower risk of metastatic prostate cancer than those who consumed fish less than twice per month ⁹². However, men who used fish oil supplements did not have a decreased risk of prostate cancer.

A number of systematic reviews and meta-analyses of prospective studies of the effects of fish intakes, omega-3 intakes, and omega-3 blood levels on prostate cancer risk have had inconsistent findings as well. For example, circulating levels of EPA, but not DHA, were positively associated with prostate cancer risk in a meta-analysis of 5,098 men with prostate cancer and 6,649 men without prostate cancer from seven studies ⁹³. Another meta-analysis of 12 studies that included 4,516 men with prostate cancer and 5,728 men without prostate cancer found that high serum levels of these LC omega-3s were positively associated with high-grade disease ⁹⁴. In other analyses, dietary intakes of LC omega-3s had no effect on prostate cancer risk ⁹⁵, whereas fish consumption decreased prostate cancer mortality but had no effect on prostate cancer incidence ⁹⁶. A 2015 meta-analysis found no significant associations between dietary intakes or blood levels of long chain omega-3s and total prostate cancer risk ⁹⁷. The authors noted that most dietary-intake studies included in their meta-analysis found inverse associations, whereas biomarker studies of blood levels of these fatty acids found positive associations.

Overall, the evidence to date shows no consistent relationships between prostate cancer risk or mortality and omega-3 intakes or blood levels.

Other cancers

Evidence is limited for a role of omega-3s in the prevention of cancers at other sites. For example, evidence is insufficient to determine whether omega-3s affect the risk of skin cancers, including basal-cell carcinoma, squamous-cell carcinoma, and melanoma ⁹⁸. Findings from the Australian Ovarian Cancer Study suggest that there is no association between total or individual omega-3 intakes from foods and ovarian cancer risk ⁹⁹.

Associations between omega-3 intakes and endometrial cancer have been mixed. Some evidence indicates that dietary intakes of EPA and DHA may provide protection from the development of endometrial cancer ¹⁰⁰. Other evidence indicates that they decrease risk in normal-weight women but have no effect or even increase risk in overweight or obese women ¹⁰¹.

A systematic review and meta-analysis of 9 prospective cohort and 10 case-control studies did not find an association between fish or long chain -omega-3 intakes and risk of pancreatic cancer ¹⁰². Similarly, systematic reviews and meta-analyses have not found significant associations between fish consumption and risk of gastric or esophageal cancers ¹⁰³.

Summary

Overall, data from observational studies show no consistent relationship between omega-3s and overall cancer risk. Although there are some suggestions of reduced risk for breast and possibly colorectal cancers with higher long chain omega-3 intakes, randomized clinical trials are needed to confirm these findings.

The VITAL trial will examine the effects of EPA (465 mg/day) and DHA (375 mg/day) supplementation (with and without 2,000 IU/day vitamin D) for 5 years in 25,875 older adults on the primary prevention of cancer and cardiovascular disease ⁷³. Results from this clinical trial will shed more light on possible associations between these omega-3s and cancer.

Infant health and neurodevelopment

Numerous studies have examined the effects of maternal seafood and omega-3 intakes on infant birth weight, length of gestation, visual and cognitive development, and other infant health outcomes. High concentrations of DHA are present in the cellular membranes of the brain and retina ¹⁰⁴, and DHA is important for fetal growth and development. The accumulation of DHA in the retina is complete by birth, whereas accumulation in the brain continues throughout the first 2 years after birth.

In 2016, Agency for Healthcare Research and Quality (AHRQ) published a review on the effects of omega-3 fatty acids on child and maternal health ¹⁰⁵. This comprehensive report evaluated the findings from 95 randomized controlled trials and 48 prospective longitudinal studies and nested case-control studies. Most studies examined the effects of fish oil supplements or other DHA and EPA combinations in pregnant or breastfeeding women or of infant formula fortified with DHA plus arachidonic acid, an omega-6. The authors concluded that, except for small beneficial effects on infant birth weight and length of gestation, omega-3 supplementation or fortification has no consistent effects on infant health outcomes.

Recommendations from the Dietary Guidelines for Americans: The 2015–2020 Dietary Guidelines for Americans states that women who are pregnant or breastfeeding should consume 8–12 ounces of seafood per week, choosing from varieties that are higher in EPA and DHA and lower in methyl mercury, such as salmon, herring, sardines, and trout. These women should not consume certain types of fish, such as king mackerel, shark, swordfish, and tilefish that are high in methyl mercury, and they should limit the amount of white (albacore) tuna they consume to 6 ounces a week. The American Academy of Pediatrics has similar advice for breastfeeding women, recommending intakes of 200–300 mg DHA per day by consuming one to two servings of fish per week to guarantee a sufficient amount of DHA in breast milk ¹⁰⁶.

Most currently available infant formulas in the United States contain DHA and arachidonic acid. However, the authors of a paper published by the American Academy of Family Physicians and of two Cochrane reviews (one on full-term infants and one on preterm infants) have concluded that the evidence is insufficient to recommend the use of infant formulas that are supplemented with these fatty acids ¹⁰⁷, ¹⁰⁸, ¹⁰⁹.

Omega-3 polyunsaturated fatty acids for type 2 diabetes mellitus

People with type 2 diabetes are known to be at increased risk of cardiovascular disease (such as heart attack or stroke). Type 2 diabetes mellitus is the fourth leading cause of death in developed countries with a two fold excess mortality and a two to four fold increased risk of coronary heart disease and stroke. The typical dyslipidemia (abnormality in blood lipids) associated with type 2 diabetes is a combination of hypertriglyceridemia (high levels of fats (triglycerides) in the blood), low levels of HDL (high density lipoprotein) cholesterol and abnormal LDL (low density lipoprotein) composition. Low levels of HDL cholesterol and high levels of LDL cholesterol are associated with an increased risk of cardiovascular disease, while the raised levels of triglycerides are less clearly linked to an increased risk of cardiovascular disease. Several pharmacologic approaches have been used to treat diabetic dyslipidemia and standard dietary approaches focus on restriction of saturated fat and limitation of simple carbohydrate and alcohol intake. In the late 1980s, several investigators reported on the use of dietary supplementation with fish oil as a means of treating diabetic dyslipidemia. Dietary fats and oils from different sources differ considerably in their fatty acid composition. Animal fat is rich in saturated fatty acids, vegetable and marine oils are rich in polyunsaturated fatty acids. Most fish oils are of the so-called omega-3 variety (omega-3 polyunsaturated fatty acids (PUFAs)).

The review (source ¹¹⁰) shows that although some types of fat in the blood are reduced through omega-3 supplementation, others including LDL cholesterol (which may promote heart disease) were increased. Control of blood sugar levels was not affected by the treatment. There were no other adverse effects of the interventions noted. Clinical outcome trials of sufficient duration are required to establish conclusively the role of omega-3 PUFA in type 2 diabetes but our results do not suggest a major harmful effect on the balance of blood fats and confirm that it has no adverse affect on blood sugar control.

They concluded Omega-3 polyunsaturated fatty acids supplementation in type 2 diabetes lowers triglycerides and VLDL cholesterol, but may raise LDL cholesterol (although results were non-significant in subgroups) and has no statistically significant effect on glycemic control or fasting insulin. Trials with vascular events or mortality defined endpoints are needed.

Alzheimer’s disease, dementia, and cognitive function

Some, but not all, observational studies suggest that diets high in long chain omega-3s are associated with a reduced risk of cognitive decline, Alzheimer’s disease, and dementia ¹¹¹, ¹¹². Because DHA is an essential component of cellular membrane phospholipids in the brain, researchers hypothesize that long chain omega-3s might protect cognitive function by helping to maintain neuronal function and cell- membrane integrity within the brain ¹¹². This hypothesis is supported by findings from case-control studies indicating that patients with Alzheimer’s disease have lower serum levels of DHA than cognitively healthy people ¹¹³, ¹¹⁴. Lower serum DHA levels are also associated with more cerebral amyloidosis (build-up of protein deposits called amyloids) in healthy older adults, whereas higher DHA is correlated with preservation of brain volume ¹¹⁵.

Several systematic reviews and meta-analyses, including a Cochrane review, have assessed the effects of omega-3 supplementation on cognitive function and dementia in healthy older adults and those with Alzheimer’s disease or cognitive impairment ¹¹², ¹¹⁶, ¹¹⁷, ¹¹⁸. Overall, the findings indicate that LC omega-3 supplementation does not affect cognitive function in healthy older adults or in people with Alzheimer’s disease compared to placebo. For people with mild cognitive impairment, omega-3s may improve certain aspects of cognitive function, including attention, processing speed, and immediate recall ¹¹⁸. However, these findings need to be confirmed in additional clinical trials.

Omega-3 fatty acids for Depression in Adults

At present, New Cochrane research concludes that there is insufficient evidence for the use of Omega-3 fatty acid supplements in treating major depressive disorder ¹¹⁹.

A new 2015 Cochrane Review, published in the Cochrane Library, gathered together data from 26 randomized trials involving a total of 1,458 participants ¹²⁰). The trials investigated the impact of giving an Omega-3 fatty acid supplement in a capsule form and compared it to a placebo (dummy pill). In one study, involving 40 participants, researchers also investigated the impact of the same supplementation compared to an anti-depressant treatment. They found that, whilst people who were given Omega-3 fatty acids reported lower symptom scores than people with the dummy pill, the effect was small and there were important limitations that undermined their confidence in the results. Their analyses showed that although similar numbers of people experienced side effects, more data would be required to understand the risks of taking Omega-3 fatty acids.

Their primary analyses suggest a small-to-modest, non-clinically beneficial effect of n-3PUFAs on depressive symptomology compared to placebo; however the estimate is imprecise, and they judged the quality of the evidence on which this result is based to be low/very low. The one study that directly compares n-3PUFAs and antidepressants in their review finds comparable benefit. More evidence, and more complete evidence, are required, particularly regarding both the potential positive and negative effects of Omega-3 fatty acids for Major depressive disorder.

Omega-3 supplements in people with Cystic Fibrosis

The Cochrane review ¹²¹ found that regular omega-3 supplements may provide some benefits for people with cystic fibrosis with relatively few adverse effects, although evidence is insufficient to draw firm conclusions or recommend routine use of these supplements in people with cystic fibrosis. This review has highlighted the lack of data for many outcomes meaningful to people with or making treatment decisions about cystic fibrosis. A large, long-term, multicentre, randomised controlled study is needed to determine any significant therapeutic effect and to assess the influence of disease severity, dosage and duration of treatment. Future researchers should note the need for additional pancreatic enzymes.

Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn’s disease

Fish oil contains omega 3 fatty acids that may be beneficial in reducing inflammation, such as seen in the bowel of Crohn’s disease patients. Randomized placebo-controlled studies that evaluated the effect of daily intake of capsules containing omega-3 fatty acids to maintain remission in Crohn’s disease were reviewed. (Source ¹²²).

Evidence from two large high quality studies suggests that omega 3 fatty acids are probably ineffective for maintenance of remission in Crohn’s disease. Omega 3 fatty acids appear to be safe although they may cause diarrhea and upper gastrointestinal tract symptoms.

Omega 3 fatty acids for maintenance of remission in Ulcerative Colitis

Fish oil contains omega 3 fatty acids that may be beneficial in reducing inflammation, such as seen in the bowel of ulcerative colitis patients. Randomized placebo-controlled studies that evaluated the effect of daily intake of omega-3 fatty acids to maintain remission in ulcerative colitis were reviewed. No evidence was found that supports the use of omega 3 fatty acids for maintenance of remission in UC. Further studies using enteric coated capsules may be justified. (Source ¹²³).

Omega 3 fatty acids for preventing and slowing the progression of age-related Macular Degeneration

Age-related macular degeneration (AMD) is an eye condition that affects the central area of the retina (light-sensitive tissue at the back of the eye). AMD is associated with a loss of detailed vision and adversely affects tasks such as reading, driving and face recognition. In the absence of a cure, there has been considerable interest in the role of modifiable risk factors to prevent or slow down the progression of AMD. Evidence from population studies suggests that people who have a diet with relatively high levels of omega 3 fatty acids (such as those derived from fish oils) are less likely to develop AMD.

This review ¹²⁴ found that omega 3 long-chain-polyunsaturated-fatty-acids supplementation in people with Age-related macular degeneration for periods up to five years does not reduce the risk of progression to advanced Age-related macular degeneration or the development of moderate to severe visual loss. No published randomised trials were identified on dietary omega 3 fatty acids for primary prevention of Age-related macular degeneration. Currently available evidence does not support increasing dietary intake of omega 3 long-chain-polyunsaturated-fatty-acids for the explicit purpose of preventing or slowing the progression of Age-related macular degeneration.

Omega 3 fatty acids for dry eye disease

About 14% of adults in the United States have dry eye disease, a chronic condition in which decreased tear volume and quality leads to ocular surface inflammation and damage, causing discomfort and visual impairment ¹²⁵. Older women, in particular, have a higher risk of dry eye disease than other groups, possibly because of hormonal changes that affect the tear-producing glands ¹²⁵. Researchers hypothesize that omega 3s—particularly EPA and DHA—might reduce the risk of dry eye disease and relieve its symptoms because of their anti-inflammatory activity, and many patients take them as adjunctive treatments to artificial tears and other medications.

Some, but not all, observational studies show inverse associations between self-reported dietary consumption of omega-3s and risk of dry eye disease. For example, in a cross-sectional study of 32,470 women aged 45–84 participating in the Women’s Health Study, those in the highest quintile of total dietary omega-3 intake (mean of 1,990 mg/day) had a 17% lower risk of dry eye disease than those in the lowest quintile (mean intake of 920 mg/day) ¹²⁶. The study found a similar association for DHA—women in the highest versus the lowest quintiles of DHA intake had a 12% lower risk of dry eye disease; however, the results showed no significant associations for EPA. But in another cross-sectional study of 322 postmenopausal women, total dietary omega-3 intakes were not correlated with the prevalence of dry eye disease ¹²⁷.

Results from clinical trials using omega-3 supplementation, primarily EPA and DHA, have had mixed results in reducing the symptoms and signs of dry eye disease. Furthermore, there is no consensus on the optimal dose, composition, or length of omega-3 treatment for this condition ¹²⁸.

The studies that have found beneficial effects from omega-3 supplementation for symptoms and signs of dry eye disease include one showing that daily supplementation with 1,000 mg omega-3s (650 mg EPA plus 350 mg DHA) for 3 months in 518 men and women (mean age about 40 years) living in northern India reduced symptoms and some signs of dry eye disease compared with placebo ¹²⁹. In another clinical trial of 105 men and women, daily treatment with supplements containing 2,240 mg omega-3s (1,680 mg EPA and 560 mg DHA as re-esterified triglycerides) for 12 weeks also reduced symptoms of dry eye disease compared with placebo ¹³⁰. In addition, the supplements increased tear break-up time and decreased tear osmolarity (which would be likely to reduce ocular surface damage).

However, another large, randomized, double-blind clinical trial conducted in the United States found that EPA and DHA from fish oil supplements are no better than placebo at relieving symptoms or signs of dry eye disease ¹²⁵. This 12-month trial included 535 participants (about 81% female) aged 18 years or older (mean age about 58 years) with at least a 6-month history of moderate to severe dry eye disease. Among them, 349 participants received daily supplements of 3,000 mg omega-3s (2,000 mg EPA plus 1,000 mg DHA), and 186 received a placebo containing 5,000 mg olive oil. Participants could continue taking medications for dry eyes, including artificial tears and prescription anti-inflammatory eye drops, as well as omega-3 supplements as long as the total dose of EPA plus DHA was less than 1,200 mg per day. At the end of the study, symptoms were less severe than at baseline in both groups, but the results showed no significant differences between groups. Groups also showed no significant differences compared with baseline in signs of dry eye disease, including conjunctive and cornea integrity as well as tear volume and quality.

Overall, the evidence to date shows no consistent relationship between omega-3s and dry eye disease. More research is warranted to fully understand whether increased intakes of dietary or supplemental omega-3s help reduce the risk of dry eye disease and whether they are beneficial as an adjunct treatment.

Omega-3 fatty acids for Autism Spectrum Disorders

It has been suggested that difficulties associated with autism spectrum disorders may be explained in part by lack of omega-3 fatty acids, and that supplementation of these essential fatty acids may lead to improvement of symptoms. To date there is no high quality evidence that omega-3 fatty acids supplementation is effective for improving core and associated symptoms of autism spectrum disorder. Given the paucity of rigorous studies in this area, there is a need for large well-conducted randomised controlled trials that examine both high and low functioning individuals with autism spectrum disorder and that have longer follow-up periods ¹³¹.

ADHD

A systematic review and meta-analysis of 10 studies in children with ADHD or related neurodevelopmental disorders, such as developmental coordination disorder, found no improvements with omega-3 supplementation on measures of emotional lability, oppositional behavior, conduct problems, or aggression ¹³². However, in subgroup analyses of only the higher-quality studies and those with strict inclusion criteria, omega-3 supplementation (60 to 1,296 mg/day EPA and/or DHA) did significantly improve parent-rated emotional lability and oppositional behavior.

Childhood allergies

A systematic review and meta-analysis of 10 prospective cohort studies and 5 randomized clinical trials on omega-3 intakes during pregnancy and outcomes of childhood allergic disease (eczema, rhino-conjunctivitis, and asthma) found inconsistent results ¹³³. Although the authors could not draw firm conclusions due to the heterogeneity of the studies and their results, they concluded that the overall findings were “suggestive” of a protective association between higher maternal intakes of LC omega-3s or fish and incidence of allergic disease symptoms in the offspring. The authors of a Cochrane review that included eight LC omega-3 supplementation trials concluded that there is limited evidence to support the use of LC omega-3 supplements by women during pregnancy and/or lactation for reducing the risk of allergic disease in their children ¹³⁴.

Omega-3 fatty acid supplementation for Intermittent Claudication

Intermittent claudication is a pain in the calf due to a lack of blood needed to supply those muscles with oxygen during exercise or movement, ultimately resulting in the person to slow or stop movement. It is the most common presenting symptom for people with long-standing lower limb arterial disease resulting from narrowing of the arteries that supply the lower limbs with blood. This narrowing most commonly occurs through the process of atherosclerosis in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol and triglycerides. People with mild lower limb arterial disease are advised to stop smoking, exercise, and take an antiplatelet agent to prevent heart attack or stroke. Medication to improve walking distance is only of limited value.

Omega-3 fatty acids appear to have little haematological benefit in people with intermittent claudication and there is no evidence of consistently improved clinical outcomes (quality of life, walking distance, ankle brachial pressure index or angiographic findings). Supplementation may also cause adverse effects such as nausea, diarrhoea and flatulence. Further research is needed to evaluate fully short- and long-term effects of omega-3 fatty acids on the most clinically relevant outcomes in people with intermittent claudication before they can be recommended for routine use ¹³⁵.

Omega-3 fatty acids for bipolar disorder

This systematic review (source ¹³⁶) investigated the efficacy of omega-3 fatty acids for bipolar disorder. Five randomised controlled trials met inclusion criteria for the review. Only one trial provided data that could be analysed, investigating ethyl-EPA as an adjunctive treatment in a mixed outpatient population. Some positive benefits were found for depressive symptoms but not for mania, and no adverse events were reported. There is currently insufficient evidence on which to base any clear recommendations concerning omega-3 fatty acids for bipolar disorder. However, given the general health benefits and safety of omega-3, the preliminary evidence from this review provides a strong case for well-powered, high-quality trials in specific index populations.

Results from one study showed positive effects of omega-3 as an adjunctive treatment for depressive but not manic symptoms in bipolar disorder. These findings must be regarded with caution owing to the limited data available. There is an acute need for well-designed and executed randomised controlled trials in this field.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. Its symptoms include pain, swelling, stiffness, and functional impairments. RA is typically treated with nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic drugs. Due to their antiinflammatory effects, some scientists hypothesize that long chain omega-3s reduce some of the symptoms of rheumatoid arthritis and patients’ reliance on NSAIDs and corticosteroids.

A 2012 systematic review concluded that the types of omega-3s found in seafood and fish oil may be modestly helpful in relieving symptoms of rheumatoid arthritis. In the studies included in the review, many of the participants reported that when they were taking fish oil they had briefer morning stiffness, less joint swelling and pain, and less need for anti-inflammatory drugs to control their symptoms.

Reviews and meta-analyses of studies that assessed whether fish oil and long chain omega-3s are beneficial for rheumatoid arthritis have had inconsistent findings. Some suggest that they do not significantly affect the clinical symptoms of RA but do reduce the amounts of NSAIDs and corticosteroids that patients need. Others indicate that LC omega-3s reduce joint swelling and pain, morning stiffness, and number of painful joints in addition to reducing NSAID use. Some researchers suggest that differences in findings could be due in part to whether patient-determined use of NSAIDs is considered a measure of pain.

Findings to date suggest that long chain omega-3s may be helpful as an adjunctive treatment to pharmacotherapy for ameliorating the symptoms of rheumatoid arthritis ¹³⁷, ¹³⁸. However, more research is needed to confirm this finding.

Diseases of the Brain and the Eye

DHA plays important roles in the functioning of the brain and the eye. Research is being conducted on DHA and other omega-3 fatty acids and diseases of the brain and eye, but there is not enough evidence to draw conclusions about the effectiveness of omega-3s for these conditions.

If You Are Considering Omega-3 Supplements

• Do not use omega-3 supplements to replace conventional care or to postpone seeing a health care provider about a health problem.
• Consult your health care provider before using omega-3 supplements. If you are pregnant, trying to become pregnant, or breastfeeding; if you take medicine that affects blood clotting; if you are allergic to fish or shellfish; or if you are considering giving a child an omega-3 supplement, it is especially important to consult your (or your child’s) health care provider.

Safety

• Omega-3 fatty acid supplements usually do not have negative side effects. When side effects do occur, they typically consist of minor gastrointestinal symptoms, such as belching, indigestion, or diarrhea.
• It is uncertain whether people with fish or shellfish allergies can safely consume fish oil supplements.
• Omega-3 supplements may extend bleeding time (the time it takes for a cut to stop bleeding). People who take drugs that affect bleeding time, such as anticoagulants (“blood thinners”) or nonsteroidal anti-inflammatory drugs (NSAIDs), should discuss the use of omega-3 fatty acid supplements with a health care provider. Intakes of about 3–4 g of EPA and DHA per day have resulted in a moderate increase in bleeding times that are generally lower than those seen with aspirin therapy. On rare occasions, mild bouts of diarrhea or other minor gastrointestinal disturbances are sometimes seen with the use of encapsulated fish oil supplementation.
• Fish liver oils, such as cod liver oil, are not the same as fish oil. Fish liver oils contain vitamins A and vitamin D as well as omega-3 fatty acids. Both of these vitamins can be toxic in large doses. The amounts of vitamins in fish liver oil supplements vary from one product to another.
• There is conflicting evidence about whether omega-3 fatty acids found in seafood and fish oil might increase the risk of prostate cancer. Additional research on the association of omega-3 consumption and prostate cancer risk is under way.

In general taking fish oil supplement is quite safe. 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 ¹¹⁸, ¹³⁹.

Common gastrointestinal symptoms like nausea occurred at rates of ≈4% at dosages <3 g/d and increased to ≈20% at a dosage of 4 g/d.

The Institute of Medicine did not establish a UL for any omega-3s, although it noted that high doses of DHA and/or EPA (900 mg/day of EPA plus 600 mg/day DHA or more for several weeks) might reduce immune function due to suppression of inflammatory responses. Doses of 2–15 g/day EPA and/or DHA might also increase bleeding time by reducing platelet aggregation ¹⁰⁴. However, according to the European Food Safety Authority, long-term consumption of EPA and DHA supplements at combined doses of up to about 5 g/day appears to be safe ¹⁴⁰. It noted that these doses have not been shown to cause bleeding problems or affect immune function, glucose homeostasis, or lipid peroxidation. The FDA recommends not exceeding 3 g/day EPA and DHA combined, with up to 2 g/day from dietary supplements. Some doses used in clinical trials exceed these levels.

Omega-3 supplements may extend bleeding time (the time it takes for a cut to stop bleeding). People who take drugs that affect bleeding time, such as anticoagulants (“blood thinners”) or nonsteroidal anti-inflammatory drugs (NSAIDs), should discuss the use of omega-3 fatty acid supplements with a health care provider.

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