Eicosapentaenoic (EPA) and Docosahexaenoic Acid (DHA)

What are eicosapentaenoic (EPA) and docosahexaenoic acid (DHA)?

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are nonessential long-chain polyunsaturated omega-3 fatty acids, which can be produced in the human body from alpha-linolenic acid, but under certain conditions, for example, in preterm infants, their production may be insufficient. In the human body, DHA can be produced from EPA and, to a lesser extent, EPA can be produced from DHA ^[3]. Foods rich in EPA and DHA include certain oily fish (see Chart 1). In fish, EPA and DHA are bound to glycerol, so they are in the form of triglycerides ^[4].

Chart 1. Foods High in EPA and DHA
FOOD	EPA (g)	DHA (g)	Amount providing 1 g EPA + DHA
Mackerel, Pacific (3 oz, 85 g)	0.6	1	1.5 oz
Salmon, chinook (3 oz, 85 g)	0.9	0.6	2 oz
Salmon, coho, cooked (3 oz, 85 g)	0.5	0.7	3 oz
Salmon, sockeye (3 oz, 85 g)	0.5	0.6	3 oz
Salmon, chum, canned (3 oz, 85 g)	0.4	0.6	3 oz
Oysters, Pacific (3 oz, 85 g)	0.7	0.3	3 oz
Halibut, Greenland (3 oz, 85 g)	0.6	0.4	3 oz
Sardines, Pacific, canned (3 oz, 85 g)	0.5	0.7	3 oz
Trout, rainbow, wild (3 oz, 85 g)	0.4	0.4	3.5 oz

Chart 1. lists foods high in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ^[20,21] and low in sodium ^[22], mercury ^[23,33] and PCBs ^[24,33]

EPA + DHA Supplements

EPA and DHA supplements without prescription (over-the-counter):

• Fish oils containing EPA and DHA are extracted from the tissues of oily fish, such as sardines, anchovies, herring or salmon.
• Cod liver oil is high in EPA and DHA, and also in vitamins A and D.
• Krill oil contains EPA, DHA, phosphatidylcholine (“marine lecithin”), folic acid and vitamin A. It is extracted from shrimp-like marine crustaceans of order Euphausiacea ^[5]. Krill oil is Generally Recognized As Safe (GRAS) by the U.S. Food and Drug Administration (FDA) ^[5].
• DHA-rich oil from the microalgae Crypthecodinium cohnii ^[9].
• Glycerol esters of EPA and DHA are compounds of glycerol and three fatty acids, one of which is either EPA or DHA; they also naturally occur in fish ^[4].

Prescription EPA and DHA supplements:

• Ethyl esters of EPA and DHA (ethyl-EPA or EPA EE and ethyl-DHA or DHA EE) are semi-synthetic compounds of ethanol and three fatty acids, from which at least two are either EPA or DHA, so ethyl esters are more concentrated source of EPA + DHA than glycerol esters ^[10]. Ethyl esters are available as prescription drugs for hypertriglyceridemia in the U.S. and EU, or as nonprescription dietary supplements elsewhere.
• Methyl esters of EPA and DHA (methyl-EPA or EPA ME and methyl-DHA or DHA ME)

Some, but not all, studies have shown that free omega-3 fatty acids from fish oil or omega-3 triglycerides from fish are better absorbed than omega-3 ethyl esters ^[4]. One study has shown that methyl esters of EPA and DHA are equally effective in lowering triglycerides than glycerol esters and they may both increase LDL cholesterol ^[11].

EPA and DHA or Fish Oil Benefits

Consumption of fish, which are high in EPA and DHA, at least once to twice weekly, or taking fish oil (EPA + DHA) supplements is PROBABLY EFFECTIVE for ^[1,12]:

• Decreasing the risk of coronary heart disease
• Lowering the blood triglycerides (but not total or LDL cholesterol) ^[7,8]
• Fish oil may slightly decrease joint stiffness and pain in rheumatoid arthritis ^[6]; it may take at least 12 weeks for supplements to take effect.
• In one small trial, fish oil has prevented symptoms of salicylate intolerance ^[15].

NOTE 1: Consumption of oily fish high in omega-3 fatty acids can decrease the risk of chronic heart disease in people with known risk factors of chronic heart disease (obesity, genetic predisposition, high blood triglycerides and LDL cholesterol), but less likely in people without known risk factors ^[16].

NOTE 2: Fish oil may have no additional heart-protective benefit for those who regularly eat fish high in omega-3 fatty acids.

There is SOME EVIDENCE that fish oil supplements (3 g/day for a week) can decrease delayed onset muscle soreness (DOMS) after exercise ^{[36,37,38,39]}. In some studies, fish oil did not reduce DOMS, though ^[40,41].

Omega-3 supplements probably have NO EFFECT on glucose tolerance (no effect on HgbA1c, the indicator of the long-term glucose levels) ^[13].

There is INSUFFICIENT EVIDENCE about the effectiveness of omega-3 fatty acids supplements (fish oil) in prevention or treatment of abnormal heart rhythms, age-related macular degeneration (AMD) ^[17], Alzheimer’s disease, angina pectoris (heart-related chest pain), asthma, atherosclerosis, autism, bipolar disorder, cancer (colorectal, breast, prostate), Crohn’s disease (inflammatory bowel disease), cystic fibrosis, depression, diabetes mellitus type 2 (insulin resistance) ^[19,35], eczema, epilepsy, fatigue, high blood pressure ^[13], high cholesterol, IgA nephropathy, kidney stones, menstrual pain, migraine, movement disorders (Tardive dyskinesia), multiple sclerosis, nephrotic syndrome, nerve pain, osteoarthritis, osteoporosis, painful menstruation, pancreatitis, psoriasis, Raynaud’s disease, schizophrenia, sickle cell disease, stroke, systemic lupus erythematosus (SLE), thrombosis, transplant rejection, ulcerative colitis or weight loss in cancer, or in enhancing immunity, sun protection, visual acuity, wound healing, or brain development in infants ^[12,18].

EPA and DHA Safety: Side Effects, Toxicity

Side effects of fish oil supplements may include fishy aftertaste and odor, belching, heartburn, nausea, diarrhea, constipation; doses greater than 3 g/day may increase the risk of bleeding ^[1]. Besides that, ethyl esters of DPA and DHA may cause jaw, arm or back pain or irregular heart beat ^[10]. Allergic reactions may include sweating, flushing, rash, chest pain, nausea, diarrhea.

Regular consumption of cod liver oil may lead to excessive intake of vitamins A, D or E ^[31]. No serious side effects of fish oil during pregnancy or breastfeeding have been reported.

Fish oil and cod liver oil supplements usually do not contain toxic amounts of mercury or other toxins ^[32].

Who should avoid omega-3 foods or supplements ^[31]?

• Individuals allergic to fish
• Pregnant and breastfeeding women, infants and small children should avoid fish high in mercury (see below).
• Children, pregnant and breastfeeding women, anyone with diabetes or taking contraceptive pills, blood thinners, beta-blockers, diuretics or other drugs should speak with a doctor before taking omega-3 supplements.

Mercury and Other Contaminants in Fish

Mercury is toxic for the brain and kidneys, especially for the fetus, infants and young children. The U.S. Food and Drug Administration (FDA) and Environmental Protection Agency (EPA) recommend pregnant women and those who may become pregnant in a year, breastfeeding women and young children to avoid eating fish high in mercury (Chart 2) ^[26].

PCBs (polychlorinated biphenyls) are toxic industrial chemicals, which are known animal carcinogens and are considered probable carcinogens for human ^[27].

In general, farmed fish, especially European fish, such as farmed Atlantic salmon tend to be high in contaminants (mercury, dioxin and PCBs from grounded fish used as feed, but also antibiotics, pesticides, growth hormone) ^[28]. Sea areas arranged by concentration of mercury and other contaminants (from highest to lowest): The Gulf of Mexico > Mediterranean > Atlantic > Pacific ^[29].

The current Food and Drug Administration (FDA) safety limit for methyl mercury in fish is 1 ppm (parts per million), and for PCBs 2 ppm ^[30], but the limit of Environmental Protection Agency (EPA) for PCBs is much lower: 0.4 ppm.

To reduce the toxin exposure, remove the skin and under-skin fat from fish, and prepare them by grilling or broiling rather than frying ^[27].

Chart 2. Fish High in Mercury and PCBs
FISH	Mercury ppm (max) [23]	PCBs [24,34]
Shark	4.5
Tilefish (Gulf of Mexico)	3.7
Swordfish	3.2
Bass, Chilean	2.2
Barramundi	PubMed, Betterhealth
Tuna, fresh	1.8	High
Mackerel, Spanish or king	1.7
Halibut	1.5
Bluefish	1.5	High
Snapper	1.4
Grouper, all species	1.2
Orange roughy	1.1
Sablefish	1
Cod	1
Bowflin	1
Bass, saltwater, black, striped	1	Moderate
Tuna, canned, light or albacore	0.9	High
Marlin	0.9 (methylmercury)
Pollock	0.8
Sea trout (weakfish)	0.7	High
Trout, freshwater	0.7
Crab	0.6
Chain pickerel	0.6
Herring	0.6	High
Tilefish, Atlantic	0.5
Walleye	?	High
Eel, American or European	?	High
Croaker, white, Atlantic	?	High
Flounder, summer or winter	?	High
Sturgeon, wild	?	High
Perch, yellow	?	High
Salmon, farmed or Atlantic	?	High

Chart 2 references: ^{[23,24,34,35]}