Scientific Name(s):Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)
Common Name(s): Marine oils , marine oil fatty acids , n-3 fatty acids , omega-3 fatty acids , omega-3 polyunsaturated fatty acids ( PUFAs ), long-chain PUFAs ( LCPUFAs ), Lovaza
Clinical benefit is strongest for lowering the risk of coronary artery disease and decreasing serum triglycerides. Reductions in the risk for all-cause mortality, cardiac death, and sudden death have been established for omega-3 fatty acid supplementation for at least 1 year's duration. The United States Food and Drug Administration (FDA) has approved the use of fish oil for reducing very high triglyceridemia (at least 5.65 mmol/L) in adults as an adjunct to diet. Evidence for use of parenteral fish oil lipid emulsion is mounting in severely ill and surgical patients. Evidence for a role in rheumatoid arthritis remains equivocal but promising. No consistent relationship between fish oil consumption and reduction in the risk of stroke or maintenance in inflammatory bowel disease has been established. Other areas of interest in the therapeutic use of fish oils requiring further study include asthma and allergy, dysmenorrhea, mental health, and the promotion of postnatal growth and development.
The American Heart Association (AHA) recommends a minimum of 2 fatty fish meals per week. Clinical trials suggest fish oil supplementation of omega-3 fatty acids 1 g/day in coronary heart disease, and where triglycerides are elevated, a minimum of omega-3 fatty acids 2 g/day up to a maximum of 4 g/day. Fish oil 1,000 mg approximates to omega-3 fatty acids (eicosapentaenoic acid [EPA]/docosahexaenoic acid [DHA]) 300 to 400 mg.
Contraindications have not yet been identified.
Potential for mercury ingestion. Avoid use.
None well documented.
Fish oil at dosages of EPA/DHA 2 to 5.4 g/day is well accepted and tolerated. Mild GI discomfort was reported in clinical trials.
Research reveals little or no information.
Fish oils are predominantly comprised of the omega-3 fatty acids EPA and DHA; “fish oil” is a term frequently used interchangeably with, and in reference to, EPA and DHA. Marine sources containing the highest content of omega-3 fatty acids are fatty fish (eg, mackerel, halibut, salmon, bluefish, mullet, sablefish, menhaden, anchovy, herring, lake trout, coho, sardines), which provide 1 g or more of omega fatty acids per 100 g (3.5 oz) of fish. Tuna, seal, and shellfish (eg, oysters) are additional sources. 1 , 2 , 3 , 4 , 5
Because marine fish stocks are limited and because many fish stocks are currently contaminated by pollutants (eg, methylmercury, organochlorine pesticides), it has been proposed that the algal genes responsible for EPA and DHA production be cloned into plants. 6 , 7 Oils from transgenic plants would be rich in EPA and DHA, and although some success has been achieved, challenges in the biosynthetic pathways in higher plants have not yet been surmounted. 8 , 9 EPA and DHA can be synthesized, albeit inefficiently, from the essential omega-3 fatty acid alpha-linolenic acid (ALA). ALA cannot be synthesized by humans and must be obtained from the diet. ALA is found in flaxseed, canola, soybean, walnut, and wheat germ oils, nuts and seeds, and vegetables. Additionally, DHA can be synthesized from EPA. 1 , 2 , 3
Most uses of fish oils have been based on the beneficial effects of EPA and DHA, specifically those related to cardiovascular, inflammatory, neural, and hormonal support. Interest in possible health benefits followed observations that populations with a high dietary intake of fish, such as Eskimo and Inuit populations, had low incidences of atherosclerotic and thrombotic disorders and inflammatory conditions. 10 , 11 In 1789, a publication described the beneficial effects of cod liver oil in rheumatism, and in 1824 the same oil was reported effective in the prevention of rickets. 12 Historically, deficiencies were noted in infants fed non- or low-fat diets or in patients receiving long-term (eg, 2 to 3 weeks) parenteral nutritional formulations lacking polyunsaturated fatty acids. 2 , 3
EPA and DHA are omega-3, long-chain (20 carbons or more) polyunsaturated fatty acids (PUFAs). EPA consists of a 20-carbon chain with 5 double bonds (20:5), while DHA is a 22-carbon chain with 6 double bonds (20:6). As represented by the omega-3 nomenclature, the first double bond is located at the third carbon from the methyl group (omega) end of the chain. 2 , 3 C-13 nuclear magnetic resonance pattern recognition has been used to analyze the species of fish from which commercial fish oil products are derived. 13 Homogenization of fish oils into milk has been explored. 14 Challenges for the incorporation of fish oils into other foodstuffs include the propensity of EPA and DHA to oxidize, as well as their off-tastes and smells. Thus, oil-filled capsules are the current preferred supplement product.
Uses and Pharmacology
Omega-3 fatty acids are metabolized into eicosanoids, which have important physiologic properties and include prostaglandins, prostacyclins, thromboxanes, and leukotrienes. Eicosanoids are potent regulators of blood pressure, blood clotting, childbirth, and gastric secretions, as well as immune and inflammatory responses. The actual location of the double bond in the fatty acid chain affects its metabolism such that the structure and function of omega-3–derived eicosanoids differ from those derived from omega-6 fatty acids (eg, arachidonic acid). For example, omega-3–derived eicosanoids tend to decrease blood clotting and inflammatory responses. This contrasts with the arachidonic acid (omega-6)–derived eicosanoids, which increase clotting and inflammatory responses. 2 , 3 , 15Asthma/Allergy
The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet make data from animal studies largely irrelevant.Clinical data
To date, clinical benefit of fish oil in asthma is controversial. 10 , 16 Omega-3 fatty acids do not have an effect on eosinophils and mast cells, which may explain a relative lack of efficacy in this inflammatory condition. 10 The role of other constituents in fish oil is unknown. Limited evidence exists of an effect of fish oils on exercise-induced asthma. 17 A potential for an enteral nutritional formula containing EPA plus gamma-linolenic acid as adjuvant therapy in the clinical management of acute respiratory distress syndrome has been suggested. 18 Use of fish oil supplementation during pregnancy and breast-feeding to reduce the incidence of food allergy in infants has also been evaluated. 19
Studies in animals have demonstrated pro- and anti-arrhythmic properties of fish oil. 24 , 25 In experimental arrhythmias, fish oil prevented arrhythmias related to ischemia, but not to reperfusion injury. 24Clinical data
Reviews have examined the utility of fish oils in treating arrhythmias. The mechanism of protection is not well understood, and some classes of patients may not benefit. 26 , 27 , 28 A meta-analysis of all studies up to the year 2008 for ventricular arrhythmias found only a trend of a protective effect of fish oil on time to first ventricular fibrillation. Dosages used in the included trials ranged from fish oil 900 to 2,600 mg. 29 , 30 A further meta-analysis found a nonsignificant reduction in the primary outcome of arrhythmias or death from all causes. For the secondary outcome of death from cardiac causes, a reduction was found. 31 Results from the 2003 Diet and Angina Randomized Trial (DART-2) found an increase in death in patients with angina pectoris, and in patients with implanted cardioverter defibrillators, no overall effect on the risk of discharge has been found, possibly because of the potential for fish oil to exhibit pro-arrhythmic properties. 25 , 32Coronary heart disease
The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies in cardiovascular conditions largely irrelevant.Clinical data
A potential role for fish oils in cardiovascular disease risk reduction first came from observations of Inuit populations in Greenland. Despite ingesting up to 40% of calories as fat (mostly from marine sources), this group exhibited a lower incidence of coronary artery disease compared with individuals on a more conventional diet. 33
Systematic reviews and meta-analyses have been published on trials evaluating the effect of fish oil supplementation on coronary heart disease. Reductions in the risk for all-cause mortality, cardiac death, and sudden death have been established for omega-3 fatty acid supplementation for at least 1 year's duration. Evidence for secondary prevention of coronary heart disease (CHD) is greater than that for primary prevention and is informed mainly by 3 large trials; the GISSI trials (Italy) and the JELIS (Japan) trial. Evidence from these meta-analyses is inconclusive for prevention of stroke and nonfatal myocardial infarction (MI). 28 , 30 , 34 , 35 , 36
The GISSI-Prevenzione trial enrolled 11,324 patients with CHD (post-MI) and evaluated omega-3 fatty acid supplementation compared with vitamin E. A reduction was found for the primary end point of a combined outcome of death, nonfatal MI, and stroke for omega-3 fatty acids. 34 , 37 Data from the GISSI heart failure trial (N = 7,046) allows for a calculation of 56 patients with preexisting heart to be treated with omega-3 fatty acid supplementation for 3.9 years to avoid 1 death, or 44 patients to be treated for the same length of time to avoid 1 death or hospital admission for cardiac causes. No benefit for the prevention of stroke was found. For the primary prevention of CHD, the GISSI heart failure trial found a nonsignificant effect for omega-3 fatty acids. The JELIS trial enrolled 18,645 persons with hypercholesterolemia and found a reduction in the risk from a major coronary event, including sudden death and MI, and found evidence of secondary protection against the risk of stroke. 30 , 34
A large (N = 13,578), older study found no effect of ALA supplementation on cardiovascular outcomes. 30 Evidence is inconclusive for the effect of fish oils on hypertension and is based on older studies. 38 , 39 , 40 , 41 , 42 Reductions in heart rate, especially where the resting rate is higher than 69 bpm, have been demonstrated in some, but not all, studies of 12 weeks of fish oil supplementation. 43 , 44 , 45 Effects of fish oil supplementation on C-reactive protein (a marker for coronary heart disease) are equivocal. 46 , 47CNS effects
The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet makes data from animal studies largely irrelevant.Clinical data
Polyunsaturated fatty acids, including DHA, are essential for normal brain development and any deviation from normal levels is associated with cognitive impairment. 12 Data from adequately controlled clinical trials are insufficient to make definitive statements about omega-3 fatty acid supplemental in specific mental health disease. Limited trials have evaluated fish oil supplementation in schizophrenia and in attention deficit hyperactivity disorder with equivocal results. 12 , 48 Clinical trials are more supportive of a place in therapy of depression for fish oils, although specific sub-populations are considered more likely to benefit, including perinatal depression, childhood/adolescent depression, and depression associated with bipolar disorder. 49 , 50 , 51 While there is evidence of an association of dementia with low levels of n-3 fatty acids in diet and plasma, supplementation with fish oil has not been shown to reverse or prevent dementia, 52 or to improve quality of life indices in elderly patients. 53Critical illness and surgical patients
The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies largely irrelevant.Clinical data
Randomized, controlled trials have been conducted in severely ill patients in intensive care units (ICUs) and among elective surgical patients units comparing fish oil–enriched lipid emulsions with standard enteral formulations. Meta-analyses have been conducted that recognize the heterogenous nature of the study populations (including medical, surgical, and trauma related) and formulations used (ranging from EPA/DHA 1 to 6.6 g/L) 54 and the difficulty in recruiting patients into trials. 54 , 55 , 56 , 57
Findings from these meta-analyses are in favor of supplemental fish oil in terms of reduced length of stay in hospital and in ICU, decreased ventilator time, decreased new organ failure, and decreased postoperative infections. 54 , 55 , 56 , 57 , 58 Twenty-eight–day mortality was decreased in 1 meta-analysis of ICU patients, 54 but not in an analysis of major abdominal surgery. No serious adverse events were recorded in the included trials. 56 Further clinical trials in patients with GI surgery, not included in the meta-analyses, have been conducted with similar positive results. 59 , 60 , 61 , 62Diabetes
The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies in diabetes largely irrelevant.Clinical data
A Cochrane systematic review of patients with type 2 diabetes mellitus revealed that fish oil 3 to 18 g/day supplementation lowered triglycerides and had no statistically significant effect on glycemic control, total cholesterol, or high-density lipoprotein (HDL) cholesterol. However, it did raise low-density lipoprotein (LDL) cholesterol by 0.21 mmol/L (especially in patients with hypertriglyceridemia on doses higher than EPA 2 g). 9 Further randomized controlled trials in overweight patients and in patients with type 2 diabetes do not demonstrate an effect of fish oils on insulin sensitivity or fasting blood glucose. 63 , 64 These findings are consistent with an Agency for Healthcare Research and Quality evidence report. 65Infant development
Dietary fat is fundamental for the growth and development of infants. DHA is an important component of structural lipids of cell membranes, and its perinatal availability has been related to visual acuity development, neurological development, behavior, and brain growth. 66 , 67 Accretion occurs primarily during the last trimester of pregnancy via the placenta and the infant's first year of life from breast milk and dietary sources. 68 , 69Animal data
Research reveals no animal data regarding the use of fish oil in postnatal growth and development.Clinical data
Evidence from systematic reviews provides little support for benefit of supplementation with long-chain PUFAs (LCPUFAs), such as DHA, to either term or preterm infants. 68 , 69 Formula-fed infants have been shown to have less DHA than infants fed breast milk. Reduced neural function and visual acuity have been documented in preterm infants fed formula relative to those who were breast-fed. A review of LCPUFA supplementation studies demonstrated no benefit to visual or cognitive development in infants born at term receiving LCPUFA-supplemented formula. 68 However, some evidence did show that omega-3 fatty acid supplementation of formula increases the early rate of visual maturation in preterm infants. 69
Malnourished infants, who may have poor fat absorption, appear to also absorb fish oil supplements well and use this source of fatty acid for more than an energy source. 70
Although formula supplemented with omega-3 fatty acids increases DHA and EPA levels in healthy and malnourished infants, this may be at the expense of omega-6–derived fatty acids (eg, arachidonic acid). Because high levels of DHA and EPA appear to successfully compete for cyclooxygenase and other eicosanoid enzymes, formula-fed infants should be supplemented with omega-3 as well as omega-6 LCPUFAs if their fatty acid status is to be comparable with that of the breast-fed infant. 66 , 67 , 71Inflammatory bowel disease
In animal models of inflammatory bowel disease, fish oil has been shown to exert a protective effect, which is considered to be via anti-inflammatory mechanisms. 72Clinical data
Cochrane meta-analyses and systematic reviews of randomized controlled trials have been undertaken for the effect of omega-3 fatty acids in induction of remission in ulcerative colitis and for maintenance of remission of ulcerative colitis and Crohn disease. 73 , 74 , 75 For induction of remission in ulcerative colitis, trials were of crossover and parallel design, and because of heterogeneity of outcomes and methodology, the data were not pooled. Of the 6 included studies, 1 small study showed benefit for induction within 3 months. The other trials showed benefit only for secondary outcome measures, and no recommendation can be made regarding the effect of fish oil supplementation. 73 For maintenance of remission in ulcerative colitis 74 and Crohn disease, 75 relapse rates were similar for omega-3 fatty acids and the control intervention. For Crohn disease, the meta-analysis included data from both of the large EPIC trials. The conclusion that omega-3 fatty acids have no effect on maintenance of remission is an update on previous meta-analyses. 75Lipid-lowering effects
The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies in hyperlipidemia redundant.Clinical data
Several meta-analyses and systematic reviews of clinical trials in hyperlipidemia have been conducted. 76 , 77 , 78 , 79 Clinical reductions in triglycerides (−0.34 mmol/L [95% CI, −0.41 to −0.27]) were found in a meta-analysis of 47 randomized, controlled trials (N = 16,511). 76 In 2004, the FDA approved the use of a fish oil for reducing very high triglyceridemia (at least 5.65 mmol/L) in adults as an adjunct to diet. 78 The investigators of the effect of fish oil in maintenance of remission in Crohn disease (the EPIC trials) reported decreases in serum triglycerides in the study populations. 75 A place in therapy is also suggested for fish oil in hypertriglyceridemia consequent to type 2 diabetes and chronic kidney disease and as add-on therapy with statins in cardiovascular disease. 11 , 76 , 78 , 79 Increases in LDL cholesterol as well as HDL have been observed, and may be clinically important. 76 , 78 , 80 Other studies have noted changes in concentration and particle size of very low-density lipoproteins. 79 , 81Rheumatoid arthritis
EPA is a competitive substrate with arachidonic acid for the generation of less active eicosanoid metabolites (eg, leukotrienes) and acts to reduce inflammation. 10 The most profound anti-inflammatory effects of n-3 fatty acids are on neutrophil function and mediator generation, providing a more likely benefit in neutrophilic inflammatory diseases, including arthritis. 82Animal data
The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies largely irrelevant.Clinical data
Inuit populations with a diet high in LCPUFAs (especially EPA and DHA from seal and fish oils), report a low incidence of rheumatoid arthritis. 83 Meta-analyses of controlled trials have been conducted with equivocal findings. 65 , 83 , 84 Issues raised by the analyses include confounding of results with the use of potentially active placebo oils (eg, corn and olive oil) and management of dropouts in the individual trials. 83 , 85 Reductions in patient-reported joint pain and morning stiffness and a reduced need for nonsteroidal anti-inflammatory drugs are potential benefits of fish oil therapy, while reduction in cardiovascular risk may also be a valuable attribute. 83
A minimum daily dose of EPA/DHA 3 g appears to be necessary to reduce the release of leukotriene B4 from stimulated neutrophils and of interleukin-1 from monocytes, while dosages of more than 6 g/day do not appear to confer any additional benefit. 48Stroke
The relatively low risk of adverse events with the use of fish oils and widespread consumption of fish in the diet, along with evidence from numerous clinical studies, make data from animal studies in stroke largely irrelevant.Clinical data
Despite data from large trials being available (including the GISSI, JELIS, and EPIC-Norfolk trials), no consistent relationship between fish oil consumption and reduction in the risk of stroke has been established. 34 , 78 , 86 , 87 The etiology of the stroke may be of relevance, with omega-3 fatty acids considered to be more likely to demonstrate positive effects on stroke related to ischemic causes than hemorrhagic stroke because of platelet anti-aggregating properties. 78 , 86 A 2004 meta-analysis of prospective cohort studies found a higher incidence of stroke in people who never consumed fish or only consumed fish less than once per month versus a higher fish intake. A reduced risk for total stroke was found for intakes of fish at least once per week. Whole fish also contain the proteins taurine, arginine, and glutamine, which may be involved in cardiovascular function. 78
A randomized, controlled trial evaluated the effect of daily fish oil supplementation 3 g for 12 weeks on quality of life outcomes in CT-confirmed ischemic stroke. No effect was found for all outcome measures, including serum triglycerides, total cholesterol, blood pressure, mood, and quality of life indicators. 88Other uses
An apparent link between inflammation and colon cancer has prompted studies of EPA and DHA in cancer prevention. EPA reduced crypt cell proliferation and increased apoptosis in subjects with a history of colorectal adenomas. 89 A molecular effect on lipid-modified protein trafficking was postulated as a mechanism by 1 review, 90 while immunomodulatory effects on T-cell function and subsets were invoked by the same group. 91 Other molecular targets of n-3 PUFAs in cancer have been reviewed. 92Cystic fibrosis
A pilot trial of intravenous fish oil emulsion in cystic fibrosis found no benefits and some potential deleterious effects. 92Dysmenorrhea
Trials are limited, but suggest a role for fish oil in the management of dysmenorrhea. Reduced requirement for analgesia and reported reduction in pain have been found after 2 to 3 months supplementation. 93 , 94 , 95Hepatic effects
A fish oil-based lipid emulsion is gaining popularity over conventional soybean oil-based parenteral nutrition because of its apparent ability to reduce the incidence of parenteral nutrition-associated liver disease or hepatobiliary dysfunction. 96 , 97 , 98 , 99Renal effects
The ability of n-3 fatty acids to reduce eicosanoid production or action has led to the testing of dietary fish oil in patients with immunoglobulin A (IgA) nephropathy. In these patients, the initial immunological renal injury evokes cytokine and eicosanoid activity. Dietary fish oil has been tested in patients with several types of renal disease with varying results. Results in patients with IgA nephropathy are conflicting. 100 The use of fish oil on lipoprotein-a in end-stage renal disease and among kidney transplant recipients has also been evaluated. 101 , 102
The AHA recommends a minimum of 2 fatty fish meals per week. 1 , 34 Clinical trials suggest fish oil supplementation of omega-3 fatty acid 1 g/day in coronary heart disease, and where triglycerides are elevated, a minimum of omega-3 fatty acid 2 g/day up to a maximum of 4 g/day. Fish oil 1,000 mg approximates to omega-3 fatty acid 300 to 400 mg (EPA/DHA). 34
Emulsified oral preparations have been developed to improve the taste over encapsulated fish oils and may increase digestion and absorption of the fatty acids via modifications in solubility. 103 Encapsulated oils have been found to oxidize and become rancid over time and with processing method, which may have an effect on total EPA/DHA delivered. 88 , 104
Documented adverse effects have occurred regarding pregnancy and lactation. Avoid use. The FDA recommends pregnant women avoid certain fish due to the potential for contamination with mercury. Farmed salmon may have greater contamination than wild sources. 78 , 86 , 104
Omega-3 fatty acids are postulated to be able to prevent preterm birth via delaying induction of labor and cervical ripening through inhibiting the production of prostaglandin F2-alpha and E2, and by relaxing the myometrium. A Cochrane meta-analysis found the mean gestation age was 2.6 days longer (95% confidence interval [CI], 1.03 to 4.07) in women who took fish oil supplementation. No significant difference was found for the relative risk (RR) of birth before 37 weeks, while a significant decrease in the risk of birth before 34 weeks gestation was found (RR 0.69; 95% CI, 0.5 to 0.99). 105
A study in which fish oil supplementation was taken after 22 weeks suggested an increase in oxidative stress in the plasma at week 30. 106 Effects of fish oil on lipids and blood pressure do not appear to be sustained during pregnancy. 107
While the evidence indicates that the DHA and EPA composition of breast milk is affected by fish oil supplementation, there is little evidence in support of benefit of supplementation to the infant. 66 , 67 , 68 , 69 Use of fish oil supplementation during pregnancy and breast-feeding to reduce the incidence of food allergy in infants has also been evaluated. 19
Fish oil at dosages of EPA/DHA 2 to 5.4 g/day is well accepted and tolerated. In clinical trials, only mild GI-related adverse effects were reported, including dyspepsia, diarrhea, and nausea. 30 , 31 , 56 , 75 An increased risk of diarrhea was noted in a meta-analysis of trials conducted among patients with inflammatory bowel disease who were given enteric-coated, time-released capsules. 72
A safety study found adverse events similar for intervention (EPA 2 g/day for 12 weeks) and placebo groups. An increased body mass index and increased (but modest) bleeding time were reported. 110
Research reveals little or no information regarding toxicology with the use of this product. Omega-3 acid ethyl esters have been shown to have an embryocidal effect in pregnant rats when given in doses resulting in exposures 7 times the recommended human dose of 4 g/day based on a body surface area comparison. 110
Bibliography1. Krauss RM, Eckel RH, Howard B, et al. AHA dietary guidelines: revision 2000: a statement for healthcare professionals from the Nutrition Committee of the American Heart Association. Circulation . 2000;102(18):2284-2299.
2. Wardlaw GM. Perspectives in Nutrition . 4th ed. Boston, MA: WBC/McGraw-Hill; 1999.
3. Whitney EN, Rolfes SR. Understanding Nutrition . 8th ed. Belmont, CA: West/Wadsworth; 1999.
4. Søyland E, Funk J, Rajka G, et al. Effect of dietary supplementation with very-long-chain n-3 fatty acids in patients with psoriasis. N Engl J Med . 1993;328(25):1812-1816.
5. Mann NJ, O'Connell SL, Baldwin KM, Singh I, Meyer BJ. Effects of seal oil and tuna-fish oil on platelet parameters and plasma lipid levels in healthy subjects. Lipids . 2010;45(8):669-681.
6. Racine RA, Deckelbaum RJ. Sources of the very-long-chain unsaturated omega-3 fatty acids: eicosapentaenoic acid and docosahexaenoic acid. Curr Opin Clin Nutr Metab Care . 2007;10(2):123-128.
7. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits [published correction appears in JAMA . 2007;297(6):590]. JAMA . 2006;296(15):1885-1899.
8. Graham IA, Larson T, Napier JA. Rational metabolic engineering of transgenic plants for biosynthesis of omega-3 polyunsaturates. Curr Opin Biotechnol . 2007;18(2):142-147.
9. Venegas-Calerón M, Sayanova O, Napier JA. An alternative to fish oils: Metabolic engineering of oil-seed crops to produce omega-3 long chain polyunsaturated fatty acids. Prog Lipid Res . 2010;49(2):108-119.
10. Woods RK, Thien FC, Abramson MJ. Dietary marine fatty acids (fish oil) for asthma in adults and children. Cochrane Database Syst Rev . 2002;(3):CD001283.
11. Farmer A, Montori V, Dinneen S, Clar C. Fish oil in people with type 2 diabetes mellitus. Cochrane Database Syst Rev . 2001;(3):CD003205.
12. Gadoth N. On fish oil and omega-3 supplementation in children: the role of such supplementation on attention and cognitive dysfunction. Brain Dev . 2008;30(5):309-312.
13. Aursand M, Standal IB, Axelson DE. High-resolution (13)C nuclear magnetic resonance spectroscopy pattern recognition of fish oil capsules. J Agric Food Chem . 2007;55(1):38-47.
14. Let MB, Jacobsen C, Sørensen AD, Meyer AS. Homogenization conditions affect the oxidative stability of fish oil enriched milk emulsions: lipid oxidation. J Agric Food Chem . 2007;55(5):1773-1780.
15. Werbach MR. Nutritional Influences on Illness: A Sourcebook of Clinical Research . 2nd ed. Tarzana, CA: Third Line Press; 1996.
16. Nagakura T, Matsuda S, Shichijyo K, Sugimoto H, Hata K. Dietary supplementation with fish oil rich in omega-3 polyunsaturated fatty acids in children with bronchial asthma. Eur Respir J . 2000;16(5):861-865.
17. Tecklenburg-Lund S, Mickleborough TD, Turner LA, Fly AD, Stager JM, Montgomery GS. Randomized controlled trial of fish oil and montelukast and their combination on airway inflammation and hyperpnea-induced bronchoconstriction. PLoS One . 2010;5(10):e13487.
18. Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group. Crit Care Med . 1999;27(8):1409-1420.
19. Furuhjelm C, Warstedt K, Larsson J, et al. Fish oil supplementation in pregnancy and lactation may decrease the risk of infant allergy. Acta Paediatr . 2009;98(9):1461-1467.
20. Søyland E, Funk J, Rajka G, et al. Dietary supplementation with very long-chain n-3 fatty acids in patients with atopic dermatitis: a double-blind, multicentre study. Br J Dermatol . 1994;130(6):757-764.
21. Bjørneboe A, Søyland E, Bjørneboe GE, Rajka G, Drevon CA. Effect of n-3 fatty acid supplement to patients with atopic dermatitis. J Intern Med Suppl . 1989;731:233-236.
22. Veale DJ, Torley HI, Richards IM, et al. A double-blind placebo controlled trial of Efamol Marine on skin and joint symptoms of psoriatic arthritis. Br J Rheumatol . 1994;33(10):954-958.
23. Berth-Jones J, Graham-Brown RA. Placebo-controlled trial of essential fatty acid supplementation in atopic dermatitis [published correction appears in Lancet . 1993;342(8870):564]. Lancet . 1993;341(8860):1557-1560.
24. Coronel R, Wilms-Schopman FJ, Den Ruijter HM, et al. Dietary n-3 fatty acids promote arrhythmias during acute regional myocardial ischemia in isolated pig hearts. Cardiovasc Res . 2007;73(2):386-394.
25. Den Ruijter HM, Berecki G, Opthof T, Verkerk AO, Zock PL, Coronel R. Pro- and antiarrhythmic properties of a diet rich in fish oil. Cardiovasc Res . 2007;73(2):316-325.
26. Reiffel JA, McDonald A. Antiarrhythmic effects of omega-3 fatty acids. Am J Cardiol . 2006;98(4A):50i-60i.
27. Leaf A. Omega-3 fatty acids and prevention of arrhythmias. Curr Opin Lipidol . 2007;18(1):31-34.
28. Nair GM, Connolly SJ. Should patients with cardiovascular disease take fish oil? CMAJ . 2008;178(2):181-182.
29. Brouwer IA, Raitt MH, Dullemeijer C, et al. Effect of fish oil on ventricular tachyarrhythmia in three studies in patients with implantable cardioverter defibrillators. Eur Heart J . 2009;30(7):820-826.
30. Wang C, Harris WS, Chung M, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr . 2006;84(1):5-17.
31. León H, Shibata MC, Sivakumaran S, Dorgan M, Chatterley T, Tsuyuki RT. Effect of fish oil on arrhythmias and mortality: systematic review. BMJ . 2008;337:a2931. doi:10.1136/bmj.a2931.
32. Jenkins DJ, Josse AR, Beyene J, et al. Fish-oil supplementation in patients with implantable cardioverter defibrillators: a meta-analysis. CMAJ . 2008;178(2):157-164.
33. Leaf A, Kang JX, Xiao YF. Fish oil fatty acids as cardiovascular drugs. Curr Vasc Pharmacol . 2008;6(1):1-12.
34. Roth EM, Harris WS. Fish oil for primary and secondary prevention of coronary heart disease. Curr Atheroscler Rep . 2010;12(1):66-72.
35. Lavie CJ, Milani RV, Mehra MR, Ventura HO. Omega-3 Polyunsaturated Fatty Acids and Cardiovascular Diseases. J Am Coll Cardiol . 2009;54(7):585-594.
36. Marik PE, Varon J. Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review. Clin Cardiol . 2009;32(7):365-372.
37. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico [published corrections appear in Lancet . 2001;357(9256):642 and Lancet . 2007;369(9556):106]. Lancet . 1999;354(9177):447-455.
38. Bønaa K. Epidemiological and intervention studies on the effect of marine polyunsaturated fatty acids on blood pressure. J Intern Med Suppl . 1989;731:105-110.
39. Bairati I, Roy L, Meyer F. Effects of a fish oil supplement on blood pressure and serum lipids in patients treated for coronary artery disease. Can J Cardiol . 1992;8(1):41-46.
40. Norris PG, Jones CJ, Weston MJ. Effect of dietary supplementation with fish oil on systolic blood pressure in mild essential hypertension. Br Med J ( Clin Res Ed ). 1986;293(6539):104-105.
41. Prisco D, Paniccia R, Bandinelli B, et al. Effect of medium-term supplementation with a moderate dose of n-3 polyunsaturated fatty acids on blood pressure in mild hypertensive patients. Thromb Res . 1998;91(3):105-112.
42. Salvig JD, Olsen SF, Secher NJ. Effects of fish oil supplementation in late pregnancy on blood pressure: a randomised controlled trial. Br J Obstet Gynaecol . 1996;103(6):529-533.
43. Mozaffarian D, Geelen A, Brouwer IA, Geleijnse JM, Zock PL, Katan MB. Effect of fish oil on heart rate in humans: a meta-analysis of randomized controlled trials. Circulation . 2005;112(3):1945-1952.
44. Buckley JD, Burgess S, Murphy KJ, Howe PR. DHA-rich fish oil lowers heart rate during submaximal exercise in elite Australian Rules footballers. J Sci Med Sport . 2009;12(4):503-507.
45. Sjoberg NJ, Milte CM, Buckley JD, Howe PR, Coates AM, Saint DA. Dose-dependent increases in heart rate variability and arterial compliance in overweight and obese adults with DHA-rich fish oil supplementation. Br J Nutr . 2010;103(2):243-248.
46. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on coronary restenosis, intima-media thickness, and exercise tolerance: a systematic review. Atherosclerosis . 2006;184(2):237-246.
47. Bowden RG, Wilson RL, Deike E, Gentile M. Fish oil supplementation lowers C-reactive protein levels independent of triglyceride reduction in patients with end-stage renal disease. Nutr Clin Pract . 2009;24(4):508-512.
48. Joy CB, Mumby-Croft R, Joy LA. Polyunsaturated fatty acid (fish or evening primrose oil) for schizophrenia. Cochrane Database Syst Rev . 2000;(2):CD001257.
49. Su KP. Biological mechanism of antidepressant effect of omega-3 fatty acids: how does fish oil act as a ‘mind-body interface’? Neurosignals . 2009;17(2):144-152.
50. Jans LA, Giltay EJ, Van der Does AJ. The efficacy of n-3 fatty acids DHA and EPA (fish oil) for perinatal depression. Br J Nutr . 2010;104(11):1577-1585.
51. Antypa N, Van der Does AJ, Smelt AH, Rogers RD. Omega-3 fatty acids (fish-oil)and depression-related cognition in healthy volunteers. J Psychopharmacol . 2009;23(7):831-840.
52. Johnson EJ, Schaefer EJ. Potential role of dietary n-3 fatty acids in the prevention of dementia and macular degeneration [published correction appears in Am J Clin Nutr . 2006;84(6):1555]. Am J Clin Nutr . 2006;83(6)(suppl):1494S-1498S.
53. van de Rest O, Geleijnse JM, Kok FJ, et al. Effect of fish oil supplementation on quality of life in a general population of older Dutch subjects: a randomized, double-blind, placebo-controlled trial. J Am Geriatr Soc . 2009;57(8):1481-1486.
54. Stapleton RD, Martin JM, Mayer K. Fish oil in critical illness: mechanisms and clinical applications. Crit Care Clin . 2010;26(3):501-514, ix.
55. Mayer K, Seeger W. Fish oil in critical illness. Curr Opin Clin Nutr Metab Care . 2008;11(2):121-127.
56. Chen B, Zhou Y, Yang P, Wan HW, Wu XT. Safety and efficacy of fish oil-enriched parenteral nutrition regimen on postoperative patients undergoing major abdominal surgery: a meta-analysis of randomized controlled trials. JPEN J Parenter Enteral Nutr . 2010;34(4):387-394.
57. Wei C, Hua J, Bin C, Klassen K. Impact of lipid emulsion containing fish oil on outcomes of surgical patients: systematic review of randomized controlled trials from Europe and Asia. Nutrition . 2010;26(5):474-481.
58. Waitzberg DL, Torrinhas RS. Fish oil lipid emulsions and immune response: what clinicians need to know. Nutr Clin Pract . 2009;24(4):487-499.
59. Jiang ZM, Wilmore DW, Wang XR, et al. Randomized clinical trial of intravenous soybean oil alone versus soybean oil plus fish oil emulsion after gastrointestinal cancer surgery. Br J Surg . 2010;97(6):804-809.
60. Badía-Tahull MB, Llop-Talaverón JM, Leiva-Badosa E, et al. A randomised study on the clinical progress of high-risk elective major gastrointestinal surgery patients treated with olive oil-based parenteral nutrition with or without a fish oil supplement. Br J Nutr . 2010;104(5):737-741.
61. Calder PC. Use of fish oil in parenteral nutrition: rationale and reality. Proc Nutr Soc . 2006;65(3):264-277.
62. Barbosa VM, Miles EA, Calhau C, Lafuente E, Calder PC. Effects of a fish oil containing lipid emulsion on plasma phospholipid fatty acids, inflammatory markers, and clinical outcomes in septic patients: a randomized, controlled clinical trial. Crit Care . 2010;14(1):R5.
63. Wong CY, Yiu KH, Li SW, et al. Fish-oil supplement has neutral effects on vascular and metabolic function but improves renal function in patients with type 2 diabetes mellitus. Diabet Med . 2010;27(1):54-60.
64. Pedersen MH, Mølgaard C, Hellgren LI, Lauritzen L. Effects of fish oil supplementation on markers of the metabolic syndrome. J Pediatr . 2010;157(3):395-400, 400.e1.
65. MacLean CH, Mojica WA, Morton SC, et al. Effects of omega-3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus, and osteoporosis. Evid Rep Technol Assess (Summ) . 2004;(89):1-4.
66. Jensen CL, Maude M, Anderson RE, Heird WC. Effect of docosahexaenoic acid supplementation of lactating women on the fatty acid composition of breast milk lipids and maternal and infant plasma phospholipids. Am J Clin Nutr . 2000;71(1)(suppl):292S-299S.
67. Smit EN, Koopmann M, Boersma ER, Muskiet FA. Effect of supplementation of arachidonic acid (AA) or a combination of AA plus docosahexaenoic acid on breastmilk fatty acid composition. Prostaglandins Leukot Essent Fatty Acids . 2000;62(6):335-340.
68. Simmer K. Longchain polyunsaturated fatty acid supplementation in infants born at term. Cochrane Database Syst Rev . 2001;(4):CD000376.
69. Simmer K, Patole S. Longchain polyunsaturated fatty acid supplementation in preterm infants. Cochrane Database Syst Rev . 2004;(1):CD000375.
70. Smit EN, Oelen EA, Seerat E, Boersma ER, Muskiet FA. Fish oil supplementation improves docosahexaenoic acid status of malnourished infants. Arch Dis Child . 2000;82(5):366-369.
71. Lapillonne A, Picaud JC, Chirouze V, et al. The use of low-EPA fish oil for long-chain polyunsaturated fatty acid supplementation of preterm infants. Pediatr Res . 2000;48(6):835-841.
72. Turner D, Shah PS, Steinhart AH, Zlotkin S, Griffiths AM. Maintenance of remission in inflammatory bowel disease using omega-3 fatty acids (fish oil): a systematic review and meta-analyses. Inflamm Bowel Dis . 2011;17(1):336-345.
73. De Ley M, de Vos R, Hommes DW, Stokkers P. Fish oil for induction of remission in ulcerative colitis. Cochrane Database Syst Rev . 2007;(4):CD005986.
74. Turner D, Steinhart AH, Griffiths AM. Omega 3 fatty acids (fish oil) for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev . 2007;(3):CD006443.
75. Turner D, Zlotkin SH, Shah PS, Griffiths AM. Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev . 2007;(2):CD006320.
76. Eslick GD, Howe PR, Smith C, Priest R, Bensoussan A. Benefits of fish oil supplementation in hyperlipidemia: a systematic review and meta-analysis. Int J Cardiol . 2009;136(1):4-16.
77. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis . 2006;189(1):19-30.
78. He K. Fish, long-chain omega-3 polyunsaturated fatty acids and prevention of cardiovascular disease—eat fish or take fish oil supplement? Prog Cardiovasc Dis . 2009;52(2):95-114.
79. Goldberg RB, Sabharwal AK. Fish oil in the treatment of dyslipidemia. Curr Opin Endocrinol Diabetes Obes . 2008;15(2):167-174.
80. Malinowski JM, Metka K. Elevation of low-density lipoprotein cholesterol concentration with over-the-counter fish oil supplementation. Ann Pharmacother . 2007;41(7):1296-1300.
81. Burdge GC, Powell J, Dadd T, Talbot D, Civil J, Calder PC. Acute consumption of fish oil improves postprandial VLDL profiles in healthy men aged 50-65 years. Br J Nutr . 2009;102(1):160-165.
82. Mori TA, Vandongen R, Mahanian F, Douglas A. Plasma lipid levels and platelet and neutrophil function in patients with vascular disease following fish oil and olive oil supplementation. Metabolism . 1992;41(10):1059-1067.
83. James M, Proudman S, Cleland L. Fish oil and rheumatoid arthritis: past, present and future. Proc Nutr Soc . 2010;69(3):316-323.
84. Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain . 2007;129(1-2):210-223.
85. Kremer JM. n-3 fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr . 2000;71(1)(suppl):349S-351S.
86. de Leiris J, de Lorgeril M, Boucher F. Fish oil and heart health. J Cardiovasc Pharmacol . 2009;54(5):378-384.
87. Myint PK, Welch AA, Bingham SA, et al. Habitual fish consumption and risk of incident stroke: the European Prospective Investigation into Cancer (EPIC)-Norfolk prospective population study. Public Health Nutr . 2006;9(7):882-888.
88. Poppitt SD, Howe CA, Lithander FE, et al. Effects of moderate-dose omega-3 fish oil on cardiovascular risk factors and mood after ischemic stroke: a randomized, controlled trial. Stroke . 2009;40(11):3485-3492.
89. Courtney ED, Matthews S, Finlayson C, et al. Eicosapentaenoic acid (EPA) reduces crypt cell proliferation and increases apoptosis in normal colonic mucosa in subjects with a history of colorectal adenomas. Int J Colorectal Dis . 2007;22(7):765-776.
90. Chapkin RS, Seo J, McMurray DN, Lupton JR. Mechanisms by which docosahexaenoic acid and related fatty acids reduce colon cancer risk and inflammatory disorders of the intestine. Chem Phys Lipids . 2008;153(1):14-23.
91. Chapkin RS, Davidson LA, Ly L, Weeks BR, Lupton JR, McMurray DN. Immunomodulatory effects of (n-3) fatty acids: putative link to inflammation and colon cancer. J Nutr . 2007;137(1)(suppl):200S-204S.
92. Berquin IM, Edwards IJ, Chen YQ. Multi-targeted therapy of cancer by omega-3 fatty acids. Cancer Lett . 2008;269(2):363-377.
93. Durieu I, Vericel E, Guichardant D, et al. Fatty acids platelets and oxidative markers following intravenous n-3 fatty acids administration in cystic fibrosis: an open pilot observational study. J Cyst Fibros . 2007;6(5):320-326.
94. Proctor ML, Murphy PA. Herbal and dietary therapies for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev . 2001;(3):CD002124.
95. Moghadamnia AA, Mirhosseini N, Abadi MH, Omranirad A, Omidvar S. Effect of Clupeonella grimmi (anchovy/kilka) fish oil on dysmenorrhoea. East Mediterr Health J . 2010;16(4):408-413.
96. de Meijer VE, Gura KM, Le HD, Meisel JA, Puder M. Fish oil-based lipid emulsions prevent and reverse parenteral nutrition-associated liver disease: the Boston experience. JPEN J Parenter Enteral Nutr . 2009;33(5):541-547.
97. de Meijer VE, Gura KM, Meisel JA, Le HD, Puder M. Parenteral fish oil monotherapy in the management of patients with parenteral nutrition-associated liver disease. Arch Surg . 2010;145(6):547-551.
98. Fallon EM, Le HD, Puder M. Prevention of parenteral nutrition-associated liver disease: role of omega-3 fish oil. Curr Opin Organ Transplant . 2010;15(3):334-340.
99. Koletzko B, Goulet O. Fish oil containing intravenous lipid emulsions in parenteral nutrition-associated cholestatic liver disease. Curr Opin Clin Nutr Metab Care . 2010;13(3):321-326.
100. Lorenz R, Weber PC, Szimnau P, Heldwein W, Strasser T, Loeschke K. Supplementation with n-3 fatty acids from fish oil in chronic inflammatory bowel disease—a randomized, placebo-controlled, double-blind cross-over trial. J Intern Med Suppl . 1989;731:225-232.
101. Beavers KM, Beavers DP, Bowden RG, Wilson RL, Gentile M. Effect of over-the-counter fish-oil administration on plasma Lp(a) levels in an end-stage renal disease population. J Ren Nutr . 2009;19(6):443-449.
102. Lim AK, Manley KJ, Roberts MA, Fraenkel MB. Fish oil for kidney transplant recipients. Cochrane Database Syst Rev . 2007;(2):CD005282.
103. Raatz SK, Redmon JB, Wimmergren N, Donadio JV, Bibus DM. Enhanced absorption of n-3 fatty acids from emulsified compared with encapsulated fish oil. J Am Diet Assoc . 2009;109(6):1076-1081.
104. Farooqui AA, Ong WY, Horrocks LA, Chen P, Farooqui T. Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans. Brain Res Rev . 2007;56(2):443-471.
105. Secher NJ. Does fish oil prevent preterm birth? J Perinat Med . 2007;35(suppl 1):S25-S27.
106. Franke C, Demmelmair H, Decsi T, et al. Influence of fish oil or folate supplementation on the time course of plasma redox markers during pregnancy. Br J Nutr . 2010;103(11):1648-1656.
107. Barden AE, Dunstan JA, Beilin LJ, Prescott SL, Mori TA. n-3 fatty acid supplementation during pregnancy in women with allergic disease: effects on blood pressure, and maternal and fetal lipids. Clin Sci (Lond) . 2006;111(4):289-294.
108. Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann Pharmacother . 2004;38(1):50-52.
109. Emsley R, Niehaus DJ, Oosthuizen PP, et al. Safety of the omega-3 fatty acid, eicosapentaenoic acid (EPA) in psychiatric patients: results from a randomized, placebo-controlled trial. Psychiatry Res . 2008;161(3):284-291.
110. Multivitamins and Minerals with Omega-3 Polyunsaturated Fatty Acids. Drug Facts and Comparisons . Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health Inc; May 2010. Accessed October 11, 2011.
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