Omega-3 fatty acids, fish oil, alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid

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Omega-3 fatty acids, fish oil, alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid

Be aware that the U.S. Food and Drug Administration does not strictly regulate herbs and dietary supplements. There is no guarantee of strength, purity or safety of products containing or claiming to contain coenzyme Q10. Decisions to use herbs or supplements should be carefully considered. Individuals using prescription drugs should discuss taking herbs or supplements with their pharmacist or health care provider before starting.

Evidence

Scientists have studied fish oil/omega-3 fatty acids for the following health problems:

Unproven Uses

Fish oil/omega-3 fatty acids have been suggested for many other uses, based on tradition or on scientific theories. However, these uses have not been thoroughly studied in humans, and there is limited scientific evidence about safety or effectiveness. Some of these suggested uses are for conditions that are potentially very serious and even life-threatening. You should consult a health care provider before taking fish oil/omega-3 fatty acids for any unproven use.

Potential Dangers

Allergies

People with allergy or hypersensitivity to fish should avoid fish oil or omega-3 fatty acid products derived from fish. Skin rash has been reported rarely. People with allergy or hypersensitivity to nuts should avoid alpha linolenic acid or omega-3 fatty acid products that are derived from the types of nuts to which they react.

Side Effects

Intake of up to 3 grams per day of omega-3 fatty acids from fish is generally regarded as safe. Intake of 3 grams per day or greater of omega-3 fatty acids may increase the risk of bleeding. Very large intakes of fish oil/omega-3 fatty acids may increase the risk of hemorrhagic (bleeding) stroke or other serious bleeding.

Potentially harmful contaminants such as dioxins, methylmercury, and polychlorinated biphenyls (PCBs) are found in some species of fish. Methylmercury accumulates in fish meat more than in fish oil, and fish oil supplements appear to contain almost no mercury. Therefore, safety concerns apply to eating fish but likely not to ingesting fish oil supplements. For farm-raised, imported, or marine fish pregnant/nursing women and young children should avoid eating types with higher levels of methylmercury (approximately 1 part per million, such as mackerel, shark, swordfish, or tilefish), and less than 12 ounces per week of other fish types. Women who might become pregnant are advised to eat 7 ounces or less per week of fish with higher levels of methylmercury (up to 1 part per million), or up to 14 ounces per week of fish types with approximately 0.5 parts per million (such as marlin, orange roughy, red snapper, or fresh tuna). Unrefined fish oil preparations may contain pesticides.

Gastrointestinal upset is common with the use of fish oil supplements, occurring in up to 5 percent of patients in clinical trials, with nausea in up to 1.5 percent of patients. Diarrhea may also occur, with potentially severe diarrhea at very high doses. There are also reports of increased burping, heartburn, abdominal bloating, and abdominal pain. Fishy aftertaste is a common effect. Gastrointestinal side effects can be minimized if fish oils are taken with meals and if doses are started low and gradually increased.

Multiple human trials report tiny reductions in blood pressure with intake of omega-3 fatty acids. Although slight increases in fasting blood sugar levels have been noted in patients with type 2 (“adult onset”) diabetes, the available scientific evidence suggests that there are no significant long-term effects of fish oil in patients with diabetes, including no changes in hemoglobin A_1c levels.

Fish oil taken for many months may cause a deficiency of vitamin E, and therefore vitamin E is added to many commercial fish oil products. Fish liver oil contains the fat-soluble vitamins A and D, and therefore fish liver oil products (such as cod liver oil) may increase the risk of vitamin A or D toxicity. Increases (worsening) in low-density lipoprotein levels (“bad cholesterol”) by 5-10% are observed with intake of omega-3 fatty acids. Mild elevations in liver function tests (alanine aminotransferase) have been reported rarely. Skin rashes have been reported rarely. There are rare reports of mania in patients with bipolar disorder or major depression. Restlessness and formication (the sensation of ants crawling on the skin) have also been reported.

Pregnancy and Breast-Feeding

Potentially harmful contaminants such as dioxins, methylmercury, and polychlorinated biphenyls (PCBs) are found in some species of fish, and may be harmful in pregnant/nursing women. Methylmercury accumulates in fish meat more than in fish oil, and fish oil supplements appear to contain almost no mercury. Therefore, these safety concerns apply to eating fish but likely not to ingesting fish oil supplements. However, unrefined fish oil preparations may contain pesticides. For sport-caught fish, the U.S. Environmental Protection Agency recommends that intake be limited in pregnant/nursing women to a single 6-ounce meal per week. For farm-raised, imported, or marine fish, the U.S. Food and Drug Administration recommends that pregnant/nursing women avoid eating types with higher levels of methylmercury (approximately 1 part per million, such as mackerel, shark, swordfish, or tilefish), and less than 12 ounces per week of other fish types. Women who might become pregnant may be advised to eat up to 7 ounces per week of fish with higher levels of methylmercury (up to 1 part per million), or up to 14 ounces per week of fish types with approximately 0.5 parts per million (such as marlin, orange roughy, red snapper, or fresh tuna).

It is not known if omega-3 fatty acid supplementation of women during pregnancy or breastfeeding is beneficial to infants. It has been suggested that high intake of omega-3 fatty acids during pregnancy, particularly DHA, may increase birth weight and gestational length. However, higher doses may not be advisable due to the potential risk of bleeding. Fatty acids are added to some infant formulas.

Interactions

Interactions with drugs, herbs and other supplements have not been thoroughly studied. The interactions listed below have been reported in scientific publications. If you are taking prescription drugs, speak with your health care provider or pharmacist before using herbs or dietary supplements.

Interactions with Drugs

In theory, omega-3 fatty acids may increase the risk of bleeding when taken with drugs that increase the risk of bleeding. Some examples include aspirin, anticoagulants (“blood thinners”) such as warfarin (Coumadin) or heparin, anti-platelet drugs such as clopidogrel (Plavix), and non-steroidal anti-inflammatory drugs such as ibuprofen (Motrin, Advil) or naproxen (Naprosyn, Aleve). Based on human studies, omega-3 fatty acids may lower blood pressure a small amount and add to the effects of drugs that may also affect blood pressure.

Fish oil supplements may lower blood sugar levels a small amount. Caution is advised when using medications that may also lower blood sugar. Patients taking drugs for diabetes by mouth or insulin should be monitored closely by a qualified healthcare provider. Medication adjustments may be necessary.

Interactions with Herbs and Dietary Supplements

In theory, omega-3 fatty acids may increase the risk of bleeding when taken with herbs and supplements that are believed to increase the risk of bleeding. Multiple cases of bleeding have been reported with the use of Ginkgo biloba, and fewer cases with garlic and saw palmetto. Numerous other agents may theoretically increase the risk of bleeding, although this has not been proven in most cases. Some examples include: alfalfa, American ginseng, angelica, anise, Arnica montana, asafetida, aspen bark, bilberry, birch, black cohosh, bladderwrack, bogbean, boldo, borage seed oil, bromelain, capsicum, cat's claw, celery, chamomile, chaparral, clove, coleus, cordyceps, danshen, devil’s claw, dong quai, evening primrose oil, fenugreek, feverfew, flaxseed/flax powder (not a concern with flaxseed oil), ginger, grapefruit juice, grapeseed, green tea, guggul, gymnestra, horse chestnut, horseradish, licorice root, lovage root, male fern, meadowsweet, nordihydroguairetic acid (NDGA), onion, papain, Panax ginseng, parsley, passionflower, poplar, prickly ash, propolis, quassia, red clover, reishi, Siberian ginseng, sweet clover, rue, sweet birch, sweet clover, turmeric, vitamin E, white willow, wild carrot, wild lettuce, willow, wintergreen, and yucca.

Based on human studies, omega-3 fatty acids may lower blood pressure a small amount, and theoretically may add to the effects of agents that may also affect blood pressure. Examples include aconite/monkshood, arnica, baneberry, betel nut, bilberry, black cohosh, bryony, calendula, California poppy, coleus, curcumin; eucalyptol; eucalyptus oil, flaxseed/flaxseed oil, garlic, ginger, ginkgo, goldenseal, green hellebore, hawthorn, Indian tobacco, jaborandi, mistletoe, night blooming cereus, oleander, pasque flower, periwinkle, pleurisy root, Polypodium vulgare, shepherd's purse, Texas milkweed, turmeric, and wild cherry.

Fish oil supplements may lower blood sugar levels a small amount. Caution is advised when using herbs or supplements that may also lower blood sugar. Blood glucose levels may require monitoring, and doses may need adjustment. Possible examples include: Aloe vera, American ginseng, bilberry, bitter melon, burdock, fenugreek, gymnema, horse chestnut seed extract (HCSE), maitake mushroom, marshmallow, milk thistle, Panax ginseng, rosemary, shark cartilage, Siberian ginseng, stinging nettle and white horehound. Agents that may raise blood sugar levels include arginine, cocoa, and ephedra (when combined with caffeine).

Fish oil taken for many months may cause a deficiency of vitamin E, and therefore vitamin E is added to many commercial fish oil products. As a result, regular use of vitamin E-enriched products may lead to elevated levels of this fat-soluble vitamin. Fish liver oil contains the fat-soluble vitamins A and D, and therefore fish liver oil products (such as cod liver oil) may increase the risk of vitamin A or D toxicity. Since fat-soluble vitamins can build up in the body and cause toxicity, patients taking multiple vitamins regularly or in high doses should discuss this risk with their healthcare practitioners.

Dosing

The doses listed below are based on scientific research, publications or traditional use. Because most herbs and supplements have not been thoroughly studied or monitored, safety and effectiveness may not be proven. Brands may be made differently, with variable ingredients even within the same brand. Combination products often contain small amounts of each ingredient and may not be effective. Appropriate dosing should be discussed with a health care provider before starting therapy; always read the recommendations on a product's label. The dosing for unproven uses should be approached cautiously, because scientific information is limited in these areas.

There are no well-established doses of fish oil/omega-3 fatty acids, and many different doses have been used and studied.

Adults (Aged 18 or Older)

For fish oil supplements, dosing should be based on the amount of EPA and DHA (omega-3 fatty acids) in a product, not on the total amount of fish oil. Supplements vary in the amounts and ratios of EPA and DHA. A common amount of omega-3 fatty acids in fish oil capsules is 0.18 grams (180mg) of EPA and 0.12 grams (120mg) of DHA. Five grams of fish oil contains approximately 0.17-0.56 grams (170 to 560mg) of EPA and 0.072-0.31 grams (72-310mg) of DHA. Different types of fish contain variable amounts of omega-3 fatty acids, and different types of nuts or oil contain variable amounts of α-linolenic acid.

For healthy adults with no history of heart disease, the American Heart Association recommends eating fish at least two times per week. In particular, fatty fish are recommended, such as anchovies, bluefish, carp, catfish, halibut, herring, lake trout, mackerel, pompano, salmon, striped sea bass, tuna (albacore), and whitefish. It is also recommended to consume plant-derived sources of α-linolenic acid, such as tofu/soybeans, walnuts, flaxseed oil, and canola oil. The World Health Organization and governmental health agencies of several countries recommend consuming 0.3-0.5 grams of daily EPA + DHA and 0.8-1.1 grams of daily α-linolenic acid.

For high triglycerides (hypertriglyceridemia), benefits are seen at doses less than 2 grams per day of omega-3 fatty acids from EPA and DHA, although higher doses may be necessary in people with marked hypertriglyceridemia (>750mg/dL). Because of the risk of bleeding from omega-3 fatty acids (particularly at doses greater than 3 grams per day), a physician should be consulted prior to starting treatment with supplements.

In people with a history of heart attack, regular consumption of oily fish (200-400 grams of fish each week equal to 0.5-0.8 grams [500-800mg] of daily omega-3 fatty acids) or fish oil/omega-3 supplements (containing 0.85-1.8 grams [850-1800mg] of EPA + DHA) appears to reduce the risk of non-fatal heart attack, fatal heart attack, sudden death, and all-cause mortality (death due to any cause). The American Heart Association, in its 2003 recommendations, suggested that people with known coronary heart disease consume approximately 1 gram of EPA and DHA (combined) each day. This may be obtained from eating fish or from fish oil capsule supplements. Because of the risk of bleeding from omega-3 fatty acids (particularly at doses greater than 3 grams per day), a physician should be consulted prior to starting treatment with supplements.

For high blood pressure the effects of omega-3 fatty acids appear to be dose-responsive (higher doses have greater effects). However, intakes of greater than 3 grams of omega-3 fatty acids per day may be necessary to obtain clinically relevant effects, and at this dose level, there is an increased risk of bleeding. Therefore, a physician should be consulted prior to starting treatment with supplements.

For rheumatoid arthritis, clinical trials have used a range of doses, most commonly between 3 and 5 grams of EPA + DHA daily (1.7 to 3.8 grams of EPA, and 1.1 to 2.0 grams of DHA). Effects beyond three months of treatment have not been well evaluated. For protection from cyclosporine toxicity in organ transplant patients, studies have used 6 grams of fish oil per day for up to one year. Some research has started at 3 grams daily for six weeks, followed by 6 grams per day. Up to 12 grams per day has been used. Omega-3 fatty acids have been used for numerous other indications, although effective doses are not clearly established.

Children (Younger than 18)

Omega-3 fatty acids are used in some infant formulas, although effective doses are not clearly established. Ingestion of fresh fish should be limited in young children due to the presence of potentially harmful environmental contaminants. Fish oil capsules should not be used in children except under the direction of a physician.

Summary

Fish oil/omega-3 fatty acids have been suggested as a treatment for many conditions. Scientific research suggests benefits in people with elevated triglyceride levels, those with a history of heart attack or significant coronary artery disease, and high blood pressure. Benefits may also occur from regular intake for the prevention of heart disease, to improve rheumatoid arthritis symptoms, and to reduce cyclosporine toxicity in organ transplant patients. There is not enough scientific evidence at this time to support use for any other medical condition. Regular use may increase the risk of bleeding, although recommended doses are generally felt to be safe. At high doses there is a risk of dangerous bleeding including stroke. Regular consumption of some fish types may increase the risk of heavy metal toxicity, although supplements likely do not carry this risk. Ingestion of fish should be limited in children, and supplements should be avoided. Specific recommendations exist for use during pregnancy. Consult your health care provider immediately if you have any side effects.

The information in this monograph was prepared by the professional staff at Natural Standard (www.naturalstandard.com), based on thorough systematic review of scientific evidence. The material was reviewed by the Faculty of the Harvard Medical School with final editing approved by Natural Standard.

Resources

1. Natural Standard: An organization that produces scientifically based reviews of complementary and alternative medicine (CAM) topics

2. National Center for Complementary and Alternative Medicine (NCCAM): A division of the U.S. Department of Health & Human Services dedicated to research

Selected Scientific Studies: Fish oil/omega-3 fatty acids

Natural Standard reviewed more than 1200 articles to prepare the professional monograph from which this version was created.

Selected studies are listed below:

1. Anonymous. 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. Lancet 1999;354(9177):447-455.

2. Appel LJ. Effects of omega-3 fatty acids on cardiovascular health. Am Fam Physician 2004;70(1):34-35.

3. Ascherio A, Rimm EB, Giovannucci EL, et al. Dietary fat and risk of coronary heart disease in men: cohort follow up study in the United States. BMJ 1996;313(7049):84-90.

4. Beckles WN, Elliott TM, Everard ML. Omega-3 fatty acids for cystic fibrosis (Protocol for a Cochrane Review). The Cochrane Library 2001;(3)

5. Bemelmans WJ, Broer J, Feskens EJ, et al. Effect of an increased intake of alpha-linolenic acid and group nutritional education on cardiovascular risk factors: the Mediterranean Alpha-linolenic Enriched Groningen Dietary Intervention (MARGARIN) study. Am J Clin Nutr 2002;75(2):221-227.

6. Bonaa KH, Bjerve KS, Straume B, et al. Effect of eicosapentaenoic and docosahexaenoic acids on blood pressure in hypertension. A population-based intervention trial from the Tromso study. N Engl J Med 1990;322(12):795-801.

7. Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann Pharmacother 2004;38(1):50-52.

8. Chamberlain JG. Omega-3 fatty acids and bleeding problems. Am J Clin Nutr 1992;55(3):760-761.

9. de Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 1999;99(6):779-785.

10. Din JN, Newby DE, Flapan AD. Omega 3 fatty acids and cardiovascular disease--fishing for a natural treatment. BMJ 2004;328(7430):30-35.

11. Djousse L, Pankow JS, Eckfeldt JH, et al. Relation between dietary linolenic acid and coronary artery disease in the National Heart, Lung, and Blood Institute Family Heart Study. Am J Clin Nutr 2001;74(5):612-619.

12. Fortin PR, Lew RA, Liang MH, et al. Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis. J Clin Epidemiol 1995;48(11):1379-1390.

13. Friedberg CE, Janssen MJ, Heine RJ, et al. Fish oil and glycemic control in diabetes. A meta-analysis. Diabetes Care 1998;21(4):494-500.

14. Gapinski JP, VanRuiswyk JV, Heudebert GR, et al. Preventing restenosis with fish oils following coronary angioplasty. A meta-analysis. Arch Intern Med 1993;153(13):1595-1601.

15. Gillum RF, Mussolino ME, Madans JH. The relationship between fish consumption and stroke incidence. The NHANES I Epidemiologic Follow-up Study (National Health and Nutrition Examination Survey). Arch Intern Med 1996;156(5):537-542.

16. Hooper L, Thompson R, Harrison R, et al. Omega 3 fatty acids for prevention and treatment of cardiovascular disease. Cochrane Database Syst Rev 2004;(4):CD003177.

17. Hu FB, Bronner L, Willett WC, et al. Fish and omega-3 Fatty Acid intake and risk of coronary heart disease in women. JAMA 2002;287(14):1815-1821.

18. Iso H, Rexrode KM, Stampfer MJ, et al. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA 2001;285(3):304-312.

19. Keli SO, Feskens EJ, Kromhout D. Fish consumption and risk of stroke. The Zutphen Study. Stroke 1994;25(2):328-332.

20. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2003;23(2):e20-e30.

21. Maachi K, Berthoux P, Burgard G, et al. Results of a 1-year randomized controlled trial with omega-3 fatty acid fish oil in renal transplantation under triple immunosuppressive therapy. Transplant Proc 1995;27(1):846-849.

22. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction. Time-course analysis of the results of the gruppo italiano per lo studio della sopravvivenza nell'infarto miocardico (GISSI)-prevenzione. Circulation 2002;105(16):1897-1903.

23. Morris MC, Manson JE, Rosner B, et al. Fish consumption and cardiovascular disease in the physicians' health study: a prospective study. Am J Epidemiol 1995;142(2):166-175.

24. Natvig H, Borchgrevink CF, Dedichen J, et al. A controlled trial of the effect of linolenic acid on incidence of coronary heart disease. The Norwegian vegetable oil experiment of 1965- 66. Scand J Clin Lab Invest Suppl 1968;105:1-20.

25. Oomen CM, Ocke MC, Feskens EJ, et al. alpha-Linolenic acid intake is not beneficially associated with 10-y risk of coronary artery disease incidence: the Zutphen Elderly Study. Am J Clin Nutr 2001;74(4):457-463.

26. Orencia AJ, Daviglus ML, Dyer AR, et al. Fish consumption and stroke in men. 30-year findings of the Chicago Western Electric Study. Stroke 1996;27(2):204-209.

27. van der Heide JJ, Bilo HJ, Donker JM, et al. Effect of dietary fish oil on renal function and rejection in cyclosporine-treated recipients of renal transplants. N Engl J Med 1993;329(11):769-773.

28. Vanschoonbeek K, Feijge MA, Paquay M, et al. Variable hypocoagulant effect of fish oil intake in humans: modulation of fibrinogen level and thrombin generation. Arterioscler Thromb Vasc Biol 2004;24(9):1734-1740.

Last updated:	August 21, 2006