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Omega-3 fatty acids, fish oil, alpha-linolenic acid

URL of this page: http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-fishoil.html

Background

Dietary sources of omega-3 fatty acids include fish oil and certain plant/nut oils. Fish oil contains both docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), while some nuts (English walnuts) and vegetable oils (canola, soybean, flaxseed/linseed, olive) contain alpha-linolenic acid (ALA).

There is evidence from multiple large-scale population (epidemiologic) studies and randomized controlled trials that intake of recommended amounts of DHA and EPA in the form of dietary fish or fish oil supplements lowers triglycerides, reduces the risk of death, heart attack, dangerous abnormal heart rhythms, and strokes in people with known cardiovascular disease, slows the buildup of atherosclerotic plaques ("hardening of the arteries"), and lowers blood pressure slightly. However, high doses may have harmful effects, such as an increased risk of bleeding. Although similar benefits are proposed for alpha-linolenic acid, scientific evidence is less compelling, and beneficial effects may be less pronounced.

Some species of fish carry a higher risk of environmental contamination, such as with methylmercury.

Synonyms

α-linolenic acid (ALA, C18:3n-3), alpha-linolenic acid, cod liver oil, coldwater fish, docosahexaenoic acid (DHA, C22:6n-3), eicosapentaenoic acid (EPA, C20:5n-3), fish oil fatty acids, fish body oil, fish liver oil, fish extract, halibut oil, long chain polyunsaturated fatty acids, mackerel oil, marine oil, menhaden oil, n-3 fatty acids, n-3 polyunsaturated fatty acids, omega fatty acids, omega-3 oils, polyunsaturated fatty acids (PUFA), salmon oil, shark liver oil, w-3 fatty acids.

Should not be confused with omega-6 fatty acids.

Evidence

These uses have been tested in humans or animals. Safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Uses based on scientific evidenceGrade*
Hypertriglyceridemia (fish oil / EPA plus DHA)

There is strong scientific evidence from human trials that omega-3 fatty acids from fish or fish oil supplements (EPA + DHA) significantly reduce blood triglyceride levels (1-6). Benefits appear to be dose-dependent, with effects at doses as low as 2 grams of omega-3 fatty acids per day. Higher doses have greater effects, and 4 grams per day can lower triglyceride levels by 25-40%. Effects appear to be additive with HMG-CoA reductase inhibitor ("statin") drugs such as simvastatin (7), pravastatin (8;9), and atorvastatin (10). The effects of fish oil on hypertriglyceridemia are similar in patients with or without diabetes (5), and in those with kidney disease receiving dialysis. It is not clear how fish oil therapy compares to other agents used for hypertriglyceridemia, such as fibrates (like gemfibrozil or fenofibrate) or niacin/nicotinic acid.Fish oil supplements also appear to cause small improvements in high-density lipoprotein ("good cholesterol") by 1-3%. However, increases (worsening) in low-density lipoprotein levels (LDL/"bad cholesterol") by 5-10% are also observed. Therefore, for individuals with high blood levels of total cholesterol or low-density lipoprotein, significant improvements will likely not be seen, and a different treatment should be selected.It is not clear if alpha-linolenic acid significantly affects triglyceride levels, and there is conflicting evidence in this area.The American Heart Association, in its 2003 recommendations, reports that supplementation with 2-4 grams of EPA + DHA each day can lower triglycerides by 20-40% (11). 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.C-Reactive Protein (CRP) levels: The data on fish oils and CRP is mixed (12;13). While omega-3 fatty acids from both plants (ALA) and fish (EPA+DHA) have been shown to reduce CRP in some studies, others have failed to show an effect. There is growing evidence that reducing CRP is beneficial towards favorable cardiovascular outcomes, although additional research is pending in this area. Although statin drugs, weight reduction, smoking cessation, and COX-2 inhibitors all appear to reduce CRP, the evidence regarding fish oil remains equivocal.
A
Secondary cardiovascular disease prevention (fish oil / EPA plus DHA)

Several well-conducted randomized controlled trials report that in people with a history of heart attack, regular consumption of oily fish (200-400 grams of fish each week equal to 500-800mg of daily omega-3 fatty acids) or fish oil/omega-3 supplements (containing 850-1800mg of EPA + DHA) reduces the risk of non-fatal heart attack, fatal heart attack, sudden death, and all-cause mortality (death due to any cause) (11;14-19). Most patients in these studies were also using conventional heart drugs, suggesting that the benefits of fish oils may add to the effects of other therapies. Benefits have been reported after 3 months of use, and after up to 3.5 years of follow-up. Benefits of supplements may not occur in populations that already consume large amounts of dietary fish (20).Multiple mechanisms have been proposed for the beneficial effects of omega-3 fatty acids. These include reduced triglyceride levels, reduced inflammation, slightly lowered blood pressure, reduced blood clotting, reduced tendency of the heart to develop abnormal rhythms, and diminished buildup of atherosclerotic plaques in arteries of the heart. Experiments suggest that omega-3 fatty acids may reduce platelet derived growth factor (PDGF), decrease platelet aggregation, inhibit the expression of vascular adhesion molecules, and stimulate relaxation of endothelial cells in the walls of blood vessels (21).The American Heart Association, in its 2003 recommendations, suggests that people with known coronary heart disease take in approximately 1 gram of EPA and DHA (combined) each day (11). 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.
A
High blood pressure

Multiple human trials report small reductions in blood pressure with intake of omega-3 fatty acids (22-28). Reductions of 2-5 mmHg have been observed, and benefits may be greater in those with higher blood pressures. Effects appear to be dose-responsive (higher doses have greater effects) (23). DHA may have greater benefits than EPA (29).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. Other approaches are known to have greater effects on blood pressure, such as salt reduction, weight loss, exercise, or antihypertensive drug therapy. Therefore, although omega-3 fatty acids do appear to have effects in this area, their role in the management of high blood pressure is limited.
A
Primary cardiovascular disease prevention (fish intake)

Several large studies of populations ("epidemiologic" studies) report a significantly lower rate of death from heart disease in men and women who regularly eat fish (30-39). Other epidemiologic research reports no such benefits (40-42). It is not clear if reported benefits only occur in certain groups of people, such as those at risk of developing heart disease. Overall, the evidence suggests benefits of regular consumption of fish oil (43-45). However, well-designed randomized controlled trials which classify people by their risk of developing heart disease are necessary before a firm conclusion can be drawn (46).The American Heart Association, in its 2003 recommendations, suggests that all adults eat fish at least two times per week (11). In particular, fatty fish are recommended, including mackerel, lake trout, herring, sardines, albacore tuna, and salmon.
B
Rheumatoid arthritis (fish oil)

Multiple randomized controlled trials report improvements in morning stiffness and joint tenderness with the regular intake of fish oil supplements for up to three months (47-61). Benefits have been reported as additive with anti-inflammatory medications such as NSAIDs (like ibuprofen or aspirin). However, because of weaknesses in study designs and reporting, better research is necessary before a strong favorable recommendation can be made. Effects beyond three months of treatment have not been well evaluated.Ingestion of fish oil omega-3 fatty acids relieved several clinical parameters used in the present study. However, patients showed a more precocious and accentuated improvement when fish oil supplements were used in combination with olive oil. (62)
B
Protection from cyclosporine toxicity in organ transplant patients

There are multiple studies of heart transplant and kidney transplant patients taking cyclosporine (Neoral®), who were administered fish oil supplements. The majority of trials report improvements in kidney function (glomerular filtration rate, serum creatinine) (63-72), and less hypertension (high blood pressure) (63;73;74) compared to patients not taking fish oil. Although several recent studies report no benefits on kidney function (75-79), the weight of scientific evidence favors the beneficial effects of fish oil. No changes have been found in rates of rejection or graft survival.
B
Secondary cardiovascular disease prevention (α-linolenic acid [ALA])

Several randomized controlled trials have examined the effects of alpha-linolenic acid in people with a history of heart attack. Although some studies suggest benefits (18;39;80;80), others do not (81-83). Weaknesses in some of this research make results difficult to interpret, such as the use of other foods that may also be beneficial. Additional research is necessary before a conclusion can be drawn in this area.
C
Primary cardiovascular disease prevention (α-linolenic acid [ALA])

Several large studies of populations ("epidemiologic" studies) report a significantly reduced risk of fatal or non-fatal heart attack in men and women who regularly consume foods high in α-linolenic acid (39;84;85). Other epidemiologic research reports no such benefits (42;83). Although the existing research is compelling, weaknesses in this research make results difficult to interpret, such as the use of other foods that may also be beneficial, or effects of risk factors for heart disease such as smoking. Additional research is necessary before a conclusion can be drawn in this area.The American Heart Association, in its 2003 recommendations, suggests that in addition to eating fish at least two times per week, all adults should consume plant-derived sources of omega-3 fatty acids, such as tofu/soybeans, walnuts, flaxseed oil, and canola oil (11).
C
Stroke prevention

Several large studies of populations ("epidemiologic" studies) have examined the effects of omega-3 fatty acid intake on stroke risk. Some studies suggests benefits (86-88), while others do not (80;89-91). Effects are likely on ischemic or thrombotic stroke risk, and very large intakes of omega-3 fatty acids ("Eskimo" amounts) may actually increase the risk of hemorrhagic (bleeding) stroke (92). At this time, it is unclear if there are benefits in people with or without a history of stroke, or if effects of fish oil are comparable to other treatment strategies.Multiple mechanisms have been proposed for the beneficial effects of omega-3 fatty acids. These include reduced triglyceride levels, reduced inflammation, slightly lowered blood pressure, reduced blood clotting, and diminished buildup of atherosclerotic plaques in blood vessels. Experiments suggest that omega-3 fatty acids may reduce platelet derived growth factor (PDGF), decrease platelet aggregation, inhibit the expression of vascular adhesion molecules, and stimulate relaxation of endothelial cells in the walls of blood vessels (21).
C
Atherosclerosis

Some research reports that regular intake of fish or fish oil supplements reduces the risk of developing atherosclerotic plaques in the arteries of the heart (93;94), while other research reports no effects (95). Additional evidence is necessary before a firm conclusion can be drawn in this area.
C
Prevention of restenosis after coronary angioplasty (PTCA)

Several randomized controlled trials have evaluated whether omega-3 fatty acid intake reduces blockage of arteries in the heart following balloon angioplasty (percutaneous transluminal coronary angioplasty/PTCA). Some research has reported small significant benefits (96;97), while other investigations have not found benefits (98-100). The evidence in this area remains inconclusive.
C
Prevention of graft failure after heart bypass surgery

There is limited study of the use of fish oils in patients after undergoing coronary artery bypass grafting (CABG). Initial research suggests possible small benefits in reducing blood clot formation in vein grafts (101;102). Additional evidence is necessary before a firm conclusion can be drawn in this area.
C
Angina pectoris

Preliminary studies report reductions in angina associated with fish oil intake (103;104). Better research is necessary before a firm conclusion can be drawn.
C
Cardiac arrhythmias (abnormal heart rhythms)

There is promising evidence that omega-3 fatty acids may decrease the risk of cardiac arrhythmias (105-107). This is one proposed mechanism behind the reduced number of heart attacks in people who regularly ingest fish oil or EPA + DHA. Additional research is needed in this area specifically before a firm conclusion can be reached.
C
Cancer prevention

Several population (epidemiologic) studies report that dietary omega-3 fatty acids or fish oil may reduce the risk of developing breast, colon, or prostate cancer (108-114). Randomized controlled trials are necessary before a clear conclusion can be drawn.
C
Colon cancer

Omega-3 fatty acids are commonly taken by cancer patients (115). Although preliminary studies report that growth of colon cancer cells may be reduced by taking fish oil, effects on survival or remission have not been measured adequately.
C
Infant eye / brain development

It has been suggested that fatty acids, particularly DHA, may be important for normal neurologic development. Fatty acids are added to some infant formulas. Several studies have examined the effects of DHA on development of vision in preterm infants (116-122). Short-term benefits have been reported compared to formulas without DHA, although these benefits may not be meaningful in the long-term. Well-designed research is necessary before a clear conclusion can be reached.
C
Ulcerative colitis

It has been suggested that effects of omega-3 fatty acids on inflammation may be beneficial in patients with ulcerative colitis when added to standard therapy, and several studies have been conducted in this area (123-134). Although results have been promising, the majority of trials are small and not well designed. Therefore, better research is necessary before a clear conclusion can be drawn.
C
Crohn's disease

It has been suggested that effects of omega-3 fatty acids on inflammation may be beneficial in patients with Crohn's disease when added to standard therapy, and several studies have been conducted in this area (125;135-137). Results are conflicting, and no clear conclusion can be drawn at this time.
C
IgA nephropathy

There are conflicting results from several trials in this area (138-144).
C
Nephrotic syndrome

There is not enough reliable evidence to form a clear conclusion in this area (145;146).
C
Lupus erythematosus

There is not enough reliable evidence to form a clear conclusion in this area (147-149).
C
Psoriasis

Several studies in this area do not provide enough reliable evidence to form a clear conclusion (150-161).
C
Eczema

Several studies of EPA for eczema do not provide enough reliable evidence to form a clear conclusion (162-164).
C
Asthma

Several studies in this area do not provide enough reliable evidence to form a clear conclusion, with some studies reporting no effects (165-170), and others finding benefits (171-177). Because most studies have been small without clear descriptions of design or results, the results cannot be considered conclusive (178).
C
Preeclampsia

Several studies of fish oil do not provide enough reliable evidence to form a clear conclusion in this area (179-185).
C
Schizophrenia

There is promising preliminary evidence from several randomized controlled trials in this area (186-189). Additional research is necessary before a firm conclusion can be reached (190).
C
Bipolar disorder

Several studies in this area do not provide enough reliable evidence to form a clear conclusion (191-193).
C
Depression

Several studies in this area do not provide enough reliable evidence to form a clear conclusion (194-196). Promising initial evidence (197-201) requires confirmation with larger, well-designed trials.
C
Dysmenorrhea (painful menstruation)

It has been suggested that anti-inflammatory or prostaglandin-mediated mechanisms associated with omega-3 fatty acids may play a role in the management of dysmenorrhea. There is preliminary evidence suggesting possible benefits of fish oil/omega-3 fatty acids in patients with dysmenorrhea (202-204). Additional research is necessary before a firm conclusion can be reached.
C
Cystic fibrosis

A small amount of research in this area does not provide enough reliable evidence to form a clear conclusion (205-212).
C
Diabetes

Although slight increases in fasting blood glucose 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 progression of diabetic nephropathy (kidney disease), albuminuria (protein in the urine), or hemoglobin A1clevels (5;213). Most studies in this area are not well designed.The effects of fish oil on hypertriglyceridemia are similar in patients with or without diabetes (5).
D
Hypercholesterolemia

Although fish oil is able to reduce triglycerides, beneficial effects on blood cholesterol levels have not been demonstrated. Fish oil supplements appear to cause small improvements in high-density lipoprotein ("good cholesterol") by 1-3%. However, increases (worsening) in low-density lipoprotein levels ("bad cholesterol") by 5-10% are also observed (dose-dependent with effects likely to occur at 1 gram per day or greater of omega-3 fatty acids). Therefore, for individuals with high blood levels of total cholesterol or low-density lipoprotein, significant improvements will likely not be seen, and a different treatment should be selected. Fish oil does not appear to affect C-reactive protein (CRP) levels (12).Several randomized trials in patients with familial hypercholesterolemia yield conflicting results (214-218).
D
Transplant rejection prevention (kidney and heart)

There are multiple studies of heart transplant and kidney transplant patients taking cyclosporine (Neoral®), who were administered fish oil supplements. The majority of trials report improvements in kidney function (glomerular filtration rate, serum creatinine) (63-72), and less hypertension (high blood pressure) (63;73;74) compared to patients not taking fish oil. However, several recent studies report no benefits on kidney function (75-79), and no changes have been found in rates of rejection or graft survival.
D
Appetite / weight loss in cancer patients

There is preliminary evidence that fish oil supplementation does not improve appetite or prevent weight loss in cancer patients (219-225).A higher ratio of n-6 to n-3 fatty acids is associated with lower bone mineral density (BMD) at the hip in both sexes. These findings suggest that the relative amounts of dietary polyunsaturated fatty acids may play a vital role in preserving skeletal integrity in older age. (226)Supplementation with 2g per day of fish oil was well tolerated and was associated with a significant increase in heart rate variability (HRV). Supplementation with 2g per day of soy oil was associated with a lesser but significant increase in HRV.Consumption of fish is associated with a significantly reduced progression of coronary artery atherosclerosis in women with coronary artery disease. (227)
D

*Key to grades
A: Strong scientific evidence for this use;
B: Good scientific evidence for this use;
C: Unclear scientific evidence for this use;
D: Fair scientific evidence against this use;
F: Strong scientific evidence against this use.

Uses based on tradition or theory
The below uses are based on tradition or scientific theories. They often have not been thoroughly tested in humans, and safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Acute myocardial infarction (heart attack), acute respiratory distress syndrome (ARDS), age related macular degeneration coenzyme Q10 (Phototrop) on the visual functions and fundus alterations in early age-related macular degeneration (AMD) (228), aggressive behavior, agoraphobia, AIDS, allergies, Alzheimer's disease, anticoagulation, antiphospholipid syndrome, attention deficit hyperactivity disorder (ADHD), anthracycline-induced cardiac toxicity, autoimmune nephritis, bacterial infections, Behcet's syndrome, borderline personality disorder (229), breast cysts, breast tenderness, cartilage destruction, chronic fatigue syndrome, chronic obstructive pulmonary disease, cirrhosis, common cold, congestive heart failure, critical illness, dementia (230), dermatomyositis, diabetic nephropathy, diabetic neuropathy, dyslexia, dyspraxia, exercise performance enhancement, fibromyalgia, gallstones, gingivitis, glaucoma, glomerulonephritis, glycogen storage diseases, gout, hay fever, headache, hepatorenal syndrome, hypoxia, ichthyosis, immunosuppression, kidney disease prevention, kidney stones, leprosy, leukemia, malaria, male infertility, mastalgia (breast pain), memory enhancement, menopausal symptoms, menstrual cramps, methotrexate toxicity (231), multiple sclerosis, myopathy, neuropathy, night vision enhancement, obesity, omega-3 fatty acid deficiency, osteoarthritis, osteoporosis, otitis media (ear infection), panic disorder, peripheral vascular disease (232;233), postpartum depression (234;235), postviral fatigue syndrome, pregnancy nutritional supplement, premature birth prevention, premenstrual syndrome, prostate cancer prevention, protection from isotretinoin drug toxicity, Raynaud's phenomenon, Refsum's syndrome, retinitis pigmentosa (236), Reye's syndrome, seizure disorder (237), suicide prevention (238), systemic lupus erythematosus (149;239;240), tardive dyskinesia, tennis elbow, ulcerative colitis (241), urolithiasis (bladder stones), vision enhancement, weight loss (242).

Dosing

The below doses are based on scientific research, publications, traditional use, or expert opinion. Many herbs and supplements have not been thoroughly tested, and safety and effectiveness may not be proven. Brands may be made differently, with variable ingredients, even within the same brand. The below doses may not apply to all products. You should read product labels, and discuss doses with a qualified healthcare provider before starting therapy.

Standardization:
General: 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.

Amounts of seafood necessary to provide 1 gram of DHA + EPA(based on USDA Nutrient Data Laboratory information): cod (Pacific): 23 ounces; haddock: 15 ounces; catfish: 15-20 ounces; flounder/sole: 7 ounces; shrimp: 11 ounces; lobster: 7.5-42.5 ounces; sardines: 2-3 ounces; crab: 8.5 ounces; cod (Atlantic): 12.5 ounces; clams: 12.5 ounces; scallops: 17.5 ounces; trout: 3-3.5 ounces; salmon: 1.4-4.5 ounces; herring: 1.5-2 ounces; oysters: 2.5-8 ounces; tuna (fresh): 2.5-12 ounces; tuna (canned, light): 12 ounces; tuna (canned, white): 4 ounces; halibut: 3-7.5 ounces; mackerel: 2-8.5 ounces. Cod liver oil: 5 grams; standard fish body oil: 3 grams; omega-3 fatty acid concentrate: 2 grams.

Amounts of α-linolenic acid in nuts and vegetable oils(based on USDA Nutrient Data Laboratory information): canola oil: 1.3 grams/tbsp; flaxseed/linseed oil: 8.5 grams/tbsp; flaxseeds: 2.2 grams/tbsp; olive oil: 0.1 grams/tbsp; soybean oil: 0.9 grams/tbsp; walnut oil: 1.4 grams/tbsp; walnuts (English): 0.7 grams/tbsp.

Calories: Fish oils contain approximately 9 calories per gram of oil.

Vitamin E: 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.  

Adults (18 years and older):
Average dietary intake of omega-3/omega-6 fatty acids: Average Americans consume approximately 1.6 grams of omega-3 fatty acids each day, of which about 1.4 grams (~90%) comes from α-linolenic acid, and only 0.1-0.2 grams (~10%) from EPA and DHA. In Western diets, people consume roughly 10 times more omega-6 fatty acids than omega-3 fatty acids. These large amounts of omega-6 fatty acids come from the common use of vegetable oils containing linoleic acid (for example: corn oil, evening primrose oil, pumpkin oil, safflower oil, sesame oil, soybean oil, sunflower oil, walnut oil, wheatgerm oil). Because omega-6 and omega-3 fatty acids compete with each other to be converted to active metabolites in the body, benefits can be reached either by decreasing intake of omega-6 fatty acids, or by increasing omega-3 fatty acids.

Recommended daily intake of omega-3 fatty acids (healthy adults): For healthy adults with no history of heart disease, the American Heart Association recommends eating fish at least two times per week (11). 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 (11). 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 (11).

Hypertriglyceridemia: The effects of omega-3 fatty acid intake on triglyceride-lowering are dose-responsive (higher doses have greater effects). 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). The American Heart Association, in its 2003 recommendations, reports that supplementation with 2-4 grams of EPA + DHA each day can lower triglycerides by 20-40% (11). Effects appear to be additive with HMG-CoA reductase inhibitor ("statin") drugs such as simvastatin (Zocor®) (7), pravastatin (Pravachol®) (8;9), and atorvastatin (Lipitor®) (10). 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.

Heart disease (secondary prevention): 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, suggests that people with known coronary heart disease consume approximately 1 gram of EPA and DHA (combined) each day (11). 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.

High blood pressure: The effects of omega-3 fatty acids on blood pressure appear to be dose-responsive (higher doses have greater effects) (23). 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.

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.

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 (70)). Up to 12 grams per day has been used.

Other: Omega-3 fatty acids are used for numerous other indications, although effective doses are not clearly established. Supplementation with 2g per day of fish oil was well tolerated and was associated with a significant increase in heart rate variability (HRV). Supplementation with 2g per day of soy oil was associated with a lesser but significant increase in HRV. (243)

Children (younger than 18 years):
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.

Safety

The U.S. Food and Drug Administration does not strictly regulate herbs and supplements. There is no guarantee of strength, purity or safety of products, and effects may vary. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy. Consult a healthcare provider immediately if you experience side effects.

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 (204;244). 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 and Warnings
General: The U.S. Food and Drug Administration classifies intake of up to 3 grams per day of omega-3 fatty acids from fish as GRAS (Generally Regarded as Safe). Caution may be warranted, however, in diabetic patients due to potential (albeit unlikely) increases in blood sugar levels, patients at risk of bleeding, or in those with high levels of low-density lipoprotein (LDL). Fish meat may contain methylmercury and caution is warranted in young children and pregnant/breastfeeding women.

Bleeding: Intake of 3 grams per day or greater of omega-3 fatty acids may increase the risk of bleeding, although there is little evidence of significant bleeding risk at lower doses (245-247). Very large intakes of fish oil/omega-3 fatty acids ("Eskimo" amounts) may increase the risk of hemorrhagic (bleeding) stroke (92). High doses have also been associated with nosebleed and blood in the urine (146). Fish oils appear to decrease platelet aggregation and prolong bleeding time, increase fibrinolysis (breaking down of blood clots), and may reduce von Willebrand factor.

Environmental contamination: 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. Heavy metals are most harmful in young children and pregnant/nursing women. 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, and in young children to less than 2 ounces per week. For farm-raised, imported, or marine fish, the U.S. Food and Drug Administration recommends that pregnant/nursing women and young children 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 symptoms: 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 (8;15;25;204;244;248). Diarrhea may also occur, with potentially severe diarrhea at very high doses (249). There are also reports of increased burping (204), acid reflux/heartburn/indigestion (250), abdominal bloating (248), and abdominal pain (96). Fishy aftertaste is a common effect (204;248). Gastrointestinal side effects can be minimized if fish oils are taken with meals and if doses are started low and gradually increased.

Blood pressure effects: Multiple human trials report small reductions in blood pressure with intake of omega-3 fatty acids (22-28). Reductions of 2-5 mmHg have been observed, and effects appear to be dose-responsive (higher doses have greater effects) (23). DHA may have greater effects than EPA (29). Caution is warranted in patients with low blood pressure or in those taking blood-pressure lowering medications.

Blood sugar levels/diabetes: Although slight increases in fasting blood glucose 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 A1clevels (5;213). Limited reports in the 1980s of increased insulin needs in diabetic patients taking long-term fish oils may be related to other dietary changes or weight gain (146;251).

Vitamin 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. 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.

Cholesterol levels: Increases (worsening) in low-density lipoprotein levels ("bad cholesterol") by 5-10% are observed with intake of omega-3 fatty acids. Effects are dose-dependent with effects likely to occur at 1 gram per day or greater of omega-3 fatty acids.

Liver (hepatic) effects: Mild elevations in liver function tests (alanine aminotransferase) have been reported rarely (252).

Dermatologic effects: Skin rashes have been reported rarely (204;244).

Neurologic/psychiatric effects: There are rare reports of mania in patients with bipolar disorder or major depression (253). Restlessness and formication (the sensation of ants crawling on the skin) have also been reported (244).

Calories: Fish oils contain approximately 9 calories per gram of oil.

Pregnancy and Breastfeeding
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 are 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 (254). However, higher doses may not be advisable due to the potential risk of bleeding. Fatty acids are added to some infant formulas.

Interactions

Most herbs and supplements have not been thoroughly tested for interactions with other herbs, supplements, drugs, or foods. The interactions listed below are based on reports in scientific publications, laboratory experiments, or traditional use. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy.

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 (255-258). Some examples include aspirin, anticoagulants ("blood thinners") such as warfarin (Coumadin®) (259) 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 and add to the effects of drugs that may also affect blood pressure (260;261).

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.

Omega-3 fatty acids lower triglyceride levels, but can actually increase (worsen) low-density lipoprotein (LDL/"bad cholesterol") levels by a small amount. Therefore, omega-3 fatty acids may add to the triglyceride-lowering effects of agents like niacin/nicotinic acid, fibrates such as gemfibrozil (Lopid®), or resins such as cholestyramine (Questran®). However, omega-3 fatty acids may work against the LDL-lowering properties of "statin" drugs like atorvastatin (Lipitor®) and lovastatin (Mevacor®).

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, 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).

Omega-3 fatty acids lower triglyceride levels, but can actually increase (worsen) low-density lipoprotein (LDL/"bad cholesterol") levels by a small amount. Therefore, omega-3 fatty acids may add to the triglyceride-lowering effects of agents like niacin/nicotinic acid, but may work against the potential LDL-lowering properties of agents like barley, garlic, guggul, psyllium, soy, or sweet almond.

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.

Methodology

This information is based on a professional level monograph edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com): Ethan Basch, MD, MSc, MPhil (Memorial Sloan Kettering Cancer Center); Stephen Bent, MD (University of California San Francisco); Catherine Ulbricht, PharmD (Massachusetts General Hospital); Michael Smith, MRPharmS, ND (Canadian College of Naturopathic Medicine); Philippe Szapary, MD (University of Pennsylvania); Paul Hammerness, MD (Massachusetts General Hospital); Serguei Axentsev, M.D., Ph. D., D. Sci. (Natural Standard Research Collaboration).

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August 01, 2005.

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