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POSSIBLY EFFECTIVE

• Osteoarthritis. Cetylated fatty acids seem to reduce pain and improve function when used orally or topically in patients with knee osteoarthritis. Details: Some clinical research in patients with knee osteoarthritis shows that taking a specific blend of cetylated fatty acids (Celadrin, Imagenetix Inc.) 350 mg combined with 50 mg soy lecithin and 75 mg fish oil twice daily for 68 days decreases pain and improves knee range of motion and function. However, it does not appear to improve morning stiffness (8924). Applying the same specific blend of cetylated fatty acids topically twice daily for 30 days, either alone or in combination with menthol for 7 days, also seems to decrease pain and improve functionality in patients with knee osteoarthritis (12076,13104,13105). Other preliminary clinical research in patients with knee osteoarthritis also shows that applying a cream containing a specific blend of cetylated fatty acids (Cetilar, PharmaNutra) to the knee twice daily for one week modestly reduces pain and improves functionality when compared with baseline. Stiffness was also improved in patients with moderate, but not mild, osteoarthritis based on radiographic measurements (101995).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Fibromyalgia. Although there has been interest in using oral cetylated fatty acids for fibromyalgia, there is insufficient reliable information about the clinical effects of cetylated fatty acids for this purpose.
• Knee pain. It is unclear if oral cetylated fatty acids are beneficial for mild knee pain. Details: A small, preliminary study in adults with idiopathic mild knee pain shows that taking a specific cetylated fatty acid product (JOINTRUS, SFC Bio, Inc) 125 mg twice daily for 12 weeks does not improve pain scores when compared with placebo (97425).
• Juvenile idiopathic arthritis (JIA). Oral cetylated fatty acids have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children 2-16 years of age with JIA shows that taking a specific supplement (Kre-Celazine, All American Pharmaceutical) containing creatine and cetylated fatty acids 750 mg twice daily for 30 days may improve pain and inflammation when compared with baseline. Over 80% of patients reported near zero pain after use (90322). The validity of this study is limited by the lack of a comparator group. Additionally, it is unclear if any benefits were due to cetylated fatty acids, creatine, or the combination.
• Myofascial pain syndrome. Topical cetylated fatty acids have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with myofascial pain syndrome of the neck shows that applying a cream containing cetylated fatty acids 5.6% with menthol 1.5% twice daily, in addition to undergoing physical therapy twice weekly for 4 weeks, reduces pain by a small amount and improves disability by a moderate amount when compared to physical therapy alone (101997). It is unclear if the benefits of the cream were due to cetylated fatty acids, menthol, or the combination.
• Pain (chronic). It is unclear if topical cetylated fatty acids are beneficial in athletes with chronic groin and lower abdominal pain. Details: A very small, uncontrolled clinical study in professional roller hockey players who are participating in physical therapy shows that applying a specific cream or patch containing cetylated fatty acids (Cetilar Crema or Cetilar Patch, PharmaNutra) to the pelvic area on both limbs daily for 12 weeks, excluding weekends, improves symptoms of athletic pubalgia, a condition characterized by chronic groin and lower abdominal pain, when compared to baseline (107915). The validity of these findings is limited by a lack of control group. It is unclear if these findings are due to cetylated fatty acids, physical therapy, or the combination.
• Psoriasis. Although there has been interest in using oral cetylated fatty acids for psoriasis, there is insufficient reliable information about the clinical effects of cetylated fatty acids for this purpose.
• Sjogren syndrome. Although there has been interest in using oral cetylated fatty acids for Sjogren syndrome, there is insufficient reliable information about the clinical effects of cetylated fatty acids for this purpose.
• Systemic lupus erythematosus (SLE). Although there has been interest in using oral cetylated fatty acids for SLE, there is insufficient reliable information about the clinical effects of cetylated fatty acids for this purpose. More evidence is needed to rate the effectiveness of cetylated fatty acids for these uses.

(Read more about CETYLATED FATTY ACIDS (CFAs))

EFFECTIVE

• Hypertriglyceridemia. Oral prescription fish oil products reduce triglyceride levels in patients with hypertriglyceridemia, especially in severe cases. Oral fish oil supplements may reduce triglyceride levels when used in very high doses of up to 12 capsules per dose. Details: Fish oil can reduce triglyceride levels by 20% to 50% (1024,2299,2300,2301,2302,2315,2317,5702,5705,5706)(6394,6399,7368,7369,7380,12921,12922,13011,13766,65846)(66154,65504,66370,66156,66338,65589,66221,66257,66278,98004,100253). The effect is dose-dependent and greatest in individuals with severe hypertriglyceridemia (triglyceride levels of 500 mg/dL and above) (5706,7380,65846,66278,100253). However, fish oil might be less effective than fibrates. One clinical study shows that fish oil in doses of 4 grams daily is not as effective as gemfibrozil (Lopid) 1200 mg daily (7377). For patients with hypertriglyceridemia associated with the atherogenic lipoprotein phenotype (ALP), which is thought to be a marker for cardiovascular disease, taking fish oil 6 grams daily might reduce triglyceride levels by 35% (8683). Preliminary clinical research shows that taking the omega-3 fatty acids found in fish oil might also reduce fatty liver disease and serum transaminase levels associated with hypertriglyceridemia (13755). Three specific fish oil preparations (Lovaza, formerly known as Omacor, GlaxoSmithKline; Omtryg, Trygg Pharma, Inc.; Epanova, AstraZeneca Pharmaceuticals), are approved by the US Food and Drug Administration (FDA) for use as an adjunct to diet to lower triglyceride levels in adults with severe hypertriglyceridemia (12982,96117). These prescription-only products are typically used at dosages of 4 grams providing 3.4-3.6 grams of omega-3 fatty acids daily (98004). When a 4-gram daily dose is used, triglycerides are lowered by about 20% to 30%. When a 2-gram daily dose is used, the triglyceride-lowering effect is reduced by about half (100253). In 2019, the American Heart Association (AHA) stated that prescription fish oil products, taken in doses of 4 grams daily, are clinically useful for lowering triglyceride levels in patients with hypertriglyceridemia or severe hypertriglyceridemia (100253). Fish oil supplements have also shown benefit in clinical research when used in doses ranging from 1-15 grams daily for up to 6 months, or when providing EPA 1.45 to 2.7 grams and DHA 1.05 to 1.8 grams daily for 2 to 12 weeks (1024,2301,2315,2317,5705,5707,6394,6399,7368,7369)(8683,13766,65589,66156,66257,66370). However, some experts view these forms of fish oil as inadequate, as the omega-3 fatty acid content of fish oil supplements is usually lower and often variable compared to prescription fish oil. Often, up to 12 capsules of fish oil supplements daily may be needed to produce the same triglyceride-lowering effect as prescription fish oil (98004). In 2019, the AHA did not recommend for or against the use of fish oil supplements for hypertriglyceridemia (100253). There is limited evidence regarding the effects of fish oil in younger patients with hypertriglyceridemia (100253). Two small clinical studies in adolescents with hypertriglyceridemia show that fish oil supplements 4 grams daily for 2-6 months do not reduce triglyceride levels when compared with placebo (89339,100253). However, the lack of benefit in this patient population might be due to the small study sizes or due to potential underlying genetic resistance to treatment.

POSSIBLY EFFECTIVE

• Angioplasty. Oral fish oil seems to prevent restenosis when started at least 3 weeks before percutaneous transluminal coronary angioplasty (PTCA). Details: Meta-analyses of clinical research show that taking fish oil orally prevents restenosis after PTCA (13750,66376,65569). Also, clinical research shows that fish oil decreases restenosis rate by up to 45% when given for at least three weeks before PTCA and continued for one month thereafter (8680,65614). In these clinical trials, two different dosing regimens were used; fish oil 6 grams daily starting at least one month before PTCA and continuing one month after PTCA, followed by 3 grams of fish oil daily for 6 months thereafter (8680); and fifteen 1 gram capsules of fish oil (containing 2.7 grams of EPA 1.8 grams of DHA daily) daily starting 3 weeks before PTCA and continuing for 6 months thereafter (65614). When given for two weeks or less before PTCA, fish oil doesn't seem to have any effect on restenosis (1028,1038,2320,65462,66390,65626,66203,66212), although some conflicting evidence exists (66202).
• Cachexia. Oral fish oil in doses of 7.5-8.1 grams daily seems to slow weight loss in patients with cachexia. Lower doses might not be effective. Details: Taking a high-dose fish oil supplement seems to slow weight loss in some patients with cancer-related cachexia (11979,62390). Lower doses (3 grams daily) do not seem to have any effect (10008). Higher doses (7.5-8.1 grams daily) have come from a specific fish oil preparation (ACO Omega-3, Pharmacia) 30 mL providing EPA 4.9 grams and DHA 3.2 grams daily for 4 weeks (62390), or fish oil 7.5 grams daily providing EPA 4.7 grams and DHA 2.8 grams for a median of 5 weeks (11979). There is also preliminary evidence that a product providing protein 32 grams, EPA 2.18 grams, and DHA 1.92 grams daily for up to 7 weeks might help to improve appetite and increase lean body mass in patients with advanced pancreatic cancer (5701). In contrast, a meta-analysis of three studies in cancer patients shows that taking fish oil for 4-25 weeks does not seem to prevent loss of fat-free mass or body weight, or prevent a decrease in upper arm circumference, when compared with placebo. However, it is unclear how many of the included patients had malnutrition and/or weight loss (106070).
• Cyclosporine-induced nephrotoxicity. Oral fish oil seems to prevent cyclosporine-induced nephrotoxicity. Details: Some clinical research shows that taking fish oil orally seems to significantly improve glomerular filtration rate (GFR) and renal blood flow in individuals taking cyclosporine after kidney or liver transplant (1021,66187). Taking fish oil orally also seems to improve kidney function during the recovery phase following a rejection episode in kidney transplant recipients taking cyclosporine when compared with coconut oil (65590). In addition, another clinical study shows that taking fish oil modestly improves kidney function in patients following a recent kidney transplant (66472). Doses used in these studies include fish oil 12 grams, containing 18% EPA and 12% DHA, daily for 2 months following liver transplant or fish oil 3-6 grams, usually containing 30% EPA and 20% DHA, daily for up to 12 months following kidney transplant (1021,66187,65590,66472).
• Dysmenorrhea. Oral fish oil seems to reduce symptoms of dysmenorrhea. Details: Clinical research in adolescents and adults with dysmenorrhea shows that taking fish oil, alone or in combination with vitamin B1 100 mg, vitamin B12 11 mcg, or vitamin E 1.5 mg or 200 IU, seems to decrease pain, nonsteroidal anti-inflammatory drug (NSAID) consumption, and interference with daily activities (7574,7575,15738,89341,99367,107174). Doses of fish oil used in these studies provided EPA 1080 mg and DHA 720 mg daily for up to 2 months or EPA 180 mg and DHA 120 mg daily for 5 days (7574,99367). Alternatively, fish oil 2.5 grams daily for 3-4 months or 500 mg daily for 2 months has been used (7575,89341).
• Gastroenteritis-associated nausea and vomiting. Oral fish oil during pregnancy seems to be beneficial for preventing gastroenteritis in early childhood. It is unclear if oral fish oil is beneficial for gastroenteritis prevention or treatment in children or adults. Details: Clinical research shows that taking fish oil 2.4 grams daily (Incromega TG33/22, Croda Health Care), containing 55% eicosapentaenoic acid (EPA) and 37% docosahexaenoic acid (DHA), from week 24 of pregnancy until one week postpartum reduces the number of days of gastroenteritis in the first 3 years of the child's life by 2.5 days or 14% when compared with an olive oil control. There was also a 16% reduction in the number of gastroenteritis episodes and a 20% reduced risk of having a gastroenteritis episode. A sub-analysis suggests that benefits are limited to the winter months and to the children of mothers with the lowest blood levels of EPA and DHA (107182). More research is needed to determine the effect of fish oil in children or adults.
• Heart failure. Dietary fish oil seems to prevent heart failure. Also, oral fish oil seems to prevent further hospitalization, and possibly mortality, in patients with heart failure. Details: Dietary fish oil might be beneficial for primary prevention of heart failure. Population research found that higher intake of DIETARY fish oil is associated with a 15% reduced risk of incident heart failure (17994). Based on this data and other population research, the American Heart Association (AHA) recommends that patients consume 1-2 weekly servings of non-fried fish in place of less healthy protein options to reduce the risk of congestive heart failure (97185). There is not enough available information to know if fish oil SUPPLEMENTS are beneficial for primary prevention of heart failure (93568). However, taking fish oil supplements seems to be beneficial for secondary prevention of outcomes in patients with heart failure. A meta-analysis of clinical research shows that taking omega-3 fatty acids 600-4300 mg orally daily for up to 12 months can improve left ventricular ejection fraction and cardiac function in patients with non-ischemic chronic heart failure (89373). Another meta-analysis shows that although taking omega-3 fatty acids 961-6000 mg orally daily for up to 6.2 years does not reduce cardiovascular mortality or first hospitalization due to heart failure, recurrent hospitalizations due to heart failure were reduced by approximately 9% when compared with placebo (106061). A large-scale clinical trial (GISSI-HF) also shows that taking fish oil 1 gram daily, providing 850-882 mg of EPA and DHA as ethyl esters in a ratio of 1:1.2, for an average of 3.9 years significantly reduces the risk of all-cause mortality, cardiovascular mortality, and hospitalization in patients with New York Heart Association class II-IV heart failure. Based on these findings, approximately 56 patients would need to be treated for 3.9 years to prevent one death. Approximately 44 patients would need to be treated for 3.9 years to prevent one cardiovascular-related death or hospitalization (16733). Based on these findings, an AHA science advisory states that it is reasonable to consider supplementation with fish oil 1 gram daily in patients with heart failure (93568).
• HIV/AIDS-related dyslipidemia. Oral fish oil seems to reduce triglyceride levels in patients with this condition. It is unclear if oral fish oil reduces levels of low-density lipoprotein (LDL) cholesterol in these patients. Details: A meta-analysis of clinical research shows that supplementation with fish oil reduces triglycerides by 12-99 mg/dL in patients with HIV treatment-related dyslipidemia when compared to control (66177,66144,65993). Two capsules of a specific fish oil supplement (Omacor, Pronova BioPharma) containing EPA 460 mg plus DHA 380 mg twice daily for 12 weeks has been used in one study (65993). The effect of fish oil on total cholesterol levels is mixed, with some evidence showing a decrease in total cholesterol of 14 mg/dL (66177), while other evidence suggests that fish oil does not affect total cholesterol levels in these patients (65993,89359). An observational cohort study has found that taking fish oil is associated with reduced triglyceride levels in patients with HIV and hypertriglyceridemia, with overall effects similar to statins but less than fibrates (89354).
• Hypertension. Oral fish oil seems to reduce systolic and diastolic blood pressure in adults with moderate or severe hypertension. It is unclear if oral fish oil reduces blood pressure in patients with mild hypertension or in those using antihypertensive drugs. Details: Most clinical research shows that taking fish oil produces modest but significant reductions in systolic and diastolic blood pressure in adults with moderate or severe hypertension (1020,2301,66215,66095). In patients with mild hypertension, however, the evidence is mixed (1001,66385,66180). The discrepancy regarding the hypotensive effect of fish oil in individuals with mild hypertension may result from the type of fish oil used for treatment (66180). Meta-analyses of clinical research suggest that, in general, fish oil reduces systolic blood pressure by 2.5-5.5 mmHg and diastolic blood pressure by 1.5-3.5 mmHg in individuals with hypertension (66358,66379,89324,89350). In 2019, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that consuming EPA and DHA in combination may be beneficial for moderating blood pressure and reducing the risk of hypertension in the general population. However, the FDA noted that this claim is based on inconsistent and inconclusive evidence (102372). It is unclear whether fish oil is beneficial in people who are already using antihypertensive drugs. Some clinical research suggests that taking fish oil 5 grams daily for 6 weeks does not further improve the hypertensive effects of ACE inhibitors in individuals being treated for hypertension (66359), while other research suggests that fish oil decreases systolic and diastolic blood pressure in hypertensive individuals currently taking beta-blockers or diuretics (66331,66100). However, taking fish oil does not seem to significantly improve blood pressure in individuals with hypertension that remains uncontrolled despite the use of antihypertensive drugs (66418). Clinical trials showing blood pressure-lowering effects have used fish oil 4-15 grams daily, in single or divided doses, for up to 36 weeks, or fish oil providing EPA 2.04 grams and DHA 1.4 grams daily (1001,1020,2301,66100,66180,66331,66385). Omega-3 fatty acids 3-15 grams daily for 4 weeks have also been used (66215). There is conflicting evidence regarding whether the hypotensive effect of fish oil is dose-dependent (66358,66379,89350). Other research has assessed whether fish oil affects the risk of developing additional cardiometabolic disorders in adults with hypertension. In a cohort of over 81,500 patients followed for 9 years, those who consumed fish oil as supplements or in the diet at baseline had a 9%, 11%, and 14% reduction, respectively, in the risk for diabetes, coronary heart disease, and cardiac death, when compared with those with hypertension who did not consume fish oil (108508).
• IgA nephropathy. When used for 2-4 years, oral fish oil seems to slow the rate of renal function loss in high-risk patients. It is unclear if oral fish oil slows renal function loss when used for shorter time periods or in low-risk patients. Details: Some clinical research shows that long-term use (2-4 years) of fish oil 1-12 grams daily can slow the rate of renal function loss in high-risk patients with IgA nephropathy (8686,8711,66343,65615). However, short-term use may not be as effective. Some research shows that fish oil 4-6 grams daily for 6 months does not attenuate the loss of renal function (66351,65593), although a combination of fish oil 3 grams containing 85% EPA plus DHA daily plus renin-angiotensin system blockers (RASB) for 6 months seems to reduce proteinuria in patients with IgA nephropathy when compared with RASB alone (65887). The conflicting data regarding the effect of fish oil on IgA nephropathy has been attributed to different factors. One analysis of clinical evidence suggests that the effects of fish oil on proteinuria in patients with IgA nephropathy is dose-dependent (65792). Another analysis suggests that the effect of fish oil may be beneficial in only IgA nephropathy patients with more proteinuria (66455).
• Nonalcoholic fatty liver disease (NAFLD). Oral fish oil seems to reduce liver steatosis in adults and children with NAFLD. Details: Meta-analyses of mainly small clinical studies show that taking omega-3 fatty acids from fish oil or seal oil reduces serum liver enzymes and liver fat when compared with control treatment in patients with NAFLD (98258,103498). However, these analyses are limited by the heterogeneity and small size of the available studies. In one small clinical trial not included in these analyses, taking fish oil providing eicosapentaenoic acid (EPA) 735 mg and docosahexaenoic acid (DHA) 1605 mg daily for 3 months modestly reduces triglyceride levels and waist circumference when compared with control. However, insulin and alanine transaminase (ALT) levels were only reduced when fish oil was used in combination with vitamin D 1680 IU daily. There was no effect of fish oil on other liver, glycemic, or lipid parameters (107186). In one meta-analysis, omega-3 fatty acids such as fish oil were used in a median dose of 2.7 grams daily for an average of 6 months (98258). Omega-3 fatty acids such as fish oil might also benefit children with NAFLD. A meta-analysis of three small clinical trials shows that taking omega-3 fatty acids modestly improves steatosis grade in children with NAFLD when compared with placebo (98241). Larger studies are needed to confirm these results.
• Rheumatoid arthritis (RA). Oral fish oil seems to reduce pain and stiffness in patients with RA; however, oral fish oil does not seem to be beneficial for RA prevention when used alone. Details: Taking fish oil orally, alone or in combination with the nonsteroidal anti-inflammatory drug (NSAID) naproxen, seems to significantly decrease the duration of morning stiffness and the number of tender joints in patients with RA (1017,1039,1041,12924,12925,15738,65629,66313,66352,66191) (66248). Use of fish oil might also reduce NSAID requirements when used concomitantly (1031,15738,65610). Also, taking omega-3 fatty acids 5.5 grams daily for 12 months upon initiating treatment with methotrexate, hydroxychloroquine, and sulfasalazine may slow time to conventional therapy failure and decrease time to first remission in patients with early onset RA (89362). In this clinical research, fish oil 10 grams daily for 6 months or fish oil preparations containing EPA 0.5-4.6 grams and DHA 0.2-3 grams, sometimes along with vitamin E 15 IU, have been used daily for up to 15 months (1017,1031,1039,1041,12924,12925,15738,65610,66352,66191,66248). The effect of oral fish oil on RA prevention has also been investigated in a large clinical trial of approximately 25,000 older adults. Taking fish oil 1 gram daily for 5 years providing EPA 0.46 grams and DHA 0.38 grams does not reduce the risk of developing definite or probable RA when compared with placebo. However, the risk of RA is reduced by 77% when fish oil is taken in combination with vitamin D3 2000 IU daily (107184). Although this study was large, the primary endpoint was the effect of taking fish oil and/or vitamin D on the development of autoimmune diseases as a group. The number of patients with a specific autoimmune disease such as RA was relatively small.

POSSIBLY INEFFECTIVE

• Age-related macular degeneration (AMD). Oral fish oil does not seem to prevent the incidence or progression of AMD. However, eating fish regularly might help to reduce the risk of AMD. Details: The best available clinical research shows that fish oil supplements (Omacor) are not beneficial for preventing AMD or its progression. A large, high-quality clinical study in over 25,800 adults at least 50 years of age shows that taking fish oil providing DHA 450 mg and EPA 550 mg daily for 3.8 to 6.1 years, with or without vitamin D, does not prevent AMD or its progression (105214). Other clinical research shows that taking fish oil containing DHA 350 mg and EPA 650 mg daily for up to 6.1 years does not prevent the development of advanced AMD (60281). Also, clinical research shows that taking fish oil containing DHA 840 mg and EPA 270 mg by mouth daily for 3 years does not prevent choroidal neovascularization in patients with AMD (89369). However, regular consumption of fish might be beneficial for preventing the incidence or progression of AMD. Observational research has found that consuming dietary fish more than once weekly is associated with a reduced risk of developing age-related maculopathy or AMD (6260,65724,65725,65889). Also, a meta-analysis of observational research has found a 6% and 22% decreased risk of early or late AMD, respectively, for every gram increase in dietary omega-3 fatty acid intake, and a 13% and 14% decreased risk, respectively, for every 15-gram daily increase in fish intake. Sub-analyses found 9% to 15% decreased risks for early or late AMD per 0.15 grams daily of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), but not alpha-linolenic acid. Although research examining the relationship between omega-3 intake and AMD progression is limited, the highest consumption of dietary fish is associated with a 36% lower risk of AMD progression when compared with the lowest consumption (107176).
• Angina. Oral fish oil does not seem to improve cardiovascular outcomes in patients with angina. Details: Clinical research shows that taking fish oil supplements does not improve mortality or cardiovascular outcomes in patients with angina (66255). In fact, some evidence suggests that fish oil supplements or increasing oily fish intake might increase the risk of cardiac death by 26% and sudden cardiac death by 54% in males with angina (17988). More evidence is needed before this potential risk can be confirmed.
• Atherosclerosis. Oral fish oil does not seem to attenuate atherosclerosis progression. Details: Most research shows that fish oil supplementation does not attenuate atherosclerosis progression when compared with placebo (1022,8681). Also, fish oil doesn't seem to improve luminal diameter (1022,2311) or decrease intima-media thickness of the carotid arteries in people with coronary artery disease (CAD) (8681). However, some research disagrees. One clinical study in adults with CAD shows that taking fish oil supplements 6 grams daily for 3 months and then 3 grams daily for 21 months modestly slows the progression, or causes mild to moderate regression, of atherosclerosis as measured by angiography (2311).
• Atopic dermatitis (eczema). Oral fish oil does not seem to treat or prevent atopic dermatitis. Details: A meta-analysis of clinical research shows that fish oil is not effective for TREATING established atopic dermatitis (13758,66151,13758). Also, despite conflicting results from preliminary clinical research (12971,17409), higher quality clinical studies show that fish oil does not PREVENT eczema development. A meta-analysis of clinical research, as well as results from more recent clinical trials, show that maternal supplementation or infant supplementation with fish oil does not reduce the risk of eczema development in infants or young children (66112,89338,89360,89361,96120). However, some population research suggests that eating fish in early childhood is associated with a reduced risk of developing childhood eczema (65992).
• Atrial fibrillation. Oral fish oil does not seem to reduce the risk of new or recurrent atrial fibrillation. Some clinical research suggests that high-dose fish oil may actually increase the risk for new atrial fibrillation. Details: Although some population research has found that consuming fish as part of the diet is associated with a reduced risk of atrial fibrillation (12055), most evidence from epidemiological and clinical research suggests that eating fatty fish or taking fish oil supplements does not reduce the risk of new onset or recurrent atrial fibrillation (12919,17995,66101,89357,105209,106075,107171,107181,109306,110332). Recent research suggests that consuming fish oil increases the risk of atrial fibrillation, particularly at higher doses. In 2023, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency issued a public statement on the use of omega-3-acid ethyl esters, concluding that exposure to omega-3-acid ethyl esters for the treatment of hypertriglyceridemia is associated with a dose-dependent increased risk of atrial fibrillation in patients with established cardiovascular disease (CVD) or risk factors for CVD when compared with placebo. The highest risk of atrial fibrillation is associated with a dose of 4 grams daily (112467). Additionally, one large, high-quality clinical study (the STRENGTH trial) in patients at high risk for CVD shows that taking a prescription fish oil product (Epanova) 4 grams daily for up to 5 years is associated with an increased risk for atrial fibrillation, with a number needed to harm of 114 when compared with a corn oil control (103491). Meta-analyses and a large epidemiological study suggest that taking fish oil supplements at doses over 1 gram daily is associated with a 25% to 37% increased risk of atrial fibrillation in individuals with or without CVD, including those with risk factors for CVD, regardless of genetic predisposition (106075,107171,107181,109306). The available meta-analyses are limited by the small number of studies in which atrial fibrillation is the primary endpoint, possibly over-estimating the effects of omega-3 fatty acid supplements on atrial fibrillation (110332,103491). Fish oil also seems to increase the risk of atrial fibrillation after myocardial infarction. In a secondary analysis of the Omega-3 fatty acids in Elderly patients with Myocardial Infarction (OMEMI) trial, adults aged 70-82 years old with recent myocardial infarction supplementing with 1.8 grams daily of omega-3 fatty acid supplements for 24 months had a 90% increased risk of developing atrial fibrillation or micro-atrial fibrillation, which is characterized by short, atrial fibrillation-like activity lasting less than 30 seconds. Changes in serum EPA levels seem to mediate this risk, with higher serum EPA levels predictive of an increased risk of atrial fibrillation and intermediate serum EPA levels predictive of an increased risk of micro-atrial fibrillation (112469). There is conflicting evidence regarding the effects of fish oil on recurrent atrial fibrillation following cardioversion. Some clinical research shows that taking fish oil 6 grams daily by mouth for one month prior to cardioversion and continuing for up to one year thereafter reduces the absolute risk of atrial fibrillation recurrence by about 39% when compared with placebo (89344). However, a meta-analysis of clinical research shows that fish oil does not reduce the risk of atrial fibrillation following cardioversion (89325). A reason for this discrepancy may be the duration of fish oil supplementation prior to cardioversion. Taking fish oil for at least 4 weeks before cardioversion appears to decrease the absolute risk of recurrent atrial fibrillation by about 18% when compared with placebo, whereas taking fish oil for less than 4 weeks before cardioversion appears to increase the absolute risk of atrial fibrillation by about 6% (89325). Most clinical research shows that fish oil does not decrease the risk of atrial fibrillation following cardiac surgery (17996,89352,89374). However, it is possible that fish oil formulations containing at least 1 gram of DHA may be beneficial. Evidence from clinical research and analysis of clinical data shows that taking fish oil containing DHA 1 gram or more reduces the risk of atrial fibrillation following cardiac surgery by about 37% to 72% (89374,96113). Fish oil containing lower doses of DHA does not appear to be beneficial (89374). A science advisory statement published by the American Heart Association (AHA) in 2017 states that fish oil is not indicated for secondary prevention of atrial fibrillation in patients with prior atrial fibrillation or those with atrial fibrillation after cardiac surgery. The cumulative evidence showed no benefit of fish oil in these populations (93568).
• Bronchopulmonary dysplasia. Oral fish oil does not seem to prevent bronchopulmonary dysplasia in preterm infants. Details: A meta-analysis of the available clinical research in over 3,500 preterm infants shows that receiving fish oil daily as part of formula or as a direct oral dose, starting within one month of birth, does not reduce the risk for bronchopulmonary dysplasia when compared with control (102390).
• Cerebrovascular disease. Oral fish oil does not seem to prevent cerebrovascular disease. Details: Although a meta-analysis of population studies has found that increased fish consumption lowers the risk of cerebrovascular disease, results from a pooled analysis of clinical trials show that fish oil supplementation does not reduce the risk of primary or secondary cerebrovascular disease (89334).
• Cognitive function. Oral fish oil does not seem to improve cognitive function in most people. Details: Most clinical research shows that fish oil supplementation does NOT improve cognitive function in healthy elderly individuals, elderly patients with self-reported cognitive decline, or adults and children (65880,66030,66492,97175,98248,103501,109310). However, fish oil supplementation may modestly help older patients with self-reported cognitive decline to perform daily activities (97181). Also, clinical research in young and middle-aged adults shows that taking a fish oil supplement providing eicosapentaenoic acid (EPA) 900 mg plus docosahexaenoic acid (DHA) 360 mg (Accelon EPA EE, BASF) daily for 6 months improves some measures of cognitive function, including overall speed and overall and memory-related accuracy, when compared with both placebo or a fish oil supplement providing DHA 900 mg and EPA 270 mg daily (Accelon DHA EE, BASF). There were no benefits on other measures of cognitive performance (109215). This suggests that any beneficial effects associated with fish oil might be related to the levels or ratio of EPA to DHA or the specific endpoints measured. Observational research has also found conflicting associations between dietary fish and fish oil intake and cognitive function (13747,15740,15741,15742).
• Helicobacter pylori. Oral fish oil does not seem to aid in the Helicobacter pylori eradication. Details: Clinical research shows that taking fish oil (Eicosapen) orally, in combination with pantoprazole and clarithromycin, is inferior for eradicating Helicobacter pylori infection when compared with a combination of pantoprazole, clarithromycin, and metronidazole (8710).
• Kidney transplant. Oral fish oil does not seem to improve survival or rejection rate following a kidney transplant. Details: A meta-analysis of a small number of clinical studies shows that taking fish oil does not improve patient survival, graft survival, or acute rejection rates when compared with placebo following kidney transplant (96121).
• Mastalgia. Oral fish oil does not seem to reduce chronic breast pain. Details: Clinical research shows that taking fish oil orally 3 grams daily for 6 months does not improve severe chronic breast pain when compared with placebo (9156).
• Multiple sclerosis (MS). Oral fish oil does not seem to improve symptoms in patients with MS. Details: Clinical research shows that taking fish oil (MaxEPA) 10 grams containing EPA 1.71 grams and DHA 1.14 grams daily for 2 years does not improve the duration, frequency, or severity of relapses when compared with placebo in patients with MS (66205). Also, in patients with relapsing remitting MS who are taking the medication fingolimod, taking fish oil 1 gram, providing EPA 180 mg and DHA 120 mg, daily for 12 months does not improve levels of inflammatory markers or symptoms of disability when compared with placebo (103502).
• Osteoarthritis. Oral fish oil does not seem to improve pain or function in patients with osteoarthritis. However, oral fish oil might be beneficial for osteoarthritis-related joint pain in overweight patients. Details: Clinical research shows that patients with osteoarthritis or knee pain taking low-dose fish oil 0.45 grams daily for 2 years have better pain and function scores when compared with those taking high-dose fish oil 4.5 grams daily (97179). The unexpected improvement in pain and function score in the low-dose fish oil group might be due to a placebo effect. Other clinical research shows that adding fish oil 444 mg to a glucosamine sulfate supplement does not further decrease osteoarthritis symptoms, such as morning stiffness or pain in the hips and knees, when compared with glucosamine alone (65998). In addition, one large study shows that taking fish oil (Omacor) 1 gram daily for an average of 5.3 years has no effect on knee pain due to osteoarthritis when compared with placebo (101548). In contrast to these findings, a meta-analysis of clinical research shows that taking fish oil seems to reduce joint pain (106066). However, only two studies were included in this analysis and both used fish oil in combination with other ingredients, including stinging nettle (76415) and lemon verbena (17748). In addition, one of these studies did not limit to patients with osteoarthritis (17748). Due to the overall negative findings, the American College of Rheumatology (ACR) conditionally recommends AGAINST the use of fish oil in patients with knee, hip, or hand osteoarthritis (102114). Taking fish oil might be beneficial for joint pain reduction in a population of older overweight or obese patients with osteoarthritis-specific pain in the knees, lower back, or shoulders. Clinical research shows that taking fish oil (Blackmores Omega Brain) providing EPA 400 mg and DHA 2000 mg daily for 16 weeks reduces pain by approximately 42%. This is significantly greater than placebo. The overall osteoarthritis burden was reduced by about 40% (103499).
• Pregnancy-induced hypertension. Oral fish oil does not seem to reduce the risk for hypertension during pregnancy. Details: Clinical research shows that fish oil does not reduce the risk of pregnancy-induced hypertension (1026,1027,12972,97174,110338).
• Pre-eclampsia. Oral fish oil does not seem to reduce the risk of pre-eclampsia. Details: Clinical research shows that fish oil does not reduce the risk of pre-eclampsia (1042,89376,97174,110338).
• Psychosis. Most research shows that oral fish oil is not beneficial for the treatment or prevention of psychosis. Details: Although some individual research shows that taking fish oil modestly reduces symptoms of psychosis and the absolute conversion rate to psychotic disorders (17084), most research disagrees (105217,105554,109308). A meta-analysis of randomized controlled trials in patients with psychosis shows that taking fish oil does not reduce psychotic symptoms when compared with placebo. However, it might modestly improve function (109308). Doses of fish oil used in the available research have ranged from 570 mg to 3000 mg daily for up to 1 year (17084,105554,109308).
• Unstable angina. Oral fish oil does not seem to prevent unstable angina. Details: In patients at high cardiovascular risk, taking a fish oil-based preparation (Epanova, AstraZeneca Pharmaceuticals) 4 grams daily for up to 5 years does not prevent unstable angina requiring hospitalization (103491).
• Ventricular arrhythmias. Oral fish oil does not seem to prevent ventricular arrhythmias or prevent mortality in patients with a history of ventricular arrhythmias. Details: Epidemiological research suggests that eating a diet high in fish has no effect on risk for premature ventricular complexes (12920). Clinical research is inconsistent. In one clinical trial, taking fish oil 2.6 grams daily did not prolong the time to the first event, such as ventricular tachycardia, ventricular fibrillation, or death, in patients with implantable defibrillators. However, in the subgroup of patients who adhered to therapy for a full 11 months, fish oil treatment did seem to significantly prolong time to first event (14436). Other clinical evidence suggests that taking fish oil 2 grams daily for 1-2 years does not reduce cardiac events such as cardiac defibrillation, ventricular tachyarrhythmia, ventricular fibrillation, or death from any cause in patients with implantable defibrillators (12986,14382). Also, other research suggests that taking fish oil supplements might actually increase the risk of ventricular tachycardia and fibrillation in some patients with implantable defibrillators (12986). Overall, meta-analyses of clinical studies show that taking fish oil does not reduce all-cause mortality in patients with an implantable defibrillator or history of ventricular arrhythmias (16732,65923,89343).

LIKELY INEFFECTIVE

• Diabetes. Oral fish oil does not improve glycemic control or prevent cardiovascular outcomes in patients with type 2 diabetes. However, oral fish oil may lower triglyceride levels in patients with type 2 diabetes. Details: Although fish oil may reduce triglyceride levels in patients with diabetes (65577,65834,65878,66027,66436,66444,101538,101541), taking fish oil orally has no clinically significant effect on fasting plasma glucose levels or glycated hemoglobin (HbA1c) in patients with type 2 diabetes in most studies (2299,2300,2302,7368,7369,12182,12925,13011,13147,13149)(65577,65834,65878,66316,66372,66426,66442,101504,101541,101542). A large, high-quality clinical study also shows that taking fish oil supplements 840 mg daily with or without aspirin for an average of 7.4 years does not decrease the risk for serious vascular complications, including myocardial infarction, stroke, or transient ischemic attack (TIA), when compared with placebo (102401). Additionally, fish oil does not seem to reduce the risk of gestational diabetes (89376,97174,110338).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute respiratory distress syndrome (ARDS). It is unclear if enteral fish oil is beneficial in patients with ARDS. Details: The effect of enteral fish oil, with or without borage oil and antioxidants, has been evaluated for improving outcomes in patients with ARDS. A meta-analysis of randomized controlled trials evaluating these ingredients, provided as a specific enteral formula (Oxepa, Abbott Nutrition) or a combination supplement given as a bolus, shows that there is no effect on overall all-cause mortality or ventilator- or ICU-free days when compared with generally isonitrogenous and isocaloric control formulas. A sub-group analysis of lower quality research shows that there may be a modest benefit for patients with a higher risk of mortality (105250). Two more recent meta-analyses have yielded similar results (105248,105249). Most studies included in these analyses investigated the use of Oxepa and found there was no effect on mortality when compared with control enteral formulas. Studies investigating other sources of enteral or intravenous fish oil were also included in these analyses (105248,105249). In one of these analyses, some overall low- to very low-quality evidence suggests that use of Oxepa modestly reduces mortality at 28 days, as well as ICU length of stay and duration of mechanical ventilation (105248). However, these benefits were not found in the second meta-analysis (105249). Most studies included in these analyses used fish oil in combination with other ingredients. Therefore, the effect of fish oil alone is unclear.
• Age-related cognitive decline. It is unclear if oral fish oil prevents age-related cognitive decline. Details: A meta-analysis of clinical research shows that there is no effect of increased dietary or supplemental omega-3 intake on global cognition in older adults (103501). The effect of fish oil supplements, specifically, is unclear.
• Allergic rhinitis (hay fever). It is unclear if taking oral fish oil during pregnancy prevents allergic rhinitis in the child. Details: Preliminary clinical research shows that maternal ingestion of fish oil 4 grams daily, providing 32% EPA and 23% DHA with tocopherol, during late pregnancy might reduce the occurrence of allergic rhinitis in the offspring at 16 years of age when compared with placebo (17409). However, higher-quality clinical research shows that maternal intake of fish oil supplements containing DHA 800 mg and EPA 100 mg by mouth daily starting at 21 weeks gestation and continuing until delivery, does not affect the development of allergic rhinitis in offspring by the age of 3 or 6 years (89361,97172).
• Alzheimer disease. It is unclear if oral fish oil is beneficial for preventing Alzheimer disease or for improving cognition in those with this condition. Details: Higher fish and fish oil intake has been linked to a decreased risk of developing Alzheimer disease in population studies (15040,15041,65817). However, in patients with existing mild-to-moderate Alzheimer disease, taking a specific fish oil supplement (EPAX1050TG, Pronova Biocare A/S) providing the omega-3 fatty acids DHA 1.7 grams and EPA 0.6 grams daily for 6 months does not significantly delay cognitive decline, although this fish oil supplement might slow cognitive decline in a subgroup of patients with very mild cognitive dysfunction (15024). Also, preliminary clinical research in patients with mild to moderate Alzheimer disease shows that taking fish oil 1 gram (providing docosahexaenoic acid 500 mg and eicosapentaenoic acid 150 mg), lutein 10 mg, zeaxanthin 2 mg, meso-zeaxanthin 10 mg, and vitamin E 15 mg (Memory Health) daily for 12 months does not affect disease severity when compared with placebo. However, there were modest increases the number of patients experiencing either an improvement or an attenuated decline in memory and mood (109764). The effect of fish oil alone is unclear from this study.
• Antiphospholipid syndrome-associated miscarriage. It is unclear if oral fish oil prevents miscarriage in patients with antiphospholipid syndrome. Details: Preliminary clinical research shows that taking fish oil 5.1 grams standardized to a 1.5 ratio of EPA:DHA, daily for 3 years seems to prevent recurrent miscarriage and increase live birth rate in pregnant patients with antiphospholipid syndrome (1032).
• Antipsychotic-induced metabolic side effects. It is unclear if oral fish oil is beneficial for metabolic side effects related to the use of olanzapine. Details: In patients with both schizophrenia and metabolic syndrome using olanzapine, clinical research shows that taking fish oil (Nature Made) providing EPA 720 mg and DHA 480 mg daily for 12 weeks reduces triglyceride levels by about 27% when compared with placebo. However, there was no effect on blood pressure or levels of fasting glucose or high-density lipoprotein (HDL) cholesterol (105225). In patients taking olanzapine with sodium valproate or lithium, a small clinical trial shows that taking fish oil (Zahravi Pharmaceutical Company), starting at a dose of 300 mg EPA plus DHA to 600 mg daily in two divided doses and titrating up to 900 mg daily in three divided doses for a total of 6 weeks, does not improve anthropometric measures or lipid parameters when compared with placebo (105226). These differing findings may be due to differences in fish oil dose and duration.
• Asthma. It is unclear if oral fish oil prevents or treats asthma. Details: Some research suggests that fish oil supplements may help TREAT asthma symptoms in some patients, but results are conflicting. Some clinical research shows that taking a fish oil supplement improves peak flow and reduces medication use and cough in children with asthma (12954,12963). Fish oil providing EPA 17-26.8 mg/kg and DHA 7.3-11.5 mg/kg has been used in one study (12954). However, other clinical research shows that taking fish oil does not improve asthma severity in children with bronchial asthma when compared to control, although asthma severity seems to be reduced when compared to baseline (65497). In adults, fish oil does not seem to improve measures of asthma such as forced expiratory volume in one second (FEV1), peak flow rate, asthma symptoms, asthma medication use, or bronchial hyper-reactivity (12954,17411,66266,1036,20546,66206). However, in asthmatic patients experiencing exercise-induced bronchoconstriction, fish oil (EPAX 3000 TG; Pronova Biocare), 20 capsules totaling 3.2 grams of EPA and 2 grams of DHA daily for 3 weeks seems to improve pulmonary function and reduce bronchodilator use when compared with placebo (65680). There is also conflicting evidence for the use of fish oil in asthma PREVENTION. For example, clinical research shows that maternal ingestion of fish oil supplements 4 grams daily or omega-3 fatty acids 0.65-3.7 grams daily during late-phase pregnancy reduces the occurrence of asthma in infants and children by 31% to 63% when compared with control (17409,66112,96120). The benefit seems to be greater for children of mothers with the lowest blood levels of EPA and DHA at baseline (96120). Conversely, other research found no benefit for asthma prevention with fish oil supplementation during lactation (66112). Also, giving fish oil containing DHA 280 mg plus EPA 110 mg daily to children during the first 6 months of life does not appear to prevent asthma development by the age of 6-12 months (89338). However, in a meta-analysis of 10 trials with follow-up of 6 months to 24 years, maternal intake of fish oil supplements at a dose of at least 1200 mg daily during pregnancy, lactation, or both, reduces the risk of asthma in the infant, but does not affect the rate of wheezing (108506).
• Athletic performance. It is unclear if oral fish oil improves athletic performance. Details: Evidence on the effect of fish oil in athletic performance is mixed. Some clinical research in athletes participating in intensive wrestling training shows that taking fish oil 1 gram daily for 12 weeks improves pulmonary function when compared with placebo (65971). In another small clinical study in professional rugby players, taking fish oil containing EPA 551 mg and DHA 551 mg twice daily for 5 weeks during training attenuates the decline in counter movement jump when compared with placebo (99357). However, taking fish oil 1 gram daily for 5 weeks does not seem to improve endurance or recovery in professional Australian Football League athletes when compared with baseline or placebo (65876).
• Atopic disease. Oral fish oil does not seem to reduce the odds of a child developing atopic disease when taken during pregnancy. Details: A moderate-sized clinical study in children of pregnant adults shows that taking fish oil capsules 2.4 grams, containing docosahexaenoic acid (DHA) 1.9 grams, eicosapentaenoic acid 0.22 grams, and other omega-3 fatty acids, starting in early pregnancy until 6 months postpartum does not lower the odds of the child developing atopic eczema, allergic rhinoconjunctivitis, recurrent wheezing, asthma, or food allergy at 12 or 24 months old when compared with placebo (112465). The study may have been inadequately powered to detect a difference between groups.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral fish oil is beneficial in children or adults with ADHD. Details: Some, but not all, preliminary clinical research shows that taking fish oil or other sources of long chain omega-3 fatty acids orally improves attention, cognitive function, and behavior in children aged 8-13 years with or without an official diagnosis of ADHD (8800,65868). Omega-3 fatty acids 250 mg esterified to phosphatidylserine 300 mg daily for 3 months has been used (65868). Additional clinical research shows that taking a specific supplement containing fish oil 400 mg and evening primrose oil 100 mg (Eye Q, Novasel), six capsules daily for 15 weeks, improves cognitive function, hyperactivity, inattentiveness, and behavior in children aged 7-12 years with ADHD (15739). It is unclear if these effects are due to fish oil, evening primrose oil, or the combination. However, research is conflicting. A meta-analysis of 22 clinical studies that include some studies mentioned above in children aged 7-12 years old with ADHD shows that taking oral fish oil 51-2513 mg daily with or without stimulants for 4 weeks to 12 months does not improve parent-rated ADHD core symptoms when compared with control. However, subgroup analysis suggests that long-term supplementation with fish oil for 4 months or longer may improve parent-rated ADHD core symptoms when compared with control (112468). Fish oil has also been evaluated in adults with ADHD and autism spectrum disorder. One clinical study in this population shows that taking fish oil 5.2 grams daily for 4 weeks modestly improves inattention when compared with control (108725). Despite some positive findings from mainly preliminary clinical research, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that omega-3 fatty acids in doses of 120 mg to 1200 mg are not currently recommended for adjunctive or monotherapy use in children with ADHD. Furthermore, there is not enough research in adults to make a recommendation (110318).
• Autism spectrum disorder. It is unclear if oral fish oil is beneficial in children or adults with autism spectrum disorder. Details: Clinical research in children with autism shows that taking omega-3 fatty acids (Zahravi Company) 1000 mg daily for 8 weeks, providing EPA 180 mg and DHA 120 mg, modestly reduces overall autism severity and modestly improves stereotyped behavior and social communication when compared with a control group taking medium chain triglycerides. However, there was no benefit on social interaction (105218). The evidence related to hyperactivity in children with autism is mixed. One small clinical study in children aged 5-17 years shows that taking 1.5 grams of fish oil providing EPA 0.84 grams and DHA 0.7 grams daily for 6 weeks reduces hyperactivity when compared with placebo. However, there was a large between-group difference in baseline hyperactivity ratings, which may have exaggerated the effect size (65732). Other clinical research in children aged 3-8 years shows that taking fish oil 1.3 grams daily for 12 weeks does not improve hyperactivity when compared with placebo (66070). Fish oil has also been evaluated in adults with autism. One small clinical study shows that taking fish oil 5.2 grams daily for 4 weeks improves neurocognition, including attention and working memory, when compared with placebo. However, it does not affect social interaction (108725). Other clinical research in adults with autism spectrum disorder and attention deficit hyperactivity disorder (ADHD) shows that taking fish oil 5.2 grams daily for 4 weeks modestly improves inattention when compared with control (108725).
• Autoimmune thyroiditis. It is unclear if oral fish oil is beneficial for autoimmune thyroiditis prevention. Details: The effect of oral fish oil on autoimmune thyroiditis prevention has been investigated in a large clinical trial of approximately 25,000 older adults. Taking fish oil 1 gram daily for 5 years providing EPA 0.46 grams and DHA 0.38 grams, alone or in combination with vitamin D3 2000 IU daily, does not reduce the risk of developing definite or probable autoimmune thyroiditis when compared with placebo (107184). Although this study was large, the primary endpoint was the effect of taking fish oil and/or vitamin D on the development of autoimmune diseases as a group. The number of patients with a specific autoimmune disease such as autoimmune thyroiditis was relatively small.
• Bipolar disorder. Oral fish oil may be beneficial for symptoms of depression in patients with bipolar disorder. However, taking fish oil does not seem to prevent mood relapses or improve symptoms of mania in these patients. Details: Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that omega-3 fatty acids in doses standardized to 1-2 grams eicosapentaenoic acid (EPA) are weakly recommended for adjunctive use in bipolar depression (110318). This recommendation is based mainly on an early meta-analysis of clinical research of flaxseed oil, EPA alone, or oil containing EPA and DHA (66126). Also, some preliminary clinical research shows that taking fish oil providing EPA 6.2 grams and DHA 3.4 grams daily for 4 months, along with conventional therapies, may improve symptoms of depression and increase length of remission when compared with placebo (7202). However, a more recent small clinical trial shows that taking omega-3 fatty acids, including EPA 1 gram plus DHA 1 gram daily for 52 weeks, in a 200 mL smoothie (Nutrifriend, Smartfish) also providing vitamin D 35 micrograms and vitamin E 1.89 mg does not reduce the number of mood episode relapses, increase the time to first mood episode relapse, or improve measures of depression when compared with placebo (105216). Omega-3 fatty acids have not been shown to be effective in attenuating mania or hypomania. Most research shows that fish oil doesn't seem to have beneficial effects on manic symptoms in patients with bipolar disorder (5713,7202,66126,105216,110318). Also, theoretically, fish oil might increase symptoms of mania in patients with bipolar disorder. Cases of hypomania have been reported in patients with bipolar disorder using fish oil (5713,7202).
• Borderline personality disorder. It is unclear if oral fish oil is beneficial for borderline personality disorder. Details: A meta-analysis of clinical research in patients with borderline personality disorder shows that taking omega-3 fatty acids modestly reduces overall symptom severity, especially impulsive behavior, when compared with control. However, one of the studies included in the analysis used eicosapentaenoic acid (EPA) alone and another was limited by the lack of a placebo group (106065).
• Burns. Oral fish oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in hospitalized adults with 20-45% surface area 2^nd or 3^rd degree burns shows that consuming a beverage containing fish oil 3 grams and collagen peptides 40 grams daily for 4 weeks shortens the time to wound healing and improves scar scores but does not limit wound infections when compared with placebo (110667).
• Cancer. It is unclear if dietary or supplemental fish oil can reduce the risk for cancer; the available research is conflicting. Details: There is conflicting evidence about the role of fish oil in cancer prevention. Many epidemiological studies have found that increased intake of supplemental or dietary fish oil, as well as higher blood levels or dietary intakes of omega-3 fatty acids, are associated with a decreased risk of several cancers including oral, pharyngeal, esophageal, pancreatic, colon, rectal, lung, breast, ovarian, and prostate cancers (6395,7378,9773,9774,10153,12958,12959,12960,12961,12962,15736,17412)(25937,101536,103494,107175). Also, a meta-analysis of epidemiological research has found that the highest fish or fish oil intake is associated with a 13% or 19% reduced incidence of mortality in patients with cancer when compared to the lowest intake (107183). However, most meta-analyses of epidemiological research have identified no benefit (14264,66078,66092,103494) and a large clinical trial shows that fish oil does not reduce the risk of invasive cancers (99362). Also, one large epidemiological study has found that dietary intake of fish oil from fatty fish twice a week or more was associated with a 16% increased risk of breast cancer when compared with eating fatty fish less than twice weekly (107175). In addition, a meta-analysis of results from the Prostate Cancer Prevention Trial suggests that higher blood percentages of docosahexaenoic acid (DHA) are associated with a 2.5-fold higher risk of aggressive prostate cancer, but not low-grade prostate cancer, when compared with lower blood percentages of DHA (25936).
• Canker sores. It is unclear if oral fish oil is beneficial for preventing or treating canker sores. Details: In patients with chronic canker sores presenting with 1-3 ulcers at baseline, preliminary clinical research shows that taking omega-3 fatty acids (Zahravi Company) 1000 mg daily, providing EPA 180 mg and DHA 120 mg, for 6 months reduces the size, number, duration, pain, and overall severity of ulcers by 32% to 63%. These changes were significant when compared with placebo. In addition, the ulcer-free period was increased by approximately 45% (105219).
• Cardiovascular disease (CVD). The effect of fish oil on cardiovascular health is controversial. Oral fish oil in doses of up to 4 grams daily does not seem to be beneficial for primary or secondary prevention of CVD. It is unclear whether dietary fish oil or a higher daily dose is beneficial for prevention of CVD. Details: In 2018, the American Heart Association (AHA) recommended that healthy individuals consume 1-2 servings of non-fried fish weekly in place of less healthy sources of protein and fat for primary prevention of CVD. This recommendation was based mainly on evidence from prospective cohort studies showing a modestly lower risk of coronary heart disease (CHD) with higher seafood intake or dietary intake of fish oil (97185). Population research has also found that increased consumption of dietary fish oil is associated with a reduced risk of all-cause mortality, cardiovascular death, sudden death, and myocardial infarction in people without CVD (2309,8676,10006,12915,12917,12977,65723,94231). However, a large meta-analysis of moderate to high quality clinical research published in 2018 shows that higher intake of fish oil as part of the diet or from supplements has little to no benefit for primary prevention of CVD, including all-cause mortality, CVD or CHD mortality, CVD or CHD events, stroke, or arrhythmias (98231). An additional meta-analysis published in 2020 shows that although fish oil supplementation had a very small protective effect overall against CVD death, there was no benefit on all-cause mortality or on primary prevention of CVD death (104547). Reasons for these conflicting results may relate to the fact that most of the primary prevention studies included in these meta-analyses evaluated fish oil supplements rather than dietary fish oil. Only two studies included in one of the meta-analyses assessed the effects of dietary fish oil, while up to 33 studies assessed the effects of fish oil supplements (98231,104547). Some newer, large, high-quality clinical studies have also found no benefit with fish oil supplements for this purpose. One high-quality study shows that taking fish oil 1 gram daily for about 5.3 years is not beneficial for primary prevention of CVD (99362). Another large study including 15,480 patients with diabetes and no evidence of CVD at baseline shows that taking fish oil supplements 1 gram daily does not reduce the risk of serious vascular events, such as nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death, when compared with placebo over a 7.4-year follow-up period (98232). Also, in patients at high cardiovascular risk, taking a prescription-only fish oil product (Epanova, AstraZeneca Pharmaceuticals) 4 grams daily for up to 5 years does not prevent major adverse cardiovascular events, such as cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization, or hospitalization for unstable angina, when compared with a corn oil placebo (103491). Based on the cumulative evidence, fish oil SUPPLEMENTS do not appear to be beneficial for primary prevention of CVD. DIETARY fish oil may reduce the risk of CVD, but results are conflicting and any benefit is probably modest at best. Research has also evaluated fish oil for prevention of cardiovascular events in people with existing CVD (secondary prevention). An analysis of two secondary prevention trials shows that consuming fatty fish 2-3 times weekly reduces the risk of overall mortality by 30%, but does not reduce the risk of nonfatal myocardial infarction (7359,8673). Also, population research in patients with at least two cardiometabolic diseases has found that use of fish oil supplements is associated with a 19% lower risk of CVD-related mortality over 12 years, and a 17% lower risk of overall mortality, when compared with not using fish oil supplements. The additional life expectancy range of 1.4 to 2.3 years was dependent on age and the severity of cardiometabolic morbidity (110333). However, in clinical research, the effect of fish oil supplements for secondary prevention of CVD is controversial and contradictory. Most older research shows that taking fish oil supplements provides benefit; however, these studies are at high risk for bias (1007,2307,8673,12916,12917,13750,65723,66495). Additionally, newer research shows that supplemental fish oil does not help with secondary prevention of CVD. A large meta-analysis of moderate to high quality clinical research published in 2018 also shows that higher intake of fish oil, mainly as supplements, has little to no benefit for secondary prevention of CVD, including all-cause mortality, CVD or CHD mortality, CVD or CHD events, stroke, or arrhythmias (98231). In addition, a meta-analysis published in 2020 shows that although fish oil supplementation had a very small protective effect overall against CVD death, there was no benefit on all-cause mortality or on the secondary prevention of CVD death (104547). A large clinical trial shows that taking fish oil 1 gram daily for 5 years does not significantly reduce cardiovascular events when compared with an olive oil control in patients with multiple cardiovascular risk factors or atherosclerosis (93576). Multiple other meta-analyses published from 2012 to 2018 also show no benefit of fish oil supplements for cardiovascular risk in patients with existing CVD (17990,94231,96116). Some meta-analyses have combined all studies related to both primary and secondary prevention. A meta-analysis published in 2021 shows that fish oil supplementation reduces the risk of CVD death by 7%, non-fatal myocardial infarction by 13%, CHD events by 9%, and major adverse cardiovascular events by 5%, with no benefit on all-cause mortality or stroke. This analysis also showed that use of eicosapentaenoic acid (EPA) alone, as investigated in only four of the 38 trials, offered the largest protective effect (107181). Another meta-analysis of a small group of randomized trials analyzing the effectiveness of fish oil for protection against CHD in patients with and without CHD at baseline shows that taking fish oil reduces CHD by 16%. However, there was no effect on angina, sepsis, or death (107185). This analysis is limited by the small number and suboptimal quality of studies, as well as the age of the publications. Since these analyses combine patients with and without CVD at baseline, it is difficult to draw any conclusions related to primary CVD outcomes. There has been speculation that patients in more recent studies were more likely to be receiving protective effects from treatment with statins and other drugs, which could reduce the potential benefit of fish oil (17990,17991). However, two meta-analyses of clinical data shows that fish oil does not reduce the risk of major vascular events, regardless of prior or concomitant statin use (96116,98231). Interestingly, in 2017 the AHA published a science advisory stating that it is reasonable to supplement with fish oil 1 gram daily for secondary prevention in patients with cardiovascular disease. The AHA concluded that the cumulative evidence generally supports that fish oil supplementation reduces cardiovascular death, though not nonfatal recurrent myocardial infarction, and the benefit of using fish oil for secondary prevention outweighs the treatment risk. However, the AHA noted that most evidence of benefit is based on research published before 2002 (93568). Furthermore, the AHA recommendation was released prior to the publication of the most recent clinical trials and meta-analyses showing no benefit of fish oil for secondary prevention of CVD. Many other guidelines including that of the Canadian Cardiovascular Society, the European Society of Cardiology, and European Atherosclerosis Society state that fish oil supplements are not significantly beneficial for secondary prevention of cardiovascular events (96116,97477). Overall, best evidence to date show that fish oil SUPPLEMENTS, typically taken in doses of 1 gram daily, are not beneficial for primary or secondary prevention of CVD. Additionally, prescription fish oil products in higher doses of 4 grams daily do not seem to be beneficial for primary prevention of CVD. DIETARY fish oil might be beneficial for primary or secondary prevention, but benefits are probably modest at best. Still, people should continue to eat fish and other foods that provide omega-3 fatty acids, as these foods make up part of a healthy diet. In fact, in 2019, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that foods containing EPA and DHA may reduce the risk of CHD. However, the FDA has determined that this claim is based on supportive, rather than conclusive, evidence (102370).
• Cataracts. It is unclear if oral fish oil prevents the development of cataracts. Details: Epidemiological research has found that eating fish three times weekly is associated with a modestly reduced risk of developing cataracts in females. Eating fish three times weekly rather than once monthly is associated with an 11% reduction in developing cataracts (12955).
• Chemotherapy-induced peripheral neuropathy. It is unclear if oral fish oil is beneficial for the prevention of peripheral neuropathy in patients receiving chemotherapy. Details: A meta-analysis of three clinical trials with unclear or high risk of bias in patients with breast, colon, lung, or ovarian cancer shows that taking omega-3 fatty acids for 3-6 months reduces the odds of developing chemotherapy-induced peripheral neuropathy by approximately 80% when compared with placebo (106070).
• Chronic kidney disease (CKD). It is unclear if oral or dietary fish oil is beneficial in patients with CKD or for CKD prevention. Details: A meta-analysis of the available clinical research in adults with CKD who are receiving hemodialysis shows that taking fish oil supplements might reduce the risk of cardiovascular mortality. However, this finding is based on low to very-low quality evidence, and there was no difference identified for risk of all-cause mortality. Additionally, adults with CKD who are not receiving hemodialysis do not seem to benefit from fish oil supplementation (102395). Observational research in adults with CKD has found that dietary omega-3 fatty acid intake of 1.93-9.65 grams daily is associated with a 33% reduced risk of mortality when compared with intakes of less than 0.86 gram daily. However, the amount of omega-3 intake from fish oil, specifically, is unknown (107173). Observational research has also been conducted to examine the association between habitual fish oil supplementation and developing CKD. A large observational study in individuals without prior CKD has found that taking fish oil supplements is associated with a 10% reduced incidence of CKD over the next 10 years when compared with not taking fish oil supplements (110330).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral fish oil is beneficial in patients with COPD or for COPD prevention. Details: A small clinical trial shows that taking fish oil (Omax3, Cenestra Health) 3 grams daily for 6 months does not improve pulmonary function, respiratory symptoms, or endothelial function when compared with placebo in patients with COPD. However, it increased the number of people experiencing improvements in health-related quality of life (104546). Another small clinical trial in patients with COPD shows that taking a specific medical nutrition product (Nutrifriend Cachexia; Smartfish) providing omega-3 fatty acids 2 grams, 25-hydroxyvitamin D3 10 mcg, and whey protein 10 grams twice daily for 12 weeks does not improve lung function when compared with an isocaloric placebo based on milk protein and sunflower oil. However, there was a modest increase in fat mass, as well as modest reductions in triglyceride levels, systolic blood pressure, and exercise-induced fatigue and dyspnea in those taking the omega-3 fatty acid combination product (107189). Observational research has also been conducted to examine the association between habitual fish oil supplementation and developing COPD. A large observational study in individuals without prior COPD has found that taking fish oil supplements is associated with a 12% reduced incidence of COPD over the next 9 years when compared with not taking fish oil supplements (110331).
• Cirrhosis. It is unclear if oral fish oil is beneficial in patients with cirrhosis. Details: Preliminary clinical research in adults with advanced cirrhosis shows that taking fish oil orally does not seem to improve the severity of renal impairment associated with cirrhosis (1013).
• Cognitive impairment. It is unclear if oral fish oil prevents or treats cognitive impairment. Details: Some clinical research suggests that taking 3 fish oil capsules (EPAX 1050TG; EPAX AS) by mouth daily for 12 months may improve memory in patients with mild cognitive impairment. Each capsule contained 1 gram of fish oil, comprised of DHA 430 mg and EPA 150 mg (89346). However, a meta-analysis of clinical research shows that increased dietary or supplemental omega-3 intake has no preventive effect on cognitive impairment in older adults (103501). The effect of fish oil is unclear. Fish oil has also been evaluated as part of combination therapy. A large clinical study in adults at least 55 years of age with cognitive impairment shows that taking fish oil, containing DHA 1.1 grams and EPA 0.4 grams, and dark chocolate containing 500 mg cocoa flavanols daily for 12 months does not improve cognitive function scores when compared with placebo (111453).
• Colorectal cancer. It is unclear if oral fish oil prevents or treats colorectal cancer. Details: Fish oil has been evaluated for the PREVENTION of colorectal cancer. A large, high-quality clinical study shows that taking fish oil 1 gram daily for a median of 5.3 years does not reduce the risk for colorectal cancer precursors, including colorectal adenomas and serrated polyps, when compared with placebo. Subgroup analyses suggest that patients with low omega-3 fatty acid levels at baseline or those with African American heritage might have a reduced risk for colorectal cancer precursors; however, further research is needed to confirm these findings (102400). Fish oil has also been evaluated for the TREATMENT of colorectal cancer. One small clinical trial shows that taking a specific fish oil supplement (Omega-3, Phytomare) 2 grams daily containing 360 mg of EPA and 240 mg of DHA for 9 weeks along with chemotherapy prolongs the time to tumor progression when compared with not receiving a fish oil supplement. However, it does not reduce the number of patients with tumor progression, hospitalizations, deaths, or chemotherapy requirements (91249). Observational research has found that increased dietary or supplemental fish oil intake is not associated with increased survival in stage three colon cancer patients overall. However, it is associated with increased survival in patients with wild-type KRAS tumors (101274). Further research is needed to confirm whether specific patient populations might benefit from fish oil supplementation.
• Contrast induced nephropathy. It is unclear if oral fish oil is beneficial for preventing contrast induced nephropathy. Details: Preliminary clinical research in patients with chronic kidney disease undergoing coronary angiography shows that taking omega-3 fatty acids (Omacor, Abbott Laboratories) 4 grams twice daily on the day before and the day of angiography does not reduce the number of patients with an increase in serum creatinine levels of at least 0.5 mg/dL within 48 hours, or the need for renal replacement therapy, when compared with taking N-acetyl cysteine 1200 mg (107193).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral fish oil is beneficial for reducing symptoms in patients hospitalized with COVID-19. Details: A small preliminary clinical trial in patients hospitalized with COVID-19 shows that taking omega-3 fatty acids 2 grams daily for 2 weeks modestly reduces body pain and fatigue and improves appetite when compared with patients not taking omega-3 fatty acids. However, there were no significant differences in olfactory symptoms between groups. All patients were also taking hydroxychloroquine 800 mg daily (107188).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral fish oil is beneficial following CABG surgery. Details: Preliminary clinical research shows that taking supplemental fish oil 4 grams orally, containing EPA 2.04 grams and DHA 1.3 grams, beginning on the first postoperative day and continuing for one year thereafter, seems to decrease the incidence of CABG occlusion following surgery when compared with control (2314).
• Crohn disease. It is unclear if oral fish oil is beneficial for reducing the risk of Crohn disease or the risk for relapse in patients with Crohn disease who are in remission; the available evidence is conflicting.
• Crohn disease. Some preliminary clinical research shows that taking a specific enteric coated fish oil supplement (Purepa, Tillotts Pharma) providing 2.7 grams omega-3 fatty acids daily for 12 months can reduce the relapse rate for patients who are in remission (6257). However, other clinical trials show that taking fish oil 4-5 grams daily does not significantly reduce relapse when compared with placebo (6259,16734). A meta-analysis of clinical research shows that treatment with enteric-coated, time-released omega-3 fatty acid or fish oil capsules containing EPA 1.2-3.3 grams and DHA 0.6-1.8 grams daily for up to one year reduces the relapse rate by 13% when compared to control (66061,89347). However, this risk reduction was not observed when only high-quality studies were considered. Also, a meta-analysis of clinical research shows that taking omega-3 fatty acids for 12-24 months does not reduce relapse rate when compared with control (105224).
• Cyclosporine-induced hypertension. Small clinical studies suggest that oral fish oil may prevent or modestly improve symptoms in patients with cyclosporine-induced hypertension. Details: Taking fish oil 3 grams daily for 3 months orally seems to prevent cyclosporine-induced hypertension following cardiac transplant (66367). There is also some evidence that fish oil 4 grams daily for 6 months can maintain pre-cyclosporine blood pressure in patients taking cyclosporine (1012). A meta-analysis of two small clinical studies shows that fish oil 2-18 grams containing 0.6-5.4 grams of EPA and DHA daily for 1-12 months reduces diastolic blood pressure by 4.5 mmHg in kidney transplant recipients using calcineurin inhibitors, including cyclosporine, when compared with placebo (65770).
• Cystic fibrosis. It is unclear if oral fish oil is beneficial in patients with cystic fibrosis. Details: Preliminary clinical research shows that taking omega-3 fatty acids (EPA plus DHA) as 1.3% of total caloric intake for up to 8 months improves pulmonary function based on forced expiratory volume and reduces the number of days during which antibiotics are needed when compared to baseline (65553).
• Dementia. It is unclear if oral fish oil, as supplements or in the diet, reduces the risk of dementia; the available research is conflicting. Details: Some epidemiological research suggests that eating fish at least once weekly or the regular use of fish oil supplements is associated with a 7% to 57% reduced risk of developing dementia in older adults and elderly individuals (65595,108507,108724,109307,111452); however, other research has found no correlation between overall dementia risk and the consumption of fish or fish oil (65962,103501). Some epidemiological research has examined the association between the regular use of fish oil supplements and the risk of individual types of dementia in large prospective studies. These studies suggest that regular use of fish oil supplements is not associated with the risk of Alzheimer disease (108507,108724,109307). Also, a study in over 215,000 older adults suggests that regular use of fish oil supplements is not associated with the risk of vascular dementia or frontotemporal dementia (108507). However, other studies suggest that regular use of fish oil supplements may be associated with 15% and 57% lower risks of vascular dementia or frontotemporal dementia, respectively (108724,109307). The reasons for these discrepancies are unclear. One large epidemiological study suggests that associations between the regular use of fish oil supplements and the risks of all-cause or vascular dementia are stronger in males (109307). Some research suggests that the apolipoprotein E (APOE) genotype may alter the association between fish oil intake and dementia risk (65817,108507,108724), however, other research disagrees (111452). One large epidemiological study suggests that regular use of fish oil supplements is associated with a 15% lower risk of vascular dementia. However, this study suggests that the risk of vascular dementia is INCREASED by 86% in individuals with two APOE-e4 alleles, whereas the risk is reduced by 19% in those with one APOE-e4 allele and by 22% in those with no APOE-e4 alleles (108724). Further research is needed to confirm the clinical relevance of this potential interaction.
• Depression. It is unclear if oral or dietary fish oil is beneficial for the prevention of depression or in patients with depressive symptoms. There is some evidence that benefits vary depending on the form of fish oil used and the patient population studied. Details: Observational research has found that higher dietary intake of fish has been associated with a lower risk of depression and suicide (10867,10868,99368). Also, low omega-3 fatty acid levels in plasma and red blood cells have been associated with depression (10859,10860). However, clinical research does not show that taking fish oil is beneficial for the prevention of depression. A large clinical trial in adults 50 years or older without depression shows that taking fish oil 1 gram daily, providing eicosapentaenoic acid (EPA) 465 mg and docosahexaenoic acid (DHA) 375 mg, for a median of 5.3 years results in a small increased risk of depression or symptoms of depression when compared with placebo (107196). Also, one small clinical study in healthy female nurses shows that taking omega-3 fatty acids containing EPA 1200 mg and DHA 600 mg daily for 90 days does not affect measures or depression or prevent a major depressive episode when compared with placebo (105220). It is also unclear whether oral fish oil is beneficial for reducing symptoms of depression. Results from meta-analyses have been mixed (48282,66129,99356,102391,104551,107191,112032). However, populations included in these analyses have included older adults with or without clinical depression (99356,112032), mixed populations (48282,66129,102391), patients with perinatal depression (104551), patients with mild depression (48282), or patients with major or unipolar depression (107191). Despite the mixed findings overall, most research suggests that taking fish oil may have a small beneficial effect in patients with clinical depression. A meta-analysis of clinical studies in patients with clinical depression shows that fish oil supplementation has a small to modest beneficial effect on symptoms when compared with placebo (107191). However, it is unknown if these benefits are clinically meaningful since most studies are small and generally low-quality. Also, this analysis combined studies investigating fish oil with studies investigating EPA or DHA alone (107191). Small clinical studies in children and adults with clinical depression support the potential for beneficial effects of fish oil (10871,65712,65869). Also, clinical research in postmenopausal females with moderate to severe psychiatric distress shows that fish oil reduces depressive symptoms when compared with placebo (65925). However, a small clinical study in Japanese workers with mild to moderate depression shows that taking fish oil containing DHA 500 mg and EPA 1000 mg daily for 12 weeks in addition to a psychological intervention is no different than the psychological intervention alone (100251). Also, a large clinical trial in patients with depression and coronary heart disease shows that adding fish oil 2 grams daily for 10 weeks, providing 930 mg of EPA and 750 mg of DHA, to sertraline 50 mg daily does not improve depression when compared with sertraline and placebo (17408). Additionally, clinical research in patients with a history of ischemic stroke shows that taking fish oil 3 grams daily for 12 weeks does not improve depression or other mood-related parameters when compared with placebo (65996). An analysis of a cohort of older adults with subthreshold depression or high-risk factors for depression from the VITAL-DEP trial shows that taking omega-3 fatty acids 1 gram daily for 2 years does not reduce the risk of major depressive disorder or improve mood scores when compared with placebo (112032). Most research in patients with perinatal depression has found no benefit. One small study using fish oil capsules 6 grams daily in divided doses for 6 weeks showed positive outcomes (48198). However, a meta-analysis and individual clinical studies show that taking EPA plus DHA does not help to prevent or improve depression in these patients, and, when used along with supportive psychotherapy, is no more effective than therapy alone (65830,89353,104551). Taking fish oil 1.9 grams daily or omega-3 fatty acids containing EPA 900-1060 mg and DHA 180-274 mg daily for 6-8 weeks does not improve depression when compared with control (65830,89353). The best dose of fish oil for reduction of depression symptoms is unknown. Doses of omega-3 fatty acids used in clinical trials in adults have included fish oil supplements providing EPA, usually 0.6-4 grams daily, alone or with DHA 0.15-2.4 grams daily for 4-16 weeks. In one study, a specific fish oil product (Isodisnatura) 1.5 grams, containing 1.05 grams ethyl-EPA and 0.15 grams ethyl-DHA, daily for 8 weeks was used. In children 6-12 years of age, fish oil 1 gram daily for 16 weeks has been used (10871,65712,65869,65925,107191). However, meta-analyses of research related to symptoms of depression in mixed populations suggest that fish oil supplements containing only EPA or at least 60% EPA are effective, whereas other fish oil supplements are not (48282,66129,102391). Also, although one subgroup analysis of 9 clinical trials found that taking at least 1.5 grams of fish oil daily reduces depressive symptoms (99356), another meta-analysis found that only fish oil formulations containing no more than 1 gram of EPA demonstrated benefit (102391). Based on these and other findings, Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that omega-3 fatty acids providing 1-2 grams EPA are recommended for adjunctive use in patients with major depressive disorder. However, omega-3 fatty acids are not recommended as monotherapy and products containing other doses of EPA are not recommended as adjunctive or monotherapy in these patients (110318).
• Developmental coordination disorder (DCD). Oral fish oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking a combination of fish oil (80%) and evening primrose oil (20%) for 3 months seems to improve reading, spelling, and behavior when given to children aged 5-12 years with DCD. The combination contains EPA 558 mg, DHA 174 mg, gamma-linolenic acid 60 mg, and vitamin E 9.6 mg daily (13748). One study shows that taking fish oil with evening primrose oil does not improve motor skills in children with DCD (13748). However, another very small study shows that taking fish oil in combination with evening primrose oil, thyme oil, and vitamin E (Efalex, Efamol Ltd), for 4 months improves motor skills including manual dexterity, ball skills, and balance in children with dyslexia and DCD (5708). The effect of fish oil when used alone is unclear.
• Diabetic nephropathy. It is unclear if oral fish oil is beneficial in patients with diabetic nephropathy. Details: Fish oil has been evaluated for the management of diabetic nephropathy in patients with both type 1 and type 2 diabetes. One small clinical study in patients with diabetic nephropathy related to type 1 diabetes shows that taking fish oil 4.6 grams daily for one year does not improve albuminuria or glomerular filtration rate (GFR) when compared with placebo (66427). In patients with type 2 diabetes, the evidence is mixed. In one study of patients taking angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs), clinical research shows that taking fish oil (Lovaza) providing EPA 1.86 grams and DHA 1.5 grams daily for one year attenuates the progression of albuminuria, but has no effect on the estimated GFR. In patients not taking ACE-inhibitors or ARBs, there was no effect on albuminuria. The patients in this study had not all been diagnosed with nephropathy (101537). In another study of patients with diabetic nephropathy taking ACE-inhibitors or ARBs, taking fish oil (Omacor) 3 grams daily for 12 weeks had no effect on proteinuria when compared with control (101538).
• Diabetic neuropathy. It is unclear if oral fish oil is beneficial for the treatment or prevention of neuropathy in patients with type 1 diabetes. Details: Preliminary clinical research in patients with type 1 diabetes shows that taking fish oil 1800 mg daily for 6 months does not prevent the development of new onset diabetic neuropathy or reduce the severity of neuropathy in patients with existing signs of disease when compared with placebo (106072). However, 86% of patients did not have neuropathy at baseline.
• Diabetic retinopathy. It is unclear if oral fish oil is beneficial in patients with diabetic retinopathy. Details: Population research in adults with type 2 diabetes has found that consuming at least 500 mg of long-chain omega-3 fatty acids from fish and seafood daily as part of a Mediterranean diet is associated with a 48% reduced risk of developing sight-threatening diabetic retinopathy when compared with consuming lower amounts (96115). In contrast, preliminary clinical research in patients with type 1 diabetes shows that taking fish oil 1800 mg daily for 6 months does not affect the severity of retinopathy when compared with placebo (106072). However, most patients did not have retinopathy at baseline and the study was designed to examine diabetic retinopathy severity as a safety assessment, not as a primary or secondary efficacy endpoint.
• Dry eye. Oral fish oil does not seem to reduce the risk of developing dry eye. It is unclear if oral fish oil is beneficial in patients with existing dry eye. Details: While some preliminary observational research has found that higher dietary intake of omega-3 fatty acids, primarily from seafood sources, is associated with a reduced risk of dry eye syndrome in females (13770), a large ancillary analysis of the VITAL study, which included over 23,500 adults aged 50 years and older, shows that taking fish oil 1 gram daily is not associated with reduced incidence of dry eye disease over a median follow-up of 5.3 years when compared with placebo (108510). There is also interest in the use of fish oil supplements for the treatment of dry eye. The American Academy of Ophthalmology Preferred Practice Pattern guidelines published in 2013 state that omega-3 fatty acids such as fish oil have been reported to be beneficial for dry eye, but the evidence is insufficient to establish effectiveness (95702). Several studies in patients with mild to moderate dry eye suggest that taking fish oil supplements providing EPA 360-1680 mg plus DHA 240-560 mg orally daily for 30 days to 12 weeks reduces tear osmolarity, increases tear film stability, and improves some symptoms of dry eye such as pain, blurred vision, and sensitivity, when compared with placebo (89342,91861,93251,96114,101544). Specific commercial fish oil products (Nippon Suisan Kaisha, Ltd; Caruso's Natural Health UltraMAX fish oil; PRN Dry Eye Omega Benefits softgels, PRN Physician Recommended Nutraceuticals) have been used (89342,91861,96114). However, many of these studies are small, and some used highly restrictive eligibility criteria, which may limit the generalizability of the results. Furthermore, some of these studies show that taking fish oil does not improve volume of tears produced, damage to the eye, or Meibomian gland dysfunction, which is a leading cause of dry eye (91861,93251). A larger study in over 500 patients shows that taking fish oil providing EPA 2000 mg plus DHA 1000 mg orally daily for 12 months does not improve symptoms of dry eye when compared with placebo in patients with moderate to severe dry eye (95701). However, the validity of these results is reduced by the use of other medications during the course of the study. Preliminary research investigating fish oil in combination with other ingredients also shows conflicting results (17523,91860). One of these studies used a specific combination product (TheraTears Nutrition, Advanced Nutrition Research) providing EPA 450 mg, DHA 300 mg, and flaxseed oil 1000 mg daily for 90 days (17523).
• Dyslexia. It is unclear if oral fish oil is beneficial in patients with dyslexia. Details: In a small clinical trial, taking fish oil containing DHA acid 480 mg daily for one month orally seems to improve night vision in children aged 5 to 12 years with dyslexia. Dyslexic children who take fish oil seem to develop significantly better darkness adaptation (5708).
• Dyslipidemia. It is unclear if oral fish oil is beneficial in patients with dyslipidemia. Details: There is contradictory evidence about the effects of fish oil on lipid levels. Consuming about 250 grams of fish in the DIET twice weekly for 8 weeks has been shown to lower total cholesterol, triglyceride, and low-density lipoprotein (LDL) cholesterol levels, as well as increase high-density lipoprotein (HDL) cholesterol levels, in patients with hyperlipidemia (97186). However, most research shows that taking fish oil SUPPLEMENTS does not improve cholesterol levels and might even increase LDL cholesterol levels in patients with hypercholesterolemia or dyslipidemia (2318,8714,12182,66196,97186,99358). Oftentimes, increases in LDL cholesterol levels occur when fish oil supplements are taken in higher doses such as 5-20 grams daily; however, doses of fish oil supplements containing as little as 2 grams of omega-3 fatty acids daily have been shown to increase LDL cholesterol levels in patients with hyperlipidemia (2318,12182,65729,66224,66267,66257,97186). Despite its unfavorable effects on LDL cholesterol, fish oil supplements might still be beneficial for patients with dyslipidemia and diabetes. Some clinical research shows that taking fish oil supplements can decrease elevated triglyceride levels, decrease secretion of very low-density lipoproteins (VLDLs), increase VLDL apolipoprotein B secretion, and increase levels of HDL cholesterol in people with type 2 diabetes and dyslipidemia (8714,8807,12182). Fish oil 4 grams daily for up to 8 weeks has been used (8714,8807). Also, preliminary clinical research shows that fish oil, 6 grams daily for 3 months taken alone, or fish oil 1 gram daily combined with pravastatin 20 mg, can correct the dyslipidemia associated with renal transplantation (8805,66454). Some research has shown that taking fish oil in combination with garlic and plant sterols reduces lipid levels in patients with hypercholesterolemia or dyslipidemia. However, it is possible that these favorable effects are due to the other ingredients, since garlic and plants sterols have been shown to independently reduce lipid levels (2318,2319,97173).
• Endometrial cancer. It is unclear if oral fish oil reduces the risk for endometrial cancer. Details: Some epidemiological research has found that consuming approximately two servings of fatty fish weekly is associated with a reduced risk for endometrial cancer. However, other epidemiological research has not found an association between fish consumption and risk of endometrial cancer (8690,9774). It is unclear if taking fish oil supplements reduces the risk of endometrial cancer.
• Endometriosis. It is unclear if oral fish oil is beneficial in patients with endometriosis. Details: Clinical research in females aged 12-25 years who had surgery for endometriosis at least 6 weeks prior shows that taking fish oil (NatureMade) 1 gram daily for 6 months has no clinical effect on pain or analgesic use when compared with placebo (101546). It is not known whether taking fish oil helps to reduce pain related to endometriosis prior to surgery.
• Epilepsy. Some clinical research suggests that oral omega-3 fatty acids may modestly reduce seizure frequency in patients with epilepsy. However, it is unclear if oral fish oil itself is beneficial in patients with epilepsy. Details: A meta-analysis of seven clinical trials in adults and children with epilepsy shows that taking omega-3 fatty acids, usually as fish oil, for 10-42 weeks modestly reduces seizure frequency when compared with placebo. The most frequent doses were 1000-2800 mg daily (106067). Although most studies included in the analysis investigated the combined effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), some studies used purified or semi-purified EPA or DHA. Also, some studies included in the analysis were very small in size (89337,106067). More recent clinical research in children with attention deficit-hyperactivity disorder (ADHD) and intractable epilepsy who are also taking risperidone 0.5 mg daily shows that taking fish oil 1 gram daily, providing EPA 180 mg and DHA 120 mg daily for 6 months, decreases monthly seizure frequency to a median of zero, compared with no change in children taking placebo. However, there was no change in seizure severity (107172).
• Exercise-induced muscle soreness. It is unclear if oral fish oil reduces the severity of exercise-induced muscle soreness. Details: Small clinical studies in untrained healthy adults in the United Kingdom show that taking fish oil orally 1.8-3 grams daily for 4-6 weeks prior to and during physical exercise does not prevent muscle soreness following elbow flexion or knee contractions (8524,89340). Also, a small clinical study in healthy young females shows that taking fish oil (Vital Atman) 3.2 grams at dinner after a resistance exercise protocol and at lunch over the next three days does not prevent muscle soreness when compared with placebo (106071). Other clinical research in trained males shows that taking fish oil 5 grams, containing EPA 1882 mg and DHA 485 mg, orally daily for 4 weeks does not reduce muscle soreness after eccentric exercises when compared with placebo (111451). However, other small clinical studies in untrained healthy adults in Japan show that taking fish oil 1.8-2.4 grams (containing about 300-600 mg EPA and 200-260 mg DHA) daily for 1-2 months ameliorates muscle soreness and improves range of motion following knee extensor exercises or eccentric contraction exercises (65958,98257,100252,109222). Also, a small clinical study in professional rugby players shows that taking fish oil containing EPA 551 mg and DHA 551 mg twice daily for 5 weeks reduces subjective ratings of whole body muscle soreness when compared with placebo (99357).These differing findings might be due to differences in patient populations due to their geographic location, but higher quality research is needed to confirm. Fish oil has also been evaluated as part of combination therapy. Preliminary clinical research in healthy untrained adults shows that taking a specific fish oil product (Nippon Suisan Kaisha Ltd) containing EPA 4.8 grams and DHA 2.08 grams, and branched-chain amino acid 9.6 grams orally daily for 8 weeks improves muscle soreness scores and range of motion after eccentric exercise when compared with placebo (111461). It is unclear if this effect is due to fish oil, branched-chain amino acid, or the combination.
• Food allergies. It is unclear if oral fish oil is beneficial in patients with food allergies. Details: A pooled analysis of clinical research shows that maternal fish oil supplementation during pregnancy reduces the risk of allergic sensitization to egg by 31%, but not to milk or peanuts (97177).
• Frailty. It is unclear if oral fish oil is beneficial for preventing frailty. Details: Preliminary clinical research in community dwelling adults at least 70 years of age shows that taking fish oil 1 gram orally daily for 3 years does not reduce the odds of becoming pre-frail or frail over 36 months when compared with placebo (110829).
• Gingivitis. It is unclear if oral fish oil is beneficial in patients with gingivitis. Details: Preliminary clinical research shows that taking fish oil 1.8 grams three times daily for 8 days does not improve severity of gingivitis on days 14, 28, or 35 when compared with placebo (1005).
• Glaucoma. Although there has been interest in using oral fish oil for glaucoma, there is insufficient reliable information about the clinical effects of fish oil for this condition.
• Hemodialysis graft dysfunction. It is unclear if oral fish oil is beneficial in patients with hemodialysis graft dysfunction. Details: The evidence on the effects of fish oil for preventing thrombosis or maintaining hemodialysis graft patency is conflicting (8684,65762,89348,96119). However, a meta-analyses of the available clinical research provides moderate evidence that taking fish oil containing omega-3 fatty acids 1.6-3.4 grams daily for 3-12 months reduces thrombosis or the need for intervention to restore arteriovenous access by about 19% to 29% when compared with placebo in patients with fistula or grafts due to kidney failure (96123,98247). Fish oil 4 grams daily for one year has been used to prevent thrombosis after graft placement (8684).
• Heart transplant. It is unclear if oral fish oil is beneficial in patients after a heart transplant. Details: A small clinical trial shows that taking fish oil orally seems to preserve renal function and reduce the long-term continuous rise in blood pressure after heart transplantation. There is evidence that a dose of 4 grams of fish oil composed of 46.5% EPA and 37.8% DHA, taken daily for one year after heart transplantation, prevents changes in systolic and diastolic blood pressures, glomerular filtration rate, and serum creatinine when compared with placebo (8687).
• HIV/AIDS. It is unclear if oral fish oil is beneficial for HIV. Details: Some clinical evidence shows that taking fish oil-containing food bars does not improve CD4 counts in patients with HIV (66414). Other clinical research shows that enteral supplementation with a fish oil-enriched peptide-based formula improves CD4 count, but not viral load, in patients with HIV when compared with standard formula (65525).
• Impaired glucose tolerance (prediabetes). It is unclear if oral fish oil is beneficial for impaired glucose tolerance. Details: Preliminary clinical research shows that fish oil supplements might reduce the risk of conversion from prediabetes to type 2 diabetes. In patients with hypertriglyceridemia and prediabetes, taking a specific fish oil product (ESAPENTR, Pharmacia and Upjohn) 1 capsule by mouth three times daily (for a total of EPA 1530 mg and DHA 1050 mg) for 6 months lowers triglycerides with no deterioration in glucose tolerance over one year (7368). Although fish oil may prevent worsening of glycemic parameters, it does not seem to improve them. A small clinical trial shows that taking a specific fish oil supplement (EPAX AS) 6 grams containing 3.9 grams of omega-3 fatty acids does not improve glycemic outcomes when compared with placebo in patients with impaired glucose regulation (98242).
• Infant development. It is unclear if oral fish oil, taken during pregnancy or by the infant, is beneficial for improving vision or cognitive development in infants. Details: Population research has found that increased consumption of seafood during pregnancy is associated with improved measures of infant and child development such as verbal intelligence, communication, and social development (15743). In contrast, supplementation with fish oil during pregnancy and/or lactation does not seem to be beneficial, or may only be beneficial in male offspring. A meta-analysis of clinical research shows that intake of long-chain omega-3 fatty acids during pregnancy and/or lactation, mainly from fish oil, does not improve cognitive outcomes in the infant up to approximately 2 years of age when compared with control (103495,105213). This is supported from the findings of most individual clinical trials providing fish oil supplements 1-4 grams daily from 20-21 weeks gestation until delivery or until 30 days after childbirth, or providing fish oil supplements or dietary fish during lactation (15162,48105,97182,99364). An additional small clinical trial shows that taking fish oil 2000 mg daily, providing eicosapentaenoic acid (EPA) 260 mg and docosahexaenoic acid (DHA) 1440 mg, from 22-24 weeks gestation until delivery, does not improve most measures of developmental or behavioral milestones in the infant at 6 months, when compared with olive oil placebo (110354). A large clinical trial shows that ingestion of fish oil (Incromega TG3322, Croda) 4 grams daily during late-phase pregnancy, providing 1.3 grams EPA and 0.9 grams DHA, results in a 17- to 21-day earlier achievement of some, but not all, late motor milestones in male infants. However, there was no improvement in earlier motor milestones. This study also identified modest improvements in male infants for early, but not late, word production, cognitive development at 2.5 years, and behavior and emotion at 6 years (105213). Providing fish oil supplementation directly to infants may improve the development of vision, but not cognition. Clinical research shows that infants supplemented with fish oil-containing formula beginning within 3-10 days of birth have improved visual acuity at 2 months and improved oscillatory potentials, which are thought to reflect retinal function, at 1 year when compared to infants supplemented with linolenic acid-containing formula (66399,66569). However, supplementing infants with omega-3 fatty acids such as fish oil does not affect cognition and neurodevelopment (89349,89363).
• Insomnia. It is unclear if oral fish oil is beneficial for insomnia. Details: In a group of healthy female nurses also undergoing a mindfulness-based stress management program or given a psychoeducation leaflet, preliminary clinical research shows that taking omega-3 fatty acids containing EPA 1200 mg and DHA 600 mg daily for 90 days modestly reduces insomnia severity when compared with placebo. However, benefits were no longer present after 6 or 12 months (105220).
• Intrauterine growth restriction (IUGR). Although there has been interest in using oral fish oil for prevention of IUGR, there is insufficient reliable information about the clinical effects of fish oil for this condition.
• Joint pain. Oral fish oil has only been evaluated in combination with other ingredients; its effects when used alone are unclear. Details: Preliminary clinical research shows that taking fish oil powder 375 mg in combination with lemon verbena extract (Monteloeder, Ltd) 230 mg six times daily for 5 weeks, followed by three capsules daily for 3 weeks, reduces symptoms of joint pain and stiffness when compared with placebo (17748). It is unclear if these effects are due to fish oil, lemon verbena, or the combination.
• Kidney failure. Small clinical studies in patients with kidney failure suggest that oral fish oil may modestly improve some blood lipid and inflammatory marker levels. Details: Some clinical research shows that taking fish oil reduces levels of inflammatory markers. A meta-analysis of clinical research and individual preliminary clinical trials in patients on hemodialysis show that taking omega-3 fatty acids, usually as fish oil, reduces C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels when compared with a control oil. Studies have used doses of up to 9 grams daily for 2-12 months (8685,65959,107190). Additional preliminary clinical research in adults on chronic hemodialysis shows that taking three packets of a specific product (Coromega) containing emulsified fish oil (EPA 350 mg and DHA 230 mg) 650 mg per packet daily for 8 weeks modestly increases hemoglobin, albumin levels, and urine output (8685). However, a meta-analysis of clinical research shows that any benefit on hemoglobin levels is small, that albumin levels are not improved, and that mortality is not reduced (107190). Oral fish oil may also improve some, but not all, blood lipid levels in patients on hemodialysis. A meta-analysis of clinical research in adults undergoing dialysis shows that taking fish oil modestly reduces triglyceride and low-density lipoprotein (LDL) cholesterol levels, but not total cholesterol levels (107190). Also, in children aged 8-17 years on chronic hemodialysis, preliminary clinical research shows that taking fish oil 2 grams daily for 3 months reduces total cholesterol, triglyceride, and LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels when compared to baseline. It also seems to improve some inflammatory markers and quality of life (102396,103596). The validity of these findings is limited by the lack of a comparator group. A small clinical trial shows that taking fish oil 2 grams, containing EPA 160 mg, DHA 100 mg, and d-alpha-tocopherol 0.9 IU, three times daily for 6 months does not reduce lipoprotein(a) levels, when compared with placebo (65997).
• Kidney transplant-related bone loss. Clinical research suggests that oral fish oil does not improve bone mineral density following a kidney transplant. Details: : Clinical research in adults shows that taking omega-3 fatty acids 2.6 grams daily, starting 8 weeks post-kidney transplant and continuing for 44 weeks, does not affect the change in bone mineral density at the hip, spine, or forearm or alter mineral metabolism when compared with olive oil as placebo. The omega-3 supplement used in the study (Omacor, Pronova Biopharma) provided eicosapentaenoic acid (EPA) 460 mg/gram capsule and docosahexaenoic acid (DHA) 380 mg/gram capsule for a total of three capsules daily (107179). A larger study population and duration are needed to confirm these findings.
• Lung cancer. It is unclear if oral fish oil can improve nutritional status in patients with lung cancer. Details: Clinical research in patients with lung cancer shows that taking fish oil providing eicosapentaenoic acid (EPA) 1.6 grams and docosahexaenoic acid (DHA) 0.8 grams daily for 12 weeks modestly increases body weight, serum albumin, and triglyceride levels, and decreases the inflammatory markers C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-alpha), when compared with sunflower oil as placebo. However, there was no effect on body mass index or arm circumference (107194).
• Lyme disease. Although there has been interest in using oral fish oil for Lyme disease, there is insufficient reliable information about the clinical effects of fish oil for this condition.
• Male infertility. It is unclear if oral fish oil is beneficial for male infertility. Details: Observational research suggests that there is a link between fish oil supplement intake and semen quantity and quality. In men who took fish oil supplements on less than 60 of the last 90 days, semen volume was 0.38 mL higher and testicular size was 0.8 mL larger than those who had taken no fish oil supplements. In men who took fish oil supplements on at least 60 of the past 90 days, semen volume was 0.64 mL higher and testicular size was 1.5 mL larger than those who had taken no fish oil supplements. These findings suggest a dose-dependent effect of fish oil. However, the validity of these findings is limited by the observational nature of the study, the unclear health status of the participants, and the lack of information on clinical fertility outcomes (102394). A meta-analysis of small randomized controlled trials in adult males with infertility shows that taking fish oil, containing DHA 400-720 mg and EPA 132-1,112 mg, orally daily for 10-32 weeks improves sperm concentration and sperm motility, but not pregnancy rates, when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (111459).
• Melanoma. It is unclear if there is a link between fish oil intake and the incidence of melanoma. Details: An analysis of the NIH-AARP Diet and Health Study, a prospective cohort study in over 491,000 older adults, has found that total intake of fish is associated with increased melanoma risk over a median follow-up of 15.5 years. When the lowest and highest quintiles of intake are compared, there is a 22% increase in the risk for malignant melanoma and a 28% increase in the risk for melanoma in situ. In sub-group analyses, all melanoma incidence is positively associated with tuna intake or non-fried fish intake, but malignant melanoma incidence is inversely associated with fried fish intake (108509). It was suggested that the positive associations could be due to contaminants in fish such as polychlorinated biphenyls, dioxins, arsenic, and mercury.
• Menopausal symptoms. It is unclear if oral fish oil is beneficial for menopausal symptoms. Details: A meta-analysis of three clinical trials shows that fish oil supplements do not affect hot flashes, insomnia, or quality of life during menopause when compared with placebo (99363). However, a larger meta-analysis of low-quality clinical research in adults with menopausal symptoms shows that taking fish oil 300 mg-1800 with or without vitamin E 850 mg orally daily for 8-12 weeks modestly improves the intensity, but not frequency, of hot flashes when compared with control (111460). Evidence from one clinical trial also suggests that fish oil supplements might reduce night sweats (99363). In addition, clinical research shows that taking fish oil (Omega-rex, Daana Pharmaceutical Co.) 1 gram, providing EPA 180 mg and DHA 120 mg, daily for 12 weeks improves overall symptoms of menopause, including hot flashes, sleep problems, and anxiety, when compared with placebo. However, there was no effect on blood lipid levels, urogenital symptoms, joint problems, or feelings of exhaustion (103492).
• Migraine headache. Supplemental fish oil does not seem to reduce the frequency or severity of migraine headaches. However, dietary fish oil may reduce the frequency and duration of migraine headaches. Details: Most research shows that taking fish oil supplements orally does not decrease the frequency or severity of migraine headaches in adolescents and adults (8712,8713,99361). However, one meta-analysis of two very small clinical trials shows that fish oil supplements might decrease the duration of migraines by an average of 3.4 hours (99361). One clinical study suggests that increasing dietary intake of fish oil may be beneficial. Increasing dietary intake of EPA plus DHA in the form of fish oil to 1.5 grams daily for 16 weeks, while maintaining dietary intake of linoleic acid at levels no greater than 7% of energy, decreases the frequency and duration of migraines, but does not improve migraine-related quality of life, when compared with intakes of EPA plus DHA of less than 150 mg daily, as is commonly found in the North American diet. Some patients also further reduced dietary linoleic acid intake. In those increasing fish oil intake and maintaining linoleic acid intake, headache duration was reduced by 1.3 hours per day; in the patients who also reduced linoleic acid intake to no more than 1.8% of energy, it was reduced by 1.7 hours per day. The duration of moderate to severe headaches was also reduced and patients had 2-4 fewer headaches each month depending on linoleic acid intake. There was no clear effect on the use of acute pain medication (105289).
• Muscle strength. It is unclear if oral fish oil is beneficial for improving muscle strength in young adults. Details: A small preliminary clinical trial in young resistance trained adults undergoing training three times weekly shows that taking fish oil (Nordic Naturals, ProOmega) 4.5 grams daily, providing eicosapentaenoic acid (EPA) 2.275 grams and docosahexaenoic acid (DHA) 1.575 grams, for 10 weeks modestly improves upper and lower body strength when compared with taking placebo. There were no differences between groups in lean body mass or fat mass changes (110341).
• Obesity. Most clinical research shows that fish oil supplements do not improve weight loss; however, dietary fish intake might be beneficial for obesity. Clinical research also shows that taking fish oil during pregnancy does not seem to prevent overweight or obesity in the infant. It is unclear if fish oil is beneficial for improving cardiometabolic risk factors in overweight or obese children. Details: Most research shows that fish oil supplementation does not improve weight loss in obese adults or children (15737,66004,89355,89356,100247,100250,106073). A meta-analysis of clinical research shows that fish oil supplementation alone or with lifestyle modification does not reduce body weight or body mass index. However, fish oil supplementation seems to modestly reduce waist to hip ratio and waist circumference (97176). The reduction in waist circumference might be due to a decrease in body fat when fish oil is combined with exercise (15737,89355). A meta-analysis of clinical research in overweight or obese children and adolescents also shows that taking omega-3 fatty acids 250 mg to 3360 mg, usually as fish oil, for 3-52 weeks does not reduce body weight or waist circumference when compared with placebo. However, there was a modest reduction in body mass index (BMI) of approximately 1 kg/m2. Taking fish oil does not seem to improve most cardiometabolic risk factors in this population, although there were modest improvements in serum triglyceride levels and systolic blood pressure (106073). This analysis is limited by the inclusion of at least one study that investigated the use of an algae-derived docosahexaenoic acid (DHA) product. Research has also investigated the effect of fish oil supplementation on the prevention of overweight or obesity in the infant or young child when taken during pregnancy by females with overweight or obesity. Clinical research shows that taking fish oil 6 grams daily from mid-pregnancy until 3 months postpartum or when breastfeeding stopped, providing a total of 3.55 grams daily omega-3 fatty acids, does not affect infant body fat percentage or most measures of body anthropometry at 2 weeks or 3 months of age when compared with olive oil placebo. However, there was a slight increase in body mass index for age at 3 months, possibly related to increased fat mass (110338). Another clinical trial shows that taking two capsules daily of fish oil (Croda Europe Ltd.) during pregnancy and for 6 months postpartum, providing eicosapentaenoic acid (EPA) 0.22 grams and DHA 1.9 grams daily, does not prevent overweight in the child at 24 months when compared with taking placebo. The odds of overweight at 24 months were reduced by approximately 78% in children of those taking fish oil along with 10 billion colony forming units each of Lacticaseibacillus rhamnosus HN001 and Bifidobacterium animalis subsp. lactis 420; however, this reduction was similar to findings related to taking the probiotics alone in the absence of fish oil (110336). In contrast to fish oil supplements, dietary fish might enhance weight loss. Some evidence shows that dietary fish intake improves weight loss and decreases blood glucose and insulin concentrations in overweight and hypertensive patients when combined with a calorie-restricted diet (2049).
• Oral mucositis. It is unclear if oral fish oil is beneficial for oral mucositis. Details: A small clinical trial in patients with chemotherapy-induced mucositis shows that taking fish oil 2000 mg containing 360 mg EPA and 240 mg of DHA daily for 21 days reduces mucositis severity and pain when compared with placebo (98246).
• Osteoporosis. Oral fish oil has predominantly been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Epidemiological research has found that increasing intake of foods including fish that are high in omega-3 fatty acids while decreasing intake of omega-6 fatty acids is associated with higher bone mineral density (BMD) at the hip in both males and females (12956,65895). Clinical research shows that taking fish oil orally, in combination with evening primrose oil and calcium, for 18 months seems to decrease bone turnover and increase spinal and femoral BMD in elderly people with osteoporosis (7611,12925). 2000 mg of a mixture of evening primrose and fish oil (containing 60% Iinoleic acid, 8% gamma-Iinolenic acid, 4% EPA and 3% DHA), taken three times daily with meals along with calcium carbonate 600 mg has been used (7611). However, taking fish oil containing 0.45 or 4.5 grams EPA plus DHA daily for 2 years does not improve BMD in middle-aged to elderly patients with knee osteoarthritis who do not have osteoporosis (96122).
• Parkinson disease. It is unclear if oral fish oil is beneficial for Parkinson disease. Details: Preliminary observational research has found that initiating supplemental fish oil is associated with a reduction in Parkinson symptoms (110343). This study is limited by its retrospective design and the lack of symptom specific information.
• Peripheral arterial disease (PAD). It is unclear if oral fish oil is beneficial for PAD. Details: A small clinical trial shows that taking fish oil orally appears to have no effect on walking distance in patients with stable claudication (1002).
• Periodontitis. It is unclear if oral fish oil is beneficial for periodontitis. Details: Preliminary clinical research in individuals with chronic mild or moderate periodontitis treated with scaling and planing shows that taking fish oil providing 180 mg EPA and 120 mg DHA daily for one or three months modestly reduces pocket depth and improves clinical attachment, when compared with taking a placebo or no fish oil (101545,110347). Other clinical research in patients with periodontitis also receiving scaling and planing shows that taking high-dose fish oil, containing EPA 2.6 grams, 1.8 grams DHA, and other ingredients, orally once daily for 6 months improves bleeding and plaque scores, but not pocket depth, when compared with no intervention (111456). It is unclear if this effect is due to fish oil, other ingredients, or the combination. One study shows that pocket depth is reduced by 21%, compared with 5% in those taking no fish oil; however there were no benefits on gingivitis or plaque (101545). Benefits seem to be maintained up to 3 months post-treatment (101545).
• Phenylketonuria (PKU). Small clinical studies suggest that oral fish oil may modestly improve symptoms in patients with PKU. Details: Some small clinical trials show that taking fish oil supplements (Ameu, Omega Pharma) containing DHA 15 mg/kg daily for 3 months improves motor skills, coordination, and visual function in children with PKU when compared to control. However, it does not affect plasma levels of phenylalanine (65771,65981).
• Pneumonia. It is unclear if oral fish oil is beneficial for pneumonia. Details: Epidemiological research found no relationship between fish consumption and the risk of developing community-acquired pneumonia (13760).
• Polycystic ovary syndrome (PCOS). Most small clinical studies suggest that oral fish oil is not beneficial for weight loss or glucose homeostasis in patients with PCOS. Details: Small clinical trials in patients with PCOS show that taking fish oil alone or with vitamin D3 does not affect body weight or body mass index (BMI) when compared with placebo or control oils (21906,107187,107197). Also, taking fish oil does not seem to affect most measures of glucose homeostasis or blood lipids when compared to control oils (21906,107197). However, when used in combination with vitamin D3, taking fish oil modestly reduces levels of testosterone and results in some overall improvement in feelings of depression and anxiety (107187). Doses used in clinical trials have included fish oil (Nordic Naturals) providing eicosapentaenoic acid (EPA) 2148 mg and docosahexaenoic acid (DHA) 1452 mg daily for 6 weeks, or fish oil 2 grams daily plus vitamin D3 50,000 IU biweekly for 12 weeks (21906,107187,107197).
• Polymyalgia rheumatica. It is unclear if oral fish oil is beneficial for polymyalgia rheumatica prevention. Details: Oral fish oil for the prevention of polymyalgia rheumatica has been investigated in a large clinical trial of approximately 25,000 older adults. Taking fish oil 1 gram daily for 5 years providing eicosapentaenoic acid (EPA) 0.46 grams and docosahexaenoic acid (DHA) 0.38 grams alone or in combination with vitamin D3 2000 IU daily does not reduce the risk of developing definite or probable polymyalgia rheumatica when compared with placebo (107184). Although this study was large, the primary endpoint was the effect of taking fish oil and/or vitamin D on the development of autoimmune diseases as a group. The number of patients with a specific autoimmune disease such as polymyalgia rheumatica was relatively small.
• Post-traumatic stress disorder (PTSD). It is unclear if oral fish oil is beneficial for PTSD. Details: Some preliminary clinical research shows that adding omega-3 polyunsaturated fatty acid supplementation to psychoeducation does not further improve symptoms of PTSD in subjects that were part of the Disaster Medical Assistance Team after the Great East Japan Earthquake (89358). Additional preliminary clinical research in patients in intensive care shows that use of fish oil 18.8 grams per liter of enteral feed is no more effective than enteral feeding without fish oil in preventing symptoms of PTSD from developing up to 6 months later (104549).
• Postmenopausal conditions. Most research shows that oral fish oil is beneficial for improving triglyceride levels after menopause. More research is needed to determine the optimal dose and duration. Details: Lipid metabolism is often altered after menopause. A meta-analysis of mainly small clinical trials in postmenopausal females shows that taking fish oil supplements for a period of 2 weeks to 24 months decreases triglyceride levels by an average of 17.8 mg/dL when compared to placebo. The greatest evidence of benefit occurred in individuals with a body mass index (BMI) of at least 30 kg/m2 or with baseline hypertriglyceridemia. Levels of high-density lipoprotein (HDL) cholesterol, as well as low-density lipoprotein (LDL) cholesterol, were modestly increased. The dose of fish oil used in the individual clinical trials ranged between 285 mg and 14 grams daily, with the most evidence of benefit associated with doses of at least one gram daily (110351).
• Postoperative fistula. Oral fish oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients undergoing head and neck cancer surgery shows that use of a specific liquid diet (Neo-Mune, Thai Otsuka Pharmaceutical Co., Ltd.), providing supplementary arginine 12.3 grams/L, glutamine 6.15 grams/L, and fish oil 5.42 grams/L, starting 7 days before surgery and continuing for 21 days, reduces the risk of a mucocutaneous fistula diagnosis to 8%, compared with 23% of those given a hospital-prepared blended diet (107178).
• Postoperative infection. Oral fish oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients undergoing head and neck cancer surgery shows that use of a specific liquid diet (Neo-Mune, Thai Otsuka Pharmaceutical Co., Ltd.), providing supplementary arginine 12.3 grams/L, glutamine 6.15 grams/L, and fish oil 5.42 grams/L, starting 7 days before surgery and continuing for 21 days, does not reduce the risk of a wound infection or general infection when compared with a hospital-prepared blended diet (107178).
• Postoperative recovery. Oral fish oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients undergoing head and neck cancer surgery shows that use of a specific liquid diet (Neo-Mune, Thai Otsuka Pharmaceutical Co., Ltd.), providing supplementary arginine 12.3 grams/L, glutamine 6.15 grams/L, and fish oil 5.42 grams/L, starting 7 days before surgery and continuing for 21 days, reduces hospital length of stay by 5 days when compared with a hospital-prepared blended diet. Also, body weight was modestly higher at treatment completion in those taking the fish oil product (107178).
• Postpartum depression. It is unclear if oral fish oil is beneficial for postpartum depression. Details: Meta-analyses of available research show that taking fish oil, usually during pregnancy, has no effect on the prevention or treatment of perinatal depression when compared with placebo. In addition, when used along with supportive psychotherapy, fish oil is no more effective than therapy alone for perinatal depression (103493,104551). However, a meta-analysis of a small number of studies shows that taking omega-3 fatty acids might have a moderate effect on the prevention of postpartum depression (103493). The studies included in this analysis were heterogeneous. Most studies used fish oil providing EPA up to 2200 mg daily and DHA up to 1638 mg daily, but some studies in the analysis used DHA alone from algal sources (103493).
• Preterm labor. Research on the use of oral fish oil for the prevention of preterm labor is conflicting; however, there may be benefit of oral fish oil in patients with low baseline omega-3 status. Details: Population research has found that eating seafood during pregnancy is associated with a reduced risk of preterm delivery when compared with never eating fish (65528). Clinical research also shows that taking a specific omega-3 fatty acids supplement (Pikasol) 2.7 to 6.1 grams, containing DHA 0.9 to 2.1 grams and EPA 1.3 to 2.9 grams, daily beginning at 20-33 weeks' gestation reduces the risk of premature delivery (8706,12972,66105). Meta-analyses of these and other studies show that taking omega-3 fatty acids, including fish oil and supplements or foods enriched in docosahexaenoic acid (DHA), during pregnancy reduces the risk of early preterm delivery (gestational age less than 34 weeks) by 22% to 27% and may reduce the risk of preterm delivery (gestational age less than 37 weeks) by 10% to 11% when compared to control (98240,106069). However, conflicting evidence exists. The most recent meta-analysis shows that taking omega-3 fatty acids during pregnancy does not reduce the risk of early preterm or preterm delivery when compared to control when only studies with low risk of bias were analyzed (106069). Numerous individual studies support this finding (66020,98255,101505,101540,102397,103496,110338). Some individual studies included in the meta-analysis have used a specific fish oil supplement (Incromega DHA 500TG) 900 mg containing DHA 800 mg and EPA 100 mg daily, starting at 20 weeks' gestation and continuing to delivery or 34 weeks' gestation (101505) or fish oil 2 grams daily, containing EPA 660 mg and DHA 440 mg, starting mid-gestation and continuing until the last day of the 37th week of gestation (102397). Other clinical trials not included in the meta-analysis also show that perinatal fish oil does not prevent preterm labor when compared with placebo. These studies have used fish oil 1000 mg containing EPA 180 mg and DHA 120 mg daily, starting at week 20 of gestation and continuing until birth (98255) or fish oil (Incromega TG33/22) 4 grams daily, providing 2.4 grams long chain omega-3 fatty acids, starting at about 24 weeks' gestation (101540). However, in this study, birth weight was increased by about 97 grams and gestation was increased by approximately 2 days when compared with olive oil placebo (101540). In one clinical trial, use of a high-DHA fish oil, providing EPA 100 mg and DHA 800 mg daily, from before 20 weeks' until 34 weeks' gestation, increases the risk of preterm birth prior to 34 weeks' gestation when compared with placebo in patients with baseline omega-3 status of greater than 4.9%. However, the risk is reduced from 3.2% to 0.7% in patients with baseline omega-3 status below 4.1%. In addition, taking fish oil had no effect on the risk of preterm birth prior to 37 weeks' gestation (103496). Other subgroup analyses also suggest that fish oil may be more effective in patients with low baseline omega-3 levels and singleton pregnancy (111457). The reasons for these discrepancies are not clear but may be due to the dose, duration, and type of omega-3 fatty acids used, or the baseline omega-3 status (102397,103496).
• Prematurity. It is unclear if oral fish oil is beneficial for improving the development of premature infants. Details: Formula supplemented with long-chain polyunsaturated fatty acids from fish oil and borage oil daily for up to 18 months seems to improve growth and neurodevelopment in preterm infants, especially boys (13745).
• Pressure ulcers. It is unclear if enteral or topical fish oil is beneficial in patients with pressure ulcers. Details: Preliminary clinical research in critically ill, hospitalized adults shows that giving enteral or parenteral formula supplemented with fish oil containing EPA 0.125-0.282 grams and DHA 0.144-0.309 grams per 100 mL for 28 days may slow the progression of grade II or higher pressure ulcers when compared with standard formula (89370). In patients with acute lung injury, other preliminary clinical research shows that giving a specific enteral emulsion (Oxepa, Ross Laboratories) providing fish oil, borage oil, and vitamins A, C and E for 7 days does not improve the healing of existing pressure ulcers when compared with a control enteral formula. Although the number of pressure ulcers in the group given the GLA-containing formula was lower when compared with the control formula, these patients also seemed to have fewer pressure ulcers at baseline and no statistical comparison was conducted. The clinical significance of this finding is unknown (105252). Topical fish oil has also been evaluated. One small clinical study shows that applying fish oil dressing once daily to the heels of immobile intensive care unit patients for 7 days does not reduce the risk for heel pressure ulcers when compared with olive oil dressing (102392). However, other clinical research in patients in the ICU shows that applying fish oil by hand to the sacrum for 30 seconds daily for up to 6 days modestly reduces the incidence of pressure ulcers when compared with soybean oil or routine care only. However, applying fish oil reduces the risk of pressure ulcers when compared with routine care, not when compared with soybean oil (110344).
• Prostate cancer. It is unclear if oral fish oil is beneficial for improving quality of life in patients with prostate cancer undergoing a prostatectomy. Details: Clinical research in patients with prostate cancer shows that taking fish oil 3.75 grams (75% EPA and 10% DHA) daily, for approximately 14 months starting 7 weeks prior to radical prostatectomy, does not improve most prostate cancer-specific quality of life measures when compared with placebo. However, urinary function was improved 12 months after surgery (110353).
• Pruritis. It is unclear if oral fish oil is beneficial in patients with pruritis. Details: A meta-analysis of low-quality clinical research in adults with pruritis while under palliative care shows that taking fish oil 2-6 grams for 20 days to 14 weeks significantly improves pruritis scores when compared with placebo (111455).
• Psoriasis. It is unclear if oral or topical fish oil is beneficial for the treatment or prevention of psoriasis. Intravenous fish oil seems to reduce symptoms in patients with acute, extended guttate psoriasis or chronic plaque psoriasis. Details: Despite some promising, low-quality studies, taking fish oil orally doesn't seem to have a significant effect on psoriasis severity (1035,8708,66585,66157,66233,102393). However, when administered in combination with sub-erythemal ultraviolet B (UVB) therapy, oral fish oil therapy providing EPA 3.6 grams and DHA 2.4 grams daily for 15 weeks seems to decrease the total body surface area of psoriasis when compared with placebo (66220). Topical fish oil has also been evaluated. Applying fish oil under an occlusive dressing for 6 hours daily for 4 weeks seems to improve scaling, but not erythema, in patients with psoriasis when compared with liquid paraffin (65575). The effect of oral fish oil on psoriasis prevention has been investigated in a large clinical trial of approximately 25,000 older adults. Taking fish oil 1 gram daily for 5 years providing EPA 0.46 grams and DHA 0.38 grams alone or in combination with vitamin D3 2000 IU daily does not reduce the risk of developing definite or probable psoriasis when compared with placebo (107184). Although this study was large, the primary endpoint was the effect of taking fish oil and/or vitamin D on the development of autoimmune diseases as a group. The number of patients with a specific autoimmune disease such as psoriasis was relatively small.
• Raynaud syndrome. It is unclear if oral fish oil is beneficial in patients with this condition. Details: A small clinical trial shows that taking fish oil orally containing EPA 3.96 grams and DHA 2.64 grams daily for 12 weeks can improve tolerance to cold and delay the onset of vasospasm in people with primary Raynaud syndrome; however, people with Raynaud syndrome caused by progressive systemic sclerosis don't seem to respond to fish oil supplements (7573).
• Salicylate intolerance. It is unclear if oral fish oil is beneficial in patients with salicylate intolerance. Details: A case series including three patients suggests that taking fish oil 10 grams daily in divided doses for 6-8 weeks might improve symptoms of salicylate intolerance (17410). High-quality, prospective research is needed to confirm this finding.
• Sarcopenia. There is conflicting evidence as to whether oral fish oil improves muscle strength in adults with sarcopenia. Details: A meta-analysis of clinical trials shows that taking omega-3 fatty acids improves lean body mass, skeletal muscle mass, and quadriceps function in older adults. Although most studies used eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA), a few studies used EPA alone and others used alpha-linolenic acid (107195). A network meta-analysis of clinical studies in adults with sarcopenia or at risk for sarcopenia shows that taking omega-3 polyunsaturated fatty acids at doses above 2.5 grams daily for 6-156 weeks improves upper-extremity muscle strength and lower-extremity physical function when compared with control or standard care. However, there was no improvement seen in skeletal muscle mass, fat mass, or overall body weight when compared with placebo or standard care. Subgroup analysis suggests that these effects endured even in the absence of concurrent resistance training programs (112470). Small clinical trials in older adults involving fish oil and increased dietary omega-3 intake show that fish oil, when used alone or in combination with a resistance exercise program, may have a small effect on some measures of muscle strength and the timed up-and-go test (89368,105222,109309,110335). However, one large study included in the most recent meta-analysis (107195) shows that fish oil is not beneficial for improving muscle strength in older adults. This large, high-quality clinical study in over 1,600 elderly adults shows that taking fish oil, providing DHA 800 mg and EPA 225 mg daily for 3 years, with or without physical activity and counselling, does not improve chair stand test performance or handgrip strength when compared with placebo and lifestyle interventions (102398). Also, an additional small clinical trial in older healthy adults shows that taking fish oil 3 grams daily for 18 weeks in addition to resistance training does not affect strength or functional ability when compared with resistance training plus placebo (98244).
• Schizophrenia. It is unclear if oral fish oil is beneficial in patients with schizophrenia. Details: There is contradictory evidence about the effects of fish oil in patients following a single episode of psychosis. A preliminary clinical study shows that taking fish oil containing 2.2 grams of EPA and DHA daily for 26 weeks modestly reduces negative and positive symptoms and improves functioning when compared with olive oil placebo. All patients were stabilized on antipsychotic medications (97183). However, conflicting evidence exists. One small clinical study shows that taking alpha-lipoic acid 150 mg, EPA 1000 mg, and DHA 500 mg twice daily does not prevent 2-year cumulative relapse or delay relapse when compared with placebo in patients who responded well to antipsychotic treatment after a single episode of psychosis (90675). A meta-analysis of these two studies shows that taking fish oil modestly reduces negative and positive symptoms and improves functioning when compared with placebo (105217). A small clinical trial shows that taking fish oil containing DHA 360 mg and EPA 540 mg daily for 12 weeks does not improve most symptoms of schizophrenia, although it may modestly reduce aggression when compared with placebo (98256). Due to the general lack of supporting evidence related to the use of omega-3 fatty acids for schizophrenia, the Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that omega-3 fatty acids in doses of 1-2 grams are not recommended for adjunctive or monotherapy use in these patients (110318).
• Sepsis. It is unclear if oral fish oil is beneficial in patients with sepsis. Details: Meta-analyses of generally low-quality clinical trials show that parenteral or enteral supplementation with lipid emulsions containing refined fish oil or other omega-3 fatty acids reduces the duration of stay in the intensive care unit (ICU) and the hospital by about 4 and 10 days, respectively, and reduces the need for mechanical ventilation by about 2 days when compared with placebo or no supplementation in patients with sepsis (98253,105221,109305). Also, although an earlier meta-analysis disagrees (98253), most meta-analyses show that use of fish oil-containing nutrition supplementation reduces mortality by up to 26% (105221,109305). This discrepancy may be related to the form of the lipid emulsion. One sub-analysis shows no beneficial effect from enteral supplementation with lipid emulsions containing fish oil. Only parenteral supplementation reduces mortality by 32% (109305). However, clinical research in patients with sepsis shows that supplementing with lipid emulsions containing refined fish oil does not prevent brain injury or delirium when compared with control (89323).
• Sickle cell disease. It is unclear if oral fish oil is beneficial in patients with sickle cell disease. Details: Preliminary clinical research shows that taking menhaden fish oil 0.25 grams/kg containing 12% EPA and 18% DHA daily for one year reduces the frequency of severe pain episodes when compared with olive oil in patients with sickle cell disease (65510).
• Stroke. It is unclear if oral fish oil is beneficial in the secondary prevention of stroke or for improving recovery from a stroke. Oral supplemental fish oil does not seem to be beneficial in the primary prevention of stroke. Details: Taking a fish oil SUPPLEMENT does not seem to be beneficial for primary prevention of stroke. Clinical research shows that taking a fish oil supplement 1 gram or 4 grams daily does not reduce the risk of stroke (2307,66185,103491). In 2017, the American Heart Association (AHA) published a science advisory stating that fish oil supplements should not be used for primary prevention of stroke in patients at high risk for CVD, as the cumulative evidence shows no benefit (93568). Furthermore, a 2018 meta-analysis including 24 studies and over 79,000 patients with or without CVD confirms that taking fish oil SUPPLEMENTS does not reduce the risk of ischemic or hemorrhagic stroke (98231). The effect of DIETARY fish oil for the primary prevention of stroke is controversial. Higher serum levels of fish oil have been associated with a decreased risk of stroke (7372). Early research found that consuming fish oil from dietary sources at least once weekly is associated with a 27% reduced risk of ischemic stroke (7373). However, the method of preparing fish may be important. Eating tuna or other broiled or baked fish has been associated with lower risk of ischemic stroke, while fried fish or fish sandwiches has been associated with higher risk of ischemic stroke in elderly people (12923). There has also been some concern that consumption of very high amounts of fish oil from dietary sources might increase the risk of stroke. People who eat more than 46 grams daily of fish appear to be nearly twice as likely to have an ischemic or hemorrhagic stroke (7603,7610,8699); however, these findings are questionable due to poor study design. In 2018, the American Heart Association (AHA) issued a science advisory recommending that patients consume 1-2 weekly servings of non-fried fish in place of less healthy protein options for the primary prevention of ischemic stroke (97185). However, dietary intake of fish oil may not be beneficial for stroke prevention in all patients. A 2018 meta-analysis including 4 studies and over 10,000 patients shows that increased dietary fish oil intake does not reduce the risk of stroke (98231). The majority of the studies included in this meta-analysis evaluated only patients with existing CVD. Therefore, it is possible that increased dietary intake of fish oil may not be beneficial in patients with a history of CVD. There is currently not enough reliable information available to know if increased intake of fish oil, either as part of the diet or as a supplement, has any benefit for stroke prevention in people who have already had a stroke (secondary prevention). Fish oil has also been evaluated for the improvement of symptoms in patients who are post-stroke. A meta-analysis of the available clinical research shows that due to the heterogeneity and low quality of the available clinical research, it is unclear if fish oil supplements are beneficial for stroke recovery, including mood, mobility, and performance on the Glasgow Outcome Scale, or for the prevention of vascular-related death when compared with placebo or control (102399). One clinical study shows that taking fish oil 1 gram daily, starting before the stroke and continuing for a total median duration of 5.3 years, does not improve functional limitations or physical disabilities over a median 1.4 years after the first stroke (104550). However, the data was heterogeneous in this study and it is unclear what effects, if any, post-stroke supplementation of fish oil might have on these outcomes.
• Systemic lupus erythematosus (SLE). It is unclear if oral fish oil is beneficial in patients with SLE. Details: A meta-analysis of five low-quality randomized controlled trials shows that taking fish oil for 12-26 weeks modestly reduces SLE symptoms (104548). However, results from individual studies are mixed (7571,7572,12925,12953,104548). A specific fish oil supplement (MaxEPA) 3-20 grams daily, alone or along with copper 3 mg daily, has been used in some studies for 24-34 weeks (7572,12953).
• Ulcerative colitis. It is unclear if oral fish oil is beneficial in patients with ulcerative colitis. Details: Some clinical research shows that taking fish oil (HiEPA) providing 4.5 grams of EPA daily for 12 months can reduce corticosteroid requirements in adults with ulcerative colitis. However, fish oil does not seem to reduce relapse rates in these patients (1040). Other clinical research shows that taking fish oil 4.2 grams daily for 8 months reduces the symptoms of ulcerative colitis when compared with placebo (65620). However, another clinical study shows that a specific commercial fish oil supplement (MaxEPA, Seven Seas Ltd) does not reduce symptoms such as disease relapse, stool frequency, rectal bleeding, or rectal histology when compared with placebo (1037). Overall, a meta-analysis of clinical research shows that fish oil does not reduce the relapse rate of ulcerative colitis when compared with control (65786,105224). Although population research has found that habitual intake of fish oil supplements is associated with a modestly reduced risk of ulcerative colitis (109303), a meta-analysis of two clinical trials shows that taking omega-3 fatty acids for about 1 year does not reduce the likelihood of an ulcerative colitis diagnosis when compared with a control group receiving monounsaturated fats (105224). Fish oil has also been evaluated in combination with other ingredients. One clinical trial shows that taking a supplement containing fish oil in combination with fructo-oligosaccharides, gum arabic, vitamin E, and vitamin C might reduce corticosteroid requirements in patients with ulcerative colitis; however, it doesn't seem to reduce disease activity or improve histology when compared with placebo (13757).
• Upper respiratory tract infection (URTI). It is unclear if oral fish oil is beneficial for URTI prevention or treatment. Details: One small clinical trial in healthy athletes shows that consuming a drink fortified with docosahexaenoic acid (DHA) 550 mg, eicosapentaenoic acid (EPA) 550 mg, vitamin D3 10 mcg, and whey protein 8 grams twice daily for 16 weeks does not reduce the incidence or duration of URTIs when compared with placebo (98243). However, a large clinical trial shows that taking fish oil (Incromega) 2.4 grams daily, providing 55% EPA and 37% DHA, starting at gestational week 24 and continuing until one week after birth, reduces the risk of developing croup by 38% in the offspring aged up to 3 years when compared with olive oil as placebo. This risk reduction remained after adjusting for the use of vitamin D 2800 IU daily, as well as for concomitant persistent wheeze and/or lower respiratory tract infections (109304).
• Venous thromboembolism (VTE). It is unclear if dietary fish or omega-3 fatty acids are beneficial in VTE prevention. Details: A meta-analysis of population research has found that the highest fish consumption is not associated with risk of VTE when compared with the lowest. However, overall intake of omega-3 fatty acids was associated with a small reduction in risk of VTE, as well as a modest reduction in risk of recurrent VTE (105223).
• Vitamin D deficiency. It is unclear if fish oil is beneficial for vitamin D deficiency. Details: A meta-analysis of clinical research shows that taking omega-3 fatty acid supplements for at least 8 weeks modestly increases 25-hydroxyvitamin D levels by an average of 3.8 ng/mL. A sub-group analysis shows that this benefit is limited to patients with vitamin D deficiency (105215). More evidence is needed to rate fish oil for these uses.

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POSSIBLY SAFE ...when used orally and appropriately. The European Food Safety Authority considers cetylated fatty acids to be safe when consumed at doses up to 1.6 grams daily (107914).. ...when used topically and appropriately. A topical cream containing a cetylated fatty acid blend (Celadrin, Proprietary Nutritionals, Inc.) has been applied twice daily with apparent safety for up to 30 days (12076,13104). A topical cream containing cetylated fatty acids 5.6% has also been applied twice daily with apparent safety for up to 28 days (101997).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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LIKELY SAFE ...when used orally and appropriately. Doses of 3 grams per day and less can be safely used by most people. Fish oil has Generally Recognized As Safe (GRAS) status in the US (1313,1024,2299,2300,2301,2302,2315,2317,4912,5702)(5705,5706,6394,6399,7368,7369,7380,12921,12922,13011)(13766,14382,16733,17408,17991,17992,66454,89325,89336,89346)(89351,89352,89373,89374,101543,103492,103499,103502,104546,105220)(107180,107181). Although higher doses of fish oil, such as 6 grams daily for up to 1 year, have been used safely (89344), there are some safety concerns about using high doses of fish oil. Some older research suggests that doses greater than 3 grams per day can inhibit blood coagulation and potentially increase bleeding risk (8671,8679,8696,66258,21223,21224). However, the most rigorous research to date shows that short-term doses of fish oil 10 grams daily and long-term doses of 1.5 grams daily for up to 52 weeks do not increase the risk of bleeding or affect coagulation parameters in chronically ill and vulnerable patients (97180). Still, doses greater than 3 grams per day might suppress immune response (1313,7384). Patients should only take high-dose fish oil while under medical supervision.

POSSIBLY SAFE ...when parenteral nutrition supplemented with a lipid emulsion enriched in fish oil is used, short-term. Fish oil or omega-3 fatty acid lipid emulsions, administered intravenously for 1-4 weeks, have been safely used (1004,66042,66421,89323,103497).

POSSIBLY UNSAFE ...when fish oil from dietary sources is consumed in large amounts. Fatty fish can contain significant amounts of toxins such as mercury, polychlorinated biphenyls (PCBs), dioxin, and dioxin-related compounds. Very frequent consumption of contaminated fish can cause adverse effects such as tremor, numbness and tingling, difficulty concentrating, and vision problems. Avoid frequent consumption of swordfish, king mackerel, tilefish (also called golden bass or golden snapper), and farm-raised salmon (12964,12965,12966). There is insufficient reliable information available about the safety of fish oil when used topically.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately (5708,5711,65732,66070). In adolescents 9 years of age and older, fish oil providing doses of up to 2250 mg omega-3 fatty acids daily have been used with apparent safety for up to 12 weeks (101543). Fish oil used in enteral feeds for up to 9 months has been shown to be safe in infants (13745). Young children should limit dietary consumption to no more than two ounces of fish per week (12967,12968). ...when given as part of parenteral nutrition in infants receiving long-term parenteral nutrition (96118,110340,110346,110352).

CHILDREN: POSSIBLY UNSAFE
when fish oil from dietary sources are consumed in large amounts. Fatty fish can contain significant amounts of toxins such as mercury, polychlorinated biphenyls (PCBs), dioxin, and dioxin-related compounds. Frequent consumption of contaminated fish can cause brain damage, mental retardation, blindness, and seizures in children. Lower levels can cause more subtle problems such as learning disabilities (12964). Young children should limit consumption to no more than 2 ounces per week of fish (12967,12968).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Intake of fish oil during pregnancy does not appear to adversely affect the fetus or nursing infant (1026,1027,1042,8706,12969,12970,12971,12972,12973,14397)(15015,15162,101540,110338). The adequate intake level of omega-3 fatty acids during pregnancy is 1.4 grams daily; the adequate intake level during lactation is 1.3 grams daily (89377). If possible, people who are trying to become pregnant, as well as those who are pregnant or lactating, should avoid swordfish, king mackerel, and tilefish (also called golden bass or golden snapper), as these may contain high levels of methylmercury. Pregnant individuals should also limit consumption of other fatty fish to 12 ounces, or about 3-4 servings, per week.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when fish oil from dietary sources are consumed in large amounts. Fatty fish can contain significant amounts of toxins such as mercury, polychlorinated biphenyls (PCBs), dioxin, and dioxin-related compounds. If possible, people who are trying to become pregnant, as well as those who are pregnant or lactating, should avoid swordfish, king mackerel, and tilefish (also called golden bass or golden snapper), as these may contain high levels of methylmercury. Pregnant individuals should also limit consumption of other fatty fish to 12 ounces, or about 3-4 servings, per week (12967,12968).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Fish oil may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs. However, evidence is conflicting.  Details While fish oil may not be a potent inhibitor of platelet function, high doses of fish oil might have antiplatelet effects. Theoretically, concomitant use of fish oil with anticoagulant or antiplatelet drugs may increase the risk of bleeding (8671,8679,8696,13769,21223,21224,66258). However, the most rigorous research shows that short-term doses of fish oil 10 grams daily or long-term doses of 1.5 grams daily for up to 52 weeks does not increase the risk of bleeding or affect coagulation parameters in chronically ill and vulnerable patients (97180). Other controlled research shows that fish oil does not affect platelet function or increase the risk of bleeding (17990,17996,66105,66267,89374,107180). Some research even suggests that perioperative fish oil use decreases bleeding risk (89352). Some research suggests fish oil does not have additive antiplatelet effects when combined with aspirin (13769), but other clinical evidence suggests that adding fish oil to low-dose aspirin treatment increases antiplatelet effects in patients who are aspirin-resistant (21226). Also, some clinical research seems to show that fish oil has additive antiplatelet effects when used with aspirin and clopidogrel compared to aspirin and clopidogrel alone (21225).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking fish oil with antihypertensive drugs might increase the risk of hypotension.  Details Clinical evidence indicates that fish oils can modestly lower blood pressure and might have additive effects in patients treated with antihypertensives (1001,1020,1030,1033,66095,66100,66215,66331,66358,66379,66385).

CONTRACEPTIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking fish oil with contraceptive drugs might decrease the triglyceride-lowering effects of fish oil.  Details There is some evidence that contraceptive drugs might interfere with the triglyceride lowering effects of fish oils (8694).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Taking fish oil with cyclosporine might increase levels and adverse effects of cyclosporine.  Details In kidney transplant recipients on a general immunosuppressive regimen, taking omega-3 fatty acids daily seems to increase peak blood levels of cyclosporine when compared with placebo. This increase was as much as 20% after one month. However, the area under the curve was not significantly affected (66472).

ORLISTAT (Xenical, Alli) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking fish oil with orlistat might decrease the absorption of fish oil fatty acids.  Details Orlistat binds lipase in the gastrointestinal tract and reduces fat absorption. Theoretically, taking fish oil with orlistat might decrease absorption of fish oil fatty acids. To avoid this potential interaction, recommend separating administration of orlistat and fish oil by at least 2 hours.

PLATINUM AGENTS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, taking fish oil with platinum agents can cause resistance to platinum agents, potentially decreasing their effectiveness.  Details Platinum-induced fatty acids (PIFAs) are fatty acids secreted from human and mouse stem cells when exposed to platinum-based chemotherapy. Animal research suggests that PIFAs cause resistance to chemotherapy by stimulating lysophospholipid production in the spleen, which interferes with the DNA damage caused by certain chemotherapy drugs (92076). One PIFA, known as 16:4(n-3), has been found in both raw fish and some commercially available fish oil products. Mackerel and herring have high PIFA concentrations, while salmon and tuna have low PIFA concentrations. Levels of PIFA in commercial fish oil products ranged from 0.2- 5.7 microMol. Animal research shows that PIFA-containing fish oil products cause resistance to cisplatin, fluorouracil, irinotecan, and oxaliplatin (91250,92075). It is unclear if all commercially available fish oil products contain PIFAs. Additionally, it is argued that levels of PIFA found in some fish oil products are too low to be of clinical concern. Furthermore, a lack of chemotherapy resistance in countries with high fish intake, such as Greenland, Japan, and Norway, suggest that this interaction may not be clinically significant (91288,91289).

SIROLIMUS (Rapamune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Taking fish oil with sirolimus might increase levels and adverse effects of sirolimus.  Details Pharmacokinetic research shows that omega-3 fatty acids increase exposure to sirolimus in kidney transplant patients on a calcineurin inhibitor-free immunosuppressive regimen. A 25% dose reduction in sirolimus was required to keep patients within the expected trough-concentration window (105232). Researchers hypothesize that this may be due to inhibition of cytochrome P450 3A4 (CYP3A4) by fish oil, although this has not been confirmed in clinical research.

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Taking fish oil with tacrolimus might increase levels and adverse effects of tacrolimus.  Details In a small group of patients, taking fish oil 2.6 grams (Omacor) daily for 4 weeks increased the 8-hour area under the curve of tacrolimus by 25% when compared with baseline. Peak levels were increased by approximately 22% (105212). Researchers hypothesize that this may be due either to an increase in bioavailability or to inhibition of cytochrome P450 3A4 (CYP3A4) by fish oil, although this has not been confirmed in clinical research.

WARFARIN (Coumadin) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Fish oil may have antiplatelet effects and might increase the risk of bleeding if used with warfarin.  Details Fish oil has antiplatelet effects at high doses. Case reports show elevated INR in patients taking warfarin and fish oil 1-2 grams daily (21222,21223). However, some clinical research shows that taking fish oil 3-6 grams daily does not significantly increase INR in patients taking warfarin (8801).

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General ...Orally, no adverse effects have been reported; however, a thorough evaluation of safety outcomes has not been conducted. Topically, cetylated fatty acids seem to be well tolerated.

Dermatologic ...Topically, hypersensitivity rash occurred in one patient in a clinical trial using a cream containing cetylated fatty acids, menthol, and other ingredients. However, it is unknown which ingredient was responsible for the adverse effect (101997).

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General ...Orally and parenterally, fish oil is generally well-tolerated. Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Abdominal pain, bad breath, fishy aftertaste, heartburn, increased low-density lipoprotein (LDL) cholesterol levels, loose stools, nausea, and rash.
Serious Adverse Effects (Rare):
Orally: Atrial fibrillation. When taken in doses of 3 grams or more daily, there are rare reports of increased risk of bleeding and stroke, as well as immune suppression.

Cardiovascular ...Orally, fish oil supplements in doses of 3-10 grams daily can cause a dose-dependent increase in low-density lipoprotein (LDL) cholesterol levels in some people (2299,2318,8678,8698,15734,15735,48120,65729) by increasing the size of LDL particles (9771). Therefore, LDL levels should be monitored in people who take fish oil supplements (15734). But fish oil doesn't seem to cause development of atherosclerosis, despite earlier concerns that polyunsaturated fatty acids, such as omega-3 fatty acids, might increase the oxidation of LDL (1011,2323,7165,7366,8695,8700,9771).
There is concern that fish oil supplements may be associated with an increased risk for atrial fibrillation (AF), particularly in patients with or at risk for cardiovascular disease (CVD). In one large clinical study (the STRENGTH trial), taking a prescription fish oil product (Epanova) 4 grams daily for up to 5 years was associated with an increased risk for AF, with a number needed to harm of 114 when compared with a corn oil control. The patients in this study were considered to be at high risk for future CVD (103491).
In a secondary analysis of the Omega-3 fatty acids in Elderly patients with Myocardial Infarction (OMEMI) trial, adults aged 70-82 years with recent myocardial infarction supplementing with 1.8 grams daily of n-3 PUFA (EPA/DHA) for 24 months had a 90% increased risk of developing AF or micro-AF, which is characterized by short, AF-like activity lasting less than 30 seconds. Changes in serum EPA levels seem to mediate this risk, with higher serum EPA levels predictive of an increased risk of AF and intermediate serum EPA levels predictive of an increased risk of micro-AF (112469).
Meta-analyses of randomized controlled trials show that taking omega-3 fatty acid supplements increases the incidence rate ratio for AF by up to 37% when compared with placebo, with an increased incidence rate associated with doses of more than 1 gram daily. One study in these analyses used eicosapentaenoic acid (EPA) alone as purified icosapent ethyl (106075,107171,107181).
In 2023, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency issued a public statement on the use of omega-3-acid ethyl esters, concluding that exposure to omega-3-acid ethyl esters for the treatment of hypertriglyceridemia is associated with a dose-dependent increased risk of AF in patients with established cardiovascular disease or risk factors for cardiovascular disease when compared with placebo. The highest risk of AF is associated with a dose of 4 grams daily. If AF occurs, treatment should be permanently discontinued (112467).

Dermatologic ...Orally, skin rashes, itching, and skin irritation have been reported (66498,66492,66488,89369,104551).
A case of severe tissue inflammation and breast tissue necrosis has been reported for a female who injected fish oil from capsules subcutaneously for breast augmentation (89371).

Gastrointestinal ...Orally, most adverse effects of omega-3 fatty acids are gastrointestinal in nature (12915,65599,65728,65770,65780,65904,66061,66104,66164,66488)(89347,89357,103491,103551,107172). Gastrointestinal upset is common with the use of fish oil supplements, occurring in up to 5% of patients in clinical trials, with nausea in up to 1.5% of patients (2307,16733,65599,65732,65762,65830,65886,65925,65974)(66020,66042,66083,66104,66130,66164,66169,66358,66370,66488)(66494,66498,89347,103491,104551,110353). Diarrhea and loose stools may also occur (6257,10871,65599,65648,65830,65935,66042,66061,66104,66119)(66130,66173,66492,89347,89359,103491,104551,107172,110353), with potentially severe diarrhea at very high doses (12986,16901,66093,66356). There have also been reports of increased burping (17963,65648,65729,65770,65830,66020,66042,66077,66164,66169)(66492,66494,104551), acid reflux, heartburn (104551,110338), indigestion (65566,65830,66061,66104,66173,89359), abdominal bloating (66083,66104), abdominal or gastrointestinal pain or discomfort (8680,17996,66119,66492,103491), anorexia (62390,89359), flatulence (66492), constipation (16901), nausea and vomiting (65728,65830,66104,66130,66488,103491,104551), steatorrhea (66119,66354,66356), fishy hiccups (66488), metallic taste (66488), and a fishy breath odor and aftertaste (16901,65648,65729,65762,66020,66042,66061,66077,66083,66104)(66130,66164,66172,66173,66424,66488,66494,89369,104551,107172). Also, some preliminary evidence suggests that increased serum levels of omega-3 fatty acids, especially DHA, might increase the risk for atrophic gastritis (8709).
Gastrointestinal side effects may be minimized if fish oils are taken with meals and if doses are started low and gradually increased. Taking supplements with meals or freezing them seems to help decrease these side effects for some patients (12975). Enteric coated fish products might also help reduce side effects (6258).

Hematologic ...Orally, 3 grams or greater of omega-3 fatty acids daily may inhibit platelet aggregation and increase the risk of bleeding; however, there is little evidence of statistically significant bleeding risk at lower doses (1313,8699,66500,66501,66334,101543). Very large intakes of fish oil or omega-3 fatty acids (more than 46 grams per day) may increase the risk of ischemic or hemorrhagic (bleeding) stroke (7603,66502).
A case of hemolytic anemia has been reported for an infant with short bowel syndrome who developed liver disease from total parenteral nutrition (TPN) and was switched to a specific TPN with fish oil (Omegaven, Fresenius-Kabi, Graz, Austria) instead. After stopping the fish oil-TPN, the anemia was reversed suggesting that parenteral fish oil might cause hemolytic anemia (66022).

Hepatic ...Orally, mild elevations in liver function tests (alanine aminotransferase) have been reported, although these events are rare (66353).

Immunologic ...A case of anaphylaxis following ingestion of a fish oil capsule has been reported for a female patient with a history of allergy to crab. The patient was treated successfully with epinephrine, but had several recurrences of stridor over the next 2 days (89378).
There is also some evidence that fish oil in doses greater than 3 grams per day might adversely affect immune function. Fish oil appears to suppress T- and B-cell function and to reduce the production of cytokines, which might be detrimental to elderly people and people with suppressed immune function such as patients with human immunodeficiency virus (HIV) infection (1313,7383,7384).

Neurologic/CNS ...Orally, fish oil may cause headache, dizziness, and inability to sleep (65599,65648,89359,103491,104551). Also, restlessness and formication have been reported in less than 1% of studied cases of patients taking fish oil (66498).

Oncologic ...There is some concern that high fish intake may increase the risk for certain types of cancer. One large epidemiological study has found that dietary intake of fish oil from fatty fish twice a week or more is associated with a 16% increased risk of breast cancer when compared with eating fatty fish less than twice weekly (107175). Additionally, an analysis of the NIH-AARP Diet and Health Study, a prospective cohort study in over 491,000 older adults, has found that total intake of fish is associated with increased melanoma risk over a median follow-up of 15.5 years. When the lowest and highest quintiles of intake are compared, there is a 22% increase in the risk for malignant melanoma and a 28% increase in the risk for melanoma in situ. In sub-group analyses, all melanoma incidence is positively associated with tuna intake or non-fried fish intake, but malignant melanoma incidence is inversely associated with fried fish intake (108509). It was suggested that the positive associations could be due to contaminants in fish such as polychlorinated biphenyls, dioxins, arsenic, and mercury.

Pulmonary/Respiratory ...Orally, fish oil has been reported to cause nasopharyngitis and upper respiratory tract infections in 3. 3% of patients in one clinical trial (65798). Exacerbation of asthma and apnea have been reported for patients using fish oil (1040,66061,66119,66354).

Other ...Fish oil can contribute to caloric intake and may cause weight gain if used long-term. One gram of fat or oil provides 9 kcal (6871). Fish oil capsules containing 500 mg omega-3 fatty acids in 1 gram of oil would supply about 13.5 kcal per capsule (6871,6874). Fish oil supplements also contain cholesterol in amounts from 1-6 mg per gram of fish oil (3022,6871).

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