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Fish Oil

Supplement Forms/Alternate Names

  • Docosahexaenoic Acid (DHA)
  • Eicosapentaenoic Acid (EPA)
  • Omega-3 Fatty Acids
  • Omega-3 Oil(s)
Fish oil contains omega-3 fatty acids, one of the two main classes of essential fatty acids. ( Omega-6 fatty acids are the other main type.) Essential fatty acids are special fats that the body needs for optimum health.
Interest in the potential therapeutic benefits of omega-3 fatty acids began when studies of the Inuit (Eskimo) people found that, although their diets contain an enormous amount of fat from fish, seals, and whales, they seldom suffer heart attacks. This is presumably because those sources of fat are very high in omega-3 fatty acids.
Subsequent investigation found that the omega-3 fatty acids found in fish oil have various effects that tend to reduce risk of heart disease and strokes. However, research into whether use of fish oil actually prevents these diseases remains incomplete and somewhat inconsistent. In recognition of this, the FDA has allowed supplements containing fish oil or its constituents to carry a label that states: "Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease."
In addition, a slightly modified form of fish oil (ethyl-omega-3 fatty acids) has been approved by the FDA as a treatment for high triglyceride levels . 237 This specially processed product, sold under the brand name Omacor (Lovaza), is widely advertised as more effective than ordinary fish oil.
Fish oil has also shown promise as an anti-inflammatory treatment for conditions such as rheumatoid arthritis, menstrual pain, and lupus. In addition, it may be helpful for various psychiatric conditions.

Requirements/Sources

There is no daily requirement for fish oil. However, a healthy diet should provide at least 5 g of essential fatty acids daily.
Many grains, fruits, vegetables, sea vegetables, and vegetable oils contain significant amounts of essential omega-6 and/or omega-3 fatty acids, but oil from cold-water fish is the richest natural source of omega-3 fats. It is commonly stated that people require a certain optimum ratio of omega-3 to omega-6 fatty acids in the diet; however, there is no real evidence that this is true, and some evidence that it is false. 231

Therapeutic Dosages

Typical dosages of fish oil are 3 g to 9 g daily, but this is not the upper limit. In one study, participants ingested 60 g daily.
The most important omega-3 fatty acids found in fish oil are called eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In order to match the dosage used in several major studies, you should take enough fish oil to supply about 2 g to 3 g of EPA (2,000 mg to 3,500 mg) and about 1.0 g to 2.5 g of DHA daily (1,000 mg to 2,500 mg). Far higher doses have been used in some studies; conversely, one study found blood-pressure lowering effects with a very low daily dosage of DHA—0.7 g. 238
DHA and EPA are not identical and might not have identical effects. Some evidence hints that DHA may be more effective than EPA for thinning the blood 176 and reducing blood pressure. 105 The reverse may be true for reducing triglyceride levels, but study results are conflicting. 160-165, 235
Some manufacturers add vitamin E to fish oil capsules to keep the oil from becoming rancid. Another method is to remove all the oxygen from the capsule.
If possible, purchase fish oil products certified as free of significant levels of mercury, toxic organochlorines, and PCBs (see Safety Issues).
Flaxseed oil also contains omega-3 fatty acids, although of a different kind. It has been suggested as a less smelly substitute for fish oil. However, it is far from clear whether flaxseed oil is therapeutically equivalent to fish oil. 1,200

Therapeutic Uses

Consumption of fish oil alters the body’s production of certain substances in the class of chemicals called prostaglandins. Some prostaglandins increase inflammation while others decrease it. The prostaglandins whose production is enhanced by fish oil fall into the anti-inflammatory category. Based on this, fish oil has been tried as a treatment for early stages of rheumatoid arthritis , with positive results. It is thought to significantly reduce symptoms without causing side effects and may magnify the benefits of standard arthritis drugs. 37,38,179 However, while some standard medications can slow the progression of the disease, there is no evidence that fish oil can do this. Much weaker evidence hints that fish oil might be helpful for the related disease ankylosing spondylitis. 232
Fish oil’s apparent anti-inflammatory properties are the likely explanation for its apparent benefit in dysmenorrhea (menstrual pain), as seen in two studies. 39,40 Similarly, fish oil may be helpful for the autoimmune disease lupus . 137,191 (However, two studies failed to find fish oil helpful for kidney disease caused by lupus. 138,139 ) Evidence has been mixed regarding whether fish oil is beneficial for Crohn's disease or ulcerative colitis , conditions in which parts of the digestive tract are highly inflamed. 49-51,61-68, 159,201 More recently, however, two well-designed trials enrolling a total of 738 patients convincingly failed to find any benefit for omega-3 fatty acid supplementations in the prevention of Crohn’s disease relapse. 254
Incomplete evidence hints but does not prove that fish or fish oil might help prevent death caused by heart disease . 152,202 This effect seems to result from several separate actions. The best documented involves reducing high triglyceride levels ; studies enrolling more than 2,000 people have substantiated this use. 1 In addition, fish oil might raise HDL ("good") cholesterol levels, "thin" the blood, lower levels of homocysteine , prevent dangerous heart arrhythmias, slow heart rate, improve blood vessel tone, and decrease blood pressure . 14,15,51,90-94,96-105,151,160-165,174,177,189,190,203-204,238 These effects also support findings that fish oil may help prevent strokes . 20,178 However, results are conflicting on whether people with angina should take fish oil or increase intake of fatty fish; one large study actually found that fish oil increased risk of sudden death. 206
For a number of theoretical reasons, it has been suggested that fish oil and its constituents (especially a slightly modified form of EPA called ethyl-EPA) might have positive effects on various psychiatric disorders, most notably depression . However, there is no convincing evidence that low levels of omega-3 fatty acids in the bloodstream leads to even mild depression. 259 Moreover, larger trials have generally failed to demonstrate a beneficial effect of fish oil-related products in depressed patients. 154,168,188,192,193,207,228,234,241,242,244 Some evidence hints that high doses of fish oil may produce benefits in  bipolar disorder , reducing risk of relapse and improving emotional state. 41,205,242,284 Other preliminary, and again not altogether consistent, evidence hints that fish oil might enhance the effectiveness of standard drugs (such as phenothiazines ) for schizophrenia. 48,148,169,170,193,247 One trial of 81 adolescents and young adults (considered at very high risk) found that daily omega-3 fatty acid supplements for 12 weeks delayed transition to a first full-blown psychotic episode (e.g., shcizophrenia) within one year. 276 Fish oil has also shown a bit of promise for borderline personality disorder. 180 In one study, DHA failed to augment the effectiveness of standard therapy for attention deficit disorder (ADD). 89 However, two studies that evaluated the potential benefits of fish oil combined with omega-6 fatty acids found some evidence of benefit for this condition. 88,194 Finally, one small trial found evidence that use of fish oil might decrease anger and aggressiveness in people with a history of aggressive behaviors, substance abuse, and problems with the law. 243
Small studies also suggest that fish oil may be helpful in Raynaud's phenomenon (a condition in which a person's hands and feet show abnormal sensitivity to cold temperatures), 42,43sickle-cell anemia , 45 and a form of kidney disease called IgA nephropathy. 47
According to some, but not all studies, fish oil may help treat the undesired weight loss often experienced by people with cancer. 181-182 In addition, highly preliminary evidence hints that DHA might enhance the effects of the cancer chemotherapy drug doxorubicin 157 and decrease side effects of the chemotherapy drug irinotecan. 158
Use of fish oil by pregnant women might help prevent premature birth, 184-185,208,236 although evidence is somewhat inconsistent. In addition, use of fish oil by pregnant women may support healthy brain function 183 and help prevent eczema and allergies in offspring. 195
Intriguing, but not yet at all reliable, evidence hints that fish oil, or its constituents, might be helpful for treating kidney stones or alleviating the symptoms of chronic fatigue syndrome , and reducing the risk of prostate cancer . 54,56,58,59 Results are inconsistent regarding whether the use of fish oil can decrease seizure frequency in people with epilepsy . 209,246
One study found that insulin metabolism in 278 young, overweight subjects improved on a calorie-restricted diet rich in fish oil from seafood or supplements compared to those on a diet low in fish oil, suggesting that fish oil may help delay the onset of diabetes in susceptible individuals. 258 Fish oil has also been proposed as a treatment for many other conditions, including diabetic neuropathy , 60allergies , and gout , but there has been little real scientific investigation of these uses.
Some, but not all, studies suggest that fish oil combined with omega-6 essential fatty acids may augment the effectiveness of calcium in the treatment of osteoporosis . 86,87 One promising, but highly preliminary, double-blind, placebo-controlled study suggests that the same combination therapy may improve symptoms of the severe neurological illness called Huntington’s disease. 155
Use of a fish oil product as part of a total parenteral nutrition regimen (intravenous feeding) may help speed recovery after major abdominal surgery . 233
For several other conditions, the current balance of the evidence suggests that fish oil is not effective.
For example, despite widely publicized claims that fish oil helps asthma , most preliminary studies have failed to provide evidence that it is effective, and one study found that fish oil can actually worsen aspirin-related asthma. 69-77,171,271 However, there is some evidence that use of fish oil could help prevent exercise-induced asthma in athletes. 196,212 And, in an interesting randomized, controlled trial with long-term follow-up, mothers who take fish-oil during late pregnancy reduced the risk of asthma in their children up to 16 years later. 263
At least two studies, including a systematic review of 4 trials, have not found evidence to support the use of fish oil for improving lung function in people with cystic fibrosis. 251,281
A 16-week, double-blind, placebo-controlled study of 167 individuals with recurrent migraine headaches found that fish oil did not significantly reduce headache frequency or severity. 149 Conflicting results have been seen in other, much smaller trials of fish oil for migraines. 172,173
One study found weak evidence that use of fish oil might decrease aggressive behavior in young girls (but, in this study, not in young boys). 213 Another study found benefit in developmental coordination disorder (a condition in which children suffer from lack of physical coordination as well as problems with learning and behavior). 214
Fish oil is also sometimes recommended for enhancing immunity in HIV infection. However, one 6-month, double-blind study found that a combination of the omega-3 fatty acids in fish oil plus the amino acid arginine was no more effective than placebo in improving immune function in people with HIV. 78 Fish oil, however, might help individuals with HIV gain weight. 79
In one large, randomized, controlled trial, diets rich in fish and omega-3 fatty acids from fish were associated with a significant reduction in the risk of developing colorectal cancer among men over a 22-year period. 255 Another study provides preliminary evidence for the benefits of fish oil in reducing the risk of prostate cancer. 57 On balance, however, there is still relatively little evidence that the consumption of fish oil reduces cancer risk . 215
Preliminary studies have suggested that fish oil could help symptoms of multiple sclerosis ; however, the largest double-blind study on the subject found no difference between people taking fish oil and those taking olive oil (used as a placebo). 80-84,216
Although one study found fish oil somewhat helpful in psoriasis , 133 a much larger study found no benefit. 134
DHA has been evaluated as a possible treatment for male infertility , but a double-blind trial of 28 men with impaired sperm activity found no benefit. 85
Combination therapy with GLA and fish oil has failed to prove effective for cyclic breast pain . 186
One study failed to find fish oil more effective than placebo for treating stress . 217 DHA has also been tried for slowing the progression of retinitis pigmentosa (a condition in which the retina gradually degenerates), but without much success. 210-211 In observational studies, people who happen to consume a diet rich in omega-3 fatty acids seem to lower their risk of age-related macular degeneration (the most common cause of blindness in the elderly). However, in the absence of randomized controlled trials, it is not possible to say whether or not it is omega-3 that produces this benefit. 260
Studies of fish oil have failed to find it helpful for Alzheimer's disease , whether for slowing its progression or improving symptoms. 230,240 In addition, two randomized trials have failed to find any benefit of fish oil for enhancing memory and mental function in older adults without dementia. 265,280
Use of essential fatty acids in the omega-3 family has also shown some promise for the treatment of non-alcoholic fatty liver. 245,270
A 12-week, double-blind, placebo-controlled trial involving 68 healthy medical students without anxiety disorders found that taking fish oil supplements may reduce anxiety (ie, stress related to test taking). 282

What Is the Scientific Evidence for Fish Oil?

Heart Disease Prevention

Studies on fish or fish oil for preventing cardiovascular disease, slowing the progression of cardiovascular disease , and preventing heart-related death have returned somewhat contradictory results. 106-125,150,156 A major review published in 2004 failed to find trustworthy evidence of benefit, 218 and a subsequent study actually found that use of fish oil increases risk of sudden death in people with stable heart disease. 219 A 2008 systematic review found that fish oil was associated with modestly reduced cardiac mortality, but not sudden cardiac death, in 11 studies totally over 32,000 patients. The reliability of these results, however, is limited by the inclusion of mostly low-to-moderate quality trials. 272 A 2009 review pooled data from 8 trials examining the effect of omega-3 fatty acids on prevention of cardiac death in almost 21,000 patients with coronary heart disease. 274 This review separated patients into two general groups (those with previous myocardial infarction versus those with angina history) and found that omega-3 supplementation reduced risk of sudden cardiac death in patients with previous myocardial infarction, but increased risk in patients with angina. Though compelling, this finding may be limited since it was derived from a retrospective analysis of original data reorganized into subgroups. Finally, a 2012 review of 14 randomized, controlled trials involving over 20,000 people further questions the supplement's value in patients with cardiovascular disease. 286 Researchers concluded that omega-3 fatty acids (ranging from 0.4-4.8 g/day) were no better than placebo at reducing rates of cardiovascular events or cardiovascular-related death.
A gigantic study (over 18,000 participants) published in 2007 was widely described in the media as finally proving beyond a shadow of a doubt that fish oil helps prevent heart problems. 239 Unfortunately, this study lacked a placebo group, and therefore failed to provide reliable evidence.
As noted earlier, fish oil is hypothesized to exert several separate effects that act together to help protect the heart. The most important action of fish oil may be its apparent ability to reduce high triglyceride levels . Like cholesterol, triglycerides are a type of fat in the blood that tends to damage the arteries, leading to heart disease. According to most, though not all studies, fish oil supplements can reduce triglycerides by as much as 25%-30%. 90-93,151,256 In a detailed review of 47 randomized trials, researchers concluded that fish oil is capable of significantly reducing triglyceride levels with no change in total cholesterol levels and only slight increases in HDL (“good”) cholesterol and LDL (“bad”) cholesterol. 268 However, in some studies, use of fish oil has markedly raised LDL cholesterol, which might offset some of the benefit. A 2009 review of 30 trials involving about 1,500 patients with type 2 diabetes demonstrated that marine-derived omega-3 polyunsaturated fatty acids (mean dose 2.4 g per day) lowered triglyceride levels about 15 mg/dL but increased LDL cholesterol by about 3 mg/dL after an average 24 weeks of treatment. 275
Fish oil has been specifically studied for reducing triglyceride levels in people with diabetes (a major risk factor for cardiovascular disease), and it appears to do so safely and effectively. 3,262 In one large trial, however, Omacor (the specially-processed, FDA-approved omega-3 product) was not found to benefit people with diabetes or prediabetes. 287 Over 12,000 such patients were randomized to receive Omacor (1 g) or placebo. All of the study participants had cardiovascular disease or had risk factors for the disease. Six years later at the follow-up, researchers found that there were no differences between the two groups in regards to cardiovascular-related death, heart attacks, strokes, or heart-related hospitalizations and surgeries. The only bright spot was that Omacor did help to reduce high triglyceride levels.
Stanols and sterols (or phytosterols) are naturally occurring substances found in various plants that can help to lower cholesterol in individuals with normal or mildly to moderately elevated levels. A study investigating the possible benefit of combining a phytosterol with fish oil found that together they significantly lowered total cholesterol, LDL-cholesterol and triglycerides, and raised HDL (“good”) cholesterol in subjects with undesirable cholesterol profiles. 257
It also seems to remain effective in individuals who are already using statin drugs to control lipid levels (both people with and without diabetes). 14,15,197 However, one study found that the standard drug gemfibrozil is more effective than fish oil for reducing triglycerides. 94 Some but not all studies suggest that fish, fish oil, or EPA or DHA separately may additionally raise the level of HDL ("good") cholesterol and possibly improve other aspects of cholesterol profile as well. 96,97,151,164,165,197 This too should help prevent heart disease.
Additionally, fish oil may help the heart by "thinning" the blood and by reducing blood levels of homocysteine , 98,176,190 although not all studies have found a positive effect. 198
Studies contradict one another on whether fish oil can lower blood pressure , 99-104,177,264 but on balance the supplement does seem to exert a modest positive effect. 174 A 6-week, double-blind, placebo-controlled study of 59 overweight men suggests that the DHA in fish oil, but not the EPA, is responsible for this benefit. 105
A large Italian trial involving almost 7,000 subjects found that fish oilmay modestly reduce the risk of death or admission to the hospital for cardiovascular reasons in patients suffering from congestive heart failure . 266 And, a smaller study involving 138 patients showed similarly beneficial results. 279
Evidence is conflicting on whether fish oil helps prevent arrhythmias . 220-224,248,285 In a 2010 study involving 663 people with intermittent atrial fibrillation (the most common cause of arrhythmia), fish oil was no more effective than placebo at reducing the number symptomatic episodes over a 24-week period. 278
Fish oil may slightly reduce heart rate . 225 This effect could contribute to preventing heart attacks and other heart problems.

Rheumatoid Arthritis

The results of numerous small double-blind trials indicate that omega-3 fatty acids in fish oil can help reduce the symptoms of rheumatoid arthritis . 126,127,179,187 At least one small study suggests that it may help rheumatoid arthritis patients lower their dose of nonsteroidal anti-inflammatory medication (eg, ibuprofen). 253 The benefits of the fish oil effect may be enhanced by a vegetarian diet. 187 Simultaneous supplementation with olive oil (about two teaspoons daily) may further increase the benefits. 226 However, unlike some conventional treatments, fish oil probably does not slow the progression of rheumatoid arthritis.

Menstrual Pain

Regular use of fish oil may reduce the pain of menstrual cramps .
In a 4-month study of 42 young women aged 15 to 18, half the participants received a daily dose of 6 g of fish oil, providing 1,080 mg of EPA and 720 mg of DHA daily. 128 After 2 months, they were switched to placebo for another 2 months. The other group received the same treatments in reverse order. The results showed that these young women experienced significantly less menstrual pain while they were taking fish oil.
Another double-blind study followed 78 women, who received either fish oil, seal oil, fish oil with vitamin B 12 (7.5 mcg daily), or placebo for three full menstrual periods. 129 Significant improvements were seen in all treatment groups, but the fish oil plus vitamin B 12 proved most effective, and its benefits continued for the longest time after treatment was stopped (3 months). The researchers offered no explanation why vitamin B 12 should be helpful.

Premenstrual Syndrome

Many women experience a variety of unpleasant symptoms in the week or two before menstruating but some can have more severe symptoms that affect day to day living. These symptoms are affected by hormonal changes of the menstrual cycle but, medical researchers do not know why only some women have premenstrual syndrome (PMS) or how to best treat it.
Regular use of fish oil may help improve symptoms in women who have PMS. In a randomized trial of 139 women, 2 g of fish oil per day for 3 months reduced depression, lack of concentration, anxiety, and bloating severity when compared to placebo. Fish oil was also associated in reduced duration time of the same symptoms, in addition to headache and breast tenderness.290

Bipolar Disorder

A 4-month, double-blind, placebo-controlled study of 30 individuals suggests that fish oil can enhance the effects of standard treatments for bipolar disorder , reducing risk of relapse and improving emotional state. 130 Eleven of the 14 individuals who took fish oil improved or remained well during the course of the study, while only 6 out of the 16 given placebo responded similarly. In addition, a systematic review of 6 randomized trials involving 320 people found that those who took omega-3 fatty acids had an improvement in their bipolar depression symptoms. 284 A small study also found that ethyl-EPA (a modified form of EPA) is helpful for the depressive phase of bipolar disease. 227 A review of 6 small trials found conflicting but generally beneficial effects of omega-3 fatty acids on depressive symptoms in adults with bipolar disorder. The review was based on mostly small trials.288

Depression

A 4-week, double-blind, placebo-controlled trial evaluated the potential benefits of fish oil in 20 individuals with depression . 154 All but one participant were also taking standard antidepressants and had been taking them for at least 3 months. By week 3, the level of depression had improved to a significantly greater extent in the fish oil group than in placebo group. Six of 10 participants given fish oil, but only one of 10 given placebo, showed at least a 50% reduction in depression scores by the end of the trial. (A reduction of this magnitude is considered a “cure.”)
A double-blind, placebo-controlled study of 70 people who were still depressed despite standard therapy (such as SSRIs ) found that additional treatment with ethyl-EPA (a modified form of EPA) improved symptoms. 175 Similar add-on benefits were also seen in other double-blind studies of ethyl-EPA or mixed essential fatty acids. 192-193,228,250 However, one study failed to find benefit with fish-oil as an add-on treatment. 229 Another double-blind study failed to find DHA alone helpful for depression. 188 A third relatively large placebo-controlled study found no benefit for fish oil in improving “mental well-being” among 320 older adults without a diagnosis of depression. 267
Postpartum Depression
The effectiveness of fish oil supplementation in treating or preventing perinatal (including postpartum) depression is, as of yet, unclear. A small preliminary study of women found that fish oil was significantly more effective than placebo at alleviating postpartum depression. 252 However, another small, placebo-controlled study was unable to show a benefit in women suffering from depression whether before or after delivery. 249 In addition, a 2009 trial of 182 pregnant women with suspected low intake of DHA found that daily DHA supplementation (with or without arachidonic acid) did not reduce risk of postpartum depression compared to placebo. 273 And, inanother much larger study involving 2,399 women, researchers found that fish oil capsules (a combination of DHA 800 mg/day and EPA 100 mg/day) did not prevent postpartum depression. Interesting, it also did not improve the cognitive and language development in their children up to four years after their birth. 277
The effectiveness of fish oil supplementation in treating or preventing perinatal (including postpartum) depression is, as of yet, unclear. A small preliminary study of women found that fish oil was significantly more effective than placebo at alleviating postpartum depression. 252 However, another small, placebo-controlled study was unable to show a benefit in women suffering from depression whether before or after delivery. 249 In addition, a 2009 trial of 182 pregnant women with suspected low intake of DHA found that daily DHA supplementation (with or without arachidonic acid) did not reduce risk of postpartum depression compared to placebo. 273 And, inanother much larger study involving 2,399 women, researchers found that fish oil capsules (a combination of DHA 800 mg/day and EPA 100 mg/day) did not prevent postpartum depression. Interesting, it also did not improve the cognitive and language development in their children up to four years after their birth. 277

Raynaud's Phenomenon

In small, double-blind studies, fish oil has been found to reduce the severe finger and toe responses to cold temperatures that occur in Raynaud's phenomenon . 131,132 However, these studies suggest that a higher than usual dosage must be used to get results, perhaps 12 g daily.

Osteoporosis

There is some evidence that essential fatty acids may enhance the effectiveness of calcium in osteoporosis . In one study, 65 postmenopausal women were given calcium along with either placebo or a combination of omega-6 fatty acids (from evening primrose oil) and omega-3 fatty acids (from fish oil) for a period of 18 months. At the end of the study period, the group receiving essential fatty acids had higher bone density and fewer fractures than the placebo group. 135
However, a 12-month, double-blind trial of 42 postmenopausal women found no benefit. 136
The explanation for the discrepancy may lie in the differences between the women studied. The first study involved women living in nursing homes, while the second studied healthier women living on their own. The latter group of women may have been better nourished and already received enough essential fatty acids in their diet.

Lupus

Lupus is a serious autoimmune disease that can cause numerous problems, including fatigue, joint pain, and kidney disease. One small, 34-week, double-blind, placebo-controlled crossover study compared placebo against daily doses of EPA (20 g) from fish oil. 137 A total of 17 individuals completed the trial. Of these, 14 showed improvement when taking EPA, while only 4 did so when treated with placebo. Another small study found similar benefits with fish oil over a 24-week period. 191 However, two small studies failed to find fish oil helpful for lupus nephritis (kidney damage caused by lupus). 138,139

Attention Deficit and Hyperactivity Disorder (ADHD)

Based on evidence that essential fatty acids are necessary for the proper development of brain function in growing children, EFAs have been tried for the treatment of ADHD and related conditions. The results has been mixed. A preliminary double-blind, placebo-controlled trial found some evidence that a supplement containing fish oil and evening primrose oil might improve ADHD symptoms. 140 However, a high drop-out rate makes the results of this trial unreliable. In a double-blind, placebo-controlled trial of children already using stimulant therapy, addition of DHA for 4 months failed to further improve symptoms. 141 A systematic review produced slightly more promising results, though. In the review, 10 randomized trials involving 699 children with ADHD found that those who took omega-3 fatty acids experienced a modest improvement in certain symptoms like inattentiveness and hyperactivity. 283 Another small study examined fish oil in children with ADHD who had thirst and skin problems. Benefits were seen with fish oil, but they also occurred with placebo and to about the same extent. 194

Canker Sores

In a small randomized trial with 50 people with recurrent canker sores, omega-3 fatty acids (1 gram, 3 times per day for 6 months) was associated with improvement in the number of ulcers, pain level of ulcers, and healing time of ulcers by up to 3 months when compared to placebo.289

Safety Issues

Fish oil appears to be generally safe. The most common problem is fishy burps. However, there are some safety concerns to consider.
For example, it has been suggested that some fish oil products contain excessive levels of toxic substances such as organochlorines and PCBs. 166 If possible, try to purchase fish oil products certified not to contain significant levels of these contaminants. Note: Various types of fish contain mercury, but this has not been a problem with fish oil supplements, according to reports on Consumerlab.com.
Fish oil has a mild blood-thinning effect; 269 in one case report, it increased the effect of the blood-thinning medication warfarin (Coumadin). 199 Fish oil does not seem to cause bleeding problems when it is taken by itself 142 or with aspirin. 143 Nonetheless, people who are at risk of bleeding complications for any reason should consult a physician before taking fish oil.
Fish oil does not appear to raise blood sugar levels in people with diabetes. 144,145 Nonetheless, if you have diabetes, you should not take any supplement except on the advice of a physician.
Fish oil may modestly increase weight and lower total cholesterol and HDL (“good”) cholesterol levels. 269 It may also raise the level of LDL ("bad") cholesterol; however, this effect may be short-lived. 146,147
If you decide to use cod liver oil as your fish oil supplement, make sure you do not exceed the safe maximum intake of vitamin A and vitamin D . These vitamins are fat soluble, which means that excess amounts tend to build up in your body, possibly reaching toxic levels. The official maximum daily intake of vitamin A is 3,000 mcg for pregnant women as well as other adults. Look at the bottle label to determine how much vitamin A you are receiving. (It is less likely that you will get enough vitamin D to produce toxic effects.)

Interactions You Should Know About

If you are taking warfarin (Coumadin) or heparin, do not take fish oil except on the advice of a physician.

References

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26 Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;2:757-761.

27 Ascherio A, Rimm EB, Stampfer MJ, et al. Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men. N Engl J Med. 1995;332:977-982.

28 Leaf A, Jorgensen MB, Jacobs AK, et al. Do fish oils prevent restenosis after coronary angioplasty? Circulation. 1994;90:2248-2257.

29 Sacks FM, Stone PH, Gibson CM, et al. Controlled trial of fish oil for regression of human coronary atherosclerosis. HARP Research Group. J Am Coll Cardiol. 1995;25:1492-1498.

30 [No authors listed]. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 1999;354:447-455.

31 de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994;343:1454-1459.

32 Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA. 1995;274:1363-1367.

33 Billman GE, Hallaq H, Leaf A. Prevention of ischemia-induced ventricular fibrillation by omega 3 fatty acids. Proc Natl Acad Sci USA. 1994;91:4427-4430.

34 Sellmayer A, Witzgall H, Lorenz RL, et al. Effects of dietary fish oil on ventricular premature complexes. Am J Cardiol. 1995;76:974-977.

35 Nilsen DW, Albrektsen G, Landmark K, et al. Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol. Am J Clin Nutr. 2001;74:50-56.

36 Angerer P, Stork S, Kothny W, et al. Effect of marine omega-3 fatty acids on peripheral atherosclerosis in patients with coronary artery disease—a randomised 2 year intervention trial [abstract]. Eur Heart J. 2001;22(suppl):162.

37 James MJ, Cleland LG. Dietary n-3 fatty acids and therapy for rheumatoid arthritis. Semin Arthritis Rheum. 1997;27:85-97.

38 Volker D, Fitzgerald P, Major G, et al. Efficacy of fish oil concentrate in the treatment of rheumatoid arthritis. J Rheumatol. 2000;27:2343-2346.

39 Harel Z, Biro FM, Kottenhahn RK, et al. Supplementation with omega-3 polyunsaturated fatty acids in the management of dysmenorrhea in adolescents. Am J Obstet Gynecol. 1996;174:1335-1338.

40 Deutch B, Jorgensen EB, Hansen JC. Menstrual discomfort in Danish women reduced by dietary supplements of omega-3 PUFA and B 12 (fish oil or seal oil capsules). Nutr Res. 2000;20:621-631.

41 Stoll AL, Severus WE, Freeman MP, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1999;56:407-412.

42 DiGiacomo RA, Kremer JM, Shah DM. Fish-oil dietary supplementation in patients with Raynaud's phenomenon: a double-blind, controlled, prospective study. Am J Med. 1989;86:158-164.

43 Ringer TV, Hughes GS, Spillers CR, et al. Fish oil blunts the pain response to cold pressor testing in normal males [abstract]. J Am Coll Nutr. 1989;8:435.

44 Bittiner SB, Cartwright I, Tucker WFG, et al. A double-blind, randomised, placebo-controlled trial of fish oil in psoriasis. Lancet. 1988;1:378-380.

45 Tomer A, Kasey S, Connor WE, et al. Reduction of pain episodes and prothrombotic activity in sickle cell disease by dietary n-3 fatty acids. Thromb Haemost. 2001;85:966-974.

46 Walton AJE, Snaith ML, Locniskar M, et al. Dietary fish oil and the severity of symptoms in patients with systemic lupus erythematosus. Ann Rheum Dis. 1991;50:463-466.

47 Donadio JV Jr, Grande JP, Bergstralh EJ, et al. The long-term outcome of patients with IgA nephropathy treated with fish oil in a controlled trial. J Am Soc Nephrol. 1999;10:1772-1777.

48 Peet M, Brind J, Ramchand CN, et al. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res. 2001;49:243-251.

49 Belluzzi A, Brignola C, Campieri M, et al. Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease. N Engl J Med. 1996;334:1557-1560.

50 Lorenz-Meyer H, Bauer P, Nicolay C, et al. Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn's disease. A randomized controlled multicenter trial. Study Group Members (German Crohn's Disease Study Group). Scand J Gastroenterol. 1996;31:778-785.

51 Lorenz R, Weber PC, Szimnau P, et al. Supplementation with n-3 fatty acids from fish oil in chronic inflammatory bowel disease—a randomized, placebo-controlled, double-blind cross-over trial. J Intern Med Suppl. 1989;225:225-232.

52 Iso H, Rexrode KM, Stampfer MJ, et al. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA. 2001;285:301-312.

54 Hibbeln JR, Salem N Jr. Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy. Am J Clin Nutr. 1995;62:1-9.

56 Buck AC, Jenkins A, Lingam K, et al. The treatment of idiopathic recurrent urolithiasis with fish oil (EPA) and evening primrose oil (GLA)—a double blind study. J Urol. 1993;149:253A.

57 Norrish AE, Skeaff CM, Arribas GLB, et al. Prostate cancer risk and consumption of fish oils: a dietary biomarker-based case-control study. Br J Cancer. 1999;81:1238-1242.

58 Behan PO, Behan WM, Horrobin D. Effect of high doses of essential fatty acids on the postviral fatigue syndrome. Acta Neurol Scand. 1990;82:209-216.

59 Warren G, McKendrick M, Peet M. The role of essential fatty acids in chronic fatigue syndrome. A case-controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA. Acta Neurol Scand. 1999;99:112-116.

60 Gerbi A, Maixent JM, Ansaldi JL, et al. Fish oil supplementation prevents diabetes-induced nerve conduction velocity and neuroanatomical changes in rats. J Nutr. 1999;129:207-213.

61 Halsted CH, Ghandi G, Tamura T. Sulfasalazine inhibits the absorption of folates in ulcerative colitis. N Engl J Med. 1981;305:1513-1517.

62 Aslan A, Triadafilopoulos G. Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. Am J Gastroenterol. 1992;87:432-437.

63 Almallah YZ, El-Tahir A, Heys SD, et al. Distal procto-colitis and n-3 polyunsaturated fatty acids: the mechanism(s) of natural cytotoxicity inhibition. Eur J Clin Invest. 2000;30:58-65.

64 Stenson WF, Cort D, Rodgers J, et al. Dietary supplementation with fish oil in ulcerative colitis. Ann Intern Med. 1992;116:609-614.

65 Hawthorne AB, Daneshmend TK, Hawkey CJ, et al. Treatment of ulcerative colitis with fish oil supplementation: a prospective 12-month randomised controlled trial. Gut. 1992;33:922-928.

66 Greenfield SM, Green AT, Teare JP, et al. A randomized controlled study of evening primrose oil and fish oil in ulcerative colitis. Aliment Pharmacol Ther. 1993;7:159-166.

67 Hawthorne AB, Daneshmend TK, Hawkey CJ, et al. Treatment of ulcerative colitis with fish oil supplementation: a prospective 12-month randomised controlled trial. Gut. 1992;33:922-928.

68 Loeschke K, Ueberschaer B, Pietsch A, et al. n-3 fatty acids only delay early relapse of ulcerative colitis in remission. Dig Dis Sci. 1996;41:2087-2094.

69 Thien FC, Woods RK, Walters EH. Oily fish and asthma—a fishy story? Med J Aust. 1996;164:135-136.

70 Arm JP, Thien FC, Lee TH. Leukotrienes, fish-oil, and asthma. Allergy Proc. 1994;15:129-134.

71 Picado C, Castillo JA, Schinca N, et al. Effects of a fish oil enriched diet on aspirin intolerant asthmatic patients: a pilot study. Thorax. 1988;43:93-97.

72 Woods RK, Thien FC, Abramson MJ. Dietary marine fatty acids (fish oil) for asthma. Cochrane Database Syst Rev. 2000;CD001283.

73 Dry J, Vincent D. Effect of a fish oil diet on asthma: results of a one-year double-blind study. Int Arch Allergy Immunol. 1991;95:156-157.

74 Stenius-Aarniala B, Aro A, Hakulinen A, et al. Evening primrose oil and fish oil are ineffective as supplementary treatment of bronchial asthma. Ann Allergy. 1989;62:534-547.

75 Arm J. The effects of dietary supplementation with fish oil on asthmatic responses to antigen. J Allergy Clin Immunol. 1988;81:183.

76 Stenius-Aarniala B, Aro A, Hakulinen A, et al. Symptomatic effects of evening primrose oil, fish oil, and olive oil in patients with bronchial asthma. Ann Allergy. 1985;55:330.

77 Lee TH, Arm JP. Prospects for modifying the allergic response by fish oil diets. Clin Allergy. 1986;16:89-100.

78 Pichard C, Sudre P, Karsegard V, et al. A randomized double-blind controlled study of 6 months of oral nutritional supplementation with arginine and omega-3 fatty acids in HIV-infected patients. Swiss HIV Cohort Study. AIDS. 1998;12:53-63.

79 Scevola D, Oberto L, Faggi A, et al. Fish oil in the treatment of wasting syndrome. Int Conf AIDS. 1996;11:122.

80 Nightingale S, Woo E, Smith AD, et al. Red blood cell and adipose tissue fatty acids in mild inactive multiple sclerosis. Acta Neurol Scand. 1990;82:43-50.

81 Cunnane SC, Ho SY, Dore-Duffy P, et al. Essential fatty acid and lipid profiles in plasma and erythrocytes in patients with multiple sclerosis. Am J Clin Nutr. 1989;50:801-806.

82 Gallai V, Sarchielli P, Trequattrini A, et al. Cytokine secretion and eicosanoid production in the peripheral blood mononuclear cells of MS patients undergoing dietary supplementation with n-3 polyunsaturated fatty acids. J Neuroimmunol. 1995;56:143-153.

83 Goldberg P, Fleming MC, Picard EH. Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Med Hypotheses. 1986;21:193-200.

84 Bates D. Dietary lipids and multiple sclerosis. Ups J Med Sci Suppl. 1990;48:173-187.

85 Conquer JA, Martin JB, Tummon I, et al. Effect of DHA supplementation on DHA status and sperm motility in asthenozoospermic males. Lipids. 2000;35:149-154.

86 Kruger MC, Coetzer H, de Winter R, et al. Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis. Aging (Milano). 1998;10:385-394.

87 Bassey EJ, Littlewood JJ, Rothwell MC, et al. Lack of effect of supplementation with essential fatty acids on bone mineral density in healthy pre- and postmenopausal women: two randomized controlled trials of Efacal v. calcium alone. Br J Nutr. 2000;83:629-635.

88 Richardson AJ, Puri BK. A randomized double-blind, placebo-controlled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:233-239.

89 Voigt RG, Llorente AM, Jensen CL, et al. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr. 2001;139:189-196.

90 Harris WS. N-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997;65(suppl 5):S1645-S1654.

91 Durrington PN, Bhatnagar D, Mackness MI, et al. An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart. 2001;85:544-548.

92 Harris WS. N-3 fatty acids and lipoproteins: comparison of results from human and animal studies. Lipids. 1996;31:243-252.

93 Nenseter MS, Osterud B, Larsen T, et al. Effect of Norwegian fish powder on risk factors for coronary heart disease among hypercholesterolemic individuals. Nutr Metab Cardiovasc Dis. 2000;10:323-330.

94 van Dam M, Stalenhoef AF, Wittekoek J, et al. Efficacy of concentrated n-3 fatty acids in hypertriglyceridaemia: a comparison with gemfibrozil. Clin Drug Invest. 2001;21:175-181.

95 Montori VM, Farmer A, Wollan PC, et al. Fish oil supplementation in type 2 diabetes: a quantitative systematic review. Diabetes Care. 2000;23:1407-1415.

96 Cobiac L, Clifton PM, Abbey M, et al. Lipid, lipoprotein, and hemostatic effects of fish vs fish-oil n-3 fatty acids in mildly hyperlipidemic males. Am J Clin Nutr. 1991;53:1210-1216.

97 Harris WS. N-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 1997;65(suppl 5):S1645-S1654.

98 Dyerberg J. N-3 fatty acids and coronary artery disease: potentials and problems. In: Omega-3, Lipoproteins, and Atherosclerosis. Paris, France: John Libbey Eurotext; 1996; 27: 251-258.

99 Lungershausen YK, Abbey M, Nestel PJ, et al. Reduction of blood pressure and plasma triglycerides by omega-3 fatty acids in treated hypertensives. J Hypertens. 1994;12:1041-1045.

100 Radack K, Deck C, Huster G. The effects of low doses of n-3 fatty acid supplementation on blood pressure in hypertensive subjects. A randomized controlled trial. Arch Intern Med. 1991;151:1173-1180.

101 Singer P, Jaeger W, Wirth M, et al. Lipid and blood-pressure-lowering effect of mackerel diet in man. Atherosclerosis. 1983;49:99-108.

102 Singer P, Melzer S, Goschel M, et al. Fish oil amplifies the effect of propranolol in mild essential hypertension. Hypertension. 1990;16:682-691.

103 Appel LJ, Miller ER III, Seidler AJ, et al. Does supplementation of diet with 'fish oil' reduce blood pressure? A meta-analysis of controlled clinical trials. Arch Intern Med. 1993;153:1429-1438.

104 Whelton PK, Kumanyika SK, Cook NR, et al. Efficacy of nonpharmacologic interventions in adults with high-normal blood pressure: Results from phase 1 of the Trials of Hypertension Prevention. Am J Clin Nutr. 1997;65(suppl 2):S652-S660.

105 Mori TA, Bao DQ, Burke V, et al. Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans. Hypertension. 1999;34:253-260.

106 Guallar E, Hennekens CH, Sacks FM, et al. A prospective study of plasma fish oil levels and incidence of myocardial infarction in US male physicians. J Am Coll Cardiol. 1995;25:387-394.

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

108 Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985;312:1205-1209.

109 Shekelle RB, Missell LV, Paul O, et al. Fish consumption and mortality from coronary heart disease [letter]. N Engl J Med. 1985;313:820-821.

110 Dolecek TA, Granditis G. Dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial (MRFIT). World Rev Nutr Diet. 1991;66:205-216.

111 Kromhout D, Feskens EJ, Bowles CH. The protective effect of a small amount of fish on coronary heart disease mortality in an elderly population. Int J Epidemiol. 1995;24:340-345.

112 Vollset SE, Heuch I, Bjelke E. Fish consumption and mortality from coronary heart disease [letter]. N Engl J Med. 1985;313:820-821.

113 Curb JD, Reed DM. Fish consumption and mortality from coronary heart disease [letter]. N Engl J Med. 1985;313:821-822.

114 Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;2:757-761.

115 Ascherio A, Rimm EB, Stampfer MJ, et al. Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men. N Engl J Med. 1995;332:977-982.

116 Leaf A, Jorgensen MB, Jacobs AK, et al. Do fish oils prevent restenosis after coronary angioplasty? Circulation. 1994;90:2248-2257.

117 Sacks FM, Stone PH, Gibson CM, et al. Controlled trial of fish oil for regression of human coronary atherosclerosis. HARP Research Group. J Am Coll Cardiol. 1995;25:1492-1498.

118 [No authors listed]. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 1999;354:447-455.

119 Angerer P, Stork S, Kothny W, et al. Effect of marine omega-3 fatty acids on peripheral atherosclerosis in patients with coronary artery disease—a randomised 2 year intervention trial [abstract]. Eur Heart J. 2001;22(suppl):162.

120 de Lorgeril M, Renaud S, Mamelle N, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994;343:1454-1459.

121 Siscovick DS, Raghunathan TE, King I, et al. Dietary intake and cell membrane levels of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest. JAMA. 1995;274:1363-1367.

122 Billman GE, Hallaq H, Leaf A. Prevention of ischemia-induced ventricular fibrillation by omega 3 fatty acids. Proc Natl Acad Sci USA. 1994;91:4427-4430.

123 Sellmayer A, Witzgall H, Lorenz RL, et al. Effects of dietary fish oil on ventricular premature complexes. Am J Cardiol. 1995;76:974-977.

124 Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet. 1989;2:757-761.

125 Nilsen DW, Albrektsen G, Landmark K, et al. Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol. Am J Clin Nutr. 2001;74:50-56.

126 James MJ, Cleland LG. Dietary n-3 fatty acids and therapy for rheumatoid arthritis. Semin Arthritis Rheum. 1997;27:85-97.

127 Volker D, Fitzgerald P, Major G, et al. Efficacy of fish oil concentrate in the treatment of rheumatoid arthritis. J Rheumatol . 2000;27:2343-2346.

128 Harel Z, Biro FM, Kottenhahn RK, et al. Supplementation with omega-3 polyunsaturated fatty acids in the management of dysmenorrhea in adolescents. Am J Obstet Gynecol. 1996;174:1335-1338.

129 Deutch B, Jorgensen EB, Hansen JC. Menstrual discomfort in Danish women reduced by dietary supplements of omega-3 PUFA and B 12 (fish oil or seal oil capsules). Nutr Res. 2000;20:621-631.

130 Stoll AL, Severus WE, Freeman MP, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1999;56:407-412.

131 DiGiacomo RA, Kremer JM, Shah DM. Fish-oil dietary supplementation in patients with Raynaud's phenomenon: a double-blind, controlled, prospective study. Am J Med. 1989;86:158-164.

132 Ringer TV, Hughes GS, Spillers CR, et al. Fish oil blunts the pain response to cold pressor testing in normal males [abstract]. J Am Coll Nutr. 1989;8:435.

133 Bittiner SB, Cartwright I, Tucker WFG, et al. A double-blind, randomised, placebo-controlled trial of fish oil in psoriasis. Lancet. 1988;1:378-380.

134 Soyland E, Funk J, Rajka G, et al. Effect of dietary supplementation with very-long-chain n-3 fatty acids in patients with psoriasis. N Engl J Med. 1993;328:1812-1816.

135 Kruger MC, Coetzer H, de Winter R, et al. Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis. Aging (Milano). 1998;10:385-394.

136 Bassey EJ, Littlewood JJ, Rothwell MC, et al. Lack of effect of supplementation with essential fatty acids on bone mineral density in healthy pre- and postmenopausal women: two randomized controlled trials of Efacal v. calcium alone. Br J Nutr. 2000;83:629-635.

137 Walton AJE, Snaith ML, Locniskar M, et al. Dietary fish oil and the severity of symptoms in patients with systemic lupus erythematosus. Ann Rheum Dis. 1991;50:463-466.

138 Clark WF, Parbtani A, Naylor CD, et al. Fish oil in lupus nephritis: clinical findings and methodological implications. Kidney Int. 1993;44:75-86.

139 Clark WF, Parbtani A. Omega-3 fatty acid supplementation in clinical and experimental lupus nephritis. Am J Kidney Dis. 1994;23:644-647.

140 Richardson AJ, Puri BK. A randomized double-blind, placebo-controlled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:233-239.

141 Voigt RG, Llorente AM, Jensen CL, et al. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr. 2001;139:189-196.

142 Harris WS. Dietary fish oil and blood lipids. Curr Opin Lipidol. 1996;7:3-7.

143 Leaf A, Jorgensen MB, Jacobs AK, et al. Do fish oils prevent restenosis after coronary angioplasty? Circulation. 1994;90:2248-2257.

144 Harris WS. Dietary fish oil and blood lipids. Curr Opin Lipidol. 1996;7:3-7.

145 Montori VM, Farmer A, Wollan PC, et al. Fish oil supplementation in type 2 diabetes: a quantitative systematic review. Diabetes Care. 2000;23:1407-1415.

146 Cobiac L, Clifton PM, Abbey M, et al. Lipid, lipoprotein, and hemostatic effects of fish vs fish-oil n-3 fatty acids in mildly hyperlipidemic males. Am J Clin Nutr. 1991;53:1210-1216.

147 Harris WS. Dietary fish oil and blood lipids. Curr Opin Lipidol. 1996;7:3-7.

148 Fenton WS, Dickerson F, Boronow J, et al. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry. 2001;158:2071-2074.

149 Pradalier A, Bakouche P, Baudesson G, et al. Failure of omega-3 polyunsaturated fatty acids in prevention of migraine: a double-blind study versus placebo. Cephalalgia. 2001;21:818-822.

150 Singh RB, Niaz MA, Sharma JP, et al. Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: the Indian experiment of infarct survival. Cardiovasc Drugs Ther. 1997;11:485-491.

151 Yam D, et. al. The effect of omega-3 fatty acids on risk factors for cardiovascular diseases. Harefuah. 2001;140:1156-1158.

152 Bucher HC, Hengstler P, Schindler C, et al. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med. 2002;112:298-304.

153 Schmitz PG, McCloud LK, Reikes ST, et al. Prophylaxis of hemodialysis graft thrombosis with fish oil: double-blind, randomized, prospective trial. J Am Soc Nephrol. 2002;13:184-190.

154 Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002;159:477-479.

155 Vaddadi KS, Soosai E, Chiu E, et al. A randomised, placebo-controlled, double blind study of treatment of Huntington's disease with unsaturated fatty acids. Neuroreport. 2002;13:29-33.

156 Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002;105:1897-1903.

157 Rudra PK, Krokan HE. Cell-specific enhancement of doxorubicin toxicity in human tumour cells by docosahexaenoic acid. Anticancer Res. 2001;21:29-38.

158 Hardman WE, Moyer MP, Cameron IL. Consumption of an omega-3 fatty acids product, INCELL AAFA, reduced side-effects of CPT-11 (irinotecan) in mice. Br J Cancer. 2002;86:983-988.

159 Middleton SJ, Naylor S, Woolner J, et al. A double-blind, randomized, placebo-controlled trial of essential fatty acid supplementation in the maintenance of remission of ulcerative colitis. Aliment Pharmacol Ther. 2002;16:1131-1135.

160 Mori TA, Burke V, Puddey IB, et al. Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. Am J Clin Nutr. 2000;71:1085-1094.

161 Rambjor GS, Walen AI, Windsor SL Eicosapentaenoic acid is primarily responsible for hypotriglyceridemic effect of fish oil in humans. Lipids. 1996;31(suppl):45-49.

162 Agren JJ, Hanninen O, Julkunen A, et al. Fish diet, fish oil and docosahexaenoic acid rich oil lower fasting and postprandial plasma lipid levels. Eur J Clin Nutr. 1996;50:765-771.

163 Childs MT, King IB, Knopp RH. Divergent lipoprotein responses to fish oils with various ratios of eicosapentaenoic acid and docosahexaenoic acid. Am J Clin Nutr. 1990;52:632-639.

164 Davidson MH, Maki KC, Kalkowski J, et al. Effects of docosahexaenoic acid on serum lipoproteins in patients with combined hyperlipidemia: a randomized, double-blind, placebo-controlled trial. J Am Coll Nutr. 1997;16:236-243.

165 Leigh-Firbank EC, Minihane AM, Minihane AM, et al. Eicosapentaenoic acid and docosahexaenoic acid from fish oils: differential associations with lipid responses. Br J Nutr. 2002;87:435-445.

166 Jacobs MN, Santillo D, Johnston PA, et al. Organochlorine residues in fish oil dietary supplements: comparison with industrial grade oils. Chemosphere. 1998;37:1709-1721.

167 Geleijnse JM, Giltay EJ, Grobbee DE, et al. Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J Hypertens. 2002;20:1493-1499.

168 Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002;59:913-919.

169 Emsley R, Myburgh C, Oosthuizen P, et al. Randomized, placebo-controlled study of ethyl-eicosapentaenoic Acid as supplemental treatment in schizophrenia. Am J Psychiatry. 2002;159:1596-1598.

170 Fenton WS, Dickerson F, Boronow J, et al. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry. 2001;158:2071-2074.

171 Nagakura T, Matsuda S, Shichijyo K, et al. Dietary supplementation with fish oil rich in omega-3 polyunsaturated fatty acids in children with bronchial asthma. Eur Respir J. 2000;16:861-865.

172 Harel Z, Gascon G, Riggs S, et al. Supplementation with omega-3 polyunsaturated fatty acids in the management of recurrent migraines in adolescents. J Adolesc Health. 2002;31:154-161.

173 Glueck CJ, McCarren T, Hitzemann R, et al. Amelioration of severe migraine with omega-3 fatty acids: a double-blind, placebo-controlled clinical trial [abstract]. Am J Clin Nutr. 1986;43:710.

174 Geleijnse JM, Giltay EJ, Grobbee DE, et al. Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J Hypertens. 2002;20:1493-1499.

175 Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002;59:913-919.

176 Woodman RJ, Mori TA, Burke V, et al. Effects of purified eicosapentaenoic acid and docosahexaenoic acid on platelet, fibrinolytic and vascular function in hypertensive type 2 diabetic patients. Atherosclerosis. 2003;166:85-93.

177 Mangoni AA, Sherwood RA, Swift CG, et al. Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. J Intern Med. 2002;252:497-503.

178 Marchioli R, Schweiger C, Tavazzi L, et al. Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. Lipids. 2001;36(suppl):119-126.

179 Cleland L, James M, Proudman S. The role of fish oils in the treatment of rheumatoid arthritis. Drugs. 2003;63:845-853.

180 Zanarini MC, Frankenburg FR. Omega-3 Fatty Acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study. Am J Psychiatry. 2003;160:167-169.

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186 Blommers J, De Lange-De Klerk ES, Kuik DJ, et al. Evening primrose oil and fish oil for severe chronic mastalgia: A randomized, double-blind, controlled trial. Am J Obstet Gynecol. 2002;187:1389-1394.

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199 Buckley MS, Goff AD, Knapp WE, et al. Fish oil interaction with warfarin. Ann Pharmacother. 2004;38:50-52.

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201 Romano C, Cucchiara S, Barabino A, et al. Usefulness of omega-3 fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric Crohn's disease: A double-blind, randomized, placebo-controlled study. World J Gastroenterol. 2006;11:7118-21.

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220 Calo L, Bianconi L, Colivicchi F, et al. N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol. 2005;45:1723-1728.

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228 Frangou S, Lewis M, McCrone P, et al. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry. 2006;188:46-50.

229 Silvers KM, Woolley CC, Hamilton FC, et al. Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids. 2005;72:211-218.

230 Freund-Levi YF, Eriksdotter-Jonhagen M, Cederholm T, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD Study. Arch Neurol. 2006;63:1402-1408.

231 Harris WS. The omega-6/omega-3 ratio and cardiovascular disease risk: uses and abuses. Curr Atheroscler Rep. 2006;8:453-459.

232 Sundstrom B, Stalnacke K, Hagfors L, et al. Supplementation of omega-3 fatty acids in patients with ankylosing spondylitis. Scand J Rheumatol. 2006;35:359-362.

233 Wichmann MW, Thul P, Czarnetzki HD, et al. Evaluation of clinical safety and beneficial effects of a fish oil containing lipid emulsion (Lipoplus, MLF541): data from a prospective, randomized, multicenter trial. Crit Care Med. 2007 Jan 25. [Epub ahead of print]

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247 Berger GE, Proffitt TM, McConchie M, et al. Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. J Clin Psychiatry. 2007;68:1867-1875.

248 Jenkins DJ, Josse AR, Beyene J, et al. Fish-oil supplementation in patients with implantable cardioverter defibrillators: a meta-analysis. CMAJ. 2008;178:157-164.

249 Rees AM, Austin MP, Parker GB. Omega-3 fatty acids as a treatment for perinatal depression: randomized double-blind placebo-controlled trial. Aust N Z J Psychiatry. 2008;42:199-205.

250 Jazayeri S, Tehrani-Doost M, Keshavarz SA, et al. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust N Z J Psychiatry. 2008;42:192-198.

251 Van Biervliet S, Devos M, Delhaye T, et al. Oral DHA supplementation in DeltaF508 homozygous cystic fibrosis patients. Prostaglandins Leukot Essent Fatty Acids. 2008 Feb 12.

252 Su KP, Huang SY, Chiu TH, et al. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008 Mar 18.

253 Galarraga B, Ho M, Youssef HM, et al. Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis. Rheumatology (Oxford). 2008 Mar 24.

254 Feagan BG, Sandborn WJ, Mittmann U, et al. Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC Randomized Controlled Trials. JAMA. 2008;299:1690-1697.

255 Hall MN, Chavarro JE, Lee IM, et al. A 22-year prospective study of fish, n-3 fatty acid intake, and colorectal cancer risk in men. Cancer Epidemiol Biomarkers Prev. 2008;17:1136-1143.

256 Damsgaard CT, Frokiaer H, Andersen AD, et al. Fish oil in combination with high or low intakes of linoleic acid lowers plasma triacylglycerols but does not affect other cardiovascular risk markers in healthy men. J Nutr. 2008;138:1061-1066.

257 Micallef MA, Garg ML. The lipid-lowering effects of phytosterols and (n-3) polyunsaturated fatty acids are synergistic and complementary in hyperlipidemic men and women. J Nutr. 2008;138:1086-1090.

258 Ramel A, Martinez A, Kiely M, et al. Beneficial effects of long-chain n-3 fatty acids included in an energy-restricted diet on insulin resistance in overweight and obese European young adults. Diabetologia. 2008 May 20.

259 Appleton KM, Gunnell D, Peters TJ, et al. No clear evidence of an association between plasma concentrations of n-3 long-chain polyunsaturated fatty acids and depressed mood in a non-clinical population. Prostaglandins Leukot Essent Fatty Acids. 2008 Jun 17

260 Chong EW, Kreis AJ, Wong TY, et al. Dietary omega-3 fatty acid and fish intake in the primary prevention of age-related macular degeneration: a systematic review and meta-analysis. Arch Ophthalmol. 2008;126:826-833.

261 Mozaffarian D. Fish and n-3 fatty acids for the prevention of fatal coronary heart disease and sudden cardiac death. Am J Clin Nutr. 2008;87:1991S-1996S.

262 Shidfar F, Keshavarz A, Hosseyni S, et al. Effects of omega-3 fatty acid supplements on serum lipids, apolipoproteins and malondialdehyde in type 2 diabetes patients. East Mediterr Health J. 2008;14:305-313.

263 Olsen SF, Osterdal ML, Salvig JD, et al. Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registry-based follow-up from a randomized controlled trial. Am J Clin Nutr. 2008;88:167-175.

264 Erkkila AT, Schwab US, de Mello VD, et al. Effects of fatty and lean fish intake on blood pressure in subjects with coronary heart disease using multiple medications. Eur J Nutr. 2008 Jul 29.

265 van de Rest O, Geleijnse JM, Kok FJ, et al. Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology. 2008;71:430-438.

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268 Eslick GD, Howe PR, Smith C, et al. Benefits of fish oil supplementation in hyperlipidemia: a systematic review and meta-analysis. Int J Cardiol. 2008 Sep 5.

269 Emsley R, Niehaus DJ, Oosthuizen PP, et al. Safety of the omega-3 fatty acid, eicosapentaenoic acid (EPA) in psychiatric patients: Results from a randomized, placebo-controlled trial. Psychiatry Res. 2008;161:284-291.

270 Zhu FS, Liu S, Chen XM, et al. Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia. World J Gastroenterol. 2008;14:6395-6400.

271 Schubert R, Kitz R, Beermann C, et al. Effect of n-3 polyunsaturated fatty acids in asthma after low-dose allergen challenge. Int Arch Allergy Immunol. 2008 Nov 11.

272 León H, Shibata MC, Sivakumaran S, Dorgan M, Chatterley T, Tsuyuki RT. Effect of fish oil on arrhythmias and mortality: systematic review. BMJ. 2008 Dec 23;337:a2931.

273 Doornbos B, van Goor SA, Dijck-Brouwer DA, Schaafsma A, Korf J, Muskiet FA. Supplementation of a low dose of DHA or DHA+AA does not prevent peripartum depressive symptoms in a small population based sample. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:49-52.

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278 Kowey PR, Reiffel JA, Ellenbogen KA, Naccarelli GV, Pratt CM. Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA. 2010;304(21):2363-2372. Epub 2010 Nov 15.

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280 Andreeva VA, Kesse-Guyot E, Barberger-Gateau P, Fezeu L, Hercberg S, Galan P. Cognitive function after supplementation with B vitamins and long-chain omega-3 fatty acids: ancillary findings from the SU.FOL.OM3 randomized trial. Am J Clin Nutr. 2011;94(1):278-286.

281 Oliver C, Jahnke N. Omega-3 fatty acids for cystic fibrosis. Cochrane Database Syst Rev. 2011;(8):CD002201.

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284 Sarris J, Mischoulon D, Schweitzer I. Omega-3 for bipolar disorder: meta-analyses of use in mania and bipolar depression. J Clin Psychiatry. 2011 Aug 9.

285 Liu T, Korantzopoulos P, Shehata M, Li G, Wang X, Kaul S. Prevention of atrial fibrillation with omega-3 fatty acids: a meta-analysis of randomised clinical trials. Heart. 2011;97(13):1034-1040.

286 Kwak SM, Myung SK, Lee YJ, Seo HG. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012 Apr 9.

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