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FISH OIL

임기종 2011. 9. 8. 17:27
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Fish Oil

 

Supplement Forms/Alternate Names

• Docosahexaenoic Acid (DHA); Eicosapentaenoic Acid (EPA); Omega-3 Fatty Acids; Omega-3 Oil(s)

Principal Proposed Uses

• Heart Disease Prevention; Rheumatoid Arthritis

Other Proposed Uses

• Allergies; Alzheimer’s Disease; Angina; Ankylosing Spondylitis; Asthma; Attention Deficit and Hyperactivity Disorder (ADHD); Bipolar Disorder (Manic-depressive Illness); Borderline Personality Disorder; Cancer Treatment Support; Chronic Fatigue Syndrome; Crohn's Disease; Depression; Diabetic Neuropathy; Dysmenorrhea (Menstrual Pain); Eczema (Prevention); Epilepsy; Gout; HIV Support; Hypertension; Kidney Stones; Liver Disease; Lupus; Male Infertility; Migraine Headaches; Multiple Sclerosis; Osteoporosis; Pregnancy Support; Prevention of Premature Birth; Prostate Cancer Prevention; Psoriasis; Raynaud's Phenomenon; Retinitis Pigmentosa; Schizophrenia; Sickle-cell Anemia; Strokes (Prevention); Surgery Support; Ulcerative Colitis; Undesired Weight Loss Caused by Cancer

 

Page Navigation

Requirements/Sources

Therapeutic Dosages

Therapeutic Uses

What Is the Scientific Evidence for Fish Oil?

Safety Issues

Interactions You Should Know About

References

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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.

생선기름은 오메가-3 지방산을 가지고 있는데 이 지방산에는 2가지 중요한 필수 지방산으로 되어 있다.( 오메가-6 지방산은 다른 종류이다) 필수 지방산은 특별한 지방으로 인체가 최적의 건강을 유지하는데 필요하다.

 

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.

오메가-3 지방산의 잠재적 치료효과에 있어 관심사는 이누이트 족(에스키모)에 대한 연구에서 이지장산이 발견이 되자 연구가 시작됐다. 이누이트 족들은 그들의 식사에 엄청난 양의 지방을 섭취하는데 이 지방은 생선, 물개,고래 등으로부터 얻어지는 것으로 이들은 거의 심장질환이 일어나지않는다. 이는 이들 지방에 오메가 -3 지방산의 함량이 매우 높기 때문인 것으로 추측된다.

 

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, while somewhat positive, 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."

결정적인 연구결과에서 생선기름에서 발견되는 오메가-3 지방산이 심장질환과 발작의 위험을 줄이는데 다양한 효과가 있음이 밝혀졌다. 그렇지만

 

 

 

In addition, a slightly modified form of fish oil (ethyl-omega-3 fatty acids) has been approved by the FDA as a treatment for hypertriglyceridemia (high triglycerides).237 This specially processed product, sold under the trade name Omacor, is widely advertised as more effective than ordinary fish oil. However, it should be noted that Omacor has undergone relatively little study itself; the physician prescribing information notes only two small trials to support its effectiveness for this use. This is a far lower level of evidence than usually required for drug approval and also substantially lower than the body of evidence supporting standard fish oil as a treatment for high triglycerides.

 

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.

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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

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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

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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, if it exists, 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. However, the best studied use of fish oil-related products for depression (its best studied use for psychiatric conditions) has shown disappointing results as larger trials have come in.154,168,188,192,193,207,228,234,241,242,244 Preliminary, and not altogether consistent, evidence hints that high doses of fish oil may produce benefits in bipolar disorder (more commonly known as manic-depressive illness), reducing risk of relapse and improving emotional state.41,205,242 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 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),42,43 sickle-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,60 allergies, 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 However, there is some evidence that use of fish oil could help prevent exercise-induced asthma in athletes.196,212 one study found that fish oil did not benefit the lung function of patients with cystic fibrosis.251

 

Similarly, 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

Studies of fish oil have failed to find it helpful for Alzheimer's disease, whether for slowing its progression or improving symptoms.230,240

Use of essential fatty acids in the omega-3 family has also shown some promise for the treatment of non-alcoholic fatty liver.245

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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 These contradictory results suggest that fish oil's benefit in heart disease, if any, is slight.

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% to 30%.90-93,151,256 A slightly modified form of fish oil (ethyl-omega-3 fatty acids) has been approved by the FDA as a treatment for elevated triglycerides. However, in some studies, use of fish oil has markedly raised LDL ("bad") cholesterol, which might offset some of the benefit.

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

 

Fish oil has been specifically studied for reducing triglyceride levels in people with diabetes, and it appears to do so safely and effectively.3 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 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

 

Evidence is conflicting on whether fish oil helps prevent heart arrhythmias.220-224,248

 

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 on 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.

 

 

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.

 

Another small study found that ethyl-EPA (a modified form of EPA) is helpful for the depressive phase of bipolar disease.227

 

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

 

Additionally, a small preliminary study of women found that fish oil was significantly more effective than placebo at alleviating post-partum 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

 

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.

 

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 dropout rate makes the results of this trial somewhat unreliable. 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

 

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

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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; 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 probably 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 also raise the level of LDL ("bad") cholesterol; it is possible, however, that this effect may be short-lived, and that levels return to normal with continued use.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.)

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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.

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References

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

2. Shekelle RB, Shryock AM, Paul O, et al. Diet, serum cholesterol, and death from coronary heart disease. The Western Electric Study. N Engl J Med. 1981;304:65-70.

3. 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.

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

5. 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.

6. 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.

7. 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.

8. 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.

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

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

11. 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.

12. von Schacky C, Angerer P, Kothny W, et al. The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999;130:554-562.

13. 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.

14. 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.

15. 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.

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

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

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

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

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 crial. 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.

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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.

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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.

 

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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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190. Grundt H, Nilsen DW, Mansoor MA, et al. Reduction in homocysteine by n-3 polyunsaturated fatty acids after 1 year in a randomised double-blind study following an acute myocardial infarction: no effect on endothelial adhesion properties. Pathophysiol Haemost Thromb. 2003;33:88-95.

 

191. Duffy EM, Meenagh GK, McMillan SA, et al. The clinical effect of dietary supplementation with omega-3 fish oils and/or copper in systemic lupus erythematosus. J Rheumatol. 2004;31:1551-1556.

 

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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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213. Itomura M, Hamazaki K, Sawazaki S, et al. The effect of fish oil on physical aggression in schoolchildren - a randomized, double-blind, placebo-controlled trial. J Nutr Biochem. 2005;16:163-171.

 

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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.

 

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

 

222. Geelen A, Brouwer IA, Schouten EG, et al. Effects of n-3 fatty acids from fish on premature ventricular complexes and heart rate in humans. Am J Clin Nutr. 2005;81:416-20.

 

223. Raitt MH, Connor WE, Morris C, et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA. 2005;293:2884-2891.

 

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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]

 

234. Hallahan B, Hibbeln JR, Davis JM, et al. Omega-3 fatty acid supplementation in patients with recurrent self-harm: single-centre double-blind randomised controlled trial. Br J Psychiatry. 2007;190:118-122.

 

235. Schwellenbach LJ, Olson KL, McConnell KJ, et al. The triglyceride-lowering effects of a modest dose of docosahexaenoic acid alone versus in combination with low-dose eicosapentaenoic acid in patients with coronary artery disease and elevated triglycerides. J Am Coll Nutr. 2006;25:480-485.

 

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238. Theobald HE, Goodall AH, Sattar N, et al. Low-dose docosahexaenoic acid lowers diastolic blood pressure in middle-aged men and women. J Nutr. 2007;137:973-978.

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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.

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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.

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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.

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