Essential Fatty Acids Overview

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, 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."

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). ¹ 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.

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. ²

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. ³ 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 ⁴ and reducing blood pressure. ⁵ The reverse may be true for reducing triglyceride levels, but study results are conflicting. ⁶ 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. ⁷

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. ⁸ A major review published in 2004 failed to find trustworthy evidence of benefit, ⁹ and a subsequent study actually found that use of fish oil increasesrisk of sudden death in people with stable heart disease. ¹⁰ 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. ¹¹ Though not entirely consistent, on balance the evidence does suggest that regulalry consuming oily fish or taking omega-3 fatty acid supplements can reduce the risk of cardiovascular events (eg, heart attacks) and deaths. ¹² 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. ¹³ 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 increasedrisk 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.

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. ¹⁴ 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%. ¹⁵ 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. ¹⁶ 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 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. ¹⁷

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. ¹⁸ Fish oil has been specifically studied for reducing triglyceride levels in people with diabetes , and it appears to do so safely and effectively. ¹⁹ It also seems to remain effective in individuals who are already using statin drugs to control lipid levels (both people with and without diabetes). ²⁰ However, one study found that the standard drug gemfibrozil is more effective than fish oil for reducing triglycerides. ²¹ 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. ²² 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 , ²³ although not all studies have found a positive effect. ²⁴ Studies contradict one another on whether fish oil can lower blood pressure , ²⁵ but on balance the supplement does seem to exert a modest positive effect. ²⁶ 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. ²⁷ Evidence is conflicting on whether fish oil helps prevent heart arrhythmias. ²⁸ A large Italian trial involving almost 7,000 subjects found that fish oil may modestly reduce the risk of death or admission to the hospital for cardiovascular reasons in patients suffering from congestive heart failure . ²⁹ Fish oil may slightly reduce heart rate. ³⁰ 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 . ³¹ At least one small study suggests that it may help rheumatoid arthritis patients lower their dose of nonsteroidal anti-inflammatory medication (eg, ibuprofen). ³² The benefits of the fish oil effect may be enhanced by a vegetarian diet. ³³ Simultaneous supplementation with olive oil (about two teaspoons daily) may further increase the benefits. ³⁴ 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. ³⁵ 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. ³⁶ 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. ³⁷ 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. ³⁸

Depression

A 4-week, double-blind, placebo-controlled trial evaluated the potential benefits of fish oil in 20 individuals with depression . ³⁹ 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. ⁴⁰ Similar add-on benefits were also seen in other double-blind studies of ethyl-EPA or mixed essential fatty acids. ⁴¹ However, one study failed to find benefit with fish-oil as an add-on treatment. ⁴² Another double-blind study failed to find DHA alone helpful for depression. ⁴³ 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. ⁴⁴ The effectiveness of fish oil supplementation in treating or preventing peripartum depression is, as of yet, unclear. A small preliminary study of women found that fish oil was significantly more effective than placebo at alleviating post-partum depression. ⁴⁵ However, another small, placebo-controlled study was unable to show a benefit in women suffering from depression whether before or after delivery. ⁴⁶ In addition, a 2009 trial of 182 pregnant women with suspected low intake of docosahexaenoic acid (DHA) found that daily DHA supplementation (with or without arachidonic acid) did not reduce risk of postpartum depression compared to placebo. ⁴⁷

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 . ⁴⁸ 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. ⁴⁹ However, a 12-month, double-blind trial of 42 postmenopausal women found no benefit. ⁵⁰ 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. ⁵¹ 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. ⁵² However, two small studies failed to find fish oil helpful for lupus nephritis (kidney damage caused by lupus). ⁵³

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. ⁵⁴ 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. ⁵⁵ In a double-blind, placebo-controlled trial of children already using stimulant therapy, addition of DHA for 4 months failed to further improve symptoms. ⁵⁶

1. McKenney JM, Sica D. Prescription omega-3 fatty acids for the treatment of hypertriglyceridemia. Am J Health Syst Pharm. 64(6):595-605.
2. Harris WS. The omega-6/omega-3 ratio and cardiovascular disease risk: uses and abuses. Curr Atheroscler Rep. 8(6):453-9.
3. Theobald HE, Goodall AH, Sattar N, Talbot DC, Chowienczyk PJ, Sanders TA. Low-dose docosahexaenoic acid lowers diastolic blood pressure in middle-aged men and women. J Nutr. 137(4):973-8.
4. Woodman RJ, Mori TA, Burke V, Puddey IB, Barden A, Watts GF, Beilin LJ. Effects of purified eicosapentaenoic acid and docosahexaenoic acid on platelet, fibrinolytic and vascular function in hypertensive type 2 diabetic patients. Atherosclerosis. 166(1):85-93.
5. 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.
6. Mori TA, Burke V, Puddey IB, Watts GF, O'Neal DN, Best JD, Beilin LJ. 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. 71(5):1085-94.
7. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 65(5 Suppl):1645S-1654S.
8. 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.
9. Hooper L, Thompson RL, Harrison RA, Summerbell CD, Moore H, Worthington HV, Durrington PN, Ness AR, Capps NE, Davey Smith G, Riemersma RA, Ebrahim SB. Omega 3 fatty acids for prevention and treatment of cardiovascular disease. Cochrane Database Syst Rev. (4):CD003177.
10. Burr ML, Dunstan FD, George CH. Is fish oil good or bad for heart disease? Two trials with apparently conflicting results. J Membr Biol. 206(2):155-63.
11. León H, Shibata MC, Sivakumaran S, Dorgan M, Chatterley T, Tsuyuki RT. Effect of fish oil on arrhythmias and mortality: systematic review. BMJ. 337():a2931.
12. Mozaffarian D. Fish and n-3 fatty acids for the prevention of fatal coronary heart disease and sudden cardiac death. Am J Clin Nutr. 87(6):1991S-6S.
13. Zhao YT, Chen Q, Sun YX, Li XB, Zhang P, Xu Y, Guo JH. Prevention of sudden cardiac death with omega-3 fatty acids in patients with coronary heart disease: a meta-analysis of randomized controlled trials. Ann Med. 41(4):301-10.
14. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 369(9567):1090-8.
15. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr. 65(5 Suppl):1645S-1654S.
16. Eslick GD, Howe PR, Smith C, Priest R, Bensoussan A. Benefits of fish oil supplementation in hyperlipidemia: a systematic review and meta-analysis. Int J Cardiol. 136(1):4-16.
17. Hartweg J, Farmer AJ, Holman RR, Neil A. Potential impact of omega-3 treatment on cardiovascular disease in type 2 diabetes. Curr Opin Lipidol. 20(1):30-8.
18. 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. 138(6):1086-90.
19. 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. 312(19):1205-9.
20. Montori VM, Farmer A, Wollan PC, Dinneen SF. Fish oil supplementation in type 2 diabetes: a quantitative systematic review. Diabetes Care. 23(9):1407-15.
21. 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.
22. Cobiac L, Clifton PM, Abbey M, Belling GB, Nestel PJ. Lipid, lipoprotein, and hemostatic effects of fish vs fish-oil n-3 fatty acids in mildly hyperlipidemic males. Am J Clin Nutr. 53(5):1210-6.
23. 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.
24. Finnegan YE, Howarth D, Minihane AM, et al. Plant and marine derived (n-3) polyunsaturated fatty acids do not affect blood coagulation and fibrinolytic factors in moderately hyperlipidemic humans. J Nutr. 2003;133:2210-2213.
25. Lungershausen YK, Abbey M, Nestel PJ, Howe PR. Reduction of blood pressure and plasma triglycerides by omega-3 fatty acids in treated hypertensives. J Hypertens. 12(9):1041-5.
26. Geleijnse JM, Giltay EJ, Grobbee DE, Donders AR, Kok FJ. Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J Hypertens. 20(8):1493-9.
27. 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.
28. Calò L, Bianconi L, Colivicchi F, Lamberti F, Loricchio ML, de Ruvo E, Meo A, Pandozi C, Staibano M, Santini M. N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol. 45(10):1723-8.
29. Gissi-HF Investigators, Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 372(9645):1223-30.
30. Mozaffarian D, Geelen A, Brouwer IA, Geleijnse JM, Zock PL, Katan MB. Effect of fish oil on heart rate in humans: a meta-analysis of randomized controlled trials. Circulation. 112(13):1945-52.
31. James MJ, Cleland LG. Dietary n-3 fatty acids and therapy for rheumatoid arthritis. Semin Arthritis Rheum. 1997;27:85-97.
32. Galarraga B, Ho M, Youssef HM, Hill A, McMahon H, Hall C, Ogston S, Nuki G, Belch JJ. Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis. Rheumatology (Oxford). 47(5):665-9.
33. Adam O, Beringer C, Kless T, Lemmen C, Adam A, Wiseman M, Adam P, Klimmek R, Forth W. Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. Rheumatol Int. 23(1):27-36.
34. Berbert AA, Kondo CR, Almendra CL, Matsuo T, Dichi I. Supplementation of fish oil and olive oil in patients with rheumatoid arthritis. Nutrition. 21(2):131-6.
35. Harel Z, Biro FM, Kottenhahn RK, Rosenthal SL. Supplementation with omega-3 polyunsaturated fatty acids in the management of dysmenorrhea in adolescents. Am J Obstet Gynecol. 174(4):1335-8.
36. 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.
37. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry. 56(5):407-12.
38. Frangou S, Lewis M, McCrone P. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry. 188():46-50.
39. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 159(3):477-9.
40. 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. 59(10):913-9.
41. Su KP, Huang SY, Chiu CC, Shen WW. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol. 13(4):267-71.
42. Silvers KM, Woolley CC, Hamilton FC, Watts PM, Watson RA. Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids. 72(3):211-8.
43. Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HF, Puryear LJ. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry. 160(5):996-8.
44. van de Rest O, Geleijnse JM, Kok FJ, van Staveren WA, Hoefnagels WH, Beekman AT, de Groot LC. Effect of fish-oil supplementation on mental well-being in older subjects: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 88(3):706-13.
45. Su KP, Huang SY, Chiu TH, Huang KC, Huang CL, Chang HC, Pariante CM. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 69(4):644-51.
46. 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. 42(3):199-205.
47. 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.
48. 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. 86(2):158-64.
49. Kruger MC, Coetzer H, de Winter R, Gericke G, van Papendorp DH. Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis. Aging (Milano). 10(5):385-94.
50. Bassey EJ, Littlewood JJ, Rothwell MC, Pye DW. 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. 83(6):629-35.
51. 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.
52. Duffy EM, Meenagh GK, McMillan SA, Strain JJ, Hannigan BM, Bell AL. The clinical effect of dietary supplementation with omega-3 fish oils and/or copper in systemic lupus erythematosus. J Rheumatol. 31(8):1551-6.
53. Clark WF, Parbtani A, Naylor CD, Levinton CM, Muirhead N, Spanner E, Huff MW, Philbrick DJ, Holub BJ. Fish oil in lupus nephritis: clinical findings and methodological implications. Kidney Int. 44(1):75-86.
54. 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. 26(2):233-9.
55. Stevens L, Zhang W, Peck L, Kuczek T, Grevstad N, Mahon A, Zentall SS, Arnold LE, Burgess JR. EFA supplementation in children with inattention, hyperactivity, and other disruptive behaviors. Lipids. 38(10):1007-21.
56. Voigt RG, Llorente AM, Jensen CL, Fraley JK, Berretta MC, Heird WC. A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder. J Pediatr. 139(2):189-96.