Omega-3

• How It Works

  Omega-3 fatty acids have not been shown to prevent cancer.

  Omega-3 fatty acids are obtained from fish oil. They have been used to protect against cardiovascular events such as heart attack. Studies have shown that omega-3 fatty acids can be taken up by the fatty deposits that line the arteries, thereby improving the stability of those deposits. Omega-3 fatty acids do not seem to affect the clotting of blood. Omega-3 fatty acids may reduce inflammation by decreasing some of the signals that cells send to each other. It is thought that patients with colitis, asthma, cystic fibrosis and those before surgery may benefit from this reduced inflammatory effect. Omega-3 fatty acid supplements have been shown to be absorbed by the skin and protect it against ultra-violet radiation damage.

  Omega-3 fatty acids may reduce the risk of breast cancer, but may increase the risk of prostate cancer.

• Purported Uses
  • To treat asthma
    A review of published trials shows no effect of omega-3 on asthma.
  • To treat fatty deposits on the inside of arteries (atherosclerosis)
    Studies have shown that omega-3 can increase the stability of these deposits, which may make them less dangerous.
  • To protect against cardiovascular disease
    Studies have shown that omega-3 can reduce the frequency and severity of cardiovascular events such as heart attacks.
  • To improve the symptoms of colitis
    Studies have shown that omega-3 may improve the symptoms associated with colitis.
  • To alleviate the symptoms associated with cystic fibrosis
    One study showed an improvement in breathing parameters for patients taking omega-3 supplements, however other trials have shown no benefit. Larger studies are necessary to determine the actual effect.
  • To treat symptoms of lupus
    A small study found a reduction in symptoms of lupus in patients who took fish oil compared with those on placebo. More trials are needed to support this claim.
  • To alleviate depression
    A study of a few thousand people in Finland found that people who ate less fish were more likely to have the symptoms of depression than those who ate more fish. Other studies have also shown a connection between omega-3 levels and depression scores, however few studies have attempted to determine if omega-3 supplementation affects depression symptoms.
  • To lower cholesterol levels
    A review of published trials of omega-3 for lowering cholesterol levels in patients with diabetes found that while omega-3 lowered triglyceride levels, it also raised LDL cholesterol levels.
  • To treat psychiatric disorders
    A recent study showed that omega-3 may be useful in reducing the risk of progression to psychiatric disorders.
  • To protect the skin against ultra-violet radiation damage.
    Studies have shown omega-3 to be incorporated into the skin and offer protection against UV damage which may reduce cancer risk.
  • To prevent cancer
    Omega-3 fatty acids may reduce the risk of breast cancer, but may increase the risk of prostate cancer.
• Do Not Take If
  • You are taking Warfarin: Elevated INR has been reported when taken with fish oil supplements (2 g/day). INR decreased after reducing supplement intake.
    High dose omega-3 supplements have been associated with subdural hematoma [6g/day] requiring craniotomy; and irreversible warfarin-induced coagulopathy following blunt head trauma.
  • You are taking glucocorticoids: Omega-3 supplements worsened some side effects caused by glucocorticoids in a mice model. Clinical significance is not known.
• Side Effects
  • Fishy aftertaste, loose stools and nausea have been reported following intake of large doses of omega-3 fatty acids.
  • Gastrointestinal events (diarrhea, nausea, and abdominal pain), and atrial fibrillation have been reported with EPA intake in a clinical study.
• Special Point

  Omega-3 fatty acids should not be confused with omega-6 fatty acids, such as those found in evening primrose oil and borage oil, which have different effects in the body.

• Brand Name

  megaven®, Max-EPA

• Clinical Summary

  A type of polyunsaturated fatty acid (PUFA) derived mainly from fish oil, omega-3 fatty acids are used as a dietary supplement for depression, to lower cholesterol, and to reduce the risk of heart attack. A large survey of Finnish adults found that depressive symptoms were significantly higher among infrequent fish consumers ⁽¹⁾ and other studies have shown that individuals with major depression have marked depletions in omega-3 fatty acids ⁽²⁾. However, omega-3 fatty acid supplementation did not relieve depression in adults with major depression ⁽³⁾, mild to moderate depression ⁽⁴⁾, or perinatal depression ⁽⁵⁾, and yielded mixed results in those with schizophrenia ⁽²³⁾. But data from a randomized trial suggest that omega-3 may be useful in reducing the risk of progression to psychiatric disorders and as a safe preventive measure in young adults at risk for psychotic conditions ⁽³⁵⁾.

  Supplementation with docosahexaenoic acid (DHA) improved learning and memory function in age-related cognitive decline ⁽⁴¹⁾. However in a large long-term study of omega-3 supplementation with or without multidomain lifestyle interventions of physical activity, cognitive training, and nutritional advice, there were no significant effects on cognitive decline in elderly adults with memory complaints ⁽⁵²⁾. Consumption of fish oil during pregnancy also did not improve cognitive or language outcomes in early childhood  ⁽³⁷⁾ and does not improve intelligence ⁽⁴²⁾. Other studies of omega-3 fatty acid supplementation and cognition in young children ⁽⁶⁾ and elderly subjects ⁽⁷⁾ are inconclusive.

  Omega-3 fatty acid supplementation lowers cholesterol ^(8) (33) and may reduce recurrence in patients with a history of stroke ⁽³²⁾. In individuals with cardiovascular risk factors, omega-3 supplementation improved cardiometabolic profiles ⁽⁵³⁾. However, it does not lower the risk of cardiovascular disease events ⁽⁹⁾. Omega-3 may help patients with ulcerative colitis ⁽¹⁰⁾, but was ineffective in the treatment of Crohn’s disease ⁽¹³⁾. In adults with rheumatoid arthritis, reductions in NSAID use were reported after omega-3 fatty acid supplementation ⁽¹⁴⁾; Omega-3 may also be effective in reducing NSAID-associated gastroduodenal damage ⁽⁴⁷⁾. Other studies indicate that omega-3 may lower the magnitude of the body’s inflammatory response ⁽¹⁸⁾, and can reduce sensitivity to sunburn ⁽²⁰⁾ and to ultraviolet radiation ⁽⁴⁴⁾. Reviews of trials using omega-3 fatty acids have shown possible benefits for patients with cystic fibrosis ⁽²¹⁾, but no benefit in those with asthma ⁽²²⁾. Dietary supplementation with fish oil may help reduce the symptoms of systemic lupus erythematosus ⁽²⁴⁾.

  In type 1 diabetic patients, long-term omega-3 supplementation had positive effects on neuropathy, as measured by increases in corneal nerve fiber length ⁽⁵⁴⁾. But among patients with dry eye disease, supplementation did not have a significant benefit ⁽⁶⁰⁾. Findings of a systematic review support benefits of polyunsaturated omega-3 fatty acid consumption on insulin sensitivity and adipocyte function ⁽⁴⁵⁾. However in a recent study among insulin-resistant adults, high-dose omega-3 supplementation did not improve features associated with metabolic syndrome such as adipose tissue lipolysis or inflammation ⁽⁵⁵⁾. In another study, DHA was found more effective compared to eicosapentanoic acid (EPA) in modulating indicators of inflammation and blood lipids ⁽⁵⁰⁾. In women with gestational diabetes, omega-3 fatty acids and vitamin E co-supplementation improved some markers of inflammation and oxidative stress as well as incidence of newborn hyperbilirubinemia ⁽⁵⁶⁾.

  In hemodialysis patients, omega-3 supplementation significantly reduced serum creatinine ⁽⁵⁷⁾, but did not reduce arteriovenous fistula failure ⁽⁵⁸⁾.

  Data on omega-3 fatty acid supplementation for cancer prevention are inconclusive. It may reduce colon cancer risk ⁽¹¹⁾ and improve immune response in patients undergoing colorectal cancer resection ⁽¹²⁾, but did not affect cancer outcomes ^(15) (43), although data from a prospective study suggest its association with reduced occurrence of renal cell carcinoma in women ⁽¹⁶⁾. Fish oil supplementation may lower the risk of breast cancer ⁽³⁶⁾. However, according to data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT), high blood concentrations of omega-3 are associated with increased risk of prostate cancer ⁽¹⁷⁾. In patients with sporadic colorectal neoplasia, EPA supplementation did not affect reductions in the proportion of patients with at least one colorectal adenoma when compared to aspirin or placebo ⁽⁶¹⁾. Also, in the prevention trial VITAL, supplementation with omega-3s did not lower incidence of invasive cancer or major cardiovascular events compared to placebo ⁽⁶²⁾.

  Preliminary findings suggest fish oil supplementation increases chemotherapy efficacy, improves survival ⁽³⁸⁾, and helps to maintain weight and muscle mass ⁽³⁹⁾ in patients with nonsmall cell lung cancer (NSCLC). However in patients with gastric cancer, perioperative immunonutrition via an EPA-supplemented diet did not reduce bodyweight loss after total gastrectomy compared with a standard diet ⁽⁵⁹⁾. An EPA-enriched oral supplement improved tolerability of chemotherapy in patients with advanced colorectal cancer ⁽⁴⁰⁾. And when combined with chemotherapy, fish oil supplementation may delay tumor progression in patients with colorectal cancer ⁽⁴⁹⁾.

• Food Sources
  • Fish Oil
  • Krill Oil
  • Cod Liver Oil
  • Flaxseed Oil
  • Linseed Oil
  • Walnuts
  • Chia seeds
• Purported Uses
  • Asthma
  • Atherosclerosis
  • Cancer prevention
  • Cardiovascular disease
  • Colitis
  • Cystic fibrosis
  • Depression
  • High cholesterol
  • Lupus symptoms
  • Schizophrenia
• Mechanism of Action

  Omega-3 fatty acids are polyunsaturated fatty acids containing two or more double bonds in their acyl chain and a double bond on carbon number ^(3) (26). Changes in omega-3 fatty acid blood levels have been associated with cardiovascular disease and depression ⁽²⁷⁾. The cardioprotective effects of omega-3 fatty acids likely are due its ability to be incorporated into and thereby enhance the stability of atherosclerotic plaques ⁽²⁶⁾. Increasing the intake of polyunsaturated fatty acids has been shown to increase lipid peroxidation. Supplementation with omega-3 fatty acids, therefore, may increase oxidative stress on the body. Studies have shown that mucosal alpha-tocopherol levels decrease upon omega-3 fatty acid supplementation, which researchers believe may result from the body’s attempt to counteract the added oxidative burden ⁽¹¹⁾. Besides reducing serum antioxidant levels, little is known about how this added oxidative stress affects the body.

  Omega-3 fatty acid supplementation has been shown to decrease IL-6 ⁽¹⁸⁾ and tumor necrosis factor-alpha ⁽²⁸⁾ levels while leaving most other mononuclear cell functions unaffected ⁽²⁹⁾. Omega-3 fatty acids may also reduce inflammation in patients with ulcerative colitis by reducing rectal dialysate leukotriene B4 ⁽¹⁰⁾. Because of their anti-inflammatory effects, omega-3 fatty acids were thought to benefit patients with asthma ⁽²²⁾ and cystic fibrosis ⁽²¹⁾, but data are inconclusive.

  Increasing PUFA intake in pregnant women increases PUFA concentration but not cytokine concentration in human milk ⁽³⁰⁾. Omega-3 fatty acid supplementation provides protection against ultra-violet radiation-induced erythema and p53 expression, a biomarker of DNA damage ⁽²⁰⁾.

• Adverse Reactions
  • Fishy aftertaste ⁽¹¹⁾ and loose stools and nausea ⁽³¹⁾ have been reported following intake of large doses of omega-3 fatty acids.
  • Gastrointestinal events (diarrhea, nausea, and abdominal pain), and atrial fibrillation have been reported with EPA intake in a clinical study ⁽⁶¹⁾.
• Herb-Drug Interactions
  • Warfarin: Elevated INR has been reported when taken with fish oil supplements (2 g/day). INR decreased after reducing supplement intake ⁽³⁴⁾.
    High dose omega-3 supplements have been associated with subdural hematoma [6g/day] requiring craniotomy ⁽⁶³⁾; and irreversible warfarin-induced coagulopathy following blunt head trauma ⁽⁶⁴⁾.
  • Glucocorticoids: Omega-3 supplementation potentiated some adverse effects of glucocorticoids in a murine model. Clinical relevance is not known ⁽⁴⁶⁾.
• Herb Lab Interactions
  • In a study of heart transplant recipients, omega-3 supplementation was found to decrease vitamin E and beta-carotene levels while increasing TNF-alpha ⁽²⁸⁾.
  • Conclusions of a meta-analysis indicate that high levels of omega-3s help reduce triglycerides, and increase LDL cholesterol ⁽⁹⁾.
  • Doses higher than 3 grams per day may increase bleeding time ⁽²⁵⁾.
• References

  1. Tanskanen A, Hibbeln JR, Tuomilehto J, Uutela A, Haukkala A, Viinamaki H et al. Fish consumption and depressive symptoms in the general population in Finland. Psychiatr.Serv. 2001;52:529-31.

  2. Mischoulon D,.Fava M. Docosahexanoic acid and omega-3 fatty acids in depression. Psychiatr. Clin North Am 2000;23:785-94.

  3. Grenyer BF, Crowe T, Meyer B, et al. Fish oil supplementation in the treatment of major depression: a randomised double-blind placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 2007 Oct 1;31(7):1393-6.

  4. Rogers PJ, Appleton KM, Kessler D, et al. No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial. Br J Nutr. 2008 Feb;99(2):421-31.

  5. 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 Mar;42(3):199-205

  6. Ryan AS, Nelson EB. Assessing the effect of docosahexaenoic acid on cognitive functions in healthy, preschool children: a randomized, placebo-controlled, double-blind study. Clin Pediatr (Phila) 2008 May;47(4):355-62.

  7. van de Rest O, Geleijnse JM, Kok FJ, et al. Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology 2008 Aug 5;71(6):430-8.

  8. Kabir M, Skurnik G, Naour N, et al. Treatment for 2 mo with n 3 polyunsaturated fatty acids reduces adiposity and some atherogenic factors but does not improve insulin sensitivity in women with type 2 diabetes: a randomized controlled study. Am J Clin Nutr 2007 Dec;86(6):1670-9.

  9. Rizos E, Ntzani E, Bika E, et al. Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events: A Systematic Review and Meta-analysis. JAMA. 2012;308(10):1024-1033.

  10. Stenson WF, Cort D, Rodgers J, Burakoff R, DeSchryver-Kecskemeti K, Gramlich TL et al. Dietary supplementation with fish oil in ulcerative colitis. Ann.Intern.Med 1992;116:609-14.

  11. Anti M, Armelao F, Marra G, Percesepe A, Bartoli GM, Palozza P et al. Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas. Gastroenterology 1994;107:1709-18.

  12. Liang B, Wang S, Ye YJ, et al. Impact of postoperative omega-3 fatty acid-supplemented parenteral nutrition on clinical outcomes and immunomodulations in colorectal cancer patients. World J Gastroenterol. 2008;14(15):2434-9

  13. 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 Apr 9;299(14):1690-7.

  14. 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 May;47(5):665-9.

  15. MacLean CH, et al. Effects of Omega-3 Fatty Acids on Cancer Risk. JAMA 2006; 295(4).

  16. Wolk A, Larsson SC, Johansson J, Ekman P. Long-term fatty fish consumption and renal cell carcinoma incidence in women. JAMA 2006;296(11):1371-1376.

  17. Brasky TM, Darke AK, Song X, et al. Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial. J Natl Cancer Inst. 2013 Aug 7;105(15):1132-41.

  18. Weiss G, Meyer F, Matthies B, Pross M, Koenig W, Lippert H. Immunomodulation by perioperative administration of n-3 fatty acids. Br J Nutr 2002;87 Suppl 1:S89-S94.

  19. Heller AR, Fischer S, Rossel T, Geiger S, Siegert G, Ragaller M et al. Impact of n-3 fatty acid supplemented parenteral nutrition on haemostasis patterns after major abdominal surgery. Br J Nutr 2002;87 Suppl 1:S95-101.

  20. Rhodes LE, Shahbakhti H, Azurdia RM, Moison RM, Steenwinkel MJ, Homburg MI et al. Effect of eicosapentaenoic acid, an omega-3 polyunsaturated fatty acid, on UVR-related cancer risk in humans. An assessment of early genotoxic markers. Carcinogenesis 2003;24:919-25.

  21. Beckles WN, Elliott TM, Everard ML. Omega-3 fatty acids (from fish oils) for cystic fibrosis. Cochrane.Database.Syst.Rev. 2002;CD002201.

  22. Woods RK, Thien FC, Abramson MJ. Dietary marine fatty acids (fish oil) for asthma in adults and children. Cochrane.Database.Syst.Rev. 2002;CD001283.

  23. Joy CB, Mumby-Croft R, Joy LA. Polyunsaturated fatty acid supplementation for schizophrenia. Cochrane.Database.Syst.Rev. 2003;CD001257.

  24. Duffy EM, et al. The Clinical effect of dietary supplementation with omega-3 fish oils and/or copper in systemic lupus erythematosus. J. Rheumatology 2004;31(8):1551-6.

  25. Lewis, C. J. Letter Regarding Dietary Supplement Health Claim for Omega-3 Fatty Acids and Coronary Heart Disease. FDA Docket No. 91N-0103. 10-31-2000. https://pdfs.semanticscholar.org/5c90/42de155b3c273a5d70c7ed88acb7bb39b2b7.pdf. Accessed February 7, 2019.

  26. Thies F, Garry JM, Yaqoob P, Rerkasem K, Williams J, Shearman CP et al. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet 2003;361:477-85.

  27. Severus WE, Littman AB, Stoll AL. Omega-3 fatty acids, homocysteine, and the increased risk of cardiovascular mortality in major depressive disorder. Harv.Rev.Psychiatry 2001;9:280-93.

  28. Holm T, Berge RK, Andreassen AK, Ueland T, Kjekshus J, Simonsen S et al. Omega-3 fatty acids enhance tumor necrosis factor-alpha levels in heart transplant recipients. Transplantation 2001;72:706-11.

  29. Wallace FA, Miles EA, Calder PC. Comparison of the effects of linseed oil and different doses of fish oil on mononuclear cell function in healthy human subjects. Br J Nutr 2003;89:679-89.

  30. Hawkes JS, Bryan DL, Makrides M, Neumann MA, Gibson RA. A randomized trial of supplementation with docosahexaenoic acid-rich tuna oil and its effects on the human milk cytokines interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha. Am J Clin Nutr 2002;75:754-60.

  31. Fugh-Berman A, Cott JM. Dietary supplements and natural products as psychotherapeutic agents. Psychosom.Med 1999;61:712-28.

  32. Tanaka K, Ishikawa Y, Yokoyama M, et al. Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: subanalysis of the JELIS trial. Stroke. 2008 Jul;39(7):2052-8.

  33. Gunnarsdottir I, Tomasson H, Kiely M, et al. Inclusion of fish or fish oil in weight-loss diets for young adults: effects on blood lipids. Int J Obes. 2008;32(7):1105-12.

  34. Buckley MS, Goff AD, Knapp WE. Fish oil interaction with warfarin. Ann Pharmacother. 2004 Jan;38(1):50-2.

  35. Amminger GP, Schäfer MR, Papageorgiou K, et al. Long-Chain {omega}-3 Fatty Acids for Indicated Prevention of Psychotic Disorders: A Randomized, Placebo-Controlled Trial. Arch Gen Psychiatry. 2010 Feb;67(2):146-54.

  36. Brasky TM, Lampe JW, Potter JD, Patterson RE, White E. Specialty Supplements and Breast Cancer Risk in the VITamins And Lifestyle (VITAL) Cohort. Cancer Epidemiol Biomarkers Prev. 2010;19(7); 1696-708.

  37. Makrides M, Gibson R,McPhee A, et al. Effect of DHA Supplementation During Pregnancy on Maternal Depression and Neurodevelopment of Young Children. A Randomized Controlled Trial. JAMA. 2010;304(15):1675-1683.

  38. Murphy RA, Mourtzakis M, Chu QS, et al. Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer. Cancer. 2011;117(16):3774-80.

  39. Murphy RA, Mourtzakis M, Chu QS, et al. Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with nonsmall cell lung cancer receiving chemotherapy. Cancer. 2011 Apr 15;117(8):1775-82.

  40. Trabal J, Leyes P, Forga M, Maurel J. Potential usefulness of an EPA-enriched nutritional supplement on chemotherapy tolerability in cancer patients without overt malnutrition. Nutr Hosp. 2010 Sep-Oct;25(5):736-40.

  41. Sinn N, Milte CM, Street SJ, et al. Br J Nutr. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br J Nutr. 2011 Sep 20:1-12.

  42. Campoy C, Escolano-Margarit MV, Ramos R, et la. Effects of prenatal fish-oil and 5-methyltetrahydrofolate supplementation on cognitive development of children at 6.5 y of age. Am J Clin Nutr. 2011; 94(6 Suppl):1880S-1888S.

  43. Andreeva VA, Touvier M, Kesse-Guyot E, Julia C, Galan P, Hercberg S. B vitamin and/or ω-3 fatty acid supplementation and cancer: ancillary findings from the supplementation with folate, vitamins B6 and B12, and/or omega-3 fatty acids (SU.FOL.OM3) randomized trial. Arch Intern Med 2012 Apr 9;172(7):540-7.

  44. Pilkington SM, Massey KA, Bennett SP, et al. Randomized controlled trial of oral omega-3 PUFA in solar-simulated radiation-induced suppression of human cutaneous immune responses. Am J Clin Nutr. 2013 Mar;97(3):646-52.

  45. Wu JH, Cahill LE, Mozaffarian D. Effect of Fish Oil on Circulating Adiponectin: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Clin Endocrinol Metab. 2013 Jun;98(6):2451-9.

  46. Fappi A, Godoy TS, Maximino JR, et al. The effects of omega-3 Fatty Acid supplementation on dexamethasone-induced muscle atrophy. Biomed Res Int. 2014;2014:961438.

  47. Park JM, Han YM, Jeong M, et al. Omega-3 polyunsaturated acids as an angelus custos to rescue patients from NSAID-induced gastroduodenal damage. J Gastroenterol. 2015 Jan 13. [Epub ahead of print]

  48. Daenen L, Geert A. Cirkel G, Houthuijzen M, et al. Increased Plasma Levels of Chemoresistance-Inducing Fatty Acid 16:4(n-3) After Consumption of Fish and Fish Oil. JAMA Oncol. 2015 Jun;1(3):350-8.

  49. Camargo Cde Q, Mocellin MC, Pastore Silva Jde A, Fabre ME, Nunes EA, Trindade EB. Fish oil supplementation during chemotherapy increases posterior time to tumor progression in colorectal cancer. Nutr Cancer. 2016;68(1):70-6.

  50. Allaire J, Couture P, Leclerc M, et al. A randomized, crossover, head-to-head comparison of eicosapentaenoic acid and docosahexaenoic acid supplementation to reduce inflammation markers in men and women: the Comparing EPA to DHA (ComparED) Study. Am J Clin Nutr.2016 Aug;104(2):280-7.

  51. Pryce R, Bernaitis N, Davey AK, Badrick T, Anoopkumar-Dukie S. The Use of Fish Oil with Warfarin Does Not Significantly Affect either the International Normalised Ratio or Incidence of Adverse Events in Patients with Atrial Fibrillation and Deep Vein Thrombosis: A Retrospective Study. Nutrients.2016 Sep 20;8(9). pii: E578.

  52. Andrieu S, Guyonnet S, Coley N, et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol. May 2017;16(5):377-389.

  53. Barbosa MM, Melo AL, Damasceno NR. The benefits of omega-3 supplementation depend on adiponectin basal level and adiponectin increase after the supplementation: A randomized clinical trial. Nutrition. Feb 2017;34:7-13.

  54. Lewis EJH, Perkins BA, Lovblom LE, et al. Effect of omega-3 supplementation on neuropathy in type 1 diabetes: A 12-month pilot trial. Neurology. Jun 13 2017;88(24):2294-2301.

  55. Hames KC, Morgan-Bathke M, Harteneck DA, et al. Very-long-chain omega-3 fatty acid supplements and adipose tissue functions: a randomized controlled trial. Am J Clin Nutr. Jun 2017;105(6):1552-1558.

  56. Jamilian M, Hashemi Dizaji S, Bahmani F, et al. A Randomized Controlled Clinical Trial Investigating the Effects of Omega-3 Fatty Acids and Vitamin E Co-Supplementation on Biomarkers of Oxidative Stress, Inflammation and Pregnancy Outcomes in Gestational Diabetes. Can J Diabetes. Apr 2017;41(2):143-149.

  57. Jabbari M, Khoshnevis T, Jenabi A, et al. The Effect of Omega-3 Supplement on Serum Lipid Profile in Patients Undergoing Hemodialysis: A Randomized Clinical Trial. Rom J Intern Med. Dec 01 2016;54(4):222-227.

  58. Irish AB, Viecelli AK, Hawley CM, et al. Effect of Fish Oil Supplementation and Aspirin Use on Arteriovenous Fistula Failure in Patients Requiring Hemodialysis: A Randomized Clinical Trial. JAMA Intern Med. Feb 01 2017;177(2):184-193.

  59. Ida S, Hiki N, Cho H, et al. Randomized clinical trial comparing standard diet with perioperative oral immunonutrition in total gastrectomy for gastric cancer. Br J Surg. Mar 2017;104(4):377-383.

  60. Dry Eye Assessment and Management Study Research Group. n-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease. N Engl J Med. 2018 Apr 13. doi: 10.1056/NEJMoa1709691. [Epub ahead of print]

  61. Hull MA, Sprange K, Hepburn T, et al. Eicosapentaenoic acid and aspirin, alone and in combination, for the prevention of colorectal adenomas (seAFOod Polyp Prevention trial): a multicentre, randomised, double-blind, placebo-controlled, 2 × 2 factorial trial. Lancet. 2018 Dec 15;392(10164):2583-2594.

  62. Manson JE, Cook NR, Lee IM, et al. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. 2019 Jan 3;380(1):23-32.

  63. McClaskey EM, Michalets EL. Subdural hematoma after a fall in an elderly patient taking high-dose omega-3 fatty acids with warfarin and aspirin: case report and review of the literature. Pharmacotherapy. 2007 Jan;27(1):152-60.

  64. Gross BW, Gillio M, Rinehart CD, Lynch CA, Rogers FB. Omega-3 Fatty Acid Supplementation and Warfarin: A Lethal Combination in Traumatic Brain Injury. J Trauma Nurs. 2017 Jan/Feb;24(1):15-18.