Omega-3 fatty acid| Volume 99, ISSUE 6, SUPPLEMENT 1, S35-S43, March 19, 2007

Safety Considerations with Omega-3 Fatty Acid Therapy

  • Harold E. Bays
    Address for reprints: Harold E. Bays, MD, Louisville Metabolic and Atherosclerosis Research Center, 3288 Illinois Avenue, Louisville, Kentucky 40213.
    Louisville Metabolic and Atherosclerosis Research Center, Louisville, Kentucky, USA.
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Published:November 29, 2006DOI:
      It has been suggested that the potential antithrombotic effect of fish oils may theoretically increase the risk for bleeding, which may be a safety concern for individual patients. However, clinical trial evidence has not supported increased bleeding with omega-3 fatty acid intake, even when combined with other agents that might also increase bleeding (such as aspirin and warfarin). Another potential safety concern is the susceptibility of omega-3 fatty acid preparations to undergo oxidation, which contributes to patient intolerance and potential toxicity. Finally, large amounts of fish consumption may result in adverse experiences due to the potential presence of environmental toxins such as mercury, polychlorinated biphenyls, dioxins, and other contaminants. The risks of exposure to environmental toxins and hypervitaminosis with fish consumption are substantially reduced through purification processes used to develop selected concentrated fish oil supplements and prescription preparations. Thus, in choosing which fish oil therapies to recommend, clinicians should be aware of available information to best assess their relative safety, which includes the US Food and Drug Administration (FDA) and Environmental Protection Agency (EPA) advisory statement regarding fish consumption, the meaning of certain labeling (such as “verification” through the US Pharmacopeia) and the differences in FDA regulatory requirements between nonprescription fish oil supplements and prescription fish oil preparations, and how all of this is important to the optimal treatment of patients.
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      1. American Heart Association. Fish and omega-3 fatty acids: AHA recommendation AHA Website. Available at: Accessed July 14, 2006.

        • Lee K.W.
        • Hamaad A.
        • MacFadyen R.J.
        • Lip G.Y.
        Effects of dietary fat intake in sudden death: reduction of death with omega-3 fatty acids.
        Curr Cardiol Rep. 2004; 6: 371-378
        • Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico
        Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.
        Lancet. 1999; 354: 447-455
        • Burr M.L.
        • Fehily A.M.
        • Gilbert J.F.
        • Rogers S.
        • Holliday R.M.
        • Sweetnam P.M.
        • Elwood P.C.
        • Deadman N.M.
        Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART).
        Lancet. 1989; 2: 757-761
        • He K.
        • Song Y.
        • Daviglus M.L.
        • Liu K.
        • Van H.L.
        • Dyer A.R.
        • Greenland P.
        Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies.
        Circulation. 2004; 109: 2705-2711
        • Kim D.N.
        • Eastman A.
        • Baker J.E.
        • Mastrangelo A.
        • Sethi S.
        • Ross J.S.
        • Schmee J.
        • Thomas W.A.
        Fish oil, atherogenesis, and thrombogenesis.
        Ann N Y Acad Sci. 1995; 748: 474-480
        • Cartwright I.J.
        • Pockley A.G.
        • Galloway J.H.
        • Greaves M.
        • Preston F.E.
        The effects of dietary omega-3 polyunsaturated fatty acids on erythrocyte membrane phospholipids, erythrocyte deformability and blood viscosity in healthy volunteers.
        Atherosclerosis. 1985; 55: 267-281
        • Kaminski W.E.
        • Jendraschak E.
        • Kiefl R.
        • von Schacky C.
        Dietary omega-3 fatty acids lower levels of platelet-derived growth factor mRNA in human mononuclear cells.
        Blood. 1993; 81: 1871-1879
        • Mayer K.
        • Merfels M.
        • Muhly-Reinholz M.
        • Gokorsch S.
        • Rosseau S.
        • Lohmeyer J.
        • Schwarzer N.
        • Krull M.
        • Suttorp N.
        • Grimminger F.
        • Seeger W.
        Omega-3 fatty acids suppress monocyte adhesion to human endothelial cells: role of endothelial PAF generation.
        Am J Physiol Heart Circ Physiol. 2002; 283: H811-H818
        • von Schacky C.
        • Baumann K.
        • Angerer P.
        The effect of n-3 fatty acids on coronary atherosclerosis: results from SCIMO, an angiographic study, background and implications.
        Lipids. 2001; 36: S99-S102
        • Schmitz P.G.
        • McCloud L.K.
        • Reikes S.T.
        • Leonard C.L.
        • Gellens M.E.
        Prophylaxis of hemodialysis graft thrombosis with fish oil: double-blind, randomized, prospective trial.
        J Am Soc Nephrol. 2002; 13: 184-190
        • Eritsland J.
        • Arnesen H.
        • Gronseth K.
        • Fjeld N.B.
        • Abdelnoor M.
        Effect of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency.
        Am J Cardiol. 1996; 77: 31-36
        • Lichtenstein A.H.
        Remarks on clinical data concerning dietary supplements that affect antithrombotic therapy.
        Thromb Res. 2005; 117: 71-73
        • Balk E.
        • Chung M.
        • Lichtenstein A.
        • Chew P.
        • Kupelnick B.
        • Lawrence A.
        • DeVine D.
        • Lau J.
        Effects of omega-3 fatty acids on cardiovascular risk factors and intermediate markers of cardiovascular disease. Agency for Healthcare Research and Quality, Rockville, MD2004 (AHRQ Publication No. 04-E010-2)
        • Wallace J.M.
        • McCabe A.J.
        • Roche H.M.
        • Higgins S.
        • Robson P.J.
        • Gilmore W.S.
        • McGlynn H.
        • Strain J.J.
        The effect of low-dose fish oil supplementation on serum growth factors in healthy humans.
        Eur J Clin Nutr. 2000; 54: 690-694
        • Kristensen S.D.
        • Iversen A.M.
        • Schmidt E.B.
        n-3 Polyunsaturated fatty acids and coronary thrombosis.
        Lipids. 2001; 36: S79-S82
        • O’Keefe Jr, J.H.
        • Abuissa H.
        • Sastre A.
        • Steinhaus D.M.
        • Harris W.S.
        Effects of omega-3 fatty acids on resting heart rate, heart rate recovery after exercise, and heart rate variability in men with healed myocardial infarctions and depressed ejection fractions.
        Am J Cardiol. 2006; 97: 1127-1130
        • Carroll D.N.
        • Roth M.T.
        Evidence for the cardioprotective effects of omega-3 fatty acids.
        Ann Pharmacother. 2002; 36: 1950-1956
        • Leaf A.
        • Jorgensen M.B.
        • Jacobs A.K.
        • Cote G.
        • Schoenfeld D.A.
        • Scheer J.
        • Weiner B.H.
        • Slack J.D.
        • Kellett M.A.
        • Raizner A.E.
        Do fish oils prevent restenosis after coronary angioplasty?.
        Circulation. 1994; 90: 2248-2257
        • Bender N.K.
        • Kraynak M.A.
        • Chiquette E.
        • Linn W.D.
        • Clark G.M.
        • Bussey H.I.
        Effects of marine fish oils on the anticoagulation status of patients receiving chronic warfarin therapy.
        J Thromb Thrombolysis. 1998; 5: 257-261
        • Thorwest M.
        • Balling E.
        • Kristensen S.D.
        • Aagaard S.
        • Hakami A.
        • Husted S.E.
        • Marqversen J.
        • Hjortdal V.E.
        Dietary fish oil reduces microvascular thrombosis in a porcine experimental model.
        Thromb Res. 2000; 99: 203-208
        • Harker L.A.
        • Kelly A.B.
        • Hanson S.R.
        • Krupski W.
        • Bass A.
        • Osterud B.
        • FitzGerald G.A.
        • Goodnight S.H.
        • Connor W.E.
        Interruption of vascular thrombus formation and vascular lesion formation by dietary n-3 fatty acids in fish oil in nonhuman primates.
        Circulation. 1993; 87: 1017-1029
        • Zhu B.Q.
        • Sievers R.E.
        • Sun Y.P.
        • Morse-Fisher N.
        • Parmley W.W.
        • Wolfe C.L.
        Is the reduction of myocardial infarct size by dietary fish oil the result of altered platelet function?.
        Am Heart J. 1994; 127: 744-755
      2. Omacor (omega-3-acid ethyl esters, capsules) [prescribing information]. Liberty Corner, NJ: Reliant Pharmaceuticals. Available at: Accessed June 1, 2006.

        • Bays H.E.
        Clinical overview of Omacor.
        Am J Cardiol. 2006; 98: 71i-76i
        • Heller A.R.
        • Fischer S.
        • Rossel T.
        • Geiger S.
        • Siegert G.
        • Ragaller M.
        • Zimmermann T.
        • Koch T.
        Impact of n-3 fatty acid supplemented parenteral nutrition on haemostasis patterns after major abdominal surgery.
        Br J Nutr. 2002; 87: S95-S101
        • Calo L.
        • Bianconi L.
        • Colivicchi F.
        • Lamberti F.
        • Loricchio M.L.
        • De R.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. 2005; 45: 1723-1728
        • Kris-Etherton P.M.
        • Harris W.S.
        • Appel L.J.
        Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.
        Circulation. 2002; 106: 2747-2757
        • Covington M.B.
        Omega-3 fatty acids.
        Am Fam Physician. 2004; 70: 133-140
        • Matsuo N.
        Studies on the toxicity of fish oil.
        Tokushima J Exp Med. 1961; 8: 96-100
        • Nair P.P.
        • Judd J.T.
        • Berlin E.
        • Taylor P.R.
        • Shami S.
        • Sainz E.
        • Bhagavan H.N.
        Dietary fish oil-induced changes in the distribution of alpha-tocopherol, retinol, and beta-carotene in plasma, red blood cells, and platelets: modulation by vitamin E.
        Am J Clin Nutr. 1993; 58: 98-102
        • Chesney R.W.
        Vitamin D: can an upper limit be defined?.
        J Nutr. 1989; 119: 1825-1828
        • Myhre A.M.
        • Carlsen M.H.
        • Bohn S.K.
        • Wold H.L.
        • Laake P.
        • Blomhoff R.
        Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations.
        Am J Clin Nutr. 2003; 78: 1152-1159
        • Russell R.M.
        The vitamin A spectrum: from deficiency to toxicity.
        Am J Clin Nutr. 2000; 71: 878-884
        • Nau H.
        Teratogenicity of isotretinoin revisited: species variation and the role of all-trans-retinoic acid.
        J Am Acad Dermatol. 2001; 45: S183-S187
        • Perrotta S.
        • Nobili B.
        • Rossi F.
        • Criscuolo M.
        • Iolascon A.
        • Di Pinto D.
        • Passaro I.
        • Cennamo L.
        • Oliva A.
        • Della R.F.
        Infant hypervitaminosis A causes severe anemia and thrombocytopenia: evidence of a retinol-dependent bone marrow cell growth inhibition.
        Blood. 2002; 99: 2017-2022
        • Brecher A.R.
        • Orlow S.J.
        Oral retinoid therapy for dermatologic conditions in children and adolescents.
        J Am Acad Dermatol. 2003; 49: 171-182
        • Johnson K.A.
        • Bernard M.A.
        • Funderburg K.
        Vitamin nutrition in older adults.
        Clin Geriatr Med. 2002; 18: 773-799
        • Rajakumar K.
        Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective.
        Pediatrics. 2003; 112: e132-e135
        • Despres C.
        • Beuter A.
        • Richer F.
        • Poitras K.
        • Veilleux A.
        • Ayotte P.
        • Dewailly E.
        • Saint-Amour D.
        • Muckle G.
        Neuromotor functions in Inuit preschool children exposed to Pb, PCBs, and Hg.
        Neurotoxicol Teratol. 2005; 27: 245-257
        • Mulvad G.
        • Pedersen H.S.
        • Hansen J.C.
        • Dewailly E.
        • Jul E.
        • Pedersen M.
        • Deguchi Y.
        • Newman W.P.
        • Malcom G.T.
        • Tracy R.E.
        • Middaugh J.P.
        • Bjerregaard P.
        The Inuit diet: fatty acids and antioxidants, their role in ischemic heart disease, and exposure to organochlorines and heavy metals: an international study.
        Arctic Med Res. 1996; 55: 20-24
        • Arisawa K.
        • Matsumura T.
        • Tohyama C.
        • Saito H.
        • Satoh H.
        • Nagai M.
        • Morita M.
        • Suzuki T.
        Fish intake, plasma omega-3 polyunsaturated fatty acids, and polychlorinated dibenzo-p-dioxins/polychlorinated dibenzo-furans and co-planar polychlorinated biphenyls in the blood of the Japanese population.
        Int Arch Occup Environ Health. 2003; 76: 205-215
        • Wilson J.F.
        Balancing the risks and benefits of fish consumption.
        Ann Intern Med. 2004; 141: 977-980
        • Sakamoto M.
        • Kubota M.
        • Liu X.J.
        • Murata K.
        • Nakai K.
        • Satoh H.
        Maternal and fetal mercury and n-3 polyunsaturated fatty acids as a risk and benefit of fish consumption to fetus.
        Environ Sci Technol. 2004; 38: 3860-3863
        • Rusyniak D.E.
        • Furbee R.B.
        • Pascuzzi R.
        Historical neurotoxins: what we have learned from toxins of the past about diseases of the present.
        Neurol Clin. 2005; 23: 337-352
        • Kales S.N.
        • Goldman R.H.
        Mercury exposure: current concepts, controversies, and a clinic’s experience.
        J Occup Environ Med. 2002; 44: 143-154
      3. US Department of Health and Human Services, US Environmental Protection Agency. What you need to know about mercury in fish and shellfish. CFSAN Website. Available at:∼dms/admehg3.html. Accessed July 14, 2006.

        • Mozaffarian D.
        • Rimm E.B.
        Fish intake, contaminants, and human health: evaluating the risks and benefits.
        JAMA. 2006; 296: 1885-1899
        • Foran S.E.
        • Flood J.G.
        • Lewandrowski K.B.
        Measurement of mercury levels in concentrated over-the-counter fish oil preparations: is fish oil healthier than fish?.
        Arch Pathol Lab Med. 2003; 127: 1603-1605
      4. Good news! These supplements have omega-3’s without contaminants found in fish! But some are better than others. Find out now! [report.] Website. Available at: Accessed July 14, 2006.

      5. Edison Electric Institute. Straight answers about electrical utilities and mercury. EEI Website. Available at: Accessed July 10, 2006.

        • Powell D.L.
        • Stewart V.
        Children: the unwitting target of environmental injustices.
        Pediatr Clin North Am. 2001; 48: 1291-1305
        • Longnecker M.P.
        • Rogan W.J.
        • Lucier G.
        The human health effects of DDT (dichlorodiphenyltrichloroethane) and PCBS (polychlorinated biphenyls) and an overview of organochlorines in public health.
        Annu Rev Public Health. 1997; 18: 211-244
        • Caban-Holt A.
        • Mattingly M.
        • Cooper G.
        • Schmitt F.A.
        Neurodegenerative memory disorders: a potential role of environmental toxins.
        Neurol Clin. 2005; 23: 485-521
        • Arisawa K.
        • Takeda H.
        • Mikasa H.
        Background exposure to PCDDs/PCDFs/PCBs and its potential health effects: a review of epidemiologic studies.
        J Med Invest. 2005; 52: 10-21
        • Melanson S.F.
        • Lewandrowski E.L.
        • Flood J.G.
        • Lewandrowski K.B.
        Measurement of organochlorines in commercial over-the-counter fish oil preparations: implications for dietary and therapeutic recommendations for omega-3 fatty acids and a review of the literature.
        Arch Pathol Lab Med. 2005; 129: 74-77
      6. US Department of Health and Human Services, Office of Inspector General. Adverse event reporting for dietary supplements: an inadequate safety valve. HHS Website. Available at: Accessed July 14, 2006.

        • Fontanarosa P.B.
        • Rennie D.
        • DeAngelis C.D.
        The need for regulation of dietary supplements—lessons from ephedra.
        JAMA. 2003; 289: 1568-1570
      7. Davis R. Statement of Ronald Davis M.D.: Senate Committee on Governmental Affairs: Dietary Supplement Safety Act: how is FDA doing 10 years later? Senate Committee on Homeland Security & Governmental Affairs Website. Available at: Accessed July 14, 2006.

      8. US Department of Health and Human Services, US Food and Drug Administration Questions and Answers on Current Good Manufacturing Practices (cGMP) for Drugs. FDA Website. Available at: Accessed July 14, 2006.

      9. US Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Nutritional Products, Labeling, and Dietary Supplements. Letter responding to a request to reconsider the qualified claim for a dietary supplement health claim for omega-3 fatty acids and coronary heart disease. FDA Website. Available at:∼dms/ds-ltr28.html. Accessed July 17, 2006.

      10. Bush L. Decoding the US Pharmacopeia. Pharmaceutical Technology Website. Available at: Accessed July 14, 2006.

        • Atwater J.
        • Montgomery-Salguero J.
        • Roll D.B.
        The USP Dietary Supplement Verification Program: helping pharmacists and consumers select dietary supplements.
        US Pharm. 2005; 6: 61-64
      11. U.S. Pharmacopeia. USP verified dietary supplements. Available at: Accessed July 13, 2006.

      12. Council for Responsible Nutrition. About CRN [CRN Website]. Available at: Accessed July 14, 2006.