By Eric Trexler, CSCS, CISSN
Former Director of Research and Education, INOV8 Elite Performance
Fish oil has been touted by many as a must-have supplement. Some, however, have spoken out against the widespread promotion of fish oil, and even warn their readers about possible adverse effects of high intakes [1, 2]. For this post, I will dive into the conflicting fish oil research, hoping to emerge with some conclusions.
There is a large body of research backing the use of fish oil for a wide range of benefits. A review article by Abeywardena & Patten concluded that fish oil improves endothelial cell function and insulin sensitivity, increases lipolysis, decreases lipogenesis, reduces inflammation, lowers triglycerides, improves LDL particle size (favoring a less-atherogenic pattern), and reduces blood pressure at higher doses . Some evidence also suggests that fish oil may increase HDL . Further, a recent review by Delgado-Lista found that higher intakes of fish oil (either from food or supplementation) were associated with decreased risks of cardiac death, suffering a cardiovascular event of any kind, and suffering a coronary event .
Researchers from my alma mater investigated the influence of fish oil on anxiety and inflammation. Their findings indicate that fish oil supplementation helps to alleviate anxiety symptoms and decrease serum TNF-α, a cytokine that is often used as a biomarker of inflammation [6, 7].
Moving on toward more fitness-related outcomes, a review by Buckley concluded that fish oil has positive effects on body composition, especially when combined with diet and/or exercise . Three other studies have indicated that fish oil may augment the anabolic response to resistance training [9-11]. But before you start chugging fish oil by the bottle, it’s important to acknowledge that these effects on body composition and anabolism are extremely modest and commonly shown in untrained and/or elderly subjects. I remain skeptical that they would make anysubstantial difference to a young, healthy trainee who is eating and training intelligently.
Another point relevant to the iron-pumping crowd is that fish oil has been shown to reduce arterial stiffness . This is good news when you consider that high-intensity resistance training (using loads >80% of 1RM) is associated with increased arterial stiffness . Reduced arterial stiffness isn’t exactly the flashy, “Lose 10 lbs in 10 days” claim that you may be accustomed to, but I’d take distensible arteries over a six-pack any day. Finally, as the followingarticle points out, fish oil has been linked to improved mental health, cognitive function, and reduced pain and stiffness in joints.
Clearly fish oil has numerous benefits, though many tend to overhype the magnitude of said benefits. With the proposed benefits out of the way, let’s take a look at the potential adverse effects of high fish oil intakes.
First, there is some evidence that high-dose fish oil supplementation may increase bleeding time by affecting platelet function . Although contrary findings have been reported [15-18], it may be prudent for certain clinical populations to avoid fish oil supplementation for this reason.
When you increase your intake of fish oil, either by food or supplementation, you increase the amount of omega-3 (n-3) fatty acids in your plasma and cell membranes. Polyunsaturated fats, including n-3’s, contain multiple double bonds in their hydrocarbon chain. These double bonds are especially susceptible to oxidation by free radicals, which increases oxidative stress and produces toxic byproducts that can damage healthy cells in the body; this chain reaction is called lipid peroxidation. A common concern is that increased plasma and cell membrane n-3 content will lead to increased lipid peroxidation, which will increase oxidative stress and the production of these cell-damaging peroxidation byproducts.
There is a similar concern pertaining to LDL. Increased n-3 intakes increase the amount of n-3 fatty acids present in LDL particles. LDL, commonly known by its ominous nickname “The Bad Cholesterol,” is actually fairly benign in its non-oxidized form. However, LDL can become embedded in the artery wall and undergo oxidation, the first step in the development of atherosclerotic plaque. The idea here is that increased n-3 intake will lead to greater rates of LDL oxidation, and thus lead to greater accumulation of atherosclerotic plaque.
So, does this mean that taking fish oil will set you up for crippling loads of oxidative stress and plaque-filled arteries?
I’ll be blunt: The research regarding n-3 intakes and oxidative stress is an absolute mess. There are plenty of studies associating n-3’s with increased oxidative stress [19-29]. There are also plenty of studies associating n-3’s with adecrease in oxidative stress [30-40]. Just to round things off, I might as well cite a couple studies showing no effect on oxidative stress [41, 42].
There is certainly evidence to suggest that somewhat “common” doses of fish oil (4-5 grams per day) can make LDL more susceptible to oxidation [43, 44]. Further, there is animal research linking very high fish oil intakes to increased atherosclerotic plaque [45, 46]. The following article at SuppVersity discusses these animal-model findings in detail, so check it out for more information. These findings seem to contradict the positive cardiovascular effects highlighted by Delgado-Lista  and Abeywardena .
Well, there you have it: Fish oil might be really good, or really bad. Or neither. After reviewing all of that literature, I was a bit disappointed with such a conclusion. So I took a step back.
Let’s forget about the minutia for a minute- in light of discrepant acute findings, it helps to consider some “big picture” outcomes. Instead of worrying about ex-vivo, synthetically-induced rates of LDL oxidation, let’s look at the relationship between fish oil and atherosclerosis. Instead of worrying about small fluctuations in lipid peroxidation byproducts, let’s look at the outcomes we might associate with increased oxidative stress and lipid peroxidation. If oxidative stress and lipid peroxidation byproducts are being increased to a physiologically meaningful degree, then shouldn’t we see a relationship between high n-3 intakes and the development of diseases in which these factors play a significant role? (According to the NIH, these include cancer, cardiovascular disease, Alzheimer’s, Parkinson’s, and eye pathologies, among others )
When it comes to cancer, more research on fish oil’s impact is needed. A number of studies have suggested that fish oil may have potential as an adjunctive therapy for cancer patients, with possible direct anticancer effects of its own [48-51]. Although research by Brasky et al. has suggested a potential association between high plasma levels of n-3’s and prostate cancer , it would be premature to suggest that fish oil supplementation causes an elevated risk of cancer development. Moving on, fish oil is associated with a protective role in atherosclerosis [53-55] and cardiovascular disease . Fish oil intake is also associated with lower risk of Alzheimer’s Disease  and Parkinson’s Disease . Regarding oxidative stress-related eye diseases, fish oil intake in inversely associated with the risk of developing age-related maculopathy .
Although a true consensus has not been reached, it appears that people consuming fish and/or fish oil in reasonable amounts appear to be reaping numerous modest health benefits without putting themselves at significantly elevated risks for disorders related to lipid peroxidation, oxidative stress, or LDL oxidation. I say “reasonable” amounts because we cannot extrapolate this data to assume that mega-dosing fish oil will not have adverse effects.
The fish oil intakes involved in most human studies generally range from 1-4 grams of combined EPA + DHA per day. Omega-3’s are essential fatty acids, and fish oil is an excellent source of n-3’s; the question is, how much fish oil intake is appropriate? A 2007 review paper by Simopoulos recommends an intake of 1-2 g of combined EPA + DHA per day for athletes . I would agree that this dose is likely sufficient for most healthy individuals and athletes, either from food or supplementation. Under the direction of a physician, slightly higher doses may be applicable to certain individuals with preexisting symptoms/pathologies. As Benjamin Franklin said, “An ounce of prevention is worth a pound of cure.”
And, it goes without saying: Consult with your doctor before making any changes to your diet or exercise habits. You’d have to be a lunatic to interpret my ramblings as sound medical advice.
- Although fish oil research is not all positive, a large body of evidence suggests fish oil may have some health benefits, especially for conditions involving the brain, eyes, cardiovascular system, or inflammation
- Fish oil is not magic— these benefits appear to be somewhat modest in magnitude
- The current body of literature does not seem to indicate that modest consumption fish oil increases LDL oxidation, lipid peroxidation, or oxidative stress to a degree that yields substantial negative health outcomes
- This does not mean that mega-dosing fish oil will not yield negative outcomes— the majority of studies utilize dosages less than 4 grams of EPA + DHA per day
- More research on fish oil is needed. However, the current body of evidence seems to suggest that daily fish oil intakes of roughly 1-3 grams of EPA + DHA, from food and/or supplementation, may play a small protective role in a number of diverse health outcomes. I personally shoot for the lower end of this range.
2. Kresser, C. When it comes to fish oil, more is not better. [Web] 2010 October 25, 2010; Available from:http://chriskresser.com/when-it-comes-to-fish-oil-more-is-not-better.
3. Abeywardena, M.Y. and G.S. Patten, Role of omega3 long-chain polyunsaturated fatty acids in reducing cardio-metabolic risk factors. Endocr Metab Immune Disord Drug Targets, 2011. 11(3): p. 232-46.
4. Brinson, B.E. and S. Miller, Fish oil: what is the role in cardiovascular health? J Pharm Pract, 2012. 25(1): p. 69-74.
5. Delgado-Lista, J., et al., Long chain omega-3 fatty acids and cardiovascular disease: a systematic review. Br J Nutr, 2012. 107 Suppl 2: p. S201-13.
6. Kiecolt-Glaser, J.K., et al., Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. Brain Behav Immun, 2011. 25(8): p. 1725-34.
7. Kiecolt-Glaser, J.K., et al., Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: a randomized controlled trial. Brain Behav Immun, 2012. 26(6): p. 988-95.
8. Buckley, J.D. and P.R. Howe, Long-chain omega-3 polyunsaturated fatty acids may be beneficial for reducing obesity-a review. Nutrients, 2010. 2(12): p. 1212-30.
9. Smith, G.I., et al., Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia-hyperaminoacidaemia in healthy young and middle-aged men and women. Clin Sci (Lond), 2011.121(6): p. 267-78.
10. Smith, G.I., et al., Dietary omega-3 fatty acid supplementation increases the rate of muscle protein synthesis in older adults: a randomized controlled trial. Am J Clin Nutr, 2011. 93(2): p. 402-12.
11. Rodacki, C.L., et al., Fish-oil supplementation enhances the effects of strength training in elderly women. Am J Clin Nutr, 2012. 95(2): p. 428-36.
12. Pase, M.P., N.A. Grima, and J. Sarris, Do long-chain n-3 fatty acids reduce arterial stiffness? A meta-analysis of randomised controlled trials. Br J Nutr, 2011. 106(7): p. 974-80.
13. Miyachi, M., Effects of resistance training on arterial stiffness: a meta-analysis. Br J Sports Med, 2012.
14. Lorenz, R., et al., Platelet function, thromboxane formation and blood pressure control during supplementation of the Western diet with cod liver oil. Circulation, 1983. 67(3): p. 504-11.
15. Donnelly, S.M., M.A. Ali, and D.N. Churchill, Effect of n-3 fatty acids from fish oil on hemostasis, blood pressure, and lipid profile of dialysis patients. J Am Soc Nephrol, 1992. 2(11): p. 1634-9.
16. Kepler, C.K., et al., Omega-3 and fish oil supplements do not cause increased bleeding during spinal decompression surgery. J Spinal Disord Tech, 2012. 25(3): p. 129-32.
17. Lempert, K.D., J.S. Rogers, 2nd, and M.J. Albrink, Effects of dietary fish oil on serum lipids and blood coagulation in peritoneal dialysis patients. Am J Kidney Dis, 1988. 11(2): p. 170-5.
18. Rogers, S., et al., Effects of a fish oil supplement on serum lipids, blood pressure, bleeding time, haemostatic and rheological variables. A double blind randomised controlled trial in healthy volunteers. Atherosclerosis, 1987. 63(2-3): p. 137-43.
19. Ghosh, S., et al., Diets rich in n-6 PUFA induce intestinal microbial dysbiosis in aged mice. Br J Nutr, 2013: p. 1-9.
20. Fukui, M., et al., EPA, an omega-3 fatty acid, induces apoptosis in human pancreatic cancer cells: role of ROS accumulation, caspase-8 activation, and autophagy induction. J Cell Biochem, 2013. 114(1): p. 192-203.
21. Hajjaji, N., P. Besson, and P. Bougnoux, Tumor and non-tumor tissues differential oxidative stress response to supplemental DHA and chemotherapy in rats. Cancer Chemother Pharmacol, 2012. 70(1): p. 17-23.
22. Crnkovic, S., et al., Docosahexaenoic acid-induced unfolded protein response, cell cycle arrest, and apoptosis in vascular smooth muscle cells are triggered by Ca(2)(+)-dependent induction of oxidative stress. Free Radic Biol Med, 2012. 52(9): p. 1786-95.
23. Filaire, E., et al., Effect of 6 Weeks of n-3 fatty-acid supplementation on oxidative stress in Judo athletes. Int J Sport Nutr Exerc Metab, 2010. 20(6): p. 496-506.
24. Filaire, E., et al., Effects of 6 weeks of n-3 fatty acids and antioxidant mixture on lipid peroxidation at rest and postexercise. Eur J Appl Physiol, 2011. 111(8): p. 1829-39.
25. Carrepeiro, M.M., et al., Effect of n-3 fatty acids and statins on oxidative stress in statin-treated hypercholestorelemic and normocholesterolemic women. Atherosclerosis, 2011. 217(1): p. 171-8.
26. Cavazos, D.A., et al., Docosahexaenoic acid selectively induces human prostate cancer cell sensitivity to oxidative stress through modulation of NF-kappaB. Prostate, 2011. 71(13): p. 1420-8.
27. Allard, J.P., et al., Lipid peroxidation during n-3 fatty acid and vitamin E supplementation in humans. Lipids, 1997.32(5): p. 535-41.
28. Kikawa, K.D., et al., Induced oxidative stress and cell death in the A549 lung adenocarcinoma cell line by ionizing radiation is enhanced by supplementation with docosahexaenoic acid. Nutr Cancer, 2010. 62(8): p. 1017-24.
29. McAnulty, S.R., et al., Effect of n-3 fatty acids and antioxidants on oxidative stress after exercise. Med Sci Sports Exerc, 2010. 42(9): p. 1704-11.
30. Nalsen, C., et al., Dietary (n-3) fatty acids reduce plasma F2-isoprostanes but not prostaglandin F2alpha in healthy humans. J Nutr, 2006. 136(5): p. 1222-8.
31. Chaung, H.C., et al., Docosahexaenoic acid and phosphatidylserine improves the antioxidant activities in vitro and in vivo and cognitive functions of the developing brain. Food Chem, 2013. 138(1): p. 342-7.
32. Mori, T.A., Effect of fish and fish oil-derived omega-3 fatty acids on lipid oxidation. Redox Rep, 2004. 9(4): p. 193-7.
33. Lakshmi, D., et al., Ameliorating effect of fish oil on acrylamide induced oxidative stress and neuronal apoptosis in cerebral cortex. Neurochem Res, 2012. 37(9): p. 1859-67.
34. Tourtas, T., et al., Preventive effects of omega-3 and omega-6 Fatty acids on peroxide mediated oxidative stress responses in primary human trabecular meshwork cells. PLoS One, 2012. 7(2): p. e31340.
35. Finocchiaro, C., et al., Effect of n-3 fatty acids on patients with advanced lung cancer: a double-blind, placebo-controlled study. Br J Nutr, 2012. 108(2): p. 327-33.
36. Takaki, A., et al., Add-on therapy of EPA reduces oxidative stress and inhibits the progression of aortic stiffness in patients with coronary artery disease and statin therapy: a randomized controlled study. J Atheroscler Thromb, 2011.18(10): p. 857-66.
37. Al-Gayyar, M.M., M.E. Shams, and E.A. Barakat, Fish oil improves lipid metabolism and ameliorates inflammation in patients with metabolic syndrome: impact of nonalcoholic fatty liver disease. Pharm Biol, 2012. 50(3): p. 297-303.
38. Farooqui, A.A., n-3 fatty acid-derived lipid mediators in the brain: new weapons against oxidative stress and inflammation. Curr Med Chem, 2012. 19(4): p. 532-43.
39. Tayyebi-Khosroshahi, H., et al., Effect of omega-3 fatty acid on oxidative stress in patients on hemodialysis. Iran J Kidney Dis, 2010. 4(4): p. 322-6.
40. Ossani, G.P., et al., The protective effect of menhaden oil in the oxidative damage and renal necrosis due to dietary choline deficiency. Food Funct, 2012.
41. Ottestad, I., et al., Oxidised fish oil does not influence established markers of oxidative stress in healthy human subjects: a randomised controlled trial. Br J Nutr, 2012. 108(2): p. 315-26.
42. Kooshki, A., et al., Effects of marine omega-3 fatty acids on serum systemic and vascular inflammation markers and oxidative stress in hemodialysis patients. Ann Nutr Metab, 2011. 58(3): p. 197-202.
43. Suzukawa, M., et al., Effects of fish oil fatty acids on low density lipoprotein size, oxidizability, and uptake by macrophages. J Lipid Res, 1995. 36(3): p. 473-84.
44. Hau, M.F., et al., Effects of fish oil on oxidation resistance of VLDL in hypertriglyceridemic patients. Arterioscler Thromb Vasc Biol, 1996. 16(9): p. 1197-202.
45. Ritskes-Hoitinga, J., et al., The association of increasing dietary concentrations of fish oil with hepatotoxic effects and a higher degree of aorta atherosclerosis in the ad lib.-fed rabbit. Food Chem Toxicol, 1998. 36(8): p. 663-72.
46. M, M.S., et al., Fish oil increases atherosclerosis and hepatic steatosis, although decreases serum cholesterol in Wistar rat. J Res Med Sci, 2011. 16(5): p. 583-90.
47. NCCAM. Antioxidants and Health: An Introduction. [Web] 2010 November 2012 [cited 2013; Available from:http://nccam.nih.gov/health/antioxidants/introduction.htm.
48. Vaughan, V.C., M.R. Hassing, and P.A. Lewandowski, Marine polyunsaturated fatty acids and cancer therapy. Br J Cancer, 2013.
49. Wendel, M. and A.R. Heller, Anticancer actions of omega-3 fatty acids–current state and future perspectives.Anticancer Agents Med Chem, 2009. 9(4): p. 457-70.
50. Wolk, A., et al., Long-term fatty fish consumption and renal cell carcinoma incidence in women. JAMA, 2006. 296(11): p. 1371-6.
51. Gleissman, H., J.I. Johnsen, and P. Kogner, Omega-3 fatty acids in cancer, the protectors of good and the killers of evil? Exp Cell Res, 2010. 316(8): p. 1365-73.
52. Brasky, T.M., et al., Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Natl Cancer Inst, 2013. 105(15): p. 1132-41.
53. Kelley, D.S. and Y. Adkins, Similarities and differences between the effects of EPA and DHA on markers of atherosclerosis in human subjects. Proc Nutr Soc, 2012. 71(2): p. 322-31.
54. Degirolamo, C., et al., Dietary n-3 LCPUFA from fish oil but not alpha-linolenic acid-derived LCPUFA confers atheroprotection in mice. J Lipid Res, 2010. 51(7): p. 1897-905.
55. Thies, F., et al., Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet, 2003. 361(9356): p. 477-85.
56. Morris, M.C., et al., Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol, 2003. 60(7): p. 940-6.
57. Bousquet, M., F. Calon, and F. Cicchetti, Impact of omega-3 fatty acids in Parkinson’s disease. Ageing Res Rev, 2011.10(4): p. 453-63.
58. Merle, B., et al., Dietary omega-3 fatty acids and the risk for age-related maculopathy: the Alienor Study. Invest Ophthalmol Vis Sci, 2011. 52(8): p. 6004-11.
59. Simopoulos, A.P., Omega-3 fatty acids and athletics. Curr Sports Med Rep, 2007. 6(4): p. 230-6.
Eric Trexler is not a doctor or registered dietitian. Eric holds no certification or licensure in the practice of nutrition or dietetics. The contents of this article should not be taken as medical advice. It is not intended to diagnose, treat, cure, or prevent any health problem – nor is it intended to replace the advice of a physician. Always consult your physician or qualified health professional on any matters regarding your health.