The chemical structure of eicosapentaenoic acid and docosahexaenoic acid. Eicosapentaenoic acid consists of 20 carbons (C20) with 5 double bonds, and the last unsaturated carbon is located third from the methyl end (n-3). Do-cosahexaenoic acid consists of 22 carbons (C22) with 6 double bonds, and also with the3 last unsaturated carbon located third from the methyl end (n-3). Adapted with permission from Frishman et al, eds. Cardiovascular Pharmacotherapeutics. New York, NY: McGraw Hill; 2003.3

A scientific review published in 2013 looked at omega-3 polyunsaturated fatty acids and prostate cancer prevention. Researchers concluded that there’s a great deal of evidence suggesting that omega-3s have antiproliferative effects – which means they inhibit cancer cell growth – in cancer cell lines, animal models and humans. In addition, the “direct effects on cancer cells” and indirect anti-inflammatory effects on the immune system fighting the cancer likely contribute to the ability of omega-3 fatty acids to inhibit tumor growth. (14)

Omega-3 FA most likely reduce serum triglyceride levels by modulating very-low-density lipoprotein (VLDL) and chylomicron metabolism. There is a consistent finding in the literature that the end effect of fish oil is decreased hepatic secretion of VLDL17—the major endogenous source of triglycerides. This effect occurs most likely through multiple mechanisms, including: (1) decreased synthesis of triglycerides because these omega-3 FA may not be the preferred substrates of the enzyme diacylglycerol O-acyltransferase,18 or they may interact with nuclear transcription factors that control lipogenesis19; cellular metabolism consequently shifts toward a decrease in triglyceride synthesis and an increase in FA oxidation; and (2) the promotion of apolipoprotein B degradation in the liver through the stimulation of an autophagic process.20 This means that fewer VLDL particles can be assembled and secreted. Fish oil may also accelerate VLDL and chylomicron clearance21 by inducing lipoprotein lipase activity.22

To avoid fish oil supplements containing mercury or other harmful contaminants, purchase supplements from a reputable source that clearly tests for these health-hazardous contaminants in its products. These tests should be ideally conducted by a third-party, and a certificate of analysis should indicate the levels of purity from environmental toxins.

Bo and I worked with Dr. Harris many years ago to measure the impact of eating one Omega Cookie® daily on the study participants’ omega-3 index levels, and we recently ran into him at ISFFAL. At the conference, we remeasured our omega-3 index and omega-6/omega-3 ratios, and a few weeks later, we got our results in the mail. For the two of us, it was exciting to get another concrete measure of how our daily omega-3 consumption impacted our scores. For the record, we take one vial of Omega Restore™ per night and frequently sneak an Omega Heaven® or Omega Cookie during the day.
A group out of India conducted a study published in Cancer Chemotherapy and Pharmacology based on the premise that “fish oil rich in n-3 polyunsaturated fatty acids has been preferred to chemosensitize tumor cells to anti-cancer drugs.” The study found that using 5-Fluorouracil (5-FU) to treat colorectal cancer along with fish oil increased the survival rate in carcinogen-treated animals. Researchers also found that the fish oil ameliorated hematologic depression, along with gastrointestinal, hepatic and renal toxicity caused by the 5-FU. (15)
Hanwell, H. E., Kay, C. D., Lampe, J. W., Holub, B. J., and Duncan, A. M. Acute fish oil and soy isoflavone supplementation increase postprandial serum (n-3) polyunsaturated fatty acids and isoflavones but do not affect triacylglycerols or biomarkers of oxidative stress in overweight and obese hypertriglyceridemic men. J Nutr 2009;139(6):1128-1134. View abstract.
Cochrane lead author, Dr. Lee Hooper from the University of East Anglia, UK said: “We can be confident in the findings of this review which go against the popular belief that long-chain omega 3 supplements protect the heart. This large systematic review included information from many thousands of people over long periods.  Despite all this information, we don’t see protective effects.

Human studies also confirm cognition and memory improvement with omega-3 supplementation. For example, a study showed that both fish oil and krill oil enhanced cognitive function in a group of older men by increasing oxygen delivery to their brains. Interestingly, for those taking krill oil this effect was more prominent than those taking fish oil, though both groups were significantly better than placebo.30 As we pointed out earlier, because the omega-3 DHA is bound to phospholipids in krill it may be more effectively incorporated into the critical cell membrane in brain cells.
Henneicke-von Zepelin, H. H., Mrowietz, U., Farber, L., Bruck-Borchers, K., Schober, C., Huber, J., Lutz, G., Kohnen, R., Christophers, E., and Welzel, D. Highly purified omega-3-polyunsaturated fatty acids for topical treatment of psoriasis. Results of a double-blind, placebo-controlled multicentre study. Br J Dermatol 1993;129(6):713-717. View abstract.
As always with such trials, you can never prove zero benefit (or zero risk), but an essentially negative trial or meta-analysis sets statistical limits on the size of any remaining plausible effect. What we can now say with a fairly high degree of confidence is that any health benefit from consuming omega-3 fatty acids is tiny, probably too small to warrant supplementing (or adding it to pasta).
The absence of DHA in many pure EPA trials, and therefore lack of competition between EPA and DHA during digestion and consequently for uptake, is considered to be partly responsible for the positive outcomes. Simply put, pure EPA delivers more EPA into cells where it is needed than combined EPA & DHA blends. Consequently, oils containing DHA may not be suitable for a variety of conditions when treatment relies on increasing levels of EPA and its end products.
Grigg, L. E., Kay, T. W., Valentine, P. A., Larkins, R., Flower, D. J., Manolas, E. G., O'Dea, K., Sinclair, A. J., Hopper, J. L., and Hunt, D. Determinants of restenosis and lack of effect of dietary supplementation with eicosapentaenoic acid on the incidence of coronary artery restenosis after angioplasty. J Am Coll Cardiol. 3-1-1989;13(3):665-672. View abstract.

Irving, G. F., Freund-Levi, Y., Eriksdotter-Jonhagen, M., Basun, H., Brismar, K., Hjorth, E., Palmblad, J., Vessby, B., Vedin, I., Wahlund, L. O., and Cederholm, T. Omega-3 fatty acid supplementation effects on weight and appetite in patients with Alzheimer's disease: the omega-3 Alzheimer's disease study. J Am Geriatr Soc 2009;57(1):11-17. View abstract.
The differing actions of EPA and DHA, together with their competitive uptake, help to explain why studies that attempt to use standard fish oil therapeutically (where DHA and EPA are combined, in a natural ratio of approximately 1.5:1) are either less beneficial than expected, or even completely ineffective. Standard EPA/DHA fish oils are more suitable for everyday wellbeing, to compensate for a lack of fish in the diet and to meet a suggested intake.
Fish oil therapy is efficacious and safe for patients with severe to moderate hypertriglyceridemia. Combination therapy with HMG-CoA reductase inhibitors is also efficacious and has not been associated with any serious adverse reactions. Fish oil therapy added to fenofibrate in patients with severe hypertriglyceridemia is also effective and safe. Accordingly, it may be a safe and effective adjunct in the pharmacotherapy of the mixed lipid disorder that is frequently encountered in patients with the metabolic syndrome and/or type II diabetes mellitus.

Other suspected health benefits of omega-3s and fish are less well established and need further study. They include suggestions of a reduced risk of breast cancer, colorectal cancer and possibly advanced prostate cancer, all related to eating fish rather than taking supplements. Some observational studies have associated omega-3s to a lower risk of cognitive decline, Alzheimer’s disease and dementia, as well as age-related macular degeneration.
Dangour, A. D., Allen, E., Elbourne, D., Fasey, N., Fletcher, A. E., Hardy, P., Holder, G. E., Knight, R., Letley, L., Richards, M., and Uauy, R. Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. Am.J.Clin.Nutr. 2010;91(6):1725-1732. View abstract.
Fish oil has only a small benefit on the risk of premature birth.[43][44] A 2015 meta-analysis of the effect of omega−3 supplementation during pregnancy did not demonstrate a decrease in the rate of preterm birth or improve outcomes in women with singleton pregnancies with no prior preterm births.[45] A systematic review and meta-analysis published the same year reached the opposite conclusion, specifically, that omega−3 fatty acids were effective in "preventing early and any preterm delivery".[46]
Funding/Support: The work was supported in part by grant 17H04253, Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science; grant 30-A-17 from the National Cancer Center Research and Development Fund; grants MOST106-2314-B-039-027-MY, 106-2314-B-038-049, 106-2314-B-039-031, 106-2314-B-039-035, 104-2314-B-039-022-MY2, and 104-2314-B-039-050-MY3 from the Ministry of Science and Technology, Taiwan; grant HRI-EX105-10528NI from the National Health Research Institutes, Taiwan; and grants CRS-106-063, DMR-107-202, and DMR-107-204 from the China Medical University, Taiwan.
Another recent study shows that fatty fish consumption can cut the risk of eye-diabetes complications. The researches tracked the seafood consumption of about 3,600 diabetic men and women between the ages of 55 and 80 for nearly five years. The researchers found that people who regularly consumed 500 milligrams each day of omega-3 fatty acid in their diets (equal to two servings of fatty fish per week) were 48 percent less likely to develop diabetic retinopathy than those who consumed less. (23)
As you likely know (and as I’ve been discussing for years), omega-3 fatty acids have anti-inflammatory properties. They have been studied for the treatment and prevention of many diseases, several of which are related to inflammation, including heart disease, stroke, cancer, and Alzheimer’s disease. They have also been shown to be extraordinarily helpful in preventing and treating other brain conditions such as depression and other psychiatric disorders, attention deficit/hyperactivity disorder (ADHD), and concussions.
Consumers of oily fish should be aware of the potential presence of heavy metals and fat-soluble pollutants like PCBs and dioxins, which are known to accumulate up the food chain. After extensive review, researchers from Harvard's School of Public Health in the Journal of the American Medical Association (2006) reported that the benefits of fish intake generally far outweigh the potential risks.
Interestingly, the results are also consistent with our recent findings that somatic anxiety is associated with omega-3 PUFA deficits and the genetic risks of PUFA metabolic enzyme cytosolic phospholipase A2 in major depressive disorder62,63 and interferon α–induced neuropsychiatric syndrome.63,64 Brain membranes contain a high proportion of omega-3 PUFAs and their derivatives and most animal and human studies suggest that a lack of omega-3 PUFAs in the brain might induce various behavioral and neuropsychiatric disorders,16,65-70 including anxiety-related behaviors.12,18,19,32,49,71 Emerging evidence suggests that omega-3 PUFAs interfere with and possibly control several neurobiological processes, such as neurotransmitter systems, neuroplasticity, and inflammation,12,72 which is postulated to be the mechanism underlying anxiety and depression.
Augood, C., Chakravarthy, U., Young, I., Vioque, J., de Jong, P. T., Bentham, G., Rahu, M., Seland, J., Soubrane, G., Tomazzoli, L., Topouzis, F., Vingerling, J. R., and Fletcher, A. E. Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr 2008;88(2):398-406. View abstract.
Peroxides can be produced when fish oil spoils. A study commissioned by the government of Norway concluded there would be some health concern related to the regular consumption of oxidized (rancid) fish/marine oils, particularly in regards to the gastrointestinal tract, but there is not enough data to determine the risk. The amount of spoilage and contamination in a supplement depends on the raw materials and processes of extraction, refining, concentration, encapsulation, storage and transportation.[51] reports in its review that it found spoilage in test reports it ordered on some fish oil supplement products.[52]
A six week, double-blind study on fish oil supplementation for body composition showed that the group taking 4 grams/day of fish oil (contained 1600mg if EPA & 800mg of DHA) experienced a significant increase in lean body mass and significant decrease in fat mass compared to a group that took safflower oil (an omega-6 oil). The fish oil group also saw a tendency for decreases in cortisol, a hormone associated with belly fat gain when elevated.
On September 8, 2004, the U.S. Food and Drug Administration gave "qualified health claim" status to EPA and DHA omega−3 fatty acids, stating, "supportive but not conclusive research shows that consumption of EPA and DHA [omega−3] fatty acids may reduce the risk of coronary heart disease".[98] This updated and modified their health risk advice letter of 2001 (see below).
Since 2004, scientists have been suggesting that the omega-3 index be used as a way to measure a person’s risk of cardiovascular disease, in a similar way to how cholesterol levels are used today (1). A recent study funded by the National Institutes for Health even indicated that the omega-3 index could be a better predictor of death risk than serum cholesterol levels (2).
However, in both observational studies and controlled clinical trials, eating fish was shown to foster optimal development of a baby’s brain and nervous system, prompting advice that pregnant women and nursing mothers eat more fish rich in omega-3s while avoiding species that may contain mercury or other contaminants like PCBs sometimes found in freshwater fish.
Grigg, L. E., Kay, T. W., Valentine, P. A., Larkins, R., Flower, D. J., Manolas, E. G., O'Dea, K., Sinclair, A. J., Hopper, J. L., and Hunt, D. Determinants of restenosis and lack of effect of dietary supplementation with eicosapentaenoic acid on the incidence of coronary artery restenosis after angioplasty. J Am Coll Cardiol. 3-1-1989;13(3):665-672. View abstract.
^ Jump up to: a b c Aung T, Halsey J, Kromhout D, Gerstein HC, Marchioli R, Tavazzi L, Geleijnse JM, Rauch B, Ness A, Galan P, Chew EY, Bosch J, Collins R, Lewington S, Armitage J, Clarke R (March 2018). "Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals". JAMA Cardiology. 3 (3): 225–34. doi:10.1001/jamacardio.2017.5205. PMC 5885893. PMID 29387889.
Additionally, total polychlorinated biphenyl (PCB) content was measured in every product. All product recorded PCB levels within the Food and Drug Administration’s (FDA) 2 PPM limit for the edible parts of fish/shellfish as well as the stricter standards enacted by California’s Proposition 65, which requires products containing greater than 0.09 PPM of PCB content to bear a cancer warning. The worst offender, Now Foods Ultra Omega-3 Fish Oil, recorded 0.04 PPM of PCB content.
Badia-Tahull, M. B., Llop-Talaveron, J. M., Leiva-Badosa, E., Biondo, S., Farran-Teixido, L., Ramon-Torrell, J. M., and Jodar-Masanes, R. A randomised study on the clinical progress of high-risk elective major gastrointestinal surgery patients treated with olive oil-based parenteral nutrition with or without a fish oil supplement. Br.J.Nutr. 2010;104(5):737-741. View abstract.
Heart rate variability, a possible surrogate outcome for the risk of sudden death, was assessed in a randomized trial of myocardial infarction (MI) survivors with an ejection fraction of 40%. In the 49 patients that were randomized to either fish oil or olive oil, Holter monitor recordings showed an increase in heart rate variability in the fish oil group.31 In a larger cohort assessed in the Japan EPA Lipid Intervention Study (JELIS),32 however, no difference in heart rate variability could be attributed to fish oil.
“Lipid peroxidation induced by DHA enrichment modifies paracellular permeability in Caco-2 cells: protective role of taurine.” We conclude that hydrogen peroxide and peroxynitrite may be involved in the DHA-induced increase in paracellular permeability and that the protective role of taurine may be in part related to its capacity to counteract the effects of hydrogen peroxide.
Fish oil can be obtained from eating fish or by taking supplements. Fish that are especially rich in the beneficial oils known as omega-3 fatty acids include mackerel, herring, tuna, salmon, cod liver, whale blubber, and seal blubber. Two of the most important omega-3 fatty acids contained in fish oil are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Make sure to see separate listings on EPA and DHA, as well as Cod Liver Oil, and Shark Liver Oil.