Sink or swim: fish oil supplements and human health

In This Section

April 2016

  • The omega-3 fatty acids DHA and EPA have physiological effects that may improve cardiovascular and neurocognitive health.
  • Clinical trials of fish oil supplements containing DHA and EPA have produced mixed results.
  • Researchers are still divided on whether omega-3 fatty acid supplements are beneficial, neutral, or even harmful to human health.

In 1970, two Danish researchers heard what sounded like a fish tale: Despite consuming a high-fat diet consisting mainly of seal and whale meat and blubber, the Inuit people of northern Greenland had a remarkably low rate of coronary artery disease (CAD) and almost nonexistent diabetes mellitus. Highly carnivorous, the traditional Inuit diet supplies about 280 grams of animal protein and 135 grams of fat per day, with few or no vegetables (Bang, H. O., et al., Lancet, 1971)—in other words, exactly the opposite of what most nutritionists recommend.

Intrigued by these reports, Hans Olaf Bang and Jørn Dyerberg mounted an expedition to the northwest coast of Greenland, traveling across an ice sheet by dog sled to reach a remote village of approximately 1,350 Inuit. The researchers collected and analyzed blood samples from 61 male and 69 female Inuit and compared their plasma lipid profiles to those of healthy Danes. Their finding: The Inuit had lower levels of several types of lipids, including total cholesterol and plasma triglycerides, than Danish controls (Bang, H. O., et al., Lancet, 1971). Bang and Dyerberg later discovered that the Inuit had higher-than-normal amounts of two omega-3 fatty acids—docosahexaenoic acid (DHA, C22:6n-3) and eicosapentaenoic acid (EPA, C20:sn-3)—in their plasma and platelet lipids that increased blood clotting time, leading the researchers to hypothesize that omega-3s could protect the Inuit from the cardiovascular consequences of their high-fat diet (Dyerberg, J., and Bang, H. O., Lancet, 1979).

Bang and Dyerberg’s hypothesis spawned an entire industry that sought to encapsulate the protective components of the Inuit diet in a convenient pill that would obviate the need to consume seal or whale blubber or even fish, which many people find unpalatable. Omega-3s were hailed as the panacea for all of Western society’s ills, from cardiovascular disease to cancer to cognitive decline. Although early clinical trials seemed to reinforce the cardioprotective effects of omega-3s, more recent trials have produced mixed results, at best. Some researchers have even suggested that a high intake of omega-3s could be harmful to certain populations.

A 2014 report questioned the entire premise behind Bang and Dyerberg’s work, claiming that the Danish researchers vastly underestimated the prevalence of CAD in the Inuit (Fodor, J. G., et al., According to the study, not only did Inuit in the 1970s have rates of CAD similar to or greater than non-Inuit populations, they also had excessive mortality from stroke and an overall mortality rate twice as high as that of non-Inuit. “Considering the dismal health status of Eskimos [Inuit], it is remarkable that instead of labeling their diet as dangerous to health, a hypothesis has been construed that dietary intake of marine fats prevents CAD and reduces atherosclerotic burden,” the researchers write.

Nevertheless, Bang and Dyerberg’s studies set a ball rolling that culminated in a large and lucrative omega-3 supplement industry. According to a recent market research report (Packaged Facts; Rockville, Maryland, USA), the market value of EPA + DHA packaged products is projected to reach $34.7 billion in 2016, with a compound annual growth rate of 6.4% from 2011 ( Fish oil, which contains a mixture of DHA, EPA, and other fatty acids extracted from fish, is now the most popular nonvitamin, nonmineral supplement in the United States, taken by approximately 7.8% of adults in 2012 (up from 4.8% in 2007; Between 2005 and 2012, fish oils sales more than doubled worldwide (O’Connor, A., The New York Times,, 2015).


Essential oils

Enzymes in the human body can synthesize low levels of EPA and DHA from α-linoleic acid (ALA, C18:3n-3) consumed in the diet from plant-derived foods, such as canola and soybean oils and walnuts. However, the process is very inefficient because ALA competes with linoleic acid (an omega-6 fatty acid) for the same enzymes. Because the human body cannot make ALA or linoleic acid, they are both essential fatty acids that must be obtained through the diet or supplements.

Other enzymes convert EPA and DHA into eicosanoids such as prostaglandins, thromboxanes, and leukotrienes—signaling molecules that have potent anti-inflammatory, antithrombotic, antiarrhythmic, and vasodilatory effects (Jain, A. P., et al., Eur. Rev. Med. Pharmacol. Sci., 2015). In contrast, omega-6 fatty acids such as linoleic acid are converted into arachidonic acid (C20:4n-6), a precursor to different eicosanoids that are pro-inflammatory and pro-thrombotic. Vegetable oils such as corn and sunflower are high in omega-6 fatty acids. Increasing consumption of vegetable oils in the past century has shifted omega-6:omega-3 ratios from 1:1 in 1900 to 15:1 in Europe and 25:1 in the United States, according to Paul Clayton, fellow at the Institute of Food, Brain & Behavior in Oxford, UK. “If you have a diet that is excessively loaded with omega-6s, creating an excessive omega-6 to omega-3 ratio, then you start producing a much more toxic mix of pro-inflammatory lipid mediators,” Clayton says. Many researchers believe that this drastic dietary change underlies the surge in diseases characterized by chronic inflammation, such as atherosclerosis, type 2 diabetes, and cancer.

DHA and EPA consumed in the diet or through supplements are key components of cell membranes. Neuronal membranes are particularly enriched in DHA, leading researchers to propose that the omega-3 fatty acid is important for brain health. Although DHA is typically present at much higher levels in cell membranes than EPA, both omega-3s can bind to membrane-bound proteins and block ion channels. Omega-3s can also enter cells and interact with enzymes and transcription factors to alter metabolism.


Success stories

Three large randomized, controlled clinical trials of fish or fish oil supplements for the treatment of cardiovascular disease bolstered the enthusiasm for omega-3s as cardioprotective agents. The Diet and Reinfarction Trial (DART) study followed for two years 2,033 men who had experienced myocardial infarction (Burr, M. L., et al., Lancet, 1989). Men who were instructed to consume at least two meals of coldwater fatty fish (for example, mackerel, sardine, or salmon; corresponding to 500–800 mg DHA/EPA per day) per week had a 32% reduced incidence of reinfarction and a 29% reduction in all-cause mortality, compared with a control group that received no instructions to eat fish.

Another major study, the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) Prevenzione, randomized 11,323 survivors of myocardial infarction to two groups: one that received a combined EPA/DHA dose of 1 gram from fish oil supplements, and a control group that received regular care (Marchioli, R., et al., Circulation, 2002). After only four months of treatment, the fish oil group had a 28% reduced risk of death from any cause, driven mainly by a 45% reduced risk of sudden cardiac death. The differences between the groups remained significant throughout the 3.5 years of the study.

The Japan EPA Lipid Intervention Study (JELIS) demonstrated that EPA supplementation alone could have beneficial effects, even in a population that has a high background consumption of fish (Yokoyama, M., et al.,, 2007). JELIS followed 18,645 patients with hypercholesterolemia, who were assigned to groups receiving statin treatment alone, or a combination of statin and 1.8g EPA. After five years, the combination treatment was associated with a 19% reduced risk of major coronary events in patients with a history of CAD compared with the statin-only group. In contrast, EPA treatment was not associated with a reduced risk of sudden cardiac death.

Another study has shown that the risk of sudden cardiac death increases with decreasing blood levels of omega-3s (Albert, C. M., et al., N. Engl. J. Med., 2002). Moreover, the amount of DHA in plasma and cellular phospholipids, which closely correlates with the amount of DHA in heart muscle, is inversely related to the risk of CAD events (Harris, W. S., Pharmacol. Res., 2007). As a result of these findings, Harris has proposed a new marker for cardiovascular risk—the omega-3 index—that reflects the proportion of omega-3 fatty acids in the membranes of red blood cells. An omega-3 index greater than 8% is associated with the lowest risk of cardiovascular events, whereas an index less than 4% is typically found in CAD patients.


Dose matters

Because most clinical trials have focused on patients who already have a history of cardiovascular disease or are at high risk, evidence for benefits of omega-3 fatty acids is stronger for secondary prevention than primary prevention. The American Heart Association (AHA) recommends two servings of fatty coldwater fish per week for people with no history of CAD, or one serving per day for people with CAD.  In 2002, the AHA endorsed omega-3 supplements for the secondary prevention of heart disease (HD), while stating that a food-based approach (i.e., eating fatty fish) is preferable (Kris-Etherton, P. M., et al., Circulation, 2002). In terms of omega-3 amounts, 300–600 mg/day combined DHA/EPA are recommended for people without a history of CAD, 900–1,200 mg/day for people with a CAD history, and 3,000–4,000 mg/day for triglyceride lowering.

Different dosages of DHA/EPA may confer different cardiovascular benefits (Lee, J. H., et al.,, 2008) (Table 1). For example, low doses (0.5–1.0 g/day DHA/EPA) can lower the risk of sudden cardiac death in people with CAD, while very high doses (8.0 g/day) can reduce inflammation and decrease body fat in patients with heart failure. In addition, the time course of different benefits may vary. With the appropriate dose of DHA + EPA, patients can achieve strong antiarrhythmic benefits in a matter of weeks, compared with months to years for triglyceride or blood pressure lowering.

Relatively high doses (3­­–4 g/day) of omega-3s can lower triglyceride levels by 30–50% (Lee, J. H., et al.,, 2008). When added to statin therapy, DHA + EPA reduces triglycerides by an additional 23–29% compared with statins alone. The US Food and Drug Administration (FDA) has approved three prescription drugs that deliver concentrated fish oil for the treatment of very high triglycerides­­.


Something fishy

Beginning in the mid-2000s, various clinical trials and meta-analyses failed to confirm the earlier successes of DART, GISSI-Prevenzione, and JELIS. Between 2005 and 2012, more than 24 studies of fish oil supplements were published in respected medical journals, most examining whether fish oil could prevent cardiovascular disease in people at high risk (O’Connor, A., The New York Times, 2015). All but two of the studies found no benefit of fish oil compared with placebo.

In 2012, a meta-analysis of 20 fish oil trials including a total of 68,680 patients found no association between omega-3 supplementation and lowered risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke (Rizos, E. C., et al., Similarly, a 2013 randomized controlled trial of 12,513 people found that 1.0 g/day of fish oil did not reduce the rate of death from cardiovascular disease or the risk of hospitalization from cardiovascular causes in people who had a history of CAD (Roncaglioni, et al., “Our findings provide no evidence of the usefulness of n-3 fatty acids for preventing cardiovascular death or disease in this population,” the researchers concluded.

Scientists have proposed several reasons for the discrepancies among fish oil trials. One possible explanation is that the standard of care for CAD has increased over the years, so that in the earlier studies, even a minor effect of fish oil would have been more noticeable. For example, in DART no patients received statin therapy, and in GISSI-Prevenzione, only 5% did. “Back then they didn’t use the cocktail of drugs they use today,” says Adam Ismail, executive director of the Global Organization for EPA and DHA Omega-3s (GOED), a not-for-profit trade association based in Salt Lake City, Utah, USA. “But today, 100% of the patients in secondary prevention studies are on at least one medicine, and more than 75% are on three to five medicines such as ACE inhibitors, beta blockers, aspirin, and statin drugs. As the standard of care increased, that’s really when you saw the change in success rates of these trials.”

“I don’t think our treatments have become substantially better,” disagrees Paul Clayton. “I think it is far more likely that the reason why current studies aren’t as successful is because the effect of omega-3 supplements depends on the extent to which you can reduce the omega-6 to omega-3 ratio. We know from studies that have been published in different ages that the 6-to-3 ratio has worsened considerably over the last few decades.”

According to Clayton, nutrition researchers need to stop looking for a magic bullet to treat disease, but instead target the real culprit in many ailments: chronic inflammation. “The idea that you can interfere with neurological disease, cancer, or diabetes with a couple of fish oil capsules is frankly laughable,” remarks Clayton. “It says more about the tunnel vision of the pharmaceutically trained doctors who are doing these studies than it has anything to do with nutritional and clinical reality.”

Another possible explanation for unsuccessful omega-3 trials is suboptimal dosage. “I’m kind of baffled by the approach a lot researchers are taking,” says Ismail. “You’ve got populations that are suffering from coronary heart disease, and yet in many of these studies you’re seeing dosages that are less than the American Heart Association recommendation of 1.0 gram per day of omega-3s for secondary prevention.” A recent meta-analysis examined 11 randomized controlled trials from 1995 to 2013, each of which treated patients with existing cardiovascular disease with at least 1 g/day of omega-3 supplements for at least one year (Casula, M., et al.,, 2013). In contrast to meta-analyses that included studies with lower doses or shorter durations, this analysis showed a 32% reduced risk of cardiac death, a 33% reduced risk of sudden death, and a 25% reduced risk of myocardial infarction for people taking omega-3 supplements compared with placebo.


Brain food

In addition to conferring possible cardiovascular benefits, omega-3 fatty acids have been proposed to help sharpen memory and to prevent cognitive decline, dementia, and neurodegenerative disease. Indeed, DHA is an essential structural component of neurons, comprising more than 40% of polyunsaturated fatty acids in the brain. Epidemiological studies have indicated that diets high in omega-3 fatty acids protect cognitive function. Also, people with Alzheimer’s disease have reduced serum levels of DHA. However, several randomized controlled trials have failed to demonstrate the effectiveness of omega-3 supplements for treating dementia.

The Age-Related Eye Disease Study 2 (AREDS2) examined the effects of omega-3 and other supplements on age-related macular degeneration (AMD) and cognitive decline (Chew, E. Y., et al.,, 2015). Like brain cells, retinal cells are highly enriched in DHA. The researchers treated 4,203 elderly patients (mean age at baseline, 72.7 years) at high risk of developing late AMD with 350 mg DHA and 650 mg EPA. Over the course of the five-year study, the participants were given cognitive function tests by telephone, which included such tests as immediate and delayed recall of 10 words and counting backwards from 100 as quickly as possible. The researchers found that test scores for both the omega-3 and placebo groups declined to the same extent with time. “Contrary to popular belief, we didn’t see any benefit of omega-3 supplements for stopping cognitive decline,” says lead author Emily Chew of the National Eye Institute, part of the National Institutes of Health (Bethesda, Maryland, USA). Nor did the researchers see benefits of any supplement that they tested for either cognitive decline or AMD.

A recent meta-analysis of six cohort studies with a total of 22,402 participants likewise failed to detect an association between fish oil intake and the risk of dementia or Alzheimer’s disease (Wu, S., et al.,, 2015). However, a higher intake of fish was associated with a 36% lower risk of Alzheimer’s disease. For each 100 g of fish eaten per week, there was an 11% reduced risk of Alzheimer’s.

Ismail suspects that negative results for neurocognitive studies may be explained by insufficient dosages of DHA. A 2015 meta-analysis indicated that greater than 1.0 g of DHA per day was required to improve memory in adults (Yurko-Mauro, K., et al., “There is a cutoff where every single study conducted with over one gram of DHA has found a benefit on cognitive function,” says Ismail. “And almost every single study that had less than one gram found no benefit.” (Fig. 1)

Figure 1

FIG. 1. Omega-3 cognitive function studies and their outcomes sorted by DHA dosage. Credit: Adam Ismail, GOED

“Obviously, when there’s not an effect, you are always concerned that you didn’t have the right dose of EPA or DHA, or it was in the wrong ratio, but we point out these limitations in our paper,” says Chew. “Also, our patients are much older, with an average age of 73, so it may be that we are getting in the game too late.” Perhaps starting omega-3 supplementation at an earlier age could have an effect on cognitive decline, she says.


More harm than good?

Some researchers have hypothesized that instead of being beneficial, omega-3 supplements may actually be harmful to human health because the polyunsaturated fatty acids are highly susceptible to oxidation (Albert, B. B., et al.,, 2013). Omega-3s contain multiple double bonds and bisallylic carbons (carbon atoms between two double-bonded carbon atoms), which make them prone to hydrogen loss and free radical formation. In a chain reaction, the lipid radical can generate lipid peroxides and more radicals from unoxidized polyunsaturated fatty acids. Lipid peroxides then degrade into secondary oxidation products—aldehydes such as 4-hydroxyhexanol and malondialdehyde. These primary and secondary oxidation products can damage cellular membranes, proteins, and DNA.

During the manufacture of fish oil, the deodorization process that removes the fishy odor often involves high temperatures, which may accelerate secondary oxidation. Antioxidants, most commonly vitamin E, added to fish oil can reduce but not prevent oxidation. As a result, fish oil supplements are a complex mix of EPA, DHA, other fatty acids, additives, and potentially toxic lipid peroxides and secondary oxidation products. Studies have shown that the frequency of excess oxidation in over-the-counter fish oil supplements is variable, affecting 11–62% of products (Albert, B. B., et al.,, 2013).

Animal studies indicate that the consumption of oxidized lipids is harmful, but usually at higher doses of oil than humans consume. One human randomized controlled trial examined the effects of oxidized versus nonoxidized oil over seven weeks (Ottestad, I., et al.,, 2012). Reassuringly, perhaps, the researchers found no difference in markers of in vivo lipid peroxidation, such as antioxidant activity, C-reactive protein, or liver function. However, the study was of short duration and did not assess other markers of atherosclerosis, inflammation, or DNA damage. “In summary, given the paucity of specific evidence, it is currently impossible to know whether marine oils, some of the world’s most popular supplements, are safe after oxidation,” Albert et al. write (, 2013).

There is increasing evidence that in vivo oxidation of LDL plays a role in atherogenesis. If this is correct, oxidized supplements could help explain the disappointing results of some primary and secondary cardiovascular prevention trials. According to Albert et al. (, 2013), clinical trials should analyze and report the oxidative status of trial oils, so that the benefits and harms could be associated with the oil’s oxidative state. The researchers say that the oxidation status can be easily estimated using two assays: the peroxide value (PV; a titration that enables quantification of peroxide groups) and the anisidine value (AV; a colorimetric test that allows estimation of secondary oxidation products). Total oxidation of the oil can be estimated by the formula: TOTOX = 2PV + AV.

“We do think oxidation is an issue, but it’s really a sensory issue more than anything because if a product is oxidized, it’s going to taste fishy, and consumers won’t want to take the product,” says Ismail. He notes that the fish oil industry has set voluntary limits on oxidation that are much lower than those for vegetable oils. “Our limit for peroxide value is 5, for refined vegetable oils it’s 10, and for extra virgin olive oil it’s 20,” he says.

In collaboration with the Council for Responsible Nutrition (Washington, D.C., USA), GOED recently published a white paper on oxidation in omega-3 oils (, 2015). The paper points out that the anisidine value is not applicable to omega-3 products that contain added flavorings or those with natural pigments, such as krill oil. In an analysis of more than 2,000 test results from the scientific literature, third-party testing labs, and GOED’s industry testing program, the authors found that greater than 94% of omega-3 products met the voluntary GOED limit for peroxide value, and almost 98% met the limit for anisidine value.


Optimizing omega-3s

Because of conflicting clinical trials, researchers and health professionals are divided on whether fish oil is truly beneficial to health. However, eating whole fish has consistently been shown to benefit cardiovascular health in epidemiological and observational studies (long-term randomized, controlled dietary trials are logistically difficult). It is possible that factors in fish other than omega-3s, such as other nutrients or antioxidants, may contribute to this cardioprotective effect. Alternatively, people who consistently eat fish may tend to have a higher socioeconomic status or a more healthful diet in general.

“I think that the current fish oil industry is selling nothing but hope,” says Clayton. “I think their fundamental premise is faulty. It was never just about omega-3s.” Instead, Clayton believes that antioxidants known as lipophilic polyphenols, which are removed or destroyed during fish oil processing, contribute to fish’s health benefits (Clayton, P. R., and Ladi, S.,, 2015). Lipophilic polyphenols such as phlorotannins from oily fish and secoiridoids from olives can protect omega-3s and other lipids from oxidation within the body. The antioxidants also exert their own anti-inflammatory effects, such as inhibiting matrix metalloproteinases in the arterial wall. Their lipophilic nature favors partitioning into adipose tissue, where they may inhibit the formation of pro-inflammatory cytokines.

Clayton and his colleagues have treated thousands of patients with combinations of omega-3s and secoridoids. “Whereas the picture with the omega-3s is, to put it mildly, diverse, when we give patients combinations of omega-3s and these lipophilic polyphenols, chronic inflammation in the body, wherever it is, just seems to stop,” says Clayton. He emphasizes that these studies are for now only case histories, and thus “scientifically worthless,” but the researchers plan to conduct a randomized controlled trial of omega-3s and lipophilic polyphenols in 2016.

Another unresolved question is whether oil extracted from fish is the best source of omega-3s. DHA and EPA in fish oil exist mainly as triglycerides, whereas in krill oil they are incorporated into phospholipids. Krill are shrimp-like crustaceans that feed on the algae that produce omega-3s. In turn, fish eat krill, and omega-3s accumulate up the trophic chain. Limited studies conducted so far suggest that DHA and EPA in phospholipid form may be more bioavailable that the omega-3s in triglyceride form (Ulven, S. M., and Holven, K. B.,, 2015). Phospholipids may help omega-3s enter the lipid bilayer of cells and pass through the intestinal wall. Krill oil also contains the antioxidant astaxanthin, which may protect fatty acids from oxidative damage.

However, krill oil has an EPA:DHA ratio of 2:1, whereas fish oil has a ratio of 1:1. Because EPA and DHA give rise to different metabolites, the two omega-3 sources may have different physiological effects. Indeed, gene expression data from animal studies has shown that fish oil and krill oil regulate different metabolic pathways (Ulven, S. M., and Holven, K. B.,, 2015). Researchers have also explored the use of algae as a source for omega-3s. Algae represent a more environmentally sustainable source of omega-3s than either fish or krill, and different algal strains can produce oils with different EPA:DHA ratios.

While consuming fish may be best, “the problem is that there are not enough oily fish to feed everyone, and many people don’t like them,” says Clayton. In addition, some health experts are concerned over levels of methyl mercury and other toxic contaminants in fish. Because mercury is bound to protein and is water soluble, fish oil supplements contain negligible amounts of the toxin.


The Inuit enigma

Since Dyerberg and Bang’s studies of the Inuit in the 1970s, thousands of papers have been published on the effects of omega-3 fatty acids on human health. Despite mixed results in clinical trials, an increasing number of people worldwide consume fish oil supplements. Whether improved formulations or optimized doses of fish oil or other marine oils will ultimately prove beneficial for human health remains to be seen.

In an interesting twist to the Inuit story, researchers led by Rasmus Nielsen at the University of California–Berkeley (USA) recently reported in Science that the Inuit have accumulated genetic mutations that may have helped them adapt to a diet high in omega-3s (Fumagalli, M., et al.,, 2015). “We were interested in finding genes in the genome of the Inuit that have evolved very fast and ultimately become different from other populations,” says Nielsen. “We were searching for the traces of natural selection.”

After sequencing the DNA of several thousand Inuit and comparing to control populations, Nielsen and his colleagues identified several genome regions that differ in Inuit compared to Europeans or Chinese. The most tantalizing of these regions corresponded to genes that encode fatty acid desaturases (FADS). FADS2 is an enzyme that converts ALA from the diet into EPA and DHA. “These genes have been downregulated in the Inuit so that they now naturally produce less omega-3 fatty acids,” says Nielsen. “Our hypothesis is that this is an adaptation to a diet rich in omega-3 fatty acids. The Inuit get so many in their diet that they produce fewer themselves.”

These findings may have important implications if, as some researchers suspect, high levels of omega-3 fatty acids can be harmful due to lipid oxidation. However, Nielsen stresses that his study cannot provide any specific guidelines regarding nutrition. “I think our study may provide a little piece of the puzzle in that it appears that you cannot extrapolate from the Inuit to other populations,” he says. “It could be very good for the Inuit to eat all these omega-3 fatty acids, but not for the rest of us.”

Laura Cassiday is an associate editor of Inform at AOCS. She can be contacted at



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